Synthesis of Functionalized Pyrroles

5.1 Introduction

vrrolcs are important heterocyclic compounds that are used for a variety

of applications horn pharmaceuticals to advanced materials. Moreover P- the pyrrolc nucleus is well represented in natural products. While numerous

pyrrole sjntheses haw been developed, many suffer from limitations such as harsh

conditions. poor availabilitj of- starting materials, limited regioselectivity etc. that

preclude thcir general application. 'These fktors have spurred the development of

new synthctic methods tbr these impc~rtant class of compounds.

A recent focus of the research in our laboratory has been the development

of neu PI-otircols for the synthesis of heterocycles under Vilsmeier-Haack

conditions. I'he ehl~~rorncthylenriminium salts derived from acid chlorides like

POCI, and K.N-disubstitutcd fonnamides such as DMF are the intem~ediates

involved in the Vilsmeicr-Haack-Arnold reactions.' The Vilsmeier-Haack reagent

is generated hy the attack of the carbonyl oxygen of the N,N-disubstituted

formamide 1 to PC)('I; to tbrm an adduct 2, which reacts further to give the

chloromcthj icncimiunl .;a1 t 3 (Schcrne 1).

I' 0 OPOCI,

K : N 4' PC)CI oPoCi2 L

R,'. FI --+ pi&<\ H: H

---- f4 HZ H R ti

1 2 3

Scheme 1

I he chloro111clh:rleneiminium salt generally reacts with an electron rich

substrate ut its elcctron rich centre. leading to the formation of an intermediate

iminium salt which on basic hydrolysis affords the corresponding aldehyde.

They have heen cxtznsively used for the formylation of activated aromatic,

hetcroaromatic and l i~ l l ) . conjugated systems."he broad synthetic utility of

these itninium salts is not onl) restricted to formylation of electron rich

compounds. but uidcly exploited for intramolecular cyclizations initiated by

iminwlkq iations. producing a variety o f heterocyclic compounds as well.

5.2 lminiurn Salt Mediated Heterocyclic Synthesis: An Overview

Se~cral groups hnve utilized the itninium salt adducts as precursors to

the synthesis 01' heterocycles. An outlook of various approaches leading to

heterocyclic compound:s under Vilsmeier-Haack conditions using different

substrates IS presented below.

5.2.1 Vilsmeirr-Huuck Reactions of'Alkmrs

I'he reactions of simple alkenes possessing alkyl substituents are rather

complex due to unpredictable multiple iminoalkylations. Multiple iminoalkylations

and subsequent conversions of thc intermediates to 2,7-naphthyidine 5 or pyridine

derivatives 7 fronl isohutene 3 and 2-phenylpropene 5 (Scheme 2 and Scheme 3)

respectively in the prcsrnce of ammonium acetate have been de~cr ibed .~

- !:p CHO

5 Scheme 2

6 7 Scheme 3

St~~tiics lrorrr our laboratory have resulted in an expedient synthesis of

aryl pjridine carbaldehydes 10 directly from carbinols 9 derived from

acetophcnunes 8. by treatment with chloromethyleneiminium salts followed by

quenching L\ ith amn-~omium acztatc (Scheme 4).4 he reaction proceeds via the

iminoalk?lation of the intermediate alkcne formed from 9 under the reaction

conditions. When the same protocol was extended to aliphatic alcohols like t-

butanol. t'unctionalizeci napthyridines were fbrmed.

0 H3C OH

3 CH3 CH,MgI ~

.%> *%H, t . PocI,/ DMF 1 1 I - II J

X Et20 -.5 2 . 8 0 ~ ~ 1 2 h 3. N H 4 0 A C

8 9 10

Scheme 4

We have also developed a facile method for the synthesis of methylthio

substituted 4-arylpyridines 13 froni aryl substituted a-hydroxyketene dithioacetals

12 viu szclucntial (irigr~ard-Vilsn~eier reactions, followed by treatment with

amnloniun~ acetate (Scheme 5).'

OH SCH, f TCHzi C H ~ M Q I ,,+ ,A;,d,scH3 POCI, IDMF(2 equiv.)

SCH3 ( CH3 . " -+ NH40Ac. 80 C. 2H

&XH3

X

Scheme 5

5.2.2 Recrctions cf(irrhony1 Compounrls with Chloromeihyleneiminium salh

The reactions of chloromethyleneiminium salts with carbonyl

compounds and their dcrivatices are highly versatile.' On treatment with

Vilsmeier reagent they provide muitit'unctiorlal synthons having potential for

further applications i n synthesis. Simple enolizablc carbonyl compounds react

with chlororr~ethylerreinium salts to afford the corresponding chloroethylenic

aldehydes. Simple aliphatic kelones can be conveniently transformed to the

substituted [3-chloroac1ylaldehq.des by the Vilsmeier-Haack reaction.'

When multiple iminoalkylations occur on enolizable ketones like

dibenzyl kctone c~clizations of the pentadienaldehyde formed during

hydrolysis irtli~rd substituted pyrones.' Investigations of Vilsmeier reactions on

a-substituted aliphatic ketones like benql methyl ketones 15 from our laboratory

revealed that the reaction proceeds with the formation of conjugated iminium salts

which on aclueous basic work up afyord 3-f'ormyl-4-pyrrones 14 and on ammonium

acetate-induccd cyclization afford 5-ql-4-chloronicotinaldehydes 16 in good

yields (Scheme 6)." "'

, C H ~ DM" ~ o c i , (3 equtv) ' 0 (a) DMFI POCI, (4 e q u ~ ) - ~ ~ - 48 h: n 4 8 h n * CH3

(b) NH,OAc. 0 'C

30 min

15 Scheme 6

Perurnal ur ul. haye shown that oximes of a,p-unsaturated ketones can

be transformed to 3-pyridine carboxaldehydes under the Vilsmeier-Haack

reaction conditions." fhe Vilsmeier cyclization of 2'-aminochalcones 17

provides a mild one pot synthesis of 2-aryl-4-chloro-N-fonnyl-1,2-

dihydroquinolines 18 (Scheme 7)." The scope of the reaction has been

extended li)r the synthesis of quinolines themselves, by replacing 2'-

an~inochalccines with 2'-a~idochalcnnes as the starting material.

0 1 1 trealrncnl with Vilsmeier-hack reagent, o-hydroxyacetophenones

19 g i ~ c the valuable intermediates 3-formyl chromones 21 in good yields

(Scheme x)." Similar protocol has been recently used for the one-pot synthesis

of cyw1ohew~opyrones. important intermediates in the synthesis of

therapeutically useilil anti-allergic drugs such as Amlexanox. I .I

19 20 21

Scheme 8

( '>cli~atii)r~ ,>I ' :I-hydroxy-a-phen~xyacetophen~ne derivatives by the

Vilsmeier reagent, catalyzed by HF3.0Et2 to 3-phenoxychromone derivatives

has also hcen reported." l'hz reaction mechanisms and kinetics of these

reactions also have been well studied." Appropriately substituted naphthalenes

and couniarins react similarly. Sin~ilarly, o-arninoacetophenones 22 react with

the Vilsnlcicr-Haack reagent IC) afford the corresponding 4-chloroquinoline

derivalives 23 (Scherrie O)."

22 23 Scheme 9

Ihe reacliori ()I' [)-enaminonitriles 24 with a Vilsmeier type reagent

providc a iiiild and highly rrgioselective route for the preparation of

nicotint~nilriles 25 (Scheme 10). I X

24 25 Scheme 10

I he synthesis of 2-substituted benzo[b]furan derivatives has been

accomplished from1 phcnyl ethers viu an intermediate iminium salt." A versatile

synthesis of benzofuran 27 was accomplished by the Vilsmeier-Haack reaction

of thc phenoxy acetophenones 26 (Scheme 1 1).20 However the Vilsmeier-Haack

reaction o f simple phenoxyacetonc gave N,N-dimethylamino substituted

pentadicnaldehydes

26 27 Scheme 1 I

L<eaction of active methylene compounds containing nitrile functionality

with Vilsrncier reagent usually affords pyridines. For instance malononitrile 28

on reaction \vith DMI.' and POCli afforded 2-amino-6-chloro-3,5-

pyridir~rdicarbonitrjle 29 in good yield (Scheme 12)."

CN POC131DMF -- A

CN CI NH2

28 29

Scheme 12

Koyam;~ el iri. reported the synthesis of thienopyridine derivative 32 born 3-

cymomethylthiophcne 30 via an intennediate iminium salt 31 (Scheme 13).L2

30 3 1 32

Scheme 13

5.2.4 Cvclizution uf'arnides and uminoaceluls

Ciupton and coworkers have explored the use of vinylogous iminium

salts in rhc synthesis of substituted pyridines23 and pyrroles. A variety of 2-

substituted ~inan~idiniwr~ salts 33 react with u-minoesters 34 under basic

conditions to atK)rd 3.4-disubstituted pynoles 35 in good yields (Scheme 14). '~

CH? X FH, H NaOC,H,.C2H,0H X

CIOn . , - N,,COOCzH5.HCI

HF N.::--~",N -,:.: R* Heat R = H , M e

33 34 35 Scheme 14

I'hc reaction ot' 3-avl-3-chloropropenirninium salts 36 with either glycine

or sarcosine esters 34 alforded. 2-casbethoxy-5-arylpymole 37 in a regioselective

manner (Scheme 1 s).'" Similar approach has also been used for synthesizing 2,3-

disubstituted pyrroles by the reaction of I-arylvinamidinium salts with sarcosine

ethyl ester. I'hc corresponding reaction with glycine ethyl ester resulted in 2,5-

disubstitutcd pYn.olcs.-"'

36 34 37

Scheme 15

l'eri~rnal t,r ul, have reported synthesis of substituted quinolines from

azides b! reacting i t with chloromethyleneiminium salt." In the literature there

are a number of reportlj on the synthesis of quinolines and their derivatives

using the chloromethyleneiminium salts prepared fi-om anilides. The Vilsmeier-

Haack reaction of acylanklides 38 atyorded the hnctionalized quinoline 40 in good

yields (Schcnle I 6);'

39

Scheme 16

Meth-C'ohn and Westwood have developed a general method for the

preparation of quinolines and fused pyridines tiom acyl anilides or related

compounds." For cxanple 5-substituted 2-acetamidothiophens 41 can be

converted into 6-chlor~)thieno[2.3-h]pyridine-5-carbaldehydes 42 by treating with

seven niol ecluivalent of POCI; and three mol equivalent of dimethyl formamide

under retluv lbr 3 hours (:Scheme 17). "

R , POCldDMF - 3h reflux ..dC: <S

4 1 42 Scheme 17

In tlic case of N-phenql acetanilides 43 Vilsmeier-Haack reaction

afforded I -phenq I-2-quinoloncs such as 45 (Scheme 18)."'

44

Scheme 18

Vilsmeicr reaction of amido alcohols 46 affords oxrvolines 47 in excellent

yields (scheme I<))."

46 47

Scheme 19

A ~ariety of N-acetyl derivatives of aminoacids like 48 and 50 have

been subiectcd to Vilsmeier-EIaack reaction to obtain 2.4-dichloro-3,5-difomyl

pyrrolcs 49 and 2-k)r11-1ylmethylene-4-substituted oxazoldin-5-ones 52 (Scheme

20 and 2 1 ) . '-'

48 49 Scheme 20

R COOH 7' DMF

HN'n -

50 5 1

Scheme 21

Similarly N-ace~.ylhomocysteine thiolactone 53 give 5-chloro-3-fomyl

thienol2.3-blpyridine 54 (Schcrrle 2.2)."

52 53

Scheme 22

1-1 i 5 1:liamines. cnamides. cncarbamates,l6 enol ethers." enol acetates etc.

also undergo iminoalkylation under Vilsmeier-Haack reaction conditions.

Electrophilic substitution of these compounds occurs readily. yielding iminiuim

salts tha~ have found substantial use in synthesis. For example, enamine

derivati~e 54, when treated with chloromethyleneiminium salt, gives alkyl

substituted iminiun~ salt 55 which on treatment with hydrazine affords pyrazole

derivative 56 in I X-6496 yields (Scheme 23)'" simple one-pot procedure for

the regiosclective syn~thesis of pyrazoles from readily available starting

materials has k e n described b) Katritrky et al. Vilsmeier type reagent reacts with

imines (via the corresponding tautomeric secondary enamines) in t e t r a h y d r o h to

give enaminoimine hydrochlorides which were trruxformed in situ to the

corresponding pyruoles in moderate to high yields by the addition ~fhydrazine.)~

54 55 56

Scheme 23

l<ec\ctions o l 11-oxokttenc-N.S-arylaminoacetals 58 with Vilsmeier reagents

has been utilized for the efTicient synthesis of highly fimctionalized quinolines 59

and their hervohctero-fused analogues. 'The cycliration is found to be facile with

N,S-acctals bearing strongly activating groups on aniline, whereas yields of

quinolines arc moderate i r ~ other cases. 'The reaction could also be extended for the

synthesis o t substituted tricyclic benz.o[h]quinoline, pyrido[2,3-hlquinoline, 4,7-

diphenylphc~ianthrolinc.~ and tctracyclic quino[8,7-hlquinoline by performing a

Vilsmeier reaction on N,S-acctals derived from I-naphthylamine, m-

phenylenediamine. o-phenylenediamine, and 1,5-diaminonaphthalene,

respecticelj hl

:5 7 58 Scheme 24

Some 2-(7-indolyl)pyrrolcs 61 have been synthesised from 4,6-

dimethoxyindoles 59 using the modified Vilsmeier reaction. An effective

sequencc uses a combination of 3-bromopyrrolidin-2-one and phosphoryl

chloride to g i ~ e 3-chloro-2-(7-indoly1)pyrrolines 61, which undergo subsequent

dehydrohalogenation tu give the indolylpyrroles (Scheme 2 ~ ) . ~ '

60

Scheme 25

I'he literature review showed that though different methods are available

for thc iminium salt mediated synthesis of pyridines and pyrans, methods tor

the synthcsis ofpyrroles under \'ilsmeier conditions are less common. We have

developed ;in eflicient rnethod ihr the synthesis of 0-oxoketene-N,S-acetals

having aminoacetate limctionality and the results were already reported in

Chapter 4 of this thesis. Since thc ketene-N,S-acetals contain different electron

rich centers. they can t)e cyclircd in different modes leading to the formation

for variet) OF hcterocy~:le:i.

5.3 Results and [)iscussion

5.3.1 C:vclizations of ~oxoketme-N,S-acetals 62 using Vilsmeier-Haack reagent

I he ketene-V.S--ac.etaIs 62a was dissolved in dry DMF and to this was

added i\\o equi\alents of Vilsrneier-Haack reagent, prepared by mixing

phosphorous ox>chloride and N,N-dimethyl formamide at 0 OC. The reaction

mixture \\as \~e l I s11rre11 at room temperature for 6 h and then heated at 80 OC

for 1 h. We envisaged tkdt treatment of the ketene-N,S-acetal with Vilsmeier-

Haack reagent would lead to irninoalkylation followed by intramolecular

cyclization to al'tord the substituted pyrrole 64. However when the product

mixture atier hydrolysis with saturated potassium carbonate solution, extraction

with dicrhyl ether and column chromatography over silica gel using

hexane:ethyl acetate !!):I) as eluent afforded a white crystalline solid in 90%

yield which was identified as ethyl 3-(4-chloropheny1)-4-formyl-5-

(methylsull:dnyl)-1 ti--pyrrole-2-carboxylate 63a on the basis of spectral data

(Schenie 36). Interestingly the carbonyl group of the aroyl moiety was involved

in the cxcliration leading to the lbrmation of the substituted pyrrole-2-

carboxylatcs 63a. 'l'he reaction was not complete when carried out at room

temperature h r 10 h and afforded only low yield of the product. Attempts to

cyclize the N.S-acetal in presence of POCI-, in dry benzene or in the presence of

other Leuis acid catalyst!; could not afford any cyclization product.

Scheme 26 R '

FJOCI3 DMF 0 - *

1 It 16h) 81 R~O,C N SR'

H

- ~ - ~~ ~-

Pyrrolc 63 R. ' R~ - ~p ~~ - ~~ ~~~ ~~

R~ - Yield (%) a cj CzIfi CH3 90

b ( till CzHc CHI 87 c t I CzIIj CH3 88 d Ijr C2Hj CzHs 89 e H CH, C ~ H S 82 f CHI CH; CzH5 85

g (:I C113 C?HS 88 h ~~ -~~ ~ ~~~~ (:1l30 ~p-p - C2Hj CZHS ___ 88

The IK spectrum (Fig. I ) showed bands at 3234, 1660, 1539, 1249,

1170. 1018. 835. 794 and 725 cm ' . The proton N M R spectrum (Fig. 2) of 63a

showed a three-proton triplet at 6 I . 1.5 ppm (J= 7 Hz) and a two-proton quartet

at 6 4.19 ppnl (J - 7 1 iz) corresponding to the ethyl moiety. The methylsulfanyl

protons appeared as a 4inglet at 6 2.62 ppm. 'I'he aromatic protons appeared as

doublets d t (5 7.13 pprn (tl. 2H, J 8 HL. aromatic) and 6 7.38 ppm (d, 2H, J = 8

Hz, arornalic) typical of an AB pattern of para substituted aromatic system. The

N H proton appears as a broad singlet at 15 9.42 ppm and a sharp singlet at 6 9.62

ppm is due to ihe fomiyl group. The structure was further confirmed by

"C NMR spectrum (Fig. 3). The signal due to methyl and methylenic carbons of

ethyl carboxjlatr were at 14.38 and 61.39 ppm respectively. The methylsulfanyl

carbon appcarcd at 6 15.55 ppni. I'he aromatic carbons appeared at 6 120.73,

123.01. 128.26. 130.44. 132.28, 13.3.69, 134.45 and 138.90 ppm. The signal due to

aldehyde d ~ l d ester carhonyl groups appeared at 186.32 and 160.88 ppm

respectivcl). I'he rnitss spectrutn (Fig. 4) shows a & +2 peak with intensity 39%

at 325 and the molecular ion peak at 323 confirming the presence of chlorine.

Other prominent peaks were at 276,244,216, 179 and 16 1.

Similarlq othcr timctit~ralized ketene-N,S-acetals 62b-h also gave the

corresponding pyrrolc carbaldehydes 63b-h in 82-89% overall yields when heated

under Vils~neier conditions (Scheme 26). The structures of these pyrroles 63b-h

were co~llirmed with the help of IR proton NMR, carbon-13 NMR and mass

spectra. Illc spectral data of thca: compounds are given in the experimental section

Figure 1: 1R Spectrum of 62a

I Figure 2: H N M H (300 MHz, CDC13) Spectrum of Compound 63a

I 3 Figure 3: C NMK (75 MHz, C:DCl,) Spectrum of Compound 63a

Average of 0.948 to 1 . ~ 1 mln. lrom ZE-d Abundmc.

Mum 7- I mum -' i

Figure 4: hlass Spectrum (GCMS) of Compound 63a

I hc li)nnation ofpyrrole carbaldehyde 63 can be rationalized as follows.

Seq~~enli;il iminoalkylations I the ketene-N,S-acetal moiety and the

enarninokctone functionality leads to the intermediate 65 and 66 respectively.

The chlorovinyl iminiurn salt 67 can be obtained by the displacement of N,N-

dimethyl li)rmamide by chloride ion from 66. Cyclization of 67, involving the

amino acctate group and the chlorovinyl iminium moiety, leads to the formation

of iminiurn salt 01' substitutcd pyrrole 68, which affords the pyrrole 63 on

hydro11 sis.

l:samples given in Scheme 26 illustrate that the substituents on the aryl

group and the ethql or methyl esters do not have much influence on the overall

yields. I he electron withdrauing nature of iminium salt moiety in 67 serve to

increase the overall yields as it facilitates the cyclization. Functionalized

ketenc-N.S-acetal 69 clerived ti-om cyclic carbonyl compounds like a-tetralone

which cannot irninoalk.ylate also underwent cyclization to afford the annulated

pyrrole 70 in 780/;1 in the presencc of POCl, and DMF in 78% yield after

heating at 80 "(' tbt- 7 h. (Schcmc 27).

69 70

Scheme 27

Vilslneier reactions of' (I-oxodithiocarboxylates afyord 0-chloro, 0- methylthio u,(<-unsaturated ketones in good yields." Our efforts to synthesize

pyrrole directly from thioamide 62a under Vilsmeier condition afforded an

unstable liquid which was tentative characterized as the N,N-dimethylan~ino

substituted pyrrolc.

5.3.2 Base cntalyzed cyclization ofPo.uoketene-N,S-acetals 62

Synthesize oi 3.4-diary1 substituted pyrroles are

important as many recently isolated natural products having

remarkable divers~ty of biological activity possess this

pyrrole is prc~bably the most difficult to prepare since most

substitution pattern. I t is noteworthy that the 3,4-disubstituted ~~s

71

electrophilic substitution reactions as well as lithiation reactions of pyrrole ring

occurs predominantly at the 2-position. Selective substitutions at one or more of

the [$-positions have been generally considered as a challenging goal in many

synthetic programs. In the previous section we have discussed the efficient

synthesis of pyrrole carhaldehydes 63 under Vilsmeier-Haack conditions. The

aldehyde group was introduced on the pyrrole ring as the N,S-acetal undergoes

an iminoalkylation at the a-position during or prior to the cyclization process.

Our attempts to cyclize the ketene-N.S-acetal 62 in the presence of POCl, or

other acid catalysts coulti not afford the pyrrole carboxylate 71. The pyrrole 71

contain an aryl group at 3-position, a removable alkylthio group at 5-position

and a carboxylate functionality at '-position. The 4-position of the pyrrole is

free to which aryl grou;ps can be substituted by a variety of cross-coupling

reactions alier- introducing a halogen. The resulting pyrrole would be very

similar in structure to many recently isolated pyrrole natural products. Thus we

have thought ot'altemate approaches towards the cyclization of the ketene N,S-

acetals leading to the fi~rnlation ofthe pyrrole 71.

We havc investigated the cyclization of a-oxoketene-N,S-acetals 62

under dit'iierent conditions. Under strongly basic media the N,S-acetal was

unstable and intractable mixture of products were formed. However, when

heated 31 100-1 10 "C in presence of non-nucleophilic base such as DBU in

toluene. trisubstituted pyrroles 71 were formed in moderate yields. The ketene-

N,S-acetal 62 was dis:iolved in dry toluene and heated at 100-1 10 'C for 3 h

with stirring. During these period two equivalents of DBU was added in three

portions in equal intervals to the reaction mixture. Toluene was evaporated

under reduced pressure and the residue was dissolved in dichloromethane,

washed will? 5% 11C'l. then with saturated bicarbonate and linally with water.

The dark brown oil obtained was purified by silica gel column chromatography

using hexanelethyl wetate (9:l) as eluent afforded the 3-aryl pyrrole-2-

carbovylates 71 in moderate yields (Scheme 28).

DBU, toluene -- 1 0 0 - l l 0 ~ ~ . 6h

62 71

Scheme 28

R~ Yield (%)

I'hc structure of' the substituted pyrrole 71a was confirmed on the basis

of spectral data. The 1K spectrum (Fig. 5 ) showed bands at 3297, 1672, 1447,

817 cin ' . I'hc ' I 1 N M K spectrum (Fig. 6) of71a shows a three-proton triplet

at h I . ( 1 7 Hz) and a two-proton quartet at 6 2.82 ( J = 7 Hz) due to the

ethyl sulphanyl group. The methyl carboxylate group appeared as a singlet at 6

3.78 ppni. The single proton on the pyrrole ring appeared as a doublet at F 6.39

( J = 3 11,) pprn due to long range coupling with NH proton. The aromatic

proton appeared as two doublets at h 7.33 (d, 2H, J = 8 Hz) and at 6 7.46 (d,

2H, J = 8 Hz) ppm due to the para substituted phenyl ring. The I3c NMR (Fig. 7)

showed the signal duc t'o methyl and methylenic carbons of methyl sulphanyl

group at 6 15.63 ancl 31.27 ppm respectively. The peak at 6 51.88 ppm is due

to methyl carbon on the carboxylate moiety. The signal due to aromatic carbons

appeared at ii 118.3'7, 119.71, 126.59, 128.36, 131.03, 133.39 and 133.49 ppm.

The signal due to cster carbonyl was 6 161.06 ppm. 'The mass spectrum (Fig. 8)

sho\vs a M' 12 peak with intensity 34% at 297 and the molecular ion peak at

295 confirming the presence ot' chlorine. Other prominent peaks are at 235,

213. 206.185. 167. 149, and 120.

Similarly other functionalized ketene-N-,S-acetals 62b-f gave the

corresponding pyrroles 71b-f when heated in toluene in presence of DBU. The

structures of these pyr'oles were confim~ed with the help of proton NMR,

carbon-1.3 NMR and mass spectra. The spectral data of these compounds are

given in the experimental section. Annulated pyrrole 70 was also formed in

good yields when thc N-S-acetal 69 derived from tetralone was heated in the

presence ol'1)Rl.i for 8 hours.

, KBr

5000

Figure 5: IR Spectrum of 71a

Figure 6: 'H NMR (300 MHz, CDC13) Spectrum of Compound 71a

Figure 7: I3C NMK (75 MHz, CDCI,) Spectrum of Compound 71a

i "

amm i

I 1 , i

lmmo *,

I 'i ,"

1 dL?;L- a IY _ v .*-.*-.- -4 rn XI a r M m m 90 ~a $ 1 0 IN ~ ) a I* ns om 110 ~m tw m n o uo m no uo ,M m u, n. lo. ar

*

Figure 8: Mass Spectrum (GCMS) of Compound 71a

Attempted one pcjt synthesis of pyrroles 71 by the reaction between P- oxodithiocarboxylatc and ethyl glycinate under conditions like potassium

carbonate/acelone. sotlium ethoxidelethanol. sodium hydridelbenzene even at

elevated temperature could recover only the unreacted starting materials or

intractable product mixtures. Attenlpts to cyclize the ketene N,S-acetals in

preserlcc 0 1 strong base also afli)rded only complex mixtures of products. When

the cyclization of the ketene N.S-acetals 62 was attempted by refluxing it in

glacial acetic acid, p d a l hydrolysis takes place leading to the formation of

P-oxothiolestcrs 72 in e)tcellent yields (Scheme 29).

CQEl

,: H - N - I

I .:,A. acetic acld SEf ~ ~p -

reflux c+J%sEl

62 72 Scheme 19

-~ ~~~ - ~p

fhiol Ester K ' R~ Yield (%) - ~ - ~- --

a~ f j c2Hs 98

In summary, we have developed straightforward and simple protocols

for synthesizing highly functionalized pyrrole derivatives. The starting N,S-

acetals mel-e easily prepared from inexpensive dithioesters and glycine esters.

The alkqlthio group at 5-position and the aldehyde functionality at 4-postion

could be L I S C ~ for t'urthcr structural modifications. Reductive removal of the

alkylthio group would provide an indirect method for 4-formylpyrrole-2-

carboxylalcs. which is not directly ;3ccessible by formylation ofpyrroles.16 The

substilutio~l pattern als~:) makes them attractive precursors for porphyrin

synthesis. I'hc pymoles prepared by DBU method can be utilized for

synthesizing various 3.4-diary1 substituted pyrrole containing natural products.

5.4 Experimental

Melting poirrts are uncorrected and were obtained on a Buchi-530

melting point apparatus. Infrared spectra were recorded on Shimadzu JASCO

FT!IK-5300 or A1313 Bomem 104 spectrometer and frequencies are reported in

cm-'. I'roton NMK spectra were recorded on a Bruker D M - 3 0 0 (300 MHz), or

on a f3ruker AMX 100 (400 MHz) spectrometer in CDCI,. Chemical shifts are

expressed in parts per million downfield from internal tetramethyl silane.

Coupling cunstants .I are given in Hz. Mass spectra (EIMS) were obtained on a

Finngen-Mar 3 I2 instrument.

5.4.1 General procedure fbr the synthesis of alkyl 3-aryl-4-formyl-5- (alkkvl.sulfanyI)-I H-pyrrole-2-carboqlafes

L'llsrnerer regent was prepared by mixing ice cold, dry DMF (25 mL)

and POCI, (2m1,. 20 mmol). I he mixture was then stirred for 30 minutes at

room temperature. I hi. N.S-acetal 62 (3.258, 10 mmol) was dissolved in dry

DMF ( 1 0 1111 ) and added to the Vilsmeier reagent over 10 minutes at 0-5 "C.

The reaction mixture was stirred for 6 hours at room temperature, heated to

80°C for 1 h with stirririg and was cooled and poured into cold, saturated aq.

KzCO3 (700 1111.). I1 wzs then extracted with diethyl ether (3 x 50 mL). The

organic l a ~ c r was washcd with water, dried over anhydrous Na2S04 and

evaporated to afford the crude product. which was chromatographed over silica

gel using hexane:cth~ lacerate ( 10: I ) as eluent to give alkyl 3-aryl-4-fomyl-5-

(a1kylsultiin~l)- 1 kl-pyrrole-2-carboxylates 63.

Eth-vl 3-14-chlorophen.vl)-~formyI-5-(methyls1~~an,vl)-

IN-pjrrole-2-curboxylate 63a was obtained by the

'Vilsmeier reaction of ethyl 2-{[(E)-3-(4-chloropheny1)-

I -(methylsulfinyl)-3-0x0- I-propenyll aminojacetate

62a (3.13 g. 10 mmol) as white crystalline solid. Yield

,c 1 2.91 g (90V/0), mp 118-1 19 "C. IR (KBr) v,,/cm-' =

/ $ 1134. 1660. 1539, 1249. 1170, 1018, 835, 794, 725. 'H OHC i

$ ? bIMR (300 MHz, CDCI,) 6 1.15 (t, 3H, J = 7 HZ, H3CS N C02C2H.

H C'H2CH,. 2.62 (s, 3H, -SCH?), 4.19 (q, 2H, J = 7 Hz, -

C,~H,,CINO,S C'HLClI?. 7..33 (d, 2H. J = 8 Hz, aromatic), 7.38 (d, 2H, J

63a - 8 Hz. aromatic) 9.43 (bs, 111, NH), 9.62 (s, lH, CHO)

ppm. "c' NMK (75.47 MHz, CDCI,) 6 = 14.38, 15.56,

61.39, 120.73, 123.01, 128.27, 130.45, 132.28, 133.70,

4 4 138.91, 160.88, 186.33; EI-MS m/z (%) = 325

(hl' + 2, 39) 323 (M', 100). 276 (38), 244 (20), 216 (42),

17') (20). 161 (5). 11 3 (3).

Eti2,vI -I~fbrmyl-3-(4-met~~he~~-5-(met~1suIfanyI)-IH-

/?w~o/e-2-<~urho~lu& 63b was obtained by the Vilsmeier

reaction of ethyl 2-{[(E)-3-(4-meh1~lphenyItl- CH:

,' s ~,methylsultBnyl) -3-0x0-1-propenyll-amino)acetate 62b , 5 ,

OHC . ~ , (2.03g, 10 mmol) as white crystalline solid. Yield 2.6 g ) 3%:.

HZCS' ,N. CO,C,H,, (87%), rnp 108-100 'C. LR (KBr) v,,,,~crn~~ = 3378, 1670, H

C,,H,,NO .S 1640, 123.3. 1 162. 1020, 799, 776. 'tI NMR (300 MHz,

C'DICI,) 8 1.15 (t, 3H, J = 7 Hr, SCH2CH3), 2.40 (s, 3H,

63b ArC:H; ), 2.61 (s, 3H. SCH3), 4.1 9 (q, 2H, J= 7 tfz, CH2CH3),

7.20 (d, 2H. .I = 8 Hz,, aromatic), 7.29 (d, 2H, J = 8 Hz,

;rromatic) 9.43 (,bs, I [I, -NH), 9.63 (s, 111, -CHO) ppm. I3c hMR (75.47 b1tIz. CIICI,) 6 = 14.43 (OCH2CH,), 15.31

(SCIH,). 2 1 .I8 (CX?), 61.1 8 (OCW2CH3), 120.35, 123.12,

128.69. 128.76. 130.88, 135.54, 138.21. 138.30 (aromatic),

160.95. 186.89 (carbonyl); EI-MS miz (%) =303 (K loo),

237(30). 256)(33), 224(27), 196(31), 159 (15), 115 (9).

15lhyl -I~ft~rm~~l-5-(met~lsuIf~~I)-3-phen~l-IH-~oIe-2-

cczrho~lute 63c was obtained by the Vilsmeier reaction of

ethyl 2- ( [ (a-1 -(methylsulfanyl)-3-0x0-3-phenyl- l-

propenyl]amino) acetate 62c (2.8 g, 10 mmol) as white

6 crystalline solid. Yield 2.54 g (88%), mp 119-120 OC. IR

OHC r : - i (1CBr) v ,,,,, icm-'= 3247, 1692, 1655, 1549, 1247, 1173, 1021, ) $L

H ~ C S - x N C O ~ C ~ H S 795. 'H NMR (300 MHz. CDCI3) 6 1.04 (t, 3H, J = 7 HZ, ti

C'ff2C14). 2.55 (s, 3H, -SCHj), 4.11 (q, 2H, J = 7 Hz, CI~HIINOIS

CCI~CHI). 7.32 (m, SH, J = 8 Hz, aromatic) 9.34 (bs, IH,

63r U.ff). 9.55 ( s . 1lI. CHO) ppm. ')c NMR (75.47 MHz.

C'I$C13) f i :- 13.93, 15.12, 60.83, 120.21, 123.02, 127.66,

128.02. 130.6'2, 131.58, 134.93. 137.70, 160.61, 186.27; EI-

MS mi^ (Vo) :- 289 (M', 90), 288 (84), 242 (76), 214 (33),

181 (100). 171 (23), 144 (71).

E l 3-/4-bromophenyr)-5-(eth~vlszrlfanyl)-4~lH-

~;wrole-2-crrrho~lute 63d was obtained by the Vilsmeier Br

(, >\, ,, ' j ~.t:action of ethyl 2-{[(a-3-(4-bromopheny1)-1-

OHC :

). -;' (etk1ylsullmyl)-3-oxo- l -propenylj arnino)acctate 62d (3.7g, 1 '),

C2H5S'- H C02C2H5 10 mmol) as white crystalline solid. Yield 3.4 g (89%). tnp

C,,HI~B~NO.,S 148-149 "C'. IR (KBr) v,,,/cm" = 3254, 1673, 1538, 1418,

63d 1214. 1013. 77'7. ' H NMR (300 MHz, CDCI,) 8 1.15 (t, 3H,

.I = 7 Hz. - O(-:fi?CH;, 1.37 (t. 3H, J = 7 HZ, SCH2CH3),

1.60 (t, 311. .J - 7 liz, SCH2CM). 3.06 (q, 2H, J = 7 Hz,

OC'HzC'tI;). 4.10 (q, 2H. J = 7 Hz, CH2CF1,), 7.26 (d, 2H, J

= 8 Hz. arort~atic), 7.53 (d, 2H. J = 8 Hz, aromatic) 9.63 (bs,

I I I. NH). 9.72 (s, 1 H, CHO) ppm. I3c NMR (75.47 MHz,

C'1)C13) = 14.29 (SCH2CH3, OCH2CH3), 27.39

('iCH2ClIl). 51.75. 119.98, 123.86, 127.70, 128.04, 130.48,

1.3 1.36. 134.80. 135.91, 160.82, 186.30, 186.47; El-MS mlz

(9') = 383 (Mi + 2. 100) 38 1 (M', 96), 350 (84), 348 (84),

302 (72). 304 170). 276 (24). 274 (23), 225 (29), 223 (38),

199 (17). 144 (16).

e t h y l 5-/ethylsu[fanyl)-4-formyl-3-phenyl-IH-pyrrole-

2-carhoxvlate 63e was obtained by the Vilsmeier

reaction 01' methyl 2-{[(E)- I-(ethylsulfany1)-3-0x0-3-

phmyl- l -propenyl] amino) acetate 62e (2.65g, 10

mmol) as white crystalline solid. Yield 2.36 g (82%). mp

,$ ) 86-87 "C'. IR (KBr) v,,,,/cm~' = 3358, 1682: 1651, 1539, OHC :L/

2- (1- 1386, 1233, 1154, 767. 'H NMR (300 MHz, CDC13) 6 1.36 CzH5S' N COzCH3

H (t, 311, J 7 HZ, CH2CH3), 3.08 (q, ZH, J = 7 HZ, CH2CH3), C,SH,,NO,S 3.159 (s, -3H. CH3), 7.39 (m, 5H, aromatic), 9.69 (s , IH,

63e I ) 0 . 7 b . 1 H, Nli) ppm. I3C NMR (75.47 MHz,

' I ) 6 14.82 (SCH2CH3), 28.47 (SCH2CH3), 61.45

(CO,CFI,). 120.65. 122.61, 124.43, 130.90. 131.03, 132.55,

133.07. 136.37 (aron~atic), 160.71, 186.48 (carbonyl); EI-

MS t n h (%) := 289 (M', 78), 256 (76), 224 (loo), 196 (39).

172 (16). 145 (60), 102 (1 1).

Meti7,i 4-formyl-3-(4-methyIpheny~-5-

(eti1~~/.srrlfunyl)-/H-pyrrole-2-curboxvlate 63f was

obtained by the Vilsmeier reaction of methyl 2-{[(Q-

3-(4-methylpheny1)-1-(ethylsulfanyl)-3-0x0-I -pope

nyll-amino)acetate 62f (2.93 g, 10 mmol) as white

crystalline solid. Yield 2.45 g (85%). mp 108-109 OC.

IR (KIlr) v ,,,$,, lcm-' = 3155, 1717. 1642. 1563, 1510,

1260. 115 I . 1098, 778. ' H NMR (300 MHz, CDCI3)

15 1.36 ( t , 3H. J:= 7 Hz, SCH,CH,. 2.40 (s, 3H, ArCH,),

3.09 (q. 2H. . I - 7 Hz, SCH2CH,), 3.72 (s, 3H, C02CH3),

7.2 1 ( d. 2H. J = 8 Hz, aromatic), 7.29 (d, 2H, J = 8 Hz,

aromatic) 9.71 (s, IH, CHO), 9.79 (bs, IH, -NH) ppm.

"C KMR (75.47 MHz, CDCI,) 6 = 14.68 (CH2CH3),

11.73 A ) . 27.75 (CH,CH,), 52.12 (C02CH3),

120.27. 124.21, 128.63, 128.86, 130.77, 135.41, 136.32,

138.23 (aromatic), 161.23, 187.02 (carbonyl); El-MS

n ~ i z ( O h ) 303 (M~', 88), 270 (551, 238 (1001, 210 (35),

186 ( I 0). 159 (36). 128 (6), 115(16).

A4eth>.l 3-(4-chlorophenylj-5-(erhylsu1fanyI)-4-

fbrmyl- IfI-pyrrole-2-carboxylate 63g was obtained

by the Vilsmeier reaction of methyl 2-{[(a-3-(4-

c11lorophenyl)- l -(ethylsulfanyl)-3-0x0- 1 -propenyl]

arnino/acetatl: 62g (3.lg, 10 mmol) as white

crystalline solid. Yield 2.8 g (88%), mp 128-129 'C.

IR (Kl3r) v ,,,,, icm-I = 3124, 1696, 1649, 1439, 1242,

1084. 878, 777. ' H NMR (300 MI-Iz, CDCI3) 6 1.34

(t. 3H. J =- 7 Hz. CH2CH3), 3.07 (q, 2H, J = 7 Hz,

CHLC'H;). 3.71 ( S 3H, C02CH3) , 7.32 (d, 2H, J = 8

Hz, aromatic). 7.36 (d, 2H, J = 8 Hz, aromatic), 9.74

(s. I . 0 10.13 (bs, IH, Nff) ppm. I3C NMR

(75.47 MHz, CDCI,) 6 = 14.78 (SCH2CH3), 28.29

(S('HzC:HI), 52.26 (COzCWj), 120.74, 124.34,

128.42. 130.34, 132.18, 133.85, 134.57, 136.73

(aromatic). 16 1.05. 186.53 (carbonyl); EI-MS mlz

( 0 325 (M' +2, 37) 323 (Mt, 93). 290 (94), 258

(I 00). 230 (3 1 ). 207 (12) 179 (52). 144 (9), 113 (5).

,°CH, Eth1.l (5-ethy~su(fanyl)-3-formyl-3-(~- ,?~~ \

OH& \:~zz,8' methoxjphmnvl)-IH-pjlrrole-2-carbo.rylate 63h was : :I

2 C?H,S N ' L - ~ 0 2 ~ , ~ , obtained by the Vilsmeier reaction of ethyl 2-{[(E)-

H I-(ethylsulfinyl)- 3-(4-methoxypheny1)-3-0x0-1-

C,;tIfs,N04S propsnyl]amino)acetate 62h (3.2 g, 10 mmol) as

63 h white crystalline solid. Yield 2.9 g (88%), mp 92-93 "C.

IR (KHr) v ,,,,, lcm-' = 3247, 1661, 1509, 1247, 1176,

1034. 816, 781. 'H NMR (300 MHz, CDCI,) 6 1.22

(t, 311, J - 7 Hz, SCH2CH3), 1.42 (t, 3H, J = 7 HZ,

OCt12CIf.j), 3.12 (q, 2H, J = 7 HZ, SCH2CHj), 3.90

(s, 3 tl. 0(.'ff3), 4.26 (q, 2H, J= 7 Hz. OCH2CH3), 6.98

(d, 211. ./ := 8 HL, aromatic), 7.38 (d, 2H, J = 8 Hz,

aromatic). 9.61 (bs, IH, NH), 9.77 (s, IH, CHO) ppm.

I3c NMK (75.47 MHz, CDCIs) 8 = 14.06 (SCH2CH,),

14.37 tOCH2CH3), 27.74 (SCH2CHj), 55.29 (OCH,),

60.82 ((~)CltILCHj), 113.13, 120.39, 123.70, 124.21,

131.86. 134.48. 135.41, 159.52 (aromatic), 160.54,

186.56(carbonyl); El-MS rnlz (%) = 333 (&, 63), 300

(23). 254 (loo), 226 (41), 174 (55). 158 (16), 132 (24).

Erh, 4 3-(rnefh,vlsufanyl)-4,5-dihydro-2H-benzo(e)

isoit~clolr-I-curboxylute 70 was obtained by the

Vilsrneier reaction of ethyl2-(fmethylsulfanyl) [l-oxo-

3.4-dihydro-2(1 H)naphthalenyliden]arnino)acetate 69

(3 g. 10 mmol) as white crystalline solid. Yield 2 g

(70%). mp 13 1-133 "C. IR (KBr) v,,/cm-' = 3271,

c;,H~o,c\ 3057. 2086. 1660. 1412, 1209. 1020, 761; 'H N M R :, N,H ' ' gL SCH, (300 M l i ~ , CDC'I,) 8 1.40 (t, 3H, J = 7, (CH2CH3), 2.33

' i . . I ... (s. 3fI. SCH3), 2.68 (t, 2H, J = 6 Hz, CH2), 2.85 (t, 2H,

C,,H ,NO?S . I - 6 Hz. CH*), 4.38 (q, 2H, J = 7 Hz, CH2CH3), 7.21

(sep. 31-1, . J = 7 Ilz, aromatic), 8.40 (d, lH, J = 7 Hz, 70

xomatic). 9. 15 (bs, I H, NH) ppm. "C NMR (75 MHz,

CDCl,) 6 14.85 (OCH2CH3), 20.14 (CH,), 20.83

( I ) . 3 I I I (SCH,), 61.07 (OGH2CH3), 11 8.74,

122.49. 126.80, 127.44, 127.60, 127.87, 128.43,

128.80. 130.92, 137.83 (aromatic), 160.85 (carbonyl)

ppm. L(IMS d z (%) = 287 (M', 94), 241 (56), 213

(43). 108 (72), 179 (LOO), 167 (32), 127 (39, 109 (18).

5.4.2 Gmrral prucrdurcifur the base catalyzed cyclizafion of P-oxoketene-N,S- acctals 62

The ketene-N.S-zlcetal 62 (10 rnmol) was dissolved in dry toluene

(15 ml.) and heated at 100-1 10 "C for 3 h with stirring. To this was added DBU

(20 mmol) in three equal intervals during this period. After the completion of

the reaction ( 1'I.C'). tolu8:ne uas evaporated under reduced pressure and the

residue was dissolved in dichloromcthane. washed with 5% HC1 (2 x 20 mL),

then with saturated hicarl-lowate ( 2 z 20 nlL! and finally with water (2 x 50mL).

'The organic layer was dricd (Na,SO,) and evaporated to get a dark brown oil

wh~ch on column chl.oniatography using hexanelethyl acetate (9:l) as eluent

afforded moderated yields of the 3-aryl pyrrole-2-carboxylates 71.

Ethyl 3-(4-ch1orophenvl)-5-fet/zylsu(fan?il)--IH-

1~vrrole-2-carboxy/ate 71a was obtained by the C I

;/ \jj cyclization of methyl 2- ([(E)-3-(4- )~..,.,

1- I!.. chloropheny1)- 1 -(ethylsulfanyl)-3-0x0- 1 - C2H5S ',N' 'C0,CH3

H propenyl]amino) acetate 62a (3. lg, 10 mmol) in

CI ,H ,~CINO~S presence of DBU (20 mmol) as white crystalline

solid. Yield 1 g (34%). mp 138-139 "C. IR

71a (KBr) v,,,lcm~' = 3297, 1673, 1447, 1262,

1002. 816, 732. 'H NMR (300 MHz, CDCI,) G

1.28 (t, 3kl, J = 7 HZ, SCt-12CH3), 2.81(q, 2H, J

= 7 Hz, SCH2CH3), 3.78 (S, 3H, OCH,), 6.39

(d. 1H. J = 3, pyrrole CH), 7.33 (d, 2H, J = 8

141. aromatic), 7.46 (d, 2H, J = 8 Hz, aromatic),

9.26 (bs, 111, NW) ppm. ',c N M R (75.47 MHz,

CIXI,) 6-15.63 (SCH2CH3),31.27 (SCH2CH,),

51.88 (CHI), 118.38, 119.71, 126.59, 128.36,

131.03, 133.39, 133.49 (aromatic), 161.06

(ester carbonyl); EI-MS m/z (%) = 297 (M+ +2,

3 5 ) 295 (M', 91), 235 (92), 206 (56), 167 (78),

I49 (67). 129 (1 00). 1 11 (42).

(;$~ '\ t<thyl 5-(ethylsulfany1)-3-phenyl-1H-pyrrole-2- L::~ >'

, < , , , carboxylate 71b was obtained by the "i..

C2HiS. ' C02C2H; ti cyclization of ethyl 2-([(E)-3phenyl-1-(ethyl

C , , H , , N O ~ S sulhnny1)-3-0x0-1-propenyl]aminoJacetate 62b

71 b (2.0g. I0 mmol) in presence of DBU (20 mmol)

as a white crystalline solid. Yield 1.2g (45%),

mp 63-64 OC. IR (KBr) v,,,,/cm-' = 3292, 1678,

1426, 1265, 1016, 822. 760. 'H NMR (300

MHz, CDC13) 6 1.28 (m, 6H, J = 7 Hz,

SCH2CH3, OCH,CH3). 2.80 (q. 2H, J = 7 HZ,

SC~HZC'II;). 4.26 (q. 2H, J = 7 11z: OCHZCH3),

h.42(d, 111, J = 3 Hz, pyrrole C:H), 7.31 (m, 3H,

J == 7.8 Hz. aromatic), 7.53 (d, 2H, J = 7 Hz,

aromatic), 9.38 (bs. 1H, NH) ppm. 13C NMR

(75.47 MHz, CDC13) 6 = 14.13 (SCH2CH3),

15.17 (OCH,CIIs), 30.85 (SCH2CH3), 60.45

0 ~ ) . 118.21, 119.61. 125.61. 127.07,

127.64, 129.42, 132.944, 134.59 (aromatic),

160.52 (ester carbonyl); EI-MS m/z (%) = 275

(M+, 92), 232 (84), 168 (52), 147 (54), 115 (19)

and 105 (100).

CI Ethyl 3-(4-~hlorophenyl)-5-(rnethylsulfanyl)- {~J /H-~7yrrrrole-2-carboxylute 71c was obtained by

i: t..co " H3CS N z i 5

the cyclization of ethyl 2-{[(E)-3-(4- H

chlorophenyl)-1-(methyl sulfany1)-3-0x0- l - C14H,4CIN0,S

propenyl]amino}acetate 62c (3. lg, 10 mmol) in

71c presence of DBU (20 mmol) as white crystalline

solid. Yield 0.94 g (32%), mp 129-130 "C. IR

(KRr) v ,,,,, lcm-' = 3275, 1672, 1493, 1259,

1087. 815, 733 'EI NMR (300 MHz, CDCI,) 6

1.30 (m, 6tl. J = 7 Hz, OCH2CH3), 2.47 (s, 3H,

S(.'HI), 4.23 (q, 2t1, J = 7 HZ, OCHZCH3), 6.33

(d. 1 H, .I - 3 Hz, pyrrole CW), 7.3 1 (d, 2H. J =

7 Hz, aromatic). 7.46 (d, 2H. J = 7 Hz,

a~.clmatic). 9.22 (bs, IH, NH) ppm. '?c NMR

(75.47 MHz, CDCI1) 6 = 14.63 (OCH2CH3),

19.85 (SCH,), 60.91 (OC312CH3), 116.05,

119.65, 128.23, 128.69, 131.13. 132.28, 133.48

(aromatic). 160.65 (carbonyl); EI-MS m/z (%)

- 297 (M', +2, 35) 295 (M*, 91). 249 (72), 221

( 1 OO), 206 (33). 187 (26). 149 (48), 136 (38).

E l 3-(4-bromopheny~-5-(ethylsuIfany~-IH- 111

. ; ~~~ ( " \\ ~~~1'0le-2-cnrboxylate 71d was obtained by the

fL>=./

$ cyclization of ethyl 2-{[(Q-3-(4-chloropheny1)-I- C2H5S ' N, 'C0,C2Hs

H (.e~~lsulfanyl)-3-oxo- 1 -propenyl]amino] acetate C,,H,,BrNO,S 62d in presence of DBU (20 mmol) as white

crysralline solid. Yield 1 g (28%), mp 110-1 1 1 "C. 71d

' H NMR (300 MHz, CDCI,) 6 1.27 (rn, 6H. J = 7

Iiz. OCH2CH3, SCH2CH,), 2.81 (q, 2H, J = 7 Hz,

SC'H2CH3), 4.26 (q, 2H, J = 7 & OCH2CH3),

6.44 (d, IH, J = 3, pyrrole CH), 7.13 (d, 2H, J = 7

flz. aromatic), 7.20 (d, 2H, J = 7 Hz, aromatic),

9.38 (bs, IkI, NH) ppm. '?c NMR (75.47 MHz,

C'DCI,) G = 14.63 (SCH2CH3), 15.60 (OCH2CH,),

3 1.29 (SCW2CH3), 6 1 .OO (OCH2CH,), 1 18.34,

120.07. 121.62, 126.40, 131.18, 131.49, 132.11,

133.98 (aromatic) and 160.70 (ester carbonyl); EI-

MS mlz ( O h ) = 355 (M', +2, 31) 353 (&, 94), 294

(75 ). ,249 ( 100). 230 (25), 181 (36), 157 (78).

Meth,'l 3-(4-methylphenyl)-5-(1riethyl.~uIfnnyl)-IH-

p,r.role-2-t.avboxyIute 71e was obtained by the

cyclisation of methyl 2-{[(I?)-3-(4-methylpheny1)-

,CH3 I -(mcthylsulfanyl)-3-0x0- 1 -propenyl]amino) :9 (,, i , ~ ,. / I acctatc 6Ze (2.8g, 10 mmol) as white crystalline

, ~-

'/ (. H3CS N ' C0,CH3

solid. Yield 0.62 g (24%), mp 120-121 OC. 'H ti

NMIR (300 MHz, CDCI,) 6 2.17 (s, 3H, ArCfi), CI4H,,NO2S 2.46, (S 3H. SCH,), 3.77 (s, 3b1. C02CH3), 6.34 (d,

71e ItI ,J=3IIz,pyrroleCH).7.17(d,2H,J=8Hz,

xornatic), 7.42 (d, 2H, J = 8 HI., aromatic), 9.09

(bs. lH, NH) ppm. El-MS d z (%) = 261 (M, 100). 229 (48), 201 (83), 186 (58), 168 (34), 115

(38) and 100 (16).

5.4.3 General procedu.re for the partial hydrolysis of alkyl 2-{[(E)-uryl-I- (rth-vl sulfnnyl)-3'-0x0-I-propeny@mino)acefare 62

'l'he ketene-N,S-acetal 62 (10 mmol) was dissolved in glacial acetic

acid(l0 ml.) and refluxed for 3h. The reaction mixture was then cooled and

poured ink) ice-cold water. I t was then extracted using chloroform and the

organic layer was washed with water, dried using sodium sulphate. Evaporation

of the solvcnt afforded an yellow liquid 72 which was further purified by

passing through a silica g,el column using hexane as eluent.

7 YO !,'tlivl i-oxo-3-phenvlpropanet/~1oate 72a was SC,H5

oblained as a mixture of keto and en01 forms

C,,H,,O,S ( i . 2 ) by the hydrolysis of ethyl 2-{[(E)-3-

phenyl- l -(ethylsulfanyl)-3-0x0-I -propenyl]arni 72a

no; acetate 62b (2g, 10 mmol) in presence of

acetic acid as yellow liquid. Yield 1.6 g (97%).

1 F1 NMK (300 MHz, CDCI,) 6 1.25 (enol forn~,

t. 1.2 t ~ I . J = 7 Hz, SCH2CH,) and 1.33 (keto

Ibrm (t, 1.8 HI J = 7 HZ, SCE12CH3), 6 2.93,

enol form (q, 0.8 H, J = 7 ppm, SCH2CH3), and

2.99. k ~ t o form (q, 1.211. J = 7 ppm,

SCHZCHI), 4.21 (s, 1.2H, keto form,

methylene), 6 6.08 (s, 0.4 H. en01 form,

methylene) 7.38-7.96 (m, 5H, aromatic). 6

13.25 (s, 0.4 H, enol OH) ppm. I3c NMR

(75.47 MHz, CDCIj) 6 15.3 1 (SCH,CH-,, keto

form). 24.42, (SCH2CH,, keto form), 54.37

(mcthylene, keto form). 13.81 (SCH2CH3, en01

Limn), 23.33 (SCH2CH, keto form), 97.65

(methylene. enol form), 6 126.77, 129.00,

129.16, 129.20, 132.00, 133.34, 134.19, 136.43

(aromatic), 6 169.1 5 (enol carbonyl carbon), 6

192.41 (ester carbonyl, keto form), 192.64,

105.47 (carbonyls, en01 form) . El-MS m/z (%)

:- 167 (M', 45) 147 (67), 129 (45 ). 121 (32),

I05 (100).

References

I [:or re\.iews see: (a) Marson. C' . M . Tetrahedron 1992, 48, 3659. (b) Jones,

( i . : Stanlhnh. 5 . P. Org. Reuc.1. 1997. -19, I . (c) Meth-Cohn, 0,; Stanforth,

S. I' in ( 'onip2p,.c,hen.si1v Orguwic Synthesis: Trost, B. M.; Fleming, I., Eds.

I'erg:~mon Press: New York lC)O0, Vol. 2, pp 777.

2 (:I) de Maheas M. I < . Bull ,SOL. ('him. Fr. 1962, 1989. (b) Minkin, V. I.;

1)oroli.enko. ( i . W . Russ. I'hctii. Rev. 1969, 29, 599.

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