of the imine that would need to be cleaved in an efficiency-
reducing additional step. While this approach would limit
the substrate scope by definition, it would also allow
unprecedented flexibility in the selection of the imine
substituent (R′), flexibility that, as will be demonstrated, may
be exploited for efficient access to unusual and interesting
structures. Herein we demonstrate that imidazoles (and
benzimidazoles) are effective activators of strained allyl-
chlorosilacycle reagents and that this may be exploited for
the highly enantioselective, efficient, and protecting group-
free synthesis of a variety of functionally and stereochemi-
cally complex imidazole-bearing chiral carbinamine struc-
tures.
Table 1. Enantioselective Imidazole-Directed Allylation
Our investigations began with imine 2, derived from
2-formylimidazole and allylamine. Treatment of 2 with
allylsilane 1 did indeed lead to smooth conversion to amine
3, but with negligible (<10% ee) enantioselectivity (Scheme
2). A survey of other allylsilanes derived from chiral
Scheme 2
a After 1 h, this reaction was heated to 45 °C for 1 h to effect
lactamization. b The enantiomeric reagent (1R,2S)-4 was employed in this
experiment. c This reaction was conducted at 10 °C for 38 h.
aminoalcohols that are available inexpensively and in bulk
led to the discovery that cis-1-amino-2-indanol-derived
allylsilane (1S,2R)-45 was effective in inducing good levels
of enatioselectivity. Upon optimization, it was found that
treating imine 2 with (1S,2R)-4 in toluene for 1 h at room
temperature provided amine 3 in 80% yield and 87% ee.
carbinamines 7 and 8 (entries 4 and 5),6 and these reactions
also demonstrate that imidazole and benzimidazole may be
used interchangeably. Remarkably, phenylketimine 9 may
be smoothly allylated as well to provide tertiary carbinamine
10 in 69% yield and 70% ee (entry 6). Despite the moderate
enantioselectivity, we contend that this is a useful reaction
as alternate methods to access enantioenriched structures of
this type are not readily apparent.7
One of the more powerful features of allylation reactions
of this type is the potential for the establishment of a second
stereocenter at the allylic position of the products by
substitution of the terminal carbon of the allylsilane. Most
often this takes the form of crotylation reactions, and we
have established that crotylation is viable in the present
context (Scheme 3). Thus, treatment of aldimine 2 wth trans-
With a readily available and effective allylsilane identified,
a survey of the scope of the reaction was carried out (Table
1). As alluded to above, a variety of imine N-substituents
(R′) are well tolerated, as demonstrated by the synthesis of
amines 3, 5, and 6 (entries 1, 2, and 3), with the latter entry
demonstrating some functional group tolerance as well. From
the standpoint of medicinal chemistry and structural diversity
this is an especially useful feature, and one not possible with
a chiral auxiliary-based approach (R′ ) chiral auxiliary),
wherein the auxiliary must be removed and the resulting
primary amine functionalized in additional steps. Ketimines
may also be allylated under surprisingly mild and practical
reaction conditions (toluene, room temperature, 1 h) as
demonstrated by the enantioselective synthesis of tertiary
(6) For other recent advances in asymmetric ketimine allylation, see:
(a) Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991,
56, 4. (b) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
(c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984. (d) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687. (e) Canales, E.;
Hernandez, E.; Soderquist, J. A. J. Am. Chem. Soc. 2006, 128, 8712.
(7) Structurally related tertiary carbinamines have been accessed with,
in some cases, very good diastereoselectivity employing the Ellman tert-
butanesulfinimine methodology. See: Shaw, A. W.; deSolms, S. J.
Tetrahedron Lett. 2001, 42, 7173.
(4) We have recently shown in two different contexts that phenols are
effective activators of our allylchlorosilane family of reagents: (a) Burns,
N. Z.; Hackman, B. M.; Ng, P. Y.; Powelson, I. A.; Leighton, J. L. Angew.
Chem., Int. Ed. 2006, 45, 3811. (b) Rabbat, P. M. A.; Valdez, S. C.;
Leighton, J. L. Org. Lett. 2006, 8, 6119.
(5) As is the case with allylsilane 1, 4 is produced, isolated, and employed
as a ∼2:1 mixture of diastereomers. See the Supporting Information.
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Org. Lett., Vol. 9, No. 18, 2007