Tandem Oxidation/Halogenation of Aryl Allylic
Alcohols under Moffatt-Swern Conditions
Jiandong Yin, Christina E. Gallis, and John D. Chisholm*
Department of Chemistry, 1-014 Center for Science and
Technology, Syracuse UniVersity, Syracuse, New York 13244
shown to be problematic.4 Activated alcohols sometimes
undergo substitution by chloride ion to provide the correspond-
ing alkyl chloride instead of the ketone.5-8 This mode of
reactivity can also be accessed by performing the reaction at
higher temperatures. Chlorination of indoles9 and aromatic
rings10 has also been reported in the presence of dimethylchlo-
rosulfonium chloride, the active reagent in the Moffatt-Swern
oxidation. Further, the use of excess reagent may result in the
formation of R-chloro ketones in some systems.11 Such halo-
genation has not previously been observed with any unsaturated
ketones.
ReceiVed June 6, 2007
The direct, one-pot conversion of allylic alcohol 1 to R-chloro
enone 3 results in a rapid increase of molecular complexity in
a single flask under mild reaction conditions. Adventitiously
this route allows for the formation of the R-halo ketone in a
single step from a stable starting material, unlike direct
halogenation of highly polymerizable ketone 212 or methylena-
tion of the hydrolytically sensitive R-halo ketone.13 The
halogenated enone product possesses multiple functional groups
that may be elaborated in a variety of ways (1,2-addition, 1,4-
addition, transition-metal-mediated coupling, etc.). Access to
similar R-halogenated enones allows for exploration of their use
in a number of synthetic projects involving natural products
and diversity-oriented synthesis.14 A study was therefore
undertaken to define reaction conditions that favor the formation
of R-chloro R,â-unsaturated ketone 3.
Treatment of allylic alcohol 1 under Moffatt-Swern condi-
tions using 1 equiv of oxalyl chloride and 2 equiv of DMSO
provided ketone 2 in 56% yield along with a 10% yield of
halogenated ketone 3 (Table 1, entry 1). Increasing the amount
of oxalyl chloride and DMSO used in the reaction increased
the amount of halogenated ketone isolated from the reaction
(entries 2-4). No ketone oxidation products were detected in
the absence of DMSO (entry 5); instead, a complex mixture
was obtained. Typically the reactions were allowed to warm to
room temperature after addition of the triethylamine (the final
Aryl allylic alcohols are converted to halogenated unsaturated
ketones or allylic halides using excess Moffatt-Swern
reagent. Electron-poor aromatic rings favor formation of the
halogenated ketone, while electron-donating substituents in
the ortho or para positions favor formation of the allylic
halide. The oxidation/halogenation reaction performs well
with both oxalyl chloride and oxalyl bromide, providing
access to the corresponding chlorides or bromides, respec-
tively.
Tandem reactions play an increasingly important role in
synthetic organic chemistry. With highly complex structures
available using stepwise synthetic methods, attention has become
focused on ways to increase efficiency, decrease costs, and
minimize environmental impact. With their ability to perform
multiple transformations in a single operation, tandem reactions
improve efficiency by using less solvent and decreasing the
number of necessary purification steps. In turn this leads to
decreased costs with regard to chromatography absorbents,
manpower, and waste disposal. Demand for more efficient and
lower cost chemical processes has resulted in the increased
development of tandem reactions for chemical synthesis in
recent years.1,2
Investigations in our laboratory have revealed an unusual
tandem oxidation/halogenation reaction that occurs under Mof-
fatt-Swern oxidation conditions. An unrelated project in our
group required the use of phenyl vinyl ketone (2). This
compound is not commercially available because of its pro-
pensity to polymerize. Oxidation of commercially available
R-vinylbenzyl alcohol (1) was performed using Moffatt-Swern
conditions3 to provide ketone 2 for our purposes. While ketone
2 was obtained as the major product, a modest amount of the
corresponding R-chloro ketone 3 was also detected.
(4) Tidwell, T. T. Org. React. 1990, 39, 297.
(5) Kende, A. S.; Johnson, S.; Sanfilippo, P.; Hodges, J. C.; Jungheim,
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(6) Lawrence, N. J.; Crump, J. P.; McGown, A. T.; Hadfield, J. A.
Tetrahedron Lett. 2001, 42, 3939.
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N. Tetrahedron 1983, 39, 3755.
(10) Olah, G. A.; Ohannesian, L.; Arvanaghi, M.; Loker, D. P.; Loker,
K. B. Synthesis 1986, 868.
(11) Smith, A. B., III.; Leenay, T. L.; Liu, H. J.; Nelson, L. A. K.; Ball,
R. G. Tetrahedron Lett. 1988, 29, 49.
(12) Chow, Y. L.; Bakker, B. H. Can. J. Chem. 1982, 60, 2268.
(13) Rodrigues, J. A. R.; Siqueira-Filho, E. P.; de Mancilha, M.; Moran,
P. J. S. Synth. Commun. 2003, 33, 331.
The Moffatt-Swern oxidation usually proceeds in high yield
with no side reactions; however, some substrates have been
(1) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551.
(2) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(3) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(14) For an example of heterocycle formation using halo ketones such
as 3 see: Henry, N.; Sanchez, I.; Sabatie, A.; Beneteau, V.; Guillaumet,
G.; Pujol, M. D. Tetrahedron 2006, 62, 2405.
10.1021/jo0711992 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/08/2007
7054
J. Org. Chem. 2007, 72, 7054-7057