Base catalyzed reaction of ethyl thioglycolate with β-aryl-β-(methylthio) acroleins: A general method for the synthesis of 2-carbethoxy-5-substituted/4,5-annulated thiophenes in high overall yields

Article abstract of DOI:10.1016/j.tetlet.2016.01.055

(Methylthio) acroleins 1a-m were shown to be stable unlike their counterpart the chloroacroleins and their efficacy as 1,3-dielectrophilic properties have now been examined successfully in this work. They are shown to react with ethyl thioglycolate in the

Full text of DOI:10.1016/j.tetlet.2016.01.055

Accepted Manuscript
Base catalyzed reaction of ethylthioglycolate with β-aryl-β-(methylthio) acro-
leins: A general method for the synthesis of 2-carbethoxy-5-substituted/4, 5-
annulated thiophenes in high overall yields
G. Byre Gowda, C.S. Pradeepa kumara, N. Ramesh, M.P. Sadashiva, H.
Junjappa
PII:
S0040-4039(16)30054-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.055
TETL 47219
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 November 2015
14 January 2016
17 January 2016
Please cite this article as: Byre Gowda, G., Pradeepa kumara, C.S., Ramesh, N., Sadashiva, M.P., Junjappa, H., Base
catalyzed reaction of ethylthioglycolate with β-aryl-β-(methylthio) acroleins: A general method for the synthesis of
2-carbethoxy-5-substituted/4, 5-annulated thiophenes in high overall yields, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.01.055
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1
Tetrahedron Letters
Base catalyzed reaction of ethylthioglycolate with β-aryl-β-(methylthio) acroleins: A
general method for the synthesis of 2-carbethoxy-5-substituted/4, 5-annulated
thiophenes in high overall yields.
G. Byre Gowda a, b, C. S. Pradeepa kumara a, b, N. Rameshb, M. P. Sadashiva a,, H. Junjappa b,
a
Department of Studies in Chemistry, University of Mysore, Mysuru 570 006, India
Department of Chemistry, REVA Institute of Science and Management, Yelahanka,, Bengaluru 560 064, India
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
(Methylthio)acroleins 1a-m were shown to be stable unlike their counterpart the
chloroacroleins and their efficacy as 1,3-dielectrophilic properties have now been
examined successfully in this work. They are shown to react with ethyl thioglycolate in the
presence of anhydrous potassium carbonate in boiling ethanol to yield the corresponding 5-
substituted / 4,5-annulated-2-carbethoxy thiophenes in 70-80% overall high yields.
Available online
Keywords:
.
Ethyl thioglycolate
Annulated thiophene
Methylthio
2009 Elsevier Ltd. All rights reserved.
Chloroacroleins
carbethoxy
Ever since Arnold and Zemlicka1 extended the then known
Vilsmeir-Haack2 formylation reaction to active methylene
carbonyl compounds they found that the course of reaction
yielded the corresponding β-chloroacroleins instead of only the
corresponding aldehydes in moderate to good yields. These
chloroacroleins have been proved to be powerful 1, 3-
dielectrophilic building blocks and employed extensively for the
synthesis of five and six member heterocycles, resulting in an
extensive literature on these developments in several reviews3,4,5,6
synthetic potential as 1, 3-dielectrophilic three carbon building
blocks. However, they are not available commercially for their
general use as synthetic intermediates due to their instability.
The identity of these intermediates with α-oxoketene
dithioacetals prompted us to examine the possible structural
change without disturbing their 1, 3-dielectrophilic centers, so
that we have a large body of stable building blocks at hand to
explore their chemistry. Our experience in organosulfur
chemistry prompted us to transform the active chlorine group to
the corresponding methylthio group so that the new class of
building blocks thus obtained may display improved stability
without sacrificing their 1,3-dielectrophilic character. There are
couple of methods to achieve the displacement of active chlorine
in organic molecules: Since the methanethiol itself is a gas
available only in cylinders, which is difficult to avail in many
laboratory facilities, there are other sources of methyl mercaptans
such as methylthiolesters,9 and methylthiouraniumsulphate10
which can produce sodium methylate under alkaline hydrolytic
conditions.
However, the chemistry of these chloroacroleins suffers
certain limitations due to their unstable nature. Hence many
workers generally prefer to synthesize them freshly and use
immediately in the following steps. In some studies attempts
have been made to develop stabilizers to prolong the life of these
intermediates. For example Paquette and co-workers7 have
suggested that a small quantity of anhydrous sodium acetate
could prolong the life of chloroacroleins derived from
cyclohexanone for two weeks without apparent decomposition.
Interestingly, recently Degani and co-workers11 have found
that Dimethyldithiocarbonate (DDC) is an excellent source of
methylmercaptan which can be generated ‘insitu’ in the presence
of 30% potassium hydroxide. We have successfully shown that
the active chlorine in chloroacroleins could be easily displaced by
Degani’s method as described in our earlier publication12.
Since the chemistry of β-(methylthio)acroleins and the
corresponding chloroacroleins are similar to that of α-oxoketene
dithioacetals in terms of their structural similarity and common
behavior towards 1,2- and 1,3 bi-nucleophiles to yield the
corresponding five and six member heterocycles8, the vast body
of literature on β-chloroacroleins therefore assumes greater
———
* Corresponding author. Tel.: +91 98453 72078
Email address: junjappa_123@rediffmail.com; mpsadashiva@gmail.com

2
Tetrahedron
We became further interested to examine their synthetic
Table-1: Synthesis of 2-carbethoxy-5-substituted/4, 5-
annulated thiophenes (Scheme 1)
applications on the lines of the corresponding chloroacroleins and
oxoketene dithioactals.
We here in report our first example of synthetic application
involving the reaction of (methylthio)acroleins with
ethylthioglycolate in the presence of base with a view to develop
a method for the synthesis of corresponding 2-carbethoxy-5-
substituted thiophenes25. Thus when a solution of equimolar
quantities of (methylthio)acroleins 1a and ethylthioglycolate
dissolved in ethanol was refluxed in the presence of anhydrous
potassium carbonate afforded the corresponding 2-carbethoxy -
5- substituted thiophene 2a in 81% yield (Scheme 1)
Mp (oC)
Liq
R2
R1
Entry
1
Product
Yield (%)
81
O
C6H5
H
S
OEt
2a
This is our first attempt to verify the reactivity of β-
(methylthio) acroleins with ethylthioglycolate and results
were presented here in comparison to that of their precursors
haloacroleins.
O
78
79
78
2
3
C6H4-p-Me
80-81
72-76
73-77
H
H
S
OEt
H3C
2b
O
C6H4-p-OMe
S
OEt
MeO
2c
O
C6H4-p-F
C6H4-p-Cl
H
4
5
S
OEt
F
2d
O
76
80
S
79-83
77-81
H
OEt
Cl
Br
2e
O
S
6
7
C6H4-p-Br
H
H
OEt
2f
Scheme 1
O
79-82
84
C6H4-m-NO2
S
However it must be noted that this thiophene was reported
earlier by Mavrova and co-workers13 by reaction between phenyl
chloroacrolein and ethylthio glycolate in the presence of base to
yield the corresponding thiophene 2a in 40% yield. Also Reddy
and co-workers have reported the synthesis of 2a under
microwave conditions using phenyl chloroacrolein in the
presence of base and obtained slightly improved yield of 62%.
They have also carried out this reaction under conventional
reaction conditions and have not reported the yields separately.
OEt
2g
O2N
O
8
H
79
S
S
liq
liq
S
OEt
2h
H3C
O
9
C6H5
CH3
72
S
OEt
2i
Mavrova and coworkers13 have also reported the synthesis of
thiophene 2b by reacting p-tolyl chloroacroleins 1b in the
presence of pyridine to yield the corresponding thiophene 2b in
56% yield. We have obtained the same thiophene 2b by reacting
the corresponding p-tolyl-(methylthio) acrolein 1b with
ethylthioglycolate as described above to yield the corresponding
thiophene in 78% yield. The same thiophene 2b was also
prepared by us by treating p-tolyl (methylthio) sulphone acrolein
3 (Scheme 2) with ethylthioglycolate in the presence of
potassium carbonate in boiling ethanol to an improved yield of
O
10
liq
liq
79
80
S
OEt
2j
O
11
12
S
OEt
2k
O
80-84
76
71
S
OEt
O
H3C
N
2l
H3C
H3C
O
OEt
N
CHO
H3C
H3C
S
N
m-CPBA
CHO
CH3
KS
124-128
N
13
OEt
SMe
K2 CO3/ EtOH
S
S
O
78%
O
OEt
2m
1b
3
O
2b
Reaction conditions25: A mixture of (methylthio) acrolein (2.07
mmol) and ethyl thioglycolate (2.07 mmol) in ethanol (10 mL)
was heated to 80 0C for 1h (monitored by TLC)
Scheme 2

3
science as organic conductors, semiconductors and light
emiting diodes etc.,
85%. The required sulphone 3 was obtained by oxidation of
(methylthio) acrolein 1b by m-Chloroperbenzoic acid (m-CPBA)
in 60% yield26. However the average yield of 2b through
sulphone is 72.5% involving two steps which is less than the
yield directly from the corresponding (methylthio) acroleins 2a.
Therefore it was decided to continue the remaining reactions
directly from (methylthio) acroleins.
In conclusion, we have demonstrated that the β-
(methylthio) acroleins developed by our group display identical
1,3-dielectrophilic reactivity similar to their precursors
chloroacroleins with the advantage of better yields of product
thiophenes. Therefore the chemistry of this group of building
blocks provides greater advantages over the counterpart
chloroacroleins in-terms of their stability and yields of the
products.
In the next series of experiments (methylthio)acroleins 1c,
1d, 1e and 1f (Table 1) were reacted with ethylthioglycolate
under the described reaction conditions to yield the
corresponding thiophenes 2c, 2d, 2e and 2f in 76-80% yields
(Table 1)
We will continue to explore these new synthetic
applications to further confirm their superiority as 1,3-
dielectrophilic building blocks.
Interestingly Reddy and co workers14 and others15,16 have
reported the synthesis of these thiophenes in comparatively low
yields both by microwave and conventional methods. We
therefore consider our yields from (methylthio) acroleins are
much higher than corresponding chloroacroleins. It must be
however noted that low yields obtained by earlier two research
groups attributed to their slow decompositions of the
chloroacroleins during the course of the reaction with
ethylthioglycolate.
Acknowledgments
H.J. is grateful to Indian National Science Academy (INSA) for
the award of Sr. Scientist. We gratefully acknowledge the CSIR,
New Delhi (02(0106)/12 EMR-II Dated 01/11/12) for the
financial support through the project. We thank J.N. Moorthy of
IIT Kanpur for helping in getting spectral analysis. The authors
thank Dr. P Shyamaraju, Chairman, REVA Institute of science
and Management, Yelahanka, Bengaluru-560 064.
We further examined the thiophenation from
(methylthio) acroleins 1h-m (Table 1) to yield the hitherto
unknown thiophenes 2h-2m respectively. The (methylthio)
acrolein 1g yielded the corresponding thiophene 2g in 84% yield.
Similarly the (methylthio) acrolein 1h derived from 2-
acetylthiophene reacted with ethylthioglycolate under the
described reaction conditions to yield the corresponding 2-
carbethoxy-5-(2-thienyl)-thiophene 2h in 79% yield. The other
(methylthio) acrolein 1i derived from propiophenone reacted with
ethylthioglycolate under identical reaction conditions to yield the
corresponding 4-methyl-5-phenyl-2-carbethoxy thiophene 2i in
72% yield. Also the (methylthio) acroleins 1j and 1k derived
from cyclohexanone and cycloheptanone respectively reacted
with ethylthioglycolate under similar reaction conditions to yield
the corresponding 4, 5-cycloannulated thiophenes 2j and 2k in 79
and 80% yields respectively. Next the (methylthio) acrolein
derived from tetralone 1l also yielded the corresponding 4, 5-
annualated -2-carbethoxy thiophene 2l in 76% yield. Finally the
(methylthio)acrolein 1m derived from 1-phenyl-3-methyl-
pyrazoline-5-one similarly reacted with ethylthio glycolate to
yield the corresponding pyrazolo-thiophene 2m in 71% yield.
The mechanism governing this transformation is
Supplementary Material
Supplementary data associated with this article can be
found, in the online version, at:
References and notes
1.
2.
Arnold, Z.; Zemlicka, J. Proc. Chem. Soc. London. 1958, 227-
251.
Vilsmeier, A.; Haack, A. Ber. Dtsch.Chem. Ges. 1927, 60B, 119-
127.
3.
4.
Masson, C.M Tetrahedron. 1992, 48, 3659-3726.
Jones, G.; Stanforth, S.P. Organic reactions, In: Larry E.Overman
et.al., John Wiley and Son’s, 2004, 56, 355-659.
Brahma, S.; Ray, J.K. Tetrahedron. 2008, 64, 2883-2896.
Rajput, A. P.; Girase, P. D. Int.J.Pharm.Chem.Biol. Sci. 1913, 3,
25-43.
5.
6.
7.
8.
9.
Paquette, L.A.; Johnson, B.A.; Hinga, F.M. Org. Syn. Coll. Vol.
1973, V, 215-217.
Junjappa, H.; Ila, H.; Asokan, C.V. Tetrahedron. 1990, 46(16)
5423-5506.
Frejd,T.; karlsson, J. O.; Gronowitz,S. J. Org..Chem. 1981, 3132-
3135.
10. Windus,W; Shildneck,P.R. Org. Syth. 1934, 14, 54.
11. Degani , I.; Fochi,R.; Regondi,V. Synthesis. 1983, 630-632.
12. Byre Gowda, G.; Charanraj ,T.P.;Pradeepakumara , C.S.; Ramesh,
N.;Thomas, S.P.; Sadashiva, M.P.; and Junjappa,H, Tetrahedron
Lett. 2014, 55, 4475-4479.
13. Mavrova A.T.; Wesselinova, D.; Tsenov, Y.A.; and Denkova. P.
Eur. J. Med. Chem. 2009, 44, 63-69.
14. Reddy G.J Latha, D.; Sailaja,S..;Pallavi K.; Srinivas Rao, K.
Heterocycl. Commun. 2004, 10 (6) 411-414.
depicted in Scheme 1. The potassium thioglycolate attacks 1 to
displace methylthio group followed by intramolecular attack by
enolate carbanian to the aldehyde carbonyl group with
elimination of water to yield the desired thiophene (Table 1).
It is therefore interesting to note that the reactivities of
both β-chloroacroleins and β-methyl thioacroleins displayed
identical reactivity with a clear difference of consistently higher
yields in the case methyl thioacroleins.
15. Hauptmann, S.; Weibenfels, M.; Scholz, Werner, E. M.; Kohler, J
Weisflog, J. Tetrahedron Lett. 1968, 11, 1317-1319.
16. Fusco, R.; Sannicolo, F. J. Org. Chem. 1982, 47, 1691-1696.
17. Holmes, J.M.; Lee G.C.M.; Wijono M.; Weinkam, R.; Wheeler,
L.A.; Garst. M.E.; J. Med. Chem. 1994, 37, 1646-1651.
18. Luker, T. J.; Beaton H.G.; Whiting, M.; Mete, A.; Cheshire, D.R
Tetrahedron Lett. 2000, 41, 7731-7735.
Thiophenes are important class of heterocycles
generally used as17-24 pharmaceuticals and in the area of material

4
Tetrahedron
19. Pinto, I.L.; Jarvest, R.L.; Serafinowska, H.T.; Tetrahedron Lett.
thiophene which was purified by column chromatography over
silica gel using ethyl acetate-petroleum ether (5:95) as eluents.
2000, 41 1597-1600.
20. Kiani, M.S.; Mitchell, G.R.; Synth.Met. 1992, 46, 293-306.
21. Wolf, J. J.; Wortmann.R. Adv. Phy.Org. Chem. 1999, 32, 121-
217.
22. Morrison , J.J.; Murray, M.M.; Li. X.C.; Holmes, A, B.; Moratti;
S.C.; Friend, R.H.; Sirringhaus, H. Synth. Met. 1999, 102,987.
23. Li, X.C. Sirringhaus, H.; Garnier, F.; Holmes, A, B.; Moratti.
S.C.; Feeder, N.; Clegg. W.; Teat, S.J.; Friend, R.H. J. Am. Chem.
Soc. 1998, 120, 2206-2207.
24. Greenham, N.C.; Moratti, S.C.; Bradley, D.D.C.; Friend, R. H.;
Holmes, A. B. N.; Nature (London) 1993, 365, 628.
25. General procedure for the preparation of 2-carbethoxy-5-
substituted/4, 5-annulated thiophenes (2a-2m):
26. Procedure for the preparation of sulfone derivative 2b: To a
solution of β-(methylthio) acrolein (0.178g 0.001mol) in
dichloromethane (10 mL) was added m-CPBA at room
temperature. The reaction mixture was stirred at room temperature
for 3h. The progress of the reaction was monitored by TLC (20%
ethyl acetate: hexane). The reaction mixture was quenched with
saturated sodium sulphite (monitored the quenching process by
using 10% potassium iodide solution). Separated the organic layer
and given wash with saturated sodium bicarbonate solution. The
organic layer was dried over anhydrous sodium sulphate and
evaporated the solvent under reduced pressure to give sulphone
derivative. The crude product as such used in the next step without
purification.
To a solution of β-(methylthio) acrolein (0.44g 2.07 mmol) in
ethanol 10 mL was added ethyl thioglycolate (0.249g 2.07 mmol)
and anhydrous potassium carbonate (0.28g, 2.07 mmol) at room
temperature. The mixture was heated to reflux for one hour
(monitored by TLC), cooled to room temperature and evaporated
the solvent. The residue was added water and extracted with ethyl
acetate. The combined extracts were dried (Na2SO4) and the
solvent was evaporated under reduced pressure to give crude

Graphical Abstract
Base catalyzed reaction of (ethylthio)
glycolate with β-(methylthio)
acroleins: A general method for the
synthesis of 2-carbethoxy-5-
Leave this area blank for abstract info.
substituted/4, 5-annulated
thiophenes in high overall yields.
G. Byre Gowda a,b, C. S. Pradeepa kumara a,b, N. Rameshb, M. P. Sadashiva a,, H. Junjappa b,
O
R2
R1
CHO
SMe
R2
KS
OEt
CO2Et
S
K2 CO3/ EtOH
R1
R1=C6H4-p-Me
R2=H
1a-m
2a-m
m-CPBA
O
O
H3C
KS
CHO
S
OEt
K2 CO3/ EtOH
OEt
H3C
2b
3
S
CH3
O
O