Stereoselective cross-coupling between allylic alcohols and aldimines

Article abstract of DOI:10.1021/ol901006c

A cross-coupling reaction between an allylic alcohol and an imine is described for stereoselective allylation of aromatic and aliphatic imines. This method provides operationally simple, enantioselective access to functionalized homoallylic amines. Partic

Full text of DOI:10.1021/ol901006c

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3132-3134
Stereoselective Cross-Coupling between
Allylic Alcohols and Aldimines
Ivan L. Lysenko, Hyung Goo Lee, and Jin Kun Cha*
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVenue,
Detroit, Michigan 48202
jcha@chem.wayne.edu
Received May 8, 2009
ABSTRACT
A cross-coupling reaction between an allylic alcohol and an imine is described for stereoselective allylation of aromatic and aliphatic imines.
This method provides operationally simple, enantioselective access to functionalized homoallylic amines. Particularly noteworthy is direct use
of a functionalized allylic alcohol as an allylating reagent without prederivatization, which obviates the use of preformed organometallic reagents
or activated imine derivatives.
Addition of organometallic reagents to imines provides a
useful method for the stereoselective preparation of amines.1
An enantioselective allylation/crotylation reaction of aldi-
mines is a valuable tool in organic synthesis, as homoallylic
amines are useful building blocks in natural product synthesis
and medicinal chemistry.2,3 Imines are less electrophilic than
carbonyl groups, and addition of organometallic reagents to
imines can be complicated by accompanying enolization,
reduction, or dimerization.4 This reactivity issue requires a
judicious choice of an allylic metal reagent and/or activation
of an imine by a suitable Lewis acid. Additionally, there is
a paucity of convenient methods for generating functionalized
allylic nucleophiles despite impressive advances in this field.5
Direct use of an allylic alcohol as an allylating reagent is
particularly attractive, as it obviates prederivatization of an
allylic alcohol substrate. We report herein regio- and
stereoselective cross-coupling between an allylic alcohol and
an imine by the action of the Kulinkovich reagent.
A cross-coupling reaction between an allylic alcohol and
a vinylsilane (or a styrene) was recently developed by use
of the Kulinkovich reagent, in which directing effects of an
allylic alkoxide were exploited via a temporary linker.6,7 An
imine was already shown by the Sato group to react with an
alkyne-Kulinkovich reagent complex to afford an allylic
amine.8 Thus, we reasoned that the use of an aldimine in
place of a vinylsilane could provide a new approach to regio-
(1) For reviews: (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
(b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (c)
Alvaro, G.; Savoia, D. Synlett 2002, 651. (d) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541.
(2) For reviews: (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(b) Ding, H.; Friestad, G. K. Synthesis 2005, 2815. (c) Kargbo, R. B.; Cook,
G. R. Curr. Org. Chem. 2007, 11, 1287. (d) Lu, Z.; Ma, S. Angew. Chem.,
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(3) For selected recent examples: (a) Schaus, J. V.; Jain, N. F.; Panek,
J. S. Tetrahedron 2000, 56, 10263. (b) Ferraris, D.; Young, B.; Cox, C.;
Dudding, T.; Drury, W. J.; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am.
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P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596. (e) Huber,
J. D.; Leighton, J. L. J. Am. Chem. Soc. 2007, 129, 14552. (f) Huber, J. D.;
Perl, N. R.; Leighton, J. L. Angew. Chem., Int. Ed. 2008, 47, 3037. (g)
Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125,
14133. (h) Shimizu, M.; Kimura, M.; Watanabe, T.; Tamaru, Y. Org. Lett.
2005, 7, 637. (i) Ramachandran, P. V.; Burghardt, T. E.; Bland-Berry, L.
J. Org. Chem. 2005, 70, 7911. (j) Tan, K. L.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2007, 46, 1315. (k) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687. (l) Kargbo,
R.; Takahashi, Y.; Bhor, S.; Cook, G. R.; Lloyd-Jones, G. C.; Shepperson,
I. R. J. Am. Chem. Soc. 2007, 129, 3846. (m) Lou, S.; Moquist, P. N.;
Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. (n) Fujita, M.; Nagano,
T.; Schneider, U.; Hamada, T.; Ogawa, C.; Kobayashi, S. J. Am. Chem.
(4) Cf. (a) Stock, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178.
(b) Bloch, R. Chem. ReV. 1998, 98, 1407.
(5) For recent developments in transition metal-catalyzed reductive
coupling of imines and carbonyl compounds see: (a) Skucas, E.; Ngai, M.-
Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394. (b)
Montgomery, J. Angew. Chem., Int. Ed 2004, 43, 3890 and references
therein.
(6) Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J. Am. Chem. Soc.
2008, 130, 15997
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(7) Belardi, J. K.; Micalizio, G. C. J. Am. Chem. Soc. 2008, 130, 16870.
10.1021/ol901006c CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

and stereoselectively preparing homoallylic amines. Our
study began with the coupling reaction between 2-cyclo-
hexen-1-ol and several imines 1a-h (Table 1). Thus,
was obtained (entry 7). This result could be attributed to
steric effects.
Coupling of acyclic Z-allylic alcohols 3 and 4 with imines
1a-c,e was next examined (Table 2). As was the case with
cross-coupling with vinylsilanes or styrenes,6 high levels of
diastereocontrol was achieved to provide E-homoallylic
amines 5a-c,e and 6a-c,e. Full compatibility with the
presence of an allylic ether is clearly seen with allylic alcohol
4 (entries 5-8).
Table 1. Cross-Coupling between 2-Cyclohexen-1-ol and Imines
Complete chirality transfer was established by the use
of enantiopure allylic alcohols 7-11 (Table 3). Coupling
entry imine
R1
Ph
R2
product yield
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
90%
75%
78%
69%
76%
55%
40%
60%
Table 3. Enantioselective Synthesis of Homoallylic Amines
p-MeOC6H4
Bn
CH2-o-MeOC6H4
n-Bu
Bn
Bn
2-furyl
i-Pr
n-C7H15 Bn
1g
1h
2g
2h
coupling of 2-cyclohexen-1-ol and 1a under previously
reported conditions afforded homoallylic amine 2a in 90%
yield in >20:1 diastereoselectivity (entry 1). A broad scope
with respect to imines (i.e., different R1 and R2) can be seen
from entries 1-8: not only aromatic, but also aliphatic imines
are amenable to cross-coupling. The resulting homoallylic
amines 2a-h were obtained as virtually single isomers. In
the case of imine 1g having an isopropyl branch, a 4:1
mixture of 2g and the byproduct (structure not shown) from
addition of the cyclopentyl Grignard reagent to the imine
Table 2. Cross-Coupling between (Z)-Allylic Alcohols and
Imines
of (S)-7 with 1a and 1c proceeded diastereo- and enan-
tioselectively to afford amines 12 and 13 in 60 and 68%
yield, respectively (entries 1 and 2). Similarly, 14 and 15
were obtained from 8 and 9, respectively (entries 3 and
4). Comparative evaluation of E-allylic alcohols 10 and
11 was undertaken next for additional stereochemical
studies. As expected by analogy to ethylation and cross-
coupling with vinylsilanes,6 these E-allylic alcohol sub-
strates produced a mixture of two diastereomers: 10 gave
Org. Lett., Vol. 11, No. 14, 2009
3133

The observed stereochemical outcome can be rational-
ized by formation of a temporary alkoxide tether and
subsequent syn addition/syn ꢀ-elimination for the 1,3-
transpositive cross-coupling reactions of acyclic and cyclic
allylic alcohols. High diastereoselectivity displayed by
Z-allylic alcohols is in accord with the involvement of
conformer A to minimize A(1,3) strain (Scheme 1). The
lack of selectivity for E-allylic alcohols and the attendant
formation of both E- and Z-alkenes suggest the coinvolve-
ment of both conformers B and C.6
Scheme 1
In conclusion, we have developed convenient cross-
coupling reactions between allylic alcohols and imines for
stereoselective allylation of aromatic and aliphatic imines.
Particularly noteworthy is direct use of a functionalized
allylic alcohol as an allylating reagent without prederiva-
tization. This convenient method obviates the use of
preformed organometallic reagents or activated imine
derivatives.10
Acknowledgment. We thank NSF (CHE-0615604) and
NIH (GM35956) for generous financial support.
Supporting Information Available: Experimental details
and spectroscopic data for key intermediates. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901006C
a 1.3:1 separable mixture of 16 and 15 in 71% yield (entry
5), whereas a 1.2:1 mixture of 17 and 14 was obtained
from 11 (entry 6). The unequivocal determination of the
absolute and relative stereochemistry of the homoallylic
amine products 12-17 was possible by these correlation
studies, as well as an independent synthesis of 13.9
(9) (a) Amine 13 was independently prepared by the Claisen-Ireland
rearrangement of the phenyl acetate of (S)-7, followed by the Curtius
rearrangement, hydrolysis, and reductive amination with benzaldehyde. (b)
The relative stereochemistry was also established by measurement of the
key vicinal coupling constant of a tetrahydropyridine derived from 5c via
allylation and ring-closing metathesis. (c) See Supporting Information for
these stereochemical studies.
(10) During the course of manuscript preparation, a related study was
reported by Professor Micalizio: Takahashi, M.; McLaughlin, M.; Micalizio,
G. C. Angew. Chem., Int. Ed 2009, 48, 3648.
(8) Gao, Y.; Harada, K.; Sato, F. Tetrahedron Lett. 1995, 36, 5913. See
also Gao, Y.; Sato, F. J. Org. Chem. 1995, 60, 8136.
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