Scheme 1 Trapping/ring opening reactions of enolate 5.
are tolerated and addition products 4c and 4d are formed with
similarly good results (Table 3, entries 3 and 4). Dimethoxy-
coumarins 3e and 3f could also be converted to the corres-
ponding conjugate addition products, albeit with lower yield
and enantioselectivity (Table 3, entries 5 and 6). This marks a
limitation of this transformation. Two electron-donating
groups on the aromatic ring result in a lower reactivity to
conjugate addition reactions compared to coumarin itself. The
lower enantioselectivity of 4f compared to 4e could be
explained by the fact that the methoxy-substituent in the
5-position of 3f interferes with the Cu-catalyst. The strongly
electron-withdrawing nitro-group (Table 3, entry 7) is not
tolerated due to fast decomposition of the starting material
under the reaction conditions.
coumarins. The corresponding chiral products are available
with excellent enantioselectivities. Furthermore, we have
demonstrated that the corresponding enolate is a highly
versatile starting point for the synthesis of a variety of chiral
products such as esters and amides which were previously
unavailable via direct conjugate addition to protocols. The
final example marks the first formal conjugate addition to
amides. The investigation of the scope of this interesting
transformation is currently underway.
Notes and references
1 T. Jerphagnon, M. G. Pizzuti, A. J. Minnaard and B. L. Feringa,
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2 S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard and
B. L. Feringa, Chem. Rev., 2008, 108, 2824–2852.
One of the major advantages of the conjugate addition to
coumarins was discovered during the course of this study: the
intermediate chiral magnesium enolate 5 is a highly versatile
chiral intermediate and can be converted in situ to a variety of
important chiral products (Scheme 1).
3 A. Alexakis, J. E. Backvall, N. Krause, O. Pamies and M. Die
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guez,
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4 F. Lo
B. L. Feringa, Angew. Chem., Int. Ed., 2005, 44, 2752–2756.
5 R. D. Mazery, M. Pullez, F. Lopez, S. R. Harutyunyan,
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pez, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard and
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A. J. Minnaard and B. L. Feringa, J. Am. Chem. Soc., 2005, 127,
9966–9967.
6 F. Lopez, S. R. Harutyunyan, A. J. Minnaard and B. L. Feringa,
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J. Am. Chem. Soc., 2004, 126, 12784–12785.
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11 H. Kim and J. Yun, Adv. Synth. Catal., 2010, 352, 1881–1885.
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16 Trace amounts of 1,2-addition products were observed.
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The high reactivity of intermediate 5 can be exploited in
subsequent transformations with both nucleophiles to invoke
a ring-opening as well as electrophiles to trap the enolate.
When enolate 5 was quenched with ethanol at À72 1C and the
solution allowed to warm to room temperature, the resulting
chiral ester 6 was isolated in a very good yield and 95% ee. It is
important to note that o-phenol esters were so far not accessible
via the known conjugate addition methodology.1–6 In a similar
fashion, amide 7 could be obtained with a good yield. This
result marks the first formal catalytic asymmetric conjugate
addition to amides, a reaction pathway that was previously
elusive. It should be emphasised that catalytic asymmetric
conjugate addition to a,b-unsaturated amides is not achieved
due to the poor electron-withdrawing ability of the amide
group.2
It is known in the literature that the enolates of conjugate
addition reactions can be trapped with
a variety of
electrophiles.14,20–22 Accordingly, enolate 5 could be reacted with
electrophiles such as benzaldehyde to give the corresponding
aldol product with three contiguous stereocenters in good yields.
As expected, the trans-disubstituted product is exclusively
formed, as only two diastereomers could be detected on the basis
of 1H NMR experiments, which we attribute to incomplete
stereocontrol at the exocyclic stereocenter.
19 The enantioselectivity was unaffected up to a temperature of
À65 1C.
20 L. A. Arnold, R. Naasz, A. J. Minnaard and B. L. Feringa, J. Am.
Chem. Soc., 2001, 123, 5841–5842.
21 G. P. Howell, S. P. Fletcher, K. Geurts, B. ter Horst and
B. L. Feringa, J. Am. Chem. Soc., 2006, 128, 14977–14985.
22 X. Rathgeb, S. March and A. Alexakis, J. Org. Chem., 2006, 71,
5737–5742.
To conclude, we have developed a new, highly selective
Cu-catalysed conjugate addition of Grignard reagents to
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2679–2681 2681