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Introduction
The Corey-Kim oxidation1 of alcohols is an important
reaction used by synthetic chemists due to its reliability and
the use of inexpensive reagents. Despite the more recent
development of alternate oxidation methodologies, such as
o-iodoxybenzoic acid (IBX),2 Dess-Martin periodinane,3 and
tetrapropylammonium perruthenate (TPAP),4 the CoreyKim oxidation demonstrates selective reactivity5 that continues to find application in synthesis. The Corey-Kim
intermediate (1) is prepared by the reaction of N-chlorosuccinimide (NCS) with dimethyl sulfide (DMS) as shown in
Scheme 1. The sequential addition of the starting alcohol
and a tertiary amine, typically triethylamine, completes the
oxidation to the ketone or aldehyde. The mechanism for the
Corey-Kim oxidation was evaluated by McCormick6 and
found to be consistent with the mechanism of dimethyl
sulfoxide oxidations.7
The Corey-Kim oxidation was essential for the largescale production of the ketolide antibiotic ABT-773 (4,
cethromycin).5b As shown in Scheme 2, the oxidation of the
C-3 hydroxyl of compound 2 provided the ketone 3 as the
final isolated intermediate. Final deprotection of the benzoate
group in 3 completed the synthesis of ABT-773.
For the application of the Corey-Kim oxidation at large
scale, the stability of the intermediate 1 was a significant
concern because Vilsmaier8 has shown that intermediate 1
undergoes decomposition via two pathways. As shown in
Scheme 3, intermediate 1 was converted into succinimide
* Author to whom correspondence should be addressed. E-mail:
russell.cink@abbott.com. Telephone: 847-937-0463. Fax: 847-938-2258.
Current address: Cayman Chemical Company, Ann Arbor, Michigan, U.S.A.
(1) (a) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586. (b) Corey,
E. J.; Kim, C. U. J. Org. Chem. 1973, 38, 1233. (c) Corey, E. J.; Kim, C.
U. Tetrahedron Lett. 1974, 287. (d) Corey, E. J.; Kim, C. U.; Takeda, M.
Tetrahedron Lett. 1972, 4339.
(2) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(3) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(4) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(5) For recent applications of the Corey-Kim oxidation, see: (a) Kuwajima,
I.; Tanino, K. Chem. ReV. 2005, 105, 4661. (b) Plata, D. J.; Leanna, M.
R.; Rasmussen, M.; McLaughlin, M. A.; Condon, S. L.; Kerdesky, F. A.
J.; King, S. A.; Peterson, M. J.; Stoner, E. J.; Wittenberger, S. J. Tetrahedron
2004, 60, 10171. (c) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.;
Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125,
1498. (d) Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org. Chem.
2002, 67, 4630. (e) Maeng, J. H.; Funk, R. L. Org. Lett. 2002, 4, 331. (f)
Katayama, S.; Fukuda, K.; Watanabe, T.; Yamauchi, M. Synthesis 1988,
178.
(6) McCormick, J. P. Tetrahedron Lett. 1974, 1701.
(7) Epstein, W. W.; Sweat, F. W. Chem. ReV. 1967, 67, 247.
(8) (a) Vilsmaier, E.; Sprugel, W. Liebigs Ann. Chem. 1971, 747, 151. (b)
Vilsmaier, E.; Dittrich, K. H.; Sprugel, W. Tetrahedron Lett. 1974, 3601.
(c) Vilsmaier, E.; Sprugel, W. Tetrahedron Lett. 1972, 625.
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271
temp (C)
[C]NCS (M)
[C]o (M)
kobs (1/h)
k (M/h)
-8
-8
0
0
0
0.535
0.271
0.793
0.535
0.271
0.492
0.239
0.725
0.480
0.235
0.0104
0.0160
0.0275
0.0377
0.0587
0.00513
0.00383
0.0199
0.0181
0.0138
(1)
(2)
(3)
[C]NCS (M)
time (h)
-12
-4
5
0.254
0.360
0.895
4
4.5
4.5
0.221
0.287
0.641
0.207
0.284
0.626
272
temp (C)
(4)
(5)
(6)
The addition of compound 2 to the Corey-Kim intermediate resulted in a slow but steady decrease in the intensity
of the 1011 cm-1 FT-IR band, as shown in Figure 5. HPLC
analysis of this reaction revealed that the desired product,
ketone 3, is formed in 20% prior to the addition of
triethylamine. In this instance, the tertiary amine in compound 2 was acting as the base to cause the oxidation. The
partial conversion of compound 2 to 3 would consume a
fraction of the Corey-Kim intermediate and was consistent
with the slow decrease in the intensity of the 1011 cm-1
FT-IR band shown in Figure 5.
Figure 5. Peak intensity of 1011 cm-1 band of the CoreyKim oxidation of compound 2.
273
274