Annulation of donor-acceptor cyclopropanes with mercaptoacetaldehyde: Application to the synthesis of tetrasubstituted thiophenes

Article abstract of DOI:10.1039/c4cc00565a

A conceptually new method for synthesis of tetrasubstituted thiophenes in two steps from trans-2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates and 1,4-dithiane-2,5-diol has been developed. It involves AlCl₃-mediated [3+3] annulation of the cyclopropane-derived 1,3-zwitterionic intermediates with in situ generated mercaptoacetaldehyde, followed by DBU-induced rearrangement of the resulting tetrahydrothiopyranols. The target thiophenes are produced in 55-82% yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00565a

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[3+3] Annulation of donor–acceptor
cyclopropanes with mercaptoacetaldehyde:
application to the synthesis of tetrasubstituted
thiophenes†
Cite this: Chem. Commun., 2014,
50, 4062
Received 22nd January 2014,
Accepted 19th February 2014
Gopal Sathishkannan and Kannupal Srinivasan*
DOI: 10.1039/c4cc00565a
www.rsc.org/chemcomm
A conceptually new method for synthesis of tetrasubstituted thiophenes
in two steps from trans-2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates
and 1,4-dithiane-2,5-diol has been developed. It involves AlCl3-mediated
[3+3] annulation of the cyclopropane-derived 1,3-zwitterionic inter-
mediates with in situ generated mercaptoacetaldehyde, followed by
DBU-induced rearrangement of the resulting tetrahydrothiopyranols.
The target thiophenes are produced in 55–82% yields.
The thiophene ring is encountered in a notable number of
pharmaceuticals1 such as articaine, cymbalta, plavix, raltitrexed and
zyprexa and also in natural products2 such as echinothiophene,
urothione and xanthopappins A–C. Further, thiophene-based materials
find widespread applications in organic electronics as semi-
conductors, field effect transistors, light emitting diodes, molecular
Scheme 1 Synthesis of tetrahydrothiopyranols and thiophenes.
wires, photovoltaic materials, and nonlinear optical materials, etc.3 annulations (with aldehydes,6 nitriles7 and isocyanates8) have been
The importance of thiophene derivatives has driven the develop- reported and no higher order annulation has been known to date.
ment of numerous methods for the synthesis of thiophenes with
1,4-Dithiane-2,5-diol (2) is also a versatile synthetic precursor
diverse substitution patterns.4 To complement these reports, we and releases mercaptoacetaldehyde in situ upon treatment with
herein report a de novo synthesis of tetrasubstituted thiophenes tertiary amines9 or certain organocatalysts.10 The phenomenon has
from tetrahydrothiopyranols, which are in turn prepared by [3+3] been exploited in many [3+2] annulations for accessing a variety of
annulation of activated donor–acceptor (D–A) cyclopropanes with tetra- and dihydrothiophenes and thiophenes.9,10 However,
in situ generated mercaptoacetaldehyde (Scheme 1).
only recently, its first ever-known [3+3] annulation with azo-
D–A cyclopropanes are valuable building blocks in organic methineimine has been reported.11
synthesis5 and upon treatment with Lewis acids, they readily
We envisaged that the [3+3] annulation of trans-2-aroyl-3-aryl-
undergo ring-opening to form 1,3-zwitterions, which participate cyclopropane-1,1-dicarboxylates 1, with in situ prepared mercapto-
in several [3+n] (n = 2, 3, 4) annulation reactions with apt partners acetaldehyde (20), would not only represent the previously unknown
giving an assortment of carbo- and heterocycles. As compared partnership in D–A cyclopropane chemistry, but also furnish useful
with [3+2] annulations of D–A cyclopropanes, only a small number tetrahydrothiopyranol derivatives 3. Pleasingly, when 1a was reacted
of [3+3] and [3+4] annulations are known. Especially, for trans- with 2 in the presence of AlCl3 (1 equiv.) in DCM at room tempera-
2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates 1, only a few [3+2] ture, a chromatographically homogeneous, diastereomeric mixture of
3a and 3a0 (dr 9 : 1) was obtained in 74% isolated yield (Scheme 2).
Our attempts to improve the yield of the mixture or prepare one of
the diastereomers exclusively by varying the Lewis acid or its loading
and also changing the solvent or reaction temperature did not
materialize. However, we were able to separate the major
diastereomer 3a in the pure form (60% yield) from the mixture by
crystallization. It may be noted that the separation of this diastereo-
meric mixture into individual components is quite unnecessary
School of Chemistry, Bharathidasan University, Tiruchirappalli 620 024,
Tamil Nadu, India. E-mail: srinivasank@bdu.ac.in; Fax: +91-431-2407045;
Tel: +91-431-2407053-538
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for all products, including copies of 1H and 13C NMR
spectra and X-ray structural information of 3m and 4d (CIF). CCDC 981071 and
981072. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4cc00565a
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Scheme 2 Formation of a diastereomeric mixture of tetrahydrothiopyranols and their conversion into a thiophene.
because both diastereomers are equally suitable for further conver- and Ar2 are thienyl, it would lead to di- and trithiophenes. Unfortu-
sion into a thiophene and, moreover, the stereochemical information nately, when Ar1 was 2-thienyl, it produced a complicated mixture.
would be lost in the final product. Thus, when the diastereomeric However, when Ar2 was 2-thienyl, we obtained the expected dithio-
mixture of 3a and 3a0 was treated with DBU in DCM, the target phenes 4j–l. Surprisingly, dithiophene 4l which has p-nitrophenyl as
thiophene 4a was produced in 97% yield (overall yield = 72%; pure 3a Ar1 was also accessible, albeit in low yield. Methyl esters of the
also gave 4a in identical yield). We also attempted to develop one-pot starting cyclopropanes were also equally compatible in the reaction
synthesis of 4a from 1a by coupling both the steps, but it resulted in a as exemplified by the formation of thiophene 4m and dithiophene
complicated mixture. Thus, the removal of the Lewis acid by at least 4n from the respective precursors. In the majority of reactions, the
filtering through Celite after the first step is mandatory before intermediate tetrahydrothiopyranols were obtained as mixtures of
proceeding to the second step.
diastereomers with 2,3,5-cis-isomers being predominant. We did not
Next, we examined the scope of the two-step transformation for attempt to separate or purify the diastereomers and proceeded to the
various 2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates (Table 1). The next step after removing the Lewis acid by passing through Celite.
placement of different electron releasing and halogen substituents on Nevertheless, in certain cases, we obtained tetrahydrothiopyranols
the two aromatic rings Ar1 and Ar2 was well tolerated and the respec- [3a (Ar1 = Ar2 = Ph, R = Et), 3k (Ar1 = 4-ClC6H4, Ar2 = 2-thienyl, R = Et)
tive thiophenes 4a–4i were produced in good overall yields. However, and 3m (Ar1 = Ar2 = Ph, R = Me)] as single diastereomers by repeated
when the nitro substituent was present on Ar1 ( p-nitrophenyl), the crystallization of the corresponding mixtures. The structures of
reaction was sluggish and no isolable amount of tetrahydrothio- tetrahydrothiopyranol 3m and thiophene 4d were unambiguously
pyranol could be obtained even after 5 days. On the other hand, the confirmed by X-ray crystallographic studies (Fig. 1).12
nitro substituent on Ar 2 ( p-nitrophenyl) produced a complicated
We propose the following mechanism for the overall transforma-
mixture, from which no traces of thiophene could be isolated. tion of trans-cyclopropanediesters 1 into thiophenes 4 (Scheme 3).
Next, we focused our attention on replacing Ar1 and Ar2 with The Lewis acid coordinates with the malonyl unit of 1, which results
heteroaromatic rings. We envisaged that when either or both of Ar1 in C1–C3 bond cleavage to form the intimate ion-pair A.6–8,13
Table 1 Scope of the two-step thiophene synthesisa,b
a
Reaction conditions: the reaction was conducted with 1 (0.5 mmol) and 2 (2.5 mmol) in the presence of AlCl3 (0.5 mmol) in DCM (5 mL) at rt for
b
24 h and then crude 3 was treated with DBU (1 mmol) in DCM (5 mL) at rt for 12 h. Isolated overall yield.
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This method is operationally simple and requires only cheap
and readily available starting materials. We are currently
exploring the synthesis of thiophene-based advanced materials
using the methodology for molecular electronics study.
The authors thank the Science and Engineering Research Board
(SERB) and the Council of Scientific and Industrial Research (CSIR),
India, for financial support; DST-FIST for instrumentation facilities
at the School of Chemistry, Bharathidasan University, India.
Fig. 1 X-ray structures of 3m (left) and 4d (right).
Notes and references
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Scheme 3 Plausible reaction mechanism for formation of thiophenes 4.
Mercaptoacetaldehyde (20) generated in situ from 2 attacks C3 of A in
a SN2 fashion to give B, which undergoes a 1201 rotation to bring the
malonate anion closer to the aldehyde carbonyl group. The ensuing
nucleophilic attack of the malonate anion on carbonyl gives the
cyclized product 3 in which the hydroxyl group is in the equatorial
position (the attack on the opposite face of the carbonyl would give
the minor diastereomer 30 in which the hydroxyl group is in an
unfavourable axial position). In the second step, the base (DBU)
removes the hydroxyl proton of 3 (+30) which leads to ring-opening
followed by the formation of a carbanion as shown in C. The anion
attacks the ketone carbonyl group to give tetrahydrothiophene D.
Base-assisted elimination of CO2 and ethanol from D gives dihydro-
thiophene E, which upon aromatization affords thiophene 4.
In summary, we have developed a new two-step procedure for the
synthesis of tetrasubstituted thiophenes from D–A cyclopropanes
and 1,4-dithiane-2,5-diol. The first step involves AlCl3-mediated
[3+3] annulation of the cyclopropane-derived zwitterionic inter- 11 X. Fang, J. Li, H.-Y. Tao and C.-J. Wang, Org. Lett., 2013, 15, 5554.
12 CCDC 981071 for compound 3m and CCDC 981072 for compound
mediates with in situ generated mercaptoacetaldehyde to afford
4d. See the ESI† for details.
tetrahydrothiopyranols, and the second step involves DBU-
13 P. Pohlhaus, S. D. Sanders, A. T. Parsons, W. Li and J. S. Johnson,
mediated rearrangement of tetrahydrothiopyranols into thiophenes.
J. Am. Chem. Soc., 2008, 130, 8642.
4064 | Chem. Commun., 2014, 50, 4062--4064
This journal is ©The Royal Society of Chemistry 2014