SYNTHESIS OF HETEROCYCLIC COMPOUNDS

ABSTRACT

THESIS

SUBMITTED FOR THE DEGREE O^

DOCTOR OF PHILOSOPHY IN CHEMISTRY

TO THE ALIGARH MUSLIM UNIVERSITY

ALIGARH

JANUARY 1972 MAHENDRA PRATAP SAXENA

A B S t EACT

tfaia thesl* e^nslflt* ef tvci jpaittt

%&the0li aai eli»siQ«l r«tetioii8 at

P«jri I ^ e t i b d t th* «j>iiih«tit of

with i^lMmasfli^lcit^ vz^ nt):^

toVbcmA I9- d^l iMtien in the prssane* of «iin(i« fteo b«aasflo9Qr

p^admlnio lM tier* eoi«trtirt«di to oorretpeaiditig l drosQr dwriirativss.

th» ir« nv aud mr ngixaetzm of tfamt oocpounit wero Also stndiod*

FoUoviDg ohwdeal rtaetiontt of

1,4-<lioxop7i«tliio(ttS-a)lado3l« tmro ttudiodt

1. 0At«3crtio l]|)rtljros«n*tim or«r pi«tiiiuii oaddo*

2. aoduotlon with lithism oIuainiixM tignirldit*

3. jOkiOiat hordroSjraia,

4. MtrttagrUtion with

5* BMotloD with bonsaldotg^*

(ti)

Part tl d»mrlh»9 tht of inaoSjo-S^cerbesainl esi

end and

•9ter* Thft Xattttx* vert ^ thss ived th t eiaidfaiMtimi of ehla^Oftefftspl

ipiioaa m^ tirtiMr with neti^l tollowad Isf oyoUs^tion In

th# ^«sttne« 0t mAim m^tmM9 audi soitos tMmagrloaddft r«fl|)eotivi^«

tbo oeiu!tn«kti(m of ib* eoxrtn^imdlsig et>|joxid« vitb

SYNTHESIS OF HETEROCYCLIC COMPOUNDS

THESIS

SUBMITTED FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY IN CHEMISTRY

TO

THE ALIGARH MUSLIM UNIVERSITY

ALIGARH

JANUARY 1972 MAHENDRA PRATAP SAXENA

nil

T1233

A C K N 0 M I, , D g B M ^ H g 3

eoithor expraAMs bis ddep a«ae« o£ gratitude to

Siiafeti fi./a^ed for tser guMaoes mi. coaatant

mGrnru imnt fchrougfemit tlii«

fflsthoy igmteftaiy «cta0wl«(if08 tlie h&lp in vorioae

reMereS to Mm Bur, Prcf.it.R.fldiwidii Dr.S.M.F Robasm,

mi Mr,P*L»G!«ptift.

Thanks are to C.S.I,R. and for finaBciaX Rssistance,

Kfthssaiya Pmtaip Serena,

Shis tbi»tl« eoiosiifca of ivo pcrtfts

I . eHmaixiwX v««otiont of

Psrt I d«seflli«s %im mpAim^M of

witli aM H-Stffelispi^oin* •tii^I osttra^

fc Xowcd iQr egcHmUm ia tlit fimsene* of tri«tf9r& Mini* fiM li«a8ijf!l03Qr

pyrtili»d»lol«o tmr* eolxvoHodi to tkt oowoaptai^ae ti^eaur d«i^iratlvii«.

tlMi w tmA tmt ii^aetra of thwm ooi|potiRaa mm also stini^ttl*

feUxnAng eltiiidoaJ. raaetlona of

1^4*^iexop3nm8ii»>(t»2*a}l»iola vara ata<Uadii

1 # Cataljrtie bjNbrogaaatlAO owr

platlmui oxida.

Radttotion tfiili l i thim altt«tt^a ti dxida,

3* AlkaXliia

4. ItetliorlaUon vith Ciy^aDKa*

5* Raaotioa vitb baoaaldatorda.

( i i )

JP«rt ZX dtseribee tht ipathtslG df

eater* fHa lat ter wero f^tliosiatd lyr tho eoadonsation of dfalorots^gtjri

asinds «ikl «8tcar idth nt t l^ l antiienmil«t« l^llovtd ejreiiflntloit In

tbir pt0tmtm oi oodSxai imthoxid* ftnS aodltoi IxiiimrioxMo

mm prti^sin^

th« o<i»d«Mnttio& of the tilth

varieiit e«tiaa.

C OB f 8 » f 3

f A R f « I

X. XMIROMt lOlj

• • • •

*

0OKII ohAHieaX rMotitm of

II, BIOTSSiOlS

a^lmtie 0f B*bom I«ii&3io iisM «steri

1,4r.di(aoigr»iiiiio{1,«**)iraJoil.et . . .

S^bMia of 8»trifiib8tittttiid 1«i^oxopstrniOmi 1 , A ) indolot • • •

Sjnntlwait of 6*tri«itwtitQt«d 1 p 4Niiox9p3miiiiio( 1, Indoltt . • • Zfi trv gxd vm of

triwbititiitod . . .

f f t p T ^ U m mod t^o««nation of

Ch««ieal rMotionc CAtalytio l:grdrof«B«tloo Uiak^Lim. with Alkali

Em&L

1

a

IS

29

34

36

41

46

48

51

56 5$

( i i )

Etdueticm with y . 10. B/ ••• ••• 5? 4

B«*etion vltH tMOitsMtt^d*

ni*

B|vithaiia of »stttr« •••

of eta^ ••• ••« fD

S^ttMsls of

f^pmrfttimi ffiid eatttJ^ie of

ChwdUwl ro&otloas

hsr^semt im «•• ••« ••• 9? with 14 A1 B^ «•• •*• ••• 9?

Bittotioa of MkaXi ••• . . . «•« 99 ••• ••• too

nti^iiotl vith l>eneiL]4«!isttd* ••• fOt »«£itr«no»t 4 • i l l

IIID0l>Br2»CimBaXMg08S

I. israoDomoB . . . 103

• •• .«. ••• 104

107

(iAi)

fhAimadologliial «oMvity of lnita»<»2*»e«rl)oiEiiiM«s

n . siaoisstoB

IH iijectri, of In!lol»«2-carl503iasl4»»

i n . m m i m m .

IC9

110

114

l i s

iai

m

129

m

141

1 - i i i

ypBUCAyioirs

ami £st«r

2. CfttiO ifii of Zf^&^tro-p^ttiml

Smuit c»d S.B«« lad* 37 (1971)*

X K f E O O V G t l O l i

X l i f R O B t l C t X O I l

Pm21BQ{ XKOQLES

Keraaelc* Perkln^ and RoMnaon (1) ^ r s t i^^heoiaed th is ring

^ s t e a naised i t as lsdoX»odiAzi^(ti4) inidl6(ti4)diaslae with

iKialMHrifig 00 in X. £At«r Johnson «nd his ooworksrs used the name

pyraeii»(%2»a)lndoXtt for this ring syetras (2)* this nem has also

bean adopted in the ring iMm (1959) with nuDbering at in XX. (Bavlssd

Bing Xi est Sjrstewi

\o

I N2

Mgpo-ox9"pyrf»iw( 11 g' ft) Iftdfflff I *

Xn an attaiqpit to prapara noiliariBan (XXX), a ooe^ound related to

- 2 -

hanilno «lkeIoi^ (X¥), Kormssk et aX. <ep« e l t , ) eoadmsed

cfeaoridA idLth ftigL^i«ti]isrl4C«taX to obtadn iitdoXo-SS-etrboiqraofttatX*

Affiide <V).

•N H

III rv

thi« sttbataeen c;y«li80dl in m eJLoohoMe soltition satai«t«ii with

ehlorid9, with the loss of t m isol«eiiles of aloohol* fhe eyt^c product

VM not tho Ic«to*aiMt^»orbarffiQn (VI)* slnea i t oould not Im

converted to noriunrm»n ,

K / ^ onHCM^cHtotiO, Q NH

O

V VI

- 3 -

flid eoi^^M oHtdnvd gem a poaitim raeetiozi i«dth SHrll,$h*9

r«ftg«at (dimtbyl§minolmnz»ld0l9yde Aiaoolv&i in nloohol ia tta«

preseset ot i^roohloric aiei4)| iaslicatiiig t it@& ponition on the

indtol« mielous. This eotiM onljr be the >-pe«itlo% sSme indol«s,

wbieh hevt 2 or 3 poKLtion give those rveetions* fber«f<a'e

this product ccm3d not b0 1,2-ai}iiy?Sr©-1-oxo-p^Sd(3#4^b)li«lolo ( t t ) .

Pf«9«BC9 of -^OHIi-gm^ toad pheaolie pr^mrtima ruled <%it th« 6orr«8pend'-

Ing ^aeelct stmctiiro (VH).

on N H < O^ci-f

N- c h

yii

7he onljr poaslbillty for tl)» eoapmnd obtainwl bar tboaa taithors

to b* 1|2''dihy<iro*1->o}i^pjrra8iao(1»S*ft)iiMloXa (VHZ).

•IM 0

NH

Vlll

•m m

Aeeording; to Xeraack^ Fomn «ad AoMnson " The fomation

of ring ^ r i n g th« action of aleofaolie t rdlrogon ehloridi* en

iniol«-l3-earbojiytte«tftl<ioM« (?) hA» taJw» iplaee with th» help of

fcQrdrogen atom of th* -NH-groap in the indole imeXaus*'. Actually

th«s« reaetio&a em het d«pict«d aat

(OEt)HC\^ MH

HCi Q - H

.N + -H

0 -H^o

Z

V\U

Latur on, John»cn et a l . (3) fbimd that lndole-2-carboxyacotalaialdo (V)

on e;yeliMtion in th« pres<me« of athanolio l^irogtn ehlorida or etharaal

ealphurlo aoid actually yielded an isoeorie sdacture of 1,a->dllQrdro-1«oxo->

- 5 -

pyr««i«o(t,2-«)indol« (mi) B0% a»d 'l,2-dlhy<lr 1-03«ipyrld(3^4-b)indole

• eo NHCH^CHCoEt)

V

HCWtOH

n •IM' o

NH

D s - ^ v H 0

VIU 6 0 % V f 20%

fhiqr aoparat^ tbsst tiro iaoners and establic^tfd thtt atruoiurt of

both thest eos^trnda \3gr ecH^parison of thair \iltr«viol49t absoi^stion

iq)ectra vith thoss of the oynth«tie isodtX eoe -ounds IX and X, {vrtparvdi

m ^

bgr blocking t- or 3- poslticm of the indoU itael«tts with a sietliyl

grmp, 90 tfcat tho ring cloaare oonH takA pltuse only mt one tbt

two potsitloBS <3- or 1- reap«ctivo3y).

Hd iJTOH ^

C H : hdiEvoH^ Or— ^ ^

0

iH

X

Sffect of mhetit^mtAa en ring forgatlom

SGUlkio and Forkln (4) and later on Jotmaon ot «!• (op. ol t . )

found tb@t tb» preaanee of «n alk^i group on tha nitrogen ato» of the

MBlnoQoatAl s t r m i ^ disfavours the fonsatlon of tlw pTresinolndole

iaoaart jrliadlng the oorrespod'Hng p^dindole .

- 7 -

«ffe«t of aiffftrant substituwita on thd onlitf »itrog«(it

«e wen es in tba indole ring, on tho ring eloear® was studlM lay

awasiy workers (^6) * This ie smanerlaed b«lowt

Xll

R

IK

M

R» » 331 yield XUX Yield

4-OGH C83 In traces Mtjor product (4) 5-OCB CHy 50 50 M 5-0C«3 B 100 m «

CH 50 50 0 \ 1 H 100 tt

20 m 11

6.CB B tyolisfttion does not oeottr« s^moost CHgPh m 100 <6)

- 21 -

fh9 rnhcm re&etjbns em so^pomA to JtoUow threugls tHe intoitiadiat««

Jda and Xlb laading to ihs formation of HI ai^ HXI raapdetiiraiy*

XI

0=HC NR

xiai

x\\

XDl

Jotmton and bis eoworkara obtaittod a mi&bMr of dM-ivatiiroa of

dioasvand t]rioxo-p3rraeino(t,£'<>a)indtola« during their work on tha atruotura

of tha antibiotic* mold aatabolita, gUotosdn (XIV). Taylor at aX. (7)

axanlnad tha cultures of PanieilHun terliHowakii for the presence of

1,2,3,4-tatrahgrdro-1,4-dioxojyraeiiio(1,2-a)lndolea. According to thaa©

- 9 -

e»thor9 ttuKCo are theoroticaX reasons for aasuaii^ thes! to be the

interao^ietee in the tjiosjmtheele of antlbiotios like fliotosdn*

riieae autlsora have also postulated 1,2,3»VtetrAlyf?Sre~t*4-3i©«»-a-

(XV) as the Moaynttaetie

ifitei^9sdU.ate of gliotoxic*

H^s KO 1 S

a ^CHt,

CHJLO H

XIV

u HO

N O

CH

xv

OliotoxLn (XIV) gave

(lf2oa}indolo (XVZ) on wariaing with Iqrdriotiie aoid eM redi phosphorus (2).

•N o

O-K^HCH^ CH,

XY|

- 10 -

Johnson et al* (op; eit«)

4iiB9t};Qrl*t#4-dio:>i39pyrasin0(1»2->a)ind0l0 (IVl) tgr eonci«xtsing thd

etlgrl •stffT of dl<»K-»fl(tt^lalaniiia with inSole-S-OdOCboityl ohXoildt

following a astbod usod •afliftt Isty Porkin et al* asltor

(XVH) pfo^dad tfi8 eyclifi^ on waming in th# pmBmc» of th« «thyl

Aoter of dL'l^awthjrlalanino (2,9) with tha loss of a asoleimlo of

athanol. 7hs ring eloeuro oouM oeeur at elthar ot 3-positioa of

the indole isioX^aa to promee th® p^ra«i2X>(1,2»a)indol« (XVI) or tha

i«MB0rie pyridijKlola (XVIII),

Q

cHj

N CH3

CO NCHCOOtl-CHa

^vrr

0 .CH

^ 0

Xviii

- 11 -

fhe ultravlelest absorption apectrua of tha coogpoand obtidnai by

eyclisetion of tho ©star (X/II) wa© found to bo striltlag3^ •iadlftr

to tbst of the eoJol coRpound (HX) In which ring <Sb8ap« at 3*poaltion

m» blocked tgr « notb^rl group. TMa modal eotipoimd wma pr^arad £ro»

3-ffletbyliiKiol«-2-oarbo3grli« acid aa follows (10)t-

|. S0d<2. '3

COOH NH CH Ch3 CHj

CH3

Johnaon at al* (op* e l t . ) found tliat the cjn:lisation of the cos^otrnds

related to XVXX tal»it placa in the preaenQe of a base, aminoaoid esters

and even anaionla ha* bean tmrA to catalyse this eyolisatlon. These

authors have also fovmd that alkylaticn at the aaidio nitrogen i s

- 12 -

absolutely •seontial for this eyoXiaation to take pXeee* In the

ftbaemse of the ftlkyi group on the ftmidlo nitrogcRi oycliaatlon does

not take place and th/» uiKi^xllsed starting omteriid i s reoovered*

Xhe steohanism of thia base oatail^sedi dyolisation can be represented

as followss

o

O

O

NCVA-CH3

8 " - H D N-

CH3

I

CHa

Johnson and Mmmw (11) obtained

3-B«thyl«n<i-'l>^ioxo-pyra8iao(1«2-ft)i{^ole (XX) passing a ohloroform-

hexane solution of ^iotoxin over a eoluioR of untfatOied alunina.

- 13 -

,fh« abevo c0ii|)0tiM was aynthaslsed (ic^. elt») by condensing indolu-^

eart^aaijrl ehlorld® with th? isHfe^l cator of 1-nstb5rlanslao-2-!!5stho3^y-

prepionie mM fblloued by cyellsation of the r0salti»g (XH).

Ihl« cyclic prodwtct eav« 1,Z,3,Vtetriil^ro-2-!80tl^l»>-a»ttsyl«na-

t»4!-^io3cop3rraj8ino{l,2*a}indole (M) \ihm passed ov^ a Qdlwrn of

unwashed alsaniiui.

Q H' H +

N H c h COOC Hj (LhjOCH^

c o d

XX

XX\

D N

SCH3 CH20CHJ

f«ylor et al* (7) bave dlreotljr coxarexted indolo-S<-oarb03^1*o( •jsatl^laitdao*

ra^thoxypropimije acid eater (XXI) into XX tgr treatiaent with aeetio ai^ydxlde

and sodlua acetate.

- 14 -

John908 oti aX*

(12) have eyntheaisad IjS^J^Vtetrslqfdro-gpJ-

disubstlti«t«i 1C-i?j'urosy'*1,4«dlosopyrflaino(1,2-a)iiKlel«a (XXll) Ibgr

tvQ differ<mt osthods.

(a) Cyolisfttion oi" the correapoMlng dl-^c«rboi8®thojqyph«Rylgl^cyel-

—U-setl^lamino aeM-aatara gava the iSaaired-prodiacts-jte'tha-praaaraBa

of wsdiun eabhoxida.

C00CH3

'N H

-0

^ o o C v ^ ^ N c n ^

NaQCHj

<;b) >Matl)03t^iiidola-2*earbosQirI ehlorid* vaa eonianaea vith H-itattiylattifio

acid astor and tha resnltlng eos{)ouni£l waa oyeliaod In tfea praaan^a of a

- 15 -

base (uaualV N-iBfftliylajBlta> acid eater i t so l f ) . The IC-ffisthoaq^

pyraainoindoles were doinatbyleted with Hl/P'ta give tha 10-bydroay-

pyrfi sine {1,2-a) Isrsdol® s,

•N H

OCH3

C-Onc Kcooy-CH3

U

.OCH-j

R

Hl/P

It {11 M ^ l n t

Fareed (13) ooMvnead diothyl 2'-eftrb03g^nd0le-1*Gus&tat« with enosda

and idth different diiuiinos. 7h« bisdiemides ( m i l ) on heating eyollsed

Q ts^^COOth I

-V RNH2

Q CHaco IHR

XXiiL-

1 6 .

y-ri exo»r>yr&gi»Q( 1. tndoXes

Johnscm ®t a l . (11) ofcSiainadi

hefttSjii; gliotojcin witfe sol^aiia®, mi also by

8rick«r airi Roberts (14) oxidation of

»etl:\ylatio-1jVt3ioxopyra»lfloi1,2-a)lMole (XX).

O ^ X ^ N C H t , o

fh t Above co8|ionnd wm synthealeed (loe* c i t . ) ^ eontonslng K-mibylaBildo

of lndoXiN'2HS«rbo9^Xio aeid with otl^xalyl eblorMe in th» prasonco of

PITidinOt Th® condonaation product (XSVI), which was mot isoXated, oyoUsod

to give 1,jJ,3f4-tetrabydrc*2*n»t^X-1,3f4-trio3reqp7ra8dno(t,a*a)iM (XXV)»

Py. C0iHUC>\3 D

c i - c o c o o a

• N-^COHCOcooa

XXV )

XXV

- 17 -

fh« fiact that the ring elosuro takes place exclusively at position -J-

of the indole melms in this ease mlso, was confirm)^ in a lais •ifidlar

to that for the dioaro co3!po'aa4B.

hm^-pm^M 11 grf ?

Reeently Btavedov et a l . (15-17) have pfvpared a smher of

1-aiyl-10-^liy2|5yra8lnoinaol«« (OTSII) trom 2^aroyl-3-aliQai»dioles

(35XVII),

R 1 By

XXVll)

R - U, Ke, OKe, CI.

R « H, (Ke, CI.

» le .

8QHS CfliiSMICAL umQUmS or

%drog«&fttion over Adan^s eaial^at (and also reduction viith

«laBSsitta-*aM^ga» in ethenol) (11) radueea tbo ^-carlxMayl ip?oup In t l»

1,Sescop^yraainoiMolet- to -give ifc ydx©- ooagpooisS; (XXIX), on"

del^'drfttim with aeetie anl^dridla givas th» iacmo-o}co*i3oirivG iva (tXJL).

•N

0

EVOH

MCH3 CH-

'N'

V O CH3

Ac o

- 19 -

Johnson's { op. c i t . ) 3-mthylea8 coapound, which gives a

positive t»st for unaatua^tion get reduicoS to IVI on li»it4sd hydrogen&ticMi

at low iiraosuro &cd tc XXIX on ibrthar bydrogonation.

h2 h a Hz

'N'

Chr

HCV\3 CH-

h'oedi (13) tea symtheaised a vmbeT oi I^Jkdioxopyraaijaoi^g-m)-

indoles end reduosd them with lithlua aluminiiia hydrido (1s2.8) in

tetraii3rd3*ofuren for 24 hours, ths fivo a»inbor«d pyrrol® ring i s not

rodneod. thmly th» two k«to gronps in tho pyr««ln® ring are r tduo^.

u

v 0

(e) JReaoetioa. wli:t>„ ^odltm aetiCl tn n . i^lcejaol t

ie reiSticed wHh

sodiuta in boiHaB tjutauol to

Ixiiole (1).

:0

NH

Sh^ddoir «t al» (15-17) ra^esd l-eryl-IO-el^lpS^msiaolaiole*

to th« conresjponling 1,S?,3,Vt«tr»l^K>pyr««laoina©l«s (XXSl) with oodium

in othanoX.

-N Na tJi-oH

X X X I

- 21 -

(ltS*a)i»(iol« ie roadlljr oxMiaed gr petassitiD pomenganate and also

radueas Tollan^a raagent (10).

H'

CH^

MCH3

1»S*Pil ]r!iit>*1*oxopyraaino(l*J?-a}lndiolea polyiwriaa lAian

heatod with eoneantrated hjrdrochloric acid (1). Thia peilymrimtion

Inirolvaa {K>8ition-10 posaihlyf as th« lOmattijirl eoa^tind doea tue/t

palymriBm but glvas a eryataXXintt h^roohloi>i<la (8).

HcJ? Poi^

1«4»0ioxDpyra8ino(1,£-a}lndol«8 do not raact with atrcHOg aclda (2).

• 22

ly^ with alkali t

(a) yK»nc-oycHt>yrft>lno( 1 .g-aHniolea:

i s soluble in

ocoieentrated potassium l^roxidn stiowing a possible toiitoi^orisfttion

into the stjolic form (l) .

.R i-

^^

1«4^0i(m>pyrft8l»oCl|2«»a)indole8 «r« reiy 8m»itiv» to i^kaXi*

These ooi^tmda are l^rolysed in aXeoholie potaasiua hjrdrojdda to a

nonobasie aeid which gets fUrthar hiydlro2yaodl to iadol9->2-carbox7Uo aoid(2),

Q Q V. ACe. KOH ^ 2.. HcP

CH3

• S ' T

h ^ o O v ^ N C H j CHjj

Qcy. KOH

H

- 83-

The dii^i^dariVttUva (XXIX) of X?I tinclergoos an intersating

r9»rtmgmm% whan hsattd tfitl3|aqueou8 alkeXi (18)* This appartntljr

tak«s piacs through tho openlog of pjrraxine ring subse^ent

rocyolisatioa of 'tlt« open cbain eildQligrde at po8itio»-3 of indole to * —

t,2-diI^o-2,3-diij»tiyX-1-o«opyrid(3,Vb)linJol« (XXXII)|

^•satli^Xatloii fitvtmri»g3hd^fo»s&tioi} of pyridindole (4) ^ f f i tlw

opm obaifi intdmradiato*

o^. KOH

CHi

Nc

i l l . Mrs^Eirm^d I i

Xbe trioxopyrasiiio(1»a-a)indolQ i s l^drol^aei witb sethanoUe

pot&sait® i^roxidn to give {XMlll). m&

©x&Mc neM. Th« former givaa inAolt^-earteagrlle aeia oetlyrl aaslna

oa vigorouB l^ ro lys i s (t9)«

NCH3

-f eoovi 1

AlS^rlfttlon of or i to

IC-fflsfelqrl d«riwtive by aagr of thi convantionia SKittooda M©gSO /lKaC38t|«,

CU t/MeB an! etren with ohloroaoatie aoid in allsaline i^dittm givaa only t i ^

K-aUgrl dariimtiiraa (3). 0-All^lation tliough tfeooraticiOly poaaibla haa

fM>t baen obaanraii.

•N

ClcH^cocH ,0 oIIOAAI

H c H2.C00H

25

cm trefttttimt with

sine glirott an orange eolourM eo^potmci. A immber of eoXour raaotioii9

hffiva also bedn diacmiSd^ Koimek ot al«{!)*

1 f 3, 3-diiBattiylL* 1, d dUiccfpyM^mim (1, iisdoija

i« indiifferant to ooM aqiiaoaa aci^a audi baaae* and 4oae not reaot idtb

reagantfl or with aeylailng ireageRta.It naSargioos ^oi ^Xing with

diaiBOtlaad sulphir-ilic acid a«i redtucas acjueout p9f!aiiRg«iMito and fQll«n*a

reagent* Failura to raaot with acyiatini; aganta a»f. loiir mM»9 for

aetlva i ^ r o ^ aug^aat that tbo i^earboiijrl group S» m t aasSXy

enolia^ (IS),

o i a c o s s i o i

«

f t 1 aio3cop;iKr«iSjtQC 1, indiolot

h9m ijossible i»t»iiie<li«tei in tfct MoijRtliosit ftt

«iitil»i$>tiea Uk« eXidioxin (?)• Jelmtati a l . (10,12) Ihkv* iipit&osistdi

ft rRiiBl»r ef d«riv«tiir»a of

(JDCXI?) in odmectiea ttatir work m tbii itniet^urai of

'Kl'

0

,0

R fL<= H, O H .

For th« of tiais* mn^mxdtk tti* Imnl to H*iait!^iiaiieo

iffiids htvt to l)a uftid. teidtt «r« wteb Aaeiar to s^iBti^^tiM*

Thtrofor*! in tho prvacmt votk, i t us* p ropoaetS to w^imMim

ina^lAs Sa taGosits unoMi t thait »mm of

thgdr eboaietl roactioiui eati

Tim only l]gnilfoa y| iiJd.fioitidQ3,«« qynthttiaai by Sohnmm ot

hat* tho hjdrca^ g^oap |3otltioi^10 (loe. <rit.)« fbato iutbora wort

- 27 -

in th i s eonqpcnand beeaase th«y originally tliea^it

«ntliy<trGd«thlegXiotoxtn to be ths tOt 11-dllsgr^ro of

Taylor et a l . (7) hav« lso3iitei

>»0tl^Xon«-1#4^i©*opyr«8iiMf{1,2-a)l«iSol« froa tli« cultures of

Pwaicilllam tarlikowsidi* Tbsjr hsvo alao eiSFnthstdsei tli« 7-aM

9'-ia0thct3(y aRAlogu«i8 of thl a in eonaeetlon with thei r work

on biosynthficde of gHotoxla. In suu^ doriv'Ativvd of iiidoXe^

iBtroSuetlon of ii j drosgr ^oup at podition^5 leads to Intorsstlfig

pharsaecolof^ciil proportt«s. Serotoaln aid bufotdniiaa ar® botfc

5-ti^roMy dorivativoa of tryptaMiio. A nuafesr of awt

dorivativaa of ttyptaalB© &« w«li as lawtryptaajiBe haw

b««a e^Athvslood with a vl«w to tholr pharisaoolioglcftl pr(^«rtl««

(20). HarcholU at a l . (21) hova iQmthasisod 4,5,6 atsS

analogaoa of inaol<i->carb03grlic aeid for tba sama parpoB», In vlaw

of thla, I t waa pw^osad to aynthaalea pyraeinoltdolao with liydroagr

group at poaltion 6,7 and 8«

oi' 1 ' i . s - p i s i r s g r i T i n ' g D t. ^sioxot agRAzrao* >itn?oi»a5i illSPI'

The9« eoittpouRds vsre sjmthosised by tbe eondonaatlon of

etn.oridQ and H-alkylfiucdjao aeid eaters i» thd prassnoo

o^ a

H' H

COCL

HVA CVA CO0£)r 0

0

ft

ll-B<m«y3ji»lno aeid ostara wer# sy»tli«8isod Ijy th® foUoidng •eheiMi

KHg - CH - 0OOH +

PhCBO

1 »H - CH - GOOH CHgPh

NH - CH - COOSt ki, ,Ph

R,- B,CHyCiy>h.

- 29 -

m m Mtids mt« tri^tetl tdth fk^asbly bsnswlitltl^ft

(1sl) in eotiitaa liy4rG;Kiad soluti^^n «ndi th« r«»etion miigtam ms troAtftd

mAim besrohjr^rtd* in with stirring, this prm&dmm wa*

witb wm &f oodiuts

Attar tlrta stiirrinf f«sr ttwthar two lnwra, tht vm w«st»iti

wltti oth«r ensJ naiifepaliaed witli Jn^s^hlufle 1© mutitil il Bomi X-

asiise eci40 tfsuo obtitinwi ware fiXtAmt, Etilod.

KH - CH - CCXHI -fr 0,H.CH - 0 1. HM-CH-COOB 8Ci CHgfb

^Pfwgy^ffp tot ...Ml*?., I

«oida if«r« tato thdip itlsisrl ••tftr* Igr

aaturating tht i r suspanalona in ftbso'JLut* othftcol with dry laiyraroehXorifi

aoidt gas. After sfituration, atbanol «nd b;y4roehlorie acid gat wtra

reaovad imdiar racluosd praegure on a atw^aotial^ mai tha a«iw> aeid atlQ^

obtainai as thidi: li smSd (to sons oaoaa tbi^ uera sapmratad

- 30 -

fiiidisg /Sry ethdr to the aleolioUe •olution) • fiMi •• tcr lgrdr«ohloH.49a

vem then dissoivdd in a sdnltatia iq^tantitsr of Mater an! eovarisd with a

of f^tasslws earbonat* (vx&^irma) mn added in portiona

t i l l tfea aquaoea l ^ a r beoana a «tah* Tha atharaiA l ^ e r vm dacantail

audi the suah was waahad iiith f!re8b ethar. fha etheraal axfcract was

dried ovar ani^ydmia poteaeiitus carboaata* i i l terod and tlmn othar waa

r«aoT0d at low irascwre. A thick liquid waa obfcairusd which waa uead

iBsnsedifttal .

R - CB - OO0H 1. CiltOH/HGl ^ • CH - COOSt

Tha «th«r axtroct,' afbar tha daootopoaition of tha h'oatathjrl^lyoina

othyl oarUr hydroehXoride <«« daataribed abova) waa coisjaatratad to about

150 aO.. at atnoapherie prftssoraj, and tt«ad aa auotv baeausa of i ta high

Tolatility.

Indol9-2-oarb6niyl efeXoridd was aeecrding to th«

followiRg «chiod;

o N O L

^ HCH cDOH

C0CH3 I

C-=0

CH3

This Asslftotocs tf«s pr«£ikre!& heaiins a Kixtur^ of

B&etyigiyeim, lUsod eo 'tiun Aoetftt« &e«tlo ashydrldl* Ibr two

aaS « half hours on a atean l>atb. Alter cooling, tba yollow ctyiriialXim

• 32 -

8sa«s vfts filtorfti* «a«iio«i with ica eoM wfttor aM drtM in • vacuMa

<3efieeator.

Q c h o C h ^ c o o h MaO Ae

^ Q ^ 1^HCOCH3 AdO " f-L o

CU3

axXaoton® to

o-.nitro|;heiigrlpyTUVic aoid Iqr roflaxing >tfith IK iJiiRirochloPic iwia for

two a httlf hfflirs. The fa^^roa^sddl prodxtct c ry s t a l l i s e out cm oooling

«fc and soratohing.

Q .CH= c — c^ O

^vo•2. T cv\

H a Q ch^cocooH

Inm^-P-fisrhomrlie neid (l)t

i>-Mtrqph«r»ylpyr»vic aeM wan eommrted^ to iMoio-S*

«arboiE; lie field V roduetlon with imrmo ao}|>bftto asd wnonlA.

Indol<N-2-eartsE»3QrHo ieid m» extraetai )«Lth hot dilut* MHoniii

aolsttioRf which <m eomiontration aoidilfieatloii ^ttlAnd th«

deslTfld product.

COC^OH

u VA

ludoliKlt^earboagrlic aold In «th«r wm traatad with firesbl^

di«tiXl«d ttiicBsyl ohlflrid* Aftar kiMping the raaetlon mSjxtara

for one hour at roos ttte^amtura, the excaae of thioi^X ohloilda and!

l^fdroohloric acid gae were renoved tinder r^tueed predsore* fha aeai*

crystalline acid ehloriilNi was taken up in drjr ether and ueed i«»aedietely.

s o d .

•N' h

C06W -V

cod

-

li^oXo-S-cafbofQrl «»t\oxl<S9 tr®at®d with tbe M-benagrl*

asdis® ©at®r tiad trietfegrl isdne (tstj£) in etfeur «t rmm t»ie»!^oratitre.

Tb» eoRt«nt« ©f th» fl»9fc w«r© r»flujE«d geatl^ for § Isewt, Th® raiuBtloit

i^Kiwe was t!iii& takwn in tiwnsdPt mO, vashtd with dilXist«

lisM und ifftter. fho I«ijr«ir vas dried temat {lodtoa

fKtlpt)at@« tetatie vim m^ovsdi ami tbs residua w&s oiystalliasd ITOB »thtt»Gl.

u •N H N

CV\2?V>

ohXoiride ooi»S<ms«ii with m «Ke99« of

K*>ffi9tl)arlel;rein9 etfc X enttrj, unj^ir ttis sase eoMitions m dtsoxlbed abov*

to giv« tha eyolie product.

H x^Cocl^

- 35 -

th» e©)R<l«n®&ti$ii |>if0ll«ot of «feloriidt dl-

^btns^lpbenjrlala&ine to oyeUee In t l» i iresimeo of mslrn*

u h

cooei-

Iw^PVs

CON-cVcOO-i ^

^m^mim

CendttDsation of i3»iol«-2*o&rtM3dnyl c!Mi»x-i<t« with li-iwtls^iifljrolntt

otfc^l •otor ( is sxoess) CTOliSfttioa of the f^asdmmd product vittout

addition of ftti^ othar Imiso IxidicAtos that oth i'l «ift«r

itaolf «cts «• the protcm noesptor fttm th« indole nltrogm. Bat in t l»

o u t of N*b*niQrIcnlno noid eycXisttlon doot not tindtr

this* oonlltionsf m stronftr tMue Ilk« t r io t t^ l «0in« hue to b« addlid to dl-

OAtftljfM the 0ji«lia&ti0n* Condonaation proiuot ofA-b«aiylph«iyl»lani*ai

do»« ts>t ojoliso ovwn in the prosoneo of trietfeQrl mlm, Froa thoM

obMnratlona, i t «ay bo conoludodi tbat K-b«Da!yl«iilno «eld «st«r« ar« not

batio mxngh to act as proton acoaptora In tbia raaotion*

- 3 6 .

ggflilttftf 1 i tiUMoAta*

5-Bonnylo^indiolj9»2«Cftrboi^l wae eoiia«ns«d with

il-«lkylefflino «teid» foUowad W tba eyeiloation to

iMoh on

i^regenolljreis yi^dad th« eoiTAi^nding h^i ta^ eoc^pomls. ajn^thoMa

warn ®arrie4 out tbreui^ follov^ing a t^s t

H O o CH WO n •HOi

o .CW-, ^ V -Q

cu COCoOH

Q h '

o codi ^

B j o -

U •N ho Q

-R

. 37 •

ve@ treated vlth sodiuft n i t r i ta in salplimrie acid

to giv g-nitroso-S-l^roagrtolaena whieh OR oadLdaitlozi with ni t r ic «cid

g&v® tho t i t l o coa|)mn<i.

H 0

u NOx

2oNitro>5*l^iIroxyt(»Ii3ene vaa tMme^latad vdl^ benigrl eldoride

in tha presence of sodiuta @thoxid«. Th© axcftas of chlorida irat«

reaoved Isgr stea^ disti l lation and tben the reaetion oixtura ma takan

in ethor, and the atharaal layer waa washed with dilute sodium hydroxida

and vatar. Froa tha atharaal tha banigrlosiy eoapound tiaa iaolatad.

ho

U

CH-

MO L- Q CH:,

N02_

- 3 8 -

i^e eecdtnswl with 09tal«t«

in t)i9 proaenee of potftsaitiii Athoxidit in ftt room ta^ankturt* th»

pota«slia» ial t ef ott url filtArcd «a«i

faifilrol^aod iidth aquecus ftlkall to ijivs tbft sodiuit aelt of ths

«old vhich on acidlifieiitioii with iigrdbroohXorie ftoid ^^eXded ths t i t l e

oo pofimd in tb0 foxu of & tar* this on eeratehii:^ anS pooling lMK>f»« «

solid.

cootv Nc OH 3 Kcl NOi.

3«re«l mt ftl. hava oHsinM S-b^z/loiQr-indiols-S-Gwrboi^llo

aoid bgr reiluxlng « oisetur* 2»nitro~5-^aiirlo3gfpN»^lpyrttVio iyeid with

r«rrottS tulphftte and amonia for om hour, (25) • In tho prasent votk,

i t WAS found naoasaary to ineraasa tha reaction tina to ona and a half

hours* Sodiun hgrdrosdda solution ($%) waa uoad In plaea of amaonia to

- 39 -

• ^ f t o t 5*b»ns^lo3^»lol»^<-eirbo3QrUe aett)* Ii«v«rtii«lMt,

ths yi«M Ikildd to go ftbe^ 555. Stoll ti«v» fediieod th« f

Vboria^loj^toesisrlpyrevie with oodiuti and iodiuiB

bgrAroxid* In yielA <26), &u« to nonavailablUty of aodiiiw l?yposalp1»lt«

thia r«aetion eoxM not ba foUotiiad

• C H ^ C O C O O H

•NO2. NH^OH COOH

S*8iiniCTlexyindol»-g«cerboi«rl ehlertda*

Schlndler (£7) baa raporfead tha pyaparatloB of 5-baiiagrlojg?^

i»3oIa<*2*eejrbozi9rI eMLorlda tegr rafltKi»g 5-b9ntgrXo;;^j'iadola-2-carb®)i5riic aoid

with thici^l chlerlda {1i3j7) in hmtmn and tha for«at4os of the dtaetfearl

a»lda ftWB i t in 80I jriald. Whan 5-i3«aj5ylo3iyinclola-»2-cii?b©«yllc aeld

WIS treated vith thJ^nyl ehlorldt in ather at rooKi tas^eraturai tha

eyolla pKJdaot of * two step r«aetio» was olstainod in 62%

sod X eo6v\ O

H •cocH

- 40 •

iM^AEi

ebXosldItt vftt with

^•eU^lAffilno mida in tht pr«seiict of tintiiir th« s«a»

•sqpffriswii^at O0iutitl<m8 as daseribad bolbr*.

H

Cod-

MH V a

-CH-cooO-

uiOKpouttdi E w CH , « H mB synthtsistd in tfeo 0C aa aaetattml

Imea Hke trietl^jrl luaind but in the presonce of <»retB8 of Kointthylig^Ljroltia

ethyl aster.

S-aiii8jflojiy|i^iraalno(1f2-a)iii!iolaa wara traated «itb PdMJ(103t)

undar bordrog»ii at 45 pad for Ibur hxmm to give ttia conrasponsiine t jftpoxiy

pjnra»ii3o( 2-a) ii^olast

u HO-

Hx

D Tbl-c: u •N 0

i

ftosso eostpounda wwb syntbssised by tho foXlowini eobtM -

OU

CVA3

D O HO

c II o /

V • CH-

4

^30 n

g j o •H' H C O O H

4 n • H-H

CocJ

>0 Q R,

In an «tt«sipt to i ^ t h t t l t s oft to

positKai to ih» t ydbrasy group or p->cr®sol, was «l»»ctlirat«d by m»%ylMttm

of l><»erosol, this adiftjl iti«rlv»tiin» vas nltarixtti, CoUowkI iQrdro^ftls

to obtain t t ^ t l t l « oossmnd. &it ttui eoi iOtt&d aotualji^ obtainsd ma

i<ld»ti£itd as 2^6-dinitre p-er®tol, (Ulaeusaod on p8g»53).

Than wae pmp&tH by a» il t«mat«

QMltbod, Fboagai^ gm wna passed i»to an a l ' ^ i n d of |>*exi>0oX at

th@ otarhm&t p vhich saparatad aa a I i# i t Ixronm praolpitata

was filtftrsd, waabeA ax:d 4xlail. t lda driod p*tolyl oairbonata %ma sltratad

witb nitr ic aei^l in olatm foUowat) t^ IngrdroSj'aia with eoneantrato^

l^roelblArio acid. Tba isoffisT waa rcnovad Ijy steaa &latillatS«8»

ac^ t t m tha raaidua tha ti t ' ia eospound vaa iaoXatad*

D OH

NaOH DO HMO 3

b 0 s.

5

HO HO l

S*Nitro>4»b«nz7lo)Qrtoludntt was prt^ftrad %or tho bwmgrlttioji

of with benzyl otOjorMfli In alcohelle aodluit

tqriroxidtt aoXution.

(vicv OH o

2-Nitro-4^1»n05flojgitolu«n« visa eondenaod with dlet!^! oxal«to

In the prsssnco of potasailiata ett^idda in toluene. 1?h» potadfduia salt of

2«Mtre«4rb0iiJiylo3igrph<!SQyl: pyruvate was Isiy^lysad with aquaotto

so<9iut lardroxia® tiolution md th« acid procipitafcad with feySrochlwic acid.

U cooyr I. K O U -

H02_ cOOU- 2.NaOH •5 Htil

^CH2.C0C00V\

N02.

- 4 4 -

9ttrto« ot a l (29a) feav® re^ccKS 2«nitiM>.4)»bimfyIoaiypht!Qrl,-

pj^nivle aoid with ferrous aulphata aikI sodiim %<ire3dd« to 5-!»ni^l03gr-

iij!iol®-2-earboj^lle acid In yieW. How0V«ar| in oar hauda this

r09«5tion gave V0P2r poer yitM, Conasquently

pyruvte acid was redtucdtS to 6-benjgrlo»yin4ol®-SS-Cflrt)©5ylie acid imaer

tho ssBrti eouflltloaa as i t s J^bensgrloxy iacsaer l a yioM.

^.^^CHiCOGOOU

6-a9ai?yloagrlMol9-2-c<srb03^2rlie acid tias convortedi to i t a acid

chloride by thioiiy ehlorids in aihsr. The oxcoao of thioisrl chloride vm

reotcved under reduced pressure and the aoid ehloride wat uaad innediately.

H O

H LOdl

- 45 -

Ukrmm-lr]

ohloridw eo«a»K««d with

^tmi^latalno aoid Agt«rs in th* pfaom9 of tr i«t l^l m im and aIoo

with «xc«8i ©f ttbyl »at«r to f l v t

on ljy«irog^noay»la with p«ll«ilM» und®!' Jns«lro«iii i t

45 pai tbs oozraajjof^ing tj^oxsr coa wsuBKla.

C o d B

WH-CH COO£l

R R.

nn O

0

Hx

R

Pol-C

Hd' u • N

o'

R . CU^PU^ ^^ , H. CW3

* is"

In ordleir to synthttSise

oat with som» tDodifioatlons in ttie efmditioiSia.

B-CrssoX Mfts n i t r a t e vith fitntas: nitric aei^ axA salphurie

mid in * of ol«aa asd milphurio aaid (30). After th«

roaotion nlxtur* a t roon teapffiraturs for 24 hoara, i t «ma steas diatiUad

with 8up«« • ltat®d atean at 1S0-170®. S-NltaPo-^a-craeol earn a« a bottar

Hko &mX$ion along with othor isoaera. the dist i i lata traa axtraotad with

ether, tha etheraal extract w«» driftdi owr anhydrcoa aoSiua 8a2|>bata wad

ather vBue rewovad laavlng a thick 1.iq!iia behind. Xhia was rafluxsd with

•xcaaa of aeotio anl^rida eod the acdiyi darivatiira of Si-iiitro-jp->eraaol

waa fractiouaiay diat inad at 132-35® ttnd!?r 5 tm, praaaura

Ol HNO3 jhzSOif SVeck-wx P\»AV»

O H

Q OH

CU3

NOi McxOH o

|so-W>e S MO2,

?vadUoviaS. ciUobv>.

• CH 3 N02

ORc

- 4 7 -

Thl<» *js) flqtteou« aodhm l^drosdde

solution gavft £»nitr<»>o-cr«8ol as a single product.

Kobin«oa 6t nl. (29b) b«»^l«t«d 2«nltr©-i!Msr©8ol with beni;^

br<>fi(l<t« p>tiit8lufB earbonat*, in fielA* due to tlKi BonavtiXftbiXity

of bsnsgrl brosldo, tbt bemer^^ion w«a eaxiriad wxt with hmwyl ctiloriiia

tiniiier th« wstn* eonSitioas «o (S«aarlb8<l Isiy Btixton aX.C^a)

in yi©M.

M OH

CH,

NO'

PW C \ i 2 d

N a O^ o M02

S-Nitro->b»iufyXQ3^Xttttrio wet trMtadi with ai«tbyX o}»Xat» in

tlM prosene* o£ potMoitiK ettioxldt. lha rtaetion vas carried out iimiar

•jeaotXjr thi atsA •s^arimntaX eoaditioas a« ^aaeribad bsfora ibr tha

S«iiitro*4>-ban«^Xo37 iamar. 2»Rltro*3-banfgrXo>i7pbQi\ P7risvie aeid vat

obtained aa a tumim tar^ tihieh eoidd not ba puriliad. Tba abova procadura

vaa r i^atad tfaras tiieaa but tba daai r^ product coaXd not ba iaoXatad.

4000 3000 2000 ISQQ cM-< 1000 900 8 0 0 lOOF I — , , 700

7 8 9 10 II

WAVELENGTH (MICRONS )

N-CHJ pi N-CHzCeHs

P|G^ \

5 P P M 6 4 I ' ~r-

«OHC HMD (COCI|)

5 PPM T 4

r ic, 2

- ^

ShSmSa:*!

Ch«s*aetcristie peaks of fM3«0 oni ssddic earboiyrl.

olMiervdd fei^imi 1700 and l jSOciT^ r«sp«jtiviajr, fheso tuo iNmtls

at 1700 m& 1650 c*"^ md tlwi «b3enc« of pmaks eimmi 54DO c which

woiHd ba rAH^niiliilA for indol* IfH) «on£ira thA o^lisaticm at |>o<iitio»-1

of fabl« 1).

SQ'mmn 9% (to) gi ® * t Slid tt f&t

1 » 3 , 1 0 - t rimst i^yl-l $ 11

also give two in th» rmig^ T^wk* £39*240 nyU.

{TabU n ) .

{1»^a)iBdtoltt tftk«n in oarboa t«tiniishlorM« oa » 60 KC initnueent.

It shewa tht folXowing f«atur«»» (Fig. £)*

PIG,. 3 .

4 <.6

230 240 250 260 270 280 290 ' 00 310

Wavalangth (m n )

iVo efettrp at 5.81 C^) iiriiisftt*

pTmmm oi tm grmip®, is^iefe e.W5 mt jaewjt

th& i3p£i«M aiagl^t cofrtapoa^Ja t o

wh©r#®s dmm tinM aiisglei nm'tmpoMa to to i i » eeupfeoasrl

gfw^, fftiltipl«t,s utT" g,7(9p) «is3 1»S<1p) cerr»i|50»d t o tii» WBmdmim

aspomtio pmtmB*

tnkozi after diRitori'yni it»lio«it#9 tlia «l>senee

&t mast «eilir« in tii« cexpotmi*

[timm*:

In " s® {7/8)-t)0Rssylei«y eoJ!!f>o*m{i»# along with tfee etear«et®ri»ti<j

baiKfa for indole IM/»0 aad earJsoisgrl asmmdi t70© md to$G em

mspwotivwlsr, hmd@ hatmm cisT^ w»r» «bf»rv»di for

fhs ooiT#i|ioiid[ii3g tgriSrosy cosfjoyoad® ggm ft ehmrp btudl bttvsvn 3300-3100 ciT^

iMcb is I w Sbr • phtnolie i^drtt:^!, l.s9oelatieii I>®tii0»» th«

eiqr «0ootint for t h i s , f be coddic earboaisirX l^nds Aim ebammi «t l o t ^

f5p«q(U«nci«». (Fig, 3,5} T«bl« 1).

5 6 7 8 9 10 II 12 13 14 15

WAVELENGTH (MICRONS)

f iG, ST

F i ^ . 6

- 50 -

jsbe

In the S^tesg'loa^' and S-bydiro]^ two vsmdmm

mrm obaerrod in the nmga ^8a r. 255-257 mj^ and X «a*. £$0-294

in the T^mhatitutttS derivatives on* leiodSMi was ot^serred

in the range 315-3S! jy^ . (Fig, 4,6j Table I I ) .

• 51 -

•(Si ilijtiolo

f A B L E ^ I

I R, Rg KC«0 (indolo)

car*

C*© Ca«ido)

cvr^

IMoltf ring etr^ Fh i^ l i e 01

cur^

1. M H 1?O0 1650 1610,1570,1440

2. GHgFfe R 1715 1635 1580,1560,1440 -

3. B 1700 1650 1625,1575,1460 1235,1210

4. CBj 8 -QCl^Fh 16&5 1640 1600,1585,1435 1240,1210

S. CH H 8 -OOigPh 1645 1590,1440 1^62,1240

H 7 -OCSigPh 1700 1650 1600,1575,1430 1240

7. CRgPli CI^ 7 -OCHgPh 17C0 1630 1600,1585,1440 1250,1200

8« CE, H 7 -Om^Ph 1705 1620,1590,1440 1240

% (M^Ph n a -6E l a o 1615 3150

10. ci^m 8 -OH 1^70 1610 3100

t1. B e -OH 1660 1600 3100 iz. CHgPb B 7 -OH 1610 1

3100

13. CHgFh OB, 7 -OH 1670 16^5 3150

14. CH H 7 -OH 1700 1630 3300

« -

Q

R Max* (m )

2«g4

1. ca^fe B B 4.29, 4.24

m^ H 246,291 4.36, 4.27

3. CHj h H 8 -OSRgPh 256,E9£ 4.43» 4.27

4. CHgfh GH 0 -OGHgPh 257,292 4.25

5. CH H § -QCKgPil 255,290 4.444»4.28

6. CffgS . H 7 -OCHgPh 317 4.35

7. CHgPli CH3 7 -CJCiyh 317 4.33

a. CKj H 7 -OCl^Pli 315 4.35 CBjgl'h K 8 -Oil 256,294 4.36, 4.22

to. CE Fh ®3 8 «0H S57,294 4.30, 4.24 11. CHj H 8 -OR 255,291 4.37, 4.23

12. Ci^Ph H 7 -OH 319 4.32 Cl^Ph 7 -OH 321 4.19

u . CB3 B 7 -OH 317 4.35

All th« a\)ov» spectra w»r« tsk«n in Mtb«nol mxo9pt JSo*1« wUieh w«s tek«n in «than<d.

hadt t^ b® i@mt%>«fi8fld as m lfit«ta»dlaft*

for Mrwjt liltrfttien ©f p^tmsol wssM

not l®ad tc dsalired proawct, baemiat of s t r o n g ©^p-dtrteting

infkamm ©f %fm fcgraroiQr eroup. This t*y<Srojgr rottp iia»«th«r»for«« to bo

iiiitiib}^ iSftaetiv«it»)S| r^ tbkt nitratioo plitco pxuf x lO^ tbo

poiition oribo to ths letthrl grmp* Coptse^v C S) detiefeiirattti tbia

tiij roscy tlbrott^ tlio jforsAtitsi of tbo carbomitof vhioli le oty&ttltMKi

hjr rmoislflg as aethitim of p-ertsol ^tfe plosgano. In nd^w &£ \ 1

tlw hiftatljr poisonms netur* of p)sx)§ifim, i t thought to t0vy

obh»ir ttoyl ipfoiips. Smiington et ml, Ol) oitrattd itio aeotyX

of VftBSlliR to etni^in IMs

rtaetion imolvmi tht 0ftl«ctiiF« dcaetivtttion of tho in ni

vii^iKi. ConM{|tt«»tljrj, p^rntol wao iioiriyli»t«d i t s nootyl doriimtiim

vm» n i t n t « i tmUtr tho •am* oonditiono. nitrittioii produet l» thie

o«M, hotiwr, w&a idontlfiedi 2«iS^din£tro*p»or*tolt iMob themgh

unittitablo for tho sjmthoalo of th« dtsifod pyi»idUio<l9ia"a)ii>doX«af

- § 4 -

« goe<S ii»fc®si8«!liat» for ^,6»digoiiie-p-<sr«aoa,, a ^^ ing «atwi»l

for leathmr O^) * ±9 unittabll^ in mir, tharoforft*

i t « i«rivmtiv»a mrsi isolatoi ,

Ritrati©ii of with fysalng ttitrie aeM

6 8 4 ftrodtaici. TM« %MI« A <disM«0T ITDIIFAYBTAI

owr tfm Urmt » i^ t ic»» (31), wfeloh l«ad« t o a tiitditii'® ©i* pm&wGtB

w etmberaoat niw&tim mM W ^ ^ nitfotis

gases (34).

SIhm txmesrl «tkar of m9 not i s

goodi yi®M % aoiaS- Bothode, tfcwi i i l w r aslt. of 2|,6-dlait3P0»p-«rei0l

vat boni^latetl with c h l o rMd *

^at iO^ie of 4iff«reiit

e«t«lyatii iit« «Kit U0ing me^it %h» tba

motion® and th# prosiueta IdaatiHad sjra in th® ^llowteg aeJaMW;

- 55 -

CVA-,

o ORc,

I. HNO3

2. KOH

CH-

o •NOi OH

P(r02.

vj/

0 6^

Hj ftcXMA^ N j

0 <

0^t HHAt

CU.

AcM H o oH

NHAc

• 56 •

CHEHICAL M m n m B m t * mOX^mAZIKOf 1. IHDQLBSt

I.^otmofelon ewir platiann oKMftt

Johnson ot (I t ) roportod the redact ion of iho 4fNSftrboii3rl

group la

to glim th» eon?«»|5oMij5® dll®r-iro coagjojud, Slueo ths datall® of

raduetion M«r» not

t»3rr«elno(1,^ft)ifulole mis 7«tueod ovar platiniiia oxMo imdor diff«r«nt

oonditions* unroaotsd mispotxnd m& roeovorod in n i l

— > u •N' .0

hO - k ^ N C H a ^ ^ i

I I . nmction with ^ k a ^ i

Mb«a 1#2f 3,4-t«tr«ti0Klro-2-beni|3rl-% indoU,

wae hMit«d with •qtiocus potasalua t tSroxido oolution^ ttko pymsitio ring

»t tho Vcarboivl gro«(p aiid th« op«n oiuiln «cld ms idontifiod.

o kOH •K

H NCH 'Pk

- § 5 7 -

p i . Rsdttetlon vrf-tb. lithiuKi elualaiing hydrides

(a) liS-Diozo-pj-rsztoolndoJ^es hava h9&n roducsd with lltteitun

aluffiinfest byifritis (13). To this reactloR with 1,4-dio5K»coinpound.

1 # 4-tetrahjdro-2-b-m2jl-i, l^^opyT&zin&i 1, C- a) indole was rdiluxed

with 21tMiMn eltiadniuw hQraridoCl.'S.gJ?), in p«rlfled tatraigrdroJtonac for

E4 hours. The asic^ss of liuliium a2ii«iijai«m wee dece^osad with

moist other, Ths «thcr estract vas dried OTsr magMaloiS

sulphate, concentrated to 50 ffll. cjid aatiirated with dry Igdrochloric

a£!id» A dark brown tar separated dat which eooM r«ot be eryiitalXisad.

(b) Oorieg « t e l . (35) raducad

phej3yl-IH-1,5-b<Hjaodiaaocii>.2»one to tb« corrtBpondiisg 1,2,3»4»5#5-h»3!a-

hydro-diaeocimusing r@zy large aisetrnt of lithinia altiminiua hydrld9(1i30)»

ci>

U AlH^

4000 3000 lOOF ' —

.80

2000 1500 CM-1 1000 900 800 700

60

z < a. ^20

3 4 5 6 7 8 9 10 II 12 13 14 15 wavelength (MICRONS)

to CH20H Hzi^NH-CHCHs

T T T T

^ 58 •

Slnea tbio involvej redbetion e£ om ftusido earboi^l (ia. »3ditl4»B to «

doablo hoi^),

uas «l30 roflussd vitt) a Xerge ftsaaoitiisi ef lithitis aluBliiliitt

in tetrat^^oflur&n. fh« of littiiuiai alumiRiua iDj^ridb was

with m i i m h^t&xMo aolutlm add tUvii th* raaotieea sdxtura m s

for another one hour ani eadraetad with Tha e^binod at bar wtraet

was driad ovar anlnirdrous stagGaaitm aolphata. Sha axiraet was thosi eimeantrat*

e i to SO sfL* anil dry hydlroc^orie aetd gaa uas paseod tht^ugh it* A brom

ta r aaparata^, which waa diaaolvad in abaoXuta etham}!. attdicg 4xf

ethar, eooline ani semtehii%» a UgM puirpla eoloarati potr;3ar aaparatad

out witb graat <Slflioulty* this powdar, altar two erystaXIlaatiofiaf gav*

a white iMmim eovpaaxA wbleh imlts at

IB apGotruB) of tha b^roehlorida of thie raduead prodaet waa takan

iA REr. Tha two oarbouyl banda at 1700 and 1650 eiT^ hava diaajq^arad

in thia apootrum anl thara ia a maw baM at 3180 eaT^ • fhia indleataa

that both tha oarboi^l groupa hava be«n raduead, o»a poaaitily to Cl^

and t\m otfatr ona to CliOH. Banda a t l6S5f U90 and 1450 and tha oaa at

1 / 1/

« / ' y /'

N^CHjOH

S, f'

220 230 240 260 2«0 t?0 MO 1*0 >00 J10 Wovtlinglh (m n )

m n r

f S 10

3 PPM S 4

tow* HW(C»6»H>

CHIOH nmt CM,C,H,

I • I 5 fl»f4 T 6

F I &

5 f -

30t50(iwiol« C4I) m'^ intlicat® that ixsdQlm ring U

th» ir? was tfiJsuR i a I t eteirs iisapfsftreasa

oC th« short wism te^ vitli 239 s>» «hioh i@

vitb a efefttneffc^r* iit^luiiifat ttae mrhot^l groapa. fh» long easS

»imuB & bypsoehnsnie sMffc with <l«ere)i9« in iil aofjptiaHa, (Hf.d)*

i m apectsuie of tiie l^dmsl^rido of tha tra«

in dautwraiM piriiUae a ffC iesfcrmsffiatt I t ahanta th t

f0l2««di^ fimtairost (Big. 9)«

Ci) f w iai«4tical tilpl«t8 at r6.74C2p) end ccmpll»g Ktfltli mm&h otiMr (4 B.5 c^s) •

( l i ) A iliiEltt a f T 5.59C%).

( m ) toother sharp Mnglat 5.29(2p).

{!•) Ao mirttaolirodi trlplot a t T 3.J?5(1p).

(•) lekiltipXoto betwowi T 2.90-g. .

(vi) A »lnfX«t « t r 0.36(2p)

(irll) A bmaii wwosolv^dl t r lplat fairly fielrt a tT

- 79 -

I'looaa featur^o o^i ha i f i t i a prosuffiod thali

ring opeaiiii^ at posltien-l h5.9 accoirpani^d ir@dbactlon, loading to tbo

foraattlon of aa opsn chain cor.potWKf,. Tfio ssquenoa of rsiRctiosis loadUng

to tb« formtion of tld.8 cos^jound my ba pcotulatsd aa folllowsi

a N

o N "^CHjOH C KzVW

L^NHoCHo^V^ a

Johneon et el.(l8) hav® reported the opening up of the amino alcohol in

their 4-l5niro3Qr ooipound under besio conditions to the intermediate open

chain aldebiyde which rtsoyclises in a different position to give the

pyridindole. (p.23).

- 80 -

Another ooneideratiQii in int«rpretting proton olgnnJUy la

tbat th« oKctonglng protons get 'AmmpXM ttm tttoifo m the

adjacent e«rl»m etona. Siltna^stein ot teira ttotu&ll^ obaervsdl

that In the efts» of loost of tfas ^Xiphetio maim ^ItSji i^ere tbo proton

maethmge ie mpldi^ lit! pn>ton(9) got decoupiod £roa tbo nitrogon atom

Mid ttom tbo protons on tho ad jec«»t oarlo^ atosso. fho IB poak ia,

a titrnxp gineiot end the «iJaoent CK protono ore mt opXlt lav

HP protons***

In view of the abo>ir«| the HI® oigttsia ean be inteo^retted aa

follovst

the tvo identical t r ip l e t s cen ti© to the protona on the

awthylene pt»ipe in the -IMSRgCH '-i ehain* fhe protons on i being

oeai^oteljr diKsoqpXod f r ^ the i^jaeent Bsdtfa lene pmtx>m ao that i t

beeoiBea a aiople eyates. The laett^lene neact to the indole

nlt^rogen can aeeoant for the v^fieM tripletf en«i the one mixt to $

Whioh i s 8»re deahliaied because of %ho positive charge on tha nitrogen

oan aoomnt for tbo oot^iarativelj^ downfleld t r i p l e t . SI»tiXarly the

einglet at ^ 5*59(S;p) say be due to the protona in the priearar aXcohoiio

group (-CKg-Oli) and the ainglet at T 5.S9(2p) my be accounted for ty the

• 63 -

protcfis flanked on m& t*

f t ^ 0ltigl«t oey bs duo to th» iMoIii prot<»i At

p08ltl(»a-3<i fbii «XtipJtMo<9p) obilQiitljr fioeountt for th« sroiiatlo

iprotofi0.

fhe e h ^ eiiigpl«t « tT 0*36(%) s»(sr ba eonsidorod to be duo

to the tvo protone on if tb« fi^id 03t0haJ»ge me^ng thn sigiaal into a

jj Mirp iiroad mresol're!! t r iplot a t T i s th«Q

ptotmW; 4ha« to th« |a*otai| oo iar ^oim JtioM duo to A

mim rossltsilo tofeeiwotion %dth Ibg . Botl; ttiose peaks dioappoarod in

ths qp^otsvA tfikon after oxftbango^ imieh eo»f3jm» this asolfiimsDt*

fh« onals^ttls f i b r e s tteigh not umci^ivoeaX in tliis oaoo aro

n«ar«r to tboas for tbt opoa ehtia ecajiotind.

fh« fcgrirogono of tbo jkeothgrleno crcop am ae t iva t^ <!tio to tbo

praaffnco of tbo 4-kotogroup, thttroforo^ alMylation vmy take placo a t thia

poaitioiu Shatt at al.(37} bava aXtt^latod attyelmind and tjomolna at a

aiailar position. 1, 4-3!atr«li Aro»2*lM»n6gKl«1» 4-dli0(X0pjnrftSl»0( t , 2-b} iMola

wa« Mitl^Iatad idth votl^l lodida in the of iodliu» aatboxMo.

4000 3000 lOOF '

2000 1500 CM~I 1000 900 800 700

3 4 5 6 7 8 9 10 II 12 13 14 15

WAVELENGTH (MICRONS)

Q-iYN-CHjCgHs CH3

FlGi.lO.

^ 63 •

t#?f 4-dio indole

M8 fti th<i isa^or wMeh was idtmtifieiS hf id«ntieaX

i r with th» i^^tbetie ceapsuna (Plf. tO)#

md the uneubstitutftd

ospen abiiiii ftei4 mm obtain^ as tli« jnimtr protluota* fhasci pr&^ets

aeparated on t ^ basis ef thdlr aoMbiliV and piirl£i«)d bf passing \

Qmt nmtr&l aluMna.

.0 NcxOr le

o HOO . N t h t P H

• 64 -

l i .

Bhatt «t ml (39) Hev atv^i&d the r«ai<i%idn of vith

Btr^QlsEdm &»<! hswaim in th» prMmxen of oodlua Ij^r^roadde in aXoobol.

fha r«aeti<»n took plftcs mt thtt Aetivo awth rlaK^ iKlJuoent to tfe*

earlTot^I and tti^jr war® abXe to i»olftto thd bdnnQrlidiRi derivaMims*

with btiisfiMftli^e tha imssanco sodlun ac«flftt« Ami noetic

plperidin* md «lso t r i«t l^l assdn * Chily ttnaal»tit>\it9(2 opo» ohais

«el<i coaia \m isolatoft* frem th» r®»t of tba raactiou wt*tur«, « t t r or

m i n defiiMia eoi poond oHidiidd iMoh oeiad not Im parili«di. Xt i«

poasibXe^ tbat in tulMtion to thw aotivo at |>ositlonp3^

th« s«aotl<m alao take* plsca at p08ltioa»tOf l^aKing a Biaetura ot

products. 2'*Sub«tltutoit iadolaa aira Jamm to oondaissa with aMal^yiaa

giving lo'odaets anaiogous to triph«ns^l iMthaiies (39)«

E X P E B I M E K f A I .

BXB BUXMBUt hh

g r o w u m m ^ m m p ^ ,

^zmmlmrn. mM§. »

Aiitii»> ftOid CO«t sol*) wat dittolvwl i s 50 of sddiuai

disUISjtd btiiimM*}^^* 10. f •a..C0»1 mM

utith i^iseHm* ntxiat*^ iil)«n sol t^im hmum

tsomgiman, 1*14 i* o t eeNlSisn Isorol^ariidA ifni ivldvd IB 8»ili |Hiitiim«»

flit wis \sm%m ^btting Aftw tfa*

«Kiditrioii» aolatimi w&« for «ix>t)iir half m hotst moA ttitm

tt)» tilbom p roo i^ f i hm ntpmtiA %wism th t ••»• ^ii)a((iiti«« of tMrnttH t SRi*

tttti aoaiua ATtsr two lioar* of stlnrins, weHnUm mm

tiiie« vitb vthtr And tnttitftilXiwKl vith h^^lfooblorie t o

pB uiidttr ir ifomit «ttrrii)i* ftui }mnjsj/!Umim uatiia^ C&t

pruoipltatid I t mn £ll.t«r«a •iietio% %ttth«d titU

with S«» ool4 wattr meA dt l id in th» fol3i>i«i»s laino

v r o i(^lMi«itifd tsar tM« mtliodit

B pg ehg • SH . ® • €<KJH

yieMC^

1* H WAt«r

e . 71 Iffttffltvotlianol.

70

,1.t ffllwai, f i l f r »

8,2 £.(0*05 a^*) WM talum tn IS5

•bsolutt •thanol In « lA. Ttui alatisr* was nttir«t«di with

(ix7 acid pi t Ibr tUtmt 10 hoar* rooa tmepwmtam* tbm

n»tk m» prot«ot«d m i i t a r t idLtli a ealeltia etOorld* tub* wM3L«

* f h i t miA iai iknaSgriWkA for G,H % A&fOraidi Sm i C, 75.27f % 6.71 j S, 5.49.

f OttoH C, 75»18| H, B, 5.11.

m * ^ i m pitssM* imftn th« foltitioii m t a m t ^

m» vmxt^H ttat«r retoed pnetiRir® m % m U r t i l l m e^mipy

t o i p t ^ y DS! ttiiai itnder r i i i i i t^ fiiriiaMr®* fh t

t ir^Mt^fi^^ 5«7 mil*)

Alas^iirad i a « i&iilJttm ^wMtit;^ of m t i r KoiatlQ^

Ira* mMrm nitfe Pi ®thcr, Jtt^^rirwut poinflate ©urtentl*

i» i^ertlona t l31 t\m m^mna Ij^r « m^ I to

Wft» W! t ^ mt*^ wm miiiii^ tritb itB»h lA.) i&m

iliBst. tt^Qf* mgtrmt mw mm m^^^semB peU^mlm

f i l U m ^ «%hm wMi tmemA m i m rMuc^d room tte^mtttr*^

k t h i c k 1i&» l i h u i m a , v m h u e i g m 1*1 i t m i t i e i » n t l ^

pir« tor IbrtlMf tis«,

17»$ g(0«l VM Uimn ixi 250 i t* of

«tlicttoI Alia Kith axgr r broetsderlo neid cm to c@st«rt

-

1% i t * «st«r th* l ^ f ^ b l o f ! ^ * mpmii-Wi

out tpm fitljimi im Mfiitioii df i f ^ •ttodri

yi«M g . O S ) .

ai t^i 6 f*^ vims

i m m ^ i ^ witb p>t«flai^ earlioQat* «a ^ e i o r i M abeint tn i t

i i ^ i t t ftti^i ttitsr, ^ f M 1*5 f •

Absolut* «t}iai}«il(1S0 la*) and mturattd vith mU

f h t •ytfO' l^riroQhlorid* tt|}«r*t<iii out tttdition of dxy m^m to th»

aypjpy U ^ i ^ ©Hmlima ul t t f i^noviog •tlwui^l, jfiwM 13 f*

AniljiifJ for C^^ggOj^l t

Foraais

dX-13-temigplptesarliAiKiR® ©tl;^ m%m B wit * fjoiASsima

ddKetlna 17.a teikmt in m§

iini witlt dx^ ^r^et i l i i r i i gm to ismmv% i t into

efl«r Aa s f i ^ w i i ^ M Cftltor mmmimg m

moA Oty ©tlKap wm m i ^ to f t . fii« wtileh

©o tamteMiig, - an $M mmim, yl«ld BB»3

( m ) [ M i . ISt-S^^'C^O)] .

S«rco»ia§ «tb}a ftstxsr i farochJLoild®, wm with

{Nitatste ttarlxmtt, iha tthvr «nt! tim 4ri*il

Aidiivet m9 eei«!»ijti«t«l to 150 A , tfeii ia tte© for» m9

usid oaloitUtdd m t»si« #f

1 « 1 , IMot* fenmS

on oonaaimtlon vltb intSole«>lS««arb(»^l ebloridt,

A aixttir* of g* of o-nitrolbmiiHiHftlQinl f 11-5 i* of

15*4 aodiuai ft§«t«t« «i»i ££0 of ftotit^

WHS b«it«)i for two and « tutlf botxrit en ft I& m

Brlmtm^W' flask, fb« r a t i o n aisEtur* Isio • solid

jallotf a»«a of er|p«t«ls m mdHag fit room te^petatirt tor mfr^ral hoiir«.

llw MoXiil smt» wtt v^, mtt&d vith ie» eold twtir af»! <Srittd la

vietia* GfT nodivm 11JS®, jpieM 110

Cmd(t ftilaetc^ of o»sitro-oC«&ett«i»£iioeii»3«^ aoid (48 «*)

imt f«fl»3ci(l for tuo • half bmre with 1^06 vil* of I ti|»!fool3lorio eelil*

Tha oolutlos wui t rwUd with 10 g. of eetlvrnted carbon mi. mitwA

whllo bot. Thf ClltrAto dtiposittd m oU wM^ orystftlXiatd m cooailog

«B«i aeimtolilBg. 7h« aolutioB wma Xefb a t for IS bottra to 0(« |a t t t th«

ei^atalliMiiciii. o-HltfwphKBjrlp^xtm^ct meU w&w filt<ix^ m^beA

icft mt^T* Alter df^ng i» intmui% pn^ltie^

£4 g. tzid 119- 20**. TIs® nether liqioor m mmnWet^^

gem m ftdditlei^i^t 16 g. of tho i8at«ri«3> eakleg « to ta l of 40

yield

(£0*9 f*) la ano»$«

(140 of a . ail^ttd tfitb ^ eH, mUr) m i » i^t mMUm of

orTatftlSiseA f«rmi8 aidphate (ISO in SW ad. m§ gmdaall^^

fibt raftetlo) alxtiitfNi f i rg t vt^md ms m mt»r ti«tli for Ifialf

ma {sour th«n boiled for m9 hour. Aitor UliMfix^ e f t f«rrie ojd<l<i

«nil iMtbinii i t idtb hot dilttt* tl)» eosd lnod ni tx^to w«s etfmm^

trttt«d* ttiMiflod in oold tmsr Is^olA-B-oariSXKt Iie

wbieta 0U,sltmA in m nmu^ torn m9 l i l t m ^ , vMti«d idtb ooldi

MAtor md ariad, ^.p. 802-4® U «. (750 .

I»d«il*-a-o«rtx»Qrlio Mid, (0«80 0.005 solo} in dry

tf*t trMtwl with 1.19 f.(0.6$ al .) of iTMhly distilXod thioegrX ehloriito.

• •

f h t reaction islxf^rn ms kapt nt roms t&s^mtum for txm limir*

Elb«r ttoo mmmm ^t thionjl nfctorid* umm rtnevttd tsi!l«r r«!!ttc«il

f^^fBtmr^ Mt t M r«»ida«l s^eii^Hd m t s 20 a l . of dty «th»r «

mi. thm tlils v«e as liMifta'*. fh i s ^^r^eetsi m»

t i l l ttit l.tt«fc traeea of t idoi^l cbltwia* hydrochloH«

•e i i gall ir»r« r»i8oy«d. f b t ««il<-ciy«t«llJlja« pifatutod indtelft-S*

osdPbciiyl vat taktta i a ^f^ vthir ma ui^d ica«d£tito3^ i&f

etaeild* (as avscrltitil igm

8 (0.05 ei i»lol»»S*earbc»sgrHc aeia i s o^e r ifus tr<MtM trith

* mlx^im of 10 weHit) of atlgrl sstar

10* t g.(0«1 m>3.«) ef tyiithifX isstlad In Alter k^sping thw iMNiotioxi

•laetuxv fcr ham At fooit twii t»>fttiir% tlis emtmtm of tbii fLaidc if«r«

r«fa.ti«id for & bcHirt. Tht iroiftotioii idxtui^ takes up in

iraeh«4 with diluta kj^ochlorle aeid (5$) mii iiat«r. Ths

fctiAntiitt larftr vaa dritd over anlijfdftma acidiiia ml^^hat*, aoliraiit wm

ratioirad and tha raiiditt iraa oryetaUiaad txm bi»0ai»»»lia]niit or ottiaaol

75*

m Uiixt y^leif nm&lm, ••p,, yteld 6 irCRSr)

I ^ S K H t w a M * 1 6 1 0 ^ 1 5 T O * I M S i l « f ) | ijflrCSfcOE)

X mm, m »A » 4 m!t(m% )T Cppia)

rnlUpm), iM'tp* iaBlMf^«t).

fmioli S, ?4#5«>| e, 5.05J 1,

mid, 1.6t gCO.fSI i^ln), ma emwrtt^ t»

I t i m M eiaorida i ^ n tM&ti^ witli m mlMt im

••lor, 2 . n t r m ^ f l m i m a.CP. g.CCJ#es a®!®)

i n othtr* tts* Mka mrk^d up miw tli« m&e mvAitim$ as

dBst^h^ h9ii(m* It ey^aUllMM iii'm mthmml, si.jp. j i ^

2 S mih M k b t ) Wt5(ii«$ol© C»0), 1580, 1440 ifUag)i A mm* m , mi log 4 4.36, 4.S7.

Iiad^tlM Cacd. for t C, fi, 5»30$ M, 9.21.

fam^ t C| 5.4S| llf

M anl^^fous of elAoi^d*

pt^pamd tmm 0.3 i;*C0»C!05 of inS&li»-£"6art»oigrlie «el4 mm

with an 93BB980 of either (ptapmi^ tr<m 6 0*04

of ataeottlcM fttlifl l ftibetieUlorliiQ) alxfKxrt u t t

tor 0 bimr«. uhioB tti^AiAd

•• B wbit« praeipltftt* during th» r etloa uai off* fl» vtbii^l

flltf&t* wm tilth mivi l^mHlwie fteM C5l) mt«r* Eiher

VMM thm •viipQf«t«i mad t\m tMok li^M ilibs tHAmtmi. m» es etalXiati

f5r<» is.p. ^OM®, [ l i t .

Z&dolo>»2*e«rlMS^ «hl<orl<l8 prci|>«rtd £ro» 0.8 g. (0.005 v»Xm)

Gt livloIt-a^ttrtKn^ifi eei4 trt»tei vltk CL*B«b«a9Qrl«ph«3grl4^jd9im

•Mi.vr, 0.41 i* (0.005 mU) e x A t M s»(O.Ot of tri«ttisa isiiM

ntlittr. AftMT kitpimg tbo rcaotioa aisetaim Ibr boiur at mm

tmspm%tixn, tb« oonttnta of th t iiiirt rwfliaxttsl Hoit B iteitrt. f

prodttot obttlnad (on itorki»c up as daacsrlbtd bafora) iraa i4a(8tl£Lad aa

ttui t^ ebaiti •stvr* I t ma ofirsiiaiiti^ ixm atliamly

f i m 1.43 c.CTODt ir(EBr) |SSO(iiKiol« m ) , 1720(««t*r 0«0)t

1506, mm rlog).

p<ni»ati e, moof a, 5.791 M,

h «tixr«d »ixtttf« g* of 150 aeid

ft»d ttOL. of 9alpli»ri« «eid ii»«i tr«Mit«d vi%h e aoltttion

of 35 g. Gf nitrliic W l i i t l * vAtor a t Aftwr » r«v

fiiimt«t, tlM »lj«tar« irat |tair«d in to ico eoM tmclsr and th*

iiitroao eei peiiiitd tms fiittr«dt mA pr»fi8»d out (m a f i l t e r pi^ier. Xt

liiui thtn iidtiAd in pcrttofift to a «tin>«a aixt^ir* of 50 a^. td i t ie aeid

(ep. cr< 1*4£) cn^ 150 iO.* of KUtw «t Stitrijng t«9 eeniiaifd

M long a i t r le 0*14* tm« Tb« rtaaltieg cmd» ait*o er«tQ3.

«»• isolttUd tor pMtrlKif inte v&tiar atM iirtasix^ e«t m • l i l t« r

I t w ciyrtnll i i td bdnavat, wup* 0 g.l90|S).

- 76 -

to m TOl«tloa of scdiuQ 3 g. In »beoIiit«

•t^nnolt ICO l a . ) , 20 g. ai«l fena^yi ebloildo

g. ¥er» adaed m^ t\m r«a«tlim alMteuro rtfluxifl m a Isitli

f©r S lioarf. Aleohol wto tfciia distiUwa of f , wiit aisioliraa

i s •th»r, with ailut® ««l4w» Mifcwddt mtm', fwm

tMs »q«eottt mluUm sfcttrtiag iwtoria t $ «*) m* r^vrnw^*

«thir«al »xferi!ct yt^MM 's ^ ich eff»tii31iee(S

t t m vUolmm «tto»r (tf>. IdlS-®)^, 70-71% j'AoM $ 4 9 0 ) •

to m iolatioH of 15.6 g. of potB»Bivm in 70 edl* of absel«U

•thtnol and MO afl.. of dry «fctey, g. aolvftim ef 4Bt6 g, o t £-aityo-

ftnd f , of d i t t t t ^ oxailwta in tOO aCL* of toltxwa«

««• add«a with ooolin^ in lea TimW^ th« x^Motion t«^p»mtiir« m s not

allowtd to go Sh» rmoUm adxtur* ma Z^fi evoftetsii^ at 10^

«nd thin nt roost t^^pffratam lor ttroi* tm^i^ mi^Atms o&Mitimm,

fho pot««i&tii9 salt which «qparat<i^ out was fiXt«ri4 md vaahed thoi uf bljr

with dty athar UKuiar aitctioii* I t imi than dltaodvad Sm TOO lA.* vaft^r mad

$£0 m ^ m mi otirrtd fisr nut hour with WO A*

ffthar. f k t cthtp l i ^ r vm mptacrn^ m^ itw toliitiim wui

with tiluHr flit aolDtioii tiMi ftsMifita

idth €»mi«iti!»t«l t^jrAroebiorie fh9 tit l^i eoi^imA vipidntttd

M a ^mm o i l vMdh s^diaified kei^is^g i t In eoXd emifwuii^.

This m s witb le* «eildl missx' «Bii diitf^i s«|)«

112-13® ^ X ^ S5 fi.

fli« i^metwSInf mM, g« (0«(I4 ttait 4i«soi¥«iS la ma t

AfSOteias seiistieii of MwoKd a w t mA9 ittim bO.*

A het toljijUefi «f isnrvoaa ialpluitii (72 la 60 wiL* watoir) iomi I

nod t ^ ulaetttm m» ^at« l m m mttr listli tm tiilf m INcur idtit aliiMbni*

thm tiM eoiit«nt« of tli« flaiile vitrt 9»ll»9GS<t for fiirtli»r m» tesiir m m

Mad tsKtti. Iron hydv&xii&m wm ifpmtvSi^ with li^t dilut*

«niO»l« and lintUjr vltli m&ixm l^ffozid* fbm eoabis^ mt»t*

ifM e(»ie«atrat««V eool.«l tnd ftQS4i£l«d with Igrdroeia^ie tiMi

light ytUoif prtoipitat* wsa UXtmrni, wa^ed ami dilad. Xt m»

ofyvtaUiMd flpoa diluta aoatic AOid txe «th«r, m,p,

5.8 c* ( 5 5 » ) . r u t . • .p . 190-I94®(85,g6)] .

m ^ m

miA, 0.66 g.<0.0025

wfts t o i t s fteld ehtocMd with g•

CCtCKSf ^ ^ fttsBilili^- fer tocii

tm^mmiMrtt, «th«r was tuBsdvr r«ltie«di pm&mafM fh«

tiftt tnwtttA Mith wsotbtr l o t of «lti«h wm aeaio tmdM'

pr««ft£r* t(B r«s0y«f t in l«tit truoM of el^rMv*

obli^dtt ii»a thfti %9km up in •tli«r sndi used iianNUjitsly^ ftxr

HiftbKr mmtimM*

a&ltt) of tlw eorrs^iondiiig teid In sthsr (SO s i . ) tens

trsfttsd Mith • solutiODi of 0.5 (0,005 «ol«) of t r i s t l ^ l sttiso m&

0*5 (O.OOSiS of K»tM»fgrlg!ljreln« s s t t r Cpr«|miwi tftm

H-bKiiylgljreiiw as dsserlbsti bs^srs) in dwy otbsr (SO ML*) in ooH.

Aitw kssping ieyr ons hour rooa Uaipmmimm, ths roftotion alatttart

i«s Mfliyovi gsnUy for 8 tjonrs trndw mBSs mx* oei»litions* tlis soHd

t^ieh sspsrstsd vaui f i l tsfodt iiashsd with l^^droohlorio aeid (5D« sodiuM

bietrbmiAttt {§$} wttr. It mm t ^ fttift

lM»iii»»-t»}(iiiift to gi'sn 0.5 £• i i # t jr^lov eirstilft^ m p*

An aSditi^s^ 0*11 ojT tlM auunfi ^^roitiiet 0tiitfiln«d tern tbd

fttlMrMl li|rer altor wasMag i t uith dUjutt ftoi4 tmA

wafttoe MeirlMmiit»i tnii dijirtitg m w Aftly^roue todlaav taApta^^

g462SJ)| SrCEar) I70e(ina«l«

I650(«idd« e«0)y 1S75« 1460Clid<»l# riMigh 1210 em'

(gtm» X mm, 292 is/Oc, log 4 4.41*

Fottods C, 75.46j H, 5.04i 7.14.

fta* lN»igpi03gr ec»ip)»ttd^O«39 f«C0«C^1 w S ) tms tHHu m idtti

100 «g. of l^«C(10l) in 25 a!L» oi «t»l«i»ol. 0!Di«r isn^gttA mt 45 Stal

for four boors, ftm ootaljrtt m§ fUtoroil off loid tho produot m*

cryB%»3Mni othiBOl. fhie oonpotma dark«o» ftt Mitt

«t 252-4® to « rod I m n oil , 0.84 « <70*)| lr(K8r) HSOCpfeoaolic 08),

I680(indolo IM^), I6l5 o '^msido C<<»)f isr(»iOII) X mm. £94 ,

log -f 4.36, 4.22.

iBol^oltt Cilcd. fbr C^^^^^O^g I C, 70.58| H, 4.61| M, 9.15.

foondi C, 70.43| 4.35| 9.01.

MM'-ut*

ebloftds itm g»

(d.<DQ25 of eorrttfoMliig mi^ wis eo^imftti ifitb 0*S4 i» dl-

mla) t t ! ^ ia tbt prosnie* o f

G«5 g* welt) of trictfj^l ttsin* in iitber t»iS«r

<$0ffilitiim8« ffe« ^ ( o d ^ taft iflGlfttdft tosl^* efjrat«lM«id Iktm

Btthanol, ibf* n f , yim I r d l r )

1600 1435(iiittol.$ rifig)^ liSIO cm^

(avoa. X mx. » log 4 4*^5.

AuOriitt C«X0d. Ibf O^fij^O^Bg I 76.0i| 5«40| K*

Fotm i C, 5.49| »»

0*41 (0«00l maUm) of tli* b«M9l.oaQr dorlirfttiiPtt «»«

dobts^liUd with Pa-C(tO]0» 100 in •coile aoli nnflor t^mgm

45 p»i for 4 ht«tr«* fb« preaueffc oryvtalliMd froit oiiiaBtil. I t

diukmx* At M^t* i t to • brown tdX, jdoXd 0.25 i4S0$)$

*>ii *

irCESr) 3100(tlieo<ai€ OH), l670(l»aol« S-CJ-O) 1610 C-05j

A 257$ M «A • ^ 4

Asaajrslat fm C ^H^ O Sg t H, »» B.75.

fmxdt e , 71.^S| K 5.091

C0«00i5 of tlw AcM) ia •tlwr m9 iritl» m •mma ot

te&m 3 of murooaliui

tts&ir . Aftcff* Umpimg itsat mm iKwr at vtK/m

maetioii ma r«llii3f»d Itor 0 l!0ur«t IBS vex^ed

up «9 l»*fiBro. I>3WuiiK>iisd«l« ei7»tamaeai •ttunoil m whit*

nMdlM. yi«l<l 0.51 g.C64$)| tfClBr) l69f(inael#

l645(ffiBi<l* C«0)t 1590, ring),

M^m) A 255, m m/i, log 4 4.88.

An^alat Caod. ter C^^^QjSg i 0, 7i.g4| g, 5.03f H,

Foa»d t C, 71.16| fl, 5.201

fh» btai^Io:^ 0.32 f . (0*001 eeil«) t»»

witis Fd*C(iO|{)| 90 vsB§»T t Q dregta at ^ etlnasoa. for i m t

fha pm^xt^ m * erj^nlUlMi S»t>w i t dftitens

t35®, Wi t t at 856-1^1 f i m 0.18 c.(78l>l iiKKar)^3t00 (pbtmUe OH),

I660(lntol« B-C-0), 1<S00 m ^ i m U * C«0)| iivC teOa) X m $ m

Itm 4 4.37t 4.S3.

toaJyiilit Oalcil. foj? C^ ^ O^Mg i 0, if

Feisttttt Q, m ^ ^ t H* 4.0d| % 12.00.

FlK>tg«M ga« ma pmama a. aoSxition ot pHitMeSL,

103 g.(0*1 »Qat*)» in ^ ot mdivm dlaaolvid Sa w t a r

(500 m.)^ Mlotstoing %\m t«i|)«r«tar« bttwMii Htm cts

m i no ioas*!* &li8orlMid« tUs p^oduet hm Il3.t«rad off «ni vatlitd with

colli soAitm l«rdn>xict« w«t»r aad b9lou 100^. thin {>»daot

wnt luffloitntly jsor* Ibr fkxrthnr rMeti«B% K«p. 113®, 11d.6

a-Nitro-]p-eir««»l{pp, e i t . ) s

A itiictsiir* of 15*3 nl. Mslphurlo iifild. (B f»ir SOJS <

75 «il* et A.!t. iQ];plsyirio neM) and 9*9 ml* <4* %•%%) of niirle

d !«• ii«attfilLl^ «Mttl to « ttirr«a tolnticm

eiupboo»t», 3B©l0) 4B 70 of i«il,pbttjrl# aeSd C|5y»piar«d

fta iilsov») «t fb» alacttii^t iNsiog atiJT«<l for two feKW^f®

«t ta^O®, w&ft pcurod oa omilioa ic« ywUow

•alidt nMob filtor«d md th i s thtm

tr«et»l witfe ja«Sltiiii MaatJuB (SO g* lu £00 Jsil. wntist) Iter

iMKira. 7hl« tointicasi mii tkijcm^ aeidifind wltl^ eomw^mttA

t^foehloirio afild ftt |»IIitro*|)«er«fel wt« hf tiUm diftilJUrtieB

•nd th« maidaiA. immeMP wm lectiwetadi Hgtm bmumm^ inifllQ«l itith

•odiiiB QlOoriila aatiarstod «Mtt*r aad drl§A ovsr ftia]isnlx«fU« nodlini

MiipbctM* fh t eoi|M»i»& wM trj^mttaMmA firos •thancily ii«p. 76*7^*

yiAA £1.1 §470$)

4 iiixbttr* of 10 f . (0.065 aoU)g btnigri

etaorid*^ 8.4 g«(0.066 •odlxui li rilYoxldio 2.75 SQ A* ii«t«r).

- § 4 -

//

in 60 ea. of mm h«itt«<l ind«i> rmtim l^r 10 ttomrt* MeoltCKl

IMS r«»Biv»d imdiffT rs^eadl ]>r«awr»» aiDa tfc* •xeasa of iKmioO. «t%(i(Mri<3»

m9 ttOKmA ^ ntdttst aistiMatloe* fh« selM w$m lum tip iUi atlssr

rniA iMtMl with aoiSl m i^roidd* (51 ) m t m l lUoror m»

dH§A emr Antrim* sodius mlj ip)^, Jki^r r«aovioi; ttui

vaut o s 7 8 t « l l i t * a ; £k> ib btne«tie-i»i^0jL«tiii «ith»r ( b .p * ^ a o P ) *

• .p . aneM t4 f . (83S6).

tc m solntiim of 7*8 g* of potfuMtoa im 35 »!• of iil»$oliit«

•tftiwca. mB& 16© ol, ©f « aolntion of 24»3 g» (Otl of

30 of dletbgrl oxttlftte in SO idL* of

toau«8« «fei «d!i«d with oooling i s k So i * ioAgrdbroaft eosditioatB, 7hi» m o t i o n m

ttus GtrvlAd m t ttui uay m a»»orjb«dl

pitxtaet otsfcttlaad Mlt* at yitW Ja!.71 g» (91%)*

hMmM^^Mf'iHtf^f^uU^, iff e

th» pxi^Mdiftff e, C0.04 mU), m» <lis9olir«S in

e w n l s soliitio»« dD ad. Cndt 56 lA. ftcptoaa ajMoalAf

0 . ^ ) «nl a hot aoltitieii of firvout fliOphBt* (72 «• In 80 i£li. wat«r)

• 85 -

warn Bdd«d to i t . Tht t^actien eArri0dl mt isfid«f mmetiy

th* tisa eeo^itiona tlcaoriM btlbr*. u»t

eth«r» inMm i l l 49iimd oryntftls vw^ obttiim^

133-5® 6 g,(36i)» [ l i t . 18S-S6® ( m )

eonviirt»a to mtil dhloridte vith ttileq^i eM-oHdCi 0*6 f •

CO,C05 » l e ) ill Sz^ 9tb*r. oos limir ftt meii

t«!)f)«rstiiri»f i t w e mrlmA loyp «• IMtiW* iistd inwdiat*]^*

ohSboria* pr«p«rtdl 0*66 g«

mitt) of tiMi HQitvmwffmMxis •eld in «tli«r ««« tr«ittd with

• «>lutio» of 0.5 i« (0«0D5 AOX*) of tri«tlQ4 aaim Mad 0«$0 g«

(0*0026 aol«) of ctl^rl •«t«r (ps-ipar^d «• daierilitd

^fOm) in dtf •th«r (80 la . ) in co34. fh t r4woti«ni •Ixtar* ktpt

tcct tm tmr «t rem tmpvtrntasem and tb«i iot B hoora isslar

eoaditioaa. tha pnOmt oHaiaad was ^ s t a U i t e d mm

- 4»

yi9U g« ir(Ear)

I7©0(i«slol® S-C-O), 1650(i»lil« H30(i8^i©i« «infi)t

1240 X m lisg 4

itoi lysias Cglea. for Cj^g^O^^ i C, 71.741 H, 5#09i

fhft tsonigr^^ eon^MfO*?? g, (0,001 aioX»)i was in /

25 ml. ©f mmi&l vlth 1CS0 i»g. «f i i ^ r Ig^regm ct ^ pal

£or tem eota ly t t itimi f l l t w e d ©ft t l » jprodwet t

ebtidnad m mrnptm^im of the fi l t jmt* *»»« esir^^^SliMa m » btssmt-^

btiwB* «tlt»ml* d«rk«n« ftt aiMt »»lts ftt

0.42 i* <80Jf)| iriKBt) mooiphrnmns mU lWine©l» S-C-0), 161C

(fUBldt C-0)| w(«iiOH) X sue. 319 » 4

AiuOysltt dOxMi. Ibr i C, ?0»58} fl, 4 .6t |

Fotsvlt C, B, 4*44| i * f«00»

obS/orMt Idmpiorad irom §•

CG.OOiS soil*) miA %nis eimdwastdi witliD.54

neat) of etl:^^ •ikI <0.005 «f

tfivthijrl «ilno «tfa9r i>nl«r taS^t^mB m^i^iotm, fhm v iqfMKrlaaatt

mn ixit iiiH$«r ssm eondiitio»« as b«D9ii>« f liui prcdotst

tMitt irm bvsttane-lwxsiwf cup* jrieH 0*67

1700(lj2de(l« JM>0)» I630{«idia« 1600 t$3l» t44e(iiil<»ia r i a ^ ,

IfiSO, %m tm^imm, CWM5)| uvCli^^X nwc. 317 i^a. , lof 4 433.

Attal^'ilif Ctled, for Cg^HggO^ i H, 5.40| B, 6,8?,

Foiandt il« Hf 7 •03*

b«n»yloay oo^pomi , 0*41 e*<0.00t soil*), hm wbjtettd to

lisnlrosiiiol^fait in «l)umol in tbn prtsme* of 100 i f , of PMiClOl)

li^rosian m% 45 pt i for fbtir hottrs* fho t l t l s eoapetmd wat a;3r«t«3.1lifl«d

fre» •tti»soX« i t darkana at SOO ami lealtt mt yloM 0*24

wmx* 321 m/^ , log 4 4.t9.

pir«|>sr«dL iron 0,66 f •

<0*00^5 M^l®) 0f th« eomMiip«ii4ing miA in ^wy ttihef met tdth an

of ^Vdfl estcir (pir«paf«i tmm 3 ef Sftmoiim

Ktljyl tiittr ISylitjeKlofiat). Affctr Jiatpiag i t fer o»t hesjir mt r«o«

riHiotion attxture w* reHaxed fer 8 bG»il>s. fii* p rJ atstoo*

MIS ittolfltwd «• btfotii mni l^oii htnmm, «.p«

yitld f.{6S$)i ir(KBr^ m5(ial©l» S-C-0), l670(B»id» C-O), l^fiO,

1590, 144D{lndol« ritjg), t£40 C-O-C)} «««•

lof 4

Amayalij C«lc<l. for *

FooisSt H, 5.Mf li,

with 90 ««. of f^CClOJO uaSor fcgrd*®^ iml in bi^ttnfMitfetaeil

for fear bi^srt. t i t i * {sfetot w«t ef:y8t«31i«id AtlMimi. Xt

dKtimm mt ei^ts ftt 276-77®, j r i t ia O.ft «(80SOl iriSQt) 1300

CpbeBoHc OH), t700(4eaiSl» li-C-©) 1630 C«0)| *w(HiOH)

517 »//- , log 4 4.55.

AniOysisi Calcd. ior O gH O Kg i C, H 4.3«|

retoidit €» 4.£tf 12.09*

mmmm w ^.uQim^

it^ydsol (20 fi.) in portitms to Itmifig maljilsiric

«eid (74 ol«a% 35 lO.. And •olphuorie aeid, ia*) vitli food

cooling in iee* k adxtur* of 8.6 nitHo aeld and 20 iiX« «a!l|il»ifle V

«cid of' thd ftbovt «02^8ltion, itt« uddod, t^aperatttr* ma »(iiot«lia»d

bttiwtn 4 to 6^* Aflar kMS>iug tht rmot im aixtuTA ftt roojt tMi|«ratiirt

for 24 houra, 30 lil. of mtmt vat «dd«d mi iii« eoHfceatt of tbt fUide

-

mtm stefto disUil*^ tsr suptr-lt«at«d itttidti ni •

e«s!« ss • Ixrtitar Ul(e «ml«tim with eilwr

tsowstrs. fh« dl0tlU.*t« mB with •th«rj| tlt« vthwraaX

VM» '^zittd mar iKMm iiiil,phat», wftc f«K0V8d

•jad « thiek U ^ d m» 25 f«(d8|)*

fh9 proittflft Ct2*5 i*) i9£tiix»a wttiai aSU

aeetie ftntig^Ha* for tV9 imr», mH^dHd^ im» m^w

reduo^ pr«si«r«, imd t ta r t a l^ t t «»• dis t iUei at $ « »

prdsmr* to tlui aectjrl derlvAtivo of a.|>» 5^}

yi«l<i» 15 g487i5).

fhd flteetyl d«rlT3tlve of (eg.) uas roftossd

vith »1* of iK|ii«oaf etoAiun fosdde aottition for tieiiar*

«lk«lin» 8oIixtio» vfttt tisatraliiMd with sulpbarie aeld

•xtrftcied with tttlisr. fhs othsroel laycer m» RgMin wshed with aodluBt

ohlorldi* tttttrttodi witt*r to nmtml pH. tha «xtr»et was dridd oiiw

•ahs^droiift todtuiB aalphut^^ Aftor remotdet etlieir^ coiaitcuaA iitt

eryiit«lli«M!, •.!>. 41®, yield 4t . (94*). l i t . a.p. 41®C30) •

• *

S-Kitro-n-ereaol (14 g.) ««• mfXm^i vttb Iwacyl e^loxld*

(t t .76 g, in tS*4 i^* ettumol) in moAhsm l ^ d f ^ d t C3«@ g, in 2$

v&ior) Ibr 10 Ixsors. was imtiiir rej^ue^ i^x^aMa*^^ h^I

the ioceftsa of bmsi^l et^oi>Me ««» f«s<<9v*d hy atmm distlUatioa. Thwi

t ^ omtatAn ei t l» llti«k m m taktu up tn snd vaids^d ^ i b tt^uii

sDd mtme* Itluir w off ai WBMiSm tnit

distilXiKl ftt at >>4 sn. presmrsf 10 g.

teeaysiai 0al««l# §i>r G jM j ^^ t 0, % H.lff H,

Fottoai C, K,

Potftssltis M t ^ 1.9 g. (0*1 mlM)^ mu dlsaeXvisi in 17 lO.* af

Absolut ethaneX* aisdl 80 ad., dxy adisd to i t . Jk ida^xtt e£

diatfea?-! oxftXat* 15 fi. C0»1 i»l«) «M

to tlw fttsomi solnitect. fteiithn ronetlcm irts c»iTi«d mit m

* 9 2 " ^

f o r mM* fim rmetim mt

«• « lifGim t ^ , tfbleh eotlit ^ di^tniaiMfii. fli* ttiof* /

reftetion wni ttsnai tittOA th» ^wtiTwA i ^ o ^ t net

ifioii^fti,

mmmmm m^ mAmiQ mmmmnon m

ft «0ltitiffla of £1*6 g, ©f pHsres&l SM im ©f

3M iodiiaa g. of erttsbo!! ioo 6a<t 30 la* of ao^feie

eiitt poftiofit m^ tlum the eontoixitt of tli* Hatk twro iluikon

Tho ofljr a^ermioai out <ma &iek,vmtM uitli ottMirt

waih«d ftnd or«r sodioei ^hor intf wmt!m&

rodboea pfMaiifo th« tldeie oil tmt dlstiUM at yUM, M6

Cc£Ld Aoobjrl-p-erotol^ g,, was «dd*d dropwifta to «oid ftirrod

Aftor ill* iddltioc, ih» rcN^otion tab^ore atlrrod for a m t ^ biif MI

boitr and thou poiarod on erushod too, tbo mhstmcB wVdob siporatod out

- 93

if&B coitmr&d^ idtb 0tb«r» fnet^efe vii8 weahM witli ioditts

emoifid* «8twatca i»ttir to is«atwa pS. t t i m inl« mmm^, cnl tli»

jfsst. k® tmtk3tm& with lif ibpcediia® ad-

tfwS wemmlt 90.450^)0 for 0 sdmUM, liatteiBjea, mmimi mi.

ttm resi<hit ma in ooM idltti to pE

Xb« tjTowfi t i r ifeuis obtaiiwiai m* tmlxmtmi with Wft8li«« with

ti»9 was i rm ^^mreX f»]|>«it

^ l i t . §4^(345 .

Aimlyslti Galet. for *

s.) was (iissoXv«d in atsr^niitii l^roxidt /

iM>liiti.<m» of Mi«K»ii« mm r«w>y<»d iiadi«r and m

ftAtmwtwi mlxibim of wUmst nitx«t« (4*2 f . ) tu t aidAd* A «oloiirtd

Mlt i)rtoisdt«t»a ottt« tihi^ m» wAtlMd wltti IntuHnM^

fhta tairmt mXt (2»3 g») ^ihxmi irltti btni^

f . ) in Absoluts •thanci itor 8 licmrf. SthamX wam tbsii

tmiffr r«iae«ai pmtmm «ni tb« imt dioaaivwl in ami «thtt««i

lagrar m* waalhttl with mMm Igrdrexid* soSiitioii va^ ii»t«r* SblMr

th«a <!iatSll»i off ami tbo i m t ^ eUtoildl* wk§ rtMsemil

«t«flue tls* f«siiila« im« oi^ctaSJlied £ tm bimf«ii»»|Mit.*

• ^ • r tl<V111®, yim, 1.29 g45M)» 0.S f . ©f tti»

VMI yWiOWSlTlldt jCiPC i lmUilMI 803Uxt>ill3KI liR

rnUimmrni. 110-lt1®(33)] ,

S,6-Dliiitro»p-crii9<3il <0.4 g) wm r«i»ui08<l witfe ©wr

j^tinspei oxliSt (50«(g.) i a afi«tie nidxfilri^t {Z

pr«»!9ur«. eitt«l/«t was fiXtorad o f t tkoetlo ii«*

mrncmd tm^tr reiaofld protntitw* fli t rosldti* m» er j f t ta l l i t f t i £rm

©tfewsea, S27-S®, 0.4S [ l i t . .

MsK^Uwi ftl' J^iHltiA^rffirBfTffirit^l tetaiyX f^few .Oft^tea

2r<^Sinitro-pN«r«aoI eth^r, 0.6K f . acl©),

•)}»i(«n with pHatinua oadtt« undmr }<^roe«8 «t tttaoflf^harle pr«star*.

Ubflo Mat 00 fiarfchtr •b^orptioB of (100 IssrdToe o m9

ftboorWl)^ thft e&taJ irirt fiXtered th« p t o ^ t obtNiiiMNl

imm ths lil&ffattt aa the triasolyl of

z&tf m ^ d g.C^sO*

AaaSytiii {^leil* iitr 8 i , 10.60.

feasSf K, 10.5!.

Itn ei«oholie eolutlen of 1,51 g.(0.004 ffioS.*} of

ertsol btfiagpl mth^v wss unler bQrdrogm «t i 50 p«l in t t e

of about the aasi ^uuuatit^ of Bae*^ ajek»3.. After ihakii^ th» ml ffyxptt

for fottr honxpB, ttie csmtmifc* of th® bottl.« q[uiekly flliert!l Into

«n excess of «ootic The ftltmfc» fdoae with aoeiie anlisniriat

was «va|iox«t«d off imder rMtiood ptmmiafm, iolid r«0idu9 wawM

idth mtwg <lrl«d end ciyitallitedl t t m teauntne-biaan® or ©tbanolp lAlte

medlot, 135-186®, y i m , 1 g.(80jl).

An»ljrfiai Caiea. for C^g^^O/^ '

Feandf ti9.10| % e.80.

flw dinewtTi <l«rivatiini of benm^

OM (C.Of mw otrnkflii vith 100 In laeob^l

un ler l^ogoi i cfc ^ f i l fbr f ^ I x r ^ f w m m ^ t S . of tbK ostal^st*

•nd tt?t e^lroaiti, ttttt djjusAtff dtriiratlv* of aj6»<liaidis&-p-er«aoX

cryttallieidi flros alcohol er hmmm, ».p. yt«M, 0.4

Jln«ly«i®j for «

Fottuas t2.47.

Thl« ainostyi fflR 3li«ldiiis wltli ttootie afilignli'ido t» alcolioX

fRW tii« triteaigrl dwlmUm, la.p. adsrtd B.p.

- § 9 7 -

O m i C A L a E f t C T I C ^ S O f

If is aol®

was elmkan with pletiams oxl4e cataJ^st laidfty Aft«r eofi^lstioo

©f tli0 rsaetion, tha Cfttalyst was filterod off and fjro» tb« ru t ra t^ ,

solvent was rmrnvaA end ttee rtoidiw was ory»t»llis»!| fSroo ©thanol.

In cmm, iiisreact©jl starting raatarial was r ovffir<a«l# Tb® exporin^tftl I

conditions are @aii:!aariised bolow:

Cos jeand GataJyst prassaro

Tim (fero,) Solvmt

1. 0,2 g. 0.04D g. Atu»sj5h«rl® 20 Kethasol

S. 0.2 0.05 g. 45 psi 8 3. 0.2 g. 0,05 g. 63 psi 10 iie^ie acid

4* 0.2 g. 0.05 g. TO pei 24 Ac«tic acid

5. 0.2 g. 0.05 g. 70 p»i 50 Acatic aeid . • Ill iiimiiiimi II

fetrah^rojEUran waa f i r s t rafluxcBS o*wr potaaatoia tj ^dit xide for

six hours and than dlatllX«i* I t was again r9nm:<!!d over stdiua wirs for

•i* boors and distlllodi. I t was finally raflASxad mw a eeall qumtitjr

o f l l t h i a i s alaatiniuD l ^ d r M t end <3ist i l l«4*

1 i 4-T«trah3rclro-2«i»njigrl-1»4h^ioxopyr«eiao( 1 i » d o l o *

sold)* was talraii 200 nl . of t»tr*l3griSi>efUran iiM thia

ftolutlon waa addad dropwisa to a suspafision of 45*6 g* <t*£: iaoI«) of

liihluts alueiniois Is^drida in S80 lal* of iatrabirdro£^an. 7ha raaetim

sAxtam raflux^d for Itours Kith atirring. fb« axeaas of lithiiam

a^Msdeivw hydrida was daooepoaad »ith 73 inl. of lOJhl aodlos l!^ro3d4a

90 a l . of wet or vfith ipao ccolisg. ffem th i s siteturo was «!fiiS.n

rofliijsad for or® hour. The issorgfinie proeipltato vas filterod off and

^mltml with ^ihsr tim»* fhm ooalxiiMid f i l t rnto and iiaahiet|«

vara 'mpt ©var aal^droua laa^iaeiuia miXphata ©viar n i^ t* Ethar end

tatrfthjrdro^ran vara resoirod imdor low praesarii and thm tho rasldua

W&8 tali»a up in di7 ethar eaiiS Hvy iiiydrochlorlc acid gaa waa paatad

thrcmfh i t . A Xight brown coloured ta r aaparatad* wMob on ooolinK and

ftoratohing geva m smtpbmsi pow^^r. Ifhia jpowdar af ter two cr^etalliaationa

gave wbita shining oiyot^a 154®, yield, 6 g. (6l$)| ir(SSf)

3l80(Mro*yl), 3C500(3aiol9 C«H), m s , Um, t450 etT^Cindole rln«)}

uv(BteH) A mm. 274, & 292 4 3.955, 3*U & 3,845? ntrCC^D^M)

r (ppa) 6.74(2p, t r ip la t , i opt), 5.35(£p, t r ip le t , Jf £.5 ^ ps)*

- § 9 9 -

iiingl0b), 3.25Clp, wxtomlvii mpXet),

2.90-E»16(9p, aromtiet imltiplefc), sifigl«t), broad

i3Bap#«©lv®!l t r i p l e t ) . Tha las t tw© peaks fttT" •2,34 4i®app®ariid

in tfaa ^eetrusi tAk«fi a l t ^

Analyalsi Ca'i«d. for C gHg C J-gCI s C, 68.27} 0, 6,63} »»

Foai»a« C, 68.44; % N, S . ^ .

1 » 4 - f ©trabjfdro-g-l^n^yl-l, s i m d $ S-a) Itidola,

(0.5 g.) was tr«at0!l with 10 Ml. of 0.5N potasalw l^droKida, and tha

raaction mixttira was heatad m a water batii for aiiaitaa* Tba eca.d

alicalina solution waa aoi4ifledl with dilute hydJwWlorie acid, Xha

wMt® praeipitat® thua ofetainad waa waefead, dr i s i a»dl crystallised froia

•tfeaiiol, o.p. 213®dac., yiald 0.47 g. (90lS)j ir(K8r) 3230(carb©3grl OH),

3000(iBdol© C-H), 1700(carbojiyl I630(awi^» C*«0), 1530, 1500,

1465 effl"^(li«lol® ring),

Analyaiai Calcd. for O^^^^O^Jig t C, 70.11| H, 5.23| J5, 9.09.

Foandi C, 69.86j H, 5.16? K, S.71.

IV. Mefeterlatliaa o£

A oolutloii of

(0.01 mli&). In tC of dr^ bAnsone amd 5.6S g.

(0«C4 noOLe) of oatl^srl iodide was to a solution &t ttodium

(300 t!^.) iu 50 xb1« of ft^solutf) m^lMeml, The r«aetion edxtuiw mB

etirrod for four and & Mlf hours et §0*60^. flacnt Atlfxljntg was AtoppM

and th® solvemt audi oscos® of etathiyl iodide war® rewoved wilder razeed

pm»mv9* Tiio rosMua m& ihOKi »ltb li^drooliloric aoid, 100 nl*

(10;^), in orusbad is®. 4 solid product obtalnadt which was filtor«i»

tfashdd find <iri@d« Thia iioXi<l proiSuet was ostn^ctM with bons mo in *

iioxhlat. ?bia white powder l e f t in tta* thittbX* mB fsrystallited Droffi

tfthaooX as whit« oryataXs* I t tf«e id«ntifi«di as open obsin fteid^a.p*

o,p, Mltb th» hjfdrol^reis prwdaot yield, 0.2 ^ ^ ^

coapoaM «Mi8 also found idamtical with that of the hydrolysis produot*

fho bsnsano AICTRECT OB j^tirthar oom>«ntxnti<m IGAIM a inAilta

erystaXlifie oonftound^ wbioh was filtarod and driad. I t was paastd m«t

neutral aluaina using a liixtura of hmt&nw^h&mtm (60t40) aa a aoXvmt.

- 101 -

A Mhit« ei^stallino eoa tooM lias.olKtatnddiy la.p* yltM 150 tsg*

Tbl® was idoiitlfied as

10-dl»®t»grl®yr«Bjji©(l,£-a)l»dol«| Ir(Rar) 17O5(in!i<ii«*K0«O), I645{«»ia« C«©), 1600, 1590» 1500 CBT^Ciudolft wimg)t X »w*.

Asalirelst Caled, f w ' 5#70| K,. 8,8,

FouukSI a, 75*48} H, 5,75$ K, 6.63.

fha be)ne«B« »&th»r iiiiuor <m eo»&«!!itr«ti(m g«v« m y«31oii eryetallino

product, ffl.p. 1£3t®i eiJ!»a ffl»pt with

iir traa also fotuid

to b« itSonticaX* '

the rasetlon of bensaXdahyda with

1,4-(lioxc^yr«sino(1,^8)iistlol« in th« ptmmm of « aiitatsiii basa vaa

• j ^ t a d to glva t,£,3,4<»tatra)Qr;lro*2»bani^l*>»filitiQrlAathyl«ii»^

pyra«iiJ0<1,2-a)lni0la. This raaction was cnrriati out imdor tfea JbHoidng

diffarant axpariisantal oozatitlonat

- 102 -

Ooipoimd CNinsaMeliQrde Base Solvent & t ine

1. 0#87 g. (O.OOJaole)

0.318 g. (0.003 nels)

Na0Ac«0.4>9 B* (0.006 iwae) & ACgO, 0.3 g. (0.015 nele)

2 hrs.

(O.OOSnoilt) 1.06 g. {0.01 aele)

H p e r i d ^ d i a l . ) EtOfi, 6 hrs.

3. 1.45 g. CQ«00$Bole)

1.06 g. (0«01 jsole)

E t ^ C n 5 la.) StOH* hrs.

K3X th« «bmr6 -mtm enxrinA out et thft stesa hath to^arat»r«*

Alter eof9:a«tio» of tbs i<etietl0% tlito r«KietioB aixtvrt was

pound into a alxtur* of lnydrocWorle 50 oCL. (10^) crushed

solid autsrial wao fil tered and iMshod thoftni^Osr with petrolena ether

to r<Keove the escoese of bensaldehyde andi beneoie acid, fhia solid |irodttct

was then esttraoted with heneene* A bmsme insoluble li^ite {jowder was

l e f t which on crystallisation fron etha&ol $e;v& tMte needles » dee.

Qixed «.p. with the open chain acid, dee*

The benwrne extract affcer reiaoval of hsnssene gave a brown ta r ,

Ciyotallisfition btA colutn ohrosiatograpl^ over elosdna in different solvents

failed to give any pure product. Sa»e results were obtained in a l l ttM

above ea wtiiMNxts*

112, 1602 Ct92l).

Z, Piitaier, Jotaaoii* aM

3. Jolmeon, hmmi, BolHir* I.f jr*ila.CltiB« Soo.« 2364 (194?).

5, S285

7. m , H.3., Stmmcm, ^•tSUm.Sodu ^ 4 4 (1968).

d* itoraMtk* U«0.f Ftfkin, St,, Bof^immmt | g t # 1378 c m s ) .

^ S370 (1947)»

10* JolmaoB, a.R.^ Tlw stmetnrd ^f in *th» Bogcr M«m JSIy^potlW Jolm & Simsji Iiio* foity 1955« pp»

11. JobnMQ, and tipibaJLiAisd obatinr«tioos {QmUof^ thtsis, OonoMO.! OBivtraitj, (19$3)»

12. Hodi, H.f., S.E., Kidind* A.il*. and Jotmson, J.Org.CbMkt (1970) •

13. tr.S. 3, 317,524 Uwy iWtp Fab. 4» 196f« pp. 7 (C.A.,68i21956k).

14. SiiGkM*, C.I., andi Robarfea, Anal.Cbaii., £b 1331 (1949).

<li>

%§* Slireiov, Altakte^, UB., Qyiaar^ Alikmm,

(C.A., ma^im vh

(Ci* Fxt». trnht&^^m Pmm O^e&iDr

1?* Shvwtot, f a*^ Al^aMftt Oxititnrt Shlji.Fft3m.2h* 8(12), 3(Bwi»4 2(12) J-?. (C.A.t 70j87750iO»

19. ttsd Unpabliabftd 4»1>tg«iflf«ti<^

19* l^tel!^! Johaaon. mH Bruet, U^f^,, a.fts.Otuie*^*^ ^ 419 (1944).

£0* foKtngi 3493 (1950)} uraS HOMVFI.* ^ 094 (1959); J ^ A* aad Mitko|$t 3.i

(19^)» SoMfiai«r« H.S, J ^ i l 21,1959 (e.A., 54iJ?35W»

jSI. Harel»lli» lNMBt»g«ir» H«acoeliy fi.H.* •Chwsi.^ 4375(1^)«

S3* 30lmmmt fiatldroiielcr Dutoli«r« SJHm, mA J.Aii.Ch«*.3o6*« 463 (1945K

24* XctlMh, » £019 (1944>«

r . , wad ICorrltQ% 4»Gliiii»Soe*^ (l^i^)*

26, Stoli, k ; tmiCLXw, aM Boftetniv A** H9lv« CliiMi Afit* » ^ 1452 (1955).

27. SehiBai«r* W,, R«ly«Chi».AoU gU 1^30 (1957).

( t l i )

Bttrtoai Stoif«o, J.U, (1937).

(1943).

Maciii, mi t*C« ^.Or^tChiiii.^ , 917(19^).

f., B»il«i«t»s HsMlKieti Orgenlebtts Vol. 13 ( I MippiifMitt), m *

33*mmh9, f., AiiA.C}tw.» lis ciaaOi ibi^ 143

B.l». ttoi f m m , 2C41 (1919)•

M.E;., Sobirttaidn«ert B.M., f t ^ , 179(19^)<

M.R., «iil H^ HI? (1965).

rr.Bb&tt, ?ti«kdf, K.A., ^ 1049 (1969).

a.ll., K.i., ^ 10S3 (1969)*

39.nisMOt, 9tin.3oo.ChM.(4) 736 (1909).

H.p S.Fta^oH.Clun., m ( m s ) .

-P -R T - I I

1 1 3 1 a 0 & i e t X 0 B

- 103 -

I J j f R O D f i G t l O K

(l-b0aKo(b)y;ywrolo, l-aaftSisdone, ketole)

Is a nc«tib«eic nitr<»|pnous compam^ in whieh & bsnKono m d n pyrrolo ring

«r« fu»0i tofsthor in positions of th® pyirol-a ring;. TH«t forsiils mv

aeeoptodt for itidolo w s propoeed tjf Bae^^r and feaerling (1). Th» carrmt

praotlce in noesncietur© ia eteown below <R.I. 881).

H'

Tho original systeo of uoHmtclaturG diavifiedi by Sseyar nnd lotor b^

Fiselisr (3) was too assste reos© eiise® i t ©ffifslojoS tiii»bari«g

for each rluu,

Iniolo nucleus i t presoot in isany natural producte. fh« «arV

uorls: on indole dorivativ is was dons ^ ^ j n ^ r i» coimootion vith his

r«3oareh«s on tha stmcturo of in jJtiO (4).

- 1 0 4 *

SniSeog if 3-h^ro^RloXe or ia m

i i ^ r t a n t l&tomediattt in tti«i s^mtliddls of indli^e* XnoaiaKL of

bioelitsfflioeA. ifeporictnos «« wftil^ i t s giuoosido occurs in oortftin

piKn(t« mi i t s sal^lnirio acid etitsr «xoret«Ki l>jr atiifittis*

3 - % d [ r o i Q r i n d o l & - 2 - c « r b c M s y l i o a l s o e a U w l i n ^ o j ^ l A c n e i a

i s « s m o f t b « 8 s e s t i i q ^ x t a n t i ! « r i V 8 t i w « o f i n d i o a q r l . I t v a t s U r t H i

^feparwA trm o->»itropb«n|a.prppio3.io aeid

H C C O O B ColdL H2SO4

D OH

H

( ^ ^ C O O E t

- -

I t hftO also boen } re f^ed by the ftision of l.'-phiBiyl^jrCina-o-ciif'bosfylic

acid with iiBlten alkali <6) or better s t t l l with (7). Xn the

lat i«r ease, tho raactlon i s c«nl®4 m t at a Ijswar t«nf!erat«ra ami

ther^fera the yiolrl© are teflittar.

•IMH CH2COOH o •OH

H

Anothar ayntbasia of irtSoxyHc acid bas baen aeeoi^llahad ^ heating

aniliao atalonic oater (B),

Q / COOEt

\COOEt "O^N-^COOEt

Itidoxylic acid undergoea r«ady <3aeartM»^XatioR to indoxyl, a

fact that Bakas i t an important intwmii&to io tha aynthasia of indigo.

- 106 -

md it® clflrJvativet «xp©ot®<i to ahow k®t©-eaaol tmtm@vtm»

Q H

'OH Q 0

H

the infirared opBetmm of t-«eetyl e»d l-aet^f^l inaoxsrl neesured in

cl3lorofor» indiea t^ thst oxofwm proeHosdmtea* Howdvevi the ipi^aftnco \

of an seetjrl groap in t]:» smmn to stftbliae the cmol fore due

to byiSr©|r«9 boniina (9^10).

0 -N R

Q H

0

CH-

H « Mo, CCCH .

Similar observations bad earlier been mdie for oxindole or

The phenolic oheraeter of Indoxyl ie ehown h r i t s solubility in

aqueciuo alkali as well as tyr the developioent of a dark red eolour wil^

ferric chloride. The ketonic character ia ahovn in the reaotiona involving

the condeneaticm of active netbylens group with the carfeociyl groura of

- w -

arDBatie ttld«hyd«8 or of koto aeido i^lvln® iRiog«aid«a. IMojcia

ooitdeiiifies with iamtixk to eni uith idatin ehlorMtt

i t givws iadig©, Metbyljtioii ©f ledos^l with Eotkarl sulptetfi givea

while mth^ Iodide j^^Ma .?,«-.tl4Bs0tiKylin«io}?yI ( t2 ) .

l»a©la<-2-©«rb©»&i8idi08 liav® bom ltett»3 to b© vm^ ti8«l^l ooRjjoimias

as iut«i?i!^ifit®8 in th@ fl^ttsosia ©f loott^rp^ophaw (13)» fi-wetfeoxyisotrypto-

phsn (14) fflw9 ©f iaoiaretonlJi (15). Thoy poseioes v«ry wseto

Fbiijn»se©l©|;icai properties.

Ki»risaok ot (16) tiavo iQmthooi@9d e^-sabstittttei

cnrboxftoidos mo int«r«Qaieto« in tl3»ir assmtteais of feaMtoe aiid harisalirto.

Olaikio aiKi Forkin (17) have syKthoaiaai 4,5»6-s»batitttt%J Indola-?-

carboxeoidtos ea intorB!oaiat»» in tboir ayntbosls of pyraaifio- arul

pyridlRtioloB. Johnsoc ot «1. (18) haw also uaodi ir^ols-^g-certoosfcaffiidea

ae i»t«rno:3iatea In tlteiz* aynthaais of pyrasdnoiniolot* /a i tbase t^orkara

start<5d with iiKlola-^-eorboxylic acid, comrarting i t to tba acid oblorld®

«al than to the aroida. Jacob and Keaser (19) had earlior wsoi tho aaida

aathoiS. A mm reaction vm oarriod m% iQf ShlrXay aaid Ecmaaal (20)

- 108 -

fcr thi» ty&theais of iudoXck-Svearboxastides*

Q ^ NCO Q ^CoNHft^ CH, CHs

iSHibstitutdd ir^olo-S-carboKasslded alao b»«a »ynt)i€ioie«Ki hy a n&v

roaie by 2€W»h {^1).

PK COTK i - M ^ 3 c n c . SF^ Q Th

- CONH C Mcj CMe.

CO eUj -V Me3CNC D N'' H

•CoNH CMe

- 109 -

Fbtarffiseologieal ftetivlty of « nxsmh&r of IMolo-S-earboxeiai'iae

baa b0en atvidiled. Th® work suemriacNSt in t&bhs I*

l A J L k J I -

H • '

tisarnacological aetlvlty Bsferoncc

1.

n-H^tyl, But.i

OSti

4. if 0}

-Wv 0 J

AntieoR'vuIssnt

IJjipotiMsalv® ftctltrit^?, taofeefl orally ewJ intra-poritoneally on rata

AntioiMtie

lurittiieproseent

CNS Depresseci

19

22

23

25

• 110 •

0 1 S 0 { r 3 5 1OK

^tlb^m^h it)do3eylits A€!ld hoe hsm tmom to be m Sm^ ortant

IntorsMjiliato In th« »ynth«aie of indigo, v«r j few of it® derivatiims i.®.

tho Betl jrl aand ethj l esters (26) «o<l the itnllido (27) haira betn syntheaised.

i t i s wall-knoMK that th© carbojtaajldo grotip i s respimalblo for the isioXogical

activity of ft fwiBlier of o r ^ i e coH5;oiai<la (20). JJ-Alko3!yindol6«2-"Carbo*«)niide«

heve bean 8hoi«ti to poasess useful pharssacologlcal jpiropertieo (Table 1). jit

ma, therefore, fe l t t!mt tbo iKttjnoiluotion of osrboKataido &N>itp at the

^-position of l-hydroxyln^ole miety giw coa iountis of phar«aeologic&l

interest, fhey can also t^ osed ea intonsedii&tee in ame iBportant

fQnnthosea* 3n the present work; a nuEber of K-«ubstit«t«i J-ity4roxyiaiolo-2-

oarboxotti I00 end befityl 3-hyir©j(3'i«dole-X-eiirb03^1«t8 have teseB es^theaieed,

Sooe 3*iBethoX7i»d[oIe- and in<$ole»2*oorboxanMea haw aleo bowa prepared.

Since diin»ot condensation of Indoagirlic acid trith wBinoa or

alcobole in the praaence of dicyclOheaylcerbaJilaiie, %fithout the prcteetlon

of 3-hydro*y g^mp, was not posalble duo to the phsnolie nature of 3-hydroxy

group, i t was proposed to prepare Batlyl 3-hydro^ln4<^«H£-oerboxylate and

« 1t1 -

trjr i ta asmnolysia accordSing to the following echett® :

o UJ

Q H

'OH

^CONHR

o-Cas?b0BK3th0»yphenylglycin» ffietligrl «st«r ma pr®por«J by heating

Bsothyl anthranilato (2 ml&a} and meth 'l chlo:^®tate < 1 ©ol«) in iBethamol

for 13 ^BfB (144 hours) on a stoan bsth. Methanol was dlai i l l i^ th«

r<9«ction Bslxtura was taken in chlcarofor», waahad with aodims carbonate

solution and then vitb vator and finallj ' dried over antisydrous sodiua

ewlphata. Chloroforo wa« distilled off . Wnraacted enthmnilata

and ssethjrl chloroaeotate were r^soved fcgr distillation under tmeaua and the

residue was crystelllea^ Iroct ffi@ti^ol*

- 112 -

Q .C0DCV\3 -V Q • COOCH^ Q COOCH^

NHvl-'d

Metfce'l |jh®iitylflyciiw8-o-carteo3Qr3dat(8 am cyeULsed in the presoiice

of a^iim In drjr m a atoa® Isatli* l ba sodium Bait

was filt«r«d» dlissolved in iet eold mMer m i f^ adding ^ihito

«eetie acid. The todoxylic eeld tsatfc^l estor waa esysiailised fpom i2«9thanol«

tOOCH^ '^S^ NHCH I OOCH^

0 \ i

COOCH3 H

U) Aaaonolyalg of 3*hydroxylodole»2>^«rbo3cylat«i

Amonolyals of wttayl 3»togrdro9grijr«telQ«-?'-earl303ylRto with unllitte

was carried out fcQr bMtinfi' tha ester and anilina directly; and also in the

pr«»9no« of e«tal}^io aaount of Asnoniuss chlorido sni eijiiivalont ssiount

- 113 -

©f seditj» ethoxa^e. fhest ©xj eriuients er« aimairiead In th© following table *

Catalyst Tiiat Belveat

1. ag.(o.oiffloi®) i©iiaL.(.to9 ®oio)

2, toi©)

bTB,

bra.

Benzene

Dipbanyl-athflsr

3. «.1oa40.f«ol9) fJtt Gl hrs.

4. -4g.(0.02isolo) 18.euil.(0.2 mole) NaOSt 78®, 4 to-a.

In th« f i r s t tbx^ •jcporiffisnfea, unreactei irdoajylic wsM ©stor was reooverei.'

In tbe iBot expdrimsmt, « feOsek mM^ product was otitainad, from which oothlng

coaM bs iooXatdd.

Q -OH

fvi'^ COOCHo H

HHx f o M • H

.OH

- tl4 -

Kfttfcarl 3-hydbro3qri«4ol8-2'KsarbM( i'lato i s m -Koto and

abould be fairly raftotive io this torn, rJut i t s ©ncaic fore i s capeblo

of vtMergolng fc(jrdrog«n bonding as sfeown fcjy i t s infrared speotniB (3t).

Aa a rdtttlt ths »mlie f&rm i s stalb3.i8«dl etttd oon^qitentlj the estor group

daactivatod. Thie my sccmmt for f&i1Uir» in tlie abew aspeilei^flts.

Q , .0

H ^ Q IM-

H

4 6 OCH^

>^Metboxy3jnilol0-£-'Cerbo3»ttl<3«» irtire propar»a witb a view to

datsethylste tli«« at tbo laat ondw ®il<i carrilitiona. Xho progosoS

acheoe ia as follows;

D • OH

H •Coocw, a

H COOCH3 Q

H COOH

^OCH^

^ ^ - c o n H - R H

o N' H

OH

COT H'R

« 115 -

Im) M«thyl S-TOtboKvin^ole-g^arboxylBto (32) t

Hethyl 3-hy»3r0»yini0l®-2»c«rfe05?yl»t« mo« ffistt®'! at<)i with dlcjaftnyl

sulphate in dry acetots® in tfie prdssnee of an^drous {;^tas»iusi carbonato.

OH ( ) I

Mo 0CH3 D H H

OCH^

C O O C H 3

>a»eth©jQ? iKdole-2-cwrbO3tylat0 was hydrolya®! witb IN

aatlianollc fotaosiuia t^ytiro*!!®. aol'i was cnystaUisoi l om benzena.

Q -OCH-KQH/cVi^oH

. j S ^ C O O C H n HCl H

a OCH3

H

(e) 3.S40thoyginiolo-g»Cflrbonyl cfetor^de floe. c t t , ) t

>.M0tho»3rJniol0«»2«-carbox^ic acid was troat^sd with Oashly distilled

tMonyl chlorido (IjS) Irs dry othor at room tOEporaturs for on© hour, th®

esreens of thionyl chloride and hydrochloric ecid gas wor« reisovrjdl under

- 116 -

reduced Th« aenisoliii csbss X ift was Cftkon iisto ether and

was uaod as such, slnc*^ i t readily.

o w

.0CH3

• C O O H

s o d , o H

,0CH3

coct

>.M«tbo3^indiol«-g-.c«rbo»jl cfelorid*, propurM froia th® eorfeapontilinj

&ei4 (O.CO$ Mm treatod viib vaHoos ansinda (0*012 sole) in dry ether»

Aft«r k^epinn; tti9 raootion fixture At roo» t«siparatura lor om mni a twXf

V»iir«, othsr ima removed and tto roai^u® tmts washed with diJiito bydrocKLorSjc

acid, aodium Mesrbomta aoXutlon and linaUly with water* Tha dried product

was oiT^aialXlfiei froa athtmol.

o 0CH3

H

-RNH: Q H

OCH3

CoHHR

- *

fti» baa btfortt tli« m^x^fl^

«a9 aietlwtfti of ^lijfdiroagr

Aetitjrljitliiii mi <m3^ to thm

formtim of O) Ixil miM «lm a«ii6«t|'li«tifm

im t&tt m&»r ^ l e h nffeet th«

eartoojsaHidA giemp idio, Bm^t &t<mt thcsigfe raaowd Igr

too Ms MBi 60 in»Qf%if>ftt«t tlw st^rie

Mfii«reno« OiS).

JolliAii fiBd PilO. Cll) Afl peU^ ^ of ^ etiQrl

of ••oroliut r«l3xucliig I t with iiuelnttni oblorM® I s etli«f*

3*ll«itbo9iariiidol«*&««arboia«iili<itf txniflni^i f i l led t^ m d w ^ dtfuftl^letiofi

tlMiMi 4M>naitl6iui.

OCH

IS-H

3

CONHPK ra H X COHHPw

• m -

3--!fivdrexyln.1ol ftyboKfisd^oiii

fho following etsbaas wss thsm ptopos®! to 3jnnth«0i@e th«

Q C00CH3 -V o

C00CVA3

u a OH

H

A bonzeip® solution of chloroacoty.l chloriie wao treatad with

various aminos dlasolvod In tsansano in th© frasenc© of sodium hydreailcl©

solution. chloroacflftyl aeddoa ware filiorod, wftshod and rlrtod.

ClCIlgC^Cl • n-NHg No- OH ^ ClCHgCKKm

- 119 -

(bV o- SarboaethQXTOheavXfflvctm maiUm..

Chloro&catjlaffiidioa wore eandenaed with enthranilato (1s4)

on a fltean bath without asiy solvdnt for S tours. H«thQrl enthmniXatQ

h^tlroeiaoridl® was rotsoved tj/ ahaktog th© raaetion »i3stwo in dry benzona

eni fl3.tsring off tha insolubla bydrochlofldo. Baaffl»«e wfts ranjoved

th© f i l t ro ta un4®r vacwttis awi the reaidua was again heetad for 6 hours.

The excsea ©f isethjrl antferanllatD wao remmi by washing th® reaction

miyturo with iwlplniric acid (10^) an4 finally with wator. tto® reaidu®

w»o crystallised ftcw ttlcoi»l.

U NHo ^ dcVAlCO^AH'R o COOCH-i

u Q . O O C H < ^

N HjHqSL

-

o«CarbGS!5tbox7pb9f iigXyoin* aisido (0*01 ml&) was eddod to a

me^maien of aodiius (O.OtI ^.tttoe) in diy Innssne alont « fev

of matbanol ixrdfiii' anhydrous flie reaction edxturo t^as

hdettjd on a %rat«ir bath. Tha soSiuiu aalt^ i<rfoloh saporatad, ma i l l terad,

dried and disaolmad In a sainiaum quantity of wBter enfl acidiflod with

cold aeatie ©fftd. Ilia wfeita |a?«ci|>itat« tims oM.als»w3 was vaslwwi, drioi

awi crystaXllsad*

u COOCLV\-i, i Na OMe

N h C H ^ C O N H R l^-OH H

,0H

CONHR

KHU • - NHI'h, -hm^il^n^p, -NHC^H^Oat-p,

All tfea abovo con|;ounda «}»v tha fraaance of cl^latad hydroxy group in

tliair Infrarodl spaetra.

- 12! -

Banssyl alcohol was treated with obIoroac£ityX ebioride to give %

bsTiayl cblcroeeotate (35)* whieh wae condonaed with aatbyl enthranilate,

cHSerboiasfttwi ypfeQnylgl iR® bawwyl est»r thus obtaiwail we eycliiwid with

sofiixus in bawzgrl alcohol to give bensyl S-by^roxyinlcrl^-S-carbosiyXats.

d C H o c o d PVyCVAiOH V dCrtiCOOCHaPk

u COOCH 3 -v

HH2_ cJCHiCOOCH^PV) D COOCH-

o . O H

M - ^ C O O C H x ? ! ^

H

A series of H-auhstitutodi irxlele-C-Cijrboxnffiides were alao j^repered.

Ch-MtropMnylpyravlc m i i was prepared the reaction of othyl oxalete

with o-nitrotolu«s0 in the presence of potassdu® otboaride (36) in B5% yield

* In the Fart 1, the preparation of thie conf ound l5|y the "azlactone jnethod has bean doacribed.

m -

Carlo (37) has reported a ^deid of 75% i»alng sojJiu® athoxide.

0^ C H 3 COO'iJr yx^oiy • c h ^ c o c O O H

N02.

o-Mtropliectf'lpyruvic bcM reducai with ferrous mi eEBonin

to give iii'iole-2-oarboxj'llc acid, wbieh was contntrfeed to i ta aeM ctfloride

with tMoiJyl chloride, and this was reacted with various afiiiB®8 to give

the correapoiidinK ealdes.

o H

c o d 'RNH^ Q CONHK

h

i%HR • - ^mh

- li .0

« 123 -

IR eoQotm. of oni.eafcgr

Ko0t of the indolo-2«earboxaiaid©o jjr«par»d give their ch&racterw

is t ic iiidolo m band botwen 3325-3355 ct f^ . l bo carbonyl band

in both iji{lol«-g-c»rboxfi«s}id«o >Hjattoa(yindol«-2-cerboxaudd0a i s

sharp ana cot©» in tb© range, 1630-1650 ceT . In th@ caee of 3-fe^roaQr-

inrtole-£-carb03tiHaid9s, this bairf is bread ai^ ia sJjdfted to

a lowor trftqu&mj du® to ^drogen bondtee with grouj^. She

3-b3rdroxyiii3ole-2-carboxa»ddiee okow a br©a4 band bafcwsan 3100-3150 csT^

for the chelated bydroxy group. Tim 3-.s®ttoxy show two bsanda

betwaan 12:35-1^5 euT for • C-OG. In the jMinaubatituted carboxasAdas,

a band dua to ii)doIa CH jgtretohin^; %irhich waa abaant in tba 3-subatitutac3.

cottf-ounde ia aaan betwean 2915-2970 . Tba inorptolidaa abo« a sotca-.

What fiiffararst bahavlour, in that the fiH ia tsroad eni i s shifta-i to

a Lowar fraqiuency (3260 chT'),

In thij caao of banzjl 3-hsytHr«»5ylndolo-2-C'»rbo3rylate, in addition

to tha othar characteristic bantia, the eatar carbonyl ba?ii ia obaarvea

at 1720

l A J L k l - n IR SoftctTO of lKrlole-g*c«rhc»comlde» ftM mUr

« -

E KII (indole)

era ' Ctrl (lutdde) Cffl"'

(indole ring) era"'

3335 1260,1^40 1650 1610,1595,1455

WIC^H^OCgHj-p 3335 1630 1610,1590,1450

0 (taroad)

1265,1^50 1605 1505,1430.

H hU {iniol|)

OH cbelntstl (broad)

eirf-i CcO

ciT^

(indole ring) Oft"''

..UC^H^XHj-p

i HC R OCgTyp

3340

3325

3355

33S5

3100

3130

3150

31C0

1620

1615

1660 (broad)

1720 (©jrtftr)

1590, U95.

1595,1510,1455.

1570,1505, H50.

1600,1575,1500.

f-.A .S I. B « I I (C<^t.)

- igj; -

• ts l^COR H

n fJH CIndole)

earl

eO-Jf (IndGlo)

ClT^ (aside)

ear^

Untele ring) ca"''

hKC Hj 3335 2915 1640 1600,1590,1445.

KRG H OCgHg-p 3335 mo 1640 1595,1515.

U 0 3260 2960 1605 1570,1450. (broad)

1570,1450.

S X F E f i l H H H f A t

« 126 -

S X F S R I H S N f A t

A sol'dtton of 500 g. (3.5 ®ole«) of ia«thyl atithmBllet© ftisd 180 g.

(1.6 ef ®«thyl ehXoioseofcat® in «S0 a l . of astbanoX was TBtlnmA

for 1M hoiurs on s staasa bath, hft&r dlafcilling off BobUanel, tb© roactlon

Kixturo wao afeakew with eWLoroforra on-i wat@r. Tha ebloroforir. leysr was

waahed with spdlam cafbensto aolMtlon, mt&r anl drisd m&t ijjshydrais

soditiis Ewlphate, Aftor distil l ing off ehloroforiB, the wnroaeteS metliiyl

chloroac«tftt« antl aattig^ ai3tlsraBilttt» w«ro rtrowed by distillaticsn at low

prestturo (up to 105® at 2 Eas.). Tho rosiciual llquM, while s t i l l wisra

was poared into 600 ml. of 95% ^tfeanol. Affcar staniine for acnrernl houra

at SO®, th® cryatela of dicwtrisyl phof^lglycino^o-carbOTiylato were coll<set®d

and W88hi»3 with coM ©thanol. Xtio product fornwd colcurXoss needles, a.p.

96®} ylold £65 g.

To ft sjixturo of pulvorisod eodiua, ?,7 g. (0.11 sole) •nd diEotbyl

ph«nylfi3ycino-o-Cftrboxylat®, 25 g . (0.11 nolo) i n djty b0»B0tta (TOO ffil.),£ ol.

« 127 -

of absolute raatlmnol wof© a^ded m4 tha ©Ixtura was gontly warwod on a

atwim bath until a vigorous reaefciCBa set In, The sodius oalt of osth^yl

>-h3rJroa5yindol®-2-oarbO3!ylat0 started separating out. Whan tba reaction

hiadi aluioat ceassji, tha raaetion rAstara was haat®! under reflux for

30 eijfaitea aiM than eoolad* fho aodiuQ aalt was collected on a

washod with dry banaaue, dried ani disaolvod in 250 liil. of ic© water.

Thia aqfiiaenis solution m» f i l tarad tmi acidified with acotio acid

Tha indoso'lic acid aotar tteu® |r.r®cli;itotad was cryataUiaodl fro® diluta

natbsnol {10%) in aiongstei gliataMng naadlao^ 157-8®, yi®M n g . i J ^ )

(c) AttaroiAa for atr-aonolvals of mthvl 3«hvdro3cyindole*g»carbexylat9i

1. ^tethyl 3-hydrojgfindola-?-eartooxylRte £ g.CO.OI oola) was

roHusrad with 10 isl. of anilina in SiO of bsnssana for SB houra. Thmt

the reaction edxtura wao waahod with hy^oohloric acid (536) # sodiua

bioarbocata solution (SJS) and firjally with wat®r« fh© aolvont l«yar waa

dried ovnr ahfeydroua BOdiuE eulphata, ooXvant waa ratsovad and the rosldua

was cryatallisod firoo mothanol, E.p. 157®, mixed m.p, with the atarting

con joundy 157-^®.

» m "

Xiidoii^lic icid (0*02 was heated with

emiiino^lrl.S s i . (0.2 sol«) for 3 boixrs. Stesrtlng cov^omd was o)3taia@d

aft«>ir working tip ttei reaction as above.

3. Indosiyllc aei4 eister^ Z g. (0.01 »ol®) was te&tad with aniline

9.1 (0.1 ffiole) at 170** in tba rrsseioo of catalytic aruount of

oRBoniua cMoride for 3 bouro on m oil bath, f ha r^e t ion Mxturo waa

takan in \mns»m and vorkad aa daooribad abova, atarting ooispound ims

ieolatod, ffl.p. IS*/*.

4* lz»ioxyXia ostar, A g. (0.0^ siaola) wao tr<^tad with aodiutc

atboxi^a praparad firom 0.02 g. atoia of ifodiuia in ©thasol a««J issl.

i0,2 taola). fha raaetion sdxtura waa ralluxed for 4 teura. After tba

rosction, atbanol was ram^vad^ a black ouddy prodoot waa obtained, fron

w iich rothins could be i a o l a t ^ .

A Bijctttr® of 16 e . (0.083 iS0il») of awt^yl >i^ro«3rinaolo-2-

earbQ3q^at0« 10.6 g* (0.08 i»l«) of diiMitlisrl sulpluitA and 30 g* of

poteseiust earbomto in 300 ad. ao^tom iifts rsfloxoiJi tiitior

anh;rdroa« oonditioss t i l l i t gava ft nogatiim test with aleoholie ferric

cblorido. Fotaseiv» earbozMite ims filter<^ off m i aeetcmci uks evftporated.

The time obtained waa or^ta l l i s t i l froo etliyX acatate - petit^Xmis

ether (b.p. ilO^&f), yield 13.7 g. iBO%)*

(^V aeid (loc. eit .>i

K«tl^ 3»»3thoi^tidio3«->£-earbe9(3rXate, 10 g* <0.G4S iw^e) m.»

di8«^3.ved in 100 ai,. of B &eth«Eaca.ie potaaMdun tsu^roilde ixnd refluied

for tlame hotars rni a water laatb. INfettuisu^ vaa dietiUed off ami tbe

potaeelxn salt of ^aitfiojQriBdoXe-^'OarlxtJi^lio aeeid waa disiolved in m

idniniai quantity of nater. the t i t le acid waa precipitated adding

dilute tiQfdroehlorio aeid in eold. This aoid waa f i l t e r ^ * dried asd

crystamaed from dry bencene, «.p. 135^ dee . , yield 8 g. (86$).

- 130 -

le) 3>M>thoxvipaol».£»cagtenyl ehleri^g

fh« mham aoid ehloxidt was pfpm«& ^ tb« r M e t i m of thionjfl

eWiorMe dtisUUsd) on 3-»itbo^inaol®»2-eftrboa^Ue «cid I n

atber. Tha rouetioii nwi earri«d out tmiar extetly th« «tum eondltlon*

s8 asseribod eljiorid*. )

to ft solution of ehlojrido in othtr

(pnpered trom ig,, 0.<K35 im^ of tti* eorr9i|ioniing csld), a solution

of 0.96 g. (0*0t i»l«) of iinllifia in ethsr was addsd* Xfae roaetlon

aSsdtors was kspt at rooa ts i^i%ts irs for osos siid a ti«a.f i^nurs* Bthsr

was raiBQwid and ths rtsidus was uashiKt with fe^oeUXorio aeld {$$)» sodiitiai

biosrbosats (5^) sM f i n a l l y with wat«r. f h s dxlsd p rodmi was erirstaSlissa

f^oii ethanol, s.p. 176% y l s M 0.66 g. (50^); ir(K3r> 3B5(i»doJji M ) ,

I650(ssdds C * 0), 1610» m S , riii£)f 1£60, 1240

Analysist Calcd. for C^^Ej^O^^^ t 7£.l6| B^ 5.30| ly 10.52.

Fottod: C, 71.76} H, 5.19| 10.4^.

3-»fetbo}grindols-2-esrboQ]a ehlorids prapsrsd C.5 g. (0.0026 mXm)

of ths oorrsfltpoBdlng acid iras oonisnssd with 0.710 g. (0.005S aola) of

- 131 -

p-pliwMitMitift In f he retttXtitif «i>ld# was iael^Ad «e dlaiKtribed

bdfoxn^ or^mtalXlsoit ito'm »«p. g*

lT(K8r) 3335(indol® SB), t630(iuaid« e • 0) 1610, 1590, 1450(indol« ring),

1255» 1835 •C-O-C).

AnilyaiBi Gelcd. for t C, 69 .% H, H» 9.03.

Fotaidi e, 69.39} H, 5,87| 8.96.

f htt alxivt ooaiiettBi isGCLisdtoA aa ttio ooni3«ii8i,tlf)n jproduet of

(prtpotiradi i ^ a 0.5 g. ol* tlM ootT«ep<»iil-

ing «ei(l) mrpholift9j0.44 mde). I t vtm er^stalMsad £ro&

«th«aol, ».p. 150®, yield 0.37 g.CSSJJ)} ir(Kgr) Iti),

1«05(«ii<i» C « 0) 1505, U30(l!Kiole ring), t£65, 1250 ciT^C • WW;).

AM l y sda i Calod. for ' i , 10.76.

FouRdt €, 64.58| E, 6.03; B, 10.^9.

1*5 g. (0.0056 mU)

mf reawwd with S.S g (0.05 ml») of ms^rous alnaiBliie staorid* ia

SO a l . dry hmmm for 12 boors. Aluainitui oblorldo m& than filtorad

* m -

off and b«Bfsdn«» ligrir vas wanlMd with tniiM* wxl dri«(S

Anhydroae eiilpltMit*. dtnamoi m» ditttiHed off and tb»

r«8Mu« was erytsHl^a^sed £rm ottuyndlt sdmSi m,p» idtb tht

fltftrting aater i t l 174®.

i f ) . »

fc fi eoM aoluti<m of 20 g. (0*E15 nole) of ea^lim in 3G ail.

btnstn* over tOO aH, of ^ ao^ua t jriArdsdd*, wart udded $0,28 g.(0.26 8o3l«)

of ottloroftC^tjrl in 40 of bma«m with eoolietg md otirring*

Obloroaootyl anilins aiartod mperMtiag out aa a i^ittt praeipitata. Aftar

the addition, tha fisaotion slxtura was atlrrad ftMr anotbsr 30 idmtaa.

PetrelMum ather ita« addai for cos^ilato praoipitation, K-etiiloroacatyl

anlliiM waa fil tarwl actd driad. I t waa aiifHoia&tljr pura Ibr l^rthar

raaetioa, ».p. 136®, 28 g (77J)| f u t . m,p. !35®(34af — « ^

In a 500 sa. ground #aad round botto»ad f l a ^ Uttad with a

raflux condansar, 5.0B g, (0.03 »ctla) of cbloroaoetyl aailina and 18.12 g.

(0.12 sola) of Battel anthraniXata wara tcOian. tbia Mixtura waa baatad on

a ataaa bath for $ houra undar anl\ydroaa eonditiona. Than about 100 aO..

- 133 -

of b«mioii« t^doA, tint alxturft was for SO ladnittts

rod timi eoo3.<»dl. «iilihrBiiiliit9 t^tlroohlorJudi* fortaed daring tlw

condenwition was flXt<ir«d off «iu3 with tiio 50 |>drtiims of

dry hmwmm, 4*1 g« of liindroetilorido vttm olsttblnad* 0tiis<»ii« mti ooe-

rmo90A vMmr redbit09d prtatiai* on « stoAffi Iteth uB^mp

ef^Mliticms. f r « » i d t t { i m» etttis imin i on m stmm for Aarth«r

six bours. fhft |]$droe%ilorldo m» roeoved b»£&t», cwOy 0*9 g« of

l^rccbXoridft elybAinisd this t l s» . In 5 g* ttg^drooKLorids vios

oMaitisd as sfs last g» of t t e thooretj^sX ii.«i about 90$ of ths

r«M3ti<m WAS eos^lstod* flis fl3.trat« a»4 imsMngs wsra etxsd ei^ baovan*

tiaa rtsoved imder raduead prassara. fha ajsoaas of nattisrl anttiraniiata I

vaa tmawtA ^ diaaoXirix^ ttoa rasidoa in banMna and washing i t i«itb %0%

suXphurio ae i^ sodiusi eafbenata (10^) and finally with watar* Bweana

ii^ar ma driad mvr anhgrdroos sodltM solphata, avaporatad and tha rasolt*

ing aollida waa cryataaXisod flro» athanol, 146% iriald 5*9 g. (70J().

Analysiai Calcd. for C^^B^^O^g i C, 67.591 H, 5.67| M, 9.85.

Foandi C, 67.19| H, 5.54f % 9.77-

- m -

Xo a tua^enaien ef 0.32 g* {0.014 of pnlif^rited sodium

Sj> UQ ml, banMne, & sol^tioa ©f 2 g* (0.007 fflol«) of o-eferbOBftthojqr*

phfonirXgl^in* iflsilitle in 10 dI* of Imseiia ims ttMvA %Ath a f«i« drops of

eba^l^t* svtlsemX. roaetion aix^um ms than hwit«d on * «tmm both

AsH^f^mn e d i t i o n s for 30 aimites idth gbaktng* I t vm ttsMi

r«flisxat! for ^rttovr ^ almtes, oa^M and ^thtar was Added to i t .

the sodiiXD aaltf which septreted oiat» vas (Sriod by filtimtion under saetien

m a IkioHiior, i t vas them dissoliro£ ia a iBiniinim ({aantitjr of mtmv and

fiXtarad* elaar f i l t r a te was atsidifial «dth acotic aeid in ooXd.

fh» t i t l a oospound jM9i:>aratad as a whita prsoipitata, whioh waa uafibtd^

driad mtd orystiaiioed f^os matluBnol, B.p. t yitild 1 g. Xt

gives a gra«a toXoar with aXofihoXie farrio ehXcarida eoXistion} ir(SSr)

3340(iniloXa KU), 31OO(ehalat0d CB), 1«E0(i»iiio C»0) 1590, 1495 em^

(ii^oXa ring).

Analyaio t Caled. for C^^U^^Q^^ t C, 71.41t H, 4.80| N, 11.11.

Found: C, 71.75| a, S.IOj 11.29.

- 135 -

fh» abovt product was prepared ©hl©roiie«tyliition of p<-«&i0i<lln««

€ g. (0.04B 390io) vi tb ehlKKToaeetyl e b l o r l ^ , solo) ID 20

of aoiius t^irojddo il«8erlb9a Ixiforo* m.}>* 9*4 g*

CKLoroaootyl^l>eni«ldint« it g. (0.03 wfti eoadttnsod with

18.1 g« (0.12 of m t ^ l «nthr«nlliit« to g tw abova aidddj^ whieh

wae ef7tte2.Xi8«d t r m «thji»ol| ».p*150% yiel^ 6.3 (66^)*

Aniasrtlet Caled. for '^ iT^tsVs *

Fotmilt 64.68; 5*79| 0*9^.

iaa {H-|>-B»t1ioi!3rpheD3d) aii'boxAtBid*

3.14 g* (0.01 iBoXa) iras cgrolisaii In tt tt pratvRca of aodlua atthoxida

praparad l!rci 0.416 g. (0.02 cola) of sodium iaspandiad in 20 aX. of df^r

bsnsana to glira tba titXa product. St was isolatad as dascribad bslbra

•nd etTstaUlssd ito* aathanol. I t darkens at and nsXts a t S38%

y i m 1.63 g. iiiKBs) ,

I6l5(as»id« C-0){ 1595, 1510, 1455 csT^diolol® ring),

Analyaiat Calca. for C M O Ug i C, 68.07} H, 5»00j H,

Vaem&i C, 67,73$ H, 5.04| 9.61.

ifil .^t^ffy^^cff^yl-p-B^l^ffltf ffs

, fMa Gorni ami m9 pr(apmted tijr tli« ehloroeft^yla^lisi of 50.3 g.

(0.4S i9oX«) of idtta £3.7 g. (Q.Sl tsoitt) ef Gtilorono«tyl

ciStorlde an b»for«, «.p. 145®, 35 g. (8156)| llt.ia»p.14i6®

(34b) .

Tha t i t l » eoafwimtS mtt ligr the esond»mfttiott of 6.3 g*

(0.03 w)!®) of ehloroiic«tyl-|s*pli9n»ti<iia0 with 18.1 g. (0.12 Bola) of

n«thyX anthranllata* I t traa ersratallised flt>!B attwnol, ».|>. 155^,

yimU 6 g. (65?i).

jbfuojraiai CaXed. for C^gfi O^Kg t C, 65.84) B, 6.14i K, fi.53.

Potuidi C, 65.86} H, 6.21} 8, d.52.

- 137 -

o- Carbomattooxysphenylfljreifidi;

3.2a (0.01 B»l®) was cjneXiaed la presano® of 0#4i6 g* »ol«)

of aM a fmr drops of nathar^l. Tha ear^xaeida oryatallieod

l oia Bsatbanol. I t ^arltona at mo^ aM laalta at g. i&0%)i

ir(KSr) 3355(laaola KH), 3150(chalftt««l OB), l660{aBido 1570,1505,

1450 ciT^Cinaolo ring).

Anaa^aiat Calod. for ^ ^.90} i , 5*44; H, $.45*

Fottwd: G, 68.95J H, 5.59| H,

11' ^ r^a^M^Mfefe l f r - fTFl i f f i l t i ^ lP t^

Chloroaeetyl etHorida, SO g, (C .031 ooXa) in 60 n l . 0tbar ima

addadt to 27.6 (0.17 mole) of ffiorfbolina in 50 ol» of atber with oooUng

and stirring. A whita |>racipitata of aorphoXina tifydroohlorida atartad

aaparating out* After tl»» addition, tha Mxtura waa atirrad for anothar

30 Mnutaa. 7ba praeipitatad tti»rpl»>Xina l^frdrochlorida waa fLXt«r«d off

and washed with athor. Tha ooabinad atharoal axtraot waa eoncantrat«l

to a thiok liquid, tdiieh waa diatiUad undar raduead praaaura. b.p. 130-135**

at 3 praaaura, yiald 22.7 g. (80$).

• 133 «

fbo above eoaspouodl was •pmptoped b j th«f cora WQafttion of IS.36 g,

(0.07B ml&) of chloroscotyl »rphol4na and 45.3 g. (0.31 i»l«) of

mthgl «nthr«j341ot« with other corboaaHBtditta oxcopt that I t was

f iml ly taken in eKlorofom mrA waohod fro* of unreiiot«4

i»tlirAnilato ^ith nilpimrlje aeid (51) andi with ao^iuia oartionftto 0%)

to ronoird ttorphoMsio* this ssxpholido waa oryataXHaad

yield 14.5

AiwOysist Geled. for * 10.07.

fottinti C, 60.0£| K, 6,495

Xfao op«n oltfiin aaddo, 2,7B g, (6.01 weH*), wa« oyoHsod in tho

proaonea of soiiuM vathoxida praparad frois 0.33 g. (0*614 nolo} of

aodiiaai in banssana to giva tha t i t l o prcduct. I t iraa oryatelliaad froa

athanod a.p. . 169-70®, yiaH I . U (60%).

An^aia i Caled. for t C, 68.40f M* 5.73| 11.38.

founii C, H, 6,20f K, 11.30.

« 139 -

i f ) aonayl €hloro>eet«tft( 35) t

A isisetur* of g. iB&l«) of cMloroseet^ oldorM*

«nd 24 g. of ftlieolsol wm vxm^A get^ljr g» • steasi

bath for mixiutes. tiar<Mict«ii etaoroaeotyl oIsIoHjI* w&« dostroyed

W a^din^ 2 nl. of siAthano}.* th» thiek liquM <iistm«i a t

under 7 preaturt, yi«M e* •

g. (0.28 laole) vm c<»idi9»8«d with

13.1 G. (0.07 sole) of banisfl ohXorcN)0»tfit« AS dasorilM»d bofoFO.

Ctaomfora vm iiidd instead of iMnsano «o th» iK>Xvitnt« fh t «st«r

ex78talXi«ed fre» bengono-pot.cihftr (b.p. ii#|i. TIT®,

yl«M 12 f . (55J0.

Analysiit C«Xed. for C yi ^O^M i C, 68.21 j B, 5.73| K, 4.68.

FoaMt C, 69.10} 5.66{ 4.80.

- 140 -

3c41uoi flHitalt jg* (0*01 8iol»)« ma addad In portien*

to t}o»syX aleobol^ 1*51 e* uele). iilh^ aH 8odii;Ai had r-

reacted with totn®^ etXeoholf m solution of g. (0.01

oH^erboiasthoj^hasylgl^lnd hmzyl «star in 25 as * ot bmteeoe

was ftddfld. fbt reei^ion miMnWi^ Ufts h@at«d <m m steass batli for

15 idnutea snd then r«fXux«d for another idiaatee tmdtr eidisfdmis

eoniSiti^ns. I t i«»m» then eooled^ ilry fttwr u&b added to i t eiid tl^e

sodiUiK ts l t forsed wee fiXti^ad *nd dried, fide eodism ealt vam

dissolved in a lainisun (pantity^ of weter and e«idi£iea in oold with

ecatis aoid. i^ i t s preoipitste vbieh seii&rated out was filtered^

d r i ^ , enil esystalUsed ftoas beaseae-petroletts etbcar (b.p. €0-S0®)»

B.p. 158-3®, yield 1.5 g. ir(KBr) 3525Cin«ole Bg), 3100(eholtted

1720(e«t«r C*0), 1600, 1575, 1500 ©•"''(indole ring).

Aftnlyeiei Calod. for C^ H^ Oyi » C, 71.90| K, 4.90| 5.24*

F«»wllt C, 71.65} H, 4.83| 5.20.

- H % -

fo a adititlon of 3.t g* of l>otiii8iuis in 14 s3l« of absolute

etfeauol «f»3 14 of a t^titlon of 5#5 g. of ©•nitrofeoluen®

iB g. of l ^ s ^ y dii9tm#i dlottgO. oxsnlat* «nd 20 of tolufiw

wm iiMod ttlth eofiaifSf «th«king. toi^emivr* m9

baaotf Murine tlw lutMtiim* f h« mmtt&n tBixturs kept o<r«might

at aiKi tbma at room tt£i§j«nitur« for undtor anbs^reui

coiiiitioiMi* Tiie.pot««»ttti5 salt which ®aparait.«d w t m» 4i«a»lir»(l in

40 lal. of vstsr . f]m ottwrMdl soliatioQ alao «xtr«ot«i tuith 100

of water* fhn aqitiooue aolution vftsbed agftiE with

t h ^ eov»r«di wittt 60 ml. of «th«r and itirr«di with 25 of iSNf aoaitm

lyritrojddo. I t was wathod t h o m i i ^ with «th«r lucti «eldiifi«t with oce*

e«ntr»t«i t^roohlorie eeidi to pB with good cooSli]^. Tho Isrown t i ^

wbieh taparatod cat was «attx«otod with bamsmt md washed with ool4 water,

the bensena extract wae dried ever anbydroiis aMitus eulphate. Seaseae

was distilled off muter reduced {jfeaaare. flMi thick liqpid l e f t wae

eryetalliaed flron bM»Mine-petrol«u» ether (b.p. m p*

y i ^ d 7.1 «. (85?^).

- 14S -

A flolx2tlo& of 0.93 g* (0*01 of aniliio® ia dry vtHwt

ma AMtfd t& A solution of IMolt-So-oarbonr^^ el^orM* in «thtr (pmpared

fiTOB O.S g,, 0*005 iK^a of itei^)* fh« j-ototion

Bdxlura ms lespt for on» esdi & half hours at room i t s^ ra tu ro , fhm

etboF vats rwnoved niiior ttclhioedl pressuro and ttot r«si(tti« nan washed

with iQrtslroehloxie acid sodi no bioarboueto mi vitb

vator* Tim solid nasa uaa driad and ex^irstalXisad ieom 9tkme^p m,p*

yield 0.9 e. lr(K8»') 3335(iiidcao SH), £9t5(ii>do3.e l640(aiaida-

1600, 1590, 1445 oiT^Ciodolo riag).

Aaalyaiat Calcd. for C^ H gOJ t C, H, 5.12| 11.86.

Fourod* C, 76,13} H, 4.96f H, 11.79.

XndoXa»S*earlx)nyl. ehlorida prfl|:ifirad UTobi 0*8 g* (0*005 isola)

of tha oovraaponiing acid was oondenaad with 1*37 i* (0.01 oola) of

p>phfm«tidiaa. tha rasultif^ piroduat was iao3.«t4iKl aa dasoribad abova.

I t was oiyatallisad from athanol, ii,p, 219®, yield 1* g, ir(ttar)

-

3335{ Indole liH)» 2970<iiHtoU CH), 1640{«sld« C-O), 1595, 15t5 ciT^

(ixySola ring).

m a y i a t Cae«. for C^^^^O^g i C, 7S.04| H, 5.75j 9.99.

FouMi C, 72.91 J M, 5.?0j H, 9.72.

wis ps^ared ^ th« ocoidensation of

elOoriao (prtptir^d itom 0*8 g*, 0.005 of

eoiT«ap«milii3ig with laorphoHn®,©.'^ g. (0.01 resulting

loi^e vas Isolftted in ttae usual wm or^arfeeOlieei from etliacol, a.]^. 179 »

3rl«M 0.85 fi. (73i)i ir itW} indole »»># 2960Cii»!lole CH)»

I605{««l<io C-0), 1570, 1450 e»r'{iii<4ol» ring).

Aoiilyalit COcd. for » ^ .81 j H, B, 12.17.

fottodi C, 68.001 B, 6.50J ii, 11.93.

R B F S R g M C B S

t . mwor, tmd Etaeeraiiig, A*» Bar., g 679(13^)$iM<l*«l» 5t7Cl370).

t . 8efl!}rar» A., (1684).

riaeh»r» jl^m., 1t6 (1386)*

4* Eafti'dr A*« Bqt,, 2^54 (13^) •

5. aasyor, 2260 (1880).

6. Hoanuni, itxid.^ ^ M34 (1890).

7. Oansaii pattnt 137,955| 1903, If 116. ^Tsm pat«nt 141>749| 1903 ^ m (1914)1 Abitr., S, 3780 (1914).

a. mjttik,, E,, Bw., 1814 (1098).

9. Holt, S.J, , Kallla, A.S,, O'SiiUliraii, tsa f.W., J.CheiB. Soe*, 1217 (1958}«

10.K«Itn, C.F.Su.f md facrn, K«C«, Soe., ^ 11^ (19^) .

11.0*aulUv«a, S.G., and BaAlw, P.W., Soe,, 876 (1959).

12.Stl«emHi, A., CeitiTt. r«n<i.|» 1£4 (1947)j Bull* Boo. CIhks. FWno*, 651, (1948).

13.Kor»ftld, g.C,, J.Org. Cham., Ife, 806 (1957).

14.Snydor, H.R., •nd Codt, L.P., J.te»,Cht«. Soe., m 96? (1956)| Sehlndl«r, M,, Holv. Ohin. Acta , 2156 (1957)} 0«»igy, Brltt 8C4,237,Hov., 12, 1958 (C.A.,53»7197c).

d 15.3ehi»ax»r, W., Malv.Chia. AoU 1130 (1957)| Sohlirilor, W.,

U.S., 288,3394, April 21, .1959 (C.A., 54i2357r; i

- ( i l ) -

16. PtrklHi Kolainvon il^Oben. Baa*, m* dm).

17* ai«ikl»# K.O., and ibid., (1924).

18. Johnion* lloll«r» «nii iinrmn, J.Aia.Cii«s. Bee., £364 (1947).

19. iTafiot) and ««s«8r, IT.M,, U.S., £a4f|590, 1950(C.A.,53J43O1d).

20. 0.4.« Eoutml* A.P., a .As. Ch«s>. Soe», 37S (1953)*

B., TiHftrahaiw© Jg, 3881 (1967).

0.1., MiUiiua, H.irf.H., gr i t . , Aag., 31, 1960 55i9429»).

S3, f m e h patwit H.15S7, Kov. 1962, (C.A., 58i78l1*)i Freneh potent 1313759, Sm,, 1963, 59i2776h).

U . Wright, U.S., 3503968, 7 S«pt.i967, (C.I., 7J i 132754^).

25. 8«ti«b«t, A.H., K.V.S., Sasiiadri, S., moi^tw, A.*. an<l Mo, M.B.a., Ind. J.Ch««., g, 704 (t970)«

26. Vorlaader, 0. , rniA Shilling, R., Aaa., 301, 351 (1898)j i m , m499(lS98)

27. Vorltndttr, D., and ytti««hr«»n«r, K., S«r., 555 (1900).

28. Sogimi, S.K., ced Osndlj^ft, P.O., €h«at», 139 <1965)| Daniflisr*, F.C., Shamn, and Mttaon, H.K*, X»i«

750 (1962)} F^tigsrft, E.B., Ooliwalu, C.V., B.S., tm^ S«th, 0.x,, J,M«d. Ch«a., I I , 332 (1968)j 0«iri», H.A., Wlntlsrop, S.O., fho»aX, R.A., fi«fT, F., Ch«r«t, U.P,, und Qtadry, fi., ibid 2» (1964).

29. O .ft., and Ai»lr««, J.H., ^•An.Cbttt* Soe,, 286JS (1950).

3D. nob»rt»en, A., J«Ch«m. $oe.« p. 1937 (1927).

31. Chong R., mi Cl»ty, ^.Cheia., 935 (196 7)»

32* Modli 13.7.* AlttMKi, S.E., Kidwui, and ^otmsot), J.Orf. Chfjs., 2228 (IfW).

33. Jiilliwt, m i Pikl, J . , aoc., ^ ?55 (1931).

34. (ft) Seil8fe«laa Biind^h dor l^mieliva Ghmlm 22,463.

(b) Jacobs, «nd Heid«lbarfidr, ft., J . Biel.ClMB*^ gjU t03(19t5).

(o) wad Ki^iftcitao* Fttesaseo, M» Sei., 2X> ""l^t (1956)1 (C.A., 50i13f33«).

35* mi Ehuraeov Sorli^v* Obstioh. KlbiJUs*! ^ I47t (1956)I (C.A., 50t14765«).

36. Bto}J» Ik*, F.^ Vymr, e»l fhitmm, H«lir. Ghiis. Acta , 28, 1452 (1955).

37. Cta%o P.J., Ct»». Soe», ^ 1420 (1944).

[Reprinted from the Journal of Medicinal Chemistry, 12, 1120 (1969).] Copyright 1969 by the American Chemical Society and reprinted by permission of the copyright owner.

Synthes i s of 3-Hydroxy- and 3-Methoxyindole-2-carboxamides and Esters

M.-vhi0N1)r.\ p. 8.\x1':na and Shakt i R,. Ahmed

J)epnnm,ent of Chemistry, Aligarh Mvslim University, A ligarh, India

Receiiied April 14, WnO

8-Alkoxyindo]e-2-carboxylates and -2-carboxamide.s have been shown to possess antienaetic properties.' Most of the compounds studied have alky] or dialkyl-aminoalkyl side chains. In this communication 1hc preparation of some 3-hydroxyiudole-2-caxboxamideR with aromatic side chains is reported (Table I).

T^iu.k I I

•COOCH,

NHCH^COY

Re-M p , crystn" Yield,

No. y ° c solvent % I'orinnla' '

1 N l l P h 146 A 70 2 N i i c , n 4 0 c i i , , - p 1.58 A 66 C„H,8N.,()4 3 NHC6H40C2H,-P 1.55 A 65 C,sH2ON204

4 N p 1.52 A 60 CuH.sNjOl

."3 O C H j P h 77 C 55 C , - H „ N 0 4 " A = Kt.OH, B = M e O H , C = CcHc-petroleum eUier (bp

00-80°) . '' All o o T n p o u i i d s analyzed correct ly for C, H, N .

(b) 3-Hydroxyindole-2-(N-p-methoxyphenyl)carboxamide.— T o a suspension of N a (0.26 g, O.OJl g -a (om) in 20 ml of d r y

T \B]>E I

P C - X

n - ^ c o y Mp, °c 220 2,38 206

169-3 70

176 211 ].-)0

200 21i)

« A = E f O H , B = M e O H , C = CsHs-peti-oleum ef,her (bp 60-80° ) . All t h e analyses wei'e pe r fo rmed for C, H, and N and results were in the range ± 0 . 4 % . ' These cornpounds first darken and then melt..

No. X Y

1 OH'- NHPh 2 OH' NHC6H40CH.,-P 3 OH' NHC6H40C2H-,-?) 4 OH' 0 .") OH OCHiPh 6 OMe NHPh 7 OMe NHCr,H40C,H,--p

s OMe N 0

9 H NHPh 10 H NH(;jt40C2H.,-?, 1 1 I I N 0

Recrystn'* Yield, solvent % Formula ' '

A 58 C,6H,2N202 B 58 C,eH,4N203 B 60 CivH.eNjO;, A 60 C,.,HJ4N20;, C 51 C,6H,3N0., A 52 CieHnNjO, A 54 C,8H„N20. A CMH.eNO,, A 76 C,.,H,2N20 A 71 C. iH.eNjO,

A 73 CK,H,4N202

Experimental Section®

3-MethoxyindoIe-2-carboxamides (Table I).—Indoxylic es ter was p repared by cyolization of o-oarbomefhoxyphein- lglycine methy l es ter in the presence of NaOMe.^ T h e eslei- was met,hyl-a ted and hydrolyzed wit.h elhanolic. K O H . ' 3 -Methoxyindole-2-carboxyli(! acid (J g, 0.00.') mole) wa.s conver ted to it.s acid chloride wit,h SOCI2 (1.42 g, 0.012 mole) in d r y EtaO. Af t e r s tand ing for 1 hr a t rocmi t empera tu re , EtizO wa.s removed under reduced pre.ssui-e and t h e residual acid chloride was flu.shed wi th d r y EtrjO to remove t h e last t races of SOCU. T h e acid chloride wa.s t,hon taken up in 1512O and treat.ed with ethej-eal P l i N H j (0.96 g, 0.01 mole) . T h e reactio\i mixlm-e was l e f t fo r 1 ..5 hr a t 30°, PJt.jO was removed, and t h e solid residue was washed ( 5 % HCl, 5 % N a H C O s , HjO) , dried, and crystalHzed ( E t O H ) , m p 376°, 0.66 g (52%) . Anal (CicHhN.^Oj) C, IT, N.

3-Hydroxyindole-2-carboxamides (Table I ) .—Chloroacety l der iva t ives of aniines aud benzj ' l alcohol were p repa red by t h e usual methods. ' '

(a) o-Carbomethoxyphenylglycine-yj-methoxyanilide (Table 11).—Chloroacetyl-p-anisidine (6.0 g, O.OH mole) and met.hyl an th ran i l a t e (18.12 g, 0.12 mole) were hea ted on a s team b a t h fo r 8 h r under anhydrous conditions. D r y CcHc (100 ml) was added, and methy l an1,hranilate hydrochlor ide was filtered off. C(,Hc, was then removed imder reduced pi-essui-e and the residue was hea ted again for another 6 hr and t.heii t.he hydrochlor ide was removed as before. T h e hydrochloi ide which separa ted weighed 6 g, i i idicatiug a 90%, completion of t h e rcact^iou. Excess methy l an th ran i l a t e was I'emoved by washing the Cr,llr, layei- wit.h 10%, 11-.SO,, 10';;. Miiil i l / ) . T h e Cr,ll,, was dried, solvent

I'eniovpd, and the resulting auilide was crystallized ( E t O H ) , m p 1.58°, yield 6.3 g (66%). Ann!. (C.jH.sNJOi) O-, H, N .

CsHo, a solut.ion of o-car l jomethoxj 'phenylglyc ine-p-methoxy-anilide (3.14 g, O.OI mole) in l.i ml of d i y CcHc and a few drops of absolute M e O H wei-e added . T h e I'eaction mix tu re was warmed on a wa te r b a t h wit.h shaking for 30 min and then refluxed for 40 min under anhydrous condit ions. Af t e r cooling, dry E t 2 0 was added, t h e N a salt was filtered a n d dissolved in a l i t t le cold H2O, and t h e solution was acidfied wi th cold AcOH. T h e car-boxamide which sepai-ated as a wh i t e p rec ip i ta te was filt.ered, dried, and crystallized ( M e O H ) , m p 238° (darkens a t 225-236°) , yield 1.63 g (58%) . Anal. (C,cHi4N203) C, H, N .

T h e compounds listed in T a b l e I were prepai 'ed b y convei'sion of indole-2-carboxj-lic acid to t,he amides via t h e acid chlorides.

Acknowledgments.—The authors wish to thank the Head of the Chemistry Department for providing the necessary facilities for this work and the C.S.I.11., j\e\v Delhi (India), for a Junior Research Fellowship (held by .AT. P. S.).

(1) Soci^tlS d 'Etudes scientifiqiies et, indu.strietles de ITle-de-France, French Pa ten t 1527 (Nov 12, 1962); Cliem. Abstr., 68, 7911a (1963).

(2) Melting points are uncorrected. (3) A. Robertson, J. Chem. Soc., 1937 (1927). (4) N. T. Modi, Ph.D. Thesis, Aligarh Muslim University, 1966.

(a) W. A. Jacobs and M. Heidelberger, . / . Biol. Chem., 21, 103 (1915); (b) P. Malatestn and G. Migliaceso, Pnrmaco, lid. Sci., 11, 113 (1956); (c) A. L. Remizov and N. V. Khromov Borizov, Zh. Obnhch. Khim., 26, M71 (19,56).

Reprinted from the Indian Journal of Technology, 1971, Vol. 9, No 1, pp. 37-38

Catalytic Hydrogenation of 2,6-Dinitro-/>-cresol

MAHENDRA P SAXENA & SHAKTI , R . AHMED

D e p a r t m e n t of Chemistry, Aligarh Muslim Universi ty Aligarh

Manuscript received 1 April 1970

The preparation of the derivatives of 2,6-diamino-p-cresol from 2,6-dinitro-p-cresol prepared by the nitra-tion of the acetyl derivative of p-cresol followed by alka-line hydrolysis is reported.

' ^ H E compound 2,6-diamino-^-cresol, an important dyeing material for leatheri is prepared by the

reduction of 2,6-dinitro-/>-cresol with tin and HCP. In this communication, its preparation from 2,6-di-nitro-^-cresol by catalytic hydrogenation under dif-ferent conditions is reported.

Nitration of the acetyl derivative of ^-cresol with fuming nitric acid (2-6°) yielded 2,6-dinitro-^-cresol as the single product. This was a distinct advantage over direct nitration^, which leads to a mixture of products or the cumbersome nitration of ^-cresol-3-sulphonic acid« by nitrous gases. Catalytic reduc-tion of 2,6-dinitro-^-cresol and its derivatives was carried out as shown in Scheme 1. In all these cases, 2,6-diamino-^-cresolwas isolated as its acetyl deriva-tive in view of the ready oxidation of the free base.

2,(i-Dinitro-p-cresol (I) —Cold acetyl-^-cresoP (26 g) was added dropwise to cold stirred HNOj (density 1-5; 86-6 ml) keeping the temperature in the range 2-6°C. After the addition, the reaction mixture was stirred for another 30 min and then poured on crushed ice. The substance which separated out was washed with NaCl-saturated water to neutral pR, ether was removed, and the residue was reiiuxed with KOH (5%, 25 ml) and aqueous MeOH (50%,

CH3

id) Fuming HNO3 f'^ (I) Ag-Salt '(IDAIc OAC OH ACHJCsHJ,

^ PIDJ/Hj „VO'

A C H N

AcHN-Vf^NHAc OH Scheme 1 — Catalytic reduction of 2,6-dinitro-jf-cresol

I N D I A N J . X E C H N O L . , V O L . 9 , J A N U A R Y 1971

50 ml) for 45 min. Methanol was removed and the residue was acidified in cold with HCl to pH 2-3. The brown tar was again extracted with ether, washed with water, dried (NagSO^) and after removing ether, the residue was crystallized from benzenc-hexane or alcohol as yellow needles (20 g, 65%); m.p. 83°C (literature* m.p. 84°C) (Found: N, 14-20. CvHeNaOs requires N, 14-14%).

2,6-Dinitro-p-cresol benzyl ether (II) — Dinitro-p-cresol (I) (3-69 g) was dissolved in ammonium hydroxide. After removing excess of ammonia, a saturated solution of silver nitrate (4-2 g) was added. The red coloured silver salt (2-5 g) precipitated out, which was filtered, washed with benzene and dried. The silver salt was refluxed with benzyl chloride (1-26 g) in absolute ethanol for 8 hr. Then alcohol was removed under reduced pressure, the residue dissolved in ether and washed with NaOH (5%) and water. After removing ether, excess of benzyl chloride was removed by steam distillation. The residue was crystallized from benzene-petroleum ether (60-80°C) (1-2 g, 53%); m.p. 110-11°C (lite-ratures m.p. 109°C) (Found: N, 9-69. Ci4Hi2N206 requires N, 9-72%). Dinitro-^-cresol (0-2 g) was recovered from NaOH solution on acidification.

Reduction of 2,(i-dinitro-p-cresol with PtO^ in acetic anhydride — Dinitrocresol (0-4 g) was taken in acetic anhydride (2 ml) and reduced with hydrogen at atmospheric pressure in the presence of PtOg (0-05 g). In all 140 ml of hydrogen was absorbed. The catalyst was filtered off, acetic anhydride removed under reduced pressure, and the residue crystallized from alcohol to give compound I I I (0-45 g, 85%); m.p. 227-8°C (literature^ m.p. 227-8°C).

Reduction of 2,6-dinitro-p-cresol benzyl ether with PtO^ in acetic anhydride — Compound II (0-62 g) was shaken in acetic anhydride with PtOg (0-05 g) under hydrogen at atmospheric pressure. When there was no further absorption of hydrogen (160 ml Ha was absorbed), the catalyst was filtered off and the product crystallized from ethanol as white needles (0-42 g, 80%); m.p. 228°, m.m.p. with III

227-8°C (Found: N, 10-51. CioHieNaO^ requires N, 10-60%).

Reduction of Ifi-dinitro-p-cresol benzyl ether with Raney nickel — Alcoholic solution of compound II (1-15 g) was reduced with hydrogen at 50 Ib/sq in. in the presence of approximately the same quantity of Raney nickel. After shaking for 4 hr the contents-of the bottle were quickly filtered into excess of acetic anhydride. The filtrate along with acetic anhydride was evaporated off under reduced pressure,, the sohd residue washed with water, dried and crystallized from benzene-hexane or alcohol as white needles (1 g, 80%); m.p. 185-6°C (Found: C, 69-10; H, 6-40; N, 8-88. CigHjoNA requires C, 69-21; H, 6-45; N, 8-97%).

Hydrogenolysis of diacetyl derivative of 2,6-diamino-p-cresol benzyl ether (IV) — Compound IV (0-625 g) was shaken with palladium charcoal (10%, 0-1 g) in alcohol under hydrogen at 40 Ib/sq in. for 4 hr. After removal of the catalyst the diacetyl derivative of 2,6-diamino-^-cresol was crystallized from ethanol-benzene (0-4 g, 90%); m.p. 225°C (literature^ m.p. 22$°C) (Found: N, 12-47. C11H14N2O3 requires N, 12'60%). This diacetyl derivative on shaking with acetic anhydride in ethanol gave compound I I I ; m.p. 227-8°C. Hydrogenolysis of compound IV with • Pd/C in acetic anhydride gave directly the triacetyl derivative (III).

The authors are thankful to the Head of the Chem-istry Department for providing the facihties and the Council of Scientific & Industrial Research, New Delhi, for the award of a fellowship to one of them (M.P.S.). References I. HOCHSTER, F., Beilsteins Handbuch der Organichen Chemie,

Vol. 13 (t supplement) , 230. 2. PROMM, E . & EBERT, R . , J . prakt. Chem., 1 0 8 (1924 ) , 8 3 . 3. p R i s c H E , P., Justus Liebigs Annln Chem., 224 (1884), 138. 4 . DATTA, R . L . & VARMA, P . S . , / . Am. chem. Soc., 4 1 (1919 ) ,

2041. 5. VoGEL, A. I., A textbook of practical organic chemistry

(Longmans, Green & Co., London), 1956, 682. 6. FRISCHE, P., Justus Liebigs Annln Chem., Hi-