Attempted Simmon-Smith reaction on β-alkylthio-α,β- unsaturated ketones: A regiospecific synthesis of 2,4-disubstituted thiophenes

Article abstract of DOI:10.1016/j.tetlet.2012.10.110

A new regiospecific route to 2,4-disubstituted thiophenes has been developed through Simmon-Smith reaction on β-methylthio-α,β- unsaturated ketones. Extension of the reaction to β-ethyl/benzylthio- α,β-unsaturated ketones also gave the corresponding 2,4-disubstituted thiophenes in a regiospecific manner. A probable mechanism involving a carbenoid methylene insertion to divalent sulfur followed by intramolecular aldol condensation has been suggested.

Full text of DOI:10.1016/j.tetlet.2012.10.110

Tetrahedron Letters 54 (2013) 147–150
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Tetrahedron Letters
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Attempted Simmon–Smith reaction on b-alkylthio-a,b-unsaturated ketones: a
regiospecific synthesis of 2,4-disubstituted thiophenes
Toreshettahally R. Swaroop a, Rangaswamy Roopashree a, Hiriyakkanavar Ila b,
Kanchugarakoppal S. Rangappa a,
⇑
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
b New Chemistry Unit, JNCASR, Jakkur, Bangalore 560 064, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new regiospecific route to 2,4-disubstituted thiophenes has been developed through Simmon–Smith
Received 15 September 2012
Revised 22 October 2012
Accepted 25 October 2012
Available online 9 November 2012
reaction on b-methylthio-a,b-unsaturated ketones. Extension of the reaction to b-ethyl/benzylthio-a,b-
unsaturated ketones also gave the corresponding 2,4-disubstituted thiophenes in a regiospecific manner.
A probable mechanism involving a carbenoid methylene insertion to divalent sulfur followed by intramo-
lecular aldol condensation has been suggested.
Keywords:
b-Alkylthio-a,b-unsaturated ketones
R1
Simmon–Smith reaction
2,4-Disubstituted thiophene
Regiospecific
R1
R2
R3
CH2I2/Zn-Cu
Et2O/THF, reflux
R2
O
S
S
R1, R2=Alkyl/Aryl/Heteroaryl and R3=Methyl/Ethyl/Benzyl
Ó 2012 Elsevier Ltd. All rights reserved.
Thiophene represents an important class of heterocyclic com-
pounds because of their presence in natural products,1 pharmaceu-
ticals,2 organic conductors,3 light emitting devices,4 and
semiconductors.5 As a result, there is a continuing interest in the
development of efficient and versatile methods for the synthesis
of thiophene derivatives. In general, construction of thiophene ring
from appropriately substituted open chain precursors6 has at-
tracted the attention of chemists rather than functionalization of
the pre-constructed thiophene nucleus7 since the former route
provides more flexible substitution patterns.
and reaction of Lawesson’s reagent with b-formyl ketones.8c How-
ever, these methods suffer from formation of regioisomeric and
undesirable side products. Also, functionalization of the pre-con-
structed thiophene involves palladium catalyzed coupling of aryl
bromides with 3-substituted thiophenes,9a oxidative coupling of
boronic acids with 2-substituted thiophenes,9b double coupling
of 2,4-dibromothiophenes with boronic acids and borates,9c
a-metallation of 3-substituted thiophenes followed by reaction
R1
R1
R2
In particular, synthesis of 2,4-disubstituted thiophenes from
open chain precursors involves one pot reaction of mono substi-
tuted acetylene and sulfur,8a thermolysis of bis(alkylthio)allenes,8b
CH2I2/Zn-Cu
R2
Et2O/THF, reflux
8-12h
O
S
S
⇑
Corresponding author. Tel.: +91 821 2419661; fax: +91 821 2500846.
E-mail addresses: rangappaks@gmail.com, rangappaks@chemistry.uni-mysore.
1a-l
2a-l
ac.in (K.S. Rangappa).
Scheme 1. Synthesis of 2,4-disubstituted thiophenes.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.110

148
T. R. Swaroop et al. / Tetrahedron Letters 54 (2013) 147–150
Table 1
Reaction scope of b-methylthio-a,b-unsaturated ketones 1a–l
Entry
1
2
Yield (%)
R4
R3
R3
R4
S
O
S
1
2
3
R3 = H, R4 = H 1a
2a
2b
2c
67
65
61
R3 = Br, R4 = OMe 1b
R3 = OMe, R4 = H 1c
R3
R3
R4
R4
O
S
S
4
5
R3 = Me, R4 = OMe 1d
R3 = H, R4 = Cl 1e
2d
2e
60
64
Cl
Cl
S
6
7
70
58
2f
O
S
1f
S
S
O
S
S
1g
2g
OMe
OMe
OMe
N
OMe
OMe
N
8
55
O
S
1h
S
OMe
2h
N
O
X
9
53
O
X
N
S
O
S
2i
1i
Y
O
S
S
Y
10
11
12
X = S, Y = S 1j
X = O, Y = S 1k
X = O, Y = NMe 1l
2j
2k
2l
57
52
56
with electrophilic reagents,9d and Negishi cross coupling at
b-position of 2-substituted thiophenes.9e However, a few of these
methods often gave either mixture of regioisomers or suffer from
lack of diverse combination of groups on thiophene ring.
Consequently, despite the existence of numerous methods for the
synthesis of thiophene derivatives, the development of new
efficient protocol is a subject of great importance.
Ph
Ph
Ph
CH2I2/Zn-Cu
Ph
Et2O/THF, reflux
O
S
S
R3
On the other hand, olefins containing various functional groups
including heteroatoms undergo Simmon–Smith cyclopropana-
tion.10 Thus vinyl ethers, ketene O,O-acetals, enamines, and vinyl
sulfones undergo facile cyclopropanation under these conditions.11
In addition, Ila and co-workers have reported the unexpected
R3=C2H5
R3=C6H5CH2 1n
1m
2a
formation of thiophenes from
a
-oxo-ketene dithioacetals12 and
Scheme 2. Reaction scope of b-ethyl/benzylthio-a,b-unsaturated ketones 1m–n.

T. R. Swaroop et al. / Tetrahedron Letters 54 (2013) 147–150
149
R1
R1
R1
R2
IZnCH2I
IZnO
R2
O
H2
R2
IZn
2(a-l)
C
H
O
S
S
S
R3
H
I
R3
I
R3
1
3
4
Scheme 3. Probable mechanism for the formation of thiophenes 2.
S
R1
R2
O
R3X
NaH/DMF
0°C to rt
3 h
1(a-n)
0°C to rt
R1
MeS
R2
O
S
3-5 h
Na
6
7
5
Scheme 4. Synthesis of b-alkylthio-a,b-unsaturated ketones 1.
acylketene-O,S-acetals13 under Simmon–Smith cyclopropanation
conditions instead of the expected cyclopropanes or the products
thereof. In continuation of this work we were interested in exam-
might assist the intramolecular nucleophilic addition–elimination
in the intermediate sulfur ylide 3. Finally, dealkylation of the sulfo-
nium salt 4 probably assisted by iodide ion furnishes thiophenes 2.
ining the behavior of b-alkylthio-
a
,b-unsaturated ketones under
The required b-alkylthio-a,b-unsaturated ketones 1a–n were
Simmon–Smith reaction conditions. Also, it is evident that carbe-
noids react preferentially on divalent sulfur in a molecule contain-
ing both a divalent sulfur and double bond.14 In the present Letter,
we wish to report a new route for the synthesis of 2,4-disubsti-
synthesized in excellent yield by Claisen type condensation of acet-
yl compounds 5 with dithioesters16 6 in the presence of excess of
sodium hydride in DMF followed by in situ alkylation of enethio-
late anion 7 by alkylating agents such as methyl iodide, ethylbro-
mide, and benzyl bromide (Scheme 4).17
tuted thiophenes by the reaction of b-alkylthio-a,b-unsaturated
ketones with Simmon–Smith reagent (Scheme 1).
In conclusion, we have reported a new synthetically important,
mechanistically interesting, regiospecific method for 2,4-disubsti-
tuted thiophenes from b-methylthio-a,b-unsaturated ketones.
The regiospecificity of the reaction has been proved in the presence
of various substituents. The protocol has also been proved to be
The requisite Simmon–Smith reagent was prepared from meth-
ylene iodide and zinc–copper couple in the presence of catalytic
amount of iodine in refluxing ether.15 When the solution of 1a in
THF reacted with the above prepared Simmon–Smith reagent, a
white solid is obtained in 67% yield which was characterized as
2,4-diphenyl thiophene 2a (Table 1, entry 1) on the basis of spec-
tral and analytical data. Also, no traces of cyclopropanated product
could be isolated from the reaction mixture.
extendable to b-ethyl/benzylthio-a,b-unsaturated ketones. The
present method is superior over the reported methods which were
associated with regio isomeric mixtures of products.8,9 Further
synthetic applications of this methodology are currently underway
in our laboratory.
Similarly, other 2,4-diarylthiophenes 2b–e were synthesized
from respective of b-methylthio-
60–65% yields (Table 1, entries 2–5). Interestingly, b-methylthio-
,b-unsaturated ketone 1f derived from acetone also gave the cor-
a,b-unsaturated ketones 1b–e in
Acknowledgment
a
responding 2-aryl-4-methylthiophene 2f in good yield (Table 1, en-
try 6). In addition, the methodology was found to be compatible
with hetero aryl and aryl substituents on 1. Thus, b-methylthio-
T.R.S. thanks CSIR, New Delhi for Junior and Senior Research Fel-
lowship, financial support to K.S.R. through BRNS Project (Vide No.
2009/37/40/BRNS/2266 Dated 23-11-2009) and UGC Major Re-
search Project (Vide No. 39-106/2010(SR) Dated 24-12-2010) is
greatly acknowledged.
a,b-unsaturated ketones 1g and 1h furnished corresponding thio-
phenes in 58% and 55% yields, respectively (Table 1, entries 7
and 8). The generality of the protocol was further explored by
keeping heteroaryl substituents on both sides of 1. Thus, 1i–l affor-
ded respective thiophenes 2i–l in 52–57% yields (Table 1, entries
9–12). It should be noted that, no traces of cyclopropanated prod-
ucts could be isolated from all the reactions which proves the reg-
iospecificity of the reaction.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.110.
Finally, b-ethyl/benzylthio-a,b-unsaturated ketones 1m and 1n
were next investigated in view to study the effect of different alkyl
groups on sulfur atom (Scheme 2). Thus, when 1m and 1n were
examined under the above reaction conditions, 2,4-diphenylthi-
ophene 2a was obtained in 60% and 53% yield in 10 and 12 h,
respectively.
The probable mechanism of thiophene formation from b-alkyl-
thio-a,b-unsaturated ketones 1 is as shown in Scheme 3. It might
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