N-(alpha-aminoalkyl)benzotriazoles

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Title:
N-(alpha-aminoalkyl)benzotriazoles equilibria and reactions
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viii, 179 leaves : ill. ; 28 cm.
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Yannakopoulou, Konstantina, 1957-
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Benzotriazole   ( lcsh )
Chemical equilibrium   ( lcsh )
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bibliography   ( marcgt )
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Thesis:
Thesis (Ph. D.)--University of Florida, 1988.
Bibliography:
Includes bibliographical references.
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by Konstatina Yannakopoulou.
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Typescript.
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Vita.

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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



AotEpcopevo aou;o Yovet; poi

nlavayLonI Kiat Awa

Me ayanl Kala oeaoaxo















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 Dom Perignons!); 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.


iii
















TABLE OF CONTENTS

page

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-(Dialkylaminomethyl)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-dialkylamines..............31

3 INFLUENCE OF STRUCTURE ON THE ISOMERIZATION
OF N-[a-(BENZOTRIAZOL-N-YL)ALKYL]-
N,N-DIALKYLAMINES............................... 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-1 and C-13 NMR
Spectra............................... 39
3.2.3 Calculation of Equilibrium Constants (K)
and Free Energies (AG)
for Isomerization....................... 48











3.2.4 Variable Temperature NMR Spectral Study:
Calculation of Tree 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-dialkylamines..............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 O-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 3-Amino Esters .........128
6.4.4 General One-Step Procedure for
Preparation of B-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











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-1 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-1 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,

vii










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 0-mono or disubstituted O-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.


viii















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 (l.la), (l.lb), and (l.lc). In the parent

molecule (and in symmetrically substituted derivatives),

position 1 is indistinguishable from position 3, therefore

structures (l.la) and (l.lc) are identical.



3



1 N
H

1.1a 1.lb 1.1c

The process is very rapid and the individual tautomers

cannot be separated. One tautomeric form, namely (l.la),

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 1H-form in solution [78JCS(P2)312] and

in the gas phase [730MS1267] (KT = 1H-/2H- >> 1).

1










Benzotriazole is more acidic (pK = 8.2) [51JA4360] than
phenol (pKa = 9.89) [85MI1] and much more acidic than other

azoles, for example, benzimidazole (pK = 13.2) [58JCS1974],

or pyrrole (pKa = 23) [81JOC632]. The electron withdrawing

-N=N- group presumably decreases the electron density on N-1

and renders additional stability to the benzotriazole anion.

Benzotriazole can be alkylated [85H2895] or acylated

(84CHC(5)6691 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(P1)799] and references cited therein).










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 x-arylaminomethyl-

benzotriazoles, and bis(benzotriazolyl)alkanes, have been

developed by Katritzky and coworkers [87JCS(P1)781, 799,

805, 811, 819].











X = Cl, OH, SPh, NH-Ar, Bt; R = Alkyl, Aryl



Owing to the both electron-withdrawing (aI = 0.55) and

electron-donating (aR = -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










centers (path B); finally, it can also provide moderate

stabilization to a-carbanions (path C).


X(X

(X=NHR)


1) Nu


NJ>


2) H+


Nu
+ X

(X = Cl)


Base


1) E+

2) H>
+
2) H3O


(R = Bt, X = Ar)


Scheme 1.1


A


Nu

R


E Ar










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(Pl)805], amides [88JCS(P2)0], thioamides [88TL1755],

and the formation of ketones via lithium bis(benzo-

triazolyl)arenes [87JCS(Pl)819] have been published.



1.3 N-(Dialkylaminomethyl)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).



+ HNR R'H
CH20 + HNR2 -> CH2=NR2 R2NCH2NR2 -> R'CH2NR2 .
(Eq. 1.2)


In basic medium, hydroxymethylamine is postulated as the

reactive species (Equation 1.3).



HNR R'H
CH20 + HNR2 -> HOCH2NR2 R2NCH2NR2 -> R'CH2NREq 1.3)
Eq. 1.3)










The reaction does not normally follow the other possible

route (Equation 1.4), although some examples are known

[73S703].

HNR2
R'H + CH20 --> RCHH > R'CH2NR 2 (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(P1)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(P1)1181].



R2




NR,

1.2a 1.2b


Scheme 1.2









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 occurring 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].





S -- -SnBu3


SnBu3
1.3
SiMe3




I
SiMe3
1.4


Scheme 1.3










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-[(-(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, 0-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.la) and (2.1b), respectively [75JCS(Pl)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(P1)1181].



4 3a 3


3a

7a
NR,




2.la 2.1b

Scheme 2.1










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(Pl)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(Pl)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(Pl)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.


















'8H,7


H,7C8


2.2b


2.2a


H, 17


2.2c


Scheme 2.2
























2.3 R =

2.4 R =

2.5 R =

2.6 R =

2.7 R =


H, NR' = NMe
2 2
H, NR2 = Pyrrolidyl

Me, NR' = NEt2

H, NR' = NEt
Me, NR Pyrrolidyl
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

studied by IR, H- and 1C-NMR spectroscopy.



1H-NMR spectroscopy. The H-NMR spectra in deuterochlo-

roform (CDC13) 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-1-yl and the

benzotriazol-2-yl isomers. Compound (2.2) displayed three










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(Pl)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 IH-NMR spectrum is not first

order even at 300 MHz. A more appropriate model is

l-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

multiple 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 CDC13] 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.










4
H-6 5
H-4 H 1 H-




I I I i H
j









7.8 76 7:4 7.2 7.0 PP


Figure 2.1 Aromatic region of the 300 MHz 1H-NMR spectrum
of 1-hydroxymethylbenzotriazole in CDC13.



4

H-4,7 H-5,6 -Me

7












6 iS, ..." .4' ,



Figure 2.2 Aromatic region of the 300 MHz 1H-NMR spectrum
of 2-methylbenzotriazole in CDC13









15


















I
a a





r-1


0
N
44
*2
E



.i
0
N
C

a)



z






L. '







I I -i
0























0 m

UL










Also consistent with literature reports [75JCS(Pl)1181]

is the observation that increasing bulkiness in the N,N-

dialkyl substituents (i.e. changing from NMe2 to pyrrolidino

to NEt2) results in increasing amounts of the 2-substituted

isomers. As expected [75JCS(Pl)1181], the change from CDC13

to the more polar solvent dimethyl sulfoxide (DMSO-d6)

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-d6

was so low that their 1H-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-] (CDC 3) [1-]/[2-] (DMSO-d6)



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.











13C-NMR spectroscopy. The aromatic region of the 13C-

NMR spectra of 1-substituted benzotriazoles displays an

easily recognizable pattern consisting of six signals.

Figure 2.4 shows the 13C-NMR spectrum of 1-methylbenzo-

triazole in CDC13. 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 1C-NMR spectra of compounds (2.2) [87JCS(Pl)2673]

in CDCl3 displayed nine aromatic signals attributed to a

mixture of 1-substituted and 2-substituted benzotriazole

groups, while the NCH2N 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 13C-NMR spectra of (2.3-2.7) in both

CDC13 and DMSO-d6 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-CH2-N absorptions appeared in the region 77.5 to 64.7 ppm

[see Table 2.2 for 13C-NMR spectra of compounds (2.3-2.7) in

CDC13]. 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.












C-6


c-


C-7a


1"


Figure 2.4 Aromatic region of the 75 MHz C-NMR
spectrum of 1-methylbenzotriazole in CDCl3.


C-5,6!


C-4,17


4

c -Me


C-3a,7a


Figure 2.5 Aromatic region of the 75 MHz 1C-NMR
spectrum of 2-methylbenzotriazole in CDC13.


'S iu,


~~ r i -. --i .......~~~


--i ~~-------CC~ U1
- --.


t .





































.0


6 .0 -


S--


a-
-


-I
>1



I-
0
N



4l





l-4
0
N
C











aU
04)
z






L -I




=-Q
4.)
u c


oJ



Z-
I
US
M C


N --I















10
*I-'










*i-i


tA Co




















4Z rOi -r- I- r- co r- ,"4 LA
-1

,10
S'0
tI m C m m m m m r oo
Z U .. ... .
"- l OOOh OO<>
O
Z I I I I N N NI I N (I-


>1 r r- c' ) O -4 -- Lr aco r- r-- ON
4-) u O7 0'i LA = LA r -a. m

z0 0 ao kD kO O 0 'O O m ko

SE o Cm m a V C m a
>1 ( I
I-4 O O o0 4 0 0 4 4 < 4
I r~ m -Oi 03 a po r o m i M r
Z I r m m m m M m m M
-rl


S I 0 N 0 N 0
0
N r I r3 al CT> D v CC0 V C- 0
a; 0 4 0 0 0 C

0) U 14 1 O r- -I r-I ,-4 r-I
o a



- .- I |' II N m r I N m M






















LA H 0 0 0 0 0 U LA 0

N L 0 U 0 U 0 0 U Q
00




OI
LI r13 c u0 co m O r13 a '0 a,










I4 U -4 -4 14 -4 -4 -4 4 -4 -
U) OD '. O Oq C- V-4 Lo' a. '0





4t S .
zU L r4N r, r N LA 9 -
4U U r1 3-I v-I .-4 v-I v-I .-m M-I C-i C-M
w) m o mv r co C) ccv I o m








-4 U-I v-I 4 r-0 v 0 -i 1 1 -4 r0
u






N >) U 0 U 0 U 0 U 0 U Q


(u (4 0 5 5 5 S C4
E-- U (N N N N NN N N


















N4 a -; .- (Ni


r- Mr % r N r4 M 0
*
C- y o ) LA LA C>C ON
2 I *: va o .




S *** I-

I I I I N (N I I NINJ -4
0
U)

(-3 LA 's LA O> I.M 0 r r '-4 'o I
wm I m i 0
*

Z ~ r N r-~ r~- r r- t-~ r


0r o CO O LA




0 41
n C ID I m N- m I m I O




D *



Ls 4 -4 4 rn -
| ,-I "I CO 4 m N r-O L- 4
14 I r- -4 i-j 1i r- 4 -4 r-4 u)
.- 0 o
I '0 '.0 '. U. '. (N (N LA '. '. I V
(NJ i (N (N ( m ro (N rI t-a

a U


















0 0. 0
S. Uo
S D I o m c i m 1 I V


0 0


V Mn IV v In mn ko kD I r E-




V 00


0 (
I a r | m | ro | | o A
r~l> -t O -l O -I .i il '










Infrared spectroscopy. IR has been used previously to

distinguish between 1- and 2-substituted benzotriazole

derivatives [63HCA1473], [87JCS(P1)811]. The 1-isomers

typically display two weak absorptions in the region 1630 to
-l
1550 cm- (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 OC: the infrared

spectrum of a neat film shows in the region 1630 to 1550
-i -i
cm1 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. CHC1 Neat or melt Ar matrix KBr
solution


1610
1590
1565

1618
1592
1519

1625
1590
1570

1627
1582
1552


1610
1590
1565


1616
1590
1517


1610
1590


1615
1587


1625
1588
1569


1631
1585


a Bromoform solution.




1*0





C
S6-
0
0:


bFT spectra.


1700 1650 1 600 1550


1 500


Wavenumbers



Figure 2.7 FT-IR spectrum of N-[(benzotriazol-N-yl)-
methyl]-N,N-dimethylamine (2.3): (a) 0.3 M
solution in CHCl3; (b) KBr pellet; (c) Ar
matrix spectrum.










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
-I
1550 cm1 in agreement with their benzotriazol-1-yl-

structures. Similarly, examination of (2.2) in a KBr disc,

or in a nujol dispersion, showed the presence of only two
-l
weak absorptions at 1610 and 1590 cm- in the diagnostic

region 1630-1550 cm-1, as expected for a 1,1'-bisbenzo-

triazolyl derivative [63HCA1473], [87JCS(P1)1811]. In

particular, no absorption was found in the region 1570 to
-i
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].



13C-NMR spectroscopy. The solid state 1C-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 splitting were observed suggests that these










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(P1)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

CDC13 or DMSO-d6 solutions of (2.4) and (2.5) and examining
1 13
the mixtures by 1H- (Table 2.4) and 13C- (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










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 CDC13 and even more so in the more

polar DMSO-d6. The H-NMR spectrum (CDC13) of the mixture

(Table 2.4) showed only seven of the expected eight peaks in

the N-CH2-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-d6 the N-CH2-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.









R2


NR2






+ C
CHl -NR2


Scheme 2.4


















CNR2


Scheme 2.5


Table 2.4 H-NMR data for the N-CH -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


6 (CDC13)

Area (%)

6 (DMSO-d6)

Area (%)


5.7

4


5.6

9


5.5

6


5.5

23

5.7

37


5.5

23

5.6

25


5.5

18

5.6

24


5.4

17

5.4

15


13
The 1C-NMR spectrum (Table 2.5) provided more widely

separated peaks. The N-CH2-N carbons appeared in CDC13 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 NCH2N after mixing (2.4) and (2.5)


(<^r R2










in deuterated chloroform. In DMSO-d6 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).



13
Table 2.5 C-NMR data for the N-CH -N groups of
benzotriazoles (2.4-2.7) from the crgss-over experiment.


Assignment 2-isomers 1- isomers



2.4 2.7 2.5 2.6 2.5 2.6 2.4 2.7



6(CDC13) 71.7 71.2 71.0 70.6 64.4 64.2 64.1 63.9

Area(%) 4 4 5 5 18 17 24 22

6 (DMSO) 64.5 64.8 64.1 64.0

Area (%) 25 29 25 21




Temperature Effect. The 1H-NMR spectra of (2.5), (2.6)

and (2.7) were also recorded at -50 OC and at 40 OC in CDC13

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

250C. Modification in the structure of the compounds re-

sulted in marked temperature effects, as shown in Chapter 3.

















































'V


- r



-U:
10

ID







































CD









































-J
-
t































r~d


4-I
0




xo



4-
X









*C


0








ON
U

4J U











E-,


N


cr4

LA-


C*l

r4




-4










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-1-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-1-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 CHBr3 solutions, or 1% KBr

pellet; the argon matrix experiment was recorded at 240K and

10-7 mm Hg was carried out by Dr. M. Szczesniak of this

department [87JCS(Pl)2376], who also operated the FT-IR

instrument.










1H- (200 MHz) and 13C- (50 MHz) solution NMR spectra

were recorded on a Varian XL 200 spectrometer. Cross-over

experiments were carried out by mixing equimolar solutions

of both substrates. Quantitative 1C-NMR spectra were

acquired at 50 MHz using a 5 sec pulse delay. Low

temperature 1H-NMR spectra were obtained at 100 MHz using a

Jeol FX-100 spectrometer under the guidance of Dr. King of

this department.

Solid state 1C-NMR spectra were acquired on a modified

Varian XL 200 NMR spectrometer using cross polarization and

magic angle spinning (CPMAS) [87JCS(P1)2673] by Dr. R.

Skarjune at 3M company.

Spectra displayed in Figures 2.1-2.6 were recorded on a

Varian 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. 1C-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. 95-980C (from diethyl ether) (lit. [75JCS(Pl)1181] m.p.

98-1000C); 6H (CDC13) 1-isomer, 8.07 (d, J = 8 Hz,










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, CH3); 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. 79-810C

(from diethyl ether) (Found, C, 65.66; H, 7.29; N, 27.88%.

C11H14 4 requires, C, 65.32; H, 6.98; N, 27.70%); 6H (CDCl3)

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)2].


N-[(5,6-Dimethylbenzotriazol-N-yl)methyl]-N,N-di-

ethylamine 2.5). It was obtained as a pale yellow powder

(91%), m.p. 95-980C (from diethyl ether) (Found, C, 67.99;

H, 8.44; N, 24.47%. C13H18N4 requires, C, 67.80; H, 7.88;

24.33%); 6H (CDC13) 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].










N-[(Benzotriazol-N-yl)methyl]-N,N-diethylamine (2.6).

The oily product was dried under vacuum over P205 (96%),

b.p. 120-1240C (at 0.65 mm Hg) (Found, C, 64.17; H, 7.73; N,

27.79%. C11 16N4 requires, C, 64.68; H, 7.89; N, 27.43%);

6H (CDC13) 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(CH2CH)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. 40-600C) (Found, C, 67.01; H, 8.98; N,

24.13%. C13H20N4 requires, C, 67.21; H, 8.68; N, 24.11%);

6H (CDC13) 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)2], 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 1H-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 AGO

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









(c) The change in AGO as a function of the size of R and
R'.
(d) The correlation between AG+ and the basicity of the
corresponding amine HNR2.


3.1b


3.la


H +
S>--NR


3.2


3.3


Scheme 3.1


In the case of adducts (3.1) the energy barrier of the
equilibrium (3.la) to (3.1b) (Scheme 3.1) should be lower
than in the case of the (2.1a) to (2.1b) interconversion


~











(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).


























X Y R'


3.4 H H H

3.5 NO2 H H

3.6 Cl H H

3.7 Me Me H

3.8 H H Pr


3.14


3.9 H

3.10 C6H5

3.11 C6H4-4-NO2

3.12 C6H4-4-OMe

3.13 Pri


3.15


Scheme 3.2










3.2 Results and Discussion



3.2.1 Preparation of Compounds



Adducts of type (3.1), (R' # 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 -300C.

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 13C- 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










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 IH-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-

mental). All 13C-NMR spectra were recorded in deuterated

chloroform. Low temperature 13C-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 1H- and

the C-13 NMR spectra. The C-13 spectra of the above com-

pounds were easier to interpret than the 1H-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.










(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)1, resulted in the generation of three

interconverting (1-, 2-, and 3- substituted) isomers in the
1 13
solutions and consequently complex H- and 1C-NMR spectra.

(b) The existence of an asymmetric carbon atom (when

R H) caused chemical shift non-equivalency to protons in

methylene and methyl groups up to three bonds away. This

resulted in complicated 1H-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 -250C

contained then 2- and 3- isomers in equal amounts, while the

1-isomer was the major component (at -250C, [1-1:[2-]:[3-1 =

44:28:28). The complete assignment of the H- and 13C-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 [64T2111 were separated by column chromatography.

The individual fractions were identified by comparing their

melting points to literature values. The least polar










fraction was identified as 2-methyl-5-nitrobenzotriazole

(m.p.185-1880C; lit. [64T211] m.p.1870C). The most polar

fraction was l-methyl-5-nitrobenzotriazole (m.p.160-1620C;

lit. [64T211] m.p.1630C). 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 1C-NMR spectra of the individual

methylation products were recorded in CDC13. 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

CDCl3.



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, ( 200C, CDC13, [1-]:[2-]:[3-] =

45:23:32) thus enabling assignment of the 13C-NMR spectrum.

The aromatic region of the 1H-NMR spectrum, with a multitude

of peaks, was impossible to assign. A two-dimensional

proton-carbon correlation spectrum (HETCOR) (Figure 3.2)



















a I-isomer
b 2-isomer
a c 3-isomer


1pp
S8 7


(b)


a I-isomer
b 2-isomer
c 3-isomer


a CHCI
1. I 3


9 8 7


Figure 3.1 Aromatic region of the 1H-NMR spectrum (CDC1 ) of
(a) N-[(5-nitrobenzotriazol-N-lyl)methyl]pyrro-
lidine (3.5) (-250C), and (b) a mixture of 1-, 2-
and 3-methyl-5-nitrobenzotriazoles (250C).








43











E-1
f i i ,
SE E o
-- 000 oI N





So L














II
I






Or




Oz
4-1




0ic oa





I 8






















0
I 0 U .







-a-








01-1
1-1 ^-
u Z)>
2 l-'X
I U 4J
"*0== *=* S 0
*o- "-






f ___________ <
s --- --- i --- i--------------1-



*^I











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

cosyY), unraveled the assignment of the aliphatic region in

the IH-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 1H-NMR spectra of all adducts are described in the

experimental section. The 1C-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).

















h-isoer

- t-isomer Ph


I .





1
a a L2









wi to IT fn Uo

a. I I I I I I I I -




Figure 3.3 A H- H correlation (COSY) spectrum of N-[a-
(benzotriazol-N-yl)-0-methyl]propyl-N,N-
dibenzylamine (3.14).











Table 3.1. 13C-NMR chemical shifts of the benzotriazol-1-yl
isomers, of compounds (3.5a)-(3.15a) at a single temperature
(below coalescence) in CDC13.

Noa Tem. -NR2 R' CH Bt
(OC)


3.5 -25


3.6 +20


3.8d -48


3.9 +20


3.10 +20


3.11 +20


3.12 +20


3.13 +20


3.14 +20





3.15 -20


49.9
23.4

49.9
23.4

47.1
22.7

66.2
50.1

66.3
49.6

66.5
49.7

66.4
49.7

66.6
48.8

138.7
128.9
128.5
127.3
53.4

50.1
25.4
23.5


b


_b


30.5, 19.8
19.0
b


134.6, 128.4
128.1, 127.2

141.9, 142.3
128.7, 123.7

159.4, 127.6
113.7, 54.8

28.4, 19.7
19.0

30.4, 29.6
19.4


65.5 144.4, 144.2, 136.4c
122.8, 116.9, 110.7

65.1 145.8,c 133.2,c 129.1c
124.5, 120.1, 109.4

81.3 144.5, 134.4, 126.9
123.5, 119.2, 109.7

68.9 145.5, 133.5, 127.2
123.6, 119.4, 109.6

82.4 145.7, 132.7, 126.9
123.5, 119.6, 111.1

81.1 145.8, 133.0, 127.8
124.2, 120.1, 110.5

82.4 145.6, 132.5, 127.1
123.8, 119.5, 111.4

85.5 145.0, 134.4, 127.2
123.7, 119.6, 109.7

80.1 144.9, 135.1, 126.9
123.7, 119.7, 109.8


134.9, 128.1 82.8 145.4,
128.0, 127.0 123.4,


132.8, 126.6
119.2, 111.5


a The complete 13C-NMR spectra of (3.4) and (3.7) were

reported in Chapter 2 [see Table 2.2, compounds (2.4) and

(2.7). b R' = H. c The 40 carbon atoms could not be

assigned with certainty, therefore peaks could be due to the

other isomers. d The INEPT pulse sequence at 25 MHz (-480C,

CDC13) was utilized for unequivocal assignment of the

spectrum.











Table 3.2. 1C-NMR chemical shifts of benzotriazol-2-yl
isomers of compounds (3.5b)-(3.15b) at a single temperature
(below coalescence) in CDCl3.

Noa Tem. -NR R' CH Bt
(C)


3.5 -25


3.6 +20


3.8 -48


3.9 +20


3.10 +20


3.11 +20


3.12 +20


3.13 +20


3.14 +20





3.15 -20


C cn b


SU.
23.7

48.9
23.7

46.4
22.7


30.5, 19.4


66.4 -b
59.8


66.7
48.6

66.6
48.6

66.1
48.8

66.8
48.3

138.8
128.5
128.3
127.3
53.3

49.4
25.4
23.5


135.0, 128.4
128.2, 127.2

147.9, 128.7
123.4

159.4, 126.6
113.9, 54.8

28.4, 19.1
18.9

30.4, 20.0
19.3




134.9, 128.1
128.0, 127.0


73.3 120.5,c 119.4, 118.8


72.4 145.8,e 133.2,e 129.1e
127.0, 119.0, 116.8

88.7 142.8, 125.8, 117.8


76.7 143.8, 126.2, 117.7


88.2 143.5, 126.1, 118.1


87.2 143.9, 126.8, 118.3


88.1 142.0, 125.2, 114.6


92.3 143.3, 125.9, 118.0


87.3 143.5, 126.0, 118.4





89.0 143.3, 125.9, 117.9


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
b c
(2.7)]. R' = H. Assignments can be interchanged with
the corresponding atoms of the 1-isomer. d The 40 carbon
atoms were not detected. e The 40 carbon atoms could not be
assigned with certainty, therefore peaks could be due to the
other isomers. The INEPT pulse sequence at 25 MHz (-480C,
CDCl3) was utilized for unequivocal assignment of the
spectrum.











Table 3.3. 1C-NMR chemical shifts of benzotriazol-3-yl
isomers of compounds (3.5) and (3.6) at a single temperature
(below coalescence) in CDC13.

No Tem. -NR2 R' CH Bt
(C)

3.5 -25 49.0 -a 65.9 120.5,b 116.4, 107.4
23.4
3.6 +20 49.8 _a 65.1 143.8,c 134.0,c 132.1c
23.4 127.7, 118.4, 110.6

a R' = H. b The quaternary atoms were not detected.

C Assignments can be interchanged between corresponding 40

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 1H-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 P 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










Table 3.4 Equilibrium constants (K) and free energies for the
isomerization (6Go) of N-[a-(benzotriazol-N-yl)alkyl]-N,N-
dialkvlaminn (3 ) and (I 7~13 1I;)


No NR2 R' X Y Solvent Tb K c
(C)


3.4 Pyr


3.7 Pyr


3.8 Pyr


3.9 Mor


3.10 Mor


Mor

Mor

Mor


3.14 Dib




3.15 Pip


H H H CDBr
CD3CA

H Me Me CDBr
CD3 C

Pr H H Toluene-d8
CD3CN

H H H CDBr
CD3 C

Ph H H CDBr
CD3 C

4-NO2-C6H4 H H CD3CN

4-MeO-C6H4 H H CD3CN

Pr H H Toluene-d8
CDC1
CD3 C

Pr H H Toluene-d8
CDBr
CDC1I
CD 3C

Ph H H Toluene-d8
CD CN


+22
+22

+23
+22

-40


+22
+23

+23
+20

+20

-20

+25
+21
+23

+25
+22
+22
+22

+21


1.6
6.2

1.7
4.9

0.4


1.8
5.6

1.2
2.5

2.5

2.7

0.4
0.5
1.1

0.4
0.7
0.8
0.9

1.1
e


AG d
(kcal/mol)

-0.25
-1.05

-0.30
-0.95

+0.60


-0.35
-1.00

-0.10
-0.55

-0.55

-0.50

+0.55
+0.40
-0.05

+0.55
+0.20
+0.15
+0.05

-0605


aPyr = pyrrolidine; Mor = morpholine; Dib = Dibenzylamine;

Pip = Piperidine. b Temperature at which the equilibrium

constant was measured. c K = P1 /P2, where P and P2 are the

populations of the 1- and 2- isomers, respectively (estimated
d
error 0.2). Estimated error +0.05-0.10 kcal/mole.
e Signals of two isomers too close to allow reliable

measurement of K.


3.11

3.12

3.13










solutions of which a 3-substituted isomer is also present,

when separation of the signals allowed, in addition to K =

PI/P2, K' = P3/P2, 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 AGO shows the

reverse. Deuterated acetonitrile was found suitable in

obtaining reliable isomeric ratios for nearly all compounds,

therefore direct comparison of the obtained AGO 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 K K' K" AGO AGO' AGO"
S(C) (kcal/mol)

3.5 Pyr H NO2 H Tol-d8 +21 1.1 0.05 -
CDC1 -25 2.5 1.0 2.5 -0.45 0.0 -0.45
CD3CR -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
CD3CA -20 6.4 5.5 1.3 -0.95 -0.85 -0.15


a Pyr = pyrrolidine. K = P /P2' K' = P3/P2, K" = P /P3

AGO = -RT InK (in kcal/mole). c The signals due to the 1-
n n
and 3- isomers resonated at the same frequency, therefore

K = [Pl + P3]/P2.










Adducts of type (3.1) (R' # H), either show little

preference toward either isomer in a common NMR solvent [e.g

(3.10) in CDBr3)], or, in extreme cases of steric hindrance,

the 2-isomer clearly becomes the most stable [e.g. (3.14) in

CDBr3)]; in these cases, K < 1 and AGO > 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(Pl)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 p (D, 250C, in C6H6)

1-Methyl 3.95
2-Methyl 0.49
1-Phenyl 4.08
2-Phenyl 0.97


Here we observe a similar effect. For example, the AGo

value of (3.14) indicates that the 1-isomer becomes more

favored on going from toluene (p = 0.36 D) [85MI1] to

bromoform (p = 0.99 D) to acetonitrile (p = 3.92), with

chloroform (p = 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










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-d8; 1-isomer in acetonitrile-d3).



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 CDBr3, (3.15) in toluene-d8], 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 IH-NMR spectrum

of the pyrrolidine-isobutyraldehyde adduct (3.8) in toluene-

d 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 -200C to -800C.

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 electron-releasing nature of

the substituents R and R' does not seem to have any

noticeable effect, as the magnitude of AGo remains the same










(within experimental error) for (3.10) and (3.11) in

acetonitrile-d3, and for (3.8), (3.13) and (3.14) in

toluene-d8, while the differences observed in (3.15) and

(3.8) in toluene-d8 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 AGo

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-NO2-Bt < 3-Me-5-NO2-Bt <1-Me-5-NO2, 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.










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 1H-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 [74MI11,

[80MI2], [82MI1] were calculated using the simplified

equation,

6G- = RTc[22.96 + ln(T /Sv)]


where T is the coalescence temperature (in oK) 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 +30C,

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




















- t-isomer
- 2-isomer


+50C



+20C





Ooc






-200C





-400C






-60C





-800C


r-E- -rT FT-T- -r I i i i-T- r- -rT-i-r- rI-T I -T--T T1I r TTT-T ---Plr
7 6 5 j 3 PPM


Figure 3.4 Temperature dependence of the 1H-NMR spectrum
[NCH(Pr )N region] of adduct (3.8) in toluene-d8.
8










unequal in most cases studied, therefore additional error is

introduced in the calculations [82MI1]. However, since only

approximate AGT 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 AGo < 0 pertain

to the 2- to 1- isomerization, whereas for those with AGo >

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. 1500C), but the AG#

values were generally lower in CDBr3 than in toluene-d8, 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 CD3CN was very small (see

Table 3.4), resulting in very weak proton resonances, and

therefore unacceptable errors in the measurement of T.
c"











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 NR R' X Y Solvent
2


H





H

H

Pr1

H

Ph


4-NO2-C6 4

4-MeO-C6 H

Pr1

Pr

Ph


CDBr3

Toluene-d8
Benzene-d
CDC13

CDBr3

CDBr3

Toluene-d8

CDBr3

CDBr.
CD3C

CD CN

CD CN

CD3CN

CDBr3

Toluene-d8


b AG+ c
T bG
(oE) (kcal/mol)

85 18.2

105 18.0
63 16.0
32 15.4

66 17.0

98 18.7

48 15.6

86 18.3

62 17.7
63 16.9

83 18.6

35 15.7

35 16.1

75 17.9

73 16.8


Pyr = pyrrolidine; Mor = morpholine; Dib = Dibenzylamine;


Pip = Piperidine.


b +20C. +0.15 kcal/mol


Effect of the solvent. The nature of the solvent

affects the magnitudes of both AG+ and AGO. Table 3.6

clearly shows that the energy barrier is highest in toluene-

d8, intermediate in bromoform-d, and lowest in acetonitrile-

d3. This is as expected, because a more polar solvent


3.4

3.5



3.6

3.7

3.8

3.9

3.10


3.11

3.12

3.13

3.14

3.15


Pyr

Pyr



Pyr

Pyr

Pyr

Mor

Mor


Mor

Mor

Mor

Dib

Pip


H

NO2



Cl

Me

H

H

H


H

H

H

H

H










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 CDBr3 are therefore classified in order of

decreasing magnitude, as follows: (3.7) > (3.4) > (3.6) >

(3.5). Compound (3.5) in CDBr3 is very near coalescence at











room temperature, so the AG in this solvent could not be

measured (the solvent freezes at +8.30C), 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 NCH2N 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-d8 and benzene-d6. The two

peaks coalesced into one as the temperature increased. In

CDC13 solution, however, three separate peaks were observed

for each isomer. The NCH2N 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 NCHCHMe2 atom. We then observe,

in order of decreasing AG4 magnitude, (3.10) > (3.15), and

(3.14) > (3.8). The order of decreasing AG4 values bears an










inverse correlation with the pKa values of the corresponding

secondary amines [72MI1]. Thus, pKa (morpholine) = 8.49] <

pK [(piperidine) = 11.20] and again pK (dibenzylamine) =

8.52 < pK [(pyrrolidine) = 11.30]. The benzotriazole

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-1-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

AGo > 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










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 +10C. 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-d8, CDCl3, CgDg, CD3CN) and Chemalog (CDBr3) 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.










Reagents and miscellaneous preparative and

chromatographic methods are described in Chapter 4.



3.4.2 Preparation of N-[(Benzotriazol-N-yl)methyl]-N,N-
dialkylamines


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(Pl)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. 76-780C

(from diethyl ether) (Found, C, 53.01; H, 5.14; N, 28.21%.

C11H13N502 requires, C, 53.44; H, 5.30; N, 28.32%); SH

(CDC13, -250C) 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










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)methyl]pyrrolidine 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%. C11H13C1N4 requires, C, 55.82; H, 5.54; N,

23.67%); 6H (CDC13, +210C) 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, NCH CH ).



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. 108-109.50C (from 95% ethanol);










lit. [52JA3868] m.p. 104-1050C; 6H (CDC13) 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)-3-methyl)-

propyl]pyrrolidine was obtained as a beige solid (41%),

which was dried under vacuum (0.2 mm Hg, 2 days); m.p.

50-53C (Found, C, 67.93; H, 7.95%. C14H20N4 requires, C,

68.82; H, 8.25; N, 22.93%); 6H (toluene-d8, -200C)

1-isomer, 7.99 (d, J = 9 Hz, H-4), 7.02 (m, H-5,6,7), 4.92










(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, CHMe2), 2.56 (m, NCH2CH2), 2.23 (m, CH2CH2),

1.04 (d, J = 10 Hz, CH3), 0.56 (m, J = 10 Hz, CH3).



N-[ c-(Benzotriazol-N-yl)benzyllmorpholine (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]morpholine was collected as a white powder (87%),

m.p. 110-1120C (from benzene) (Found, C, 69.01; H, 6.19; H,

19.00%. C17H18N40 requires, C, 69.37; H, 6.16; N, 19.03%);

6H (C6D6, +210C) 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-[f-(Benzotriazol-N-yl)-a-(4-nitrophenyl)methyl]-

morpholine (3.11). The product was obtained as a hard

yellowish solid (21.5 g, 96%) m.p. 145-1480C (from 95%

ethanol) (Found, C, 60.35; H, 5.03; N, 20.50%. C17H17N503










requires, C, 60.17; H, 5.05; N, 20.64%); 6H (CDCl3, +210C)

1-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, NO2CC2H2C2H2), 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 1-isomer), 7.93 (AA' m, J = 3

Hz, H-4,7), 7.52-7.35 (BB' m, H-5,6 and protons of

1-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 1H- (see below),

and 13C-NMR spectra at -20C (see Tables 3.1 and 3.2); 6H

(CD3CN, at -200C) 1-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).










N-[a-(Benzotriazol-N-yl)-S-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.

101-1030C (Found, C, 64.89; H, 8.20; N, 21.79%. C1420N40

requires, C, 64.59; H, 7.74; N, 21.52%); 6H (CDCl3, +210C)

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, CH3), 0.63 (d, J = 10 Hz, CH3); 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, CH3), 0.67 (d, J = 10

Hz, CH3).



N-[a-(Benzotriazol-N-yl)-o-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.

83-850C (Found, C, 77.76; H, 7.11%. C24H26N4 requires, C,

77.80; H, 7.07, N, 15.12%); bH (toluene-d8, +200C)

1-isomer, 8.03 (d, J = 8 Hz, H-4), 7.30 (d, J = 8 Hz, H-7),










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, CH3), 0.32 (d, J = 10 Hz, CH3); 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)benzyl]piperidine (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 13C- (Tables 3.1 and 3.2), and H-NMR

spectra: 8H (toluene-d8, +210C) 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) (CH2)2],

1.20-1.00 [m, N(CH2)4CH2]; 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)2], 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










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 elutedd with hexanes/Et20, 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

Et20. Total recovery 0.20 g, 80%. The following compounds

were collected as column fractions (in order of elution):


2-Methyl-5-nitrobenzotriazole. (Rf = 0.62, 0.094 g,

46%, m.p. 180-4C, lit. [64T211] m.p. 1870C); 6H (300 MHz,

CDCl3) 8.87 (dd, Jm = 2 Hz, J = 0.7 Hz, H-4), 8.24 (dd, J

= 9 Hz, Jm = 2 Hz, H-6), 7.98 (dd, J = 9 Hz, J = 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. (Rf = 0.37, 0.048 g,

24%, m.p. 154-1570C, lit. [64T211] m.p. not reported)

(Found, C, 45.29; H, 3.48%. C7H6N402.1/2H20 requires, C,

44.92; H, 3.77; N, 29.94%); 6H (300 MHz, CDCl3), 8.55 (d,

Jm = 2 Hz, H-4), 8.27 (dd, J = 9 Hz, Jm = 2 Hz, H-6), 8.18
(d, J = 9 Hz, H-7), 4.45 (s, 3 H, CH3); 6C (75 MHz, CDC13)

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. (Rf = 0.19, 0.06 g, 30%,

m.p. 160-2 OC, lit. [64T211] m.p. 1630C); 6H (300 MHz,

CDC13) 8.99 (d, J = 2 Hz, H-4), 8.42 (dd, J = 9 Hz, Jm = 2

H,, H-6), 7.69 (d, Jo = 9 Hz, H-7), 4.41 (3 H, s, Me); 6C

(75 MHz, CDC13) 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).





























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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 electrophilicity 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(Pl)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










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).




R'R2NH + 11 'Yj + R3CHO


-H20


4.2


R4MgX


NaBH4


4.3a 4.31


R
R CH,2-N
I I
R4m -


4.3m 4.3p


Scheme 4.1










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 0-

elimination in substrates having suitably placed hydrogens

[79MI1].


RR2 NH + RX --> R 2 R3N + 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].



+ (S ]
1 2 + 1 2 [H 12
CH20 + HNR1R --> CH2=NR R --> CH3-NR R (Eq. 4.2)


1 2 3 [H 1 23
R CONR2R > RCH2 NRR3 (Eq. 4.3)


Reductive carbonylation [83S723] or carboxylation

[78S766], [85TL5367] of 20 amines (Equation 4.4), although

versatile and high yielding, requires tedious procedures:










S 1. BunLi 12 + CICO2Me
R R2NH > RR2NCO2 Li > [ RR2NCO2CO2Me ]
2. CO

A 2N LiAlH4 1
--> R NCO2Me > R R NMe (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).



HNO2
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 RMgX 1
RNH2 + CH20 + (CH2OH)2 -> RN(CH2OCH2)2 >1 RN(CH2R )2

(Eq. 4.6)

Methods involving metal catalysts are available

[84JOC33591, especially in the patent literature [61MI1],

[85JAP60258145] but almost invariably require heating under

pressure.










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].



COC12 + 2 R MgX 1
HCONR2 > C1-CH=NR2 Cl ---> RCH-NR2

(Eq. 4.7)

In view of the continuous interest in the physiological

properties of amines ([59BP8141521, [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, R3 = H) i.e. derived from

formaldehyde was reported in Chapter 2. The corresponding

adducts (4.2, R3 H), i.e. derived from higher aldehydes










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

(Na2SO4/MgSO4) 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. PhCH2CH(OH)Ph from PhCHO and

PhCH2MgC1], were detected by GLC/MS. Therefore the

azeotropic distillation described above, remained the method

of choice.










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 [84MI1] 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











Table 4.1 Preparation of tertiary amines (4.3) R4R3CHNR1R2


1 2 3 4
Add. R R R3 Reagent R Amine Yield

4.2 4.3 (%)


CH2Ph

CH2Ph

CH2Ph

n-CgH^
n-C8 H17

CH3

Et


CH2Ph

CH2Ph

CH2Ph

n-CgH^
n-C8 H17
Ph

Et


-(CH2 4-

-(CH2)4-

CH2Ph CH2Ph

-(CH2)5-

-(CH2)20(CH2)2

-(CH )20(CH2)2

CH3 Ph

CH2Ph CH2Ph

CH2Ph CH2Ph

-(CH2)20(CH2)2-


H

H

H

H

H

H

Pr1

Pr1

Pr'

Ph

Prn

Ph

H

H

Pr1

Ph


PhMgBr

PhCH2MgC1

MeMgI

PhMgBr

BunMgBr

PhCH2MgCl

PhCH2MgCl

PhMgBr

MeMgI

Pr MgBr

PrnMgBr

BunMgBr

NaBH4

NaBH4

NaBH4

NaBH4


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).


Ph

CH2Ph

Me

Ph

Bun

CH2Ph

CH2Ph

Ph

Me

Pr

Prn

Bun

H

H

H

H


83

88

80

58

74

91

76a

64a

78a

59a

79a

82a

82

75

83

91


a This










conditions reported here (simply stirring at room

temperature) are milder than those reported for reduction of

adducts derived from primary aromatic amines [87JCS(P1)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.














+ R4-Mg-X


Bt-Mg-X


+ R3 3 NRI'R X-









R 4


R'R


Scheme 4.2


Independent evidence for the activating role of benzo-

triazole has been reported previously [87JCS(Pl)805] in the

reduction of a bis(benzotriazolyl)aminoalkyl adduct, in

which only the Bt group a- to the amine was replaced by

hydride (Scheme 4.3).
















N H-



H


H





Scheme 4.3


All amines were characterized as their picrate salts and

by their H- and 1C-NMR spectra (see Experimental section).

Chemical shift nonequivalency of the methyl groups of the

isopropyl moiety adjacent to the asymmetric carbon atom was

observed in the 1H- and 1C-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
in 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], [61GP10937991, [61MI2],

[62BEP17762], [63AP728], [85JAP60258145], [87AG(E)320].










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. 1H-NMR spectra were

recorded on a Varian XL 200 spectrometer, using TMS (6 = 0.0
13
ppm) as internal reference. 1C-NMR spectra were recorded

either on JEOL FX-100 (25 MHz), or Varian XL 200 (50 MHz)

instruments as solutions in deuterochloroform (CDCl3), using

the solvent signal at 6 = 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.










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 = 2500C).

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 H20). Silica gel (230-400 mesh)

was purchased from Merck.


4.4.2 Preparation of N-[(a-Benzotriazol-N-yl)alkyl]-
N,N-dialkylamines


The preparation of compounds (4.2a)-(4.2c) was based

on a general literature procedure [46JA24961 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










in formation of a white solid. N-[(Benzotriazol-N-

yl)methyl]-N,N-dibenzylamine was collected by filtration as

white microcrystals (95%), m.p. 120-1220C (from 95%

ethanol); lit. [75JCS(Pl)1181] m.p. 121-1230C; 6H (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,

NCH2N, 2-isomer), 5.40 (s, NCH2N, 1-isomer), 3.79 (s,

NCH2Ph, 2-isomer), 3.74 (s, NCH2Ph, 1-isomer); 6C (CDC13,

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 (NCH N), 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 EtOAc:CHCl3, 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 (MgSO4), the










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 (1500C at 0.25 mm Hg). The

analytical sample was obtained by drying a small amount of

the oil under 10 mm Hg, over P205 at 78C for 5 days (Found,

C, 74.07; H, 10.85; 14.94%. C23H40N4 requires, C, 74.14; H,

10.82; N, 15.04%); 6H (CDC13, 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, NCH2CH2, both isomers), 1.25

(m, methylene groups, 20 H, both isomers), 0.88 (m, 6 H,

CH3, both isomers); &C (CDC13, 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 (CH3) 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-yl)methyl]-N-methylaniline (4.2c).

The product was prepared according to literature methods

[75JCS(P1)1181] and was collected as white needles (64%),

m.p. 72-750C (from diethyl ether/hexane, 10:1, v/v); lit.

[75JCS(P1)1181] m.p. 76-78C; 6H (CDC13, 200 MHz) 7.98-7.93










(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, NCH3, 2-isomer), 3.01 (s, NCH3, 1-isomer); 6C

(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]pyrrolidine (4.2e), N-[a-(benzotriazol-N-

yl)-0-methylpropyl]-N,N-dibenzylamine (4.2f), N-[a-(benzo-

triazol-N-yl)benzyl]piperidine (4.2g), N-fa-(Benzotriazol-N-

yl)benzyl]morpholine (4.2) were described in Chapter 3

[compounds (3.8), (3.14), (3.14), and (3.10), respectively].



N-[a-(Benzotriazol-N-yl)butyl]morpholine (4.2h). The

compound was prepared using the general method described in

Chapter 3, for compounds (3.1, R3 4 H). After evaporation

of solvent benzene under reduced pressure, an oily substance

was recovered which was dried under 0.2 mm Hg for several










days. N-f[-(Benzotriazol-N-yl)butyl]morpholine was
1 13
characterized by its H- and 1C-NMR spectra: 6H (toluene-

d8, 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, CH2CH3,

both isomers); 6c (CDC13, -200C, 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 (CH3); 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










(100 g), and stirred with aq. sat. ammonium chloride (20-50

ml) and/or IN HC1 (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

(MgSO4) 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. 91-930C

(from 95% ethanol), lit. m.p. 91-940C (commercially

available from Aldrich Chemical Company); 8H (CDCl3, 200

MHz) 7.39-7.14 (m, 15 H, aromatic), 5.51 (s, 6 H, Ph-CH );

6C (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. 180-1850C (at 0.5 mm Hg); lit.

[47JOC760] b.p. 206-211C (at 3 mm Hg); 8H (CDCl3, 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); 6C (CDCl3, 25 MHz)

aromatic (140.5, 139.6, 128.8, 128.6, 125.7, 126.7), 58.1

(NCH Ph), 55.0 (NCH2CH2Ph), 33.4 (NCH2CH2Ph). N,N-Dibenzyl-

N-phenylethylamine was characterized as its picrate salt,










m.p. 118-120C (Found, C, 62.99; H, 4.94; N, 10.36%.

C28H26N407 requires, 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. 132-1360C (at

0.5 mm Hg); lit. [78S766] b.p. 101-1060C (at 0.35 mm Hg);

6H (CDC13, 200 MHz) 7.38-7.17 (m, 10 H, aromatic), 3.54 (s,

4 H, NCH Ph), 2.53-2.43 (q, J = 7 Hz, 2 H, CH2CH3),

1.07-1.00 (t, J = 7 Hz, 3 H, CH2CH3); &6 (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. 116-1180C; lit. [78S766]

m.p. 110-1110C.



N-Benzyl-N,N-dioctylamine (4.3d). The product was

obtained as a yellow oil, b.p. 110-1120C (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. C23H41N requires, Mt

331.3238); 6H (CDC13, 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, NCCH2CH), 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); SC

(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).










N-Methyl-N-pentylaniline (4.3e). A very clean oil was

obtained (73.5%), b.p. 97-980C (at 0.8 mm Hg); lit.

[67JOC2892] b.p. 107-1080C (at 4-5 mm Hg); 6H (CDCl3, 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); SC (CDCI3, 25 MHz)

149.3, 128.9, 115.7, 112.9 (aromatic), 52.6 (NCH2), 38.0

(NCH3), 29.3 (NCH CH ), 22.5 (NCH2CH CH ), 14.0 (CH3). N-

Methyl-N-pentylaniline was converted to its picrate salt,

m.p. 94-960C (Found C, 52.55; H, 5.41; N, 13.65%.

C18H22N407 requires, 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. 90-920C; lit. [45JCS438] m.p. 93-940C; NMR

spectra of the oil: 6H (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, NCH CH ), 1.06-0.99 (t, J = 7 Hz, 6 H, NCH2CH3);

6C (CDC13, 25 MHz) aromatic (140.4, 128.4, 128.1, 126.5),
54.5 (PhCH CH N), 46.5 (PhCH CH N), 32.9 (NCH2CH3), 11.3

(NCH CH ).



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