PREPARATIOI OF 4-4M»0-.3-Hfimi.2I10-5-MBfTO-

S~TR1AZQW DIHYDROCHLQRIDE AID

COSDEHSAflOI PRODUCTS

APPROVED:

/ / <Uc'( / , . ;

ErofesBor

Minor i¥0res80r /S

'/V )J . ^f 'tlae Departfflent "of Chemistry'

Dean or the Graduate School

PBIPABAflOI Of 4-^MIIO-3^3nBAZIIO-5-«B9fHn.~

** ml) TA 7 AT IS1 "hTUVTffi AI^UT AD Y l W A 1JTI

S«*5JR JUL-6 vJUS JPittXJMyv.MJyyiC4iJs JUiJJ

GOEDENSASIOI PROBACIES

XHB8I8

Presented to the Graduate Council of the

North Texas State University in Partial

fulfillment of the Requirements

For the Degree of

MASTER Of SCIENCE

By

Thomas D. Westmoreland, Jr., ®* S.

Benton, $em®

August* 1965

TABLE OF C0N5EKS

Page

l i s t Of TABLES i T

LISf OF mflSSRATIOHS • Y

Cimpter

I . IHTRODOCTIOH 1

I I . DISCUSSIQ* 6

I I I . EXPMIMENTAL 12

I ? . COHCI2JSIOH . . 20

BIBMOORAPHT . • 21

i l i

LIST Of fmiMB

f&fele Page

I. AryltoenEiliden# Derivatives of 4-Amino-3-%drasino«5-Met333rl-s-*1!rlaEole Bifcydroohloride (III) 10

iv

l i s* m mMmmmm f l for* H^p

1* ayntheftiB of %arooialbrides of 4nlattM«f«* %(lrar.irio-5-i£3cti^l-a-triaKole . » f • * » « « .2

3y»t)»«ia &£ mm** woA Barlifttives

c m w m i

IHTRODXJCSIGH

s-friazoles with alkyl or aryl aubstituents in the

4-posltion were first prepared by dehydrating 2~4iacyl~

hydrazines in the presence of a primary amine (4).

4^ala©»3#5*41aubstitut®d-«-triaj5©l@fs war# obtained fey

replacing the primary amine with hydrazine hydrate to react

with s-diaoylhydraislnes or fey hasting the carboxylle acid

aad hydrazine hydrate in an apparatus that allows th@

continuous removal of water (2). friaaiinoguanidl ne hydro-

chloride has been refluxed with various carboxylic acids to

produce the respective 4~^mino~3,5-disuhstituted-s—tria-

zole©. far example, triaminoguanidine hydrochloride (I)

will react with glacial acetic aoii to give 4-acetamido~3-«

acethydraalao-S-aathyl-e-triaBOl® (la) (5)# (figure 1, p* 2.)

fhe nucleophllic character Of the 3~hydrazino group

would indicate the possibility of oarbonyl condensation

with various aldehydes and ketone®. Sine© triazoles have

been ahowa to possess a high degree of stability and aroma-

tic character (4), hydrazino-substituted triazoles would be

expected to possess reactivities similar to that of phenyl-

hydrazine in the formation of hydrazones in weakly acidic

media, fhus, 4-aiaino»3-hydra2ino-5-Biethyl-0«-triaziole hydro-

chlorides would b© expected to react with various aromatic

1

H2n-N=C ( m - m . 2 ) 2 * HCI

1

AcOH

v

N N 0

II ^ . H 3 C ' ^ N ^ N H - N H - C - C H 3

I NH-C-CHo

II 3

0

HCI, H20

l a

HCI, H20

N N

X HCI

H3C S N X NH-UH2

nh 2

I I

IT N I I H3C ^ N ' " N H - m 2

NH2 2 HCI

I I I

Fig* of hMrocM-or ides of 4«amino-3* h j a r a z i n Q - S - a e t l i y l - s - t r i a z i o l © •

3

aldehydes and ketones to produce stable hydrazone deriva-

tives . Since the benziliden© derivative of 4-araino«-3-»

hy dr a a ino~5^M thy l~s~tr ia zale hydrochloride has been

effected in good yields from benzaldehyde (5)» the con-

densation of substituted benssaldehydes aeems feasible.

fhe reactivity of 4~aminotria2;ole with carbonyl groups

indicates that the triazole readily form® Schiff'a bases

(4)* the infrared study of aminotriazoles reveals f-H

deformation characteristic of a primary amine and aromatic

Q-H absorptions, indicating the similarity M resonance

structure between the aminotriazolea and aromatic amines

(4). A® would have been expected the monobenjaoyl derivative

of 4»5-diamino«3«ph©nyl-3-triazole has been isolated under

mildly basic conditions and further reaction of the mono-

benzoyl derivative or,treatment ©f the diamine with an

excess of benzoyl chloride gave the dibenaoyl derivative (3).

Condensation of carbonyl groups with nitrogen o<w-

pounds are characterized by general aoid catalysis. Al-

though it 1® difficult to prepare hydra zones fro®, hydrazine

because the hydrazones tend to react further# produoing azines,

the hydrazones of aromatic amine0 are generally easy to iso-

late | however, further polymerization aad condensation have

been observed for the derivatives of aromatic amines#

Catalysis by strong acids ha® proved to be rather in-

effective because the protonation of the nucleophiles tends

4

to forci inactive derivatives of the ammonium ion# Effective

catalysis can toe induced "by til® us® of weak acids, such as

ac@tio acid, which do not inactivate large amounts of th«

nueleoj)Mle (1) •

CHAPTER BIBLIOGRAPHY

1. Gram, Donald J . and George S. Hawtond» Organic Ohemlrfcry, l#w York, McGraw-Hill Book Company, InoT, i$59.

2. Herbal;, Robert M. and James A. Garrison, "Studies on the foraation of 4-Aiainotriazol© Derivative. from Aeyl Hydra aides #

M fit® Journal of Organic Chemistry, X?III # * L . ^ MM. rwtlTTh-it-tfriiiiri 'iTff11Wwia''ijWWiinif-'irrTntr-rnrr-•'r.jr1^ lar i i in ,,. iiiTiitiiMpwrrT-iritiiirt rtfr--~tr'~ *

{July-DecemberT^1953), 872P877T 3. Haggarth, Brie, "Compounds Related to f hioaemioarbassid©.

Part T. 4 i 5~M&mino~3~l>heayl*4 i Is 2-tr iazole,« Journal of the Chemical Society, m m , 614-617. ' :

4. Pot t s . K. tt$h« Chemistry of 1,2,4-friaaol.es,« Chemical Reviews. IXI (1961)* 87-127. '

5. $akladt0| B. H., G. B. Iteaamlt, and S« Botta, "Syntheses and Reactions of 5-Allcyl-4~amino-3-hydra2iino*s^ ( S t o o h l e i | 6 5 f r ? f f ^ ^ ~ Chemistry, SX

CH4PTBR II

DISCUSSION

fi le procedure of Sakimoto, Dsnault, a M Hotta (3) was

followed la order to prepare 4-amino~3-hydrazino-5~methyl-

s - t r i a z o l e hydrochlor ide ( I I ) and its p r e c u r s o r , triami»G«

guanidin® hydrochloride ( I ) . (Pigure I , p. 2.) fhe product

melted t h i r t y - e i g h t degrees below the r epo r t ed mel t ing point

for I I . f l t r o g e n analysis and quantitative chloride analysis

were in agreement with those of the compound 4-amino-3-hy<ira~

zlno-.5-methyl~a~triazol® dihydrochloride ( I I I ) , Although

the procedure was repeated e igh t t imes , only the d ihydro-

chloride (III) was obtained. An alternate procedure for

the preparation of the monohydrochloride (II) ( r e f l u x i n g

4Hac©taiaido-*3-ac©thydrazino-5-methyl*-s-triaaole hydrochlor ide

(3) in dilute hydrochloric aold) was employed? again only the

dihydrochlor ide ( I I I ) was obtained.

$he benzilidene d e r i v a t i v e (V) of III was prepared for

comparison with the reported (3) benisilidene derivative of

I I . She melting point of the yellow c r y s t a l s was identical

to that reported by fakiraoto, Denault and Hotta (3), with

a comparable per cent yield. A nitrogen analysis confirmed

the isolation of l~pheny 1-3-benzilid©nehydrazino-5*-iae thyl-

a-triazole hydrochloride (V).

6

$he benzill&ene hydrochloride (?) was readily isolated

as a 3-substitution product when a snail excess of hydro-

chloric acid was used. The 3~m@thylben2iilidin@ hydro-

chloride was isolated using the same general procedure.

l-Phenyl~5-*aethyl-3~acetyl-s-trlazol@ (2), prepared

by the method of Reglta and Bistert (2)» condensed readily

with III to give 4-amlno-3~{l~ [3-(l~phenyl~5-raethyl~0~

triassolyl) ] ethylidene} hydrasdno-5~methyl~8~triajsol© (I?)

in aqueous solution containing an excess of sodium acetate,

(figure 2, p. 8.) Disubstltutlon did not ooour nor was the

hydrochloride of If formed. Mo reaction was observed when

the preparation ©f If was attempted In aqueous hydrochloric

acid.

fhe addition of sodium acetate enhanced the conversion

of III to If# fh© sodium acetate not only converted the

ammonium ion t© the free hydrazine group hut also made avail-

able acetic acid which, 1® known to he a useful catalyst In

the condensation of carhonyl groups with, nitrogen compound®

(1). Several mmo- and disubstituted benzaldehydes were added

to aqueous solutions of III and sodium acetate. In most cases

precipitation occurred within the hour and within twenty-four

hours in the rewining oases.

Mas majority of the derivatives were isolated as

3-arylidene hydrochlorides, but 3-arylidene free bases and

N N

A,i, I m2 2 HCL

H3C

N N-CAH*

JLi HQC-C ^ N - ^ C H O

3 II 3

0

NAOAC

N N N N-CXHRJ JI I J H ^ C ^ I T NK-N=C ^ ! T X H O

3 I I 3

NH2 CH3

P I G . 8*«A|R»«TAM&I ®F

9

N N

A-i HqC N NH-N=CHAr J I

NHo

N N

1 il HoC ^ N x NH-NHo 3 ,

m 0 2 HCl

ArCHO N N

X.i » ^T\T^ TV HoC N NH-N=CHAr

3 I NH2

H C 1

N N

X i HoC ^ N - ^ MH-N=CHAp

J I N=CHAr

t i g . 3~~Syntheaia of mono- and diaryl ldene der ivat ives ©f 4-amiao-3-liy<iraKino-5-Hi@t]ayl-s«-triazole *

10

3,4-diarylidene derivatives were also Isolated, (figure 3,

p. 9^ Tmfcl® I list® the particular derivatives for tiie

corresponding arylaldehydes and tit® conditions accompanying

the reactions.

*mm i

m t m s m i M M m derivatives of 4-&miso-

DIHYDROCHLORIDB (III)

Aldehyde Isolated GompouMs

Aldehyde 3~Arylid0n« 3-&ryXxds£« Hiydroclalorid® 3f 4-Diarylidene

Benzaldekyde (T) 3-*«thyl-

(VI) kenzaldslayd® (VI) 4-Methyl-

(VII) benzaldehyde (VII) (XI) 4-Metiioxy<-

(VIII) feenssalde&yde (VIII) 4-Acetamido-fcenaalde&yde (IX)

2 # 4-Biiiydroxy-(X) benisaldehyde (X)

2-Hydroxy-(XII) toenzaldefeyde (XII)

4-Hitro-"fcenzaldeliyd© (XIII)

2'-®yTidiM-carfcoxBld©-&yde

1 ny 1 *»$ » (XIV)

metliyl«»3~

(IV) trlasol* (IV)

cmPiEB

1. Oram, Donald J. and George S. Haantond, Cranio Ciitmiatryt lew York, McGraw-Hill took Company, lic77Tf5fI

2. Roglts* Manfred and BornA Bistort, MITbor Me Bildung von 1,2t4-®riazoldarivatan aus oUAoetamina*-?* dicarbonyl-Z)ia«oQlui&8altzen9

tt Chemlaohe Berio&te, X0?I (Stptomfcer-December, 1963)> 5120-51577

3.- Takimoto, H. 1., G. C. Domuirt, and S. Hotta, *Synth*w and Reactions of 5^1kyl--4~eu&ino-3-4iydrasino-£-triaz@l®Sf,, $he Journal of Or&antc Ohgmiatr^, X H (March, 196517^^^7137

11

cmasm i i i

qgW» M«W»*T.

•©Glalerid# {til)

fm 0mm (0.071 sk&m) of I (2) *«r« p3ao«A i© 30 a i l U -

®f gkamUX mmtte mi& m& reflttawii tm mix%mii imwm9

giving a Xlglit~er«0ft aoltttteB* Sb« *o*tio a«M WW reaovni

imOur gartlftX leaving * frotfay,

f t s id^ , &m hunftr«d ttiUilltm of § 1 tiy&ros&ierlo *ei4

nwfi added t# tb» reside ®M tft* r«»ultlug solution «s@

n M for tm Inns?#* fl»' *oid mm mm&md

untor jtrttftl mouuss, iMnriag grtioiiMliilt ory*tal*. fte

m i i t i mm ti»ii«a?irfc©4 wiHi to* etiiaool to yitld 10.11 grwii

(70*5 y«r vblofe awltad at 21O«2110 o 4«o«

Amly»i»i Cftlad* tm l t 44»ff| 01* 55*32

fouadt I t 4&«9»» 01» 36M

4^4MrnmfmSm

tm

Oct p h i (0*00? »el««) tf 111 m» *iMM»lv»d in * alaiaua

amount ©f attir* ©»® ®rm (0#005 »©!©») of I-#latayXw^nHkqrlw

5-©eotyl-s-tria2;oi'3 (1) (Xf) a&6 0«XS pi*®® (0*0082 molea) of

rn&im m®1»t® nwr« *dd«d9 &»a tia# mu hmtwk

m m t*th for thirty aiiwt#»» fte wait.® ml$A v/tiich f§r«»4

3Lt

13

was suction filtered and dried In the oven overnight. Re-

crystallisation from water, followed by s t w i l washings with

acetone, gave 0.34 grams (21.9 per cent), melting at 251-252.5°

0 dee.

Analysis* Calcd. for H» 40• 2?

foundt !* 40.58

4-Amino -3 -be nzilidenehydra ssino-5 -methy1-s-triazole Hydrochloride (?)

On© and sixty-five hundredths of a gram (0.0082 moles)

of III wire dissolved in a solution of 30 milliliters of

water, two milliliter® of ethanol, and one drop of concentrated

hydroohlorio mold. One and one-tenth grma (0.01 moles) of

benzaldehyde were added dropwiae. She resulting solution was

gently heated on a steam "bath until the yellow precipitate

began to settle. After an hour the solution m a filtered and

the solid was dried in air. fhe crystals melted at 249-250°

C dec., whioh agreed with the value reported by faMmoto,

Denault, and Hotta (2). fht crude product gave 2.03 grams

(98 per oent).

Analysis! Calod. for I, 27.79

founds N, 27.63

4-^ino-3-®ethylbe»ssilld@nehydraJSino-S~iaethyl-s-triaiole Hydrochloride (VI)

One gram (0.005 moles) of 111 was dissolved in a

solution of 30 milliliters of v*t«r» two milliliter® of

14

ethanol* and two drops of concentrated hydrochloric acid.

Seventy-two hundredths of a gram (0.006 moles) of 3-msthyl-

henzaldehyde were added with stirring. fhe solution was

heated m a steam "bath for 30 minutes and allowed to stand

overnight* fhe long green crystals were r©crystallised froa

ethanol t© yield 0.87 grams (75*3 t@r cent) of light-yellow

crystals which melted at 248-250° 0 dec.

Analysis* Calod. fop 0nHi§0U6i V» 31.50

foundi I # 31 #31

4« 4ffiino-3~( 4-©athylbensiHdene) hydrasino-5-methyl-8-triasola (YII)

four hundredths of a gram (0*002 molee) of III were

added t@ a solution containing 0.1S grama (0.0022 molea) of

anhydrous sodium acetate, 15 aillilit«rs ©f water, two milli-

liters of ethanol, and on® drop of concentrated hydrochloric

acid, fhe resulting solution was allowed to stand overnight.

A small volume of dilute sodium acetate solution was added

t® the solution before filtration, fhe solid wan dried in

the oven overnight. Recrystallization from ethanol/water

gave 0.32 grass (60.2 per cent) ©f light-green crystals

which melted at 216-220° C deo.

Analysis* Calcd. for C11H14I6: 3» 36#52

found* H, 36.11

15

4~( 4-Methoxybenailidene) amino-3-( 4-©ethoxyben»il-idene) -fay dr a z ino-s ~®e thy 1 ~s-»

triazole (Till)

To a solution ©f 0.18 grams (0.0022mol®s) of anhydrous

sodium acetate in 15 milliliters of water and two milli-

liters of ethanol was added 0*4 grama (0.002 moles) of III

and 0*27 grams (0*002 moles) of 4hm thoxyfcenzaldehyde. The

resultlag solution was left overnight. A small volume of

dilute sodium acetate solution was added before the solution

was filtered, fhe solid wa# washed several times with water

and then dried in the oven# Becrystallization from glacial

aoetio acid produced 0.09 grams (18#3 per cent) of yellow

crystals which melted with deoompouition at 228-233° C.

Analysis? Oalod. for G19ag0%Ogs K, 23.08

foundt V, 24.12

4-Aiain©~3~( 4-aeetaaidofeenalliden®) hydrazino-4-fflethyl-s-tr iazole Hydrochloride (IX)

fo a solution of 15 milliliter# of water and two milli-

liters of ethanol were added 0.18 grass (0.0022 moles) of

anhydrous aodium acetate, 0.4 gram® (0.002 moles) ©f III

and 0.3 grams (0.002 moles) ,<&$ 4-acetamidohenzaldehyde. the

solution was allowed to stand overnight. A email volume of

dilute a»ftiam<jacetate -solution was added to the solution

before it filtered and dried in the oven. Heerystalli-

ssation from glacial acetic acid gave 0.25 grams (40.4 per cent)

of orange crystals which melted at 279-281° 0 dec.

16

Analysiss Calod. for Cl2H16GH70s 1, 31.77s 01# 11.5

founds I, 30.491 <31, 10.1

4-AmiQQ-3-( 2j4Miihydroxyh@nzllid®ne) hydrazine-^* m#"fe%l-a»tria2sole Hydrochloride (X)

Into a solution of ten milliliters of water and ten

milliliters @f ©thanol were placed 0*4 grams (0.002 moles)

of 1X1 and 0.2 gram# (0.0024 stole®} of anhydrous sodium

acetate j 0.28 grams (0*002 moles) of 2,4-dihydroxyhenzal-

dehyde was added dropwis©. After the solution was left over-

night , it was filtered, washed with water and acetone, and

dried in an oven for several hours. $h@ solid was re*

crystallized trm glacial aoetia aoId/water and dried In

the una overnight, giving 0.06 grams (10.6 per cent).

$h® yellow crystals melted with decomposition at 280° C.

Analysisi Oalod. for 010H1501H602t 1, 29.52

founds I, 31.00

4-(4~m®thylhenzllidene)amin©~3-(4-methylhenallidene) hydrazino-5-ffl«thyl»8«triagol8 (XI)

J® a solution of fifteen milliliters of water and ten

milliliters of ethanol were added 0»35 grans (0.0042 moles)

of anhydrous sodium acetate and 0.4 grass (0*002 solos) of

111 I 0.15 grams (0.00121 moles) of 4«-methylfeenallld@n© war©

added dropwise. She resulting solution was heated on a

steam hath for one hour and then allowed to stand.for

several hours, the solution was auction filtered and the

17

solid wae washed with wattr before it was dried oyer phos-

phorus ptntoxide overnight. T'h& yellow crystals, whioh

represented less than a 10 per cent yield, melted at 190.4-

192.5° 0 with decomposition.

Analysis! Calod. for C^lgQlg* N, 25*30

Founds I, 24*93

4-Amino~3~( 2~hydrGxyb@nzilid@ne) hydrasino-5-methyl-s»tria zole hydrochloride (III)

$0 a solution of 15 milliliters of water, two milli-

liters of ethanol, 0.18 gram® (0.0022 moles) of anhydrous

sodium aoetate, and 0.4 grams (0.002 moles) of III were

added 0.244 grams (0*002 moles) of 2-hydroxyhenaaldehyde.

fhe solution was allowed to stand overnight. A small volusui

of dilute sodium acetate solution was added to the reaction

mixture before filtering and drying in the own. Reorys-

tallissation from glacial aoetio acid/water gave lea® than

10 per ©eat of yullow crystal# whioh melted at 220-223° 0

dee#, after having turned rei at 200° C.

Analysis: Calod. for C10H13Cl%0s 1, 31.28

found* I, 30.17

4-4ain®-3-( 4-nitr ohenzilidene) hydrazino-5-iaethyl-s-triazole Hydrochloride (XIII)

Four-tenths of a gram (0.002 moles) of III were dis-

solved in 15 milliliters of water.- fwo milliliters of

ethanol and 0*18 grams (0.0022 moles) of anhydrous sodium

18

acetate wars added te the solution, flares-tenths of « gram

(0.002 moles) of i-nltrotoenzaldehyde were then added and tit

solution was left overnight. A small •volume ©f dilute sodium

acrtate solution was added to the solution before it was

filtered and dried. ®h@ orange crystals which melted at 212<»

2$®# 0 represented less than 10 ptr cent yield.

Analysis? Calcd. for C ^ ^ C l K ^ i H, 32.94

founds If 31.77

4-( 2»J,yri41nyl)m«tliylidaa«Miino-.3-( 2-pyridinyl) m@thyli&ene~hydra2dno~5^ethyl~

8»triazol« (XIV)

fo a solution containing 0*13 grams (0.0022 moles) of

anhydrous sodim acetate and 0.4 grams (0*002 moles) of XXI

In 15 milliliter® of water and two aillilitsrs of ethanol

were added 0.24 grams (0.002 moles) of 2-pyridineoar\>oxylio

aoid. fhs result lag solution was left o w r night. fhe

solution m a filtered, washed with dilute sodium acetate

solution and water# and dried in the own, fhe yellowiah-

orange solid melted at 218*»224° 0 dec.» giving lass than 10

ftr ©ant yield.

Analysist Calcd. for Cx5%4%f K» 32.03

founds 1, 32.44

CKlPfffi BIBLIOGRAPHY

1, Regitz, Manfred and Bernd Blatant, "Ufcer Die Bilduag iron 1,2 ,4~®rlmzolderiva'ten m ® ©tWUetwaid©- 0 «• dloarfeonyl-Siazoniumealt ssaia,M Ohemleohe BerioMe, ICTI (September-December, 1963), 5120-31 2•

2. faklaoto, 1* H., G. G. Benault, and S. Hotta, "Syntheses and Reactions of 5 1kyl~4 mifi0~3~i drai3inG~s~« triazoles»w Journal of Ormnl® Chemistry, XXX (Maroh, 196577^11-712 •

19

CHAJPTER IT

CGICBJS10I

The 3-arylidene hydrochlorides were obtained from

aquftous acidic solutions of III and the aryl&ld©hydes « Sub-

atitution did not take place at the tHudno position because

of the formation of the ammonium ion from the 4-emi»o group.

3}he addition of sodium acetate to the reaction mixtures

gave rise to varying degrees of substitution, fhe 2~arylid©n@

hydrochlorides were prepared from aldehydes which contained

deactivating groups. These aldehydes m m aot reactive though

to condense with the less nueleophillio 4-amino nitrogen.

Arylaldehydes which possessed activating groups gave 3,4-

diarylideaes.

20

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few, 9®saM jr. mm m m ^ s. Jtaioi*!* §M§ai£ glggfato l«w f«rkt Stoftr&Mwttlll Book 0«ai*w •*»»•# IIW"

Articles

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ftagilMt flwIMtftttft Boraft £l»t«r«9 wWi«r M * BiMtt* wn-..

aiii«oBiu«a»lt»aB,» JbM|gBgg. IWffiMftf* *0*1 (Sojrtwataoi JNH$iNlNHrt|i lf65J # #IJW^I2W*

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21