Highly regioselective nucleophilic carbon - Carbon bond formation on furans and thiophenes initiated by pummerer-type reaction

Article abstract of DOI:10.1021/ol0484310

(Chemical Equation Presented) The reactions of (phenylsulfinyl)furans or -thiophenes with carbon nucleophiles in the presence of trifluoroacetic anhydride allowed the nucleophilic installation of carbon functional groups on the furan and thiophene nuclei

Full text of DOI:10.1021/ol0484310

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3793-3796
Highly Regioselective Nucleophilic
Carbon Carbon Bond Formation on
−
Furans and Thiophenes Initiated by
Pummerer-Type Reaction
Shuji Akai, Norihito Kawashita, Hideharu Satoh, Yasufumi Wada,
Keisuke Kakiguchi, Ikumi Kuriwaki, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
kita@phs.osaka-u.ac.jp
Received August 9, 2004
ABSTRACT
The reactions of (phenylsulfinyl)furans or -thiophenes with carbon nucleophiles in the presence of trifluoroacetic anhydride allowed the
nucleophilic installation of carbon functional groups on the furan and thiophene nuclei with complete regioselectivity.
Furans and thiophenes serve as useful synthetic intermediates
and building units for various compounds1-3 as well as
conductive molecules.4 Therefore, the development of carbon-
carbon bond-forming reactions of these compounds has
received significant attention. The most popular methods are
based on electrophilic reactions such as (i) the direct
electrophilic substitution reactions of these nuclei2,5 and (ii)
the generation of metalated intermediates by either the
halogen-metal exchange reaction or the directed metalation
reaction followed by the reaction with carbon electrophiles.3,6
The transition metal-catalyzed reactions of (halogenated)
heteroaromatics have also been extensively employed re-
cently.7 On the other hand, direct nucleophilic substitution
reactions on these heteroaromatic compounds have been
limited to the specific combination of the substrates having
powerful electron-withdrawing group(s), such as nitro or
carbonyl groups, and highly reactive carbanions.8,9
(1) For reviews, see: (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795-
819. (b) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc.
ReV. 2000, 29, 109-118.
Over the past several years, we have disclosed the
preparation of benzofurans and indoles III via the aromatic
Pummerer-type reaction10 of p-sulfinyl-phenols and -anilines
(2) Rodr´ıguez, A. R.; Spur, B. W. Tetrahedron Lett. 2003, 44, 7411-
7415.
(3) (a) Apsel, B. Bender, J. A.; Escobar, M. Kaelin, D. E., Jr.; Lopez,
O. D.; Martin, S. F. Tetrahedron Lett. 2003, 44, 1075-1077. (b) Krishna,
U. M.; Srikanth, G. S. C.; Trivedi, G. K.; Deodhar, K. D. Synlett 2003,
2383-2385. (c) de la Torre, M. C.; Garc´ıa, I.; Sierra, M. A. J. Org. Chem.
2003, 68, 6611-6618.
(4) For a recent review, see: McCullough, R. D. AdV. Mater. 1998, 10,
93-116.
(5) For an example, see: Roberts-Bleming, S. J.; Davies, G. L.; Kalaji,
M.; Murphy, P. J.; Celli, A. M.; Donati, D.; Ponticelli, F. J. Org. Chem.
2003, 68, 7115-7118.
(6) For an example, see: Ponomarenko, S.; Kirchmeyer, S. J. Mater.
Chem. 2003, 13, 197-202.
(7) For a review, see: Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359-1470. For examples, see:
Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 12557-12565. Glover, B.; Harvey, K. A.; Liu, B.;
Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301-304.
10.1021/ol0484310 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/17/2004

I. In these reactions, the treatment of I with trifluoroacetic
anhydride caused the successive O-acylation and elimination
of the acyloxy group, both of which were accelerated by
the electron-donation of the p-hydroxyl or the p-amino group.
The generated p-quinone sulfonium intermediates A allowed
regioselective nucleophilic attack of the external olefins II
followed by cyclization to give III (Scheme 1).11
Scheme 3
Scheme 1
We first investigated the reaction of 2-sulfinylfuran 1a and
acetylacetone 2a as a typical example. The reaction of a
mixture of these compounds with trifluoroacetic anhydride
(2 equiv) in MeCN was immediately completed at room
temperature to give the product 3a (75% yield), in which
the nucleophile was installed at the C3-position. The forma-
tion of other regioisomers was not observed upon 1H NMR
analysis. On the other hand, the use of other solvents such
as toluene, CH2Cl2, CHCl3, and acetone resulted in unsat-
isfactory yields of 3a (up to 46% yield).
Similar intramolecular cyclizations using the Pummerer-
type reaction of 2-sulfinylindoles IV having a nucleophilic
alkyl chain at the C3-position have been reported to give
spirooxindoles V (Scheme 2).12
Similar reactions of the 2-sulfinylfurans (1a,b) or the
thiophenes (1c-e) with carbon nucleophiles (2a,b) took place
to afford the C3-substituted products (3b-g), each as a single
regioisomer, in moderate to high yields (entries 2-8). Some
features are noteworthy: First, the thiophene derivative 1c,
which has a higher degree of aromaticity than the furans,14
also accepted the nucleophilic attack to give the C3-
substituted products (3d and 3e) in 78 and 86% yields,
respectively (entries 4 and 6). Second, the thiophene 1d
having an electron-withdrawing group was less reactive when
forming 3f at 80 °C (entry 7), whereas the methylthiophene
1e was a good substrate to give 3g at 0 °C (entry 8). Third,
some reactions at room-temperature suffered low yields of
the products due to the formation of sulfides 4 as a side
product (for example, entry 5), although the reaction mech-
anism for their generation has not yet been clarified. In such
cases, similar reactions at 0 °C suppressed their formation
to give the products in better yields (for example, entry 6).
In a like manner, the reactions of the 3-sulfinyl derivatives
(5a,b) with 2a,b took place to give the C2-substituted
products (6a-d) in high yields with exclusive regioselectivity
(entries 9-12).15
Scheme 2
As an extension of these Pummerer-type reactions, we
present here novel intermolecular nucleophilic carbon-
carbon bond-forming reactions of the 2-sulfinyl-furans and
-thiophenes 1 to give C3-substituted heteroaromatics 3.
Similarly, the 3-sulfinyl derivatives 5 afforded the C2-
substituted products 6 with exclusive regioselectivity (Scheme
3).13
The sulfur functional group that remained in the products
permitted the installation of a second carbon functional group
(8) For examples, see: (a) Ma¸kosza, M.; Stalin´ski, K. Synthesis 1998,
1631-1634. (b) Lawrence, N. J.; Lamarche, O.; Thurrab, N. Chem.
Commun. 1999, 689-690. (c) Migaud, M. E.; Wilmouth, R. C.; Mills, G.
I.; Wayne, G. J.; Risley, C.; Chambers, C.; Macdonald, S. J. F.; Schofield,
C. J. Chem. Commun. 2002, 1274-1275.
(9) For examples, see: (a) Moosa, B. A.; Abu Safieh, K. A.; El-Abadelah,
M. M. Heterocycles 2002, 57, 1831-1840. (b) Iesce, M. R.; Graziano, M.
L.; Cermola, F.; Montella, S.; Gioia, L. D. Tetrahedron Lett. 2003, 44,
5781-5784.
(10) (a) Kita, Y.; Takeda, Y.; Matsugi, M.; Iio, K.; Gotanda, K.; Murata,
K.; Akai, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 1529-1531. (b) Akai,
S.; Takeda, Y.; Iio, K.; Takahashi, K.; Fukuda, N.; Kita, Y. J. Org. Chem.
1997, 62, 5526-5536.
(11) (a) Akai, S.; Morita, N.; Iio, K.; Nakamura, Y.; Kita, Y. Org. Lett.
2000, 2, 2279-2282. (b) Akai, S.; Kawashita, N.; Morita, N.; Nakamura,
Y.; Iio, K.; Kita, Y. Heterocycles 2002, 58, 75-78.
(12) (a) Feldman, K. S.; Vidulova, D. B. Org. Lett. 2004, 6, 1869-
1871. (b) Feldman, K. S.; Vidulova, D. B. Tetrahedron Lett. 2004, 45,
5035-5037.
(13) Sulfoxides 1 and 5 were readily available by the oxidation of the
corresponding sulfides, obtained by the lithiation at the C2-position of the
furans and the thiophenes (for the 2-sulfinyl derivatives) or the bromo-
lithium exchange reactions of commercial 3-bromofuran or 3-bromo-
thiophene (for the 3-sulfinyl derivatives) followed by sulfanylation with
PhSSO2Ph.
(14) Bird, C. W. Tetrahedron 1985, 41, 1409-1414.
(15) Strong electron donation of oxygen and sulfur in the furan and
thiophene rings must accelerate the elimination of the acyloxy groups of
the O-acylated sulfonium intermediates, respectively. In addition, the effect
that the electron-donating group of the C-5 substituent (Me group, entry 8
in Table 1) accelerates the reaction, while the electron-withdrawing CO2Me
group deactivates it (entry 7), suggests the participation of the 6π-electrons
of the heteroaromatics. Therefore, the aromatic Pummerer-type mechanism
(Scheme 3) seems to be more plausible than the additive Pummerer
mechanism,12 although we cannot rule out the possibility of the latter one.
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Org. Lett., Vol. 6, No. 21, 2004

Table 1. Regioselective Nucleophilic Substitution on 1 or 5 with 2a,b
a Compound exists as the enol form. b Besides 3e, the corresponding sulfide 4c (X ) S, R ) H) was obtained in 30% (for entry 5) and <10% yield (for
entry 6). c 1d (50% yield) was recovered.
at the ipso-position. For instance, mCPBA oxidation of the
furan 3c gave the corresponding sulfoxide 7a, which was
treated with PhLi in toluene to generate the 2-lithiofuran B
via the sulfur-lithium exchange reaction.11a Quenching this
nucleophilic intermediate with ClCO2Me provided the furan-
2-carboxylate 8a in 71% yield. This type of reaction is also
effective on the thiophenes; e.g., 7b, prepared from 3e, was
converted to 8b and 8c in good yields (Scheme 4).
regioselectivity was attained and found to be dependent on
the position of the sulfinyl group. The iterative use of a single
Scheme 4
In conclusion, we have developed regioselective substitu-
tion reactions of furans and thiophenes via the Pummerer-
type reaction. Our method features the nucleophilic substi-
tutions under mild acidic conditions, in which even weak
nucleophiles such as acetylacetone 2a can be used. Complete
Org. Lett., Vol. 6, No. 21, 2004
3795

sulfinyl group for the introduction of two different carbon
functional groups is another feature of this method. The
extension of this method to other π-sufficient heteroaromatics
and nucleophiles is now under study in our laboratory.
and Technology, Japan, and the Shorai Foundation for
Science and Technology.
Supporting Information Available: Experimental details
and spectroscopic data for all products (3, 6, and 8). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This research was financially sup-
ported in part by a Grant-in-Aid for Scientific Research (S)
from the Ministry of Education, Culture, Sports, Science,
OL0484310
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Org. Lett., Vol. 6, No. 21, 2004