Synthesis of 2,3,5-trisubstituted furans from α-formylaroylketene dithioacetals

Article abstract of DOI:10.1016/j.tetlet.2011.01.128

A new strategy for the synthesis of 2,3,5-trisbustituted furans from α-formylketene dithioacetals is described. The protocol involves a facile conversion of α-formylketene dithioacetals to vinylketene dithioacetals via Wittig reaction and subsequent N-bro

Full text of DOI:10.1016/j.tetlet.2011.01.128

Tetrahedron Letters 52 (2011) 1667–1669
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Synthesis of 2,3,5-trisubstituted furans from
a-formylaroylketene dithioacetals
K. A. Sasikala a, K. A. Kalesh b, E. R. Anabha a, P. Madhavan Pillai a, C. V. Asokan a, K. S. Devaky a,
⇑
a School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam, Kerala 686560, India
b Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy for the synthesis of 2,3,5-trisbustituted furans from
a
-formylketene dithioacetals is
Received 13 December 2010
Revised 24 January 2011
Accepted 27 January 2011
Available online 3 February 2011
described. The protocol involves a facile conversion of
a-formylketene dithioacetals to vinylketene
dithioacetals via Wittig reaction and subsequent N-bromosuccinimide-mediated cyclization to 2,3,5-tris-
bustituted furans. Further conversion of the 2-thioalkylfurans thus obtained to 2-aminofurans shows the
potential synthetic utility of this new approach.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Furan
a-Formylketene dithioacetal
Vinylketene dithioacetal
N-Bromosuccinimide
Bromination
Furans are key structural units in many natural products,1 phar-
maceuticals2 and a broad spectrum of biologically relevant syn-
thetic molecules.3 Extensive synthetic efforts have been devoted
by various research groups on polysubstituted furans. Owing to
their unique and versatile biological activities, there is a continuing
interest in this area of heterocyclic synthetic chemistry. Paal–Knorr
furan synthesis,4 which is essentially an acid-catalyzed cyclocon-
densation of 1,4-dicarbonyl compounds or their equivalents, and
Feist–Benary synthesis,5 which involves condensation of b-dicar-
dithioacetals 2 was accomplished via a simple Wittig reaction17
in 78–90% yields (Table 1). But, unfortunately the dienes 2 failed
to react in Diels–Alder reactions toward various dienophiles, such
as maleic anhydride, dimethyl acetylene dicarboxylate, p-benzo-
quinone, etc. At this point, we presumed that a bromination reac-
tion of the diene 2 followed by amination might be developed as a
useful route toward the synthesis of trisubstituted pyrroles, which
form key scaffolds in many inhibitors investigated in medicinal
chemistry/pharmaceutical research.
bonyl compounds with
a
-haloketones, are the most established
Bromination reactions of the vinylketene dithioacetals 2 with
bromine in THF, however, resulted in complex reaction mixtures
with severe difficulty in isolating and characterizing any useful
product. However, our previous experience on the use of N-bromo-
general methods for the construction of furan ring. A number of
strategies utilizing cycloisomerization of alkyne or allene contain-
ing acyclic precursors6 and several novel annulation approaches,
such as reactions of carbonyls with fluoropropargyl chloride,7 alde-
succinimide (NBS) on polymer support for the
a-bromination reac-
hydes with allylic sulfoxides,8
a,b-acetylenic ketones with
a
-diazo
tions of
a
-oxoketene dithioacetals18 prompted us to investigate the
esters,9 aldehydes with ketimines,10 acyl chlorides with 2,3-bis
(trimethylsilyl)buta-1,3-diene,11 and Ag or Au catalyzed conversion
of alkynyloxiranes12 have recently been reported. Herein, we report
a new strategy (Scheme 1) for the synthesis of 2,3,5-trisubstituted
possibility of brominating 2 with NBS. Thus the vinylketene dithio-
acetals 2 were treated with NBS in acetonitrile at room tempera-
ture for 24 h. Contrary to the expected bromo-adduct, we
observed the formation of trisubstituted furans 3 as major prod-
ucts (Scheme 1 and Table 1).
furans in a two-step process starting from
a-formylaroylketene
dithioacetals 1, which we have previously demonstrated to be
highly useful intermediates for the synthesis of a variety of hetero-
cycles.13–15
O
H
SR
SR
O
O
H
SR
SR
SR
O
Cl
C6H5CH2PPh3
NBS
The use of vinylketene dithioacetals as 1,3-dienes in Diels–Alder
Ar
Ar
Ar
reactions has been extensively documented.16 In line with these
NaOH, CH2Cl2
1h, r.t
CH3CN, H2O
24h, r.t
O
studies, we decided to explore the synthetic utility of our
a-form-
Ph
Ph
2
3
ylaroylketene dithioacetals 1. Conversion of 1 to vinylketene
1
Scheme 1. General scheme showing the conversion of
dithioacetals 1 to vinylketene dithioacetals 2 and subsequent N-bromosuccini-
mide-mediated conversion of 2 to 2,3,5-trisubstituted furans 3.
a-formylaroylketene
⇑
Corresponding author. Tel.: +91 9496720967.
E-mail address: ksdevakyscs@yahoo.com (K.S. Devaky).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.128

1668
K. A. Sasikala et al. / Tetrahedron Letters 52 (2011) 1667–1669
Table 1
Vinylketene dithioacetals 2a–g and corresponding 2,3,5-trisubstituted furans 3a–g (Scheme 1) and aminofurans 11a and 11e (Scheme 3)
b
Sl. No.
Ar
R
% Yield (2)a
% Yield (3)
% Yield (3) (11)c
a
b
c
d
e
f
4-OMeC6H4
C6H5
Me
Me
Me
Me
Me
CH2C6H5
CH2C6H5
90
83
85
80
86
82
78
70
63
66
64
65
63
60
95
—
—
—
94
—
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-CH3C6H4
C6H5
g
—
a
b
c
See Ref. 23 for the general procedure for the synthesis of these derivatives. See Supplementary data for spectral data.
See Ref. 23 for the general procedure for the synthesis of these derivatives. See Supplementary data for spectral data.
See Ref. 25 for the general procedure for the synthesis of these derivatives. See Supplementary data for spectral data.
SCH3
O
SCH3
SCH3
O
SCH3
O
SCH3
SCH3
OH
O
OH2
SCH3
Br
SCH3
Br
NBS
H2O
Br
R
R
R
-H+
R
CH3CN
8
2
7
9
O
SCH3
SCH3
O
SCH3
O
OH
R
-CH3SH
R
H
10
3
Scheme 2. Proposed mechanism for the formation of the 2,3,5-trisubstituted furans 3 from vinylketene dithioacetals 2, mediated by N-bromosuccinimide.
A plausible mechanism for the formation of the furan is out-
lined in Scheme 2 below.
O
O
NHEt
O
SCH3
O
EtNH2, EtOH
Reflux, 24 h
Ar
Ar
Similar to the polar mechanism for the formation of bromohy-
drins from simple alkenes,19 bromination at C-4 carbon atom of
the diene 2 by NBS might lead to the intermediate 7, which under-
goes hydrolysis followed by deprotonation to the key intermediate
9. A subsequent nucleophilic substitution reaction of the bromine
with the hydroxyl group on the C-1 carbon atom would result in
the cyclic intermediate 10, which is aromatized with the elimina-
tion of one molecule of methane thiol resulting in the formation
of the 2,3,5-trisubstituted furan 3. It should be noted that in this
proposed mechanism, the hydrolysis of the intermediate 7 occurs
prior to the aqueous work-up (quenching of the NBS reaction on
ice-cold water)24 although in-principle it could take place during
the work-up as well. We, however, unfortunately could not detect
the intermediate 7 in the GC–MS analysis of the crude reaction
mixture (prior to work-up). Presumably this intermediate is short
lived and most of its conversion to the final furan occurs relatively
quickly (in a few minutes), although the reactions were run for
longer time for isolating maximum yields.
We have subsequently explored the possibility of converting
the newly prepared trisubstituted furan derivatives 3 to 2-amin-
ofurans by replacing the thioalkyl group with alkylamino group.
2-Aminofurans have been reported to be useful intermediates in
many natural product syntheses.20–22 Thus 3 were treated with
ethylamine in refluxing ethanol under the reaction conditions re-
ported by Fu et al.8 resulted in the amino derivatives 11 in excel-
lent yield (Scheme 3).25 This reaction also reveals the scope for
further functionalizing/derivatizing the newly prepared furan
derivatives.
Ph
Ph
11
3
Scheme 3. Synthesis of 2-aminofurans from 2-thiomethylfurans.
thetic intermediate 2-aminofurans shows the potential utility of
this new approach in natural product synthesis. We believe that
this new method would be highly useful in a range of research
and pharmaceutical development endeavors. Detailed investiga-
tions on the applications of this new strategy in medicinal chemis-
try as well as detailed mechanistic investigations are in progress
and will be reported in due course.
Acknowledgments
K.A.S. thanks KSCSTE Trivandrum for the award of research fel-
lowship and Prof. Ibnu Saud IIRBS, Kottayam for providing spectral
data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.128.
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The
appropriate
2-aroyl-3,3-bis(alkylthio)-