Direct synthesis of highly substituted thiophenes through copper(i)-catalyzed tandem reactions of alkylidenethiiranes with terminal alkynes

Article abstract of DOI:10.1039/b909284f

A novel copper(i)-catalyzed tandem addition/cycloisomerization reaction of 1-phenylsulfonylalkylidenethiiranes with terminal alkynes for the convergent assembly of 2-(α-phenylsulfonylalkyl)-thiophenes is reported, which could directly assemble various fun

Full text of DOI:10.1039/b909284f

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Direct synthesis of highly substituted thiophenes through
copper(I)-catalyzed tandem reactions of alkylidenethiiranes
with terminal alkyneswz
Yiping Zhang, Ming Bian, Weijun Yao, Jianming Gu and Cheng Ma*
Received (in Cambridge, UK) 11th May 2009, Accepted 9th June 2009
First published as an Advance Article on the web 30th June 2009
DOI: 10.1039/b909284f
A novel copper(I)-catalyzed tandem addition/cycloisomerization
reaction of 1-phenylsulfonylalkylidenethiiranes with terminal
alkynes for the convergent assembly of 2-(a-phenylsulfonylalkyl)-
thiophenes is reported, which could directly assemble various
functional groups incorporated into the thiophene ring.
Substituted thiophenes are important synthetic targets given
their application in natural product total synthesis, drug
discovery and materials science.1 Thus, methods to assemble
Scheme 1 Cu(I)-catalyzed tandem reactions of 1 with 2.
such diverse functionalized thiophenes are of considerable
importance. Polysubstituted thiophenes are generally obtained,
either by direct functionalization of a thiophene ring,2 or by
annulation reactions of some suitably substituted acyclic
precursors.3 The latter may allow regioselective preparation
of the thiophene derivatives and therefore represents an
attractive approach.
from low functional group tolerance. As part of our ongoing
research concerning the synthesis of heterocycles via ring
transformations,6 we present herein, a novel Cu(I)-catalyzed
tandem addition/cycloisomerization reaction7 of 1-phenyl-
sulfonylalkylidenethiiranes 18 with terminal alkynes 2 for the
convergent assembly of functionalized thiophenes 3 (Scheme 1).
We initiated our study with the reaction of thiirane 1a
(R1 = CH3, R2 = H) and phenylacetylene 2a, treated by
various coin-metal catalysts under argon in the presence of
10 mol% DBU (Table 1). Whereas silver or gold catalysts
afforded no product or only trace amounts (entries 2 and 3), a
variety of Cu(I) catalysts, such as [(SIPr)CuCl] (SIPr = N,N-
bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene), CuCl, CuBr,
or CuI carried out the tandem process to produce the
2-(a-phenylsulfonylalkyl) thiophene 3a in moderate to good
yields (Table 1, entries 4–7). Among these salts, however, CuCl
is the most efficient catalyst based on reaction yield. Upon
reducing the catalyst loading from 20 mol% to 10 mol%, the
Transition metal-catalyzed transformations such as cyclo-
isomerizations, cyclizations and rearrangements have recently
emerged as powerful tools for the synthesis of various hetero-
cycles, except sulfur-containing ones.4 A rationale for this
might be that organosulfur compounds such as thiols, sulfides
and disulfides are known to strongly coordinate to transition
metals, which does not render the use of transition metal
catalysts in the presence of these functional groups very
promising. To date, only a few successful methods have been
developed for the preparation of substituted thiophenes in the
presence of transition metal catalysts. Gabriele et al.
demonstrated the first palladium-catalyzed cycloisomerization
of (Z)-2-en-4-yne-1-thiols to furnish substituted thiophenes.3a
Recently, a very interesting gold-catalyzed cyclization of
(a-alkoxyalkyl)(ortho-alkynyl phenyl) sulfides leading to
2,3-disubstituted benzothiophenes was disclosed by Nakamura
and coworkers.5 However, these protocols require a complex
substrate with predetermined functionalities, and often suffer
Table 1 Optimization of the reaction conditions of 1a with 2aa
Entry Catalyst
Base
Solvent
Temp. Yield (%)b
1
2
3
4
5
6
—
DBU
DBU
DBU
DBU
DBU
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Reflux
Reflux
—
—
AgOTf
AuCl3
CuI
CuBr
[(SIPr)CuCl] DBU
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Reflux o5
Reflux 68
Reflux 72
Reflux 69
Reflux 86
Reflux 85
Reflux 73
Reflux 71
Department of Chemistry, Zhejiang University, Hangzhou, China.
E-mail: mcorg@zju.edu.cn; Fax: +86 571 87953375;
Tel: +86 571 87953375
w Electronic supplementary information (ESI) available: Experimental
details, crystallographic information files (CIF) for compound 3m,
and characterization data for new products. CCDC 731411. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b909284f
z Crystal data for 3m (CCDC 731411): C19H17BrO3S2; M = 437.37;
T = 296(1) K; monoclinic; space group: P-1; a = 5.4744(4),
b = 24.9708(17), c = 13.4472(11) A, a = 90.0000, b = 91.662(2),
g = 90.00001, V = 1837.5(2) A3; Z = 4; reflections collected: 17 315,
unique: 4132; Rint = 0.095; R1 = 0.0607, wR2 = 0.0899 (observed
data).
7
DBU
DBU
iPr2EtN Toluene
Et3N
DBU
DBU
DBU
DBU
DBU
8c
9
10
11
12
13
14
15
Toluene
ClCH2CH2Cl Reflux 84
1,4-Dioxane
MeCN
Toluene
Toluene
Reflux 73
Reflux 51
50 1C 91
25 1C o5
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), catalyst (0.1 mmol),
b
base (0.05 mmol), 10 h. Isolated yield. CuCl (0.05 mmol).
c
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reaction proceeded slowly over 24 h and gave 3a in a similar
yield (Table 1, entry 8). In contrast, the reaction in the absence
of any copper salt led to recovery of the starting material.
Moreover, DBU proved to be the optimum base among those
we examined, and the yield decreased slightly when another
base such as Et3N or iPr2EtN was used (Table 1, entries 9 and
10). The reaction proceeded much better in non-polar solvents
than in polar ones. For example, reactions in 1,4-dioxane, or
CH3CN, instead of in toluene, afforded 3a in 73% and 51%
yield, respectively (Table 1, entries 11–13). Finally, reaction
temperature also played a significant role in this process. The
reaction was quite sluggish at room temperature and only a
trace amount of 3a was obtained after 10 h (Table 1, entry 15).
However, presumably due to the instabilities of substrates or
reaction intermediates, the reaction at 50 1C gave highest yield
(Table 1, entry 14).
Table 2 Copper-catalyzed reaction for the synthesis of thiophenes 3a
Entry Alkyne 2
Time/hb Product 3, yieldc (%)
1
2a 10
3a
91
2
3
4
2b 10
3b
86
2c
8
3c
68
2d 10
2e 10
3d
65d
5
3e
67
Next, the reactions of 1a with a set of alkynes 2a–o under
the optimized conditions were investigated. The results are
summarized in Table 2. We were pleased to see that electron-
rich or electron-poor aryl- and alkyl-substituted alkynes were
readily accommodated, producing the expected products 3 in
moderate to good yields. Notably, a free amino group was also
tolerated in this transformation, and gave 3e in 67% yield. A
number of heterocycles, including a thiophene, a furan and a
pyridine, have also successfully been employed in this process,
although an extended reaction time was required to get a good
yield (Table 2, entries 6–8). Alkyl-substituted substrates were
more active than their aryl counterparts in this conversion.
The presence of a cyclopropane, an olefin, an a-chloro ester,
an aryl ether, and an alcohol on the remote end of the triple
bond of alkynes 2 presented no difficulties to give the expected
products in good yields (Table 2, entries 9–14).
6
7
8
2f 12
2g 12
3f
68
3g
73
2h
8
3h
85
9
2i
2j
2k
2l
5
3
6
3
3i
91
10
11
12
3j
88
3k
67
3l
79
Moreover, the generality of the reaction was demonstrated
by variation of the thiirane partner (1b: R1 = Bn, R2 = nBu;
1c: R1 = nBu, R2 = nPr). The tandem reaction is obviously
sensitive to steric hindrance in the thiiranes 1. Consequently,
formation of 3o–q required 14–20 h at refluxing temperature in
toluene (Table 2, entries 15–17).
13
2m
2n
8
6
3m
81
14
3n
75
Nevertheless, thiirane 1a reacted with 1,3-diethynylbenzene
(4) under the same conditions, resulting in a mixture of 3r and
5. To our satisfaction, only by changing the ratio of 1a to 4, we
could obtain almost a sole product of 3r, or 5 in good yield,
respectively (Scheme 2).
15e
2a 14
3o
76
16e
2a 16
2o 20
3p
72
These Cu(I)-catalyzed processes not only quickly construct a
functionalized thiophene, but also provide a very useful handle
for further structural manipulation (Scheme 3). For example,
mono-bromination of 3a by an N-bromosuccinimide
(NBS)–FeCl3 system9 gave rise to the corresponding 3-bromo-
thiophene 6, which can carry out the Suzuki–Miyaura
cross-coupling reaction with p-tolylboronic acid to furnish a
fully substituted thiophene 7. On the other hand, the phenyl-
sulfonyl group could easily direct additional diversity10 at the
side-chain of the thiophene ring and be subsequently removed
by magnesium-mediated reductive desulfonylation.11
17e
3q
68
a
Reaction conditions: thiirane 1 (0.5 mmol), alkyne 2 (0.75 mmol),
b
CuCl (0.1 mmol), DBU (0.05 mmol), toluene, 50 1C. Reaction time
for consuming the starting material 1. Isolated yield. Crystallization
e
yield. At refluxing temperature.
c
d
sulfur atom of enthiol A at the alkynyl moiety, followed by
protonation, would afford a cyclized intermediate B.13 Finally,
the latter undergoes a 1,3-hydrogen shift reaction to furnish
2-(a-phenylsulfonylalkyl) thiophene 3.
A plausible mechanism for the current copper(I)-catalyzed
tandem reaction is illustrated in Scheme 4. The ring-opening
reaction of thiirane 1 upon treatment with an in situ generated
copper acetylide gave the enthiol A,12 which could coordinate
to CuCl with its triple bond. Next, nucleophilic attack of the
In conclusion, we have developed a novel Cu(I)-catalyzed
addition/cycloisomerization reaction of alkylidenethiiranes with
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4730 | Chem. Commun., 2009, 4729–4731

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(b) H. J. Bertram, R. Emberger, M. Guntert, H. Sommer and
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Scheme 2 Reactions of thiirane 1a with 1,3-diethynylbenzene (4).
3 For the substrates from alkyne, see: (a) B. Gabriele, G. Salerno and
A. Fazio, Org. Lett., 2000, 2, 351; (b) J. A. Marshall and
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M. Sabbaghan, Tetrahedron Lett., 2008, 49, 844.
4 For selected reviews, see: (a) N. T. Patil and Y. Yamamoto, Chem.
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Scheme 3 The transformations of thiophenes 3a and 3o.
5 I. Nakamura, T. Sato and Y. Yamamoto, Angew. Chem., Int. Ed.,
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6 (a) C. Ma and Y. Yang, Org. Lett., 2005, 7, 1343; (b) C. Ma,
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Y. Na, H. Han and S. Chang, Chem. Soc. Rev., 2004, 33, 302;
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Chem. Rev., 2005, 105, 1001.
8 For the facile synthesis of 1-phenylsulfonylalkylidenethiiranes 1,
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9 (a) Y. Zhang, K. Shibatomi and H. Yamamoto, Synlett, 2005,
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367; (c) P. R. Blackmore, J. Chem. Soc., Perkin Trans. 1, 2002,
2563.
Scheme 4 Cu(I)-mediated addition/cycloisomerization reactions.
terminal alkynes for the synthesis of 2-(a-phenylsulfonylalkyl)-
thiophenes. The reaction proceeds under mild conditions and
allows easy introduction of various functional groups directly
incorporated into the thiophene ring. Further studies are focused
on mechanism details as well as synthetic utility of this prompt
approach.
´
11 For a review, see: C. Najera and M. Yus, Tetrahedron, 1999, 55,
10547.
We are grateful to the Science and Technology Commission
of Zhejiang Province (Grant Nos. 2007C21G2010067), and
National Natural Science Foundation of China (Grant Nos.
20672096) for financial support.
12 Ring-opening reaction of alkylidenethiiranes by a copper acetylide
generated in situ has no precedent to the best of our knowledge.
For Palladium(0)-catalyzed intra- and intermolecular cyclization
of allene episulfides, see: N. Choi, Y. Kabe and W. Ando,
Tetrahedron Lett., 1991, 32, 4573.
13 For precedent of nitrogen atom attacking at a triple bond in Cu(I)-
catalyzed three-component coupling, and cyclization of N-protected
ethynylanilines, amine and aldehyde, see: H. Ohno, Y. Ohta,
S. Oishi and N. Fujii, Angew. Chem., Int. Ed., 2007, 46, 2295.
Notes and references
1 For books and reviews, see: (a) J. B. Press, in The Chemistry of
Heterocyclic Compounds: Thiophenes and Its Derivatives, ed.
S. Gronowitz, John Wiley & Sons, New York, 1991, vol. 44;
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 4729–4731 | 4731