Transformation of carbonates into sulfones at the benzylic position via palladium-catalyzed benzylic substitution

Article abstract of DOI:10.1021/ol0509787

(Chemical Equation Presented) The nucleophilic substitution of benzylic carbonates with sodium arenesulfinates was catalyzed by the palladium complex generated in situ from [Pd(η³-C₃H₅)Cl] ₂ and DPEphos [bis(2-diphenylphosphinophenyl)ether]. The catalytic reaction proceeded in DMSO at 80°C and gave a variety of benzylic sulfones in high yields.

Full text of DOI:10.1021/ol0509787

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2973-2975
Transformation of Carbonates into
Sulfones at the Benzylic Position via
Palladium-Catalyzed Benzylic
Substitution
Ryoichi Kuwano,* Yutaka Kondo, and Tsuyoshi Shirahama
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
rkuwascc@mbox.nc.kyushu-u.ac.jp
Received April 30, 2005
ABSTRACT
The nucleophilic substitution of benzylic carbonates with sodium arenesulfinates was catalyzed by the palladium complex generated in situ
from [Pd( C and gave a
3-C3H5)Cl]2 and DPEphos [bis(2-diphenylphosphinophenyl)ether]. The catalytic reaction proceeded in DMSO at 80
η
°
variety of benzylic sulfones in high yields.
The sulfonyl group is a strong electron-withdrawing group
and stabilizes its R-carbanion.1 The R-carbanion is readily
generated by reaction with a base and reacts with various
electrophiles such as alkyl halides and aldehydes.2 The
sulfonyl group is readily removed under mild reductive
conditions. Reductive elimination of R-acetoxysulfones,
which are obtainable through the aldol-type reaction of
sulfones, yields olefins with high (E)-selectivity as compared
to Wittig olefination.3 Therefore, aryl alkyl sulfones are
frequently used as key synthetic intermediates for various
natural products.4
halide with sodium arenesulfinate. In the latter case, benzyl
sulfones are prepared from benzylic halides. However,
benzylic halides are sometimes lachrymatory and not always
stable and easy to handle. A new synthetic pathway that does
not use benzylic halides will expand the utility of benzylic
sulfones in organic synthesis.
Allylic sulfones can be prepared from allylic acetates by
means of homogeneous palladium catalysis, which involves
the activation of an allylic C-O bond by palladium(0) and
the nucleophilic attack of alkali metal arenesulfinate on (η3-
allyl)palladium.5 This reaction has been utilized to prepare
optically active allylic sulfones by means of asymmetric
catalysis.6
Aryl alkyl sulfones are typically prepared either by
oxidation of thioether or by nucleophilic substitution of alkyl
Recently, we reported the palladium-catalyzed alkylation
of stabilized carbanions or amines with benzylic carbonates.7,8
The catalytic benzylation may involve an (η3-benzyl)-
palladium intermediate. Herein, we describe a palladium-
(1) (a) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. J. Org. Chem.
1976, 41, 1883-1885. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-
463.
(2) Reviews: Magnus, P. D. Tetrahedron 1977, 33, 2019-2045.
(3) (a) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833-4836.
(b) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563-2585.
(4) Recent examples: (a) Adams, C. M.; Ghosh, I.; Kishi, Y. Org. Lett.
2004, 6, 4723-4726. (b) Trost, B. M.; Shen, H. C.; Surivet, J.-P. J. Am.
Chem. Soc. 2004, 126, 12565-12579. (c) Wang, Q.; Sasaki, N. A. J. Org.
Chem. 2004, 69, 4767-4773.
(5) Representative examples: (a) Julia, M.; Nel, M.; Saussine, L. J.
Organomet. Chem. 1979, 181, C17-C20. (b) Tamura, R.; Hayashi, K.;
Kakihana, M.; Tsuji, M.; Oda, D. Tetrahedron Lett. 1985, 26, 851-
854.
10.1021/ol0509787 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/15/2005

catalyzed nucleophilic substitution of benzylic carbonates
with sodium arenesulfinates. The catalytic reaction provides
a new pathway for synthesizing benzylic sulfones from the
corresponding alcohols, because benzylic carbonates are
readily obtained from the esterification of benzylic alcohols
with methyl chloroformate.
Table 1. Sulfonylation of Benzylic Carbonates (1)a
In our previous studies on palladium-catalyzed benzyla-
tion,7 the yields of the benzylation products were strongly
affected by the bite angle of the bidentate bisphosphine ligand
on the palladium catalyst. The ligands DPPF9 and DPEphos10
were preferred for the benzylation of stabilized carbanions
and amines, respectively. We evaluated the role of DPPF-
and DPEphos-palladium catalysts in the reaction of benzyl
methyl carbonate (1a) with sodium benzenesulfinate (2a) in
THF at a catalyst loading of 5% palladium. Both the
palladium catalysts efficiently promoted the sulfonylation of
1a, thus producing the desired benzyl phenyl sulfone (3a)
in 60-70% yields after 3 h. No benzyl benzenesulfinate
resulting from O-attack of 2a was detected by GC analysis
of the reaction mixture. Use of DMSO as a solvent brought
about significant enhancement of the reaction rate. The yield
of 3a by DPEphos was slightly higher than that of DPPF.
The reaction of 1a with 2a was completed within 1 h at 80
°C in the presence of 1% DPEphos-0.5[Pd(η3-C3H5)Cl]2,
and 3a was isolated in 95% yield (Scheme 1).
Scheme 1. Reaction of Benzyl Methyl Carbonate (1a) with
Sodium Benzenesulfinate (2a)
a Reactions were conducted in DMSO (1.0 mL) at 80 °C. The ratio of 1
(1.0 mmol):2:[Pd(η3-C3H5)Cl]2:DPEphos was 100:110:0.5:1.1. b Isolated
yield. c Reaction was conducted with 2 mol % palladium. d Reaction was
conducted with 5 mol % palladium.
As seen in Table 1, a variety of benzylic sulfones were
synthesized from benzylic carbonates by DPEphos-pal-
ladium catalysis. The ortho-substituted 1b was converted into
sulfone 3b in 95% yield after 3 h (entry 1). However, the
reaction of 1c bearing two ortho-methyl groups proceeded
sluggishly and afforded 3c in 89% yield after 48 h (entry
2). Both electron-rich 1d and electron-poor 1f reacted rapidly
with 2a to yield 3d and 3g, respectively (entries 3 and 6).
The sulfonylation of 1e proceeded slowly compared to the
above reactions (entry 5). The benzylation of sodium
p-toluenesulfinate (2b) with 1d proceeded well, and 3e was
produced efficiently (entry 4). However, the use of p-chloro-
benzenesulfinate 2c brought about a remarkable decrease in
the catalytic efficiency and produced the corresponding
sulfone in only 15% yield after 72 h. Methanesulfinate 2d
failed to react with 1d, and no sulfone was obtained. In
contrast, naphthylmethyl carbonate 1g reacted with 2c and
2d as well as 2a, and the sulfonylation products were
obtained in high yields in all cases (entries 7-9). The
palladium-catalyzed benzylic sulfonylation was effective in
the preparation of 3k and 3l11 (entries 10 and 11). The former
(6) Representative examples: (a) Trost, B. M.; Organ, M. G.; O’Doherty,
G. A. J. Am. Chem. Soc. 1995, 117, 9662-9670. (b) Trost, B. M.; Crawley,
M. L.; Lee, C. B. J. Am. Chem. Soc. 2000, 122, 6120-6121. (c) Eichelmann,
H.; Gais, H.-J. Tetrahedron: Asymmetry 1995, 6, 643-646. (d) Gais, H.-
J.; Eichelmann, H.; Spalthoff, N.; Gerhards, F.; Frank, M.; Raabe, G.
Tetrahedron: Asymmetry 1998, 9, 235-248.
(7) (a) Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003,
125, 12104-12105. (b) Kuwano, R.; Kondo, Y. Org. Lett. 2004, 6, 3545-
3547.
(8) Palladium-catalyzed substitution of (R-naphthyl)methyl acetate with
malonate carbanion had been reported by Legros and Fiaud; see: (a) Legros,
J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1992, 33, 2509-2510. (b) Legros, J.-
Y.; Toffano, M.; Fiaud, J.-C. Tetrahedron 1995, 51, 3235-3246.
(9) DPPF ) 1,1′-bis(diphenylphosphino)ferrocene: Sishop, J. J.; Davison,
A.; Katcher, M. L.; Lichtenberg, D. W.; Merrill, R. E.; Smart, J. C. J.
Organomet. Chem. 1971, 27, 241-249.
(10) DPEphos ) bis(2-diphenylphosphinophenyl)ether: Kranenburg, M.;
van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081-3089.
2974
Org. Lett., Vol. 7, No. 14, 2005

sulfone was a building block of (-)-calicopherol B,12 and
the latter was employed in the total synthesis of (+)-
trienomycins A and F.13
A plausible mechanism of the catalytic sulfonylation is
shown in Scheme 2. The benzylic C-O bond of 1 is cleaved
with the remarkable difference between the reactivities of
1b and 1c (Table 1, entry 1 vs entry 2). The two ortho
substituents of 1c sterically hinder the formation of A, while
1b can afford (η3-benzyl)palladium at the ortho position with
no methyl group.
To confirm whether the nucleophilic attack of 2 on A is
irreversible, the mixture of 3a and 2b was heated at 80 °C
in DMSO in the presence of 5% DPEphos-palladium. No
benzyl p-tolyl sulfone was detected in the GC analysis, and
3a was recovered quantitatively. During the catalytic sulfo-
nylation, the C-S bond of product 3 was never cleaved by
palladium(0), contrary to the case of allylic sulfones.16
In summary, we have realized the palladium-catalyzed
sulfonylation of benzylic carbonates. To the best of our
knowledge, the present sulfonylation is the first catalytic
reaction involving the attack of an S-nucleophile on the
(η3-benzyl)palladium complex. This novel catalytic reaction
will offer a new pathway for synthesizing sulfones from
benzylic alcohols and is useful for the preparation of benzylic
sulfone building blocks.
Scheme 2. Plausible Mechanism of Catalytic Sulfonylation
by palladium(0) through a reaction pathway similar to the
formation of (η3-allyl)palladium from allylic esters.14 The
resulting (η3-benzyl)palladium A reacted with nucleophile
2 to produce sulfone 3. The intermediate A may isomerize
to (η1-benzyl)palladium B in the presence of methoxide.15
However, B can revert to A when A is consumed during the
nucleophilic attack of 2. This mechanistic insight is consistent
Acknowledgment. This work was supported by the
Sumitomo Foundation and a Grant-in-Aid for Young Sci-
entists (A) (No. 16685011) from MEXT.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) No benzylation of the unprotected amino group in 1i was observed.
(12) Taber, D. F.; Jiang, Q.; Chen, B.; Zhang, W.; Campbell, C. L. J.
Org. Chem. 2002, 67, 4821-4827.
(13) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1996, 118, 8316-8328.
OL0509787
(14) MO study on oxidative addition of allylic ester to palladium(0):
Suzuki, T.; Fujimoto, H. Inorg. Chem. 1999, 38, 370-382.
(15) Nagayama, K.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn.
1999, 72, 799-803.
(16) Allylic sulfones are usable as substrates in palladium-catalyzed
allylic substitutions; see: Trost, B. M.; Schmuff, N. R.; Miller, M. J. J.
Am. Chem. Soc. 1980, 102, 5979-5981.
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