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SCHEME 1. Synthesis of N-tert-Butanesulfinyl Ketimines
Racemization Free Protocol for the Synthesis
of N-tert-Butanesulfinyl Ketimines
Gopal K. Datta† and Jonathan A. Ellman*,‡
†Department of Chemistry, University of California,
Berkeley, California 94720, and ‡Department of Chemistry,
Yale University, New Haven, Connecticut 06520
Received June 28, 2010
has proven to be generally effective.2b,3 Recently, a personal
communication alerted us to the susceptibility of the sulfinyl
stereocenter to racemization upon Ti(OR)4-mediated con-
densation of a proprietary ketone under particularly harsh
conditions.4 This observation prompted us to reinvestigate
Ti(OR)4-mediated ketone condensations under different
conditions, including extended reaction times and elevated
temperatures. Herein, we report the racemization-free con-
densation of tert-butanesulfinamide (1) with a variety of
ketones even under forcing conditions. Moreover, by monitor-
ing the rate of condensation, optimal conditions for the
preparation of N-sulfinyl ketimines for different substrate
classes were also established. Finally, for challenging sub-
strates that require prolonged reaction times, the importance
of performing reactions under an inert atmosphere is docu-
mented.
Our investigation began with a model condensation reac-
tion with enantiomerically pure 1 and the electron-rich and
therefore unreactive aromatic ketone 4-methoxyacetophe-
none (2a) (Scheme 1). All condensation reactions were care-
fully monitored by 1H NMR using the nonperturbing
internal standard diglyme, and yields were quantitated on
the basis of the production of ketimine 3a at 3, 6, 12, 24, and
48 h time points (Table 1). Under previously reported
conditions, 0.5 M 1, ketone (1.1 equiv), and Ti(OEt)4
(2.0 equiv) in THF at reflux the reaction was slow and required
48 h for imine 3a to be obtained in 84% yield (entry 1).
Interestingly, performing the reaction at double the concen-
tration resulted in only modest acceleration in the rate of
reaction (entry 2). The effect of reversing the stoichiometry
of 1 and 2a was next evaluated by using 1.1 equiv of 1 rather
than a slight excess of ketone (entry 3). Under these condi-
tions, the initial reaction rate was modestly faster, and based
upon the limiting ketone starting material also resulted in a
comparable overall yield (86%). For each of the reaction
conditions, the enantiomeric purity of the imine product was
determined by HPLC analysis, and in all cases no racemiza-
tion to the limits of detection (<0.5% ee) was observed even
at the longest reaction times. To enable convenient reaction
conditions that enabled higher conversion at shorter reaction
times, the reaction was also performed by replacing THF
(bp = 66 °C) with the higher boiling solvent cyclopentyl
methyl ether (bp = 106 °C), which has become increasingly
popular in process research because of its higher chemical
stability and lower flammability relative to that of other
A general and robust racemization-free protocol for the
synthesis of a variety of N-tert-butanesulfinyl ketimines is
reported. Reaction progress was monitored by 1H NMR
using the nonperturbing internal standard diglyme, and
ketimines were formed in good to high yields in either
THF or CPME (cyclopentyl methyl ether) as solvent with
heating to reflux.
N-tert-Butanesulfinyl imines are now among the most
extensively used compounds in asymmetric synthesis.1 The
popularity of N-tert-butanesulfinyl imines derives not only
from the chiral directing ability of the sulfinyl group but also
the fact that they are stable to hydrolysis and tautomeriza-
tion and consequently are easily manipulated, stored, and
purified while at the same time showing high reactivity for
the addition of a wide range of nucleophiles in excellent
yields. A further desirable feature of N-tert-butanesulfinyl
imines is their high-yielding one-step synthesis by direct
condensation of tert-butanesulfinamide (1) with carbonyl
compounds. Indeed, a number of mild and general methods
have been reported for the condensation of 1 with
aldehydes.1a,2 In contrast, for the condensation of the com-
paratively less electrophilic and more sterically encumbered
ketones, heating is required and only the use of titanium alko-
xides, which serve as both Lewis acids and water scavengers,
(1) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110,
3600. (b) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc.
Rev. 2009, 38, 1162. (c) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
8869. (d) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou,
I. Aldrichimica Acta 2005, 38, 93. (e) Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003.
(2) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913. (b) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278. (c) Higashibayashi, S.; Tohmiya, H.; Mori, T.;
Hashimoto, K.; Nakata, M. Synlett 2004, 457. (d) Huang, Z.; Zhang, M.;
Wang, Y.; Qin, Y. Synlett 2005, 1334. (e) Jiang, Z.-Y.; Chan, W. H.; Lee,
A. W. M. J. Org. Chem. 2005, 70, 1081. (f) Ardej-Jakubisiak, M.; Kawecki,
R.; Swietlinska, A. Tetrahedron:Asymmetry 2007, 18, 2507. (g) Fan, R.; Pu,
D.; Wen, F.; Ye, Y.; Wang, X. J. Org. Chem. 2008, 73, 3623.
(3) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(4) Observation reported by Todd Grote and Thomas Beauchamp, Eli
Lilly and Company, Indianapolis, IN.
DOI: 10.1021/jo1011625
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Published on Web 08/25/2010
J. Org. Chem. 2010, 75, 6283–6285 6283
2010 American Chemical Society