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Preparation and synthetic transformations of benzotriazole derivatives

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Title:
Preparation and synthetic transformations of benzotriazole derivatives
Creator:
Hughes, Craig V., 1961-
Publication Date:
Language:
English
Physical Description:
vii, 84 leaves : ill. ; 28 cm.

Subjects

Subjects / Keywords:
Adducts ( jstor )
Aldehydes ( jstor )
Amines ( jstor )
Ethers ( jstor )
Iodides ( jstor )
Ketones ( jstor )
Protons ( jstor )
Reactivity ( jstor )
Reagents ( jstor )
Sodium ( jstor )
Benzotriazole ( lcsh )
Genre:
bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

Notes

Thesis:
Thesis (Ph. D.)--University of Florida, 1988.
Bibliography:
Includes bibliographical references (leaves 76-83).
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Craig V. Hughes.

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University of Florida
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University of Florida
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Copyright [name of dissertation author]. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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AHC0769 ( NOTIS )
21663248 ( OCLC )

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PREPARATION AND SYNTHETIC TRANSFORMATIONS
OF BENZOTRIAZOLE DERIVATIVES








BY


CRAIG V. HUGHES


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


L9&-


















Prayer is the heart's sincere desire

Uttered or unexpressed


Thomas Troward














ACKNOWLEDGMENTS


First and foremost I wish to thank my graduate research director, Dr. Alan

Katritzky for his guidance and support over the past few years. I would also like to

thank the other members of my graduate committee, Drs. Jim Deyrup, William Jones,

Ken Wagener and Stephen Schulman for their insight and advice. My sincere

appreciation is also extended to Paul Savage, Jamshed Lam, Greg Hitchings, Glen

Noble, Franz Luxem, and Ramiah Murugan for their helpful suggestions during the

preparation of this work. A special thanks to Dawn Jones and Elizabeth Rich --

without their diligent efforts our office could not function.

To all my friends in the Katritzky group, both past and present, I thank you for

the warm-hearted comradery. I especially wish to mention my contemporaries,

Margaret, Dina, Mats, Jamshed, Franz, Saumitra, and Jose whom I shall fondly

remember in the years to come. Most of all, I wish to thank Rhonda, who shared so

much with me and will always occupy a special place in my heart.

Lastly, I would like to acknowledge my mother, Barbara, and my father,

Houston, who have each in their own way elevated my consciousness and have

allowed me to enter into the spirit of life.














TABLE OF CONTENTS



paMe


ACKNOWLEDGMENTS........................................................................................................... iii

A B ST R A C T ....................................................................................................................................... vii

CHAPTERS

1. MONO-N-ALKYLATION OF SULFONAMIDES......................................................... 1

1.1 Introduction...................................................................................................... ...... 1

1.2 Sulfonamidoalkylbenzotriazoles............................................................................... 5

1.3 N -A lkylsulfonam idcs................................................................................................ 11

1.4 E xperim ental............................................................................................................. 17

1.4.1 Preparation of 1-(Benzcnesulfonamidoalkyl)benzotriazoles General
Procedure......................................................................................................... 17

1.4.2 Reaction of Benzenesulfonamidoalkylbenzotriazoles with Sodium
Borohydride..................................................................................................... 18

1.4.3 Reaction of Benzenesulfonamidoalkylbenzotriazoles with Grignard Reagents... 19


2. SYNTHESIS AND REACTIVITY OF BENZOTRIAZOL-1-YLMETHYLAMMONIUM
S A L T S ................................................................................................................................... 20

2.1 Introduction.................................. .......................................... ............................... 20

2.1.1 The Mannich Reaction.................................................................................. 20

2.1.2 Aminomethylation of Five-membered Nitrogen Heterocycles........................... 21

2.1.3 Reactivity of Quaternary Ammonium Salts of N-Mannich Bases...................... 23

2.2 Synthesis of Benzotriazol-1-ylmethylammonium Salts................................................. 26

2.2.1 Preparation of Benzotriazol-1-ylmethylamines..................... .................... 26

2.2.2 Quaternization of Benzotriazol-1-ylmethylamines......................... .......... 26









2.2.3 Reaction of Iodomethylbcnzotriazole with Tertiary Amines................................ 28

2.2.4 Spectroscopic Investigations of Benzotriazol-1-ylmethylammonium Salts......... 30

2.3 Reactivity of Benzotriazol-1-ylmcthylammonium Salts................................. ....... 35

2.3.1 Background..................................................................................................... 35

2.3.2 Reactivity of N-Ylide from N-(Benzotriazol-l-ylmethyl)-N-
methylpyrrolidinium Iodide.......................................................................... 36

2.3.3 Reactions of N-(Benzotriazol-1-ylmethyl)-N-methylpyrrolidinium Iodide at
Elevated Temperatures.................................................................................. 37

2.3.4 Reactions of N-(Benzotriazol-1 -ylmethyl)-N-methylpyrrolidinium Iodide with
G rignard Reagents........................................................................................... 39

2.4 C onclusions................................................ ........................................................... 42

2.5 E xperim ental................................ .............. ............................................................ 43

2.5.1 Synthesis of Benzotriazol-1-ylmethylamines .............................................. 43

2.5.2 Method A General Procedure for Quaternization of Benzotriazol-1-
ylm ethylam ines.............................................................................................. 45

2.5.3 Method B General Procedure for the Reaction of Iodomethylbenzotriazole
with Tertiary Amines........................................................... ......................... 46

2.5.4 Thermal Decomposition of N-(Benzotriazol-l-ylmethyl)-N-
m ethylpyrrolidinium Iodide.............................................................................. 47

2.5.5 Reaction of N-(Benzotriazol-1-ylmethyl)-N-methylpyrrolidinium Iodide with
N ,N -D iethylaniline.......................................................................................... 48

2.5.6 Reaction of N-(Benzotriazol-1-ylmethyl)-N-methylpyrrolidinium Iodide with
Benzylmagnesium Chloride............................................... ................................ 49

2.5.7 Reaction of N-(Benzotriazol-1-ylmethyl)-N-methylpyrrolidinium Iodide with
Ethylm agnesium Iodide.............................................................. ...................... 49

2.5.8 Reaction of N-(Benzotriazol-1-ylmethyl)-N-methylpyrrolidinium Iodide with
M ethylmagnesium Iodide................................................................................ 50


3. THE REACTIONS OF BENZOTRIAZOLE AND AN AMINE WITH UNSATURATED
ALDEHYDES AND KETONES............................................................................ 51

3.1 Introd uction.................................................................................................................... 5 1

3.1.1 The Addition of Nuclcophiles to ct,P-Unsaturated Aldehydes and Ketones......... 51









3.1.2 The Reaction of Amines and Related Compounds with a,P-Unsaturated
Aldehydes and Ketones................................................................................ 54

3.1.3 Reactivity of Triazoles with a,P-Unsaturated Carbonyl Compounds................ 57

3.2 Reactions of Benzotriazole with a,P-Unsaturated Ketones....................................... 59

3.3 Reactions of Benzotriazole with Crotonaldehyde........................................................ 60

3.4 Addition of Benzotriazole and Amines to a,P-Unsaturated Aldehydes......................... 62

3.5 Reaction of 1,3-Bis(benzotriazolyl)alkylamines with Nucleophiles............................ 66

3.6 C onclusions............................................................................................................... 66

3.7 Experim ental............................................................................................................. 70

3.7.1 Preparationtion of 3-Benzotriazolylketones.............................. .................... 70

3.7.2 Preparation of 1,3-Bis(benzotriazolyl)alkylamines General Procedure............ 73

3.7.3 Reduction of 1,3-Bis(benzotriazolyl)alkylamines with Sodium Borohydride -
G general Procedure........................................................................................... 73

3.7.4 Reaction of N-[1,3-Bis(benzotriazolyl)propyl]morpholine with
Phenylmagnesium Bromide.......................................................................... 74

4. SUMMARY AND CONCLUSIONS............................................................................ 75

R E FER E N C E S.................................................................................................................................. 76

BIOGRAPHICAL SKETCH.................................... ......................................................................... 84














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

PREPARATION AND SYNTHETIC TRANSFORMATIONS
OF BENZOTRIAZOLE DERIVATIVES

By

Craig V. Hughes

August, 1989

Chairman: Dr. Alan R. Katritzky
Major Department: Chemistry


Benzotriazole has been utilized as an activating group for carbon-carbon bond

formation in organic synthesis. The nitrogen-hydrogen bond is sufficiently labile to

undergo Mannich-like reactions with an aldehyde and an amine or similar compound

which contains a nitrogen functionality (e.g. hydroxylamines, carboxamides, and

thioamides). The benzotriazolyl group can subsequently be displaced by the action of

sodium borohydride, Grignard reagents or organolithium reagents, thereby affording

mono-N-substituted adducts.

Benzotriazole is also a moderately nucleophilic species which can attack electron

deficient carbon centers. Benzotriazole undergoes 1,4-addition with a, -unsaturated

aldehydes and ketones. When two or more molar equivalents of benzotriazole are

reacted with an oa,-unsaturated aldehyde and an amine, a second equivalent

benzotriazole adds across the carbon-oxygen double bond to give an N-[1,3-bis-

(benzotriazolylalkyl)]amine. This procedure incorporates two synthetically important

reactions in organic chemistry, the Mannich reaction and the Michael reaction.












CHAPTER 1
MONO-N-ALKYLATION OF SULFONAMIDES


1.1 Introduction



The alkylation of sulfonamides is normally carried out by reaction of the sodium

salt of a sulfonamide 1.2 with an alkyl halide or a similar reagent [79CO(4)365,

79CO(3)345, 61BSF486, 64UKZ1070] as shown in Figure 1-1. Recently, Gajda and

Zwierzak [81S1005] utilized a heterogeneous two-phase system along with tetra-n-

butylammonium hydrogen sulfate (TBAS) as a phase transfer catalyst. These workers

found that a mixture of 50 % aqueous sodium hydroxide and benzene, or a mixture of

powdered sodium hydroxide and potassium carbonate in benzene or toluene, in the

presence of 10 mole % TBAS, afforded higher yields of alkylated sulfonamides than

when TBAS was not used. They could not perform stepwise alkylation; however, they

obtained good yields of symmetrical N,N-dialkylated products 1.4 using primary alkyl

or benzyl halides.

A few similar but less general methods for the mono-N-alkylation of

sulfonamides have been reported. Cheeseman [57JCS115] prepared

N-(diphenylmethyl)sulfonamides 1.5 from diphenylmethyl nitrate and two equivalents

of a sulfonamide in the absence of base; however, nitrates are not commonly available

starting materials. Markov and Burmistrov characterized arenesulfonamides by

reaction with diphenylcarbinol in acetic acid in the presence of zinc chloride to afford

high yields of N-diphenylmethylarenesulfonamides [64UKZ1070] (1.5, R2 = Aryl).








R R3CHX
R2SO2NH Na + R'R R2H SO2NHCHR'R3
1.2 1.3

NaOH

ZnCI2 TBAS, NaOH
R2SO2NHCH(Ph)2 R2SONH2 3 R2SO2NH(CHR R )2
AcOH, (Ph)2CHOH C6H6 R'R CHX
1.5 1.1 1.4

(Ph)2CHNO2

R2S02NHCH(Ph)2
1.5



Figure 1-1 Known Methods for Alkylation of Sulfonamides



Primary sulfonamides have been derivatized to afford mono-N-substituted

products where the acidity of the remaining N-H is significantly enhanced. Gensler

and coworkers [71JOC4102] reported a procedure for mono-N-alkylation of

arenesulfonamides by reacting them with ethyl chloroformate to afford the

corresponding ethyl N-sulfonylcarbamates 1.7 (Figure 1-2). The carbamates were

converted to their sodium salts and subsequently treated with alkyl or benzyl bromides

to afford the N-substituted analogs 1.9. Saponification of these adducts afforded the

mono-N-substituted sulfonamides 1.10. In all the reactions discussed so far, a

compound of type R2SO2NHCHR1R3 is constructed from R2SO2NH2 and R1R3CHX.

A number of other methods for the N-alkylation of sulfonamides have been

reported. Barluenga and coworkers [84JCS(P1)721] found that simple, non-

functionalized olefins react with p-toluenesulfonamide in the presence of anhydrous

mercuric nitrate to afford organomercury complexes. These complexes were

subsequently reduced with sodium borohydride to give N-substituted

p-toluenesulfonamides.









CICOgEt /CO2Et
----- ArSO2N
NaOH H
1.7



RBr /CO0Et
ArSO2N
R


NaOMe
a ArSO2N CO2Et Na +

1.8


NaOH
IN


ArSO2NHR


1.10


Figure 1-2 Saponification of Ethyl N-Sulfonylcarbamates


The reactions of organoboranes with chloramine-T (sodium N-chloro-p-

toluenesulfonamide) were described by Smith et al. (Figure 1-3) [78TL181]. A

possible mechanism for this reaction is the formation of a nitrogen-boron bond to give

an anionic intermediate 1.12 followed by migration of an R group onto nitrogen,

thereby displacing chloride ion (NaCI forms). The intermediate sulfonamidoborane

1.13 was not isolated, but was decomposed by heating in 4 M sodium hydroxide at

60 OC to afford a dialkyl borinic acid and an N-alkyl-p-toluenesulfonamide 1.14.


BR3


MeCGH4SO2NCI Na +


1.11


R

i02-N- BR2


1.13


r '
MeCH4SO2 N -- BR2

(I
1.12 -
1.12


R
NaOH
MeC6H4SO2 NH +


1.14


Figure 1-3 Hydrolysis of Sulfonamidoboranes


ArSO2NH2

1.6


- NaCI

60 C


R2BOH








Apparently, the only previous convergent method for the N-alkylation of a

sulfonamide was the reaction of benzenesulfonamide with triethyl orthoformate to give

N-ethoxymethylbenzenesulfonimine 1.15. Stetter and Thiesen [68CB1641] showed

that these imines could be converted by two equivalents of a Grignard reagent into

N-(dialkylmethyl)benzenesulfonamides 1.16 (Figure 1-4).



-- 2 EtOH
SOgNH2 + HC(OEt)3 EH SON = CHOEt

1.15


R = Et, nPr, 'Pr, Ph 2 RMgX



S- ONHCHR2

1.16



Figure 1-4 Reactivity of Ethoxymethyl Benzenesulfonimine with Grignard Reagents


The two-step procedure to be discussed provides a convenient and general

synthesis of mono-N-alkylated sulfonamides. Sulfonamidoalkylbenzotriazoles 1.17

(Figure 1-5) were prepared by reacting benzotriazole, an aryl or alkyl aldehyde, and a

primary sulfonamide under Dean-Stark conditions. Sulfonamidoalkylbenzotriazoles

were reacted with either sodium borohydride or Grignard reagents to give mono-N-

alkylsulfonamides 1.18 or 1.19, respectively.

Alkylation of primary sulfonamides is not the only major route by which

N-alkylsulfonamides may be obtained. The reactions of primary and secondary amines

with sulfonyl chlorides give N-alkyl- and N,N-dialkylsulfonamides, respectively. In






5


terms of yield and ease of preparation, this procedure is comparable to the

benzotriazole-assisted method. However, the versatility of the benzotriazole method is

greater as the range and complexity of groups which can be introduced at the N-atom is

considerably extended.

4
3a 3

U L N 2
6 7N i R CH2NHSO2R2
7 H NaBH4
N 1.18
RiCHO -N
Nr R3MgX
SCH
R2SO2NH2 R1 'NHSO2R2 R
CHNHSO2R2
R3

1.17 1.19


Figure 1-5 Preparation and Reactivity of Sulfonamidoalkylbenzotriazoles


1.2 Sulfonamidoalkylbenzotriazoles



An equimolar mixture of benzotriazole, a sulfonamide, and an aldehyde were

heated in either benzene or toluene under reflux. Water was formed as a by-product

and was removed via azeotropic distillation using a Dean-Stark adapter. When the

theoretical amount of water had been collected, the reaction was cooled to room

temperature whereupon the sulfonamidoalkylbenzotriazole crystallized from the

mother liquor. Attempts to prepare the corresponding adduct from formaldehyde and a

secondary sulfonamide (N-methyl-p-toluenesulfonamide) failed. These adducts were

characterized and are presented in Table 1-1. The attempted preparation of

l-(benzenesulfonamido-p-tolylmethyl)benzotriazole (1.20, X = Me) gave

N-(p-tolylmethyl)benzenesulfonimine (1.21, Figure 1-6).













NHSO2Ph X CH= NSOPh + N

H
1.21
X
1.20 X = H, Me



Figure 1-6 Formation of Sulfonimines




In the two cases where formaldehyde was used to prepare 1.17 (RI = H, Figure

1-5), the methylene protons adjacent to benzotriazole resonated as a singlet at 8 5.9 (R2

= Ph) and 8 6.1 (R2 = Me) in the 'H NMR spectra, but the proton attached to nitrogen

could not be seen. Where R' = alkyl, the N-H proton resonated at 8 9.7-9.8 and was

split into a doublet by the adjacent methine proton. When R' = 2-pyridyl, the methine

proton was apparently shifted far downfield due to the anisotropic effect of the aryl

ring and was obscured by the large aryl multiple.

When R' = H or alkyl, a doublet of doublets was observed at 8 8.0-8.2 which

could be assigned to H-7 and H-4 of the benzotriazole ring based upon published data

[75JCS(P2)1695, 83H1787, 870MR260]. Both ortho coupling and fine meta coupling

could be seen unless R' was an aromatic substituent, in which case it was obscured by

the aryl multiple (Table 1-2).

Previous work has demonstrated that adducts obtained from benzotriazole, an

aldehyde and an amine [87JCS(P1)799, 87JCS(P1)805, 890PP(UP)] or from a

thioamide [88JCS(P1)2339, 88JOC5854] existed as a mixture of 1- and 2-positional








isomers in solution. However, the 13C NMR spectra of the sulfonamide adducts 1.17

showed precisely the number of resonances in the aryl region required to account for

the 1-substituted isomer only (Table 1-3). When R' = H or alkyl and R2 = phenyl

(1.17a), ten resonances could be seen in the aryl region of which six were assigned to

the benzotriazol-1-yl group and four to the phenyl ring. The carbon adjacent to

benzotriazole appeared as a single resonance in the range of 54-73 ppm except where

R' = phenyl. Hence, facile isomeric interconversion did not take place in solution.

In the case where R' = phenyl, no signal was observed below 8 125, but a unique

resonance at 8 171.8 was present. Although the recrystallized starting material gave

the correct elemental analysis, in DMSO-d6 this benzotriazole-sulfonamide adduct was

in equilibrium with N-(phenylmethyl)benzenesulfonimine (1.21, X = H) and

benzotriazole, as shown in Figure 1-6. This sulfonimine was also prepared by an

independent method [81JCS(P1)2435] and characterized by 'H and 13C NMR

spectroscopy. Comparison of its spectral properties with those of the benzotriazole-

sulfonamide adduct showed similar chemical shifts and coupling constants.


















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Treatment of 1.17 with 3 equivalents of anhydrous sodium borohydride gave

mono-N-substituted sulfonamides 1.18 which contain a methylene group adjacent to

the N-atom. Similarly, 2.5 equivalents of a Grignard reagent were employed in the

conversion of 1.17 to 1.19, which contains a branched substituent attached to the

N-atom. The sulfonamidoalkylbenzotriazoles were insoluble in both diethyl ether and

tetrahydrofuran at ambient temperature, and were only slightly soluble at their

respective boiling temperatures. To insure that intimate contact between the reactive

species was achieved, 1.17 was placed in a soxhlet apparatus and extracted into the

reaction mixture with hot solvent.

During isolation and purification of products 1.18 and 1.19, an aqueous buffer of

pH 9.7 was used to remove the bulk of the benzotriazole (pKa = 8.2) [79CO(4)365]

which was formed as a side-product. The pKa of mono-substituted sulfonamides lie in

the range of 10-12 [79CO(3)345, 61BSF486], therefore this buffer was more basic than

benzotriazole but less basic than the sulfonamide, and thus selectively removed

benzotriazole. In all cases, however, it was necessary to purify the crude product by

column chromatography to remove residual benzotriazole.

All mono-N-alkylbenzenesulfonamides had a few spectral properties in common.

The H-2 and H-6 protons about the benzenesulfonamido moiety (R2 = Ph) resonated in

the range of 8 7.5-7.9 with the H-3, H-4 and H-5 protons appearing as a distinct

multiple 0.2 to 0.3 ppm further upfield in the 'H NMR spectra. For N-benzyl or

N-a-alkylbenzyl substituted products, the aromatic benzyl protons appeared as a

multiple at 8 7.1-7.2 which integrated for five protons. The position and multiplicity


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o; od
0N 00<


0c eI
Nq -0


r-~
od


00 -
4N N .
00




00 00(1
C 42


CO C-4





t- 00
cr) nC C


0


C;
ct




; c,


0 00 -i
00 O 0































o 1 a
03


N






















w 0 ^w
N 0 0
m n^ na


r- 0 I-i *- rl r- V i; ,I: I,*
n0 m N- Nl) I
' Id0 'C 'D W" 0 N ( c N
tT '. 'Cb '0 /in 'C ^t


SC
Cl Cl



Cn N

'r^ *vf

^6 '.
\d \d


00

00
N N)
Inl C<


- Cl Cl Cl

N" 'C 'C 'C


c14 N4 ( c
In oC -'
N 'C & 00



In" 'C ^f (
r-N C
m ^ l


In 0 -I 'C 00
\o Nr 00 r 00 r-





Cl (4 C4 C4 C1 4


cl In 00 I
cl -


C 6 6 -
C) 14 C=


- B -


SO -
& 3 & &
- l l


S-

0
















in


00
CO

*I Sr)



u
Ocq



u


6
Z




















00


oo


0


ON
00



-N











N r






-













00 CN
4 r


(5 06 (-










N q M C4
kK -

00 06
q M Cli











O C14





00
W) 0<) 06 0l

0 en
c U



o



C ,


C c] o I o 1
CJ^ ^ ;







d "
rd








of the N-H proton varied from compound to compound, and was often obscured by

signals from the aromatic protons.





1.4 Experimental



Melting points were obtained on a Kofler hot stage apparatus and are uncorrected.

All 1H and 13C NMR spectra were run on a Varian XL 200, or a Varian VXR 300

NMR spectrometer using tetramethylsilane as an internal standard with DMSO-d6 as

solvent and internal lock. Ethereal solvents were freshly distilled from sodium

benzophenone ketyl. Glassware for organometallic reactions was dried overnight at

110 OC prior to use. All such reactions were carried out under an atmosphere of either

dry nitrogen or argon. An aqueous buffer solution which was 0.015 M sodium

hydroxide and 0.0213 M sodium borate decahydrate (measured pH = 9.7) was used to

selectively remove benzotriazole.



1.4.1 Preparation of 1-(Benzenesulfonamidoalkyl)benzotriazoles General Procedure


The following method gives the experimental details for the preparation of

compound 1.17b. This method is representative of the general procedure for the

preparation of 1-(benzenesulfonamidoalkyl)benzotriazoles.



1-(1-Benzenesulfonamido-2-methylpropyl)benzotriazole 1.17b. A 100 ml round-

bottom flask was charged with benzotriazole (5.96 g, 50 mmole), isobutyraldehyde

(3.60 g, 50 mmole), benzenesulfonamide (7.86 g, 50 mmole) and dry toluene (50 ml).








The flask was equipped with a Dean-Stark adapter and condenser. The reaction

mixture was heated under reflux with stirring for 24 h, after which time the theoretical

amount of water (0.9 ml) had been removed by azeotropic distillation. The solution

was cooled and the crystalline precipitate was filtered, washed with cold toluene, and

dried. Recrystallization from 95 % ethanol afforded 1.17b (13.91 g, 84 %).



1.4.2 Reaction of Benzenesulfonamidoalkylbenzotriazoles with Sodium Borohydride


The following method gives the experimental details for the preparation of

compound 1.18b. This method is representative of the general procedure for the

reaction of benzenesulfonamidoalkylbenzotriazoles with sodium borohydride.



N-(2-Methylpropyl)benzenesulfonamide 1.18b. A 50 ml round-bottom flask was

charged with 1.17b (2.0 g, 6.1 mmole), sodium borohydride (0.7 g, 18.5 mmole), and

absolute ethanol (30 ml). The flask was equipped with a condenser and drying tube,

and the contents were heated under reflux for 10 h. The solvent was removed in vacuo

and the aqueous buffer solution (30 ml) was added to the residue. The contents were

stirred for 30 min and extracted with diethyl ether (3 x 15 ml). The combined ethereal

layers were dried over magnesium sulfate and concentrated to afford

N-(2-methylpropyl)benzenesulfonamide (0.92 g, 71 %). Purification by

chromatography (1:1 petroleum ether:ethyl acetate) and recrystallization from

ethanol:petroleum ether afforded an analytical sample.








1.4.3 Reaction of Benzenesulfonamidoalkylbenzotriazoles with Grignard Reagents


The following method gives the experimental details for the preparation of

compound 1.19c. This method is representative of the general procedure for the

reaction of benzenesulfonamidoalkylbenzotriazoles with Grignard reagents.



N-(Diphenylmethyl)benzenesulfonamide. A 250 ml, three-neck round-bottom

flask was charged with magnesium turnings (0.5 g, 20.6 mmole). The flask was

equipped with a soxhlet adapter, a soxhlet thimble containing 1.17c (2.0 g, 5.5 mmole),

a soxhlet condenser, a drying tube, and a side-arm addition funnel. The system was

sealed, purged with nitrogen and flame dried. A solution of bromobenzene (2.1 g, 13.3

mmole) in dry tetrahydrofuran (120 ml) was added dropwise with stirring and the

mixture was heated to 50 C for 4 h. The soxhlet adapter was then insulated with glass

wool and the temperature was increased to 70 OC for 24 h.

Excess Grignard reagent was quenched with 3 M hydrochloric acid (50 ml) and

the organic and aqueous layers were separated. The aqueous layer was washed with

diethyl ether (3 x 25 ml), and the combined organic layers were washed with aqueous

buffer solution (2 x 30 ml). The organic layers were dried over magnesium sulfate and

concentrated in vacuo. Chromatography (1:1 petroleum ether:ethyl acetate) and

recrystallization from 95 % ethanol gave N-(diphenylmethyl)benzenesulfonamide

(1.34 g, 75 %).












CHAPTER 2
SYNTHESIS AND REACTIVITY OF
BENZOTRIAZOL-1 -YLMETHYLAMMONIUM SALTS


2.1 Introduction



2.1.1 The Mannich Reaction


The Mannich reaction is one of the most synthetically useful carbon-carbon bond

forming reactions in organic chemistry. In general, the Mannich reaction is the

condensation of ammonia or a primary or secondary amine (usually in the form of its

hydrochloride salt) with formaldehyde and a compound which contains an active

proton. The overall transformation involves replacement of the active proton by an

aminomethyl or substituted aminomethyl group, as shown in Figure 1-1. If R2 and/or

R3 is a proton, then further condensation may occur to give secondary amines 2.2, or

tertiary amines 2.3. Over time, the definition of the Mannich reaction has been

extended to include aldehydes other than formaldehyde. The products formed from the

Mannich reaction are commonly referred to as Mannich bases.

The first example of the Mannich reaction was reported by Tollens et al. when

they isolated a tertiary amine from a mixture of ammonium chloride, formaldehyde and

acetophenone [03CB1351, 06CB2181]. In 1912, Mannich and Krosche obtained a

tertiary amine hydrochloride by reacting antipyrine salicylate with formaldehyde and

ammonium chloride [12AP647]. With this discovery, they began a systematic

investigation which demonstrated the generality and applicability of this reaction to

organic synthesis.









CHR'Y
Y- CH-N
2 = H R R
R2 2.2
Y-H + R'CHO + HNR2R3 Y-CH-N
R1 \ R3= H
2.1
CHR'Y
Y-CH-N
i CHR'Y
R'
2.3


Figure 2-1 The Mannich Reaction



2.1.2 Aminomethylation of Five-membered Nitrogen Heterocycles


The aminoalkylation of several five-membered N-heterocycles (either

monocyclic or fused-ring systems) which contain a labile nitrogen-hydrogen bond (2.4,

Figure 2-2) have been the subject of numerous reviews in the literature [58JO707,

62JO1714, 73S703]. The most widely studied system, phthalimide, can be

aminomethylated with sundry primary aliphatic amines, primary aromatic amines,

arylalkylamines and dialkylamines [42JA222, 46JA 1657, 54CB 1690, 54JCS1329,

56JA672]. Even indole, which typically undergoes electrophilic substitution at the

3-position can be selectively N-aminomethylated under the appropriate conditions

[66CB889]. Upon warming, however, these indole adducts rearrange to their

1-substituted isomers.


R2

N N-H + R'CHO + HNRR3 N- -H-N-R3

2.4 R1 2.5


Figure 2-2 Aminomethvlation of Nitrogen Heterocvcles








In 1960, Stavrovskaya and Kolosova reported that aminomethylation of

2-mercaptobenzothiazole occurs exclusively on the ring N-atom rather than on the

exocyclic S-atom [60JGU689]. In solution, 2-mercaptobenzothiazole, 2.6 is in

equilibrium with it tautomer, benzothiazole-2-thione, 2.7 (Figure 2-3). It is possible,

however, that 2.9 is formed in situ and subsequently rearranges to 2.8.


N NNR R2
-: N \-SH N

2.6 S
HCHO 2.8
1 H HNR'R '
SN N /--NR'R2


2.7 2.9


Figure 2-3 Aminomethylation of 2-Mercaptobenzothiazole



The aminomethylation of heterocycles containing more than one N-atom have

been reported. Bachmann and Heisey prepared Mannich bases from benzotriazole and

benzimidazole using secondary aliphatic amines; however, they reported that no

products could be obtained from imidazole, 2-ethylimidazole or 2-ethylbenzimidazole

[46JA2496]. Orth and coworkers prepared a series of aminomethylated derivatives

from indazole, benzimidazole and benzotriazole [68JPS1814]. These investigators

found that the benzotriazole and benzimidazole derivatives were stable compounds,

whereas the indazole adducts could only be isolated as their hydrochloride or

methiodide salts. The relative instability of aminomethylindazoles was also reported

by Pozharskii et al. [64JGU3367].








Mannich bases obtained from nitrogen heterocyclic systems can be converted to

quaternary ammonium salts 2.12 by treatment with alkylating agents (Figure 2-4).

Alternatively, quaternary salts of N-Mannich bases are also prepared by treatment of a

tertiary amine either with an iminium salt, 2.10 [72CB2233, 82AP40] or with an

a-halomethylamine, 2.11 [67LA147].




SN-CH--N -R

R 2.5 R2 x-

SN-CH- N-R3
O 1
R' R4
X-
+ H / NRR4 2.12
( N=C or N- CH-X
RR

2.10 2.11


Figure 2-4 Preparation of Quaternary Salts from Heterocyclic N-Mannich Bases


2.1.3 Reactivity of Quaternary Ammonium Salts of N-Mannich Bases


The quaternary salts of heterocyclic N-Mannich bases have been shown to

undergo a wide array of reactions, ranging from substitutive displacement of a tertiary

amine to formation of reactive intermediates under thermolytic conditions. The

trimethylamine moiety of N-(trimethylammoniomethyl)phthalimide iodide, 2.13 can be

displaced by sodium salts of diphenylphosphine or diphenylarsine [74JPR851], or by

sodium salts of activated methylene compounds [54CB 1690] to give N-phthalimido

derivatives, 2.14. Similarly, both cyanide and hydroxide can displace trimethylamine.








0 I-

N N(CH3)3



2.13
2.13


0

+ Na+ Z N


0
2.14


Z = As(Ph)2, P(Ph)2, CH(CO2Et)2, CN, OH


Figure 2-5 Reaction of N-(Trimethylammoniomethyl)phthalimide Iodide with
Nucleophiles


Swaminathan and coworkers prepared the quaternary methiodide salts of both

1-dimethylaminomethyl-3-methylindole, 2.15a and 1-dimethylaminomethyl-3-

cyanoindole, 2.15b [58JO707]. These researchers treated 2.15a and 2.15b with sodium

cyanide, sodium diethyl malonate, phenylmagnesium bromide, piperidine and

morpholine in order to determine the reactivity of these salts toward nucleophiles. Salt

2.15b was found to be inert to each of the aforementioned nucleophiles, but 2.15a

underwent substitution in all cases to give 2.17 (Figure 2-6). These investigators

reasoned that the reaction proceeded via a cationic intermediate 2.16. Carbon-nitrogen

bond scission leading to 2.16 would be favored by an electron-donating substituent

such as methyl, whereas an electron-withdrawing substituent would disfavor this

process.


x




N(CH3)3
2.15
a X=CH3 b X=


x x x


- N + N "N
VCH \ +
CH2 CH2 Z


2.16


CN


Figure 2-6 Reactivity of 3-Substituted I-(Trimethylammoniomethyl)Indoles


2.17








N-(Ammoniomethyl) derivatives of pyrrole and indole dissociate at elevated

temperatures to give 5-azoniafulvene cation, 2.19 and its benzo-annellated analog,

respectively [85HCA2275, 88TL4415]. The cationic intermediate 2.19 reacts with

dimethylaniline to give a mixture of o- and p-(pyrrol-l-ylmethyl)-N,N-

dimethylanilines (2.20 and 2.21, Figure 2-7). Both nitrones and azomethine imines

add to 2.19 to give the respective products (2.23a and 2.23b) from a formal 67 + 47t

cycloaddition.




N N
\ II +
+ 1 CH2
NR'R2R3
2.18 2.19

R1, R2, R3 =Me, Et / R + H
PhNMe2 N=C
y- R
2.22



(NN

S~Y+ R5

Me2N NMe2 2.23

2.20 2.21 a Y R, R, R6MeP
b Y = NR6

Figure 2-7 Reactivity of 5-Azoniafulvene Cation



Recent work by Katritzky et al. has shown that benzotriazole 2.24 condenses

with equimolar quantities of an aldehyde and primary amine [87JCS(P1)799,

87JCS(P1)805, 890PP(UP)] or secondary amine [87JCS(P1)799, 87JCS(P1)2673] to

afford N-Mannich bases, 2.25 (Figure 2-8). Further synthetic utilization of these








adducts was achieved by nucleophilic substitution of the benzotriazolyl moiety by the

action of Grignard reagents or sodium borohydride. By converting 2.25 into a

quaternary salt, 2.27, one could obtain a compound with two potential leaving groups;

the benzotriazolyl moiety and the trisubstituted ammonio group. The investigation to

be discussed focuses upon the synthesis of benzotriazolylmethylammonium salts and

their reactivity.





2.2 Synthesis of Benzotriazol-1-ylmethylammonium Salts



2.2.1 Preparation of Benzotriazol- 1-ylmethylamines



Secondary amines were N-benzotriazolylmethylated using benzotriazole and

formaldehyde in either methanol or diethyl ether. Less reactive amines such as

4-N-methylaminopyridine and N-methylaniline were reacted under Dean-Stark

conditions (as described in Chapter 1) to give 4-N-(benzotriazol-l-ylmethyl)-N-

methylaminopyridine and N-(benzotriazol-1-ylmethyl)-N-methylaniline, respectively.



2.2.2 Quaternization of Benzotriazol- 1-ylmethylamines



Several of the salts 2.27a-2.27i were prepared by treatment of benzotriazol-1-

ylmethylamines with 1.5 equivalents of an alkylating agent in dry acetonitrile (Method

A, Figure 2-8). The salts precipitated from the solution and were purified by

recrystallization (see Table 2-1 for characterization). The choice of electrophile

appeared to be limited to methyl iodide, ethyl iodide or 1-chloromethylbenzotriazole.















I I
z
zI \z--





I I


x
ml


z
r-z z-i:


zz
\ z/ m


z
zb \z--


\ y
+ z

zz C,
z-,- "---/"
C*4


EC.

1r
z


z
zv tz


+z
II
C,



z
z, z


CO "x
CV
c








Ethyl bromoacetate and benzyl bromide were also investigated; however, they failed to

give the expected benzotriazolylmethylammonium salts in either acetonitrile or when

heated in the absence of solvent with benzotriazolylmethylamines. Methyl tosylate did

give the corresponding salt, 2.27b, with benzotriazol-1-ylmethylpyrrolidine; however,

it did not react with any of the other benzotriazolylmethylamines.

One explanation for why several benzotriazolylmethylamines failed to undergo

quaternization with an electrophile is that these adducts are in equilibrium with the

ion-pair 2.28 (Figure 2-8) in solution [87JCS(P1)2673]. The benzotriazolate anion

competes successfully with 2.25 in the reaction with electrophiles, thus decreasing the

concentration of 2.28 and shifting the equilibrium towards further ionization of 2.25.

In several cases the 1,3-dialkylbenzotriazolium salts, 2.30 precipitated from the

reaction mixtures.

Quaternization of the benzotriazolylmethylaminopyridines occurred on the

N-atom of the pyridyl ring to afford 2.31 and 2.32 (Figure 2-9). This phenomenon can

be explained in terms of the higher basicity of the pyridine nitrogen as compared to the

exocyclic nitrogen [76AHC(S1)154]. For example, 4-(N,N-dimethylamino)pyridine

undergoes protonation or methylation exclusively on the heterocyclic nitrogen atom

[790MR159].



2.2.3 Reaction of Iodomethylbenzotriazole with Tertiary Amines


An alternative method which was found to be more general (Method B) for the

preparation of 2.27 is the reaction of iodomethylbenzotriazole with tertiary amines

(Figure 2-8). Iodomethylbenzotriazole reacts more rapidly than chloromethyl-

benzotriazole and forms less soluble and less hygroscopic ammonium salts in



















e "c ~ 't CC c a~ 000,,
a w : n i N n m 0 p w
CO( W) S in It %n en 't tn no a00 Wd0 W0 M r- a,
SS 16 ii wi i ,i W) %n 06 0 r4f mE C; r4






cnoo r-) r- W)
00 47 cn cn ^'t ^ (S li ^r- rncn Os o 09~ .io q cn cn





'S 't 0 E 0 i C '
Srn (71-o (7 N) C,\^ k-- n cno 0-1 0-0o kn^ m V, r- r









O OO
.00 c. I n -q 0t In V: c In
en'-< cncn 00o o00 (71 0 t cnc V) N rl- r- C-4 cs







) o ;a o C)l 0


Sa' 00 m g


o l
- U,








So


Cl


uu





l l C Cl
N N (S
M n N rj r


- -


N



5 0 -


z u

U. al
CIT


N N N N N N N
1 ci 19 pei ei 9 1
C l C4 C4 C4 e4 eq


z:




Ca
.


w
U5



00


11


0
0"








comparison with analogous chlorides. Dimethylaminopyridine reacts at the pyridyl

N-atom rather than the amine nitrogen to afford 1-(benzotriazol-l-ylmethyl)-4-(N,N-

dimethylamino)pyridinium iodide, 2.33. An attempt to extend this method to 1-

(a-chlorobutyl)benzotriazole [87JCS(P1)811] led only to the product from

dehydrochlorination, l-(benzotriazol-1-yl)butene. Pyrrolidine failed to add across the

carbon-carbon double bond of this product.


N N Q N


NCH3
NH N
OCH


I +
CH3

2.31 2.32 2.33

Figure 2-9 Quaternary Pyridinium Salts



2.2.4 Spectroscopic Investigations of Benzotriazol-l-ylmethylammonium salts 2.18


In DMSO-d6, resonances arising from the H-4 and H-7 protons of the

benzotriazole ring in 2.27 often either overlap or are superimposed (see Table 2-2).

Since the H-7 and H-4 on the benzotriazolyl ring of 2.27 often have similar chemical

shifts, it was of interest to firmly establish which proton resonated furtherest downfield

when their signals were resolved. Salt 2.27f, l-(benzotriazol-1-

ylmethyl)trimethylammonium iodide was dissolved in a 1:1 mixture of D20:DMSO-d6,

and the aryl region of the 'H NMR spectrum showed four distinct resonances:











I i


CO
6



























CC
(D




CO













CO


0_


i I I


0


u
CIJ 0


+I
.z





z z -,


cu C a
ce)(


























N 5*
00
II E

E
Cl

S~ 00
o





N c-




*~ 0~
*Cl)





N c)
moT '
*- c^
r-mr


0n '0

m



6 g





0 r-
' 00


0O























O
V0























CJ
N
c0








































-a





0
CO









































0)
.d








U









Cl





di







t^


*f-



IS


,I-
C900
Cl II







r-!
00 -







oo r~^
N









r-0




oN _











os


N
00 -




Ni


00
SII







00
(S- II
N-,l






00
















00
Cl II




r-~ II
r~ 1-







*c
n |
r~ 1-1




e^h
00^


r-
Cl
00



00




























* E


',
o\






Cl)
t- E
00













Ci
N
r-:
N







oo E



C'n
- u



ooE




'I,
N cs

N


o
N
Ci
00


00




\%


- II
r-1








I


oo
'I, II










\o E
'0


Cl Cl C


II






o o

aE










00 1
vC
Ven 0-


C',




*l C14
ci







Cl4
N
E


m a"
cn






n s
en e


'e -





am
o N,






Ei E
Ef








o\ n
en cn
Cl r4





qclj;
'0 cn


00 00o
'0 'd 'd \ d d \d \


Y II


r-


0"







r~:
t- II












c II

ods
N








*00


SII







r2
00 e'




t-.




f- II








0r
*n t-
in |


C, 00
C II
00 -0






'02

r- II




















r-h
n II










C4
t^i >


N E
00










00








00


00


Cle


0.r-
N- II




t.- 1-




N -I





Cl2 II




Cl
C |










rj


0
Ud











































































































0
u


0"

o0







00
-' "




















































00


EE






N 00 Oj
r- en C14



CC' 00 CT\




t-00 %C
N CC 0~
t-~ cn Nl


r- m^ C.
lii


















'0



C,4 00
-'nc i






























Co-
r- -,
~en6












N









Cn II
NI~














00 -
to"











F:
f
M II


















i-a
C- II



t-s



t-




m |
(-d-


en
N 0?










Fi


C





"S -
4.
0








o

>0
a0














00
u 0




"0
0






>
0)
0e.










-t











00
Cg)
*as











A 0
"8












a00
f0
0-


0a
o 0
. N
-CO



%s
=1

M






^S








3 S

o


'B)
^" 'c


0
-o


I)



a




Hl
[-




































0


d
C,



0q C4
0 od0
tr W)


O o r- 'l "l cl 'r N I "
S i d 0 6 o% nT '
'0 0 '

z 0 00 00 00 00 00
OE TOR OR Eo R E R


I
\0
-a



















(d





















z
Q












s

















E


(-


U


N N N N N N N N N C N N
Cl l Cl l Cl Cl Cl Cl Cl Ci Cl cl








8 7.68 (t, 1H, J = 7.6 Hz), 7.87 (t, 1H, J = 7.4 Hz), 8.11 (d, 1H, J = 8.5 Hz) and 8.22 (d,

1H, J = 8.4 Hz). A two-dimensional carbon-proton coupled spectrum of the aryl region

of 2.27f (Figure 2-10) was obtained. Using previously reported assignments for the

carbon-13 NMR of 1-substituted benzotriazole derivatives [87JCS(P1)799,

87JCS(P1)805, 87JCS(P1)811, 87JCS(P1)2339, 87JCS(P1)2673, 88J05854,

890PP(UP)], it was observed that H-4 was the most deshielded proton on the

benzotriazole ring. This was the expected finding since the positively charged

ammonium center should be highly solvated, and the nearest ring proton (H-7) would

therefore be more shielded than H-4.





2.3 Reactivity of Benzotriazol-1-ylmethylammonium Salts



2.3.1 Background



Strong base often promotes either a Stevens rearrangement [52JA5179,

69TL1937, 700R403] or a Sommelet-Hauser rearrangement [51JA4122, 57JA5512,

700R403, 88J0194] of quaternary ammonium salts when none of the groups attached

to the quaternary center contain 1-hydrogens. In a Stevens rearrangement, one alkyl

group migrates from the quaternary nitrogen to the a-carbon of a second alkyl group.

A Sommelet-Hauser rearrangement involves migration of an alkyl or aryl substituent

from the quaternary nitrogen to the ortho position of a benzyl group. An example of a

quaternary ammonium salt, benzyltrimethylammonium iodide (2.34) which can

undergo either of these rearrangements is shown in Figure 2-11. Ylide-like species








have been suggested as reaction intermediates in both the Stevens [52JA5179] and

Sommelet-Hauser [88J0194] rearrangements. Babayan and coworkers observed that

under basic conditions (sodium metal in DMSO), phenacylmethyltrimethylammonium

iodide forms a stable, non-rearranged N-ylide [81JOU1256]. Treatment of this ylide

with diethyl malonate, followed by excess allyl bromide gave diethyl allylmalonate,

diethyl diallylmalonate, and a small quantity of alkylated ylide. Similarly, the ylide

derived from 1-benzoylmethyl-4-dimethylaminopyridinium cation was reported to be

stable in alcohol, and to readily react with alkylating agents [85MI1]. Quaternary salts

which do contain P-hydrogens usually undergo Hofmann elimination [600R317].



CH3 I -
S1+ /\ CH3
CH2 -N-CH3 CH-N
CH CHa
OH3 CH3
2.3436 CH3
2.34 ^ Stevens 2.36

Sommelet-Hauser /CH2-CH2-NCH

S2.37
SCH 2CH C HCH3

CH2-N C-NH3
CH3
2.35 2.38


Figure 2-11 Rearrangements of Quaternary Ammonium Salts



2.3.2 Reactivity of N-Ylide from N-(Benzotriazol-1-ylmethyl)-N-methylpyrrolidinium
Iodide


When salt 2.27a was treated with two equivalents of potassium hydroxide in a

D20/DMSO-d, mixture, the strong singlet at 8 6.45 in the 'H NMR spectrum of 2.27a

which is due to the methylene group adjacent to benzotriazole (Table 2-2) was absent.

It seems likely that these methylene protons may exchange with deuterium to give








2.40, therefore it may be expected that treatment of this salt with base may form an

intermediate N-ylide species, 2.39, which could further react with an electrophile to

afford an a-substituted adduct. However, when 2.27a and two equivalents of

potassium hydroxide were dissolved in D20/DMSO-d6 and one equivalent of either

methyl iodide, benzyl bromide, benzoyl chloride or benzaldehyde was added, no such

reaction was found.



2.3.3 Reactions of N-(Benzotriazol-l-ylmethyl)-N-methylpyrrolidinium Iodide at
Elevated Temperatures


Heating compound 2.27a at 200 OC in diphenyl ether afforded bis(benzotriazol-

1-yl)methane, 2.42 and methylbenzotriazole, 2.43. The reaction may proceed via

cation 2.41 which can be attacked by a molecule of benzotriazole (formed by

decomposition of 2.27a) to give 2.42. Low resolution mass spectral analysis of several

of the quaternary salts revealed an ion at m/z = 132, which is the formula weight of

2.41.

1-Methylbenzotriazole may be formed from 2.41 via a reductive pathway (eg.

with hydrogen iodide). More probable, however, seems to be the route via

rearrangement of 2.27a to 2.47 (Figure 2-13) which then decomposes to give 2.43.

Support for such a reaction mechanism was obtained from decomposition of 2.27a in

the presence of N,N-diethylaniline leading to 1-ethylbenzotriazole, 2.46. In this case,

electrophilic attack of 2.41 on the aniline nitrogen afforded the ammonium cation 2.44.

This cation subsequently rearranges to benzotriazolium cation 2.45, which in turn

undergoes further decomposition to 2.46 (Figure 2-12).












IN




H3CN2

2.27a


OH"

HPO


N

N


H3C N

2.39


D20


N


DD
SHaC/

2.40
2.40


A


N
/






2.42


+ N


CH3
2.43


KN



2.46


2.45


2.27a


N
N +
CH2
2.41


PhN(Et)2


2.44


Figure 2-12 Formation of N-Ylide and Thermal Decomposition of N-(Benotriazol-
1-ylmethyl)-N-methylpyrrolidinium Iodide








CH3
I

+ N



2.47

Figure 2-13 1-(Pyrrolidinomethyl)-3-methylbenzotriazolium Cation



The formation of bis(benzotriazol-1-yl)methane from 2.27a at elevated

temperatures was observed via high-resolution MS. A relatively strong peak at m/z

250.0985 was found to have composition C13H10N6 and was assigned to 2.42.

Fragment ions at m/z 222.0890 (loss of one molecule of nitrogen) and 193.0763 (loss

of two molecules of nitrogen and one proton) support this conclusion. Benzotriazole

derivatives substituted at the 1-position have been shown to undergo facile loss of

nitrogen in this manner [700MS367]. Another major fragment ion was also seen at

m/z 132.0562 which is likely to be the cationic intermediate 2.41 (Figure 2-12).



2.3.4 Reactions of N-(Benzotriazol-1-ylmethyl)-N-methylpyrrolidinium Iodide with
Grignard Reagents


The reaction of 2.27a with a large excess of ethylmagnesium iodide gave a

complex mixture of products (Figure 2-14). Some products were isolated, others were

identified by their spectral features, and still others remained unidentified.

Spectroscopic analysis of the crude reaction mixture obtained from 2.27a with ten

equivalents of ethylmagnesium iodide indicated the following three products:

n-propylbenzotriazole (10 %), methylbenzotriazole (40 %), and various ring-opened

o-phenylenediamine derivatives (50 %). Propylbenzotriazole was identified by a








characteristic triplet at 8 4.60 (BtCH2) in the 1H NMR spectrum, whereas

methylbenzotriazole gave a distinct singlet at 8 4.20 (BtCHf). The aryl protons of the

ring-opened products resonate in the range of 8 6.45-7.00, which is further upfield than

the signal due to the benzotriazole moiety (Table 2-2).

Purification by chromatography allowed separation of the benzotriazole

derivatives from the ring-opened products. Low resolution GC/MS of the mixture of

phenylene diamines showed the major product (85 %) to have an M+1 ion at 207, and

a molecular ion at 206. The major fragment peaks at m/z 177 (M-C2H5) and 119

(EtC6H3NH-+ or C6H4NEt.+) are characteristic of N-alkylated phenylenediamines

[690MS375, 74AJC727]. High resolution MS with molecular fragment analysis

showed the molecular ion of the major product to be C13H22N2, which fits structure

2.52 (R = Et). Fragments which can be assigned to an aryliminium species

(ArN=CH2+) were also observed. These species typically lose 14 (CH2) or 28 (NCH2)

mass units to give aryl radical cations. After one amino group is lost, the

fragmentation pattern of the resulting cation is very similar to that observed for

N-substituted anilines. A minor impurity (m/z = 204.1616) is likely due to the

o-benzodiimine analog, which is the product of oxidation.

Further support for the suggested ring-opened products comes from the 'H and

13C NMR spectra of these components. Comparison with literature values

[860MR1093] for chemical shifts of unsubstituted, N-substituted and

N,N' -disubstituted phenylenediamines are in agreement with the postulated structures.

Six aryl resonances can be seen in the 13C NMR spectrum, which may indicate an

unsymmetrically N,N' -disubstituted product such as 2.50 or 2.51; however, the

presence of an ethyl group in the 4- or 5-position on the benzene ring would also

destroy the symmetry of the compound, thereby giving rise to six non-equivalent aryl






41







N



No



2.27a





RMgX


I
LN


CH3



2.43


R
I
NH



NH
CHI
CH2R


2.50


N
+ N
N

CH2R


2.48


NH
H3
CH 3


2.51


.N

+/
N


R R

2.49


R

NH

R-

NH

CH2R

2.52


R = Me, Et


Figure 2-14 Reaction of N-(Benzotriazol-1-vlmethyl)-N-methylpyrrolidinium Iodide with
Grignard Reagents








resonances. The signal in the aryl region of the 1H NMR spectrum integrates for 3

protons, and the splitting pattern suggests a 1,2,4-trisubstituted benzene ring. The

reaction seems to be similar to a nucleophilic attack of Grignard reagents on the aryl

ring of nitroarenes [87T4221], and indicates that an ammoniomethyl group at

nitrogen-1 of the benzotriazole ring exerts an electron-withdrawing effect on the

benzotriazole system.

The experiment was repeated using methylmagnesium iodide. The major

products were ethylbenzotriazole and isopropylbenzotriazole, with a small amount of

methylbenzotriazole (as identified by NMR spectroscopy and GC/MS). the formation

of 1-isopropylbenzotriazole, (2.49, R = Me) was quite unexpected. This product may

arise by deprotonation of 1-ethylbenzotriazole at the c-position followed by transfer of

a methyl group from 2.27a





2.4 Conclusions



Benzotriazole can be readily aminomethylated with formaldehyde and an amine

to afford the corresponding Mannich base. These adducts can be converted to

quaternary ammonium salts with a select group of alkylating agents. Alternatively,

these salts may be prepared from the reactive of iodomethylbenzotriazole and tertiary

amines. These salts are deprotonated in basic media to form stable, unreactive ylides.

In contrast to previous reports where benzotriazole was used as a synthetic template,

benzotriazol-1-ylmethylammonium salts are not useful synthetic intermediates. A

large excess of Grignard reagent is needed in order to transform these quaternary salts

into alkylbenzotriazoles, and then only as a mixture with other by-products.








2.5 Experimental



Melting points were determined on a Fisher hot-stage apparatus and are

uncorrected. The 'H and 13C NMR chemical shifts were measured in ppm on the 6

scale using tetramethylsilane as a reference. All NMR spectra were recorded on either

a Varian XL-200 or Varian VXR-300 NMR spectrometer. Gas chromatography/mass

spectrometry data was obtained using a Varian 3400 gas chromatograph and Finigan-

Mat Model 700 Ion Trap Detector. High resolution MS were obtained on a

Kratos/AEI-MS30 mass spectrometer. Diethyl ether and tetrahydrofuran were distilled

from sodium/benzophenone ketyl prior to use. Purification by chromatography was

performed using silica gel as a stationary phase and an eluent as specified in each case.



2.5.1 Synthesis of Benzotriazol- 1-ylmethylamines (2.25)



2-(Benzotriazol-1-ylmethyl)aminopyridine. Hydroxymethylbenzotriazole

(14.92 g, 100 mmole) and 2-aminopyridine (9.40 g, 100 mmole) were added to 40 ml

of absolute ethanol. The mixture was heated to reflux for 3 h, and upon cooling the

crude product crystallized from the solution and was isolated. Recrystallization from

toluene afforded 15.99 g (71 %) of the product; 1H NMR (CDC13) 5 6.25-6.40 (m, 3H),

6.57 (d, 1H, J = 8.3 Hz), 6.66 (dd, 1H, J = 7.2 Hz), 7.26-7.49 (m, 3H), 7.99 (dd, 2H, J =

8.4 Hz), 8.20 (d, 1H, J = 5.0 Hz); 13C NMR 6 54.2, 108.8, 111.3, 114.9, 119.4, 123.9,

127.2, 132.8, 137.8, 146.0, 147.7, 156.2; mp 143-146 C (lit mp 137-138 C

[87JCS(P1)799]).

Anal. Calcd. for C12HI1Ns: C, 63.99; H, 4.92; N, 31.09; Found: C, 63.74; H,

4.92; N, 31.31.








1-(Benzotriazol-l-ylmethyl)pyrrolidine. Benzotriazole (3.97 g, 33 mmole), 37

% aqueous formaldehyde (3.4 ml, 33 mmole) and pyrrolidine (2.63 g, 37 mmole) were

added to 20 ml methanol and stirred at room temperature for 4 h. The solution was

concentrated in vacuo and the crude residue was recrystallized from diethyl ether to

afford 6.37 g (95 %) of the product; 'H NMR (CDC13) 8 1.55-1.75 (m, 4H), 2.60-2.80

(m, 4H), 5.60 (s, 2H), 7.20-8.05 (m, 4H); 13C NMR 8 23.6, 23.8, 49.2, 50.0, 64.9, 72.4,

109.7, 118.0, 119.4, 123.5, 126.0, 127.1, 133.9, 143.9, 145.6; mp 75-78 OC (lit mp 79-

81 C [87JCS(P1)2673]).

Anal. Calcd. for ClIH14N: C, 65.54; H, 7.02; N, 28.05; Found: C, 65.32; H,

6.98; N, 27.70.



N-(Benzotriazol-1-vlmethyl)-N-methyl-4-pyridylamine. Benzotriazole (4.76 g,

40 mmole), 37 % aqueous formaldehyde (1.20 g, 40 mmole), N-methyl-4-

aminopyridine (4.32 g, 40 mmole) and 60 ml benzene were heated to reflux in a Dean-

Stark adapter for 10 h. The contents were concentrated in vacuo and unreacted

N-methyl-4-aminopyridine was removed by vacuum sublimation (0.8 torr/ 80 oC).

The crude residue was purified by chromatography (39:1 chloroform:ethanol).

Trituration with dry acetonitrile afforded N-(benzotriazol-l-ylmethyl)-N-methyl-4-

pyridylamine as colorless microcrystals (6.02 g, 63 %); 'H NMR (CDC13) 8 3.10 (s,

3H), 6.15 (s, 2H), 6.85 (d, 2H, J = 4.8 Hz), 7.25-7.45 (m, 3H), 8.05 (d, 1H, J = 7.8 Hz),

8.30 (d, 2H, J = 4.8 Hz); 13C NMR 5 37.1, 63.6, 107.9, 109.4, 120.2, 124.2, 128.0,

132.2, 146.2, 150.5, 152.5; mp 146-149 OC.

Anal. Calcd. for C,3HI3N5: C, 65.26; H, 5.48; N, 29.27; Found: C, 65.24; H,

5.45; N, 29.46.








2.5.2 Method A General Procedure for Quaternization of Benzotriazol-1-
ylmethylamines


Aminomethylbenzotriazoles (2.25, Figure 2-8) were dissolved in a minimal

amount of acetonitrile with stirring at room temperature. To the solution was added

1.5 equivalents of either methyl iodide, ethyl iodide, methyl tosylate or

chloromethylbenzotriazole, and stirring was continued for 48 h. The crude precipitate

was removed by filtration, and to the filtrate was added 10 ml of diethyl ether. Stirring

was continued for an additional 24 h, and any further precipitate was isolated and

combined with the initial crop. The crude product (2.27) was dried, recrystallized and

characterized (Table 2-1).



2-(Benzotriazol-l-ylmethyl)aminopyridinium methiodide (2.31). This

compound was prepared by the general method described for quaternization of

benzotriazol-1-ylmethylamines (Method A). Quaternization occurs on the pyridyl ring

rather than the amine N-atom (23 % from methanol:pet ether); 1H NMR (DMSO-d6) 8

3.95 (s, 3H), 6.50 (d, 2H, J = 6.1 Hz), 7.19 (t, 1H, J = 6.8 Hz), 7.48 (t, 1H, J = 7.7 Hz),

7.67 (t, 1H, J = 7.7 Hz), 7.87 (d, 1H, J = 8.8 Hz), 8.09 (d, 1H, J = 8.4 Hz), 8.18-8.31

(m, 2H), 8.42 (d, 1H, J = 6.0 Hz), 9.40 (t, 1H, J = 6.0 Hz); '3C NMR 8 42.6, 54.1,

111.1, 111.5, 114.7, 119.2, 124.4, 127.8, 132.2, 142.6, 143.9, 145.2, 152.4; mp 216-

219 OC.

Anal. Calcd. for C13H4Ns5I: C, 42.52; H, 3.84; N, 19.07; Found: C, 42.41; H,

3.81; N, 19.13.








4-N-(Benzotriazol-1-ylmethyl)-N-methylaminopyridinium methiodide (2.32).

This salt was prepared via the method described for quaternization of benzotriazol-1-

ylmethylamines where quaternization occurs on the N-atom of the pyridyl ring (16 %

from methanol:pet ether); 1H NMR (DMSO-d6) 6 3.32 (s, 3H), 4.02 (s, 3H), 6.70 (s,

2H), 7.44 (t, 2H, J = 7.6 Hz), 7.62 (t, 2H, J = 7.6 Hz), 8.00-8.10 (dd, 2H, J = 8.2 Hz),

8.50 (d, 2H, J = 7.5 Hz); 13C NMR 6 38.4, 44.7, 62.0, 109.1, 110.6, 119.3, 124.5,

128.2, 132.5, 143.9, 144.9, 156.0; mp 193-196 C.

Anal. Calcd. for C14HI6NsI: C, 44.11; H, 4.23; N, 18.37; Found: C, 44.15; H,

4.19; N, 18.41.



1,3-Dibenzvlbenzotriazolium bromide (2.30). Benzyl bromide (1.71 g, 10

mmole) and 1-(benzotriazol-1-ylmethyl)pyrrolidine (1.01 g, 5 mmole) were heated

together in a sealed tube at 60 OC for 16 h, and then at 80 OC for an additional 8 h. The

crude solid was recrystallized from 2:1 ethyl acetate:methanol to give 1.24 g (65 %)

1,3-dibenzylbenzotriazolium bromide; 'H NMR (DMSO-d6) 8 6.35 (s, 4H), 7.35-7.50

(m, 6H), 7.50-7.65 (m, 4H), 7.90-8.05 (m, 2H), 8.40-8.55 (m, 2H); 13C NMR 8 54.6,

114.1, 128.7, 128.9, 129.1, 131.3, 132.5, 134.5; mp 187-188 oC; MS: fragment ions at

m/z 300 (dibenzylbenzotriazolium), 210 (benzylbenzotriazolium) and 91 (C6H5CH2+).

Anal. Calcd. for C20H,8N3Br: C, 63.17; H, 4.77; N, 11.05; Found: C, 62.91; H,

5.15; N, 11.03.



2.5.3 Method B General Procedure for the Reaction of Iodomethylbenzotriazole
with Tertiary Amines


Chloromethylbenzotriazole was dissolved in dry acetone with stirring at room

temperature. One equivalent sodium iodide was added and the mixture was stirred for








4 h. Sodium chloride was removed by filtration and to the filtrate was added 1

equivalent of tertiary amine. The reaction mixture was stirred for 24-48 h and the

crude material was removed by filtration. The product (2.27) was recrystallized and

characterized (Table 2-1).



1-(Benzotriazol-l -lmethyl)-4-(N,N-dimethylamino)pyridinium iodide (2.33).

This compound was prepared by the method described for the reaction of

iodomethylbenzotriazole with tertiary amines (Method B) and was obtained as prisms

from methanol (75 %); 'H NMR (DMSO-d6) 8 3.15 (s, 6H), 7.10 (d, 2H, J = 7.7 Hz),

7.25 (s, 2H), 7.45 (t, 1H, J = 7.1 Hz), 7.70 (t, 1H, J = 8.3 Hz), 8.10 (d, 1H, J = 8.9 Hz),

8.60 (d, 2H, J = 7.7 Hz); 13C NMR 8 30.7, 40.1, 64.6, 108.2, 110.5, 119.6, 125.0,

128.8, 132.1, 141.3, 145.2, 156.3; mp 201-203 OC.

Anal. Calcd. for C14H,6NI5: C, 44.11; H, 4.23; N, 18.37; Found: C, 44.08; H,

4.19; N, 18.47.



2.5.4 Thermal Decomposition of N-(Benzotriazol-l-ylmethyl)-N-
methylpyrrolidinium Iodide


A mixture of 2.27a (3.40g, 10 mmole) and diphenyl ether was stirred at 200 C

under argon for 2 h. Column chromatography (methylene chloride) of the mixture

allowed separation of diphenyl ether from the other two components. Trituration with

diethyl ether afforded bis(benzotriazol-1-yl)methane (0.45 g, 38 %) as colorless

prisms; IH NMR (CDCI3) 7.38 (m, 1H), 7.43 (s, 2H), 7.52 (m, 1H), 7.87 (d, 1H, J =

8.3 Hz), 8.02 (d, 1H, J = 8.4 Hz); 13C NMR 5 58.0, 109.8, 120.2, 124.8, 128.7, 132.2

and 146.3; mp 191 OC (lit. mp 192 OC [52JA3868]). Methylbenzotriazole (0.20g, 15

%) was recovered from the ether solution.








2.5.5 Reaction of N-(Benzotriazol-l-ylmethyl)-N-methylpyrrolidinium Iodide with
N,N-Diethylaniline


A mixture of salt 2.27a (3.40 g, 10 mmole) and N,N-diethylaniline (2.40 g, 15

mmole) were heated together at 200 OC for 4 h under an argon atmosphere. After

cooling to room temperature, the reaction mixture was dissolved in chloroform (15

ml), filtered and separated by flash chromatography (CH2CI2).

The first fraction appeared to be unreacted N,N-diethylaniline. The second

fraction gave 1-ethylbenzotriazole (0.55 g, 37 %) as a colorless oil; 'H NMR (CDC13)

1.58 (3H, t, J = 7.3 Hz), 4.63 (2H, q, J = 7.3 Hz), 7.32 (1H, t, J = 8.2 Hz), 7.43 (1H, t, J

= 7.8 Hz), 7.49 (1H, d, J = 8.3 Hz), 8.01 (1H, d, J = 8.3 Hz); 13C NMR 8 14.9, 43.1,

109.4, 119.7, 123.8, 127.1, 132.5 and 146.0. The product was further characterized as

its picrate salt: orange prisms, mp 111 OC.

Anal. Calcd. for C14H,2N607: C, 44.69; H, 3.21; N, 22.33; Found: C, 44.31; H,

3.01; N, 21.99.

The third fraction appeared to be a mixture of bis(benzotriazol-1-yl)methane and

1-methylbenzotriazole. Trituration of the mixture with diethyl ether gave pure

bis(benzotriazol-l-yl)methane as colorless prisms (0.33g, 28 %); mp 191 OC (lit. mp

192 OC [52JA3868]).

The ethereal filtrate was concentrated to 5 ml and upon storage at 5 C for 24 h

afforded 1-methylbenzotriazole as colorless prisms (0.10 g, 8 %).








2.5.6 Reaction of N-(Benzotriazol-l-ylmethyl)-N-methylpyrrolidinium Iodide with
Benzylmagnesium Chloride


A solution of benzylmagnesium chloride (30 mmole) in diethyl ether (20 ml)

was added to a suspension of salt 2.27a in tetrahydrofuran (15 ml). The resulting

mixture was stirred at 45 OC for 3 h under argon.

Methanol (1.0 ml) was added to quench the reaction followed by water (1.0 ml)

and anhydrous potassium carbonate (5 g). The mixture was stirred at room

temperature for 30 min, filtered and the solid material was washed with chloroform.

The combined filtrate and washings were concentrated to give 2.30 g of an oil.

Column chromatography (methylene chloride) afforded 1-phenethylbenzotriazole (1.42

g, 64 %) as an oil; IH NMR (CDCI3) 6 3.28 (t, 2H, J = 7.4 Hz), 4.83 (t, 2H, J = 7.4 Hz),

7.05-7.38 (m, 8H), 8.03 (d, 1H, J = 8.2 Hz); 13C NMR 5 36.2, 49.6, 109.1, 119.8,

123.7, 126.9, 127.1, 127.4, 128.4, 128.6, 137.3, 141.0. The product was further

characterized as its picrate salt, dark-orange prisms from methanol; mp 115-117 C.

Anal. Calcd. for C20H,6N607: C, 53.10; H, 3.56; N, 18.50; Found: C, 53.08; H,

3.53; N, 18.54.



2.5.7 Reaction of N-(Benzotriazol-1-vlmethyl)-N-methylpyrrolidinium Iodide with
Ethylmagnesium Iodide


Salt 2.27a (3.44g, 10 mmole) was added in one portion to ethylmagnesium

iodide (100 mmole) in 35 ml diethyl ether and the reaction mixture was heated to

reflux for 44 h. Upon cooling the reaction mixture was slowly added to 150 ml ice

with vigorous stirring. The pH was adjusted to 8 with glacial acetic acid and the

organic and aqueous phases were separated. The aqueous layer was extracted with

chloroform. The combined organic layers were washed with water, dried over sodium

sulfate and concentrated in vacuo to afford the crude mixture.








Purification by chromatography (39:1 CHCl3:MeOH) afforded three fractions

which were analyzed by NMR spectroscopy and GC/MS. The first fraction was 85 %

pure with the main product being 2.52 (R = Et); 'H NMR (CDC13) 8 0.80-1.00 (m, 7H),

1.15-1.33 (m, 6H), 1.46-1.70 (m, 3H), 3.02-3.22 (m, 3H), 6.60-6.80 (m, 3H); 13C NMR

8 10.1, 15.1, 26.4, 29.7, 39.0, 55.3, 112.15, 112.29, 118.4, 119.1,136.8 and 137.5; MS

m/z 206 (molecular ion, C,3H22N6).

The second fraction was comprised of three compounds. The first compound,

N-methyl-N' -ethyl-o-phenylenediamine (2.51, 16 %) gave a molecular ion at m/z 150

and major fragment peaks at m/z 135 (loss of CH3) and 119 (C7H7N2). The second (26

%) and third (58 %) compounds each gave molecular ions at m/z 178 and major

fragment ions at m/z 149 (loss of C2H5) and 119 (C7H7N2). One of these compounds

was tentatively identified as N-ethyl-N' -propyl-o-phenylenediamine (2.50, R = Et)

and the other is an isomer of this product. The last fraction from chromatography was

a mixture of 1-ethylbenzotriazole (71 %, m/z 147, 119) and 1-propylbenzotriazole (29

%, m/z 161).



2.5.8 Reaction of N-(Benzotriazol-l-ylmethyl)-N-methylpyrrolidinium Iodide with
Methylmagnesium Iodide


The same procedure was used as in the reaction of ethylmagnesium iodide using

methyl iodide (6.2 ml, 100 mmole). The GC/MS of the crude product mixture

indicated six compounds were present. The two major components were

1-ethylbenzotriazole (59 %, m/z 147) and 1-isopropylbenzotriazole (24 %, m/z 161).

The 1H NMR spectrum contained a quartet at 8 4.62 (CH2, J = 7.1 Hz) and a triplet at 6

1.59 (CHJ, J = 7.1 Hz) which are characteristic of 1-ethylbenzotriazole. The isopropyl

group is defined by a multiple at 6 5.05 (CH(CH3)2) and two doublets (CH(CH3)2)at

1.68 and 1.18.












CHAPTER 3
THE REACTIONS OF BENZOTRIAZOLE AND AN AMINE
WITH UNSATURATED ALDEHYDES AND KETONES


3.1 Introduction



Simple or unactivated olefins are inert to nucleophilic addition. However, when

they are conjugated with a carbonyl group or other functional group possessing a

negative mesomeric effect, they become acceptors for a wide variety of nucleophiles.

Such olefins can be represented by two canonical structures which illustrate their

electronic delocalization (3.la, 3.1b, Figure 3-1). In the case of Xa,3-unsaturated

carbonyl compounds 3.1, there are two electron-deficient centers, the carbonyl carbon

and the P-carbon atoms. Therefore, the position of nucleophilic attack is not always

predictable, and has been the subject of numerous investigations [590R179]. In

general, soft nucleophiles (where the electron density is not highly localized) tend to

add to the 3-carbon atom, whereas hard nucleophiles attack the carbonyl carbon atom.

These two modes of reactivity, 1,2- and 1,4-addition, are shown in Figure 3-1.



3.1.1 The Addition of Nucleophiles to ca,~-Unsaturated Aldehydes and Ketones


When Y is the alkali metal salt of an active methylene compound, the mode of

addition is usually 1,4- (also called conjugate) addition and the reaction is referred to

as the Michael reaction. Ethylenic carbonyl compounds which contain enolizable

protons often undergo self-condensation, especially in alkaline media. This difficulty

may be overcome by using nucleophiles which are not generated under basic








conditions. Enamines, have been shown to add via conjugate addition to

op3-unsaturated carbonyl compounds [63JA207]. The reaction of a, P-unsaturated

carbonyl compounds with neutral electron donors is often reversible and retro-addition

frequently occurs in the presence of weak acid or upon heating.


0


R3
R2/ a
3.1a


1,2-addition


3.2

1 H'


HO
R1 Y

p2R

3.3


o -
R'

R2 a
3.1b

1,addiion
1,4-addition


3.4

1


OH 0

Jp3 y pA
R2 R2


Figure 3-1 Addition of Nucleophiles to a,D-Unsaturated Carbonyl Compounds


Organometallic reagents derived from unstable carbanions and alkali metals (i.e.

organolithiums and Grignard reagents) are highly reactive and generally give

1,2-addition products. Benzalacetophenone 3.7, a stable and non-enolizable ketone,

was shown to add a phenyl group at both the 3-carbon atom and the carbonyl carbon


I








atom when reacted with an excess of phenylmagnesium bromide (Figure 3-2)

[62JO1221]. Recently, Yamamoto and coworkers developed an aluminum catalyst,

bis(2,6-di-tert-butyl-4-methylphenoxide)methylaluminum (MAD), which alters the

regioselectivity of nucleophilic addition of alkyllithiums to a,P-unsaturated ketones to

exclusively afford 1,4-addition products (Figure 3-3) [87TL5723].


0 Ph OH
|j XS PhMgBr ,|-
Ph Ph Ph Ph
3.7 3.8


Figure 3-2 Reaction of Benzalacetophenone with Excess Phenylmagnesium Bromide


R R H
I RU 1. MAD | |
--C=C-C--OH -C=C-C=0 ---O --C--C-C=0
I I I I 2. RU



Figure 3-3 Regioselective Addition of Organolithiums to a, -Unsaturated Carbonyl
Compounds


Several specific organometallic reagents have also been developed which

undergo 1,4-addition with a,P-unsaturated aldehydes and ketones. Most of the work in

this area has focused on alkyl derivatives of lithium-copper (I) salts [66JO3128,

71JA7320, 72JA7210, 720R1, 73CC88, 73JA7788, 73TL1815]; boron [67JA5208,

68JA4165, 70JA710, 71JA3777, 72AG(E)692]; and aluminum [71JA7320,

73CJC2098, 73JA4428, 74JO3297, 74JOM(74)365, 75AJC801, 88T5001]. Although

these reagents have been successfully applied in organic synthesis, they usually require

scrupulously anhydrous conditions and precise stoichiometric combinations of starting

materials.








3.1.2 The Reaction of Amines and Related Compounds with ao,-Unsaturated
Aldehydes and Ketones


Aliphatic amines generally add to ca,-unsaturated aldehydes and ketones via

conjugate addition as shown in Figure 3-4. The first reported example of this type of

reaction involved the addition of gaseous ammonia to mesityl oxide 3.10 (R3, R4, R5 =

Me) to afford 4-amino-4-methyl-2-pentanone 3.11 [1874CB1384]. These same

researchers later reported similar reactions using methylamine, dimethylamine and

ethylamine [1874CB1776]. In 1886, Beyer reacted acrolein 3.10 (R3, R4, R5 = H) with

a series of substituted anilines which presumably gave intermediates analogous to 3.11.

These intermediates were not isolated, but cyclized in situ to give the substituted

quinolines 3.12 [1886JPC393]. In an attempt to prepare N-substituted quinolines,

Tambor and Wildi treated acrolein with both diarylamines and arylalkylamines,

however, they found these secondary amines to be unreactive [1898CB349].

Morpholine readily adds to benzalacetophenone (3.10, R3 = H, R4, R5 = Ph) to give

a-(N-morpholinophenylmethyl)acetophenone [37JA2702]. Both phthalimide and

succinimide can be N-substituted with crotonaldehyde or similar aldehydes

[49JA1251]. One molar equivalent of the imide adds to one equivalent of the olefinic

aldehyde at the P-position. No attempt was made to treat the aldehyde with an excess

of the imide.

There have been few reports where an unsaturated carbonyl compound has

reacted with two or more molar equivalents of an amine. Crotonaldehyde and its

a,p-disubstituted derivatives (3.14, R5 = H) react with two moles of

(trimethylsilyl)dialkylamine 3.13 to give P-aminoenamines 3.18 (Figure 3-5)

[84TL3449]. The same reaction with the corresponding ketones (R5 # H) affords silyl

enol ethers 3.15. Presumably, crotonaldehyde reacts with one equivalent of 3.13 to









give a silyl ether which is hydrolyzed in situ to regenerate a P-aminoaldehyde 3.16.

This aldehyde then reacts with a second mole of (trimethylsilyl)dialkylamine to give

the diamino silyl ether 3.17, which subsequently eliminates trimethylsilanol to afford

3.18.


0

+ R R5
R43
3.10


0
R3
R1R2N 2N R5
R4
3.11

R1, R3, R4, R5 = H





N312
3.12


Figure 3-4 Reaction of Amines with oa,-Unsaturated Aldehydes and Ketones


Me3SiNR'R2 +

3.13





R'R2N NR'R2

R3 R4
3.18


0
R5.

R3 R4
3.14


OSiMe3
R1 R2NR5


3.15
3.15


OSiMe3
R'R2N NR'R2

R3 R4
3.17


=H

0

3.13 R1R2N H

93 R4
3.16


Figure 3-5 Addition of (Trimethylsilyl)dialkylamines to a,3-Unsaturated Aldehvdes


and Ketones


HNR'R2

3.9


. = j rl I








Primary alkyl carbamates 3.19 reacted with aP-unsaturated aldehydes under

alkaline conditions to give products which contain three carbamoyl groups, 3.23, as

illustrated in Figure 3-6 [45JO478, 48JA3569]. Crotonaldehyde added only two

equivalents of alkyl carbamates to give 3.22, presumably because dehydration was

more rapid than substitution of the hydroxyl group by carbamate. The reaction of

a-ethylcinnamaldehyde 3.20 (R2 = Ph, R3 = Et) with alkyl carbamates gave a bicyclic

product, 2-ethylindanone 3.24, upon neutralization of the reaction mixture.



0 R'CHN OH

H2NCO2R1 + R2 H R2 NHCOR
(excess)R3 R3

3.19 3.20 3.21

SR= Ph, R = Et R2, R3 = alkyl/ RMe, R3=H


0 RO2CHN NHCO2R

I Et R2 NHCO2R1 R1O2CHN NHCO2R1

3.24 3.23 3.22


Figure 3-6 Reaction of Alkyl Carbamates with a, 3-Unsaturated Aldehydes



The reactivity of iodine complexes of ammonia, cyclohexylamine, benzylamine,

morpholine and piperidine toward a,p-unsaturated carbonyl compounds was

investigated by Southwick and Christman [52JA 1886, 53JA629]. These workers

found that two equivalents of the secondary amine complexes 3.25 (R1, R2 # H) added

across the carbon-carbon double bond to give a,p-diamino adducts, 3.27. When a

primary amine complex was used, only one equivalent added across the carbon-carbon








double bond to afford aziridinyl aldehydes and ketones 3.28. The carbonyl carbon is

unaffected in these reactions.


R'R2N O

Ph R3
R1, R2 lkNRyR2
0
J3.27
12 HNR1R2 + Ph R
3.25 3.26 Ph 0

R"R3
N
3.28



Figure 3-7 Reaction of Amine-Iodine Complexes with ao-Unsaturated Carbonyl
Compounds


3.1.3 Reactivity of Triazoles with xa,-Unsaturated Carbonyl Compounds


Benzotriazole and 1,2,3-triazole, in the presence of a catalytic amount of

trimethylbenzylammonium hydroxide, add to the P-position of a,3-unsaturated

carbonyl compounds [54JA4933]. The ultraviolet spectra of the benzotriazole adducts

showed double maxima at 255 mg and 283 mp, which confirmed that benzotriazole

was substituted at the 1-position. Benzotriazol-2-yl derivatives usually show a single

absorption maximum at 275 myn [38CB596, 42CB1338]. Two molar equivalents of

benzotriazole were found to add to cinnamaldehyde to afford 1,3-bis(benzotriazol-1-

yl)-3-phenylpropanol, 3.29 (Figure 3-8) [54JA4933].

The reaction of aldehydes with benzotriazole has previously been reported by

Katritzky et al. to afford 1-(1-hydroxyalkyl)benzotriazoles [87JCS(P1)791,

87JCS(P1)799]. Such compounds have been shown to undergo displacement of the








hydroxyl group by a variety of nucleophiles including amines, alcohols, and acetate.

Upon reacting trans-cinnamaldehyde with two equivalents of benzotriazole, it was

found that addition across both the carbon-carbon and carbon-oxygen double bonds

took place to give 1,3-bis(benzotriazolyl)-3-phenylpropanol 3.29. An analogous

compound starting from crotonaldehyde was also prepared in situ and treated with

2-aminopyridine to give 2-[1,3-bis(benzotriazol-1-yl)]butylaminopyridine, 3.30.



\N NX? QJVN N Q


Ph "OH MeNH

-^N
3.29 3.30


Figure 3-8 Derivatives from the Reaction of Benzotriazole with a, -Unsaturated
Aldehydes


The benzotriazolyl moiety has been shown to undergo nucleophilic substitution

by the action of sodium borohydride and Grignard reagents as previously discussed in

the preceding chapters. In light of this knowledge, it seemed probable that compounds

such as 3.29 and 3.30 may undergo transformations to give adducts which are not

easily available from a,p-unsaturated carbonyl compounds. It was observed that bis-

benzotriazolyl alcohols 3.29 were only moderately stable and could not be stored for an

extended period of time. In contrast, the corresponding amines were found to be

relatively stable. The following sections (3.2-3.5) describe the reaction of both

aP-unsaturated aldehydes and ketones with benzotriazole and an amine. Two

benzotriazolyl substituents of different liability in such an adduct allow for potentially

diverse synthetic applications.








3.2 Reactions of Benzotriazole with a, 3-Unsaturated Ketones


Methyl vinyl ketone readily underwent condensation with two molar equivalents

of benzotriazole to give predominantly 4-(benzotriazol-l-yl)-2-butanone, 3.33a.

Proton NMR spectroscopy showed the product to consist of a 95:5 ratio of

benzotriazol-1-yl to benzotriazol-2-yl isomers (Figure 3-9). 1-Phenyl-3-buten-2-one,

3.32b was less reactive than methyl vinyl ketone, but here too the benzotriazol-1-yl

adduct, 3.33b, was the major product. Benzotriazole also reacted with 2-cyclohexen-1-

one, trans-1,2-dibenzoylethene, and mesityl oxide to afford adducts 3.33c, 3.33d and

3.33e, respectively. Compounds 3.33a and 3.33b were characterized as the

corresponding semicarbazone and 2,4-dinitrophenylhydrazone, respectively.

Benzotriazole did not afford any products from 1,2-addition; nor was the addition of

more than one equivalent to a,3-unsaturated ketones observed as in the case of

a,P-unsaturated aldehydes (see section 3.4).




N R1 0 N

: N/ + N 0 + NNN
RN RR2 R RN R

3.31 3.32 R2 R2
3.33 3.34

a. R1, R2 = H; R3 = Me c. R' = H R2,; R3 = -( 2)3- R1, R2, R3 = Me
b. R' = Ph ; R2 = H ; R3 = Me d. R1 = PhCO R2 = H R3 = Ph



Figure 3-9 Addition of Benzotriazole to ca,3-Unsaturated Ketones



In the 'H NMR spectra of 3.33b-3.33d, the two diastereotopic methylene protons

resonated as non-equivalent multiplets. The H-7 and H-6 protons of the benzotriazolyl








group of 3.33c overlap in the range of 6 7.48-7.56. This is a lower than average

chemical shift for the H-7 proton of benzotriazole derivatives, and may arise from the

anisotropic effect of the carbonyl group. In contrast, 3.33e shows four distinct

resonances for each of the benzotriazolyl protons which is ordinarily observed. The

P-methyl groups apparently induces a greater steric effect, and therefore tends to keep

the benzotriazolyl protons remote from the carbonyl group. The 'H and '3C NMR

spectra of both 3.33c and 3.33d indicate that none of the benzotriazol-2-yl isomer was

present after purification. The a-protons of 3.33e resonate as a sharp singlet since the

adjacent carbon atom is attached to two methyl groups and no stereogenic center is

present.





3.3 Reactions of Benzotriazole with Crotonaldehyde


The reaction of equimolar quantities of benzotriazole and crotonaldehyde (3.35,

R1 = Me) in CDC13 was followed by 'H NMR spectroscopy. The reaction mixture

showed diminishing intensity of the double doublet of the aldehyde methyl group at 6

2.03 with time, and the appearance of new resonances at higher field. After two days

at 20 OC, 83 % of the starting aldehyde remained. When the molar ratio of

benzotriazole to crotonaldehyde was increased to 2:1, four unique resonances were

observed in the methyl region. A double doublet at 8 1.90 (J = 7.0 and 1.7 Hz) was

tentatively assigned to 3.36 (Figure 3-10) because its chemical shift and coupling

constants are characteristic of a methyl group attached to a carbon-carbon double bond.

The intensity ratio of this signal to that of the starting aldehyde reached 0.22 after a

few hours and remained unchanged for the next fifteen days. Three resolved doublets

at 8 1.69 (J = 6.8 Hz), 1.71 (J = 6.7 Hz) and 1.77 (J = 6.9 Hz) were also observed.

After four days, the signals at 6 1.69 and 1.77 became the most intense resonances;














N


3.31


SN
\\ "N
3N 0

R I-" H

3.37


3.31


N N
\\ N N/YI,
N N

R1HH
OH


3.39


N ,N


N 0H

3.38



3.31






N
N ,N N I
N N-

R H
OH

3.40


Figure 3-10 Reactivity of Benzotriazole with a, -Unsaturated Aldehydes


0

Rl'-H


fast


3.35


N-o

N

Rj,,H
OH

3.36


slow








they are likely to arise from the bis-benzotriazolyl adducts 3.39 and 3.40. The

resonance at 8 1.71 was tentatively assigned to 3.37 since it was previously found that

benzotriazol-1-yl derivatives are the major products from conjugate addition of

benzotriazole with a,0-unsaturated ketones. Although the aryl region of the 'H NMR

spectrum showed that benzotriazol-2-yl derivatives were present, a unique methyl

resonance for 3.38 was not detected; however it is assumed to be an intermediate

leading to 3.40.



3.4 Addition of Benzotriazole and Amines to a, 1-Unsaturated Aldehydes


When an amine was added to a mixture of two equivalents of benzotriazole and

one equivalent of an unsaturated aldehyde, further reactions were observed. The

products usually precipitated from the reaction mixture and were recrystallized.

Elemental analysis revealed a 2:1:1 benzotriazole to aldehyde to amine ratio indicating

a stoichiometry corresponding to substitution of the hydroxy group in 3.39 and 3.40 by

the amine. However, the NMR spectra indicated the products were complex mixtures

of several isomeric benzotriazol-1-yl and benzotriazol-2-yl derivatives (3.41-3.44,

Figure 3-11). The various aldehydes (R'CHO) and amines (HNR2R3) are given in

Table 3-1.

The product compositions depended on the type of amine used for the reaction.

Primary aromatic amines reacted smoothly and gave the adducts in high yields. The

product obtained from n-octylamine could be observed spectroscopically, but could not

be isolated or converted to its picrate salt. Many dialkylamines gave only the

dialkylammonium salts with the benzotriazolate anion. Morpholine (a weakly basic

dialkylamine) gave crystalline adducts with acrylaldehyde, crotonaldehyde and

cinnamaldehyde.







3.39



HNR2R3






N NN


NR2R3

3.41



1





N
'N NN

RHN
NR2R3


3.43


3.40


HNR R


3.42



11


N, N N N

RNR
NR2R3


3.44


NaBH4 or R4MgX


N
Nl R4
R H
NR2R3

3.45


N N
sN R4

R H
NR2R3

3.46


Figure 3-11 Preparation and Reactivity of 1.3-Bis(benzotriazolvl)alkylamines








The bis-benzotriazolyl adducts are presented in Table 3-1. They are mixtures of

several isomers in proportions of which may differ depending upon the precise reaction

conditions, hence the observed melting points can not be treated strictly as an invariant

physical property.

The NMR spectra of the various adduct mixtures 3.41-3.44 show a complex

array of isomers giving numerous overlapping signals. As the benzotriazolyl groups

can be attached at N-1 or N-2 [87JCS(P1)2673], and as there are two stereogenic

centers in the molecule when R1 : H, the possibility for a complex mixture of

diastereomers 3.41-3.44 exist. Full characterization of isomers 3.41-3.44 by NMR

spectroscopy was not possible as the individual isomers could not be separated. Only

the various ranges where the characteristic groups of 3.41-3.44 resonate could be

distinguished. The '3C NMR resonances of these groups do not differ significantly

between individual isomers, and assignments for the major isomers are highly

speculative at best.

Recrystallization of the adduct mixtures 3.41-3.44 usually changed the ratio of

isomers. A single recrystallization of 3.41c-3.44c (R' = Me, R2 = p-ClC6H4, R3 = H)

gave a product consisting of only two isomers, the erythro and threo forms of 3.41c (no

signals from a benzotriazol-2-yl moiety were observed by NMR spectroscopy in

CDCl3).





































kn M C0



i 00 O1 (N
C1 C4 N1 N
00 s 0C


m n W C4 o r \ o 00 Nr
o00 0 N 00 N N N O







S C( C4


e 9 o a 9 9 u u x
0. U t o c- U U U
C4


z,



U


0j 0
'3 L
S"-


Cl .0 t 0 C C V --








3.5 Reaction of 1,3-Bis(benzotriazolyl)alkylamines with Nucleophiles


Bis-benzotriazolyl adduct mixtures 3.41-3.44 were treated either with a 0.5

molar equivalent of sodium borohydride, or with one equivalent of a Grignard reagent,

to afford mono-benzotriazolyl adduct mixtures 3.45-3.46 (Figure 3-12). The

benzotriazolyl moiety attached to C-1 was selectively displaced whereas the C-3

benzotriazole group was unaffected. The oily products were characterized as their

picrate salts (Table 3-2) as well as by 'H and 13C NMR spectroscopy (Tables 3-3 and

3-4).

The a-protons (attached to C-2) were observed to resonate in the 1H NMR

spectrum as non-equivalent multiplets when R' # H. This observation was similar to

that for adducts 3.33c and 3.33d which were prepared from unsaturated ketones.

Furthermore, when R1' H, the presence of a significant amount of 3.46 was confirmed

by proton and carbon-13 NMR. When R' = H, the benzotriazol-l-yl 3.45 isomer

represents 90 % or more of the mixture.





3.6 Conclusions



Benzotriazole reacts with ca,P-unsaturated aldehydes and ketones via conjugate

addition. It is believed that initial 1,2-addition across the carbon-oxygen bond takes

place to give an alcohol (3.36, Figure 3-10), which is the kinetic product. The

equilibrium for formation of 3.36 is unfavorable, however, and the starting materials

are gradually converted to the isomeric 1,4-addition products 3.37 and 3.38. When an

excess of benzotriazole is used, a second equivalent of benzotriazole attacks the

carbonyl carbon atom of an unsaturated aldehyde to give an isomeric mixture of

































1 '0 m
0\ cq C) e
kn W) tn


0\ 0
0 0



t- O\



0 00






0^
- N
; (-l
>n


N d* 0
Ir 0 C
0cn


"It o0 o I 0o n 0
r- N 00 00 N- 00 V


u
N




U f U '0:


0 .0 U u = -


U









z




0
U.
U


0 4
3|

o5
S1"





















8S \0^ -(S -3- ^ -o




ti i i i e -i






mr- 00# r') eq N
V) c l h hh i

4 C4 r4 a ^ ? i E


00 -
'F)d
-- 0E 1.
*0*~ *-~ "


N






00
(I


00 00 mN
ti"mm \mq
Sm o ^Co m aa
^i 01 S^v Se ^^ Si
N tS '-' i-n ^r


I


























'.4
0
Ci
r-




U')















0
CA
















c0
0






























IJ


(l Cl 0 0'
en en en e
r CN O
m m m


0



c4 C
c"'


W)
CU l
c -


C- en ^ .

n- : ; 3 :

Cl C4 "m O e
ur t N CJ E r .,C( \0 W) 0
ri m r m wl rj

Cd ci cl ""


%0 %0
\R-z : ]




m ~
i4 n o6
S S





'nod



Ef

t-:
I? ^

mh
N



Oi
m,


0a 0
N^
ci
r-'


00 0\ 0'' 00
6a 6 6 m6
N" Nd *~d
-m m -m r4l
S0 C o


s~ s.- s ^


'n0 s '.00
000
N" ~



\D~mm


~90
E .
r4s
^- 5g- *

Nl Cl) M.
N- t- r-


00 00 000 000
000 0* 00




as v v u -


Uo au n






'" 300' '0 00 -"^

ooo .6 '
S0\0






-^ C-
C N



r nt
o cr c? c
00 0S.0



C-N C; 0 l0
Nv N










0 6
N m t






\o2- SSo
"m mnr-
r-. &,














00 000
0Clj 0gcmi- gC' o 00.




00 .; ., 00


m 0


U
tt:




















A
a








00
IU











0
0.























E 6
^s

























cli
co









0'
)01
* g-
Kll









s90
MCS
*,"m











*a
-o






"-I
S 0"
|a















mS "



50
^a
a.^
o1


a|














S-.~


" 00
'tM




SN^







BsCJ

S C

rds
































-0 -0 M0 0


o In oIR 9 C-n 00 ol
a,00 O'c- l 00 c- c-. l V) '0 I N 00 0


-1~ i i s C l F I 'l M- T ^ i ^ ( C ( C -o C i C' i
C' r -00 00" V) 0r '0
S^ 5
-N m.- V. V. \


Cn m

C9O 05
-~ N 0 0 00 Cl'-
CM Cl Cl Cl> Cl
'0'0s
OS'0


O
00 C

00 N
! 00 Cl C

O' 00
en rCl


0
O r ^r o\ Co 0 C
tci m ~cn c od /i v-i TT d '-'
v v v r \ \o00





Sl M r- C o0 N 0- vM 1 n C
'6 '6 'i o6 oI ov id o C -I
c' m m cc Cl Cl cr C) P





m \D d< Tf r^ c oo n O- o c
6 6 0 -^ c-4 6 m V. i


o o0 0 0
Cn Cn cn m


- 0C 0
'6 V.i '


rN- 'o a, 0 00
*n ti d i





oR eo oo oR on
S 0\ O 0
0 0 0 0



- 05' 00 05 -*
'6 '6 '6d -:
cl Cl cl4 c c-i


t)i






C





'C









0
O





N












S






cs














z

Q





01

u


s0 t~; O oo


'0 N\ 05 00<


'0 Os 05 0\
05 o~ C o


O 05* 0

Os N




oR 6 oR
- cl -


CM CM
c ,


o 0


S os -4
t& '6
Cl Cl C


- 0,
6 o;
Cl


a u = .- -








bis-benzotriazolyl adducts 3.39 and 3.40, but ketones do not undergo such a reaction.

These bis-benzotriazolyl alcohols can be converted in situ to their more stable amino

analogs 3.41-3.44 by reaction with a primary or secondary amine of low basicity.

Further synthetic manipulation of 3.41-3.44 can be achieved by selective substitution

of the 1-benzotriazolyl moiety with either hydride (from sodium borohydride) or

Grignard reagents.





3.7 Experimental



All melting points and NMR spectra were recorded as previously described in

the Experimental sections of the preceding chapters.



3.7.1 Preparation of 3-Benzotriazolylketones.


4-Benzotriazolyl-2-butanone 3.33a,3.34a. A mixture of benzotriazole (1.19 g,

10 mmole), and methyl vinyl ketone (0.35 g, 5 mmole) in CDC13 (4 ml) was heated

under reflux for 2 h. 'H NMR (CDC13) 8 2.19 (s, 3H), 3.29 (t, 2H, J = 6.5 Hz), 4.87 (t,

2H, J = 6.5 Hz), 7.34-7.44 (m, 1H), 7.50 (dt, 1H, Jo = 8.4 Hz, Jm = 0.9 Hz), 7.57 (d, 1H,

J = 8.5 Hz), 8.04 (d, 1H, J = 8.4 Hz); 13C NMR 5 30.1, 42.25, 42.27, 109.9, 119.5,

124.3, 127.6, 133.2, 145.5, 205.4.

A 2:1 mixture of ethanol:glacial acetic acid (15 ml) containing

2,4-dinitrophenylhydrazine (1.0 g, 5 mmole) was added and the resulting mixture was

stirred for 2 days at room temperature. The crude hydrazone which precipitated from

the solution was filtered, washed successively with water and methanol, and dried.

Recrystallization from dioxane:acetic acid:dimethyl sulfoxide (2:1:2) afforded the

product as orange needles; mp 219 OC.








Anal. Calcd. for C16HiN704: C, 52.03; H, 4.09; N, 26.55; Found: C, 51.88; H,

4.01; N, 26.70.



3-Benzotriazolyl-4-phenyl-2-butanone 3.33b,3.34b. A mixture of benzotriazole

(1.19 g, 10 mmole), and 4-phenyl-3-buten-2-one (0.73 g, 5 mmole) in CDC13 (4 ml)

was stirred at room temperature for 3 days; 'H NMR (CDCI3) 8 2.26 (s, 3H), 3.34 (dd,

1H, J = 17.8, 4.6 Hz), 4.29 (dd, 1H, J = 17.8, 9.5 Hz), 6.34 (dd, 1H, J = 9.5, 4.6 Hz),

7.25-7.45 (m, 3H), 8.03 (d, 1H, J = 8.2 Hz); 13C NMR 8 30.4, 48.7, 58.4, 110.1, 119.6,

124.4, 126.6, 127.5, 128.6, 129.1, 133.0, 138.6, 145.7, 209.9.

Saturated aqueous sodium acetate was added dropwise to a stirred solution of

semicarbazide hydrochloride (5 mmole) in water (10 ml) until the pH was 6.5. The

CDC13 solution of 3.33b,3.34b was added to the semicarbazide and the resulting

mixture was stirred at room temperature for 5 h. Ethanol (7 ml) was added to make the

mixture homogeneous and the solution was chilled to 0 OC for 2 days. The crude

product solidified and was washed successively with water, ethanol and diethyl ether;

mp 165 C.



3-Benzotriazolylcyclohexanone 3.33c,3.34c. A mixture of benzotriazole (2.38 g,

20 mmole), and 2-cyclohexen-l-one (0.96 g, 10 mmole) in CHCI3 (15 ml) was heated

under reflux with stirring for 12 h, after which time the reaction was observed to be

complete by TLC. The product was purified by chromatography (CHCl3/silica gel) to

afford 1.93 g (90 %) of 3-benzotriazolylcyclohexanone (mixture of 1- and 2-isomers).

Recrystallization from 1:1 ethanol:diethyl ether afforded a pure sample of the 1-

isomer; IH NMR (CDC13) 8 1.77-1.93 (m, 1H), 2.14-2.26 (m, 1H), 2.37-2.60 (m, 4H),

2.96 (d, 1H, J = 14.5 Hz), 3.30 (dt, 1H, J = 12.6, 1.7 Hz), 4.99-5.12 (m, 1H), 7.38-7.45








(m, 1H), 7.48-7.58 (m, 2H), 8.10 (dd, 1H, Jo = 8.3 Hz, Jm = 1.0 Hz); 3C NMR 8 21.9,

31.0, 40.6, 47.1, 56.9, 109.0, 120.3, 124.2, 127.5, 132.1, 145.0, 206.8; mp 96-97 OC.

Anal. Calcd. for C12H,3N30: C, 66.96; H, 6.09; N, 19.52; Found: C, 66.91; H,

6.13; N, 19.85.



1-Benzotriazolyl-1,2-dibenzoylethane 3.33d,3.34d. A mixture of benzotriazole

(2.38 g, 20 mmole) and trans-1,2-dibenzoylethene (2.36 g, 10 mmole) in CHC13 (15

ml) was heated under reflux with stirring for 12 h. The reaction was followed by TLC.

The sample was concentrated in vacuo and triturated with hot methanol to afford 2.38

g (79.6 %) of 1-benzotriazolyl-l,2-dibenzoylethane. Recrystallization from a 1:1

mixture of ethanol:diethyl ether afforded an analytical sample; 'H NMR (CDC13) 8

3.76 (dd, 1H, J = 17.6, 4.9 Hz), 4.53 (dd, 1H, J = 17.8, 8.5 Hz), 7.25-7.65 (m, 9H), 7.68

(d, 1H, J = 8.5 Hz), 7.95-8.08 (m, 5H); 13C NMR 8 39.3, 58.4, 109.9, 120.2, 124.1,

127.98, 128.09, 128.61, 128.70, 128.76, 132.2, 133.72, 133.96, 134.08, 135.6, 146.2,

191.8, 195.7; mp 150-151 OC.

Anal. Calcd. for C22H,7N302: C, 74.35; H, 4.82; N, 11.82; Found: C, 74.34; H,

4.64; N, 11.74.



4-Benzotriazolyl-4-methyl-2-pentanone 3.33e,3.34e. A mixture of benzotriazole

(2.38 g, 20 mmole) and mesityl oxide (0.98 g, 10 mmole) in CHC13 (15 ml) was heated

under reflux for 36 h. The sample was concentrated in vacuo and purified by

chromatography (CHCl3/silica gel) to give an oil (1.66 g, 76.5 %). The product was

shown by NMR spectroscopy to be a 9:1 mixture of the benzotriazol-1-yl and

benzotriazol-2-yl isomers; 'H NMR (CDCI3) 8 1.96 (s, 6H), 2.09 (s, 3H), 3.36 (s, 2H),








7.34 (dd, 1H, Jo = 7.3 Hz), 7.44 (dd, 1H, Jo = 7.1 Hz), 7.75 (d, 1H, J = 8.5 Hz), 8.05 (d,

1H, J = 8.3 Hz); 13C NMR 8 27.6, 31.2, 53.2, 61.5, 111.7, 120.2, 123.3, 126.7, 131.6,

146.8, 204.8; m/z = 217 (M+-), 119 (C6H5N3+'), 91 (C6HSN+').



3.7.2 Preparation of 1,3-Bis(benzotriazolyl)alkylamines General Procedure.


1,3-Bis(benzotriazolyl)alkyl]amines 3.41-3.44. To a suspension of benzotriazole

(71.66 g, 0.60 mole) in diethyl ether (300 ml) was added the a,13-unsaturated aldehyde

(0.30 mole) and the resulting mixture was vigorously stirred at room temperature for

15 h. To the reaction mixture was added a solution of the amine (0.30 mol) in diethyl

ether (100 ml) in one portion and the mixture was stirred an additional 6 h at room

temperature. The precipitate was filtered, washed with diethyl ether (100 ml) and with

a 1:1 mixture of diethyl ether:hexanes (200 ml), and dried in a vacuum oven at 80 OC.

The crude product was recrystallized to afford an analytical sample.



3.7.3 Reduction of 1,3-Bis(benzotriazolyl)alkylamines with Sodium Borohydride -
General Procedure.


To a solution of 3.41-3.44 (100 mmole) in dioxane (100 ml) was added sodium

borohydride (1.89 g, 50 mmole) and the mixture was stirred under reflux for 4 h. The

reaction mixture was poured into a beaker containing 10 % aqueous sodium hydroxide

(100 ml) with stirring. The resulting solution was extracted with diethyl ether (3 x 30

ml), and the combined ethereal extracts were washed with water, dried over anhydrous

sodium sulfate and concentrated in vacuo. The crude amine 3.45,3.46 was

subsequently purified by chromatography (39:1 CHCl3:MeOH/silica gel) and

converted to its picrate salt for further characterization.








3.7.4 Reaction of N-[1,3-Bis(benzotriazolyl)propyl]morpholine with
Phenylmagnesium Bromide.


N-[(3-Benzotriazolyl- -phenyl)propyl]morpholine 3.22k,3.23k. A solution of

phenylmagnesium bromide (11.4 mmole) in THF (35 ml) was added dropwise to

3.41h-3.44h (3.63 g, 10 mmole) under a nitrogen atmosphere. The contents were

stirred for 30 min at room temperature, and then heated under reflux for 12 h. Excess

Grignard reagent was quenched with cold saturated aqueous ammonium chloride and

the organic and aqueous layers were separated. Some insoluble matter which was also

obtained was removed by filtration.

The aqueous layer was extracted with diethyl ether (3 x 30 ml), and the

combined organic phases were washed with water (30 ml), brine (30 ml), and again

with water (30 ml). The ethereal extracts were dried with sodium sulfate and

concentrated. The insoluble matter was subjected to soxhlet extraction (CHCY3); the

extract was dried over sodium sulfate, concentrated, and combined with the previously

obtained crude material. Purification by chromatography (19:1 CHC13:MeOH/silica

gel) afforded 1.60 g of N-[(3-benzotriazolyl- -phenyl)propyl]morpholine.














CHAPTER 4
SUMMARY AND CONCLUSIONS


Benzotriazole reacts with one molar equivalent of an aldehyde and an amine, or

similar compound containing an -NH2 group, to give benzotriazol-1-ylalkylamines.

The benzotriazolyl moiety acts as a leaving group when these adducts are treated with

nucleophiles. The amine nitrogen of benzotriazol- 1-ylalkylamines can be quaternized

with a variety of alkylating agents. Benzotriazol-1-ylalkylammonium salts may also

be prepared by reacting 1-halomethylbenzotriazoles with tertiary amines. These salts

do not undergo nucleophilic substitution as in the case of their amine precursors.

Benzotriazole also undergoes conjugate addition with a,3-unsaturated aldehydes

and ketones. When more than one equivalent of benzotriazole is employed, a second

benzotriazole group can add across the carbon-oxygen double bond of ca,3-unsaturated

aldehydes, but unsaturated ketones do not undergo further addition. Unsaturated

aldehydes can also be reacted with two equivalents of benzotriazole and one equivalent

of an amine to afford N-[1,3-bis(benzotriazolyl)alkyl]amines. The benzotriazolyl

group adjacent to the amine nitrogen can be selectively displaced by hydride or by

alkyl anion donors to give 3-benzotriazolylalkylamines.














REFERENCES


The system adopted for designation of references in the main body of the text is

that developed by Professor A. R. Katritzky for use in "Comprehensive Heterocyclic

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(1985).

The references are designated by a number-letter code of which the first two

digits (or the first four digits for references before 1900) denote the year of publication,

the next one to four letters the source (journal or patent) and the final digits the page or

patent number. Less common journals and books are given the code 'MI' for

miscellaneous, the first digit following 'MI' designated the order that reference occurs

in the text, i.e., the '2' following 'MI' in 76MI2 means that it is the second

miscellaneous reference for the year 1976. A list of codes (in alphabetical order) is

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A two-letter code for works which have been accepted for publication or are

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Where the name of a journal has changed, the original journal code is retained

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1986, but both are designated OMR).








CODE FULL TITLE



AG(E) Angewandte Chemie International Edition (English).

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CO Comprehensive Organic Chemistry

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JOU Journal of Organic Chemistry of the USSR, English Translation

JPS Journal of Pharmaceutical Sciences

MI Miscellaneous.

OMR Organic Magnetic Resonance/Magnetic Resonance in Chemistry

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S Synthesis.
T Tetrahedron.

TL Tetrahedron Letters.

UP Unpublished Work.








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BIOGRAPHICAL SKETCH



Craig V. Hughes was born on April 4, 1961 in Sarasota, Florida. He began his

collegiate studies at Manatee Junior College and after two years matriculated to the

University of Central Florida where he earned his Bachelor of Science degree in

chemistry in the spring of 1984. In the fall of that same year, he entered graduate

school at the University of Florida where he joined the research group of Dr. Alan

Katritzky.








I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.




Alan R. Katritzky, Chrman
Kenan Professor of Organic Chemistry




I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.




Kenneth B. Wagener
Associate Professor of Chemistry




I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.




A. Deyrup /
essor of Chemistry




I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.


William M. Jones
Professor of Chemistry








I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.




Stephen G. chulmrn
Professor f Ph eutics




This dissertation was submitted to the Graduate Faculty of the Department of
Chemistry in the college of Liberal Arts and Sciences and to the Graduate School and
was accepted as partial fulfilment of the requirements for the degree of Doctor of
Philosophy.

August, 1989


Dean, Graduate School







































UNIVERSITY OF FLORIDA
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