Novel synthesis of substituted thiophenes by palladium-catalyzed cycloisomerization of (Z)-2-En-4-yne-1-thiols

Article abstract of DOI:10.1021/ol991297c

(formula presented) The first example of palladium-catalyzed cycloisomerization of (Z)-2-en-4-yne-1-thiols 1 to give substituted thiophenes 2 is reported. Cycloisomerization reactions are carried out under nitrogen at 25-100 °C in N,N-dimethylacetamide as

Full text of DOI:10.1021/ol991297c

ORGANIC
LETTERS
2000
Vol. 2, No. 3
351-352
Novel Synthesis of Substituted
Thiophenes by Palladium-Catalyzed
Cycloisomerization of
(Z)-2-En-4-yne-1-thiols
,†
Bartolo Gabriele,* Giuseppe Salerno,* and Alessia Fazio
Dipartimento di Chimica, UniVersita` della Calabria, 87030 ArcaVacata di Rende,
Cosenza, Italy
b.gabriele@unical.it
Received December 1, 1999
ABSTRACT
The first example of palladium-catalyzed cycloisomerization of (Z)-2-en-4-yne-1-thiols 1 to give substituted thiophenes 2 is reported.
Cycloisomerization reactions are carried out under nitrogen at 25−100 °Cin N,N-dimethylacetamide as the solvent in the presence of catalytic
amounts of PdI2 in conjunction with KI to give the corresponding thiophenes in 43−94% yield.
Thiophenes are a very important class of heterocyclic
compounds. A variety of molecules containing the thiophene
ring display a wide range of biological activity and find
application as pharmaceuticals1 or fragrance compounds.2
Moreover, they are also useful synthetic intermediates: for
example, in the preparation of new conducting polymers3
or nonlinear optical materials.4
We report herein a novel synthesis of substituted thiophenes
2, based on Pd-catalyzed cycloisomerization6 of the readily
available7 (Z)-2-en-4-yne-1-thiols 1 (eq 1).8
Substituted thiophenes can be prepared by proper func-
tionalization of the thiophene ring, usually through R-meta-
lation or â-halogenation.1 However, annulation reactions of
suitably substituted acyclic precursors represent an attractive
alternative methodology, which may allow direct regio-
selective preparation of the target molecule. Recently, several
new methods have been developed which illustrate the utility
of the last approach.5
Table 1 reports the results obtained with different enyne-
thiols 1. Reactions were carried out at 25-100 °C in the
(5) For representative examples, see: (a) Fazio, A.; Gabriele, B.; Salerno,
G.; Destri, S. Tetrahedron 1999, 55, 485-502. (b) Tarasova, O. A.; Klyba,
L. V.; Vvedensky, V. Y.; Nedolya, N. A.; Trofimov, B. A.; Brandsma, L.;
Verkruijsse, H. D. Eur. J. Org. Chem. 1998, 253-256. (c) Ong, C. W.;
Chen, C. M.; Wang, L. F. Tetrahedron Lett. 1998, 39, 9191-9192. (d)
Stephensen, H.; Zaragoza, F. J. Org. Chem. 1997, 62, 6096-6097. (e)
Marson, C. M.; Campbell, J. Tetrahedron Lett. 1997, 38, 7785-7788. (f)
Obrecht, D.; Gerber, F.; Sprenger, D.; Masquelin, T. HelV. Chim. Acta 1997,
80, 531-537. (g) Guan, H.-P.; Luo, B.-H.; Hu, C.-M. Synthesis 1997, 461-
464. (h) Reddy, K. R.; Rao, M. V. B.; Ila, H.; Junjappa, H. Synth. Commun.
1996, 26, 4157-4164. (i) Coppola, G. M.; Damon, R. E.; Yu, H. Synlett
1995, 1143-1144. (j) Kang, K.-T.; U, J. S. Synth. Commun. 1995, 25,
2647-2653. (k) Marshall, J. A.; DuBay, W. J. Synlett 1993, 209-210. (l)
Waldvogel, E. HelV. Chim. Acta 1992, 75, 907-912. (m) Mohareb, R. M.
Gazz. Chim. Ital. 1992, 122, 147-150. (n) Eichinger, K.; Mayr, P.;
Nussbaumer, P. Synthesis 1989, 210-211.
† E-mail: g.salerno@unical.it.
(1) The Chemistry of Heterocyclic Compounds: Thiophene and Its
DeriVatiVes; Gronowitz, S., Ed.; Wiley: New York, 1991; Vol. 44.
(2) Bertram, H. J.; Emberger, R.; Gu¨ntert, M.; Sommer, H.; Werkhoff,
P. In Recent DeVelopments in FlaVor and Fragrance Chemistry; Hopp, R.,
Mori, K., Eds.; VCH: Weinheim, Germany, 1993.
(3) (a) Roncali, J. Chem. ReV. 1992, 92, 711-738. (b) Handbook of
ConductiVe Polymers; Skotheim, T. A., Ed.; Marcel Dekker: New York,
1986.
(4) Nalwa, H. S. AdV. Mater. 1993, 5, 341-358.
10.1021/ol991297c CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/12/2000

Scheme 1
Table 1. Synthesis of Thiophenes 2 by Pd-Catalyzed
Cycloisomerization of (Z)-2-En-4-yne-1-thiols 1a
entry
1
R1
R2
R3
R4
time (h)
yield (%)b
1c,d
2c
3
4
5
6e
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
Et
Me
Me
Me
Me
Me
H
H
H
H
Bu
Ph
Bu
2
1
1.5
15
8
45 (36)
80 (71)
65 (58)
52 (44)
64 (56)
94 (89)
Et
Ph
H
H
H
Since the triple bond necessarily coordinates to Pd(II) at the
beginning of the catalytic cycle, a higher reactivity is
expected for substrates bearing a less hindered triple bond.
This is confirmed by the experimental results. Thus, enyne-
thiols bearing an external triple bond were more reactive than
analogous substrates substituted at C-5 (compare entry 3 with
entries 4 and 5 in Table 1). Analogously, substitution at C-2
rather than C-3 led to a dramatic increase in reaction rates,
and the reaction could be carried out at room temperature
rather than 100 °C (compare entries 4 and 6). This also
ensured a higher product yield, owing to the diminished
tendency for decomposition at this temperature. Even
substitution at C-1 favored the annulation process (compare
entries 1 and 2), probably by the “reactive rotamer” effect.10
Electronic effects, however, also play a role in determining
the reactivity of enynethiols. For example, phenyl rather than
alkyl substitution at C-5 led to a faster reaction (compare
entries 4 and 5). This could be due to the higher electrophilic
character of the triple bond when conjugated to an aryl group,
which tends to promote the cyclization step, even though
coordination to palladium is conceivably less favored.
To our knowledge, the reaction described here is the first
example of a synthesis of substituted thiophenes via a Pd-
catalyzed cycloisomerization reaction. Formation of thiophenes
through annulation of (Z)-2-en-4-yne-1-thiols bearing an
internal triple bond substituted with an alkyl group has been
reported to occur under strongly basic conditions using
KOBut in ButOH in the presence of 18-crown-6.5k In contrast,
the present methodology works catalytically under essentially
neutral conditions and can be applied to a variety of
enynethiols, including base-sensitive substrates such as those
bearing an external triple bond.
1
a Unless otherwise noted, all reactions were carried out under nitrogen
in anhydrous DMA (2 mmol of 1/mL of DMA) at 100 °C using PdI2:KI:
substrate molar ratio 1:2:100. b GLC yields (isolated yields) based on 1.
c The reaction was carried out without solvent. d Substrate:PdI2 molar ratio
50. e The reaction was carried out at 25 °C.
presence of PdI2 (1-2%) in conjunction with 2 equiv of KI,
the latter being necessary for solubilizing PdI2 in the reaction
medium. As we already observed in the Pd(II)-catalyzed
cycloisomerization of (Z)-2-en-4-yn-1-ols leading to furans,8a
iodide rather than chloride or bromide as a counterion to
Pd(II) ensured faster reaction rates and better yields in final
products. Only traces of thiophenes 2 were obtained when
reactions were carried out in the absence of catalyst, with
partial decomposition of starting enynethiols 1. Substrates
leading to low-boiling thiophenes were caused to react with
2-
PdI4 without additional solvent, to facilitate product
recovery. In other cases, N,N-dimethylacetamide (DMA) was
used as the solvent. This ensured lower viscosity of the
medium and better yields in thiophenes (even though the
kinetics were slowed). It is conceivable that substrate and/
or thiophene decomposition becomes less favored with
dilution.
A likely mechanism for the cycloisomerization process
involves the electrophilic activation of the triple bond by
Pd(II)9 followed by intramolecular nucleophilic attack by the
-SH group, protonolysis, and aromatization (Scheme 1).
(6) For a recent review on transition-metal-catalyzed cycloisomerizations,
see: Trost, B. M.; Krische, M. J. Synlett 1998, 1-16.
(7) (Z)-2-En-4-yne-1-thiols 1 can be easily prepared by reductive cleavage
of the corresponding thioacetates with LiAlH4, as described in the Supporting
Information. The use of DIBAL rather than LiAlH4 has also been reported.5k
(8) The synthesis of furans via cycloisomerization of (Z)-2-en-4-yn-1-
ols has been described: (a) Gabriele, B.; Salerno, G.; Lauria, E. J. Org.
Chem. 1999, 64, 7687-7692 and references therein. For a review on
regioselective syntheses of substituted furans, including transition-metal-
catalyzed cyclizations, see: (b) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.;
Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998,
54, 1955-2020. For recent reviews on synthesis of aromatic heterocycles,
see: (c) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2849-2866.
(d) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998, 615-628.
(9) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York, 1995.
(10) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205-1222.
Acknowledgment. Financial support from the Ministero
dell’Universita` e della Ricerca Scientifica e Tecnologica is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL991297C
352
Org. Lett., Vol. 2, No. 3, 2000