sulfur chiral center. Of particular interest in the context of
the aza-Mannich reaction was Ellman’s recent7d report on
the self-condensation of sulfinimines for the construction of
heterocycles. Both inter- and intramolecular variants were
reported to proceed in good yield with reasonable dia-
stereoselectivity. However, as with the analogous aldol
condensation, the best results were observed when the
sulfinimines were either self-condensed or were derived from
a symmetrical dialdehyde.
Our goal was to develop a general methodology for the
intermolecular cross coupling of enamides and imines.
Taking our lead from the carbonyl condensation literature,
we recognized that the use of coupling partners with very
different reactivity would be a straightforward way to address
the problem of complicated product distribution. Cognizant
of Ellman’s observations regarding the high reactivity of
sulfinyl aldimines, we initiated our study utilizing the less
reactive N-tert-butylsulfinimine of acetophenone (1a) as the
nucleophile and a 2:1 E/Z mixture of the more reactive
N-tert-butanesulfonyl (Bus8) benzaldehyde imine (2a9) as the
electrophile (Scheme 1).
required to deliver the product in the reported yield, Z-2a
did not react at low temperature and decomposition of both
starting materials occurred after the mixture was gradually
warmed to room temperature. We were able to unambigu-
ously establish the (S) absolute configuration of the newly
formed stereocenter by converting 3a to a diastereomeric
pair of known amino alcohols11 in two steps.7k,l
Placing these observations in the context of Ellman’s
enamide-aldehyde condensations, it becomes apparent that
the same mechanism must be in operation. Both the higher
degree of stereocontrol and the lack of imine reactivity can
be rationalized within this framework when one takes into
account the steric bulk and orientation of the tert-butyl
sulfonyl group.7l
Armed with this information, we proceeded to explore the
scope of the condensation reaction with a variety of sulfin-
imines and E-sulfonyl imines10 (Table 1). The reaction
Table 1. Reaction Scope
Scheme 1. Initial Condensation
sulfinimine
(R1)
sulfonyl imine
(R2)
product
(yield (%), dr)
1a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
3a (93, >99:1)
3b (81, >99:1)
3c (84, >99:1)
3d (85, >99:1)
3e (80, >99:1)
3f (50, >99:1)
3g (65, >99:1)
3h (88, 4:1)
1b ((4-CN)Ph)
1c ((4-OMe)Ph)
1d (pyrid-3-yl)
1e (pyrid-2-yl)
1f ((2-OMe)Ph)
1g (furan-2-yl)
1h (Me)
Although we were pleased to see that the reaction of the
lithium enamide with this sulfonyl imine mixture worked
efficiently and with nearly complete stereocontrol at -78
°C, we noted the reaction required a significant excess of
the electrophile mixture to proceed to completion. Even more
significantly, we recovered only the Z configuration N-Bus
imine after workup and purification of the reaction mixture.
Independent reaction of enamide 1a with the E and Z isomers
of 2a revealed that while only a slight excess of E-2a was
1i (Et)
1j (BnOCH2)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
2a (Ph)
2a (Ph)
2b (Et)
2c (tBu)
2d ((4-NO2)Ph)
2e ((4-OMe)Ph)
2f (pyrid-2-yl)
2g (cinnamyl)
3i (85, >99:1)
3j (64, >99:1)
3k (54, >99:1)
3l (80, >99:1)
3m (91, >99:1)
3n (85, >99:1)
3o (61, >99:1)
3p (85, >99:1)
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Yang, B.; Deng, J.; Wu, Y.; Zhang, Y.; Rao, A.; Fang, T.; Goswami, R.;
Prasad, K.; Nolt, M.; Anilkumar, G. Phosphorus, Sulfur Silicon - Relat.
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proceeded with a high degree of stereocontrol with both aryl
and heteoraryl sulfinimine nucleophiles (1a-g). The reac-
tions of alkyl substituted sulfinimines (1h-j) proceeded with
similar efficiency and diastereoselectivity as their aryl
counterparts with only the acetone-derived nucleophile (1h)
showing diminished diastereoselectivity. An interesting
feature of these alkyl enamide condensations was the
tendency of the anion to react exclusively on the less
substituted carbon (1i and 1j).
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Org. Lett., Vol. 7, No. 26, 2005