B-GHOXYMETHYLTETRAZOLE AND
DEREVAYWES 143- ACTEVE
METHYLENE EQ-MFQURflg

The”: ‘04- fit. Dogma 0* pk. D.
HECHEGRN STR’FE EINEYERSET‘!
George Warren Beebe

1963

THESI‘S' '

This is to certify that the

thesis entitled

5-CARBOXYME'IT1YLTE‘I‘RAZOIE AND DERIVATIVES AS

ACTIVE ME‘I'HYIENE COMPOUNDS
presented by

George W. Beebe

has been accepted towards fulfillment
of the requirements for

___Ph‘D‘ degree in ___1;yChemist

FMM Mi”

Major professor

October 18, 1965
Date

 

0-169

LIBRARY

' Michigan State
University

 

ABSTRACT

5-CARBOXYMETHYLTETRAZOLE AND DERIVATIVES AS
ACTIVE METHYLENE COMPOUNDS

by'Geor-ge' Warren Beebe

The phenomenon of methylene activation by electron withdrawing
groups, such as carboxyl or carboalkoxy, is well-known. The in-
creased acidity of the methylene protons, enabling their facile removal
, by base, renders the compounds active as synthetic intermediates.
They enter into two distinct classes of reactions, condensations'and
alkylations. .Condensations require the addition of methylene anion
to an unsaturated bond such as an‘aldehyde and result in the formation
of addition complexes which may lose water toform carbon-carbon
unsaturated systems. Alkylations involve the attack of the anion on
.alkyl halides with the formation of an alkyl substituted methylene group.

The similarity between the carboxyl group'and the 5—tetrazoly1
group has been summarized (1) by Herbst with respect to resonance
stabilization, ring proton acidity, and substituent effects. Therefore,
activation of a methylene group by a 5-tetrazolyl group was considered
a possibility. To test this idea, 5-carboxymethyltetrazole, S-carbo-
ethoxymethyltetrazole, and 2-benzyl-5-carboethoxymethyltetrazole
were synthesized as analogs of malonic acid, monoethyl malonate, and
diethyl malonate, respectively. They were subjected to-conditions
normally associated with the -Knoevenagel condensation'and anionic
alkylation. -From the-conditions required for reaction and the products
obtained, conclusions were drawn as to the activating ability of the

S-tetrazolyl group.

George «Warren Beebe

5-Carboethoxymethyltetrazole was condensed with benzaldehyde
and p-methoxy- and p-nitro-benzaldehydes in pyridine with piperidine
as catalyst.to give moderate yields of the corresponding 5-(2-ary1-l-
carboethoxyvinyl_)_tetrazoles. The moderate yields were attributed
to the inability of the tetrazole ring to as effectively stabilize the inter-
mediate anion, which resulted in low concentration of reactive inter-
mediate and thus low conversion to product.

Analogous tO‘Knoevenagel condensations involving malonic
acids, 5-carboxymethyltetrazole reacted with the above aldehydes in
pyridine with piperidine as catalyst to yield 5-(Z-arylvinyl)tetrazoles.
The ability of the intermediate to undergo decarboxylation helped to
increase the ease of reaction by shifting the equilibrium steps toward
product.

These 5-(2-arylvinyl)tetrazoles were also prepared by hydrolysis
and decarboxylation of the 5-(2-aryl-1-carboethoxyvinyl)tetrazoles
obtained from the previous condensations. The saponification, contrary
to that experienced with malonate esters (2, 3) was found to-progress
with extreme ease and under much milder conditions. Some of the
5-(2-aryl-l-carboethoxyvinyl)tetrazoles underwent attack at‘the benzylic
position in strong aqueous base resulting in reversal of the initial
condensation rather than the desired saponification. This parallels
observations‘with diethyl arylidinemalonate saponification'(2).

Attack. of base was almost 100% at this point in the case of Eq-[l-carbo-
ethoxy-Z-(p-nitrophenyl)vinyl]tetrazole so that acid hydrolysis was
necessary to obtain the corresponding acid. The amount of attack at

.. the benzylic position was related to the gala-substituent and its
resonance effects. The ease of reaction was attributed to participation

of thertetrazole anion in the saponification.

George Warren Beebe

The 5-(2-aryl-l-carboxyviny1)tetrazoles underwent decar-
boxylation analogous to that of the arylidinemalonic acids. The
temperatures for decomposition of analogous compounds were quite
similar. The 5-(2-arylviny1)tetrazoles produced were the same as
those prepared by condensation of the aldehydes with 5-carboxymethy1-
tetrazole.

The conditions necessary for alkylation of the methylene of
2-benzyl-5-carboethoxymethyltetrazole were determined. A No re-
action was observed in sodium ethoxide - ethanol medium. The use of
sodium hydride was probably necessary to produce the anion. In ad-
dition only the more reactive halides, benzyl, p-chlorobenzyl, and
allyl, would react with the anion. All attempts utilizing alkyl halides
failed. The conclusion was drawn that the anion was present in very
small quantities and that the reactivity of the halide determined
whether products formed.

The debenzylation of the 2-benzy1 group on the tetrazole ring was
found to proceed very smoothly by sodium reduction in liquid ammonia.
The ease of benzylation and debenzylation makes this an effective

blocking group for‘the tetrazole ring hydrogen.

REFERENCES CITED

1. Graff, S. , "Essays in Biochemistry,- " John Wiley andSons, Inc. ,
New York: 1956, p. 141.

Z..Claisen, 1..., and L. Crismer, Ann., 218, 131 (1883).
3. Meyerberg, A., Ber., fig, 786 (1895).

5-CARBOXYMETHYLTETRAZOLE AND DERIVATIVES AS
ACTIVE METHYLENE COMPOUNDS

By

George Warren Beebe

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPH Y

, Department of Chemi str y

1963

G 990%?

7/8/o4

ACKNOWLEDGMENT

The writer wishes to express his gratitude to Dr. Robert
M. Herbst for his guidance and helpful suggestions throughout the
course of this work.

Also, thanks are extended to the Department of Chemistry,
Michigan State University for Graduate ‘Assistantships during
the years 1958—1962, and to the National Science Foundation for
a Cooperative Fellowship during 1962-1963.

To his friends, parents, and especially his wife, Donna, the
author would like to express his appreciation for their encourage-
ment and understanding.

**>’.<>l<>i<**********

ii

TABLE OF CONT ENTS

INTRODUCTION 0 O 0 O O O 0 O O O O 0 O O O O O O O O O O O O O 1
HISTORICAL .............. . . . . ......... 4
RESULTS AND DISCUSSION . . . . . . . . ........ . . . l3

Fundamental Reactions and the Preparations of Starting

Materials........................ 13
The Condensation Reactions . . . . . . . . . . . . . . . . 16
The Hydrolysis of 5-(2-Aryl-1-carboethoxyviny1)-
tetrazoles...... ....... 27
The Decarboxylation of 5- (Z— -Ary1- 1- carboxyvinyl)-
tetrazoles....................... 34
Alkylation Reactions Involving Z-Benzyl-S-carboethoxy-
methyltetrazole ........... . . . . . . . . . . 39
EXPERIMENTAL ..... . . ........ . ........ 47

Section 1: Starting Materials and Fundamental Reactions. 47
An Evaluation of Procedures for the Preparation of

5-carboethoxymethyltetrazole. . . . . ..... . 47
Procedurel........ ..... 47
ProcedureZ.............. ...... 48

Procedure3.................... 48
‘Procedure4.................... 49
The Preparation of 5-Carboxymethyltetrazole . . . . 49

Procedurel............... ..... 49
ProcedureZ........ 50
The Preparation of 5- -Methy1tetrazole ....... . . 51
5- -Methyltetrazole . . . . . . . . . . . . ..... 51
The Preparation of 2-Benzyl-5-carboalkoxymethyl-
tetrazoles..................... 51

Reaction of 5-Carbobutoxymethyltetrazole with
Benzleromide................ 51

2---Benzy1-5-carboethoxymethyltetrazole by
Benzylation............. ..... 52

iii

TABLE OF CONTENTS - Continued

Page

2-Benzy1-5-carboethoxymethyltetrazole by
.Esterification . . . . . . . . . . . . ..... 52
The Debenzylation of 2, 5-Disubstituted Tetrazoles . . 53
Attempted Debenzylation of 2-Benzy1-5-carboxy-
methyltetrazole...........v..... 53
The Preparation of 2-Benzyl-S-phenyltetrazole . 53
A Study of the Debenzylation of 1- or 2-Benzy1-
5-phenyltetrazoles . . . . . . . . . . . . . . 54
5-Carboxymethy1tetrazole by Debenzylation . . . 55
Section 2: Condensation Sequences Involving 5-Carbo—
ethoxymethyltetrazole ..... . . . . . . . . . 56
The Preparation of 5- (2- -Phenylviny1)tetrazole . . . . 56
(a) 5- (1- --Carboethoxy 2- -pheny1viny1)tetrazole. . . 56
(b) 5-(1-Carboxy-2-pheny1vinyl)tetrazole. . . . . 56
(c) 5-(2-‘Pheny1vinyl)tetrazole. . . . . . . . . . . 57
The Preparation of 5-[2-(p-Methoxyphenyl)viny1]-
tetrazole.................... .58
(a) 5- [1- ”Carboethoxy 2- (p- -methoxyphenyl)viny1]-
tetrazole..... . ............58
(b) 5- [1- -Carboxy-2- (p- -methoxypheny1)vinyl]-
tetrazole....................58
(C) 5-[2-(p-Methoxyphenyl)viny1]tetrazole. . . . . 59
The Preparation of 5-[2-(p-Nitropheny1)viny1]-
tetrazole........~..............59
(a) 5-[1 -Carboethoxy- 2- (p- nitropheny1)vinyl]-
tetrazole....................59
(b) 5-[1-Carboxy-2-(p-nitropheny1)viny1]-
tetrazole....-._...............6O
(c) 5—[2-(p-Nitrophenyl)viny1]tetrazole . . . . . . 61
Attempted Condensation Reactions. . . . . . . . . . . 62
Condensation of p-Methoxybenzaldehyde and
5-Carboethojcymethyltetrazole . . . . . . . . 62
Attempted Condensation of p-Nitroaldehyde and
5-Carboethoxymethyltetrazole . . . . . . . . 62
Attempted Saponification’Reaction . . . . . . . . . . . 63
5-(1-Carboxy-2-pheny1viny1)tetrazole. . . . . .. . 63
Section 3: Condensations Involving 5-Carboxymethyl-
tetrazole........................64
The Preparation of 5-(2-Ary1vinyl)tetrazoles . . . . . 64
5-(Z-Phenylviny1)tetrazole Monohydrate ..... 64

iv

TABLE OF CONTENTS - Continued

Page
5-[2-:(p-Methoxypheny1)viny1]tetrazole ...... 64
5-[2-(p-Nitrophenyl)viny1]tetrazole . . ...... 65

The Attempted Preparation of 5-[2-(p-Nitropheny1)-
vinyl]tetrazole Hydrate . . . . .—. . . . . . . . . 66
' Reaction of 5-Carboxymethy1tetrazole with
p-Nitrobenzaldehyde ....... . . . . . . 66
Section4: The Alkylation Reactions . . . . . . . . 67
The Preparation of 5- (2-Pheny1ethyl)tetrazole . . . . 67
(a) 2- --Benzy1 5- (1- --carboxy --2 phenylethy1)-
tetrazole . . . . . . ............. 67
(b) 5- (1- --Carboxy-2 -phenylethy1)tetrazole . . . . 69
(C) 5- (2- Phenylethyl)tetrazole . . . . . . . . . . 69
The Attempted Preparation of 5-[2-(p-Chlorophenyl)-
ethy1]tetrazole.................. 70
(a) 2-Benzy1-5-[1-Carboxy-2-(p-chlorophenylb
ethy1]tetrazole................ 70
(b) Debenzylation of 2-Benzyl-5-[1-carboxy-2-
(p-chlorophenyl)ethy1]tetrazole . . . . . . . . 71
The Preparation of 2-Benzy1-5-(1-carboxy-3-buteny1)-
tetrazole...................... 71
2-Benzy1-5-(1-carboxy-3-butenyl)tetrazole . . . 71
Alkylations Attempted in Sodium Ethoxide - Ethanol . 72
Attempted Preparation of 2-Benzy1-5-(1-carbo-
ethoxy-2-pheny1ethy1)tetrazole . . . . . . . . 72
Attempted Preparation of 2—Benzy1-5-(l-carbo-
ethoxy-3-butenyl)tetrazole . . . . . . . . . . 73
Attempted Preparation of 2-Benzyl-5-
(l-carboxy-3-butenyl)tetrazole . . T . . . . 73
Attempted Preparation of 2-Benzyl-5-(1-car-
boxypropyl)tetrazole . . . . . . . . . . . . . 74
Alkylations Attempted in-Sodium Hydride -- Ether . . 75
Attempted Preparation of 2-Benzy1-5-(1-carboxy-
3-cyclohexylpropyl)tetrazole . . . . . . . . 75
Attempted Preparation of 2-Benzy1-5-(1-carboxy-
3-methy1butyl)tetrazole . . . . . . . . . . . 76

SUMMARY 7'7
BIBLIOGRAPHY. . . . . . . . . . ...... . ...... . . 80

APPENDICES.......................... 83

LIST OF TABLES

TABLE

10

InfraredAbsorption of Several 5-(2-Aryl-1-carboethoxy-
v‘iny1)tetrazoles......................

Reaction Orders and Overall Rates of p-Substituted
Benzaldehyde Condensations with Ethyl Cyanoacetate . .

Infrared Carbonyl Absorption for Various 5-(2-Ary1-1-
carboethoxyvinyl)- and 5-(2-Ary1-1-carboxyviny1)-
tetrazoles.........................

. Basicities of Substituted trans-Chalcones in 5% Dioxane-

95%AqueousSulfuricAcid. . . . . . . . . . . . . . . .

- Melting Points of Arylidinemalonic Acids and 5-(2-Ary1-

1-carboxyviny1)tetrazoles. . . . . . . . . . . . . . . . .

vi

Page

18

19

29

31

36

LIST OF FIGURES

FIGURE Page

1. The ultra-violet spectra of 5-(2-pheny1viny1)tetrazole
and 5—(2-pheny1vinyl)tetrazole monohydrate . . . . . . 25

2. The'NMR spectrum of 2-benzy1-5-(1-carboethoxy-2-
phenylethyl)tetrazole in carbon tetrachloride ..... 68

vii

LIST OF APPENDICES

APPENDIX Page

II.

Infrared spectra (Figures 1-17) . . . . . . . . . . . . 84

1. 5~Carboxymethy1tetrazole . . . . . . . . . . . . . 85
2. 2—Benzyl-5-carboethoxymethyltetrazole ...... 86
3. 2-Benzyl-5-carboxymethyltetrazole . . . . . . . . 87
4. 5-(1-Carboethoxy-2-phenylvinyl)tetrazole ..... 88
5. 5-[1-Carboethoxy—2-(p-methoxypheny1)vinyl]-

tetraZOIe O O O O O O O O O O O O O O O O O O 0' O O O 89

6. 5- [1- --Carboethoxy 2- (p- nitrophenyl)vinyl]tetrazole. 90
7. 5- (1— —-Carboxy-2 -pheny1viny1)tetrazole . . . . . . 91
8. 5- [1- --Carboxy-2 (p-methoxyphenyl)viny1]tetrazole. 92
9. 5- [1- -Carboxy- 2- (p-nitrophenyl)vinyl]tetrazole. . . 93
10. 5-(2-Pheny1viny1)tetrazole . . . . . . . . ..... 94
11. 5-[2-(p-Methoxyphenyl)viny1]tetrazole . . ..... 95
12. 5-[2-(p-Nitropheny1)vinyl]tetrazole. . . . . . . . . 96
13. 54-(2-Phenylvinyl)tetrazole monohydrate ...... 97

14. 2-Benzy1-5-(1-carboxy-2-pheny1ethyl)tetrazole . . 98
15. 2-Benzyl—5-[1-carboxy-2-(p-chlorophenyl)ethy~l]-

tetrazole ....... 99
16. 2-Benzyl-5—(1-carboxy-3-butenyl)tetrazole . . . . 100
17. 5-(1-Carboxy-2-pheny1ethy1)tetrazole ....... 101

Attempted preparations of 2, 5-disubstituted tetra-
zoles....... ......... ..........102

viii

INTR ODtUC TION

‘ Early workers in the field of tetrazoles noted that tetrazole and
5-substituted tetrazoles dissociate readily into a tetrazole anion and a
proton (1, 2). This acidity is promoted by the ability of the tetrazole
v?- n

R-fi—ZEH :_—\ R-E ‘ "

\N

1‘} +
I‘11 +H
/

L .1

 

 

hydrogen to tautomerize and resonance-stabilization of the anion

analogous to a carboxyl group (see Chart 1).

Chart I
0-H
R- / ——>- R-C<\
0-H S o
R-fi—I‘m RTE—D:
<---_——\
N\N/N \N/
H
O: —
‘R-C/ ea R-C<
0-: \O
_R-C——1IJ.' xvii—fl xvii—Isl:
4 6-9 <-——> .

 

 

Although only one ester can be formed from a carboxyl group due

to equivalence of the oxygens, the tetrazole ring can give rise to either

the 1- or 2- substituted compounds. Studies on the dipole moments of
tetrazoles in dioxane bear out the existence of the l, 2-tautomers with
van-equilibrium ratio of 70:30 respectively (3).

While many tetrazole compounds containing substituents in the
1 or 2 position have been prepared (4), procedures involving direct
alkylation of 5-substituted tetrazoles in various systems give predomi-
nately 2,5-disubstituted tetrazoles (57-7). ,.

-In either case, replacement of the acidic hydrogen of the tetra-
zole ring by an alkyl or aryl group alters the physical properties in
much the same way as ester formation. The melting points are generally
lowered and the solubility decreased in water and polar organic solvents;
solubility in non-polar organic solvents usually increases. The com-
pounds lose all acidic properties such as salt formation with bases.)is

This similarity to a carboxyl group has promoted the synthesis
of various 5-substituted tetrazole derivatives and determination of their
acidity (8, 9). The results of these studies summarized by Herbst (10)
showed that the effect of substituents in the 5-position on the acidity of
the tetrazole hydrogen were relatively the same as the effect of similar
substituents on the acidity of the carboxyl group.

The previous work has been concerned with the inherent acidity
of the tetrazole ring hydrogen and its similarity to that of a carboxyl
group. It would be of interest to know whether this analogy could be
expanded to include those reactions which utilize the activating influence
of the carboxyl group. For example, it is well-known that the methylene
group of diethyl malonate is activated to such an extent that the sodio
salt may be prepared with strong base. -This anion is stabilized through

resonance with the carboxylate group as:

 

*
Comparison of tables found in reference 4.

 

% :.O\' (15
/C"OCZH5 / "OCsz / "OCsz
:cg <-——> H \ {—9 HC\
éI—OCZHS g-ocsz \guoczn5
__ J

 

The synthetic utilization of this phenomenon is manifold. The
reactions may be divided into two general types. The first, alkylation,
involves the replacement of a leaving group such as bromide or iodide
by the enolate anion; this results in the formation of an alkyl substituted
methylene. The second, condensation, requires the addition of the
anion with or without the elimination of water to an unsaturated system
such as the carbonyl group; the modifications here are extremely
numerous depending both on the substituents on the active methylene
and the unsaturated system used.

In 'an‘attempt to determine the activation effect of the tetrazole
ring, the compounds 5-carboxymethyltetrazole, 5-carboethoxymethy’l-
tetrazole and 2-benzy1-5-carboethoxymethyltetrazole, similar in'acidic
properties and structure to malonic acid, monoethyl malonate and
diethyl malonate respectively, were selected for study. The work pre-
sented involved a synthetic study of base catalyzed alkylations of 2-benzy1-
5-carboethoxymethyltetrazole and Knoevenagel type condensations of
aromatic aldehydes with 5-carboxy'methyl- and 5-carboethoxymethyl-
tetrazole. vFrom the products formed and the conditions used, conclusions

were drawn concerning the influence of the tetrazole ring.

HISTORIC AL

The methods utilized for the preparation of tetrazole and substi-
tuted tetrazoles are many and varied. The reactions are of two general
types; those involving ring formation and those involving modification of
side chains on an existing ring to give the desired product. The litera-
ture up to the early 1940's has been reviewed by Benson (4), and serves
as a ready source of methods. The work of Bladin, Pinner‘and Oliveri-
Mandala and their co-workers in the late 1800's andearly 1900's
presents a vast background of information upon which many of the newer
methods or refinements are based.

5-Substituted-(primarily aryl) tetrazoles have been prepared by
diazotization of amidrazones. - Imido esters, after conversion to the
amidrazone by reaction with hydrazine hydrate, are also useful starting

mate rials (1 1- 14) .

N
/
N/

The direct interaction of a nitrile group with hydrazoic acidto
give 5-substituted tetrazoles was noted by Oliveri-Mandala (15) who
prepared 5‘, 5-ditetrazolyl, 5-cyanotetrazole, or 5-tetrazolylformamide
by condensing hydrazoic acid with cyanogen under varying conditions.
5-Carboxytetrazole is unstable, but its esters, amide, andsalts are
known stable compounds. .5-Carboethoxytetrazole is formed directly

from hydrazoic acid and ethyl cyanoformate (16).

This -method and recent modifications have accounted for a vast
number of 5-a1ky1 or 5-aryl-tetrazoles. The hydrazoic acidvmay be
a previously prepared benzene or chloroform solution or may be pre-
pared in §_i_t.1_1_ by reaction of an acid such as acetic acid with sodium
azide (8, 9). The more reactive lithium (17), ammonium (18), and
aluminum azides (19), prepared in flu from sodium azide andthe
corresponding chlorides, react with cyano groups to give 5-substituted
tetrazoles. 5-Carboethoxymethyltetrazole has been prepared in this
manner by interaction of sodium azide, ammonium chloride and ethyl
cyanoacetate in dimethylformamide (18).

Except for several instances where the tetrazole ring has been
alkylated, _1_.3. , the preparation of 2-ethy1 or 2-methy1-5-cyanotetra-
zole by reaction of the corresponding iodide and the silver salt of
S-cyanotetrazole (20), the main reactions for the preparation of pure
2, 5-disubstituted tetrazoles has involved ring formation. The first
tetrazole prepared by Bladin was 2-pheny1-5-cyanotetrazole, formed

by diazotization of the substituted amidrazone (21).

QNHNH-fi-CN 3&3; Nc-(l: III
NH -N .N

The reaction of hydrazones and azides has been utilized for the

 

 

preparation of 2, 5-disubstituted tetrazoles. The preparation of
2-phenyl-5-carboxytetrazole by Dimroth and Merzbacher was also

extended to other 2, 5-disubstituted tetrazoles (22).

'Br
Br N3 , +HOOCCH=N-NH© NaOCzH5>
Br

HOOC-f

N Br
N 1 N + Br 'NH
Br

 

 

 

Studies on the ultra-violet spectra of 1, 5- and 2, 5-disubstituted
tetrazoles suggest that direct alkylation of 5-substitutedtetrazoles
produces the 2, 5-isomer’ (5, 7). This observation was supported by
Mihina and Herbst who benzylated 5-pheny1tetrazole; the product
isolated had the correct empirical formula, but was shown to be other
than 1-benzy1-5-pheny1tetrazole (8). A study of alkylations in various
systems has shown that the 2, 5-isomer is only the predominate not
the sole isomer produced. When 5-pheny1tetrazole was methylated,
both the 1- and Z-methyl-5-pheny1tetrazoles were isolated in a 1 to 4
ratio respectively (6).

At the time of Benson's review on tetrazoles (4), the compounds
containing a carboxyl or carboalkoxy group were limited mainly to
those with the group attached directly to the ring at the 5 position.
The exceptions were those ‘where the carboxyl group was attached
to a phenyl ring which in turn was substituted on the 1 or 5 position of
the tetrazole ring. Garbrecht and Herbst have reported the preparation

of a 1-carboethoxy-5-substituted tetrazole formed by direct alkylation

(23).

CHZNH-f -H

Q l 1’ + also; can, 559—939
N N H30
\V

CHZNH-c— -COOCZH5
I 1’
N N

\Né

 

The preparation of 5-carboethoxytetrazole from ethyl cyanoformate
and aluminum azide in tetrahydrofuran has been reported (19).

An interesting reaction of sodium azide with 1-carbomethoxy-1-chloro-
4-cyano-4-phenyl-2, 3-diaza-1, 3-butadiene results in a tetrazole

containing a carbomethoxy group (24).

 

 

 

 

 

c1 N

\c=N-N=c DMF J\c=N-N=c

/ \ NaN3

cozcn, CN COZCH3 \L CNJ

/N\

HC T-NHc-o Ll)a1k.hydr. 1's \1!

11 11 ‘2)H3O+ 1

N /N O C N'N=
COZCH3 CN

In recent years, methods for the preparation of tetrazoles
containing a carboxyl separated from the ring by a methylene have
appeared. Fusco and Rossi (25) prepared a mixture of 1(5)-carboxy-
methyl-5(1)-phenyltetrazole by interaction of 8-pheny1 propionic
acid with hydrazoic acid and sulfuric acid. The mixture was not
separated but decarboxylated and the 1(5)-methy1-5(l)-pheny1tetrazoles
separated by fractional crystallization and identified.

Unsaturated 5-oxazalones (I) have been used in a specific ring
opening and recyclization reaction with hydrazoic acid to prepare

u-substituted-a-(1—tetrazoly1)acetic acids (II) (26).

RKC¢N\N
RCH= xlv HN | ‘ "IL
I ——3—> RCH=c—.-N.__
//C\ /C-R' I
o o coon
I 11

The mechanism proposed was a specific attack of the hydrazoic acid

as denoted in the following scheme.

 

 

 

RCH\ RCH=p———N
\r': hf c lCi—R' ———->' 11
/C\ l\ 7‘ (IDH 1!:
0/ if — I, 1
N3

H

The utilization of saturated 5-oxazalones (III) led to analogous
saturated products, but in much reduced yields; while reduction of II

was nearly quantitative to give the saturated analogs.

H
RCHz-Clli—‘IN
o//C\o/ R'
111

A general method for preparing 5-substituted-1-tetrazolyl-
acetic acids (IV) by means of standard reactions has appeared (27),

see Scheme 1.

 

Scheme 1
R R
I PC15 \ I
.czH,ozc-c-NHfiR " , cszozc-c-Nw-R"
R' O R' C1

iHN;

1 H .+ i
Hooc-c-N— -R" <——3—— cszozc- - N—c-R"
l1 1 Lil: or OH- , l I
'NaN/ NeN/N

Iv

Using a slightly modified starting material (V) in Scheme 1,

l-substituted-5—tetrazoly1acetic acids (VI) were prepared.

 

_ . CzHSOzC-CliH-fiNHR' Hooc-cle- ~I|\I-R'

RO RN\I‘//N

V VI

Jacobson-andAmstutz have prepared 5-tetrazolylacetic acids,

by means of metalation reactions (28).

.Scheme 2
R' R'
l |
R-N—"C-CH R-N———- -C-M 1) co -
I II I £49 I II I +2) H
\ N R" p N R"
N\N/ kN/R

2:0
”—0—”
O
O
0
IE

Utilizing a base catalyzed condensation, these workers also prepared

several e-keto-[i-(5-tetrazolyl)propionic acids (VII).

Scheme 3

 

II" 0
R-N—(‘S-CHZR' R- -N——-lcl: g—HCOZCZHS
IL I :~ ~ NaOCzH5\ I\IKI NNaL+
\ ’ \
+ VIII
(cozczns)z if
lb-T—E—CHCOCOOH CH co H R-Ilq———<f—-CHcocozczH,
‘ H o‘F .N R'
KN/ 3 I\\N/
v11 IXa, 11 = phenyl, R' = H

IXb, R = CH3, -R' = phenyl

The sodio derivatives (VIII) were exceptionally stable. A determination
of the enol content by the method of Meyer and Kappelmeier (29) of

compounds‘IXa and b, gave 93% and 87% respectively. ‘ .Structure X

10

proposed to account for this behavior involves resonance stabilization

with the tetrazole ring.
I

R-N——— \ COZCsz
N N o
\ x

x

On the other hand, compound XI prepared by condensing VIII (R = phenyl,
R' = H) with ethyl chloroformate gave an enol content too small to be

detected by the method used.

QDII—fi—(IIH-CO-COZCZHS

N cozczH5
KN/

XI

LaForge, D'Adamo, Cosgrove, and Jacobson (30), utilizing the
methods of Jacobson and Amstutz (27, 28), prepared a variety of substi-
tuted 1- and 5-tetrazolylacetic acids and subsequently converted the
carboxyl group to the acid chloride. From the acid chlorides, these
workers further modified the carboxyl group by amide or ester

formation to give 53 variations of structures X11 and XIII.

R-N fi—EHCOR' = R-fi—E—E\ tlx-R'

 

 

N N H I"
%N/ 1
R, R" = alkyl, aryl R', R", R'" = alkyl, aryl
R' = substituted amino, alkoxy R = substituted amino, alkoxy
XII XIII

One reference has appeared in which the methylene group of

5-carboethoxymethyl-2-methy1tetrazole underwent a Claisen

11

condensation (31). The condensation product was not isolated, but

saponified and decarboxylated to yield 5-acetony1-2-methyltetrazole
(XIV).

 

 

 

 

CszozCCHz- H CZHSOZCCHZ- If
H V CHZNZ
\N/ \N/ CH
NaOCsz
I— -I
CH3CCHz-C TI 1) aq. FaOH CZH503C- -CH-
I (V N 7‘) 11100— N
\ - 0" H\N/N
\N/ \CH3 3) CO7- \CH3
1—

 

 

Of the few remaining compounds containing both a carboxyl group
and a tetrazole ring, only two studies are pertinent. Wiley and co-
workers have prepared 8-(l-tetrazolylprropionic acid by pyridine or
Triton B catalyzed addition of tetrazole to acrylic acid (32).

Jacobson, rKerr, and Amstutz (33) have utilized 5-chloromethy1-
l-phenyltetrazole as the alkyl halide in the base catalyzed alkylation
of diethyl malonate. Saponification, acidification, and decarboxylation
resulted in XV. ~In~addition a small amount of XVI was isolated; formed

by dialkylation of the diethyl malonate.

QN—lc-CHZCHZCOZH
N% /N

XV

COZH
N/lc- CHZCHCHz- «fr—LNG

XVI

 

QT

12

In both studies the stability of the 8-propionic acid derivatives to

decarboxylation was noted.

R ESU LTS AND DISC USSION

Fundamental Reactions and the Preparations
of Starting Materials

Except for the method of Finnegan, Henry and Lofquist (18)
which utilized ammonium azide in dimethyl formamide, the preparation
of 5-carboethoxymethyltetrazole (XVII) from ethyl cyanoacetate was
not successful by several known methods for tetrazole formation from
the corresponding nitriles without modifications. The methods involved
solvents such as ethylene glycol monomethyl ether and n-butyl alcohol
- (9, 17), and, while the condensation of the azide with the cyano group
did occur, the starting material or the product also exchanged-alkoxy
groups with the solvent so that the product isolated was the ester of
5-carboxymethyltetrazole corresponding to the solvent.

The procedure which lent itself to the preparation of the desired
product in large quantities combined ethyl cyanoacetate with sodium
azide and acetic acid in refluxing ethanol. A 45 hour reflux period was
sufficient for reaction and a 72 hour reflux period only increased the
yield by about 5%.

While a prolonged reflux period was necessary, the method was
not complicated by the necessity of a temperature controlled bath and
stirrer as was the method of Finnegan, Henry, and Lofquist (18), nor
by transesterification. The compound was produced in overall yield of
60% by this method and had a melting point of 126-127. 50~ C. Reported
melting point was 128-13OOC. (18).

. Saponification of 5-carboethoxymethyltetrazole resulted in the

corresponding free acid (XVIII) in good yield. A few hours reflux with

13

14

10-15% aqueous sodium hydroxide was sufficient to carry out this
conversion. The product of several runs was isolated by acidification
of the basic reaction mixture and melted at either 171-1720C. or
181-1820C. with gas evolution. The higher melting product was not
soluble in hot ethyl acetate as was the lower melting form. -Heating

a weighed sample of the higher melting solid 2 flat 100QC.
resulted in the loss of 22. 6% of the weight, and a decrease in melting
point to 171-1720C. Calculations for two molecules of water of hydration
predicted a weight loss of 21. 9%. The dehydrated sample was then
identical with the lower melting solid; it gave the correct analysis and
neutralization equivalent for 5-carboxymethy1tetrazole (XVIII), and
the infrared spectrum (see Appendix I, Figure 1). agreed with the
proposed structure. Also XVIII could be decarboxylated at its melting
point to yield 5-methyltetrazole.

The ease of saponification was in contrast to experiences with
diethyl malonate or o-substituted diethyl malonates which utilize 50-90%
aqueous or alcoholic potassium hydroxide with reflux times of 3-5
hours (34-36). The ease of saponification can be seen in the attempted
benzylation of 5-carboethoxymethyltetrazole by the method of Mihina
and Herbst (8). The ester, benzyl bromide and potassium carbonate
were refluxed in 90% ethyl alcohol, the reaction mixture was evaporated
todryness and extracted with ethyl acetate. The product isolated on
cooling and filtration was 2-benzyl-5-carboxymethyltetrazole' (XIX).

The discussion of this difference in reactivity will be deferred to the
section on saponification of the condensation products of 5-carboethoxy-
methyltetrazole.

2-Benzy1-5-carboethoxymethyltetrazole (XX) can be prepared
from 5-carboethoxymethyltetrazoleI (XVII) by formation of the tetrazole
anion under anhydrous conditions. .Sodium ethoxide and absolute ethanol

served as the basic solution for proton removal and to this was added

15

the benzyl bromide. A few hours reflux was sufficient for benzylation,
however, in order to purify the product, it was necessary to use an
excess of XVII so that a minimum amount of benzyl bromide was left
in the reaction mixture at completion. After removal of the solvent,
the excess starting material was separatedefrom the product by ether-
aqueous sodium bicarbonate extraction. The ether. solution containing
the product was cooled in Dry Ice and the precipitate recrystallized
from absolute ethanol. Fischer esterification of 2-benzy1-5-carboxy-
methyltetrazole(XIX) also yielded the corresponding ethyl ester XX
identical with that prepared by the above method. The assignment of
the position of the benzyl group in compounds XIX and XX was made on
the basis of the work of Elpern (5, 7) and Henry (6), who have shown
that in a variety of alkylation systems the 2 isomer predominates.

Using the method of Birkofer (37) for debenzylation of l-subs-tituted
tetrazoles, samples of 2-benzyl-5-carboxymethyltetrazole in both
absolute ethanol and acetic acid were hydrogenated under low pressure
using palladium oxide as a catalyst. Only starting material was iso-
lated. - In order to determine the feasibility. of the reaction, samples
of 1-benzy1-5-phenyltetrazole and 2-benzy1-5-pheny1tetrazole were
each hydrogenated over palladium oxide. The ethanolic reaction mixture
after removal of the catalyst by filtration was concentrated and treated
with ether and dilute sodium hydroxide. . Separation and acidification
of the aqueous layer yielded»5-phenyltetrazole. In the case of the
1-benzy1 isomer, the yield of 5-phenyltetrazole was 44%, while the
2-benzyl compound formed 5-pheny1tetrazole in only 8. 7% yield.
.Attempts to debenzylate 2-benzyl-5-phenyltetrazole over 5% palladium
oncharcoal were equally unsuccessful. - It can, be seen from the above
that catalytic reductive debenzylation from the 2 position on the tetrazole
ring was either much slower or requires more drastic conditions and as

such was not a practical method.

l6

Debenzylation from the Zaposition was readily accomplished by
means of sodium reduction in liquid ammonia. The compound, either
Z-benzyl-5-carboxymethyltetrazole or an a-substituted derivative,
was suspended or dissolved in the liquid ammonia and small bits of
sodium added with stirring until a presistant blue color indicated excess
sodium. Removal of the sodium with ammonium chloride and evapora-
tion of the ammonia resulted in a residue which was dissolved in water,
cleaned up by extraction with ether, and the product precipitated by
acidification. The procedure gave pure products in good to excellent

yields.
The Condensation Reactions

In terms of model systems with which to compare the Knoevenagel
type condensations of ester tetrazole XVII and acid tetrazole XVIII,
monoethyl malonate and malonic acid, respectively, most closely
approximate the acidic properties and steric requirements. The re-
action sequences (see below) parallel those of the malonic half ester or

malonic acid synthesis of a, (B-unsaturated esters or acids.

 

Scheme 4
CszOzCCHz“ NH ‘ . . CszQzC'C— H
II + new Pride? e g i
N\ / P1per1d1ne Ar H /N
N -HzO I N/
XVII ‘ 1) aq. PlaOH

2) H3O

ArCH=CH-fi—j H 1 heat HOOC-fi—ff—IIVH

N ‘-co Ar. H N N
\N/ 3 \PK/

 

17

 

 

Scheme 5
HOzCCHZ- H . . AICH=CH-C H
il l 32:23:? N
\1\l//\I "Hzo \ /
-COZ

One important difference should be noted in comparing S-carbo-
ethoxymethyltetrazole with monoethyl malonate. That is, in
. Knoevenagel condensations of aromatic aldehydes (38, 39) with malonate
half esters, decarboxylation occurs which does not take place with
ester tetrazole XVII.

Aryl aldehydes were found to react most readily with 5-carbo-
ethoxymethyl- and 5-carboxymethyl-tetrazole. Attempts to use aliphatic
aldehydes even under very mild conditions led to polymeric condensation
products of the aldehyde and recovery of unchanged tetrazole starting
material. The solvent system used was pyridine containing piperidine as
catalyst. A typical condensation involved refluxing equimolar quantities
of 5-carboethoxymethyltetrazole and the aldehyde for 5-10 hours.
Purification was effected by removal of the pyridine under vacuum and
dissolving the residue in weak base (aqueous sodium bicarbonate was
found to work the best). After purifying the aqueous portion by ether
extraction, the solution was acidified and cooled to precipitate the
product. By this method condensation products XXI, XXII, and XXIII
were prepared from XVII and benzaldehyde, _p-methoxybenzaldehyde and

_p- nitrobenzaldehyde r e spec tively .

/C02C2H5H XXI, X = H
x -CH=C\ XXII, X = CH3O
c\c[:| XXIII, X = NO;

”\N/“H

 

18

Infrared spectroscopy, elemental analysis, and neutralization
equivalents were utilized to establish the structure of the compounds
prepared. Thevinfrared spectra of XXI, XXII, and XXIII (see Appendix
I,- Figures 4-6). were very similar with respect to the absorption wave
lengths attributed to the general structure. The more important

absorption bands are summarized in Table l.

> Table 1. Infrared Absorption of Several 5-(Z-Aryl-l-carboethoxyviny1)-

 

 

tetrazoles
a r
Absorption Band, p, for Compound Assignmenta
XXI XXII XXIII
5.87 5.85 5. 84 carbonyl group
6 . 15 6 . 22 6 . 25 phenyl nucleus
7. 94 7. 95 7 . 90 tetrazole ring
9. 20 8.96 8. 9O tetrazole ring
12. 55 11 . 95 ll . 90 trisubstituted double bond
--- 7. 48 -- methoxy group
_,.. 8. 51 -- methoxy group
-~- -- 6 . 60 nitro group
-- I -- 7 . 44 - nitro group

 

aThe assignments were made with reference to tables prepared by
Nakanishi (40) and the published spectra of tetrazole (41).

- Inicontrast to the good yields (70-90%) experienced with diethyl
malonate (42, 43) and monoethyl malonate (44, 45), the yields from the
condensations with the tetrazole analogs were quite low (35-40%).

. A possible explanation rests on the mechanism developed for the

' Knoevenagel condensation of aromatic aldehydes with diethyl malonate
or ethyl cyanoacetate. Cope (46) has suggested that the amine salts
were'effective catalysts, I since the mechanism involved three steps.
First, enol formation, second, addition of the enol to the aldehyde,

and finally, eliminationiof water. This mechanism would be catalyzed

19

by both acids and bases. The enol content would be higher in base,
while the water elimination would go faster in acid; hence the use of
amine salts such as piperidine acetate as catalysts capable of acting
both as an acid or base.

Two more recent studies (47,48) on the condensation of diethyl
malonate and Bag-substituted benzaldehydes catalyzed by piperidine
and organic acids showed that the rate was accelerated by addition of
small amounts of organic acid, but that large amounts of acid retarded
the condensation. The effect of the various gala-benzaldehyde sub—
stituents was not as pronounced as the effect of added acid. The first
study (47) demonstrated a gradual rate decrease which was in the same
direction as the electron donating ability of the para-substituent, i_._e_. ,
CH3O > H > C1 > N02.

The second study (48) stated that both electron attracting and
releasing groups in the par—a position retarded the condensation. These
variations, while significant, were small as compared to the effect
of added acid on the overall reaction.

-Patai and Zabicky (49) have studied the Knoevenagel condensation
of ethyl cyanoacetate with para-substituted benzaldehydes in ethanol
or ethanol-water. The kinetics were not clearly either first or second

order. — The series of aldehydes used fell into the pattern shown in

Table 2.

Table Z-a Reaction Orders and Overall Rates of p-Substituted
Benzaldehyde Condensations With'Ethyl Cyanoacetate

 

 

 

Eara—Substituent CH30 CH3 H C1 B1“ N02
Reaction order 2nd 3t lst—-———§an
Overall rate slow ) fast

 

 

aReproduced in part from a table found in reference 49.

20

In addition, the reaction showed marked inhibition by added acid,
catalysis by small amounts of added piperidine, and a positive salt
effect. It was felt that these data could best be explained on the basis

of the following reaction scheme.

CHZ(CN)cozczH5 --k‘—->- [:CH(CN)cozczH,]' + H+ (1)
k-l
< k I-
+ -’- O

X CHO several
steps (3)
XQCH=CH(CN)COZCZH5 <-—

The authors suggested that equation (I) was a near instantaneous

 

equilibrium and that the rate controlling step was the reaction of the
anion with the carbonyl compound, _i_. e_. , k1 = k_1 > k2. Important and
irrespective of the rate controlling step was the fact that the reaction
could be retarded or stopped completely by added acid. That is, the
concentration of the anion in equation (1) would be so small as to pre-
clude conversion to products.

Analogously, the intermediate in the condensations of 5-carbo-
ethoxymethyltetrazole must involve anion formation at the methylene.
However, formation of a methylene anion without first removing the

more acidic proton on the tetrazole ring is unlikely.

 

- '1
CZHSOZCCHz-p— H cansozccnz- ' ’
l ——" il
N /E (_— N 7+ H+ (4)
\N/ \
L _

 

XXIV

21

 

 

 

cszozcfiH-i: . I"! I +
XXIV ————-> NI N + H (5)
t \N¢
XXV

The above reactions describe the steps necessary for the
formation of intermediate XXV which could then react with aldehyde

and-subsequently lead to the observed products.

XXV + X CHO-—-—-'>‘ X C-CH/
5 |_ \
‘ O
+
'+2H 9 'IiLC) \ X CH=C/
Several steps I .— \

In the pyridine-piperidine system, equilibrium (4) would be

COzCsz

7E—

'fi
”\N/

 

 

shifted far to the right due to the removal of the protons by the organic
base. On the other hand, the concentration of intermediate XXV in
equilibrium- (5) would be small. since the methylene anion, even though
resonating with the carboethoxy group, is a stronger base than the
pyridine-piperidine solvent. In addition, the existing dipole in the
tetrazole ring (XXIV) would be toward the methylene group thereby

destabilizing any negative charge deve10ping on the methylene.

 

_ _ 5+ _ _
H\(5:/H
/ \c ._ "
“flu E
\V
_ J

 

 

22

The net result of the low concentration of XXV would be a low yield of
product.

The condensations of aryl aldehydes with 5-carboxymethy1tetra-
zole' (XVIII) followed the pattern outlined in-Scheme 5. ‘Analogous to
the malonic acid synthesis of 0., B-unsaturated acids, the products
isolated were 5-(2-arylvinyl)tetrazoles. . The reaction of benzaldehyde
with XVIII was of interest since the product isolated conformed to. the
molecular formula of- C9H10N4O.

The procedure involved condensation of equimolar quantities of
benzaldehyde and 5-carboxymethyltetrazole in pyridine catalyzed by
piperidine. The reaction mixture after a reflux period was concen-
trated and water was added. The entire solution was then acidified.
The product isolated melted at 174-1760 C. with decomposition and
‘ exhibited hydroxyl absorption at 2. 95 u in the infrared spectrum
(Appendix I, Figure 13). On this basis the following structures were

proposed.

QiH-CHz-fi ~1le QCH=CH-fi

\Nyv \N/

XXVIa XXVIb

 

 

The isolation of hydroxyl containing compounds from condensations
of this type has been reported by several workers. Gault and Roesch
(50) condensed diethyl malonate with formaldehyde in aqueous solution
catalyzed by potassium carbonate. 7 The product they obtained was shown

to be XXVII.

» CHZOH H
CZH5OZC-C-COZCZH5 cszozc-c-cozczH5
I HZOH CH3CHOH

XXVII XXVIII

23

Under the same conditions Roesch‘ (51) condensed diethyl malonate
with acetaldehyde to obtain monoadduct XXVIII. ~Hauser and Breslow
(52) showed that fi-hydroxy esters were formed when the sodimn tri-
phenyl methide catalyzed condensation of aliphatic esters and benzal-
dehyde was quenched with acid.

A subsequent preparation of 5-(2-phenylvinyl)tetrazole (XXIX) by
decarboxylation of 5-(l-carboxyl-2-phenylvinyl)tetrazole [see following
discussion on decarboxylation of 5-(2-aryl-l-carboxylvinyl)tetrazoles]
gave a compound which gave the correct elemental analysis for XXIX.

It melted at; 175-1760C. with decomposition and its infrared spectrum
(Appendix I, Figure 10) was identical with that of XXVI except that it
lacked-absorption at 2. 95 p.

. An investigation of the mixture melting point of the two compounds,
,XXVI and XXIX, showed no depression, but the liberation of water was
noted. ~Of the two compounds when melted alone, only XXVI showed
signs of water liberation. This suggested that the correct structure
was not XXVIa, but rather the monohydrate of XXIX, 1.3. , . XXVIb.

Since B-hydroxy acids are known to lose water on heating, the
following method was formulated to distinguish between structures
XXVIa and b. The ultra-violet spectrum (see Figure 1) of XXIX (1. 501 x
10"5 mole/liter in 95% ethanol) run on a Beckmann DK-2 Spectro-
photometer gave a maximum absorption at 283 mp. ( € =§ 24300). -The
spectrum of XXVI (0. 946 x 10'5 mole/liter-in 95% ethanol) also
exhibited a *maximum at 283 mu (6 = 24900). Since structure XXVIa,
would not be expected to show carbon-carbon double bond absorption
in the ultra-violet, . structure XXVIb was as signed to the product of the
reaction of benzaldehyde with 5-carboxymethyltetrazole.

No tendency toward hydrate formation was observed in the conden-
sations of XVIII with p-methoxys or p-ni‘trobenzaldehyde under-the same

conditions as above. ' An alternate work up which involved the complete

24

removal of the pyridine solvent in vacuo on a steam bath and dissolving

 

the residue in aqueous sodium bicarbonate, extracting with ether, and
precipitating by acidification with hydrochloric acid gave reasonable
yields of 5-[2-’(_p-methoxyphenyl)vinyl]tetrazole and 5-[2—(p-nitrophenyl)-
viny1]tetrazole, XXX and XXXI respectively.

X CH=CH- NH
I l XXIX, X = H

”\Ny‘“ XXX, X = CH3O

XXXI, X = NoZ

 

Patai, Pfeffermann, and Rozner (53) have studied the decarboxyl-
ative condensation of malonic acid with benzaldehyde in pyridine-
piperidine solvent. Their work entailed the determination of the orders
and rates of the condensation and decarboxylation steps. The conden-
sation which was followed by water formation was shown to be 2nd order
and faster than the lst order decarboxylation which was followed by
carbon dioxide evolution. The authors state that, since there was a
time lag from initial water formation to initial carbon dioxide formation,
the simultaneous condensation-decarboxylation mechanism proposed
by Corey (54) for monoalkyl alkylidinemalonates was not operating in
this case. Rather, the benzalmalonic acid or its anion forms in the
reaction and builds up to 30-40% of the initial amount of reactants.

. It was also noted that in pure piperidine only benzaldipiperidine
was formed with no reaction with the malonic acid. In pyridine-
piperidine mixtures where the concentration of piperidine was higher
than that of the acidic reactants, only the piperidine salt of benzal-
malonic acid was formed which did not lose carbon dioxide. The pro-
posed reaction scheme involved benzaldipiperidine as the initial
condensation product as was suggested by Knoevenagel (55). . Its con-
version to benzalmalonic acid or anion and then to cinnamic acid or
anion was dependent on the piperidine/pyridine ratio and the malonic

acid still in solution.

25

15 .nquoamcrmg

owm omm com Ohm owN mwm com com 0:” omm omm ovm

 

 

a _ a _ _ _ _ _ _ _ _

 

Hocmguo gammy GM H0fi<308 muoa N 356
0338:3288 oHONwfi—oifncgacmxmumvum II III.

Hocmgoo osmo cw nofi<oHoE mica x Hmoé
.oHONmuuoiacgacofimnNVum Ill

.oumup>£ocoe
oHonSoigcgasoamquum cam oHonhoiacggcoaflumvum mo .930on 6303:9395 9:. .H 6.3th

oo.o

0H6

om.o

om.o

 

 

 

 

 

Aoueqlosqv

26

Since an analogy of 5-carboxymethyltetrazole to malonic acid
has been suggested, the supposition that the course of the condensation
of aryl aldehydes with 5-carboxymethyltetrazole parallels the above
mechanism is not unreasonable. This is depicted in the following

scheme.

-XOCHO + 2 HN ) -—3 X‘Q-CH: N > + 1430(1)
Z
‘ /COZH
‘ X CH: N X CH=C\
i: H
2 I T

+ ——-> “K &N ‘2’

HOZCCHZ- NH
13 1.
\ é

N

wa

X = H,. CH30, N02

 

02H

 

1m ——'£9-3—> X‘QrCI-hCH-WH
/

It should be noted that the reaction of 5-carboxymethyltetrazole
with the aldehyde dipiperidine (equation 2) must involve negative charge
on the methylene. {In this respect, the reaction might be governed by
the stability of this anion or its concentration. However, the fact that
decarboxylation can occur, contrary to the condensation involving
5-carboethoxymethyltetrazole, allows the equilibrium steps to shift

continually to the right resulting in good conversion to products.

27

The Hydrolysis of
5-(2-Ary1-1-carboethoxyvinyl)tetrazoles

As early as 1883 it was noted that a, B-unsaturated malonic esters
hydrolyzed very slowly in aqueous base ’(56-58). Not only was very
concentrated base required, but the hydrolysis was complicated by the
conversion of the cub-unsaturated ester into a carbonyl compound and
malonic acid. . Claisen and Crismer (56) reported that aqueous basic
saponification of diethyl benzylidinemalonate yielded a mixture of
benzaldehyde, ,malonic acid, and benzylidinemalonic acid. More recent
saponification procedures for diethyl malonate or o- substituted malonates
also call for very concentrated base and prolonged reflux times ‘(34-36).

In contrast to these severe conditions, the hydrolysis of 5-(Z-aryl-
l-carboethoxyvinyl)tetrazoles goes with‘amazing ease and speed. ~ The
synthetic procedure first tried involved a two hour reflux period with
10% aqueous sodium hydroxide, however, with the benzaldehyde and
p-nitrobenzaldehyde condensation products XXI and XXIII, this was too
severe and led to undesired side reactions. It was noted in the initial
attempts to isolate the condensation products of 5-carboethoxymethyl-
tetrazole with aromatic aldehydes that mere treatment of the condensation
residue with dilute base, such that the compound could be cleaned up by
ether extraction, resulted in the formation of 5—(2-aryl-1-carboxyvinyl)-
tetrazoles on acidification of the aqueous solution. The esters‘were
found to be stable in weakly basic solutions. for longer periods of time,
and could be purified by ether extraction of sodium bicarbonate solu-
tions followed by acidification of the aqueous portion to precipitate the
esters.

- The procedure calling for a two hour reflux period for the saponi-
fication of the three ~5-(Z-ary1-l-carboethoxyvinyl)tetrazoles, XXI, XXII,

XXIII, with aqueous 10% sodium hydroxide gave rather divergent results.

28

5-[1-Carboethoxy-2(p-methoxyphenyl)vinyl]tetrazole (XXII) gave an
excellent yield of the expected 5-[l-carboxy-2(_p-methoxyphenyl)vinyl]-
tetrazole (XXXII). No formation of p-methoxybenzaldehyde was noted.
5-(1~Carboethoxy-Z-phenylvinyl)tetrazole (XXI) gave only a moderate
yield of the corresponding acid XXXIII and benzaldehyde could be readily
detected in the reaction mixture. Treatment of 5-[1-carboethoxy-2-
(p-nitrophenyl)vinyl]tetrazole(XXIII) with base, even without heating,

. resulted in extreme darkening and tar formation; no product could be
isolated.

. It was necessary therefore to devise alternate methods for the
hydrolysis of XXI and XXIII. 5-(1-Carboxy-2-pheny1vinyl)tetrazole
(XXXIII) could be prepared in good yield without excessive benzaldehyde
formation by allowing the ester XXI to stand at room temperature with
10% sodium hydroxide for several hours. Acidification of the basic
solution yielded the productin quite pure form. .No successful base
catalyzed hydrolysis of XXIII could be devised and it was necessary to
carry out acid hydrolysis in _c_a_. 85% acetic acidcatalyzed by concen-

--trated sulfuric acid. -Isolation of the product-involved removal _i_r_1 vacuo

 

of most of the solvent and treatment with water and sufficient sodium
bicarbonateto neutralize the acidic material. Extraction with ether and
acidification of the aqueous layer resulted in 5-[l-carboxy-Z-(p-nitro-
pheny1)viny1]tetrazole (XXXIV) in 65% yield. (Attemptsto purify the acid
were unsuccessful as shown by the elemental analysis for nitrogen and
the neutralization equivalent. (It was felt that the impurity was-mainly
decarboxylated acid and calculations on this basis from the nitrogen
analysis and neutralization equivalent set the amount of acid present in
the isolated solidat 77-83%.

The analytical data and infrared spectra. (Appendix I,- Figures 7-9)

support the structures of the tetrazole acids as shown below.

29

xxxm, x = H
K XXXIV, x = Noz

‘COOH
5X CH;C<
fi—I‘VH XXXII, X = CH3O
N N
\ /
_ Comparison of the infrared spectra of the acids with those of the
corresponding esters» (Appendix 1, Figures 4-6), reveals a shift in the
position of the carbonyl absorption. vThe other bands assigned to the

general structure are essentially unchanged.

- Table-3. Infrared Carbonyl Absorption for Various 5-(2-Ary1-l-carbo-
ethoxyviny1)- and 5-(2-Ary1- 1-carboxyviny1) -t_etrazoles

 

 

 

/C OOR
X4: :>—CH=C\
9 "EH
\N’//
m: m
‘ Carbonyl absorptidndl
X R = Cal-15 R = H
H 5. 87 5. 95
CH3O 5. 85 5. 98
'NO; 5. 84 5. 80

 

The _c_a_. 0. 1 (.1. shift to a slightly. longer xwavelength is that pre-
dicted by a change in the structure from ester to acid in a dimeric form.
The nitroacid would be expected to form the stronger carboxy-nitro
hydrogen bond in preference to dimer formation and this stronger hydrogen

bond. would account for the shift to a shorter wavelength.(59).

30

Having established procedures for the conversion of the tetrazole
esters to the corresponding acids, a closer examination of the behavior
of the esters in refluxing sodium hydroxide in the light of several
related studies is quite revealing. The explanation for the formation of
carbonyl compound from a, B-unsaturated malonic esters and their
tetrazole analogs most probably involves the opportunity for hydroxyl

attack at either of two positions in the a, B-unsaturated system.

3 2 1 OH
XOCHZCIZ'EQ 4% X-Q—CHzC-Czo
R oczH5 R H
+ -
OH attaCk Cal—150
at 3
HfoH i
x cle-f‘c=<':-o‘ XQCH=C-Cll=0
/0 1L oczH5 R o-
Hoq‘ H +
CZHSOH
‘\ -
HO”H RCHZCOO

 

X CHO+ Hoyle-fox several? +
I Steps
1L ocsz C2H50H

R : COOCZHS or M
/N

 

 

L

This line of reasoning brings one to the conclusion that the ratio
of attack at carbon 1 versus carbon 3 should depend on the relative
positive charge located on carbons 1 and 3. - Since the charge on. carbon 1
should depend primarily on the effect of the oxygens associated with it,

anylong range effects should have relatively little affect on its overall

31

charge. Carbon 3, on the other hand, being in a benzylic position should
be relatively more affected by the electronic nature of the gala-substituent.
Streitwieser, Jr. (60) presented some data on the chloride displace-
ment reaction of benzyl and _p- substituted benzyl chlorides by iodide.
The reaction was run under Sn2 conditions (RC1, - KI, acetone, 20°C.)
and for R = benzyl and p-nitrobenzyl the relative rates of displacement
were 1. 00 and 6. 19. This denotes that even in the ground state the
amount of positive charge localized on the benzyl carbon is much greater
with a p-nitro substituent than hydrogen.
rNoyce and Jorgenson (61) have determined the basicities of 133—13;
substituted m-chalcones (XXXV) in 5% dioxane-95% aqueous sulfuric

acid by means of Hammet indicators.

‘?
MC>C> ‘
O

XXXV

Table 4 is a partial listing of their results.

Table 4. (Basicities of Substituted trans-Chalcones in 5% Dioxane -
95% Aqueous Sulfuric Acid

 

 

 

 

 

p, ara-Chalcone Substituent pKHB+a
CH3O -4. 25
H -5. 00
N02 -6. 22

 

3'Best value determined by several methods.

While the protonation was on the oxygen, the authors stated that there
were resonance contributions from the 0., fi-double bond which in turn

transmitted the effects of the para-substituent.

32

When the results of the previous studies were applied to the
reaction of base with the 5-(2-aryl-1—carboethoxyvinyl)tetrazoles, the
following conclusions were drawn. Due to the strong electron with-
drawal of the gala-nitro group, the main point of attack of base was at
the highly positive benzylic position (carbon 3) of resonance structure

XXXVIa resulting in little or no saponification. Only polymeric

O

+ /C-OC2H5 XXXVIa, X 3 N02
/ 1 _
X CH-C XXXVIb, X — H
XXXVIc, x = CH3O

3 z\ -
if I
“Ky

condensation products of the liberated p-nitrobenzaldehyde were
formed.

The case of the unsubstituted ester (XXXVIb) fell into an inter-
mediate class where the attack at both carbons 1 and 3 resulted in the
observed mixture of products. The explanation of the behavior of the
flamethoxy compound (XXXVIc) was not as obvious since a reasonably
high positive charge could be expected on carbon 3. However, this
would be stabilized by resonance with the methoxy group resulting in

the following limiting resonance form.

0

\C 0C H

+ " 2 5
xxxvxc: <————> CH,o=<:>=CH- C1 _
3 2 fi T

N N
\Né

 

Attack at the center of this resonating system, _1_.3. , carbon 3, would
destroy the stability imparted, and therefore, the attack was at carbon 1
resulting in the observed good yield of 5-[1-carboxy-2-(p-methoxyphenyl)-

vinyl]tetrazole.

33

An explanation of the ease and speed of hydrolysis may be found
in the work presented by Scott and Holland (62) concerning anchimeric
assistance by a neighboring tetrazole group. By product isolation and
independent synthesis, it was shown that compound XXXVII on treat-
ment with 95% ethyl alcohol at 25°C. was easily converted (ti/z = 85

minutes) into compound XXXVIII in 60% yield.

C=NNH- NH 95% CZHSOHA =
Q' U I 25°C. ’ f
B N H
l

 

r /N
N/

xxxvn xxxvm N3

Dimer XXXIX was ruled out on the basis of molecular weight determin-

ations and XXXVIII was confirmed by independent synthesis.

 

/N
HN—I fi'u \r I *3:
N N N N-C H
QN/ \
XXXIX

The mechanism proposed to account for these observations in-

volved tetrazolyl participation as shown below.

 

N

II I _H+ _—
E z <———-> BEE???

 

 

N
“Ky

 

 

V

©C\ 45% ———> xxxvm
K T

 

 

 

34

Direct extension of the above observation would require a four
membered transition state for the participation of the tetrazole anion
in the saponification of the tetrazole esters XXI, XXII, and XXIII.

The possibility of intermolecular participation was not ruled out, but
it would seem highly unlikely that the bulky tetrazole anion could
effectively compete with the more basic hydroxyl group in an inter-
molecular reaction. Therefore it was felt that the tetrazole anion
participated in the displacement of the ethoxide anion and this was
followed by hydroxyl attack to form the observed acid. This would ac-

count for the ease and fast rate of the reaction.

 

 

 

 

> C- —
(Ecsz |oI OH
: C :0
._ C - _

>\ /N\ ‘9 / \‘h/ \h“ 0H9 /C\‘EI T

C

H I N N N

N N c. _ \N7N

 

The Decarboxylation of
5-(2-Aryl-1-carboxyvinyl)tetrazoles

The final step in the preparation of 5—(2-ary1vinyl)tetrazoles
involved the decarboxylation of the corresponding 5-(2-aryl-1-carboxy-
vinyl)tetrazoles, XXXII, XXXIII, and XXXIV. This was accomplished by
warming the compound in ethylene glycol to obtain a solution and then
heating in an oil bath to a temperature at which gas evolution was noted.
The temperature was maintained until gas evolution stopped, the solu-
tion cooled, and the product isolated by treatment with weak aqueous
base, extraction with e ther, and filtration of the acidified aqueous
solution. The temperature at which decarboxylation occurred in solu-
tion was lower by 23. 200C. than the normal melting point. Attempts to

carry out the decarboxylation by mere melting led to decomposition of

35

the tetrazole ring. Benson (4) states that tetrazoles melting above
150°C. generally do so with deep-seated decomposition.
The products obtained gave the correct elemental analyses and

neutralization equivalents for the expected structures (XXIX, XXX,

XXXn.
XXIX, X = H
X CH=CH-C NH XXX, X = CH3O
NI N XXXI, X = NO;

\N%

 

The infrared spectra (Appendix 1, Figures 10-12) showed no carbonyl
absorption, but did show a new band at 6.07-6. 10 p. corresponding to

a disubstituted double bond. Since trisubstituted double bonds show
little or no absorption in the infrared (63), absorption at this time
established the integrity of the double bond throughout the reaction
sequence. All three spectra showed a strong new band at 10. 3-10. 4 p.
which was attributed to the tra__n_s relationship about the double bond.
While 2.13 absorption is somewhat weaker and not as well defined (63),

it would appear that at least a good share of the 5-(2-arylvinyl)tetrazoles
was in the tra_nj configuration. A study of the cis-trans ratio in the con-
densation reaction should yield information as to the configuration of

the intermediate prior to losing water and hence to the effective size of
the tetrazole group versus the carboethoxy group. -It is quite likely that
the condensation intermediate,if present for any length of time,would
assume one of the configurations shown below. The preference for one

or the other would show up. as a predominance of cis or trans isomer.

H
Ar ~.\ /H Ar.\K /H
“C——C~‘ or \‘G—C\
X‘COOCZHS / \‘Tz
OH 2 OH cooczH5

T z = 5 - T etrazolyl

36

The stability of the tetrazole acids toward decarboxylation closely
paralleled that of the arylidinemalonic acids. As exhibited by the high
melting points (see Table 5), neither series showed any tendency to

decarboxylate at low temperatures.

Table 5. Melting Points of Arylidinemalonic Acids and 5-(2-Ary1-l-
carboxyvinyl)tetrazoles

 

 

Melting point with gas evolution, OC.

COOH COOH
x W©e< x©eee< H
COOH ? Ir

 

 

N N
\V
~ H 195-196a 175-176
CH,o . 195-196at 201.5-202
N02 227a 190 (loses C02),

210 (melts)

 

8'Melting points reported in Beilstein, "Organische Chemie, " 2, 891;
_9_, 897;l_0_ (II), 362, respectively.

Prolonged reflux of the tetrazole acids in water or aqueous acid gave no
sign of decarboxylation and starting materials were recovered in good
yields.

This contrasted with the much lower decarboxylation temperatures
of mono- and di-alkylated malonic acids. Generally these compounds
lose carbon dioxide on refluxing in water or acid. -In a study by Norris
and Tucker (64) it was found that the neat heating of malonic acid itself
liberated carbon dioxide at 129°C. (melting point 135°C.), while the
12 d-monoalkylmalonic acids studied all lost carbon dioxide at a lower

temperature. The range of decomposition temperatures for the

37

monoalkylated malonic acids was 98-1230C. Disubstituted malonic
acids with like alkyl groups decomposed either above or below the
decomposition temperature of malonic acid, but always above the
corresponding monoalkyl malonic acid. Dialkylated malonic acids
where the alkyl groups were unlike all decomposed below 1299C.
It was noted that the o—naphthylalkylmalonic acids prepared by Blicke
and Feldkamp (65) decarboxylated at room temperature.

From the similarity in physical properties, it was concluded
that the 5-(Z-ary1-1-carboxyviny1)tetrazoles are quite analogous to the
corresponding arylidinemalonic acids.

The decarboxylation of carboxymethyltetrazoles has been
studied by Jacobson and Amstutz who prepared a series of tetrazoles
which contained the carboxymethyl group in both the 1 and 5 positions
on the tetrazole ring (27). Their results indicated that the 5-tetrazolyl-
acetic acids underwent decarboxylation more readily than the corres-
ponding 1 isomers. The 5-tetrazolyl acids underwent simple decarboxyl-
ation at their melting point ((1500C.) while the l-tetrazolyl acids
required temperatures in excess of 175°C. and also resulted in tetrazole
ring decomposition. The 5-tetrazolyl acids were prone to undergo loss
of carbon dioxide below their melting points in solution, while the
l-tetrazolyl acids were stable under such conditions. Their conclusion
was that the decarboxylation of the 5-tetrazoly1 acids went by way of a

6-membered chelate ring.

R2 H
#0 R1 _
|N o ‘
~“H/

I
”N/

 

Rl-N

n-C4H9, R2 = H
92, R; = H
R1 3 ¢, R2 = Csz

’9.
I

This conclusion was similar to that of Doering and Pasternack
(66) who worked on the decarboxylation of o-pyridylacetic acids. Their

results also support a 6-membered ring intermediate as the initial step

38

in decarboxylation. .They believed the inner salt XL to be the most

probable starting point for decarboxylation in the pyridylacetic acid

-series.

 

XL

However, they state that their work did not exclude a chelate
decarboxylation mechanism.
011 this basis, it would seem probable that the decarboxylation of

5-(2-aryl—l-carboxyvinyl)tetrazoles would go by the following reaction

scheme.

. Mechanism 1

   

 

 

 

HAr (- / HA:
C
Hi .3  ° Iii—{fl
-——-> . ——>
kN/N\\H £02 Kit/“(3% J

- CH=CHAr

' A mechanism which bypasses the need for the allene system fused to

the tetrazole ringinvolves the adjacent double bond as a proton

acc eptor .

39

Mechanism 2

 

 

 

+ .0
H d-OH o
A CHCC/ + lc:| o
r _ .-
\c':| NH—eArCH-QE \AH £99 ArCHzcle
N N T I'm C NH
\ ¢ II I
N \ ¢N N N
N \ &

Either of these mechanisms is compatible with the observed results.
Most mechanisms for the decarboxylation of a, B-unsaturated acids call
for isomerization to the 6, 7 -form. In this form they can easily decar-
boxylate _v_i_a_ a 6-membered cyclic transition state analogous to the

chelate structures for the decarboxylation of the 5-tetrazolylacetic

acids.
H HO :le H O=C=O
___> __>
_ V‘- \W __ H
H

But when this isomerization can not take place due to the lack of
'y-hydrogens, the decarboxylation must go by a more direct and higher
energy process. This is borne out by the higher temperatures required
for decarboxylation in both the alkylidinemalonic acids and the 5-(2-aryl-
l-carboxyvinyl)tetrazoles. The determination of the true mechanism of
this reaction would be informative and provide a more direct correla-

tion between these two seemingly similar classes of compounds.

Alkylation Reactions Involving
2 - Benz yl- 5 - carboethoxymethyltetrazole

Since the methylene groups in 5-carboethoxymethyltetrazole and

its corresponding acid were sufficiently activated to undergo

40

Knoevenagel type condensations, it was felt that a base catalyzed proton
removal and subsequent reaction of the anion formed with alkyl halides
might be feasible. . In order to prevent tetrazole ring alkylation, the
acidic hydrogen of 5-carboethoxymethyltetrazole was blocked by prior

A reaction of the tetrazole anion with benzyl bromide. The resulting
Z-benzyl-S-carboethoxymethyltetrazole was then utilized in the alkyla-
tion reactions.

. While the size of the benzyl group would not be the same as an
ethyl group 'when compared to the reactions of diethyl malonate, it was
felt that little or no difference would be imparted to the methylene group
by‘a benzyl versus an ethyl group on the tetrazole ring. In addition,
the benzyl group had the advantage of easy removal if the S-substituted
tetrazoles were desired.

- The alkylation of the sodio derivative of diethyl malonate with a
wide variety of alkyl halides (67), followed by saponification and
decarboxylation is a well-known reactionsequence leading to 31213.:
substituted acetic acids. The normal reaction medium for the initial
, sodio derivative formation and subsequent alkylation is sodium ethoxide
in absolute ethanol.

. The range of reactivity of the halides which will react with diethyl
malonate runs from the most active, such as benzyl and allyl halides,
to theless reactive alkyl halides. The normal restrictions of SnZ
reactions on the alkyl halides do apply. That is, the reactive halides
and primary halides arethe most. reactive, 7 secondary halides less re-
active and generally tertiary halides and aromatic halides do not react
(68). '

.With these relationships in mind, it was thought that a study of
the conditions necessary for substitution to occur and an evaluation of

the reactivity of the halides would produce some information on the

~41

activating influence of the tetrazole ring in Z-benzyl-S-carboethoxy-
methyl-tetrazole.

. Initially the procedure tried utilized sodium ethoxide in absolute
ethanol as the reaction medium. Reactive halides, benzyl and allyl
bromide, were used. ~ The oils obtained after refluxing the ethanol
solution of reactants, concentrating and precipitating with water were
extracted into ether. Isolation by. ether removal gave in bothcases an
oil which proved to be impure starting material.

- Since the melting points of 2, 5-disubstituted tetrazoles are
generally quite low, it was thought that a better isolation technique
would be to saponify the alkylated Z-benzyl-5-carboethoxymethyltetra-
~ zoles, thereby creating a higher melting acid. This procedure was
attempted with ethyl bromide as the alkyl halide. The ethanol solvent
after alkylation-was removed and replaced by aqueous sodium hydroxide.
This was refluxed to saponify any esters present. . Acidification of the
basic reaction mixture gave only Z-benzyl-S-carboxymethyltetrazole
in 99.4% crude yield.

.It was concluded that the sodium ethoxide‘was not sufficiently
basic toremove the proton from the methylene of the Z-benzyl-S-
carboethoxymethyltetrazole. Therefore, it was felt that the stronger
base, sodium hydride, should effect proton removal.

-Solway and LaForge (69) have utilized the strong proton affinity
of sodium hydride for the preparation of ethyl fl-keto-caproic acid.
They added 2-heptanone slowly to a refluxing mixture of diethylcarbonate
and sodium hydride in ether and isolated the product in 55% yield.

Green and‘LaForge (70) have also used sodiurnhydride to prepare
sodio derivatives of fl-keto-esters. They state that the reaction was
easy and, readily controlled by addition of the B-keto ester. The solVent

generally used was dry ether, however, , dioxane was also‘used.

42

,Alkylation of 2-benzyl-5-carboethoxymethyltetrazole was success-
ful with the use of sodium hydride. The tetrazole compound was added
slowly to the sodium hydride in ether. Either because the sodium
hydride was suspended on mineral oil and therefore less active, or the
acidity of the methylene hydrogens was very low the reaction was slow.
Generally stirring and refluxing for 1-2 hours was necessary to give
complete salt formation. The sodio derivative precipitated from the
ether as a granular, white solid. The alkyl halide was added slowly,
and the reaction mixture refluxed. ’- Since the isolation of the free acids
was easier, the alkylation mixture was refluxed with aqueous sodium
hydroxide after removal of the ether. Acidification of the basic solution

yielded the product.

— —

CZHSOZCCHZ- -— cszozcEEH- N —
I) )1)” 33129 T) I) +
N N ether N i N Na + H2

(I3H2¢ J”12¢

 

 

 

 

L _)
1) RX
2) H20, NaOH
Hooc-cH-t': fix: 3) H,o+
.R N
CH2¢ XLI, R = ¢CH3-

XLII, R = CHZ=CHCH2-
XLIII, R = p-CIC6H4CH2-
By this method 2-benzyl-5-carboethoxymethyltetrazole was alkylated
by benzyl and allyl bromides and a,_p-dichlorotoluene to yield acids,
XLI, XLII, and XLIII.
The infrared spectra of these three compounds (Appendix I,
.Figures 14-16), exhibited carbonyl absorption at 5. 80-5. 86 it.

In addition, spectra 14 and 15 were almost identical except in the

43

12-14. 5 untr‘egion. .Since the only difference in the two structures was
a Ea-chloro substituent on therphenyl ring, this similarity was to be
expected.

When. fl-cycl‘ohexylethylInbromide‘. or] i-‘butyl'. bromide :werelused: in the
above procedure, there was no reaction. The alkylation and) saponifi-
cation were carried out in the same manner, but the onlyproduct
isolated after acidification was 2—benzyl-5-carboxymethy‘ltetrazole
in good yields.

.Since dioxane was 'alsolused in reactions ofthis type (70), . the
reaction was repeated with fi-cyclohexylethyl bromide and refluxing
dioxane as the solvent. .Although higher reaction temperature and
greater solubility of the sodio derivative were obtained, the only product
isolated was Z-benzyl-5-carboxymethyltetrazole in good yield».

.An all inclusive explanation of these observations is not possible
without more information; however, certain points are worth -men'tion.
.First, it would seem that the acidity of the methylene group in Z-benzyl-
.5-carboethoxymethyltetrazole is less than that in diethyl malonate as
seenzin its lack of reaction with sodium ethoxide-ethanol. ‘Schaal and
‘Jacquinot-Vermes-se‘(7l) have calculated the ionizationconstant of di-
ethyl malonate in reference towater as 6 x 10”". This would mean that
the ionization constant of 2-benzy1-5-carboethoxymethyltetrazole would
be less than 10"16 and might be less than that of ethyl alcohol. .It would
be of interest to determine the relationship of the ionizationconstants
as a means of determining whether any anionic form of‘Z-benzyl-S-
carboethoxymethyltetrazole exists in sodium ethoxide-ethanol solutions.

The formation of the sodio derivative was not a problem with
sodium hydride in ether. , The stronger base and the removal of one
product (Hz) from the reaction gave the sodio derivative. However, '

. several other factors must be considered. The sodio derivative pre-

cipitates out of the ether solvent, which -means the concentration of

44

anion left to react is very small. Also, in the very poor ionizing solvent,
ether, the small amount of anion in solution may exist as an ion pair.
This would further decrease the amount of reactive anion present.

~ Since the overall rate of the reaction depends on the concentration of

the anion, the result should be a slow reaction.

In addition, the bimolecular reaction of the anion with the alkyl
halides should be a function not only of the concentration of the anion, but
also of the reactivity of the halide. The more reactive halides, such as
the benzyl or allyl halides, should be more able, due to a lower enthalpy
of reaction, to compete with the return to ion pair; whereas, the alkyl
halides with higher activation energys would permit little or no conversion
to products.

The debenzylation of acids XLI and XLIII with sodium in liquid
ammonia proved to be an extremely effective means of benzyl group
removal from the tetrazole ring. The ease of benzylation and debenzyl-
ation makes this an effective blocking group for the acidic proton on
the tetrazole. The removal no doubt involves a free electron attack on
the tetrazole ring to form the radical-anion XLIV. This would on reaction
with a second electron give dianion XLV, which would stabilize itself by
displacement of the benzyl anion. The benzyl anion would then pick up
a proton from the ammonia to give toluene while the tetrazole anion as
its sodium salt would be a stable ion in solution. Acidification of the
aqueous solution prepared after removal of the ammonia liberated the

free tetrazole.

 

 

C00 C00
/ /
R-CH R-CH
\ _ +€- \C N
i 13.. . ——> . l c. .
§N/ 2 ° N\N/ Z

45

XLIV -——>

 

, '_ -)
coo (SI-13¢ '

I
/ -
’XLV——-> com-CH + : CHZCD LEI-’—> + I
:TJ : NHZ' !
|

= ¢C Hz, _E' C1C6I‘14CH3

The only disadvantage to this reaction was that the ELa-chloro
derivative XLIII also underwent dechlorination resulting in the same
product as the debenzylation of XLI, _i_._e. , 5-(l-carboxy-2-phenylethyl)-
tetrazole (XLVI).

COOH
© /
CHZCH
\C H
II T

N\ N¢VN

 

X LVI

Compound XLVI underwent ready decarboxylation at its melting
point (176-177OC.) to yield 5-(2-phenylethyl)tetrazole, which was the
same as that prepared by Mihina and Herbst (8). In contrast to the
decarboxylation of the 5-(2-aryl-l-carboxyvinyl)tetrazoles, the de-_
carboxylation of XLVI was best run as the melt and little or no decompo-

sition of the tetrazole ring was noted. , While only this one compound

46

was prepared, it wouldappear that this sequence of reactions should

provide a means of synthesizing 5-(2-arylethyl)tetrazoles.

>1: 2::

EXPERIMENT Alf: '

Section 1:

Starting Materials and Fundamental Reactions

An Evaluation of Procedures for the
Preparation of 5-Carboethoxymethyltetrazole

Procedure 1 (l7)

 

Forty-eight and seven-tenths grams (0. 75 mole) of sodium azide
and 31.8 g. (0. 75 mole) of lithium chloride was placed in a 1.1. flask
and to this was added 55. 55 g. (0. 50 mole) of ethyl cyanoacetate in
500 m1. of ethylene glycol monomethyl ether. The mixture was
refluxed 127 hours and the solvent removed under reduced pressure on
a steam bath. The residue was dissolved in 350 ml. of hot water and
acidified to pH 2 with concentrated hydrochloric acid. . Cooling caused
a precipitate to form which was collected by suction filtration to yield
13.5 g. of crude solid, melting point loll-108°C. Concentration of the
aqueous filtrate afforded an additional 4. 5 g. of material, melting
point loo-103°C. The combined solid was recrystallized from ethyl
acetate to yield 12. 9 g. of colorless crystals, melting point 108-109OC.
Repeated recrystallizations from either ethyl acetate or i-propyl
alcohol failed to raise the melting point above 108. 5-109. 59c. This
material was subsequently shown to be the monomethyl ethylene glycol
ester of 5-carboxymethyltetrazole by saponification to 5-carboxymethyl-

, >',< 9,: >§<

tetrazole and ethylene glycol monomethyl ether.

 

*
All analyses were done by Micro-Tech Laboratories, Skokie, 111.

a):
All melting points were taken in open capillaries and were not
corrected.

***
See page 50 of Experimental.

47

48

Procedure 2 (18)

 

In a 300 ml. flask fitted with stirrer and condenser was placed
7.15 g. (0.11 mole) of sodium azide and 5.88 g. (0-. 11 mole) of
ammonium chloride. A solution of 11.3 g. (0.10 mole) of ethyl
cyanoacetate in 50 ml. of dimethylformamide was added to the solids
and the mixture stirred for 8 hours while maintaining the temperature
of the reaction flask at 95°C. by means of an oil bath. The solvent

was removed in vacuo on a steam bath and the residue dissolved in

 

50 ml. of hot water, acidified to pH 2 with concentrated hydrochloric
acid (caution-t-hydrazoic acid evolved), and finally chilled in an ice
bath. Suction filtration, washing with ice water, and drying afforded
solid product which was recrystallized from ethyl acetate to give

7. 2 g. (46. 2% of theory) of 5-carboethoxymethyltetrazole, melting
point 124. 5-1259C. Finnegan, it a_._1. , report a melting point of
128-1300C. and yields of near 80% (18). In a subsequent rerun of the
above procedure ona one mole scale, the yield was increased to

64. 3% of theory.

Proc edure 3 (9)

 

Eleven and three-tenths grams (0. 10 mole) of ethyl cyanoacetate,
9. 56 g. (0. 15 mole) of sodium azide and 400 m1. of n-butyl alcohol
were mixed in'a l l. flask. ~ Eight and seven-tenths milliliters '(0. 15
mole) of glacial acetic acid was added and the mixture refluxed 3
days. The solvent was removed on a steam bath under reduced pressure.
The solid residue was dissolved in 100 ml. of hot water and acidified
to pH 2 with concentrated hydrochloric acid. Two layers formed in the
hot solution which on cooling overnight yielded solid product. This was
filtered and recrystallized from ethyl acetate to give 5. 2 g. of color-
less crystals, melting point 92-93. 59C. The aqueous filtrate, upon

concentration, chilling, and filtration, afforded an additional 1.59 g. of

49

crystals after one recrystallization from ethyl acetate. The total yield
was 36. 9% of theory assuming transesterification occurred to give
5-carbobutoxymethyltetrazole as the product. This was shown to be
the case by saponification to 5-carboxymethyltetrazole and n-butyl

a):
alcohol.

Procedure 4

 

A typical run involved mixing 113. 1 g. (1. 00 mole) of ethyl
cyanoacetate, 97. 5 g. (1. 50 mole) of sodium azide, and 90. 75 g.
(1.50 mole) of glacial acetic acid in 350 m1. of absolute ethyl alcohol.
This mixture was refluxed 45 hours (note: a 72 hour reflux only in-

creased the yield by about 5%). The ethyl alcohol was removed _12 vacuo

 

on a steam bath and the residue dissolved in a minimum of hot water.
Concentrated hydrochloric acid was added until the solution was pH 2
and the mixture was cooled to precipitate the product. Filtration and
recrystallization from ethyl acetate to separate insoluble inorganic
material yielded in two crops 89. 2 g. of 5-carboethoxymethyltetrazole,
melting point 126-127. 50C. The original aqueous filtrate was concen-
trated, cooled, and filtered to give 4. 5 g. of product, melting point
125-127.50C. after one recrystallization from ethyl acetate. This
total yield of 93.6 g.,was 60.0% of theory. Additional runs on a two
mole scale gave yields of 57-58% of theory. This procedure, since

it gave reasonable yields and lent itself to large scale preparations,
was selected as the best over-all procedure for the preparation of

5-carboethoxymethyltetrazole.
The Preparation of 5-Carboxymethyltetrazole

Procedure 1

 

Thirty-eight and one-tenths grams (0. 244 mole) of

 

*
See page 50 of Experimental.

50

5-carboethoxymethyltetrazole was refluxed 5 hours in a solution of
20 g. (0.50 mole) of sodium hydroxide in 150 m1. of water. The solu-
tion was concentrated LI}. w on a steam bath until solid began to
precipitate. Water was added to the cooled mixture to give a saturated
basic solution. Concentrated hydrochloric acid was added until the
solution was pH 1-2; the solution was chilled and filtered. The color-
less crystals were dried under vacuum at 100°C. overnight to yield
27. 3 g. (87. 3% of theory) of 5-carboxymethyltetrazole, melting point
171-1720C. with gas evolution.

'Analysis. Calculated for C3H4N4Oz: C, 28.13; H, 3.15; N, 43.74;

neut. equiv., 69.
Found: C, 28.29; H, 3.03; N, 43.54;

neut. equiv., 69.

Procedure 2

 

To a mixture of 3.4 g. (0. 0184 mole) of 5-carbobutoxymethyl-
tetrazole and 7. 5 g.- (0. 0403 mole) of 5-[(fi-methoxycarboethoxy)methy‘1]-
tetrazole in 40 ml. of water was added 4. 8 g. (0. 12 mole) of sodium
hydroxide dissolved in 20 m1. of water. The mixture was refluxed 6
hours and concentrated to the point where solid began to precipitate.

The cooled mixture was acidified to pH 2 with concentrated hydrochloric
acid and the colorless crystals collected. The air dried product melted
at 181-1820C. with decomposition. A weighed sample after drying at

100°C. ill-vacuo to constant weight showed a loss of 22. 6% which corres-

 

ponds to two-molecules of water of hydration (theory 21. 9%); the melting
point dropped to 171. 5-172. 5°C. with gas evolution. The total yield of
5-carboxymethyltetrazole after dehydration-was 5. 0 g. , equivalent to
66.5% of theory based on the) total of combined esters. ‘ The initial
aqueous filtrate on fractional distillation gave fractions corresponding to

'n-butyl alcohol and ethylene glycol monomethyl ether.

51

The ' Preparation of 5-Methy1tetrazole

5-Methyltetrazole

 

Five-tenths gram (0.0039 mole) of 5-carboxymethyltetrazole was
placed in a 50 ml. Erlenmeyer flask and heated in an oil bath to 185°C.
The temperature was maintained at 1850C. for five minutes. Gas evolu-—
tion stopped approximately one minute after melting. The residue in
the cooled flask was recrystallized twice from i-amyl acetate to give
5-methy1tetrazole as colorless needles, melting point 142. 5-1430C.

VA mixture melting point with an authentic sample of 5-methyltetrazole,

melting point 148-148. 50C. (corr.) (8), was not depressed.

The Preparation of
2-Benzyl-5-carboalkoxymethyltetrazoles

‘Reaction of 5-Carbobutoxymethyltetrazole
with Benzyl Bromide

 

 

A mixture of 3.68 g. (0. 02 mole) of 5-carbobutoxymethyltetrazole,
4.14 g. (0.03 mole) of potassium carbonate, and 3.42 g. (0.02 mole)
of benzyl bromide in 100 m1. of 90% ethyl alcohol was refluxed on a
steambathfor 20 hours. The reaction mixture in which a small amount
.of solid had formed was evaporated to dryness and extracted with hot
ethyl acetate. The hot extract was treated with ‘Norite and filtered.
-Cooling gave 1.06 g. of colorless needles, melting point 142. 5-143OC.
.with gas evolution. Rather than the desired 2-benzyl-5-carbobutoxy-
methyltetrazole, the product was shown to be Z-benzyl-S-carboxymethyl-
tetrazole (yield 41. 2% of theory). The product was the same when the
ethyl ester was used as the starting material.

-Analysis. Calculated for C10H10N4Oz: C, .55. 04; H, 4.62; N, (25.68.

Found: C, 55.25; H, 4.80; N, 25.59.

52

2- Benzyl- 5 -carboethoxymethyltetrazole
by Benzylation

 

Six and nine-tenths grams (0. 30 mole) of freshly cut sodium was
dissolved in 200 m1. of absolute ethyl alcohol. To the ethoxide solution
was added with shaking, 46. 8 g. (0. 30 mole) of 5-carboethoxymethyl-
tetrazole. The mixture was refluxed one-half hour to complete the salt
formation. Benzyl bromide, 34.2 g. (0.20 mole), was added dropwise
to the refluxing solution over a period of 1 hour. The mixture was
stirred and refluxed for 5 hours. Suction filtration of the warm re-
action mixture removed inorganic salts. The filtrate was concentrated
in a Rinco evaporator, treated with 175 m1. of water and sufficient
sodium bicarbonate to give a solution of pH 8-9. The aqueous solution
was extracted with ether, and the extracts dried over anhydrous
magnesium sulfate, filtered, and concentrated to gel. 75 m1. Cooling in
Dry Ice gave several crops of low melting solid which were combined
and recrystallized from absolute ethyl alcohol to give in three cr0ps
23.4 g. of colorless needles, melting point 51-520C. Concentration
and cooling of the filtrate yielded 9. 1 g. of slightly impure product.

The aqueous portion of the above extraction was acidified to pH 1 with
concentrated hydrochloric acid, cooled, and filtered to yield 12.0 g.
—(0..0781mole) of recovered 5-carboethoxymethyltetrazole. The total
yield of 2-benzyl-5-carboethoxymethyltetrazole based on benzyl bromide
was 66. 1%.
Analysis. .Calculated for CIZHMN‘Oz: C, 58.52; H, 5.73; N, .22. 75.
Found: C, 58.63; H, 5.80; N, 22.73.

2- Benzyl- 5-carboethoxyrnethyltetrazole
by'Esterification

 

 

To 100 m1. .of absolute ethanol containing 1 m1. of concentrated
sulfuric acid was added 10. 0 g. (0.0458 mole) of Z-benzyl-S-carboxymethyl-

tetrazole. The mixture was refluxed for 4 hours. The solvent was

53

removed under an air jet leaving an oily residue. Fifty milliliters of
water was added and the mixture extracted with ether. The ether
extract was dried over Norite and anhydrous magnesium sulfate. The
solution was filtered, the ether removed, and the clear, oily residue
cooled in Dry Ice. A near solid mass formed which after slight warm-
ing was filtered to give a solid melting at 40-500C. The solid was
dissolved at room temperature in absolute ethanol, cooled in Dry Ice,
and filtered to give 4. 0 g. (35. 5% of theory) of 2-benzyl-5-carboethoxy-
methyltetrazole, melting point 50. 5-51. 50C. , identical with a previously

prepared sample.

The Debenzylation of 2, 5-Disubstituted Tetrazoles

Attempted Debenzylation of 2-Benzy1-5-
carboxymethyltetrazole

 

 

Three grams (0. 0137 mole) of 2-benzy1-5-carboxymethy1tetrazole
was dissolved with warming in 150 m1. of absolute ethanol and approxi-
mately 0. 1 g. of palladium oxide was added. The mixture was hydro-
genated in a Paar hydrogenator at 50 p. s. i. for 36 hours while maintain-
ing the temperature at 50-600C. The catalyst was filtered off and the
solution concentrated to a volume of 50 m1. , cooled, and the crystals
collected by filtration and air dried. The crystals melted at 142-143. 5°C.
with gas evolution and proved to be starting material by comparison
with an authentic sample. The use of acetic acid as a solvent was

equally unsucc es sful.

The ‘Preparation of 2- Benzyl- 5-phenyltetrazole

 

A solution of 4.64 g. (0.025 mole) of 5-pheny1tetrazole and 5. 2 g.
(0.0375 mole) of potassium carbonate in 100 m1. of 90% ethanol was

refluxed 15 minutes. The solution was cooled slightly and 6.4 g.

54

' (0. 0375 mole) of benzyl bromide was added. The solution was then
refluxed 20 hours on a steam bath. Cooling and the addition of a small
amount of water precipitated the product as colorless needles.
Filtration and recrystallization from methanol gave in two-crops 3. 4
g. (57. 7% of theory) of 2-benzy1-5-pheny1tetrazole, melting point
64-66o-C. The reported melting point was 65. 5-660C. - (8).

-A Study of the Debenzylation of 1- or 2-Benzyl-
5—phenyltetrazole

 

With warming, 2.36 g. (0.01 mole) of 1-benzy1-5-phenyltetrazole
(sample obtained from R. M. Herbst) was dissolved in 150 ml. of
absolute ethanol and 300 mg. of palladium oxide added. . The-mixture
was hydrogenated in‘a Paar apparatus for 16 hours at 50 p. s.i. with
warming at aboutSOoC. Filtration to remove the catalyst and evapora-
tion to dryness gave a solid residue which was suspended in ether
and dilute sodium hydroxide solution added toldissolve acidicmaterial.
In the ether-aqueous‘layers a small amount of insoluble solid remained
which was filtered off. The aqueous layer was separated and acidified
with concentrated hydrochloric acid to pH 2. 1Cooling and filtering
yielded 0. 65 g. (44.4% of theory) of 5-phenyltetrazole, melting point
209-2119c. Reported melting points: 212-213°c. l(dec.) (7), 217-21896.
(corr.) (8). A mixture melting point with a known sample obtained from
R. :M.>Herbst was not depressed.

Using 2.. 2g. (0. 0093 mole) of 2-benzyl-5-phenyltetrazole in the
above procedure with a hydrogenation time of 24 hours, gave a solid
residue after removal of the solvent which was treated with dilute
sodiumhydroxide and filtered. The insoluble residue was recrystallized
from ethyl acetate to give 0. 9 g. (41%) of recovered starting material,
melting point 63. 5-69OC. The basic solution was acidified with hydro-

chloric acid to yield 0. 15 g. (8. 7% of theory based on the total amount of

55

starting material) of 5-phenyltetrazole, melting point 209-2109C.
-Other "attempts using 5% palladium on carbon as the catalyst were

equally unsuc c e s sful.

5 -Carboxymethyltetrazole by Debenzylation

 

2-Benzyl-5-carboxymethy1tetrazole, 1.0 g. (0.00438 mole), was
suspended with stirring in _c_a: 50 m1. of liquid ammonia. Small bits -
of freshly cut sodium metal were added until the blue color persisted.
The-excess sodium was reacted with a small amount of ammonium
chloride and the colorless mixture allowed to evaporate to dryness.
The residue was dissolved in a minimum of water, heated briefly under
reduced pressure to remove toluene, filtered with Norite and cooled.
The clear solution was acidified with concentrated hydrochloric acid
to pH 1. 5-Carboxymethy1tetrazole precipitated as colorless crystals,
melting point 171-1720C. with gas evolution. Identity was confirmed

by comparison to a previously prepared sample.

56

Section ‘2:
Condensation Sequences Involving
5-Carboethoxymethyltetrazole

The Preparation of 5-(2-Phenylvinyl)tetrazole

(a) 5 - (1 -Carboethoxy- 2-pheny1vinyl)tetrazole

 

In a 250 m1. flask was placed 20. 0 g. (0. 128 mole) of 5-carbo-
ethoxymethyltetrazole, 13. 6 g. (0. 128 mole) of benzaldehyde, 100 ml. of
pyridine, and 4 m1. of piperidine. <The mixture was refluxedrfor5
hours, cooled slightly, and the solvent removed _13 won a steam
bath. To the residue suspended in 500 ml. of water was added with
warming sufficient sodium bicarbonate to give a clear solution of
approximately pH 8. This was extracted well witha total of about 400
m1. of ether, placed under an air jet until no more ether could be
detected, treated with Norite and filtered. The filtrate was warmed on
a steam-bath while acidifying with concentrated hydrochloric acid to
pH 2. The solution was cooled overnight and the precipitated product
collected and recrystallized from methyl alcohol to give 11. 0 g. (35. 2%
of theory) of 5-(1-carboethoxy-2-phenylviny1)tetrazole, melting point
175-17690.

.Analysis. .Calculated for'CanN-‘Oz: C, .59.00;'-H, 4. 9-5; N, 22. 94;

neut. equiv., 244.
.Found: . C, 59.40; H, 4. 27; N, 22.49;

neut. equiv., 241.

 

- (b) 5-(1-Carboxy-Z-phenylvinyl)tetrazole

Ten grams of sodium hydroxide pellets and 10.4 g. (0. 0426 mole)
of 5-t(1-carboethoxy-2-phenylvinyl)tetrazole was dissolved in 100 m1. . of
water and allowed to stand 23 hours at room temperature. The aqueous

solution was acidified with concentrated hydrochloric acid to'pH 1, cooled,

57

filtered, and the solid recrystallizedfrom methyl alcohol. The yield
of product from two crops of crystals, melting point 173-174gC. with
gas evolution, was 4. 9 g. (53. 5% of theory).
Analysis. Calculated for C10H8N403: C, 55.55; H, 3.73; N, 25. 92;
neut. equiv., 108.
Found: c, 55.43; H, 3.74; N, 26.09;

neut. equiv., 110.

(c) 5 - (2 - Phenylvinyl)tetrazole

 

In 25 m1. of diethylene glycol was suspended with stirring 5. 0 g.
(0.0231 mole) of 5-(1-carboxy-2-phenylvinyl)tetrazole and the mixture
heated gradually. Gas evolution was noted at 2. 130°C. at which point
all compound had dissolved. The solution was heated to 170-1800C.
resulting in rapid evolution of carbon dioxide. After maintaining the
temperature at this point for one-half hour, the slightly cooled solution
was poured slowly with stirring into 100 m1. of water saturated with
sodium bicarbonate. -An additional 150 ml. of water was added to obtain
a solution of pH 8. This solution was extracted well with ether, filtered
with‘Norite, and brought to pH 2 with concentrated hydrochloric acid.
.Cooling and filtering give 2. 7 g. (67. 8% of theory) of 5-(2-pheny1vinyl)e
tetrazole which melted at 170°C. . Recrystallization from absolute ethyl
alcohol and drying {new at 100°C. raised the melting point to 174-175. 5°C.
with slight discoloration.

Analysis. Calculated for'C9HgN4: C, 62. 78; H, 4.68; N, 32.54;

neut. » equiv. , 172.
Found: C, 63.06;H, 4.76; N, 32.47;

neut. equiv., 170.

58

The Preparation of
5 - [2 - (p-Methoxyphenyl)vinyl]tetrazole

(a) 5 -[1- Carboethoxy- 2 - (p-methoxyphenyl)vinyfltetrazole

 

A mixture of 10. 0 g. (0.0641 mole) of 5-carboethoxymethyl-
tetrazole and 8. 7 g. (0. 0641 mole) of p-methoxybenzaldehyde in 150
ml. of pyridine together with 2 ml. of piperidine was refluxed 4 hours.
The solvent was removedflm and to the residue was added 50 m1.
of water and sufficient dilute ammonium hydroxide to give aclear
solution of pH 9. - The basic solution was washed four times with
ether (100 ml. total) and with cooling was acidified with dilute hydro-
chloric acid to pH 2. The crude yellow powder was filtered, air dried,
and recrystallized from methyl alcohol to give 9. 0 g. of crude product
melting point 166. 5-1680C. with slight decomposition. Further recrystal-
lizations raised the melting point to 176. 5-177OC. with slight decompo-
sition and yielded 8. 8 g. (50. 1% of theory) of 5-[l-carboethoxy-2-
(_p-methoxyphenyl)vinyl]tetrazole.

- Analysis. -Calculated for C13H14N403: —C, 56.93; H, ,5. 14; N, 20. 43;

neut. equiv. , 274.
Found: c, 56.69; H, 5. 25; N, 20. 51;

neut. equiv., 273.

(b) 5 -i1-Carboxy- 241-methoxyphenyl)viny1]t_etrazole

 

5-[l-Carboethoxy-2-(p-methoxyphenyl)vinyl]tetrazole, 10.0 g.

- (0. 0404'mole), was dissolved in a solution of 4.0 g. (0. 1 mole) of
sodium hydroxide in 40 ml. of water and the solution refluxed 2 hours.
The cooled solution was acidified to pH 2 with concentrated hydrochloric
acid. The chilled solution was filtered and the solid recrystallized from
95% ethanol to yield in two crops 8.0 g. (80.4% of theory) of product,

melting point 201. 5-2020C. withagas evolution.

59

Analysis. Calculated for C11H10N403: C, 53.66; H, 4.09; N, 22.76;
neut. equiv., 123.
Found: C, 53.77; H, 4.00; N, 23.09;

neut. equiv., 124.

(c) 5-[2=(p-Methoxyphenyl)viny11tetrazole

 

Five grams (0. 0203 mole) of 5-[1-carboxye-2-(B-methoxyphenyl)-
vinyl]tetrazole was suspended in 50 m1. of diethylene glycol. The
stirred mixture was heated to 185°C. at which point the evolution of
gas was noted. The solution was maintained at 190-1950C. for one-
half hour with stirring. The resulting light-orange solution was allowed
to cool and poured with stirring into 150 ml. of water. The crude
product which precipitated was redissolved at pH 8-9 with sodium
bicarbonate and warmed to drive out carbon dioxide. The solution
was extracted well with ether, placed under an air jet to remove ether,
filtered with Norite, and adjusted to pH 1-2 with concentrated hydro-
chloric acid. The light yellow precipitate was filtered, recrystallized
from water, and dried 33 @933 at 100°C. to yield 1.4 g. (34. 2% of
theory) of 5-[2-(p-methoxyphenyl)vinyl]tetrazole as a colorless solid,
melting point l93-194OC. with decomposition.

Analysis. Calculated for C10H10N4O: ~C, 59.39; H. 4.99; N. 27.71;

neut. equiv. , 202.
Found: C, 59.49; H, 4.86; N, 27.79;

neut. equiv., 203.

The Pr eparation of
5 - [2- (p-Nitrophenyl)viny1]tetrazole

(a) 5- [1 -Carboethoxy- 2- (p-nitrophenyl)vinyl]tetrazole

 

Ten grams (0.0641 mole) of 5-carboethoxymethyltetrazole, 9.2

g. (0. 0641 mole) of p-nitrobenzaldehyde, and 2 m1. of piperidine were

'60

'mixed in 150 ml. of pyridine and refluxed'3 hours. The solution was
divided into two equal portions andreach evaporated to remove pyridine.
To one was added 10% sodium hydroxide solution; an inxmediate
darkening occurred. After standing for four days the mixture was
acidified yielding nothing but brown tar from which no product could
be obtained.
The second fraction of residue was treated with 50 ml. of water
at which point a gummy precipitate formed. . This was dissolved with
dilute ammonium hydroxide to give a clear solution at pH 9. The solu-
tion was extracted with ether, cooled, and with shaking acidified with
dilute hydrochloric acid to pH 1-2. The impure solid was filtered and
recrystallized from methyl alcohol. The product crystallized as fine,
yellow needles, melting point 211. 5-212. 5°C. with decomposition.
Theneutralization equivalent and analysis agreed for 5-[l-carboethoxy-
2-(2- nitrophenyl) vinyl]tetrazole .
(Analysis. .Calculated for C12H11N504: C, 49.82; H, 3.83; N, 24.21;
neut. equiv. , 289.
Found: C, 49. 79; H, 3.97; N, 24. 13;

neut. equiv., 291.

(b) 5 -[1-Carboxy- 2-(p- nitrophenyl) vinyl]tetraz ole

 

_ A mixture of 1. 7 g. (0.00588 mole) of 5-[1-carboethoxy-2-
(p-nitrophenyl)viny~l]tetrazole, 10 ml. of glacial acetic acid, 2 m1. of
water, and 1 drop of concentrated sulfuric acid was refluxed 12 hours.
The solvent was removed _12 w on a steam bath and to the residue
was addedi30 ml. of water and sufficient sodium bicarbonate to nearly
neutralize the mixture. The solution was extracted with ether and the
ether extracted with 10 ml. of 10% sodium bicarbonate. The combined
aqueous extracts (pH 8-9) was acidified to pH 1 with concentrated

hydrochloric acid. The impure precipitate was filtered, recrystallized

61'

once from aqueous methanol. andfinally from water to give 1. 0 g.
(65. 3% of theory) of 5-[1-carboxy-2-(p-nitrophenyl)vinyl]tetrazole.
The compound softens and foams at 190°C. and finally melts with
decomposition at £3. 210°C.
Analysis. Calculated for C10H7N504: , C, 45. 98; H, 2. 70; N, 26. 82;
neut. equiv. , 130.5.
Found: N, 27.97, 27.86;
neut. equiv. , 145.
. Since the nitrogen did not agree, but the compound could be
decarboxylated to 5-[2-(p-nitrophenyl)vinyl]tetrazole in good yield,
it was assumed that the compound isolated above contained some
decarboxylated material. Calculations based on this assumption using
the found nitrogen percentage and the found neutralization equivalent

set the acidvcontent of the material at 77.4-82. 7%.

(c) 5 - [A- (p-Nitrophenyl) vinyl]tetrazole

In 1. 5'ml. of diethylene glycol was suspended 0. 12 g. (0.00046
mole) of 5-[1-carboxy-2-(p-nitrophenyl)vinyl]tetrazole. With stirring
. the mixture was gradually heated until gas evolution stopped, £8:
165°C. The solution was maintained at 165°C. for an additional 10
minutes, cooled to room temperature and-a solution of O. 045 g. of
sodium bicarbonate in 10 m1. of water was added. The mixture was
warmed gently to drive off carbon dioxide. The resulting solution
' (pH 7-8) was extracted well with ether and adjusted to pH 1-2 with
dilute hydrochloric acid. The crude product which precipitated was
collected and recrystallized from aqueous ethanol to yield 0. 07 g). of
product (33. 1%of theory) which melted at 240-2410C. with decompo-
sition, A

Analysis. Calculated for C9'H7N502: ;C, 49.77; H, 3.25; N, 32.25;

neut. equiv. , 217.
-Found: C, 49.90; H, 3.29; N, 32.32;

neut. equiv., 220.

62

'Attempted Condensation Reactions

Condensation of p-methoxybenzaldehyde and
and 5-carboethoxymethyltetrazole

To a solution of 10.0 g. (0.0641mole) of 5-carboethoxymethyl-
tetrazole in 100 ml. of pyridine was added 8. 72 g. (0.0642 mole) of
p-methoxybenzaldehyde dissolved in 50 m1. of pyridine. Two milli-
liters of piperidine was added and the mixture refluxed 12 hours.
The solvent was removedifl m and the residue dissolved in 10%
sodium hydroxide solution and extracted with ether. The aqueous
solution was cooled and made acidic (pH 2) to precipitate the product.
~After recrystallization from 95% ethyl alcohol, 6. 2 g. of yellow needles,
. melting point 202-202. 5°C. with gas evolution, was isolated.» Compari-
son with an authentic sample and neutralization equivalent showed the
product to be 5-[1-carboxy-2-(p-methoxyphenyl)vinyl]tetrazole. This
amounts to an overall yield of 39. 2% based on starting 5-carboethoxy-

methyltetrazole.

- Attempted Condensation of p-Nitrobenzaldehyde and
5-Carboethoxymethyltetrazole

 

 

Two milliliters of piperidine was added to-a solution of 10. 0 g.
(0.0641 mole) of 5-carboethoxymethyltetrazole and 9.70 g. (0.0641
mole) of _p-nitrobenzaldehyde in 150 ml. of pyridine and the mixture
refluxed 10 hours. The mixture darkened on reflux toa brown-red.

The solvent was removed under vacuum on a steam bathand the dark
residual oil dissolved in 501ml. of 10% sodium hydroxide. The basic
solution was extracted four times with-a total of 200 ml. of ether.

The aqueous solutionwas briefly placed under an air jet to remove
residual ether. Cooling and acidification with concentrated hydrochloric
acid to pH 2 precipitated a fine yellow powder): The product could not

bepurified although a small sample dissolved in ethyl acetate and

63

precipitated with-ether -melted at 122-1250C. with decomposition

indication starting material present.

Attempted Saponification R eaction

5 - (1 - Car boxy- 2 -phenylvinyl) tetraz ole

 

To a solution of 1. 6 g. (0. 04 mole) of sodium hydroxide in 20 ml.
of water was added 4. 6 g. (0.0188 mole) of 5-(1-carboethoxy-2-pheny1-
vinyl)tetrazole. The solution was refluxed 2 hours, cooled, and
acidified with concentrated hydrochloric acid. The product precipitated
as a colorless powder. Recrystallization from methyl alcohol gave 0. 8
g. of product, melting point 172-173OC. with gas evolution. The yield
was only 36. 5% of theory. The smell of benzaldehyde was detected in
the reaction mixture which meant that reversal of the condensation
took place. A mixture melting point with 5-carboxymethy1tetrazole was
depressed, whereas a mixture melting point with a known sample of

5- (1-.carboxy-2-pheny1vinyl)tetrazole was not.

64

Section 3:

Condensations Involving S-Carboxymethyltetrazole

The Preparation of 5-(2-Ary1vinyl)tetrazoles

5 - (2 - Phenylvinylfietrazole Monohydrate

 

To 150 ml. of pyridine was added 10.0 g. (0.078 mole) of
5-carboxymethyltetrazole and a solution of 8. 3 g.- (0.078 mole) of
benzaldehyde in 50 m1. of pyridine. ~Two milliliters of piperidine
was added and the mixture refluxed 4 hours. The solution was concen-
trated infill—o to approximately 80 ml. and mixed with 50 m1. of water.
This solution was acidified with concentrated hydrochloric acid and
cooled to precipitate a cream-yellow solid. Recrystallization from
95% ethanol gave 4. 2 g. of 5-(2-phenylvinyl)tetrazole monohydrate,
melting point 174-176OC. with decomposition. This amounted to
29.4% of theory.

Analysis. Calculated for C9H10N40: C, 56.83; H, 5.30; N, 29.46.

Found: C, 56.80; H, 5.20; N, 29.60.

The determination of the structure of this compound was based
on a comparison of its infrared; spectra with that of 5-.(2-pheny1vinyl)-
tetrazole (Appendix 1, Figures 10 and 13), prepared by different
method,which showed them to be identical except that this compound
showed hydroxyl group absorption at 2. 95 it. The presence of a
double bond in both compounds was confirmed by the ultra-violet
spectra (Figure l) which exhibited in both cases an absorption maximum

-at 283 mu.

5 - [2 - (p-Methoxtheryl) vinylltetrazol e

 

Ten grams (0. 078 mole) of 5-carboxymethy1tetrazole, 10.63 g.
- (0. 078 mole) of B-methoxybenzaldehyde, 4 ml. of piperidine were mixed

65

in 150 ml. of pyridine and refluxed 5 hours. The solvent was removed
_i_n_ w on a steam bath and the residue added to 150 m1. of water
containing 6. 7 g. (0.08 mole) of sodium bicarbonate. The solution was
warmed to drive out carbon dioxide, extracted three times with ether,
and placed under an air jet to remove residual ether. The basic

solution was filtered with Norite and acidified to pH 2 with concentrated
hydrochloric acid to yield, after one recrystallization from 50% aqueous
ethanol, 8. 0 g. of solid, melting point 158-1820C. . Subsequent recrystal-
lizations yielded 5. 0 g. (31. 6% of theory) of 5-[2-(p-methoxyphenyl)vinyl]-
tetrazole, melting point 193-193. 5°C. with decomposition. The identity
of the product was established by comparison with a previously prepared

sample.

5 -[2- (p-Nitrophe nyl) vinyl]tetrazol e

 

Ten grams (0. 078 mole) of 5-carboxymethyltetrazole, ll. 8 g.
» (0. 078 mole) of p-nitrobenzaldehyde, and 4 ml. of piperidine were
4mixed in‘150 ml. of pyridine and refluxed for 5 hours. The residue

after removal of the solvent in vacuo on a steam bath was mixed with

 

150 m1. of water containing 6. 7 g. (0. 08 mole) of sodium bicarbonate.
The basic solution was warmed to drive off carbon dioxide, cooled,
extracted with ether, and, after removal of residual ether under an air
jet, acidified thH 1 with concentrated hydrochloric acid. -The pre-
cipitated product was filtered and dried to give 13. 8 g. (81.4% crude
yield) of yellow solid. Recrystallization from absolute ethanol gave
5-[2-(p-nitrophenyl)vinyl]tetrazole,. melting point 234-2360C. with

decomposition, which was identical with a previously prepared sample.

66

The Attempted'Preparation of
5-[2 -(p-Nitrophenyl)vinyl]tetrazole Hydrate

“Reaction of 5-Carboxymethy1tetrazole with
- g- Nitrobenzaldehyde

 

 

_ In an attempt to determine whether the condensation of _p_—nitro-
benzaldehyde with~5-carboxymethyltetrazole resulted in hydrate form-
ation, the following reaction was run. Two and eight-hundredths grams
- (0.0168 mole) of 5-carboxymethy1tetrazo1e and 2. 54 g. (0. 0168 mole)

of p-nitrobenzaldehyde was mixed in 40 ml. of pyridine and 1 m1. of
piperidine was added. The mixture was refluxed 6 hours, the volume
areducedrig w on a steam bath to 32:. 10 m1. and poured into 75 m1.
of water. During acidification to pH 1 with concentrated hydrochloric
acid an additional 50 ml. of water was added. . Filtration of the solid and
recrystallization from methyl alcohol gave 1. 8 g. (49. 3% of theory) of
yellow needles, melting point 239. 5-2410C. No sign of water liberation
‘was noted. . Comparison with a previously prepared sample showed the
product to be 5-[2-.(_p-nitropheny1)viny1]tetrazole. Hydrate formation

did not occur.

67

* Section 4:

The Alkylation Reactions

The Preparation of 5-(2-Pheny1ethy‘l)tetrazole

(a) 2- Benzyl- 5 -(1- c arboxL- 2 -phenylethyl)tetrazole

Three hundred fifty-four milligrams of 52. 8% sodium hydride
on‘mineral oil (0.0078mole NaH) was suspended in 25 ml. .of ether
distilled from calcium hydride and 2. 0 g. - (0. 0078 mole) of 2-benzy1-
5-carboethoxymethyltetrazole was added in small portions with
stirring. To the stirred, refluxing slurry of sodio derivative which
was protected from moisture by a drying tube,was added dropwise
(1/2 hour) 1. 37 g. (0.008 mole) of benzyl bromide in 25 ml. of ether.
Thewmixture was refluxed for 12 hours, allowed to-stand overnight,
and poured into 50 m1. of water containing 5 ml. of concentrated
hydrochloric acid. The layers were separated and the aqueous layer
extracted with ether. The combined ether extracts were dried over
anhydrous magnesium sulfate, filtered and the ether removed.
Attempts to purify the crude ester by chromatography on Alumina
containing. 3% water or by distillation at 220°C./_c_a_. 1 mm. were
unsuccessful. The NMR spectrum‘(see Figure 2) agreed with the
structural assignment of 2-benzyl—5-(1-carboethoxy-2-pheny1ethyl)-
tetrazole.

The crude tester was refluxed'42 hours in 50 ml. of 10% sodium
hydroxide, diluted with 100 ml. . of water, cooled, and extracted with
2. 200 ml. of ether. The aqueous layer was acidified with dilute
hydrochloric acid to pH 1-2. An oil formed which solidified on cooling.
.Filtration‘and recrystallization from benzene gave 0. 88 g.- (36. 7% of.

theory) of slightly impure product. -Subsequent recrystallizations gave

68

.opwuozomnueu confine

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Z U / 0 .
. moans
o 5%3
w o .\
nmoamoo -o

5 odoumhuoiafioaconmumimosa—connectSumtgnflonuN mo gauoomm M22. .N oudmfm,
AIL, f. ._ H
No.6. wmé mod Nw 4. REM in.
x Q . _
. x} m f m
A. _
fimuo+o C
I N u n
m N u o .m. u

 

 

69

pure product which had a melting point of llO-llZOC. with gas evolu-
tion.
-Analysis. .Calculated for CHI-115N402: C, 66.44; H, 4.92; N, 18.23.
Found: C, 66.85; H, 5.29; N, 17.99.

(b) 5 - (1 -Carboxy- Zjhenylethylfletrazole

 

2-Benzyl-5-(1-carboxy-2-phenylethy1)tetrazole,. 0. 50 g. (0. 00148
mole), was suspended in 23. 20 ml. of liquid ammonia and with stirring,
small bits of sodium were added until a blue color persisted. The color
was removed with a small amount of ammonium chloride and the ammonia
allowed to evaporate. To the residue was added 40 m1. of water and the
solution extracted with ether. The aqueous layer was adjusted to pH 1
with 1:1 aqueous hydrochloric acid. The crystals formed were collected
and dried to give 0. 32 g. (99. 2% of theory) of product, melting point
176-177OC. with gas evolution. AA mixture melting point with 5-carboxy-
methyltetrazole was depressed.

Analysis. Calculated for'C10H10N4Oz: C, 55.04; H, 4.62; N, 25.68;

neut. equiv., 109.
Found: C, 55.11;‘H, 4. 58;; N, 25. 62;

neut. equiv., 110.

(c) 5-(2-Phenylethy1)tetrazole

 

Forty milligrams (0.000183 mole) of 5-(1-carboxy-2-phenyl-
ethy1)tetrazole was placed in a test tube and with stirring heated at its
melting point (176-1770C. gas evolved) for 15 minutes. The liquid was
cooled and the resulting solid recrystallized twice from benzene to give
0.02 g. (62.8% of theory) of 5-(2-phenylethyl)tetrazole, melting point
97. 5-98. 5°C. A mixture melting point with an authentic sample 1

obtained from‘RyM. Herbst was not depressed.

70

The‘Attempted Preparation of
5-[2-(p-Chlorophenyl)ethyl]tetrazole

(a) 2- Benzyl- 5 i1 -c arboxy- 2-(p-chloropheny‘1)-
ethylltetrazole

 

 

In a 300 ml. three necked flask fitted with stirrer and condenser
topped by a drying tube was placed 0. 925 g- (0. 0204 mole NaH) of
52.8% sodimn hydride on mineral oil. This was coveredrat once with
.100 m1. of ether freshly distilled from calcium hydride. With stirring,
5.0 g. (0. 0203 mole) of 2-benzy1—5-carboethoxymethyltetrazole was
added in small portions. The mixture was refluxed briefly to complete
salt formation. -A solution of 4. 02 g. (0. 025 mole) of a,p-dichloro-
toluene in 20 ml. of dry ether was added dropwise to the refluxing salt
slurry. The mixture was refluxed with stirring for 12 hours. One
hundred milliliters of water, 10 ml. of 10% sodium hydroxide was
added. The solution was warmed to drive off the ether and then refluxed
for 4 hours. The solution was cooled, extracted with ether, and
acidified to pH 1 with concentrated hydrochloric acid. The precipitated
solid was filtered off, and the filtrate evaporated to dryness. Extraction
of the residue with hot methanol, removal of the methanol and recrystal-
lization of the methanol residue from aqueous methanol gave 0. 97 g. of
2-benzyl-5-carboxymethyltetrazole(21. 8% recovery of starting material
as the acid). The filtered solid above amounted to 3. 86 g. (68. 8%, of
theory based on unrecovered starting ester) of 2-benzyl-5-[l-carboxy-2-
‘ .(‘p-chlorophenyl) ethy1]tetrazole,. melting point 128-130°C. A sampletrecryse
.tallized from.50;50 aqueous methanol and air dried melted at 128-128. 59C.
.Analysis. -Ca1cu'lated for C17H15C1N4Oz: _ C, 59. 56; H, _ 4. 41;. Cl, 10. 84;
~N, 16.35; neut. equiv., 343.
.Found: C, 59.72; H, 4.67; C1, 10-33;
N, 16.42;. Beilstein Test,

positive; neut. equiv., 346.

71

(b) Debenzylation of 2-Benzyl-5-[l-carboxy-2-(p-chloro-
phenyl) ethyl]tetr az ole

 

 

Two grams (0.00583 mole) of 2-benzyl-5-[1-carboxy-2-(p—chloro-
phenyl)ethy1]tetrazole was suspended with stirring in _cg. 50ml. of
liquid ammonia. Small pieces of freshly cut sodium were added until
the blue color produced was permanent. The color was removed
with ammonium chloride and the ammonia allowed to evaporate. The
residue was dissolved in a minimum of water, extracted with ether,
and the aqueous portion acidified to pH 1 with concentrated hydrochloric
acid. Filtration and air drying gave 1.01 g. of solid. The solid was
recrystallized from water to give colorless crystals, melting point
172-173OC. The solid gave a negative Beilstein Test for halogen.
.Comparison of infrared and mixture melting points with those of a
previously prepared sample showed the solid to be 5-(1-carboxy-2-phenyl-
ethyl)tetrazole. The amount isolated amounts to 79. 3% of theory on

this basis.

The Pr eparation of
2- Benzyl- 5-(1-carboxy- 3-butenyl)tetrazole

2- Benle- 5 - (1 -C arboxy- 3 - butenyl)tetraz ole

 

In a 300 ml. three necked flask fitted with stirrer and condenser
topped by a drying tube was placed 0. 925 g. (0.0204 mole'NaH) of
52.8% sodium hydride on mineral oil. This was covered with dry
pentane, stirred briefly and the pentane decanted. The hydride was
then covered with ether freshly, distilled from calcium hydride and
.5. 0 g. (0. 0203 mole) of 2-benzyl-5-carboethoxymethyltetrazole added
with stirring. -After the; salt formation was complete (23. 20 minutes»),
2. 54 g. (0.021 mole) of allyl bromide was added dropwise to the stirred,
refluxing slurry of salt. The mixture was refluxed and stirred for 17

hours, then the ether. was distilled out. To the residue was added

72

25 ml. of water and 50 ml. of 10% sodium hydroxide. Over a one hour
period, the volatile material (< 90°C.) was distilled from the flask.
The solution was then refluxed 10 hours, cooled, and adjusted to pH 1
with concentrated hydrochloric acid. The solid was filtered and
mixed with 100 ml. of boiling water. Filtration of the hot mixture and
cooling of the filtrate resulted in the formation of an oil which solidified
on further cooling. The solid, melting point 90-920C. , was filtered,
dissolved in ether and reprecipitated with pentane to give 1. 7 g. (32. 4%
of theory) of colorless crystals, melting point 91-930C. Extraction of
the hot water insoluble portion above with ether and precipitation with
pentane yielded 1.03 g. of additional crude product, melting point
80-90°C.

Analysis. Calculated for C13H14N402: C, 60.45; H, 5.46; N, 21.70;

neut. equiv. , 258.
Found: C, 60.52; H, 5. 55;) N, 21.87;

neut. equiv., 260.

Alkylations Attempted in
Sodium Ethoxide - Ethanol

Attempted Preparation of 2-Benzy1-5-(1-carbo-
ethoxy-2-phenylethy1)tetrazole

 

 

To a solution of 0.17 g. (0.0078 mole) of sodium in 40 m1. of
absolute ethanol was added 2. 0 g. (0. 0078 mole) of 2-benzy1-5-carbo-
ethoxymethyltetrazole with shaking. A condenser with drying tube
was attached to the flask and the mixture refluxed 15 minutes. The
flask was cooled slightly and 1. 34 g. (0. 0078 mole) of benzyl bromide
added. The mixture was refluxed overnight, after which 30 m1. of
ethanol was distilled out of the reaction mixture. The residue was
cooled and treated with 25 ml. of water, the oil which separated was

extracted with ether, dried over anhydrous magnesium sulfate and

73

Norite, filtered, and the ether removed. The oil which remained

(1-2 g.) would not solidify and recrystallization attempts were
unsuccessful. The crude oil gave the same infrared spectrum as that
of the starting material. Therefore, it was concluded that no reaction

occurred.

Attempted Preparation of 2-Benzyl-5~(l-carboethoxy-
3-butenyl)tetrazole

 

 

In a 100 ml. flask was placed 40 ml. of absolute ethanol and 0. 17
g. (0.0078 mole) of sodium. After the sodium had all reacted, 2.0 g.
(0.0078 mole) of 2-benzyl-5-carboethoxymethyltetrazole was added with
shaking. The mixture was refluxed briefly and then cooled. Ninety-
five hundredths gram (0. 00785' mole) of allyl bromide was added and the
mixture refluxed overnight. Removal of the ethanol by distillation and
treatment with 25 m1. of water resulted in an insoluble oil which was
extracted into ether. The ether solution was dried over anhydrous
magnesium sulfate and Norite, filtered, and the ether removed. The
resulting oil was shown to be crude starting material by comparison of

the infrared spectra.

Attempted'Preliaration of 2-Benzyl-5-(1-carboxy-
3-buteny_l)tetrazole

 

 

Three grams (0. 0122 mole) of 2-benzyl-5-carboethoxymethyl-
tetrazole was added with shaking to a solution of 0. 29 g. (0. 0122 mole)
of sodium in 50 m1. of absolute ethanol, and the mixture refluxed 15
minutes. A solution of 3. 2 g. (0.025 mole) of allyl bromide in 15 m1. of
ethanol was added dropwise to the refluxing solution. The mixture was
stirred-and refluxed for 3 hours. The reflux condenser was replaced
by a distilling head and 40 m1. of solvent removed. The solvent was
replaced by 50 ml. of 10% sodium hydroxide and the mixture refluxed
for 3 hours. An additional 40 ml. of liquid (b.p. 78-1000C.) was

74

distilled from the flask and replaced by 40 m1. of water. The aqueous
solution was refluxed overnight.
The cooled solution was extracted with ether and the aqueous

layer acidified to pH 2 with concentrated hydrochloric acid. The gummy
precipitate which formed was extracted from the water with ethyl acetate.
The ethyl acetate solution was dried over anhydrous magnesium sulfate,
filtered, and the solvent removed. -Over heating caused some decompo-
sition, so the residual oil was further heated until nomore gas evolution
was noted. Two recrystallizations from methanol yielded solid, melting
point 46-47OC. It was thought that the solid was 2-benzyl—5-(3-butenyl)-
tetrazole, but subsequent debenzylation with sodium in liquid ammonia
yielded only 5-methyltetrazole. This means that the solid was probably

2-benzyl-5-methyltetrazole and that no initial alkylation occurred.

Attempted Preparation of 2-Benzll-5-(1—carboxy-
propyl)tetrazole

 

 

To a solution of sodium ethoxide prepared by dissolving 0.445 g.
(0. 0193 mole) of sodium in 50 ml. of absolute ethyl alcohol was added
4. 76 g. (0. 0193 mole) of 2-benzyl-5-carboethoxymethyltetrazole.
-After gentle warming to complete salt formation, 5.45 g. (0. 050 mole)
of ethyl bromide in 25 ml. of absolute ethanol was added dropwise to the
stirred mixture over an hour period. The reaction was stirred with
gentle warming for 17 hours. Solvent was distilled tora residual
volume of _c_a: 20 ml. Fifty milliliters of 10% sodium hydroxide and
50 m1. of water were added and the mixture was refluxed. After 1 hour,
an additional 10ml. of ethyl alcohol was distilled from the reaction.
The basic solution was refluxed an additional 9 hours, cooled, adjusted
to pH 1 with concentrated hydrochloric acid, and chilled. Filtration-
yielded 4. 18 g.) (99. 5% of theory) of slightly impure 2-benzyl-5-carboxy-

methyltetrazole. Recrystallization from methanol gave product having

75

a smelting point of 144-145. 5°C. with gas evolution. . _ No depression
was noted in a mixture melting point with known 2-benzyl-5-carboxy-
methyltetrazole. Essentially no alkylation occurred with sodium

ethoxide as the base.

Alkylations Attempted in
Sodium Hydride - Ether

Attempted'Preparation of 2-Benzyl-5-(1-carboxy-
3-cyclohexylpropyl)tetrazole

 

 

To a slurry of 0.925 g. (0.0204 mole NaH) of 52. 8% sodium
hydride on mineral oil in 100 ml. of ether (distilled from calcium
hydride) contained in a 300 ml. three necked flask fitted with stirrer
and condenser topped with a drying tube was added 5. 0 g. (0. 0203 mole)
of 2-benzyl-5-carboethoxymethyltetrazole. The mixture was stirred
and refluxed 2 hours. A solution of 4. 78 g. (0.025 mole) of (3- cyclo-
hexylethyl bromide in 20 ml. of dry ether was added dropwise. The
mixture was refluxed an additional 18 hours. One hundred milliliters
of water and 10 m1. of 10% sodium hydroxide was added, the mixture
warmed to drive off ether, and then refluxed 4 hours. The solution
was cooled, extracted three times with ether and acidified to pH 1
.with concentrated hydrochloric acid. The product precipitated as
colorless needles. Filtration and drying yielded 4. 11 g. of solid,
melting point 150-1519C. Recrystallization from aqueous acetone did
not change the melting point. Comparison with a previously prepared
sample showed the solid to be 2-benzyl-5-carboxymethyltetrazole.
This amounted to a 92. 8% recovery of starting material as the acid.

The acid was also converted by debenzylation with sodium in
liquid ammonia to 5-carboxymethyltetrazole as further proof of the 1
structure. . An attempted alkylation using the same procedure with dry

dioxane was equally unsuccessful.

76

Attempted Preparation of 2-Benzylw5-(l-carboxy-
3-methy1butj1)tetrazole

 

 

In a dry 300 m1. three necked flask fitted with condenser with
drying tube and stirrer was placed 0. 895 g- (0. 019 mole NaH) of 52.8%
sodium hydride on mineral oil and covered with 100 m1. of ether freshly
.distilled from calcium hydride. To the stirred mixture was added in
small portions, 4. 25 g. (0. 0173 mole) of 2-benzyl-5«carboethoxymethyl-
tetrazole. The slurry was refluxed for 2 hours. - A solution of 2. 37 g.
(0.0173 mole) of i-butyl bromide in 25 m1. of dry ether was added
dropwise. The mixture was refluxed 6 hours, cooled, and l or 2 small
ice chips added to decompose excess hydride. The reaction mixture
was treated with 100 ml. of water and 10 ml. of 10% sodium hydroxide.
The mixture was warmed to drive off ether and then refluxed overnight.
The solution was cooled, extracted three times with ether, filtered
with Norite and adjusted to pH 1 with concentrated hydrochloric acid.
Cooling, filtration, and recrystallization from aqueous acetone afforded
2.88 g. of 2-benzy1-5-carboxymethyltetrazole as shown by comparison
to a previously prepared sample. This amounts to a 79.5% recovery

of starting material as the acid.

SUMMARY

1. It was found that the methylene group of 5-carboethoxymethyl-
tetrazole would undergo condensation with benzaldehyde, para-nitrofi
and para-methoxy-benzaldehyde in pyridine catalyzed by piperidine.
The products obtained were analogs of monoethyl arylidinemalonates.
The reaction scheme presented was analogous to that for malonate
esters. The conclusion was drawn that the tetrazole ring, while
sufficiently activating to allow reaction, was not as effective as a

carboethoxy group in stabilizing the intermediate methylene anion.

2. Condensations with the same aldehydes and 5-carboxymethyl-
tetrazole were found to occur quite readily. The products obtained were
para-substituted cinnamic acid analogs. It was suggested that the

formation of carbon dioxide facilitated product formation.

3. A series of 5-(2-aryl-l-carboxyviny1)tetrazoles was prepared
from the corresponding esters. In contrast to the malonates, the
saponification was found to go faster and under milder conditions.

This was attributed to the participation of the tetrazole anion in the
removal of the ethoxide group, followed by hydroxyl attack toform the
product. .Also, it was noted that the 5-(2-aryl-1-carboethoxyvinyl)-
tetrazoles were attacked by base at the benzylic position on prolonged
treatment. This behavior was analogous to that of the arylidinemalonates,
and was related to the resonance effects of the p_a_r_a_-substituent on the

aromatic ring .

4. Decarboxylation of several 5-(2-aryl-1-carboxyvinyl)tetra-
zoles was carried out in diethylene glycol producing para-substituted

cinnamic acids. As was noted by other workers, the compounds

77

78

decarboxylated in solution at a temperature below their melting point.
In these respects, the tetrazole analogs of the arylidinemalonic acids
appear to be quite similar. Two mechanisms were proposed to account
for the product formation, however, it was felt that additional work on
the mechanism should be done before a direct comparison of the two

series can be made.

5. The base catalyzed proton removal from 2-benzy1-5-carbo-
ethoxymethyltetrazole was studied. No alkylation was observed in
ethanol in the presence of sodium ethoxide and it was concluded that the
2-benzyl-5-carboethoxymethyltetrazole was not sufficiently acidic to
undergo anion formation in this medium. Sodium hydride would form
the sodio derivative analogous to diethyl malonate, but the anion formed
did not appear to be as reactive. Alkylation was effected only with the
more reactive benzyl and allyl halides. Attempts to alkylate with

primary alkyl halides were unsuccessful.

6. Since it was found that catalytic removal (Hz - PdO or‘ Pd on
charcoal) of the benzyl group from the 2 position of a tetrazole ring
was very slow, sodium in liquid ammonia was used as a debenzyl-
ating reagent. This was very successful with several 2-benzyl-5-
(2-aryl-1-carboxyethyl)tetrazoles. The high yields and ease of reaction
suggest it as a general method for removal of Z-benzyl blocking groups

on the tetrazole ring.

7. The preparation of 5-(2-phenylethyl)tetrazole from 2-benzyl-
5-carboethoxymethyltetrazole by means of alkylation with benzyl
bromide, saponification, debenzylation and decarboxylation was
described. It was suggested that this would serve as a method of
preparing 5-(2-arylethyl)tetrazoles with the limitation that the sub--
stituents on the aryl ring must be stable toward reduction by sodium

in liquid ammonia.

79

8. The preparation of several new tetrazole compounds was
described in detail in the experimental section and their infrared

spectra are shown in Appendix 1.

H
o

sooouomdxuw

H
O

11.

12..

13.
140
15.

16.
17.

18.

19.
20.

21.
.22.

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Nakanishi,- K. ,~ "Infrared Absorption Spectroscopy - Practical,- "
HOlden-Day, Inc. , San-Francisco: 1962, pp. 17-57.

Otting,~W., Chem. Ber., _8_9, 2887 (1956).
Wojcik, B., and H. Adkins, J. Am. Chem. Soc., 26, 2424 (1934).

Allen,~ C. , and F. Spangler,- "Organic Syntheses, " é,
John Wiley and Sons, Inc. , - New York: 1945, p. 42.

Martin,.C., A. Schepartz, and B. Daubert, J- Am. Chem. Soc.,
19, 2601 (1948).

45.

46..
47..

48.
49.

50.;

51.
52.
53.

54.
55.
56.
57.
58.
59.

60..

61.

62..

63.
64.
65.
66.

67.

68.

69.

70..

71.

82

Galat, A., J.-Am. Chem. Soc., 68, 377(1946).

Cope, A., J.~Am. Chem. Soc., 52, 2327 (1937).

Pratt, E., and E. Werble, J. Am. Chem. Soc., 12, 4638* (1950).
Ogata, Y., and M. Tsuchida, J. Am. Chem. Soc., _8_1_, 2092(1959).
Patai, S., and J. Zabicky, J. Chem. Soc., 2030 (1960).

Gault,~H., and A. Roesch, Bull. soc. chim. France, (5) _4, 1411

Roesch, A., ibid., p. 1643.
Hauser,.C., and D. Breslow, J. Am. Chem. Soc., 61, 743 (1939).

Patai, S., J. Pfeffermann, and Z. Rozer, J. Am. Chem. Soc.,
16, 3446 (1954).

Corey, E., J. Am. Chem. Soc., _7_4_:_, 5897 (1952).
Knoevenagel, E., Ber., _3_1_, 2596 (1898).

Claisen, L., and L. Crismer, Ann., _2_1_8, 131 (1883).
Meyerberg, A., Ber., 28, 786 (1895).

-Scheiber,‘ J., and F. Meisel, Ber., :48, 238 (1915).

Nakanishi, 1oc. c_:1_t., pp. 42-44.

Streitwieser, Jr. , A. ,- "Solvolytic Displacement Reactions,- "
McGraw-Hill Book Company, Inc. , New York: 1962, p. 19.

Noyce, D., and M. Jorgenson, J. Am. Chem. Soc., _8_4_, 4312 (1962).
Scott, F., and M. Holland, Proc. Chem. Soc., 106 (1962).
Nakanishi, L02; git” p. 24.

Norris, J., and H. Tucker, J. Am. Chem. Soc., _5_5, 4697 (1933).
Blicke, F., and R. Feldkamp, J. Am.-Chem. Soc., 99, 1087 (1944).

von E. Doering, W., and V.-Pasternack, J. Am. Chem- Soc.,
17:, 143 (1950).

Wagner. R., and H., Zook,- "Synthetic Organic Chemistry,"
John Wiley and Sons, Inc. ,~ New’York: 1953, pp. 426-429.

Gould, E.,» "Mechanism and-Structure in Organic Chemistry,- "
Henry Holt and Company, New York: 1959, p. 274.

Solway, S., and F. LaForge, J. Am- Chem. Soc., 62, 2677 (1947).
Green, 'N., and F. LaForge, J. Am. Chem. Soc., _7_0_, 2287 (1948).

.Schaal, R., and C. Jacquinot-Vermesse,Compt. rend., 249, 2201
. (1959).

APPENDICES

83

APPENDIX I

(Infrared Spectra)
(Nujol Mulls)

84

85

an an on e m e

 

 

 

 

 

 

.oHONmSouanuoéxopumU .. m

 

 

 

 

 

 

 

 

 

 

 

.H 0.“:th

 

 

 

v—

 

 

 

86

S 2 2. 2 S

1 0‘

 

 

 

 

_ m _J, _4

. oHonmauofiuguoesmonofioonumo..m 139.com 1N

 

 

 

 

.N ohswflrm

 

 

 

 

 

 

 

 

 

 

87

a;

CH

 

 

 

 

 

 

 

. ofionmnpofiuguogxoaumnou m tandem 1N

.m oudwfim

 

 

 

 

 

 

 

 

 

 

 

 

 

88

3 .2 S S o m e c m a. an

 

 

.ofioumuuoiacgfwcogmtm1>X0£poonum01 H v ..m .w onswfih

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

89

2 .2 2 S, e m e, e. m

 

 

 

 

.oHonmSoéacgSumcofimunxofioanytNuswxofioonumUtLtm .m onsmfm

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

90

3 OH m m N. o m

 

 

 

.ofioumboomH>cfl>3>co£moufictmnvtNLAxoauoonumUtltm .0 oufimfim

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ma Ma 3 0H 0 m N. o m

 

91

 

_ _ _ _ _ _ _ _ _

.odoumboiadgfmcoxmnmt>xonum0131m .m. oudmfim _

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

‘92

Ma.

Ma dd 0H m m h

 

 

 

 

 

. oHoumh—oumgaggnoamsbxonuofilmw t N LCSQHMU 1:1 m

a

 

 

 

 

 

 

 

 

 

 

 

 

 

.w 0&9th

 

 

 

 

 

 

 

 

 

 

 

93

NH

2 2 a m e e

 

 

. oHoumhuoaHTndgAaconmoufic 13....N nunxonumnuu H a t m . m ousmfm

 

 

 

 

 

 

 

 

 

94

NH

2 OH o

 

 

 

 

 

 

. oHoNdH—oiacggnosmt NV 1 m

 

 

 

 

 

.2 enemas

 

 

 

 

 

 

 

 

95

 

 

 

.o ouch o in > sacofienxofio m o Hm
H u a: w 3 2.. TE m
.. .2 u Tm

 

 

 

 

 

 

 

 

 

96

Ma NH 2 on o w

 

 

 

 

 

_ x m _ x

. oaonmuuoumgcgSeasonamouuwztmuv in; t m . NH euswwh

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

97

 

2
_ my 3 0.. o w h
b
_ _ _ _ _ _ _ ..
cumup>£osoe oHonmSoiacfiwgnonamlmv1m .2 ohdm
Tm

 

 

 

m.

 

 

 

 

 

 

 

 

 

 

 

2 2 2 a m e m

 

98
S

 

 

 

 

 

 

 

 

 

 

.oHoumSoufisfifivacogmtm 13339.net H v 1m tandem 1N .2: 0.“:th

 

 

 

 

 

 

 

 

 

 

99

a;

 

 

 

 

 

. oHonuuoaTeEuo Afiuwconmonogotmv 1N1>xoonemot Z1 mtgucom 1N . mg 0.19th

 

 

 

 

 

 

 

 

 

 

 

 

 

 

100

 

E 2 .2 2 8 o m e 1..
.oHoumSofiinnousntm1333.39.Ctmtfmudom 1N A: 0.32th

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

101

¢~

NH

1
2 0H 0 w m. m m w

 

.oHoumHuoigfioTwcoCQtN{$33th.4vum .NH 0.2”th

 

 

 

 

 

 

 

 

 

 

 

APPENDIX 11

' (Attempted Preparations of
2, 5-Disubstituted Tetrazoles)

102

103

Attempted Preparation of 2, 5-Diphenyltetrazole

 

Three and five-hundredths grams (0. 052 mole) of benzamide was
suspended in 20 ml. of benzene and added together with an additional
20 ml. of benzene to a solution of 3. 0 g. (0. 0252 mole) of phenyl azide
in 20 ml. of benzene contained in-a 250ml. flask equipped with stirrer
and reflux condenser. The mixture was cooled in an ice bath-and with
stirring, 5.48 g. (0.0252 mole) of phosphorous pentachloride was
added. ~ The ice bath was removed and with stirring, the contents were
allowed to warm to room temperature. The reaction mixture was re-
fluxed 15 hours. -After slight cooling the brown-black solution was con-
centrated under an air jet to approximately. 20 ml. The residue was
extracted three times with a total of 45 m1. of water. The water
extracts were shownto contain only inorganic salts. The benzene
solution after drying over anhydrous magnesium sulfate and evaporation
yielded a solid-liquid residue which was shown to be unchanged

benzamide and phenyl azide.

Attempted Preparation of 2, 5-Diphenyltetrazole

 

Benzamide, 2. 2 g- (0.0168 mole) and 50 m1. of benzene‘were
placed in a 250 m1. flask fitted with reflux condenser, stirrer, and
dr0pping funnel. With stirring and cooling, 2. 0 g. (0. 0168 -mole) of
thionyl chloride in 20 ml. of benzene was added dropwise. The pale
yellow solution was refluxed 30 minutes and 2. 0 g. (0.0168 mole). of
phenyl azide in 15 ml. of benzene was added. A solution of 4. 2 g.
(0.0177 mole) of pyridine in35 ml. of benzene was added dropwise and
.the mixture refluxed 22 hours. The resulting benzene solution was
evaporated, resulting in an oil consisting mainly of benzonitrile..
.Dilution of this oil with methyl alcohol afforded no precipitate which

could be identified as 2,.5-diphenyltetrazole.

104

Attempted Preparation of 2, 5=Diphenyltetrazole

 

To a sodium ethoxide solution prepared by dissolving 0. 76 g.
(0. 033 mole) of sodium metal in 20 ml. of absolute ethanol was added
3. 3 g. (0. 032 mole) of benzonitrile and 3.8 g. (0.0319 mole) of phenyl
azide. The mixture was refluxed 48 hours, and then poured into 100
ml. of water. The aqueous layer was separated, extracted three
times with a total of 80 m1. of ether. The ether extracts were com-
bined with the initial layer, dried over magnesium sulfate and evaporated
to give a small amount of yellow oil in which crystals formed. This
mixture was dissolved in hot carbon tetrachloride and filtered through
Norite. On cooling the solution yielded crystals, melting point 123-
124°C.

The water layer was evaporated to dryness, boiled withethyl
alcohol, filtered and the ethyl alcohol removed. The residue was
recrystallized from carbon tetrachloride to yield solid, melting point
119-1200C. A mixture melting point of the two above materials was
120-1220C. , while a mixture melting point with benzoic acid was

depressed.

Reaction of Benzonitrile with Strong Base -
Preparation of Benzamide

 

 

In an effort to determine the identity of the product from the
previous reaction, 1. 2 g. (0.052 mole) of sodium metal was dissolved
in 40 ml. of absolute ethanol and 5. 15 g. (0. 05 mole) of benzonitrile
added together with 10 ml. of ethanol. The mixture was refluxed over-
night during which time a quantity of white solid precipitated. .A portion
of the solid after filtration was ignited leaving a residue. ‘The remaining
material on reaction with water gave a compound identical with that
from the previous reaction as shown by infrared spectra, melting point

and mixture melting point. The compound was shown to be benzamide

105

by comparison-withanauthentic sample. Therefore in strong anhydrous
base, the predominate reaction of the nitrile appears to be, in both

cases, conversion to the'N-sodiobenzimido ethyl ester which on reaction

with water forms benzamide.

CszO' '=C N- Na+ 03C; "NI'iz

om» o a o

CHLmSIRY LIBRARY

 

 

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