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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21