An easy access to variously substituted thieno[2,3-b]pyrroles by using isothiocyanates

Article abstract of DOI:10.1055/s-2001-18092

Thieno[2,3-b]pyrroles 2 can easily be synthesised in two steps by using isothiocyanates and activated methylene compounds.

Full text of DOI:10.1055/s-2001-18092

LETTER
1731
An Easy Access to Variously Substituted Thieno[2,3-b]pyrroles by Using
Isothiocyanates
An
Easy
A
ccess to
e
Variously
o
S
ubstituted
T
f
hieno[2
f
, 3-
b
]pyr
r
r
oles oy Sommen, Alain Comel, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et de Biochimie Pharmacologique, Faculté des Sciences, Ile du Saulcy, 57045 METZ Cedex, France
E-mail: kirsch@sciences.univ-metz.fr
Received 19 July 2001
Dedicated to Professor Jan Bergmann on the occasion of his 60th birthday
K2CO3 was used as the basic condensation promoter in or-
Abstract: Thieno[2,3-b]pyrroles 2 can easily be synthesised in two
der to obtain the intermediate ketene aminothioacetals.
steps by using isothiocyanates and activated methylene compounds.
The addition of two or more equivalents of alkyl bro-
Key words: thieno[2,3-b]pyrrole, isothiocyanate, ketene-N,S-ace-
moacetate (or chloroacetonitrile) did not lead to the N,S-
tal, thiophene
disubstituted ketene aminoacetals reported by El-Shafei1
but only to the thiophenes 1 in moderate to good yields
(Table 1).
Substituted thieno[2,3-b]thiophenes and their preparation
Condensation of the intermediate salt ketene N,S-acetal
with the halide leads to the corresponding aminothioacetal
methods are known since the 50’s. One of the most recent
synthetic pathways for their preparation is based on the
which smoothly undergo a Dieckmann type cyclisation in
cyclisation of ketene dithioacetals, obtained from carbon
disulfide, in basic media.1–4 We decided to extend this
strategy to the formation of thieno[2,3-b]pyrroles, using
an alkyl or aryl isothiocyanate, instead of carbon disul-
fide, under similar conditions. Our first attempt with phe-
nyl isothiocyanate allowed us to isolate a 2-phenylamino-
thiophene by filtration when the reaction is quenched with
water. Condensation with ethyl bromoacetate under
harsher conditions led us to the expected thieno[2,3-
b]pyrroles with good yields.
basic medium at room temperature (Scheme 1).
This two-step method offers some advantages in compar-
ison with those described in the literature generally based
on cyclisation reactions of accurately substituted
thiophenes9 or pyrroles.10
By-products were not isolated from the resinous residue
but the reaction products described by El-Shafei1 should
have been observed if formed, even if the basic media was
not exactly the same (K2CO3/benzene under PTC condi-
tions). Thiophenes 1 were easily removed from the crude
reaction mixture by rapid hydrolysis in water followed by
filtration.
These first results, different from those reported by El-
Shafei1 and the lack of practical details and analytical da-
ta, prompted us to investigate this reaction.
We have shown that the preparation of thieno[2,3-b]pyr-
roles cannot be carried out in a one-pot procedure but our
two-step pathway allows us to increase the diversity of the
substituants on the thienopyrrole framework.
With ethyl acetylacetate, only thiophene 1l was formed by
cyclisation of the ketone has been observed, which is in
agreement with previous work on similar compounds.
Formation of the pyrrole-fused rings 2 and 3 was achieved
by prolonged reflux of 1 in acetone for 4 to 5 days in the
presence of 1.5 equivalents of an alkyl bromoacetate10 (or
chloroacetonitrile) (Scheme 2). All other attempts to ob-
tain the corresponding thieno[2,3-b]pyrrole 2 and 3 failed,
even the one described by El-Shafei1 which was very sur-
prising. Nevertheless, the yields of cyclisation (60 to
The first step is the condensation of activated methylene
compounds with alkyl or aryl isothiocyanates in a basic
medium, as has been already described for the preparation
of a great number of heterocyclic compounds5,6 especially
thiophenes.2,7 According to the results that we have re-
cently reported in the field of thieno[2,3-b]thiophene8,
O
O
O
R2
R1
O
O
R1
R2
X-CH2-Y
1) K2CO3/DMF/RT
2) Ph-NCS
R1
R2
K2CO3/DMF/RT
HN
Ph
S
HN
Ph
Y
S
1
Scheme 1
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1731,1734,ftx,en;G15001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1732
G. Sommen et al.
LETTER
Table 1 Synthesis of Thiophenes 2 from Compounds 1
Entry
Compound 1
Product 2
Yield (%)
a
b
40 (R=Me)
47 (R=Et)
O
O
Ac
Me
CO2R
PhHN
Bz
S
c
d
65 (R=Me)
71 (R=Et)
Ph
O
O
Ph
Ph
CO2R
PhHN
Ac
S
S
S
S
e
34
Me
NH2
OH
O
O
CN
PhHN
NC
f
g
10 (R=Me)
19 (R=Et)
NC
CN
CO2R
PhHN
EtO2C
h
34
EtO2C
CO2Et
CO2Me
PhHN
i
j
43 (R=Me)
50 (R=Et)
O
O
O
CO2R
S
PhHN
Bz
k
42
46
O
O
Me
Me
Ph
CO2Et
PhHN
EtO2C
S
S
l
O
EtO2C
CO2Et
PhHN
85%) were in accordance with the literature.10 Although vated methylene substrates even though only one example
this strategy has already been described, our modifica- of thienopyrrole has been described by El-Shafei.1
tions offer some advantages. Formation of the thiophene
The influence of the substituents of the isothiocyanate on
and pyrrole rings are independent and can be extended to
its behaviour during the condensation under basic condi-
a large number of symmetrical and unsymmetrical acti-
tions has been investigated in a last step. Phenyl isothio-
Synlett 2001, No. 11, 1731–1734 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Easy Access to Variously Substituted Thieno[2,3-b]pyrroles
1733
R2
R1
Br-CH2-CO2Et
O
Y
Y
EtO2C
R2
R1
N
S
acetone, reflux, 4-5d
2
3
Ph
R1
PhHN
Y
R2
S
1
Cl-CH2-CN
R
1 =R2 = Me, Ph, OEt, -(CH2)3-
Y = CO2Et,CO2Me
NC
acetone, reflux, 4-5d
S
N
Ph
Scheme 2
Table 2 Synthesis of Thienopyrroles 2 and 3 from Thiophenes 1
Entry
Compound
Product
Yield (%)
2a
2b
71(R=Me)
73(R=Et)
Ac
Me
Me
Me
EtO2C
CO2R
CO2R
PhHN
S
N
S
Ph
Ph
2d
2e
3b
61
65
85
Bz
Ph
Me
Me
Ph
EtO2C
EtO2C
NC
CO2Et
CO2Et
PhHN
S
S
S
N
S
Ph
Ac
Me
Me
CN
CN
PhHN
N
S
Ph
Ac
Me
Ph
Me
CO2Et
CO2Et
PhHN
N
S
cyanate has been almost exclusively used for related Our second goal was to obtain a N-substituted thieno[2,3-
studies and this choice could be explained by the avail- b]pyrrole 2 that could be deprotected in an additional step.
ability of this compound, but above all it appeared to be Until now, all our attempts were unsuccessful using ben-
the best candidate for this reaction (Scheme 3). The re- zyl, methyl, carbethoxy or p-methoxyphenyl isothiocyan-
placement of phenyl isothiocyanate by other commercial- ates, which can actually be a limitation of this synthetic
ly available ones decreases dramatically the yields of way.
thiophene 1.
Synlett 2001, No. 11, 1731–1734 ISSN 0936-5214 © Thieme Stuttgart · New York

1734
G. Sommen et al.
LETTER
O
R2
R1
R3 = Ph 40-47%
O
O
1) K2CO3/DMF
Et
27%
R1
R2
2) R3-NCS
Me
Allyl
-
-
HN
R3
CO2Et
S
3) Br-CH2-CO2Et
1
R1 =R2 = Me, Ph, OEt, -(CH2)3-
Scheme 3
was stirred 2 h at r.t. The alkyl bromoacetate (or chloro-
acetonitrile) (10.0 mmol, 1 equiv) was added and dried
K2CO3 (10.0 mmol, 1 equiv). The reaction was quenched
with 100 mL of H2O after having stirred 4 h at r.t. The crude
product precipitated and was purified by filtration followed
by crystallisation in EtOH.
4-Acetyl-3-methyl-5-phenylamino-thiophene-2-
carboxylic Acid Ethyl Ester(1b): mp : 125 °C.
1H NMR (250 MHz, CDCl3): 1.34 (t, 3 H, J = 7.1 Hz),
2.58 (s, 3 H), 2.82 (s, 3 H), 4.28 (q, 2 H, J = 7.1 Hz), 7.35–
7.42 (m, 5 HAr), 12.1 (s, 1 H). 13C NMR (62.5 MHz,
CDCl3): 14.3 (CH3), 16.5 (CH3), 31.3 (CH3), 60.5 (CH2),
108.9 (CAr), 119.2 (Car), 120.5 (CHAr), 124.7 (2 CHAr),
129.5 (2 CHAr), 139.6 (CAr), 145.8 (CAr), 162.7 (CAr),
163.4 (CO2), 195.7 (CO).
In summary, we have shown that facile formation of di-
versily substituted thieno[2,3-b]pyrrole 2 or 3 can be car-
ried out in two steps using phenyl isothiocyanate and
K2CO3/DMF as the condensation promoter. The de-
scribed method is easy and can be applied to a large num-
ber of activated methylene compounds.
References and Notes
(1) El-Shafei, A. K.; Abdel-Ghany, H. A.; Sultan, A. A.; El-
Saghier, A. M. M. Phosphorus, Sulfur, and Silicon 1992, 73,
15.
(2) Augustin, M.; Rudorf, W. D.; Schmidt, U. Tetrahedron
1976, 32, 3055.
(3) Gompper, R.; Schaefer, H. Chem. Ber. 1967, 100, 591.
(4) Mashraqui, S. H.; Hariharasubrahmanian, H.; Kumar, S.
Synthesis 1999, 12, 2030.
(5) Mukerjee, A. K.; Ashare, R. Chem. Rev. 1991, 91, 1.
(6) Sharma, S. Sulfur Reports 1989, 8, 327.
(7) Rudorf, W. D.; Schierhorn, A.; Augustin, M. Tetrahedron
1979, 35, 551.
(8) Comel, A.; Kirsch, G. J. Heterocycl. Chem. 2001 in press.
(9) For a review, see: Garcia, F.; Galvez, C. Synthesis 1985,
143; and references therein.
(12) Typical procedure for the preparation of thieno[2,3-
b]pyrroles 2: Alkyl bromoacetate (or chloroaceto nitrile)
(15.0 mmol, 1.5 equiv) was added to a stirred solution of
thiophene 1 (10.0 mmol, 1 equiv) in 30 mL of dry acetone
and dried K2CO3 (10.0 mmol, 1 equiv). The reaction mixture
was heated at reflux for 5 days before quenching in 100 mL
of water. The crude product precipitated and was purified by
filtration followed by recrystallisation in EtOH.
3,4-Dimethyl-6-phenyl-6H-thieno[2,3-b]pyrrole-2,5-
dicarboxylic Acid Diethyl Ester(2b): mp : 127 °C. 1H
NMR (250 MHz, CDCl3): 1.08 (t, 3 H, J = 7.2 Hz), 1.33 (t,
3 H, J = 7.2 Hz), 2.71 (s, 3 H), 2.83 (s, 3 H), 4.14 (q, 2 H,
J = 7.2 Hz), 4.16 (q, 2 H, J = 7.2 Hz), 7.30–7.34 (m, 5 Har).
13C NMR (62.5 MHz, CDCl3): 11.7 (CH3), 13.8 (CH3),
14.3 (CH3), 14.5 (CH3), 60.1 (CH2), 60.5 (CH2), 120.3
(CAr), 124.8 (CAr), 125.0 (CAr), 126.1 (CHAr), 127.5 (2
CHAr), 128.9 (2 CHAr), 130.7 (CAr), 139.7 (CAr), 139.9
(CAr), 143.5 (CAr), 161.1 (CO2), 163.1 (CO2).
(10) Wierzbicki, M.; Cagniant, D.; Cagniant, P. Bull. Soc. Chim.
Fr. 1975, 7-8, 1786.
(11) Typical procedure for the preparation of thiophenes 1:
A 100 mL three-necked round-bottom flask equipped with
magnetic stirrer, condenser and septum was charged with a
solution of 1,3-diketone (10.0 mmol, 1 equiv) in DMF (30
mL). Dried K2CO3 (10.0 mmol, 1 equiv), was added and the
mixture was stirred for 1 h at r.t. The isothiocyanate (10.0
mmol, 1 equiv) was then added dropwise and the mixture
Synlett 2001, No. 11, 1731–1734 ISSN 0936-5214 © Thieme Stuttgart · New York