Synthesis of thiophenes and pyranone fused thiophenes by base induced inter and intramolecular C-S and C-C bond formation: A non-catalytic approach

Article abstract of DOI:10.1016/j.tetlet.2011.12.066

An efficient and concise one pot synthesis of highly functionalized thiophenes and pyranone fused thiophenes has been delineated through base induced ring transformation of suitably functionalized 2H-pyran-2-ones by ethyl thioglycolate by inter and intramolecular C-S and C-C bond formation.

Full text of DOI:10.1016/j.tetlet.2011.12.066

Tetrahedron Letters 53 (2012) 1056–1059
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of thiophenes and pyranone fused thiophenes by base induced
inter and intramolecular C–S and C–C bond formation: a non-catalytic approach
Pushyamitra Mishra a, Hardesh K. Maurya a, Brijesh Kumar b, Vishnu K. Tandon a, , Vishnu Ji Ram c,
⇑
⇑
a Department of Chemistry, Lucknow University, Lucknow 226007, India
b Division of SAIF, Central Drug Research Institute, Lucknow 226001, India
c Department of Organic Chemistry, Universität Saarland, Saarbrücken 66123, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and concise one pot synthesis of highly functionalized thiophenes and pyranone fused thio-
phenes has been delineated through base induced ring transformation of suitably functionalized 2H-
pyran-2-ones by ethyl thioglycolate by inter and intramolecular C–S and C–C bond formation.
Ó 2011 Published by Elsevier Ltd.
Received 3 November 2011
Revised 15 December 2011
Accepted 16 December 2011
Available online 24 December 2011
Keywords:
Thiophene
Thieno[3,2-c]pyran-4-one
Ethyl thioglycolate
Ring transformation reaction
Thienylacetonitrile
Thiophenes are important class of heterocyclic system, abun-
dantly present as sub-structure in various natural products1 and
pharmaceuticals.2 These are useful intermediates in the prepara-
tion of novel conducting polymers,3 nonlinear optical materials4
and for isosteric replacement for phenyl group in medicinal chem-
istry.5 Diazathiophenes, derived from the coupling of 2-aminothi-
ophenes with various heterocycles are highly colored brilliant
shade dyes6 as well as aroylthiophenes are agonist allosteric en-
hancer at A1 adenosine receptor.7,8
One of the principal routes for the construction of highly func-
tionalized 3-aminothiophenes is the interaction of b-halonitriles
with mercaptans having reactive methylene, activated by the pres-
ence of electron acceptor.9 This reaction is very useful even for the
construction of fused thiophene ring system with amino substitu-
ent at position 3. Another alternative route for the synthesis of 3-
aminothiophene is based on the reaction of sodium or potassium
is developed for the synthesis of ethyl 3-aminothiophene-2
-carboxylate by the reaction of mercaptoacetic acid and 2-chloro-
acrylonitrile followed by esterification.21 A reaction of alkylnitrile
(RCH2CN) with ethyl formate followed by ring-closure on reaction
with ethyl thioglycolate led to the formation of functionalized 3-
aminothiophenes.22
The wide ranging applications of thiophene derivatives aroused
considerable interest to develop new methodology which could be
efficient, economical and compatible to the functional groups,
without use of expensive catalyst/reagent, easy work up and mild
reaction conditions. Our methodology relies on mild conditions,
with easy workup using economically viable reagents. The advan-
tage of the procedure lies in the synthesis of cyanomethyl tethered
SMe
1-cyanoethylene-2,2-dithiolates with
a-halocarbonyl compounds
CN
O
MeOOC
MeS
CN
KOH
DMF
or activated alkyl halide in basic medium.10 3,5-Diaminothioph-
enes are also prepared by the base induced reaction of ketene
N,S acetals, obtainable from the reaction of activated nitriles with
isothiocyanates with activated alkyl or aralkyl halide.11–15 Besides
these, they are also prepared by ring opening and ring-closure of
1,3-oxathiolium salt with malononitrile in the presence of
base.16–20 Recently, a practical and high yield two steps procedure
ArCOCH3
+
Ar
O
3
SMe
2
1
Ar
3
Ar
3
f
4-biphenyl
1-naphthyl
2-naphthyl
a
b
c
d
e
3-NHCOCH3C6H4
4-pyridinyl
g
h
i
2-furyl
4-(2-(phenylthio)ethoxy)phenyl
4-NHCOCH3C6H4
2-thienyl
Scheme 1. Synthesis of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitrile 3.
⇑
Corresponding authors. Tel.: +91 522 2960779; fax: +91 522 2623405.
E-mail address: vjiram@yahoo.com (V.J. Ram).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.12.066

P. Mishra et al. / Tetrahedron Letters 53 (2012) 1056–1059
1057
Table 1
SMe
Yields and Mps of compounds synthesized in Scheme 2
CN
O
5, 6 Compound
Mp (oC)
112
Yield (%)
38
+HSCH2CO2Et
Ar
O
CN
3
4
S
COOEt
5a
5b
MeOH
NaOH
NHCOCH3
PathB
PathA
MeS
CN
Waxy
40
O
S
COOEt
SCH2COOEt
CN
MeS
O
N
CN
CN
5c
5d
5e
Waxy
121
41
42
42
H
O
S
COOEt
SCH2COOEt
Ar
Ar
O
O
CN
COOEt
-CO2
N
H3COCHN
S
COOEt
CH
CN
MeS
152
S
S
COOEt
N
C
S
S
S
COOEt
Ar
CN
COOEt
Ar
O
O
5f
108
50
46
49
50
S
CN
COOEt
5g
5h
S
H
N
COOEt
C
S
MeS
H
NH
O
CN
142
S
COOEt
COOEt
Ar
CN
Ar
O
COOEt
5i
118
60
S
-SHCH3
S
O
O
O
Ar
O
CN
NHCOCH
3
O
H N
H2N
2
6a
6b
130
124
30
30
COOEt
H
EtOOC
H N
S
EtOOC
5,6 Ar
S
S
O
Ar
6
2
O
N
EtOOC
a
b
c
d
e
f
g
h
i
3-NHCOCH3C6H4
4-pyridyl
S
S
O
2-furyl
H N
2
CN
O
O
4-NHCOCH 3C6H4
2-thienyl
6c
6d
6e
6f
117
167
124
218
37
25
38
21
EtOOC
biphenyl-4-yl
1-naphthyl
COOEt
Ar
S
O
2-naphthyl
H2N
EtOOC
5
O
4-(2-(phenylthio)ethoxy)phenyl
NHCOCH3
S
Scheme 2. Plausible mechanism for the synthesis of ethyl 3-cyanomethyl-5-
arylthiophene-2-carboxylates (5) and 3-amino-6-aryl-2-carbethoxy-4H-thieno[3,2-
c]pyran-4-ones (6).
O
H
N
2
O
S
EtOOC
S
S
thiophenes at position 3 and carbethoxy group at position 2, which
can be further exploited for the construction of new heterocycles.
Herein, we report a novel approach to the synthesis of highly
functionalized thiophenes from base induced ring transformation
of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles23 obtain-
able from the reaction of aryl methyl ketones (2) and methyl 3,3-
dimethylthio-2-cyanoacrylate (1) by ethyl thioglycolate, Scheme
1. The molecular makeup of the lactone (3) reveals that positions
2,4 and 6 are electron deficient and prone to nucleophilic attack.
The electrophilicity of these three position is in order of C-6 > C-
4 > C-2.26 Thus, C-6 position is highly vulnerable to nucleophiles
because of extended conjugation and the presence of electron
withdrawing CN substituent at position 3. Regioselectivity of reac-
O
H2N
EtOOC
O
O
H N
2
O
O
6g
6h
110
118
43
39
EtOOC
S
S
O
H N
2
EtOOC

1058
P. Mishra et al. / Tetrahedron Letters 53 (2012) 1056–1059
Table 2
Reaction conditions for the synthesis of 5f and 6f
SCH3
O
N
O
CN
EtOOC
S
CN
O
CN
O
NH
SMe
X
X
HS
COOEt
CN
O
COOEt
4
EtOH
S
NH2
8
O
a
b
X=S
X=CH2
7
O
O
3f
5f
6f
X
S.No
Base
Solvent
Temp
T (h)
Yield (%) 5f
Yield (%) 6f
1
2
3
4
5
6
7
Et3N
DBU
NaOH
NaH
KOH
NaOH
NaOH
MeOH
MeOH
DMF
Reflux
Reflux
rt
7
7
8
24
7
7
—
—
71
62
10
46
45
39
21
COOEt
NH2
O
20
40
42
44
46
S
THF
rt
CN
COOEt
MeOH
EtOH
MeOH
Reflux
Reflux
Reflux
X
X
7
O
S
9
10
Yields(%)from
tion depends upon the nature of nucleophile and size of aromatic
substituent used for the ring transformation.
9
a
b
X
Mp (ºC)
7
8
S
>310
90
78
CH2
170
85
63
Thus, the reaction of 2-pyranones (3) with ethyl thioglycolate in
the presence of triethyl amine as a base in methanol at reflux tem-
perature exclusively gave 3-amino-6-aryl-2-carbethoxy-4H-thie-
no[3,2-c]pyrane-4-ones (6).24 The plausible mechanism of the
reaction is depicted in Scheme 2, Path A.
Scheme 3. Synthesis of tetracyclic thienopyrans.
All the synthesized compounds were characterized by spectro-
scopic analyses.27
However, when powdered NaOH was used as a base in metha-
nol at reflux temperature besides product 6, ethyl 3-cyanomethyl-
5-(aryl)thiophene-2-carboxylates (5) was also isolated due to com-
petitive reaction at C-6 position of the lactone (3) with bulky aro-
matic substituent. Basically the reaction is initiated by attack of
mercaptide ion generated in situ from ethyl thioglycolate with for-
mation of Michael adduct which undergoes ring-closure with liber-
ation of carbon dioxide followed by elimination of methyl
mercaptan to give thiophene as shown in Scheme 2, Path B. Obser-
vation of various reactions and their yields as shown in Table 1,
demonstrated that as the bulky Ar group has been introduced at
position 6 in lactone (3), the yield of thiophene (5) has been
increased.
In conclusion, we have developed an expeditious one pot syn-
thesis of (2-carbethoxythiophen-3-yl)acetonitriles from 2H-pyr-
an-2-ones not reported so far. These thiophene derivatives can be
used as useful precursors for the preparation of ketenedithioace-
tals28 as synthons for making various class of heterocycles depend-
ing upon the reagents used and will open a new avenue for the
synthesis of thiophene based heterocycles. The pyranone fused
thiophenes derived from 2-pyranone, benzo[c]chromenone and
benzo[c]thiochromenone will be further used for making polycy-
clic heterocycles.
Acknowledgments
In order to optimize the reaction conditions and to improve the
yields of 5, a pilot reaction was performed using different solvents,
bases, time and, temperature as summarized in Table 2. It is perti-
nent to note that use of NaOH as a base and DMF as a solvent (Ta-
ble 2) due to the formation of complex mixture only compound 5f
and 6f was isolated in 20% and 10% yields, respectively, the other
compounds could not be isolated from the complex mixture by col-
umn chromatography.(See Scheme 3)
The various cyanomethyl substituted thiophenes (5) and thien-
opyrans (6), prepared are listed in Table 1. Thus, use of strong base
as NaOH in methanol leads to the formation of both the products 5
and 6 in which 5 has been isolated in better yields. This methodol-
ogy provides a new avenue for the construction of thiophenes (5)
as well as thienopyrans (6) as a useful precursor for the synthesis
of variety of heterocyclic ring systems.
The authors are thankful to UP CST and CSIR, New Delhi for
financial support.
References and notes
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and tricyclic thiphene-2-carboxylates (10) based on the nucleo-
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sibly due to steric factor.

P. Mishra et al. / Tetrahedron Letters 53 (2012) 1056–1059
1059
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6-aryl-4H-thieno[3,2-c]pyran-4-one (6).
A
mixture of 3-cyano-6-aryl-4-
methylthio-2H-pyran-2-one (3a) (1 mmol) and ethyl thioglycolate (4)
(1 mmol) in methanol was refluxed in the presence of powdered NaOH
(1.2 mmol) for 6–8 h and thereafter reaction mixture was poured onto crushed
ice with vigorous stirring. The precipitate obtained was filtered and the crude
product was purified on silica gel column, using hexane:chloroform (5–10%) as
eluent.
Ethyl 3-(cyanomethyl)-5-(2-thienyl)thiophene-2-carboxylate (5e): white solid;
mp. 152 °C, yield 42%; Rf: 0.92 (hexane/chloroform, 9:1); IR (KBr): 2936 (CH2),
2200 (–CN) 1747 (>C@O) cmÀ1 1H NMR (300 MHz, DMSO-d6): d 1.34 (t, 3H,
;
CH3), 4.35 (br s, 4H, CH2), 6.63 (s, 1H, Ar-H), 7.19 (m, 1H, Ar-H), 7.21 (s, 1H, Ar-
H), 7.41 (d, 1H, Ar-H). 13C NMR (100 MHz, DMSO-d6): d 14.27, 15.66, 59.96,
117.25, 124.17 (2C), 127.16, 129.35, 137.09, 145.17 (2C), 148.73, 161.55; HRMS
(ESI): m/z calcd for C13H11NO2S2: 277.0231 (M+); found: 277.0234 (M+).
19. Hirai, K.; Ishiba, T. Chem. Pharm. Bull. 1971, 19, 2194.
20. Hirai, K.; Ishiba, T. Chem. Pharm. Bull. 1972, 20, 2384.
Amino-2-carbethoxy-6-(2-thienyl)-4H-thieno[3,2-c]pyran-4-one
yellow solid; mp. 124 °C, yield 38%; Rf: 0.33 (hexane/chloroform, 9:1); IR
(KBr): 3490, 3380 (-NH2), 2936 (–CH2), 1740(>C@O) cmÀ1 1H NMR (300 MHz,
(6e):
light
21. Jiang, D.; Cai, D.; Fan, F. Yingyong Huangong 2011, 40, 1019.
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;
DMSO-d6): d 1.34 (t, 3H, CH3), 4.47 (m, 2H, -CH2), 4.80 (s, 2H, NH2), 6.21 (s, 1H,
Ar-H), 7.14 (t, 1H, Ar-H), 7.21 (s, 1H, Ar-H), 7.41 (d, 1H, Ar-H); 13C NMR
(100 MHz, DMSO-d6): d 14.27, 59.90, 103.25, 124.83, 128.15 (2C), 130.57,
135.17 (2C), 137.89, 145.87, 148.74, 153.01, 160.45; HRMS (ESI): m/z calcd for
C
14H11NO4S2: 321.0129 (M+); found: 321.0128 (M+).
Ethyl
carboxylate (9b): yellow tiny crystal from chloroform; mp 170 °C, yield 63%;
IR (KBr): 3487, 3383 (–NH2), 2932 (–CH2), 1734 (>C@O) cmÀ1 1H NMR
1-amino-11-oxo-5,11-dihydro-4H-benzo[h]thieno[3,2-c]chromene-2-
;
(400 MHz, DMSO-d6): d 1.28 (t, J = 7.2 Hz, 3H, CH3), 2.76 (t, J = 5.6, 2H, CH2),
3.00 (t, J = 5.6, 2H, CH2), 4.25 (q, J = 7.2 Hz, 2H, OCH2), 6.91 (br sH, NH2), 7.39
(m, 3H, Ar-H), 7.69 (m, 1H, Ar-H); HRMS (ESI): m/z calcd for C18H15NO4S2:
342.0800 (MH+); found: 342.0812 (MH+).
27. Data for Compounds: General procedure for the synthesis of ethyl 3-
(cyanomethyl)-5-(aryl)thiophene-2-carboxylate (5) and 3-amino-2-carbethoxy-
28. Sturrock, K. R.; Bremner, D. H.; Wishart, G. Heterocycles 2011, 82, 1657.