kd- (Ix,

 

M ICHmA N STN‘F U .‘VJI'VTRSJTY

m

 

TV? SYVTHSSIS 0F DFVIV’TIVSS OF

I O I

B-AVINO-h-n,1,2,u-TRIA20LE

BY

Emerson A. Cooper

A THESIS

Submitted to the School for Advanced Graduate Studies of
Michigan State University of Agriculture and
Applied Science in partial fulfillment of

the requirements for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1959

a

To Ia-‘Earjorie, Roslyn and Stephen

11

A c K N o W L R D G M E N T

I am indebted to Dr. Robert V. Herbst
for his generous and invaluable counsel.
His sage suggestions in the course of
this investigation were indeed a source
of much encouragement and inspiration.

I am also thankful for the support given
me by Oukwood College and the Danforth

Foundation.

111

TWP svvmnssts or U”RIVPTIV?S 0?

O o o

3-AVTKC-L-U,1,2,L-TRIAZOLF

Emerson A. COOper

Submitted to the School for Advanced Graduate Studies of
Michigan State University of Agriculture and
Applied Science in partial fulfillment of

the requirements for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

Year ‘ 1959

’ ' -7 a/ ' .
Approved /<3;{flgqf2422 /F£f7:4gL..'

‘ \

0... "_~- .—I»-. 4-

"‘-A.

I‘-‘4

7

It has been observed that rearrangements some-
times occur in certain heterocyclic systems containing
the N-C-N arrangement where one of the nitrogens is an
amino group. Dimroth (1) has described the thermal re-
arrangement of a number of l-phenyl-S-emino-, and 1-
phenyl-S-methylauino-l,2,3-triazoles to 5-phenylamino-,
and l-methyl-S—phenylemino-l,2,3-triazoles. Lieber'gt g;
(2.3) have investigated the rearrangement of 5-smino-
1.2;3ctriszoles. The rearrangement of S-alkylaminotetra—
soles to l-alkyl-S-eminotetrazoles has also been studied
(h).

The original purpose of this investigation was
to determine whether 3-amino-h-phenyl-l,2,h—triasole and
its homologs would undergo a similar rearrangement.

Aiter preliminary experimentation indicated the absence
of such rearrangement in the 1,2,h-triazole series;
attention was then directed to the synthesis of three
different series of compounds having varied substituents
in the fifth position of 3-amino-h-pheny1-k-H,1,2‘4-
triazole.

B‘Amino~h-H;l,2,h-triazole is presently of
considerable interest because of its remarkable effect
on the physiological processes of plants and animals.

It is able to inhibit the synthesis of chlorOphylls and
carotenoids in plants (5); it reduces the level of hepatic

and renal catalase activity in rats thus producing an

vi

effect similar to that observed in animals having malig-
nant growth (6); and it is also capable of lowering the
activity of’auaminolevulinic acid dehydrase, an enzyme
that catalyzes the conversion of 3-aminolevulinic acid

to porphobilinogen (6). The last effect is also produced
by tumors.

Since stuiies relating phytotoxicity to chemical
structure indicate the importance of chloro, methyl,
methoxy and phenoxy groups on herbicides (7), it was
decided to prepare a representative group of substituted
phenoxymethyltriazoles and some thiophenoxymethyltriasoles.

A number of dialkylaminomethyltriasoles was also
prepared since the presence of two different heterocyclic
nuclei in some, and the existence of two basic centers in
all could possibly produce anesthetic action as well as
some other useful physiological effect. It is of interest
to note that B-ethyloh-cyclohexyl-l,2,h-triasole is
similar to adrenaline in some of its actions on the body.
It has been found to stimulate the heart and respiratory
center (8).

The starting material for these syntheses,
phenylaminoguanidinium bisulfate, was first prepared in
the course of this work. This compound was allowed to
react with a number of aliphatic acids (foreic, acetic,
glycolic; lactic and phenoxyacetic acid) to form the

corresponding 3-amino-t-phenyl-5-alkyl-l,2,h-triasoles.

In

’.

vii

n procedure was perfected ,or the conversion
of 3oamino-h-phenyl-S-hydroxymethyl-l,2,h-triezole to
the hydrochloride of 3-amino-h-phenyl~5~Chlorumethyl-
1,2,h-triazole in good yield.

The 5-dialhylaminomethyltriazoles were prepared
by allowing the hydrochloride of 3-anino-h-phenyl-5-chloro-
methyl-1,2,4-triazole to react with an excess of each of
the following amines: piperidine, morpholine, pyrrolidine,
dimethylamine, diethylamine, diallylamine, di-n-prOpyl-
amine, di-isoprOpylamine, di-n-butylamine and di-isobutyl-
amine.

The 5-phenoxymethyl-, and the S-thiOphenoxy-
methyltriazoles were prepared by allowing the hydrochloride
of 3-amino-h-phenyl-S-chloromethyl-l,2,L-triazole to react
with an excess of the sodium salt of each of the following
phenols and thiophenols: phenol, p-bromOphenol, p-chloro~
phenol, p-methoxyphenol, p-cresol, o‘erescl, m-cresol,
thiophenol and p-chlorothiOphenol. V

Phenylthiourea derivatives of most of these new
aminotriazoles were prepared. In a few cases, a number of

the hydrochlorides and acetyl derivatives were prepared.

.
. (
PI ‘ ' ‘
. -,
. .
v.
. - a
- _- u
. \
’ .
l “‘ ‘ ‘
. . ' '
. ,
I L '
7 e
v
1 I I ‘ r
..
,
. I
I N
.
. w ~ I
p l > e
.I ‘ .
U
n .
O

,,,—

References

(1) Dimroth, Ann. Chem., fiéfi, 183 (1909)

 

(2) Liobor Chao,T .3. and Rao, C.N.R., J. Org. Chem.,
25,E 65a (1957

(3) Lieber, E.,M

.N. R. and Chao, T. 8., J. Am. Chem.
Soc” 12.0§962(157)
(h) Garbrccht W. L. and )Herbst, R.M., J. Org. Chem.,
_,i269 (1953)

(5) Miller, c.s. and Hall, w.c., Weeds, 2, 301 (1957)
(6) Tschudy D.P. and Collins, A., Science, 139, 168
(1957)

(7) Shaw, W.A. and Swanson, C.R., Weeds,‘g, #3 (1953)
(a) Lewenetein, M.J., u. 3. Pat., 2,683,106 (195A)

'Q

{0

-~

v.-.

0‘

TABLE OF CONTENTS

PAGE
I INTRODUCTION 1
II HIST RICAL 3
III DISC SSION 5
Nomenclature and Properties 5
Phenylaminoguenidinium Bisulfate 6
3¢Aeino-L-phenyl-5ualkyl-1,2,h-triazoles 7

3oAmino-h-phenyl-S-chloromethyl-l,2,L-triazole
Hydrochloride 10

Dialkyleminomethyltriazolee ll

Phenoxymethyl- and thiOphenoxymethyltriazoles 15

Phenylthioureas of Aminotriazoles 13
Biological Preperties of Aminotriazoles 20
IV EXPLRIKLNIAL 2h
Phenylaminoguenidinium Bisulfete 24
3-Amino-h-phenyl-h-H,l,2,L-triazole 25
3—Amino-h—phenyl-4-H,l,2,h-triazole
Hydrochloride 26
B-Acetamido-h-phenyl-h-H,l,2,4-triazole 27

3oAmino-h-phenyl-5-methyl~h-H,l,2,h-triazole 27
3-Anino-h-phenyl-S-methyl-h-H,l,2,h-triazole

Hydrochloride 28
1'(h"Ph9nY1'5'“methyl-h'-H.1'.2',L'-triazolyl-
c 3')-3-phenylthiourea 29

3-Amino-h-phenyl-5~hydroxymethyl-h-H,l,2,h-
triezole 29

3-Amino-h-phenyl-5-hydroxymethyl-h-H,l,2,4-
triezole Hydrochloride 30

B-Amino-h-phenyl-S-(iphydroxyethyl)-h-H,l,2,h-
triazole 30

ix

t. .
t

‘ I
r .
I' c
.‘ . r. (- .‘ .
. ) v. . .
\ V
. A . ,
. (
‘0 )' pl 5'
, J t ’ _
. .
. - .
, 1
. .
,
) u
( , . (
, l
n. ,. 1 .1
l v - ‘ ’
S s
v “ C ‘ (
‘ . ‘ ~ ,
. \
‘ . .
a . ~- 0 n u
_, x. y A . o —
. . .
r ' ‘
, ’ ' ‘ .4. 4‘. ' 5, I a
a ' Q ' o r , . - x . ~
, .
.n ' .a I -- u, - '- N ‘
r 9: .-
-.
'
. , I f. — t
. ‘ l . . .A _' ' n. ‘
i ’ ' '
§ v
. l’ >)
n! .s
,' n' ’
.J. -V ' ‘ I ' ‘l .3
. p. -
t 5- s . r‘ ‘J.
. . 1
1 . v- e '
O . .
.
. ~ , , , ,
i 4‘ “I

O. L“ ‘ -1

3-Acetemido-bnphenyl-5-QX-ecetoxyethyl)-

h-H,l,2,h~triazole 3 l
3oAmino-h—phenyl-S~phenoxymethyl-h-H,1,2,h-
triazole 31
3oAmino~h-phenyl-S-phenoxymethyl-h-H,l,2,h-
triazole Hydrochloride 32
1-(L'oPhenyl-S'ophenoxymethyl-h'~H,1‘,2',h'-
triazolyl-B')o3-phenylthi urea 32
3-Amino-h-phenyl-5-chloromethyl-h-H,1,2,h-
triazole Hydrochloride 32
3«Amino-h-phenyl-B-piperidinomethyl—h-H,1,2,h-
triazole 33
l-(h'-Pheny1-S'-piperidinomethyl-A'-H,1',2',h'-
triazolyl—B')-3-phenylthiourea 3b
3-Amino-h-phenyl-5-morpholinomethyl-A-H,l,2,L-
triazole 35
1-(A'-?henyl-5'-morpholinomethyl-h'-H,l’,2',4'-
triazolyl-B')-3-phenylthiourea 36

3-Amino-h-phenyl-S-pyrrolidinomethyl-h-H,l,2,h-
triazole

1-(k'-Phenyl-5'-pyrrolidinomethyl-h'~H,1',2',4'-

triazolyl-B')-3-phenylthiouree 37
3-Amino~h-phenyl-S-dimethylaminomethyl-h-H,-

l,2,h-triazole 38
1-(h'-Phenyl-§'-dimethyleminomethyl-b'oh,-

l',2',h'ctr1azolyl-3')-3-phenylthiouree 39

3-Amino-L-phenyl-5-diethylaminomethyl-h-H,1,2,h-
triazole 3

1~(L'-Phenyl-5'-diethylaminomethyl-h'~H,-
l',2', '-triczolyl-3')-3-phenylthiourea ho

B-Amino-h-phenyl-S-diallylaminomethyl-h-H,1,2,4-
triezole L1

1-(h'-Phenyl-5’-diallylaminomethyl-h'-H,-
l',2?,h'-triazolyl-3')-3-phenylthiourea L1

W.

X.

0'

‘ .
-a -
l . I) '
, -
v
_; i.
.
I - .
v
e... ‘ l
t t
‘1. H ‘ ‘ '
3
n. , < ' .
‘ )
v) :4 -
I ,
. u
,- v-

W- 40-:

db

0 . .1
e v-~
(‘-
’ .
‘ ,
C
. .-
s ‘ 9
. no
.
do
, 1
5 '-
l I
o g.
n
V, -'
1. .‘
‘ . I
.
.
v n 1
I. "
, .
_ 1
.,
_ .4
~ 1
‘1.
C ‘ ‘
‘ " ~v

0V

.6

DU

«-
‘.
l
k
|
.
o

3-(m3no‘h‘phenv1-5-di-n-pronylaminomethyl-
Len,1,2,h-triazole

l-(h'ophenVI-S'adi-napropylaninomethyl-h'-
H,l',2',h'~triazolyl-3' ~3-phenylthiouree

3-Amino-L-phenyl—5-di-isoprOpyleminomethyl-

1-(h'-Phenyl-5'-di-isonro ylamincmethyl.4'-
H,l',2',h’-triazolyl-3’ ~3-phenylthiourea

3-Amino-h-phenyl-5udi-n-butylnminomethyl-

1*(h'-Fheny1-5'-dicn-butylaminomethyl-L'c
H,1‘,2',L'-triazolyl-3')-3-phenylthiourea

3-Amino-h-phenyl-5-di-isobutylaminomethyle
h~H,l,2,h-triazole

l-(h'-Phenyl-5'-*i-isobutVlaminomethyl-h'o
H,l',2',h'-triazolyl-3')-3-phenylthiourea

3~fimin0~h-phenyl-5-phenoxymethyl-h-H,l,2,4-
triezole

3-Amino-h~phenyl-5-(p-bromophenoxymethyl)-

l-[A'-Phenyl-5'-(p-brom0phenoxymethyl)-4'-
H,l',2',h'ntriezolyl-BIJ-B-phenylthiouree

3-Amino~h-phenyl-5-(p-chloroyhenoxymethyl)-
h-H,l,2,h-triazole

l-Eh'-Phenyl-5'-(p-chlorophenoxymethyl)~h'-
H,l',2',h'~triezolyl-3'J-B—phenylthiourea

B-Rmino-h-p?enyl-5-(p-methoxyphenoxymethyl)-

l-Eh'-Pheny1-5'-(p-methoxyphenoxymethyl)-h'-
H,1',2',h'-triezolyl-3'1-3-phenylthiourea

3-3mino-L-phenyl-5-(p-methylphenoxymcthyl)-

l-EL'-Phenyl-5'-(p-methylphenoxymethyl)-h'-
H,l',2',h'-triazolyl—3{j—B-phenylthiourea

3-hnino-h~phenyl-5-(o-methylphenoxymethyl)-
L-H,l,2,h-triaeole

#2

#3

AB

Lb

Lb

#5

A6

#6

L7

#8

#9

50

50

51

52

52

53

xi 1

1-Chv-vhenv1-5i-fo~methv1phenoxvmethvl)-h'-

F,l',2',L'-triezolvl-3KJ-B-phenvlthiourea 5h
3-Am5noghephenvl-5-(m—methvlnhenorymethvl)-
h-H,l,2,h-triazole 5L
1_[17-phpnv1-5?-(m.methv1nhenoxvccthvl)-h’-
n,1',2',Lv-triazoly1-3'J-B-Dhenylthiourea 55
3-Amino-L~phenyl-5-thiophenoxymethyl-b-H,l,2,h-
triazole 55
l~(h'-?henyl-5'-thioghenoxymethyl-4'-H,-
1'92'94'“tria201flr3')-3-phenylthiourea 55
B-Amino-h-phenyl-5-(p-chlorothiophenoxymethyl)-
h-H,l,2,h-trieeole 57
l-CL'uPhenyl-S’-(p—chlorothiOphenoxymethylJ-h'-
H,l',2',L'-triazolyl-3'J-B-pheng thiouree 57
summed? 59

Ra‘zizxczs CITED 60

r".

"

l ‘ ‘
.
J ‘
D ‘ '
\
.. ’ I I
1
O Av .
-
u ‘r J
r I
,- F-
‘4
,
v
Q ll
.
> .

a ‘ ‘ ' . \
, ‘0 ~ '8
.
‘ r ‘ ..
I
.. l
. ‘ '\
f
‘ _ ,
l- 'k . I ‘1 I
n F ‘
(
. .
o ' - .-
O 9- fl .
n x
. l
4 ‘ . r -
l t .
'
n ‘ ’
‘(
.
~
9 . P
or v.
1 I ‘
1 ;~
.
-,
. 0
d" - no
> 7 v ‘ A v ‘ ‘J
. I ‘
r - .
v .
I
y .
, ‘ . l
‘ c v

lDtFOIQEtiCH

It has been obserVed that rearrangements some-
times occur in certain heterocyclic systems containing
the N-C-N arrangement where one of the nitrogens is an
amino group. Dimroth (1) has described the thermal re-
arrenrement of a number of l-phenyl-S-amino-, and l-phenyl-
5-methylemino-l,2,B-triczoles (I) to 5-phenylemino-, and

lumethyl-S-phenylamino-l,2,3-triazoles (II).

CéHSOf-————fNUR' C6H5NHofi—————?R'
N CR Ru N
\/ \/

N N
I II

Lieber et a1 (2 3) have investigated the rearrangement of
-. ~ ' J ,

S-amino-l,2,3-triazoles. The rearrangement of 5-slkyl-

aminotetrazoles to l-alkyl-S-aninotctrazoles has also

been studied (4).

 

 

)1.chst Ion-“.0 NH
l H .3 = Aryl ( H I
N\ /N 1: fi' N\ //N

Hzrilkyl ,
\N N/

The original purpose of this investigation was
to determine whether B-amino-h-phenyl-l,2,#-triazole and
its homologs would undergo a similar rearrangement. After
preliminery experimentrtion indicated the absence of such
rearrangement in the 1,2,h-triazole series, attention was
then directed to the synthesis of three different series

1

A-
i .
. ~4-
.‘
I .
- ..
.
i ..
at
4
- 7 .e - -- .7 -
~
\
, .o.— v :3. . l'
. ‘-
.- . ‘ *
" l
.
o
r
1
~.. -
’ O ‘
~h
I ' n‘

' s
. _ ‘v
---- “~ . 9." p - ~ . - -‘
.
' f
' v r 1
- - o.
‘ .
i ,
o ,
I

.
h .
.
‘ ~ -uA . ,
. , I
- «' .\‘..
._. ... ..
“C ' I
.
n.
" 9 '
,
.
‘
.
‘ _
‘
L , l A.

2.

of comnnunds having varied substituents in the fifth
position of 3-anino-h~phenyl-4-H,l,2,h-triazole.
3-Amino-h-H,l,2,A-triazole is presently of Count
siderable interest because of its remarkable effect on
the physiological processes of plants and animals. It is
able to inhibit the synthesis of chlorophylls and carote-
noids in plants (5); it reduces the level of hepatic and
renal catalase activity in rats thus producing an effect
similar to that observed in animals having malignant
growth (6); and it is also capable of lowering the activiV’
of S-aminolevulinic acid dehydrase, an enzyme that cata~
lyzes the conversion of S—aminolevulinic acid to porpho-
bilinogen (6). The last effect is also produced by tumors.

Since stuiies relating phytotoxicity to chemical
structure indicate the importance of chloro, methyl,
methoxy and phenoxy groups in herbicides (7), a represen-
tative group of substituted phenoxymethyltriszoles was
prepared.

A number of dialkylaninomethyltriasoles was also
prepared since the presence of tro different heterocyclic
nuclei in some, and the existence of two basic centers in
all could possibly produce anesthetic action as well as
some other useful physiological effect. It is of interest
to note that 3-ethyl-L-cyclohexyl-l,2,4-triasole is simi-
lar to adrenaline in some of its actions on the body. It
has been found to stimulate the heart and respiratory

center (8).

pfi

3.

Pistorical . '

The first derivatives of 1, 2 ,h-triezole were
orepnred by “ladin (9) in 1885. ix years later, in 1891,
Bledin (10) and findreocci (11), working indenendently, syn—
thesized the parent compound, 1,2,h-triasole. In the same
year, Thiele (12) discovered the first general method of
preparing derivatives of 3-amino-l,2,L-triasole. He found
that aminoguanidine reacts with acetic acid to form
3-amino-5-methyl-l,2,h-triazole. Later, Thiele and Manchot
(13) showed the general nature of this reaction by prepar-
ing 3-amino-l,2,h-triazole from aminoguanidine and formic
acid; and 3~amino~l,2,h-triazole-S-carboxylic acid from
aminoguanidine and oxalic acid. This method has been
termed the dehydration of acyl derivatives of aminoguani-
dines.

Some other methods that have been employed in
the synthesis of derivatives of B-amino-l,2,h-triazole
are summarized below:

(1) The elimination of methylmercaptan from an

S-methyl ether of phenylguany'lthiosemiCarbazide (1h):

 

.H
C6H5-NH )-30H3 06H5.N cuaz
-. “—z‘-* . - .
HI~I=C hd Hzl'vC N + 011333
N N
H

‘

(2) The fusion of a diar~iue of hydrazine-N:N:'

dithiodicarboxylic acid (15):

 

k,..

(16):

h.
Hgfl-g-HH-NH-B-th H4————fisa

A ,Hsz\ N

n}
H

(3) Reaction of dicyandiamide with hydrazine

NH————caH2 ' caaz
| I) -F ”23% H
CH NH . , [{2th N
\\a//
H

A number of reviews on the chemistry of 1,2,h-triazoles

are available (17,18,19,20).

5.

Discussion
Womenclature and Properties

The nomenclature used in the discussion of deri-

vatives of Boamino-L-phenvl-h-H,1,2,h-triasole in this

O

thesis, is based upon the following formulas for this

compound:

 

 

(1+) (3) (1+) (3)
06H50T CNHZ C6H50T :NH
(5) H, J (2) (5) Ht NH (2)

. \/
(l) (l)

A survey of the literature shows that amino-
triazoles exhibit many of the properties of aromatic
amines. However, they also react both as weak bases and
weak acids as is shown by the formation of hydrochlorides,
nitrates, and picrates on the one hand, and of metal salts
on the other. They are quite stable toward oxidizing
agents, forming only azo derivatives.) They diazotize to
form diasonium salts which can couple with phenols and
amines. These diazonium salts can be reduced to give 0-
hydrazino~l,2,h-triasoles and can react with hydrogen
halides to form C-helogeno-l,2,h-triazoles (21). C-methyl
groups can be oxidized to carboxyl groups, and N-phenyl
groups can be oxidatively removed after nitration and
reduction. The amino group can also react with aldehyde:

to form condensation products (22).

——...‘-.

4 ‘.|
l
, .7
J
K

_. x
l.-

o r

‘

. I

F.

"C..A

.6.

Phenylsminonuanidinium Bisulfate

Phenvlsminosuanidinium bisulfete was an impor-
tant intermediate in the synthesis of various derivatives
of é-amino-h-nhenvl-1,2,h-triasole. It was prepared from
scmethvl phenvlisothiourea hydriodide by the method used
by Kirsten and qmith (23) to prepare:x-alkyl-K-aminogua-
niuines. Kirsten and Smith were unsuccessful in obtain-
ing phenylaminoguaniiine, but Finnegan 33's; (2L) have
prepared the hydriodide. The bisulfate was first pre-
pared in the course of this investigation since the
hydriodide was found to be unsuitable for the synthesis
of 3-amino-l,2,h-triazoles. The following sequence of

reactions illustrates the method:

8 “CH

06H5-I-:H-t-I==§a2 + CH3I——906H§-NH-§m%§ I‘

"(221351-312

C6H5nhT H_E:3 ’M :12 I + N2} {Eh—90615-NH-u-1 {-IQH2 I
N32

(361-15-r3n-d-rzs-1xzsg I’+ Aggsoz, + stoh—+

rr+
T11

06:515-r‘xm-Cas-uu2 use;
The method of Finnegan, Henry and Lieher (2A)
was employed in preparing the S-methyl phenylisothiourea
hydriodide. An alcoholic solution of the isothiourea was
obtained by treating a slurry of phenylthiourea in alcohol
at 5° C. with methyl iodide and then permitting the reac-
tion to go to completion at room t nperature. The second

reaction was carried out without isolating the isothiourea.

 

 

J .
I. '
, _ .
.
n l ' '
O
1
.
, , . .
, i .« .0 '
, .—
Q
t .
-.. o
14..-
. A
v , ‘ t.. _
u' ‘ ,‘
7 ....i
r . a 4- ~ ..
' '1
.
.u..._._...-.u - . .
.
a. .
. n u ._
.
I
\ r , l
‘ ,
. a ,
7 .
.
.~ ,r .
. .
e v
. .
« » o
_, A

..

A.
‘01
_
n

 

a-ox-

7.

In this reaction, the S-methyl phenylisothiourea reacts
with hydrazine to form phenylaminoguanidinium iodide and
methyl mercaptan. In the final reaction, the phenylamino-
guanidinium iodide is converted to the bisulfate by a
metatheticel reaction with silver sulfate in the presence

of sulfuric acid.

3;Amino-t-phenyl~5-alhyl-14249-triazoles

The method used in the synthesis of these com~
pounds is basically the one discovered by Thiele (12) in
1891. He observed that aminoguanidine reacts with acetic
acid to form acetylaminoguanidine which on warming or
treatment with alkali loses a molecule of water and

cyclizes to form an inner anhydro base:

 

 

H 2N-———-—(') : NH I) C'Izh’H HI‘; fins 2
cs33 as cn3c NH CH3C N
\I‘JH/ r 1 \N/

Thiele and Heidenreich (25) found that this
substance had the properties of an acid and that on oxi-
dation an azomethyltriazole was formed; later work showed
that an amino group capable of diacotization was present
(21). Thiele and fianchot (13) showed the general nature
of this reaction by preparing 3-amino-l,2,h-triazole from
aminoguanidine and formic acid, and 3-amino-l,2,h-triazole-

S-carboxylic acid from aminotuanidine and oxalic acid.

8..

Reilly and Kadden (26) have prepared the corresponding
5-ethyl-, 5-i80propyl-, and S-isobutylaminotriazoles; and
Reilly and Druam (22) have prepared the 3-amino-5—n-propyl-
1,2,L-triazole.

By the reaction of phenylaminoguanidinium bisul-
fate with an apprOpriate aliphatic acid or its derivative,
it was possible to prepare 3-amino-h-phenyl-l,2,b-triazole
and a number of 3~amino-t-phenyl-5-elkyl-l,2,h-triazoles.

These syntheses are illustrat d on the next page:

  

r7 +
.C6H5-NH-C-NH-HH2 H30;

HCOOH )

 

_CH3CHOHCOOH g,

 

C6H507 NHz

HOCH2Q§§ //y

N

06H5.u—————finuz
HOCh-‘

CH3 \\

06H5.T-——-—fiNH2

CéHgOCHZCOOH A CéHSOCHzc N

 

—“ —.,

10.
3:Amino-hephenyl-5-chloromethyl-l.2.A-triazole
hydrochloride

Some difficulties were encountered in the prepa-
ration of this important intermediate. Several attempts
to synthesize it by the reaction of phenylaminoguanidinium
bisulfate and chloroacetic acid (Thiele's method) were
fruitless. Bloom and Day (27) had succeeded in preparing
2-chloromethylbenzimidazole in good yields by using the
method of Phillips (28). They heated o-phenylenediamine
with chloroacetic acid in AN hydrochloric acid for forty-
five minutes, allowed the mixture to stand overnight at
room temperature and then neutralized it in the cold with
63 ammonium hydroxide. When phenylaminoguanidinium bisul-
fate and chloroacetic acid were allowed to react under
comparable conditions, 3-amino-h-phenyl-5-chloromethyl~
1,2,h-triazole was obtained in poor yield. It was finally
decided to attempt to prepare this compound from the
corresponding hydroxymethyltriazole. After several experi-
ments, a procedure was worked out for the smoeth conversion
of the hydroxymethyltriazole to the chloromethyltriazole in
good yield.

The hydrochloride of 3-amino-A-phenyl-Sahydroxy-
methyl-1,2,h-triazole was prepared and then treated with
an excess of thionyl chloride in chloroform. After reflux-
ing for ten hours and allowing the mixture to stand over-
night, the chloromethyltriazole could be isolated in good
yield.‘

4-.
,_i
*c
s
‘M
a-

-‘o- a

II

11.

6635-? ”HH2.HC1 06H5o?—————fiNH2.HCl
HOCHzC N 4. 30012 ._____; ClCHgC '
\/ \/"
N N
This intermediate was employed in the synthesis of the

various dielkylaminomethyl- and phenoxymethyltriazoles.

Dialkylamin methyltriaz les

The presence of both a reactive halogen and a
moderately reactive amino group in the molecule of the
intermediate was a source of some difficulty in the syn-
thesis of these compounds.

In preparing these compounds, an alcoholic
solution of the hydrochloride of 3-amino-h-phenyl-Se
chloromethyl-l,2,h-triazole was treated with the calcu-
lated amount of a secondary amine necessary to (l)
liberate the amino group of the chloromethyltriazole,
(2) react with the reactive halogen and (3) combine with
the hydrogen chloride produced in the course of the
reaction. Since the amino grOUp of the secondary amine
is much more basic than the amino group of the triazole,
these reactions were allowed to proceed for a day or
more at room temperature. These conditions were found
to be most favorable for the reaction of the amino group
of the secondary amine, and least favorable for the

reaction of the amino group of the aminotriazole.

a.

12.

Sufficient sodium hydroxide was then added to liberate
the excess secondary amine from its hydrochloride. The
excess secondary anine was then removed along with the
solvent by evaporating to dryness under reduced pressure.
The product was then extracted from the sodium chloride
with toluene. The best yields were obtained from those
reactions involving the more basic secondary amines.
These syntheses are illustrated on the following two

pages:

13.

 

 

 

 

CéflsoT—firn‘iz
% \ N/h
C6H5 WW
\ Omsk /
/OH > N
CéHS'N T'HZOHC]. CéHSolii' CKHZ

nlftflf\%/jl DH \ /

N/
a
II:
N
O
/
2

 

 

 

c H .N CNH
CH3 6 5 I H 2
(CH3 )2NH A :cngc N
' CH3 \
N..
P C6H5-I'J————-'C'3NH2
BUZHH A “gauze N
’ Et \ /

N,

 

 

 

 

 

 

 

 

 

(A11y1)2mn /nC'zc N
, Allyl §§N//
n DrCéH5O? finsz
(n-Fr)oNH NCHZC N
n-Pr V§§N
06H50N-———-CNHZOHCI C61-150N CNHZ
f 01 n A g (1 r ) "H 1-Pn‘n H é g
C 2 .\ “’1‘ 214 A / C 2
§§N//\ ’ i-Pr '§§N//
C H 0N {CH
( ) n-Bu\6 5 H 2
n-su ZNH NCHZC N
‘) /
n-Bu ‘§§N//’
C6H .N CNH
) i-Bu\ 5 | H 2
'--B UH {CH C
(1 u 2 ) i-Bu/ 2 \\ /N

N

15.

Phenoxvmethvl- and thiorhenoxvvethyltriesoles

The same conditions employed in the synthesis
0’ the dielkvlaminomethvltriazoles were used in order
to minimize the reaction of the amino creep of the-
chloromethvltrinzole.

In preoering the ohenoxvmethyltriazoles, an
alcoholic solution of the hydrochloride of 3-amino-h-
phenyl-S-chloromethyl-l,2,L-triazole was treated with
a solution containing at least the stoichioretric amount
of the apprOpriately substituted sodium phenoxide in
alcohol. These reactions were then allowed to proceed
for a day or more at room temperature. In the case of
those reactions involving sodium phenoxides with
electron-repelling groups substituted in the ortho or
para positions, precipitation of the product usually
began promptly after the initial reaction had subsided.
The best yields were usually obtained in these reactions.
In those reactions in which no product precipitated at
the end of the reaction time, the ni~ ure was heated on
the steam bath for about one hour to ensure completion
of the reaction. Water was then added to the cooled
solution to precipitate the product. These syntheses

are illustrated on the following pages:

5.
A" --..-
-.
O
i

q

06H5°N

 

-fiNH2-H01

B 0014a

C / \ ‘Na

cn3o<:>osa

16.

CéHSO' Hafiz

Onset

VI!

C6H5oN—CNH2

sn<:>ocnch

w

06H5.n—-———cnnz

n I I
C OOCHzc\ /N

W

06H5.N—-———an2

I
CH3©CHZC\
\/

C6H5-N

 

ICin

II
CH OiNCfizC\ /

' \.. N/

o-CH366HhONa ‘

 

m-CHBCéthNa_1 m-cn3c6nhocszc

 

 

06H5-? fisa2-301

ClCHzC N

\/

NI!

17.

06H5o?—-——~fNH2

o-CH306H40CHZC N

06H5.n——-~fisn2
N

\/

N

06H5-n—————CHH2

<:>scu2£ N
Q§NV//

 

18.

Phenylthioureas of Aminotriazolas

Fromm (29) and other investigators were the
first to note the remarkable fact that the phenylthioureas
derived from a number of heterocyclic compounds containing
the group:

‘—N ___s ~NH

II V—

‘—CEH2 —C:KH
occurred in two isomeric forms. The low melting isomer is
obtained by allowing the heterocyclic amine to react with
phenylisothiocyannte at room temperature. The higher
melting isomer is formed when the reaction is carried out
at a higher temperature. The low melting labile isomer
can be converted into the high melting stable form by
heating it above its melting point. The reverse of this
change is not observed. Fromm suggested that the labile
isomer is derived from a secondary amine and the stable
form from a primary amine.

Fantl and Silbermann (30) have studied the
behavior of aminotriazoles toward phenylisothiocyanate.
They found that 3-amino-5-methyl-l,2,h-triazole reacted
with phenylisothiocyanate in the cold to produce a sub-
stance melting at 137° C., which solidified at 140° C. and
then melted at 1970 C. They also obtained the higher melt-
ing compound directly by heating the reactants in a high
boiling solvent (n-amyl alcohol) for two hours. They

assigned the following formulas to their two products:

- .fi

r'vnu

 

19.

C6H oNHoCoN—CNH
5 I H 2
CEBU

n

C6H50N3033

 

N
4% §§N//'

Dope 137° C.

xii—fimsjmuwéss

CéHSONZCZS % CH3C

 

N
In ‘§§N//’

m.p. 197° C.

Further studies showed that the presence of isomerism

among the phenylthioureas of aminotriazoles was not a

general occurrence since 2-phenyl-3-allylamino-1,2,h-

triazole reacted with phenylisothiocyanate to yield

only one stable phenylthiourea.

In preparing the phenylthioureas of the amino-

triazoles which were synthesized in the course of this

study, the author did not observe the presence of

isomerism.

It

20.

Biological Properties of Aminotriazoles

Interest in the study of the biological prepar-
ties of aminotriazoles was strongly stimulated in 1952
when Hall gt a; (31) first noted that aminotriazole had
defoliating and regrowth inhibiting prOperties on cotton
during the course of tests conducted at the Texas Agri-
cultural Experimental Station.

In 1953. Shaw and Swanson (7) reported their
study of the relationship between phytotoxicity and
chemical structure of herbicides. Aminotriazole was
again found to have the desirable properties of a promis-
ing herbicide.

The following year, s.a. Allen (32) of the
American Chemical Paint Co. was granted a patent on the
use of aminotriazole as a herbicide and cotton defolianto
After a number of field tests, aminotriazole was marketed
by the American Chemical Paint Co. as a herbicide under
the trade names - nAmizol" and "Weedazol". The American
Cyanamid Co. was also licensed to manufacture and sell
aminotriazole.

This compound whose derivatives had been used
only sparingly as fog inhibitors in photographic emulsions
(33) was reported to be more effective against Canada
thistle than any other known herbicide. Prior to the use
of aminotriazole, Canada thistle could only be kept under
control by dosing with large amounts of soil sterilants

or repeated applications of 2,h-D. Other weeds that were

-
,
O
I
.t
.

0.

-~.- 4

-"O

“

I
‘ c
a
f
I .
u. u. '
‘ I 3
~- i
r
‘ x
a.
. ,. ."

21.

also suscentihle to control by aminotriazole included the
followinp: ouackerass, nutcrass, Bermuda grass, poison
ivy, poison oak, scrub oak, sow thistle, milkweed, horse-
tail rush, cattails, ash and red maple.

The fundamental reasons for the inherent herbi-
cidal preperties of aminotriazole are still obscure. It
has been observed to cause chlorosis in plants. Some-
times the plant dies after the chlorosis. Generally,
only new growth, in which pigment is being formed, becomes
chlorotic. This has caused some (5) to suggest that
chlorOphyll synthesis is being affected. It has also been
found that the degree of chlorosis is proportional to the
amount of aminotriazole applied.

Kenneth A. Sund of the American Cyanamid Co. (3h)
has suggested that aminotriazole may affect plant physio-
logical processes in three different ways: (1) as a pre-
cursor in the formation of some porphyrin similar to chloro-
phyll but unable to carry out the functions of chlorOphyll;
(2) it may bind by complex formation some metal or metals
required for the develOpment of chlorOphyll; (3) it may
upset some oxidation-reduction reactions within the plant.)

By using radioactive 3-amino-l,2,L-triazole with
the fifth position labeled with carbon~lh, Killer and Hall
(5) made a study to determine how aminotriazole effects
chlorosis in plants. They suggested that aminotriazole in
sub-lethal doses causes chlorosis by inhibiting the syn-

thesis of chlorothylls and czrotanoids. But when it is

Q.

22.

0

applied in hich concentrations, chlorosis is caused by
the destruction of chlorOphyll. From their studies they
concluded that the possibility that aminotriazole acts
as a precursor in the formation of an abnormal porphyrin
is quite remote and that the complexing of an essential
metal is unlikely. They agreed with Rogers (35) that
aminotriazole inhibits rlastii development.

while studying the depressing effect of amino-
triazole on chlorOphyll synthesis in plants, Heim gt a;
(36) observed that the chemical also senses a great
decrease in the catalase activity of plant tissue. This
led them to study the effect of aminotriazole on catalase
activity in rats. They found that aminotriazole reduced
hepatic and renal catalase activity levels, but not that
of red cells, thus producing an effect similar to that
observed in tumor-bearing animals.

Tschudy and Collins (6) concluded that the
ability of aminotriazole to affect two different por-
phyrin-containinc compounds - catalase and chlorophyll -
suggested a possible interference with porphyrin synthe-
sis. They then studied the effect of aminotriazole on an
enzyme known to be involved in porphyrin synthesis. They
studied the effeCt of aminotriazole on S-aminolevulinic
acid dehydrase activity. This enzyme catalyzes the con-
version of S-aminolevulinic acid to porphobilinogen - an

intermediate in the synthesis of porphyrins. They found

\

23.

that sninotriazole reduces the level oféP-aminolevulinic
acid dehydrnse activity in the kidneys. It is signifi-
cant that this ef’ect is also produced by tumors. Thus
tumors and aminotriazole are capable of causing a decrease
in activity of both 8~sminolevulinic acid dehydrase and

catalase.

2h.

Experimental
Phenylsninoquan‘diniun Bisulfate

A slurry of 304 g. (2.0 moles) of phenylthio-
urea (Eastman Kodak Co.) in 600 ml. of absolute methanol
was cooled to 5° C. and then treated with 132 ml., 301 g.
(2.12 moles) of methyl iodide. The mixture was allowed
to remain in an ice bath as it warmed up to room temper-
ature and stand for forty-eight hours. it the end of
this period, 100 ml. of methanol were removed by distil-
lation and then replaced by 100 ml. of fresh methanol.
The flask was then placed in an ice bath and 67.L g.
(2 moles) of 95$ hydrazine was added. The ice bath was
then removed and the solution refluxed gently for four
hours in the hood. The methyl mercaptan which is a by-
product of this reaction was collected in a trap which
was cooled in an ice-salt bath. The alcohol was then
removed under reduced pressure until a viscous liquid
remained. A volume of water equal to the volume of the
viscous liquid was then added. This solution was again
evaporated to a viscous liquid under reduced pressure.
The viscous liquid was used in preparing the phenylamino-
gunnidinium bisulfate.

The viscous solution of the phenylaminoguanidi-
nium iodide was dissolved in a solution of 60 ml. of con-
centrated sulfuric acid in 300 ml. of water. This solu-

tion was then added to a slurry of 327 g. (2.05 moles) of

25.

silver sulfate in 200 m1. of water. The mixture became
quite warm and yellow silver iodide precipitated. The
mixture was stirred occasionally and permitted to stand
overnight. The yellow silver iodide was collected on a
filter and the filtrate was treated with hydrogen sulfide
for about one hour until the precipitation of silver
sulfide was complete. The solution was heated to coagu-
late the colloidal silver sulfide and then filtered.
Next. it was treated with ”Norit". After filtering, the
colorless solution was evaporated to a viscous liquid
under reduced pressure. The viscous liquid solidified
on standing. It was dried in a vacuum desiccator and
crushed while still soft to colorless granules. The yield
of product was 400 g. (80% of theory based on the phenyl-
thiourea). A sample for analysis was recrystallized from
isOprOpyl alcohol and dried under a vacuum at 80° C. It
melted at 9h-96o C. (heated slowly) and near 85° C. when
heated rapidly.

Anal. Calc'd. for C7H12N40AS: N, 22.57; 8.12.92

Found: H, 22.31; 8, 12.81

3-Amino-q-phenquQ-H.l£2.4-triasole

A mixture of 25 g. (0.1 mole) of phenylamino-
guanidinium bisulfate and 50 ml. of 886 formic acid was
refluxed for six hours. The excess formic acid was

removed under reduced pressure and #0 ml. of water was

26.

added. The solution was evaporated unier reduced pres~'
sure to a viscous liquid, and 35 ml. of water was added.
The solution was then carefully neutralized with solid
sodium carbonate. Colorless crystals precipitated; they
were separated by filtration and recrystallized from
methanol. The yield of triazole was 12 g. (75; of theory)..
A sample for analysis was recrystallized twice from metha-
nol and melted at 218-2190 0.

Anal. Calc'd. for Csfigth C, 60.00; H, 5.00;

N, 35.00
Found: C, 59.99; H, 5.03;.N. 3ho98

fi—Amino-hophenyl-h-H,1,2,h-triazole Hydrochloride

A solution of 0.8 g. (0.005 mole) of 3-amino-
h-phenyl-l,2,h-triazole in 5 ml. of concentrated hydro-
chloric acid was evaporated to dryness on the steam bath.
The crystalline residue was recrystallized three times
from an ethanol-ether solvent pair. The yield of pro-
duct was O.88 g. (90% of theory). The colorless crystals
melted at 190-1910 C.

Anal. Calc'd. for CgflgClNh: C, h8.86; H, h.61;

Cl, 13.03; N, 28.h9
Found: C, 48.55; H, h.85; Cl, 18.03;
N, 28.7h

I.

ll

L-.

o
O
l

0.
I
o 71--

27.

, O l l

3«Acetenido-h-phenvl-h-H,l,?,h-triazole

Two grams (0.012 mole) of B-amino-A-phenyl-
1,2,h-triazole was treated with 20 ml. of acetic anhydride
and refluxed for three hours. The excess acetic anhydride
was removed under reduced pressure and no ml. of water was
added to precipitate the product. The crystalline product
was removed by filtration and washed with water. Recrys-
tallization of the product three times from ethanol gave
V1.5 g. (60% of theory) of colorless crystals melting at
201~202° C.

Anal. Calc'd. for Clofiloflhoz C, 59.40; H, b.98

N, 27.71
Found: C, 59.58; H, 5.15; N, 27.72

The hydrolysis of B-acetanido-hephenyl-l,2,h—
triazole by heating with concentrated hydrochloric acid
produced a product which was identical with 3-amino-h-
phenyl-l,2,h-triazole as shown by a mixture melting point
determination. This suggests the absence of rearrangement
of the original triazole in the process of acetylation.
The original triazole also did not rearrange when heated

above its melting point.

3-Amino-Agphenyl-5-methyl~5-H,1,2,5-triazole

A mixture of 25 g. (0.1 mole) of phenylaminogua-
nidinium bisulfate and 50 ml. of glacial acetic acid was
refluxed for twelve hours. The excess acetic acid was

removed under reduced pressure and to m1. of water was

I.

.

4...;

 

0‘
0‘

vo—A.

_.-.- _

a
l,‘
u

23,
added. The solution was evaporated under reduced pressure
to a viscous liquil, and 35 ml. of water was added. The
solution was then neutralized with solid sodium carbonate.
Colorless crystals precipitated; they were removed by
filtration anl extracted with hot methanol. This solution
was filtered while hot and cooled in an ice bath. Preci-
pitation of the crystalline product took place. The yield
of crude triazole was 13 g. (753 of theory). A sample for
analysis was recrystallized twice from methanol and melted
at 161-1620 C.

Anal. Calc'd. for CngoNL: C, 62.10; H, 5.75;
N, 32.20
Found: C, 62.05; H, 5.79; N, 32.17

3-fimino-k-phenyl-S-methyl-4-H,l.2,4-triasole Hydrochloride

A solution of 0.87 g. (0.005 mole) of B-amino-L-
phenyl-S-methyl-l,2,4-triazole in 5 ml. of concentrated
hydrochloric acid was evaporated to dryness on the steam
bath. The crystalline residue was recrystallized three
times from an ethanol-ether solvent pair. The yield was
0.97 g. (925 of theory) of colorless crystals melting at
223-2250 0.

Anal. Calc'd. for C9H1101N4: C, 51.31; H, 5.26

Cl, 16.83; N, 26.60

Found: C, 51.09; H, 5.hh; Cl, 16.92; N,26.76

O\

29.

I I o

lo(A'-Phenqu§'omethyl-h'-H.l',2[,h'-triezoly123')-3—
Dhenvlthiourea

h mixture of 0.5 a. (0.003 mole) of B-emino-h-
phenVI-S-nethvl-l:21h-triesole end 2 ml. of phenvlisothio-
cvanate was heated on the steam bath for two hours and then
cooled in an ice hath. The flask was scratched until pre-
cinitntion of the product occurred. The Dhenylthiourea
derivntive was removed hv filtration; washed with 50 m1.
of lieroin, and rocrvstellized twice from methanol to yield
0.78 g. (905 of theory) of product melting at 186-1880 C.

Anal. Calc'd. for 016H15N5S: N, 22.6h; 8, 10.36

Found: N, 22.82; 8, 10.28

3-Amino-4-pheny1-5-hydroxymethyl-g-H,142.b-triezole

A mixture of 25 g. (0.1 mole) of phenylnminogua-
nidinium bisulfate, 10 m1. of 70; glycolic acid, and 12 m1.
of water was refluxed for twenty-two hours. The solution
was then cooled and carefully neutralized with 7.5 H ammonia.
Fine, cream-colored crystals precipitated. They were re-
moved by filtration and washed with methanol. The yield of
crude triazolo was It g. (75; of theory). A sample for
analysis was recrystallized three times from methanol and
melted at 239-2h0° C.

Anal. Calc'd. for CngONhO: C, 56.84; H, 5.26;

N. 29.1.7
Found: C, 56.98; H, 5.18; N, 29.57

.. ,
-._. .-.. -I
-.
1'
I a.
, i
o
i
. ..

.
.
o ‘ ' I
v
Q .
\
.
.
. . I
.
' I
. 4
q 5 O i
a
t.
.
O
I. 0 °

:1
- .b- .4..- :4.
. ; ~.
~‘
'\
o
' ’ V f
. . . o
. . \
v , .
A .. .‘
c ,.
-. ' s p .\
9 O
c " I
,. hi
0
.
‘\
i
.
’ 0
l
. .

30.

3-Amino-&-ghenyl-3-hydrox‘ eth 1- -H 2 -tria o e
y roc oriwe ’

A solution of 9.5 g. (0.05 mole) of 3-anino-h-

 

phenyl-S-hydroxynethyl-l,2,h-triazole in 10 ml. of concen-
trated hydrochloric acid was evaporated to dryness on the
steam bath. The crystalline residue was washed with
acetone. A sample for analysis was recrystallized three
times from an ethanol-ether solvent pair. The yield of
hydrochloride was 10.6 g. (94% of theory). The colorless
crystals melted at 218-2200 0.

Anal. Calc'd. for 09n1101mh0: c, 47.69; H, 4.89

Cl, 15.64; N, 2A.72
Found: C, 47.66; H, b.97; Cl, 15.65;
N, 2h.77

lgimino-Q-phenyle5-(d-hydroxyethyl)34-fi,1,2.g-triezole

A mixture of 25 g. (0.1 mole) of phenylaminogua-
nidinium bisulfate, 12 m1. of 85? lactic acid and 24 m1.
of water was refluxed for sixteen hours. The solution was
then carefully neutralized with solid sodium carbonate.
Colorless crystals precipitated, were removed by filtra-
tion and recrystallized from methanol. The yield of tria-
zole was 7 g. (355 of theory). A small sample was further
recrystallized once from ethanol and twice from isopropyl
alcohol and melted at 205-2070 C.

Anal. Calc'd. for clonlgnho: C, 58.81; H, 5.92;

N, 27.n4
Found: C, 58.88; H, 6.09; N, 27.26

_ . ‘ r 71!..- v

\
7
o
s
n ' ‘
. C
.0
,
0
l
b
I
, L
.
.m ‘ '
A . A
b
..

1"

 

31.

1-!catngijo-g-phenvlg5-Gi.acetoxyethyl)-g-H,1,2,h-triazole

Two grams (0.01 mole) of 3-amino-k-phenyl-5-
ki-hydroxyethyl)-l,2,h-triazole was treated with 20 ml. of
acetic anhydride and refluxed for three hours. The excess
acetic anhydride was removed under reduced pressure and
L0 m1. of water was added to precipitate the product. The
crystalline product was removed by filtration and washed
with water. Recrystallization of the product three times
from ethanol gave 1 g. (35% of theory) of colorless
crystals melting at 201-2030 C.

Anal. Calc'd. for Cthl6Nh03: C, 58.32; H, 5.60;

N, 19.h3
Found: C, 58.26; H, 5.73; N, 19.22

szmino-h-phenyl-S—phenoxymethyl-§:H,l,2,4-triazole

A mixture of 7.6 g. (0.05 mole) of phenoxgacetic
acid, 12.4 g. (0.05 mole) of phenylaminoguanidinium bi-
sulfate, and 25 ml. of water was refluxed for twenty-two
hours. The solution was then carefully neutralized with
solid sodium carbonate; a gummy product precipitated. The
aqueous layer was decanted and the product was recrystal-
lized four times from toluene to yield 2.5 g. (20$ of
theory) of colorless crystals melting at 195-1960 C.

Anal. Calc'd. for 015H14N40: C, 67.65; H, 5.30;

N, 21.04
Found: C, 67.81; H, 5.hh; N, 21.06

.5

.-..-

,‘fln

32.
1:dmino-L-phenyl-Sgphenoxymethyl-g-H,l,2,4-triasole
hydrochloride

A solution of 1.3 g. (0.005 mole) of 3—amino-h-
pheny1-5-phenoxymethyl-1,2,h-triezole in 5 ml. of concen-
trated hydrochloric acid was evaporated to dryness on the
steam bath. The crystalline residue was recrystallized
three times from an ethanol-ether solvent pair. The yield
of product was 1 g. (705 of theory), m.p. 198-1990 C.

Anal. Calc'd. for 015H15$1hh0: Cl, 11.71;

N, 18.51
Found: 01, 11.8h; N, 18.35

l-(k'-Qhenyl-5'-?henoxvmethvl-h'-Hil'42'14"tri3391Y1’3')‘
3gpheny1thiourea

A mixture of l g. (0.004 mole) of 3-anino-h-
phenyl-S-phenoxymethyl-l,2,A-triazole and 3 ml. of phenyl-
isothiocyanate was heated on the steam bath for two hours.
It was then cooled in an ice bath and treated with 50 ml.
of ligroin to precipitate the phenylthiourea derivative.
The product was removed by filtration and recrystallized
twice from methanol to yield 0.6 g. (373 of theory) of
product melting at 165.167o C.‘

Anal. Calc'd. for 022H19N503: N, l7.4h; S, 7.98

Found: N, 17.63; 3, 7.9A

lgimino-A-phen'l-5-chloronethyl-h-H,1,2,A-triazcle
hydrochloride

A slurry of 10.8 g. (0.048 mole) of the hydro-

chloride of B-amino-h-phenyl-S-hydroxymethyl-l,2,h-triazole

n.

l .
.
D
'N
. .
A
e O
a.
.r .A . , l. r .. A,
,, . ‘ on
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Do

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- v o.-
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33.

O

in 25ml. of chlorotorm was treated with 10 g. (6 m1., 0.08
mole) of thionvl chloride in 15 ml. of chloroform. After
thirty minutes at room temperature, the mixture was re-
fluxed for six hours. Another addition of 6 g. (A ml.,
0.053 mole) of thionyl chloride in 10 ml. of chloroform
was made and refluxing continued for four hours. The mix-
ture became dark red and was permitted to stand overnight.
The mixture was then cooled and stirred; a cream-colored
solid precipitated. An additional crop of crystals was
obtained by the addition of a small amount of ether to the
filtrate. The product was washed with ether. The yield
of chloromethyl triazole hydrochloride was 10.b g. (86$ of
theory). A sample for analysis was recrystallized twice
from a methanol-acetone solvent pair and melted at 18?-
190° C.

Anal. Calc'd. for CngoClgfih: C, AL.10; H, L.ll;

Cl, 28.93; N, 22.86
Found: C, hh.26; H, b.23; 31, 28.98;
N, 22.59

l-Amino-h—phenyl—S~piperidinomethyl-A—H.1,g,&-triazole

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of 3-amino-h-phenylé5-chloromothyl-l,2,4-triazole
in 50 ml. of methanol was treated with 12.75 g. (1h.8 m1.,
0.15 mole) of piperidine and allowed to stand for twenty-
four hours. The piperidine hydrochloride was precipitated

by the addition of ether. It was removed by filtration

~--- -—-

3A.

and the filtrate was evaporated under reduced pressure
until only a viscous liquid remained. The residue was
treated with 25 ml. of concentrated hydrochloric acid,
and the solution was again evaporated under reduced pres-
sure until only a viscous liquid remained. Upon cooling,
this liquid solidified to a colorless mass. The amine
hydrochloride was washed with acetone and treated with a
large excess of concentrated ammonia. Lustrous crystals
appeared which were washed with concentrated ammonia and
then with water. The yield of product was 11 g. (8a; of
theory). The amine was recrystallized twice from toluene
and melted at 153-151.0 C.

Anal. Calc'd. for CltHl9N5: C, 65.33; H, 7.4L;

N, 27.22
Found: C, 65.L3; H, 7.47; N, 27-39

When the free amine was refluxed in acetic anhy-
dride for five hours, no product could be isolated. when
acetic acid was used in place of the anhydride, the free

amine was recovered unchanged.

lgjh'oghenyl-fi'gpi eridinomethyl-h'-H,l',2'44'-triezolyl-
- ephenylthiourea

 

A mixture of 0.5 g. (0.002 mole) of 3-amino-h-
phenyl-5-piperidinonethyl-l,2,h-triazole and 2 n1. of
phenylisothiocyanate was heated on the steam bath for one
hour and then cooled in an ice bath. The flask was

scratched until precipitation of the product began. The

«a

v '.
x , ,_ . ~ . .‘

‘ .

o -, ' ‘ ' ' ' ‘ L
l I

; I
‘ .
l ' . V n .
. I

._ . . , t
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I. |- . 7 7,‘."“ we'lr"

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A ' u '_ I‘ I ‘ “v7.” . f, ‘ ‘ .. , ' ‘ -- ~. , . . 7‘ N. -7... _ _,. ‘u «‘.-M' ~.---.. 4... no.
.
(- . n
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fi.—~.,‘ ‘m

35.

phenylthiourea derivative was removed by filtration,
shed with li3roin, and recrystallized twi so from methanol
to yield 0.6 g. (773 of theory) of product melting at 18h-
1360 C.
Anal. Calc'd. for C21H23N53: N, 21.41; S, 8.17
Found: N, 21.39; S, 8.03

3-“r‘uo_§gs.er'l-5-nor Holinonethy ~4-H.l 2 4-tri ”JQLQ
A solution of 24.5 g. (0.1 mole) of the hydro-

chloride of 3-ami.. o-b-phen3l- 5- chloromethyl- -l, 2 ,h-tria-
solo in 100 ml. of methanol was treated with 26.13 g.

(26 ml., 0.3 mole) of morpholine and allowed to stand
for twenty-four hours. The morpholine hydrochloride was
precipitated by the addition of ether and re ved by
filtration. The filtrate was evaporated under reduced
pressure until only a viscous liquid remained. The resi-
due wes treated with 25 ml. of concentrated hydrochloric
acid, and the solution was again evaporated under reduced
pressure until only a viscous liquid remained. Upon cool-
ing, this liquid solidified to a colorless mass. The
amine hydrochloride was washed with acetone and treated
with a large excess of concentrated enmor is. Lustrous
crystalse apps red 3hich were wz2 s‘ed with corcentrated

nmonia and then with water. The yield of base was 13
(503 of theory). The product was recrystallized twice

from methanol and melted at 234-2050 C.

O.

r '-.'..O

. .r
.4-,4- a u... ..,,.~... 9- M.

k
. I
-u c u ‘ 0‘ ‘ ‘
\
r n
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u
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‘. tr " -

a .2. r" “at: ‘~dlA¢.W~-o

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no.

36.

Anal. Calc'd. for CI3H17N50: C, 60.20; H, 6.61;
N, 27.01
Found: C, 59.91; H, 6.69; N, 26.89

1-(L'aPhen11-fi'omorgholinomethyl-A‘-H.1'.2’.h'-triazoly1-
- -phenylthiourea

A mixture of 0.5 g. (0.002 mole) of 3-eninoéb-
phenyl-S-morpholinonethyl-l,2,A-triasole and 2 m1. of)
phenylisothiocyanate was heated on the steam bath for one
hour and then cooled in an ice bath. The flask was
scratched until precipitation of the product occurred.
The phenylthiourea derivative was removed by filtration,
washed with ligroin, and recrystallized twice from metha-
nol to yield 0.6 g. (77% of theory) of product melting at
176-1780 C. .

Anal. Cslc'd. for C20H22N6OS: N, 21.31; S, 8.13

Found: N, 21.LO; S, 8.15

39Amino-Qgphenyl-S-pyrrolidinomethyl-Q-HLI,2,g-triazole

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of Bosnino-h-phenylo5~chloromethylol,2,b—triazole
in 50 ml. of methanol was treated with 10.65 g. (12.2 m1.,
0.15 mole) of pyrrolidine and allowed to stand for forty-
eight hours. The pyrrolidine hydrochloride was precipi-
tated as a dark heavy 011 by the addition of 200 m1. of
anhydrous ether. The clear upper layer of the mixture

was decanted and evaporated under reduced pressure until

‘~

4‘.

o"

a
4
_ .
D
O
U
.1. .w

37.

only a viscous liquid remained. The residue was treated
with 25 m1. of concentrated hydrochloric acid, and the
solution was again evaporated under reduced pressure until
only a viscous liquid remained. Upon cooling, the amine
hydrochloride precipitated as a hygroscopic, colorless
solid. After triturating with acetone, it was treated
with a large excess of concentrated anaemia. Lustrous
crystals appeared which were washed with concentrated
ammonia and then with water. The yield of base was 6 g.
(50% of theory). It was recrystallized three times
from toluene and melted at 158-1600 C. A sample was
further recrystallized once from toluene, three times
from acetone and treated with "Norit"; it also melted
at 158-1600 0.

Anal. Calc'd. for 013H17h5: C, 6A.17; H, 7.05;

N, 28.79
Found: C, 64.3h; H, 7.17; N, 28.75

13(4'-Pheny1—§'opyrrolidinomethyl-§'-H.l'.2{.4'-triazolyl-
- -phenyIthiourea

 

A mixture of 0.5 g. (0.002 mole) of 3-amino-h-
pheny1-5~pyrrolidinomethyl-l,2,h-triazole and 2 m1. of
phenylisothiocyanate was heated on the steam bath for
one hour and then cooled in an ice bath. The flask was
scratched until precipitation of the product occurred.
The phenylthioures derivative was removed by filtration,

washed with ligroin, and recrystallized twice from

‘v

3‘

PP

38.

methanol to yield O.h g. (53% of theory) of product melt-
ing at 178-1800 0.
Anal. Calc'd. for C20H22N63: N, 22.21; s, 8.47
Found: a, 22.43; S, 8.40

lgAminofb-phenylgfigdimethylaminomethyl-h-H.1,2,g-triazole

A solution of dimethylamine was prepared by
treating 24.5 g. (0.3 mole) of dimethylamine hydrochloride
with a solution of 12 g. (0.3 mole) of sodium hydroxide in
10 m1. of water and 50 ml. of methanol. After cooling the
mixture, the sodium chloride which had precipitated was
removed by filtration. This solution of dinethylamine was
then treated with a solution of 12.25 g. (0.05 mole) of
the hydrochloride of 3-amino-h-pheny1-5-chloromethyl-
1,2,A-triazole in 50 ml. of methanol contained in an
Erlenmeyer flask. After the initial reaction had subsided,
the flask was stoppered and permitted to stand for ninety-
six hours. It was then treated with a solution of h g.
(0.1 mole) of sodium hydroxide in 10 ml. of water and
50 m1. of methanol. The sodium chloride which precipitated
was removed by filtration and the filtrate was evaporated
to dryness under reduced pressure. a yellow solid remained
in the flask. The solid was extracted with hot toluene.
A colorless proiuct precipitated from the toluene extract
upon cooling. The product was recrystallized from toluene

five times to yield h g. (36% of theory) of colorless

-mc‘

J
in.
_.’ I

an. .
.
5

..~ . -‘J‘

, i ..
J .. .
I
J l .
‘ I
. .
‘ I
.
. .

.
n. ]
L a
. _
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. w. .
§
' r
... o - _4
/ o 1
fl
.. .
‘ .
.
, . i
' l
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. T ‘ '
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- .
.
-
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I. '
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_ .7 ‘
§

39.

crystals meltine at 139¢1b0° C.
Anal. Calc'd. for 011H15N5: 0; 60.80; H, 6.96;
N, 32.23
Found: C, 60.60; H, 7.07; N, 32.0A

 
 

l-(A'-Fhen ’-H l' ‘-
w - -p any t iourea

   

A mixture of 0.5 g. (0.002 mole) of 3-amino-hu
phenyl-S~dimethyleminomethyl-l,2;L-triazole and 2 ml. of
phenylisothiocyanate was heated on the steam bath for one
hour and then cooled in an ice bath. The flask was
scratched until precipitation of the product occurred.
The phenylthiourea derivative was removed by filtration;
washed with 50 m1. of ligroin, and recrystallized twice
from methanol to yield 0.7 g. (87% of theory) of product
melting at 182-1830 C.

Anal. Calc‘d. for 518H20N6S‘ N, 23.85; S, 9.10

Found: N, 23.65; S, 8.96

3-Amino-A-phenyl-5-diethyleninomethyl-g-H;l.2.5-triazole

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of 3-amino-b-phenyl-5-chloromethyl-l,2,L-triazole
in 50 ml. of absolute ethanol was placed in an Erlenmeyer
flask and cooled. It was then treated with 62 ml. (0.6
mole) of diethylamine. Twenty-five milliliters of methanol
was added; cooling was discontinued and the flask was
stoppered and permitted to stand for sixty-eight hours.

A solution of L g. (0.1 mole) of sodium hydroxide in

o
$
)
D
I
. .

...-

O.

#0.

25 m1. of water was diluted with 50 ml. of methanol and
then added to the reaction mixture. The sodium chloride
which precipitated was removed by filtration and the
excess solvent and liberated diethylauine were removed
under reduced pressure. A pinkish-white solid remained
in the flask. The solid was extracted with hot toluene.
A colorless product precipitated from the toluene extract
upon cooling. It was recrystallized three times from
toluene and melted at 148-1500 C. The yield of product
was 8 g. (75% of theory).

Anal. Calc'd. for 013H19N5: C, 63.65; H, 7.81;

N, 28.55
Found: C, 63.65; H, 8.00; N, 28.40

l‘(4'-PhenYl-fl'-diethylaminometh l- '-H 11 2: v-
triasolyl:

  

A mixture of 0.5 g. (0.002 mole) of 3-amino-h-
phenyl-S-diethylaminomethylal,2,h-triazole and 2 ml. of
phenylisothiocyanate was heated on the steam bath for one
hour and then cooled in an ice bat . The flask was
scratched until precipitation of the product occurred.
The phenylthiourea derivative was removed by filtration,
washed with ligroin, and recrystallized twice from metha-
nol to yield 0.7 g. (90% of theory) of product melting at
l71-l72° C.

Anal. Calc‘d. for 020324N63: N, 22.09; S, 8.L3

Found: N, 21.90; S, 8.22

.l s.
r a
' ¢
1’
A I

c~~ ‘ . — ..
' I a -
sauces -IM' .., § ..- ' ~o v o . v .1 7,
I ~
‘ n
.v ' A -- r... a v. . v .- i
. Q C
. I
. ~-
4 . 3 . Q c n
n 0
. r
. ‘ ' .
‘
.1
. _
. ‘
' ‘ ‘Q
. O 9
\
O ( O

L1.

3aimino-h-phenyl-S-diallylaminomethyl-h-H.1.2.&~triasole

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of 3-a inc—tephonyl-S-chlorcmethyl-l,2;h-triazole
in 50 ml. of methanol was placed in an Erlenmeyer flask
and treated with 29 g. (38 ml., 0.3 mole) of diallylamine.
After the initial reaction had subsided, the flask was
steppered and permitted to stand for seventy-two hours.
The reaction mixture was then treated with a solution of
h g. (0.1 mole) of sodium hydroiide in 10 ml. of water and
50 ml. of methanol. The sodium chloride which precipitated
was reroed by filtration and the filtrate evaporated to
dryness under reduced pressure. A yellow solid remained
in the flask. The solid was recrystallized five times
from ligroin to yield 3.4 g. (25% of theory) of product
as yellow crystals melting at 92-930 C.

Anal. Celc'd. for C15H19H5: C, 66.88; H, 7.11;

m, 26.00
Found: C, 66.56; H, 7.37; N, 26.16

l-(AF-Phenyl-fi}~diallvlaninomethyl-h'~H l[.2[.4'-
triazoiyl-lTIA3-phenylthiourea

 

 

 

 

A mixture of 0.5 g. (0.002 mole) of 3-amino-h-
phe yl-S-diallylaminonethyl-l,2,h-triazole and 2 ml. of
phenylisothiocyanate was heated on the steam bath for one
hour and then coolrd in an ice bath. The flask was
scratched until precipitation of the product occurred.

The phenylthiourea derivative was removed by filtration,

O
.'

fl

‘ I 7V
.- .-
J. O -.
,
U
-
O
5

. . —.-...

42.

v.'ashed with ligroin and recrystallized twice from met? anol
to yield 0.5 3. (71; of th cry) of product melting at
Ike-165° C.
Anal. Calc'd. for szhgkhgd: N, 20.78; S, 7.93
Found: N, 20.76; 3, 7.95

lensino-grpr~5~ci~nepronllcmiio*ct111~4~H , 2,&-
mtriazole

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of 3-amino-h-phenyl-5-chloromethyl-l,2,A-triazole
in 50 ml. of metha 01 was placed in an Erlenmeyer flask
and treated with 15 g. (20.h m1.. 0.15 mole) of di-n-
propylamine. After the initial reaction had subsided, the
flask was stoppered and permitted to stand for seventy-two
hours. The reaction mixture was then treated with a solu-
tion of L g. (0.1 mole) of sodium hydroxide in 10 ml. of
water and 50 ml. of methanol. ihe sodium chloride which
precipit ate:1 was re moved by filtration and the filtrate
was evaporated to dryness under reduced pressure. The
yellow solid that remained in the flask was recrystallized
four times from toluene and twice from an ethanol-water
solvent pair to yield 4 g. (265 of theory) of faintly
yellow crystals melting at lh2-lt30 C.

Anal. Calc'd. for 015H23N5: C, 65.90; H,8.h8;

N, 25.62
Found: C, 65.72; H, 8.60; N, 25.45

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#3.
1-(i'-°honv195'-di-n~pronvlaminomethyl-L'~H,l',2',h'-
trioaolylEETngiphenvlthiourea

A mixture of 0.5 a. (0.002 mole) of B-amino-h-
phenv1-5-di-n-pronylaninomethyl-l,2,h-triazole and 2 m1.
of phenylisothiocyanate was heated on the steam bath for
one hour and then cooled in an ice bath. The flask was
scratched until precipitation of the product occurred.
The phenylthiourea derivative was removed by filtration,
washed with ligroin, and recrystallized twice from metha-
nol to yield 0.6 g. (82% of theory) of product melting at
157-1580 0.

Anal. Calc'd. for 022H28N68: N, 20.58; S, 7.85

Found: N, 20.46; S, 7.68

3-Amino-4-phenyl-5-di-isepropylaninomethyl-A-H.1,2,§-
triazole

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of 3~amino-h-phenyl-5-chloromethyl-l,2,h-triazole
in 50 ml. of methanol was placed in an Erlenmeyer flask
and treated with 15 g. (21 n1., 0.15 mole) of di-iSOprOpyl-
amine. After the initial reaction had subsided, the flask
was steppered and permitted to stand for one week. The
reaction mixture was then treated with a solution of h g.
(0.1 mole) of sodium hydroxide in 10 ml. of water and 50 ml.
of methanol. The sodium chloride which precipitated was
removed by filtration and the filtrate evaporated to dry-
ness under reduced pressure. The yellow solid which re-

mained in the flask was recrystallized four times from

II. M

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I v ‘
x
I ' ~ ’ V
‘ f
A -. .. _ .J. .— ._ ,. h‘ .
I . .
3 .0 D ‘ g 5‘ v , , _ . I. . v . ~--~...—.“....u—. . ‘ -.-- - I-O-c&
.1 .
‘ .
D I . ‘
- . ‘ . h A . ‘M ,
, u 4 .1 7 v up C~ ,
Q a ‘ k .. '
~
L I
.— r V r
| ' . ‘L . ,
,. Q ~' ‘ ., ‘
. ‘ ’
I e ' ‘ I I ‘ ‘ ,
. '
‘ v 0 A .‘ ' . ~ . I .

I
- 7' .v
A ‘ ‘ - , . . ,~ - - .
p. A \
A ' '
, » , a
.
4 v ' .
r ' ' r
‘ v A 3
‘ _ , ‘ -. y
s . . ‘ ‘ .
A ' ‘ ‘ ~J '
_ _ y .
. . A- r 1 ' 7‘
. . , . . .

— q—‘FFEA I, ‘

LA.

toluene and twice from methanol to yield h g. (26% of
theory) of faintly yellow crystals melting at 192-1930 C.
Anal. Calc'd. for 015H23N5: C, 65.90; H, 8.h8;
N, 25.62
Found: C, 65.71; H, 8.45; N, 25.92

l:ih'-Pheayl- '-d1- ' pro laminometh 1- '-H 1' 2c

  

 

A mixture of 0.5 g. (0.002 mole) of 3-amino-
h-phenyl-S-di-isepropylaminomethylcl,2,L-triasole and
2 ml. of phenylisothiocyanate was heated on the steam
bath for one hour and then cooled in an ice bath. The
flask was scratched until precipitation of the product
occurred. The phenylthiourea derivative was removed
by filtration, washed with ligroin and recrystallized
twice from methanol to yield 0.66 g. (90; of theory)
of product melting at 170-17l° C.

Anal. Calc'd. for C22H25N633 N, 20.58; S, 7.85

Found: N, 20.6h; S, 7.79

 

2:Amino-h-phenxl-fi~di-n-butylaminomethyl-Q-H,1,2,go
triazo e

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of 3-amino-h-phenyl-S-chloromethyl-l,2,h-triazole
in 53 ml. of absolute methanol was placed in an Erlenmeyer
flask and treated with 19.35 g., 26 ml. (0.15 mole) of di-

n-butylamine. After the initial reaction had subsided,

I‘m- ‘ 0“...” «t.

O.

 

 

 

 

   

4
a - '
,.
O
t O ' O ' O .
o ;
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. . - - . _ - . . - . I
‘ i --ov' IJ ‘ L; . . H {‘9- '00 13"; a. o ' ..' ‘ .-
—- A , - ~ NI - 4- - . 'rfil 0 .~. 0 . . J o b- . J,
ovu- h-v—o Ho-......-. w «nun—a. .4. co .7 «nun—anh- oavw-u?‘ “Hey-~00.-- .oLM—W 4.-....“ and.
‘ U
. . . :. I . - v - “ ' " g I I.- b ': . . ' ' x".
' ‘ . .u -\ O, ... ~' ‘ ' w; I h. “ '\ :o ‘ . : -:- :5
0-.'.~\.~ hanma *‘a' '-..I'. ‘W"' 0"“" '1 U‘-’m-"|fl_l ‘3‘...” 'oc‘
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. I. ‘ ' - 0 . n r ‘ o o ,. o. a
. - , . ‘" ‘4 ' ’ .' i t ‘t‘ . ‘r "a .0 " '. - .’ r x ., ,
".I‘J"'L 1-14-J.' --‘ J.‘:‘.’-.¢..‘.o ~, ,"‘\'4,..--."*- ,'.’ “ "“-.«E o}...
- .— - 5 .:‘_““ ’75— -w— __..7 h $.M“”-o- "in *- -!.uc..3~--1-.a~-au. «Ur-C ‘- -.nw
. r. _ #1 ._, -
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. “A‘W-m “gar
’ . I I ,4 r‘ ‘ ‘ , - t . ‘
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_ ‘~ ‘- .... .‘k. , -,...- L. ts J .551.
.r . . - 3 ‘ , _:..‘” ‘ ' ‘ 'A ,. . ‘. -, 1A .0. -
- I v . ) l A . ‘ a _ ‘
“-J‘ a._"'.‘...* . '_ c5“, ‘-. .“‘ '° 1 ._'. .4.) ~L..:
. Q . § ‘ . . . . o x

45.

the flank was stoppered and permitted to stand for seventy-
two hours. The reaction mixture was then treated with a
solution of h g. (0.1 mole) of sodium hydroxide in 10 ml.
of water and 50 ml. of methanol. The sodium chloride
which precipitated was removed by filtration and the fil-
trate was evaporated to dryness under reduced pressure.
The yellow solid which remained in the flask was extracted
with hot toluene. A colorless projuct precipitated from
the toluene extract upon cooling. The yield of product
was 13.5 g. (90% of theory). A small sample was recrys-
tallized three times from toluene and melted at 135—1360 C.

Anal. Calc'd. for Cl7fiz7fi5: C, 67.74; H, 9.03;

‘ ' N, 23.21.
Found: C, 67.h8; H, 9.22; N, 23.07

l:ié'-Phenyl-5'~di-n-butylaminomethyl-h'- ,1',2'IQ'
*triasolyléj’)-3-phenylthiourea

A mixture of 0.5 g. (0.002 mole) of 3-amino-h-
phenyl-5-di-n-butylaminomethyl-l,2,h-triazole and 2 ml.
of phenylisothiocyanate was heated on the steam bath for
one hour and then cooled in an ice bath. The flask was
scratched until precipitation of the product occurred.
The phenylthiourea derivative was removed by filtration,
washed with ligroin and recrystallized twice from metha-
nol to yield 0.63 q. (905 of theory‘ of product melting
at 129-1300 C.

Anal. Calc'd. for CZAH32N63: N, 19.25; S, 7.3h

Found: N, 19.12; S, 7.36

l‘

J
O I
Q .
O ' A
‘
. .
~ ' .tl . "‘
h~ ‘r- .-.- (o ~~-. . g, -V;_ p
> I
.. H .. . i- a ......
.~ .
i C
q“
. w * k 0
, .
l . \ , a "I '.
.
— u .‘ ., 1 ‘4
. _ ,
.
. .
I " a
a , u. - ,
y ‘
. .-
. . . » ' .
r I . e

‘06.
3-Amino-h-nhenvl-5-di-isobutvlcmiropethyl-h-H,1,2,5- ,
trinzSTe

A solution of 12.25 g. (0.05 mole) of the hydro-
chloride of 3oamino-h-phenyl-S-chloromethyl-l,2,h-triasole
in 50 ml. of absolute methanol was placed in an Erlenmeyer
flask and treated with 19.35 £., 26 ml. (0.15 mole) of di-
isobutylamine. After the initial reaction had subsided,
the flask was stOppered and permitted to stand for five
days. The reaction mixture was then treated with a solu-
tion of h g. (0.1 mole) of sodium hydroxije in 10 ml. of
water and 50 m1. of methanol. The sodium chloride which
precipitated was removed by filtration and the filtrate
evaporated to dryness under reduced pressure. The yellow
solid which remained in the flask was extracted with hot
toluene. A colorless product precipitated from the toluene
extract upon cooling. The yield of product was 10 g.
(66% of theory). A small sample was recrystallized three
times from toluene and melted at 189-1910 C.

Anal. Calc'd. for 017H27N5: C, 67.74; H, 9.03;

N, 23.24
Found: C, 67.88; H, 9.03; N, 23.19

AELA"PhenY1-5'-di-isobutylaminomethyl-hj-H11:42"5'-
triozolyIs371:3-phenylthiourea

A mixture of 0.5 g. (0.002 mole) of 3-amino-L-
phenyl-S-di-isobutylaminomethyl-l,2,h-triazole and 2 ml.
of phenylisothiocyanate was heated on the steam bath for

one hour and then cooled in an ice bath. The flask was

, . . ~ . < ‘ * a b
l ‘ - V‘ ‘ . '7‘ "I ’l .
n ¢ : ‘ 5' 5‘ “a
"0 F . .l u ._ A - - ..
‘ , - - , w >- , » » - 9—- -v-A .
.
f." I. w
.
' 0 O - '
. , . r "W . , A ' >
‘ O .. A
' » O
.
, I ‘ .
w 7
' 4 a . O O . .
. .
8 ' ‘
’ , .
, .
I ' .-
AA
. O .
I ‘ - . I
. r
O I
’ .
H ‘ v .
t .
- I ' I l
. > . 1‘
, A r 1' ,
, . w _ . l
,. _ A , _
. . . , . . -
_ . . ~ . ‘ . ,
.
l ‘ ‘
. 5 ., , ' . _ ' e ‘
c ‘I‘ I I r
r .
- . . . , f o 8 Q ‘ ‘
. . .
I .1 '
.
,
t I V v ‘
» I i ‘ O a Q r ‘ I ... _
.. t
5 ~ ' " * I v
‘. . . ' o h v
f ‘ '
- I.» -.l. .A .- v -.- - -- - . O- , ‘4 -.> ‘- - I. -x. o
. . - . v
.3 . . » I \ , '- . u. . , - 1 . . - ~-.,- 0' .- ~- .-
I
.
' 7 "‘ '
-. . .
. -' o o n ‘ -
- , . 0 '
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. A . p t . ‘ ‘ '. _.
I ,. . . - ~
,‘ ‘A l ‘ « ' v , ,4 l ,, . .
. .
. , . ,. , , ,

L7.

scratched until precipitation of the product occurred. The
phenylthiourea derivetive was removed by filtration,
washed with ligroin end recrystallized twice from methanol
to yield 0.6 g. (855 of theory) of product melting at 168-
1690 C.
Anal. Calc'd. for 024H32N63: x, 19.25; s, 7.34
Found: N, 19.13; S, 7.50 1

3-Amino~4-phenyl-S-phenoxymethyl-A-H.1.2.A-triazole

A solution of ho? g. (0.05 mole) of phenol in
25 m1. of methanol was treated with a solution of h.5 5-1
(0.11 mole) of sodium hydroxide in 10 ml. of water. This
solution of sodium phenoxide was then added to a solution
of 12.25 g. (0.05 mole) of the hydrochloride of 3-emino-
h-phenyl-5-chloromethyl-l,2,h-triazole in 50 m1. of metha-
nol. After the initial reaction had subsided, the flask I
was stoppered and permitted to stand for twenty-four hours.
The precipitated product was removed by filtration, and-
additional crystals were obtained by aiding water to the
filtrate. Both crops of crystals were combined and w shed.
three times with 200 ml. of water. The product was re-
crystallized four times from toluene to yield 8 g. (60% of
theory) of colorless crystals melting at 195-1960 C. The
product obtained in this reaction was identical with that
obtained from the reaction of phenoxyacetic acid with
phenylaminoguenidinium bisulfate as shown by a mixture

melting point determination.

0
,
.
1.
s.
9 I
.
, v V!
I
, r
_ r. .
. .-
.H
«Al
. o
i.
.5
M.
v
4 V
I

.~

o—t- ’4

 

 

f
. _
.
i. l,
. n
.
. .
4.
o
.
o
O
In
9'
1 .
.
.
.
I.
_
u
. . o
. . D
. I . ‘ .
. (u
f
\
cl. r a
v

L3.
3-hsin ~4-pheL'1- 5- (p-bforonne treat '1)-k-H.1,2,4- ~
triazole
A solution of 8.6 g. (0.05 hole) of p-bromophenol
in 10 ml. of methanol wa.s treated x.ith a solution of 3 g.
(0.075 mole) of sodium hydroxide in 6 ml. of water. This

solution of sodium o-bromophenoxide was then aided to a

solution of 6 g. (0.025 mole) of the hydrochloride of 3-
amino-h-phenyl- -5- chloromc thyl- 1,2,h-triazaole in 25 ml. of
methanol. After the initial reaction had subsided, the
flask was stoppered and permitted to st nd for forty hours.
Precipitation of the product began within five minutes. The
product was removed by filtration and additional product
was obtained by adding water to the filtrate. Both crors
of crystals were combined and washed three times with 200
ml. of water. The product was then recrystallized three
times from methanol to yield 3 g. (35$ of theory) of color-
less crystals melting at 182-1830 C.

Anal. Calc'd. for 015H13B rWhO: C, 52.19; H, 3. 79;

Br, 23.15; N, 16.23
Found: C, 52.26; H, 3.82; Br, 23.2b;

N, 16.28

1*[4'-Pheny1-5'~(p-brononhedot'reth l)-t'-d 1' 2',h'-
triazoly1—3.1-3-rienyltn“01rea

A mixture of l g. (0.003 mole) of 3-anino-h-
phenyl-5-(p-bromophenoxymethyl)-l,2,L-triasole and 3 ml.
of phenylisothiocyanate was heated on the steam bath for

two hours. It v13 then cool d in an ice bath and treated

or

L9.

with 50 ml. of ligroin to precipitate the phehylthiourea
derivative. The product was removed by filtration and
recrystallized twice from methanol to yield 1 g. (695
of theory) of product melting at 188-1900 C.
Anal. Calc'd. for CZZngBrNSOS: Br, 16.63;
N, 1A.58; S, 6.67
Found: Br, 16.47; W, lh.80; S, 6.67

3-1:ino-A-pheny1-5-(p-chlorophenovvrethV1)-4-H.1, It-
triazdle

A solution of 6.5 g. (0.05 mole) of p-chloro-
phenol in 25 ml. of methanol was treated with a solution
of 5 g. (0.125 mole) of sodium hydroxide in 10 m1. of
water. This solution of sodium p-chlorOphenoxide was
then added to a solution of 12.25 g. (0.05 mole) of the
hydrochloride of 3-amino-b-phenyl-S-chloromethyl-l,2,L-
triazole in 50 ml. of methanol. After the initial
reaction had subsided, the flask was stOppered and
permitted to stand for one week. The precipitated pro-
duct was removed by filtration. Additional crystals
were obtained by adding water to the filtrate. Both
crops of crystals were combined and washed three times
with 200 ml. of water. The product was recrystallized
three times from methanol to yield 8 g. (55} of theory)
of colorless crystals melting at 197—1980 C.

Anal. Calc'd. for CI5H13Clth: C, 59.90;

H, 4.35; Cl, 11.79; N, 18.63
Found: C, 59.81; H, 4.L3; 01, 12.08; N,18.86

50.

O c

l-Eh'-Phenvl-5‘c(p-chloronhenoxvmethV1)-A'-H,1',2'li'.
triazoly1:3Tj:E-nhenvlthiourea

A mixture of l g. (0.003 mole) of 3-amino-L-
phenyl-5-(p-chlorophenoxymethyl)-1,2,h-triazole and 3 m1.
of phenylisothiocyanate was heated on the steam bath for
two hours. It was then cooled in an ice bath and treated
with 50 m1. of ligroin to precipitate the phenylthiourea
derivative. The product was removed by filtration and
recrystallized twice from methanol to yield 0.6 g. (htfi
of theory) of product melting at 185-1860 C.

Anal. Calc’d. for 022H1801N503: Cl, 8.13;
N. 16007; S. 7.36
Found: Cl, 8.03; N, 16.22; 3, 7.28

 

A solution of 7 g. (0.056 mole) of p-methoxy-
phenol in 25 ml. of methanol was treated with a solution
of 5 g. (0.125 mole) of sodium hydroxide in 10 ml. of
water. This solution of sodium p-methoxyphenoxide was
then added to a solution of 12.25 g. (0.05 mole) of the
hydrochloride of 3-amino-h-pheny1-5-chloromethyl-l,2,A—
triazole in 50 m1. of methanol. After the initial f 6
reaction had subsided, the flask was steppered and per-
mitted to stand for twenty-four hours. The solution
became intensely red and after five hours beautiful,

colorless needles precipitated. The precipitated

C.

“no a:-

a
.
.
.
u
-w. .,
.
C

 

 

. u
a
ll - ‘ -- ,, > . . -- ‘ , _.
,)
I ' '
O 0
~» I.)
‘ .
'~ .
.
- C
n
. .
'3

 

“1.1,

b
I
n
v... .
’ r
u
I
. o
I
.
a.
c_~
_. ‘

   

 

-..
.4
I I 'Dr I.
l
u - a...
. . .
,-
l
J x
g -
‘ o 0
A
0 ~—'
"--“’- A
,.

 

.‘ ’
v.
o
Y
a
n
.
.
>‘V

‘55-..u... M-

.
.
1
I
, .
o. 0
. A
.
, \l
, .

51.

product was removed by filtration and additional crystals
were obtained by adding water to the filtrate. Both
crops of crystals were combined and washed three times
with 200 ml. of water. The product was recrystallized
three times from methanol to yield 9 g. (60$ of theory)
of colorless needles melting at 179-1800 C.

Anal. Calc'd. for CI6H16Nh02‘ C, 6h.85; H, 5.tt;

N, 18.91.
Found: C, 6L.82; H, 5oh2; N, 18.85

 

lgCA'-Pheny1-5'-(3-methoxyphenoxymethyl)-h'-H,1'.2'.4'-
triazolyle3'J-3-phenylthiourea

 

 

A mixture of 1 g. (0.003 mole) of 3-amino-h-
pheny1¢5-(p-methoxyphenoxymethyl)-L-H,1,2,h-triazole
and 3 m1. of phenylisothiocyanate was heated on the
steam bath for two hours. It was then cooled in an ice
bath and treated with 50 ml. of ligroin to precipitate
the phenylthiourea derivative. The product was remived
by filtration and recrystallized twice from methanol to
yield 0.7 g. (50$ of theory) of product melting at 177-
1780 0.

Anal. Calc'd. for C23H21N5028: N, 16.23; S, 7.h3

'Found: N, 16.43; S, 7.11

0" ‘9‘

3
l.

52.
3-Amino-hgphenyl-§~(p-methvlohenoxymethyl)~g-H,l.2,&-
triazole

A solution of 5.h go (5.h m1., 0.05 mole) of
p-cresol in 10 ml. of methanol was treated with a solu-
tion of 3 g. (0.075 mole) of sodium hydroxide in 6 ml.
of water. This solution of sodium p-methylphenoxide
was then aided to a solution of 6 g. (0.025 mole) of the
hydrochloride of 3-amino-L-phenyl-S-chloromethyl-l,2,h-
triazole in 25 m1. of methanol. After the initial
reaction had subsided, the flask was stOppered and per-
mitted to stand for twenty-four hours. Precipitation_
of the product began within five minutes. The precipi-
tated product was removed by filtration and additional
crystals were obtained by adding water to the filtrate.
Both crops of crystals were combined and washed three
times with 200 ml. of water. The product was recrys-
tallized feur times from methanol to yield 5 g. (71%
of theory) of colorless crystals melting at 168-1690 C.

Anal. Calc'd. for CléHléNLO: C, 68.55; H, 5.75;

N, 19.99
Found: C, 68.41; H, 5.92; N, 19.99

legk‘rPhen11-5'-(p-methr1 henomeethyl)-4'-Hll',2',A'-
triazoly -§[J-§-phenylthiourea

 

A mixture of 1 g. (0.0035 mole) of 3-amino-L-
phenyl-5-(p-methylphenoxymethyl)~1,2,h-triazole and 3 ml.

of phenylisothiocyanate was heated on the steam bath for

‘5

D.
' u
1
Q
I
\
s.
I- "
‘. ‘° ”'" r‘---— “, .
. o

 

~~
.
- .
.

n

A .

53.

two hours. It was then cooled in an ice bath and treated
with 50 ml. of ligroin to precipitate the phenylthiourea
derivative. The product was removed by filtration and
recrystallized twice from methanol to yield 0.7 g. (50%
of theory) of product melting at 168-1690 0.
Anal. Calc'd. for 023H21N5OS: N, 16.85; S, 7.71
Found: N, 17.07; S, 7.56

3«Amino-h-phenyl-jejo-methylphonoxymethyl)—§-H2;I2,5-

_. triazole .

A solution of 5.4 g. (5.h ml., 0.05 mole) of
o-cresol in 10 m1. of methanol was treat d with a solu-
tion of 3 g. (0.075 mole) of sodium hydroxide in 6 ml.
of water. This solution of sodium o-methylphenoxide
was then added to a solution of 6 g. (0.025 mole) of the
hydrochloride of 3~amino~4~pheny1-5-chloronethyl-l,2,h-
triazole in 25 ml. of methanol. After the initial .
reaction had subsided, the flask was stoppered and per-
mitted to stand for twentyofour hours. Precipitation
of the product began within thirty minutes. Finally the
mixture was heated for thirty minutes on the steam bath,
cooled and treated with water. The colorless, crystal-
line product was removed by filtration and recrystallized
three times from ethanol to yield 2 g. (30} of theory) of
colorless crystals melting at 186-1870 C.

Anal. Calc'd. for 016316NLO: C, 68.55; H, 5.75;

N, 19.99
Found: C, 68.61; H, 5.76; N, 19.87

/..
. .-
. .5
o I\
.n ,,
0
v
V
,. v ..
i C
. 0‘
,( I.
. i O
. U
_ .—
.
y
u. 0
. . o .
. IV 4'
O
0.. C

5h.
l:E4'uPhenylo5}~(o-nethylnrenotymethvlj-h'-H 1'.2' 4'-
triizzolyl~ ~3;2:35ph erjlthi ourea
A mixture of 1 g. (0.0035 mole) of 3-amino-h-
phenyl-5-(o-methylphenoxymethyl)«1,2,h-triasole and 3 m1.
of phenylisothiocyenate was heated on the steam bath for
two hours. It was then cooled in an ice bath and treated
with 50 m1. of ligroin to precipitate the phenylthiourea
derivative. The product was removed by filtration and
recrystallized twice from methanol to yield 0.6 g. (#35
of theory) of product melting at 182.1830 0.
Anal. Calc'd. for 023H21N503: N, 16.85; S, 7.71
Found: H, 17.00; S, 7.61

3‘!mine-gepnenyle5~(m-nethy;phen0tyr.thyl)~§-H,l,2,§
triaaole

A solution of 5. A g. (5. b m1., 0.05 mole) of
m-cresol in 10 m1. of methanol was treated with a solu-
tion of 3 g. (0.075 mole) of sodium hydroxide in 6 m1.
of water. This solution of sodium m-methylphenoxide was
then added to a solution of 6 g. (0.025 mole) of the
hydrochloride of 3-amino-h-pheny1-5-chloromethyl-l,2,L-
triazole in 25 ml. of methanol. After the initial J
reaction had subsided, the flask was stOppered and per-
mitted to stand for forty-eight hours. The solution
was then heated on the steam bath for thirty minutes,
cooled and treated with water. An oil separated which

crystallized upon cooling in an ice bath. The p: oduct

0

fl

.
a
_,
, .
4
. a o
.. J-
l
r
v y
;
‘1
n

.-
s
'v
‘
.
u. ‘
-
.
v
I
1
l
'. .
\,.'

 

u.
-q
.
.
.
~_ .'
v :7
.u.
.
.
I
’ ( .
, .,a
.
.
i
. a
‘ .
. J
”)‘t
.
~ .
.

55.

was recrystallized three times from toluene to yield 2 g.
(30% of theory) of colorless needles melting at 155-1570 C.
Anal. Calc'd. for 016H16NLO: C, 68.55; H, 5.75;
N, 19.99
Found: C, 68.55; H, 5.90; N, 20.23

 

 

l-[gtgPhenyl-fi'-(m-methv1 henoxymethyllcg'-H.1',2'.A'-
triazo yL-gij-fi-phenylthiourea

A mixture of 1 g. (0.0035 mole) of 3-amino-h-

 

phenyl-S-(m-methylphenoxywethyl)-1,2,h-triazole and 3 ml.
of phenylisothiocyanate was heated on the steam bath for
two hours. It was then cooled in an ice bath and treated
with 50 ml. of ligroin to precipitate the phenylthiourea
derivative. The product was removed by filtration and
recrystallized twice from methanol to yield 0.5 g. (35%
of theory) of product melting at 166-1670 6.

Anal. Calc'd. for C23H21N503: H, 16.35; S, 7.71

Found: N, 17.15; S, 7.53

1:§gino-hgpheny — ~thio henox eth l- -H 2. otriazole

A solution of 5 g. (5 ml., 0.05 mole) of thio-
phenol in 10 m1. of methanol was treated with a solution
of 3 g. (0.075 mole) of sodium hydroxide in 6 ml. of water.
This solution of sodium thiOphenoxide was then added to a
solution of 6 g. (0.025 mole) of the hydrochloride of
3-8mino-h-phenyl-S-chloromethyl-l,2,h-triazole in 25 ml. of

VI

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56.

methanol. af‘ter the initial reaction had subsided, the
flask was stoppered and permitted to stand for seventy-
two hours. The mixture was then heated on the steam bath
for one hour, cooled and treated with 200 ml. of water.
The product which precipitated was removed by filtration
and washed with water. It 153 recrystallized three times
from toluene to yield b 3. (57s of theory) of colorless
crystals melting at 130-1320 c. '

Anal. Calc'd. rap algnlhuhs: c, 63.80; H, 4.97;

N, 19.8h; 3, 11.35
Found: C, 63.72; H, 5.1h; N, 19.86; S,ll.h7

l: -(h'-Phenyl-5'othiophenoxymethy1-4'- .1'.2',§' ~triazoly1-
unhenvlthiourea

A mixture of 1 g. (0.0035 mole) of B-amino-h-
phenyl-S~thiOphenoxymethyl-l,2,h-triazole and 3 ml. of“
phenylisothiocyanate was heated on the steam bath for two
hours. It was then cooled in an ice bath and treated with
50 ml. of ligroin to precipitate the phenylthiourea deri-
vative. The product was removed by fi1tration and recrys-
tallized twice from methanol to yield 0.5 g. (433 of
theory) of product melting at 1h1-1h30 0.

Anal. Calc'd. for C22H19fi532: N, 16.77; 3, 15.36

Found: N, 16.70; 3, 15.50

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57.
Qfdmino-hgphenyl-S-(p-chlorothiophen xymethyl)-h-H.l.2,a-
5' triazole

~A solution of 7.2 g. (0.05 mole) of p-chloro-
thiophenol in 25 ml. of methanol was treated with a solu-
tion of 3 g. (0.075 mole) of sodium hydroxide in 6 ml. of
water. This solution of sodium p-chlorothiophenoxide was
then added to a solution of 6 g. (0.025 mole) of the
hydrochloride of 3-amino oh-phenyl-5-chloromethylul,2,L-
triazole in 25 ml. of methanol. After the initial reac-
tion had subsided, the flash vas stoppered and permitted
to stand for sixty hours. The solution was then heated
on the steam bath for thirty minutes, cooled and treated
with 200 m1. of water. An oil separated which crystal-
lized upon cooling in an ice bath. The product was re-
crystallized three times from toluene to yield h g. (50%
of theory) of colorless crystals melting at 121~1220 0.

Anal. Calc'd. for 015H1301NL3: C, 56.86; h, b.13;
Cl, 11.19; N, 17.69; 3, 10.12;
Found: C, 57.13; H, 4.25; Cl, 11.22;
N, 17.90; S, 9.92

l-[gy-Phenyl-fij~jp-chlorothlo henoxymethyl)-lv-s.l:.2'.41-
triazolyl- - -phenyIthiourea

A mixture of 0.5 g. (0.002 mole) of 3-amino-h-
phenyl-5-(p-chlorothiophenoxymethyl)o1,2,h-triazole and

3 ml. of phenylisothiocyanate was heated on the steam bath

v - . .n
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at '
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58.

for two hours. It was then cooled in an ice bath and
treated with 50 ml. of ligroin to precipitate the phenyl-
thiourea derivative. The product was removed by filtra-
tion and recrystallized twice from methanol to yield 0.h g.
(57% of theory) of product melting at 167-1680 0.

Anal. Calc'd. for 022H1301N582: Cl, 7.8h;

N, 15.50; S, 1h.19
Found: Cl, 7.96; N, 15.52; 3, 1h.06

r4-

-9.

59.

Summarv
_ In the course of this investigation, three
different series of compounds having varied substituents
in the fifth position of 3-smino-h-phenyl-A-H,1,2,h-
triazole were.synthesized. The starting material for
these syntheses, phenylaninoguanidinium bisulfete, was
first prepared in the course of this work.

| A procedure was perfedted for the conversion
of 3-amino~h-phsnyl-S-hydroxymethyl—l,2,4-triazole to
the hydrochloride of 3~amino-hcphenyl-5ochloromethylo
1,2,hatriazole in good yield. The latter was a required
intermediate for.the synthesis of the 5-dia1ky1amino-
methy1~, the 5-phenoxymethyl~, and the 5-thiophenoxy«
methyltriazoles.

Phenylthiourea derivatives of most of these

new aminotriazoles were prepared. In a few cases, a

number of the hydrochlorides and acetyl derivatives

were prepared.

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60.

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g...

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V‘s

a“

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t

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C...“
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t .‘..'f.:

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5

, -
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Y

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f '\
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u .‘v
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I ‘t
‘_. V
-. , ‘1 ,

_. 4
,. .

' u

I —-.

-

» .-
r
>~

( r
.
.

. -?

1 .

7

a ' -M
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J...

i

k .
a
.
....

A 7

0‘ -

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A

~ 0‘

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