A one-pot multicomponent synthesis of polysubstituted thiophenes via the reactions of an isocyanide, α-haloketones, and β-ketodithioesters in water

Article abstract of DOI:10.1016/j.tetlet.2014.01.014

An efficient synthesis of polysubstituted thiophene derivatives is achieved via the multicomponent reaction of β-ketodithioesters, α-haloketones, and cyclohexylisocyanide in aqueous medium.

Full text of DOI:10.1016/j.tetlet.2014.01.014

Tetrahedron Letters 55 (2014) 1251–1254
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A one-pot multicomponent synthesis of polysubstituted thiophenes
via the reactions of an isocyanide,
a-haloketones,
and b-ketodithioesters in water
⇑
Firouz Matloubi Moghaddam , Mohammad Reza Khodabakhshi, Arash Latifkar
Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, Azadi Street, PO Box 11155-9516, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of polysubstituted thiophene derivatives is achieved via the multicomponent
Received 24 August 2013
Revised 16 December 2013
Accepted 6 January 2014
Available online 10 January 2014
reaction of b-ketodithioesters,
a
-haloketones, and cyclohexylisocyanide in aqueous medium.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Polysubstituted thiophene
Isocyanide
Multicomponent reactions
Thiophenes are important targets for organic synthetic and
medicinalchemists because of their applications inpharmaceuticals,1
organic semi-conductors,2 conducting polymers, organic light-emit-
ting diodes (OLEDs),3 and lasers.4 The synthesis of highly substituted
thiophenes has also attracted considerable attention in organic
synthesis due to their significant biological activity. For example:
adimanine(I) acts as an anti-inflammatory agent5 and anticaine(II)
is the most commonly used dental anesthetic in Europe6 (Fig. 1).
Moreover, monocyclic, bicyclic, and tricyclic thiophene derivatives
have shown inhibition of protein tyrosine phosphatase 1B, which is
a fascinating target for Type 2 diabetes treatment.7
Numerous synthetic routes to polysubstituted thiophene deriv-
atives have been reported, such as the Fisselmane, Gewald,
Hinsberg, and Paal–Knorr syntheses of thiophene.8 Previously sev-
eral synthetic methods for the synthesis of 2,3,4-trisubstituted
thiophenes have been described. Asokan and co-workers reported
the synthesis of highly functionalized thiophene derivatives via a
two-component [3+2] cycloaddition/annulation,9 while Singh and
co-workers used two-component reactions.10 The regioselective
synthesis of polysubstituted thiophenes from Baylis–Hillman ad-
ducts has been carried out by Kim and co-workers.11 To the best
of our knowledge, there are only a few reports on the synthesis
of 2,3,5-trisubstituted thiophenes.12 In continuation of our re-
search devoted to the synthesis of highly substituted thiophenes,13
we sought to apply specific synthetic strategies to prepare such
derivatives that could be utilized as possible therapeutic inhibitors
and to disrupt certain protein–protein interactions. The application
of b-ketodithioesters as substrates led to two distinct advantages.
First, it allowed us to have a thiomethyl group as a masked methi-
onine side chain. Second, owing to its leaving group ability, we
found that (data not yet published), in the presence of appropriate
nucleophiles, and with stepwise substitution and intramolecular
condensation, the thiomethyl group and the nearby carbonyl can
be utilized for the preparation of fused heterocycles. In addition,
the presence of carbonyl groups enables us to introduce other ami-
no acid side chains by converting the carbonyl group into the de-
sired side-chain containing group. We herein report an efficient
methodology for the preparation of highly substituted thiophenes
via the one-pot, three-component reactions of b-ketodithioesters
with an isocyanide and a-haloketones in water.
Initially, we prepared the starting b-ketodithioesters 3a–c via
the reaction of acetophenone derivatives 1a–c with trithiocarbon-
ate (2) in the presence of sodium hydride according to the reported
procedure14 (Scheme 1).
S
O
OH
H
N
S
N
O
N
H
NH2
OMe
O
(II)
(I)
⇑
Corresponding author. Tel.: +98 21 66165309; fax: +98 21 66012983.
E-mail address: matloubi@sharif.edu (F. Matloubi Moghaddam).
Figure 1. Biologically important molecules containing a polysubstituted thiophene
skeleton.
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.014

1252
F. Matloubi Moghaddam et al. / Tetrahedron Letters 55 (2014) 1251–1254
O
O
S
Next, we examined the three-component reaction of b-ketodi-
thioester (3a), cyclohexylisocyanide (4), and phenacyl bromide
(5a) as a model system. The conditions were optimized by screen-
ing various bases and using different solvents. The best results
were obtained in water as the solvent with potassium bicarbonate
as the base to afford polysubstituted thiophene 6a in 74% yield
(Scheme 2).
S
NaH
DMF
Ar
CH3
Ar
SMe
MeS
SMe
3a-c
2
1a-c
R: Ph, 4-MeOC6H4, 2-Naphthyl
Ar: Ph, 4-MeOC6H4, 2-Naphthyl
Scheme 1. Synthesis of b-ketodithioesters 3a–c.
To investigate the scope of this procedure, we reacted b-ketodi-
thioesters 3a–c with cyclohexylisocyanide (4) and
a-haloketones
5a–d which gave the derivatives 6a–k in good yields (Table 1).
The results showed that the reaction of b-ketodithioesters
derivatives with a phenyl ring (3a,b) gave better yields compared
to that with a naphthalene moiety (3c). This can be attributed to
the low reactivity of naphthalene rings in comparison with phenyl
rings.
O
NC ,
1)
Ar
4
O
S
H2O, 6 h
R
Ar
SMe
MeS
S
O
Br
, K2CO3, 6 h
In an effort to extend the applicability of this reaction, b-ketodi-
3a-c
O
2)
R
6a-k
5a-d
thioester 3a was reacted with
a-chloroamides, a-chloroesters, or
a-chloroacetone and cyclohexylisocyanide under the optimized
Scheme 2. Synthesis of polysubstituted thiophene derivatives 6a–k.
Table 1
Synthesis of polysubstituted thiophene derivatives 6a–k
O
Ar
NC ,
O
S
1)
2)
4
Ar
SMe
R
MeS
O
S
Br
5a-d
3a-c
R
O
6a-k
a
Entry
1
Ar
Ph
R
Product
Yieldb (%)
O
Ph
74
MeS
S
6a
O
O
Me
2
3
4
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
4-Br C6H4
70
68
73
MeS
MeS
S
O
O
6b
6c
O
Cl
Br
S
O
MeS
MeO
S
O
O
6d
5
6
4-MeOC6H4
4-MeOC6H4
Ph
69
68
MeS
MeS
S
O
O
6e
O
MeO
Me
4-MeC6H4
S
6f

F. Matloubi Moghaddam et al. / Tetrahedron Letters 55 (2014) 1251–1254
1253
Table 1 (continued)
a
Entry
Ar
R
Product
Yieldb (%)
O
MeO
Cl
Br
7
4-MeOC6H4
4-ClC6H4
70
73
60
59
56
MeS
MeS
S
O
O
6g
O
MeO
8
4-MeOC6H4
2-Naphthyl
2-Naphthyl
2-Naphthyl
4-BrC6H4
S
6h
O
9
Ph
MeS
S
6i
O
O
Me
10
4-MeC6H4
MeS
MeS
S
O
6j
O
Cl
11
4-ClC6H4
S
6k
O
a
The products were characterized by IR and NMR spectroscopy and by elemental analysis.
Isolated yield after recrystallization.
b
O
S
O
SMe
S
O
S
NC
Ph
SMe
Ph
deprotonation
nucleophilic addition
isomerization
Ph
SMe
N
NH
7
8
Br
Ph
Ph
O
O
O
O
SMe
S
S
S
MeS
Ph
MeS
Ph
Ph
Ph
H
elimination of
deprotonation
cyclohexylamine
NH
O
N
nucleophilic addition
O
Ph
O
6a
9
Scheme 3. A plausible mechanism for the formation of thiophenes 6.
conditions, but unfortunately the desired products were not
obtained.
respectively. In the 13C NMR spectrum of 6a, the thiomethyl and
two carbonyl carbons resonated at d 19.3, d 187.0, and d 188.7.
A proposed mechanism for the reaction is shown in Scheme 3.
The first step is the abstraction of the acidic proton of the b-keto-
dithioester by cyclohexyl isocyanide followed by nucleophilic at-
tack on the positively charged ion obtained from the isocyanide
to generate imine 7, which easily isomerizes into enamine 8. Next
The structures of products 6a–k were characterized by IR, 1H
NMR, and 13C NMR spectroscopy and by elemental analysis.15 For
example, the IR spectrum of cycloadduct 6a showed characteristic
absorptions at 1630 and 1705 cmÀ1 corresponding to the carbonyl
groups. In the 1H NMR spectrum of 6a two singlets appeared at d
2.74 and d 7.81 for the SCH3 and CH of the thiophene ring,
enamine 8 undergoes an S-alkylation with the
a-haloketone to

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F. Matloubi Moghaddam et al. / Tetrahedron Letters 55 (2014) 1251–1254
7. (a) Moretto, A. F.; Kirincich, S. J.; Xu, W. X.; Smith, M. J.; Wan, Z. K.; Wilson, D.
P.; Follows, B. C.; Binnun, E.; Joseph-McCarthy, D.; Foreman, K.; Erbe, D. V.;
Zhang, Y. L.; Tam, S. K.; Tam, S. Y.; Lee, J. Bioorg. Med. Chem. 2006, 14, 2162–
2177; (b) Wan, Z. K.; Lee, J.; Xu, W.; Erbe, D. V.; Joseph-McCarthy, D.; Follows, B.
C.; Zhang, Y. L. Bioorg. Med. Chem. Lett. 2006, 16, 4941–4945.
8. Li, J. J. Name Reactions in Heterocyclic Chemistry; Wiley-Interscience: Hoboken,
2005.
9. Samuel, R.; Chandran, P.; Retnamma, S.; Sasikala, K. A.; Sreedevi, N. K.; Anabha,
E. R.; Asokan, C. V. Tetrahedron 2008, 64, 5944–5948.
10. Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2011, 76, 8009–8014.
11. Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 6480–6483.
12. Rudorf, W.-D.; Köditz, J.; Tersakian, A.; Chatterjee, S. K. Liebigs Ann. Chem. 1992,
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afford the iminium ion 9. Finally, intramolecular cyclization with
the elimination of cyclohexylamine yields the thiophene 6a.
In conclusion, we have developed
a novel and efficient
procedure for the synthesis of polysubstituted thiophene deriva-
tives via the reaction of b-ketodithioesters, cyclohexylisocyanide,
and
a-haloketone derivatives. The reaction was performed in
aqueous medium and proceeds via a catalyst-free procedure. Other
advantages include good yields of products and a simple work-up,
which should make it a useful and attractive method for the
synthesis of polysubstituted thiophenes.
13. (a) Matloubi Moghaddam, F.; Zali-Boinee, H. Tetrahedron 2004, 60, 6085–6089;
(b) Matloubi Moghaddam, F.; Zali-Boinee, H. Tetrahedron Lett. 2003, 44, 6253–
6255; (c) Moghaddam, F.; Saeidian, H.; Mirjafary, Z.; Taheri, S.; Kheirjou, S.
Synlett 2009, 1047–1050; (d) Moghaddam, F. M.; Bardajee, G. R.; Dolabi, M. J.
Sulfur Chem. 2010, 31, 387–393.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
01.014.
14. Samuel, R.; Asokan, C. V.; Suma, S.; Chandran, P.; Retnamma, S.; Anabha, E. R.
Tetrahedron Lett. 2007, 48, 8376–8378.
15. Typical procedure for the synthesis of polysubstituted thiophenes 6a–k: a mixture
of b-ketodithioester 3a (0.5 mmol) and cyclohexylisocyanide (4) (0.6 mmol) in
H2O (6 ml) was stirred at 50 °C for 6 h. After completion of the reaction, the
halocarbonyl compound (0.6 mmol) in MeCN (2 ml) and K2CO3 (0.6 mmol) was
added. The progress of the reaction was monitored by TLC using petroleum
ether–EtOAc (4:1) as the eluent. After completion of the reaction (5 h) the
mixture was extracted with CH2Cl2 (3 Â 6 ml). The combined organic layer was
dried over MgSO4, filtered, and concentrated under vacuum. The residue
was recrystallized with EtOH to afford pure [5-(methylthio)thiene-2,4-
diyl]bis(phenylmethanone) (4a): yellow powder, mp 135–137 °C, 1H NMR
d = 2.74 (3H, s, SMe) 7.49 (2H, t, J = 7.2 Hz, ArH) 7.51 (2H, t, J = 7.2 Hz, ArH) 7.59
(1H, t, J = 7.5 Hz, ArH) 7.61 (1H, t, J = 7.4 Hz, ArH) 7.77 (2H, d, J = 7.5 Hz, ArH)
7.81 (1H, s, ArH) 7.84 (2H, d, J = 7.5 Hz, ArH) 13C NMR d = 19.3, 104.2, 129.1,
129.4, 131.6, 131.8, 132.9, 134.7, 137.7, 137.8, 139.1, 163.5, 187.0, 188.7; IR
(KBr): 1630,1705, 2956, 3059 cmÀ1; Anal. Calcd for C19H14O2S2: C, 67.43; H,
4.17; N, 18.95. Found: C, 67.61; H, 4.09; N, 18.90.
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