An efficient synthesis of highly substituted pyrroles from β-oxodithiocarboxylates

Article abstract of DOI:10.1016/j.tet.2005.11.076

α-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinate hydrochlorides with β-oxodithiocarboxylates followed by alkylation, underwent cyclization in presence of chloromethyleneiminium salt derived from POCl₃/DMF to afford alkyl-3-a

Full text of DOI:10.1016/j.tet.2005.11.076

Tetrahedron 62 (2006) 1708–1716
An efficient synthesis of highly substituted pyrroles
from b-oxodithiocarboxylates
†
Paulson Mathew and C. V. Asokan
*
School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam 686560, India
Received 1 August 2005; revised 8 November 2005; accepted 24 November 2005
Available online 27 December 2005
Abstract—a-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinate hydrochlorides with b-oxodithiocarboxylates followed by
alkylation, underwent cyclization in presence of chloromethyleneiminium salt derived from POCl3/DMF to afford alkyl-3-aryl-4-formyl-5-
(alkylsulfanyl)-1H-pyrrole-2-carboxylates in excellent yields. Alkyl-3-aryl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates were formed in
moderate yields when the same N,S-acetals were treated with DBU.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2-carboxylates in excellent yields. The utility of this
method has been demonstrated by the formal total
synthesis of the marine natural products lukianol A and
lamellarin Q.7
Pyrroles are heterocycles of great importance because of
their presence in numerous natural products like heme,
chlorophyll, vitamin B12, and various cytochrome
enzymes.1 Some of the recently isolated pyrrole containing
marine natural products have been found to exhibit
considerable cytotoxicity and function as multi drug
resistant (MDR) reversal agents.2 Many of these biologi-
cally active compounds have emerged as chemotherapeutic
agents. In addition, polysubstituted pyrroles are molecular
frameworks having immense importance in material
science.3 The unique structural array and the unusual
biological activity displayed by many pyrrole containing
natural products have made them attractive synthetic
targets. Classical methods like Knorr reaction, Paal–
Knorr synthesis4 and Hantzsh synthesis5 are still widely
in use for the synthesis of substituted pyrroles. Since these
methods and more recent pyrrole syntheses6 that showcase
newer methodologies have limitations like functional
group compatibility and regiospecificity, newer, simple
and more convenient methods leading to highly substituted
pyrroles are still desirable. In our recent communication,
we have shown that a-oxoketene-N,S-acetals undergo
cyclization in presence of Vilsmeier–Haack reagent to
afford alkyl 3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-
b-Oxoketene-N,S-acetals are versatile building blocks
widely used for heterocyclic synthesis.8,9 In continuation
of a research program directed towards the total synthesis of
some pyrrole containing natural products like lamellarins10
and the cholesterol lowering drug atorvastatin (Fig. 1),11 we
needed to develop an efficient method for the preparation of
highly functionalized pyrroles.
Figure 1.
Keywords: Pyrroles; Dithiocarboxylates; Ketene-N,S-acetals; Vilsmeier–
Haack reagent.
We envisioned that appropriately substituted ketene-N,S-
acetals, prepared by the reaction of dithiocarboxylates with
alkyl glycinate followed by alkylation, could be transformed
into the corresponding pyrrole derivatives. Herein we
*
Corresponding author. Tel.: C91 481 2730751; fax: C91 481 2731009;
e-mail: asokancv@yahoo.com
† Present address: Department of Chemistry, St. Thomas’ College, Thrissur
680001, Kerala, India.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.076

P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
1709
Scheme 1.
present a facile and high yielding regioselective method for
synthesizing 2,3,4,5-tetra and 2,3,5-tri substituted pyrroles
from readily available inexpensive starting materials by a
simple sequence of reactions. The key step in this method is
the iminium salt or base catalyzed cyclization of a-oxo-
ketene-N,S-acetals 4.
DMF, they underwent iminoalkylation followed by
intramolecular cyclization to afford substituted pyrroles
5 (Scheme 2). Interestingly the carbonyl group of the
aroyl group rather than the iminium moiety was involved
in the cyclization. Attempts to cyclize the N,S-acetal in
presence of POCl3 in THF or in the presence of other
Lewis acid catalysts did not afford any cyclization
product. When cyclization of the ketene N,S-acetals 4
was attempted by refluxing it in glacial acetic acid, partial
2. Results and discussion
Dithiocarboxylates 1, prepared12 by the condensation of
enolates of active methylene ketones with dialkyl
trithiocarbonates, are valuable multifunctional synthetic
intermediates.13,14 They are also used as precursors for
a-oxoketene dithioacetals, a-oxoketene-N,S-acetals and
a-oxoketene-O,S-acetals.15 Reaction of enolizable carbon-
yl compounds with dialkyl trithiocarbonates in DMF using
sodium hydride as base afforded b-oxodithiocarboxylates
1 in excellent yields within 1 h at room temperature.
Treatment of the dithiocarboxylates 1 with ethyl glycinate
in absolute alcohol in presence of triethyl amine at room
temperature gave the thioamide 3 in nearly quatitative
1
yields. The H NMR spectrum of thioamide 3 in CDCl3
shows two sets of peaks corresponding to the keto and
enol forms. The thioamides 3 underwent facile alkylation
in presence of potassium carbonate using alkyl iodide in
acetone to give the N,S-acetal 4 in good yield. (Scheme
1). The ketene-N,S-acetals 4 thus generated were unstable
in strongly basic medium and intractable mixture of
products were formed during their attempted base
catalyzed cyclization. However, in the presence of
Vilsmeier–Haack reagent,16 prepared from POCl3 and
Scheme 2.

1710
P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
Scheme 3.
hydrolysis takes place leading to the formation of
corresponding b-oxothiolesters.
underwent cyclization under Vilsmeier–Haack conditions to
afford the annulated pyrrole 13 in 78% yield after heating at
80 8C for 7 h (Scheme 3).
Cyclization of the ketene N,S-acetals 4 was also examined
under non nucleophilic bases. When 4 was heated in toluene
in presence of DBU at 100–110 8C trisubstituted pyrroles 14
was formed in moderate yields (Scheme 4). The yield of 14
could be increased by adding DBU in three portions in equal
intervals. The structure of 14 was confirmed on the basis of
1
spectral and analytical data. In H NMR, the single proton
on the pyrrole ring appeared as a doublet at d 6.39 (JZ
3 Hz) ppm due to long range coupling with NH proton.
Annulated pyrrole 13 was also formed in 56% yield when
the N,S-acetal 12 derived from tetralone was heated in the
presence of DBU for 8 h.
–
The formation of pyrrole carbaldehydes 5 can be rational-
ized as follows. Sequential iminoalkylations of the ketene-
N,S-acetal moiety and the enaminoketone functionality
leads to the intermediate 6 and 7, respectively. The
chlorovinyl iminium salt 8 can be obtained by the
displacement of N,N-dimethyl formamide by chloride ion
from 7. Cyclization of 8, involving the imino acetate group
and the chlorovinyl iminium moiety, leads to the formation
of iminium salt 9, which affords the pyrrole 5 on hydrolysis.
The electron withdrawing nature of iminium salt moiety in 6
serve to increase the overall yields as it facilitates the
cyclization. Vilsmeier–Haack reactions of b-oxodithiocar-
boxylates are known to afford b-chloro, b-methylthio a,b-
unsaturated ketones.17 Our efforts to synthesize pyrroles
directly from thioamide 3 under Vilsmeier condition
afforded complex product mixtures containing N,N-
dimethylamino substituted pyrroles. Functionalized
ketene-N,S-acetal 12 derived from cyclic carbonyl com-
pounds like a-tetralone, which cannot iminoalkylate also
Scheme 4.
In summary, we have developed straightforward and simple
methods for the regiocontrolled formation of tetra and tri-
substitued pyrroles starting from readily available and
inexpensive dithioesters and glycine esters. The substitution
pattern can be selectively tuned by the use of appropriately
functionalized ketene-N,S-acetals. As an illustrative
example, we have extended the scope of the cyclization
procedure for the synthesis of a benzannulated isoindole
ring system. The removable alkyl sulphanyl group present

P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
1711
on the pyrrole ring can extend the scope of this method for
the synthesis of indoles, thienopyrroles, pyrridinopyrroles
as well as isoquoline annulated pyrroles found in various
natural products.
6.05 (s, 0.4H, vinylic, enol form), d 7.39 (d, 0.4H, JZ8 Hz,
aromatic), d 7.47 (d, 1H, JZ8 Hz, aromaticC0.4H, NH,
enol form), d 7.72 (d, 0.4H, JZ8 Hz, aromatic), 7.98 (d,
0.6H, JZ8 Hz, aromatic), 9.50 (br s, 0.6H, NH, keto form)
14.36 (s, 0.4H, OH, enol form). 13C NMR (75.47 MHz,
CDCl3)18 dZ14.5, 48.1, 53.1, 62.5, 127.7, 129.6, 130.6,
141.2, 168.8, 192.1, 194.9. EIMS m/z (%) 301 (MCC2, 7),
299 (MC, 18), 266 (12), 181 (17), 139 (100), 111 (54). Anal.
Calcd for C13H14ClNO3S: C, 52.09; H, 4.71; N, 4.67.
Found: C, 52.15; H, 4.64; N, 4.71.
3. Experimental
3.1. General
Melting points are uncorrected and were obtained on a
Buchi-530 melting point apparatus. Infrared spectra were
recorded on Shimadzu JASCO FT/IR-5300 or ABB Bomem
104 spectrometer. Proton NMR spectra were recorded on a
Bruker DRX-300 (300 MHz) spectrometer in CDCl3.
Chemical shifts are expressed in parts per million downfield
from internal tetramethyl silane. Coupling constants J are
given in Hertz. Mass spectra (EIMS) were obtained on a
Finngen-Mat 312 instrument. Elemental analyses were
recorded on an elementar vario EL III analyzer.
3.3.2. Ethyl 2-{[3-(4-methylphenyl)-3-oxopropanthioyl]-
amino}acetate (3b). Obtained as pale yellow needles by the
reaction of methyl 3-(4-methylphenyl)-3-oxopropane-
dithioate (2.24 g, 10 mmol) with glycine ethylester hydro-
chloride in ethanol. Yield 2.60 g (96%), mp 120–121 8C. IR
1
(KBr) nmaxZ3316, 1751, 1668, 1535, 1218, 815 cmK1. H
NMR (300 MHz, CDCl3), keto/enolZ7:3; d 1.31 (t, 3H, JZ
7 Hz, CH2CH3), 2.42 (s, 3H, CH3), 4.28 (q, 2H, JZ7 Hz,
CH2CH3), 4.41 (d, 0.6H, JZ4 Hz, NCH2, enol form), 4.44
(d, 1.4H, JZ4 Hz, NCH2, keto form), 4.51 (s, 1.4H,
methylene, keto form), 6.08 (s, 0.3H, vinylic, enol form),
7.22 (d, 0.6H, JZ8 Hz, aromatic) 7.28 (d, 1.4H, JZ8 Hz,
aromatic), 7.68 (d, 0.6H, JZ8 Hz, aromatic) 7.93 (d, 1.4H,
JZ8 Hz, aromaticC0.3H, NH, enol form), 9.81 (br s, 0.7H,
NH, keto form), 14.36 (s, 0.3H, OH, enol form). 13C NMR
(75.47 MHz, CDCl3) dZ14.5, 22.1, 48.1, 52.5, 62.5, 126.4,
129.2, 133.7, 145.8, 168.8, 192.3, 196.0. EIMS m/z (%) 279
(MC, 22), 246 (15), 177 (12), 148 (13), 119 (100), 91 (54).
Anal. Calcd for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01.
Found: C, 60.07; H, 6.18; N, 5.12.
3.2. General procedure for the synthesis of dithio
esters (1)
Sodium hydride (50% suspension in mineral oil, 0.96 g,
20 mmol) was washed with anhydrous petroleum ether and
suspended in ice cooled anhydrous DMF (10 ml). To this
was added the appropriate ketone (10 mmol) and stirred for
1 h, allowing the mixture to attain room temperature during
this period. The reaction mixture was then poured over
crushed ice (100 g) and extracted with diethyl ether (3!
50 mL). The organic layer was washed with water and dried
using anhydrous Na2SO4. The solvent was removed in
vacuum and the crude product was purified by passing
through a short column of silica gel using hexane. The
dithioesters prepared were characterized by comparing the
spectral and physical data with reported values.12
3.3.3. Ethyl 2-[(3-oxo-3-phenylpropanthioyl)amino]-
acetate (3c). Obtained as pale yellow needles by the reaction
of methyl 3-oxo-3-phenylpropanedithioate (2.1 g, 10 mmol)
with glycine ethylester hydrochloride in ethanol. Yield 2.5 g
(97%), mp82–83 8C. IR(KBr) nmaxZ3292, 1724, 1609, 1538,
1
1208, 755 cmK1. H NMR (300 MHz, CDCl3), keto/enolZ
3.3. General procedure for the synthesis of b-oxothio
amides (3a–h)
7:3; d 1.33 (t, 3H, JZ7 Hz, CH2CH3), 4.28 (q, 2H, JZ7 Hz,
CH2CH3), 4.41 (d, 0.6H, JZ4 Hz, NCH2, enol form), 4.45 (d,
1.4H, JZ4 Hz, NCH2, keto form), 4.54 (s, 1.4H, methylene,
keto form), 6.10 (s, 0.3H, vinylic, enol form), 7.36–8.04 (m,
5.6H, aromaticC0.3NH enolform), 9.66(br s, 0.7H, NH, keto
form), 14.35 (s, 0.3H, OH, enol form). 13C NMR (75.47 MHz,
CDCl3) dZ14.0, 47.7, 52.4, 61.9, 126.4, 128.8, 134.2, 135.7,
168.4, 192.3, 195.8. EIMS m/z (%) 265 (MC, 97), 232 (51),
163(11), 121(35), 105(100). Anal.Calcdfor C13H15NO3S: C,
58.85; H, 5.70; N, 5.28. Found: C, 58.76; H, 5.61; N, 5.42.
Triethylamine (20 mmol) was added to a mixture of
b-oxodithioester 1 (10 mmol) and glycine ester hydro-
chloride 2 (10 mmol) in appropriate dry alcohol (20 mL) at
room temperature. After stirring for 4 h at room temperature
the reaction mixture was poured into 100 mL of ice cold
water. The reaction mixture was extracted with chloroform
(3!50 mL), washed with water (2!25 mL), dried
(Na2SO4) and evaporated to afford the crude product 3,
which were purified by recrystalizing from hexane–ethyl
acetate (7/3).
3.3.4. Ethyl 2-{[3-(4-bromophenyl)-3-oxopropanthioyl]-
amino}acetate (3d). Obtained as pale yellow needles by the
reaction of methyl 3-(4-chlorophenyl)-3-oxopropanedithio-
ate (2.80 g, 10 mmol) with glycine ethylester hydrochloride
in ethanol. Yield 3.30 g (98%), mp 88–90 8C. IR (KBr)
3.3.1. Ethyl 2-{[3-(4-chlorophenyl)-3-oxopropanthioyl]-
amino}acetate (3a). Obtained as pale yellow needles by the
reaction of methyl 3-(4-chlorophenyl)-3-oxopro-
panedithioate (2.45 g, 10 mmol) with glycine ethylester
hydrochloride (10 mmol) in ethanol. Yield 2.90 g (97%),
mp 87–88 8C. IR (KBr) nma1xZ3291, 1727, 1611, 1537,
1210, 1094, 818, 770 cmK1. H NMR (300 MHz, CDCl3),
keto/enolZ3:2; d 1.32 ppm (t, 3H, JZ7 Hz, OCH2CH3),
4.28 (m, 2H, OCH2CH3, keto and enol forms), d 4.40 (d,
0.8H, JZ4 Hz, NCH2, enol form), d 4.42 (d, 1.2H, JZ4 Hz,
NCH2, keto form), d 4.50 (s, 1.2H, methylene, keto form),
1
nmaxZ3293, 1716, 1609, 1537, 1208, 766 cmK1. H NMR
(300 MHz, CDCl3), keto/enolZ3:2; d 1.32 ppm (t, 3H, JZ
7 Hz, OCH2CH3), 4.28 (m, 2H, OCH2CH3, keto and enol
forms), d 4.40 (d, 0.8H, JZ4 Hz, NCH2, enol form), d 4.43
(d, 1.2H, JZ4 Hz, NCH2, keto form), d 4.49 (s, 1.2H,
methylene, keto form), 6.05 (s, 0.4H, vinylic, enol form), d
7.37 (br s, 0.6H, NH, keto form), d 7.54 (d, 0.6H, JZ8 Hz,
aromatic), d 7.64 (d, 2.8H, JZ8 Hz, aromatic), d 7.91 (d,
0.6H, JZ8 Hz, aromatic), 9.49 (br s, 0.4H, NH, enol form),

1712
P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
14.35 (s, 0.4H, OH, enol form). 13C NMR (75.47 MHz,
CDCl3) dZ14.5, 48.1, 52.9, 62.5, 127.9, 130.6, 132.6,
134.4, 168.6, 192.1, 195.2. EIMS m/z (%) 345 (MCC2, 22),
343 (MC, 22), 312 (16), 243 (8), 183 (100), 155 (52) and
102 (12). Anal. Calcd for C13H14BrNO3S: C, 45.36; H, 4.10;
N, 4.07. Found: C, 45.44; H, 4.02; N, 4.21.
(MCC2, 5), 285 (MC, 16), 224 (18), 141 (24), 139 (100) and
111 (64). Anal. Calcd for C12H12ClNO3S: C, 50.44; H, 4.23;
N, 4.90. Found: C, 50.33; H, 4.34; N, 4.84.
3.3.8. Ethyl 2-{[3-(4-methoxyphenyl)-3-oxopropanthioyl]-
amino}acetate (3h). Obtained as pale yellow needles by the
reaction of ethyl 3-(4-methoxyphenyl)-3-oxopropane dithio-
ate (2.4 g, 10 mmol) with glycine ethyl ester hydrochloride in
3.3.5. Methyl 2-[(3-oxo-3-phenylpropanthioyl)amino]-
acetate (3e). Obtained as pale yellow needles by the
reaction of ethyl 3-oxo-3-phenylpropanedithioate (2.10 g,
10 mmol) with glycine methyl ester hydrochloride in
methanol. Yield 2.40 g (96%), mp 90–92 8C. IR (KBr)
ethanol. Yield 2.8 g (95%), mp 84–86 8C. IR (KBr) nmax
.
Z
3304, 1722, 1608, 1537, 1209, 771 cmK1 1H NMR
(300 MHz, CDCl3), keto form only d 1.31 (t, 3H, JZ6 Hz,
OCH2CH3), 3.88 (s, 3H, ArOCH3), 4.27 (q, 2H, JZ6 Hz,
CH2CH3), 4.44 (d, 2H, JZ4 Hz, NCH2), 4.48 (s, 2H,
methylene), 6.94 (d, 2H, JZ9 Hz, aromatic), 8.02 (d, 2H,
JZ9 Hz, aromatic), 9.81 (br s, 1H, NH). 13C NMR
(75.47 MHz, CDCl3) dZ14.5, 48.1, 52.4, 55.9, 62.2, 114.4,
129.1, 131.6, 164.8, 168.8, 194.7, 196.2. EIMS m/z (%) 295
(MC, 34), 262 (15), 135 (100) and 121 (24). Anal. Calcd for
C14H17ClNO4S: C, 56.93; H, 5.80; N, 4.74. Found: C, 56.84;
H, 5.89; N, 4.85.
1
nmaxZ3301, 1726, 1609, 1537, 1211, 747 cmK1. H NMR
(300 MHz, CDCl3), keto/enolZ7:3; d 3.82 (s, 2.1H, OCH3
keto form), 3.84 (s, 0.9H, OCH3, enol form), 4.44 (d, 0.6H,
JZ3 Hz, NCH2 enol form), 4.48 (d, 1.4H, JZ3 Hz, NCH2
keto form), 4.55 (s, 1.4H, methylene, keto form), 6.09 (s,
0.3H, vinylic, enol form), 7.42–7.80 (m, 4.4H, aromaticC
NH 0.3, keto form), 8.79 (d, 0.9H, JZ8 Hz, aromatic), 9.72
(br s, 0.7H, NH, enol form), 14.35 (s, 0.3H, OH, enol form).
13C NMR (75.47 MHz, CDCl3) dZ45.4, 47.9, 52.8, 126.4,
129.2, 131.4, 136.2, 169.3, 192.3, 196.4. EIMS m/z (%) 251
(MC, 26), 236 (12), 187 (18), 149 (13), 105 (100) and 97
(44). Anal. Calcd for C12H13NO3S: C, 57.35; H, 5.21; N,
5.57. Found: C, 57.46; H, 5.12; N, 5.68.
3.3.9. Ethyl 2-{[(1-oxo-1,2,3,4-tetrahydro-2-naphtha-
lenyl)carbothioyl]amino}acetate (11). Obtained as white
needles by the reaction of methyl 1-oxo-1,2,3,4-tetrahydro-
2-naphthalene-carbodithioate (2.3 g, 10 mmol) with glycine
ethyl ester hydrochloride in ethanol. Yield 2.7 g (95%), mp
62–64 8C. IR (KBr) nm1axZ3499, 3207, 1738, 1680, 1548,
1224, 785, 734 cmK1. H NMR (300 MHz, CDCl3), keto/
enolZ4:1; d 1.29 (m, 3H, OCH2CH3, keto and enol forms),
2.68 (m, 2H, CH2CH2, keto and enol forms) 2.89 (m, 0.4H,
CH2CH2, enol form), 3.05 (m, 0.8H, CH2CH2, keto form),
3.17 (m, 0.8H, CH2CH2, keto form), 3.76 (t, 0.8H, JZ7 Hz,
CH, keto form), 4.43 (m, 4H, OCH2CH3 and NCH2, keto
and enol forms), 6.16 (d, 0.2H, JZ8 Hz, aromatic, enol
form), 7.23–8.02 (m, 2.8H, aromatic, keto and enol forms),
7.90 (d, 0.2H, JZ8 Hz, aromatic, enol form), 8.01 (d, 0.8H,
JZ8 Hz, aromatic, keto form), 9.27 (br s, 1H, NH), 14.76 (s,
0.2H, OH, enol). 13C NMR (75.47 MHz, CDCl3) dZ14.5,
28.7, 30.1, 48.1, 59.6, 62.4, 127.2, 128.3, 129.1, 132.2,
134.6, 144.7, 169.1, 196.3, 200.6. EIMS m/z (%) 291 (MC,
64), 273 (18), 240 (17), 187 (24), 145 (100), 128 (54), 115
(84) and 115 (34). Anal. Calcd for C15H17NO3S: C, 61.83;
H, 5.88; N, 4.81. Found: C, 61.95; H, 5.74; N, 4.89.
3.3.6. Methyl 2-{[3-(4-methylphenyl)-3-oxopropanthioyl]-
amino}acetate (3f). Obtained as pale yellow needles by the
reaction of methyl 3-(4-methylphenyl)3-oxopropanedithioate
(2.24 g, 10 mmol) with glycine methyl ester hydrochloride
in methanol. Yield 2.5 g (95%), mp 110–111 8C. IR
1
(KBr) nmaxZ3314, 1726, 1611, 1211, 764 cmK1. H NMR
(300 MHz, CDCl3), keto/enolZ3:1; d 2.39 (s, 0.75H, ArCH3,
enol form), 2.42 (s, 2.25H, ArCH3, keto form), 3.82 (s, 3H,
OCH3), 4.43 (d, 0.5H, JZ4 Hz, NCH2, enol form), 4.45 (d,
1.5H, JZ4 Hz, NCH2, keto form), 4.52 (s, 1.5H, methylene,
keto form), 6.10 (s, 0.25H, methyne, enol form), 7.22 (d,
0.5H, JZ8 Hz, aromatic), 7.34 (d, 1.5H, JZ8 Hz, aromatic),
7.68 (d, 0.5H, JZ8 Hz, aromatic), 7.93 (1.5H, JZ8 Hz,
aromatic), 7.35 (br s, 0.75H, NH, keto form), 9.79 (br s,
0.25H, NH, enol form), 14.33 (s, 0.25H, OH enol form). 13C
NMR (75.47 MHz, CDCl3) dZ21.1, 45.5, 47.9, 52.4, 129.2,
130.0, 133.7, 145.8, 169.2, 189.3, 196.0. EIMS m/z (%) 265
(MC, 44), 232 (18), 204 (17), 177 (14), 144 (15), 119 (100)
and (105). Anal. Calcd for C13H15NO3S: C, 58.85; H, 5.70; N,
5.28. Found: C, 58.94; H, 5.62; N, 5.19.
3.4. General procedure for the synthesis of alkyl 2-{[(E)-
3-aryl-1-(alkylsulfanyl)-3-oxo-1-propenyl]amino}acetate
(4)
3.3.7. Methyl 2-{[3-(4-chlorophenyl)-3-oxopropanthioyl]-
amino}acetate (3g). Obtained as pale yellow needles by the
reaction of methyl 3-(4-chlorophenyl)-3-oxopropanedithioate
(2.45 g, 10 mmol) with glycine methyl ester hydrochloride
in methanol. Yield 2.7 g (97%), mp 80–81 8C. IR (KBr)
A suspension of the thioamide 3 (10 mmol) and anhydrous
K2CO3 (3 g, 20 mmol) in dry acetone (30 ml) was refluxed
with stirring for 30 min. The mixture was cooled and alkyl
iodide (20 mmol) was added and again stirred at room
temperature for 3 h. When the reaction was completed
(TLC), the mixture was poured into ice-cold water (100 mL)
and extracted using dichloromethane (2!50 mL). The
organic layer was washed with water (2!100 mL) and
dried using anhydrous Na2SO4. Evaporation of the solvent
afforded a yellow glass, which solidifies on standing.
Recrystallisation of the crude product from hexane–ethyl
acetate (7/3) afforded title compound 4 in 88–95% yields.
1
nmaxZ3340, 1736, 1611, 1513, 1204, 768 cmK1. H NMR
(300 MHz, CDCl3), keto/enolZ3:2; d 3.80 (s, 1.8H, OCH3,
keto form), 3.81 (s, 1.2H, OCH3, enol form), 4.42 (d, 0.8H,
JZ4.8 Hz, NCH2, enol form), 4.45 (d, 1.2H, JZ4 Hz, NCH2,
keto form), 4.50 (s, 1.2H, methylene, keto form), 6.09 (s,
0.4H, methyne, enol form), 7.36 (d, 0.8H, JZ8 Hz, aromatic)
7.44 (d, 1.2H, JZ8 Hz, aromatic), 7.68 (d, 0.8H, JZ8.7 Hz,
aromatic), 7.95 (d, 1.2H, JZ8 Hz, aromatic), 9.51 (br s, 0.6H,
NH, enol form), 14.31 (s, 0.4H, enol, OH). 13C NMR
(75.47 MHz, CDCl3) dZ45.7, 47.9, 53.1, 127.7, 129.6,
137.4, 141.3, 169.35, 192.2, 195.0. EIMS m/z (%) 287
3.4.1. Ethyl 2-{[(E)-3-(4-chlorophenyl)-1-(methyl-
sulfanyl)-3-oxo-1-propenyl]amino}acetate (4a). Obtained

P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
1713
as yellow prisms by the methylation of ethyl 2-{[(3-
4-chlorophenyl)-3-oxopropanthioyl]amino}acetate 3a
(2.60 g, 10 mmol) using methyl iodide. Yield 2.90 g
(95%), mp 96–98 8C. IR (KBr) nmaxZ3072, 1744, 1559,
1533, 1470, 1203, 760 cmK1. 1H NMR (300 MHz, CDCl3)
d 1.30 (t, 3H, JZ7 Hz, CH2CH3), 2.49 (s, 3H, SCH3), 4.17
(d, 2H, JZ5 Hz, NCH2), 4.27 (q, 2H, JZ7 Hz, CH2CH3),
5.68 (s, 1H, vinylic), 7.37 (d, 2H, JZ8 Hz, aromatic), 7.80
(d, 2H, JZ8 Hz, aromatic), 11.99 (br s, 1H, NH). 13C NMR
(75.47 MHz, CDCl3) dZ14.5, 14.9, 45.8, 62.2, 87.8, 128.2,
128.8, 137.1, 139.1, 168.8, 169.5, 184.9. EIMS m/z (%) 315
(MCC2), 313 (MC, 23), 266 (36), 238 (25), 181 (24), 139
(100), 111 (43). Anal. Calcd for C14H16ClNO3S: C, 53.58;
H, 5.14; N, 4.46. Found: C, 53.74; H, 5.03; N, 4.32.
Anal. Calcd for C15H18BrNO3S: C, 48.39; H, 4.87; N, 3.76.
Found: C, 48.22; H, 5.97; N, 3.96.
3.4.5. Methyl 2-{[(E)-1-(ethylsulfanyl)-3-oxo-3-phenyl-1-
propenyl]amino}acetate (4e). Obtained as yellow prisms by
the ethylation of methyl 2-[(3-oxo-3-phenylpropanthioyl)-
amino]acetate 3e (2.50 g, 10 mmol) using ethyl iodide as
1
a yellow glass. Yield 2.40 g (91%). H NMR (300 MHz,
CDCl3) d 1.41 (t, 3H, JZ7 Hz, SCH2CH3), 3.80 (s, 3H,
OCH3), 3.01 (q, 2H, JZ7 Hz, SCH2CH3), 4.20 (d, 2H, JZ
3 Hz, NCH2), 5.79 (s, 3H, vinylic), 7.37–7.44 (m, 3H,
aromatic), 7.83–7.88 (m, 2H, aromatic), 12.09 (br s, 1H,
NH). 13C NMR (75.47 MHz, CDCl3) dZ14.8, 15.3, 46.0,
54.3, 88.6, 126.7, 129.2, 130.5, 136.3, 169.1, 171.4, 185.9.
EIMS m/z (%) 279 (MC, 22), 251 (17), 218 (23), 190 (28), 158
(14) and 105 (100). Anal. Calcd for C14H17NO3S: C, 60.19; H,
6.13; N, 5.01. Found: C, 60.05; H, 6.23; N, 5.15.
3.4.2. Ethyl 2-{[(E)-3-(4-methylphenyl)-1-(methyl-
sulfanyl)-3-oxo-1-propenyl]amino}acetate (4b). Obtained
as yellow prisms by the methylation of ethyl 2-{[(3-4-
methylphenyl)-3-oxopropanthioyl]amino}acetate 3b (2.70 g,
10 mmol) using methyl iodide. Yield 2.70 g (92%), mp
110–111 8C. IR (KBr) nmaxZ2994, 1744, 1588, 1544, 1210,
3.4.6. Methyl 2-{[(E)-3-(4-methylphenyl)-1-(ethyl-
sulfanyl)-3-oxo-1-propenyl]amino}acetate (4f). Obtained
as yellow prisms by the ethylation of methyl 2-{[(3-4-
methylphenyl)-3-oxopropanthioyl]amino}acetate 3f (2.60 g,
10 mmol) using ethyl iodide. Yield 2.70 g (92%), mp 90–
91 8C. IR (KBr) nmaxZ2932, 1742, 1589, 1555, 1243,
1
760 cmK1. H NMR (300 MHz, CDCl3) d 1.29 (t, 3H, JZ
7 Hz, CH2CH3), 2.37 (s, 3H, ArCH3), 2.42 (s, 3H, SCH3), 4.15
(d, 2H, JZ5 Hz, NCH2), 4.25 (q, 2H, JZ7 Hz, OCH2CH3),
5.72 (s, 1H, vinylic), 7.2 (d, 2H, JZ8 Hz, aromatic), 7.78 (d,
2H, JZ8 Hz, aromatic), 11.96 (br s, 1H, NH). 13C NMR
(75.4 MHz, CDCl3) dZ14.5, 14.9, 21.8, 45.8, 62.1, 88.0,
127.5, 129.3, 138.0, 141.4, 168.7, 168.9, 186.3. EIMS m/z (%)
293 (MC, 27), 246 (37), 218 (15), 172 (19), 161 (14), 119
(100) and 91 (52). Anal. Calcd for C15H19NO3S: C, 61.41; H,
6.53; N, 4.77. Found: C, 61.28; H, 6.65; N, 4.62.
1
759 cmK1. H NMR (300 MHz, CDCl3) d 1.41 (t, 3H, JZ
7 Hz, SCH2CH3), 2.38 (s, 3H, ArCH3), 3.79 (s, 3H, OCH3),
3.00 (q, 2H, JZ7 Hz, SCH2CH3), 4.20 (d, 2H, JZ3 Hz,
NCH2), 5.79 (s, 3H, vinylic), 7.20 (d, 2H, JZ8 Hz, aromatic),
7.76 (d, 2H, JZ8 Hz, aromatic), 11.99 (br s, 1H, NH). 13C
NMR (75.47 MHz, CDCl3) dZ13.4, 21.3, 26.1, 45.2, 52.5,
88.5, 127.0, 128.8, 137.5, 140.9, 167.3, 169.0, 185.9. EIMS m/
z (%) 293 (MC, 27), 265 (15), 232 (39), 172 (8), 119 (100) and
105 (12). Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N,
4.77. Found: C, 61.28; H, 6.45; N, 4.92.
3.4.3. Ethyl 2-{[(E)-1-(methylsulfanyl)-3-oxo-3-phenyl-1-
propenyl]amino}acetate (4c). Obtained as yellow prisms by
the methylation of ethyl 2-[(3-oxo-3-phenylpropanthioyl)-
amino]acetate 3c (2.7 g, 10 mmol) using methyl iodide. Yield
2.6 g (93%), mp 90–92 8C. IR (KBr) nmaxZ3074, 1745,
15568, 1523, 1205, 727 cmK1. 1H NMR (300 MHz, CDCl3) d
1.31 (t, 3H, JZ7 Hz, OCH2CH3), 2.48 (s, 3H, SCH3), 4.17 (d,
2H, JZ5 Hz, NCH2), 4.27 (q, 2H, JZ7 Hz, OCH2CH3), 5.73
(s, 1H, vinylic), 7.36–7.45 (m, 3H, aromatic), 7.85–7.89 (dd,
2H, aromatic), 11.98 (br s, NH). 13C NMR (75.47 MHz,
CDCl3) dZ14.5, 14.9, 45.8, 62.1, 88.2, 127.8, 128.6, 131.1,
140.7, 168.9, 169.1, 186.4. EIMS m/z (%) 279 (MC, 17), 232
(35), 204 (15), 176 (8), 147 (24)and 105 (100). Anal. Calcd for
C14H17NO3S: C, 60.19; H, 6.13; N, 5.01. Found: C, 60.07; H,
6.26; N, 4.87.
3.4.7. Methyl 2-{[(E)-3-(4-chlorophenyl)-1-(ethyl-
sulfanyl)-3-oxo-1-propenyl]amino}acetate (4g). Obtained
yellow prisms by the ethylation of methyl 2-{[(3-4-chlor-
ophenyl)-3-oxopropanthioyl]amino}acetate 3g (2.80 g,
10 mmol) using ethyl iodide. Yield 3 g (94%), mp 94–95 8C.
1
nmaxZ3063, 2965, 1744, 1575, 1285, 755 cmK1. H NMR
(300 MHz, CDCl3) d 1.42 (t, 3H, JZ7 Hz, SCH2CH3), 3.02
(q, 2H, JZ7 Hz, SCH2CH3), 3.80 (s, 3H, OCH3), 4.20 (d, 2H,
JZ3 Hz, NCH2), 5.79 (s, 3H, vinylic), 7.20 (d, 2H, JZ8 Hz,
aromatic), 7.76 (d, 2H, JZ8 Hz, aromatic), 12.02 (br s, 1H,
NH). 13C NMR (75.47 MHz, CDCl3) dZ13.8, 26.5, 45.7,
52.0, 88.6, 128.3, 128.8, 137.1, 139.0, 168.6, 169.3, 184.9.
EIMS m/z (%) 315 (MCC2, 9), 313 (MC, 28) 285 (14), 252
(32), 224 (30), 192 (7), 139 (100) and 115 (42). Anal. Calcd for
C14H16ClNO3S: C, 53.58; H, 5.14; N, 4.46. Found: C, 53.45;
H, 5.25; N, 4.34.
3.4.4. Ethyl 2-{[(E)-3-(4-bromophenyl)-1-(ethylsulfanyl)-
3-oxo-1-propenyl]amino}acetate (4d). Obtained as yellow
prisms by the ethylation of ethyl 2-{[(3-4-bromophenyl)-3-
oxopropanthioyl]amino}acetate 3d (3.40 g, 10 mmol) using
ethyl iodide. Yield 3.50 g (95%), mp 97–98 8C. IR (KBr)
3.4.8. Ethyl 2-{[(E)-1-(ethylsulfanyl)-3-(4-methoxy-
phenyl)-3-oxo-1-propenyl]amino}acetate (4h). Obtained
as yellow prisms by the ethylation of ethyl 2-{[3-(4-
methoxyphenyl)-3-oxopropanthioyl]amino}acetate 3h
(2.90 g, 10 mmol) using ethyl iodide. Yield 2.8 g (88%),
mp 105–106 8C. IR (KBr) nmaxZ3085, 1748, 1521, 1466,
1245, 770 cmK1. 1H NMR (300 MHz, CDCl3) d 1.28 (t, 3H,
JZ7 Hz, SCH2CH3), 1.41 (t, 3H, JZ7 Hz, OCH2CH3), 3.01
(q, 2H, JZ7 Hz, SCH2CH3), 3.84 (s, 3H, ArOCH3), 4.17 (d,
2H, JZ3 Hz, NCH2) 4.27 (q, 2H, JZ7 Hz, OCH2CH3),
5.77 (s, 1H, vinylic), 6.90 (d, 2H, JZ8 Hz, aromatic), 7.85
1
nmaxZ3093, 1750, 1587, 1526, 1210, 759 cmK1. H NMR
(300 MHz, CDCl3) d 1.31 (t, 3H, JZ7 Hz, SCH2CH3), 1.42 (t,
3H, JZ7 Hz, OCH2CH3), 3.02 (q, 2H, JZ7 Hz, SCH2CH3),
4.17 (d, 2H, JZ3 Hz, NCH2) 4.27 (q, 2H, JZ7 Hz,
OCH2CH3), 5.73 (s, 1H, vinylic), 7.53 (d, 2H, JZ8 Hz,
aromatic), 7.72 (d, 2H, JZ8 Hz, aromatic), 11.99 (br s, 1H,
–NH). 13C NMR (75.47 MHz, CDCl3) dZ13.9, 14.5, 26.5,
45.8, 62.1, 88.5, 125.5, 129.0, 131.7, 139.6, 168.7, 168.8,
184.9. EIMS m/z (%) 373 (MCC2, 18), 371 (MC, 17), 345
(15), 310 (19), 282 (14), 183 (100), 157 (42) and 102 (11).

1714
P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
(d, 2H, JZ8 Hz, aromatic), 11.92 (br s, 1H, –NH). 13C
NMR (75.47 MHz, CDCl3) dZ13.9, 14.5, 26.5, 45.8, 55.6,
62.0, 88.6, 113.7, 129.2, 133.3, 162.1, 167.3, 169.1, 185.6.
EIMS m/z (%) 323 (MC, 17), 262 (25), 234 (9), 188 (18),
135 (100) and 121 (22). Anal. Calcd for C16H21NO4S: C,
59.42; H, 6.54; N, 4.33. Found: C, 59.57; H, 6.39; N, 4.43.
3.5.2. Ethyl 4-formyl-3-(4-methylphenyl)-5-(methyl-
sulfanyl)-1H-pyrrole-2-carboxylate (5b). Obtained by
the Vilsmeier reaction of ethyl 2-{[(E)-3-(4-methylphe-
nyl)-1-(methylsulfanyl)-3-oxo-1-propenyl]amino}acetate
4b (2.93 g, 10 mmol) as colorless plates. Yield 2.60 g
(87%), mp 108–109 8C. IR (KBr) nmaxZ3378, 1670, 1640,
1
1233, 1162, 1020, 799, 776 cmK1. H NMR (300 MHz,
CDCl3) d 1.15 (t, 3H, JZ7 Hz, OCH2CH3), 2.40 (s, 3H,
ArCH3), 2.61 (s, 3H, SCH3), 4.19 (q, 2H, JZ7 Hz,
OCH2CH3), 7.20 (d, 2H, JZ8 Hz, aromatic), 7.29 (d, 2H,
JZ8 Hz, aromatic) 9.43 (br s, 1H, NH), 9.63 (s, 1H, CHO).
13C NMR (75.47 MHz, CDCl3) dZ14.4, 15.3, 21.1, 61.1,
120.3, 123.1, 128.6, 128.7, 130.8, 135.5, 138.2, 138.3,
160.9, 186.8; EI-MS m/z (%)Z303 (MC, 100), 257, 256
(33), 224 (27), 196 (31), 159 (15), 115 (9). Anal. Calcd for
C16H17NO3S: C, 63.34; H, 5.65; N, 4.62. Found: C, 63.18;
H, 5.52; N, 4.73.
3.4.9. Ethyl 2-({methylsulfanyl)[1-oxo-3,4-dihydro-
2(1H)-naphthalenyliden]amino}acetate (12). Obtained as
white prisms by the methylation of ethyl 2-{[(1-oxo-
1,2,3,4-tetrahydro-2-naphthalenyl)carbothioyl]amino}ace-
tate 11 (2.90 g, 10 mmol) using methyl iodide. Yield 2.8 g
(88%), mp 132–134 8C. IR (KBr) nmaxZ2986, 1736, 1315,
1022, 744 cmK1. 1H NMR (300 MHz, CDCl3) d 1.29 (t, 3H,
JZ7 Hz, OCH2CH3), 2.33 (s, 3H, SCH3), 2.86 (m, 2H,
CH2), 2.97 (m, 2H, CH2), 4.27 (q, 2H, JZ7 Hz, OCH2CH3),
4.33 (s, 2H, NCH2), 7.26–7.38 (m, 3H, aromatic), 8.08 (d,
1H, JZ8 Hz, aromatic), 13.40 (br s, NH). 13C NMR
(75.47 MHz, CDCl3) dZ14.6, 18.0, 27.7, 29.9, 47.3, 61.8,
108.0, 126.9, 127.3, 127.7, 131.7, 135.9, 142.1, 162.4,
170.4, 186.1. EIMS m/z (%) 305 (MC, 24), 258 (78), 228
(23), 184 (72), 173 (100), 128 (58), 115 (92) and 105 (34).
Anal. Calcd for C16H19NO3S: C, 62.93; H, 6.27; N, 4.59.
Found: C, 62.78; H, 6.37; N, 4.42.
3.5.3. Ethyl 4-formyl-5-(methylsulfanyl)-3-phenyl-1H-
pyrrole-2-carboxylate (5c). Obtained by the Vilsmeier
reaction of ethyl 2-{[(E)-1-(methylsulfanyl)-3-oxo-3-
phenyl-1-propenyl]amino}acetate 4c (2.80 g, 10 mmol) as
colorless plates. Yield 2.54 g (88%), mp 119–120 8C. IR
(KBr) nmaxZ3247, 1692, 1655, 1549, 1247, 1173, 1021,
1
795 cmK1. H NMR (300 MHz, CDCl3) d 1.04 (t, 3H, JZ
7 Hz, OCH2CH3), 2.55 (s, 3H, SCH3), 4.11 (q, 2H, JZ7 Hz,
OCH2CH3), 7.32 (m, 5H, aromatic) 9.34 (br s, 1H, NH),
9.55 (s, 1H, CHO). 13C NMR (75.47 MHz, CDCl3) dZ13.9,
15.1, 60.8, 120.2, 123.0, 127.6, 128.0, 130.6, 131.5, 134.9,
137.7, 160.6, 186.2; EI-MS m/z (%)Z289 (MC, 90), 288
(84), 242 (76), 214 (33), 181 (100), 171 (23), 144 (71). Anal.
Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84. Found:
C, 62.12; H, 4.70; N, 4.95.
3.5. General procedure for the synthesis of alkyl
3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-
2-carboxylates (5)
Vilsmeier reagent was prepared by mixing ice cold, dry
DMF (25 mL) and POCl3 (2 mL, 20 mmol). The mixture
was then stirred for 30 min at room temperature. The N,S-
acetal 4 (3.25 g, 10 mmol) was dissolved in dry DMF
(10 mL) and added to the Vilsmeier reagent keeping the
temperature at 0–5 8C. The reaction mixture was stirred for
6 h at room temperature, heated to 80 8C for 1 h with stirring
and was cooled and poured into cold, aqueous saturated
K2CO3 (200 mL). It was then extracted with diethyl ether
(3!50 mL). The organic layer was washed with water,
dried over anhydrous Na2SO4 and evaporated to afford the
crude product, which was chromatographed over silica gel
using hexane–ethylacetate (4/1) as eluent to give alkyl
3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-2-car-
boxylates 5.
3.5.4. Ethyl 3-(4-bromophenyl)-5-(ethylsulfanyl)-
4-formyl-1H-pyrrole-2-carboxylate (5d). Obtained by
the Vilsmeier reaction of ethyl 2-{[(E)-3-(4-bromo-
phenyl)-1-(ethylsulfanyl)-3-oxo-1-propenyl]amino}acetate
4d (3.70 g, 10 mmol) as colorless plates. Yield 3.4 g (89%),
mp 148–149 8C. IR (KBr) nmaxZ3254, 1673, 1538, 1418,
1234, 1013, 777 cmK1. 1H NMR (300 MHz, CDCl3) d 1.15
(t, 3H, JZ7 Hz, OCH2CH3), 1.37 (t, 3H, JZ7 Hz,
SCH2CH3), 3.06 (q, 2H, JZ7 Hz, SCH2CH3), 4.19 (q, 2H,
JZ7 Hz, OCH2CH3), 7.26 (d, 2H, JZ8 Hz, aromatic), 7.53
(d, 2H, JZ8 Hz, aromatic) 9.74 (br s, 1H, NH), 9.85 (s, 1H,
CHO) ppm. 13C NMR (75.47 MHz, CDCl3) dZ14.2, 27.3,
51.7, 119.9, 123.8, 127.7, 128.0, 130.4, 131.3, 134.8, 135.9,
160.8, 186.3, 186.4; EI-MS m/z (%)Z383 (MCC2, 100)
381 (MC, 96), 350 (84), 348 (84), 302 (72), 304 (70), 276
(24), 274 (23), 225 (29), 223 (38), 199 (17), 144 (16). Anal.
Calcd for C16H16BrNO3S: C, 50.27; H, 4.22; N, 3.66.
Found: C, 50.45; H, 4.11; N, 3.52.
3.5.1. Ethyl 3-(4-chlorophenyl)-4-formyl-5-(methyl-
sulfanyl)-1H-pyrrole-2-carboxylate (5a). Obtained by
the Vilsmeier reaction of ethyl 2-{[(E)-3-(4-chlorophe-
nyl)-1-(methylsulfanyl)-3-oxo-1-propenyl]amino}acetate
4a (3.13 g, 10 mmol) as colorless plates. Yield 2.91 g
(90%), mp 118–119 8C. IR (KBr) nmaxZ3234, 1660, 1539,
1249, 1170, 1018, 835, 794, 725 cmK1. 1H NMR (300 MHz,
CDCl3) d 1.15 (t, 3H, JZ7 Hz, OCH2CH3), 2.62 (s, 3H,
SCH3), 4.19 (q, 2H, JZ7 Hz, OCH2CH3), 7.33 (d, 2H, JZ
8 Hz, aromatic), 7.38 (d, 2H, JZ8 Hz, aromatic) 9.43 (br s,
1H, NH), 9.62 (s, 1H, CHO). 13C NMR (75.47 MHz,
CDCl3) dZ14.3, 15.5, 61.3, 120.7, 123.0, 128.2, 130.4,
132.2, 133.7, 134.4, 138.9, 160.8, 186.3; EI-MS m/z (%)Z
325 (MCC2, 39) 323 (MC, 100), 276 (38), 244 (20),
216 (42), 179 (20), 161 (5), 113 (3). Anal. Calcd for
C15H14ClNO3S: C, 55.64; H, 4.36; N, 4.33. Found: C,
55.50; H, 4.48; N, 4.42.
3.5.5. Methyl 5-(ethylsulfanyl)-4-formyl-3-phenyl-1H-
pyrrole-2-carboxylate (5e). Obtained by the Vilsmeier
reaction of methyl 2-{[(E)-1-(ethylsulfanyl)-3-oxo-3-
phenyl-1-propenyl]amino}acetate 4e (2.65 g, 10 mmol) as
colorless plates. Yield 2.36 g (82%), mp 86–87 8C. IR
(KBr) nmaxZ3358, 1682, 1651, 1539, 1386, 1233, 1154,
1
767 cmK1. H NMR (300 MHz, CDCl3) d 1.36 (t, 3H, JZ
7 Hz, SCH2CH3), 3.08 (q, 2H, JZ7 Hz, SCH2CH3), 3.69 (s,
3H, OCH3), 7.39 (m, 5H, aromatic), 9.69 (s, 1H, CHO), 9.72
(br s, 1H, NH) ppm. 13C NMR (75.47 MHz, CDCl3) dZ

P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
1715
14.8, 28.4, 61.4, 120.6, 122.6, 124.4, 130.9, 131.0, 132.5,
133.0, 136.3, 160.7, 186.4; EI-MS m/z (%)Z289 (MC, 78),
256 (76), 224 (100), 196 (39), 172 (16), 145 (60), 102 (11).
Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84.
Found: C, 62.08; H, 5.38; N, 4.71.
colorless plates. Yield 2 g (78%), mp 131–133 8C. IR (KBr)
nmaxZ3271, 3057, 2986, 1660, 1412, 1209, 1020, 761 cmK1
.
1H NMR (300 MHz, CDCl3) d 1.40 (t, 3H, JZ7 Hz,
OCH2CH3), 2.33 (s, 3H, SCH3), 2.68 (t, 2H, JZ6 Hz,
CH2CH2), 2.85 (t, 2H, JZ6 Hz, CH2CH2), 4.38 (q, 2H, JZ
7 Hz, OCH2CH3), 7.21 (m, 3H, aromatic), 8.40 (d, 1H, JZ
7 Hz, aromatic), 9.15(br s, 1H, NH) ppm. 13C NMR(75 MHz,
CDCl3) d 14.8, 20.1, 20.8, 31.1, 61.0, 118.7, 122.5, 126.8,
127.4, 127.6, 127.8, 128.4, 128.8, 130.9, 137.8, 160.8 ppm.
EI-MS m/z (%)Z287 (MC, 94), 241 (56), 213 (43), 198 (72),
179 (100), 167 (32), 127 (35), 109 (18). Anal. Calcd for
C16H17NO2S: C, 66.87; H, 5.96; N, 4.87. Found: C, 66.72; H,
6.08; N, 4.72.
3.5.6. Methyl 4-formyl-3-(4-methylphenyl)-5-(ethyl-
sulfanyl)-1H-pyrrole-2-carboxylate (5f). Obtained by the
Vilsmeier reaction of methyl 2-{[(E)-3-(4-methylphenyl)-1-
(ethylsulfanyl)-3-oxo-1-propenyl]amino}acetate 4f (2.93 g,
10 mmol) as colorless plates. Yield 2.45 g (85%), mp
108–109 8C. IR (KBr) nmaxZ3155, 1717, 1642, 1563, 1510,
1260, 1151, 1098, 778 cmK1. 1H NMR (300 MHz, CDCl3) d
1.36(t, 3H, JZ7 Hz, SCH2CH3), 2.40(s, 3H, ArCH3), 3.09(q,
2H, JZ7 Hz, SCH2CH3), 3.72(s, 3H, OCH3), 7.21(d, 2H, JZ
8 Hz, aromatic), 7.29 (d, 2H, JZ8 Hz, aromatic) 9.71 (s, 1H,
CHO), 9.79 (br s, 1H, NH) ppm. 13C NMR (75.47 MHz,
CDCl3) dZ14.6, 21.7, 27.7, 52.1, 120.2, 124.2, 128.6, 128.8,
130.7, 135.4, 136.3, 138.2, 161.2, 187.0;EI-MSm/z (%)Z303
(MC, 88), 270 (55), 238 (100), 210 (35), 186 (10), 159 (36),
128 (6), 115 (16). Anal. Calcd for C16H17NO3S: C, 63.34; H,
5.65; N, 4.62. Found: C, 63.48; H, 5.54; N, 4.47.
3.6. General procedure for the base catalyzed cyclization
of b-oxoketene-N,S-acetals (14)
A solution of ketene-N,S-acetal 4 (10 mmol) in dry toluene
(15 mL) was heated at 100–110 8C for 3 h. During this period
DBU (20 mmol) was added in three equal portions to the
reaction mixture. After the completion of the reaction (TLC),
toluene was evaporated under reduced pressure and the
residue was dissolved in dichloromethane, washed with 5%
HCl (2!20 mL), then with saturated bicarbonate (2!20 mL)
and finally with water (2!50 mL). The organic layer was
dried (Na2SO4) and evaporatedtogiveadarkbrown oil, which
on column chromatography using hexane–ethyl acetate (9/1)
as eluent afforded moderated yields of the 3-aryl pyrrole-2-
carboxylates 14.
3.5.7. Methyl 3-(4-chlorophenyl)-5-(ethylsulfanyl)-
4-formyl-1H-pyrrole-2-carboxylate (5g). Obtained by
the Vilsmeier reaction of methyl 2-{[(E)-3-(4-chlorophe-
nyl)-1-(ethylsulfanyl)-3-oxo-1-propenyl]amino}acetate 4g
(3.1 g, 10 mmol) as colorless plates. Yield 2.8 g (88%),
mp 128–129 8C. IR (KBr) nmaxZ3124, 1696, 1649, 1439,
1242, 1084, 878, 777 cmK1. 1H NMR (300 MHz, CDCl3) d
1.34 (t, 3H, JZ7 Hz, SCH2CH3), 3.07 (q, 2H, JZ7 Hz,
SCH2CH3), 3.71 (s 3H, OCH3), 7.32 (d, 2H, JZ8 Hz,
aromatic), 7.36 (d, 2H, JZ8 Hz, aromatic), 9.74 (s, 1H,
CHO), 10.13 (br s, 1H, NH) ppm. 13C NMR (75.47 MHz,
CDCl3) dZ14.7, 28.2, 52.2, 120.7, 124.3, 128.4, 130.3,
132.1, 133.8, 134.5, 136.7, 161.0, 186.5; EI-MS m/z (%)Z
325 (MCC2, 37) 323 (MC, 93), 290 (94), 258 (100), 230
(31), 207 (12), 179 (52), 144 (9), 113 (5). Anal. Calcd for
C15H14ClNO3S: C, 55.64; H, 4.36; N, 4.33. Found: C,
55.48; H, 5.50; N, 4.12.
3.6.1. Methyl 3-(4-chlorophenyl)-5-(ethylsulfanyl)-1H-
pyrrole-2-carboxylate (14a). Obtained by the cyclization of
methyl 2-{[(E)-3-(4-chlorophenyl)-1-(ethylsulfanyl)-3-oxo-
1-propenyl]amino}acetate 4a (3.10 g, 10 mmol) in presence
of DBU (20 mmol) as colorless plates. Yield 1 g (34%), mp
138–139 8C. IR (KBr) nmaxZ3297, 1673, 1447, 1262, 1002,
1
816, 732 cmK1. H NMR (300 MHz, CDCl3) d 1.28 (t, 3H,
JZ7 Hz, SCH2CH3), 2.81 (q, 2H, JZ7 Hz, SCH2CH3), 3.78
(s, 3H, OCH3), 6.39(d, 1H, JZ3 Hz, pyrrole CH), 7.33 (d, 2H,
JZ8 Hz, aromatic), 7.46 (d, 2H, JZ8 Hz, aromatic), 9.26 (br
s, 1H, NH) ppm. 13C NMR (75.47 MHz, CDCl3) dZ15.6,
31.2, 51.8, 118.3, 119.7, 126.6, 128.3, 131.0, 133.4, 133.5,
161.0; EI-MS m/z (%)Z297 (MCC2, 35) 295 (MC, 91), 235
(92), 206 (56), 167 (78), 149 (67), 129 (100), 111 (42). Anal.
Calcd for C14H14ClNO2S: C, 56.85; H, 4.77; N, 4.74. Found:
C, 56.68; H, 4.88; N, 4.82.
3.5.8. Ethyl (5-ethylsulfanyl)-4-formyl-3-(4-methoxy-
phenyl)-1H-pyrrole-2-carboxylate (5h). Obtained by the
Vilsmeier reaction of ethyl 2-{[(E)-1-(ethylsulfanyl)-3-
(4-methoxyphenyl)-3-oxo-1-propenyl]amino}acetate 4h
(3.2 g, 10 mmol) as colorless plates. Yield 2.9 g (88%), mp
92–93 8C. IR (KBr) nmaxZ3247, 1661, 1509, 1247, 1176,
1034, 816, 781 cmK1. 1H NMR (300 MHz, CDCl3) d 1.22 (t,
3H, JZ7 Hz, SCH2CH3), 1.42 (t, 3H, JZ7 Hz, OCH2CH3),
3.12 (q, 2H, JZ7 Hz, SCH2CH3), 3.90 (s, 3H, ArOCH3), 4.26
(q, 2H, JZ7 Hz, OCH2CH3), 6.98 (d, 2H, JZ8 Hz, aromatic),
7.38 (d, 2H, JZ8 Hz, aromatic), 9.61 (br s, 1H, NH), 9.77 (s,
1H, CHO) ppm. 13C NMR (75.47 MHz, CDCl3) dZ14.0,
14.3, 27.7, 55.2, 60.8, 113.1, 120.3, 123.7, 124.2, 131.8, 134.4,
135.4, 159.5, 160.5, 186.5; EI-MS m/z (%)Z333 (MC, 63),
300 (23), 254 (100), 226 (41), 174 (55), 158 (16), 132 (24).
Anal. Calcd for C17H19NO4S: C, 61.24; H, 5.74; N, 4.20.
Found: C, 61.39; H, 5.92; N, 4.07.
3.6.2. Ethyl 5-(ethylsulfanyl)-3-phenyl-1H-pyrrole-2-car-
boxylate (14b). Obtained by the cyclization of ethyl 2-{[(E)-
3-phenyl-1-(ethylsulfanyl)-3-oxo-1-propenyl]amino}acetate
4b (2.90 g, 10 mmol) in presence of DBU (20 mmol) as
colorless plates. Yield 1.2 g (45%), mp 63–64 8C. IR (KBr)
1
nmaxZ3292, 1678, 1426, 1265, 1016, 822, 760 cmK1. H
NMR (300 MHz, CDCl3) d 1.28 (m, 6H, JZ7 Hz, SCH2CH3-
COCH2CH3), 2.80 (q, 2H, JZ7 Hz, SCH2CH3), 4.26 (q, 2H,
JZ7 Hz, OCH2CH3), 6.42 (d, 1H, JZ3 Hz, pyrrole CH), 7.31
(m, 3H, JZ7.8 Hz, aromatic), 7.53 (d, 2H, JZ7 Hz,
aromatic), 9.38 (br s, 1H, NH) ppm. 13C NMR (75.47 MHz,
CDCl3) dZ14.1, 15.1, 30.8, 60.4, 118.2, 119.6, 125.6, 127.0,
127.6, 129.4, 132.9, 134.5, 160.5; EI-MS m/z (%)Z275 (MC,
92), 232 (84), 168(52), 147(54), 115(19)and105(100). Anal.
Calcd for C15H17NO2S: C, 65.43; H, 6.22; N, 5.09. Found: C,
65.62; H, 6.08; N, 5.22.
3.5.9. Ethyl 3-(methylsufanyl)-4,5-dihydro-2H-benzo(e)-
isoindole-1-carboxylate (13). Obtained by the Vilsmeier
reaction of ethyl 2-({methylsulfanyl)[1-oxo-3,4-dihydro-
2(1H)naphthalenyliden]amino}acetate 12 (3 g, 10 mmol) as

1716
P. Mathew, C. V. Asokan / Tetrahedron 62 (2006) 1708–1716
3.6.3. Ethyl 3-(4-chlorophenyl)-5-(methylsulfanyl)-1H-
pyrrole-2-carboxylate (14c). Obtained by the cyclization
of ethyl 2-{[(E)-3-(4-chlorophenyl)-1-(methylsulfanyl)-3-
oxo-1-propenyl]amino}acetate 4c (3.10 g, 10 mmol) in
presence of DBU (20 mmol) as colorless plates. Yield
0.94 g (32%), mp 129–130 8C. IR (KBr) nmaxZ3275, 1672,
References and notes
1. Sundberg, R. J. In Katritzky, A., Rees, C. W., Scriven, E. F. V.,
Eds.; Comprehensive Heterocyclic Chemistry; Pergamon:
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2. (a) Tao, H.; Hwang, I.; Boger, D. L. Bioorg. Med. Chem. Lett.
2004, 14, 5979–5981. (b) Boger, D. L.; Boyce, C. W.; Labroli,
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54–62.
1493, 1259, 1087, 815, 733 cmK1 1H NMR (300 MHz,
.
CDCl3) d 1.30 (t, 3H, JZ7 Hz, OCH2CH3), 2.47 (s, 3H,
SCH3), 4.23 (q, 2H, JZ7 Hz, OCH2CH3), 6.33 (d, 1H, JZ
3 Hz, pyrrole CH), 7.31 (d, 2H, JZ7 Hz, aromatic), 7.46 (d,
2H, JZ7 Hz, aromatic), 9.22 (br s, 1H, NH) ppm. 13C NMR
(75.47 MHz, CDCl3) dZ14.6, 19.8, 60.91, 116.0, 119.6,
128.2, 128.6, 131.1, 132.2, 133.4, 160.6;EI-MSm/z (%)Z297
(MCC2, 35) 295 (MC, 91), 249 (72), 221 (100), 206 (33), 187
(26), 149 (48), 136 (38). Anal. Calcd for C14H14ClNO2S: C,
56.85; H, 4.77; N, 4.74. Found: C, 56.68; H, 4.88; N, 4.87.
3. (a) Baumgarten, M.; Tyutyulkov, N. Chem. Eur. J. 1998, 4,
987–989. (b) Deronzier, A.; Moutet, J.-C. Curr. Top.
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Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem. 2003, 68,
7853–7861. (c) Ooi, T.; Ohmatsu, K.; Ishii, H.; Saito, A.;
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Sanchez-Jimenez, G.; Zard, S. Z. Synlett 2003, 75–78. (f)
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3.6.4. Ethyl 3-(4-bromophenyl)-5-(ethylsulfanyl)-1H-
pyrrole-2-carboxylate (14d). Obtained by the cyclization
of ethyl 2-{[(E)-3-(4-chlorophenyl)-1-(ethylsulfanyl)-3-
oxo-1-propenyl]amino}acetate 4d (3.70 g, 10 mmol) in
presence of DBU (20 mmol) as colorless plates. Yield 1 g
(28%), mp 110–111 8C. 1H NMR (300 MHz, CDCl3) d 1.27
(m, 6H, JZ7 Hz, SCH2CH3COCH2CH3), 2.81 (q, 2H, JZ
7 Hz, SCH2CH3), 4.26 (q, 2H, JZ7 Hz, OCH2CH3), 6.44
(d, 1H, JZ3 Hz, pyrrole CH), 7.13 (d, 2H, JZ7 Hz,
aromatic), 7.20 (d, 2H, JZ7 Hz, aromatic), 9.38 (br s, 1H,
NH) ppm. 13C NMR (75.47 MHz, CDCl3) dZ14.6, 15.6,
31.3, 61.0, 118.3, 120.0, 121.6, 126.4, 131.1, 131.5, 132.1,
133.9 and 160.7; EI-MS m/z (%)Z355 (MCC2, 31) 353
(MC, 94), 294 (75), 249 (100), 230 (25), 181 (36), 157 (78).
Anal. Calcd for C15H16BrNO2S: C, 50.86; H, 4.55; N, 3.95.
Found: C, 50.98; H, 4.68; N, 3.80.
7. Mathew, P.; Asokan, C. V. Tetrahedron Lett. 2005, 46,
475–478.
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3.6.5. Methyl 3-(4-methylphenyl)-5-(methylsulfanyl)-1H-
pyrrole-2-carboxylate (14e). Obtained by the cyclization of
methyl 2-{[(E)-3-(4-methylphenyl)-1-(methylsulfanyl)-3-
oxo-1-propenyl]amino}acetate 4e (2.80 g, 10 mmol) as color-
11. Roth, B. D. Prog. Med. Chem. 2002, 40, 1–22.
12. Singh, G.; Bhattacharjee, S. S.; Ila, H.; Junjappa, H. Synthesis
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1
less plates. Yield 0.62 g (24%), mp 120–121 8C. H NMR
13. (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46,
5423–5506. (b) Roy, A.; Nandi, S.; Ila, H.; Junjappa, H. Org.
Lett. 2001, 3, 229–232.
(300 MHz, CDCl3) d 2.17 (s, 3H, ArCH3), 2.46, (s 3H, SCH3),
3.77 (s, 3H, OCH3), 6.34 (d, 1H, JZ3 Hz, pyrrole CH), 7.17
(d, 2H, JZ8 Hz, aromatic), 7.42 (d, 2H, JZ8 Hz, aromatic),
9.09 (br s, 1H, NH) ppm. EI-MS m/z (%)Z261 (MC, 100),
229 (48), 201 (83), 186 (58), 168 (34), 115 (38) and 100 (16).
Anal. Calcd for C14H15NO2S: C, 64.34; H, 5.79; N, 5.36.
Found: C, 64.18; H, 5.88; N, 5.52.
14. (a) Tominaga, Y.; Okuda, H.; Kohra, S.; Mazume, H.
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2133–2135.
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Gilchrist, T. L., Eds.; Progress in Heterocyclic Chemistry;
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Acknowledgements
This work was supported by Kerala State CSTE and CSIR
New Delhi (Project No. 01(1954)/04/EMR-II). We thank
MK University, Madurai for providing spectral and
analytical data. P.M. thanks the UGC for assistance under
the Faculty Improvement Program.
17. Suma, S.; Asokan, C. V. Synth. Commun. 1996, 26, 847–853.
18. 13C NMR spectra of compound 3 showed signals of keto
and enol tautomers. The values given are of the major
tautomer.