Mendeleev Commun., 2004, 14(1), 29
A novel approach to 4H-thieno[3,2-b]pyrroles
Mikhail M. Krayushkin,* Felix M. Stoyanovich and Sergei V. Shorunov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
DOI: 10.1070/MC2004v014n01ABEH001877
The condensation of 3-nitro-5-carboxy-2-methylthiophene with acetals of amides proceeds smoothly, and further ammonium formate–
Pd/C reduction of nitroenamines thus obtained affords 2-carboxythieno-(5-R)-[3,2-b]pyrroles (R = H, Me) in good yields.
Thieno[3,2-b]pyrroles, close indole analogues, are of particu-
OMe
1
lar interest as biologically active compounds and the moieties
O N
O N
2
2
MeO
NMe2
2
–4
of photochromic compounds. The most common synthetic
R
R
5
methods of construction of the thieno[3,2-b]pyrrole core employ
CO H
CO Me
2
6
S
2
Me N
cyclisation of azidovinyl thiophene derivatives, condensation
2
S
of nitromethylthiophenes with diethyl oxalate with further reduc-
1
2 R = H, 80%
3 R = Me, 60%
II
tion of obtained nitrothienylpyruvic acids with either Fe , SnCl
2
7
or NaHSO , reduction of nitrovinylthiophenes with trialkyl
3
8
H
phosphites, and also Fischer-reminiscent cyclisation of hydrazino-
N
5
R
thiophenes. Each of the above methods has some drawbacks.
HCO NH –Pd/C
2
4
Moreover, none of them leads to 2-carboxy-5-alkylthieno[3,2-b]-
pyrroles. Thus, the construction of these compounds is still of
prime interest.
MeOH
MeO2C
S
4
5
R = H, 71%
R = Me, 72%
In our search for a convenient preparative method for the
synthesis of thieno[3,2-b]pyrroles, we noted the Batcho and
9
–11
Leimgruber indole synthesis,
which employs condensation
of substituted o-nitrotoluenes with N,N-dimethylformamide di-
methyl acetal followed by the reduction of the resulting nitro-
enamines to the corresponding indoles. We found that this reac-
tion can be extended to methyl nitrothiophenes, which possess a
considerable CH acidity of the methyl group. 3-Nitro-5-carboxy-
References
1
2
3
J. L. Treadway, European Patent 1, 136 071 A2, 2001 (Chem. Abstr.,
2
-methylthiophene 1 was chosen as an expedient starting com-
pound. Reactions of 1 with dimethyl acetals of N,N-dimethyl-
formamide and N,N-dimethylacetamide provides enamines 2
and 3 in 80% and 60% yields, respectively. Condensation is
followed by the conversion of a carboxylic acid into its methyl
ester. Compounds 2 and 3 are reduced easily with ammonium
4
M. M. Krayushkin, V. Z. Shirinyan and D. M. Nikalin, Izv. Akad. Nauk,
Ser. Khim., 2004, in press.
5
6
7
F. Garcia and C. Galvez, Synthesis, 1985, 143.
H. Hemetsberger and D. Knittel, Monatsh. Chem., 1972, 103, 194.
W. W. Gale, A. N. Scott and H. R. Snyder, J. Org. Chem., 1964, 29,
†
formate–Pd/C to form corresponding thienopyrroles 4 and 5 in
7
1 and 72% yields, respectively.
Taking into account the availability of 1 and amide acetals
2
160.
8
9
K. Srinivasan, K. G. Srinivasan, K. K. Balasubramanian and S. Swaminathan,
Synthesis, 1973, 313.
A. D. Batcho and W. Leimgruber, US Patent 3.976.639, 1976 (Chem.
Abstr., 1977, 86, 29624).
and the possibility of introducing different alkyl groups into the
-position of thienopyrrole by varying the amide acetal, good
5
yields of products, and simplicity of experiments, the above
method can be considered as useful and universal for the syn-
thesis of thienopyrroles.
1
1
0 A. D. Batcho and W. Leimgruber, Org. Synth., 1985, 63, 214.
1 R. D. Clark and D. B. Repke, Heterocycles, 1984, 22, 195.
†
Compounds 2–5 were characterised using spectroscopic methods and
elemental analysis.
(
E)-2-(2-Dimethylamino)vinyl-3-nitro-5-methoxycarbonylthiophene 2:
1
mp 155–158 °C. H NMR (250 MHz, CDCl ) d: 3.05 (s, 6H), 3.87 (s,
3
3
H), 6.54 (d, 1H, J 14.6 Hz), 7.30 (d, 1H, J 14.6 Hz), 8.10 (s, 1H). MS,
+
+
+
m/z: 258 (M + 2), 257 (M + 1), 256 (M ), 224, 150, 86. Found (%): C,
4
6.75; H, 4.65; N, 10.68; S, 12.42. Calc. for C H N O S (%): C, 46.86;
10 12 2 4
H, 4.71; N, 10.93; S, 12.51.
2
-(2-Dimethylamino-2-mehyl)vinyl-3-nitro-5-methoxycarbonylthiophene
1
3
3
(
: mp 203 °C. H NMR (250 MHz, CDCl ) d: 2.39 (s, 3H), 3.17 (s, 6H),
3
+
.87 (s, 3H), 7.02 (s, 1H), 8.22 (s, 1H). MS, m/z: 272 (M + 2), 271
+
+
M + 1), 270 (M ), 164, 100. Found (%): C, 48.75; H, 5.35; N, 10.38; S,
1
1.52. Calc. for C H N O S (%): C, 48.87; H, 5.22; N, 10.36; S, 11.86.
11 14 2 4
4
H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester 4: mp 123–
1
1
24 °C. H NMR (250 MHz, CDCl ) d: 3.90 (s, 3H), 6.49 (s, 1H), 7.19
3
–
1
(
t, 1H, J 2.76 Hz), 7.70 (s, 1H), 8.65 (s, 1H). IR (KBr, n /cm ): 3280,
max
+
+
+
1
664. MS, m/z: 183 (M + 2), 182 (M + 1), 181 (M ), 150, 122. Found
(
5
%): C, 53.02; H, 3.67; N, 7.89; S, 17.85. Calc. for C H NO S (%): C,
8 7 2
3.02; H, 3.89; N, 7.72; S, 17.69.
-Methyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester 5:
5
1
mp 175–178 °C. H NMR (250 MHz, CDCl ) d: 2.43 (s, 3H), 3.88 (s,
3
1
3
–
1
H), 6.17 (s, 1H), 7.60 (s, 1H), 8.20 (s, 1H). IR (KBr, n /cm ): 3320,
684. MS, m/z: 197 (M + 2), 196 (M + 1), 195 (M ), 164, 136. Found
max
+
+
+
(
5
%): C, 55.30; H, 4.45; N, 7.14; S, 16.20. Calc. for C H NO S (%): C,
5.36; H, 4.64; N, 7.17; S, 16.42.
9 9 2
Received: 15th December 2003; Com. 03/2203
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