Researchers at Sepracor encountered sufficient difficulty
scaling the oxidation reaction of 2 that they developed an
alternative route to 1.17 While their novel route provides
access not only to 1 but also to a range of other sulfinamides,
the sequence is not suitable for large-scale production. It
requires stoichiometric use of cis-1-amino-indan-2-ol as a
chiral auxiliary, four transformations, and four purification
steps, including chromatography on silica gel.
Scheme 2. Original tert-Butanesulfinamide Synthesis
Herein we report a new homogeneous oxidation procedure
that proceeds efficiently, independent of the reaction scale,
and is performed at high concentrations using the inexpensive
and relatively nontoxic solvent acetone. In addition, the
procedure utilizes an inexpensive ligand that can be prepared
as either enantiomer in a single step from commercially
available materials. Indeed, the new oxidation procedure
proceeds with sufficiently high conversion and fidelity that
tert-butanesulfinamide 1 may be prepared by direct addition
of lithium amide to the oxidation product 3 without purifica-
tion of 3.
Investigations on the mechanism of the asymmetric
oxidation of 2 showed that, under homogeneous conditions,
addition of stoichiometric H2O2 destroyed the oxidation
catalyst, resulting in very poor conversions and enantio-
selectivities. As shown in Table 1, good conversions, albeit
Although the reaction sequence is short and efficient and
has enabled extensive use of the reagent, several improve-
ments in the oxidation of 2 to 3 are necessary to enable large-
scale production of 1. First, ligand 4 is derived from tert-
butyl glycinol, for which the (S)-enantiomer is quite
expensive15 and the (R)-enantiomer is currently not com-
mercially available. In addition, the expensive and toxic
solvent chloroform is required to achieve high conversion
and enantioselectivity. Also, to achieve high yield in the
conversion of 3 to 1, the thiosulfinate ester must be purified
away from the starting material by bulb-to-bulb distillation.
Most seriously, the oxidation reaction does not scale well
beyond 1 mole. The oxidation reaction is biphasic (chloroform/
water) with the hydrogen peroxide dissolved in the aqueous
layer and the substrate and catalyst dissolved in the chloro-
form layer. Consequently, the reaction is inefficient with slow
stirring. However, if stirring is too vigorous the catalyst is
exposed to excess hydrogen peroxide and is destroyed.16 This
biphasic reaction is therefore very sensitive to the vessel
shape and the rate of stirring and does not proceed with high
conversion or selectivity on a large scale (>1 mole).
Table 1. Solvent and Temperature Screen with Ligand 4
entry
solventa
iPrOH
T (°C)
conversion (%)b
ee (%)c
1
2
3d
23
23
23
23
0
96
80
51
44
74
53
68
80
83
75
83
81
THF
(5) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819-7832.
(6) Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R.
G. J. Org. Chem. 2002, 67, 8276-8279.
CF3CH2OH
acetone
acetone
CH3NO2
CH3NO2
CH3CN
CH3CN
CH3CN
nd
4
94
(7) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396-3397.
(b) Mabic, S.; Cordi, A. A. Tetrahedron 2001, 57, 8861-8866. (c) Davis,
F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65, 8704-
8708. (d) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001, 42,
1433-1436.
5
59
6
23
0
89
7
93
8
23
0
100
100
97
(8) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589-590. (b) Prakash, G. K. S.; Mandal, M.; Olash, G. A.
Org. Lett. 2001, 3, 2847-2850.
9
10
-20
(9) (a) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001,
66, 3707-3709. (b) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H.
G.; Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051-2054.
(10) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124,
6518-6519.
a Reactions were carried out with 0.1 mol of disulfide (1.4 M). H2O2
(0.11 mol) was then added via syringe pump. b Conversion determined by
1H NMR of the crude reaction mixture. c Determined by HPLC analysis
using a chiral column (see Supporting Information). d Results from ref 16.
(11) See ref 7b.
(12) (a) Shaw, A. W.; deSolms, S. J. Tetrahedron Lett. 2001, 42, 7173-
7176. (b) Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.;
Senanayake, C. H. Tetrahedron Lett. 2002, 43, 923-926. (c) Han, Z.;
Krishnamurthy, D.; Pflum, D.; Grover, P.; Wald, S. A.; Senanayake, C. H.
Org. Lett. 2002, 4, 4025-4028.
(13) (a) Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003,
68, 3-10. (b) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A.
J. Am. Chem. Soc. 2001, 123, 1539-1540. (c) Tsujimoto, T.; Ishihara, J.;
Horie, M.; Murai, A. Synlett 2002, 399-402. (d) Schenkel, L. B.; Ellman,
J. A. Org. Lett. 2003, 5, 545-548.
(14) Cogan, D. A.; Liu, Guangcheng, L.; Kim, K.; Backes, B. J.; Ellman,
J. A. J. Am. Chem. Soc. 1998, 120, 8011-8019.
(15) Cost for the available (S)-enantiomer is $45/g or more.
(16) Blum, S. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2003,
68, 150-155.
with modest selectivity, could be accomplished by slow
addition of hydrogen peroxide using a syringe pump (entries
1-3). A more thorough investigation of the reaction solvent
and temperature has resulted in conditions that provide
significant improvement in the reaction selectivity (entries
7 and 9). Use of acetonitrile as a solvent at 0 °C provides
the highest conversion and selectivity (entry 9). Further
(17) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake,
C. H. J. Am. Chem. Soc. 2002, 124, 7880-7881.
1318
Org. Lett., Vol. 5, No. 8, 2003