Flexible routes to thiophenes

Article abstract of DOI:10.1021/ol403310f

Three convergent routes to thiophenes are described, hinging on the radical addition of α-xanthyl ketones to ethyl vinyl sulfide or to vinyl pivalate. The latter route ultimately proved to be the most versatile and efficient (61-94%).

Full text of DOI:10.1021/ol403310f

Letter
pubs.acs.org/OrgLett
Flexible Routes to Thiophenes
Helene Jullien, Beatrice Quiclet-Sire, Thomas Tetart, and Samir Z. Zard*
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Laboratoire de Synthes
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e Organique, CNRS UMR 7652 Ecole Polytechnique, 91128 Palaiseau Cedex, France
S
* Supporting Information
ABSTRACT: Three convergent routes to thiophenes are
described, hinging on the radical addition of α-xanthyl ketones
to ethyl vinyl sulfide or to vinyl pivalate. The latter route
ultimately proved to be the most versatile and efficient (61−
94%).
hiophenes represent a fundamental class of five-
Scheme 1. Waldvogel’s Approach to Thiophenes
Tmembered heteroaromatics. They are found in many
natural products as well as in biologically active substances.1,2
Three examples of clinically important thiophenes are displayed
in Figure 1: Plavix,1b a nonpeptide fibrinogen receptor
the accessibility of the xanthate precursors. We present herein
three convergent pathways leading to substituted thiophenes 3.
Our first strategy relied on the sequential fragmentation of
geminal sulfoxide-xanthates 4 (Scheme 2). Moderate heating
Figure 1. Three examples of biologically active thiophenes.
Scheme 2. Sulfoxide-Based Route to Thiophenes
antagonist; Duloxetine,1c a potent inhibitor of serotonin and
norepinephrine uptake carriers; and Dup-697,1d a nonopiate
antinociceptive agent. Thiophenes and polythiophenes are also
useful intermediates in organic synthesis3 and, perhaps more
importantly, constitute key components in material sciences.4
Their aromaticity, relative chemical stability, and polar-
izability constitute key features that have been broadly
exploited. Thus, wide-ranging applications in the fields of
liquid crystals, organic semiconductors, conducting polymers,
nonlinear optics, electroluminescence, and photochromic
materials have been reported.4
Not surprisingly, therefore, numerous methods have been
described for their synthesis.5,6 The classical Paal−Knorr
reaction is still the most frequently used.7 Substituted
thiophenes can also be obtained from a naked thiophene ring
by functionalization through α-metalation or β-halogenation.5
In view of the special importance of thiophenes, new routes are
nevertheless still needed. We envisaged, therefore, to exploit
the broad applicability of the radical addition of xanthates to
design flexible routes to such heteroaromatics.8 Only Waldvogel
seems to have used xanthates to access thiophenes 3 through
the ionic route outlined in Scheme 1.9 It involves acid mediated
closure and dehydration of mercaptans 2 derived by aminolysis
of xanthates 1. This, otherwise efficient approach, is limited by
should first cause elimination of ethanesulfenic acid to give
vinyl xanthate 5. As the temperature is increased, a Chugaev
elimination sets in leading to thioenols 6 as an equilibrating E
and Z isomers 6a and 6b.10 The latter thioenol then cyclizes
onto the carbonyl group to form the desired thiophenes 3.
Compound 4 was easily prepared in a two-step process
(Scheme 3). First, radical addition of an α-xanthyl ketone 7 to
the ethyl vinyl sulfide furnished adduct 8, in accord with a
previous study from our group.11 The reaction occurs in the
presence of a substoichiometric quantity of lauroyl peroxide
Received: November 15, 2013
Published: December 3, 2013
© 2013 American Chemical Society
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Letter
a
1,3-Dithiethanones have been very little studied as a class.
We noted that they were surprisingly resistant to heating. In
our initial study, we could convert the phenyl-substituted 1,3-
dithiethanone (10, R= Ph) into the corresponding thiophene
(3, R = Ph) by heating it for 48 h in refluxing o-
dichlorobenzene, but the yield was only 20%.13 Building on
this sole example, we have now found that a more drastic
heating (215 °C) with silica gel without solvent was a much
more efficient procedure to form the thiophene ring, in yields
in the range of 61 − 81% (Scheme 4). This transformation
presumably proceeds by way of the intermediate thioaldehyde
generated by decomposition of the dithietanone moiety (see
Scheme 5 and discussion below).
Scheme 3. Examples of Thiophenes by the Sulfoxide Route
a
Conditions: (a) 185 °C; (b) lauric acid (1 equiv), 185 °C; (c) lauric
acid (1 equiv), heating from 200 to 235 °C.
Scheme 5. Mechanism of Thiophene Formation
(DLP) as the initiator and provides the desired adduct 8 in 58 -
76% yield. Even though xanthates and other thiocarbonyl
derivatives are known to react readily with peracids,12 we found
that it was possible to oxidize the sulfide group selectively using
one equivalent of m-CPBA. The requisite sulfoxides 4a−c were
thus obtained in 65 − 88% yield.
We were pleased to find that gradual heating of compound
4a in octadecane to about 185 °C resulted in the formation of
the desired thiophene 3a in 76% yield. Other solvents such as
diphenyl ether and 1,2-dichlorobenzene were also tested;
however the separation of the product from the solvent proved
somewhat tedious.
When the procedure was extended to the other two
substrates 4b and 4c, the yield unfortunately dropped to
about 45%. We reasoned that the electron donating nature of
the substituents was slowing down the dehydration step and
that the addition of a weak acid should improve the rate of this
step. Indeed, addition of one equivalent of lauric acid and
slightly increasing the reaction temperature essentially doubled
the yield of thiophenes 3b and 3c. Other slightly acidic
adjuvants such as silica gel or NaHSO4 were tried without
notable success.
In parallel to this first approach, we explored another route,
where again we hoped to incorporate one of the two sulfur
atoms in the xanthate group into the thiophene ring. A few
years ago, we found that treatment of adduct 9, derived by the
radical addition of xanthates such as 7 to vinyl pivalate, with
TiCl4 in dichloromethane at low temperature unexpectedly
gave the corresponding 1,3-dithiethanones 10 (Scheme 4; Piv =
Me3CO).13
Our success with converting 1,3-dithiethanones 10 into
thiophenes encouraged us to go one step back and ask whether
it would not in fact be possible to produce the thiophenes
directly from the radical adduct 9. These adducts have the
correct oxidation level, the same as that of the corresponding
1,3-dithiethanones 10, and their conversion into thiophenes
required a procedure for the selective cleavage of the xanthate
motif allowing the preferential ring-closure of the resulting
thiols onto the neighboring ketone.
Unfortunately, despite much effort and many trials, the
conversion of adduct 9 into thiophenes remained poor and the
yields erratic and low. It appeared that under most condition
tried, the xanthate was the group that was eliminated leading to
the observation of only little thiophene, if any. Finally, we
discovered that heating adduct 9 in acetic acid using microwave
irradiation in the presence of potassium iodide furnished the
desired thiophenes in high yield (Figure 2). The reaction
required only a few minutes in the microwave oven.
Scheme 4. Thiophenes by the Dithietanone Route
This transformation appears to be fairly general and
applicable to the formation of thiophenes with aromatic,
heteroaromatic, and aliphatic substituents. Both electron-
donating and electro-withdrawing groups on the aromatic
ring are tolerated. Bis-thiophene 3h, fluorenyl thiophene 3k,
and bis-thienylbenzene 3u are especially remarkable examples
with potential utility in material science. Thiophenes
substituted in the 1,2- and 1,3-positions can be rapidly
assembled. The presence of long alkyl chains in products 3m
and 3n is noteworthy, because such appendages improve
solubility in compounds desired for organic conductors. The
introduction of substituents at the 2- and 3-positions is easiest
by the present approach, since the radical addition to vinyl
pivalate is generally very efficient. It is possible nevertheless to
also introduce a substituent at position 4, as in thiophene 3n,
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Finally, thiophenes bearing fused 5-, 6-, or 7- membered rings
such as 3p, 3q, 3r, 3s and 3t can be prepared by the same
procedure. In the case of 3s, the acidic conditions caused
cleavage of the acetal group initially present in 9s, whereas the
unusual bicyclic thiophene 3t derived from tosyl-piperidone
contains the core structure of Plavix.
A plausible mechanism for the formation of the thiophenes
by this third approach is depicted in Scheme 5. The iodide acts
as a nucleophile with assistance from the acetic acid solvent to
cleave the xanthate in adduct 9, without affecting the pivalate
group. This leads to the unstable dithiocarbonic acid 11, which
readily extrudes a molecule of carbon oxysulfide to furnish thiol
12. This compound is well poised to undergo ring-closure into
intermediate 13 and loss of water and pivalic acid to give the
desired thiophene 3. Thiol 12 may also first expel pivalic acid
and collapse into thioaldehyde 14, which would also lead to
thiophene 3 by cyclization and loss of water (cf cyclization of
enethiols 6 in Scheme 2). These pathways are not mutually
exclusive and both could be operating simultaneously in the
medium.
In summary, we have presented here three convergent and
efficient entries to substituted thiophenes. In particular, our
third route allows the preparation of a large variety of mono-,
bis- and tri- unsymmetrically substituted thiophenes in only two
steps and in high yield. The process uses cheap and readily
available starting materials and is operationally very simple to
perform. It nicely complements existing methods for thiophene
synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full spectroscopic data, and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zard@poly.polytechnique.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the ANR for financial support.
■
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