An improved method for the synthesis of aminothiophenes precursors of thieno[2,3-b]pyrrole

Article abstract of DOI:10.1016/S0040-4039(01)02130-X

Thiophenes 2 can easily be synthesized in two steps by using phenyl isothiocyanate and activated methylene compounds.

Full text of DOI:10.1016/S0040-4039(01)02130-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 257–259
An improved method for the synthesis of aminothiophenes
precursors of thieno[2,3-b]pyrrole
Geoffroy Sommen, Alain Comel and Gilbert Kirsch*
Laboratoire d’Inge´nierie Mole´culaire et de Biochimie Pharmacologique, Faculte´ des Sciences, Ile du Saulcy, 57045 Metz Cedex 1,
France
Received 24 October 2001; revised 7 November 2001; accepted 9 November 2001
Abstract—Thiophenes 2 can easily be synthesized in two steps by using phenyl isothiocyanate and activated methylene
compounds. © 2002 Elsevier Science Ltd. All rights reserved.
Ketene dithioacetals are key intermediates for the
A similar strategy had already been used3 but the
formation of thieno[2,3-b]pyrrole from the obtained
thiophenes 2 was poorly related.
preparation of
a
large number of heterocyclic
structures1. Various nucleophiles (amines, hydrazines,
organometallic reagents,…) can displace one of the
methylthio group and cyclisation of the intermediate
can generally occur during the same stage.
In order to improve the yields described in our previous
work and to extend this method to starting compounds
that failed to give the expected thiophenes 2, we
decided to isolate ketene phenylamino methylthio
acetals 1. These compounds were easily obtained in
yields around 90% in all cases following the same
conditions2 using methyl iodide (Scheme 1).
We described recently2 a one-pot procedure to obtain
thiophenes in moderate to good yields, by reacting
1,3-diketones or equivalents with isothiocyanates (gen-
erally phenyl isothiocyanate) in
a basic medium
(K2CO3/DMF), followed by a condensation with bro-
macetate or chloracetonitrile and a Dieckmann-type
cyclisation in the same step.
We therefore, investigated in a second step the ability
of thioglycolate to react with compounds 1 what is well
Method A
O
O
S
R1
R2
O
O
O
R2
R1
R1
R2
Ref 2
1) K2CO3/DMF/RT
2) Ph-NCS
1) BrCH2CO2Et
R1
R2
EtO2C
CO2Et
2) K2CO3/DMF/RT
HN
N
S
HN
Ph
CO2Et
S
Ph
Ph
2
CH3-I
HSCH2CO2Et
K2CO3/EtOH
O
O
Method B
R1
R2
HN
SMe
Ph
1
Scheme 1.
* Corresponding author. Tel.: (0033)387315295; fax: (0033)387315333; e-mail: kirsch@sciences.univ-metz.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02130-X

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G. Sommen et al. / Tetrahedron Letters 43 (2002) 257–259
Table 1. Comparison of the two methods for the preparation of thiophenes 2
known for other various nucleophiles1 like amines,
hydrazines or organometallics reagents but surprisingly
never used for thiols. To the best of our knowledge, the
displacement of the thiomethyl group of a ketene
dithioacetal or aminothioacetal using a thiol is just
described in one case in the literature4 even though our
initial results indicated that this was the way of choice
for the preparation of thiophenes 2. Similarly to what
we described for our one-step method, we have not
been able to isolate the new ketene aminothioacetals
formed and cyclization occurred under our experimen-
tal conditions to furnish thiophenes 2 in moderate to
good yields (Table 1).
In summary, this two-step method is an accurate com-
plement to the one we described earlier and should be
used each time the one-step pathway does not allow to
obtain thiophenes 2 in reasonable yields.
References
1. (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990,
46, 5423; (b) Kolb, M. Synthesis 1990, 3, 171; (c) Tomi-
naga, Y. J. Heterocyclic Chem. 1989, 26, 1167; (d) Wang,
M. X.; Liu, Y.; Huang, Z. T. Tetrahedron Lett. 2001, 42,
2553; (e) Su, M.; Ma, H.; Ma, Q.; Wang, Z.; Yang, J.;
Wang, X. Chem. Commun. 2001, 960; (f) Barun, O.;
Mohanta, P. K.; Ila, H.; Junjappa, H. Synlett 2000, 5, 653.
2. Sommen, G.; Comel, A.; Kirsch, G. Synlett 2001, 11, 1731.
3. (a) Gronowitz, S. The Chemistry of Heterocyclic Com-
pounds Part 1; John Wiley & Sons: New York, 1985; Vol.
44, p. 66; (b) El-Shafei, A. K.; Abdel-Ghany, H. A.;
Sultan, A. A.; El-Saghier, A. M. M. Phosphorus Sulfur
Silicon 1992, 73, 15.
Although two steps are required for the preparation of
the thiophene ring the yields for the two steps, in the
cases we reported here, have been increased by a factor
of 2–3.
On the other hand, thiophenes 2d–e could be obtained
by this way in moderate yields when our one-step
method completely failed. We must note that in some
cases, our previous one-step method remains attractive
for the preparation of thiophenes 2 (see 2f).
4. (a) Wilson, K. J.; Illig, C. R.; Subasinghe, N.; Hoffman, J.
B.; Rudolph, M. J.; Soll, R.; Molloy, C. J.; Bone, R.;
Green, D.; Randall, T.; Zhang, M.; Lewandowski, F. A.;

G. Sommen et al. / Tetrahedron Letters 43 (2002) 257–259
259
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lais, R. L.; Spurlino, J. Bioorg. Med. Chem. Lett 2001, 11,
915; (b) Tominaga, Y.; Luo, J.-K.; Castle, R. N. J. Hetero-
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NMR (62.5 MHz, CDCl3): l 14.3, 23.8, 111.6, 118.9, 120.1,
123.9, 128.8, 149.6, 164.9, 190.3.
4-Acetyl-3-methyl-5-phenylaminothiophene-2-carboxylic
acid ethyl ester 2a:Mp: 125°C. 1H NMR (250 MHz, CDCl3):
l 1.34 (t, 3H, J=7.1 Hz), 2.58 (s, 3H), 2.82 (s, 3H), 4.28
(q, 2H, J=7.1 Hz), 7.35–7.42 (m, 5Har), 12.1 (s, 1H). 13C
NMR (62.5 MHz, CDCl3): l 14.3, 16.5, 31.3, 60.5, 108.9,
119.2, 120.5, 124.7, 129.5, 139.6, 145.8, 162.7, 163.4, 195.7.
3-(Methylsulfanyl-phenylamino-methylene)-pentane-2,4-
1
dione 1a: Mp: 72°C. H NMR (250 MHz, CDCl3): l 2.12
(s, 6H), 2.50 (s, 3H), 6.70 (d, 2Har, J=7.3 Hz), 7.04 (d, 1Har,
J=7.3 Hz), 7.26 (dd, 2Har, J=7.3 Hz), 15.04 (s, 1H). 13C