Modification of the Swern Oxidation: Use of a Soluble Polymer-Bound, Recyclable, and Odorless Sulfoxide

Full text of DOI:10.1021/jo972304i

J . Org. Chem. 1998, 63, 2407-2409
2407
Sch em e 1
Mod ifica tion of th e Sw er n Oxid a tion : Use
of a Solu ble P olym er -Bou n d , Recycla ble,
a n d Od or less Su lfoxid e
J oanna M. Harris, Yaoquan Liu, Shengyong Chai,
Mark D. Andrews, and J ohn C. Vederas*
Department of Chemistry, University of Alberta,
Edmonton, Alberta, Canada T6G 2G2
Received December 22, 1997
The Swern procedure, using oxalyl chloride activation
of dimethyl sulfoxide (DMSO), is one of the most widely
used methods of oxidizing primary and secondary alco-
hols to aldehydes and ketones.1 Although very effective,
this process produces the unpleasant-smelling, volatile
(bp 37 °C) byproduct, dimethyl sulfide. We have previ-
ously reported the use of 6-(methylsulfinyl)hexanoic acid
(2) as an efficient substitute for DMSO in Swern oxida-
tion reactions.2 This modification generates the non-
volatile sulfide 1, which is easily separable from the
reaction mixture by extraction or filtration through silica
gel. Also described was preliminary work on the attach-
ment of 2 to commercial chloromethyl polystyrene beads
(Merrifield resin) to form a polymer-bound reagent 3
(Scheme 1). The present study expands on these inves-
tigations and reports the attachment of 2 to soluble
poly(ethylene glycol) (PEG) supports to form polymer-
bound reagents that can be easily removed from the
reaction mixture by precipitation and filtration. After
use in the Swern procedure, the PEG-bound reagent can
be readily recycled by periodate oxidation, with no
observable loss of oxidation capacity.
Initial studies on supports to bear the sulfoxide func-
tionality necessary for Swern oxidation focused on in-
soluble solid-phase polymers such as Merrifield resin.
Use of a 2-fold excess of polymer-supported sulfoxide 3
in the Swern process quantitatively oxidizes endo-borneol
to camphor, with no residual acohol remaining. However,
after regeneration by sodium metaperiodate oxidation,3
the oxidation capacity of the polymer-bound reagent is
reduced from 92% to 78%. This may be due to cross-
linking of the polystyrene backbone by reaction with
oxalyl chloride. Clearly, if the reagent is to be recyclable,
the polymer-support must be inert to the reaction condi-
tions for both the Swern oxidation and periodate regen-
eration of the sulfoxide functionality. A rapidly expand-
ing area of polymer-supported chemistry is the use of
soluble scaffolds.4 These have the advantage of forming
a homogeneous phase in the reaction medium, but having
polymeric properties that simplify product separation and
reagent recovery. One of the most versatile and widely
used polymer supports for such liquid-phase synthesis
is poly(ethylene glycol) (PEG).5 PEG is soluble in a wide-
range of organic solvents and water, thereby facilitating
homogeneous reaction, but is insoluble in hexane, diethyl
ether, and tert-butyl methyl ether.6 It is therefore easily
separated from the reaction mixture by precipitation and
filtration.
When choosing a polymer for liquid-phase synthesis a
compromise must be made between loading capacity and
solubility. PEG is commercially available in a range of
molecular weights up to 20 000; those between 2 000 and
20 000 are crystalline with loading capacities between 1
and 0.1 mmol/g, whereas the lower molecular weight
PEG’s exist as liquids at room temperature. A number
of different size PEG’s (with hydroxyl functionalities at
both ends) and MeO-PEG’s (with the polyether termi-
nated by a methoxy group at one end and a free hydroxyl
at the other) were investigated in an attempt to optimize
the reaction conditions and loading capacity. Reagent 2
is easily coupled to PEG in the presence of DCC and
DMAP.7 The reduced sulfide acid 1 can be similarly
coupled and subsequently oxidized to the sulfoxide 5 with
sodium metaperiodate (Scheme 2).3 Although they have
higher loading capacities, the low molecular weight
(below 2 000) liquid polymers present problems with
* Tel (403)-492-5475. FAX (403)-492-8231. e-mail: J ohn.Vederas@
ualberta.ca.
(1) (a) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185. (b)
Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978, 43, 2480-
2482. (c) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660. (d)
Mancuso, A. J .; Brownfain, D. S.; Swern, D. J . Org. Chem. 1979, 44,
4148-4150.
(2) Liu, Y.; Vederas, J . C. J . Org. Chem. 1996, 61, 7856-7859.
(3) (a) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282-
284. (b) J ohnson, C. R.; Keiser, J . E. Organic Syntheses, Wiley: New
York, 1973; Collect. Vol. 5, pp 791-793.
(4) Gravert, D. J .; J anda, K. D. Chem. Rev. 1997, 97, 489-509 and
references therein.
(5) (a) Han, H.; Wolfe, M. M.; Brenner, S.; J anda, K. D. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 6419-6423. (b) Han, H.; J anda, K. D. J .
Am. Chem. Soc. 1996, 118, 7632-7633.
(6) Harris, J . M. In Poly(Ethylene Glycol) Chemistry: Biotechnical
and Biomedical Applications; Harris, J . M., Ed.; Plenum Press: New
York, 1992.
(7) Han, H.; J anda, K. D. J . Am. Chem. Soc. 1996, 118, 2539-2544.
S0022-3263(97)02304-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/10/1998

2408 J . Org. Chem., Vol. 63, No. 7, 1998
Notes
Ta ble 1. Oxid a tion of Alcoh ols w ith Mod ified Sw er n
P r oced u r e
Sch em e 2
isolated
isolated
R1R2CO
yield (%)
with
R1R2CO
yield (%)
with
PEG-
sulfoxide
(5)
sulfoxide
acid
lit.
yield
(%)a
alcohol
endo-borneol
3,5-dimethoxybenzyl alcohol
n-dodecanol
cinnamyl alcohol
benzoin
cholesterol
(2)
91
94
99
94
99
94
99
90
94
92
93
94
-
98
-
99
98
95
95
98
sec-phenethyl alcohol
-
a
See ref 1a.
reaction mixture to approximately 10 mL, addition of
diethyl ether (approximately 100 mL) to precipitate the
polymer (cooling to -20 °C for 10 min accelerates
precipitation), and filtration. The filtrate is concentrated
to give the oxidized product, which typically contains a
trace of polymer contamination (1%). This can be easily
removed by passing an ethereal suspension through a
pad of silica. The solid polymer reagent, which is a 1:1
mixture of the sulfide and sulfoxide, is contaminated with
triethylammonium hydrochloride. Although this does not
affect the subsequent periodate oxidation, it can be
removed by washing a dichloromethane solution with
water. In each case an essentially quantitative oxidation
of alcohol to aldehyde or ketone was observed by 1H NMR
spectrometry. The yields of isolated product, after re-
moval of the polymer contamination, compare favorably
with those of the original Swern reaction.1a
To test the recyclability of the PEG-supported sulfoxide
5, endo-borneol was oxidized under limiting conditions,
using a slight excess of sulfoxide (1.2 oxidizing equiv) and
oxalyl chloride (1.1 equiv). After the Swern reaction, the
recovered PEG-supported sulfide 4 was oxidized with
sodium metaperiodate to regenerate the PEG-supported
sulfoxide 5 in a 91% recovered yield. This regenerated
sulfoxide can be used again to transform endo-borneol
to camphor and shows no loss of oxidation capacity. Five
such oxidation/regeneration cycles with a single batch of
5 could be repeated with no observable reduction in
oxidation capability.
In conclusion, a recyclable, soluble polymer-supported
sulfoxide has been developed that can be used in place
of DMSO in Swern oxidation procedures with no loss of
efficiency. The reagent greatly simplifies the reaction
workup and does not produce any of the unpleasant
byproducts (e.g. dimethyl sulfide) produced by use of
DMSO. It can be repeatedly recycled and reused without
diminishing its effectiveness, and thus has potential for
application in combinatorial chemistry.
separation after completion of the reaction. The higher
molecular weight (above 5 000) polymers have signifi-
cantly lower loading capacities and therefore large
amounts of material are required for stoichiometric
oxidation reactions. The optimum size was determined
to be 2 000. At this molecular weight the polymer is solid
at room temperature and therefore can be easily precipi-
tated from the reaction mixture. The loading capacity
of PEG is twice that of MeO-PEG, and, therefore, since
no differences in synthesis or reactivity between the
mono- and bifunctional polymers were observed, PEG-
2000 was used to study the oxidation capacity and
recyclability of the reagent.
As was found for the polystyrene-supported reagent,2
if a stoichiometric amount of the PEG-supported reagent
5 is used to oxidize endo-borneol, a small amount (ap-
proximately 4%) of the alcohol remains unchanged.
However, use of 1 mol equiv of the bifunctional reagent
in the Swern process results in quantitative oxidation of
endo-borneol to camphor, with no residual alcohol re-
maining. To examine the scope of this soluble polymer-
supported sulfoxide reagent 5, a number of alcohols were
tested using optimal conditions for complete oxidation
(Table 1). In a typical procedure, a dichloromethane
solution of 5 (1.0 equiv [2 oxidizing equiv]) is treated at
-50 to -60 °C with oxalyl chloride (1.5 equiv) followed
by a solution of the alcohol (1.0 equiv), and after 45 min,
excess triethylamine (6 equiv). The solution is then kept
at -45 °C for 2.5 h before being warmed to room
temperature. Workup involves concentration of the
Exp er im en ta l P r oced u r es
Gen er a l. Most common procedures and instrumentation
have been previously described.8 Cross-linked (divinyl benzene)
chloromethylated polystyrene resin (4.15 mequiv/g, Bio-Beads
S-X1) was obtained from Bio-Rad Laboratories (Mississauga,
ON). Poly(ethylene glycol) was obtained from Aldrich Chemical
Co. Inc. Solvents were dried and distilled prior to use according
to standard procedures.9
(8) Witter, D. J .; Vederas, J . C. J . Org. Chem. 1996, 61, 2613-2623.

Additions and Corrections
J . Org. Chem., Vol. 63, No. 7, 1998 2409
6-(Meth ylth io)h exa n oic Acid (1) and 6-(Meth ylsu lfin yl)-
h exa n oic Acid (2) were synthesized as described previously.2
P oly(eth ylen e glycol) Bis(6-(Meth ylth io)h exa n oa te) (4).
A solution of PEG-2000 (10.0 g, 5.0 mmol), sulfide acid 1 (2.80
g, 17.5 mmol), and DMAP (0.21 g, 1.7 mmol) in dichloromethane
(50 mL) was treated with DCC (3.60 g, 17.5 mmol) and stirred
overnight. The white urea precipitate was removed by filtration
through Celite and washed with CH2Cl2. The filtrate was
concentrated to ∼15 mL, and diethyl ether (150 mL) was added
with vigorous stirring to precipitate the polymer. The precipita-
tion was enhanced by stirring in an ice bath for 2 h. The
precipitate was removed by filtration, washed with diethyl ether,
and dried in vacuo to give 11.17 g (98%) of polymer-bound sulfide
4 as a white solid: IR (CH2Cl2 cast) 1733 (m), 1113 (s) cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.21 (t, 2H, J ) 4.8 Hz), 3.64 (s, 88H),
2.48 (t, 2H, J ) 7.3 Hz), 2.33 (t, 2H, J ) 7.4 Hz), 2.08 (s, 3H),
1.63 (m, 4H), 1.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.44,
70.45, 69.06, 63.30, 33.90, 28.65, 28.09, 24.37, 15.39.
P oly(eth ylen e glycol) Bis(6-(Meth ylsu lfin yl)h exa n oa te)
(5). A solution of 4 (10.5 g, 4.6 mmol) in methanol (80 mL) and
water (20 mL) at 0 °C was treated with 0.50 M sodium
metaperiodate (19.4 mL, 9.7 mmol) overnight, during which time
a white precipitate formed. The methanol was removed in vacuo
below 10 °C, and the residue was extracted with CH2Cl2 (5 ×
50 mL). Combined extracts were dried (Na2SO4) and evaporated
to give 10.6 g (99%) of polymer-bound sulfoxide 5 as a white
solid: IR (CH2Cl2) 1732 (m), 1114 (s) cm-1; 1H NMR (300 MHz,
CDCl3) δ 4.20 (t, 2H, J ) 4.7 Hz), 3.61 (s, 88H), 2.66 (m, 2H),
2.53 (s, 3H), 2.33 (t, 2H, J ) 7.3 Hz), 1.76 (m, 2H), 1.65 (m, 2H),
1.48 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.08, 70.37, 68.93,
63.30, 54.17, 38.44, 33.56, 27.99, 24.20, 22.09.
solution is kept at -45 °C for 2.5 h before warming to room
temperature. Workup involves concentration of the reaction
mixture to approximately 10 mL, followed by addition of diethyl
ether (100 mL) to precipitate the polymer. The precipitation is
accelerated by cooling to -20 °C for 10 min. After filtration the
filtrate is concentrated in vacuo to give the oxidized product,
which typically contains a trace of polymer contamination (1%).
This is easily removed by passing an ethereal suspension
through a pad of silica. The solid polymer reagent, which is a
1:1 mixture of the sulfide and sulfoxide, is contaminated with
triethylammonium hydrochloride. Although this does not affect
the subsequent periodate oxidation, it can be removed by
washing a dichloromethane solution with water to give recovered
polymer-bound reagent in
a 98% yield. The product was
analyzed by 1H NMR spectrometry, which showed complete
oxidation with no trace of alcohol. All the carbonyl products
obtained from the Swern oxidation were characterized by
comparing chromatographic and/or spectral properties (1H NMR,
IR, MS) with the authentic samples or literature.
In experiments to determine the recyclabilty of the PEG-
bound sulfoxide, limiting conditions were used. Thus, 1 equiv
of endo-borneol was used for the reaction with 0.6 equiv of
polymer-supported sulfoxide 5 and 1.1 equiv of oxalyl chloride:
96% of the alcohol was oxidized to give camphor with 4% left
unchanged. The polymer-bound reagent recovered was a 6:1
mixture of sulfide:sulfoxide. It was reoxidized by the above
procedure for periodate oxidation, giving a 91% recovery of PEG-
bound sulfoxide 5.
Ack n ow led gm en t. These investigations were sup-
ported by Merck Frosst Ltd., the Natural Sciences and
Engineering Research Council of Canada, and the
Alberta Heritage Foundation for Medical Research
(postdoctoral fellowships J .M.H. and M.D.A.). Y.L.
acknowledges support from an Izaak Walton Killam
Scholarship.
Gen er a l P r oced u r e for th e Mod ified Sw er n Oxid a tion .
A solution of 5 (1.74 g, 0.75 mmol) in dichloromethane (30 mL)
is cooled to -50 to -60 °C, oxalyl chloride (0.098 mL, 1.125
mmol) is added dropwise, followed after 15 min by a solution of
the alcohol (0.75 mmol) in CH2Cl2 (5 mL). The mixture is stirred
for 45 min, triethylamine (0.63 mL, 4.5 mmol) is added, and the
(9) Purification of Laboratory Chemicals, 3rd ed.; Perrin, D. D.,
Armarego, W. L. F., Ed.; Pergamon: New York, 1988.
J O972304I
Additions and Corrections
Vol. 62, 1997
Ma tth ia s Ko1ck * a n d J och en J u n k er . How Many NOE
Restraints Are Necessary for a Reliable Determination of the
Relative Configuration of an Organic Compound: Application
to a Model System.
Page 8614. The configuration of compound 1 is cor-
rectly designated as 1R,6R,8R,11R,12S,16R in the text.
The centers 6, 8, 11, and 12 should be switched in the
2D drawing of 1.
J O984000H
S0022-3263(98)04000-6
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