Phenol-directed enantioselective allylation of aldimines and ketimines

Article abstract of DOI:10.1021/ol062589y

(Chemical Equation Presented) Phenols are effective directing and activating groups for our allylchlorosilane reagents, allowing the highly enantioselective allylation of a range of 2-aminophenol-derived aldimines. When the phenol is incorporated into the

Full text of DOI:10.1021/ol062589y

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6119-6121
Phenol-Directed Enantioselective
Allylation of Aldimines and Ketimines
Philippe M. A. Rabbat, S. Corey Valdez, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
leighton@chem.columbia.edu
Received October 20, 2006
ABSTRACT
Phenols are effective directing and activating groups for our allylchlorosilane reagents, allowing the highly enantioselective allylation of a
range of 2-aminophenol-derived aldimines. When the phenol is incorporated into the substrate ketimines may be allylated highly enantioselectively,
leading to the experimentally simple synthesis of a range of tertiary carbinamine structures.
Chiral carbinamines represent an important target for the
development of asymmetric reaction methodology, due to
their importance in a range of disciplines including medicinal
chemistry and natural product synthesis. Especially for the
former purpose, it is essential that such methodology be
general, reliable, and user-friendly. To this end, we have
reported a new class of allyl- and crotylsilane reagents for
the enantioselective allylation and crotylation of aldehyde-
and ketone-derived acylhydrazones.1,2 This chemistry suffers
from an important limitation, however, in that the use of
aliphatic aldehyde-derived acylhydrazones typically results
in poor levels of enantioselectivity.1a Herein, we report a
solution to the problem of aliphatic aldehyde-derived imines
and an expansion in the scope of effective ketimine substrates
leading to the protecting group free synthesis of interesting
heterocycle motifs.
(Scheme 1). This reaction generates an equivalent of HCl
which protonates the amino group of the pseudoepehedrine
chiral controller, resulting in a significant increase in the
Lewis acidity of the silicon center. It was therefore straight-
forward to design new imine derivatives for use with this
family of silane reagents, the only requirement being that
they carry an appropriately configured nucleophile for
chloride displacement and concomitant HCl generation.
2-Aminophenol-derived imines3-5 seemed well suited for this
purpose and their oxidative cleavage from the product amines
has been extensively documented as well,4,5b,e,g,6 and we
therefore prepared cyclohexanecarboxaldimine 2. The selec-
tion of the 2-amino-3-methylphenol in this case was guided
by observations made by Kobayashi that with aliphatic
aldehydes the added methyl group significantly improves
imine stability.5c,7 Reaction of 2 with silanes 1 did indeed
result in the desired allylation product, and after optimization
it was found that the reaction was best performed in Et2O at
Mechanistic studies1b have revealed that the acylhydrazone
reactions operate by nucleophilic displacement of the chloride
on the silane reagent 1 by the oxygen of the acylhydrazone
(3) We have recently demonstrated that a related phenol-based strategy
may be employed for asymmetric ketone allylation reactions. See: Burns,
N. Z.; Hackman, B. M.; Ng, P. Y.; Powelson, I. A.; Leighton, J. L. Angew.
Chem., Int. Ed. 2006, 45, 3811.
(4) Kobayashi has previously made a similar analogy between acylhy-
drazones and 2-aminophenol-derived imines for imine allylation with
allyltrichlorosilane: Sugiura, M.; Robvieux, F.; Kobayashi, S. Synlett 2003,
1749.
(1) (a) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc.
2003, 125, 9596. (b) Berger, Duff, R.; K.; Leighton, J. L. J. Am. Chem.
Soc. 2004, 126, 5686.
(2) Methods for the asymmetric addition of allylic nucleophiles to various
imine derivatives have recently been reviewed: Ding, H.; Friestad, G. K.
Synthesis 2005, 2815.
10.1021/ol062589y CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/29/2006

Scheme 1
Scheme 2
ambient temperature. Under these conditions, 3 was isolated
in 85% overall yield (from cyclohexanecarboxaldehyde) and
92% ee. Consistent with our mechanistic analysis, the
corresponding methyl ether of phenol 2 does not react at all
with silanes 1. This result thus validated the underlying
mechanistic hypothesis and represented a solution to the
problem of aliphatic aldimines.
A survey of substrate scope was carried out with allylsilane
1 and cis- and trans-crotylsilanes 4 and 5, and the results
are outlined in Scheme 2. In an effort to address the
generality of the initial success with aliphatic aldimine 2, it
was quickly discovered that while sterically less hindered
aliphatic aldimines did indeed lead to good levels of
enantioselectivity, the efficiency was poor (6, 40% yield,
87% ee). Pursuing the theory that this inefficiency was due
to imine instability, we prepared the corresponding aldimine
derived from 2-amino-3,5-di-tert-butylphenol, and indeed,
this imine provided superior results in the allylation reaction
with allylsilane 1 (7, 82% yield, 98% ee). Aromatic aldehyde-
derived imines were excellent substrates for the allylation
reaction with 1 as well, although in these cases CH2Cl2
proved to be a better solvent in terms of both efficiency and
enantioselectivity (8-10). As expected, it was found that
both the aromatic and aliphatic aldehyde-derived imines
could be crotylated with excellent diastero- and enantiose-
lectivity (11-13). In all cases, it is noteworthy that the
reaction conditions involve simply mixing the imine and
silane in the appropriate solvent at ambient temperature. With
a supply of the requisite silane (150 g batches of allylsilane
1 are prepared routinely) in hand, and given the commercial
availability of both 2-aminophenol and 2-amino-3-meth-
ylphenol, these reactions are thus experimentally trivial to
perform.
Seeking to expand the scope of useful transformations
based on this concept, we decided to examine the possibility
that the phenol activating/directing group might be a part of
the substrate rather than an auxiliary attached to the imine
nitrogen. A potential advantage of this strategy would be
that, in principle, there would be significant flexibility in
the choice of the N-substituent of the imine, and we were
also interested in the possibility that this strategy would allow
success with ketimines.8 Thus, the simple N-allyl ketimine
14 was prepared and treated with allylsilane reagent 1
(Scheme 3). Remarkably, although the reaction only pro-
ceeded at a reasonable rate in refluxing toluene, amine 15
(5) For other examples of the use of 2-aminophenol-derived imines in
asymmetric nucleophilic addition reactions, see: (a) Kobayashi, S.; Ko-
miyama, S.; Ishitani, H. Angew. Chem., Int. Ed. 1998, 37, 979. (b) Ishitani,
H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 762. (c) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 8180. (d) Ueno, M.; Ishitani, H.; Kobayashi, S. Org. Lett. 2002, 4,
3395. (e) Kobayashi, S.; Kobayashi, J.; Ishiani, H.; Ueno, M. Chem. Eur.
J. 2002, 8, 4185. (f) Kobayashi, S.; Ueno, M.; Saito, S.; Mizuki, Y.; Ishitani,
H.; Yamashita, Y. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5476. (g) Xue,
S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2001, 40, 2271.
(h) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566. (i) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe,
K. Synlett 2006, 141. (j) Jagtap, S. B.; Tsogoeva, S. B. Chem. Commun.
2006, 4747.
(6) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409. (b) Josephsohn, N. S.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734.
(7) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997,
119, 7153. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc.
1998, 120, 431.
(8) For other reports of enantioselective allylation of ketimines and related
derivatives, see ref 1b and: (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.
6120
Org. Lett., Vol. 8, No. 26, 2006

Scheme 3
Scheme 4
to the metathesis reaction were met with complete failure.
The one-pot procedure described here is therefore not only
convenient but also necessary at least in this case. It is further
noteworthy that this methodology proceeds without recourse
to any protecting groups and produces these nitrogen-
containing heterocycles in their free NH state.
We have described how the phenol functionality may be
employed in different contexts for the highly enantioselective
allylation and crotylation of a variety of aldimines and
ketimines using our previously reported family of allylsilane
reagents. The reactions may reasonably lay claim to high
degree of practicality and allow ready access not only to a
range of homoallylamine derivatives but also to tertiary
carbinamine-containing heterocycles such as 19 and 20.
Further exploitation of these allylsilane reagents and of the
mechanistic paradigm described herein for access to more
unusual structures may be anticipated.
was isolated in excellent yield (93%) and with superior
enantioselectivity (98% ee). Ketimine 16 performed similarly,
providing access to amine 17 in 90% yield and 96% ee.
Ketimine 14 could also be successfully crotylated with trans-
crotylsilane 5 to provide amine 18 as a single diastereomer
in 62% yield and 95% ee, attesting to the robustness of the
silane reagents to prolonged and significant heating.
That there is some flexibility in the choice of imine
N-substituents allows the possibility that they might be
chosen so as to be useful for the synthesis of a given target,
rather than being viewed as a group to be removed after the
allylation reaction. For example, simply by adding the
second-generation Grubbs catalyst9 to the allylation reactions
of ketimines 14 and 16 prior to workup, the efficient one-
pot synthesis of piperidine and azepine (ring systems of
potential medicinal relevance) derivatives 19 and 20 could
be readily achieved in excellent overall yield and with
superior enantioselectivity (Scheme 4). It is important to note
that in the case of 20, attempts to subject isolated amine 17
Acknowledgment. This work was supported by a grant
from the National Science Foundation (CHE-04-53853) and
a Focused Giving Award from Johnson & Johnson.
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543.
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