Novel aerobic oxidation of primary sulfones to carboxylic acids

Article abstract of DOI:10.1021/ol200135m

Primary alkyl aryl sulfones are converted to the corresponding carboxylic acids in fair to excellent yield through double deprotonation and exposure to atmospheric oxygen. The methodology allows for the convenient synthesis of ¹³C labeled carboxylic acids.

Full text of DOI:10.1021/ol200135m

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1447–1449
Novel Aerobic Oxidation of Primary
Sulfones to Carboxylic Acids
Amy C. Bonaparte, Matthew P. Betush, Bettina M. Panseri, Daniel J. Mastarone,
Ryan K. Murphy, and S. Shaun Murphree*
Department of Chemistry, Allegheny College, Meadville, Pennsylvania 16335,
United States
smurphre@allegheny.edu
Received January 17, 2011
ABSTRACT
Primary alkyl aryl sulfones are converted to the corresponding carboxylic acids in fair to excellent yield through double deprotonation and
exposure to atmospheric oxygen. The methodology allows for the convenient synthesis of 13C labeled carboxylic acids.
Carboxylic acids are widely distributed in nature, and
they find broad importance as food components,1
pharmacophores,2 and synthetic precursors.3 As a conse-
quence, the preparation of carboxylic acids occupies a
place of particular importance in organic chemistry.4
Conventional synthetic routes include the oxidation of
primary alcohols5 and aldehydes;6 the hydrolysis of acyl
derivatives, such as acyl halides,7 anhydrides,8 esters,9 and
amides;10 and the addition of Grignard reagents11 or
transition metal complexes12 to carbon dioxide. Despite
the many existing methods, innovations continue to be
reported, ranging from the aqueous aerobic oxidation of
aldehydes13 to electrocatalytic carboxylation of aliphatic
halides.14
In our ongoing studies of sulfone-mediated furan synth-
esis, we require the conversion of the phenylsulfonylmethyl
furan 1 to the corresponding furoic acid 2. We originally
envisioned using one of the literature methods for oxidizing
the sulfonyl anion derived from 1 to introduce the desired
carbonyl group. In the event, however, treatment of the
anion of 1 with bis-(trimethylsilyl)peroxide,15 tert-butyl
trimethylsilylperoxide,16 and chlorodimethoxyborane17
resulted in disappointingly low conversions (<10%).
Other methods of oxidative desulfonylation have been
ꢀ
(1) Velioglu, Y. S. Food Acids: Organic Acids, Volatile Organic
Acids, and Phenolic Acids. In Advances in Food Biochemistry; Yildiz,
F., Ed.; CRC Press: Boca Raton, FL, 2010; p 313.
(2) Kalgutkar, A. S.; Daniels, J. S. Carboxylic acids and their
bioisosteres. In Metabolism, Pharmacokinetics and Toxicity of Func-
tional Groups; Smith, D. A., Ed.; RSC Publishing: Cambridge, 2010; p 99.
(3) Riemenschneider, W. Carboxylic Acids, Aliphatic. Ullmann’s
Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2002.
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tional Group Transformations II; Katritzky, A. R., Taylor, R. J. K., Eds.
Elsevier: Oxford, 2005; p 19. (b) Franklin, A. S. J. Chem. Soc., Perkin
Trans. 1 1999, 3537. (c) Ogliaruso, M. A.; Wolfe, J. F. Synthesis of
carboxylic acids, esters, and their derivatives; Patai, S., Rappoport, Z., Eds.;
Wiley: New York, 1991.
(5) (a) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323. (b)
Lifshitz, E.; Goldfarb, D.; Vega, S.; Luz, Z.; Zimmermann, H. J. Am.
Chem. Soc. 1987, 109, 7280. (c) Newman, M. S.; Arkell, A.; Fukunaga,
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Trans. 2 1993, 1091.
r
10.1021/ol200135m
2011 American Chemical Society
Published on Web 02/14/2011

Table 1. Oxidative Desulfonylation to Furoic Acid
Table 2. Preparation of Primary Sulfones
entry
basea
oxidant
time (min)
yieldb
1
2
3
4
5
6
1.0 n-BuLi
O2
50
50
0c
85
88
91
96
93
2.5 n-BuLi
O2
2.5 LiHMDS
2.5 NaHMDS
2.5 KHMDS
2.5 KHMDS
O2
50
O2
45
O2
25
dry air
120
a 2.5 equiv. b Isolated yield. c Recovered starting material.
reported, using reagents such as MoOPh18 and the Davis
oxaziridine,19 but it seemed prudent first to explore routes
less constrained by toxicity and expense.
Toward this end, an earlier report by Horner and co-
workers was particularly compelling, in which they ob-
served the formation of benzoic acid from benzyl phenyl
sulfone upon treatment with potassium tert-butoxide, a
process in which the oxidant must have been atmo-
spheric oxygen.20 Curiously, however, this had not been
developed into a preparative methodology. While, there
are some examples of the aerobic oxidative desulfonyla-
tion of secondary sulfones to ketones,21 the correspond-
ing protocol for primary sulfones has been oddly absent in
the literature.
a Crude yield (isolated).
Table 3. Carboxylic Acids from Primary Sulfones
Thus, we set about adapting Horner’s conditions for our
system. Initial attempts were not encouraging: treatment
of furan 1 with 1 equiv of various bases (n-BuLi, KOtBu,
KHMDS) in THF and exposure to oxygen for up to 1 h led
only to recovered starting material (Table 1, entry 1). This
outcome was surprising, given the documented behavior of
secondary sulfones under similar conditions (vide supra).
Perhaps, however, the stability of the anion (primary and
benzylic) prevented facile reaction with oxygen.
On this assumption, we considered the possibility of
using the dianion of furan 1 for aerobic oxidation. Sulfonyl
dianions are well established in the literature, and they are
easily formed under conventional conditions.22 To our
delight, treatment of furan 1 with 2.5 equiv of n-
a Isolated. b Benzyl phenyl sulfone (commercial material).
(18) (a) Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547. (b) Capet,
M.; Cuvigny, T.; Herve du Penhoat, C.; Julia, M.; Loomis, G. Tetra-
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(19) Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am. Chem. Soc.
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Chem. 2001, 66, 2394. (b) Arjona, O.; Menchaca, R.; Plumet, J. Org.
Lett. 2001, 3, 107. (c) Yamada, S.; Nakayama, K.; Takayama, H.
Tetrahedron Lett. 1984, 25, 3239.
butyllithium in THF at -78 °C, followed by sparging with
oxygen for 50 min, led to the production of furoic acid 2 in
very good yield (Table 1, entry 2). The oxidation exhibits a
mild counterion effect, so that a progression from lithium
to potassium leads to higher yields and shorter reaction
times. Dry air can also be used as the oxidant, although the
oxidation is predictably slower (entry 6).
(22) (a) White, J. D.; Blakemore, P. R.; Milicevic, S. Org. Lett. 2002,
4, 1803. (b) White, J. D.; Avery, M. A.; Choudhry, S. C.; Dhingra, O. P.;
Kang, M.; Whittle, A. J. J. Am. Chem. Soc. 1983, 105, 6517.
Emboldened by this result, we launched an examination
of the scope of this novel oxidative desulfonylation; thus
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Org. Lett., Vol. 13, No. 6, 2011

Scheme 1. Possible Mechanism for Oxidative Desulfonylation
Scheme 2. Synthesis of [13C]-4-Pentenoic Acid
access to several primary sulfones was needed. Fortunately,
there are many convenient methods to prepare primary
sulfones from readily available starting materials, includ-
ing the alkylation of methyl phenyl sulfone,23 the reaction
of alkyl halides with phenylsulfinate24 or phenylsulfide,25
and the conjugate addition onto vinyl sulfones. For this
study, the methyl phenyl sulfone route was chosen (Table 2),
although careful chromatographic separation was required
to remove products of dialkylation.26
With the additional primary sulfones in hand, we sub-
jected them to the oxidative desulfonylation conditions.
Much to our satisfaction, all examples cleanly provided the
corresponding carboxylic acids in fair to excellent yields
(Table 3). To our knowledge, this represents the first such
preparative aerobic oxidative desulfonylation of primary
sulfones to their corresponding carboxylic acids, and thus
represents a novel entry into this important class of
compounds.
peroxides from organometallic reagents and oxygen is
well-known,27 so a reasonable first step might be the
formation of the peroxide intermediate 7 (Scheme 1).
Subsequent loss of a potassium-stabilized oxide moiety,
followed by hydrolysis of the labile R-oxysulfone inter-
mediate 8,28 would provide the carboxylate 10.
In conclusion, a novel oxidative desulfonylation strategy
is disclosed, in which primary sulfones are cleanly con-
verted to carboxylic acids. Inasmuch as several robust
routes to primary sulfones are available, the present work
represents a new versatile route to carboxylic acids. In
particular, the methyl phenyl sulfone methodology can
be viewed as an alternative to the well-known cyanide
route,29 but with advantages with respect to acute toxicity.
Furthermore, since 13C-labeled methyl phenyl sulfone30 is
commercially available, useful carbonyl-labeled acids31
can be accessed using this chemistry (Scheme 2). Further
work is underway in this direction and will be reported in
due course.
The mechanism of the desulfonylation is unknown, but
a number of possibilities clearly exist. The formation of
Acknowledgment. The authors gratefully acknowledge
the Petroleum ResearchFund(PRF 42382-B1) for support
of this work.
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Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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labeling R-carbons of ketones, see: Kajiwara, Y.; Scott, A. I. Tetrahe-
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