results were found to depend strongly on the nature of the
amine used.7 For example, while aromatic amine bearing
an electron-deficient group on the aromatic ring (p-CF3-
C6H4NH2) afforded high enantioselectivity (83% ee), neg-
ligible asymmetric induction (∼2% ee) was observed in the
case of amines of higher nucleophilicity such as anisidine
and benzylamine (2.5 mol % 1 in toluene).7 Independently,
Hii et al. reported a similar reaction last year,4c and their
most recent work described excellent enantioselectivity using
aromatic amines.8 However, they also found a tendency
similar to that seen in our results, and the reaction with
electron-rich amines did not achieve a synthetically useful
level. We speculated that this phenomenon is due to the basic
character of amines, causing deactivation of Lewis acid
catalysts by coordination to the metal center, while amines
of higher nucleophilicity react spontaneously, resulting in
uncontrolled reactions (Scheme 1). Thus, a novel reaction
Table 1. Optimization of Reaction Conditions
catalyst
(mol %)
TfOH
time
(h)
yield
(%)
ee
entry
(equiv to 4a )
(%)
1
2
3a
4
5a
1 (2)
-
1 (2)
1 (1)
2 (1)
-
-
24
24
24
24
12
35
41
25
98
92
2
-
88
4
98
TfOH (1.0), 6a
TfOH (0.5)
TfOH (1.0), 6a
a TfOH was added as a salt of 4a (6a).
1 reacted with excess amine, and several less active pal-
ladium complexes were formed.
Scheme 1
Furthermore, the control experiment revealed that spon-
taneous reaction proceeded at a comparable rate (entry 2).
These may be the reasons poor results were obtained in entry
1. On the basis of our finding that the cationic Pd complexes
1 and 2 work well in the presence of a Brønsted acid,6 we
envisaged that the usage of a salt to block the lone pair of
amines with a proton might be effective to suppress such
unfavorable side reactions (Scheme 1). Among the protic
acids examined, TfOH was found to be effective.9,10 When
the isolated salt 6a (4a/TfOH) was used, the reaction of 3a
proceeded slowly (25% after 24 h), probably because the
formation of 4a from 6a was not favorable (entry 3).11
Encouragingly, however, the enantioselectivity was greatly
improved to 88%. In entry 4, it was found that the addition
of a 0.5 equiv of TfOH to 4a accelerated the reaction, but
only negligible asymmetric induction was observed.12 Thus,
we considered that the generation of an appropriate amount
of free amine would be necessary. For this purpose, the Pd
complex 2, in which the hydroxyl group shows a basic
character,6f,g was employed instead of 1 (entry 5). The
reaction of 2 with 6a adequately regulated the generation of
free amine, thus avoiding unfavorable side reactions. As
shown in entry 5, the reaction of 3a with 6a was carried out
in THF using 1 mol % 2. Gratifyingly, the reaction
proceeded smoothly, and the desired product was obtained
in 92% yield and 98% ee (rt, 12 h).
system is required to realize a generally effective reaction
using various amines. Herein, we report a novel reaction
system for catalytic asymmetric conjugate addition of various
amines to alkenoyl oxazolidinones 3, in which the combined
use of the Pd complex 2 and amine salt is the key to suc-
cessful results. In addition, preliminary experiments on cata-
lytic enantioselective protonation in the conjugate addition
of amines are also described.
Initially, anisidine 4a was chosen as a nucleophile because
electron-rich amines gave poor results as described above.
The reaction of 3a with 4a was carried out using 2 mol %
Pd aqua complex 1 (Table 1, entry 1). Unfortunately, the
reaction was sluggish, and the ee of the product 5aa was
only 2%. As we speculated, NMR experiments indicated that
This method was also applicable to other starting materials,
as depicted in Table 2.13 The reaction with simple aniline or
(5) A recent example of the addition of Li amide of BnNHSiMe3 using
a chiral ether ligand: Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka,
K. J. Am. Chem. Soc. 2003, 125, 2886-2887.
(8) Li, K.; Cheng, X.; Hii, K. K. Eur. J. Org. Chem. 2004, 959-964.
This paper appeared during the preparation of our manuscript.
(9) AcOH, HCl, and MsOH gave less satisfactory results.
(10) An interesting proton effect was reported previously: Seligson, A.
L.; Trogler, W. C. Organometallics 1993, 12, 744-751.
(11) A trace amount of the product was formed in toluene, probably
because the salt was not dissolved.
(12) Recently, Spencer et al. reported that the proton itself can be an
active achiral catalyst for aza-Michael reaction. See: Wabnitz, T. C.; Yu,
J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484-493. In contrast, high
enantioselectivity was observed under our optimized conditions even in the
presence of a stoichiometric amount of proton source (Table 1, entry 5).
(6) (a) Sodeoka, M.; Ohrai, M.; Shibasaki, M. J. Org. Chem. 1995, 60,
2648-2649. (b) Sodeoka, M.; Tokunoh, R.; Miyazaki, F.; Hagiwara, E.;
Shibasaki, M. Synlett 1997, 463-466. (c) Sodeoka, M.; Shibasaki, M. Pure
Appl. Chem. 1998, 70, 411-414. (d) Hagiwara, E.; Fujii, A.; Sodeoka, M.
J. Am. Chem. Soc. 1998, 120, 2474-2475. (e) Fujii, A.; Hagiwara, E.;
Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450-5458. (f) Hamashima,
Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240-11241.
(g) Hamashima, Y.; Yagi, K.; Takano, H.; Tama´s, L.; Sodeoka, M. J. Am.
Chem. Soc. 2002, 124, 14530-14531. (h) Hamashima, Y.; Takano, H.;
Hotta, D.; Sodeoka, M. Org. Lett. 2003, 5, 3225-3228.
(7) Unpublished results. See Supporting Information.
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Org. Lett., Vol. 6, No. 11, 2004