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N-(alpha-aminoalkyl)benzotriazoles

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N-(alpha-aminoalkyl)benzotriazoles equilibria and reactions
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Yannakopoulou, Konstantina, 1957-
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viii, 179 leaves : ill. ; 28 cm.

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Adducts ( jstor )
Amines ( jstor )
Atoms ( jstor )
Ethers ( jstor )
Isomerization ( jstor )
Isomers ( jstor )
Protons ( jstor )
Reagents ( jstor )
Signals ( jstor )
Solvents ( jstor )
Benzotriazole ( lcsh )
Chemical equilibrium ( lcsh )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 1988.
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Includes bibliographical references.
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Typescript.
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Vita.
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by Konstatina Yannakopoulou.

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N-(a-AMINOALKYL)BENZOTRIAZOLES:
EQUILIBRIA AND REACTIONS






BY

KONSTANTINA YANNAKOPOULOU


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY







UNIVERSITY OF FLORIDA


1988


JJ OF F LIBRARIES




N-(a-AMINOALKYL)BENZOTRIAZOLES
EQUILIBRIA AND REACTIONS
BY
KONSTANTINA YANNAKOPOULOU
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1988
jj OF F LIBRARIES


Dedicated to my parents
Panagyotis and Anna
Acfnepropevo oxovc, -yoveiq pon
navayioyrn Koa Awa
Me ayaio] Koa aepaapo


ACKNOWLEDGMENTS
First of all, I would like to express my gratitude to
Prof. Katritzky for his help, guidance and open mind during
the years of my graduate work. Sincere thanks are also
extended to my former teachers, Dr. Jones and Dr. Deyrup,
for their friendly and positive attitude and for the
chemistry I have learned from them, and to Drs. Brajter-Toth
and E. Goldberg for serving as members of my supervisory
committee.
There is a great number of people, past and present
members of our group, whom I would like to thank. Among
them are Drs. Steve Cato, R. Murugan, L. Urogdi and J. Lam
for suggestions, discussions and help during the preparation
of this manuscript; Dr. J. Gallos for his thoughtful
supervision and great help during a part of this work (and
for some Dorn PerignonsI); Drs. J. Aurrecoechea and W.
Kuzmierkiewicz (left but not forgotten) for productive
cooperation and party times.
The friendship and company of Margaret Drewniak-Deyrup
has been invaluable and she will always keep a special place
in my heart, together with the smiling memory of Marcela.
Last but not least I want to thank my wonderful family,
for their continuous support, love and encouragement, and
Kostas, for standing by me all these years.
in


TABLE OF CONTENTS
Pa9e
ACKNOWLEDGMENTS iii
ABSTRACT vi
CHAPTERS
1 GENERAL INTRODUCTION 1
1.1 Structure and Reactivity of Benzotriazole 1
1.2 Recent Advances in the Chemistry of
Benzotriazole 3
1.3 N- ( Di alkyl ami nomethyl )benzotriazoles 5
1.4 Aim of the Work 8
2 THE ISOMERIC COMPOSITION AND MECHANISM
OF INTERCONVERSION OF SOME
N-(a-AMINOMETHYL)BENZOTRIAZOLE DERIVATIVES 9
2.1 Introduction 9
2.2 Results and Discussion 12
2.2.1 Solution Phase 12
2.2.2 Solid Phase 24
2.2.3 Inert Gas Matrix Phase 25
2.2.4 Mechanistic Studies 25
2.3 Conclusions 30
2.4 Experimental 30
2.4.1 Instruments and Methods 30
2.4.2 Preparation of N-[(Benzotriazol-N-yl)-
methyl ] -N, N-di alkyl amines 31
3 INFLUENCE OF STRUCTURE ON THE ISOMERIZATION
OF N-[a-(BENZOTRIAZOL-N-YL)ALKYL]-
N N-DI ALKYLAMINES 34
3.1 Introduction 34
3.2 Results and Discussion 38
3.2.1 Preparation of Compounds 38
3.2.2 Characterization of Compounds and
Assignment of the H-l and C-13 NMR
Spectra 39
3.2.3 Calculation of Equilibrium Constants (K)
and Free Energies (AG)
for Isomerization 48
IV


3.2.4Variable Temperature NMR Spectral Study:
Calculation of Free Energies of
Activation (AG*) 54
3.3 Conclusions 60
3.4 Experimental 61
3.4.1 Methods and Reagents 61
3.4.2 Preparation of N-[(Benzotriazol-N-yl)-
methyl]-N,N-dialkylamines 62
3.4.3 Preparation of N-[a-(Benzotriazol-N-yl)-
alkyl]-N,N-dialkylamines 64
3.4.4 Methylation of 5-Nitrobenzotriazole 68
4 A GENERAL METHOD FOR THE PREPARATION
OF STRUCTURALLY DIVERSE TERTIARY AMINES 73
4.1 Introduction 73
4.2 Results and Discussion 77
4.2.1 Preparation of Benzotriazole Adducts 77
4.2.2 Preparation of Tertiary Amines 79
4.3 Conclusions 84
4.4 Experimental 84
4.4.1 Methods and Reagents 84
4.4.2 Preparation of N-[a-(Benzotriazol-N-yl)-
alkyl ]-N,N-dialkylamines 85
4.4.3 Preparation of Tertiary Amines by
Alkylation: Two-Step Procedure 89
4.4.4 Preparation of Tertiary Amines by
Alkylation: One-Step Procedure 92
4.4.5 Preparation of Tertiary Amines by
Reduction 96
5 A NEW GENERAL SYNTHESIS OF TERTIARY
PROPARGYLAMINES 99
5.1 Introduction 99
5.2 Results and Discussion 102
5.3 Conclusions 108
5.4 Experimental 108
5.4.1 Methods and Reagents 108
5.4.2 Preparation of N-[a-(Benzotriazol-N-yl)-
alkyl]-N,N-dialkyl amines 108
5.4.3 General Two-Step Procedure for
Preparation of Propargylamines 110
5.4.4 General One-Step Procedure for
Preparation of Propargylamines 112
6 THE PREPARATION OF (3-AMINO ESTERS 116
6.1 Introduction 116
6.2 Results and Discussion 118
6.2.1 Characterization of the Compounds 119
6.2.2 Order of Addition 120
6.2.3 Reaction Time 121
6.2.4 Stereochemistry 122
6.2.5 Side Reactions 123
v


6.2.6 Extension to Different Benzotriazole
Adducts 124
6.3 Conclusions 126
6.4 Experimental 126
6.4.1 Methods and Reagents 126
6.4.2 Preparation of Benzotriazole Adducts.... 126
6.4.3 General Two-Step Procedure for
Preparation of p-Amino Esters 128
6.4.4 General One-Step Procedure for
Preparation of 8-Amino Esters 131
6.4.5 Miscellaneous Reactions 135
7 SYMMETRICAL AND UNSYMMETRICAL AMINALS:
STUDIES ON THEIR PREPARATION AND EQUILIBRIA 137
7.1 Introduction 137
7.2 Results and Discussion 141
7.2.1 Preparation of Symmetrical Aminals 141
7.2.2 Preparation of Unsymmetrical Aminals....146
7.2.3 Cross-Over Reactions
of Symmetrical Aminals 153
7.3 Conclusions 159
7.4 Experimental 160
7.4.1 Preparation of Benzotriazole Adducts.... 160
7.4.2 Preparation of Aminals 162
8 SUMMARY AND CONCLUSIONS 166
BIBLIOGRAPHY 169
BIOGRAPHICAL SKETCH 179
vi


Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
N-(a-AMINOALKYL)BENZOTRIAZOLES:
EQUILIBRIA AND REACTIONS
BY
Konstantina Yannakopoulou
December 1988
Chairman: Alan R. Katritzky
Major Department: Chemistry
Some aspects of the chemistry of benzotriazole have been
studied in this work. Several N-(a-aminoalkyl)benzo-
triazoles have been prepared and studied by IR and NMR
spectroscopy in the solid, liquid and gas phases. We have
found that the aminoalkyl groups reside at the N-l position
of benzotriazole in the solid state. A rapid isomerization
process commences upon changing to the liquid phase, and the
aminoalkyl groups interchange between the N-l and N-2
positions of benzotriazole. By measuring the equilibrium
constants in various solvents, we have found that the
1-isomers are generally more stable than the 2-isomers by
no more than 1.0 kcal/mole, depending on substituent size
and solvent polarity. Small aminoalkyl substituents and
polar solvents favor the 1-isomers, whereas 1- and the
2-isomers become sometimes equally favored when compounds
with large substituents are dissolved in non-polar solvents.
The isomerization process has been found to occur inter-
molecularly. On the basis of the spectroscopic evidence,
vi 1


the proposed mechanism is an ionic process, in which iminium
cations and benzotriazole anions are the intermediate
species. The required activation energy for the 2- to 1-
isomerization has been estimated by coalescence experiments
to be in the range between 15.7 to 18.6 kcal/mole, for the
examples studied, depending on the electronic features of
the substituents and the polarity of the solvents. Stabili
zation provided to the intermediate iminium ions and
benzotriazole anion by electron donating and electron
withdrawing substituents, respectively, and by solvation
energy in polar solvents, lowers the AG^ values toward the
lower limit of the range.
By virtue of their ability to behave as masked iminium
ions, N-(a-aminoalkyl)benzotriazoles are reactive toward
nucleophiles of various strengths. Thus, reactions with
Grignard reagents have produced diversely substituted
tertiary amines (aromatic or aliphatic) in high yields.
Lithium acetylenides, have replaced benzotriazole to yield
otherwise unaccessible 3-alkyl- or 3-aryl-propargyl amines
in very good yields. In a similar fashion, Reformatsky
reagents afford a- or p-raono or disubstituted p-amino esters
in good yields. Finally, several of the benzotriazole
adducts have reacted under very mild conditions with
secondary amines to produce symmetrical and unsymmetrical
aminals, in a reversible process. The produced aminals have
been shown to spontaneously disproportionate in polar and
non-polar solvents.
vi 11


CHAPTER 1
GENERAL INTRODUCTION
1.1 Structure and Reactivity of Benzotriazole
Benzotriazole (BtH) is a 1,2,3-triazole fused with a
benzene ring across the C-C double bond. The proton
attached to the N-atom undergoes annular tautomerism shown
by structures (1.1a), (1.1b), and (1.1c). In the parent
molecule (and in symmetrically substituted derivatives),
position 1 is indistinguishable from position 3, therefore
structures (1.1a) and (1.1c) are identical.
H
1.1a 1.1b 11c
The process is very rapid and the individual tautomers
cannot be separated. One tautomeric form, namely (1.1a),
predominates [84CHC(5)669], [76AHC(S)295]. Specifically,
benzotriazole has been found to exist solely in the 1H-
tautomeric form in the solid state [74AC1490], and
predominantly in the lH-form in solution [78JCS(P2 ) 312] and
in the gas phase [730MS1267] (= 1H-/2H- >> 1).
1


2
Benzotriazole is more acidic (pK = 8.2) [51JA4360] than
phenol (pK = 9.89) [85M11] and much more acidic than other
azoles, for example, benzimidazole (pK = 13.2) [58JCS1974],
or pyrrole (pK = 23) [81JOC632]. The electron withdrawing
-N=N- group presumably decreases the electron density on N-l
and renders additional stability to the benzotriazole anion.
Benzotriazole can be alkylated [85H2895] or acylated
[84CHC(5 ) 669] easily to give mainly products of 1-substitu
tion. In addition, benzotriazole condenses with formalde
hyde and amines to afford Mannich bases. Section 1.3 deals
with these compounds in detail.
Aspects of the chemistry of benzotriazole have been
studied primarily in two fields:
(a) Formation of stable complexes between the parent
molecule (or its derivatives) and metals, such as copper,
zinc, or silver [81ACS(A)739 ], [83ICA109]. This property is
presumably responsible for the marked anticorrosion activity
of benzotriazoles, compounds which are extensively used as
corrosion inhibitors and antioxidants. The large number of
related patents reflects the interest in this field.
(b) Use of N-hydroxybenzotriazole as an acyl transfer
agent in peptide synthesis [77JCS(P2 ) 224 ] Due to its
enhanced nucleophilicity (a-effect), this molecule readily
forms "active" carbamate esters, important synthetic
auxiliaries in peptide coupling. On the other hand,
benzotriazole derivatives themselves often show marked
biological activity (antihypertensives, antidiabetic agents)
(see [87JCS(Pi)799] and references cited therein).


3
1.2 Recent Advances in the Chemistry of Benzotriazole
The use of benzotriazole in synthesis has been rather
limited. However, considerable progress has been made
recently in the chemistry of benzotriazoles, regarding their
utilization as synthetic intermediates.
General methods for the preparation of several
benzotriazole derivatives, such as a-chloroalkyl-, a-
hydroxyalkyl-, a-phenylthioalkyl-, and a-arylaminomethyl-
benzotriazoles, and bis(benzotriazolyl)alkanes, have been
developed by Katritzky and coworkers [87JCS(Pi)781, 799,
805, 811, 819].
X = Cl, OH, SPh, NH-Ar, Bt; R = Alkyl, Aryl
Owing to the both electron-withdrawing = 0.55) and
electron-donating (= -0.32 or -0.10) [87AHC1] ability of
the Bt-group, a dichotomous behavior of benzotriazole
derivatives is expected (Scheme 1.1). In particular,
benzotriazole can act as a leaving group, thus providing
activation toward Bt-C bond cleavage (path A);
alternatively, it could stabilize a-electron deficient


4
centers (path B); finally, it can also provide moderate
stabilization to a-carbanions (path C).
C
Base
Y
Scheme 1.1


5
The synthetic potential of benzotriazole derivatives
toward reactions with nucleophiles or electrophiles has been
successfully exploited in several instances, and
applications involving the N-monoalkylation of arylamines
[87JCS(Pi)805 ], amides [ 88JCS ( P2)0] thioamides [88TL1755 ],
and the formation of ketones via lithium bis(benzo-
triazolyl)arenes [87JCS(Pi)819 ] have been published.
1.3 N-(Pialkylaminomethyl)benzotriazoles
The title molecules are easily prepared by the Mannich
reaction [73S703], in which benzotriazole (BtH) condenses
with formaldehyde and a secondary amine, with concurrent
removal of a molecule of water (Equation 1.1) [46JA2496].
BtH + CH20 + HNR2 > Bt-CH2-NR2 + H20 (Eq. 1.1)
The typical Mannich reaction is carried out in acidic
medium, where an iminium ion is considered to be the
reactive intermediate (Equation 1.2).
ch2o + hnr2 > ch2=nr2 y r2nch2nr2 > r'ch2nr2
(Eq. 1.2)
In basic medium, hydroxymethylamine is postulated as the
reactive species (Equation 1.3).
1.3)


6
The reaction does not normally follow the other possible
route (Equation 1.4), although some examples are known
[73S703].
HNR?
R'H + CH20 > R'CH2OH > R'CH2NR2 ( Eq 1.4)
The Mannich reaction involving benzotriazole does not
require addition of acid catalyst [46JA2496]. In cases
where dialkylamines are used, the reaction is expected to be
base catalyzed (Eq. 1.3). With arylamines, the amino-
alkylation is carried out under acidic conditions (added
acetic acid or benzotriazole itself serving as the acid
catalyst), and evidence exists favoring the intermediacy of
a benzotriazolium iminium ion which reacts with the
arylamines [87JCS(Pi)7 99 ] .
N-[(Benzotriazol-l-yl)methyl]-N,N-dialkylamines (1.2a)
are of special interest: they spontaneously isomerize to
the 2-substituted compounds (1.2b) in solution, and an equi
librium is quickly established (Scheme 1.2). A preliminary
investigation of the process has been reported but detailed
mechanistic studies have not been carried out
[75JCS(Pi)1181].
1.2a
1.2b
Scheme 1.2


7
Analogous examples of azoles undergoing "substituent
tautomerism" are few known. In particular, the exchange of
the tributylstannyl substituent ("stannotropy") between the
two N atoms of pyrazole [compound (1.3), Scheme 1.3] has
been described and studied using variable temperature NMR
spectroscopy [77JOM69]. The similar isomerization of
trialkylsilylbenzimidazole ("silylotropy") [compound (1.4),
Scheme 1.3] has been reported [83H1713] as occuring in the
solution at room temperature and disappearing in the solid
phase. However, a detailed investigation of this process
has not been described yet [88MRC134].
SnBu3
1.3
SiMe3
1.4
Scheme 1.3


8
1.4 Aim of the Work
The main objectives of the research presented in this
dissertation were:
(i) To study in detail the isomerization of simple N-
[(benzotriazol-l-yl)alkyl]-N,N-dialkylamines of type (1.2)
in terms of isomeric composition and mechanism of
interconversion (Chapter 2).
(ii) To investigate the effect of the structure of
several novel N-[a-(benzotriazol-l-yl)alkyl- or -aryl]-N,N-
dialkylamines on the isomerization process, as regards both
equilibria and kinetics (Chapter 3).
(iii) To develop new synthetic methodologies, using the
above benzotriazole adducts as synthetic intermediates in
the preparation of tertiary amines, propargylamines, 3-amino
esters and aminals (Chapters 4, 5, 6 and 7).


CHAPTER 2
THE ISOMERIC COMPOSITION AND MECHANISM OF INTERCONVERSION
OF SOME N-(a-AMINOMETHYL)BENZOTRIAZOLE DERIVATIVES
2.1 Introduction
N,N-Disubstituted aminomethylbenzotriazole derivatives
(2.1) exist in solution as equilibrium mixtures of the
corresponding benzotriazol-l-yl- and benzotriazol-2-yl-
methylamines (2.1a) and (2.1b), respectively [75JCS(Pi)1181]
(Scheme 2.1). While the 1-isomer normally predominates, the
position of this equilibrium depends strongly on the
polarity of the solvent and also on the substrate structure
[75JCS(Pi)1181].
4
3
3a
6
5
nr2
2.1a
2.1b
Scheme 2.1
9


10
Thus, as the polarity of the medium increases so does
the amount of the 1-isomer relative to the 2-isomer, whereas
increased bulkiness in the N-aminomethyl substituents favors
2-substitution [75JCS(Pi)1181].
Work carried out previously in our group [86UP1]
involved the preparation of N,N'-bis(benzotriazolylmethyl)-
N,N'-dioctylethylenediamine (2.2) (Scheme 2.2). During the
characterization of this compound significant differences in
its spectral properties were observed depending on whether
(2.2) was in a solid or liquid phase [87JCS(Pi)2673 ] The
data showed that (2.2) existed as a single isomer (2.2a) in
the solid state whereas a rapid equilibrium was established
upon dissolution to afford a mixture of the isomeric
diamines (2.2a), (2.2b) and (2.2c) (Scheme 2.2).
Previous literature [75JCS(Pi)1181] on the isomerization
of simple N,N-disubstituted aminomethylbenzotriazoles had
implied that these compounds existed as single isomers in
the solid state and an ionic dissociative mechanism was
proposed for their isomerization in solution; however, no
evidence for these conclusions was presented. The results
obtained with (2.2) [86UP1] prompted us to begin a detailed
study on the equilibria of a representative set of N-
[(benzotriazol-l-yl)methyl]-N,N-dialkylamines (2.3-2.7)
(Scheme 2.3) in the solid, liquid and vapor phases. Our aim
was to compare the properties of these compounds in
different phases, as well as to elucidate the mechanism of
their isomerization.


11
2.2c
Scheme 2.2


12
2.3 R
2.4 R
2.5 R
2.6 R
2.7 R
H, NR^ = NMe2
H, NR^ = Pyrrolidyl
Me, NR^ = NEt2
H, NR2 = NEt2
Me, NR2 = Pyrrolidyl
Scheme 2.3
2.2 Results and Discussion
2.2.1 Solution Phase
The structure of compounds (2.3-2.7) in solution was
1 13
studied by IR, H- and C-NMR spectroscopy.
1 1
H-NMR spectroscopy. The H-NMR spectra in deuterochlo-
roform (CDCl^) solutions of (2.3-2.7) exhibited in all cases
two singlets of unequal intensity in the region 5.70 to 5.40
ppm, corresponding to the N-CH2~N protons, and indicating
the presence of both the benzotriazol-l-yl and the
benzotriazol-2-yl isomers. Compound (2.2) displayed three


13
such singlets corresponding to the 1,1'- and 2,2'-isomers
(2.2a,c) and also to the unsymmetrical 1,2'-dioctylethyl-
enediamine (2.2b) [87JCS(Pi)2673]. The aromatic regions
were characteristic of the type of substitution and the
resonances were readily assigned to ring protons of the
individual isomers. These assignments were based on
chemical shifts and coupling constants reported for simple
1- and 2-substituted benzotriazoles [63JCS5556], [80MI1],
[690MR311], [75JCS(P2)1695]. 1-Methylbenzotriazole is a
simple Bt-derivative, but its ^H-NMR spectrum is not first
order even at 300 MHz. A more appropriate model is
1-hydroxymethylbenzotriazole which displays a typical
1-substitution pattern: H-4 appears as the downfield
doublet followed by the doublet of H-7, whereas H-5 and H-6
are the upfield multiplets (Figure 2.1).
On the other hand, 2-methylbenzotriazole shows a
characteristic AA'BB' pattern [80MI1] (Figure 2.2), with two
multiplets at about 7.5 and 7.3 ppm. Compounds (2.3-2.7),
as mixtures of the two isomers, show both patterns in the
aromatic region. Therefore, doublets at about 8.01 and 7.60
ppm were assigned to H-4 and H-7, respectively, in the ring-
unsubstituted-l-substituted isomers, (2.3a-2.7a) whereas a
multiplet at about 7.90 ppm was due to the same protons in
the 2-substituted isomers. A representative ^H-NMR spectrum
[of (2.4) in CDCl^] is shown in Figure 2.3. The 5,6-dime-
thylbenzotriazoles (2.5) and (2.7) showed H-4 and H-7 as two
singlets at about 7.80 and 7.35 ppm, respectively, in the
1-isomers, and as one singlet at 7.30 ppm in the 2-isomers.


14
! ! I : 1 1 1 f T T ¡TH ? T r IT? H I I I r I It ¡ T
6 7.4 7.2 7.0 PPM'
7,8
Figure 2.1 Aromatic region of the 300 MHz 1H-NMR spectrum
of 1-hydroxymethylbenzotriazole in CDCl^.
4
7
Figure 2.2 Aromatic region of the 300 MHz ^H-NMR spectrum
of 2-methylbenzotriazole in CDCl^


4
3a
3
5
6
2.4a
a
rpm | rrvi I 111 I I I I I I | i i 111 11111 11 i i 11 rrrri n i | i i i i p ri 111 m pi nr |-n i I | i i i I pn i 11 r 11 i 11 i i i I I111 11! iT-rrn r| i n rp 1111111 i i i n~n~n 11
a 2 8 0 7.B 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 3.6 3
Figure 2.3 Partial 300 MHz '*'H-NMR spectrum of N-[(benzotriazol-N-yl)methyl]-
pyrrolidine (2.4) in CDCl^.


16
Also consistent with literature reports [75JCS(Pi)1181]
is the observation that increasing bulkiness in the N,N-
dialkyl substituents (i.e. changing from to pyrrolidino
to NEt2) results in increasing amounts of the 2-substituted
isomers. As expected [75JCS(Pi)1181), the change from CDCl^
to the more polar solvent dimethyl sulfoxide (DMSO-dg)
resulted in increased amounts of the major 1-substituted
isomers at the expense of the 2-substituted ones. Indeed,
the concentration of the 2-substituted isomers in DMSO-dg
was so low that their ^H-NMR signals were frequently
obscured: in such cases the ratio of isomers was estimated
as >9 favoring the 1-isomer. Table 2.1 shows the ratio
[1-isomer]/[2-isomer] as obtained by integration of the
signals.
Table 2.1 Isomeric ratios of compounds (2.3-2.7)
Compound [1]/[2-] (CDC13) [1-]/[2-] (DMSO-dg)
2.3
4.3
a
2.4
5.5
>9
2.5
2.5
a
2.6
2.2
>9
2.7
5.1
a
a The signals of the 2-isomer were totally obscured.


17
13 13
C-NMR spectroscopy. The aromatic region of the C-
NMR spectra of 1-substituted benzotriazoles displays an
easily recognizable pattern consisting of six signals.
1 3
Figure 2.4 shows the C-NMR spectrum of 1-methylbenzo-
triazole in CDCl^. When the substituent resides at the
2-position of the ring, as in 2-methylbenzotriazole, the
additional symmetry results in only three peaks in that
region (Figure 2.5).
The ^C-NMR spectra of compounds (2.2) [87JCS(Pi)2673]
in CDCl^ displayed nine aromatic signals attributed to a
mixture of 1-substituted and 2-substituted benzotriazole
groups, while the NCF^N region of this molecule contained
three signals between 76.0 and 64.0 ppm, one for each of the
three isomers. In other solvents the picture of the spectra
remained basically the same, the only variations being the
intensities of the peaks of the individual isomers, due to
solvent dependent changes in the isomeric composition.
Similarly, the '*'^C-NMR spectra of (2.3-2.7) in both
CDCl^ and DMSO-dg clearly demonstrated the presence of
isomeric mixtures (Figure 2.6). Thus, more than six
aromatic carbon signals were observed in all cases and two
N-CI^-N absorptions appeared in the region 77.5 to 64.7 ppm
13
[see Table 2.2 for C-NMR spectra of compounds (2.3-2.7) in
CDCl^]. The assignments are concordant with data reported
for 1- and 2-substituted bis(benzotriazolyl)methanes
[83H1787] and are illustrated in Figures 2.4, 2.5, and 2.6.


18
Figure 2.4 Aromatic region of the 75 MHz ^C-NMR
spectrum of 1-methylbenzotriazole in CDCl^.
13
Figure 2.5 Aromatic region of the 75 MHz C-NMR
spectrum of 2-methylbenzotriazole in CDCl^.


4
3a
3
Figure 2.6 Partial 75 MHz 13C-NMR spectrum of N-[(benzotriazol-N yl)
methyl]pyrrolidine (2.4) in CDCl^.


Table 2.2
(2.3-2.7).
C-NMR spectra of N-[a-(benzotriazol-N-yl)methyl]-N,N-dialkylamines
13
1-isomers
Com.
Solvent
C-3a
C-4
C-5
C-6
C-7
C-7a
nch2n
ArCH3
NR
r
2
2.3a
cdci3
145.4
119.4
123.5
127.1
109.7
133.6
69.7
-
42.1
2.3a
DMSO-dg
144.8
118.9
123.8
127.3
111.1
134.0
69.2
-
41.9
2.4a
CDCl 3
145.6
119.6
123.6
127.2
109.8
133.8
65.0
-
50.1,
23.6
2.4a
DMSO-dg
144.8
118.9
123.8
127.3
110.9
133.9
64.1
-
49.4,
23.2
2.5a
CDCl,
144.9
118.7
137.4
136.4
109.3
133.4
65.1
20
.9
45.4,
12.6
J
20
.2
2.5a
DMSO-d,
144.1
117.8
137.0
136.1
110.0
133.0
64.5
20
. 3
44.7,
12.5
o
19
.7
2.6a
CDC13
145.1
119.0
123.1
126.7
109.6
133.2
64.8
-
44.8,
12.1
2.6a
DMSO-d,
6
144.9
118.8
123.5
127.0
110.8
133.6
64.7
-
44.7,
12.4
2.7a
CDCl,
144.8
118.6
137.5
136.5
109.1
133.3
64.7
20
.6
50.1,
23.6
J
20
.2
2.7a
DMSO-d,
144.0
117.8
137.2
133.1
110.0
132.9
63.9
20
. 3
49.5,
23.2


Table 2.2Continued.
2-isomers
Com.
Solvent
C-3a
C-4
C-5
C-6
C-7
C-7a
nch2n
ArCH3
NR'
2.3b
cdci3
143.7
117.9
126.0
126.0
117.9
143.7
77.5
-
41.7
2.3b
DMSO-dg
a
118.1
126.3
126.3
118.1
a
77.4
-
a
2.4b
cdci3
144.0
118.1
126.4
126.4
118.1
144.0
72.5
-
49.3,
23.9
2.4b
DMSO-dg
a
117.8
126.1
126.1
117.8
a
71.9
-
48.6,
_b
2.5b
cdci3
143.4
116.6
132.8
132.8
116.6
143.4
71.6
20.7
45.7,
12.8
2.5b
DMSO-d,-
6
142.8
116.3
132.7
132.7
116.3
142.8
71.0
20.2
45.2,
12.8
2.6b
cdci3
143.5
117.7
125.5
125.5
117.7
143.5
71.4
-
45.2,
12.4
2.6b
DMSO-dg
a
117.9
126.0
126.0
117.9
_b
71.4
-
45.2,
_b
2.7b
cdci3
143.4
116.5
136.5
136.5
116.5
143.4
72.1
20.6
20.2
49.4,
23.8
2.7b
DMSO-dg
_b
116.4
b
_b
116.4
b
71.6
20.3
19.8
48.7,
23.6
a Too weak to be detected. ^ Obscured by signals of the 1-isomer.


22
Infrared spectroscopy. IR has been used previously to
distinguish between 1- and 2-substituted benzotriazole
derivatives [63HCA1473], [87JCS(Pi)811]. The 1-isomers
typically display two weak absorptions in the region 1630 to
1550 cm 1 (where the C=C and C=N stretching vibrations are
most probably located), whereas the 2-isomers show instead
one weak absorption in the same region. The infrared
spectra of bromoform or chloroform solutions of (2.3-2.7)
(Figure 2.7) displayed in all cases all three of these
absorption bands supporting the presence of both the
benzotriazol-l-yl and the benzotriazol-2-yl isomers in
solution. A similar behavior was demonstrated by 1,1'-,
1,2'- and/or 2,2'-bis(benzotriazolylmethyl) derivatives
(2.2) [87JCSP(1)2673].
Compound (2.6) is a liquid at 25 C: the infrared
spectrum of a neat film shows in the region 1630 to 1550
-1 -1
cm three absorptions at 1625, 1588 and 1569 cm ,
indicating that in the liquid state, just as in solution,
N-[(benzotriazolyl)methyl]-N,N-dialkylamines exist as
mixtures of two isomers.
The weak C=N, C=C and N=N absorptions of compounds
(2.3), and (2.6) could be clearly detected only by an FT
instrument, while signals of (2.2) were detectable by a
conventional spectrometer. Data are collected in Table 2.3.


23
Table 2.3. IR data of N-[(benzotriazolyl-N-yl)methyl]-N,N-
dialkylamines (2.2), (2.3), (2.6) and (2.7).
Comp.
chci3
solution
Neat or melt
Ar matrix
KB r
2.2a
1610
1610
1610
1590
1590
1590
1565
1565
2.3b
1618
1616
1615
1592
1590
1587
1519
1517
2.6b
1625
1625
1590
1588
1570
1569
2.7b
1627
_
1631
1582
1585
1552
a Bromoform solution.
b FT spectra.
Wavenumbers
Figure 2.7 FT-IR spectrum of N-[(benzotriazol-N-yl)-
methyl]-N,N-dimethylamine (2.3): (a) 0.3 M
solution in CHCl^; (b) KBr pellet; (c) Ar
matrix spectrum.


24
2.2.2 Solid Phase
Infrared spectroscopy. The infrared spectra of the
aminomethylbenzotriazoles (2.3-2.7) in KBr discs (Table 2.3,
Figure 2.7) each displayed only two absorptions at 1570 to
1550 cm ^ in agreement with their benzotriazol-l-yl-
structures. Similarly, examination of (2.2) in a KBr disc,
or in a nujol dispersion, showed the presence of only two
weak absorptions at 1610 and 1590 cm *" in the diagnostic
region 1630-1550 cm-'*', as expected for a 1,1'-bisbenzo-
triazolyl derivative [63HCA1473], [87JCS(Pi)1811]. In
particular, no absorption was found in the region 1570 to
1550 cm *" confirming the absence of benzotriazol-2-yl
groups. The IR results agree with the structure of
N,N'-[l,l'-bis(benzotriazolylmethyl)]-N,N'-dioctylethylene-
diamine (2.2a) determined by an X-ray analysis
[87JCS(P1)2673].
13 13
C-NMR spectroscopy. The solid state C-NMR spectra
of compounds (2.3), (2.4) and (2.5) were also examined. The
spectrum of compound (2.5) showed a simple 1:1
correspondence between the six signals and the aromatic
carbon atoms. The spectra of compounds (2.3) and (2.4)
showed asymmetric splitting in the peaks attributable to
atoms C-3a and C-methyl [compound (2.3)], and C-5 or C-6
[compound (2.4)]. The lack of correlation of carbon types
for which splittings were observed suggests that these


25
features are due to crystallographic factors and do not
indicate the presence of two isomers. Thus, the solid state
NMR results also support the existence of only the 1-isomer
in the solid phase.
2.2.3 Inert Gas Matrix Phase
Infrared spectroscopy of (2.3) condensed in an inert gas
matrix (where molecular interactions are negligible) was
used as an approximation for the study of the properties of
this compound in the gas phase. Thus, the infrared spectrum
of (2.3) in an Ar matrix showed the presence of the
characteristic three bands diagnostic of both the 1- and
2-benzotriazole isomers (Figure 2.7).
2.2.4 Mechanistic Studies
The most likely mechanism for the isomerization observed
in the liquid and solution phases is a dissociation-
recombination process (Scheme 2.4) [75JCS(Pi)1181 ] but a
concerted mechanism (Scheme 2.5) had not been previously
ruled out. To distinguish between these two possibilities,
a cross-over experiment was carried out by mixing together
CDCl^ or DMSO-dg solutions of (2.4) and (2.5) and examining
the mixtures by ^H- (Table 2.4) and ^C- (Table 2.5) NMR
spectroscopy. These spectra revealed the presence of eight
compounds that could be readily assigned as both the 1- and
2-isomers of each of (2.4), (2.5), (2.6) and (2.7), by


26
direct comparison with the spectra of the individual pairs.
The relative intensities (Tables 2.4 and 2.5) are also
consistent with these assignments. As expected, the
1-isomers predominate in CDCl^ and even more so in the more
polar DMSO-dg. The ^H-NMR spectrum (CDCl^) of the mixture
(Table 2.4) showed only seven of the expected eight peaks in
the N-CI^-N region 5.70 to 5.30 ppm. The missing signal is
apparently hidden under the rather broad peak at 5.60 ppm.
In DMSO-dg the N-CB^-N signals for the 2-isomers are
obscured by the corresponding 1-isomer signals (see above),
and only four signals corresponding to the 1-isomers are
observed.
Scheme 2.4


27
Scheme 2.5
Table 2.4 ^H-NMR data for the N-C^-N group of compounds
(2.4-2.7) from the cross-over experiment.
Assignment
2-isomers
1-isomers
2.4 2.6,2.7
2.5
2.4
2.7
2.6
2.5
S (CDC13)
5.7 5.6
5.5
5.5
5.5
5.5
5.4
Area (%)
4 9
6
23
23
18
17
S (DMSO-dg)
-
-
5.7
5.6
5.6
5.4
Area (%)
- -
-
37
25
24
15
11
The C-
NMR spectrum (Table
2.5) provided
more
widely
separated peaks. The N-CH
2~N carbons appeared
in CDCl3 as
two groups of four signals
each
between
71.7 and 70
.5 ppm,
and 64.6 to
63.8 ppm, corresponding to
the 2-
and 1
-isomers
respectively
. The ratios
were
measured
by integration of
these signals in a quantitative experiment. Figure 2.8
shows the region of the NC^N after mixing (2.4) and (2.5)


28
in deuterated chloroform. In DMSO-dg the signals for the
2-isomers were too weak to allow precise measurements. An
identical equilibrium mixture as regards both chemical
shifts and ratios was obtained by mixing together solutions
of (2.6) and (2.7).
Table 2.5 ^C-NMR data for the N-CH^-N groups of
benzotriazoles (2.4-2.7) from the cross-over experiment.
Assignment 2-isomers
1- isomers
2.4 2.7 2.5 2.6 2.5 2.6 2.4 2.7
6(CDCl3)
Area(% )
5 (DMSO)
Area (%)
71.7 71.2
4 4
71.0 70.6
5 5
64.4 64.2
18 17
64.5 64.8
25 29
64.1 63.9
24 22
64.1 64.0
25 21
Temperature Effect. The ^H-NMR spectra of (2.5), (2.6)
and (2.7) were also recorded at -50 C and at 40 C in CDCl^
and the ratios of isomers measured. The results indicate no
significant change in the isomer distribution or in the
shape of the signals with respect to the data obtained at
25C. Modification in the structure of the compounds re
sulted in marked temperature effects, as shown in Chapter 3.


yvy^
+ 2-isomers
VJ
Nyv
r ^ T I I T
7 2
1Ii ]IIIIIlIlI|IIlIIIIII|llllIIlII|Ir
70 6B 66 64 PPM
Figure 2.8 50 MHz ^C-NMR spectrum (NCH^N region) of the mixture of
(2.4) and (2.5) in CDC13.


30
2.3 Conclusions
The work described in this chapter shows that N-[(benzo-
triazol-N-ylmethyl]-N,N-dialkylamines exist as single
benzotriazol-l-yl- isomers in the solid phase. However, in
liquid, solution and vapor phases these compounds undergo
isomerization and mixtures of the benzotriazol-l-yl- and
benzotriazol-2-yl- isomers are observed. Our studies prove
that the isomerization process is intermolecular and are
consistent with a dissociative pathway to iminium ions and
the benzotriazole anion. The subsequent recombination of
these two species furnishes equilibrium mixtures of
benzotriazol-l-yl- and benzotriazol-2-yl- isomers in which
the 1-isomers always predominate.
2.4 Experimental
2.4.1 Instruments and Methods
Melting points were determined on a Kofler hot-stage
microscope, and are uncorrected. IR spectra were recorded
on a FT-IR Nicolet 7000 Series spectrometer; measurements
were done with 0.3 M CHC13 or CHBr^ solutions, or 1% KBr
pellet; the argon matrix experiment was recorded at 24K and
10 ^ mm Hg was carried out by Dr. M. Szczesniak of this
department [87JCS(Pi)2376 ] who also operated the FT-IR
instrument.


31
^H (200 MHz) and ^C- (50 MHz) solution NMR spectra
were recorded on a Varan XL 200 spectrometer. Cross-over
experiments were carried out by mixing equimolar solutions
of both substrates. Quantitative ^C-NMR spectra were
acquired at 50 MHz using a 5 sec pulse delay. Low
temperature ^H-NMR spectra were obtained at 100 MHz using a
Jeol FX-100 spectrometer under the guidance of Dr. King of
this department.
13
Solid state C-NMR spectra were acquired on a modified
Varan XL 200 NMR spectrometer using cross polarization and
magic angle spinning (CPMAS) [87JCS(Pi)2673] by Dr. R.
Skarjune at 3M company.
Spectra displayed in Figures 2.1-2.6 were recorded on a
Varan VXR 300 NMR instrument for better presentation.
2.4.2 Preparation of N-[(Benzotriazol-N-yl)methyl]-N,N-
dialkylamines
General method. All compounds were prepared according
to a general literature procedure [46JA2496] by stirring
equimolar amounts of a secondary amine, 37% aq. formaldehyde
and benzotriazole in methanol for 24 h. Evaporation of the
solvent under reduced pressure gave the product. ^^C-NMR
and IR data are given in Tables 2.2 and 2.3, respectively.
N-[ (Benzotriazol-N-yl)methyl]-N,N-dimethylamine (2.3).
The product was obtained as a white crystalline solid (97%),
m.p. 95-98C (from diethyl ether) (lit. [75JCS(Pi)1181] m.p.
98-100C); (CDCl^) 1-isomer, 8.07 (d, J = 8 Hz,


32
H-4), 7.62 (d, J = 8 Hz, H-7), 7.49 (m, H-5), 7.41 (m, H-6,
overlapping with signals of the 2-isomer), 5.40 (s, NCH2N),
2.40 (s, CH^); 2-isomer, 7.90 (AA' m, H-4, H-7), 7.49 (m,
H-5,6, obscured by signals of 1-isomer), 5.51 (s, NCH2N),
2.46 (s, CH3).
N-[(Benzotriazol-N-yl)methyl]pyrrolidine (2.4). The
product was collected as a white solid (98%), m.p. 79-81C
(from diethyl ether)
(Found,
C, 65
.66; H, 7.29;
N,
27.88%.
C11H14N4 rec3uires'
c,
65.32;
H, 6 .
98; N, 27.70%)
r
sH (cdci3)
1-isomer, 8.01 (d,
J
= 8 Hz,
H-4 ) ,
7.60 (d, J =
8
Hz, H-7),
7.44 (t, J = 7 Hz, H-5), 7.30 (t, J = 7 Hz, H-6), 5.51 (s,
NCH2N), 2.75 [m, N(CH2CH2)2], 1.72 [m, (NCH2CH2)2) ] ;
2-isomer, 7.87 (m, H-4, H-7), 7.38 (m, H-5,6, obscured by
signals of 1-isomer), 5.70 (s, NCH2N), 2.87 [m, N(CH2CH2)2),
1.72 [m, N(CH2CH2)2J.
N-[(5,6-Pimethylbenzotriazol-N-yl)methyl]-N,N-di-
ethylamine 2.5). It was obtained as a pale yellow powder
(91%), m.p. 95-98C (from diethyl ether) (Found, C, 67.99;
H, 8.44; N, 24.47%. C13H18N4 rec3uires' C, 67.80; H, 7.88;
24.33%); &H (CDCl3) 1-isomer, 7.77 (s, H-4), 7.35 (s, H-7),
5.44 (s, NCH2N), 2.66 [q, J = 7 Hz, N(CH2CH3)2), 2.42 (s,
ring -CH3), 2.39 (s, ring -CH3), 1.14 [t, J = 7 Hz,
N(CH2CH3)2]; 2-isomer, 7.62 (s, H-4, H-7), 5.57 (s, NCH2N),
2.68 [q, J = 7 Hz, N(CH2CH3)2], 2.39 (s, ring -CH3), 1.16
[t, J = 7 Hz, N(CH2CH3)2] .


33
N-[(Benzotriazol-N-y1)methyl]-N,N-diethylamine (2.6) .
The oily product was dried under vacuum over P-^O^ (96%),
b.p. 120-124C (at 0.65 mm Hg) (Found, C, 64.17; H, 7.73; N,
27.79%. chh16N4 rec3uires C, 64.68 ; H, 7.89; N, 27.43%);
(CDCl^) 1-isomer, 8.05 (d, J = 8 Hz, H-4), 7.62 (d, J = 8
Hz, H-7), 7.48 (t, J = 8 Hz, H-5), 7.36 (t, J = 8 Hz, H-6) ,
5.52 (s, NCH2N), 2.68 [q, J = 7 Hz, N(CH2CH3)2], 1.15 [t, J
= 7 Hz, N(CH2CH3)2]; 2-isomer, 7.91 (m, H-4, H-7), 7.36 (m,
H-5,6, obscured by signals of 1-isomer), 5.64 (s, NCH2N),
2.68 [q, J = 7 Hz, N(CH2CH3)2], 1.15 [t, J = 7 Hz,
n(ch2ch3 )2 ] .
N-[(5,6-Dimethylbenzotriazol-N-yl)methyl]pyrrolidine
(2.7). A beige solid was obtained (88%), m.p. 39-41C (from
petroleum ether, b.p. 40-60C) (Found, C, 67.01; H, 8.98; N,
24.13%. <13H20N4 rec3ui-re s > C, 67.21; H, 8.68; N, 24.11%);
&H (CDCl3) 1-isomer, 7.79 (s, H-4), 7.37 (s, H-7), 5.51 (s,
NCH2N), 2.75 [m, N(CH2CH2 ) 2 ] 2.43 (s, ring CH3), 2.40 (s,
ring -CH3), 1.72 [m, N(CH2CH2)2]; 2-isomer, 7.62 (s, H-4,
H-7), 5.63 (s, NCH2N), 2.84 (s, ring -CH3), 2.84 [m,
N(CH2CH2)2J, 1.72 [m, N(CH2CH2)2].


CHAPTER 3
INFLUENCE OF STRUCTURE ON THE ISOMERIZATION OF
N-[a-(BENZOTRIAZOL-N-YL)ALKYL]-N,N-
DIALKYLAMINES
3.1 Introduction
The isomerization of N-(benzotriazol-N-ylmethyl)-N,N-
dialkylamines was investigated and discussed in Chapter 2.
The responsible dissociative process was convincingly
explained by the intermediacy of iminium ions and the
benzotriazole anion (Scheme 2.4, Chapter 2).
As an extension of that work, the present chapter
reports a study of the '"H-NMR spectra of a series of
benzotriazole adducts at variable temperatures, it provides
estimates of the AG^ values for the isomerization process,
and discusses the parameters affecting the rates and
equilibrium positions of the dissociation process as a
function of the molecular structure. In particular, we
examine series of compounds with the objective of evaluating
the effects of the following features:
(a) The influence of the solvent on the magnitude of AG
and AG^.
(b) The effect of the electron-withdrawing or -donating
character of a-substituents (R') in the iminium ion
intermediate, or in the benzotriazole benzene ring (X, Y) on
AG^ [see generalized structures (3.1), Scheme 3.1].
34


35
(c) The change in AG as a function of the size of R and
R' .
(d) The correlation between AG^ and the basicity of the
corresponding amine HNR2.
3-2 3.3
Scheme 3.1
In the case of adducts (3.1) the energy barrier of the
equilibrium (3.1a) to (3.1b) (Scheme 3.1) should be lower
than in the case of the (2.1a) to (2.1b) interconversion


36
f
(Scheme 2.1, Chapter 2): the R group stabilizes the
intermediate iminium ion (3.2) compared to the unsubstituted
ion (R' = H). The availability of the lone pair of the
amine nitrogen is also expected to contribute to the
stability of this intermediate. On the other hand, if the
benzene ring of benzotriazole is suitably substituted with
an electron-withdrawing substituent (X and/or Y), then anion
(3.3) should become a better leaving group, thus again
facilitating the dissociation; on the contrary,
substitution with electron donating substituents X or Y
should raise the barrier to interconversion (Scheme 3.1).
As mentioned in Chapter 2, the size of the substituents
NR2 in the side chain affects the isomeric ratio in the
solution. A more pronounced effect is expected if a
substituent R' ^ H is introduced in the structure.
The isomeric ratio was also found to change in different
solvents (Chapter 2). A more systematic study is sought
here in order to assess the influence of the solvent
polarity on the two isomers and on the invoked iminium ion
intermediate.
To acquire a more quantitative picture of how the
relative energy levels of the 1- and 2- isomers can be
changed by manipulating the electronic factors that
influence the rearranging part of the molecule, we prepared
a series of compounds, namely (3.4-3.15) (Scheme 3.2).


37
X
y
R'
R'
3.4
H
H
H
3.9
H
3.5
no2
H
H
3.10
C6H5
3.6
Cl
H
H
3.11
c6h4-4-n2
3.7
Me
Me
H
3.12
CgH^-4-OMe
UJ

OB
H
H
Pr1
3.13
Pr1
3.14
3.15
Scheme 3.2


38
3.2 Results and Discussion
3.2.1 Preparation of Compounds
Adducts of type (3.1), (R' t H) have not been described
in the literature except for the adduct prepared from
benzaldehyde and dimethylamine [76JCS(P2)741], which was
characterized only by a proton NMR spectrum at -30C.
Previous attempts in this group to obtain products of
condensation of benzotriazole with aliphatic aldehydes and
amines had resulted in complex mixtures [87JCS(Pi)799].
Compounds of type (3.1) were successfully prepared from
benzotriazole, an aldehyde (aromatic or aliphatic) and a
secondary amine by azeotropic removal of water in benzene.
Initial attempts to isolate some of these adducts were not
very successful. The oily products could not be purified,
as distillation and column chromatography results in
decomposition and/or hydrolysis of the crude materials. The
solid adducts, however, were much easier to handle, since
recrystallization was always possible. Methods were event
ually worked out for the isolation and complete character
ization of the vast majority of compounds (3.1) (R' H)
(see experimental). For most of them, however, the ^C- and
^H-NMR spectra near or at room temperature were much
affected by peak broadening coalescence, especially when
examined in chloroform solution. This can give the
incorrect impression that the compounds are not pure. In
general, the most convenient and effective way to handle


39
adducts (3.1) was to use them directly for synthetic
applications without prior purification (see Chapters 4, 5,
6 and 7).
3.2.2 Characterization of Compounds and Assignment of the
H-l and C-13 NMR Spectra
Compounds (3.5), (3.8) and (3.12) were best characterized
by low temperature ^H-NMR spectra in a solvent where a large
dispersion of chemical shifts was observed and peaks due to
the two isomers could be readily detected (see Experi-
13
mental). All C-NMR spectra were recorded in deuterated
chloroform. Low temperature ^C-NMR spectra were obtained
in the cases of (3.5), (3.8), and (3.15), where broad peaks
were observed at room temperature.
As discussed in Chapter 2, all the compounds unsubsti
tuted in the benzene ring of benzotriazole are mixtures of
the 1- and 2- isomers and show both benzotriazol-l-yl and
benzotriazol-2-yl type substitution patterns in the ^H- and
the C-13 NMR spectra. The C-13 spectra of the above com
pounds were easier to interpret than the ^H-NMR spectra,
where frequently considerable overlapping of some benzo-
triazole protons by signals of R and R' resulted in obser
vation of complex multiplets. In most cases, however,
assignment was achieved (see Tables 3.1 3.3 and Experi
mental) using literature information [75JCS(P2)1695],
[83H1787].
Two structural features introduced increased complexity
in the spectra of some compounds.


40
(a) Substitution on the C-5 atom of the benzotriazole
ring without equivalent substitution at the C-6 position [as
in (3.5) and (3.6)], resulted in the generation of three
interconverting (1-, 2-, and 3- substituted) isomers in the
1 13
solutions and consequently complex H- and C-NMR spectra.
(b) The existence of an asymmetric carbon atom (when
r
R t H) caused chemical shift non-equivalency to protons in
methylene and methyl groups up to three bonds away. This
resulted in complicated '*'H-NMR spectra, especially in the
compounds bearing aliphatic side chains, but fortunately the
C-13 spectra were not affected.
In these cases, additional experiments were carried out
to aid the complete assignment as will be discussed next.
Spectral assignment of N-[(5-nitrobenzotriazol-N-yl)-
methyl]pyrrolidine (3.5). Chloroform solutions of N-
[(5-nitrobenzotriazolyl)methyl]pyrrolidine (3.5) at -25C
contained then 2- and 3- isomers in equal amounts, while the
1-isomer was the major component (at -25C, [1-]:[2-] :[3-] =
44:28:28). The complete assignment of the ^H- and ^C-NMR
spectra of this adduct could be achieved only by preparation
of model compounds.
Thus, 5-nitrobenzotriazole was methylated, and the
products 1-methyl-, 2-methyl- and 3-methyl-5-nitrobenzo-
triazole [64T211] were separated by column chromatography.
The individual fractions were identified by comparing their
melting points to literature values. The least polar


41
fraction was identified as 2-methyl-5-nitrobenzotriazole
(m.p.185-188C; lit. [64T211] m.p.l87C). The most polar
fraction was l-methyl-5-nitrobenzotriazole (m.p.160-1620C;
lit. [64T211] m.p.l63C). Fractional crystallization had
been used in the literature to separate the two isomers.
Column chromatography, however, of our methylation mixture
yielded an additional isomer, of intermediate polarity,
which was reasoned to be 3-methyl-5-nitrobenzotriazole, and
had not been reported previously [64T211].
1 13
The H- and C-NMR spectra of the individual
methylation products were recorded in CDCl^. The spectra of
the mixture of the three compounds were then easily
assigned, and they showed a very good correspondence to
those of (3.5) (see Experimental). Figure 3.1 shows the
aromatic proton region of (3.5) as compared to that of the
mixture of 1-, 2-, and 3-methyl-5-nitrobenzotriazoles in
cdci3.
Spectral assignment of N-[(5-chlorobenzotriazol-N-yl)]-
methyl]pyrrolidine (3.6). In the case of the chloro-
compound (3.6), the populations of the three isomers were
all significantly different, ( 20C, CDCl^, [1-]:[2-]:[3-] =
45:23:32) thus enabling assignment of the C-NMR spectrum.
The aromatic region of the ^H-NMR spectrum, with a multitude
of peaks, was impossible to assign. A two-dimensional
proton-carbon correlation spectrum (HETCOR) (Figure 3.2)


42
( a)
Figure 3.1 Aromatic region of the 1H-NMR spectrum (CDC1-.) of
(a) N[(5-nitrobenzotriazol-N-lyl)methyl]pyrro
lidine (3.5) (~25C), and (b) a mixture of 1-, 2-
and 3-methyl-5-nitrobenzotriazoles (25C).


Figure
3.2 A correlation spectrum (HETCOR) of N-[(5-chlorobenzotria
zol-N-yl)methyl]pyrrolidine (3.6).


44
helped in assigning each of the aromatic peaks in the ^H-NMR
spectrum to the correct isomer. Literature ^H-NMR spectra
[79HCA2129] of 1-methyl-, 2-methyl-, and 3-methyl-
5-chlorobenzotriazole are in agreement with our assignments.
Spectral assignment of isobutyraldehyde adducts (3.8),
(3.13) and (3.14). Adduct (3.14) contained only two
isomers, however, both the benzylic methylene and the two
methyl groups resonated at different frequencies for each of
the two isomers. A proton-proton correlation spectrum
(COSY), unraveled the assignment of the aliphatic region in
the "''H-NMR spectrum of this molecule (Figure 3.3) and of
molecules (3.8) and (3.13) which had similar structure. The
aromatic region of (3.14), having signals due to the four
different ring protons was too complex, and therefore
complete assignment was impossible. However, the assignment
of the C-13 spectra did not pose any difficulties.
The "''H-NMR spectra of all adducts are described in the
1 3
experimental section. The C-NMR spectra of the 1-isomers
are listed in Table 3.1, of the 2-isomers in Table 3.2, and
of the 3-isomers of (3.5) and (3.6) in Table 3.3. 'H-NMR
spectra above coalescence were also recorded and are listed
in Table 3.7 (see end of this Chapter).


bt-chipr-oibenzy
EXP* PULSE SEQUENCE; COSY
45
u_ cDr^tDin,rmoj^o
Figure 3.3 A *H- H correlation (COSY) spectrum of N-[ a-
(benzot riazol-N-yl)-g-methyl]propyl-N,N-
dibenzylamine (3.14).
F2 (PPM)


46
1 3
Table 3.1. C-NMR chemical shifts of the benzotriazol-l-yl
isomers, of compounds (3.5a)-(3.15a) at a single temperature
(below coalescence) in CDCl^.
NO3
Tem.
( C)
-NR2
R'
CH
Bt
3.5
-25
49.9
_b
65.5
144.4,
144.2,
136.4C
23.4
122.8,
116.9,
110.7
3.6
+ 20
49.9
_b
65.1
145.8,
C 133.2
,C 129.1C
23.4
124.5,
120.1,
109.4
3.8d
-48
47.1
30.5,
19.8
81.3
144.5,
134.4,
126.9
22.7
19.0
123.5,
119.2,
109.7
3.9
+ 20
66.2
_b
68.9
145.5,
133.5,
127.2
50.1
123.6,
119.4,
109.6
3.10
+ 20
66.3
134.6,
128.4
82.4
145.7,
132.7,
126.9
49.6
128.1,
127.2
123.5,
119.6,
111.1
3.11
+ 20
66.5
141.9,
142.3
81.1
145.8,
133.0,
127.8
49.7
128.7,
123.7
124.2,
120.1,
110.5
3.12
+ 20
66.4
159.4,
127.6
82.4
145.6,
132.5,
127.1
49.7
113.7,
54.8
123.8,
119.5,
111 4
3.13
+ 20
66.6
28.4,
19.7
85.5
145.0,
134.4,
127.2
48.8
19.0
123.7,
119.6,
109.7
3.14
+ 20
138.7
30.4,
29.6
80.1
144.9,
135.1,
126.9
128.9
19.4
123.7,
119.7,
109.8
128.5
127.3
53.4
3.15
-20
50.1
134.9,
128.1
82.8
145.4,
132.8,
126.6
25.4
128.0,
127.0
123.4,
119.2,
111. 5
23.5
a The complete
13
C-NMR
spectra
of ( 3
. 4) and
(3.7)
were
reported in Chapter 2 [see Table 2.2, compounds (2.4) and
(2.7)]. k R' = H. c The 4 carbon atoms could not be
assigned with certainty, therefore peaks could be due to the
other isomers. ^ The INEPT pulse sequence at 25 MHz (-48C,
CDC1^) was utilized for unequivocal assignment of the
spectrum


47
13
Table 3.2. C-NMR chemical shifts of benzotriazol-2-yl
isomers of compounds (3.5b)-(3.15b) at a single temperature
(below coalescence) in CDCl^.
No3
Tern.
( C)
-NR2
R'
CH
Bt
3.5
-25
50.1
b
73.3
120.5,
C 119.4,
118.8d
23.7
3.6
+ 20
48.9
_b
72.4
145.8,
6 133.2,
e 129.1'
23.7
127.0,
119.0,
116.8
3.8f
-48
46.4
30.5, 19.4
88.7
142.8,
125.8,
117.8
22.7
3.9
+ 20
66.4
_b
76.7
143.8,
126.2,
117.7
59.8
3.10
+ 20
66.7
135.0, 128.4
88.2
143.5,
126.1,
118.1
48.6
128.2, 127.2
3.11
+ 20
66.6
147.9, 128.7
87.2
143.9,
126.8,
118.3
48.6
123.4
3.12
+ 20
66.1
159.4, 126.6
88.1
142.0,
125.2,
114.6
48.8
113.9, 54.8
3.13
+ 20
66.8
28.4, 19.1
92.3
143.3,
125.9,
118.0
48.3
18.9
3.14
+ 20
138.8
30.4, 20.0
87.3
143.5,
126.0,
118.4
128.5
19.3
128.3
127.3
53.3
3.15
-20
49.4
134.9, 128.1
89.0
143.3,
125.9,
117.9
25.4
128.0, 127.0
23.5
a The complete C-
13 NMR spectra
of ( 3
.4) and
(3.7) were
reported in Chapter 2 [see Table 2.2, compounds (2.4) and
to c
(2.7)]. R' = H. Assignments can be interchanged with
j
the corresponding atoms of the 1-isomer. The 4 carbon
atoms were not detected. The 4 carbon atoms could not be
assigned with certainty, therefore peaks could be due to the
other isomers. ^ The INEPT pulse sequence at 25 MHz (-48C,
CDCl^) was utilized for unequivocal assignment of the
spectrum.


48
Table 3.3. C-NMR chemical shifts of benzotriazol-3-yl
isomers of compounds (3.5) and (3.6) at a single temperature
(below coalescence) in CDCl^.
No Tern. -NR7 R' CH Bt
(C)
3.5 -25 49.0 -a 65.9 120.5,b 116.4, 107.4
23.4 ^ r r r
3.6 +20 49.8 65.1 143.8, 134.0, 132.lc
23.4 127.7, 118.4, 110.6
ci b
R' = H. The quaternary atoms were not detected.
Assignments can be interchanged between corresponding 4
carbon atoms of the 2-isomer; unambiguous assignment of the
quaternary carbon atoms could not be made, because a two-
dimensional correlation was not possible.
3.2.3 Calculation of Equilibrium Constants (K) and Free
Energies (AG) for Isomerization
The equilibrium constants were measured for each
compound in several solvents, at the temperatures specified
in Table 3.4 (see also footnotes), by integrating the areas
of each of the isomers in the "''H-NMR spectra. Positions 1
and 3 of the benzotriazole ring are degenerate [except for
adducts (3.5) and (3.6)], and this was taken into account
when calculating the populations of the 1-isomers. The free
energies of the isomerization process were then calculated
from the equation AG = -RTlnK, where K = Pi/P2 (Table 3.4).
The populations Pn were determined from the integration of
the N-CH(R)-N proton signals or from the aromatic region of
each of the isomers. For adducts (3.5) and (3.6), in


49
Table 3.4 Equilibrium constants (K) and free energies for the
isomerization ( AG ) of N- [ a- ( benzot. r iazol-N-yl ) alkyl ] -N, N-
dialkylamines (3.4) and (3.7)(3.15).
NO
NR0a R'
X
Y
Solvent
T b
K C
AG d
( C)
(kcal/mol)
3.4
Pyr H
H
H
CDBr,
cd3cn
+ 22
1.6
-0.25
+ 22
6.2
-1.05
3.7
Pyr H
Me
Me
CDBr,
cd3cr
+ 23
1.7
-0.30
+ 22
4.9
-0.95
3.8
Pyr Pr1
H
H
Toluene-d
cd3cn
-40
:|
+ 0.40
e
3.9
Mor H
H
H
CDBr 3
cd3cr
+ 22
1.8
-0.35
+ 23
5.6
-1.00
3.10
Mor Ph
H
H
CDBr 3
cd3cr
+ 23
1.2
-0.10
+ 20
2.5
-0.55
3.11
Mor 4-N02-CgH4
H
H
cd3cn
+ 20
2.5
-0.55
3.12
Mor 4-MeO-C^-H.
6 4
H
H
cd3cn
-20
2.7
-0.50
3.13
Mor Pr1
H
H
Toluene-d,
cdci3 0
cd3cn
+ 25
0.4
+ 0.55
+ 21
0.5
+ 0.40
+ 23
1.1
-0.05
3.14
Dib Pr1
H
H
Toluene-d
CDB r 3
+ 25
0.4
+ 0.55
+ 22
0.7
+ 0.20
CDCl 3
cd3cn
+ 22
0.8
+ 0.15
+ 22
0.9
+ 0.05
3.15
Pip Ph
H
H
Toluene-dfi
+ 1X
-0 05
cd3cn 0
Pyr = pyrrolidine; Mor = morpholine; Dib = Dibenzylamine;
Pip = Piperidine. Temperature at which the equilibrium
constant was measured. c K = P^ /P2, where P^ and P2 are the
populations of the 1- and 2- isomers, respectively (estimated
error +0.2). d Estimated error +0.05-0.10 kcal/mole.
e Signals of two isomers too close to allow reliable
measurement of K.


50
solutions of which a 3-substituted isomer is also present,
when separation of the signals allowed, in addition to K =
Pf/P^, K' = P3/P2, and K" = P^/P3 could also be calculated.
The values so obtained are collected in Table 3.5 (see also
footnotes) .
A negative AG value indicates that the 1-isomer is more
stable than the 2-isomer, while a positive AG shows the
reverse. Deuterated acetonitrile was found suitable in
obtaining reliable isomeric ratios for nearly all compounds,
therefore direct comparison of the obtained AG values could
be made, although the temperatures at which equilibrium
constants were measured varied (Tables 3.4, 3.5). In
general, in solutions of compounds of type (3.1) [R' = H,
i.e (3.4)(3.7) and (3.9)], the 1-isomer is the most
thermodynamically favored component in the mixture.
Table 3.5. Equilibrium constants and free energies for the
isomerization of N-[(5-nitro and 5-chlorobenzotriazol-N-
yl)-methyl]pyrrolidines (3.5) and (3.6), respectively.
No NR R' X Y SolV. T Kb K' K" AG0 AG0' AG"
Z (C) (kcal/mol)
3.5 Pyr H N07 H Tol-dp +21 1.1 - 0.05
Z CDC1, -25 2.5 1.0 2.5 -0.45 0.0 -0.45
CD3CN -48 5.6 2.3 3.0 -0.75 -0.35 -0.50
3.6 Pyr H Cl H CDCl, +21 2.0 1.4 1.4 -0.40 -0.20 -0.20
CD3CN -20 6.4 5.5 1.3 -0.95 -0.85 -0.15
a Pyr = pyrrolidine. bK = P1/P2, K' = P3/P2, K" = Pl/P3'
AGn = -RT lnKn (in kcal/mole). c The signals due to the 1-
and 3- isomers resonated at the same frequency, therefore
K = [P1 + P3]/P2.


51
Adducts of type (3.1) (R' H), either show little
preference toward either isomer in a common NMR solvent [e.g
(3.10) in CDBr^)], or, in extreme cases of steric hindrance,
the 2-isomer clearly becomes the most stable [e.g. (3.14) in
CDBr^)]; in these cases, K < 1 and AG > 0. Increasing
solvent polarity can move the equilibrium toward the
1-isomer, as will be discussed next.
Effect of the solvent. Polar solvents have been shown
(Chapter 2) [75JCS(P1)1181] to favor the 1-isomer in
solutions of compounds of type (3.1) (R' = H). Dipole
moment measurements of simple 1-substituted benzotriazole
derivatives [50CR1], [61MI1], [75BSF1675], indicate that
(somewhat surprisingly) they are more polar than their
2-substituted isomers:
R-benzotriazole
/j (D, 2 5 C in CgHg )
1-Methyl
2-Methyl
1-Phenyl
2-Phenyl
3.95
0.49
4.08
0.97
Here we observe a similar effect. For example, the AG
value of (3.14) indicates that the 1-isomer becomes more
favored on going from toluene {/j 0.36 D) [ 8 5M11 ] to
bromoform (p = 0.99 D) to acetonitrile (/j = 3.92), with
chloroform ( // = 1.01 D) in an intermediate position. A very
marked effect is observed in acetonitrile solutions of
(3.4)-(3.8), and (3.9), where the 1-isomer has increased to


52
more than 83% in the equilibrium mixture. Compound (3.13)
exemplifies a case in which solvent polarity can determine
which isomer will predominate in the solution (2-isomer in
toluene-dg,* 1-isomer in acetonitrile-dg).
Effect of substituents R and R'. Increased bulkiness of
R' results in increased amounts of the 2-isomer in the
equilibrium mixture. This is reflected by a decreasing
magnitude of K in acetonitrile on going, for example, from
(3.9) to (3.13). When R' is a phenyl or a p-substituted
phenyl group, the equilibrium constant is often close to
unity [e.g. (3.10) in CDBr^, (3.15) in toluene-dg], meaning
that no actual preference is expressed for either of the two
isomers in the particular solvent. The results in Table 3.4
indicated that the peri-interactions (buttressing between H-
7 and the aminoalkyl substituent) are rather important
[75JCS(P2)1695] in the 1-isomer. This was further
demonstrated by a different experiment: the ^H-NMR spectrum
of the pyrrolidine-isobutyraldehyde adduct (3.8) in toluene-
dg, showed that the benzotriazole H-7 and methine NCHN
signals of the 1-isomer became broad and moved toward each
other as the temperature was lowered from -20C to -80C.
Restricted rotation about the Bt-CHR'NR2 bond was evidently
responsible for this phenomenon, which was observed only for
the 1-isomer (Figure 3.4).
The electron-withdrawing or elect ron-releasing nature of
the substituents R and R' does not seem to have any
noticeable effect, as the magnitude of AG remains the same


53
(within experimental error) for (3.10) and (3.11) in
acetonitrile-dg, and for (3.8), (3.13) and (3.14) in
toluene-dg, while the differences observed in (3.15) and
(3.8) in toluene-dg would rather be attributed to steric
effects.
Effect of substituents X and Y. The 5-nitro- (3.5) and
5-chloro- substituted (3.6) compounds, each contain three
interconverting isomers in their solutions, occupying
different energy minima, as reflected by different AG
values for each isomerization process (Table 3.5). The
1-isomer is again the predominant and the 2-isomer the least
abundant, in both cases and all solvents studied.
Literature information on the polarity of 5-nitro-
[64T211] and 5-chloro- [79HCA2129] methylbenzotriazoles, was
combined with our observations (see Experimental), deduced
from the order of elution of these compounds from column
chromatography (silica gel), ranks them, according to
increasing polarity:
2-Me-5-N02~Bt < 3-Me-5-N02-Bt 2, and
2-Me-5-Cl-Bt < l-Me-5-Cl-Bt < 3-Me-5-Cl-Bt.
By analogy, the polarity of isomeric compounds in each
of (3.5) and (3.6), is expected to follow the same order.
This is verified by the magnitude of the K values observed
for (3.5). However, K values for (3.6) show that the
1-isomer is more polar than the 3-isomer, which is in
contrast to the literature report.


54
3.2.4 Variable Temperature NMR Spectral Study; ,
Calculation of Free Energies of Activation ( AG^)
The temperatures at which the characteristic proton
resonances of the 1- and 2- isomers coalesced were measured.
Specifically, the signals of the methylene groups, located
between the amino and the benzotriazole nitrogen atoms, of
the two isomers, were monitored for compounds (3.4)(3-7)
and (3.9). The corresponding methinic proton signals were
monitored for compounds (3.8) and (3.10)-(3.15). The ranges
of temperatures within which coalescence occurred were
visually estimated from the lineshape of the signals under
observation, and are listed in Table 3.6. Figure 3.4 shows
the temperature dependence of the ^H-NMR spectrum of (3.8)
in deuterated toluene. The doublets of the two isomers
slowly coalesce to a single broad peak at 5.3 ppm. The
other broad signal at about 6.3 ppm originates from the
aromatic region and its assignment is uncertain.
Approximate free energies of activation [74MI1],
[ 80M12] [82MI1] were calculated using the simplified
equation,
AG^ = RTc [22.96 + ln(Tc/S\>)]
where Tc is the coalescence temperature (in K) and 6v the
chemical shift difference (in Hz) of the two separate peaks
in the slow exchange region. The error in Tc is 2 to 3C,
and this corresponds to +0.1 to +0.2 kcal./mole in AG^
[74MI1], The 1- to 2-isomerization process is intermo
lecular (Chapter 2) and the populations of the isomers are


55
Figure 3.4 Temperature dependence of the ^H-NMR spectrum
[NCH(Pr)N region] of adduct (3.8) in toluene-dg.


56
unequal in most cases studied, therefore additional error is
introduced in the calculations [82MI1]. However, since only
approximate AG^ values are desired for evaluation of the
relative ease of isomerization of the compounds, the free
energies of activation listed in Table 3.6 give satisfactory
indication. The activation energies, calculated from the
equation mentioned above, represent the barrier to
conversion of the least to the most stable isomer. Thus,
the calculated AG^ values for compounds with AG < 0 pertain
to the 2- to 1- isomerization, whereas for those with AG >
0 pertain to the reverse. However the numbers in Table 3.6
for (3.8) and (3.14) have been adjusted so that all pertain
to 2- to 1- conversion.
The choice of a suitable solvent for VT work is not
always easy [88JOC2629]. Both low and high temperature
spectra were obtained in deuterated toluene, but for most
compounds coalescence did not occur below the boiling point
of this solvent. Coalescence was obtained in the higher
boiling solvent, bromoform-d (b.p. 150C), but the AG^
values were generally lower in CDBr^ than in toluene-dg, due
to solvent polarity effects. In cases where the proton re
sonances under observation were not well resolved or ob
scured by other signals in the above solvents, (e.g (3.11),
(3.12)], deuterated acetonitrile was used but this could not
be extended to all molecules: the amount of the 2- isomer
in (3.4) and (3.7) and (3.9) in CD^CN was very small (see
Table 3.4), resulting in very weak proton resonances, and
therefore unacceptable errors in the measurement of Tc>


57
Table 3.6 Free energies of activation for the isomerization
of N-[a-(benzotriazol-N-yl)alkyl]-N,N-dialkylamines
(3.4)-(3.15).
No
Nr2
R'
X
Y
Solvent
T
( 6)
AGT
(kcal/mol)
3.4
Pyr
H
H
H
CDB r g
85
18.2
3.5
Pyr
N0o
H
Toluene-dg
105
18.0
M
Benzene-d^
63
16.0
CDClg
32
15.4
3.6
Pyr
H
C1
H
CDB r g
66
17.0
3.7
Pyr
H
Me
Me
CDB r g
98
18.7
3.8
Pyr
Pr1
H
H
Toluene-dg
48
15.6
3.9
Mor
H
H
H
CDB r g
86
18.3
3.10
Mor
Ph
H
H
CDB r ,
62
17.7
CDgCN
63
16.9
3.11
Mor
4-N02-C6H4
H
H
CDgCN
83
18.6
3.12
Mor
4-MeO-CgH4
H
H
CDgCN
35
15.7
3.13
Mor
Pr1
H
H
CDgCN
35
16.1
3.14
Dib
Pr1
H
H
CDB r 3
75
17.9
3.15
Pi p
Ph
H
H
Toluene-dg
73
16.8
Pyr = pyrrolidine; Mor = morpholine; Dib = Dibenzylamine;
Pip = Piperidine.
b 20C. c 0.15 kcal/mol
Effect of the solvent. The nature of the solvent
affects the magnitudes of both AG^ and AG. Table 3.6
clearly shows that the energy barrier is highest in toluene
dg, intermediate in bromoform-d, and lowest in acetonitrile
dg. This is as expected, because a more polar solvent


58
provides more stabilization to the ion pair [(3.2) + (3.3)]
than to the individual isomers (Scheme 3.1), thus lowering
the energy difference between the ion pair and either of the
isomers.
Effect of R'. The results in Table 3.6 clearly show
that the free energy of activation is lower when resonance
stabilization is provided to the intermediate (3.2) through
the substituent R' (Scheme 3.1), compared to the unsubsti
tuted cases. Specifically, in acetonitrile, the order of
decreasing AG^ values is (3.11) > (3.10) > (3.12). Strong
stabilization to the electron deficient iminic carbon is
also provided by isopropyl substituents, as indicated in the
case of (3.8) vs (3.4), and to a lesser extent, (3.13) vs
(3.9).
Effect of substituents in the benzotriazole ring. The
electron-withdrawing nitro substituent of (3.5) stabilizes
the negative charge developed on anion (3.3), and therefore
facilitates N-CHNR2 bond dissociation leading to recombi
nation on the N-2 atom of benzotriazole. The electron-
donating methyl groups of (3.7) have the opposite effect,
raising the energy barrier to a relatively high value. The
5-chloro substituent is intermediate. The calculated AG^
values in CDBr^ are therefore classified in order of
decreasing magnitude, as follows: (3.7) > (3.4) > (3.6) >
(3.5). Compound (3.5) in CDBr^ is very near coalescence at


59
room temperature, so the AG^ in this solvent could not be
measured (the solvent freezes at +8.3C), but the
corresponding value in chloroform-d suggests it will be less
than 15.4 kcal/mol.
For compounds (3.5) and (3.6) one coalescence
temperature was observed. The NCH^N protons of the 1- and
3- isomers of the nitro adduct (3.5) resonated at the same
frequency, while the singlet of the 2-isomer emerged at 0.4
ppm downfield, in both toluene-dg and benzene-dg. The two
peaks coalesced into one as the temperature increased. In
CDClg solution, however, three separate peaks were observed
for each isomer. The NCI^N singlets due to 1- and 3-
isomers were very close, and they overlapped very soon with
a moderate increase in temperature, whereas true coalescence
came later at a higher temperature. Similar behavior was
demonstrated by (3.6).
Effect of the nature of secondary amine. The
availability of the lone pair of electrons on the amine
nitrogen for donation to the adjacent electron-deficient
carbon in adducts of type (3.1), plays a significant role in
determining the height of the barrier. This is best
illustrated by the compounds bearing the isopropyl
substituent, where a significant amount of positive charge
could be developed on the NCHCHMe? atom. We then observe,
in order of decreasing AG^ magnitude, (3.10) > (3.15), and
(3.14) > (3.8). The order of decreasing AG^ values bears an


60
inverse correlation with the pK values of the corresponding
cl
secondary amines [72MI1]. Thus, pK [(morpholine) = 8.49] <
cl
pK [(piperidine) = 11.20] and again pK (dibenzylamine) =
a a
8.52 < pK [(pyrrolidine) = 11.30]. The benzotriazole
cl
adducts of morpholine are consequently more easily isolable
and stable compounds than the adducts of pyrrolidine or
piperidine, most of which are readily hydrolyzed oils or low
melting solids.
3.3 Conclusions
The free energy of activation for the benzotriazol-l-yl
to benzotriazol-2-yl rearrangement of N-[a-(benzotriazol-N-
yl)alkyl]-N,N-dialkylamines, is greatly dependent on the
degree of stabilization provided to either of the inter
mediate ions (3.2) or (3.3): the greater the stabilization
the lower the energy barrier. The greater the polarity of
the solvent the lower the value of AG^. Finally, the
bulkier the dialkylaminoalkyl- or aryl- substituent the more
abundant the 2-isomer, which in extreme cases becomes the
predominent component, as shown by values of of K < 1 and
AG > 0.
The chemical reactivity of the compounds studied can
therefore be tailored according to the appropriate
substitution. Compounds for which AG^ is low, react rapidly
and cleanly with weak nucleophiles such as amines with
concurrent removal of benzotriazole. Compounds having high
AG^ values are much less reactive toward the same


61
nucleophiles. The following Chapters, and in particular
Chapter 7, demonstrate results due to the enhanced
reactivity of benzotriazole adducts (3.1) in detail.
3.4 Experimental
3.4.1 Methods and Reagents
^H-NMR spectra were recorded on a Varian VXR 300 MHz
instrument using TMS as the internal reference and as a
standard peak for linewidth comparisons. The samples were
solutions of 50-70 mg of compound in 0.55 ml of solvent, in
5 mm nmr tubes. The temperature was raised in 10C
increments allowing at least 10 min for equilibration at
each setting. High temperature calibration of the
instrument with an ethylene glycol standard sample, showed
that the set and actual temperatures were in agreement
within +1C. Variable temperature measurements were
repeated twice and equilibrium constant values were the
average of at least three measurements.
Deuterated solvents were purchased from MSD Isotopes
(toluene-dg, CDClg, CgDg, CD^CN) and Chemalog (CDBr^) and
13
were used directly. C-NMR spectra were recorded on either
a JEOL-FX 100 (25 MHz, FT mode) or a Varian XL 200 (50 MHz),
or a Varian VXR 300 (75 MHz) instrument. Two-dimensional
spectra were recorded on the VXR 300 spectrometer using the
standard software for COSY and HETCOR pulse sequences
provided by Varian.


62
Reagents and miscellaneous preparative and
chromatographic methods are described in Chapter 4.
3.4.2 f N-[(Benzotriazol-N-yl)methyl]-N,N-
The preparation of the following compounds has been
described in Chapter 2: N-[(benzotriazol-N-yl)methyl]-
pyrrolidine (3.4), and N-[(5,6-dimethylbenzotriazo-N-lyl)-
methyl]pyrrolidine (3.7) [see preparation of compounds (2.4)
and (2.7), respectively].
N-[(5-Nitrobenzotriazol-N-yl)methyl]pyrrolidine (3.5).
5-Nitrobenzotriazole (5.42 g, 0.033 mol), pyrrolidine (0.038
mol, 3.1 ml), and 37% aq. formaldehyde (0.04 mol, 3.4 ml)
were stirred in methanol according to the standard
literature procedure [75JCS(Pi)1181] (see also Chapter 2).
Following evaporation of the solvent the compound was at
first obtained as an oil, which then solidified gradually
after stirring with diethyl ether in a dry ice/acetone bath.
N-[(5-Nitrobenzotriazol-N-yl)methyl]pyrrolidine was
collected as a yellow solid (7.22 g, 88.5%), m.p. 76-78C
(from diethyl ether) (Found, C, 53.01; H, 5.14; N, 28.21%.
C11H13N52 rec3u:>-res' C, 53.44 ; H, 5.30; N, 28.32%);
(CDC13, -25C) 1-isomer, 9.04 (d, J = 2 Hz, H-4), 8.46 (dd,
J = 9 Hz, J = 2 Hz, H-6), 7.88 (d, J = 9 Hz, H-7), 5.76 (s,
NCH2N), 2.78 (br s, NCH2CH2), 1.80 (br s, NCH2CH2);
2-isomer, 8.94 (d, J = 2 Hz, H-4), 8.32 (dd, J = 9 Hz, J = 2


63
Hz, H-6), 8.08
(d,
J = 9 Hz, H-7), 5.85
(s, nch2n)
, 2.
87 (br
s, nch2ch2), 1.
80
(br s, NCH2CH2); 3-isomer, 8.71
(d,
J = 2
Hz, H-4), 8.28
(dd
, J = 9 Hz, J = 2 Hz,
H-6), 8.25
(d,
J = 9
Hz, H-7), 5.78
( s,
NCH2N), 2.78 (br, s,
nch2ch2),
1.80
(br
s, nch2ch2).
N[(5-Chlorobenzotriazol-N-yl)methyl]pyrrolidine (3.6).
It was prepared as (3.5), using the same molar amounts of
the required starting materials. The oily residue remained
after evaporation of the solvent soon started crystallizing.
N[(5-Chlorobenzotriazol-N-yl)methylJpyrrolidine was
obtained as an off-white solid (5.75 g, 71%), m.p. 58-60C
(from diethyl ether/hexanes (7:1, v/v) (Found, C, 55.57 ; H,
5.40; N, 23.82%. requires, C, 55.82; H, 5.54; N,
23.67%); (CDCl^, +21C) 1-isomer, 7.96 (d, J = 9 Hz, H-
7), 7.45 (d, J = 2 Hz, H-4), 7.31 (d, J = 9 Hz, H-6,
overlaps with same proton of other isomer), 5.54 (s, NCH2N),
2.74 (br m, NCH2CH2), 1.73 (m, NCH2CH2); 2-isomer, 7.87 (d,
J = 2 Hz, H-4), 7.82 (d, J = 9 Hz, H-6), 7.31 (d, J = 9 Hz,
H-7), 5.68 (s, NCH2N), 2.85 (br m, NCH2CH2), 1.73 (m,
CH2CH2); 3-isomer, 8.02 (d, J = 2 Hz, H-4), 7.59 (d, J = 9
Hz, H-7), 7.43 (dd, J 9 Hz, J = 2 Hz, H-6), 5.57 (s,
NCH2N), 2.74 (br m, CH2CH2), 1.73 (m, NCH2CH2>.
N[(Benzotriazol-N-yl)methyl]morpholine (3.9). The
compound was prepared according to the general literature
method [52JA3868] (see also Chapter 2), and was obtained as
a white solid (95%), m.p. 108-109.5C (from 95% ethanol);


64
lit. [52JA3868] m.p. 104-105C; S (CDCl-,) 1-isomer, 8.06
(dd, J = 8 Hz, J = 1 Hz, H-4), 7.48 (td, J = 8 Hz, J = 1 Hz,
H-5 or H-6), 7.37 (m, H-7, H-6 or H-5), 5.41 (s, NCH2N),
3.65 (m, OCH2), 2.6 (m, CH2N); 2-isomer, 7.88 (AA' m, J =
6.5 Hz, H-4, H-7), 7.37 (BB' m, H-5, H-6, partially
overlapping with signals of 1-isomer), 5.53 (s, NCH2N), 3.65
(m, OCH2), 2.69 (m, CH2N).
3.4.3 Preparation of N-[a-(Benzotriazol-N-yl)alkyl]-N,N-
dialkylamines
General method. Benzotriazole (7.942 g, 0.0667 mol) and
a secondary amine (1 equiv.) were stirred in dry benzene (50
ml) and then the aldehyde (1 equiv.) was added. The mixture
was heated under reflux in a Dean-Stark apparatus, until the
theoretically calculated amount of water (~ 1.2 ml) had been
collected (1-5 days). Isolation and purification is
described below for each compound.
N-[a-(Benzotriazol-N-yl)-p-methyl)propyl]pyrrolidine
(3.8). The solvent was evaporated at room temperature under
reduced pressure (0.2 mm Hg), and the resulting oil was
triturated with petroleum ether/diethyl ether in a dry
ice/acetone bath. N-[ a-( Benzotr iazol-N-yl)-|3-me thyl)-
propyl]pyrrolidine was obtained as a beige solid (41%),
which was dried under vacuum (0.2 mm Hg, 2 days); m.p.
50-53 C ( Found, C, 67.93 ; H, 7.95%. ci4H20N4 rec3ui res c >
68.82; H, 8.25; N, 22.93%); (toluene-dg, -20C)
1-isomer, 7.99 (d, J = 9 Hz, H-4), 7.02 (m, H-5,6,7), 4.92


65
(d, J = 10 Hz, NCHN), 3.01 (m, CHMe2), 2.85 (m, NCH2CH2),
2.23 (m, NCH2CH2), 1.06 (d, J = 10 Hz, CH3), 0.44 (d, CH3);
2-isomer, 7.87 (AA' m, J = 6.5 Hz, H-4, H-7), 7.37 (BB' m,
H-5,6 and protons of other isomer), 5.38 (d, J = 10 Hz,
NCHN), 3.02 (m, CHMe 2) 2.56 (m, NCH2CH2), 2.23 (m, CU2CU_2) ,
l.04 (d, J = 10 Hz, CH3), 0.56 (m, J = 10 Hz, CH3).
N-[a-(Benzotriazol-N-yl)benzyl]morpholine (3.10).
Cooling of the hot benzene solution resulted in
precipitation of a solid, which was thinned with diethyl
ether in a cold bath and filtered. N-[a-(Benzotriazol-N-
yl ) benzyl ] morphol ine was collected as a white powder (87%),
m.p. 110-112C (from benzene) (Found, C, 69.01; H, 6.19; H,
19.00%. C17H18N4 rec3uires C, 69.37 ; H, 6.16; N, 19.03%);
&H (CgDg, +21C) 1-isomer, 8.03 (dd, J = 8 Hz, J = 1 Hz,
H-4), 7.26 (m, H-5,6 and protons of Ph groups), 7.05 (m,
Ph), 6.45 (s, NCHN), 3.42 (m, OCH2), 2.29 (m, CH2N,
superimposed on signals of other isomer); 2-isomer, 7.89
(AA' m, J = 3 Hz, H-4, H-7), 7.26 (BB' m, H-5,6 and Ph
protons), 7.05 (m, Ph), 6.78 (s, NCHN), 3.44 (m, OCH2), 2.69
(m, CH2N).
N-[a-(Benzotriazol-N-yl)-g-(4-nitrophenyl)methyl]-
morpholine (3.11). The product was obtained as a hard
yellowish solid (21.5 g, 96%) m.p. 145-148C (from 95%
ethanol) (Found, C, 60.35; H, 5.03; N, 20.50%. C17H17N53


66
requires, C, 60.17; H, 5.05; N, 20.64%); (CDCl-,, +21C)
l-isomer, 8.22 (d, J = 8 Hz, NO2-CC2H2, overlapping with
corresponding signals of other isomer), 8.13 (dd, J = 8 Hz,
J = 1 Hz, H-4), 7.63 (d, J = 8 Hz, N02CC2H2C2H2), 7.52-7.35
(m, H-5,6 overlapping with signals of other isomer), 6.79
(s, NCHN), 3.77 (m, OCH2), 2.64 (m, CH2N); 2-isomer, 8.21
(d, NO2CC2H2, overlapping with l-isomer), 7.93 (AA' m, J = 3
Hz, H-4,7), 7.52-7.35 (BB' m, H-5,6 and protons of
l-isomer), 6.85 (s, NCHN), 3.64 (m, OCH2), 2.85 (m, CH2N).
N-[a-(Benzotriazol-N-yl)-a-(4-methoxyphenyl)]methyl]-
morpholine (3.12). The product was a low melting (m.p. less
than 20C) solid, which could not be purified (remained as a
very viscous oil) and was characterized by H- (see below),
and ^^C-NMR spectra at -20C (see Tables 3.1 and 3.2); S
H
(CD^CN, at -20C) l-isomer, 8.07 (d, J = 8 Hz, H-4), 7.68
(d, J = 8 Hz, H-7), 7.50-7.32 (m, H-5,6 and corresponding
signals of other isomer), 7.35 (d, J = 9 Hz, MeO-CC2H2C2H2,
partially overlapping with corresponding signals of other
isomer), 6.89 (d, J = 9 Hz, MeO-CC2H2), 6.71 (s, NCHN), 3.70
(m, OCH2), 3.57 (s, OMe), 2.51 (br s, CH2N); 2-isomer, 7.93
(AA' m, J = 3 Hz), 7.50-7.32 (BB' m, H-5,6 overlapping with
corresponding signals of other isomer and with phenyl
protons), 6.79 (s, NCHN), 3.77 (s, OMe), 3.70 (m, OCH2),
2.51 (br s, CH2N).


67
N-[a-(Benzot riazol-N-yl)-g-methyl)propyl]morpholine
(3.13). After evaporation of benzene, the product was
obtained as an oil which solidified when treated with
diethyl ether in a dry ice acetone bath (11.2 g, 65%), m.p.
101-103C (Found, C, 64.89; H, 8.20; N, 21.79%. ci4H20N4
requires,
c,
, 64
.59;
H,
7.74; N,
21.52%)
; 8h (CDClg
, +21C)
1-isome r,
8 .
.08
(dd,
J
= 8 Hz, J
= 1 Hz,
H-4), 7.59
(d, J = 8
Hz, H-7),
7.
.45
(td,
J
= 8 Hz, J
= 1 Hz,
H-5 or H-6)
, 7.37
(m, H-6 or H-5, overlapping with corresponding signals of
the 2-isomer), 5.01 (d, J = 10 Hz, NCHN), 3.68 (2m, OCH2),
3.08 (qd, J = 8 Hz, J = 1 Hz, CHMe2), 2.60 (m, CH2N), 1.20
(d, J = 10 Hz, CH^), 0.63 (d, J = 10 Hz, CHg); 2-isomer,
7.90 (AA' m, J = 3 Hz, H-4,7), 7.37 (BB' m, H-5,6, over
lapping with corresponding signals of 1-isomer), 5.10 (s,
NCHN), 3.68 (m, OCH2), 2.97 (qd, J = 8 Hz, J = 1 Hz, CHMe2),
2.60 (m, CH2N), 1.20 (d, J = 10 Hz, CHj), 0.67 (d, J = 10
Hz, CH3).
N- [ g-(Benzotriazol-N-yl )-|3-methyl )propyl ]-N,N-
dibenzylamine (3.14). The compound was obtained as a white
solid after complete evaporation of benzene at room
temperature (at 0.2 mm Hg), and trituration with dry diethyl
ether. N-[a-(Benzotriazol-N-yl)-8-methyl)propyl]-N,N-
dibenzylamine was collected by filtration (78%), m.p.
83-85C (Found, C, 77.76 ; H, 7.11%. C24H26N4 rec3ui res' C,
77.80; H, 7.07, N, 15.12%); 8H (toluene-dg, +20C)
1-isomer, 8.03 (d, J = 8 Hz, H-4), 7.30 (d, J = 8 Hz, H-7),


68
7.12 (m, rest of ring protons), 6.90 (t, J = 6.5 Hz, H-5 or
H-6), 5.01 (d, J = 10 Hz, NCHN), 4.13 (d, J = 14 Hz, CH2Ph),
3.07 (d, J = 14 Hz, CH2Ph), 2.95 (m, CHMe2>, 1.16 (d, J = 10
Hz, CH^), 0.32 (d, J = 10 Hz, CH^); 2-isomer, 7.92 (AA' m,
J = 3 Hz, H-4,7), 7.44 (BB' m, J = 3 Hz, H-5,6), 7.22-7.06
(m, Ph ring protons of both isomers), 5.31 (d, J = 10 Hz,
NCHN), 4.17 (d, J = 14 Hz, CH2Ph), 3.17 (d, J = 14 Hz,
CH2Ph), 2.95 (m, CHMe2), 1.07 (d, J = 10 Hz, CH3), 0.39 (d,
J = 10 Hz, CH3).
N-[a-(Benzotriazol-N-yl)benzyljpiperidine (3.15). The
oil obtained after evaporation of benzene did not solidify
under a variety of conditions. The oily residue (59%) was
characterized by its ^C- (Tables 3.1 and 3.2), and ^H-NMR
spectra: &H (toluene-dg, +21C) 1-isomer, 8.02 (m, H-4),
7.25-7.00 (m, H-5,6 and Ph ring protons), 6.61 (s, NCHN),
2.80-2.25 [m, N(CH2)2], 1.40 [br s, N(CH2)2(CH2)2],
1.20-1.00 [m, N(CH2)^CH2]; 2-isomer, 7.25-7.00 (m, all Bt
and Ph ring protons), 6.86 (s, NCHN), 2.80-2.25 [m,
N(CH2)2-], 1.40 [br s, N(CH2)2(CH2)21, 1.20-1.00 [m,
n(ch2)4ch2].
3.4.4 Methylation of 5-Nitrobenzotriazole
5-Nitrobenzotriazole (0.5 g, 0.03 mol) was dissolved in
aq. 2N NaOH (25 ml) and water (10 ml) was added to achieve a
clear solution. Dimethyl sulfate (10 g, 0.076 mol) was
added and a yellow precipitate appeared. The suspension was


69
stirred at room temperature for 1/2 h and at 0C for 1 1/2
h, then the solid was filtered, washed with water and air
dried. The crude solid contained three products, as
indicated by TLC (eluted with hexanes/Et2, 1/1, v/v) with
Rj values 0.62, 0.37, 0.19. A portion of the crude solid
(0.25 g) was placed on a silica gel column and eluted with
hexanes/Et20 (8:2, 7:3, 6:4, 5:5, 2:8, v/v) and finally
Et2. Total recovery 0.20 g, 80%. The following compounds
were collected as column fractions (in order of elution):
2-Methyl-5-nitrobenzotriazole. (= 0.62, 0.094 g,
46%, m.p. 180-4 C, lit. [64T211] m.p. 187C); S (300 MHz,
CDC13) 8.87 (dd, Jm = 2 Hz, Jp = 0.7 Hz, H-4), 8.24 (dd, JQ
= 9 Hz, Jm = 2 Hz, H-6), 7.98 (dd, Jq = 9 Hz, Jp = 0.7 Hz,
H-7), 4.61 (3H, s, Me); &c (75 MHz, CDC13) 146.6 (C-3a or C-
5, small br), 143.0 (C-7a), 120.7 (C-6), 119.1 (C-7),
116.0 (C-4), 44.0 (Me).
3-Methyl-5-nitrobenzotriazole. (R^ = 0.37, 0.048 g,
24%, m.p. 154-157C, lit. [64T211] m.p. not reported)
(Found, C, 45.29 ; H, 3.48%. C^N^. 1/2H20 requires, C,
44.92; H, 3.77; N, 29.94%); §H (300 MHz, CDCl3), 8.55 (d,
Jm = 2 Hz, H-4), 8.27 (dd, Jq = 9 Hz, Jm = 2 Hz, H-6), 8.18
(d, JQ = 9 Hz, H-7), 4.45 (s, 3 H, CH3); Sc (75 MHz, CDCl3)
148.0 (C-3a or C-5), 146.8 (C-5 or C-3a), 132.7 (C-7a),
120.9 (C-5), 118.8 (C-7), 106.5 (C-4), 43.8 (CH3).


70
l-Methyl-5-nitrobenzotriazole. (R^ = 0.19, 0.06 g, 30%,
m.p. 160-2 C, lit. [64T211] m.p. 163C); Su (300 MHz,
CDC13) 8.99 (d, Jm = 2 Hz, H-4), 8.42 (dd, Jq = 9 Hz, Jm = 2
H,, H-6), 7.69 (d, Jq = 9 Hz, H-7), 4.41 (3 H, s, Me); $c
(75 MHz, CDCl3) 144.9 (C-3a or C-5, small br), 136.0 (C-7a),
122.4 (C-5), 117.2 (C 3), 109.0 (C-7 ), 34.70 (Me).


Table 3.7. ^H-NMR chemical shifts of compounds (3.4-3.15) at a single temperature (above
coalescence)
Noa
Solv.
Temp.
(C)
-nr2
R'
CH
Bt
3.4
CDBr3
110
2.8
(br s,
4 H)
_b
5.6 (s, 2 H)
8.1-7.7 (br m, 4 H)
1.7
(br s,
4 H)
(br m, 4 H)
3.5
cdci3
45
1.7
(br s,
4 H)
b
5.8 (br s, 2 H)
9.1-7.7
2.7
(br s,
4 H)
(v. br m, 3 H)
3.6C
CDBr3
84
2.8
(br s,
4 H)
b
5.7 (s, 2 H)
8.0-7.4 (br m, 3 H)
1.7
(br s,
4 H)
3.7d
CDBr3
110
2.8
(br s,
4 H)
b
5.5 (s, 2 H)
7.8-7.3(v. br m, 2 H)
1.7
(br s,
4 H)
2.4 (br s, Me)
3.8
toi-dg
70
2.9-2
!.7 (m,
4 H)
0.9e
5.3 (d, 1 H)
7.8 (br s, 2 H)
1.4
(s, 4
H)
(m, 7 H)
(J = 10 Hz)
7.2-7.1 (m, 2 H)
3.9
CDBl'3
110
3.6
(br s,
4 H)
b
5.4 (s, 2 H)
8.7 (v. br s, 2 H)
2.7
(br s,
4 H)
7.4 (s, 2 H)
3.10
CDBr3
90
3.9
(br s,
1 H)
_g
6.7 (s, 1 H)
7.9 (br m, 3 H)^
3.7
(br s,
3 H)
7.5-7.3 (m, 6 H)
3.2
(br s,
1 H)
2.6
(br s,
3 H)
3.11h
CDBr3
110
4.1
(br s,
1 H)
_g
6.8 (br s)
9.5 (v. br s, 1 H)
3.8
(br s,
3 H)
(1 H)
8.2-7.2 (m, 7 H)
3.2
(br s,
1 H)
2.8
(br s,
3 H)


Table 3.7continued.
No
Solv.
Temp.
(C)
-nr2
R'
CH
Bt
3.12
cd3cn
60
3.7 (m, 4
H)
6.85g
6.7
9.9 (s, 1 H)
2.5 (br m,
3 H)
(d, 2 H)
(s, 1 H)
8.6 (br s, 1 H)
2.8 (br s,
1 H)
3.7 (s, 3 H)
8.0-7.7 (m, 1 H)
7.5-7.3 (br m, 3 H)
3.13
cd3cn
50
3.6 (m, 4
H)
3.0 (m, 1 H)
5.1 (d, 1 H)
8.2-7.7 (m, 2 H)
2.6 (m, 4
H)
1.2 (m, 6 H)
(J = 10 Hz)
7.6-7.3 (m, 2 H)
3.14
CDBr3
90
4.2 (br m,
2 H)
3.1 (br m)
5.30
7.9 (v. br s, 3 H)
3.3 (br m,
2 H)g
(1 H)
(br s, 1 H)
7.3 (br m, 6 H)
1.2 (m, 3 H)g
0.5 (m, 3 H)
3.15
tol-d
90
2.29 (br m,
4 H)
6.80 (m, 5 H)
6.42 (s, 1 H)
7.5 (v. br s, 4 H)
1.15 (m, 4 H)
0.94 (m, 2 H)
Many peaks did not become entirely sharp, even at several degrees above coalescence. ^ R' = H.
Some decomposition must have occurred as evidenced by additional aliphatic peaks. ^ In addition,
& 3.4 (br m), 2.0 (br m), probably due to free pyrrolidine. The CHMe0 signal is hidden under
broad peaks. In addition, S 10.30 (v. br, 1 H). g Phenyl protons come together with
benzotriazole protons. ^ The spectrum was recorded in CDBr^, since b.p. (CD-,CN) = 82C and
T = 84C in CD-CN.
c 3


CHAPTER 4
A GENERAL METHOD FOR THE PREPARATION
OF STRUCTURALLY DIVERSE TERTIARY AMINES
4.1 Introduction
In the preceding chapters, the isomerization of N-[a-
(benzotriazol-N-yl)alkyl]-N,N-dialkylamines was
investigated, and the influence of the structure on this
process was assessed: all the evidence gathered is in
support of the proposed ionic mechanism (Chapter 3, Scheme
3.1). Consequently, the carbon atom located between the
benzotriazole and the amine nitrogens (Bt-CH(R)-NR2) must
possess enhanced electrophi1icity and therefore is expected
to react easily with various nucleophiles. In this and in
the following chapters, the reactions of benzotriazole
adducts with strong and weak nucleophiles are investigated.
The classification is based on the nature of the end-product
rather than the type of the reaction.
In the present chapter, the knowledge gained so far
(Chapter 3) has been combined with previous experience in
this [87JCS(Pi)805 ] and other research groups [84TL1635 ]
regarding the reactivity of primary aromatic amine/benzo-
triazole adducts toward alkylation. Thus, benzotriazole
adducts of the type (4.2) are expected to undergo facile
alkylation upon reaction with Grignard reagents, thereby
73


74
converting secondary amines (4.1) into variably substituted
tertiary amines (4.3). In a similar fashion, replacement of
benzotriazole by hydride, by the action of a hydride ion
donor, should also be feasible (Scheme 4.1).
4.3a 4.31 4.3m 4.3p
Scheme 4.1


75
Tertiary amines can be prepared by many and varied
methods [79MI1]. Alkylation of secondary amines is a useful
tool (Equation 4.1); however, in unhindered cases there is
danger of over-reaction to yield quaternary salts, and
sterically hindered tertiary amines are not easy to prepare
in this way, as the reactions are slow and the yields low to
moderate [60JA4908], [78S766] Alkyl branching in R3X
brings with it the probability of competing amine induced 13-
elimination in substrates having suitably placed hydrogens
[79MI1].
R1R2NH + R3X > R1R2R3N + HX (Eq. 4.1)
Reductions of iminium salts (largely confined to
formaldehyde derivatives) or tertiary amides [79MI1]
(Equations 4.2, 4.3, respectively), require availability of
the appropriate precursor and do not allow for versatility
in the structural features of the products [79MI1].
CH20 + HNR1R2 > CH2=NR1R2 > CHj-NR^2 (Eq. 4.2)
R1CONR2R3 -> R1CH2NR2R3 (Eq. 4.3)
Reductive carbonylation [83S723] or carboxylation
[78S766], [85TL5367] of 2 amines (Equation 4.4), although
versatile and high yielding, requires tedious procedures:


76
- 1. BunLi 1 9 ClCO^Me .. y
R R NH > R R NCO, Li > [ R R NCO,CO,He ]
2. C02 2 2
A .y LiAlH- .. y
> RXRZNC02Me -> RiRZNMe ( Eq. 4.4)
Reductive dealkylation of quaternary ammonium salts
[79MI1], often gives good yields but the starting material
is usually itself made from a tertiary amine. Deamination
of dimethylhydrazinium salts [82SC801] affords N,N-dimethyl-
alkyl- or -aryl- amines in high yields, but involves the
carcinogenic N,N-dimethylhydrazine (Equation 4.5).
_ HN02
RX + Me2NNH2 > R(Me)2N NH2 X -> RNMe2 (Eq. 4.5)
The conversion of primary amines with formaldehyde and
ethylene glycol into perhydrodioxazepines and subsequent
treatment with Grignard reagents [83TL1597] leads to
tertiary amines in a more direct way, but is limited to
compounds containing two identical alkyl groups (Equation
4.6) .
2 R1MgX .
RNH2 + CH20 + (CH2OH)2 > RN(CH2OCH2)2 > RN(CH2Ri)2
(Eq. 4.6)
Methods involving metal catalysts are available
[84JOC3359], especially in the patent literature [61MI1],
[85JAP60258145] but almost invariably require heating under
pressure.


77
Reaction of organometallic reagents with iminium salts
[81JOM275], or chloromethylene iminium salts [85LA2178],
provides a direct route to tertiary amines (Equation 4.7),
however the required intermediate salts are very hygroscopic
[63JOC302], [71AG(E)330].
COCl? + 2 R^MgX 1
hconr2 -> ci-ch=nr2 cl > r2ch-nr2
(Eq. 4.7)
In view of the continuous interest in the physiological
properties of amines ([59BP814152 ] [61MI2], [62BEP617762],
[63AP728], [79MI1], [87AG(E)320]), new general methods for
their preparation are of considerable significance. Within
the context of researching the chemistry and properties of
benzotriazole derivatives, the possibility of converting the
benzotriazole adducts (4.2) into a variety of tertiary
amines was investigated.
4.2 Results and Discussion
4.2.1 Preparation of Benzotriazole Adducts
Adducts of type (4.2), as previously shown in Chapters 2
and 3, exist in solution as mixtures of the benzotriazol-
1-yl and benzotriazol-2-yl adducts. The preparation of
compounds of the type (4.2, R^ = H) i.e. derived from
formaldehyde was reported in Chapter 2. The corresponding
adducts (4.2, R^ H), i.e. derived from higher aldehydes


78
were prepared by the azeotropic distillation of the water
produced from a benzene solution containing benzotriazole,
an amine and an aldehyde (Scheme 4.1) in equimolar amounts,
as was fully described in Chapter 3. The benzene solutions
could be used to react directly with preformed Grignard
reagents. Alternatively, the adducts could be isolated,
purified and characterized prior to their reaction with the
Grignards, although somewhat lower overall yields were then
observed, due to unavoidable loses during the isolation
step.
An alternative method of preparation of the adducts
under milder conditions was also tested. Thus, the three
starting materials (Scheme 4.1) were mixed in dry
tetrahydrofuran (THF) in the presence of drying agents
(Na2S0^/MgS0^) and stirred at room temperature for 1-2 days
[76JCS(P2)741]; however with this method it was difficult
to decide at which point the reversible reaction leading to
(4.2) (Scheme 4.1) was complete. Grignard reactions using
the THF solutions thus obtained, did provide the expected
amines (4.3) but the yields were low and byproducts,
resulting from reaction of the Grignard reagents with the
starting aldehyde [eg. PhCH-^CH ( OH) Ph from PhCHO and
PhCH2MgCl], were detected by GLC/MS. Therefore the
azeotropic distillation described above, remained the method
of choice.


79
4.2.2 Preparation of Tertiary Amines
The Grignard reagents, prepared conventionally in ether,
reacted very rapidly, and with evolution of heat, with the
adducts (4.2) yielding tertiary amines (4.3) by replacement
of benzotriazole (Scheme 4.1, Table 4.1). Amines
(4.3a)-(4.3f) were prepared using THF solutions of the
isolated adducts (4.2a)-(4.2d). Advantageously, adducts
(4.2e)-(4.2i) were not isolated and the benzene solutions
from the azeotropic distillation were reacted directly with
the Grignard reagents; the overall yields were then very
good.
The reactions were generally complete within one hour.
The free benzotriazole, obtained after hydrolysis of the
reaction mixture, was easily removed by basic extraction (2N
NaOH). Byproducts originating from coupling of the Grignard
reagents were routinely observed and were removed either by
chromatography or by acid extraction of the amine and
neutralization of the obtained salt.
Although Grignard reactions are sensitive to steric
effects [84M11] neither retardation of the reaction rate nor
side products were observed during the reaction of the
dibenzylamine/isobutyraldehyde adduct (4.2f) with
methylmagnesium iodide, in which the transition state is
expected to be sterically crowded.
In a similar fashion, sodium borohydride reduction of
the adducts (4.2a), (4.2c), (4.2f) and (4.2i) proceeded very
smoothly to afford amines (4.3m)-(4.3p). The reduction


80
Table 4.1 Preparation of tertiary amines (4.3) R^R3CHNR^R2
Add.
4.2
R1
R2
R3
Reagent
4
R Amine
4.3
Yield
(%)
a
CH2Ph
CH2Ph
H
PhMgBr
Ph
a
83
a
CH2Ph
CH2Ph
H
PhCH2MgCl
CH2 Ph
b
88
a
CH2Ph
CH2Ph
H
MeMgl
Me
c
80
b
n CgH17 n CgH17
H
PhMgBr
Ph
d
58
c
CH3
Ph
H
BunMgBr
Bu11
e
74
d
Et
Et
H
PhCH2MgCl
CH2Ph
f
91
e
- Pr1
PhCH2MgCl
CH2Ph
g
76a
e
-4-
Pr1
PhMgBr
Ph
h
64a
f
CH2Ph
CH2Ph
Pr1
MeMgl
Me
i
7 8a
g
~(CH2)5-
Ph
Pr1MgBr
Pr1
j
59a
h
-(CH2]
12(CH2 J 2
Prn
PrnMgBr
Prn
k
79a
i
-ICh2]
I20(Ch2I2
Ph
BunMgBr
Bu11
1
82a
c
ch3
Ph
H
NaBH4
H
m
82
a
CH2Ph
CH2Ph
H
NaBH4
H
n
75
f
CH2Ph
CH2Ph
Pr1
NaBH4
H
o
83
i
-(CH2)20(CH2)2-
Ph
NaBH4
H
P
91
a This
is the overall yield, as
calculated from
starting
benzotriazole;
the other
numbers in this column,
represent
yields of the alkylations and reductions, as calculated from
the corresponding adduct (4.2).


81
conditions reported here (simply stirring at room
temperature) are milder than those reported for reduction of
adducts derived from primary aromatic amines [87JCS(Pi)805].
Table 4.1 shows that the products were obtained in
generally high yields. The diversity in the structures of
the products is also reflected in this Table, in which
examples of aliphatic (4.3k), or aromatic (4.3e) amines,
simple (4.3m) or sterically crowded (4.3i), bearing short
(4.3f) or long (4.3d) aliphatic groups, are collected.
It is not certain whether the Grignard or sodium
borohydride reactions proceed via the iminium ion inter
mediates, invoked in Chapters 2 and 3. The concentration of
these reactive intermediates in the solution may be
negligible in some cases. On the other hand, the reagents
used are reactive nucleophiles, and benzotriazole itself a
good leaving group. In addition, no difference in
reactivity was displayed among the various adducts toward
reactions with the organometallic reagents, although the
reactions were fast and slight differences could not have
been detected. If indeed an iminium ion is involved, then
Grignard addition must be preceded by benzotriazole
elimination catalyzed by magnesium acting as a Lewis acid
(Scheme 4.2) [84MI1]. The ability of benzotriazole to form
complexes with a number of metals is well documented
[81ACS(A)739], [83ICA109]. An alternative, but less likely
mechanism, is an SN2 type process, in which the departure of
benzotriazole, aided by coordination with the metal, and the
nucleophilic attack occur simultaneously.


82
Scheme 4.2
Independent evidence for the activating role of benzo-
triazole has been reported previously [87JCS(Pi)805] in the
reduction of a bis(benzotriazoly1)aminoalkyl adduct, in
which only the Bt group a- to the amine was replaced by
hydride (Scheme 4.3).


83
Scheme 4.3
All amines were characterized as their picrate salts and
1 13
by their H- and C-NMR spectra (see Experimental section).
Chemical shift nonequivalency of the methyl groups of the
isopropyl moiety adjacent to the asymmetric carbon atom was
i 1 3
observed in the H- and C-NMR spectra of (4.3g), (4.3h),
and (4.3i). Thus, the methyl groups appeared as two
doublets in the ^H- and as two distinctly different signals
13
m the C-NMR spectra. In spite of their slight
complexity, assignments of all spectra were generally
possible.
Many of these amines are either novel compounds or found
only in the patent literature where they have received
considerable interest due to their physiological activity
(central nervous system stimulants, antihypertensives,
spasmolytics, etc.) [59BP814152 ] [61GP1093799], [61MI2],
[62BEP17762], [63AP728], [85JAP60258145], [87AG(E)320].


84
4.3 Conclusions
The work described in this Chapter, demonstrates the
synthetic utility of benzotriazole adducts in alkylation and
reduction reactions, in which facile displacement of the Bt-
moiety leads to tertiary amines. The present method has
many advantages over other literature methods, including
simplicity of procedure, readily available starting
materials, possibility for one-pot reaction and good yields.
Benzotriazole acts as both an activating and a leaving group
and can be recycled at the end, for large scale
preparations.
4.4 Experimental
4.4.1 Methods and Reagents
Melting points were determined on a hot stage
microscope and are uncorrected. ^H-NMR spectra were
recorded on a Varian XL 200 spectrometer, using TMS (6 = 0.0
1 3
ppm) as internal reference. C-NMR spectra were recorded
either on JEOL FX-100 (25 MHz), or Varian XL 200 (50 MHz)
instruments as solutions in deuterochloroform (CDCl^), using
the solvent signal at 5 = 77.00 ppm as reference.
Exact mass spectra were recorded on a AEI MS 30 mass
spectrometer. Combustion analyses were carried out using a
Carlo Erba 1106 elemental analyser, under the supervision of
Dr. King of this department, or by the Atlantic Microlab.


85
GLC was carried out on a Hewlett Packard 5890A
instrument using a 5 m HP-1 column (conditions: initial
temperature = 70C; initial time = 0 min; rate = 15
deg./min; final temperature = 250C).
Tetrahydrofuran (THF) and diethyl ether (Et20) were
distilled under nitrogen from sodium/benzophenone
immediately before use. Thiophene free, reagent grade
benzene (obtained from Fisher Scientific) was used without
further drying (0.02 ppm H2O). Silica gel (230-400 mesh)
was purchased from Merck.
4.4.2 Preparation of N-[(-Benzotriazol-N-yl)alkyl]~
N,N-dialkylamines
The preparation of compounds (4.2a)-(4.2c) was based
on a general literature procedure [46JA2496] which was
described in Chapter 3, with modifications according to the
particular compound, as specified below.
N-[(Benzotriazol-N-yl)methyl]-N,N-dibenzylamine
(4.2a). Benzotriazole (0.1 mol, 11.9 g), dibenzylamine
(0.11 mol, 21.1 ml) and 37% aq. formaldehyde (0.12 mol, 9.7
ml), were mixed in methanol (45 ml). The resulting two-
layer system was stirred vigorously at room temperature for
8 h. Diethyl ether was added to homogenize the mixture, and
the whole was heated under reflux overnight to complete the
reaction. The mixture was then poured on crushed ice,
diethyl ether was added and the mixture stirred, resulting


86
in formation of a white solid. N-[(Benzotriazol-N-
yl)methyl]-N,N-dibenzylamine was collected by filtration as
white microcrystals (95%), m.p. 120-122C (from 95%
ethanol); lit. [75JCS(Pi)1181] m.p. 121-123C; (CDCl3,
200 MHz) 8.07-8.02 (d, J = 9 Hz, H-4, 1-isomer), 7.96-.91
(AA' m, J = 8 Hz, H-4, H-7 of 2-isomer), 7.47-7.25 (m,
phenyl protons and H-5, H-6 of both isomers), 5.50 (s,
NC^N, 2-isomer), 5.40 (s, NCH2N, 1-isomer), 3.79 (s,
NCH2Ph, 2-isomer), 3.74 (s, NCH2Ph, 1-isomer); (CDCl^,
25 MHz) 145.3 (C-3a, Bt), 137.7 (C-ipso, Ph), 133.7 (C-7a,
Bt), 128.7 (C-o, Ph), 128.3 (C-p, Ph), 127.0 (C-m, Ph),
125.3 (C-5 or C-6, Bt), 123.5 (C-6 or C-5, Bt), 119.5 (C-4,
Bt), 109.7 (C-7, Bt), 64.0 (NCH2N), 55.6 (NCH2Ph) of the
1-isomer; 143.2 (C-3a, C-7a), 138.1 (C-ipso, Ph), 128.9 (C-
o, C-p, Ph), 127.0 (C-m, Ph ), 126.0 (C-6, C-5, Bt), 118.2
(C-4, C-7, Bt), 72.0 (NCH2N), 55.4 (NCH2Ph) of the 2-isomer.
N-[(Benzotriazol-N-yl)methyl]-N,N-dioctylamine (4.2b).
Benzotriazole (0.1 mol, 11.9 g) was dissolved with stirring
in methanol (45 ml) and then N,N-dioctylamine (0.11 mol,
26.56 g) was added, followed by 37% aq. formaldehyde (0.12
mol, 9.7 ml). A two layer system resulted which still
contained starting materials after 7 h of stirring (TLC on
silica gel; eluted with EtOAciCHCl^, 1:1 v/v). The mixture
was made homogeneous with Et20 and heated under reflux
overnight. It was then poured on ice (100 g), extracted
with Et20 (5 x 40 ml), the extracts dried (MgSO^), the


87
solvent evaporated and the residue heated .in vacuo (10 mm
Hg, 24 h; 1.5 mm Hg, 1 h), to give an almost colorless thick
oil in quantitative yield (38 g). The oil decomposed on
attempted distillation (150C at 0.25 mm Hg). The
analytical sample was obtained by drying a small amount of
the oil under 10 mm Hg, over P25 78C for 5 days (Found,
C, 74.07 ; H, 10.85; 14.94%. C23H40N4 rec3uires > C' 74.14; H,
10.82; N, 15.04%); (CDCl,, 200 MHz) 8.08-8.03 (dd, J =
8, 1 Hz, H-4, Bt, 1-isomer), 7.91-7.86 (AA' m, J = 7 Hz, H-
4, H-7, Bt, 2-isomer), 7.62-7.29 (m, H-5, H-6, Bt, both
isomers), 5.59 (s, NCH2N, 2-isomer), 5.48 (s, NCH2N,
1-isomer), 2.61-2.54 (t, J = 8 Hz, 4 H, NCH2CH2, both
isomers), 1.56-1.48 (m, 4 H, NC^Ct^, both isomers), 1.25
(m, methylene groups, 20 H, both isomers), 0.88 (m, 6 H,
CH3, both isomers); §c (CDCl^, 25 MHz), 145.6 (C-3a), 133.6
(C-7a), 126.9 (C-5, or C-6), 123.3 (C-6 or C-5), 119.5 (C-
4), 109.7 (C-7), 66.2 (NCH2N), and octyl group carbons, 51.7
(NCH2), 31.6, 29.2, 29.1, 27.3, 26.9, 22.9, 13.8 (CHj) of
1-isomer; 143.9 (C-3a, C-7a), 125.7 (C-5,6), 118.0 (C-4,5),
73.2 (NCH2N), and octyl group carbons 51.7, 31.6, 29.2,
29.1, 27.3, 26.9, 22.9, 13.8, of the 2-isomer.
N-[(Benzotriazol-N-y1)methyl]-N-methylaniline (4.2c).
The product was prepared according to literature methods
[75JCS(Pi)1181] and was collected as white needles (64%),
m.p. 72-75C (from diethyl ether/hexane, 10:1, v/v); lit.
[75JCS(Pi)1181] m.p. 76-78 C; §H (CDC13 200 MHz) 7.98-7.93


88
(d, J = 8 Hz, H-4, 1-isomer), 7.89-7.83 (AA' m, J = 7 Hz, H-
4 and H-7, 2-isomer), 7.33-7.25 (m, phenyl groups, both
isomers), 7.33-7.25 (m, benzotriazole protons, both iso
mers), 6.15 (s, NCH2N, 2-isomer), 6.13 (s, NCH2N, 1-isomer),
3.30 (s, NCH^, 2-isomer), 3.01 (s, NCH^, 1-isomer);
(CDC13, 25 MHz) 147.7 (C-ipso, Ph), 146.0 (C-3a, Bt), 133.0
(C-7a, Bt), 129.3 (C-o, Ph), 127.3 (C-5 or C-6, Bt), 123.8
(C-6 or C-5, Bt), 119.9 (C-p, Ph), 119.1 (C-7, Bt), 115.1
(C-m, Ph), 110.0 (C-4, Bt), 66.7 (NCH2N), 37.4 (Me) of
1-isomer, and 144.0 (C-3a and C-7a, Bt), 129.1 (C-o, Ph),
126.7 (C-5, C-6, Bt), 120.0 (C-p, Ph), 118.2 (C-4, C-7, Bt),
113.6 (C-m, Ph), 72.6 (NCH2N), 38.7 (NCH3) of 2-isomer.
The preparation and spectroscopic data of N-[(benzo-
triazol-N-yl)methyl]-N,N-diethylamine (4.2d) was described
in Chapter 2 (compound 2.6), and of N-[a-(benzotriazol-N-
yl ) -3-methylpropyl ] pyr rol idine (4.2e), N-[a-(benzotriazol-N-
yl) (3-methyl propyl ] -N, N-di benzyl amine (4.2f), N-[a-(benzo-
triazol-N-yl)benzylJpiperidine (4.2g), N-[a-(Benzotriazol-N-
yl)benzylJmorpholine (4.2) were described in Chapter 3
[compounds (3.8), (3.14), (3.14), and (3.10), respectively].
N-[g-(Benzotriazol-N-yl)butyl]morpholine (4.2h). The
compound was prepared using the general method described in
Chapter 3, for compounds (3.1, H). After evaporation
of solvent benzene under reduced pressure, an oily substance
was recovered which was dried under 0.2 mm Hg for several


89
days. N-1 a-(BenzotriazolN-yl)butyl]morpholine was
characterized by its ^H- and 13C-NMR spectra: (toluene-
dg, 300 MHz) 8.00 (d, J = 8 Hz, H-4, 1 isomer), 7.87-7.84
(AA' m, J = 7 Hz, H-4,7, 2-isomer), 7.15 (d, J = 8 Hz, H-7,
1-isomer), 7.14-7.08 (m, all other ring protons), 5.21 (t, J
= 6 Hz, NCHN, 2-isomer), 4.93 (t, J = 6 Hz, NCHN, 1-isomer),
3.44 (m, OCH2, both isomers), 2.39 (t, J = 4 Hz, CH2N, 2 H,
both isomers), 2.30 (t, J = 4 Hz, CH2N, 2 H, both isomers,
overlapping with signals of the aliphatic chain), 2.10 (m, 2
H, CH2CH3, both isomers), 0.88 (t, J = 6 Hz, 3 H, C^CHg,
both isomers); §c (CDClg, -20C, 25 MHz) 1-isomer, 145.0
(C-3a), 133.5 (C-7a), 127.1 (C-5 or C-6), 123.7 (C-6 or C-
5), 109.7 (C-7), 78.7 (NCH2N), 66.5 (OCH2), 47.9 (CH2N),
32.6 (NCHCH2CH2), 18.6 (NCHCH2CH2), 13.3 (CHg); 2-isomer,
143.1 (C-3a, C-7a), 126.0 (C-5,6), 117.9 (C-4,7), 85.7
(NCHN), 66.6 (OCH2), 48.4 (CH2N), 32.8 (NCHCH2>, 18.8
(NCHCH2CH2), 13.3 (CH3).
4.4.3 Preparation of Tertiary Amines by Alkylation:
Two-Step Procedure-
General method. The Grignard reagent was prepared
from magnesium turnings (0.0114 mol) and the alkyl or aryl
halide (0.0114 mol) in dry diethyl ether (10 ml). To this
solution, the benzotriazole adducts (4.2a)-(4.2d) (0.004
mol) dissolved in dry THF (20 ml) were added dropwise.
Immediate frothing and evolution of heat was observed, and
reflux was sustained by slow addition. The mixture was
heated under reflux for 1 h and then poured on crushed ice


90
(100 g), and stirred with aq. sat. ammonium chloride (20-50
ml) and/or IN HCl (10 ml) until all solids dissolved.
Extraction with ether (3 x 40 ml), washing with 2N NaOH
(until TLC showed no presence of benzotriazole), drying
(MgSO^) and removal of the solvent under reduced pressure
afforded the crude product which was purified as described
for each particular compound. The oily products were
characterized as their picrate salts, which were all
prepared in and recrystallized from 95% ethanol.
Tribenzylamine (4.3a). Recrystallization of the crude
material removed the byproduct biphenyl and afforded
tribenzylamine (4.3a) as white flakes (83%), m.p. 91-93C
(from 95% ethanol), lit. m.p. 91-94C (commercially
available from Aldrich Chemical Company); Su (CDCl-,, 200
MHz) 7.39-7.14 (m, 15 H, aromatic), 5.51 (s, 6 H, Ph-CH2);
Sc (CDC13, 50 MHz) 139.6 (C-ipso), 128.7 (C-o), 128.2 (C-p),
126.8 (C-m), 57.8 (Ph-CH2).
N,N-Dibenzyl-N-phenylethylamine (4.3b). The product
was obtained as a very clean (as shown by its NMR spectra)
pale yellow oil (88%), b.p. 180-185C (at 0.5 mm Hg); lit.
[47JOC760] b.p. 206-211C (at 3 mm Hg); 6U (CDCl-., 200 MHz)
7.28-7.02 (m, 15 H, aromatic), 3.60 (s, NCH-,Ph, 4 H),
2.87-2.63 (2m, 4 H, N-CH2CH2Ph); Sc (CDC13, 25 MHz)
aromatic (140.5, 139.6, 128.8, 128.6, 125.7, 126.7), 58.1
(NCH2Ph), 55.0 (NCH2CH2Ph), 33.4 (NCH2CH2Ph). N,N-Dibenzyl-
N-phenylethylamine was characterized as its picrate salt,


91
m.p. 118-120 C (Found, C, 62.99; H, 4.94; N, 10.36%.
('28H26N4<^7 ret3u:*-res' C> 63.39 ; H, 4.94; N, 10.56).
N-Ethyl-N,N-dibenzylamine (4.3c). Distillation of the
crude afforded the clean product (80%), b.p. 132-136C (at
0.5 mm Hg); lit. [78S766] b.p. 101-106C (at 0.35 mm Hg);
(CDCl2, 200 MHz) 7.38-7.17 (m, 10 H, aromatic), 3.54 (s,
4 H, NCH2Ph), 2.53-2.43 (q, J = 7 Hz, 2 H, CH2CH3),
l.07-1.00 (t, J = 7 Hz, 3 H, CH2CH3); §c (CDCl3, 25 MHz)
aromatic (134.0, 128.7, 128.1, 126.7), 57.0 (NCH2Ph), 47.0
(CH2CH3), 11.8 (CH2CH3). N-Ethyl-N,N-dibenzylamine was
converted to its picrate, m.p. 116-118C; lit. [78S766]
m.p. 110-111C.
N-Benzyl-N,N-dioctylamine (4.3d). The product was
obtained as a yellow oil, b.p. 110-112C (at 0.4 mm Hg). A
portion of this oil (0.7 g) was purified by column
chromatography on silica gel [eluent: hexane, hexane:chloro
form (7:3 and then 3:7), chloroform]; 0.435 g of oil were
collected (58%) (Found, Mt 331.3253. ^23H41N requires, mI
331.3238); &H (CDClj, 200 MHz) 7.33-7.17 (m, 5 H,
aromatic), 3.52 (s, 2 H, CH2Ph), 2.42-2.34 (t, J = 7 Hz, 4
H, NCH2CH2), 1.48-1.42 (m, 4 H, NCH2CH2), 1.25 (ap. s, 20 H,
methylene groups), 0.90-0.84 (t, J = 6 Hz, 6 H, CH3); §c
(CDC13, 25 MHz) aromatic (140.2, 128.7, 127.9, 126.6), 58.7
(NCH2Ph), 53.8 (NCH2CH2), methylene groups of N-octyl chain
(31.8, 29.5, 29.3, 27.4, 27.0, 22.6), 14.0 (CH3).


Full Text
UNIVERSITY OF FLORIDA
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N-(a-AMINOALKYL)BENZOTRIAZOLES
EQUILIBRIA AND REACTIONS
BY
KONSTANTINA YANNAKOPOULOU
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1988
jj OF F LIBRARIES

Dedicated to my parents
Panagyotis and Anna
Acfnepropevo oxovc, -yoveiq pon
navayioyrn Koa Awa
Me ayaio] Koa aepaapo

ACKNOWLEDGMENTS
First of all, I would like to express my gratitude to
Prof. Katritzky for his help, guidance and open mind during
the years of my graduate work. Sincere thanks are also
extended to my former teachers, Dr. Jones and Dr. Deyrup,
for their friendly and positive attitude and for the
chemistry I have learned from them, and to Drs. Brajter-Toth
and E. Goldberg for serving as members of my supervisory
committee.
There is a great number of people, past and present
members of our group, whom I would like to thank. Among
them are Drs. Steve Cato, R. Murugan, L. Urogdi and J. Lam
for suggestions, discussions and help during the preparation
of this manuscript; Dr. J. Gallos for his thoughtful
supervision and great help during a part of this work (and
for some Dorn PerignonsI); Drs. J. Aurrecoechea and W.
Kuzmierkiewicz (left but not forgotten) for productive
cooperation and party times.
The friendship and company of Margaret Drewniak-Deyrup
has been invaluable and she will always keep a special place
in my heart, together with the smiling memory of Marcela.
Last but not least I want to thank my wonderful family,
for their continuous support, love and encouragement, and
Kostas, for standing by me all these years.
in

TABLE OF CONTENTS
Pa9e
ACKNOWLEDGMENTS iii
ABSTRACT vi
CHAPTERS
1 GENERAL INTRODUCTION 1
1.1 Structure and Reactivity of Benzotriazole 1
1.2 Recent Advances in the Chemistry of
Benzotriazole 3
1.3 N- ( Di alkyl ami nomethyl )benzotriazoles 5
1.4 Aim of the Work 8
2 THE ISOMERIC COMPOSITION AND MECHANISM
OF INTERCONVERSION OF SOME
N-(a-AMINOMETHYL)BENZOTRIAZOLE DERIVATIVES 9
2.1 Introduction 9
2.2 Results and Discussion 12
2.2.1 Solution Phase 12
2.2.2 Solid Phase 24
2.2.3 Inert Gas Matrix Phase 25
2.2.4 Mechanistic Studies 25
2.3 Conclusions 30
2.4 Experimental 30
2.4.1 Instruments and Methods 30
2.4.2 Preparation of N-[(Benzotriazol-N-yl)-
methyl ] -N, N-di alkyl amines 31
3 INFLUENCE OF STRUCTURE ON THE ISOMERIZATION
OF N-[a-(BENZOTRIAZOL-N-YL)ALKYL]-
N , N-DI ALKYLAMINES 34
3.1 Introduction 34
3.2 Results and Discussion 38
3.2.1 Preparation of Compounds 38
3.2.2 Characterization of Compounds and
Assignment of the H-l and C-13 NMR
Spectra 39
3.2.3 Calculation of Equilibrium Constants (K)
and Free Energies (AG°)
for Isomerization 48
IV

3.2.4Variable Temperature NMR Spectral Study:
Calculation of Free Energies of
Activation (AG*) 54
3.3 Conclusions 60
3.4 Experimental 61
3.4.1 Methods and Reagents 61
3.4.2 Preparation of N-[(Benzotriazol-N-yl)-
methyl]-N,N-dialkylamines 62
3.4.3 Preparation of N-[a-(Benzotriazol-N-yl)-
alkyl]-N,N-dialkylamines 64
3.4.4 Methylation of 5-Nitrobenzotriazole 68
4 A GENERAL METHOD FOR THE PREPARATION
OF STRUCTURALLY DIVERSE TERTIARY AMINES 73
4.1 Introduction 73
4.2 Results and Discussion 77
4.2.1 Preparation of Benzotriazole Adducts 77
4.2.2 Preparation of Tertiary Amines 79
4.3 Conclusions 84
4.4 Experimental 84
4.4.1 Methods and Reagents 84
4.4.2 Preparation of N-[a-(Benzotriazol-N-yl)-
alkyl ]-N,N-dialkylamines 85
4.4.3 Preparation of Tertiary Amines by
Alkylation: Two-Step Procedure 89
4.4.4 Preparation of Tertiary Amines by
Alkylation: One-Step Procedure 92
4.4.5 Preparation of Tertiary Amines by
Reduction 96
5 A NEW GENERAL SYNTHESIS OF TERTIARY
PROPARGYLAMINES 99
5.1 Introduction 99
5.2 Results and Discussion 102
5.3 Conclusions 108
5.4 Experimental 108
5.4.1 Methods and Reagents 108
5.4.2 Preparation of N-[a-(Benzotriazol-N-yl)-
alkyl]-N,N-dialkyl amines 108
5.4.3 General Two-Step Procedure for
Preparation of Propargylamines 110
5.4.4 General One-Step Procedure for
Preparation of Propargylamines 112
6 THE PREPARATION OF (3-AMINO ESTERS 116
6.1 Introduction 116
6.2 Results and Discussion 118
6.2.1 Characterization of the Compounds 119
6.2.2 Order of Addition 120
6.2.3 Reaction Time 121
6.2.4 Stereochemistry 122
6.2.5 Side Reactions 123
v

6.2.6 Extension to Different Benzotriazole
Adducts 124
6.3 Conclusions 126
6.4 Experimental 126
6.4.1 Methods and Reagents 126
6.4.2 Preparation of Benzotriazole Adducts.... 126
6.4.3 General Two-Step Procedure for
Preparation of 0-Amino Esters 128
6.4.4 General One-Step Procedure for
Preparation of 0-Amino Esters 131
6.4.5 Miscellaneous Reactions 135
7 SYMMETRICAL AND UNSYMMETRICAL AMINALS:
STUDIES ON THEIR PREPARATION AND EQUILIBRIA 137
7.1 Introduction 137
7.2 Results and Discussion 141
7.2.1 Preparation of Symmetrical Aminals 141
7.2.2 Preparation of Unsymmetrical Aminals....146
7.2.3 Cross-Over Reactions
of Symmetrical Aminals 153
7.3 Conclusions 159
7.4 Experimental 160
7.4.1 Preparation of Benzotriazole Adducts.... 160
7.4.2 Preparation of Aminals 162
8 SUMMARY AND CONCLUSIONS 166
BIBLIOGRAPHY 169
BIOGRAPHICAL SKETCH 179
vi

Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
N-(a-AMINOALKYL)BENZOTRIAZOLES:
EQUILIBRIA AND REACTIONS
BY
Konstantina Yannakopoulou
December 1988
Chairman: Alan R. Katritzky
Major Department: Chemistry
Some aspects of the chemistry of benzotriazole have been
studied in this work. Several N-(a-aminoalkyl)benzo-
triazoles have been prepared and studied by IR and NMR
spectroscopy in the solid, liquid and gas phases. We have
found that the aminoalkyl groups reside at the N-l position
of benzotriazole in the solid state. A rapid isomerization
process commences upon changing to the liquid phase, and the
aminoalkyl groups interchange between the N-l and N-2
positions of benzotriazole. By measuring the equilibrium
constants in various solvents, we have found that the
1-isomers are generally more stable than the 2-isomers by
no more than 1.0 kcal/mole, depending on substituent size
and solvent polarity. Small aminoalkyl substituents and
polar solvents favor the 1-isomers, whereas 1- and the
2-isomers become sometimes equally favored when compounds
with large substituents are dissolved in non-polar solvents.
The isomerization process has been found to occur inter-
molecularly. On the basis of the spectroscopic evidence,
vi 1

the proposed mechanism is an ionic process, in which iminium
cations and benzotriazole anions are the intermediate
species. The required activation energy for the 2- to 1-
isomerization has been estimated by coalescence experiments
to be in the range between 15.7 to 18.6 kcal/mole, for the
examples studied, depending on the electronic features of
the substituents and the polarity of the solvents. Stabili¬
zation provided to the intermediate iminium ions and
benzotriazole anion by electron donating and electron
withdrawing substituents, respectively, and by solvation
energy in polar solvents, lowers the AG^ values toward the
lower limit of the range.
By virtue of their ability to behave as masked iminium
ions, N-(a-aminoalkyl)benzotriazoles are reactive toward
nucleophiles of various strengths. Thus, reactions with
Grignard reagents have produced diversely substituted
tertiary amines (aromatic or aliphatic) in high yields.
Lithium acetylenides, have replaced benzotriazole to yield
otherwise unaccessible 3-alkyl- or 3-aryl-propargyl amines
in very good yields. In a similar fashion, Reformatsky
reagents afford a- or p-raono or disubstituted p-amino esters
in good yields. Finally, several of the benzotriazole
adducts have reacted under very mild conditions with
secondary amines to produce symmetrical and unsymmetrical
aminals, in a reversible process. The produced aminals have
been shown to spontaneously disproportionate in polar and
non-polar solvents.
vi 11

CHAPTER 1
GENERAL INTRODUCTION
1.1 Structure and Reactivity of Benzotriazole
Benzotriazole (BtH) is a 1,2,3-triazole fused with a
benzene ring across the C-C double bond. The proton
attached to the N-atom undergoes annular tautomerism shown
by structures (1.1a), (1.1b), and (1.1c). In the parent
molecule (and in symmetrically substituted derivatives),
position 1 is indistinguishable from position 3, therefore
structures (1.1a) and (1.1c) are identical.
H
1.1a 1.1b 1.1c
The process is very rapid and the individual tautomers
cannot be separated. One tautomeric form, namely (1.1a),
predominates (84CHC(5)669], [76AHC(S)295]. Specifically,
benzotriazole has been found to exist solely in the 1H-
tautomeric form in the solid state [74AC1490], and
predominantly in the lH-form in solution [78JCS(P2 ) 312] and
in the gas phase [730MS1267] (= 1H-/2H- >> 1).
1

2
Benzotriazole is more acidic (pK = 8.2) [51JA4360] than
phenol (pK = 9.89) [85M11] and much more acidic than other
azoles, for example, benzimidazole (pK = 13.2) [58JCS1974],
or pyrrole (pK = 23) [81JOC632]. The electron withdrawing
-N=N- group presumably decreases the electron density on N-l
and renders additional stability to the benzotriazole anion.
Benzotriazole can be alkylated [85H2895] or acylated
[84CHC(5 ) 669] easily to give mainly products of 1-substitu¬
tion. In addition, benzotriazole condenses with formalde¬
hyde and amines to afford Mannich bases. Section 1.3 deals
with these compounds in detail.
Aspects of the chemistry of benzotriazole have been
studied primarily in two fields:
(a) Formation of stable complexes between the parent
molecule (or its derivatives) and metals, such as copper,
zinc, or silver [81ACS(A)739 ], [83ICA109]. This property is
presumably responsible for the marked anticorrosion activity
of benzotriazoles, compounds which are extensively used as
corrosion inhibitors and antioxidants. The large number of
related patents reflects the interest in this field.
(b) Use of N-hydroxybenzotriazole as an acyl transfer
agent in peptide synthesis [77JCS(P2 ) 224 ] . Due to its
enhanced nucleophilicity (a-effect), this molecule readily
forms "active" carbamate esters, important synthetic
auxiliaries in peptide coupling. On the other hand,
benzotriazole derivatives themselves often show marked
biological activity (antihypertensives, antidiabetic agents)
(see [87JCS(Pi)799] and references cited therein).

3
1.2 Recent Advances in the Chemistry of Benzotriazole
The use of benzotriazole in synthesis has been rather
limited. However, considerable progress has been made
recently in the chemistry of benzotriazoles, regarding their
utilization as synthetic intermediates.
General methods for the preparation of several
benzotriazole derivatives, such as a-chloroalkyl-, a-
hydroxyalkyl-, a-phenylthioalkyl-, and a-arylaminomethyl-
benzotriazoles, and bis(benzotriazolyl)alkanes, have been
developed by Katritzky and coworkers [87JCS(Pi)781, 799,
805, 811, 819].
X = Cl, OH, SPh, NH-Ar, Bt; R = Alkyl, Aryl
Owing to the both electron-withdrawing = 0.55) and
electron-donating (= -0.32 or -0.10) [87AHC1] ability of
the Bt-group, a dichotomous behavior of benzotriazole
derivatives is expected (Scheme 1.1). In particular,
benzotriazole can act as a leaving group, thus providing
activation toward Bt-C bond cleavage (path A);
alternatively, it could stabilize a-electron deficient

4
centers (path B); finally, it can also provide moderate
stabilization to a-carbanions (path C).
C
Base
Y
Scheme 1.1

5
The synthetic potential of benzotriazole derivatives
toward reactions with nucleophiles or electrophiles has been
successfully exploited in several instances, and
applications involving the N-monoalkylation of arylamines
[87JCS(Pi)805 ], amides [ 88JCS ( P2)0] , thioamides [88TL1755 ],
and the formation of ketones via lithium bis(benzo-
triazolyl)arenes [87JCS(Pi)819 ] have been published.
1.3 N-(Pialkylaminomethyl)benzotriazoles
The title molecules are easily prepared by the Mannich
reaction [73S703], in which benzotriazole (BtH) condenses
with formaldehyde and a secondary amine, with concurrent
removal of a molecule of water (Equation 1.1) [46JA2496].
BtH + CH20 + HNR2 > Bt-CH2-NR2 + H20 (Eq. 1.1)
The typical Mannich reaction is carried out in acidic
medium, where an iminium ion is considered to be the
reactive intermediate (Equation 1.2).
CH20 + HNR2 —> CH2=NR2 y R2NCH2NR2 —> R'CH2NR2
(Eq. 1.2)
In basic medium, hydroxymethylamine is postulated as the
reactive species (Equation 1.3).
1.3)

6
The reaction does not normally follow the other possible
route (Equation 1.4), although some examples are known
[73S703].
HNR?
R'H + CH20 > R'CH2OH —> R'CH2NR2 ( Eq . 1.4)
The Mannich reaction involving benzotriazole does not
require addition of acid catalyst [46JA2496]. In cases
where dialkylamines are used, the reaction is expected to be
base catalyzed (Eq. 1.3). With arylamines, the amino-
alkylation is carried out under acidic conditions (added
acetic acid or benzotriazole itself serving as the acid
catalyst), and evidence exists favoring the intermediacy of
a benzotriazolium iminium ion which reacts with the
arylamines [87JCS(Pi)799 ] .
N-[(Benzotriazol-l-yl)methyl]-N,N-dialkylamines (1.2a)
are of special interest: they spontaneously isomerize to
the 2-substituted compounds (1.2b) in solution, and an equi¬
librium is quickly established (Scheme 1.2). A preliminary
investigation of the process has been reported but detailed
mechanistic studies have not been carried out
[75JCS(Pi)1181].
1.2a
1.2b
Scheme 1.2

7
Analogous examples of azoles undergoing "substituent
tautomerism" are few known. In particular, the exchange of
the tributylstannyl substituent ("stannotropy") between the
two N atoms of pyrazole [compound (1.3), Scheme 1.3] has
been described and studied using variable temperature NMR
spectroscopy [77JOM69]. The similar isomerization of
trialkylsilylbenzimidazole ("silylotropy") [compound (1.4),
Scheme 1.3] has been reported [83H1713] as occuring in the
solution at room temperature and disappearing in the solid
phase. However, a detailed investigation of this process
has not been described yet [88MRC134].
SnBu3
1.3
SiMe3
1.4
Scheme 1.3

8
1.4 Aim of the Work
The main objectives of the research presented in this
dissertation were:
(i) To study in detail the isomerization of simple N-
[(benzotriazol-l-yl)alkyl]-N,N-dialkylamines of type (1.2)
in terms of isomeric composition and mechanism of
interconversion (Chapter 2).
(ii) To investigate the effect of the structure of
several novel N-[a-(benzotriazol-l-yl)alkyl- or -aryl]-N,N-
dialkylamines on the isomerization process, as regards both
equilibria and kinetics (Chapter 3).
(iii) To develop new synthetic methodologies, using the
above benzotriazole adducts as synthetic intermediates in
the preparation of tertiary amines, propargylamines, 3-amino
esters and aminals (Chapters 4, 5, 6 and 7).

CHAPTER 2
THE ISOMERIC COMPOSITION AND MECHANISM OF INTERCONVERSION
OF SOME N-(a-AMINOMETHYL)BENZOTRIAZOLE DERIVATIVES
2.1 Introduction
N,N-Disubstituted aminomethylbenzotriazole derivatives
(2.1) exist in solution as equilibrium mixtures of the
corresponding benzotriazol-l-yl- and benzotriazol-2-yl-
methylamines (2.1a) and (2.1b), respectively [75JCS(Pi)1181]
(Scheme 2.1). While the 1-isomer normally predominates, the
position of this equilibrium depends strongly on the
polarity of the solvent and also on the substrate structure
[75JCS(Pi)1181].
4
3
3a
6
5
nr2
2.1a
2.1b
Scheme 2.1
9

10
Thus, as the polarity of the medium increases so does
the amount of the 1-isomer relative to the 2-isomer, whereas
increased bulkiness in the N-aminomethyl substituents favors
2-substitution [75JCS(Pi)1181].
Work carried out previously in our group [86UP1]
involved the preparation of N,N'-bis(benzotriazolylmethyl)-
N,N'-dioctylethylenediamine (2.2) (Scheme 2.2). During the
characterization of this compound significant differences in
its spectral properties were observed depending on whether
(2.2) was in a solid or liquid phase [87JCS(Pi)2673 ] . The
data showed that (2.2) existed as a single isomer (2.2a) in
the solid state whereas a rapid equilibrium was established
upon dissolution to afford a mixture of the isomeric
diamines (2.2a), (2.2b) and (2.2c) (Scheme 2.2).
Previous literature [75JCS(Pi)1181] on the isomerization
of simple N,N-disubstituted aminomethylbenzotriazoles had
implied that these compounds existed as single isomers in
the solid state and an ionic dissociative mechanism was
proposed for their isomerization in solution; however, no
evidence for these conclusions was presented. The results
obtained with (2.2) [86UP1] prompted us to begin a detailed
study on the equilibria of a representative set of N-
[(benzotriazol-l-yl)methyl]-N,N-dialkylamines (2.3-2.7)
(Scheme 2.3) in the solid, liquid and vapor phases. Our aim
was to compare the properties of these compounds in
different phases, as well as to elucidate the mechanism of
their isomerization.

11
2.2c
Scheme 2.2

12
2.3 R
2.4 R
2.5 R
2.6 R
2.7 R
H, NR^ = NMe2
H, NR^ = Pyrrolidyl
Me, NR^ = NEt2
H, NR2 = NEt2
Me, NR2 = Pyrrolidyl
Scheme 2.3
2.2 Results and Discussion
2.2.1 Solution Phase
The structure of compounds (2.3-2.7) in solution was
1 13
studied by IR, H- and C-NMR spectroscopy.
1 1
H-NMR spectroscopy. The H-NMR spectra in deuterochlo-
roform (CDCl^) solutions of (2.3-2.7) exhibited in all cases
two singlets of unequal intensity in the region 5.70 to 5.40
ppm, corresponding to the N-CH2~N protons, and indicating
the presence of both the benzotriazol-l-yl and the
benzotriazol-2-yl isomers. Compound (2.2) displayed three

13
such singlets corresponding to the 1,1'- and 2,2'-isomers
(2.2a,c) and also to the unsymmetrical 1,2'-dioctylethyl-
enediamine (2.2b) [87JCS(Pi)2673]. The aromatic regions
were characteristic of the type of substitution and the
resonances were readily assigned to ring protons of the
individual isomers. These assignments were based on
chemical shifts and coupling constants reported for simple
1- and 2-substituted benzotriazoles [63JCS5556], [80MI1],
[690MR311], [75JCS(P2)1695]. 1-Methylbenzotriazole is a
simple Bt-derivative, but its ^H-NMR spectrum is not first
order even at 300 MHz. A more appropriate model is
1-hydroxymethylbenzotriazole which displays a typical
1-substitution pattern: H-4 appears as the downfield
doublet followed by the doublet of H-7, whereas H-5 and H-6
are the upfield multiplets (Figure 2.1).
On the other hand, 2-methylbenzotriazole shows a
characteristic AA'BB' pattern [80MI1] (Figure 2.2), with two
multiplets at about 7.5 and 7.3 ppm. Compounds (2.3-2.7),
as mixtures of the two isomers, show both patterns in the
aromatic region. Therefore, doublets at about 8.01 and 7.60
ppm were assigned to H-4 and H-7, respectively, in the ring-
unsubstituted-l-substituted isomers, (2.3a-2.7a) whereas a
multiplet at about 7.90 ppm was due to the same protons in
the 2-substituted isomers. A representative ^H-NMR spectrum
[of (2.4) in CDCl^] is shown in Figure 2.3. The 5,6-dime-
thylbenzotriazoles (2.5) and (2.7) showed H-4 and H-7 as two
singlets at about 7.80 and 7.35 ppm, respectively, in the
1-isomers, and as one singlet at 7.30 ppm in the 2-isomers.

14
! ! ! I ' ! : 1 1 1 f T T ! ¡TH ! ? T r 1~H H I I I r I It ¡ T
6 7.4 7.2 ’ 7.0 PPM'
7,8
Figure 2.1 Aromatic region of the 300 MHz 1H-NMR spectrum
of 1-hydroxymethylbenzotriazole in CDCl^.
4
7
Figure 2.2 Aromatic region of the 300 MHz ^H-NMR spectrum
of 2-methylbenzotriazole in CDCl^

4
3a
3
Figure 2.3 Partial 300 MHz '*'H-NMR spectrum of N-[(benzotriazol-N-yl)methyl]-
pyrrolidine (2.4) in CDCl^.

16
Also consistent with literature reports [75JCS(Pi)1181]
is the observation that increasing bulkiness in the N,N-
dialkyl substituents (i.e. changing from to pyrrolidino
to NEt2) results in increasing amounts of the 2-substituted
isomers. As expected [75JCS(Pi)1181), the change from CDCl^
to the more polar solvent dimethyl sulfoxide (DMSO-dg)
resulted in increased amounts of the major 1-substituted
isomers at the expense of the 2-substituted ones. Indeed,
the concentration of the 2-substituted isomers in DMSO-dg
was so low that their ^H-NMR signals were frequently
obscured: in such cases the ratio of isomers was estimated
as >9 favoring the 1-isomer. Table 2.1 shows the ratio
[1-isomer]/[2-isomer] as obtained by integration of the
signals.
Table 2.1 Isomeric ratios of compounds (2.3-2.7)
Compound [1—]/[2-] (CDC13) [1-]/[2-] (DMSO-dg)
2.3
4.3
a
2.4
5.5
>9
2.5
2.5
a
2.6
2.2
>9
2.7
5.1
a
a The signals of the 2-isomer were totally obscured.

17
13 13
C-NMR spectroscopy. The aromatic region of the C-
NMR spectra of 1-substituted benzotriazoles displays an
easily recognizable pattern consisting of six signals.
1 3
Figure 2.4 shows the C-NMR spectrum of 1-methylbenzo-
triazole in CDCl^. When the substituent resides at the
2-position of the ring, as in 2-methylbenzotriazole, the
additional symmetry results in only three peaks in that
region (Figure 2.5).
The ^C-NMR spectra of compounds (2.2) [87JCS(Pi)2673]
in CDCl^ displayed nine aromatic signals attributed to a
mixture of 1-substituted and 2-substituted benzotriazole
groups, while the NCF^N region of this molecule contained
three signals between 76.0 and 64.0 ppm, one for each of the
three isomers. In other solvents the picture of the spectra
remained basically the same, the only variations being the
intensities of the peaks of the individual isomers, due to
solvent dependent changes in the isomeric composition.
Similarly, the '*'^C-NMR spectra of (2.3-2.7) in both
CDCl^ and DMSO-dg clearly demonstrated the presence of
isomeric mixtures (Figure 2.6). Thus, more than six
aromatic carbon signals were observed in all cases and two
N-Cí^-N absorptions appeared in the region 77.5 to 64.7 ppm
13
[see Table 2.2 for C-NMR spectra of compounds (2.3-2.7) in
CDCl^]. The assignments are concordant with data reported
for 1- and 2-substituted bis(benzotriazolyl)methanes
[83H1787] and are illustrated in Figures 2.4, 2.5, and 2.6.

18
C-5
C-6 i
t ** 130 1Í0 110 tOO 90 90 T o Pp*
Figure 2.4 Aromatic region of the 75 MHz ^C-NMR
spectrum of 1-methylbenzotriazole in CDCl^.
13
Figure 2.5 Aromatic region of the 75 MHz C-NMR
spectrum of 2-methylbenzotriazole in CDCl^.

Figure 2.6 Partial 75 MHz 13C-NMR spectrum of N-[(benzotriazol-N yl)
methyl]pyrrolidine (2.4) in CDCl^.

Table 2.2
(2.3-2.7).
C-NMR spectra of N-[a-(benzotriazol-N-yl)methyl]-N,N-dialkylamines
13
1-isomers
Com.
Solvent
C-3a
C-4
C-5
C-6
C-7
C-7a
nch2n
ArCH3
NR
r
2
2.3a
cdci3
145.4
119.4
123.5
127.1
109.7
133.6
69.7
-
42.1
2.3a
DMSO-dg
144.8
118.9
123.8
127.3
111.1
134.0
69.2
-
41.9
2.4a
CDCl 3
145.6
119.6
123.6
127.2
109.8
133.8
65.0
-
50.1,
23.6
2.4a
DMSO-dg
144.8
118.9
123.8
127.3
110.9
133.9
64.1
-
49.4,
23.2
2.5a
CDCl,
144.9
118.7
137.4
136.4
109.3
133.4
65.1
20
.9
45.4,
12.6
J
20
.2
2.5a
DMSO-d,
144.1
117.8
137.0
136.1
110.0
133.0
64.5
20
. 3
44.7,
12.5
o
19
.7
2.6a
CDC13
145.1
119.0
123.1
126.7
109.6
133.2
64.8
-
44.8,
12.1
2.6a
DMSO-d,,
6
144.9
118.8
123.5
127.0
110.8
133.6
64.7
-
44.7,
12.4
2.7a
CDCl,
144.8
118.6
137.5
136.5
109.1
133.3
64.7
20
.6
50.1,
23.6
J
20
.2
2.7a
DMSO-d,
144.0
117.8
137.2
133.1
110.0
132.9
63.9
20
. 3
49.5,
23.2

Table 2.2—Continued.
2-isomers
Com.
Solvent
C-3a
C-4
C-5
C-6
C-7
C-7a
nch2n
ArCH3
NR'
2.3b
cdci3
143.7
117.9
126.0
126.0
117.9
143.7
77.5
-
41.7
2.3b
DMSO-dg
a
118.1
126.3
126.3
118.1
a
77.4
-
a
2.4b
cdci3
144.0
118.1
126.4
126.4
118.1
144.0
72.5
-
49.3,
23.9
2.4b
DMSO-dg
a
117.8
126.1
126.1
117.8
a
71.9
-
48.6,
_b
2.5b
cdci3
143.4
116.6
132.8
132.8
116.6
143.4
71.6
20.7
45.7,
12.8
2.5b
DMSO-d,-
6
142.8
116.3
132.7
132.7
116.3
142.8
71.0
20.2
45.2,
12.8
2.6b
cdci3
143.5
117.7
125.5
125.5
117.7
143.5
71.4
-
45.2,
12.4
2.6b
DMSO-dg
a
117.9
126.0
126.0
117.9
_b
71.4
-
45.2,
_b
2.7b
cdci3
143.4
116.5
136.5
136.5
116.5
143.4
72.1
20.6
20.2
49.4,
23.8
2.7b
DMSO-dg
_b
116.4
b
_b
116.4
b
71.6
20.3
19.8
48.7,
23.6
a Too weak to be detected. ^ Obscured by signals of the 1-isomer.

22
Infrared spectroscopy. IR has been used previously to
distinguish between 1- and 2-substituted benzotriazole
derivatives [63HCA1473], [87JCS(Pi)811]. The 1-isomers
typically display two weak absorptions in the region 1630 to
1550 cm 1 (where the C=C and C=N stretching vibrations are
most probably located), whereas the 2-isomers show instead
one weak absorption in the same region. The infrared
spectra of bromoform or chloroform solutions of (2.3-2.7)
(Figure 2.7) displayed in all cases all three of these
absorption bands supporting the presence of both the
benzotriazol-l-yl and the benzotriazol-2-yl isomers in
solution. A similar behavior was demonstrated by 1,1'-,
1,2'- and/or 2,2'-bis(benzotriazolylmethyl) derivatives
(2.2) [87JCSP(1)2673].
Compound (2.6) is a liquid at 25 °C: the infrared
spectrum of a neat film shows in the region 1630 to 1550
-1 -1
cm three absorptions at 1625, 1588 and 1569 cm ,
indicating that in the liquid state, just as in solution,
N-[(benzotriazolyl)methyl]-N,N-dialkylamines exist as
mixtures of two isomers.
The weak C=N, C=C and N=N absorptions of compounds
(2.3), and (2.6) could be clearly detected only by an FT
instrument, while signals of (2.2) were detectable by a
conventional spectrometer. Data are collected in Table 2.3.

Table 2.3. IR data of N-[(benzotriazolyl-N-yl)methyl]-N,N-
dialkylamines (2.2), (2.3), (2.6) and (2.7).
Comp. CHCl , Neat or melt Ar matrix
solution
2.2a
1610
1610
1590
1590
1565
1565
2.3b
1618
1616
1592
1590
1519
1517
2.6b
1625
1625
1590
1588
1570
1569
2.7b
1627
_
1582
1552
a Bromoform
solution.
b FT spectra.
Wavenumbers
Figure 2.7 FT-IR spectrum of N-[(benzotriazol-N-yl)
methyl]-N,N-dimethylamine (2.3): (a) 0.
solution in CHCl,; (b) KBr pellet; (c)
matrix spectrum.
KB r
1610
1590
1615
1587
1631
1585
3 M
Ar

24
2.2.2 Solid Phase
Infrared spectroscopy. The infrared spectra of the
aminomethylbenzotriazoles (2.3-2.7) in KBr discs (Table 2.3,
Figure 2.7) each displayed only two absorptions at 1570 to
1550 cm * in agreement with their benzotriazol-l-yl-
structures. Similarly, examination of (2.2) in a KBr disc,
or in a nujol dispersion, showed the presence of only two
weak absorptions at 1610 and 1590 cm â– *" in the diagnostic
region 1630-1550 cm-'*', as expected for a 1,1'-bisbenzo-
triazolyl derivative [63HCA1473], [87JCS(Pi)1811]. In
particular, no absorption was found in the region 1570 to
1550 cm â– *" confirming the absence of benzotriazol-2-yl
groups. The IR results agree with the structure of
N,N'-[l,l'-bis(benzotriazolylmethyl)]-N,N'-dioctylethylene-
diamine (2.2a) determined by an X-ray analysis
[87JCS(P1)2673].
13 13
C-NMR spectroscopy. The solid state C-NMR spectra
of compounds (2.3), (2.4) and (2.5) were also examined. The
spectrum of compound (2.5) showed a simple 1:1
correspondence between the six signals and the aromatic
carbon atoms. The spectra of compounds (2.3) and (2.4)
showed asymmetric splitting in the peaks attributable to
atoms C-3a and C-methyl [compound (2.3)], and C-5 or C-6
[compound (2.4)]. The lack of correlation of carbon types
for which splittings were observed suggests that these

25
features are due to crystallographic factors and do not
indicate the presence of two isomers. Thus, the solid state
NMR results also support the existence of only the 1-isomer
in the solid phase.
2.2.3 Inert Gas Matrix Phase
Infrared spectroscopy of (2.3) condensed in an inert gas
matrix (where molecular interactions are negligible) was
used as an approximation for the study of the properties of
this compound in the gas phase. Thus, the infrared spectrum
of (2.3) in an Ar matrix showed the presence of the
characteristic three bands diagnostic of both the 1- and
2-benzotriazole isomers (Figure 2.7).
2.2.4 Mechanistic Studies
The most likely mechanism for the isomerization observed
in the liquid and solution phases is a dissociation-
recombination process (Scheme 2.4) [75JCS(Pi)1181 ] but a
concerted mechanism (Scheme 2.5) had not been previously
ruled out. To distinguish between these two possibilities,
a cross-over experiment was carried out by mixing together
CDCl^ or DMSO-dg solutions of (2.4) and (2.5) and examining
the mixtures by ^H- (Table 2.4) and ^C- (Table 2.5) NMR
spectroscopy. These spectra revealed the presence of eight
compounds that could be readily assigned as both the 1- and
2-isomers of each of (2.4), (2.5), (2.6) and (2.7), by

26
direct comparison with the spectra of the individual pairs.
The relative intensities (Tables 2.4 and 2.5) are also
consistent with these assignments. As expected, the
1-isomers predominate in CDCl^ and even more so in the more
polar DMSO-dg. The ^H-NMR spectrum (CDCl^) of the mixture
(Table 2.4) showed only seven of the expected eight peaks in
the N-CI^-N region 5.70 to 5.30 ppm. The missing signal is
apparently hidden under the rather broad peak at 5.60 ppm.
In DMSO-dg the N-CB^-N signals for the 2-isomers are
obscured by the corresponding 1-isomer signals (see above),
and only four signals corresponding to the 1-isomers are
observed.
Scheme 2.4

27
Scheme 2.5
Table 2.4 ^H-NMR data for the N-Cí^-N group of compounds
(2.4-2.7) from the cross-over experiment.
Assignment
2-isomers
1-isomers
2.4 2.6,2.7
2.5
2.4
2.7
2.6
2.5
S (CDC13)
5.7 5.6
5.5
5.5
5.5
5.5
5.4
Area (%)
4 9
6
23
23
18
17
S (DMSO-dg)
-
-
5.7
5.6
5.6
5.4
Area (%)
- ~
-
37
25
24
15
11
The C-
NMR spectrum (Table
2.5) provided
more
widely
separated peaks. The N-CH
2~N carbons appeared
in CDCl3 as
two groups of four signals
each
between
71.7 and 70
.5 ppm,
and 64.6 to
63.8 ppm, corresponding to
the 2-
and 1
-isomers
respectively
. The ratios
were
measured
by integration of
these signals in a quantitative experiment. Figure 2.8
shows the region of the NCí^N after mixing (2.4) and (2.5)

28
in deuterated chloroform. In DMSO-dg the signals for the
2-isomers were too weak to allow precise measurements. An
identical equilibrium mixture as regards both chemical
shifts and ratios was obtained by mixing together solutions
of (2.6) and (2.7).
Table 2.5 ^C-NMR data for the N-CH^-N groups of
benzotriazoles (2.4-2.7) from the cross-over experiment.
Assignment 2-isomers
1- isomers
2.4 2.7 2.5 2.6 2.5 2.6 2.4 2.7
6(CDCl3)
Area(% )
6 (DMSO)
Area (%)
71.7 71.2
4 4
71.0 70.6
5 5
64.4 64.2
18 17
64.5 64.8
25 29
64.1 63.9
24 22
64.1 64.0
25 21
Temperature Effect. The ^H-NMR spectra of (2.5), (2.6)
and (2.7) were also recorded at -50 °C and at 40 °C in CDCl^
and the ratios of isomers measured. The results indicate no
significant change in the isomer distribution or in the
shape of the signals with respect to the data obtained at
25°C. Modification in the structure of the compounds re¬
sulted in marked temperature effects, as shown in Chapter 3.

yvy^
+ 2-isomers
VJ
Nyv
r ^ T I I T
7 2
1—i—i ]—I—i—i—i—|—I—I—I—I—|—I—I—I—I—|—I—I—I—I—|—I—I—I—I—|—i—I—i—i—|—i—r
70 6B 66 64 PPM
Figure 2.8 50 MHz ^C-NMR spectrum (NCH^N region) of the mixture of
(2.4) and (2.5) in CDC13.

30
2.3 Conclusions
The work described in this chapter shows that N-[(benzo-
triazol-N-ylmethyl]-N,N-dialkylamines exist as single
benzotriazol-l-yl- isomers in the solid phase. However, in
liquid, solution and vapor phases these compounds undergo
isomerization and mixtures of the benzotriazol-l-yl- and
benzotriazol-2-yl- isomers are observed. Our studies prove
that the isomerization process is intermolecular and are
consistent with a dissociative pathway to iminium ions and
the benzotriazole anion. The subsequent recombination of
these two species furnishes equilibrium mixtures of
benzotriazol-l-yl- and benzotriazol-2-yl- isomers in which
the 1-isomers always predominate.
2.4 Experimental
2.4.1 Instruments and Methods
Melting points were determined on a Kofler hot-stage
microscope, and are uncorrected. IR spectra were recorded
on a FT-IR Nicolet 7000 Series spectrometer; measurements
were done with 0.3 M CHC13 or CHBr^ solutions, or 1% KBr
pellet; the argon matrix experiment was recorded at 24°K and
10 ^ mm Hg was carried out by Dr. M. Szczesniak of this
department [87JCS(Pi)2376], who also operated the FT-IR
instrument.

31
^H— (200 MHz) and ^C- (50 MHz) solution NMR spectra
were recorded on a Varían XL 200 spectrometer. Cross-over
experiments were carried out by mixing equimolar solutions
of both substrates. Quantitative ^C-NMR spectra were
acquired at 50 MHz using a 5 sec pulse delay. Low
temperature ^H-NMR spectra were obtained at 100 MHz using a
Jeol FX-100 spectrometer under the guidance of Dr. King of
this department.
13
Solid state C-NMR spectra were acquired on a modified
Varían XL 200 NMR spectrometer using cross polarization and
magic angle spinning (CPMAS) [87JCS(Pi)2673] by Dr. R.
Skarjune at 3M company.
Spectra displayed in Figures 2.1-2.6 were recorded on a
Varían VXR 300 NMR instrument for better presentation.
2.4.2 Preparation of N-[(Benzotriazol-N-yl)methyl]-N,N-
dialkylamines
General method. All compounds were prepared according
to a general literature procedure [46JA2496] by stirring
equimolar amounts of a secondary amine, 37% aq. formaldehyde
and benzotriazole in methanol for 24 h. Evaporation of the
solvent under reduced pressure gave the product. ^^C-NMR
and IR data are given in Tables 2.2 and 2.3, respectively.
N-[ (Benzotriazol-N-yl)methyl]-N,N-dimethylamine (2.3).
The product was obtained as a white crystalline solid (97%),
m.p. 95-98°C (from diethyl ether) (lit. [75JCS(Pi)1181] m.p.
98-100°C); (CDCl^) 1-isomer, 8.07 (d, J = 8 Hz,

32
H-4), 7.62 (d, J = 8 Hz, H-7), 7.49 (m, H-5), 7.41 (m, H-6,
overlapping with signals of the 2-isomer), 5.40 (s, NCH2N),
2.40 (s, CH^); 2-isomer, 7.90 (AA' m, H-4, H-7), 7.49 (m,
H-5,6, obscured by signals of 1-isomer), 5.51 (s, NCH2N),
2.46 (s, CH3).
N-[(Benzotriazol-N-yl)methyl]pyrrolidine (2.4). The
product was collected as a white solid (98%), m.p. 79-81°C
(from diethyl ether)
(Found,
C, 65
.66; H, 7.29;
N,
27.88%.
C11H14N4 rec3uires'
c,
65.32;
H, 6 .
98; N, 27.70%)
r
sH (cdci3)
1-isomer, 8.01 (d,
J
= 8 Hz,
H-4 ) ,
7.60 (d, J =
8
Hz, H-7),
7.44 (t, J = 7 Hz, H-5), 7.30 (t, J = 7 Hz, H-6), 5.51 (s,
NCH2N), 2.75 [m, N(CH2CH2)2], 1.72 [m, (NCH2CH2)2) ] ;
2-isomer, 7.87 (m, H-4, H-7), 7.38 (m, H-5,6, obscured by
signals of 1-isomer), 5.70 (s, NCH2N), 2.87 [m, N(CH2CH2)2),
1.72 [m, N(CH2CH2)2J.
N-[(5,6-Pimethylbenzotriazol-N-yl)methyl]-N,N-di-
ethylamine 2.5). It was obtained as a pale yellow powder
(91%), m.p. 95-98°C (from diethyl ether) (Found, C, 67.99;
H, 8.44; N, 24.47%. ('13H18N4 rec3uires' C, 67.80; H, 7.88;
24.33%); &H (CDCl3) 1-isomer, 7.77 (s, H-4), 7.35 (s, H-7),
5.44 (s, NCH2N), 2.66 [q, J = 7 Hz, N(CH2CH3)2), 2.42 (s,
ring -CH3), 2.39 (s, ring -CH3), 1.14 [t, J = 7 Hz,
N(CH2CH3)21; 2-isomer, 7.62 (s, H-4, H-7), 5.57 (s, NCH2N),
2.68 [q, J = 7 Hz, N(CH2CH3)2], 2.39 (s, ring -CH3), 1.16
[t, J = 7 Hz, N(CH2CH3)2] .

33
N-[(Benzotriazol-N-y1)methyl]-N,N-diethylamine (2.6) .
The oily product was dried under vacuum over P20^ (96%),
b.p. 120-124°C (at 0.65 mm Hg) (Found, C, 64.17; H, 7.73; N,
27.79%. chh16N4 rec3uires» 64.68 ; H, 7.89; N, 27.43%);
(CDCl^) 1-isomer, 8.05 (d, J = 8 Hz, H-4), 7.62 (d, J = 8
Hz, H-7), 7.48 (t, J = 8 Hz, H-5), 7.36 (t, J = 8 Hz, H-6) ,
5.52 (s, NCH2N), 2.68 [q, J = 7 Hz, N(CH2CH3)2], 1.15 [t, J
= 7 Hz, N(CH2CH3)2]; 2-isomer, 7.91 (m, H-4, H-7), 7.36 (m,
H-5,6, obscured by signals of 1-isomer), 5.64 (s, NCH2N),
2.68 [q, J = 7 Hz, N(CH2CH3)2], 1.15 [t, J = 7 Hz,
n(ch2ch3 )2 ] .
N-[(5,6-Dimethylbenzotriazol-N-yl)methyl]pyrrolidine
(2.7). A beige solid was obtained (88%), m.p. 39-41°C (from
petroleum ether, b.p. 40-60°C) (Found, C, 67.01; H, 8.98; N,
24.13%. <“13H20N4 rec3u:*-re s < c» 67.21; H, 8.68; N, 24.11%);
&H (CDCl3) 1-isomer, 7.79 (s, H-4), 7.37 (s, H-7), 5.51 (s,
NCH2N), 2.75 [m, N(CH2CH2 ) 2 ] , 2.43 (s, ring CH3), 2.40 (s,
ring -CH3), 1.72 [m, N(CH2CH2)2]; 2-isomer, 7.62 (s, H-4,
H-7), 5.63 (s, NCH2N), 2.84 (s, ring -CH3), 2.84 [m,
N(CH2CH2)2J, 1.72 [m, N(CH2CH2)2].

CHAPTER 3
INFLUENCE OF STRUCTURE ON THE ISOMERIZATION OF
N-[a-(BENZOTRIAZOL-N-YL)ALKYL]-N,N-
DIALKYLAMINES
3.1 Introduction
The isomerization of N-(benzotriazol-N-ylmethyl)-N,N-
dialkylamines was investigated and discussed in Chapter 2.
The responsible dissociative process was convincingly
explained by the intermediacy of iminium ions and the
benzotriazole anion (Scheme 2.4, Chapter 2).
As an extension of that work, the present chapter
reports a study of the ‘'"H-NMR spectra of a series of
benzotriazole adducts at variable temperatures, it provides
estimates of the AG^ values for the isomerization process,
and discusses the parameters affecting the rates and
equilibrium positions of the dissociation process as a
function of the molecular structure. In particular, we
examine series of compounds with the objective of evaluating
the effects of the following features:
(a) The influence of the solvent on the magnitude of AG°
and AG^.
(b) The effect of the electron-withdrawing or -donating
character of a-substituents (R') in the iminium ion
intermediate, or in the benzotriazole benzene ring (X, Y) on
AG^ [see generalized structures (3.1), Scheme 3.1].
34

35
(c) The change in AG° as a function of the size of R and
R' .
(d) The correlation between AG^ and the basicity of the
corresponding amine HNR2.
3-2 3.3
Scheme 3.1
In the case of adducts (3.1) the energy barrier of the
equilibrium (3.1a) to (3.1b) (Scheme 3.1) should be lower
than in the case of the (2.1a) to (2.1b) interconversion

36
f
(Scheme 2.1, Chapter 2): the R group stabilizes the
intermediate iminium ion (3.2) compared to the unsubstituted
ion (R' = H). The availability of the lone pair of the
amine nitrogen is also expected to contribute to the
stability of this intermediate. On the other hand, if the
benzene ring of benzotriazole is suitably substituted with
an electron-withdrawing substituent (X and/or Y), then anion
(3.3) should become a better leaving group, thus again
facilitating the dissociation; on the contrary,
substitution with electron donating substituents X or Y
should raise the barrier to interconversion (Scheme 3.1).
As mentioned in Chapter 2, the size of the substituents
NR2 in the side chain affects the isomeric ratio in the
solution. A more pronounced effect is expected if a
substituent R' ^ H is introduced in the structure.
The isomeric ratio was also found to change in different
solvents (Chapter 2). A more systematic study is sought
here in order to assess the influence of the solvent
polarity on the two isomers and on the invoked iminium ion
intermediate.
To acquire a more quantitative picture of how the
relative energy levels of the 1- and 2- isomers can be
changed by manipulating the electronic factors that
influence the rearranging part of the molecule, we prepared
a series of compounds, namely (3.4-3.15) (Scheme 3.2).

37
X
y
R'
R'
3.4
H
H
H
3.9
H
3.5
no2
H
H
3.10
C6H5
3.6
Cl
H
H
3.11
c6h4-4-n°2
3.7
Me
Me
H
3.12
CgH^-4-OMe
LO
•
OB
H
H
Pr1
3.13
Pr1
3.14
3.15
Scheme 3.2

38
3.2 Results and Discussion
3.2.1 Preparation of Compounds
Adducts of type (3.1), (R' t H) have not been described
in the literature except for the adduct prepared from
benzaldehyde and dimethylamine [76JCS(P2)741], which was
characterized only by a proton NMR spectrum at -30°C.
Previous attempts in this group to obtain products of
condensation of benzotriazole with aliphatic aldehydes and
amines had resulted in complex mixtures [87JCS(Pi)799].
Compounds of type (3.1) were successfully prepared from
benzotriazole, an aldehyde (aromatic or aliphatic) and a
secondary amine by azeotropic removal of water in benzene.
Initial attempts to isolate some of these adducts were not
very successful. The oily products could not be purified,
as distillation and column chromatography results in
decomposition and/or hydrolysis of the crude materials. The
solid adducts, however, were much easier to handle, since
recrystallization was always possible. Methods were event¬
ually worked out for the isolation and complete character¬
ization of the vast majority of compounds (3.1) (R' * H)
(see experimental). For most of them, however, the ^C- and
^H-NMR spectra near or at room temperature were much
affected by peak broadening coalescence, especially when
examined in chloroform solution. This can give the
incorrect impression that the compounds are not pure. In
general, the most convenient and effective way to handle

39
adducts (3.1) was to use them directly for synthetic
applications without prior purification (see Chapters 4, 5,
6 and 7).
3.2.2 Characterization of Compounds and Assignment of the
H-l and C-13 NMR Spectra
Compounds (3.5), (3.8) and (3.12) were best characterized
by low temperature ^H-NMR spectra in a solvent where a large
dispersion of chemical shifts was observed and peaks due to
the two isomers could be readily detected (see Experi-
13
mental). All C-NMR spectra were recorded in deuterated
chloroform. Low temperature ^C-NMR spectra were obtained
in the cases of (3.5), (3.8), and (3.15), where broad peaks
were observed at room temperature.
As discussed in Chapter 2, all the compounds unsubsti¬
tuted in the benzene ring of benzotriazole are mixtures of
the 1- and 2- isomers and show both benzotriazol-l-yl and
benzotriazol-2-yl type substitution patterns in the ^H- and
the C-13 NMR spectra. The C-13 spectra of the above com¬
pounds were easier to interpret than the ^H-NMR spectra,
where frequently considerable overlapping of some benzo-
triazole protons by signals of R and R' resulted in obser¬
vation of complex multiplets. In most cases, however,
assignment was achieved (see Tables 3.1 - 3.3 and Experi¬
mental) using literature information [75JCS(P2)1695],
[83H1787].
Two structural features introduced increased complexity
in the spectra of some compounds.

40
(a) Substitution on the C-5 atom of the benzotriazole
ring without equivalent substitution at the C-6 position [as
in (3.5) and (3.6)], resulted in the generation of three
interconverting (1-, 2-, and 3- substituted) isomers in the
1 13
solutions and consequently complex H- and C-NMR spectra.
(b) The existence of an asymmetric carbon atom (when
r
R t H) caused chemical shift non-equivalency to protons in
methylene and methyl groups up to three bonds away. This
resulted in complicated ^H-NMR spectra, especially in the
compounds bearing aliphatic side chains, but fortunately the
C-13 spectra were not affected.
In these cases, additional experiments were carried out
to aid the complete assignment as will be discussed next.
Spectral assignment of N-[(5-nitrobenzotriazol-N-yl)-
methyl]pyrrolidine (3.5). Chloroform solutions of N-
[(5-nitrobenzotriazolyl)methyl]pyrrolidine (3.5) at -25°C
contained then 2- and 3- isomers in equal amounts, while the
1-isomer was the major component (at -25°C, [1-]:[2-] :[3-] =
44:28:28). The complete assignment of the ^H- and '^C-NMR
spectra of this adduct could be achieved only by preparation
of model compounds.
Thus, 5-nitrobenzotriazole was methylated, and the
products 1-methyl-, 2-methyl- and 3-methyl-5-nitrobenzo-
triazole [64T211] were separated by column chromatography.
The individual fractions were identified by comparing their
melting points to literature values. The least polar

41
fraction was identified as 2-methyl-5-nitrobenzotriazole
(m.p.185-188°C; lit. [64T211] m.p.l87°C). The most polar
fraction was l-methyl-5-nitrobenzotriazole (m.p.160-1620C;
lit. [64T211] m.p.l63°C). Fractional crystallization had
been used in the literature to separate the two isomers.
Column chromatography, however, of our methylation mixture
yielded an additional isomer, of intermediate polarity,
which was reasoned to be 3-methyl-5-nitrobenzotriazole, and
had not been reported previously [64T211].
1 13
The H- and C-NMR spectra of the individual
methylation products were recorded in CDCl^. The spectra of
the mixture of the three compounds were then easily
assigned, and they showed a very good correspondence to
those of (3.5) (see Experimental). Figure 3.1 shows the
aromatic proton region of (3.5) as compared to that of the
mixture of 1-, 2-, and 3-methyl-5-nitrobenzotriazoles in
cdci3.
Spectral assignment of N-[(5-chlorobenzotriazol-N-yl)]-
methyl]pyrrolidine (3.6). In the case of the chloro-
compound (3.6), the populations of the three isomers were
all significantly different, ( 20°C, CDCl^, [1-] :[2-] :[3-] =
45:23:32) thus enabling assignment of the C-NMR spectrum.
The aromatic region of the ^H-NMR spectrum, with a multitude
of peaks, was impossible to assign. A two-dimensional
proton-carbon correlation spectrum (HETCOR) (Figure 3.2)

42
(a)
Figure 3.1 Aromatic region of the 1H-NMR spectrum (CDC1-.) of
(a) N—[(5-nitrobenzotriazol-N-lyl)methyl]pyrro¬
lidine (3.5) (-25°C), and (b) a mixture of 1-, 2-
and 3-methyl-5-nitrobenzotriazoles (25°C).

Cl
OJ
Figure 3.2 A ^H-^C correlation spectrum (HETCOR) of N-[(5-chlorobenzotria-
zol-N-yl)methyl]pyrrolidine (3.6).

44
helped in assigning each of the aromatic peaks in the ^H-NMR
spectrum to the correct isomer. Literature ^H-NMR spectra
[79HCA2129] of 1-methyl-, 2-methyl-, and 3-methyl-
5-chlorobenzotriazole are in agreement with our assignments.
Spectral assignment of isobutyraldehyde adducts (3.8),
(3.13) and (3.14). Adduct (3.14) contained only two
isomers, however, both the benzylic methylene and the two
methyl groups resonated at different frequencies for each of
the two isomers. A proton-proton correlation spectrum
(COSY), unraveled the assignment of the aliphatic region in
the "''H-NMR spectrum of this molecule (Figure 3.3) and of
molecules (3.8) and (3.13) which had similar structure. The
aromatic region of (3.14), having signals due to the four
different ring protons was too complex, and therefore
complete assignment was impossible. However, the assignment
of the C-13 spectra did not pose any difficulties.
The "''H-NMR spectra of all adducts are described in the
1 3
experimental section. The ' C-NMR spectra of the 1-isomers
are listed in Table 3.1, of the 2-isomers in Table 3.2, and
of the 3-isomers of (3.5) and (3.6) in Table 3.3. ‘'‘H-NMR
spectra above coalescence were also recorded and are listed
in Table 3.7 (see end of this Chapter).

bt-chipr-oibenzy
EXP* PULSE SEQUENCE; COSY
45
U. CX3P^lDin,,Tm(M^O
Figure 3.3 A *H-*H correlation (COSY) spectrum of N-[ a-
(benzot riazol-N-yl)-3-methyl]propyl-N,N-
dibenzylamine (3.14).
F2 (PPM)

46
Table 3.1. C-NMR chemical shifts of the benzotriazol-l-yl
isomers, of compounds (3.5a)-(3.15a) at a single temperature
(below coalescence) in CDCl^.
NO3
Tem.
( °C)
-NR2
R'
CH
Bt
3.5
-25
49.9
_b
65.5
144.4,
144.2,
136.4C
23.4
122.8,
116.9,
110.7
3.6
+ 20
49.9
_b
65.1
145.8,
C 133.2
,C 129.1C
23.4
124.5,
120.1,
109.4
3.8d
-48
47.1
30.5,
19.8
81.3
144.5,
134.4,
126.9
22.7
19.0
123.5,
119.2,
109.7
3.9
+ 20
66.2
_b
68.9
145.5,
133.5,
127.2
50.1
123.6,
119.4,
109.6
3.10
+ 20
66.3
134.6,
128.4
82.4
145.7,
132.7,
126.9
49.6
128.1,
127.2
123.5,
119.6,
111.1
3.11
+ 20
66.5
141.9,
142.3
81.1
145.8,
133.0,
127.8
49.7
128.7,
123.7
124.2,
120.1,
110.5
3.12
+ 20
66.4
159.4,
127.6
82.4
145.6,
132.5,
127.1
49.7
113.7,
54.8
123.8,
119.5,
111 . 4
3.13
+ 20
66.6
28.4,
19.7
85.5
145.0,
134.4,
127.2
48.8
19.0
123.7,
119.6,
109.7
3.14
+ 20
138.7
30.4,
29.6
80.1
144.9,
135.1,
126.9
128.9
19.4
123.7,
119.7,
109.8
128.5
127.3
53.4
3.15
-20
50.1
134.9,
128.1
82.8
145.4,
132.8,
126.6
25.4
128.0,
127.0
123.4,
119.2,
111. 5
23.5
a The complete
13
C-NMR
spectra
of ( 3
. 4) and
(3.7)
were
reported in Chapter 2 [see Table 2.2, compounds (2.4) and
(2.7)]. k R' = H. c The 4° carbon atoms could not be
assigned with certainty, therefore peaks could be due to the
other isomers. ^ The INEPT pulse sequence at 25 MHz (-48°C,
CDC1^) was utilized for unequivocal assignment of the
spectrum

47
13
Table 3.2. C-NMR chemical shifts of benzotriazol-2-yl
isomers of compounds (3.5b)-(3.15b) at a single temperature
(below coalescence) in CDCl^.
No3
Tern.
( °C)
-NR2
R'
CH
Bt
3.5
-25
50.1
b
73.3
120.5,
C 119.4,
118.8d
23.7
3.6
+ 20
48.9
_b
72.4
145.8,
6 133.2,
e 129.1'
23.7
127.0,
119.0,
116.8
3.8f
-48
46.4
30.5, 19.4
88.7
142.8,
125.8,
117.8
22.7
3.9
+ 20
66.4
_b
76.7
143.8,
126.2,
117.7
59.8
3.10
+ 20
66.7
135.0, 128.4
88.2
143.5,
126.1,
118.1
48.6
128.2, 127.2
3.11
+ 20
66.6
147.9, 128.7
87.2
143.9,
126.8,
118.3
48.6
123.4
3.12
+ 20
66.1
159.4, 126.6
88.1
142.0,
125.2,
114.6
48.8
113.9, 54.8
3.13
+ 20
66.8
28.4, 19.1
92.3
143.3,
125.9,
118.0
48.3
18.9
3.14
+ 20
138.8
30.4, 20.0
87.3
143.5,
126.0,
118.4
128.5
19.3
128.3
127.3
53.3
3.15
-20
49.4
134.9, 128.1
89.0
143.3,
125.9,
117.9
25.4
128.0, 127.0
23.5
a The complete C-
13 NMR spectra
of ( 3
.4) and
(3.7) were
reported in Chapter 2 [see Table 2.2, compounds (2.4) and
to c
(2.7)]. R' = H. Assignments can be interchanged with
j
the corresponding atoms of the 1-isomer. The 4° carbon
atoms were not detected. The 4° carbon atoms could not be
assigned with certainty, therefore peaks could be due to the
other isomers. ^ The INEPT pulse sequence at 25 MHz (-48°C,
CDCl^) was utilized for unequivocal assignment of the
spectrum.

48
Table 3.3. C-NMR chemical shifts of benzotriazol-3-yl
isomers of compounds (3.5) and (3.6) at a single temperature
(below coalescence) in CDCl^.
No Tern. -NR7 R' CH Bt
(°C)
3.5 -25 49.0 -a 65.9 120.5,b 116.4, 107.4
23.4 ^ r r r
3.6 +20 49.8 - 65.1 143.8 , 134.0, 132 . lc
23.4 127.7, 118.4, 110.6
ci b
R' = H. The quaternary atoms were not detected.
Assignments can be interchanged between corresponding 4°
carbon atoms of the 2-isomer; unambiguous assignment of the
quaternary carbon atoms could not be made, because a two-
dimensional correlation was not possible.
3.2.3 Calculation of Equilibrium Constants (K) and Free
Energies (AG°) for Isomerization
The equilibrium constants were measured for each
compound in several solvents, at the temperatures specified
in Table 3.4 (see also footnotes), by integrating the areas
of each of the isomers in the "''H-NMR spectra. Positions 1
and 3 of the benzotriazole ring are degenerate [except for
adducts (3.5) and (3.6)], and this was taken into account
when calculating the populations of the 1-isomers. The free
energies of the isomerization process were then calculated
from the equation AG° = -RTlnK, where K = Pi/P2 (Table 3.4).
The populations Pn were determined from the integration of
the N-CH(R)-N proton signals or from the aromatic region of
each of the isomers. For adducts (3.5) and (3.6), in

49
Table 3.4 Equilibrium constants (K) and free energies for the
isomerization ( AG° ) of N- [ a- ( benzot. r iazol-N-yl ) alkyl ] -N, N-
dialkylamines (3.4) and (3.7)—(3.15).
NO
NR0a R'
X
Y
Solvent
T b
K C
AG° d
( °C)
(kcal/mol)
3.4
Pyr H
H
H
CDBr,
cd3cn
+ 22
1.6
-0.25
+ 22
6.2
-1.05
3.7
Pyr H
Me
Me
CDBr,
cd3cr
+ 23
1.7
-0.30
+ 22
4.9
-0.95
3.8
Pyr Pr1
H
H
Toluene-d„
cd3cn
-40
0:|
+ 0.40
e
3.9
Mor H
H
H
CDBr 3
cd3cr
+ 22
1.8
-0.35
+ 23
5.6
-1.00
3.10
Mor Ph
H
H
CDBr 3
cd3cn
+ 23
1.2
-0.10
+ 20
2.5
-0.55
3.11
Mor 4-N02-CgH4
H
H
cd3cn
+ 20
2.5
-0.55
3.12
Mor 4-MeO-C^H.
6 4
H
H
cd3cn
-20
2.7
-0.50
3.13
Mor Pr1
H
H
Toluene-d,
cdci3 0
cd3cn
+ 25
0.4
+ 0.55
+ 21
0.5
+ 0.40
+ 23
1.1
-0.05
3.14
Dib Pr1
H
H
Toluene-d„
CDB r 3
+ 25
0.4
+ 0.55
+ 22
0.7
+ 0.20
CDCl 3
cd3cn
+ 22
0.8
+ 0.15
+ 22
0.9
+ 0.05
3.15
Pip Ph
H
H
Toluene-d,
+ 1X
-0 05
cd3cn 0
Pyr = pyrrolidine; Mor = morpholine; Dib = Dibenzylamine;
Pip = Piperidine. Temperature at which the equilibrium
constant was measured. c K = P^ /P2, where P^ and P2 are the
populations of the 1- and 2- isomers, respectively (estimated
error +0.2). d Estimated error +0.05-0.10 kcal/mole.
e Signals of two isomers too close to allow reliable
measurement of K.

50
solutions of which a 3-substituted isomer is also present,
when separation of the signals allowed, in addition to K =
Pl//P2' K' = and K" = pi/p3 could also be calculated.
The values so obtained are collected in Table 3.5 (see also
footnotes).
A negative AG° value indicates that the 1-isomer is more
stable than the 2-isomer, while a positive AG° shows the
reverse. Deuterated acetonitrile was found suitable in
obtaining reliable isomeric ratios for nearly all compounds,
therefore direct comparison of the obtained AG° values could
be made, although the temperatures at which equilibrium
constants were measured varied (Tables 3.4, 3.5). In
general, in solutions of compounds of type (3.1) [R' = H,
i.e (3.4)—(3.7) and (3.9)], the 1-isomer is the most
thermodynamically favored component in the mixture.
Table 3.5. Equilibrium constants and free energies for the
isomerization of N-[(5-nitro and 5-chlorobenzotriazol-N-
yl)-methyl]pyrrolidines (3.5) and (3.6), respectively.
No NR® R' X Y SolV. T Kb K' K" AG0 AG0' AG°"
Z (°C) (kcal/mol)
3.5 Pyr H N07 H Tol-dp +21 1.1 - - 0.05
Z CDC1, -25 2.5 1.0 2.5 -0.45 0.0 -0.45
CD3CN -48 5.6 2.3 3.0 -0.75 -0.35 -0.50
3.6 Pyr H Cl H CDC1-. +21 2.0 1 . 4 1.4 -0.40 -0.20 -0.20
CD3CN -20 6.4 5.5 1.3 -0.95 -0.85 -0.15
a Pyr = pyrrolidine. bK = P]_/P2' K' = P3^P2' K" = Pl/P3'
AG°n = -RT lnKn (in kcal/mole). c The signals due to the 1-
and 3- isomers resonated at the same frequency, therefore
K = [P1 + P3]/P2.

51
Adducts of type (3.1) (R' * H), either show little
preference toward either isomer in a common NMR solvent [e.g
(3.10) in CDBr^)], or, in extreme cases of steric hindrance,
the 2-isomer clearly becomes the most stable [e.g. (3.14) in
CDBr^)]; in these cases, K < 1 and AG° > 0. Increasing
solvent polarity can move the equilibrium toward the
1-isomer, as will be discussed next.
Effect of the solvent. Polar solvents have been shown
(Chapter 2) [75JCS(P1)1181] to favor the 1-isomer in
solutions of compounds of type (3.1) (R' = H). Dipole
moment measurements of simple 1-substituted benzotriazole
derivatives [50CR1], [61MI1], [75BSF1675], indicate that
(somewhat surprisingly) they are more polar than their
2-substituted isomers:
R-benzotriazole
/j (D, 2 5 °C, in CgHg )
1-Methyl
2-Methyl
1-Phenyl
2-Phenyl
3.95
0.49
4.08
0.97
Here we observe a similar effect. For example, the AG°
value of (3.14) indicates that the 1-isomer becomes more
favored on going from toluene {/j - 0.36 D) [ 8 5M11 ] to
bromoform (p = 0.99 D) to acetonitrile ( /j = 3.92), with
chloroform ( // = 1.01 D) in an intermediate position. A very
marked effect is observed in acetonitrile solutions of
(3.4)-(3.8), and (3.9), where the 1-isomer has increased to

52
more than 83% in the equilibrium mixture. Compound (3.13)
exemplifies a case in which solvent polarity can determine
which isomer will predominate in the solution (2-isomer in
toluene-dg,* 1-isomer in acetonitrile-dg).
Effect of substituents R and R’. Increased bulkiness of
R' results in increased amounts of the 2-isomer in the
equilibrium mixture. This is reflected by a decreasing
magnitude of K in acetonitrile on going, for example, from
(3.9) to (3.13). When R' is a phenyl or a p-substituted
phenyl group, the equilibrium constant is often close to
unity [e.g. (3.10) in CDBr^, (3.15) in toluene-dg], meaning
that no actual preference is expressed for either of the two
isomers in the particular solvent. The results in Table 3.4
indicated that the peri-interactions (buttressing between H-
7 and the aminoalkyl substituent) are rather important
[75JCS(P2)1695] in the 1-isomer. This was further
demonstrated by a different experiment: the ^H-NMR spectrum
of the pyrrolidine-isobutyraldehyde adduct (3.8) in toluene-
dg, showed that the benzotriazole H-7 and methine NCHN
signals of the 1-isomer became broad and moved toward each
other as the temperature was lowered from -20°C to -80°C.
Restricted rotation about the Bt-CHR'NRg bond was evidently
responsible for this phenomenon, which was observed only for
the 1-isomer (Figure 3.4).
The electron-withdrawing or elect ron-releasing nature of
the substituents R and R' does not seem to have any
noticeable effect, as the magnitude of AG° remains the same

53
(within experimental error) for (3.10) and (3.11) in
acetonitrile-dg, and for (3.8), (3.13) and (3.14) in
toluene-dg, while the differences observed in (3.15) and
(3.8) in toluene-dg would rather be attributed to steric
effects.
Effect of substituents X and Y. The 5-nitro- (3.5) and
5-chloro- substituted (3.6) compounds, each contain three
interconverting isomers in their solutions, occupying
different energy minima, as reflected by different AG°
values for each isomerization process (Table 3.5). The
1-isomer is again the predominant and the 2-isomer the least
abundant, in both cases and all solvents studied.
Literature information on the polarity of 5-nitro-
[64T211] and 5-chloro- [79HCA2129] methylbenzotriazoles, was
combined with our observations (see Experimental), deduced
from the order of elution of these compounds from column
chromatography (silica gel), ranks them, according to
increasing polarity:
2-Me-5-N02~Bt < 3-Me-5-N02-Bt 2, and
2-Me-5-Cl-Bt < l-Me-5-Cl-Bt < 3-Me-5-Cl-Bt.
By analogy, the polarity of isomeric compounds in each
of (3.5) and (3.6), is expected to follow the same order.
This is verified by the magnitude of the K values observed
for (3.5). However, K values for (3.6) show that the
1-isomer is more polar than the 3-isomer, which is in
contrast to the literature report.

54
3.2.4 Variable Temperature NMR Spectral Study; ,
Calculation of Free Energies of Activation (AG*)
The temperatures at which the characteristic proton
resonances of the 1- and 2- isomers coalesced were measured.
Specifically, the signals of the methylene groups, located
between the amino and the benzotriazole nitrogen atoms, of
the two isomers, were monitored for compounds (3.4)—(3-7)
and (3.9). The corresponding methinic proton signals were
monitored for compounds (3.8) and (3.10)-(3.15). The ranges
of temperatures within which coalescence occurred were
visually estimated from the lineshape of the signals under
observation, and are listed in Table 3.6. Figure 3.4 shows
the temperature dependence of the ^H-NMR spectrum of (3.8)
in deuterated toluene. The doublets of the two isomers
slowly coalesce to a single broad peak at 5.3 ppm. The
other broad signal at about 6.3 ppm originates from the
aromatic region and its assignment is uncertain.
Approximate free energies of activation [74MI1],
[80M12], [82MI1] were calculated using the simplified
equation,
AG^ = RTc[22.96 + ln(Tc/Sv)]
where Tc is the coalescence temperature (in °K) and 6v the
chemical shift difference (in Hz) of the two separate peaks
in the slow exchange region. The error in Tc is ±2 to ±3°C,
and this corresponds to +0.1 to +0.2 kcal./mole in AG^
[74MI1], The 1- to 2-isomerization process is intermo¬
lecular (Chapter 2) and the populations of the isomers are

55
Figure 3.4 Temperature dependence of the ^H-NMR spectrum
[NCH(Pr)N region] of adduct (3.8) in toluene-dg.

56
unequal in most cases studied, therefore additional error is
introduced in the calculations [82MI1]. However, since only
approximate AG^ values are desired for evaluation of the
relative ease of isomerization of the compounds, the free
energies of activation listed in Table 3.6 give satisfactory
indication. The activation energies, calculated from the
equation mentioned above, represent the barrier to
conversion of the least to the most stable isomer. Thus,
the calculated AG^ values for compounds with AG° < 0 pertain
to the 2- to 1- isomerization, whereas for those with AG° >
0 pertain to the reverse. However the numbers in Table 3.6
for (3.8) and (3.14) have been adjusted so that all pertain
to 2- to 1- conversion.
The choice of a suitable solvent for VT work is not
always easy [88JOC2629]. Both low and high temperature
spectra were obtained in deuterated toluene, but for most
compounds coalescence did not occur below the boiling point
of this solvent. Coalescence was obtained in the higher
boiling solvent, bromoform-d (b.p. 150°C), but the AG^
values were generally lower in CDBr^ than in toluene-dg, due
to solvent polarity effects. In cases where the proton re¬
sonances under observation were not well resolved or ob¬
scured by other signals in the above solvents, (e.g (3.11),
(3.12)], deuterated acetonitrile was used but this could not
be extended to all molecules: the amount of the 2- isomer
in (3.4) and (3.7) and (3.9) in CD^CN was very small (see
Table 3.4), resulting in very weak proton resonances, and
therefore unacceptable errors in the measurement of Tc>

57
Table 3.6 Free energies of activation for the isomerization
of N-[a-(benzotriazol-N-yl)alkyl]-N,N-dialkylamines
(3.4)—(3.15).
No
Nr2
R'
X
Y
Solvent
T
( °6)
AGT
(kcal/mol)
3.4
Pyr
H
H
H
CDB r g
85
18.2
3.5
Pyr
N0o
H
Toluene-dg
105
18.0
z
Benzene-d^
63
16.0
CDClg
32
15.4
3.6
Pyr
H
C1
H
CDB r g
66
17.0
3.7
Pyr
H
Me
Me
CDB r g
98
18.7
3.8
Pyr
Pr1
H
H
Toluene-dg
48
15.6
3.9
Mor
H
H
H
CDB r g
86
18.3
3.10
Mor
Ph
H
H
CDB r ,
62
17.7
CDgCN
63
16.9
3.11
Mor
4-N02-C6H4
H
H
CDgCN
83
18.6
3.12
Mor
4-MeO-CgH4
H
H
CDgCN
35
15.7
3.13
Mor
Pr1
H
H
CDgCN
35
16.1
3.14
Dib
Pr1
H
H
CDB r g
75
17.9
3.15
Pi p
Ph
H
H
Toluene-dg
73
16.8
Pyr = pyrrolidine; Mor = morpholine; Dib = Dibenzylamine;
Pip = Piperidine.
b ±20C. c ±0.15 kcal/mol
Effect of the solvent. The nature of the solvent
affects the magnitudes of both AG^ and AG°. Table 3.6
clearly shows that the energy barrier is highest in toluene
dg, intermediate in bromoform-d, and lowest in acetonitrile
dg. This is as expected, because a more polar solvent

58
provides more stabilization to the ion pair [(3.2) + (3.3)]
than to the individual isomers (Scheme 3.1), thus lowering
the energy difference between the ion pair and either of the
isomers.
Effect of R'. The results in Table 3.6 clearly show
that the free energy of activation is lower when resonance
stabilization is provided to the intermediate (3.2) through
the substituent R' (Scheme 3.1), compared to the unsubsti¬
tuted cases. Specifically, in acetonitrile, the order of
decreasing AG^ values is (3.11) > (3.10) > (3.12). Strong
stabilization to the electron deficient iminic carbon is
also provided by isopropyl substituents, as indicated in the
case of (3.8) vs (3.4), and to a lesser extent, (3.13) vs
(3.9).
Effect of substituents in the benzotriazole ring. The
electron-withdrawing nitro substituent of (3.5) stabilizes
the negative charge developed on anion (3.3), and therefore
facilitates N-CHNR2 bond dissociation leading to recombi¬
nation on the N-2 atom of benzotriazole. The electron-
donating methyl groups of (3.7) have the opposite effect,
raising the energy barrier to a relatively high value. The
5-chloro substituent is intermediate. The calculated AG^
values in CDBr^ are therefore classified in order of
decreasing magnitude, as follows: (3.7) > (3.4) > (3.6) >
(3.5). Compound (3.5) in CDBr^ is very near coalescence at

59
room temperature, so the AG^ in this solvent could not be
measured (the solvent freezes at +8.3°C), but the
corresponding value in chloroform-d suggests it will be less
than 15.4 kcal/mol.
For compounds (3.5) and (3.6) one coalescence
temperature was observed. The NCH^N protons of the 1- and
3- isomers of the nitro adduct (3.5) resonated at the same
frequency, while the singlet of the 2-isomer emerged at 0.4
ppm downfield, in both toluene-dg and benzene-dg. The two
peaks coalesced into one as the temperature increased. In
CDClg solution, however, three separate peaks were observed
for each isomer. The NCI^N singlets due to 1- and 3-
isomers were very close, and they overlapped very soon with
a moderate increase in temperature, whereas true coalescence
came later at a higher temperature. Similar behavior was
demonstrated by (3.6).
Effect of the nature of secondary amine. The
availability of the lone pair of electrons on the amine
nitrogen for donation to the adjacent electron-deficient
carbon in adducts of type (3.1), plays a significant role in
determining the height of the barrier. This is best
illustrated by the compounds bearing the isopropyl
substituent, where a significant amount of positive charge
could be developed on the NCHCHMe? atom. We then observe,
in order of decreasing AG^ magnitude, (3.10) > (3.15), and
(3.14) > (3.8). The order of decreasing AG^ values bears an

60
inverse correlation with the pK values of the corresponding
cl
secondary amines [72MI1]. Thus, pK [(morpholine) = 8.49] <
cl
pK [(piperidine) = 11.20] and again pK (dibenzylamine) =
a a
8.52 < pK [(pyrrolidine) = 11.30]. The benzotriazole
cl
adducts of morpholine are consequently more easily isolable
and stable compounds than the adducts of pyrrolidine or
piperidine, most of which are readily hydrolyzed oils or low
melting solids.
3.3 Conclusions
The free energy of activation for the benzotriazol-l-yl
to benzotriazol-2-yl rearrangement of N-[a-(benzotriazol-N-
yl)alkyl]-N,N-dialkylamines, is greatly dependent on the
degree of stabilization provided to either of the inter¬
mediate ions (3.2) or (3.3): the greater the stabilization
the lower the energy barrier. The greater the polarity of
the solvent the lower the value of AG^. Finally, the
bulkier the dialkylaminoalkyl- or aryl- substituent the more
abundant the 2-isomer, which in extreme cases becomes the
predominent component, as shown by values of of K < 1 and
AG° > 0.
The chemical reactivity of the compounds studied can
therefore be tailored according to the appropriate
substitution. Compounds for which AG^ is low, react rapidly
and cleanly with weak nucleophiles such as amines with
concurrent removal of benzotriazole. Compounds having high
AG^ values are much less reactive toward the same

61
nucleophiles. The following Chapters, and in particular
Chapter 7, demonstrate results due to the enhanced
reactivity of benzotriazole adducts (3.1) in detail.
3.4 Experimental
3.4.1 Methods and Reagents
^H-NMR spectra were recorded on a Varian VXR 300 MHz
instrument using TMS as the internal reference and as a
standard peak for linewidth comparisons. The samples were
solutions of 50-70 mg of compound in 0.55 ml of solvent, in
5 mm nmr tubes. The temperature was raised in 10°C
increments allowing at least 10 min for equilibration at
each setting. High temperature calibration of the
instrument with an ethylene glycol standard sample, showed
that the set and actual temperatures were in agreement
within +1°C. Variable temperature measurements were
repeated twice and equilibrium constant values were the
average of at least three measurements.
Deuterated solvents were purchased from MSD Isotopes
(toluene-dg, CDClg, CgDg, CD^CN) and Chemalog (CDBr^) and
13
were used directly. C-NMR spectra were recorded on either
a JEOL-FX 100 (25 MHz, FT mode) or a Varian XL 200 (50 MHz),
or a Varian VXR 300 (75 MHz) instrument. Two-dimensional
spectra were recorded on the VXR 300 spectrometer using the
standard software for COSY and HETCOR pulse sequences
provided by Varian.

62
Reagents and miscellaneous preparative and
chromatographic methods are described in Chapter 4.
3.4.2“ ‘ f N-[(Benzotriazol-N-yl)methyl]-N,N-
The preparation of the following compounds has been
described in Chapter 2: N-[(benzotriazol-N-yl)methyl]-
pyrrolidine (3.4), and N-[(5,6-dimethylbenzotriazo-N-lyl)-
methyl]pyrrolidine (3.7) [see preparation of compounds (2.4)
and (2.7), respectively].
N-[(5-Nitrobenzotriazol-N-yl)methyl]pyrrolidine (3.5).
5-Nitrobenzotriazole (5.42 g, 0.033 mol), pyrrolidine (0.038
mol, 3.1 ml), and 37% aq. formaldehyde (0.04 mol, 3.4 ml)
were stirred in methanol according to the standard
literature procedure [75JCS(Pi)1181] (see also Chapter 2).
Following evaporation of the solvent the compound was at
first obtained as an oil, which then solidified gradually
after stirring with diethyl ether in a dry ice/acetone bath.
N-[(5-Nitrobenzotriazol-N-yl)methyl]pyrrolidine was
collected as a yellow solid (7.22 g, 88.5%), m.p. 76-78°C
(from diethyl ether) (Found, C, 53.01; H, 5.14; N, 28.21%.
C11H13N5°2 re<3uires' C, 53.44 ; H, 5.30; N, 28.32%);
(CDC13, -25°C) 1-isomer, 9.04 (d, J = 2 Hz, H-4), 8.46 (dd,
J = 9 Hz, J = 2 Hz, H-6), 7.88 (d, J = 9 Hz, H-7), 5.76 (s,
NCH2N), 2.78 (br s, NCH2CH2), 1.80 (br s, NCH2CH2);
2-isomer, 8.94 (d, J = 2 Hz, H-4), 8.32 (dd, J = 9 Hz, J = 2

63
Hz, H-6), 8.08
(d,
J = 9 Hz, H-7), 5.85
(s, nch2n)
, 2.
87 (br
s, nch2ch2), 1.
80
(br s, NCH2CH2); 3-isomer, 8.71
(d,
J = 2
Hz, H-4), 8.28
(dd
, J = 9 Hz, J = 2 Hz,
H-6), 8.25
(d,
J = 9
Hz, H-7), 5.78
( s,
NCH2N), 2.78 (br, s,
nch2ch2),
1.80
(br
s, nch2ch2).
N—[(5-Chlorobenzotriazol-N-yl)methyl]pyrrolidine (3.6).
It was prepared as (3.5), using the same molar amounts of
the required starting materials. The oily residue remained
after evaporation of the solvent soon started crystallizing.
N—[(5-Chlorobenzotriazol-N-yl)methylJpyrrolidine was
obtained as an off-white solid (5.75 g, 71%), m.p. 58-60°C
(from diethyl ether/hexanes (7:1, v/v) (Found, C, 55.57 ; H,
5.40; N, 23.82%. requires, C, 55.82; H, 5.54; N,
23.67%); (CDCl^, +21°C) 1-isomer, 7.96 (d, J = 9 Hz, H-
7), 7.45 (d, J = 2 Hz, H-4), 7.31 (d, J = 9 Hz, H-6,
overlaps with same proton of other isomer), 5.54 (s, NCH2N),
2.74 (br m, NCH2CH2), 1.73 (m, NCH2CH2); 2-isomer, 7.87 (d,
J = 2 Hz, H-4), 7.82 (d, J = 9 Hz, H-6), 7.31 (d, J = 9 Hz,
H-7), 5.68 (s, NCH2N), 2.85 (br m, NCH2CH2), 1.73 (m,
CH2CH2); 3-isomer, 8.02 (d, J = 2 Hz, H-4), 7.59 (d, J = 9
Hz, H-7), 7.43 (dd, J - 9 Hz, J = 2 Hz, H-6), 5.57 (s,
NCH2N), 2.74 (br m, CH2CH2), 1.73 (m, NCH2CH2>.
N—[(Benzotriazol-N-yl)methyl]morpholine (3.9). The
compound was prepared according to the general literature
method [52JA3868] (see also Chapter 2), and was obtained as
a white solid (95%), m.p. 108-109.5°C (from 95% ethanol);

64
lit. [52JA3868] m.p. 104-105°C; S„ (CDCl-,) 1-isomer, 8.06
(dd, J = 8 Hz, J = 1 Hz, H-4), 7.48 (td, J = 8 Hz, J = 1 Hz,
H-5 or H-6), 7.37 (m, H-7, H-6 or H-5), 5.41 (s, NCH2N),
3.65 (m, OCH2), 2.6 (m, CH2N); 2-isomer, 7.88 (AA' m, J =
6.5 Hz, H-4, H-7), 7.37 (BB' m, H-5, H-6, partially
overlapping with signals of 1-isomer), 5.53 (s, NCH2N), 3.65
(m, OCH2), 2.69 (m, CH2N).
3.4.3 Preparation of N-[a-(Benzotriazol-N-yl)alkyl]-N,N-
dialkylamines
General method. Benzotriazole (7.942 g, 0.0667 mol) and
a secondary amine (1 equiv.) were stirred in dry benzene (50
ml) and then the aldehyde (1 equiv.) was added. The mixture
was heated under reflux in a Dean-Stark apparatus, until the
theoretically calculated amount of water (~ 1.2 ml) had been
collected (1-5 days). Isolation and purification is
described below for each compound.
N-[a-(Benzotriazol-N-yl)-p-methyl)propyl]pyrrolidine
(3.8). The solvent was evaporated at room temperature under
reduced pressure (0.2 mm Hg), and the resulting oil was
triturated with petroleum ether/diethyl ether in a dry
ice/acetone bath. N-[a-(Benzotriazol-N-yl)-S-methyl)-
propyl]pyrrolidine was obtained as a beige solid (41%),
which was dried under vacuum (0.2 mm Hg, 2 days); m.p.
50-53 °C ( Found, C, 67.93 ; H, 7.95%. ci4H20N4 rec3ui res» c >
68.82; H, 8.25; N, 22.93%); (toluene-dg, -20°C)
1-isomer, 7.99 (d, J = 9 Hz, H-4), 7.02 (m, H-5,6,7), 4.92

65
(d, J = 10 Hz, NCHN), 3.01 (m, CHMe2), 2.85 (m, NCH2CH2),
2.23 (m, NCH2CH2), 1.06 (d, J = 10 Hz, CH3), 0.44 (d, CH3);
2-isomer, 7.87 (AA' m, J = 6.5 Hz, H-4, H-7), 7.37 (BB' m,
H-5,6 and protons of other isomer), 5.38 (d, J = 10 Hz,
NCHN), 3.02 (m, CHMe 2 ) , 2.56 (m, NCH2CH2), 2.23 (m, CU2CU_2) ,
l.04 (d, J = 10 Hz, CH3), 0.56 (m, J = 10 Hz, CH3).
N-[a-(Benzotriazol-N-yl)benzyl]morpholine (3.10).
Cooling of the hot benzene solution resulted in
precipitation of a solid, which was thinned with diethyl
ether in a cold bath and filtered. N-[a-(Benzotriazol-N-
yl ) benzyl ] morphol ine was collected as a white powder (87%),
m.p. 110-112°C (from benzene) (Found, C, 69.01; H, 6.19; H,
19.00%. C17H18N4® rec3uires» C, 69.37 ; H, 6.16; N, 19.03%);
&H (CgDg, +21°C) 1-isomer, 8.03 (dd, J = 8 Hz, J = 1 Hz,
H-4), 7.26 (m, H-5,6 and protons of Ph groups), 7.05 (m,
Ph), 6.45 (s, NCHN), 3.42 (m, OCH2), 2.29 (m, CH2N,
superimposed on signals of other isomer); 2-isomer, 7.89
(AA' m, J = 3 Hz, H-4, H-7), 7.26 (BB' m, H-5,6 and Ph
protons), 7.05 (m, Ph), 6.78 (s, NCHN), 3.44 (m, OCH2), 2.69
(m, CH2N).
N-[a-(Benzotriazol-N-yl)-«-(4-nitrophenyl)methyl]-
morpholine (3.11). The product was obtained as a hard
yellowish solid (21.5 g, 96%) m.p. 145-148°C (from 95%
ethanol) (Found, C, 60.35; H, 5.03; N, 20.50%. C17H17N5°3

66
requires, C, 60.17; H, 5.05; N, 20.64%); (CDCl-,, +21°C)
l-isomer, 8.22 (d, J = 8 Hz, NO2-CC2H2, overlapping with
corresponding signals of other isomer), 8.13 (dd, J = 8 Hz,
J = 1 Hz, H-4), 7.63 (d, J = 8 Hz, N02CC2H2C2H2), 7.52-7.35
(m, H-5,6 overlapping with signals of other isomer), 6.79
(s, NCHN), 3.77 (m, OCH2), 2.64 (m, CH2N); 2-isomer, 8.21
(d, NO2CC2H2, overlapping with l-isomer), 7.93 (AA' m, J = 3
Hz, H-4,7), 7.52-7.35 (BB' m, H-5,6 and protons of
l-isomer), 6.85 (s, NCHN), 3.64 (m, OCH2), 2.85 (m, CH2N).
N-[a-(Benzotriazol-N-yl)-a-(4-methoxyphenyl)]methyl]-
morpholine (3.12). The product was a low melting (m.p. less
than 20°C) solid, which could not be purified (remained as a
very viscous oil) and was characterized by ^H- (see below),
and '*'^C-NMR spectra at -20°C (see Tables 3.1 and 3.2); S
H
(CD^CN, at -20°C) l-isomer, 8.07 (d, J = 8 Hz, H-4), 7.68
(d, J = 8 Hz, H-7), 7.50-7.32 (m, H-5,6 and corresponding
signals of other isomer), 7.35 (d, J = 9 Hz, MeO-CC2H2C2H2,
partially overlapping with corresponding signals of other
isomer), 6.89 (d, J = 9 Hz, MeO-CC2H2), 6.71 (s, NCHN), 3.70
(m, OCH2), 3.57 (s, OMe), 2.51 (br s, CH2N); 2-isomer, 7.93
(AA' m, J = 3 Hz), 7.50-7.32 (BB' m, H-5,6 overlapping with
corresponding signals of other isomer and with phenyl
protons), 6.79 (s, NCHN), 3.77 (s, OMe), 3.70 (m, OCH2),
2.51 (br s, CH2N).

67
N-[a-(Benzot riazol-N-yl)-g-methyl)propyl]morpholine
(3.13). After evaporation of benzene, the product was
obtained as an oil which solidified when treated with
diethyl ether in a dry ice acetone bath (11.2 g, 65%), m.p.
101-103°C (Found, C, 64.89; H, 8.20; N, 21.79%. ci4H20N4°
requires,
c.
, 64
.59;
H,
7.74; N,
21.52%),
; 8h (CDClg
, +21°C)
1-isomer,
8 .
.08
(dd,
J
= 8 Hz, J
= 1 Hz,
H-4), 7.59
(d, J = 8
Hz, H-7),
7.
.45
(td,
J
= 8 Hz, J
= 1 Hz,
H-5 or H-6)
, 7.37
(m, H-6 or H-5, overlapping with corresponding signals of
the 2-isomer), 5.01 (d, J = 10 Hz, NCHN), 3.68 (2m, OCH2),
3.08 (qd, J = 8 Hz, J = 1 Hz, CHMe2), 2.60 (m, CH2N), 1.20
(d, J = 10 Hz, CH^), 0.63 (d, J = 10 Hz, CHg); 2-isomer,
7.90 (AA' m, J = 3 Hz, H-4,7), 7.37 (BB' m, H-5,6, over¬
lapping with corresponding signals of 1-isomer), 5.10 (s,
NCHN), 3.68 (m, OCH2), 2.97 (qd, J = 8 Hz, J = 1 Hz, CHMe2),
2.60 (m, CH2N), 1.20 (d, J = 10 Hz, CHg), 0.67 (d, J = 10
Hz, CH3).
N-[ g-(Benzotriazol-N-yl )-|3-methyl )propyl ]-N,N-
dibenzylamine (3.14). The compound was obtained as a white
solid after complete evaporation of benzene at room
temperature (at 0.2 mm Hg), and trituration with dry diethyl
ether. N-[a-(Benzotriazol-N-yl)-3-methyl)propyl]-N,N-
dibenzylamine was collected by filtration (78%), m.p.
83-85°C (Found, C, 77.76 ; H, 7.11%. C24H26N4 rec3ui res' C,
77.80; H, 7.07, N, 15.12%); 8H (toluene-dg, +20°C)
1-isomer, 8.03 (d, J = 8 Hz, H-4), 7.30 (d, J = 8 Hz, H-7),

68
7.12 (m, rest of ring protons), 6.90 (t, J = 6.5 Hz, H-5 or
H-6), 5.01 (d, J = 10 Hz, NCHN), 4.13 (d, J = 14 Hz, CH2Ph),
3.07 (d, J = 14 Hz, CH2Ph), 2.95 (m, CHMe2>, 1.16 (d, J = 10
Hz, CHg), 0.32 (d, J = 10 Hz, CHg); 2-isomer, 7.92 (AA' m,
J = 3 Hz, H-4,7), 7.44 (BB' m, J = 3 Hz, H-5,6), 7.22-7.06
(m, Ph ring protons of both isomers), 5.31 (d, J = 10 Hz,
NCHN), 4.17 (d, J = 14 Hz, CH2Ph), 3.17 (d, J = 14 Hz,
CH2Ph), 2.95 (m, CHMe2), 1.07 (d, J = 10 Hz, CHg), 0.39 (d,
J = 10 Hz, CH3).
N-[a-(Benzotriazol-N-yl)benzyljpiperidine (3.15). The
oil obtained after evaporation of benzene did not solidify
under a variety of conditions. The oily residue (59%) was
characterized by its ^C- (Tables 3.1 and 3.2), and ^H-NMR
spectra: (toluene-dg, +21°C) 1-isomer, 8.02 (m, H-4),
7.25-7.00 (m, H-5,6 and Ph ring protons), 6.61 (s, NCHN),
2.80-2.25 [m, N(CH2)2], 1.40 [br s, N(CH2)2(CH2)2],
1.20-1.00 [m, N(CH2)^CH2]; 2-isomer, 7.25-7.00 (m, all Bt
and Ph ring protons), 6.86 (s, NCHN), 2.80-2.25 [m,
N(CH2)2-], 1.40 [br s, N(CH2)2(CH2)21, 1.20-1.00 [m,
n(ch2)4ch2].
3.4.4 Methylation of 5-Nitrobenzotriazole
5-Nitrobenzotriazole (0.5 g, 0.03 mol) was dissolved in
aq. 2N NaOH (25 ml) and water (10 ml) was added to achieve a
clear solution. Dimethyl sulfate (10 g, 0.076 mol) was
added and a yellow precipitate appeared. The suspension was

69
stirred at room temperature for 1/2 h and at 0°C for 1 1/2
h, then the solid was filtered, washed with water and air
dried. The crude solid contained three products, as
indicated by TLC (eluted with hexanes/Et2Ü, 1/1, v/v) with
Rf values 0.62, 0.37, 0.19. A portion of the crude solid
(0.25 g) was placed on a silica gel column and eluted with
hexanes/Et20 (8:2, 7:3, 6:4, 5:5, 2:8, v/v) and finally
Et2Ü. Total recovery 0.20 g, 80%. The following compounds
were collected as column fractions (in order of elution):
2-Methyl-5-nitrobenzotriazole. (= 0.62, 0.094 g,
46%, m.p. 180-4 °C, lit. [64T211] m.p. 187°C); S„ (300 MHz,
CDC13) 8.87 (dd, Jm = 2 Hz, Jp = 0.7 Hz, H-4), 8.24 (dd, JQ
= 9 Hz, Jm = 2 Hz, H-6), 7.98 (dd, Jq = 9 Hz, Jp = 0.7 Hz,
H-7), 4.61 (3H, s, Me); &c (75 MHz, CDC13) 146.6 (C-3a or C-
5, small br), 143.0 (C-7a), 120.7 (C-6), 119.1 (C-7),
116.0 (C-4), 44.0 (Me).
3-Methyl-5-nitrobenzotriazole. (R^ = 0.37, 0.048 g,
24%, m.p. 154-157°C, lit. [64T211] m.p. not reported)
(Found, C, 45.29 ; H, 3.48%. C-^gN^. 1/2H20 requires, C,
44.92; H, 3.77; N, 29.94%); §H (300 MHz, CDCl3), 8.55 (d,
Jm = 2 Hz, H-4), 8.27 (dd, Jq = 9 Hz, Jm = 2 Hz, H-6), 8.18
(d, JQ = 9 Hz, H-7), 4.45 (s, 3 H, CH3); Sc (75 MHz, CDCl3)
148.0 (C-3a or C-5), 146.8 (C-5 or C-3a), 132.7 (C-7a),
120.9 (C-5), 118.8 (C-7), 106.5 (C-4), 43.8 (CH3).

70
l-Methyl-5-nitrobenzotriazole. (R^ = 0.19, 0.
m.p. 160-2 °C, lit. [64T211] m.p. 163°C); Su (300
CDC13) 8.99 (d, Jm = 2 Hz, H-4), 8.42 (dd, Jq = 9
H,, H-6), 7.69 (d, Jq = 9 Hz, H-7), 4.41 (3 H, s,
(75 MHz, CDCl3) 144.9 (C-3a or C-5, small br), 136
122.4 (C-5), 117.2 (C—3), 109.0 (C-7 ), 34.70 (Me).
06 g, 30%,
MHz ,
Hz, J = 2
Me); Sc
.0 (C-7a ) ,

Table 3.7. ^H-NMR chemical shifts of compounds (3.4-3.15) at a single temperature (above
coalescence)
Noa
Solv.
Temp.
(°C)
-nr2
R'
CH
Bt
3.4
CDBr3
110
2.8
(br s,
4 H)
_b
5.6 (s, 2 H)
8.1-7.7 (br m, 4 H)
1.7
(br s,
4 H)
(br m, 4 H)
3.5
cdci3
45
1.7
(br s,
4 H)
b
5.8 (br s, 2 H)
9.1-7.7
2.7
(br s,
4 H)
(v. br m, 3 H)
3.6C
CDBr3
84
2.8
(br s,
4 H)
b
5.7 (s, 2 H)
8.0-7.4 (br m, 3 H)
1.7
(br s,
4 H)
3.7d
CDBr3
110
2.8
(br s,
4 H)
b
5.5 (s, 2 H)
7.8-7.3(v. br m, 2 H)
1.7
(br s,
4 H)
2.4 (br s, Me)
3.8
toi-dg
70
2.9-2
!.7 (m,
4 H)
0.9e
5.3 (d, 1 H)
7.8 (br s, 2 H)
1.4
• (s, 4
H)
(m, 7 H)
(J = 10 Hz)
7.2-7.1 (m, 2 H)
3.9
CDBl*3
110
3.6
(br s,
4 H)
b
5.4 (s, 2 H)
8.7 (v. br s, 2 H)
2.7
(br s,
4 H)
7.4 (s, 2 H)
3.10
CDBr3
90
3.9
(br s,
1 H)
_g
6.7 (s, 1 H)
7.9 (br m, 3 H)^
3.7
(br s,
3 H)
7.5-7.3 (m, 6 H)
3.2
(br s,
1 H)
2.6
(br s,
3 H)
3.11h
CDBr3
110
4.1
(br s,
1 H)
_g
6.8 (br s)
9.5 (v. br s, 1 H)
3.8
(br s,
3 H)
(1 H)
8.2-7.2 (m, 7 H)
3.2
(br s,
1 H)
2.8
(br s,
3 H)

Table 3.7—continued.
No
Solv.
Temp.
(°C)
-nr2
R'
CH
Bt
3.12
cd3cn
60
3.7 (m, 4
H)
6.85g
6.7
9.9 (s, 1 H)
2.5 (br m,
3 H)
(d, 2 H)
(s, 1 H)
8.6 (br s, 1 H)
2.8 (br s,
1 H)
3.7 (s, 3 H)
8.0-7.7 (m, 1 H)
7.5-7.3 (br m, 3 H)
3.13
cd3cn
50
3.6 (m, 4
H)
3.0 (m, 1 H)
5.1 (d, 1 H)
8.2-7.7 (m, 2 H)
2.6 (m, 4
H)
1.2 (m, 6 H)
(J = 10 Hz)
7.6-7.3 (m, 2 H)
3.14
CDBr3
90
4.2 (br m,
2 H)
3.1 (br m)
5.30
7.9 (v. br s, 3 H)
3.3 (br m,
2 H)g
(1 H)
(br s, 1 H)
7.3 (br m, 6 H)
1.2 (m, 3 H)g
0.5 (m, 3 H)
3.15
tol-d„
90
2.29 (br m,
4 H)
6.80 (m, 5 H)
6.42 (s, 1 H)
7.5 (v. br s, 4 H)
1.15 (m, 4 H)
0.94 (m, 2 H)
Many peaks did not become entirely sharp, even at several degrees above coalescence. ^ R' = H.
Some decomposition must have occurred as evidenced by additional aliphatic peaks. ^ In addition,
& 3.4 (br m), 2.0 (br m), probably due to free pyrrolidine. The CHMe0 signal is hidden under
broad peaks. In addition, 5 10.30 (v. br, 1 H). g Phenyl protons come together with
benzotriazole protons. ^ The spectrum was recorded in CDBr^, since b.p. (CD-^CN) = 82°C and
T = 84°C in CD-CN.
c 3

CHAPTER 4
A GENERAL METHOD FOR THE PREPARATION
OF STRUCTURALLY DIVERSE TERTIARY AMINES
4.1 Introduction
In the preceding chapters, the isomerization of N-[a-
(benzotriazol-N-yl)alkyl]-N,N-dialkylamines was
investigated, and the influence of the structure on this
process was assessed: all the evidence gathered is in
support of the proposed ionic mechanism (Chapter 3, Scheme
3.1). Consequently, the carbon atom located between the
benzotriazole and the amine nitrogens (Bt-CH(R)-NR2) must
possess enhanced electrophi1icity and therefore is expected
to react easily with various nucleophiles. In this and in
the following chapters, the reactions of benzotriazole
adducts with strong and weak nucleophiles are investigated.
The classification is based on the nature of the end-product
rather than the type of the reaction.
In the present chapter, the knowledge gained so far
(Chapter 3) has been combined with previous experience in
this [87JCS(Pi)805 ] , and other research groups [84TL1635 ]
regarding the reactivity of primary aromatic amine/benzo-
triazole adducts toward alkylation. Thus, benzotriazole
adducts of the type (4.2) are expected to undergo facile
alkylation upon reaction with Grignard reagents, thereby
73

74
converting secondary amines (4.1) into variably substituted
tertiary amines (4.3). In a similar fashion, replacement of
benzotriazole by hydride, by the action of a hydride ion
donor, should also be feasible (Scheme 4.1).
4.3a - 4.31 4.3m - 4.3p
Scheme 4.1

75
Tertiary amines can be prepared by many and varied
methods [79MI1]. Alkylation of secondary amines is a useful
tool (Equation 4.1); however, in unhindered cases there is
danger of over-reaction to yield quaternary salts, and
sterically hindered tertiary amines are not easy to prepare
in this way, as the reactions are slow and the yields low to
moderate [60JA4908], [78S766] . Alkyl branching in R3X
brings with it the probability of competing amine induced 13-
elimination in substrates having suitably placed hydrogens
[79MI1].
R1R2NH + R3X > R1R2R3N + HX (Eq. 4.1)
Reductions of iminium salts (largely confined to
formaldehyde derivatives) or tertiary amides [79MI1]
(Equations 4.2, 4.3, respectively), require availability of
the appropriate precursor and do not allow for versatility
in the structural features of the products [79MI1].
â– I- [ H ]
CH20 + HNR1R2 > CH2=NR1R2 > CB^-NR^2 (Eq. 4.2)
R1CONR2R3 -> R1CH2NR2R3 (Eq. 4.3)
Reductive carbonylation [83S723] or carboxylation
[78S766], [85TL5367] of 2° amines (Equation 4.4), although
versatile and high yielding, requires tedious procedures:

76
- - 1. BunLi 1 9 _ ClCO^Me .. y
R R NH > R R NCO, Li — > [ R R NCO,CO,He ]
2. C02 2 2
A .y LÍA!!!. .. y
> RXRZNC02Me -> RiRZNMe ( Eq. 4.4)
Reductive dealkylation of quaternary ammonium salts
[79MI1], often gives good yields but the starting material
is usually itself made from a tertiary amine. Deamination
of dimethylhydrazinium salts [82SC801] affords N,N-dimethyl-
alkyl- or -aryl- amines in high yields, but involves the
carcinogenic N,N-dimethylhydrazine (Equation 4.5).
_ HN02
RX + Me2NNH2 > R(Me)2N NH2 X -> RNMe2 (Eq. 4.5)
The conversion of primary amines with formaldehyde and
ethylene glycol into perhydrodioxazepines and subsequent
treatment with Grignard reagents [83TL1597] leads to
tertiary amines in a more direct way, but is limited to
compounds containing two identical alkyl groups (Equation
4.6) .
2 R1MgX .
RNH2 + CH20 + (CH2OH)2 > RN(CH2OCH2)2 > RN(CH2Ri)2
(Eq. 4.6)
Methods involving metal catalysts are available
[84JOC3359], especially in the patent literature [61MI1],
[85JAP60258145] but almost invariably require heating under
pressure.

77
Reaction of organometallic reagents with iminium salts
[81JOM275], or chloromethylene iminium salts [85LA2178],
provides a direct route to tertiary amines (Equation 4.7),
however the required intermediate salts are very hygroscopic
[63JOC302], [71AG(E)330].
COCl? + 2 R^MgX 1
hconr2 -> ci-ch=nr2 cl > r2ch-nr2
(Eq. 4.7)
In view of the continuous interest in the physiological
properties of amines ([59BP814152 ] , [61MI2], [62BEP617762],
[63AP728], [79MI1], [87AG(E)320]), new general methods for
their preparation are of considerable significance. Within
the context of researching the chemistry and properties of
benzotriazole derivatives, the possibility of converting the
benzotriazole adducts (4.2) into a variety of tertiary
amines was investigated.
4.2 Results and Discussion
4.2.1 Preparation of Benzotriazole Adducts
Adducts of type (4.2), as previously shown in Chapters 2
and 3, exist in solution as mixtures of the benzotriazol-
1-yl and benzotriazol-2-yl adducts. The preparation of
compounds of the type (4.2, R^ = H) i.e. derived from
formaldehyde was reported in Chapter 2. The corresponding
adducts (4.2, R^ * H), i.e. derived from higher aldehydes

78
were prepared by the azeotropic distillation of the water
produced from a benzene solution containing benzotriazole,
an amine and an aldehyde (Scheme 4.1) in equimolar amounts,
as was fully described in Chapter 3. The benzene solutions
could be used to react directly with preformed Grignard
reagents. Alternatively, the adducts could be isolated,
purified and characterized prior to their reaction with the
Grignards, although somewhat lower overall yields were then
observed, due to unavoidable loses during the isolation
step.
An alternative method of preparation of the adducts
under milder conditions was also tested. Thus, the three
starting materials (Scheme 4.1) were mixed in dry
tetrahydrofuran (THF) in the presence of drying agents
(Na2S0^/MgS0^) and stirred at room temperature for 1-2 days
[76JCS(P2)741]; however with this method it was difficult
to decide at which point the reversible reaction leading to
(4.2) (Scheme 4.1) was complete. Grignard reactions using
the THF solutions thus obtained, did provide the expected
amines (4.3) but the yields were low and byproducts,
resulting from reaction of the Grignard reagents with the
starting aldehyde [eg. PhCH-^CH ( OH) Ph from PhCHO and
PhCH2MgCl], were detected by GLC/MS. Therefore the
azeotropic distillation described above, remained the method
of choice.

79
4.2.2 Preparation of Tertiary Amines
The Grignard reagents, prepared conventionally in ether,
reacted very rapidly, and with evolution of heat, with the
adducts (4.2) yielding tertiary amines (4.3) by replacement
of benzotriazole (Scheme 4.1, Table 4.1). Amines
(4.3a)-(4.3f) were prepared using THF solutions of the
isolated adducts (4.2a)-(4.2d). Advantageously, adducts
(4.2e)-(4.2i) were not isolated and the benzene solutions
from the azeotropic distillation were reacted directly with
the Grignard reagents; the overall yields were then very
good.
The reactions were generally complete within one hour.
The free benzotriazole, obtained after hydrolysis of the
reaction mixture, was easily removed by basic extraction (2N
NaOH). Byproducts originating from coupling of the Grignard
reagents were routinely observed and were removed either by
chromatography or by acid extraction of the amine and
neutralization of the obtained salt.
Although Grignard reactions are sensitive to steric
effects [84M11] neither retardation of the reaction rate nor
side products were observed during the reaction of the
dibenzylamine/isobutyraldehyde adduct (4.2f) with
methylmagnesium iodide, in which the transition state is
expected to be sterically crowded.
In a similar fashion, sodium borohydride reduction of
the adducts (4.2a), (4.2c), (4.2f) and (4.2i) proceeded very
smoothly to afford amines (4.3m)-(4.3p). The reduction

80
Table 4.1 Preparation of tertiary amines (4.3) R^R3CHNR^R2
Add.
4.2
R1
R2
R3
Reagent
4
R Amine
4.3
Yield
(%)
a
CH2Ph
CH2Ph
H
PhMgBr
Ph
a
83
a
CH2Ph
CH2Ph
H
PhCH2MgCl
CH2 Ph
b
88
a
CH2Ph
CH2Ph
H
MeMgl
Me
c
80
b
n CgH17 n CgH17
H
PhMgBr
Ph
d
58
c
CH3
Ph
H
BunMgBr
Bun
e
74
d
Et
Et
H
PhCH2MgCl
CH2Ph
f
91
e
- Pr1
PhCH2MgCl
CH2Ph
g
76a
e
-4-
Pr1
PhMgBr
Ph
h
64a
f
CH2Ph
CH2Ph
Pr1
MeMgl
Me
i
7 8a
g
-(ch2)5-
Ph
Pr1MgBr
Pr1
j
59a
h
-(ch2]
i20(CH2)2
Prn
PrnMgBr
Prn
k
79a
i
- i20(CH2I2
Ph
BunMgBr
Bu11
1
82a
c
ch3
Ph
H
NaBH4
H
m
82
a
CH2Ph
CH2Ph
H
NaBH^
H
n
75
f
CH2Ph
CH2Ph
Pr1
NaBH4
H
o
83
i
-(CH2)20(CH2)2-
Ph
NaBH4
H
P
91
a This
is the overall yield, as
calculated from
starting
benzotriazole;
the other
numbers in this column,
represent
yields of the alkylations and reductions, as calculated from
the corresponding adduct (4.2).

81
conditions reported here (simply stirring at room
temperature) are milder than those reported for reduction of
adducts derived from primary aromatic amines [87JCS(Pi)805].
Table 4.1 shows that the products were obtained in
generally high yields. The diversity in the structures of
the products is also reflected in this Table, in which
examples of aliphatic (4.3k), or aromatic (4.3e) amines,
simple (4.3m) or sterically crowded (4.3i), bearing short
(4.3f) or long (4.3d) aliphatic groups, are collected.
It is not certain whether the Grignard or sodium
borohydride reactions proceed via the iminium ion inter¬
mediates, invoked in Chapters 2 and 3. The concentration of
these reactive intermediates in the solution may be
negligible in some cases. On the other hand, the reagents
used are reactive nucleophiles, and benzotriazole itself a
good leaving group. In addition, no difference in
reactivity was displayed among the various adducts toward
reactions with the organometallic reagents, although the
reactions were fast and slight differences could not have
been detected. If indeed an iminium ion is involved, then
Grignard addition must be preceded by benzotriazole
elimination catalyzed by magnesium acting as a Lewis acid
(Scheme 4.2) [84MI1]. The ability of benzotriazole to form
complexes with a number of metals is well documented
[81ACS(A)739], [83ICA109]. An alternative, but less likely
mechanism, is an SN2 type process, in which the departure of
benzotriazole, aided by coordination with the metal, and the
nucleophilic attack occur simultaneously.

82
Scheme 4.2
Independent evidence for the activating role of benzo-
triazole has been reported previously [87JCS(Pi)805] in the
reduction of a bis(benzotriazoly1)aminoalkyl adduct, in
which only the Bt group a- to the amine was replaced by
hydride (Scheme 4.3).

83
Scheme 4.3
All amines were characterized as their picrate salts and
1 13
by their H- and C-NMR spectra (see Experimental section).
Chemical shift nonequivalency of the methyl groups of the
isopropyl moiety adjacent to the asymmetric carbon atom was
i 1 3
observed in the H- and C-NMR spectra of (4.3g), (4.3h),
and (4.3i). Thus, the methyl groups appeared as two
doublets in the ^H- and as two distinctly different signals
13
m the C-NMR spectra. In spite of their slight
complexity, assignments of all spectra were generally
possible.
Many of these amines are either novel compounds or found
only in the patent literature where they have received
considerable interest due to their physiological activity
(central nervous system stimulants, antihypertensives,
spasmolytics, etc.) [59BP814152 ] , [61GP1093799 ] , [61MI2],
[62BEP17762], [63AP728], [85JAP60258145], [87AG(E)320].

84
4.3 Conclusions
The work described in this Chapter, demonstrates the
synthetic utility of benzotriazole adducts in alkylation and
reduction reactions, in which facile displacement of the Bt-
moiety leads to tertiary amines. The present method has
many advantages over other literature methods, including
simplicity of procedure, readily available starting
materials, possibility for one-pot reaction and good yields.
Benzotriazole acts as both an activating and a leaving group
and can be recycled at the end, for large scale
preparations.
4.4 Experimental
4.4.1 Methods and Reagents
Melting points were determined on a hot stage
microscope and are uncorrected. ^H-NMR spectra were
recorded on a Varian XL 200 spectrometer, using TMS (6 = 0.0
1 3
ppm) as internal reference. C-NMR spectra were recorded
either on JEOL FX-100 (25 MHz), or Varian XL 200 (50 MHz)
instruments as solutions in deuterochloroform (CDCl^), using
the solvent signal at 5 = 77.00 ppm as reference.
Exact mass spectra were recorded on a AEI MS 30 mass
spectrometer. Combustion analyses were carried out using a
Carlo Erba 1106 elemental analyser, under the supervision of
Dr. King of this department, or by the Atlantic Microlab.

85
GLC was carried out on a Hewlett Packard 5890A
instrument using a 5 m HP-1 column (conditions: initial
temperature = 70°C; initial time = 0 min; rate = 15
deg./min; final temperature = 250°C).
Tetrahydrofuran (THF) and diethyl ether (Et20) were
distilled under nitrogen from sodium/benzophenone
immediately before use. Thiophene free, reagent grade
benzene (obtained from Fisher Scientific) was used without
further drying (0.02 ppm H2O). Silica gel (230-400 mesh)
was purchased from Merck.
4.4.2 Preparation of N-[(«-Benzotriazol-N-yl)alkyl]~
N,N-dialkylamines
The preparation of compounds (4.2a)-(4.2c) was based
on a general literature procedure [46JA2496] which was
described in Chapter 3, with modifications according to the
particular compound, as specified below.
N-[(Benzotriazol-N-yl)methyl]-N,N-dibenzylamine
(4.2a). Benzotriazole (0.1 mol, 11.9 g), dibenzylamine
(0.11 mol, 21.1 ml) and 37% aq. formaldehyde (0.12 mol, 9.7
ml), were mixed in methanol (45 ml). The resulting two-
layer system was stirred vigorously at room temperature for
8 h. Diethyl ether was added to homogenize the mixture, and
the whole was heated under reflux overnight to complete the
reaction. The mixture was then poured on crushed ice,
diethyl ether was added and the mixture stirred, resulting

86
in formation of a white solid. N-[(Benzotriazol-N-
yl)methyl]-N,N-dibenzylamine was collected by filtration as
white microcrystals (95%), m.p. 120-122°C (from 95%
ethanol); lit. [75JCS(Pi)1181] m.p. 121-123°C; (CDCl3,
200 MHz) 8.07-8.02 (d, J = 9 Hz, H-4, 1-isomer), 7.96-.91
(AA' m, J = 8 Hz, H-4, H-7 of 2-isomer), 7.47-7.25 (m,
phenyl protons and H-5, H-6 of both isomers), 5.50 (s,
NC^N, 2-isomer), 5.40 (s, NCH2N, 1-isomer), 3.79 (s,
NCi^Ph, 2-isomer), 3.74 (s, NCH2Ph, 1-isomer); (CDCl^,
25 MHz) 145.3 (C-3a, Bt), 137.7 (C-ipso, Ph), 133.7 (C-7a,
Bt), 128.7 (C-o, Ph), 128.3 (C-p, Ph), 127.0 (C-m, Ph),
125.3 (C-5 or C-6, Bt), 123.5 (C-6 or C-5, Bt), 119.5 (C-4,
Bt), 109.7 (C-7, Bt), 64.0 (NCH2N), 55.6 (NCH2Ph) of the
1-isomer; 143.2 (C-3a, C-7a), 138.1 (C-ipso, Ph), 128.9 (C-
o, C-p, Ph), 127.0 (C-m, Ph ), 126.0 (C-6, C-5, Bt), 118.2
(C-4, C-7, Bt), 72.0 (NCH2N), 55.4 (NCH2Ph) of the 2-isomer.
N-[(Benzotriazol-N-yl)methyl]-N,N-dioctylamine (4.2b).
Benzotriazole (0.1 mol, 11.9 g) was dissolved with stirring
in methanol (45 ml) and then N,N-dioctylamine (0.11 mol,
26.56 g) was added, followed by 37% aq. formaldehyde (0.12
mol, 9.7 ml). A two layer system resulted which still
contained starting materials after 7 h of stirring (TLC on
silica gel; eluted with EtOAczCHCl^, 1:1 v/v). The mixture
was made homogeneous with Et20 and heated under reflux
overnight. It was then poured on ice (100 g), extracted
with Et20 (5 x 40 ml), the extracts dried (MgSO^), the

87
solvent evaporated and the residue heated .in vacuo (10 mm
Hg, 24 h; 1.5 mm Hg, 1 h), to give an almost colorless thick
oil in quantitative yield (38 g). The oil decomposed on
attempted distillation (150°C at 0.25 mm Hg). The
analytical sample was obtained by drying a small amount of
the oil under 10 mm Hg, over P2®5 78°C for 5 days (Found,
C, 74.07 ; H, 10.85; 14.94%. C23H40N4 rec3uires > C' 74.14; H,
10.82; N, 15.04%); (CDCl,, 200 MHz) 8.08-8.03 (dd, J =
8, 1 Hz, H-4, Bt, 1-isomer), 7.91-7.86 (AA' m, J = 7 Hz, H-
4, H—7, Bt, 2-isomer), 7.62-7.29 (m, H-5, H-6, Bt, both
isomers), 5.59 (s, NCH2N, 2-isomer), 5.48 (s, NCH2N,
1-isomer), 2.61-2.54 (t, J = 8 Hz, 4 H, NCH2CH2, both
isomers), 1.56-1.48 (m, 4 H, NC^CI^, both isomers), 1.25
(m, methylene groups, 20 H, both isomers), 0.88 (m, 6 H,
CH^, both isomers); &c (CDCl^, 25 MHz), 145.6 (C-3a), 133.6
(C-7a), 126.9 (C-5, or C-6), 123.3 (C-6 or C-5), 119.5 (C-
4), 109.7 (C-7), 66.2 (NCH2N), and octyl group carbons, 51.7
(NCH2), 31.6, 29.2, 29.1, 27.3, 26.9, 22.9, 13.8 (CHj) of
1-isomer; 143.9 (C-3a, C-7a), 125.7 (C-5,6), 118.0 (C-4,5),
73.2 (NCH2N), and octyl group carbons 51.7, 31.6, 29.2,
29.1, 27.3, 26.9, 22.9, 13.8, of the 2-isomer.
N-[(Benzotriazol-N-y1)methyl]-N-methylaniline (4.2c).
The product was prepared according to literature methods
[75JCS(Pi)1181] and was collected as white needles (64%),
m.p. 72-75°C (from diethyl ether/hexane, 10:1, v/v); lit.
[75JCS(Pi)1181] m.p. 76-78 °C; §H (CDCl3 , 200 MHz) 7.98-7.93

88
(d, J = 8 Hz, H-4, 1-isomer), 7.89-7.83 (AA' m, J = 7 Hz, H-
4 and H-7, 2-isomer), 7.33-7.25 (m, phenyl groups, both
isomers), 7.33-7.25 (m, benzotriazole protons, both iso¬
mers), 6.15 (s, NCH2N, 2-isomer), 6.13 (s, NCH2N, 1-isomer),
3.30 (s, NCH^, 2-isomer), 3.01 (s, NCH^, 1-isomer); &c
(CDC13, 25 MHz) 147.7 (C-ipso, Ph), 146.0 (C-3a, Bt), 133.0
(C-7a, Bt), 129.3 (C-o, Ph), 127.3 (C-5 or C-6, Bt), 123.8
(C-6 or C-5, Bt), 119.9 (C-p, Ph), 119.1 (C-7, Bt), 115.1
(C-m, Ph), 110.0 (C-4, Bt), 66.7 (NCH2N), 37.4 (Me) of
1-isomer, and 144.0 (C-3a and C-7a, Bt), 129.1 (C-o, Ph) ,
126.7 (C-5, C-6, Bt), 120.0 (C-p, Ph), 118.2 (C-4, C-7, Bt),
113.6 (C-m, Ph), 72.6 (NCH2N), 38.7 (NCH3) of 2-isomer.
The preparation and spectroscopic data of N-[(benzo-
triazol-N-yl)methyl]-N,N-diethylamine (4.2d) was described
in Chapter 2 (compound 2.6), and of N-[a-(benzotriazol-N-
yl ) -3-methylpropyl ] pyr rol idine (4.2e), N-[a-(benzotriazol-N-
yl) - (3-methyl propyl ] -N, N-di benzyl amine (4.2f), N-[a-(benzo-
triazol-N-yl)benzylJpiperidine (4.2g), N-[a-(Benzotriazol-N-
yl)benzylJmorpholine (4.2) were described in Chapter 3
[compounds (3.8), (3.14), (3.14), and (3.10), respectively].
N-[«-(Benzotriazol-N-yl)butyl]morpholine (4.2h). The
compound was prepared using the general method described in
Chapter 3, for compounds (3.1, * H). After evaporation
of solvent benzene under reduced pressure, an oily substance
was recovered which was dried under 0.2 mm Hg for several

89
days. N-1 a-(Benzotriazol—N-yl)butyl]morpholine was
characterized by its ^H- and 13C-NMR spectra: (toluene-
dg, 300 MHz) 8.00 (d, J = 8 Hz, H-4, 1 isomer), 7.87-7.84
(AA' m, J = 7 Hz, H-4,7, 2-isomer), 7.15 (d, J = 8 Hz, H-7,
1-isomer), 7.14-7.08 (m, all other ring protons), 5.21 (t, J
= 6 Hz, NCHN, 2-isomer), 4.93 (t, J = 6 Hz, NCHN, 1-isomer),
3.44 (m, OCH2, both isomers), 2.39 (t, J = 4 Hz, CH2N, 2 H,
both isomers), 2.30 (t, J = 4 Hz, CH2N, 2 H, both isomers,
overlapping with signals of the aliphatic chain), 2.10 (m, 2
H, CH2CH3, both isomers), 0.88 (t, J = 6 Hz, 3 H, C^CHg,
both isomers); §c (CDClg, -20°C, 25 MHz) 1-isomer, 145.0
(C-3a), 133.5 (C-7a), 127.1 (C-5 or C-6), 123.7 (C-6 or C-
5), 109.7 (C-7), 78.7 (NCH2N), 66.5 (OCH2), 47.9 (CH2N),
32.6 (NCHCH2CH2), 18.6 (NCHCH2CH2), 13.3 (CHg); 2-isomer,
143.1 (C-3a, C-7a), 126.0 (C-5,6), 117.9 (C-4,7), 85.7
(NCHN), 66.6 (OCH2), 48.4 (CH2N), 32.8 (NCHCH2>, 18.8
(NCHCH2CH2), 13.3 (CH3).
4.4.3 Preparation of Tertiary Amines by Alkylation:
Two-Step Procedure-
General method. The Grignard reagent was prepared
from magnesium turnings (0.0114 mol) and the alkyl or aryl
halide (0.0114 mol) in dry diethyl ether (10 ml). To this
solution, the benzotriazole adducts (4.2a)-(4.2d) (0.004
mol) dissolved in dry THF (20 ml) were added dropwise.
Immediate frothing and evolution of heat was observed, and
reflux was sustained by slow addition. The mixture was
heated under reflux for 1 h and then poured on crushed ice

90
(100 g), and stirred with aq. sat. ammonium chloride (20-50
ml) and/or IN HCl (10 ml) until all solids dissolved.
Extraction with ether (3 x 40 ml), washing with 2N NaOH
(until TLC showed no presence of benzotriazole), drying
(MgSO^) and removal of the solvent under reduced pressure
afforded the crude product which was purified as described
for each particular compound. The oily products were
characterized as their picrate salts, which were all
prepared in and recrystallized from 95% ethanol.
Tribenzylamine (4.3a). Recrystallization of the crude
material removed the byproduct biphenyl and afforded
tribenzylamine (4.3a) as white flakes (83%), m.p. 91-93°C
(from 95% ethanol), lit. m.p. 91-94°C (commercially
available from Aldrich Chemical Company); Su (CDCl,, 200
MHz) 7.39-7.14 (m, 15 H, aromatic), 5.51 (s, 6 H, Ph-CH2);
Sc (CDC13, 50 MHz) 139.6 (C-ipso), 128.7 (C-o), 128.2 (C-p),
126.8 (C-m), 57.8 (Ph-CH2).
N,N-Dibenzyl-N-phenylethylamine (4.3b). The product
was obtained as a very clean (as shown by its NMR spectra)
pale yellow oil (88%), b.p. 180-185°C (at 0.5 mm Hg); lit.
[47JOC760] b.p. 206-211°C (at 3 mm Hg); 6U (CDCl,, 200 MHz)
7.28-7.02 (m, 15 H, aromatic), 3.60 (s, NCH2Ph, 4 H),
2.87-2.63 (2m, 4 H, N-CH2CH2Ph); Sc (CDC13, 25 MHz)
aromatic (140.5, 139.6, 128.8, 128.6, 125.7, 126.7), 58.1
(NCH2Ph), 55.0 (NCH2CH2Ph), 33.4 (NCH2CH2Ph). N,N-Dibenzyl-
N-phenylethylamine was characterized as its picrate salt,

91
m.p. 118-120 °C (Found, C, 62.99; H, 4.94; N, 10.36%.
('28H26N4<^7 ret3u:*-res' C> 63.39 ; H, 4.94; N, 10.56).
N-Ethyl-N,N-dibenzylamine (4.3c). Distillation of the
crude afforded the clean product (80%), b.p. 132-136°C (at
0.5 mm Hg); lit. [78S766] b.p. 101-106°C (at 0.35 mm Hg);
(CDCl2> 200 MHz) 7.38-7.17 (m, 10 H, aromatic), 3.54 (s,
4 H, NCH2Ph), 2.53-2.43 (q, J = 7 Hz, 2 H, CH2CH3),
l.07-1.00 (t, J = 7 Hz, 3 H, CH2CH3); §c (CDCl3, 25 MHz)
aromatic (134.0, 128.7, 128.1, 126.7), 57.0 (NCH2Ph), 47.0
(CH2CH3), 11.8 (CH2CH3). N-Ethyl-N,N-dibenzylamine was
converted to its picrate, m.p. 116-118°C; lit. [78S766]
m.p. 110-111°C.
N-Benzyl-N,N-dioctylamine (4.3d). The product was
obtained as a yellow oil, b.p. 110-112°C (at 0.4 mm Hg). A
portion of this oil (0.7 g) was purified by column
chromatography on silica gel [eluent: hexane, hexane:chloro¬
form (7:3 and then 3:7), chloroform]; 0.435 g of oil were
collected (58%) (Found, Mt 331.3253. ^23H41N rec3uires'
331.3238); &H (CDClj, 200 MHz) 7.33-7.17 (m, 5 H,
aromatic), 3.52 (s, 2 H, CH2Ph), 2.42-2.34 (t, J = 7 Hz, 4
H, NCH2CH2), 1.48-1.42 (m, 4 H, NCH2CH2), 1.25 (ap. s, 20 H,
methylene groups), 0.90-0.84 (t, J = 6 Hz, 6 H, CH3); §c
(CDC13, 25 MHz) aromatic (140.2, 128.7, 127.9, 126.6), 58.7
(NCH2Ph), 53.8 (NCH2CH2), methylene groups of N-octyl chain
(31.8, 29.5, 29.3, 27.4, 27.0, 22.6), 14.0 (CH3).

92
N-Methyl-N-pentylani1ine (4.3e). A very clean oil was
obtained (73.5%), b.p. 97-98°C (at 0.8 mm Hg); lit.
[67JOC2892] b.p. 107-108°C (at 4-5 mm Hg); §H (CDClj, 200
MHz) 7.21-6.63 (m, 5 H, aromatic), 3.26-3.19 (t, J = 7 Hz, 2
H, NCH2), 2.84 (s, 3 H, CH3), 1.53 (q, J = 7 Hz, 2 H), 1.29
(m, 4 H), 0.89 (t, J = 6 Hz, 3 H, CH3); §c (CDCl3, 25 MHz)
149.3, 128.9, 115.7, 112.9 (aromatic), 52.6 (NCH2), 38.0
(NCH3), 29.3 (NCH2CH2), 22.5 (NCH2CH2CH2), 14.0 (CHj). N-
Methyl-N-pentylani1ine was converted to its picrate salt,
m.p. 94-96°C (Found C, 52.55; H, 5.41; N, 13.65%.
C18H22N4°7 re<3uires • c» 53.20; H, 5.46; N, 13.79%).
N,N-Diethyl-N-phenylethylamine (4.3f). The oily amine
[23JCS (1)532] (91%, GLC yield) was converted directly to its
picrate, m.p. 90-92°C; lit. [45JCS438] m.p. 93-94°C; NMR
spectra of the oil: (CDC13, 200 MHz) 7.30-7.12 (m, 5 H,
aromatic), 2.69-2.65 (m, 4 H, PhCH2CH2N), 2.60-2.50 (q, J =
7 Hz, 4 H, NCH2CH3), 1.06-0.99 (t, J = 7 Hz, 6 H, NCH2CH3);
Sc (CDC13, 25 MHz) aromatic (140.4, 128.4, 128.1, 126.5),
54.5 (PhCH2CH2N), 46.5 (PhCH2CH2N), 32.9 (NCH2CH3), 11.3
(nch2ch3).
4.4.4 Preparation of Tertiary Amines by Alkylation:
One-step Procedure
General Method. The Grignard reagents (from 0.04 mol
Mg and 0.04 mol halide) in dry diethyl ether (30 ml) were
prepared as in section (4.4.3). Adducts ( 4.2e)-(4.2i)
[(0.033 mol), prepared from benzotriazole (0.033 mol), a

93
secondary amine (0.033 mol) and an aldehyde (0.033 mol) by
refluxing in benzene using a Dean-Stark trap, until the
calculated amount of water (0.6 ml) had been collected, (cf
Chapter 3)] were added dropwise as benzene solutions
(without isolation) to the Grignard reagent. The reaction
mixture was heated under reflux for 2-4 h and worked up as
described in section (4.4.3). For amine (4.3j) half amounts
of all reagents were used. For (4.31) the adduct (4.2i) was
isolated, then dissolved (0.004 mol) in benzene (30 ml) and
added to the Grignard reagent made from the same amounts as
described in section (4.4.3). All amines were characterized
as their picrate salts and purified as detailed below for
each compound.
N-[(g-Benzyl-g-methyl)propyl]pyrrolidine (4.3g). The
product was obtained as a very clean oil (76%, yield
calculated from benzotriazole), b.p. 105-112°C (at 0.3 mm
Hg); lit. [59BP814152] b.p. 88°C (at 0.2 mm Hg); 6U
(CDC13, 200 MHz) 7.30-7.10 (m, 5 H, aromatic), 2.78-2.72 (t,
J = 6 Hz, 2 H, CH2Ph), 2.56-2.49 [m, 4 H, N(CH2CH2)2J,
2.35-1.55 (m, 1 H, Me2CH), 1.72-1.66 [m, 4 H, N(CH2CH2)2),
0.97-0.92 (2d, J = 7 Hz, 6 H, CH3); §c (CDClj, 25 MHz)
aromatic (143.1, 129.5, 128.5, 125.8), 70.5 (NCH), 51.9
(NCH2), 35.4 (CH2Ph), 31.4 (CHMe 2), 24.0 [ (NCH2CH2)2], 20.7
(CH3), 18.4 (CH 3). N-[(a-Benzyl-8-methyl)propyl]pyrrolidine
was derivatized to its picrate salt, m.p. 136-139°C (Found,
C, 56.49; H, 6.02; N, 12.41%. C2^H2gN40^ requires, C,
56.50; H, 5.87; N, 12.55%).

94
N-[(g-Phenyl-g-methyl)propyl]pyrrolidine (4.3h). Part
of the liquid product (0.51 g) was purified by column (2 cm
x 17 cm) chromatography on silica gel packed in chloroform
[eluent: chloroform, chloroform/ethyl acetate (6:2 and then
2:6, v/v), ethyl acetate]; a colorless oil was collected
(0.38 g, 64%, yield calculated from benzotriazole) , b.p.
86-91°C (at 0.25 mm Hg); lit. [62AP728] b.p. 91-98°C (at
0.4 mm Hg); &H (CDCl3, 200 MHz) 7.27-7.23 (m, 5 H,
aromatic), 3.03-3.01 (d, J = 4 Hz, 1 H, NCHN), 2.45-2.41 (m,
2 H, NCH2CH2), 2.28-2.12 (m, 1 H, CHMe2), 1.70-1.68 (m, 2 H,
NCH2CH2), 0.86-0.74 (2d, J = 7 Hz, 6 H, CH3); &c (CDCl3, 25
MHz) aromatic (139.7, 129.4, 127.2, 126.5), 75.6 (NCH), 51.9
(NCH2CH2), 31.4 (CHMe2), 24.0 (NCH2CH2), 20.6 (CH3), 16.3
(CH3). N-[(a-Phenyl-6-methyl)propyl]pyrrolidine was
converted to its picrate salt, m.p. 129-132°C (Found, C,
55.58; H, 5.50; N, 12.83%. ('20H24N4^7 rec3uires C, 55.55; H,
5.59; N, 12.96%).
N-[(a,g-Dimethyl)propyl]-N,N-dibenzylamine (4.3i).
The crude material contained a small amount of dibenzyl-
amine, which was removed by treating the ethereal extracts
with cone. HCl. The white precipitate was filtered and the
filtrate was washed with aq. 2N NaOH until neutral to pH
paper, and then until the organic layer was free of benzo-
triazole (by TLC). After evaporation of the solvent, and
drying, the product was collected as a very clean oil (78%,
yield calculated from benzotriazole), b.p. 125-150°C (at 0.2
mm Hg); (CDCl3, 200 MHz) 7.40-7.24 (m, 10 H, aromatic),

95
3.80-3.73 (d, J = 14 Hz, 2 H, CH2Ph), 3.34-3.27 (d, J = 14
Hz, 2 H, CH2Ph), 2.30-2.16 (dq, J = 7 Hz, J = 1 Hz, 1 H,
NCHMe), 1.75-1.63 (m, 1 H, CHMe2 ), 1.03-0.96 [2d, J = 8 Hz,
6 H, CH(CH3)2), 0.81-0.77 (d, J = 6.5 Hz, 3 H, NCHCH3); &c
(CDC13, 25 MHz) aromatic (140.7, 128.8, 128.0, 126.5), 56.0
(NCHMe), 53.7 (NCH2Ph), 31.7 (CHMe2), 21.1 [CH(CH3)CH3],
20.6 [CH(CH3)CH3] , 9.6 [NCH(Pr1)CH3]. N-[ (a, 13-
Dimethyl ) propyl ]-N,N-dibenzylamine was converted to its
picrate salt, m.p. 124-127°C (Found, C, 60.20; H, 5.84; N,
11.09%. C25H28N4°7 re(3u*res > C' 60.48 ; H, 5.68; N, 11.28%).
N-[(g-Methyl-g-phenyl)propyl]piperidine (4.3j). After
distillation the clean product was an oil (59%), b.p.
107-112 °C (at 0.8 mm Hg); §H (CDC13 , 200 MHz) 7.27-7.08 (m,
5 H, Ph), 2.98-2.93 (d, J = 9 Hz, 1 H, PhCHN), 2.33-2.19 (m,
4 H, NCH2), 2.19 (overlapping with the previous signal, 1 H,
CHMe2), 1.57-1.47 (m, 4 H, NCH2CH2), 1.33-1.02 (m, 2 H,
NCH2CH2CH2), 1.02-0.99 [d, J = 6.5 Hz, 3 H, CH(CH3)CH3],
0.71-0.68 [d, J = 7 Hz, 3 H, CH(CH3)CH31; &c (CDC13, 25
MHz) aromatic (138.2, 129.0, 128.1, 127.4), 77.0 (NCHPh),
50.8 (NCH2), 28.0 (CHMe2), 26.0 (NCH2CH2CH2), 24.9
(NCH2CH2CH2 ) , 20.7 [ CH( CH3 )CH3 ] , 19.6 [ CH ( CH3 ) CH3 ] . N- [((3-
Methyl-a-phenyl)propyl]piperidine was converted to its
picrate salt, m.p. 157-159°C (Found, C, 56.12; H, 5.90; N,
12.26%. ('21H26N4<^>7 rec3u^-res' C, 56.50 ; H, 5.87; N, 12.55%).
N-Isoheptylmorpholine (4.3k). The product was
collected as a very clean oil (79%, yield calculated over

96
two steps), b.p. 71-74°C (at 0.6 mm Hg); (CDCl^, 200
MHz) 3.69-3.65 (t, J = 4 Hz, 4 H, CH20), 2.52-2.48 (t, J = 4
Hz, 4 H, CH2N), 2.33-2.27 (t, J = 6.5 Hz, 1 H, NCH),
l.50-1.16 [m, 8 H, NCH(CH2)2], 0.93-0.86 (t, J = 4 Hz, 6 H,
CH3); Sc (CDC13, 50 MHz) 67.6 (OCH2), 63.6 (NCHN), 51.0
(NCH2), 32.1 (NCHCH2), 20.2 (CHCH2£H2), 14.3 (CH3). N-
Isoheptylmorpholine was characterized as its picrate salt,
m.p. 115-116.5°C (Found, C, 49.01; H, 6.54; N, 13.02%.
<"17H26N4^8 rec3uires' C, 49.27; H, 6.32; N, 13.52%).
N-[a-(Phenyl)butyl]morpholine (4.31) . The product was
collected as a very clean oil (82%, yield calculated over
two steps), b.p. 120-121°C (at 0.6 mm Hg); 8H (CDC13, 200
MHz) 7.28-7.18 (m, 5 H, aromatic), 3.67-3.61 (m, 4 H, OCH2),
3.21-3.14 (dd, J = 9 Hz, J = 2 Hz, 1 H, NCHPh), 2.41-2.34
(m, 4 H, CH2N), 1.88-1.83 (m, 1 H, CHHCHPh), 1.72-1.64 (m, 1
H, CHHCHPh), 1.26-1.19 (m, 2 H, CH2), 1.11-1.03 (m, 2 H,
CH2), 0.84-0.76 (t, 3 H, CHj); &c (CDCl3, 25 MHz) aromatic
(140.7, 128.4, 127.9, 126.8), 70.5 (NCHPh), 67.1 (CH20),
51.0 (CH2N), 32.1 (PhCHCH2), 20.2 (CH2), 13.8 (CH3). N-[ a-
(Phenyl)butyl]morpholine was characterized as its picrate
salt, m.p. 161-162°C (Found, C, 54.20, H, 5.93, N, 11.93%.
^21H26N4^8 «quires, C, 54.54; 5.67; 12.11%).
4.4.5 Preparation of Tertiary Amines by Reduction
General method. The adducts (4.2c) (0.01 mol), (4.2b)
(0.003 mol), (4.2f) (0.001 mol) and (4.2i) (0.003 mol) in

97
THF (20 ml, 20 ml, 10 ml and 15 ml, respectively) were each
stirred at room temperature with 1 mol equivalent of NaBH^
for 15 h. The reaction was quenched with a small amount of
ice (5 g - 15 g), the product extracted with Et20, dried
(MgSO^) and the solvent was removed under vacuum to give the
amines as oils. They were characterized as picrate salts,
which were prepared and recrystallized from 95% ethanol.
N,N-Dimethylaniline (4.3m). It was obtained as an oil
(82%), b.p. 192-193°C (at 760 mm Hg), and characterized by
comparison with a commercially available sample [b.p.
193-4 °C (at 760 mm Hg)]; &H (CDCl3 , 200 MHz) 7.23-7.15 (m,
5 H, aromatic), 2.82 (s, 6 H, CH^); ¿c (CDCl^, 25 MHz)
aromatic ( 150.4, 128.8 , 116.5, 112.8), 40.5 (CH 3)-
N-Methyl-N,N-dibenzylamine (4.3n). After distillation
an oily product was collected (75%), b.p. 134-135°C (at 0.7
mm Hg); lit. [76CPB342] b.p. 114-115°C (at 2 mm Hg); 8„
(CDCl3) 7.35-7.15 (m, 10 H, aromatic), 3.51 (s, 4 H, CF^Ph),
2.16 (s, 3 H, CH3); &c (CDC13) aromatic (138.8, 128.9,
128.1, 126.9), 61.6 (CH2Ph), 42.0 (CH3). N-Methyl-N,N-
dibenzylamine was characterized as its picrate salt, m.p.
105-108°C; lit. [76CPB342] m.p. 101-103°C.
N-(g-Methylpropyl)-N,N-dibenzylamine (4.3o). A clean
oily product was collected (83%), b.p. 132°C (at 0.3 mm Hg);
SH (CDC13, 200 MHz) 7.38-7.18 (m, 10 H, aromatic), 3.50 (s,
4 H, CH2Ph), 2.16-2.13 (d, J = 7 Hz, 2 H, NCH2), 1.91-1.75

98
(m, 1 H, CHMe2), 0.87-0.84 (d, J = 7 Hz, 6 H, CH3); &c
(CDC13, 25 MHz) 139.9, 128.8, 128.0, 126.7, 62.2 (NCH2Ph),
58.8 [NCH2( Pr1 ) ] , 26.1 ( CHMe2 ) , 20.8 (CH3). N-( f3-Methyl-
propyl)-N,N-dibenzylamine was converted to its picrate salt,
m.p. 132-135°C (Found, C, 59.53; H, 5.07; N, 11.93%.
C24H26N4°7 rec3uires' C, 59.74; H, 5.43; N, 11.61%).
N-Benzylmorpholine (4.3p). A clean oil was obtained
(91%), lit. [67JOC272] b.p. 252°C (at 760 mm Hg); Su
(CDC13, 200 MHz) 7.30-7.15 (m, 5 H, aromatic), 3.65-3.60 (t,
J = 5 Hz, 4 H, CH20), 3.39 (s, 2 H, CH2Ph), 2.38-2.33 (t, J
= 5 Hz, 4 H, CH2N); (CDCl3, 50 MHz) aromatic (137.3,
128.7, 127.8, 126.7), 66.4 (CH20), 62.9 (CH2Ph), 53.1
(CH2N). N-Benzylmorpholine was converted to its picrate
salt, m.p. 186-189 °C; lit. [67JOC272 ] m.p. 188-190°C.

CHAPTER 5
A NEW GENERAL SYNTHESIS OF TERTIARY
PROPARGYLAM1NES
5.1 Introduction
Alkylations of N-[a-(benzotriazol-N-yl)alkyl]-N,N-
dialkylamines via Grignard reactions were described in the
previous chapter. Given the ease by which these reactions
took place, alkylations with other organometallic reagents
should also occur readily. Organolithium reagents in
general should react, and lithium acetylenides in
particular, are expected to replace benzotriazole by an
alkynyl group. This part of the research was also expected
to test the effect of a different metal and the
compatibility of the reaction conditions with the alkynyl
group. The resulting products should be tertiary amines
bearing a triple bond 8- to the nitrogen atom
(propargylamines).
Tertiary propargylamines constitute a class of
compounds of great pharmacological importance, as reflected
by a plethora of reports in the medicinal literature
[70MI1]. N,N-Disubstituted-l-ary1-3-aminopropynes (5.1)
show antiulceration, sedative and antispasmodic effects on
smooth muscles, and analgesic-antiinflammatory properties
[67BP1055548]. N-(Aminoalkynyl)substituted succinimides and
99

100
maleimides compose a class of central anticholinergic agents
[70JMC651]. N,N-Dialkyl-N-(prop-2-ynyl)amines, commonly
called "pargylines" (5.2), have been evaluated ^n vitro and
in vivo. Thus, N-methyl-N-propargyl-N-benzylamine
irreversibly inhibits aldehyde dehydrogenase by oxidative
depropargylation to propionaldehyde [79JMC463], while N-
(phenylpropyloxy)pargylines showed marked antidepressant
activity in severely depressed patients [79MI3]. Finally,
compounds possessing the 1,3-enyne structure are
biologically active analogues of the important antimycotic
terbinafine (5.3), which interferes by squalene epoxidase
inhibition in the biosynthesis of ergosterol, a constituent
in the cell membranes of fungi [87AG(E)320].
Ar
â– H
5.1
5.2
5.3

101
The biological action of these compounds is thought to
be due, at least in part, to the corresponding N-oxides,
which are thermally unstable and undergo isomerization to 0-
allenylhydroxylamines [80OMR161], [810MR285]. Scheme 5.1
illustrates the Meisenheimer-type rearrangement.
o~
1+ A
R2-N1CH2-ChC-H > R2N-0-CH=C=CH2
Scheme 5.1
A number of methods exists for the preparation of
tertiary propargylamines. Mannich reactions of an
arylacetylene with formaldehyde and a secondary amine
[33CB418], [73S703], sometimes with a catalytic amount of
copper(ll) acetate and copper(I) chloride or iodide
[67BP1055548], [70JMC651], [78JMC253] give good yields, but
are limited to compounds in which the triple bond and N-atom
are connected by a methylene group (Equation 5.1). The same
compounds can be obtained from reactions of propargyl
bromide with secondary amines to give 3-unsubstituted
propargylamines [80OMR161], [810MR285], [87JCR(S)184].
Ar—C=C—H + CH20 + HNR2 > Ar-CsC-CH2-NR2 (Eq. 5.1)
Aryl iodides couple with copper acetylenides [78JMC253]
to afford propargyl alcohols which are then converted to

102
propargylamines in two additional steps, making the method
rather tedious (Equation 5.2).
Py H+
ArI + Cu-C=C-CH2OTHP > Ar-CsC-CH2OTHP > Ar-C=C-CH2OH
PBr, hnr2
-> Ar-C=C-CH2Br -> Ar-C=C-CH2NR2 (Eq. 5.2)
According to a recent publication [87JOU1198], aminals
react with phenylacetylene in the presence of copper(I)
halides to give 3-substituted propargylamines. The scope of
this reaction is, however, limited to 3-aryl substituents
[72TL3607] (Equation 5.3).
CuX
R9N-CH(Ar)-NR9 + Ph-C=C-H > Ph-CsC-CH(Ar)-NR9
Z (Eq. 5.3)
3-Substituted propargylamines are produced in base
catalyzed rearrangements of allylpropynyl cations, however
these reactions are not of synthetic interest
[80JCS(PI)1463].
Following new directions in studying the reactivity and
versatility of benzotriazole derivatives as synthons (see
previous Chapter), the possibility of devising a general
methodology for the synthesis of both simple and 3-substi-
tuted tertiary propargylamines was investigated.
5.2 Results and Discussion
As discussed in Chapter 2, N-[(benzotriazol-N-
2
yl)methyl]-N,N-dialkylamines (5.4, R = H), are readily

103
available in almost quantitative yields by reaction of
benzotriazole, formaldehyde and the appropriate secondary
amine. The corresponding N-[a-(benzotriazolyl)alkyl]-N,N-
2
dialkylamines (5.4, R t H) can be prepared if another
aldehyde is used instead of formaldehyde, as described in
Chapters 3 and 4. These latter compounds, need not be iso¬
lated: the benzene solutions (see Chapter 4) can be used to
react directly at ambient temperature with an equimolar
amount of an acetylene lithium salt, prepared _in situ by
reaction of alkyl- or arylacetylenes with n-butyllithium, to
give high yields of the propargylamines (5.5) in an essen¬
tially one-pot procedure (Scheme 5.2, Table 5.1).
Satisfactory purity of the products was achieved by
simply washing the reaction mixture with IN sodium hydroxide
solution and water, and in some cases passing the resulting
oil through a silica gel column. Examples (5.5i)-(5.5n) of
Table 5.1 demonstrate that starting from an aldehyde, a
secondary amine and an acetylene, the corresponding pro¬
pargylamines can be obtained in very good overall yields
without isolation of the intermediates (5.4). Products
(5.5a)-(5.5g) and (5.5i) were characterized as their picrate
salts. Except for (5.5b), (5.5c) and (5.5f) all are novel
1 13
compounds. In all cases, comparison of the H- and C-NMR
spectra to those of structurally similar compounds reported
in the literature [80OMR161], [87SA(A)1121], aided the
complete characterization of the amines. Specifically, the

104
hnr'r'
+
+ r2cho
I
R3-C-C-Li
v
R3
I
5.5a - 5.5c,h
(R2 = H)
5.5d - 5.5g
5.5i - 5.5n
(R2 = alkyl or aryl)
Scheme 5.2

105
3 2 1
Table 5.1. Preparation of propargylamines R jC=C-CHR -NR?
(5.5) from benzotriazole adducts Bt-CH(RZ)-NR^ (5.4).
Add.
5.4
â„¢2
R2
R3
Amine
5.5
Yield
(%)
m.p.
(pier.)
a
N(CH2 Ph ) 2
H
Ph
a
75
a, b
172-174
b
n(ch2ch2)2
H
Ph
b
73
a, b
154-157
c
NMe2
H
Ph
c
79
a, b
115-118
d
N(CH2CH2 ) 2
Pr1
Ph
d
67
a, b
116-118
e
N(CH2Ph)2
Pr1
Ph
e
95
b
130-132
f
N(CH2CH2 ) 20
Ph
Ph
f
33
a, c
175-177
e
N(CH2Ph)2
Pri
n-c6Hi3
9
96
b
76-78
9
N«n-C8H17»2
H
n~C4H9
h
90
b
-
h
N(CH2CH2)2CH2
Ph
Ph
i
73
d
157-162e
d
N(CH2CH2)2
Pr1
n-C6Hl3
j
71
d
-
i
N(CH2CH2)20
Prn
Ph
k
76
d
-
i
N(CH2CH2)20
Pr11
n~C6Hl3
1
72
d
-
j
N(CH2CH2)20 n-
"C7H15
Ph
m
97
d
-
j
N(CH2CH2)20 n-
-C7H15
n_C6Hl3
n
81
d
-
The yield refers to the product obtained after column
chromatography. One-step yield Benzalacetophenone was
obtained as the main product in 50% yield. ^ Overall yield
based on starting secondary amine. Reactions without
isolation of the intermediate N-[a-(benzotriazol-N-
yl)-alkyl]-N,N-dialkylamines (5.4) (R2 t H). e The amine
has m.p. 52-55°C (lit. [87JOU1198] m.p. 52-53°C).

106
acetylenic carbon atoms appeared as two weak resonances
13
between 77.0 and 87.0 ppm in the C-NMR spectrum, whereas
2 1
the characteristic ChC-CHR NR£ signals appeared around 50
ppm. In the spectra of compounds bearing two long but not
identical aliphatic chains [e.g. (5.5j), (5.51)] or in cases
where two or more unsymmetrically placed phenyl groups were
present, [e.g. (5.5a), (5.5i)], considerable overlapping of
signals was observed, however the majority of resonances
could be eventually assigned. The ^^C-NMR chemical shifts
are collected in Table 6.2.
1 13
The H-NMR spectra were less descriptive than the C-
NMR spectra. Several multiplets were observed, especially
in compounds with long aliphatic chains. The typical signal
2 1
of the proton a- to the amino group (-CsC-CHR NR£), either
as a singlet or as a multiplet, was however always located
sufficiently downfield from the bulk of the aliphatic peaks
to confirm the correct structure of the compound (see
Experimental).
In a few cases [(5.5h), (5.5j), and (5.5n)], attempted
vacuum distillation led to partial decomposition of the
crude oily amines, as evidenced by additional peaks in the
1 13
H- and C-NMR spectrum. It is possible that air oxidation
of the initially pure products, resulted in partial
formation of the N-oxides, whose facile thermal
rearrangement is known to produce O-allenylhydroxylamines
(see Scheme 5.1), or even acroleins and imines [80TL667].

107
1 3
Table 5.2. - CjNMR Chemical shifts (S) of amines
R -C=C-CH(RZ)NR2 (5.5) in CDCl3.
Amine
5.5
R3
i
n
in
n
i
>CH-
R
2
"NR2
a
131.7, 128.2
85.8
41.9
138.8
, 128.9
127.9, 123.3
84.4
128.2
, 127.0
57.6
ba
131.5, 128.0
85.1
43.6
—
52.4,
23.6
127.7, 123.1
84.2
c
131.3, 127.8
84.9
48.1
—
43.8
127.6, 122.9
84.2
d
131.6, 128.0
87.6
62.3
31.9,
20.1
50.1,
23.5
127.6, 123.6
85.6
19.4
e
131.8, 128.2
87.3
59.7
30.8,
21.0
139.7
, 128.9
86.2
20.0
128.2
, 126.9
55.2
f
131.6, 128.0
88.4
61.8
137.6
, 128.4
49.7,
66.9
127.5, 122.8
84.9
128.0
g
31.2, 29.1
85.6
59.1
30.8,
20.8
139.9
, 128.7
28.4, 22.5
77.0
19.8
128.0
, 126.6
18.6, 14.9
54.8
h
31.0, 21.8
84.8
53.7
—
42.1,
31.8
18.3, 13.5
74.6
29.5,
29.2
27.5,
27.4
22.6,
14.0
i
131.7, 128.2
87.8
62.3
138.6
, 128.2
50.6,
26.1
127.3, 123.3
86.0
127.9
24.4
j
31.3, 29.1
85.3
62.2
31.7,
20.1
23.4,
50.3
28.5, 22.5
77.6
19.0
18.6, 14.0
k
131.6, 128.1
87.0
57.7
34.9,
19.7
49.6,
67.0
127.8, 123.1
86.0
13.7
1
31.2, 29.0
86.0
57.3
35.3,
19.8
49.5,
67.0
28.5, 22.5
77.1
13.8
18.6, 14.0
m
131.5, 128.0
87.0
57.9
32.8,
31.6
49.6,
66.9
127.7, 123.1
85.9
29.2,
29.0
26.4,
22.5
13.9
n
31.2, 28.9
85.9
57.6
33.1,
31.7
49.5,
67.0
28.4, 22.4
77.2
29.2,
29.1
18.5, 14.0
26.5,
22.5
13.9
a Literature data [80OMR161]: 5 131.8, 128.3, 123.6, 85.5,
84.5, 52.7, 43.9, 24.0.

108
5.3 Conclusions
In this chapter, the utility of N-[a-(benzotriazol-N-
yl)alkyl]-N,N-dialkylamines for synthesis was extended to
reactions with lithium acetylenides. A general method of
preparation of tertiary propargylamines was developed, which
was found to be of wide scope and to have virtually no
limitations in the variety of the substituents that can be
introduced. The simple, one-pot procedure and the high
yields of the products, should make the method very useful
for the preparation of propargylamines not readily access¬
ible by previously described methods.
5.4 Experimental
5.4.1 Methods and Reagents
Melting points were measured on a hot-stage apparatus
and are uncorrected. 1H (200 MHz) and 13C- (50 MHz) NMR
spectra were recorded on a Varian XL 200 (FT mode)
spectrometer, using the TMS peak (S 0.00), and the solvent
peak (CDCl^, 6 77.0), respectively as references. Other
methods and reagents were described in Chapter 4.
5.4.2 Preparation of N-[a-(Benzotriazol-N-y1)alkyl]-N,N-
dialkylamines.
The preparation of the following compounds was carried
out as reported previously: N-[(benzotriazol-N-yl)methyl]-

109
N,N—dimethylamine (5.4c) and N-[(benzotriazol-N-yl)methyl]-
pyrrolidine (5.4b), were described in Chapter 2 [compounds
(2.3) and (2.4), respectively]. N-[ a-( Benzot r iazol-N-yl )-|3-
methylpropyl ] pyr rol idine (5.4d), N-[ a-( benzot r iazol-N-yl)-f3-
methylpropyl]-N,N-dibenzylamine (5.4e), N-[a-(benzotriazol-
N-yl ) benzyl ] pipe r idine (5.4h), and N-[a-(benzotriazol-N-
yl )benzyl]morpholine (5.4f), were described in Chapter 3
[compounds (3.8), (3.14), (3.15), and (3.10), respectively],
N-[(Benzotriazol-N-yl)methyl]-N,N-dibenzylamine (5.4a), N-
(benzotriazol-N-yl)methyl]-N,N-dioctylamine (5.4g) and N-[a-
(benzotriazol-N-yl)butyl]morpholine (5.4i) were described in
Chapter 4 [compounds (4.2a), (4.2b), and (4.2h), respec¬
tively] .
N—[a-(Benzotriazol-N-yl)octyl]morpholine (5.4j). The
compound was prepared by refluxing equimolar amounts of
benzotriazole, morpholine and octanal in benzene, until the
theoretical amount of water had been produced (3 days) and
the resulting benzene solution was used directly for
lithiation (see below). The compound was characterized by
its NMR spectra, which showed some line broadening in CDCl^
at room temperature: (CDCl^, 300 MHz) 8.0 (d, J = 7 Hz,
H-4), 7.8-7.2 (br m, all ring protons), 5.43 (m, NCHN,
2-isomer), 5.32 (m, NCHN, 1-isomer), 3.55 (m, OCH2, both
isomers), 2.5 (m, CH2N), overlapping with 2.35 (m, 2 H,
CH2), 1.2 (m, 10 H), 0.75 (m, 3 H); 6C (CDCl3, 25 MHz)
1-isomer, 145.3 (C-3a), 133.6 (C-7a), 127.9 (C-5 or C-6),

110
123.4 (C-6 or C-7), 119.6 (C-4), 109.8 (C-7), 79.3 (NCHN),
66.6 (Cf^O), 48.6 (CF^NO), aliphatic chain 31.3, 30.9,
30.7, 28.7, 25.3, 22.2, 13.7; 2-isomer, 143.3 (C-3a,7a),
117.9 (C-4,7), 126.9 (C—5,6), 86.1 (NCHN), and aliphatic
chain, 31.3, 30.9, 30.7, 28.7, 25.4, 22.2, 13.7.
5.4.3 General Two-Step Procedure for Preparation of
Propargylamines.
To a cold (-70°C) solution of the aryl- or alkyl-
acetylene (0.005 mol) (see Table 5.1 for the specific alkyl-
or aryllithium reagents) in freshly distilled tetrahydro-
furan (THF, 20 ml), a solution (2.2 ml) of n-butyllithium
(0.0055 mol) in hexane (2.5 M) was added under argon.
Stirring at room temperature for 2 h was followed by the
addition of the appropriate benzotriazole adduct (5.4)
(0.005 mol) dissolved in THF (30 ml). After 1 h the
reaction was quenched with a few drops of water, the solvent
evaporated under reduced pressure and the residue was
dissolved in diethyl ether (150 ml) and washed with IN
sodium hydroxide (50 ml). The aqueous layer was extracted
again with diethyl ether (50 ml) and the combined organic
solutions were washed with water (100 ml), dried (MgSO^) and
the solvent was removed under reduced pressure once again.
The oil obtained was purified by column chromatography on
silica gel eluted with dichloromethane [compounds (5.5a),
(5.5d), ( 5.5i ) ] , dichloromethane/ethyl acetate [compound
(5.5b)], and dichloromethane/hexane [compound (5.5f)]. The

Ill
yields are reported in Table 5.1. The majority of the
products were characterized as their salts with picric acid,
which were prepared from 90% ethanol and recrystallized from
the same solvent. All elemental analyses data are collected
in Table 5.3 (see end of the present Chapter).
N-(3-Phenylprop-2-ynyl)-N,N-dibenzylamine (5.5a).
Proton NMR data: S„ (CDC1-.) 7.50-7.35 (m, 6 H, Ph) ,
H 3
7.35-7.15 (m, 9 H), 3.73 (s, 4 H, PhCH2), 3.45 (s, 2 H,
C=CCHN).
N-(3-Phenylprop-2-ynyl)pyrrolidine (5.5b). Proton NMR
data: $H (CDC13) 7.40 (m, 2 H, Ph), 7.26 (m, 3 H, Ph), 3.6
(s, 2 H, C =CCHN), 2.7 (m, 4 H, NCH2), 1.8 (m, 4 H, NCH2CH2).
N-(3-Phenylprop-2-ynyl)-N,N-dimethylamine (5.5c).
Proton NMR data: &H (CDC13) 7.40 (m, 2 H, Ph), 7.25 (m, 3
H, Ph), 3.43 (s, 2 H, C=CCHN), 2.33 (s, 6 H, CH3).
N-(1-Isopropyl-3-phenylprop-2-ynyl)pyrrolidine (5.5d).
Proton NMR data: 8H (CDClj) 7.40 (m, 2 H, Ph), 7.20 (m, 3
H, Ph), 3.25 [d, J = 8 Hz, 1 H, CHiPr1)], 2.7 (m, 4 H,
NCH2), 1.9 (m, 1 H, CHMe2), 1.76 (m, 4 H, NCH2CH2), 1.10 (d,
J = 6 Hz, 3 H, CH3), 1.05 (d, J = 6 Hz, 3 H, CHj).
N-(l-Isopropyl-3-phenylprop-2-ynyl)-N,N-dibenzylamine
(5.5e). Proton NMR data: §H (CDC13) 7.45 (m, 6 H, Ph),
7.25 (m, 9 H, Ph), 3.90 (d, J = 14 Hz, 2 H, CH2Ph), 3.48 (d,

112
J = 14 Hz, 2 H, CH2Ph), 3.15 [d, J = 10 Hz, 1 H, NCHiPr1)],
1.98 (m, 1 H, CHMe2), 1.04 (d, J = 6 Hz, 3 H, CH3), 1.03 (d,
J = 6 Hz, 3 H, CH3).
N-(1,3-Diphenylprop-2-ynyl)morpholine (5.5f). Proton
NMR data: Su (CDC1-.) 7.52 (m, 2 H, Ph) , 7.39 (m, 2 H, Ph),
H j
7.18 (m, 6 H, Ph), 4.65 (s, 1 H, CHN), 3.58 (t, J = 4 Hz, 4
H, OCH2), 2.49 (t, J = 4 Hz, 4 H, CH2N).
N-(1-1sopropyl-3-hexylprop-2-ynyl)-N,N-dibenzylamine
(5.5g). Proton NMR data: (CDCl3) 7.3 (m, 10 H, Ph),
3.78 (d, J = 14 Hz, 2 H, CH2Ph), 3.35 (d, J = 14 Hz, 2 H,
CH2Ph), 2.85 [d, J = 10 Hz, 1 H, NCHfPr1)], 2.30 (t, J = 6
Hz, 2 H, CH2), 1.85 (m, 1 H, CHMe2), 1.45 (m, 8 H), 0.95 (m,
9 H) .
N-(3-Butylprop-2-ynyl)-N,N-dioctylamine (5.5h). Proton
NMR data: §H (CDC13) 3.35 (t, J = 2 Hz, 2 H), 2.40 (m, 4
H), 2.2 (m, 2 H), 1.45 (m, 8 H), 1.27 (br m, 20 H), 0.90 (m,
9 H) .
5.4.4 General One--Step Procedure for Preparation
of Propargylamines
To the lithium acetylene salt (0.005 mol), prepared as
indicated above (Section 5.4.3), the appropriate
benzotriazole adduct (0.005 mol) in a benzene solution
(obtained after heating to reflux equimolar amounts of

113
benzotriazole, aldehyde and secondary amine in a Dean-Stark
apparatus until the theoretical amount of water was
collected) was added and the reaction proceeded and worked
up as described in Section 5.4.3 above. Analytical samples
of the oily products (5.5k), (5.51), (5.5m) were obtained by
column chromatography on silica gel, using as eluents
diethyl ether/hexanes. Yields of the overall reactions are
reported in Table 5.1. Only (5.5i) gave a crystalline
picrate, whereas the picrate salts of the other compounds
did not solidify. The elemental analyses data are collected
in Table 5.3 (see end of this Chapter).
N-(1,3-Diphenylprop-2-ynyl)piperidine (5.5i). Proton
NMR data: §H (CDClj) 7.64 (m, 2 H, Ph), 7.50 (m, 2 H, Ph),
7.30 (m, 6 H, Ph), 4.78 (s, 1 H, NCHC), 2.55 (br m, 4 H,
NCH2), 1.57 (m, 4 H, NCH2CH2), 1.43 [m, 2 H, N(CH2)2CH2].
N-(1-1sopropyl-3-hexylprop-2-ynyl)pyrrolidine (5.5j).
Proton NMR data: §H (CDCl^) 3.00 (dt, J = 2 and 7 Hz, 1 H,
NCH), 2.60 (m, 4 H, NCH2), 2.25 (dt, J = 2 and 7 Hz, 1 H),
1.75 (m, 6 H), 1.35 (m, 8 H), 0.95 (m, 9 H, CH3).
N-(1-Phenyl-3-propylprop-2-ynyl)morpholine (5.5k).
Proton NMR data: &H (CDCl3) 7.41 (m, 2 H, Ph), 7.3 (m, 3 H,
Ph), 3.75 (m, 4 H, NCH2), 3.5 (t, J = 8 Hz, 1 H), 2.71 (m, 2
H, OCH2CH2N), 2.55 (m, 2 H, CH2), 1.65 (m, 4 H), 0.97 (t, J
= Hz, 3 H, CH3).

114
N-(3-Hexyl-l-propylprop-2-ynyl)morpholine (5.51).
Proton NMR data: §H (CDCl3) 3.70 (m, 4 H, NCH2), 3.25 (dt,
J = 2 and 7 Hz, 1 H, NCHC), 2.62 (m, 2 H), 2.49 (m, 2 H),
2.21 (dt, J = 2 and 7 Hz, 2 H), 1.40 (m, 12 H), 0.9 (m, 6 H,
ch3) .
N-(l-Heptyl-3-phenylprop-2-ynyl)morpholine (5.5m).
Proton NMR data: &„ (CDCl,) 7.42 (m, 2 H, Ph), 7.27 (m, 3
H j
H, Ph), 3.74 (m, 4 H, OCH2), 3.46 (t, J = 7 Hz, 1 H, NCHC),
2.70 (m, 4 H, NCH2), 2.56 (m, 4 H), 1.70 (m, 4 H), 1.5 (m, 4
H), 0.89 (m, 3 H, CH3).
N-(l-Heptyl-3-hexylprop-2-ynyl)morpholine (5.5n).
Proton NMR data: (CDCl3) 3.73 (m, 4 H, CH20), 3.23 (dt, J
= 2 and 7 Hz, 1 H), 2.62 (m, 4 H), 2.50 (m, 2 H), 2.20 (dt,
J = 2 and 7 Hz, 2 H), 1.30 (br m, 21 H), 0.90 (m, 6 H, CH3).

Table 5.3. Characterization of propargylamines (5.5)
Amine Molecular
5.5a Formula
( FW)
Mt
Found
Mt
Calc.
C
Found
H
N
Required
C H
N
a
C29H24N4°7
-
-
64.43
4.45
10.05
64.44
4.48
10.37
b
C19H18N4°7
-
-
54.86
4.19
13.36
55.07
4.38
13.52
c
C17H16N4°7
-
-
52.54
4.01
14.45
52.58
4.15
14.43
d
C22H24N4°7
-
-
57.75
5.30
12.02
57.89
5.30
12.27
e
C32H30N4°7
-
-
65.60
5.14
9.37
65.97
5.99
9.62
f
C25H22N4°8
-
-
59.60
4.29
10.81
59.29
4.38
11.06
g
C32H38N4°7
-
-
64.76
6.88
9.31
65.07
6.48
9.49
h
C23H45N
335.3550
335.3552
-
-
-
-
-
-
i
C26H24N4°7
-
-
61.68
4.74
10.97
61.90
4.80
11.11
j
C16H29N
235.2286
235.2299
-
-
-
-
-
-
k
C16H21NO
-
-
78.87
8.72
5.71
78.97
8.70
5.76
1
C16H29NO
-
-
76.29
11.59
5.53
76.44
11.63
5.57
m
C20H29NO
-
-
80.14
9.76
4.68
80.22
9.76
4.68
n
C20H37NO
307.2854
307.2874
-
-
-
-
-
-
a
Compounds (5.5a)-(5.5g) and (5 - 5i) have been characterized as their picrates.
115

CHAPTER 6
THE PREPARATION OF g-AMINO ESTERS
6.1 Introduction
Powerful nucleophiles, such as organomagnesium and
organolithium reagents react easily with N-[a-(benzotriazol-
N-yl)alkyl]-N,N-dialkylamines (Chapters 4 and 5, respec¬
tively). We now show that the above benzotriazole adducts
also react with milder nucleophiles. Reformatsky reagents
link the ester functionality to the electrophilic substrates
(Bt-adducts), yielding g-(N,N-dialkyl)amino esters.
The Reformatsky reaction, is a powerful method of
carbon-carbon bond formation under mild conditions
[720CR(A)183], [750R423]. Classically it involves the
synthesis of g-hydroxy esters by reaction of a-bromo esters
with carbonyl compounds in the presence of zinc metal.
Several examples of modified Reformatsky reactions have been
reported, in which substrates other than aldehydes or
ketones have been used. Nitriles give, after hydrolysis, g-
keto esters [74JOM139] (Equation 6.1), while imines lead to
either g-amino esters or g-lactams depending on the reaction
conditions [72BSF3841] (Equation 6.2).
R-CsN + BrZnCH2C02Et > R-C0-CH2C02Et (Eq. 6.1)
116

117
R—CH=N—R'
-10°C
+ BrZnCH2C02Et >
RT1
H
R—C—CH_
I I
R'—N—C=0
R'-NH-CH(R)-CH2C02Et
(Eq. 6.2)
In a variation of the latter procedure, salts of a-bro-
moacids and benzaldimines in the presence of zinc give di¬
rectly N-monosubstituted 6-amino acids [82JOM185] (Equation
6.3), however this method is limited to derivatives of
aromatic aldehydes.
Br-CH2-C02ZnBr + Zn + Ph-C=N-R' > R'NH-CH(Ph)-CH2C02H
(Eq. 6.3)
General methods used in the synthesis of primary 8-amino
acids, usually via hydrolysis of a suitable precursor,
involve the rather lengthy Arndt-Eistert homologation of N-
protected a-amino acids [79MI2], and the [2+2] cycloaddition
of C1SC>2NC0 to olefins under mild but unpleasant conditions
(liq. S02) to give 6-lactams, which are hydrolyzed to 6-
amino acids [79MI2], Michael addition of nitrogen
nucleophiles to a,6-unsaturated acids, esters or nitriles
(Equation 6.4) is an easy route to 6-amino acid derivatives,
however it can not be used for preparation of a,a-disubsti-
tuted products.
H,0+
PhtNH + CH2=CHCN > PhtNCH2CH2CN — > H2NCH2CH2C02H
(Pht = phthalyl) (Eq. 6.4)

118
Reactions of benzotriazole adducts with Reformatsky
reagents are expected to provide an alternative path to both
a-mono- and a, a-di subst i tuted-6- ( N, N-dial kyl) amino esters,
carrying alkyl or aryl substituents at the 3-position.
6.2 Results and Discussion
The reactions of the benzotriazole adducts (6.1a-f) with
various Reformatsky reagents (6.2) (Scheme 6.1) proceeded
smoothly, under mild conditions (refluxing in diethyl ether
or THF) to give the expected 8-amino esters (6.3) in good
yields (Table 6.1).
6.1
6.2
1) reflux
2) NH40H
nr'r1
6.3
Scheme 6.1

119
The preparations of compounds (6.3a) and (6.3b) using
conjugate addition of morpholine on commercially available
ethyl acrylate [77JHC615], and ethyl cinnamate [62BSF1379],
respectively, have been previously reported. However, the
rest of the compounds listed in Table 6.1 are novel.
The majority of the prepared 3-amino esters represent
possibilities in structural diversity not easily accessible
by Michael addition or other routes. In the reactions
leading to (6.3d), (6.3 f), (6.3g), and (6.3h), the inter¬
mediate benzotriazole adducts (6.1b) and (6.1e) were not
isolated. Instead, direct reaction with the Reformatsky
reagents, gave very good yields of the desired products.
This demonstrates the "one-pot" possibility of the present
method and can be also extended to other examples.
6.2.1 Characterization of the Compounds
The ^H-NMR spectra of some of the products were compli¬
cated by the presence of the asymmetric 3-carbon atoms
(Scheme 6.1). The products of the reactions with ethyl a-
bromoisobutyrate the two diastereotopic a-methyl groups gave
different signals in the NMR spectra. In the ^H-NMR spec¬
trum of (6.3h) even the two methylene protons of the ethoxy
group were differentiated, giving two quartets for the
-OCH2CH3 group. Since all products were liquids,
characterization was achieved by converting most of them
into stable, crystalline picrate salts (Table 6.1), whereas
for the remaining products the molecular ion formula was
obtained.

120
Table 6.1 Preparation of g-amino esters (6.3) from
benzotriazole adducts (6.1) (see Scheme 6.1).
Add.
6.1
«ia
R2
R3
R4
Time
(h)
Product
6.3
Yield
(%)
m.p. (°C)
(picrate)
a
Mor
H
H
H
2
a
37b
105-108
b
Mor
Pr*
H
H
1.5
b
XI
LO
CO
79-82
c
Mor
Ph
H
H
2
c
00
cr
187-1896
b
Mor
Pr1
Me
H
2
d
u
JO
oo
162-164
d
Dib
Ph
Me
Me
18
e
59
oilf
b
Mor
Pr1
Me
Me
2
f
56c,d
127-129
e
Pip
Ph
Me
H
21
g
7 9c
oilf
e
Pip
Ph
Me
Me
21
h
7 3C'd
200-203
f
Dib
H
Me
Me
3
i
80d
197-201
Mor = morpholine; Dib = dibenzylamine; Pip = piperidine,
k The NMR spectra of the "crude" product (as obtained from
P
the reaction) indicated pure compound. The number
represents the overall (two-step) yield as calculated from
the secondary amine. Represents the yield of the product
after column chromatography. e HCl salt (lit. [62BSF1379]
m.p. 190°C). ^ The picrate did not crystallize.
6.2.2 Order of Addition
In an initial trial, the reaction was at first carried
out using the previously formed Reformatsky reagent

121
(BrZnCH2C02Et), to which a solution of the benzotriazole
adduct (prepared from N-methylaniline and formaldehyde) was
slowly added (Method A). The resulting reaction mixture,
however, was not clean, although the desired product was
present, as indicated by the NMR spectra of the crude
material. Inverse addition (Method B, i. e. adding the Bt-
adduct solution to the suspension of Zn, then injecting the
bromoester) gave a much cleaner product. Method B was
therefore adopted for all the reported reactions. For some
examples, especially those requiring long reaction times
(see Table 6.1) Method A could also work, but this
possibility was not tested.
6.2.3 Reaction Time
Most reactions were complete
period in either Et20 or THF/Et2
times proved inadequate for addu
reactions, after workup, gave ei
or mixtures originating from hyd
materials. The results were imp
cases when heating was extended
(see Table 6.1), resulting in hi
products. Table 6.1 shows that
faster than the other adducts, t
It is possible that the presence
provides additional coordination
results to "free" Reformatsky re
after a 2-
0 solvents,
cts (6.Id)
ther uniden
rolysis of
roved drama
over longer
gher yields
the morphol
oward the s
of oxygen
sites for
agent which
3 hour
hea
ting
These
re
action
and (6.
le)
, whose
tifiabl
e p
roducts
the sta
r ti
ng
tically
in
both
period
s o
f time
and cleaner
ine adducts react
ame nucleophiles,
in morpholine
zinc, and this
react faster.

122
6.2.4 Stereochemistry
In reactions between adducts having an asymmetric carbon
atom and ethyl a-bromopropionate, mixtures of diastereomeric
1 13
products were obtained, as shown by the H- and C-NMR
spectra [see Experimental of compounds (6.3d) and (6.3g)].
The diastereomeric ratio was nearly 1:1 in the case of
(6.3d) whereas in the mixture of (6.3g) was somewhat greater
(5:3). Several solvent systems were tested on TLC but none
resulted in separation of the diastereomers.
In general, the diastereoselectivity in Reformatsky
reactions is moderate [720CR(A)183], although progress has
been reported lately in intramolecular reactions [87JA6556].
In most cases the results can be rationalized with metal
chelated structures of minimum steric interactions
[750R423]. Consequently, coordination of benzotriazole with
zinc must play a role in the present reactions also:
polymeric Bt4Zn2 has been well characterized [81ACS(A)739].
The structures of the two transition states leading to
products (6.3d) and (6.3g) should be similar, but the longer
reaction time required for (6.3g) may be responsible for the
higher selectivity observed in this case, since base
catalyzed equilibration of the products would favor the
thermodynamically more stable isomer. However, general
trends and conclusions cannot be drawn, unless more examples
are examined.

123
6.2.5 Side Reactions
In the reaction of (6.Id) with ethyl a-bromopropionate
and ethyl a-bromoisobutyrate, a side product was consist¬
ently isolated as a white solid, which was identified as the
1 13
dimer (6.4) (Scheme 6.2) by H-, and C-NMR spectra, mass
spectra and elemental analysis (see Experimental). This
compound was isolated in similar yields (20-22%) regardless
of the reaction time (2-18 hours). The same product, in
somewhat higher yield (~45%) was isolated from a "blank"
experiment in which adduct (6.Id) was heated under reflux in
a suspension of zinc in THF for three hours.
This product presumably originates from a zinc-mediated
coupling of the adduct with removal of two molecules of
benzotriazole to form Bt2Zn or, more accurately, Bt^Zn2
[81ACS(A)739] (Scheme 6.2). A radical or radicaloid
species, having the tribenzylamine structure and stabilized
by resonance, could be responsible for the observed
dimerization. In none of the other reactions was the dimer
observed, meaning that either it was not formed at all, or
was present in undetectable amounts and removed during
purification of the products.
Expected a,8-unsaturated ester side products, usually
formed in Reformatsky reactions from base-induced
elimination of the amine grouping, were not observed. The
produced benzotriazole, was removed during the hydrolysis
step, which was carried out using cold concentrated ammonium
hydroxide.

124
Scheme 6.2
6.2.6 Extension to Different Benzotriazole Adducts
The possibility of extending the Reformatsky reaction to
benzotriazole adducts other than those of type (6.1), was
briefly investigated. Thus, zinc/ethyl bromoacetate reacted
easily with adduct (6.5) to afford the protected 3-amino
ester (6.6) in about 80% yield (Scheme 6.3). Products of
type (6.6) are important, since hyrogenolysis of the N-
protecting carbobenzyloxy group and hydrolysis of the ester
group could eventually give the free 3-amino acid (Scheme
6.3) .

125
This example indicates the wide scope of the Reformatsky
reactions with benzotriazole adducts and opens new
possibilities for successful preparation of a variety of
interesting compounds in which the ester group will be
introduced (by substitution of benzotriazole) in addition to
other existing functionalities.
Scheme 6.3

126
6.3 Conclusions
A new method for the preparation of the g- (N,N-dialkyl)-
amino esters was described in this Chapter, based on the
facile replacement of the benzotriazole group in reactions
of N-[a-(benzotriazol-N-yl)alkyl]-N,N-dialkylamines with
Reformatsky reagents. The products were obtained in good
overall yields. The methods can be also extended to
different benzotriazole adducts.
6.4 Experimental
6.4.1 Methods and Reagents
Diethyl ether and tetrahydrofuran were distilled from
sodium/benzophenone immediately before use. All reactions
were carried out under a nitrogen atmosphere. Miscellaneous
reagents, purification and characterization methods were
described in Chapters 4 and 5. ^H- (300 MHz) and ^C- (75
MHz) NMR spectra were obtained on a Varian VXR 300 spectro¬
meter, unless otherwise stated.
6.4.2 Preparation of Benzotriazole Adducts
The following adducts were prepared as described in
Chapter 3: N-[a-(Benzotriazol-N-yl)methyl]morpholine
(6.1a), N-[a-(benzotriazol-N-yl)-g-methy1propyl]morpholine
(6.1b), N—[a—(benzotriazol—N-yl)benzyl]morpholine (6.1c), N-

127
[a-(benzotriazol-N-yl)benzyl]piperidine (6.1e) [compounds
(3.9), (3.13), (3.10), and (3.15), respectively]. N-[a-
(Benzotriazol-N-yl)methyl]-N,N-dibenzylamine was described
in Chapter 4 [compound (4.2a)]. N-[a-(Benzotriazol-N-yl)-y-
methylbutyl]-N-carbobenzoyloxyamine (6.6) was kindly donated
by Ms. A. Mayence of our group.
N-[a-(Benzotriazol-N-yl)benzyl]-N,N-dibenzylamine
(6.Id). Benzotriazole (5.95 g, 0.05 mol), dibenzylamine
(9.85 g, 0.05 mol), and benzaldehyde (5.30 g, 0.05 mole)
were mixed in benzene and heated under reflux until the
calculated amount of water had been collected (0.9 ml, 6 h).
The solvent was removed iri vacuo and the residual oil was
triturated with diethyl ether. The resulting precipitate
was removed by filtration and dried (76%). N-[a-(Benzo-
triazol-N-yl)benzyl]-N,N-dibenzylamine was collected as
white microcrystals, m.p. 157-160°C (from benzene/Et20).
(Found, C, 87.45 ; H, 7.17; N, 5.86%. ('35H34N2 recIui-res' C,
87.10; H, 7.10; N, 5.86%); (CDCl^) 1-isomer, 8.18 (d, J
= 8 Hz, H-4), 7.37-7.13 (m, H-5, H-6, and all phenyl
protons, both isomers), 6.88 (d, J = 8 Hz, H-7), 6.84 (s,
NCHN), 4.25 [d, 2 H, J = 14 Hz, NCH(H)Ph, NC'H'(H')Ph], 3.47
[d, 2 H, J = 14 Hz, NC(H)HPh, NC'(H')H'Ph]; 2-isomer, 8.05
(AA' m, H-4, H-7), 7.73-7.13 (all aromatic protons), 7.00
[S, NCH(Ph)N], 4.25 [d, 2 H, J = 14 Hz, NCH(H)Ph,
NC'H'(H')Ph], 3.55 (d, 2 H, J = 14 Hz, CH2Ph); (CDC13):
due to the great number of aromatic signals, unequivocal
assignment to the 1- or 2-isomer was not possible: 145.2

128
(C-7a, Bt, 1-isomer), 143.9 (C-3a, C-7a, Bt, 2-isomer),
138.6, 138.4, 136.7, 133.9, 128.7, 128.6, 128.5, 128.4,
128.0, 127.3, 127.2, 127.1, 127.0, 126.9, 126.3, 123.9,
119.8, 118.5, 110.3 (C-7, Bt, 1-isomer), 83.6 (-NCH(Ph)N-,
2-isomer], 75.9 [-NCH(Ph)N-, 1-isomer], 53.7 (NCI^Ph,
2-isomer), 53.5 (NCi^Ph, 1-isomer).
6.4.3 General Two-Step Procedure for Preparation of g-
Amino Esters
The method reported recently by Picotin and Miginiac
[87JOC4796] was adopted. Thus, to a three necked flask,
equipped with a reflux condenser and a nitrogen inlet and
containing dry zinc powder (0.525 g, 0.008 mol) and
anhydrous ether (15 ml), trimethylchlorosilane (0.2 ml,
0.0016 mol) was added. The mixture was stirred for 15 min
at room temperature. The benzotriazole adduct (0.005 mol)
was added slowly to the suspension of activated zinc as a
solution in Et20 or in THF (20-30 ml). After the mixture
was heated to reflux, the heating was stopped, and the pure
bromoester (0.005 mol) was added in three portions under
nitrogen. The suspension was then heated to mild reflux,
and bubbling of nitrogen was stopped. In most cases the
grey powder soon turned to a thin white suspension. The
reaction was allowed to proceed for the time period
indicated in Table 6.1. The mixture was then poured onto
cone, ammonium hydroxide (25 ml) containing ice (10 g), and
stirred until all solids dissolved. The organic material
was extracted with ether (3 x 40 ml), washed with water (2 x

129
50 ml) and dried (MgSO^). The liquid product was obtained
after removal of the solvent under reduced pressure, and
purified as indicated for each particular case.
Ethyl 3-morpholinylpropionate (6.3a). The compound was
a colorless oil (37%); &H (60 MHz, CDCl^) 4.2 (q, J = 6 Hz,
2 H, OCt^CH^), 3.7 (m, 4 H, CH2O, morpholine), 2.5 (m, 8 H,
NCH2, morpholine, and CH2CH2CO), 1.3 (t, J = 6 Hz, 3 H,
CH3); &c (CDC13, 25 MHz) 171.6 (C=0), 66.2 (OCH2, morpho¬
line), 59.7 (OCH2Me), 53.3 (NO^C^CO), 52.8 (NCH2,
morpholine), 31.5 (NCHjC^CO), 13.6 (CH3). Ethyl
3-morpholinylpropionate was converted to its picrate salt,
m.p. 105-108°C (from 95% EtOH) (Found, C, 43.46; H, 4.83; N,
13.44%. C15H20N4^10 rec3uires > C, 43.27 ; H, 4.48; N,
13.46%) .
Ethyl 4-methyl-3-morpholinylpentanoate (6.3b). The
product was obtained as a clean liquid (85%); S (200 MHz,
H
CDC13) 4.13 (q, J = 7 Hz, 2 H, OO^Me) , 3.63 (t, J = 5 Hz, 4
H, OCH2, morpholine), 2.55 [m, 7 H, CH2NCH(Pr1)Ci^CO], 1.80
(m, 1 H, CHMe2), 1.27 (t, J = 7 Hz, 3 H, CHj), 0.98 (d, J =
8 Hz, 3 H, CH(CH3)CH31, 0.87 [d, J = 8 Hz, 3 H, CH(CH3)CH3);
(50 MHz, CDCl3) 173.2 (C=0), 67.2 (CH2O, morpholine),
60.0 (OC^Me), 49.1 (NCH-, overlapping with CH3N,
morpholine), 32.9 (CH2CO), 30.0 (CHMe 2), 20.7 [CH(CH3)CH3] ,
19.5 [CH(CH3)CH3], 13.9 (OCH2CH3). Ethyl 4-methyl-
3-morpholinylpentanoate was characterized as its picrate
salt, m.p. 79-82°C (from 95% EtOH) (Found, C, 47.29; H,

130
5.73; N, 12.43%. C18H26N4°10 rec3ui-res' c> 47.16; H, 5.72;
N, 12.22%).
Ethyl 3-morpholinyl-3-phenylpropionate (6.3c). The
product was obtained as a clean oil (84%); S„ (200 MHz,
H
CDC13) 7.29 (m, 5 H, Ph), 4.04 (q, J = 7 Hz, 2 H, OCH2CH3),
3.90 (t, J = 8 Hz, 1 H, NCHPh), 3.63 (t, J = 5 Hz, 4 H,
CH20, morpholine), 2.97 [2d, J = 8 Hz, 1 H, C(H)HC=0], 2.62
[2d, J = 8 Hz, 1 H, C(H)HC=0], 2.39 (m, 4 H, CH2N,
morpholine), 1.12 (t, J = 7 Hz, 3 H, OCH2CH3); &c (25 MHz,
CDC13), 171.2 (C=0), 138.3, 128.8, 128.0, 127.8, 66.8 (OCH2,
morpholine), 66.0 (OCH2Me), 59.9 (NCHPh), 50.1 (NCH2,
morpholine), 38.0 (CH2CO), 13.8 (OCH2CH3). Ethyl
3-morpholinyl-3-phenylpropionate was converted into its
hydrochloride salt, m.p. 187-189°C (lit. [62BSF1379] m.p.
190 °C).
Ethyl 3-dibenzylaminy1-2,2-dimethy1-3-phenylpropio-
nate (6.3e). After workup, the oily residue was triturated
with ether and hexanes. The solid that separated [dimeric
product (6.4), 22%] was filtered, and the filtrate was
concentrated and dried under vacuum (1 cm Hg, 24 h) to give
a thick oil (59%); m/z (rel. intensity) 400 (MÍ-1, 0.6),
286 (MÍ - Me2CC02Et, 51), 91 (100, C?H7); §H (CDCl3)
7.35-6.90 (m, 15 H, Ph protons), 3.80 (d, J = 14 Hz, 2 H,
CH2Ph), 3.75 (s, 1 H, NCHPh), 2.95 (d, J = 14 Hz, 2 H,
CH2Ph), 3.55 (m, 2 H, OCH2CH3), 1.1 (s, 3 H, CH3), 1.0 (s, 3

131
H, CH3), 0.78 (t, J = 7 Hz, 3 H, OCH2CH3); 6C (CDCl3)
176.5 (C=0), 139.7, 135.8, 130.9, 129.1, 128.7, 128.0,
127.7, 126.8, 69.3 (NCHPh), 60.3 (OCH2), 56.2 (CH2Ph), 47.3
(CMe2), 25.1 (CH3), 24.2 (CH3), 13.7 (OCH2CH3>.
Ethyl 3-dibenzylaminyl-2,2-dimethylpropionate (6.3i).
After workup and drying, the crude oil (1.67 g) was purified
on a column chromatography (silica gel, 21 cm x 2.5 cm)
packed in hexane and eluted with hexane/Et20 (8:2, 7:3,
v/v). Ethyl 3-dibenzylaminyl-2,2-dimethylpropionate was
collected as a colorless oil (80%); m/z (rel. intensity)
325 (Ml, 3.7), 324 [(MÍ-l), 16], 210 (100), 181 (13), 91
(88); SH (CDC13) 7.35-7.20 (m, 10 H, Ph), 4.01 (q, J = 6
Hz, 2 H, OCH2), 3.53 (s, 4 H, CH2Ph), 2.72 (s, 2 H, NCH2),
I.64 (t, J = 6 Hz, 3 H, OCH2CH3), 1.1 (s, 6 H, 2CH3); &c
(CDC13) 177.6 (OO), 139.4, 128.9, 128.0, 126.7, 62.9
(OCH2CH3), 60.2 (NCH2CMe2), 59.2 (NCH2Ph), 43.5 (-CMe2~),
24.0 (2 CH3), 14.0 (OCH2CH3). The product was characterized
as its picrate salt, m.p. 197-201°C (from 95% EtOH) (Found,
C, 55.71; H, 5.45; N, 11.48%. C^H^N^Og. 3/2H20 requires,
C, 55.76; H, 5.72; N, 9.63%).
6.4.4 General One-step Procedure for Preparation of (3-
Amino Esters
Adducts (6.1b,e) were prepared by heating a benzene
solution of benzotriazole (5.96 g, 0.05 mol), the secondary
amine (0.05 mol) and the aldehyde (0.05 mol) in a Dean-Stark

132
trap until the theoretical amount of water (0.9 ml) had been
collected (~15 h). Benzene was removed under reduced
pressure and the oily substance (without isolation) was
redissolved in Et20 or Et20/THF (1:2, v/v) (70-90 ml). Half
volume of the solution (0.025 mol) was added directly to a
suspension of activated zinc (2.62 g, 0.04 mol) in Et20 (25
ml), prepared as described in Section 6.4.3. Addition of
the bromoester (0.025 mol) (see Table 6.1) was followed by
heating to reflux, for the time specified in Table 6.1.
Workup was carried out as in Section 6.4.3.
Ethyl 2,4-dimethyl-3-morpholinylpentanoate (6.3d).
After workup and drying, ethyl 2,4-dimethyl-3-morpholinyl-
pentanoate was obtained as a clean, colorless oil (overall
yield 82%), mixture of two diastereomers; S„ (CDCl,)
(signals of both diastereomers given) 4.01 (2q, J = 7 Hz, 2
H, OCf^CH^, both isomers), 3.60 (2d, J = 4 Hz, 1/2 H, one
isomer, NCH), 3.45 (q, J = 5 Hz, 4.5 H, OCH2, morpholine,
both isomers, and NCH, second isomer), 2.77-2.45 (3m, 6 H,
NCH2, MeCHC=0, both isomers), 1.92-1.20 (2m, CHMe2, both
isomers), 1.27 (t, J = 7 Hz, CH^, OEt, one isomer), 1.26 (t,
J = 7 Hz, CH3, OEt, other isomer), 1.17 [d, J = 6 Hz,
CH(CH3)C=0, one isomer], 1.14 [d, J = 6 Hz, CH(CH^)CO, other
isomer], 0.96 [d, 3 = 1 Hz, 3 H, CH(CH^)CH^, one isomer],
0.97 [d, J = 7 Hz, 3 H, CH(CH3)CH3, one isomer], 0.25 [d, J
= 7 Hz, CH(CH3)CH3, other isomer]; &c (CDCl,) 176.1 (C=0),

133
175.7 (C=0), 71.5 (NCH, both isomers), 67.7 (OCH2,
morpholine), 67.6 (OCH2, morpholine), 59.9 (OCH2CH3, both
isomers), 51.3 (NCH2, morpholine), 50.2 (NCH2, morpholine),
41.6 [C(Me)CO], 39.9 [C(Me)CO], 28.8 [CH(CH)3CO], 27.1
[CH(CH3)CO], 21.1 (CH3), 20.8 (CH3), 20.7 (CH3), 19.9 (CH3).
The oil (most likely only one of the diastereomers)
crystallized with picric acid to form the corresponding
salt, m.p. 162-164°C (from 95% EtOH) (Found, C, 48.71; H,
6.02; N, 11.90%. C19H28N4°10 rec3u*res' C' 48.30 ; H, 5.97;
N, 11.86%).
Ethyl 3-morpholinyl-2,2,4-trimethylpentanoate (6.3f).
Part of the crude product (1.2 g) was purified by column
chromatography on silica gel (50 g) packed in hexane and
eluted with hexane and hexane/Et20 (8:2, 6:4, v/v). After
drying (12 h, 1 cm Hg, RT), ethyl 3-morpholinyl-
2,2,4-trimethylpentanoate was collected as a yellowish oil
(56%); $H (CDC13) 4.09 (q, J = 7 Hz, 2 H, OCH2CH3), 3.59
(m, 4 H, OCH2, morpholine), 2.98-2.88 (m, 2 H, NCH2,
morpholine), 2.2.78-2.75 (m, 2 H, NCH2, morpholine), 2.64
(d, J = 10 Hz, 1 H, NCH), 2.00 (m, 1 H, CHMe2), 1.25 (t, J =
7 Hz, 3 H, OCH2CH3), 1.27 (s, 3 H, CH3), 1.15 (s, 3 H, CH3),
1.02 (d, J = 10 Hz, 3 H, CII3), 0.85 (d, J = 10 Hz, 3 H,
CH3); &c (CDC13) 178.2 (C=0), 74.7 (NCH), 67.8 (OCH2,
morpholine), 59.9 (OCH2CH3), 51.9 (NCH2, morpholine), 48.8
(CCO), 29.1 (CH3), 25.4 (CH3), 23.1 (CH3), 20.8 (CH3), 13.9
(OCH2CH3). The product was converted to its picrate salt,

134
m.p. 127-129°C (from 95% EtOH) (Found, C, 49.48; H, 6.22; N,
11.69%. ('20H30N4°10 rec3u^res' C, 49.38 ; H, 6.22; N,
11.52%).
Ethyl 2-methyl-3-phenyl-3-piperidylpropionate (6.3g).
After drying ( 1 cm Hg, 1 h, 70°C), ethyl 2-methyl-3-phenyl-
3-piperidylpropionate was collected as a very clean pale
yellow oil (mixture of two diastereomers, overall yield 79%)
(Found, fit 275.1924 . ^17H25N®2 rec3u:*-res' 275.1882); m/z
(rel. intensity) 275 (m!, 2.4), 91 (32), 117 (12), 174
(100); SH (CDC13) 7.40-7.20 (m, 3 H, Ph), 7.20-7.09 (m, 2
H, Ph), 4.20 (m, OCHHCH^, 1.5 H, both isomers), 3.83 (q, J =
7 Hz, 0.5 H, OCHHCH3, one isomer), 3.66 (d, J = 12 Hz, 1 H,
NCHPh, one isomer), 3.64 (d, J = 12 Hz, 1 H, NCHPh, other
isomer), 3.30-3.10 (2m, 1 H, CHMeCO, both isomers),
2.55-2.05 (m, 4 H, NCH2, piperidine, both isomers), 1.6-1.40
(m, 4 H, NCH2CH2, piperidine, both isomers), 1.37 (d, J = 7
Hz, CHCH3, one isomer), 1.31 (d, J = 7 Hz, CHCH3, other
isomer), 1.30-1.20 (m, 2 H, C^, piperidine), 0.92 (d, J = 7
Hz, CH3, OEt, one isomer), 0.87 (d, J = 7 Hz, CH3, other
isomer); (CDC13) 175.8 (C=0), 175.4 (C=0), 136.0, 134.5,
129.0, 128.9, 127.7, 127.3, 127.2, 126.9, 73.5 (NCHPh), 71.5
(NCHPh), 59.9 (OCH2CH3), 59.8 (OO^CH^, 50.4 (NCHj), 50.2
(NCH2), 41.7 (NCH2CH2), 41.4 (NCH2CH2), 26.4 (NCH2CH2CH2),
24.5 (NCH2CH2CH2), 15.5 (CH3), 14.6 (CH3), 14.3 (CH3), 13.7
(CH3). The picrate salt did not crystallize.

135
Ethyl 2,2-dimethyl-3-phenyl-3-piper idylpropionate
(6.3h). Part of the crude oily product (1.8 g) was purified
on a silica gel column (22.5 cm x 2.5 cm) packed in
petroleum ether (b.p. 40-60°C), and eluted with petroleum
ether and petroleum ether/Et20 (8:2, v/v). Ethyl
2,2-dimethyl-3-phenyl-3-piperidylpropionate was a colorless
oil (1.6 g, overall yield 73%); [Found, (Flt-CC^Et)
216.1733 . 15H22N rec3uires' (Mt-CC^Et) 216.1552];
(CDC13) 7.40-7.20 (m, 5 H, Ph), 4.20-4.08 (2q, J = 7 Hz, 2
H, OCimCH3), 3.83 (s, 1 H, NCHPh), 2.45-2.20 (2m, 4 H,
NCH2), 1.55-1.40 (m, 4 H, NCH2CH2), 1.40-1.30 (m, 2 H,
NCH2CH2CH2), 1.30 (s, 3 H, CCH3), 1.22 (t, J = 7 Hz, 3 H,
CH3, OEt), 0.89 (s, 3 H, CCH3); 6 (CDCl3> 178.3 (C=0),
139.3, 129.8, 127.4, 126.8, 75.3 (NCHPh), 60.3 (OCH2), 53.2
(NCH2), 46.2 (CMe2), 26.7 (NCH2CH2), 26.5 (CH3), 24.4
(NCH2CH2CH2), 19.5 (CH3), 14.0 (CH3, OEt). The product
formed a solid with picric acid, m.p. 200-203°C (from 95%
EtOH).
6.4.5 Miscellaneous Reactions
Preparation of a,a’-dibenzylaminobibenzyl (6.4J. To an
ether (20 ml) suspension of zinc (0.525 g, 0.008 mol),
activated by addition of trimethylchlorosilane (0.2 ml,
stirring at RT for 15 min), N-[a-(benzotriazol-N-
yl)benzyl]-N,N-dibenzylamine (6.Id) (1.01 g, 0.0025 mol) was
added as a solution in THF (20 ml). The mixture was heated
under reflux for 3 h, then poured into iced ammonium

136
hydroxide (25 ml), extracted with ether (3 x 40 ml), and
dried (MgSO^). Following removal of the solvent, the
residue was triturated with Et20 and the resulting solid
(1S^ and 2nc* crops, 0.3 g, 42%) was filtered,
a,a'-Dibenzylaminobibenzyl was a white crystalline solid,
m.p. 248-251°C (Found, C, 86.68; H, 6.95; N, 4.61%.
C42H40N2 rec3uires' C' 88.07 ; H, 7.04; N, 4.89%); m/z (rel.
intensity) 286 (m!/2, 63), 181 (12), 91 (100); (CDCl,)
H ó
7.47 (m, 4 H), 7.16-7.07 (m, 20 H, Ph), 6.81 (m, 6 H), 4.42
(s, NCHPh, 2 H), 3.57 [d, J = 12 Hz, 4 H, C(H)HPh], 2.88 [d,
J = 12 Hz, 4 H, C(H)HPh]; (CDCl3) 139.1, 130.1, 130.0,
128.8, 127.4, 127.2, 126.7, 126.3, 62.2, 53.3.
Ethyl p-benzyloxycarbonylamino-8-methylhexanoate (6.6).
The reaction was carried out as described in Section 6.4.2,
by heating a solution of N-[a-(benzotriazol-N-yl)-y-
methylbutyl]-N-benzyloxycarbonylamine (6.5) (1.69 g, 0.005
mol) and ethyl bromoacetate (0.7 ml, 0.006 mol) in ether (30
ml) for 18 h. After workup, the crude oil was collected
(1.22 g, ~80%); m/z (rel. intensity) 308 [(mT+1), 3], 307
(Mt, 3), 250 (8), 206 (21), 108 (25), 107 (18), 91 (100), 65
(14); &H (CDC13) 7.18-7.15 (m, 5 H), 5.24 (br d, J = 10 Hz,
1 H, NH), 4.92 (s, 2 H, PhCH20), 3.95 (m, 3 H, NCH,
OCH2CH3), 2.33 (m, 2 H, CH2CO), 1.50-1.20 (2m, 2 H,
CH2Pr1 ), 1.08-1.03 (t, J = 7 Hz, 4 H, OCH2CH3, CHMe2), 0.76
[m, 6 H, CH(CH3)2J; Sc (CDCl3) 171.3 (Et0C=0), 155.6
(NHC=0), 136.4, 128.2, 128.0, 127.8, 66.2, 64.4, 60.2, 46.2,
43.4, 39.4, 24.7, 22.7, 13.9.

CHAPTER 7
SYMMETRICAL AND UNSYMMETRICAL AMINALS:
STUDIES ON THEIR PREPARATION AND EQUILIBRIA
7.1 Introduction
N-[a-(Benzotriazol-N-yl)alkyl]-N,N-dialkylamines react
easily with a range of different organometallic reagents.
Replacement of benzotriazole gives rise to a variety of a-
functionalized N,N-dialkylamines, as shown in Chapters 4, 5
and 6. The presence of the metal ions was considered
instrumental in removing benzotriazole by means of a Bt-
metal complex. However, according to the results obtained
in Chapter 3, some benzotriazole adducts should be highly
electrophilic, so that use of organometallic reagents would
not be necessary. Thus, reactions of sufficiently reactive
adducts with simple nucleophiles such as secondary amines,
should take place to afford either symmetrical or
unsymmetrical 1,1-diamines.
Aminals (1,1-diamines or gem-diamines) are N,N-acetals
formed by the condensation of carbonyl compounds with amines
[82MI2]. Aminals are, as expected, sensitive to acids.
Their stability depends on their structure and their mole¬
cular weight. Decomposition upon heating and hydrolysis
under mild conditions constitute a typical behavior of these
137

138
compounds. However, compounds derived from secondary amines
and aldehydes (Equation 7.1) are generally easier to handle.
Ar-CHO + 2 RR1NH > RR1N—CH-NRR1 + H-0 (Eq. 7.1)
<- I
Ar
7.1
Aromatic aldehydes react with secondary amines at room
temperature or under Dean-Stark conditions to form symme¬
trical aminals [82MI2] of type (7.1): yields of 50-90% are
typical for nucleophilic, unhindered amines (Equation 7.1)
[55JA1098], [72MI2J. Older literature (25JA1348) describes
the preparation of aminals (7.1) from gem-dihalides, a
method useful for the preparation of not easily accessible
keto aminals [82MI2]. Compounds (7.1) are stable in
alkaline but not acidic media and some are unaffected by
heat, so that they may be distilled [79MI1]. However, if
the 2-position bears a hydrogen atom, aminals can be easily
converted to an enamine and an amine [75BSF908] (Equation
7.2) .
RR1N-CH-NRR1
2 I
r2C-h
12 1
> RR NH + R^C^H-NRR
(Eq. 7.2)
Symmetrical aminals (7.2), derived from primary amines,
are often easily formed, especially from aldehydes and
aromatic primary amines but they are cleaved to the

139
corresponding imines and the primary amines upon attempted
distillation [65MI1] (Equation 7.3).
NH-R1
/
R-CH
\ 1
NH-R
7.2
h2nr
+ RCH=NR
(Eq. 7.3)
Unsymmetrical aminals are far less known. Zinner
reported examples of the type R2N-CH2-NR2 where R^ (but not
R) was very bulky, prepared by reaction of equimolar amounts
of formaldehyde and two different amines in aqueous solution
[67CB2515]. Fractional distillation of the resulting
mixture afforded the unsymmetrical aminals in yields ranging
from 6% to 15%.
Boehme and coworkers reported the formation of
unsymmetrical aminals (7.3) by addition of a hindered amine
on methylene iminium salts (Scheme 7.1) [67CB2131].
Scheme 7.1

140
Reaction of pyrrolidinomethanol with other amines also
afforded low yields of unsymmetrical 1,1-methylene diamines.
Unsymmetrical aminals derived from aldehydes other than
formaldehyde, however, have not been described.
More recently cyclic unsymmetrical aminals of type (7.4)
have been prepared [86S657 ] and studied [87JOC68] by Lambert
who found that their cations (7.5) underwent a ring chain
tautomerism (7.5) to (7.6) (Scheme 7.2).
I
7.4
7.5
7.6
Scheme 7.2
Within the context of explori
possibilities of N-[a-(benzotria
dialkylamines (see previous Chapt
these compounds with secondary am
Attempts were particularly focuss
unsymmetrical aminals which are n
methods described above.
ng
the
synthetic
zol
-N-
yl) a
lkyl)-N,N-
e r s
) ,
the
reactions of
i ne
s were
investigated.
ed
on
the
preparation of
ot
eas
ily
accessible by the

141
7.2 Results and Discussion
7.2.1 Preparation of Symmetrical Aminals
Using conventional methods [55JA1098], [72MI2], (Equa¬
tion 7.1), we carried out a series of reactions to prepare
the symmetrical aminals (7.1). The results are collected in
Table 7.1 (Method A). The products were characterized by
comparing their physical properties with literature values,
and by their H- and ^C-NMR spectra, which display
characteristic signals for the methinic proton NCH(Ar)N at
3.5-4.5 ppm and the corresponding carbon at 78.0-90.0 ppm
(in CDC13). We also found that these compounds are easily
prepared by reactions of the benzotriazole adducts (7.7)
with secondary amines (Scheme 7.3, Table 7.1, Method B).
The adducts (7.7), prepared as described previously, need
not be isolated.
7.7
2 HNRR
+
Ar
7.1
Scheme 7.3

Table 7.1. Preparation of symmetrical aminals R^N-CH(Ar)-NR^ (7.1)
Method
A
Method B
Entry
Aminals Ar
7.1
”r2
Yield
(%)
m. p.
( °C)
Adducts
7.7
Yield
(%)
m. p.
( °C)
1
a
Ph
n(ch2)4
60
36-8
a
61
36.5-7.5
2
b
Ph
N(CH?)r
68.5
77-9
b
65
75-7
3
c
4-MeO-CgH4
n(ch2)4o
90
96-9
c
89
98-101
4
d
4-MeO-CgH4
N(CH9)q
82
oil
d
79
oil
5
e
Me tCH
N(CH2)4o
no rxn
e
no rxn
6
f
Ph
N(Me)Ph
no rxn
f
_a
7
g
Ph
N(CH?Ph)9
33
138-41
g
b
8
h
Ph
«"2
no rxn
h
a
9
i
2-furyl
N(CH2)4
c
c
a The Bt-adduct was successfully prepared but it failed to react with the amine.
The Bt-adduct reacted with the amine but the reaction did not go to
completion. c The desired product was not isolated; tars were obtained
instead.
142

143
Use of two equivalents of the amine conveniently
removed benzotriazole as its amine salt, which precipitated
from the solution and therefore the reaction was rapidly
driven to completion at room temperature. Alternatively, if
one equivalent of the amine was used, benzotriazole could be
removed as its sodium salt, by the action of solid or
aqueous sodium hydroxide.
The reactivity of adducts (7.7) as related to their
structure and the solvent, was discussed in Chapter 3.
Here, observations confirming the predicted behavior were
made. Thus, adducts (7.7a) and (7.7b), derived from
pyrrolidine and piperidine and benzaldehyde, reacted rapidly
(3-5 min) with the corresponding amines to afford aminals
(7.1a) and (7.1b), respectively (Table 7.1). The high
reactivity is a consequence of a low barrier to
isomerization of the adducts and higher concentration of the
intermediate iminium ions in the solution, in this case
captured by the secondary amines (Equation 7.4).
+ +2 HNR?
Bt-CH(Ph)-NR? —> Bt + PhCH=NR9 — > R_N-CH(Ph)-NR~
-BtH.HNR,
(Eq. 7.4)
As also anticipated, lack of reactivity was displayed by
other adducts, under similar, mild conditions. Thus, no
reaction took place between morpholine and the corresponding
benzaldehyde adduct at room temperature (20 min) (Equation
7.5), whereas the adduct bearing a methoxy group at the

144
para-position of the phenyl ring reacted very smoothly
(Table 7.1, entry 3).
No reaction
(Eq. 7.5)
Reactions such as that exemplified in Equation 7.4 are
of considerable importance in demonstrating the reactivity
of some benzotriazole adducts. However, the synthetic value
of the benzotriazole method (B) is limited, as shown in
Table 7.1, for the following reasons:
(a) The two methods, A and B, are comparable in yield
and purity of the resulting symmetrical aminals.
(b) Sterically hindered aminals cannot be prepared by
the conventional method A (entries 5, 6 and 8). The
corresponding benzotriazole adducts could be prepared,
however reaction with 1 equivalent of the amines did not
lead to the desired, bulky, symmetrical aminals, under the
conditions attempted. The reaction of the benzotriazole
adduct with N,N-dibenzylamine in the presence of powdered
NaOH did result in the expected product (entry 7), but the
reaction was not complete and starting material was present
in small amounts even after several days. Purification of
the resulting mixture was not successful.

145
Confirmation of the structure and purity of the aminals,
1 13
was possible by studying their H-, and especially C-NMR
spectra and by comparing their melting points with litera¬
ture values whenever possible. Table 7.2 lists the di-
13
agnostic C-NMR chemical shifts of several symmetrical
aminals
, pre
pared as
shown
in Table 7
.1. The presence of
the methoxy
group doe
s not
seem to cause any
significant
changes
, whe
reas the
struc
ture of the
amine
has a noticeabl
effect
on the chemica
1 shi
ft of the N
-CH(Ar)
-N carbon atom.
Thin layer,
column and gas
chromatogr
aphy we
re proven
unreliable,
since par
tial
or complete
decomposition of the
aminal
produ
cts takes
plac
e whenever
any of
the above
techniques was used.
Recr
ystallizati
on could be used as a
pur ific
ation
but not
as a
separation
method.
Table 7
.2.
13
C-NMR c
hemi c
al shifts o
f the methinic carbon
atom [N
— CH (A
,r)-N] of
symme
trical aminals (7.
1) in CDC13.
7.1
Ar
nr2 3
6 (ppm)
a
Ph
Pyr
85.3
b
Ph
Pip
89.8
c
4-MeO-C
6H4
Mor
88.5
d
4-MeO-C
6H4
Pip
89.1
g
Ph
Dib
79.6
j
Ph
Mo r
88.5
a Pyr =
pyrr
olidine,
Pip =
piperidine
, Mor =
morpholine,
Dib =
dibe
nzylamine
•

146
In conclusion, the benzotriazole method although does
not offer a distinct advantage over the conventional method
for the preparation of symmetrical aminals, it demonstrates
the high reactivity of some adducts and furnishes evidence
for the existence of iminium ion intermediates in the
solutions of these compounds.
7.2.2 Preparation of Unsymmetrical Aminals
In an attempt to extend the previously described
method B to the preparation of unsymmetrical aminals, which
are not easily prepared by the conventional methods, we
treated the benzotriazole adducts with different amines than
those already present in the adducts (Equation 7.6).
Attempted GC analysis of the mixture resulted in complete
decomposition in the injection port. Analysis of the
reaction mixtures was possible only by 3H-, or even better,
13
C-NMR spectroscopy, which showed mixtures of the unsymme¬
trical (7.8) and the two symmetrical aminals, (7.9) and
(7.1), regardless of the number of amine equivalents used.
3 Bt-CH-NRR1 + 3 HNR2R3
Ar
3 NaOH
7.7
V
(Eq.7.6 )
Ar
Ar
Ar
+ 3 H20
7.8
7.9
7.1
3 BtNa

147
When the reacting amine was very hindered, (e.g diiso¬
propylamine, Scheme 7.4), a fast reaction took place (as
indicated by immediate precipitation of a solid), and the
unsymmetrical aminal (7.11) was initially thought to be
present, since a ^C-NMR spectrum of the mixture revealed
new carbon signals in addition to those of the benzotriazole
adduct. Formation of the symmetrical aminals (7.1b) and
(7.10) (Scheme 7.4) was also considered possible. However,
the reaction required a long time and starting material
(7.7b) was detected, in some cases, even two weeks later and
after repeated workups to remove the side benzotriazole
salts. This behavior indicated an equilibrium process: the
produced benzotriazole amine salt (7.12) presumably reacted
with the aminal to give a benzotriazole adduct (Scheme 7.4).
This hypothesis was tested by recording the ^C-NMR
spectrum of a mixture of diisopropylamine-benzotriazole salt
(7.12) (prepared from benzotriazole and diisopropylamine in
benzene) and aminal (7.1b) in CDCl^: a typical
1-substituted benzotriazole pattern consisting of six peaks
was observed (see Chapter 2). The spectrum was in all
respects identical to that obtained by the forward reaction
(Scheme 7.4). The diagnostic N-CH(Ar)-N region suggested
that in both forward and reverse reactions, the major
component of the mixture was the simple symmetrical aminal
(7.1b), whereas the unsymmetrical desired product (7.11) was
very minor (if this assignment is correct) and the
sterically crowded aminal (7.10) non-existent.

148
Scheme 7.4
In general, the relative amounts of the produced
aminals in the mixture seemed to vary according to their
steric congestion: if the incoming amine (Equation 7.6)
were very crowded (e.g. = Pr1), then the symmetrical
(7.8) and most probably the unsymmetrical (7.9) aminals

149
would be undetectable; if the steric factor were of
2 3
intermediate size (e.g. R = R = CB^Ph), then (7.9) would
exist in small amounts and (7.8) would rather be the major
product; if the size of the incoming amine were comparable
1 2
to that already existing on adduct (7.7) (e.g. R = R
2 3
piperidyl and R = R morpholinyl), then the symmetrical
aminals would be the major components.
The chemical shift of the methinic N-CH(Ar)-N carbon
atom of the unsymmetrical aminal (7.8) should be located
between the corresponding signals of the two symmetrical
aminals (7.1) and (7.9) (see Equation 7.6). The detection
of the unsymmetrical aminals was therefore based solely on
this criterion. The weak point in this method is that
sterically hindered symmetrical aminals, cannot be prepared,
and their diagnostic chemical shifts can only be hypothe¬
sized. In addition, slight changes in chemical shifts due
to solvent, concentration, and solute variations could be
confused as indicating new products: there is danger of
13
arriving to the wrong conclusions by only considering C-
NMR chemical shifts; however no other reliable method is
available for analysis of the product composition.
The results reported so far suggest that unsymmetrical
aminals (7.1) of intermediate size can be prepared, but they
exist in equilibrium with the symmetrical ones and, in some
cases, with the starting materials, and separation is not
possible. Table 7.3 summarizes the reactions carried out
and the observations made regarding product composition. An
uncertainty in the interpretation of the results is evident.

Table 7.3. Composition of products from reactions of benzotriazole adducts
(7.7) with 2° amines.
3 Bt-CH-NRR1 +
1
Ar
(7.7)
3 hnr2r3 —> r1rn-ch-nr2r3 +
1
Ar
(7.8)
r3r2n-ch-nr2r
1
Ar
(7.9)
3 + R1RN-CH-NR1R
1
Ar
(7.1)
Ar
NRR1
2 3
NR R
(7.8)
(7.9)
(7.1)
Ph
n(ch2)5
n(ch2)4
moderate3
major3
minor
4-MeO-CgH4
n(ch2)4o
n(ch2)4
moderate3
a
major
very minor
Ph
n(ch2)5
N(Pr1)2
-
-
major
4-MeO-CgH4
n(ch2)5
N(Pr1)2
-
-
major
Ph
n(ch2)4
N(cyclohexyl)2
-
major
4-MeO-C6H4
n(ch2)4o
N(cyclohexyl)2
-
-
major
Ph
N(CH2)5
N[C(Me)2CH2]2CH2
-
-
major
Ph
n(ch2)5
N(CH2Ph)2
major
minor
minor
a
Assignments can be interchanged.
150

151
The reaction conditions tested were either aqueous or
powdered NaOH in diethyl ether. A few attempts to use NaH
in toluene resulted in either no reaction (RT, 15 min) or a
complex mixture of products (A, 4 h). Earlier attempts to
use the lithium or magnesium salts of amines in THF as
nucleophiles in reactions with adducts (7.7), were only
partially successful. Proton abstraction was preferred over
substitution in cases where the substrate contained an
active hydrogen (see Scheme 7.5).
+ other products
7.13
Scheme 7.5
The formation of the dimerization product (7.13), (E-
or Z-), whose structure is consistent with NMR and mass
spectra, can be rationalized either by an a-elimination
leading to a carbene, or more likely, initial dissociation
of the benzotriazole adduct followed by ylide formation
which in turn dimerized to give (7.13) (Scheme 7.6).

152
Scheme 7.6
In conclusion, the best conditions for aminal formation
were treatment of a Bt-adduct with a different secondary
amine and/or solid sodium hydroxide, in diethyl ether at
room temperature. In order to drive this reversible process
to completion, continuous removal of the precipitating
benzotriazole salts from the reaction mixture was necessary
(filtration or aqueous workup). Some Bt-adducts were not
sufficiently reactive, therefore no reaction took place,
regardless of the type of the incoming amine. With reactive
adducts, the reaction proceeded to give mixtures of
unsymmetrical and symmetrical aminals in ratios determined
by the degree of steric congestion in the products.

153
7.2.3 Cross-Over Reactions of Symmetrical Aminals
The production of mixtures of symmetrical and
unsymmetrical aminals in the above reactions (see Equation
7.6) indicated that an additional equilibrium process was
operation, namely between the aminals themselves. The
disproportionation of aminals was studied by following the
1 13
H- and C-NMR spectra of equimolar mixtures of two
different aminals. Specifically, when two symmetrical
aminals, such as (7.1b) and (7.1g) were mixed, an
equilibrium was established between reactants and the
unsymmetrical aminal product (7.1bg) (Scheme 7.7).
7.1 bg
in
Scheme 7.7

154
The equilibrium position was reached very fast in
CDCl^ , even when the solvent was previously shaken with
sodium carbonate. The intensity and number of peaks in a
13
C-NMR spectrum recorded 5 minutes after mixing, had not
changed when examined several hours later. On the other
hand, the process was slower in either deuterated dioxane or
toluene and the rate of appearance of the methine proton
signal of the unsymmetrical product could be readily
1 13
followed by H- or C-NMR spectroscopy.
Figure 7.1 illustrates the slow equilibration between
(7.1b), (7.1g) and (7.1bg) as reflected in their ^H-NMR
spectrum. The region of benzylic and methinic protons
(2.5-5.5 ppm) was monitored as a function of time. To a
toluene-dg solution of (7.1g) [spectrum at 0 min], an
equimolar amount of (7.1b) was added and spectra, acquired
after two pulses, were recorded at times shown in Figure
7.1. The singlet growing at 3.95 ppm and the two doublets
at 4.13 and 3.12 ppm are due to the NCH(Ph)N hydrogen and
the two benzylic proton groups, respectively, of the
unsymmetrical aminal (7.1bg). The singlet at 4.57 is due to
NCH (Ph)N of (7.1g), whereas the corresponding peak of (7.1b)
normally appearing at 3.55 ppm, is covered under the foreign
peak at 3.55 ppm, which was also present in the spectrum of
analytically pure (7.1g).
A more clear picture can be obtained by monitoring the
1 3
region 90-70 ppm of the C-NMR spectrum, where the
resonances of NCH(Ar)N usually appear (see Table 7.2).

7.1b 7.1g 7.1 bg
toluene-d0 as a function of time.
155

156
Figure 7.2 illustrates the changes in the 13C-NMR
spectra of an equimolar mixture of (7.1b) and (7.1g) as a
function of time. The NCH(Ph)N carbon-13 resonance of
(7.1g) in 1,4-dioxane-dg emerges at ~80 ppm (Figure 7.2,
spectrum at 0 min). To the solution of (7.1g), one
equivalent of (7.1b) was added and the spectra were recorded
at intervals indicated in Figure 7.2. The peak at ~87.5 ppm
is due to (7.1b). The new signal, emerging between the
NCH(Ph)N peaks of the symmetrical starting aminals,
presumably originates from the unsymmetrical compound
13
(7.1bg). Similar observations were made for the C-NMR
spectrum of the mixture of (7.1a) and (7.1b) (see Table
7.2), but in this case the new C-atom [NCH(Ar)N] signal of
the mixed aminal (7.lab) was extremely close to that of
(7.1a), so that detection of the equilibrium process was
possible only at 75 MHz (^C-NMR spectrum). When (7.1b) and
the methoxy substituted aminal (7.1c) were mixed together
13
(Figure 7.3), four additional peaks appeared in the C-NMR
spectrum (88-90 ppm), due to all possible cross-aminal
products. The composition of this mixture was also time
dependent.
In order to explain the foregoing observations a
mechanistic scheme is suggested (Scheme 7.8), which is
consistent with the benzotriazole chemistry discussed in
previous chapters, and with a recent report [87JOU1198]
according to which aminals react via previous dissociation
to iminium ions, in metal catalyzed alkylations.

157
7 1 bg
22 h
t$wtfwémqPrh********
25 min
â–  1 i ' y ' t i ; ~| t "i i i | i i i r~|~i i i i ; i i : v
90 80 70 ppm
15 min
0 min
7.1g only)
i 3
Figure 7.2 Partial C-NMR spectra (64-95 ppm) of a mixture
of (7.1b) + (7.1g) as a function of time
(in 1,4-dioxane-dg).

158
7.1b
i

159
Bt" +
HNRR1
1/2
/NR R
f *
Ar
+.NRR1
1/2 "NRR1 + 1/2^/ +
Ar
BtH
1/2 ~NRZR3
Scheme 7.8
In conclusion, a-aryl substituted symmetrical aminals
1 13
disproportionate in solution, as shown by H- and C-NMR
cross-over experiments in various solvents.
7.3 Conclusions
The reactions of benzotriazole-arylaldehydes adducts
with secondary amines to afford symmetrical aminals were
described in this Chapter. Unsymmetrical aminals could also
be prepared, but they were always obtained as mixtures with
the symmetrical compounds. This was the result of

160
disproportionation of the products, a process which occurs
when two different a-arylaminals are mixed in solution.
7.4 Experimenta1
Methods and reagents were described in previous
Chapters.
7.4.1 Preparation of Benzotriazole Adducts
The preparations of N-[a-(benzotriazol-N-yl)benzyl]-
piperidine (7.7b) and N-[a-(benzotriazol-N-yl)-a-
(4-methoxyphenyl)methyl]morpholine (7.7c), were described in
Chapter 3 [compounds (3.15) and (3.12), respectively] and of
N-[a-(benzotriazol-N-yl)benzyl]-N,N-dibenzylamine (7.7g) was
described in Chapter 6 [compound (6.1d)]. Adducts (7.7a),
and (7.7c)-(7.7h) were prepared according to the general
method described in Chapter 3. All showed broad signals in
the NMR spectra at room temperature and had to be
characterized by low temperature spectra. Purification of
these compounds was generally not attempted, and they were
used directly for reactions with the secondary amines.
N-[a-(Benzot riazol-N-yl)benzyl]pyrrolidine (7.7a). The
compound was a viscous dark oil (prepared according to the
general method, but at room temperature) which partially
decomposed to benzotriazole on attempted distillation;

161
§H (100 MHz, CDCl3 , +20°C) 8.20-7.30 (m, 11 H, all aromatic
protons), 6.68 (s, NCHN, 1 H), 2.68 (br s, 4 H), 1.74 (br m,
4 H). Presumably this is the spectrum above coalescence;
8C (25 MHz, CD2C12, -50°C) 145.8 , 136.9 , 132.2 , 128.5,
127.3, 123.9, 119.3, 112.0, 81.4, 67.4, 50.3, 25.2, 23.1
(mixture of two isomers).
N-[g-(Benzotriazol-N-yl)-a-(4-methoxypheny1)]methyl]-
piperidine (7.7d). It was obtained as an oil which was
characterized spectroscopically: $H (300 MHz, CDCl^, -20°C)
8.2-7.8 (2m, 3 H, Bt), 7.6-7.2 (m, 3 H, Ph, Bt), 7.1-6.7 (m,
3 H, Ph and NCHN), 3.77 (s, 3 H, OMe), 2.8-2.1 (br m, 6 H,
piperidine), 1.9-1.2 (3m, 4 H, piperidine); &c (75 MHz,
CDC13, -20 °C) 159.0, 145.5, 142.0 , 132.8 , 128.4 , 127.9 ,
126.9, 126.6, 123.4, 119.3, 113.4, 111.9, 89.0 (NCHN,
2-isomer), 82.9 (NCHN, 1-isomer), 54.8 (OMe), 45.0 (br s),
25.6, 23.7. The aromatic peaks were not present at room
temperature.
N-[a-(Benzot riazol-N-yl)benzyl]-N-methylani1ine (7.7f).
The compound was obtained as a clean, white solid (86%),
m.p. 85-88°C (from benzene/pet. ether) (Found, C, 76.05; H,
5.68; N, 18.17%. C20H18N4 re<3uires» C, 76.41; H, 5.77; N,
17.82%); &H (60 MHz, CDCl3) 8.2-7.8 (2m, 4 H, Bt, Ph),
7.5-6.8 (m, 11 H, Bt, Ph), 3.2 (Me, 2-isomer), 3.0 (Me,
1-isomer); 8^ (25 MHz, CDCl3) (all expected aromatic peaks
due to two isomers are present, but unequivocal assignment
is not possible) 148.7, 148.3, 144.0, 136.8, 135.9, 132.9,

162
129.3, 129.2, 128.8, 128.7, 128.6, 128.5, 127.5, 127.1,
126.7, 126.4, 123.9, 119.9, 119.8, 119.4, 118.4, 114.7,
114.0, 110.0, 82.4, 77.1, 34.8, 34.3.
N-[a-(Benzotriazol-N-yl)benzyl]-N,N-diethylamine (7.7h).
It was obtained as a viscous oil: (300 MHz, CDCl^,
-200C) 8.2-8.1 (m, 2 H, Bt), 8.1-7.9 (m, 3 H, Bt, Ph),
7.8-7.2 (m, 4 H, Bt, Ph), 7.1 (s, 1 H, NCHN), 3.2-3.1 (q, J
= 7 Hz, 3 H, NCH2), 3.1-2.9 (m, 3 H, PhCH2, NCH3), 2.5-2.2
(m, 6 H, CH^), mixture of two isomers; &c (75 MHz, CDCl^,
-30°C) 146.0, 136.4, 134.5, 128.5, 128.2, 127.2, 126.9,
126.8, 123.6, 119.6, 115.5, 111.4, 85.4 (NCHN, 2-isomer),
78.7 (NCHN, 1-isomer), 43.2, 42.6, 13.3, 12.1.
7.4.2 Preparation of Aminals
General method (A). The aminals (7.la)-(7.Id) and
(7.1g) were prepared by heating a 2:1 molar ratio of
amine/arylaldehyde (see Table 7.1) in benzene, by means of a
Dean-Stark trap, until the theoretical amount of water had
been collected. The solvent was removed under vacuum and
the residue was triturated with diethyl ether or petroleum
ether, and the product was usually obtained as a solid. In
general, further purification products was avoided, since
they tended to hydrolyze or decompose.
General method (B). The benzotriazole adducts were
dissolved in diethyl ether and treated with 1 equivalent of
a secondary amine and powdered NaOH, or (better) with 2

163
equivalents of the secondary amine. After stirring for 15
min at room temperature the resulting precipitate (water
soluble) was either removed with alkaline washing (2N NaOH)
or filtered and the solvent evaporated. Yields of aminals
(7.la)-(7.Id) were listed in Table 7.1. This method was
also used in the attempted preparation of unsymmetrical
aminals shown in Table 7.3.
g,q-Bis(pyrrolidinyl)toluene (7.7a). It was obtained as
a white solid, m.p. 36.5-37.5°C (lit. [75BSF196] m.p.
40-41°C); &H (300 MHz, CDCl3) 7.29 (m, 5 H), 3.91 (s, 1 H,
NCHN), 2.48 (m, 8 H, NCH2), 1.65 (m, 8 H, NCH2CH2); $c (75
MHz, CDC13) 136.3, 128.9, 127.2, 127.1, 85.3, 49.3, 22.9.
g,g-Bis(piperidyl)toluene (7.7b). The compound was
obtained as a white solid, m.p._77-79°C (lit. [55JA1098]
m.p. 80-810C); ( 200 MHz, CDCl3) 7.30-7.16 (m, 5 H, Ph),
3.55 (s, 1 H, NCHN), 2.33 (m, 8 H, NCH2), 1.50 (m, 8 H,
NCH2CH2), 1.36 [m, 4 H, N(CH2CH2)2CH2]; Sc (25 MHz, CDC13)
136.1, 128.5, 127.1, 126.9, 89.7, 50.0, 26.1, 25.2.
g,g-Bis(morpholinyl)-4-methoxytoluene (7.7c). The
product was a white solid, m.p. 106-108°C (lit. [75BSF196]
m.p. 119-120°C) (Found, C, 65.24; H, 7.73; N, 11.47%.
C16H24N2°3 rec3uires' c' 65.73 ; H, 8.27; N, 9.58%); 8H (300
MHz, CDC13) 7.11 (d, JQ = 9 Hz, 2 H, MeO-CC^C^) , 6.88
(d, JQ = 9 Hz, 2 H, MeO-C2H2), 3.80 (s, 3 H, OMe), 3.66 (t,

164
J = 5 Hz, 8 H, CH20), 3.59 (s, 1 H, NCHN), 2.43 (m, 8 H,
NCH2); &c (75 MHz, CDCl3) 159.1, 129.8, 126.3, 113.1, 88.5,
67.2, 55.2 (OMe), 49.5.
a,tt-Bis(piperidyl)-4-methoxytoluene (7.7d). The product
did not solidify; (60 MHz, CDCl^) 7.3-6.8 (A2B2> J = 9
Hz, 4 H, aromatic), 3.8 (s, 3 H, OMe), 3.7 (s, 1 H, NCHN),
2.3 (m, 8 H, NCH2), 1.4 [m, 12 H, N(CH2CH2)2CH2); ¿c (25
MHz, CDC13) 158.5, 129.4, 128.4, 112.5, 89.1, 50.0, 26.2,
25.3.
a,g-Bis(N,N-dibenzylaminyl)toluene (7.7g). The compound
was a white solid, m.p. 138-141°C (Found, C, 87.45; H, 7.17;
N, 5.86%. C35H34N2 rec3uires» C, 87.10; H, 7.10; N, 5.80%);
&H (300 MHz, CDC13) 7.39-7.12 (m, 25 H, Ph), 4.49 [s, 1 H,
NCH(Ph)N], 4.00 (s, 2 H, CH2Ph), 3.95 (s, 2 H, CH2Ph), 3.57
(s, 2 H, CH2Ph), 3.53 (s, 2 H, CH2Ph); 6 (75 MHz, CDCl3)
139.4, 135.1, 129.6, 129.1, 128.0, 127.7, 126.9, 126.5,
79.7, 52.7.
g,g-Bis(morpholinyl)toluene (7.7j) . The compound was
prepared using method A, m.p. 97-98°C (lit. t 7 2 M12] m.p.
101-101.5°C); Su (300 MHz, CDCl,) 7.33-7.17 (m, 5 H, Ph),
H j
3.66 (t, J = 5 Hz, 8 H, OCH2), 3.63 (s, 1 H, NCHN), 2.42 (m,
8 H, NCH2); Sc (75 MHz, CDCl3) 133.8, 128.6, 127.7, 127.6,
88.5 (NCHN), 67.0, 49.4.

165
«,g'-Bis(piperidyl)stilbene (7.13) . A three-necked
flask was evacuated and flushed with Ar three times, then
charged with freshly distilled pyrrolidine (0.005 mol, 0.42
ml) in a THF solution (20 ml). The liquid was cooled to
-78°C (10 min) and n-BuLi (2.5 M in hexanes, 2.1 ml, 0.0055
mol) was added slowly. The suspension was left to stir for
1 h. The oily N-[a-(benzotriazol-N-yl)benzyl]piperidine
(7.7b) (1.46 g, 0.005 mole) in THF (25 ml) was introduced
slowly into the flask at -78°C. A deep purple color was
immediately developed. After stirring for 1 h, the mixture
was allowed to warm up slowly. At room temperature, a brown
coloration was observed. After 1 h, a little water was
added and then aq. sat. ammonium chloride (to pH ~ 8.5).
The solution was extracted with ether (3 x 20 ml), washed
with 2N NaOH (1 x 10 ml) and dried (MgSO^). Evaporation of
the solvent gave a semi-solid, which, upon attempted
recrystallization from 90% EtOH, yielded a bright yellow
solid (0.13 g, 15%), m.p. 108-110°C (Found, C, 82.34; H,
10.04; N, 7.74%. C24H30N2 rec3uires' 83.19; 8.73; 8.08);
m/z (rel. intensity) 346 (MÍ, 100), 289 (33), 178 (53), 84
(50); ( 200 MHz, toluene-dg) 8.0-6.8 (m, 10 H), 3.5 (m, 8
H), 2.5 (m, br, 12 H); &c (50 MHz, toluene-dg) 137.6,
131.9, 130.3, 128.3, 127.1, 53.5, 27.7, 25.0. From the
above data, the structure of the compound was assigned as
that of (7.13), but the geometry (E- or Z-) could not be
determined.

CHAPTER 8
SUMMARY AND CONCLUSIONS
In this work, we have studied the kinetic and
thermodynamic aspects of the isomerization of N-(a-amino-
aklyl)benzotriazoles. We have also investigated the
reactions of these compounds with different nucleophiles,
and developed several synthetic methodologies for synthesis
of N-a- functionalized secondary amines.
In Chapter 2, the exchange of the N,N-dialkylaminoalkyl
substituents between the 1- and 2- positions of
benzotriazole was studied using simple N-(a-aminomethyl)-
benzotriazoles as model compounds. We found that the 1- to
2- isomerization takes place in the liquid and gas phases
but not in the solid phase, in which they exist solely as
the 1-substituted isomers. The 1- to 2- isomerization was
shown to be intermolecular. The proposed mechanism,
consistent with the spectroscopic evidence, involves the
dissociation of the compounds to iminium ions and the
benzotriazole anion.
In Chapter 3, the influence of the structure on the
isomerization process was studied. The 1-isomer was found
to be favored in compounds bearing small N-substituents and
in polar solvents. The 1- and 2- isomers were nearly
equally favored in compounds with large N-substituents and
166

167
non-polar solvents, however the 1-isomer predominated in
most mixtures. The energy barrier to isomerization was
estimated to be in the range of 15.7 to 18.6 kcal/mole.
Substituents that provide stabilization to the intermediate
ions, by donating or withdrawing electrons, and polar
solvents, tend to lower the magnitude of the activation
energy. The reactivity of the benzotriazole adducts could
then be predicted in the basis of their structure.
In the Chapters that followed, the ability of the
benzotriazole adducts to behave in solution as sources of
iminium ions was exploited in many ways. Thus, Chapter 4
described their reactions with Grignard reagents and with
sodium borohydride which led to variously substituted
tertiary amines in high yields. The sequence could be
carried out in one step, bypassing the isolation of the
benzotriazole adducts. In Chapter 5, a new general method
was established in which lithium acetylenides reacted with
the benzotriazole adducts to produce 3-substituted
propargylamines in very high yields. Again the one-step
possibility was utilized. In Chapter 6, preparation of (3-
aminoesters was demonstrated, in reactions of the adducts
with Reformatsky reagents. In Chapter 7, reactions with
secondary amines led to symmetrical and unsymmetrical
aminals. Interestingly, these products were found to
undergo disproportionation in solution. This behavior
justified the inability to prepare unsymmetrical aminals not
contaminated with the corresponding symmetrical compounds.

168
In conclusion, the present work has demonstrated the
enhanced electrophilicity of N-(a-aminoalkyl)benzotriazoles
and established their reactivity limits toward a wide range
of nucleophiles. It has also paved the way for new
synthetic possibilities, and further exploitation and
understanding of the chemistry of benzotriazole.

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BIOGRAPHICAL SKETCH
The author was born in November 1957 in Filiatra
Messinias, Greece. She graduated from the University of
Athens in June of 1981 with a B.S. in chemistry. The same
year she enrolled as a graduate student in the Chemistry
Department of the Nuclear Research Center "Democritus",
where she had a brief contact with organic photochemistry in
the lab of Dr. Hadjudis. She joined the graduate school of
Clemson University in August 1982, where she obtained a M.S.
degree in organic chemistry under the supervision of Dr.
Abramovitch. She moved to the University of Florida to
pursue her Ph.D. in January 1985. She joined Dr.
Katritzky's group six months later.
179

I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality, as
a dissertation for the degree of Doctor of Philosophy.
Alan R. Katritzky, Chairman
Kenan Professor of Organic Chemistry
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality, as
a dissertation for the degree of Doctor of Philosophy.
4r.
Anna Brajter-Toth
Assistant Professor of Chemistry
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality, as
a dissertation for the degree of Doctor of Philosophy.
/¿Tames A. Deyrup )
Professor of Chemistry
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality, as
a dissertation for the degree of Doctor of Philosophy.

I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality, a
a dissertation for the degree of Doctor of Philosophy.
C.
if
Eugene P. Goldberg
Professor of Materials
Engineering
A
Science and
This dissertation was submitted to the Graduate Faculty
of the Department of Chemistry in the College of Liberal
Arts and Sciences and to the Graduate School and was
accepted as partial fulfillment of the requirements for the
degree of Doctor of Philosophy.
December, 1988
Dean, Graduate School

UNIVERSITY OF FLORIDA
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