Synthesis of 2,3-disubstituted thiophenes from 2-aryl-3-nitro-cyclopropane-1,1-dicarboxylates and 1,4-dithiane-2,5-diol

Article abstract of DOI:10.1039/c5ra09111j

A two-step synthesis of 2,3-disubstituted thiophenes from trans-2-aryl-3-nitrocyclopropane-1,1-dicarboxylates and 1,4-dithiane-2,5-diol is described. The nitrocyclopropane dicarboxylates when treated with boron trifluoride etherate formed aroylmethylidene

Full text of DOI:10.1039/c5ra09111j

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((TOC graphic))
Synthesis of 2,3-disubstituted thiophenes from 2-Aryl-3-Nitro-Cyclopropane-1,1-
Dicarboxylates and 1,4-Dithiane-2,5-Diol
Thangavel Selvi, Govindhraj Vanmathi and Kannupal Srinivasan*
A two-step synthesis of 2,3-disubstituted thiophenes from trans-2-aryl-3-nitrocyclopropane-1,1-
dicarboxylates and 1,4-dithiane-2,5-diol is described.
CO2Et
EtO2C
EtO2C CO2Et
EtO2C
O
OH
1) BF3 OEt2, CH2Cl2, rt
S
p-TsOH
O
°
PhMe, 90 C
S
S
Ar
NO2
2)
HO
OH
Ar
Ar
S
61-88%
25-87%
Et3N

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Synthesis of 2,3ꢀDisubstituted Thiophenes from 2ꢀArylꢀ3ꢀNitroꢀ
Cyclopropaneꢀ1,1ꢀDicarboxylates and 1,4ꢀDithianeꢀ2,5ꢀDiol
Thangavel Selvi, Govindhraj Vanmathi and Kannupal Srinivasan*
School of Chemistry, Bharathidasan University, Tiruchirapalli 620 024, Tamil Nadu, India
srinivasank@bdu.ac.in
A twoꢀstep synthesis of 2,3ꢀdisubstituted thiophenes from transꢀ2ꢀarylꢀ3ꢀnitrocyclopropaneꢀ
1,1ꢀdicarboxylates and 1,4ꢀdithianeꢀ2,5ꢀdiol is described. The nitrocyclopropane
dicarboxylates when treated with boron trifluoride etherate formed aroylmethylidene
malonates in situ through ringꢀopening followed by rearrangement and Nef reaction, and
subsequent addition of 1,4ꢀdithianeꢀ2,5ꢀdiol and triethylamine to the same flask gave
tetrahydrothiophenes via tandem thiaꢀMichael addition/aldol reaction in a sequential oneꢀ
pot manner. The product tetrahydrothiophenes upon treatment with pꢀtoluenesulphonic
acid underwent dehydration followed by monodecarbethoxylation to afford 2,3ꢀ
disubstituted thiophenes.
Donorꢀacceptor (DꢀA) cyclopropanes are versatile building blocks for accesing a variety
of carboꢀ and heterocycles including natural products.1 The typical reactions of donorꢀacceptor
cyclopropanes include ringꢀopening,2 rearrangement3 and annulations4 are generally mediated by
Lewis acids. The reactions are operationally simple, of wide substrate scope and display high
regioꢀand stereoselectivities. Of various donorꢀacceptor cyclopropanes, the nitroꢀsubstituted ones
have received surprisingly scant attention despite the fact that they could afford a range of
important products.5,6
A great deal of attention has been paid to the synthesis of substituted thiophenes largely
owing to their use as functional materials and pharmaceuticals.7 Neverthless, the regioselective
synthesis of substituted thiophenes is always a challanging task. Especially, 2,3ꢀdisubstituted
thiophenes are difficult to prepare by direct electrophilic or metallation procedures (which are
handy to introduce substituents in 2,5ꢀpositions).8 The aromatisation of suitably substituted
tetrahydrothiophenes could be one of the alternative and useful approach for the synthesis of
such 2,3ꢀdisubstituted thiophenes.

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We have recently reported that the action of boron trifluoride etherate (BF3ꢁOEt2) or
tin(IV) chloride on transꢀ2ꢀarylꢀ3ꢀnitroꢀcyclopropaneꢀ1,1ꢀdicarboxylates 1 (a type of donorꢀ
acceptor cyclopropanes) generates aroylmethylidene malonates 2 via ringꢀopening followed by
rearrangement and Nef reaction (Scheme 1, eqn 1).9 These malonates can serve as potential
building blocks like chalcones and furnish heterocycles such as imidazoles, quinoxalines,
benzo[1,4]thiazines and 2,4,5ꢀtrisubstituted oxazoles upon treatment with suitable nucleophilic
reaction partners.9 Yamazaki et al., have reported that diethyl benzoylmethylidene malonate and
related compounds are excellent Michael acceptors and adds with various carbon, nitrogen and
oxygen nucleophiles.10 However their Michael addition reaction with sulfur nucleophiles has
been scarcely investigated. It is well known that 1,4ꢀdithianeꢀ2,5ꢀdiol (3), the dimer of
mercaptoacetaldehyde releases the monomer (i.e., 3′) in situ upon treatment with tertiary amines,
organocatalysts or Lewis acids (Scheme 1, eqn 2).4j,8,11 The released mercaptoacetaldehyde is
capable of undergoing tandem thiaꢀMichael addition/aldol reaction with α, βꢀunsaturated
carbonyl compounds and βꢀnitroalkenes to furnish tetrahydrothiophenes.8,11 We envisaged that
when treated with BF3ꢁOEt2, the nitrocyclopropane dicarboxylates 1 would form
aroylmethylidene malonates 2 in situ and further reaction of 2 in the same flask with 1,4ꢀ
dithianeꢀ2,5ꢀdiol (3) in the presence of triethylamine (Et3N) [for neutralizing the Lewis acid as
BF3ꢁOEt2ꢀEt3N complex and generating mercaptoacetaldehyde (3′) in situ] would afford
tetrahydrothiophenes 4 via a tandem conjugate addition/intramolecular aldol reaction between 2
and 3′ (Scheme 1, eqn 3). Such oneꢀpot sequential reactions are more promising than the
corresponding stepꢀwise synthesis since they avoid the separation and purification of the
intermediate products, resulting in reduced time and minimal chemical wastage.12 Southern and
coꢀworkers have synthesized 2ꢀarylꢀ3ꢀnitroꢀthiophenes via dehydration and oxidation of 2ꢀarylꢀ
3ꢀnitroꢀ4ꢀhydroxyꢀtetrahydrothiophenes.8 Since a similar functional group pattern is present in
tetrahydrothiophenes 4, we envisioned that these compounds could be aromatised to obtain 2,3ꢀ
disubstituted thiophenes (Scheme 1, eqn 3).

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O
CO2Et
CO2Et
CO2Et
EtO2C
Ar
LA
... eqn 1
... eqn 2
Ar
NO2
2
1
LA = BF3 OEt2, SnCl4
S
Z
HO
OH
HS
CHO
S
3'
3
Z = Et3N, organocatalysts, LA
CO2Et
S
EtO2C
O
O
LA
3
1
2
Et3N
'Sequential one-pot synthesis'
Ar
... eqn 3
EtO2C
CO2Et
EtO2C
O
OH
Aromatisation
O
S
S
4
Ar
5
Ar
Scheme 1 Oneꢀpot sequential synthesis of tetrahydrothiophenes and
subsequent aromatisation to 2,3ꢀdisubstituted thiophenes
To test our hypothesis, we required a variety of donorꢀacceptor nitrocyclopropane
dicarboxylates which were prepared from Michael adducts of βꢀnitrostyrenes with diethyl
malonate as reported by us earlier.9a We began the study by treating the nitrocyclopropane
dicarboxylate 1a with BF3ꢁOEt2 (1 equiv.) in dichloromethane (DCM) at room temperature.
After complete conversion of 1a into aroylmethylidene malonate 2a (required about 24 h as
judged by TLC), 2 equiv. of Et3N followed by 0.5 equiv. of 1,4ꢀdithianeꢀ2,5ꢀdiol (3) were added
to the same reaction flask and the reaction was continued for another 4 h. After workꢀup and
column chromatographic purification of the reaction mixture, the desired tetrahydrothiophene 4a
1
was obtained as a mixture of diastereomers (dr 1:1.5, determined by H NMR) in 83% yield
(Table 1, entry 1). The diastereomeric mixture was chromatographically homogeneous and thus
could not be separated into individual components. Since both diastereomers are equally suitable
for further transformation into a thiophene, the separation of diastereomers is not required. We
also carried out a stepwise synthesis of 4a for comparison, which afforded the product in an
overall yield of 79%. We next focused attention on exploring the scope of the sequential oneꢀpot
synthesis for other nitrocyclopropane dicarboxylates 1bꢀi. The presence of electron donating and
halogen substituents on the aromatic ring of the nitrocyclopropanes was well tolerated and the
corresponding tetrahydrothiophenes 4bꢀf are obtained in good yields (entries 2ꢀ6). However, the

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reaction failed when the electron withdrawing, nitro substituent was present on the aromatic ring
(entry 7). This is likely due to the destabilization caused by the pꢀnitrophenyl group to the
carbocation that would be generated during the ringꢀopening of the cyclopropane.9a We also
tested the cyclopropane 1h having a naphthyl ring and the expected tetrahydrothiophene 4h was
obtained in 81% yield (entry 8). No satisfactory results could be obtained for nitrocyclopropane
1i containing 2ꢀthienyl ring at room temperature (entry 9). However, when the generation of
thienoylmethylidene malonate was performed at −15 °C and then reaction with 3 was carried out
at room temperature, the desired tetrahydrothiophene 4i was produced in 25% yield. All the
products were obtained as chromatographically inseperable mixtures of diastereomers with dr
values ranging from 1:1.1 to 1:2.2 (determined from their 1H NMR spectra). However, in case of
4d, the liquid diastereomeric mixture when kept at room temperature for 3ꢀ4 days formed
crystals of one of the diastereomers. The impure crystals were collected and further recrystallized
from CHCl3/MeOH (1:1v/v) to obtain the diastereomer 4d in pure form.
Table 1 Synthesis of tetrahydrothiophenes from donorꢀacceptor nitrocyclopropanes
CO2Et
EtO2C CO2Et
EtO2C
O
OH
1) BF3 OEt2, DCM, rt
2) 1,4-dithiane-2,5-diol
Et3N, DCM, rt
S
Ar
NO2
1
Ar
4
Entry Ar
Time (h)a Yield (%)b drc
1
2
3
4
5
6
7
8
9
Ph (1a)
28 (24)
18 (12)
15 (12)
13 (12)
83 (4a)
80 (4b)
85 (4c)
81 (4d)
87 (4e)
74 (4f)
NRd
1:1.5
1:1.6
1:2.2
1:1.1
1:1.5
1:1.1
ꢀ
4ꢀMeC6H4 (1b)
3,4ꢀ(Me)2C6H3(1c)
4ꢀMeOC6H4 (1d)
3,4ꢀ(MeO)2C6H3(1e) 16 (12)
4ꢀClC6H4 (1f)
4ꢀNO2C6H4 (1g)
1ꢀNaphthyl (1h)
2ꢀThienyl (1i)
27 (24)
48
13 (12)
4 (2)
81 (4h)
25 (4i)e
1:1.2
1:1.1
aTime in parenthesis indicates the time required for the formation of aroylmethylidene malonate. bIsolated yield.
cDetermined from the 1H NMR spectra (based on one of the ester methyl protons). dNo reaction. eThe ringꢀopening
was carried out at − 15 °C.

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With the availability of various tetrahydrothiophenes, we next focused attention on
transforming them into target 2,3ꢀdisubstituted thiophenes. Pleasingly, when we subjected the
tetrahydrothiophenes 4 to dehydration using pꢀTsOH (PTSA) in toluene at 90 °C,13 they
underwent dehydration as well as monodecarbethoxylation under the reaction conditions to yield
2,3ꢀdisubstituted thiophenes 5aꢀf and 5i directly (Table 2, entries 1ꢀ6 and 8). Although
tetrahydrothiophene 4h produced thiophene 5h, the product could not be isolated in pure form
due to inseparable impurities with the same Rf value (entry 7). The yield was best for
tetrahydrothiophene 4d which is having a 4ꢀmethoxyphenyl ring (entry 4). A plausible
mechanism for the transformation of 4 into 5 is shown in Scheme 2. The reaction may proceed
through pꢀtoluenesulphonic acid promoted dehydration, ester cleavage,14 decarboxylation and
dehydrogenation (auto oxidation). The product thiophenes possess two electron withdrawing
substituents in 2,3ꢀpositions and synthesis of such compounds is always a challenging
endeavour.
Table 2 Synthesis of 2,3ꢀdisubstituted thiophenes from tetrahydrothiophenesa
CO2Et
EtO2C
EtO2C
O
OH
PTSA
O
°
PhMe, 90 C
S
S
Ar
Ar
4
5
Entry Ar
Time (h) Yield (%)a
1
2
3
4
5
6
7
8
Ph (4a)
24
24
15
18
72 (5a)
68 (5b)
79 (5c)
88 (5d)
81 (5e)
63 (5f)
ꢀb (5h)
61 (5i)
4ꢀMeC6H4 (4b)
3,4ꢀ(Me)2C6H3(4c)
4ꢀMeOC6H4 (4d)
3,4ꢀ(MeO)2C6H3(4e) 20
4ꢀClC6H4 (4f)
1ꢀNaphthyl (4h)
2ꢀThienyl (4i)
24
16
20
a Isolated yield; bThiophene 5h could not be isolated in pure form

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H
OTs
Et
O
O
OEt
OH
H
HO
C
C
EtO2C
O
EtO2C
O
OH2
p-TsOH
EtOTs
H2O
S
4
H
S
Ar
Ar
H
O
O
EtO2C
C
EtO2C
EtO2C
O
O
O
S
CO2
H2
S
S
Ar
Ar
5
Ar
Scheme 2 Plausible mechanism for the formation of 5 from 4
The thiophenes obtained in the present study could serve as versatile precursors for other
useful compounds. To prove the point, we subjected one of the thiophenes, 5b to a palladiumꢀ
mediated homocoupling to obtain a bis(thiophene).15 Accordingly, when 5b was treated with
PdCl2(PPh3)2 (3 mol%) in the presence of AgOAc (2 equiv.) in DMSO at 60 °C for 24 h, the
bis(thiophene) 6 in 52% yield (Scheme 3). It is worth noting that bisthiophenes are valuable
materials in organic electronics.16
EtO2C
EtO2C
O
CO2Et
O
O
PdCl2(PPh3)2
(3 mol %)
S
S
S
AgOAc (2 equiv.)
DMSO, 60 °C
24 h, 52%
6
Me
5b
Me
Me
Scheme 3 Synthesis of a bis(thiophene)
In summary, we have developed a convenient twoꢀstep procedure for the synthesis of 2,3ꢀ
disubstituted thiophenes from 2ꢀarylꢀ3ꢀnitrocyclopropaneꢀ1,1ꢀdicarboxylates and 1,4ꢀdithianeꢀ
2,5ꢀdiol. The first step involves sequential oneꢀpot synthesis of substituted tetrahydrothiophenes
by the treatment of donorꢀacceptor nitrocyclopropane dicarboxylates with BF3⋅OEt2 to generate
aroylmethylidene malonates in situ followed by Et3Nꢀmediated tandem thiaꢀMichael
addition/aldol reaction with mercaptoacetaldehyde. In the second step, the tetrahydrothiophenes

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were aromatised to target thiophenes using pꢀtoluenesulfonic acid. To prove the synthetic utility
of the synthesised thiophenes, one of the thiophenes was transformed into a bis(thiophene) by a
palladiumꢀmediated homocoupling. Further scope of the methodology is under investigation.
Acknowledgments
The authors thank Science and Engineering Research Board (SERB), India for financial support;
DSTꢀFIST for NMR facility at School of Chemistry, Bharathidasan University and Sophisticated
Analytical Instrumentation Facility (SAIF), Lucknow for HRMS. T.S. thanks Department of
Science and Technology (DST) for an INSPIREꢀSRF fellowship.
Notes and references
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((TOC graphic))
Synthesis of 2,3ꢀdisubstituted thiophenes from 2ꢀArylꢀ3ꢀNitroꢀCyclopropaneꢀ1,1ꢀ
Dicarboxylates and 1,4ꢀDithianeꢀ2,5ꢀDiol
Thangavel Selvi, Govindhraj Vanmathi and Kannupal Srinivasan*
A twoꢀstep synthesis of 2,3ꢀdisubstituted thiophenes from transꢀ2ꢀarylꢀ3ꢀnitrocyclopropaneꢀ1,1ꢀ
dicarboxylates and 1,4ꢀdithianeꢀ2,5ꢀdiol is described.
CO2Et
EtO2C
EtO2C CO2Et
EtO2C
O
OH
1) BF3 OEt2, CH2Cl2, rt
S
p-TsOH
O
°
PhMe, 90 C
S
S
Ar
NO2
2)
HO
OH
Ar
Ar
S
61-88%
25-87%
Et3N