1
Tetrahedron Letters
Triisopropyl borate mediated N-sulfinyl imine formation
Michael D. Visco,a Jonathan T. Reeves,b,* Maurice A. Marsini,b Ivan Volchkov,b Carl A. Busacca,b Anita
E. Mattson,a and Chris H. Senanayakeb
aDepartment of Chemistry and Biochemistry, Ohio State University, Columbus, Ohio 43210, USA
bChemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut 06877-0368, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Triisopropyl borate effects the condensation of aldehydes with sulfinamides to give N-sulfinyl
imines. The reaction is amenable to 1°, 2°, and 3° alkyl aldehydes, as well as aryl, heteroaryl,
and α,-unsaturated aldehydes. In addition to tert-butanesulfinamide, the condensation is also
effective with 4-toluenesulfinamide and 2,4,6-triisopropylphenylsulfinamide. This protocol
proceeds under homogeneous reaction conditions and requires no post-reaction filtration of
insoluble reagents or byproducts. 2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Borate
Imine
Sulfinamide
Condensation
N-Sulfinyl imines are exceptionally useful intermediates in
organic synthesis.1 The addition of nucleophiles to N-sulfinyl
imines generally occurs in a highly diastereoselective manner to
give valuable chiral amine products. The condensation of
sulfinamides with carbonyl compounds is among the most
general and convenient methods for the synthesis of N-sulfinyl
imines. N-tert-Butanesulfinyl imines, developed by Ellman and
co-workers, are by far the most versatile and well-explored class
of N-sulfinyl imines.1b,c Ellman and co-workers reported the first
asymmetric synthesis of tert-butanesulfinamide 1 and its
condensation with aldehydes and ketones to give N-sulfinyl
imines.2 Recently, we described a general method for imine
formation using B(OCH2CF3)3.3 This procedure was amenable to
not only N-sulfinyl imines, but also N-toluenesulfonyl, N-
compared with B(OCH2CF3)3.5 Herein, we report the scope of the
use of B(Oi-Pr)3 as a reagent for N-sulfinyl aldimine formation.
Table 1. N-tert-Butanesulfinyl Imine Formation with B(Oi-Pr)3.
a Conversion of 4-bromobenzaldehyde to 2 as measured by HPLC
analysis (220 nm).
(dimethylamino)sulfamoyl
and
N-diphenylphosphinoyl
aldimines. In the course of screening various trialkyl borates, we
found that triisopropyl borate, though not as powerful a
condensation reagent as B(OCH2CF3)3, nonetheless gave clean
conversion of 4-bromobenzaldehyde to N-tert-butanesulfinyl
imine 2 at rt after 72 h (Table 1, entry 1). By increasing the
temperature to 60 °C, the reaction time decreased to a more
reasonable 18 h (entry 2). Triisopropyl borate has convenient
physical properties: it is a non-viscous liquid that is easily
transferred by either syringe or pouring, and it is non-volatile
(boiling point of 140 °C at 1 atm) and odorless. It also has an
excellent safety profile, with NFPA and HMIS health ratings of 0
and 1, respectively, and NFPA and HMIS reactivity hazard and
physical hazard ratings of 0 and 0.4 Furthermore, B(Oi-Pr)3 is
inexpensive and widely commercially available, especially
The reaction of 4-bromobenzaldehyde with tert-
butanesulfinamide 1 was performed under the optimal reaction
conditions (Scheme 1). The reaction workup proved simple and
convenient: after completion of the reaction as determined by
HPLC analysis (consumption of 4-bromobenzaldehyde), the
cooled reaction mixture was diluted with EtOAc and water,
resulting in two clear phases. Importantly, B(Oi-Pr)3 gave no
solids or emulsions on addition of water, and thus no filtration
was required. The reagent is hydrolyzed to i-PrOH and B(OH)3,
with the former remaining in the organic phase and the latter
going into the aqueous phase. After a simple extractive workup,
drying and concentration of the organic phase, chromatographic
purification provided the product 2 in 92% yield. Importantly, no
epimerization of the sulfur stereocenter was observed, since 1 of
>99.5% ee gave 2 of >99.5% ee.6
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