Methylsulfenylation of thioacetals as a method for synthesizing 2-thio-substituted furans.

Article abstract of DOI:10.1021/ol990865l

[formula: see text] The dimethyl(methylthio)sulfonium tetrafluoroborate induced cyclization of various bis(methylsulfanyl) carbonyl compounds is described. The reaction proceeds by methylthiolation of the thioacetal group to give a thionium ion which unde

Full text of DOI:10.1021/ol990865l

ORGANIC
LETTERS
1999
Vol. 1, No. 10
1559-1561
Methylsulfenylation of Thioacetals as a
Method for Synthesizing
2-Thio-Substituted Furans
Albert Padwa,* John D. Ginn, and Michael S. McClure
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received July 26, 1999
ABSTRACT
The dimethyl(methylthio)sulfonium tetrafluoroborate induced cyclization of various bis(methylsulfanyl) carbonyl compounds is described. The
reaction proceeds by methylthiolation of the thioacetal group to give a thionium ion which undergoes subsequent cyclization with the neighboring
carbonyl group. This is followed by an elimination reaction to furnish the furan ring.
Substituted furans have often been employed as sources of
latent functionality for the synthesis of natural products.1
Thio-substituted furans are particularly attractive intermedi-
ates that have found widespread usage in organic synthesis.
They undergo a variety of reactions including addition/
elimination,2 nickel-catalyzed Grignard coupling,3 Michael
addition,4 ortho-metalation,5 acid hydrolysis to butenolides,6
and [4 + 2]-cycloaddition chemistry.7 Although a number
of synthetic procedures are available for their formation,5,8
most of the existing methods often require harsh conditions
and are frequently based on the use of a preexisting furan
ring. Examples include the addition/elimination of thiols,9
sulfanylation of ortho-metalated anions,10 metalation of
disulfides,5 and alkylation of furan thiolates.11 Our own
interest in this area stems from the facility with which
2-amino- and 2-thioalkyl-substituted furans undergo Diels-
Alder cycloaddition chemistry and the potential use of the
resulting oxabicyclic adducts for alkaloid synthesis.12 In this
Letter we describe a highly efficient synthesis of 2-alkylthio-
substituted furans which is based on an aldol condensation
of a carbonyl compound with bis(methylsulfanyl)acetalde-
hyde (2) followed by acetylation with Ac2O (Scheme 1).
Scheme 1
(1) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. Sargent, M. V.; Dean, F.
M. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p 599. Frey, H. Synlett 1993,
905.
(2) Kada, R.; Knoppova, V.; Kovac, J.; Vecera, Z. Collect. Czech. Chem.
Commun. 1980, 45, 1831.
(3) Takei, H.; Miura, M.; Sugimura, H.; Okamura, H. Chem. Lett. 1979,
1447.
(4) Kraus, G. A.; Gottschalk, P. Tetrahedron Lett. 1983, 27, 2727.
(5) Nolan, S. M.; Cohen, T. J. Org. Chem. 1981, 46, 2473.
(6) Okazaki, R.; Negishi, Y.; Inamoto, N. J. Org. Chem. 1984, 49, 3819.
(7) Eugster, C. H.; Balmer, M.; Prewo, R.; Bieri, J. H. HelV. Chim. Acta
1981, 64, 2636. Kotsuki, H.; Mori, Y.; Ohtsuka, T.; Nishizawa, H.; Ochi,
M.; Matsuoka, K. Heterocycles 1987, 26, 2347. Harwood, L. M.; Ishikawa,
T. J.; Phillips, H.; Watkin, D. J. Chem. Soc., Chem. Commun. 1991, 527.
Wu, H. J.; Yen, C. H.; Chuang, C. T. J. Org. Chem. 1998, 63, 5064.
(8) McDougal, P. G.; Oh, Y. I. Tetrahedron Lett. 1997, 38, 6869. Tsay,
H. Tetrahedron Lett. 1997, 38, 6869.
Methylsulfenylation of one of the thiomethyl groups of the
resulting acetate 3 with dimethyl(methylthio)sulfonium tetra-
fluoroborate (DMTSF)13 induces a Pummerer cyclization to
(9) Dann, O.; Moeller, F. Chem. Ber. 1949, 82, 76.
10.1021/ol990865l CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/06/1999

give dihydrofuran 4. This is followed by elimination of acetic
acid to furnish the desired furan 5 in excellent yield.
The above method was discovered in the course of an
attempted synthesis of several 2-thiomethyl-5-alkoxy or
5-dialkylamino cyclic furans such as 17 or 24 (vide infra).
In planning an approach to these compounds, we relied on
earlier studies in our laboratory which showed that the acid-
catalyzed reaction of â-oxo ketene thioacetals 8 and 9 gave
furans 12 and 13 in 70% and 83% yields, respectively. This
reaction most probably proceeds by a protonation/cyclization/
elimination sequence as outlined in Scheme 2.
Scheme 4
Scheme 2
step leading to the formation of 19 involves an initial 1,3-
hydrogen shift of 15 to give 18 which is followed by
conjugate addition of the neighboring thiomethyl group onto
the activated π-bond. Once formed, episulfonium ion 19 can
undergo a subsequent ring opening in the opposite direction
to produce thionium ion 16 by deprotonation and double
bond isomerization. A related set of reactions also takes place
when 16 is subjected to the acidic conditions, eventually
giving thioketene acetal 15 as the minor product (20%) from
the equilibrating mixture.
The series of steps shown in Scheme 4, although credible
in retrospect, was totally unexpected. Our inability to prepare
furan 17 from the acid-catalyzed reaction of thioketene acetal
15 led us to consider some alternate ways to synthesize this
compound.14 It was known from earlier work in the literature
that treatment of thioketals with DMTSF causes the carbon-
sulfur bond to become labile upon methylthiolation.15 The
initially formed alkylthiosulfonium ion easily dissociates to
produce a thionium ion and methyl sulfide. We reasoned
that by converting the hydroxyl group present in lactone 14
into the corresponding acetate, it should be possible to
promote cyclization of the lactone carbonyl group onto the
resulting thionium ion formed from the DMTSF-induced
reaction. Once the dihydrofuran ring has been forged,
elimination of acetic acid should proceed readily to furnish
However, when this reaction sequence was applied to
thioketene acetal 15, prepared by dehydration of the aldol
condensation product 14, none of the desired furan 17 could
be detected. Instead, the only product isolated (80%) cor-
responded to the rearranged thio-conjugated lactone 16.
Subjection of a sample of 16 to the acidic conditions gave
thioketene acetal 15 (20%) in addition to recovered starting
material (80%). This same equilibrium mixture (i.e., 15:16
) 1:4) was observed in the acid-catalyzed reaction of 15
(Scheme 3).
Scheme 3
(10) Alvarez-Ibarra, C.; Quiroga, M. L.; Toledano, E. Tetrahedron 1996,
52, 4065.
(11) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron
Lett. 1989, 30, 5013.
(12) Padwa, A.; Rudiger, H.; Kappe, C. O.; Reger, T. S. J. Org. Chem.
1998, 63, 1144. Kappe, C. O.; Padwa, A. J. Org. Chem. 1996, 61, 6166.
Padwa, A.; Kappe, C. O.; Cochran, J. E.; Snyder, J. P. J. Org. Chem. 1997,
62, 2786.
(13) Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529.
Trost, B. M.; Sato, T. J. Am. Chem. Soc. 1985, 107, 719. Commercially
available from Aldrich Chemical Co.
(14) The difference in the acid-catalyzed behavior of 14 from that
encountered with ketene thioacetals 8 and 9 may possibly be related to the
lower concentration of the enol tautomer of the lactone, thereby permitting
thiomethyl group migration to compete with cyclization. Further studies
with other lactones are currently underway to help clarify this issue.
(15) Rice, J. L.; Favstritsky, N. A. J. Am. Chem. Soc. 1969, 91, 1751.
Smallcombe, S. H.; Caserio, M. C. J. Am. Chem. Soc. 1971, 93, 5826. Kim,
J. K.; Pau, J. K.; Caserio, M. C. J. Org. Chem. 1979, 44, 1544.
The interconversion of 15 and 16 is believed to occur via
the transient episulfonium ion 19 (Scheme 4). The critical
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Org. Lett., Vol. 1, No. 10, 1999

In conclusion, we have described a mild method for the
preparation of differentially substituted 2-thiomethyl furans
from readily available starting materials. This method should
be useful for the preparation of a wide assortment of thio-
substituted furans containing acid sensitive functional groups.
We are presently exploring the synthetic use of these furans
in [4 + 2]-cycloaddition chemistry and will report our
findings at a later date.
Scheme 5
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (GM 60003-01) for their generous
support of this work.
the 2-thio-5-alkoxy-substituted furan 17. Indeed, this two-
step protocol worked extremely well and led to the formation
of 17 in 77% overall yield.
The facility of this reaction sequence prompted us to
investigate its use with several cyclic lactams. We found that
this protocol could be successfully utilized with N-substituted
lactams 22 and 23, giving rise to the corresponding cyclic
aminofurans 24 and 25 in 98% and 78% yields, respectively
(Scheme 5).
Supporting Information Available: Text giving experi-
mental procedures and characterization data for the com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL990865L
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