Allylsilane-vinylarene cross-metathesis enables a powerful approach to enantioselective imine allylation

Article abstract of DOI:10.1002/anie.200705621

Cinnamylation-flavored synthesis: Cross-metathesis (CM) reactions between an allylsilane andvinylarenes enable the rapidgeneration of various cinnamylsilanes, which may be usedin situ for the highly enantioselective, and diastereodivergent, cinnamylation of imines (see example in scheme). Under this new, simple, and efficient protocol, the potential of imine cinnamylation to produce stereochemically andfunctionally complex products has been more fully realized. Ar = thienyl, Ar′ = 2-hydroxyphenyl. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200705621

Angewandte
Chemie
DOI: 10.1002/anie.200705621
Asymmetric Synthesis
Allylsilane–Vinylarene Cross-Metathesis Enables a Powerful
Approach to Enantioselective Imine Allylation**
John D. Huber, Nicholas R. Perl, and James L. Leighton*
The development of methods for the asymmetric addition of
allyl metal reagents to imines has received a significant
amount of attention in recent years,[1] as the homoallylic
amine products are useful in natural products synthesis and
medicinal chemistry. Importantly, a second stereocenter may
be established in the allylic position of the homoallyl amine
products by substitution at the terminal carbon atom of the
allyl fragment. In practice, however, the majority of published
work in this regard,[1] including our own,[2] has described only
the incorporation of simple methyl groups, and many of these
methods allow access to only one of the two possible
diastereomeric products. Furthermore, the methods that do
allow access to both diastereomers uniformly require the
synthesis of both the trans- and the cis-substituted allyl
fragments. When one seeks to go beyond methyl substitution
and toward the use of aryl-substituted allyl fragments, the
limitations of this paradigm becomes starkly apparent: each
different aryl fragment to be incorporated, and each diaste-
reomeric product would require a separate, multistep, and
otherwise nontrivial synthesis of the requisite trans- or cis-
cinnamyl metal reagent (Scheme 1A). If one were to design
the “ideal” way to carry out imine cinnamylation, we contend
it would resemble the process outlined in Scheme 1B,
wherein the parent allyl-metal reagent is combined with
vinylarenes in a cross-metathesis (CM) reaction,[3] and the
resulting trans-cinnamyl metal reagent may be used in situ for
the synthesis of either diastereomer, based only upon the
choice of imine. Such an approach would dramatically
increase the power of the method to assemble stereochem-
ically and functionally complex carbinamine products from
extraordinarily simple starting materials. As a step towards
testing this design proposal, we have reported that cinnamyl-
silane 1 is effective for highly enantioselective imine cinna-
mylation reactions,[4] and further reported that either product
diastereomer may be accessed from the same trans-cinna-
mylsilane 1 based upon a subtle change to the structure of the
Scheme 1. A) Current approach requires the multistep synthesis ofa
separate trans- or cis-cinnamyl metal reagent for every different
(hetero)aryl group to be incorporated and for each diastereomer. B) A
new paradigm for imine cinnamylation with vastly improved efficiency
and flexibility.
imine, resulting in a “diastereochemical switch” (Scheme 2).[5]
Herein, we describe the use of cross-metathesis to facilitate
the incorporation of a diverse collection of arenes and
heteroarenes at the allylic position of the homoallylamine
products, as well as preliminary examples of how the
methodology may be employed for the rapid construction of
complex heterocyclic structures.
The investigation began with examination of the CM
reaction between allylsilane 2[6,7] and styrene (Scheme 3).
1
This process could be monitored by H NMR spectroscopy,
[*] J. D. Huber, N. R. Perl, Prof. Dr. J. L. Leighton
Department ofChemistry
Columbia University
New York, NY 10027 (USA)
Fax: (+1)212-932-1289
E-mail: leighton@chem.columbia.edu
[**] This work was supported by a grant from the NSF (CHE-04-53853)
and a Focused Funding Award from Johnson & Johnson. We thank
Merck Research Laboratories and Amgen for unrestricted support.
J.D.H. was the recipient ofan NDSEG Fellowship rfom the
Department of Defense, and N.R.P. was supported by a fellowship
provided by Boehringer-Ingelheim.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Enantioselective imine cinnamylation with a “diastereo-
chemical switch.”
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Scheme 3. Successful and selective cross-metathesis reactions with
styrene and allylchlorosilane 2. Ar=2-hydroxyphenyl, DCE=1,2-
dichloroethane.
and it was observed that the second-generation Grubbs
catalyst[8] was effective for this reaction and that the trans
isomer (1) was produced with excellent selectivity (> 20:1).
Allylsilane 2 did dimerize during the reaction, but over time,
in the presence of styrene, the dimer was converted into
cinnamylsilane 1, albeit accompanied by some decomposi-
tion. The use of an excess of styrene (5 equiv) thus became
standard procedure, and the optimized reaction conditions
(2.6 mol% catalyst in refluxing DCE) were applied to the
reaction with imines 3 and 4. Consequently, amines 5 and 6
were isolated in 64% and 68% yield, respectively, and the
diastereoselectivities were identical to those of the reactions
described in Scheme 2 and enantioselectivities were margin-
ally lower.
Scheme 4. Tandem cross-metathesis imine cinnamylation. Standard
reaction conditions: 2.6 mol% Grubbs II cat., DCE, CHCl3 or CH2Cl2,
reflux. [a] The imine derived from p-bromobenzaldehyde and 2-amino-
phenol was employed in this reaction. Ar’=2-hydroxyphenyl.
An examination of the scope of the process, with respect
to the vinylarene, was carried out and the results (5–15) are
compiled in Scheme 4. A selection of substituted styrenes and
vinylheteroarenes was employed and all participated in the
CM/cinnamylation process successfully. Although the focus of
this study is cinnamylation, we have demonstrated in one
example that vinylalkanes may be employed (vinylcyclohex-
ane to give 12) with good efficiency and excellent diastereo-
and enantioselectivity. Finally, although the yields for these
reactions are moderate (54–68%), this is offset by the concise
nature of the reaction; a traditional approach would require
independent multistep syntheses of seven different cinnamyl-
silane reagents.
The products described in Scheme 4 may be rapidly
transformed into potentially useful heterocyclic structures.
For example, hydroformylation of 5 with xantphos[9] as the
ligand, followed by a reductive workup provided piperidine
16 in 86% yield (Scheme 5). Two additional examples of this
process are shown, and it is a testament to the flexibility of the
methodology that piperidines 16, 17, and 18 may be assem-
bled in two steps from allylsilane 2, the vinylarene, and imine
3. Armed only with a diverse supply of vinylarenes and
imines, one may rapidly install various arenes onto these
piperidine structures, a feature that may facilitate application
of methods such as this in medicinal chemistry. Finally, we
have demonstrated that our method for the removal of the 2-
Scheme 5. One-pot conversion ofthe cinnamylation products into an
important hetrocyclic motif(piperidines), with the lfexibility to rapidly
incorporate, in principle, any arene or heteroarene at the 2- and 3-
positions. Ar=2-hydroxyphenyl, xantphos=9,9-dimethyl-4,5-bis(diphe-
nylphosphino)xanthene.
hydroxybenzyl group[5] is applicable in this context. Thus,
transfer hydrogenation of 16 gave piperidine 19 in 72% yield.
We have recently described how the aminoindanol-
derived allylsilane 20 may be employed in the enantioselec-
tive allylation of 2-iminoimidazoles,[2c] and it seemed desir-
able to demonstrate that the CM process is also effective in
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Angewandte
Chemie
this context. Thus, CM with 20 and styrene catalyzed by the
Hoveyda–Grubbs II catalyst (21),[10,11] followed by addition of
imine 22 led to 23 in 62% yield as a single diastereomer and
92% ee (Scheme 6). When the process was repeated with 2-
chloro-3-vinylpyridine, 24 was isolated in 58% yield as a 12:1
mixture of diastereomers and 87% ee. While ring-closing
method and on other ways of exploiting the products of the
methodology.
Received: December 8, 2007
Published online: March 12, 2008
Keywords: allylsilanes · asymmetric synthesis · cinnamylation ·
.
cross-coupling · homoallylic amines
[1] For a recent review, see: a) H. Ding, G. K. Friestad, Synthesis
2005, 2815; for reports since publication of this review, see:
b) D. J. Lipomi, J. S. Panek, Org. Lett. 2005, 7, 4701; c) P. V.
Ramachandran, T. E. Burghardt, Chem. Eur. J. 2005, 11, 4387;
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Shibasaki, J. Am. Chem. Soc. 2006, 128, 7687; e) E. Canales, E.
Hernandez, J. A. Soderquist, J. Am. Chem. Soc. 2006, 128, 8712;
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g) K. L. Tan, E. N. Jacobsen, Angew. Chem. 2007, 119, 1337;
Angew. Chem. Int. Ed. 2007, 46, 1315; h) R. Kargbo, Y.
Takahashi, S. Bhor, G. R. Cook, G. C. Lloyd-Jones, I. R. Shep-
person, J. Am. Chem. Soc. 2007, 129, 3846; i) S. Lou, P. N.
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[2] a) R. Berger, P. M. A. Rabbat, J. L. Leighton, J. Am. Chem. Soc.
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Org. Lett. 2006, 8, 6119; c) N. R. Perl, J. L. Leighton, Org. Lett.
2007, 9, 3699.
[3] For cross-metathesis reactions between allylboranes and various
alkenes in the context of aldehyde allylboration reactions, see:
a) S. D. Goldberg, R. H. Grubbs, Angew. Chem. 2002, 114, 835; .
Chem. Int. Ed. 2002, 41, 807; b) Y. Yamamoto, M. Takahashi, N.
Miyaura, Synlett 2002, 128.
[4] For other reports of enantioselective imine cinnamylation
reactions, see: a) Y. Gao, F. Sato, J. Org. Chem. 1995, 60, 8136;
b) M. Nakamura, A. Hirai, E. Nakamura, J. Am. Chem. Soc.
1996, 118, 8489; c) S. Hanessian, R.-Y. Yang, Tetrahedron Lett.
1996, 37, 5273; d) R. Yanada, A. Kaieda, Y. Takemoto, J. Org.
Chem. 2001, 66, 7516; e) C.-L. K. Lee, H. Y. Ling, T.-P. Loh, J.
Org. Chem. 2004, 69, 7787.
[5] J. D. Huber, J. L. Leighton, J. Am. Chem. Soc. 2007, 129, 14552.
[6] J. W. A. Kinnaird, P. Y. Ng, K. Kubota, X. Wang, J. L. Leighton,
J. Am. Chem. Soc. 2002, 124, 7920.
[7] Allylsilane 2 has been prepared on a multikilogram scale by
Gelest, Inc., Morrisville, PA, USA.
[8] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953.
[9] M. Kranenburg, Y. E. M. van der Burgt, P. C. J. Kamer,
P. W. N. M. van Leeuwen, K. Goubitz, J. Fraanje, Organometal-
lics 1995, 14, 3081.
[10] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
Chem. Soc. 2000, 122, 8168.
Scheme 6. Tandem cross-metathesis imidazole-directed cinnamylation,
and one-pot synthesis ofcomplex heterocyclic structures without the
use ofprotecting groups.
metathesis (RCM) was unsuccessful with 23, it proved
possible to develop a triple tandem process, taking advantage
of the in situ silylation of the imidazole to allow the RCM
process to proceed. In this fashion, 26 could be isolated in
48% yield and 89% ee. The one-pot synthesis of 26 from 20,
styrene, and 25 without the use of protecting groups, further
illustrates the practical utility of the CM/cinnamylation
methodology.
A new and powerful approach to imine cinnamylation has
been established. Cross-metathesis with allylsilane 2 and a
variety of vinylarenes allows the rapid generation of a variety
of stereochemically and functionally complex homoallylic
amines. In addition, methods to exploit this chemistry for the
synthesis of heterocyclic structures have been developed.
Future efforts will focus on expanding the scope of the
[11] Use of the Hoveyda–Grubbs catalyst for this reaction gave
slightly higher yields. For the most part, however, the catalysts
may be used interchangeably.
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