An easy access to variously substituted pyrroles starting from ketene dithioacetals

Article abstract of DOI:10.1081/SCC-200050365

Variously substituted pyrroles 4 can easily be synthesized in two steps by reacting a primary or secondary amine and a ketene dithioacetal in a basic medium in moderate to good yield. Ketene dithioacetals 2 are readily prepared from acetylaceton or malononitrile, carbon disulfide, and methyl iodide.

Full text of DOI:10.1081/SCC-200050365

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An Easy Access to Variously Substituted
Pyrroles Starting From Ketene Dithioacetals
a
b
b
Geoffroy L. Sommen , Alain Comel & Gilbert Kirsch
a
Organisch‐Chemisches Institut der Universität Zürich, Zürich, Switzerland
b
Laboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique,
Faculté des Sciences, Université de Metz, Metz, France
Published online: 20 Aug 2006.
To cite this article: Geoffroy L. Sommen , Alain Comel & Gilbert Kirsch (2005) An Easy Access to Variously
Substituted Pyrroles Starting From Ketene Dithioacetals, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:5, 693-699, DOI: 10.1081/SCC-200050365
To link to this article: http://dx.doi.org/10.1081/SCC-200050365
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Synthetic Communications , 35: 693–699, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050365
An Easy Access to Variously Substituted
Pyrroles Starting From Ketene
Dithioacetals
Geoffroy L. Sommen
Organisch-Chemisches Institut der Universit a¨ t Z u¨ rich, Z u¨ rich,
Switzerland
Alain Comel and Gilbert Kirsch
Laboratoire d’Ing e´ nierie Mol e´ culaire et Biochimie Pharmacologique,
Facult e´ des Sciences, Universit e´ de Metz, Metz, France
Abstract: Variously substituted pyrroles 4 can easily be synthesized in two steps by
reacting a primary or secondary amine and a ketene dithioacetal in a basic medium in
moderate to good yield. Ketene dithioacetals 2 are readily prepared from acetylaceton
or malononitrile, carbon disulfide, and methyl iodide.
Keywords: Ketene dithioacetals, amines, pyrroles, nucleophiles, addition-elimination
INTRODUCTION
Ketene dithioacetals are key intermediates for the preparation of a wide
[
1]
variety of heterocyclic structures. Although their synthesis and reactions
receive much attention, their corresponding N,S-acetals have been studied
[
2]
in only a few cases. Various nucleophiles (thiols, hydrazines, organometal-
lic reagents, etc.) can remove one of the methylsulfanyle group and cycliza-
tion of the intermediate can generally occur during the same stage. Several
Received in Poland 2 November 2004
Address correspondence to Geoffroy L. Sommen, Organisch-Chemisches Institut
der Universit a¨ t Z u¨ rich, Wintherthurerstrasse 190, CH-8057, Z u¨ rich, Switzerland.
E-mail: sommen@oci.unizh.ch

6
94
G. L. Sommen, A. Comel, and G. Kirsch
Scheme 1.
reports have appeared during these last years on the ability of an amine to
displace a methylsulfanyle group on a ketene dithioacetal to synthesize oxazo-
[
3]
[4]
[5]
[6]
lidine, pyrazole, benzodiazepine, or imidazolidine. Amines used here
glycin, sarcosin, or ethyl sarcosinate) are well-known reagents used to
prepare pyrrole in two steps via a-chloro-acrolein 2 obtained from a methyl
(
[7]
keton by the Vilsmeier-Haack-Arnold reaction (POCl -DMF).
3
A procedure was recently described that was used to obtain 5-
methylsulfanyl-thiophenes and selenophenes and thieno[2,3-b]thiophenes in
[
10–15]
moderate to good yields,
sulfide followed by a condensation with an activated methylene compound
such as alkyl bromoacetate, chloracetonitrile, chloraceton, or a-bromoaceto-
phenone) and a Dieckman-type cyclization in the same step in a basic medium
by reacting ketene dithioacetals with sodium
(
(
K CO /DMF).
2
3
To the best of our knowledge, only one paper, which was written in 1988
[
16]
by Liebscher, deals with this kind of reaction. In an extension of our recent
studies on the application of ketene dithioacetals in heterocyclic synthesis,
the easy synthesis of pyrroles from ketene dithioacetals is reported here
(Scheme 1). Different primary or secondary amines bearing an activated
methylene are used to build the pyrrole ring in a one-pot reaction by a
monosubstitution of a methylsulfanyle group. Liebscher describes a similar
approach to this synthesis but surprisingly only one compound has been
reported. The procedure cited therein, i.e., triethylamine in refluxing ethanol
leading to the formation of a noncyclized intermediate 5 (Scheme 2). This
is due to the soft conditions applied. A second step with a stronger base and
harsher condition is then needed to afford pyrroles. The method we report
here directly gives the pyrrole and no intermediate are observed. Potassium
carbonate in dimethyl formamide (DMF) appears to be more convenient,
Scheme 2.

Access to Variously Substituted Pyrroles
695
cheaper, and applicable to every ketene dithioacetal. Several pyrroles were
synthesized from ketene dithioacetals and ethyl glycinate, sarcosin, ethyl
sarcosinate, and glycin in moderate to good yield (Table 1).
The mechanism of this reaction seems to be similar to those observed pre-
[
10–15]
viously,
namely, a Michael addition reaction, followed by elimination
of one equivalent of a thiomethyl group and a Dieckman-type cyclization
on the carbonyl group (or equivalent).
Pyrroles 4a-f are obtained from symmetrical ketene dithioacetals in
4
9%–89% yield. A very interesting point is that unsymmetrical starting
compounds give two different pyrroles in equivalent yield. Absolutely no
regioselectivity is observed on this type of compound 2g. Dieckman-type
cyclization affords 3-hydroxy-pyrrole 4h (ester site) and an 3-amino pyrrole
4
(
g (cyanide site) on a Thorpe-Ziegler-type reaction in 87% overall yield
Scheme 3).
To sum up, primary and secondary amines bearing an activated methylene
react with ketene dithioacetals to afford the pyrrole ring in a one-pot reaction in
moderate to good yields. Indeed, the method of synthesis of five-membered het-
erocycles starting from ketene dithioacetals, potassium carbonate in DMF is more
convenient, cheaper, and generalized to a wider variety of heterocyclic syntheses.
EXPERIMENTAL
All melting points were determined on a binocular apparatus from Stuart
Scientific SMP3 and were uncorrected. Elemental analysis data were obtained
1
13
by use of a Carlo Erba 1106. H and C NMR spectra were recorded on a
Bruker AC 250 (250 MHz) spectrometer using tetramethylsilane (TMS) as
an internal reference.
Ketene Dithioacetals: General Procedure
A 250 mL three-necked round-bottom flask equipped with magnetic stirrer,
condenser, and septum was charged with a solution of 1,3-diketon
(100 mmol) in DMF (100 mL). Dried K CO (13.8 g, 100 mmol) was added
and the mixture was stirred for 2 h at room temperature. CS (18.0 mL,
2 3
2
3
00 mmol) was added and the mixture was stirred for an additional 2 h at
room temperature. Methyl iodide (12.5 mL, 200 mmol) was then added and
the mixture was stirred for 4 h before being poured onto water (400 mL).
The precipitated crude product was purified by filtration followed by crystal-
lization from EtOH. When the product was an oil, the organic phase was
extracted with Et O (3 ꢀ 100 mL). The combined organic extracts were
2
washed with H O (2 ꢀ 100 mL), dried (MgSO ), and concentrated in vacuo
2
4
to afford ketene dithioacetal directly used for the next step.

6
96
G. L. Sommen, A. Comel, and G. Kirsch
Table 1. Preparation of pyrroles 4 from dithioacetals 2
Entry
Amine 3
R ¼ H
Dithioacetals 2
Pyrroles 4
Yield (%)
68
a
Y ¼ CO
2
Et
R ¼ H
87
89
84
b
c
Y ¼ CO Et
2
R ¼ H
Y ¼ COOH
R ¼ Me
d
Y ¼ CO Et
2
R ¼ Me
49
67
47
e
Y ¼ COOH
R ¼ Me
f
Y ¼ COOH
g
R ¼ H
Y ¼ CO
2
Et
4
0
h
Typical Procedure for the Preparation of Pyrroles 4
A 100 mL three-necked round-bottom flask equipped with magnetic stirrer,
condenser, and septum was charged with a solution of ketene dithioacetals

Access to Variously Substituted Pyrroles
697
Scheme 3.
(10.0 mmol) in DMF (30 mL). Dried K CO (10.0 mmol) followed by the
2 3
amine (10.0 mmol) was added and the mixture was stirred for 4 h at 608C.
The reaction mixture was then cooled down to room temperature, poured
into ice water (100 mL), and stirred for 1 h before usual standard work-up.
When the product was an oil, the organic phase was extracted with diethyl
ether (3 ꢀ 100 mL). The combined organic extracts were washed with H O
2
(
2 ꢀ 100 mL), dried (MgSO ), concentrated in vacuo, and purified on silica
4
gel with dichloromethane as eluant. When precipitated, the product is
filtered, washed with water, and purified by recrystallization from ethanol.
4-Acetyl-3-methyl-5-methylsulfanyl-1H-pyrrole-2-carboxylic acid
ethyl ester (4a)
Mp: 128–1308C; d (250 MHz, CDCl ): 1.37 (t, 3H, J ¼ 7.1 Hz), 2.48 (s, 3H),
H
3
1
3
2
.51 (s, 3H), 2.58 (s,3H), 4.34 (q, 2H, J ¼ 7.1 Hz), 8.96 (br s, 1H); C NMR
(
62.5 MHz, CDCl ). 14.2 (CH ), 14.4 (CH ), 15.7 (CH ), 30.5 (CH ), 60.6
3 3 3 3 3
(CH ), 117.5 (C ), 120.7 (C ), 125.1 (C ), 156.9 (C ), 161.4 (CO ), 194.3
2 ar ar ar ar 2
(CO); Anal. Calcd for C H NO S: C, 54.75; H, 6.27; N, 5.80. Found: C,
11 15 3
5
4.57; H, 6.01, N, 5.48.
-Amino-4-cyano-5-methylsulfanyl-1H-pyrrole-2-carboxylic acid ethyl
3
ester (4b)
[
16]
Mp: 183–1858C; d NMR (250 MHz, CDCl ). 1.09 (t, 6H, J ¼ 7.2 Hz), 2.26
H
3
1
3
(
s, 6H), 4.34 (q, 4H, J ¼ 7.2 Hz); C NMR (62.5 MHz, CDCl ) 12.2(CH ),
3
3
1
4.0(CH ), 61.6(CH ), 75.3 (C ), 98.7 (C ), 114.9(CN), 167.8(CO ), 174.1
3 2 ar ar 2
(C ), 177.2 (C ); Anal. Calcd for C H N O S: C, 47.99; H, 4.92; N,
ar ar 9 11 3 2
1
8.65. Found: C, 47.97; H, 4.78, N, 18.55.
-Amino-4-cyano-5-methylsulfanyl-1H-pyrrole-2-carboxylic acid (4c)
3
Mp: 137–1398C; d NMR (250MHz, CDCl ) 2.58 (s, 3H), 3.62 (sl, 1H), 4.26
H
3
1
sl, 2H), 8.82 (sl, 1H); C NMR (62.5 MHz, CDCl ) 19.3 (CH ), 81.4 (C ),
3
(
3 3 ar
1
for C H N O S: C, 42.63; H, 3.58; N, 21.31. Found: C, 42.58; H, 3.53, N, 21.22.
15.6 (CN), 116.9(C ), 139.9 (C ), 160.8 (C ), 169.8 (COOH); Anal. Calcd
ar ar ar
7
7 3 2

6
98
G. L. Sommen, A. Comel, and G. Kirsch
4-Acetyl-1,3-dimethyl-5-methylsulfanyl-1H-pyrrole-2-carboxylic acid
ethyl ester (4d)
Yellow oil; d NMR (250 MHz, CDCl ) 1.35 (t, 3H, J ¼ 7.2 Hz), 2.29 (s, 3H),
H
3
1
3
2
.31 (s, 3H), 2.89 (s, 3H), 3.07 (s, 3H), 4.30 (q, 2H, J ¼ 7.2 Hz); C NMR
(
62.5 MHz, CDCl ) 14.1 (CH ), 14.3 (CH ), 14.7 (CH ), 18.8 (CH ), 33.5
3
3
3
3
3
(
CH ), 59.2 (CH ), 121.8 (C ), 129.2 (C ), 131.6 (C ), 151.8 (C ),
3 2 ar ar ar ar
161.6 (CO ), 192.8 (CO); Anal. Calcd for C H NO S: C, 56.45; H, 6.71;
2 12 17 3
N, 5.49. Found: C, 56.54; H, 6.82, N, 5.42.
-Acetyl-1,3-dimethyl-5-methylsulfanyl-1H-pyrrole-2-carboxylic acid (4e)
Orange oil; dH NMR (250 MHz, CDCl ) 2.23 (s, 3H), 2.50 (s, 3H), 2.68
4
3
1
3
(
s, 3H), 2.85 (s, 3H), 12.95 (s, 1H); C NMR (62.5 MHz, CDCl3)
1
1
5
9.3 (2CH ), 28.2 (CH ), 36.4 (CH ), 102.1 (C ), 123.1 (C ), 135.6 (C ),
3 3 3 ar ar ar
38.4 (C ), 173.1 (COOH), 191.5 (CO).; Anal. Calcd for C H NO S: C,
ar
10 13
3
2.85; H, 5.77; N, 6.16. Found: C, 52.66; H, 5.87, N, 6.02.
3-Amino-4-cyano-1-methyl-5-methylsulfanyl-1H-pyrrole-2-carboxylic
acid (4f)
Brown oil; dH NMR (250 MHz, CDCl ) 2.38 (s, 3H), 3.47 (s, 3H), 5.92
3
1
3
(
sl, 2H), COOH nonvisible; C NMR (62.5 MHz, CDCl ) 16.8 (CH ), 36.2
3 3
(
CH ), 88.1 (C ), 102.4 (C ), 112.1 (CN), 138.9 (C ), 153.9 (C ),
3 ar ar ar ar
165.8 (COOH); Anal. Calcd for C H N O S: C, 45.49; H, 4.19; N, 19.89.
Found: C, 45.82; H, 3.98, N, 19.53.
8 9 3 2
3-Amino-5-methylsulfanyl-1H-pyrrole-2,4-dicarboxylic acid diethyl
ester (4g)
Mp: 69–718C; d NMR (250MHz, CDCl ) 1.26 (m, 6H), 2.28 (s, 3H), 4.22
H
3
1
m, 4H), 9.74 (sl, 1H), NH non visible.; C NMR (62.5 MHz, CDCl3)
3
(
2
13.0 (CH ), 13.8 (CH ), 15.0 (CH ), 60.0 (CH ), 61.6 (CH ), 70.7 (C ), 117.7
3 3 3 2 2 ar
(
C H N O S: C, 48.52; H, 5.92; N, 10.29. Found: C, 48.66; H, 6.12, N, 10.04.
C ), 123.4 (C ), 168.2 (CO ), 169.0 (CO ), 171.3 (C ); Anal. Calcd for
ar ar 2 2 ar
1
1 16 2 4
4-Cyano-3-hydroxy-5-methylsulfanyl-1H-pyrrole-2-carboxylic acid
ethyl ester (4h)
Mp: 138–1408C; d NMR (250MHz, CDCl ). 1.20 (t, 3H, J ¼ 7.2 Hz), 2.20
H
3
1
3
(
s, 3H), 3.70 (br s, 1H), 4.18 (q, 2H, J ¼ 7.2 Hz), OH non visible; C NMR
(
62.5 MHz, CDCl ) 13.6 (CH ), 15.5 (CH ), 60.5 (CH ), 80.7 (C ),
3
3
3
2
ar
109.3 (C ), 117.7 (CN), 124.3 (C ), 168.6 (CO ), 174.3 (C ); Anal. Calcd for
C H N O S: C, 47.79; H, 4.42; N, 12.39. Found: C, 48.12; H, 4.12, N, 12.04.
ar ar 2 ar
9
10 2 3

Access to Variously Substituted Pyrroles
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