Fluorous Swern reaction [14]

Full text of DOI:10.1021/ja016057i

J. Am. Chem. Soc. 2001, 123, 7449-7450
7449
In designing the fluorous Swern reagent our primary concern
was with the length of the spacer linking the fluorous chain to
the sulfoxide. Reagents lacking a spacer, i.e., with the fluorous
chain directly bound to the sulfoxide sulfur, were excluded from
consideration as it was anticipated that they would reduce the
nucleophilicity of the sulfoxide and so reduce activity. Linkers
consisting of one methylene were tried and found wanting on
the basis of the facile elimination of HF from the sulfoxide.
Linkers with three or more methylene groups, while undoubtedly
effective, were eliminated from consideration on the grounds that
they would require a longer fluorous chain for efficient extraction.
We therefore settled on a two methylene group spacer and initially
selected perfluorohexyl as the fluorous chain as this would lead
to a reagent with 60.2% fluorine, with 60% usually considered
the lower cutoff point for efficient fluorous extraction.10 Reduction
of dimethyl disulfide with sodium borohydride in ethanol followed
by treatment with commercial 2-perfluorohexylethyl iodide
provided, after stirring overnight and standard work up, the
fluorous sulfide 1 in 74% yield. This direct synthesis of 1 is a
considerable improvement over an earlier multistep protocol,
involving reaction of the iodide with sodium thiocyanate, reduc-
tion, and methylation.11 Oxidation with hydrogen peroxide in
methanol7 then provided the sulfoxide 3 in high overall yield with
no overoxidation to the sulfone, it having been previously
determined that more forcing conditions are required for the
exhaustive oxidation of 1.11 Sulfoxide 3 was crystalline, white,
and odorless but unfortunately insoluble in dichloromethane below
ca. -30 °C. We therefore prepared the lower homologous sulfide
(2) and its sulfoxide (4) in the analogous manner in 71% overall
yield from commercial perfluorobutylethyl iodide (Scheme 1).
Fluorous Swern Reaction
David Crich* and Santhosh Neelamkavil
Department of Chemistry, UniVersity of Illinois at Chicago
845 West Taylor Street, Chicago, Illinois 60607-7061
ReceiVed April 20, 2001
ReVised Manuscript ReceiVed May 31, 2001
The oxidation of primary and secondary alcohols to aldehydes
and ketones is one of the most fundamental and commonly applied
transformations in organic chemistry, be it in the research lab or
the production plant. It is not surprising therefore that methodol-
ogy for this functional group interconversion is consistently being
refined and improved. Major advances in recent years include
Ley and Griffith’s introduction of the catalytic tetrapropylam-
monium perruthenate oxidant1 and the user-friendly version of
the Dess-Martin reagent, namely 2-iodoxybenzoic acid,2 with
its rapidly broadening spectrum of reactivity.3 Nevertheless, the
Swern oxidation and its numerous variants4,5 remain some of the
most widely used methods in fine organic chemistry. Environ-
mental pressure is currently serving to focus interest on cleaner
oxidation methods and notable advances in this area have been
made by the Marko group with their catalytic processes based
on oxygen as overall oxidant.6 Unfortunately, the Swern reaction,
with the stoichiometric generation of dimethyl sulfide, falls down
badly on environmental grounds that militate against its use on a
large scale. In this laboratory we have been interested for several
years in the development of recoverable, environmentally friendly
fluorous7 organoselenium compounds,8 from where it is but a
small step up the periodic table to fluorous organosulfur chemistry
and the fluorous Swern reaction as set out here.
Scheme 1. Preparation of Fluorous DMS and Fluorous
DMSO
The need to modify the Swern reaction so as to eliminate the
formation of the volatile, malodorous dimethyl sulfide has been
previously addressed by the Vederas group who have introduced
polymer-supported and extractable nonvolatile reagents.9 We
reasoned that this task might be more conveniently achieved
through the preparation of a simple fluorous sulfoxide, which
would be readily recovered and recycled by fluorous extraction.
In doing so all the desirable properties of the original Swern
reaction would be retained and the problems of adapting condi-
tions to the modified reactivity of a polymer-supported reagent
avoided.
Sulfoxide 4 is also crystalline, white, and odorless but it is soluble
in dichloromethane down to -45 °C. It has a fluorine content of
55.1% and is recoverable by continuous fluorous extraction, our
preferred protocol,8 and no doubt, by chromatography over
fluorous silica gel.12 The intermediate sulfide (2), however, is
relatively volatile and in general we have converted it directly to
sulfoxide 4.13
(1) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(2) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem.
1995, 60, 7272.
(3) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000,
122, 7596. (b) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2001, 123, 3183.
(4) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(5) Reviews: (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165. (b)
Tidwell, T. T. Org. React. 1990, 39, 297. (c) Tidwell, T. T. Synthesis 1990,
857.
(6) (a) Marko´, I.; Giles, P. R.; Tsukazaki, M.; Chelle-Regnaut, I.; Urch, C.
J.; Brown, S. M. J. Am. Chem. Soc. 1997, 119, 12661. (b) Marko´, I. E.; Gautier,
A.; Chelle-Regnaut, I.; Giles, P. R.; Tsukazaki, M.; Urch, C. J.; Brown, S.
M. J. Org. Chem. 1998, 63, 7576. (c) Marko´, I. E.; Giles, P. R.; Tsukazaki,
M.; Chelle-Regnaut, I.; Gautier, A.; Brown, S. M.; Urch, C. J. J. Org. Chem.
1999, 64, 2433.
(7) (a) Horva´th, I. T. Acc. Chem. Res. 1998, 31, 641. (b) Curran, D. P.
Angew. Chem., Int. Ed. Engl. 1998, 37, 1174.
(8) (a) Crich, D.; Hao, X. Org. Lett. 1999, 1, 269. (b) Crich, D.; Hao, X.;
Lucas, M. Tetrahedron 1999, 55, 14261. (c) Crich, D.; Barba, G. R. Org.
Lett. 2000, 2, 989. (d) Crich, D.; Neelamkavil, S.; Sartillo-Piscil, F. Org. Lett.
2000, 2, 4029.
A series of oxidations were conducted in which fluorous DMSO
(4) was activated with oxalyl chloride in dichloromethane at -30
(10) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(11) Dieng, S.; Bertaina, B.; Cambon, A. J. Fluorine Chem. 1985, 28,
425.
(12) Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000, 65, 8866.
(13) Preparation of 2 and 4: NaBH4 (1.4 g, 37.0 mmol) was added under
Ar to a stirred solution of Me2S2 (3.3 g, 35.0 mmol) in EtOH (25 mL). After
being stirred for 30 min the reaction mixture was cooled to 0 °C and a solution
of perfluorobutylethyl iodide (10 g, 26.7 mmol) in anhydrous THF (15 mL)
was added dropwise over 1 h. The reaction mixture was then stirred overnight
at room temperature before further Me2S2 (1.0 g, 10.6 mmol) reduced with
NaBH4 (0.45 g, 11.9 mmol) in EtOH (10 mL) was added. After the reaction
mixture was stirred for 6 h more, it was diluted with hexanes (20 mL) and
washed with H2O and brine. The hexane layer was diluted with MeOH (10
mL) and H2O2 (3.1 mL of 30%, 27 mmol) and stirred for 1 h before it was
diluted with CH2Cl2 (25 mL), washed with H2O, dried (Na2SO4), and
concentrated in vacuo to give 4 (5.9 g, 19.0 mmol, 71%) as a white, crystalline
solid with mp 46 °C.
(9) (a) Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J.
Org. Chem. 1998, 63, 2407. (b) Liu, Y.; Vederas, J. C. J. Org. Chem. 1996,
61, 7856.
10.1021/ja016057i CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/03/2001

7450 J. Am. Chem. Soc., Vol. 123, No. 30, 2001
Table 1. Fluorous Swern Oxidations
Communications to the Editor
practicality of the classical Swern protocol is therefore retained.
Workup involved brief partitioning of the reaction mixture with
water, concentration of the dichloromethane solution, and parti-
tioning of the residue between toluene and FC72 (a commercial
fluorous hydrocarbon) in the continuous extractor for ∼4 h.8 The
oxidized product (aldehyde or ketone) was then recovered from
the toluene phase, while treatment of the FC72 phase with
hydrogen peroxide returned the sulfoxide ready for reuse.14 The
results of these oxidations, together with the yields of recovered
sulfoxide, are presented in Table 1.15
An important practical consideration in these oxidations is the
exchange of dichloromethane, the reaction solvent, for toluene
before the fluorous extraction. At this stage most of the sulfoxide
(4) has been reduced to the sulfide 2, which, itself, is very
nonpolar and readily recovered in the extraction protocol.
However, any residual sulfoxide is not readily extracted from
dichloromethane solution, presumably because of its somewhat
polar nature. Replacing dichloromethane by the apolar toluene
reduces the affinity of 4 for the organic phase and enables the
efficient recoveries recorded in Table 1.
As is apparent from Table 1, the fluorous Swern reaction retains
the mildness of conditions and applicability in the presence of a
wide range of functional groups that have contributed to the
popularity of the original reaction. In addition to the typical
oxidations of primary and secondary alcohols we note the
compatibility with Lipshutz’s new triisopropylsiloxycarbonyl
protecting group (entry 2),16 the absence of â-elimination of a
tert-butyldimethylsiloxy group (entry 3), and the oxidation of
lactols to lactones (entries 11 and 12), again without â-elimination.
The Swern oxidation is but one variant on oxidation with
activated DMSO or other oxidized forms of dimethyl sulfide. All
suffer the same problem of release of the malodorous volatile
dimethyl sulfide. We anticipate that the fluorous DMS and DMSO
reagents described herein may be successfully employed in several
of these protocols. Toward this end we have simply investigated
the oxidation of 1-octanol to octanal using the fluorous DMS and
N-chlorosuccinimide, i.e., the fluorous version of the Corey Kim
reaction.17 This reaction employs the sulfide and not the sulfoxide
and hence it was possible to work with the higher homologue
(2), taking advantage of its convenient, less volatile nature. In
the event the yield of aldehyde was 96% with 81% of the fluorous
DMS recovered clean and ready for reuse.
Acknowledgment. We thank the NSF (CHE 9986200) for support
of this work.
JA016057I
(14) Recovered 4, as expected for a well-defined chemical entity, performed
analogously to freshly synthesized 4. Indeed, samples of 4 were routinely
recovered and recycled with no attempt to discriminate from the virgin
material.
(15) Typical protocol for oxidation with 4 and its recovery: To a well-
stirred solution of anhydrous CH2Cl2 (5 mL) under Ar at -30 °C was added
oxalyl chloride (0.14 mL, 1.6 mmol). 4 (1.0 g, 3.2 mmol) was then added
dropwise and the reaction mixture stirred for an additional 20 min. Isoborneol
(0.153 g, 1.0 mmol) dissolved in CH2Cl2 (5 mL) was then added to this solution
followed, after an additional 0.5 to 1 h, by EtN(i-Pr)2 (0.88 mL, 5.0 mmol).
The reaction mixture was then allowed to warm to room temperature and
stirred for a period of 30 min before it was quenched with H2O, washed with
ammonium chloride (5 mL), extracted with CH2Cl2 (10 mL), and carefully
concentrated under aspirator vacuum in a cold water bath. The reaction mixture
was then dissolved in toluene (6 mL) and extracted continuously with FC 72
(15 mL) in a cooled continuous extractor8 for 4 h. After decantation,
concentration of the toluene layer and chromatography on silica gel yielded
camphor (0.142 g, 94%). The FC-72 phase, containing a mixture of 3 and 4,
was then stirred with MeOH (3 mL) and H2O2 (0.23 mL of 30%, 2 mmol) for
1 h after which it was diluted with H2O (5 mL) and extracted with CH2Cl2
(10 mL) in a three-phase system. Concentration of the CH2Cl2 layer then gave
recovered 4 (0.9 g, 90%).
a Isoborneol. b Diacetone glucofuranose. c myo-Inositol. d (R)-Alcohol,
f
DAM ) dianisylmethyl. e 17â-Alcohol. A mixture of anomers was used.
°C and subsequently treated with the substrate and then diiso-
propylethylamine almost as in the standard Swern oxidation. The
(16) Lipshutz, B. H.; Papa, P.; Keith, J. M. J. Org. Chem. 1999, 64, 3792.
(17) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586.