Efficient Cu-catalyzed asymmetric conjugate additions of alkylzinc reagents to aromatic and aliphatic acyclic nitroalkenes

Article abstract of DOI:10.1021/ol0488338

An efficient and highly enantioselective (up to 95% ee) Cu-catalyzed method for asymmetric conjugate addition (ACA) of alkylzinc reagents to acyclic disubstituted nitroalkenes is presented. Reactions are typically effected at ambient temperature in the presence of 2 mol % chiral dipeptide phosphine and 1 mol % (CuOTf)₂·C₆H₆. Nitroalkenes bearing aromatic as well as aliphatic substituents readily undergo asymmetric additions.

Full text of DOI:10.1021/ol0488338

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2829-2832
Efficient Cu-Catalyzed Asymmetric
Conjugate Additions of Alkylzinc
Reagents to Aromatic and Aliphatic
Acyclic Nitroalkenes
Dawn M. Mampreian and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
amir.hoVeyda@bc.edu
Received June 18, 2004
ABSTRACT
An efficient and highly enantioselective (up to 95% ee) Cu-catalyzed method for asymmetric conjugate addition (ACA) of alkylzinc reagents
to acyclic disubstituted nitroalkenes is presented. Reactions are typically effected at ambient temperature in the presence of 2 mol % chiral
dipeptide phosphine and 1 mol % (CuOTf)2‚C H . Nitroalkenes bearing aromatic as well as aliphatic substituents readily undergo asymmetric
6
6
additions.
Optically enriched molecules that contain a nitro group are
of considerable significance in synthesis, as they may be
converted to a variety of useful N-containing organic
molecules.1 The development of catalytic asymmetric meth-
ods that lead to the formation of optically active nitroalkanes
has thus been the focus of research in a number of
laboratories.2 In this context, we have reported a highly
enantioselective method for Cu-catalyzed conjugate addition
(ACA) of alkylzinc reagents to cyclic nitroalkenes.3,4
Another important but underdeveloped class of transfor-
mations is the catalytic ACA of alkylmetals to acyclic
nitroalkenes (eq 1). Several disclosures have focused on this
(1) (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877-1894. (b) Ono, N. In The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001.
(2) For related reviews, see: (a) Krause, N.; Hoffmann-Roder, A. Synlett
2001, 171-196. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221-3236. (c) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In
Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
2002; pp 224-258. For representative recent reports, see: (d) Sewald, N.;
Wendisch, V. Tetrahedron: Asymmetry 1998, 9, 1341-1344. (e) Rimkus,
A.; Sewald, N. Org. Lett. 2003, 5, 79-80. (f) Versleijen, J. P. G.; van
Leusen, A. M.; Feringa, B. L. Tetrahedron Lett. 1999, 40, 5803-5806. (g)
Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2002, 58, 5773-
5778. (h) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2003, 125, 3700-3701. (i) Ongeri, S.; Piarulli, U.; Jackson, R. F. W.;
Gennari, C. Eur. J. Org. Chem. 2001, 803-807. (j) Alexakis, A.; Benhaim,
C. Org. Lett. 2000, 2, 2579-2581. (k) Alexakis, A.; Benhaim, C.; Rosset,
S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262-5263. (l) Eilitz, U.;
Lessmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry
2003, 14, 189-191.
particular problem, and in limited cases, high asymmetric
induction has been observed. One noteworthy example
(3) Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124,
8192-8193. Also see ref 2k for related examples.
(4) For Rh-catalyzed conjugate additions of arylboronic acids to nitro-
alkenes, see: (a) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc.
2000, 122, 10716-10717. (b) Hayashi, T. Synlett 2001, 171-196.
10.1021/ol0488338 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/02/2004

involves enantioselective Cu-catalyzed ACA to acyclic
nitroalkenes that bear an activating R-acetal group (R )
CH(OR)2 in eq 1).2h The same class of chiral catalysts
(derived from a Cu salt and a phosphoramidite) has only
been examined with the more reactive Et2Zn and usually
delivers low selectivities in reactions of aryl- or alkyl-
substituted acyclic nitroalkenes.5 Efficient Cu-catalyzed
asymmetric hydride additions to trisubstituted acyclic nitro-
alkenes have been reported;6 however, stereoisomerically
pure trisubstituted nitroolefin substrates must be prepared,
and enantioselectivities for reactions of aliphatic substrates
can be moderate (66-90% ee).
Table 1. Cu-Catalyzed ACA with Various Chiral Ligands
Herein, we report a general method for efficient and highly
enantioselective synthesis of â,â′-arylalkyl and â,â′-dialkyl
nitroalkanes by Cu-catalyzed ACA of alkylzincs to acyclic
nitroalkenes, promoted by a readily available dipeptide
phosphine (9); catalytic alkylations are typically carried out
at room temperature (low temperatures required in some
cases) in the presence of 1-4 mol % catalyst.7 The requisite
substrates are easily prepared (>98% trans) in two steps from
commercially available nitromethane and various aromatic
and aliphatic aldehydes (by the Henry reaction in ∼60%
overall yield). The aliphatic and aromatic nitroalkanes can
be readily converted to various optically enriched amines
that can be used in the enantioselective synthesis of biologi-
cally important compounds. Moreover, we disclose the
unexpected observation that a subtle modification of the
chiral ligand structure leads to significant improvement in
asymmetric induction. Use of the chiral ligand employed in
related additions to cyclic nitroalkenes3 affords products in
significantly lower enantioselectivities.
Our studies commenced with screening8 of different amino
acid based ligands in order to examine their ability to
promote ACA of Et2Zn to aryl nitroalkene 1a. As illustrated
in entry 1 of Table 1, we established that dipeptide phosphine
3, the ligand used to promote additions to cyclic nitroalkenes,
initiates the formation of the desired product 2a, but only in
82% ee. To understand the origin of enantioselectivity better
and hopefully obtain improved levels of asymmetric induc-
tion, we set out to alter the structure of the chiral ligand in
a systematic fashion. Selected results of our investigation
are summarized in Table 1.
a Determined by chiral GLC (betadex column).
1). Comparison of the data in entries 1 and 2 indicate that
chirality at the AA1 site (amino acid that forms the Schiff
base through its amine site), although not required to ensure
high conversion, is necessary for achieving high asymmetric
induction. As illustrated by the catalytic ACA with phosphine
5, chirality at the AA2 site has a minimal influence on
enantioselectivity (entry 1 vs 3, Table 1). We also included
in our screening studies dipeptide phosphines bearing dif-
ferent carboxyl termini. Accordingly, as depicted in entries
5 and 6 of Table 1, we discovered that, whereas the derived
methyl ester 7 leads to efficient but less enantioselective
additions (50% vs 82% ee with 3), dimethylamide 8 provides
significantly enhanced asymmetric induction (93% ee).
The identity of the optimal amide terminus was established
by examination of the ability of various chiral phosphines
in promoting the synthesis of 2a. Representative results from
these studies are summarized in Table 2. These findings
indicate that chiral phosphine ligand 9 bearing a diethylamide
terminus provides the highest level of enantioselectivity.9
Thus, as indicated in entry 1 of Table 3, in the presence of
2 mol % 9, 1 mol % (CuOTf)2‚C6H6, and 3 equiv of Et2Zn,
The data illustrated in entries 2-5 of Table 1 suggest that
the presence of a second amino acid moiety (AA2) is critical
to efficiency and enantioselectivity (entry 1 vs 4, in Table
(5) In two instances, with Et2Zn as the alkylating agent, enantioselec-
tivities >80% ee have been reported (R ) Cy, 96% ee and R ) Ph, 84%
ee). See ref 2g,h.
(6) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42,
4793-4795.
(7) For other Cu-catalyzed ACA of alkylzincs to unsaturated carbonyls
promoted by related amino acid-based chiral phosphines, see: (a) Degrado,
S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755-
756. (b) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 779-781. (c) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J.
Am. Chem. Soc. 2002, 124, 13362-13363. (d) Hird, A. W.; Hoveyda, A.
H. Angew. Chem., Int. Ed. 2003, 42, 1276-1279. (e) Cesati, R. R., III; de
Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 96-101.
(8) For screening strategies and significant attributes of the amino acid
based ligands, see: Hoveyda, A. H. In Handbook of Combinatorial
Chemistry; Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH:
Weinheim, 2002; pp 991-1016.
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Org. Lett., Vol. 6, No. 16, 2004

nitroalkanes in high optical purity. Other important aspects
regarding the data presented in Table 3 merit discussion: (i)
The positive effect of the dialkylamide terminus is not limited
to the reaction shown in entry 1. For example, when ligand
3 is used to promote the Cu-catalyzed ACA, additions in
entries 4, 8, and 12 in Table 3 afford the desired products in
only 78%, 70%, and 77% ee, respectively. (ii) Alkylzinc
reagents other than Et2Zn can be readily employed. Unlike
some other C-C bond forming reactions involving this class
of amino acid based ligands,10 even with the less reactive
Me2Zn, reactions readily proceed to >98% conversion (24
h) in the presence of 2 mol % catalyst without the need for
a larger excess of the alkylmetal. (iii) Regardless of the
substitution pattern of the aromatic substituent (e.g., the
sterically demanding 1e) or whether the substituent is
electron-donating (e.g., entries 5-7) or electron-withdrawing
(e.g., entries 8-12, Table 3), catalytic ACA reactions occur
efficiently and with high enantioselectivity (78-95% ee).
One of the most noteworthy and unique attributes of the
present method is that substrates bearing aliphatic substituents
(entries 1-4, Table 4) can be used in efficient Cu-catalyzed
Table 2. Examination of Chiral Ligands with Different
Termini
catalytic ACA to 1a proceeds to completion (1 h, 22 °C) to
afford 2a in 79% yield and 95% ee.
As the data in Table 3 demonstrate, the Cu-catalyzed ACA
can be used efficiently to synthesize readily a range of chiral
Table 4. Cu-Catalyzed Enantioselective Conjugate Additions
of Alkylzincs to Acyclic Aliphatic Nitroalkenesa
Table 3. Cu-Catalyzed Enantioselective Conjugate Additions
of Alkylzincs to Acyclic Aromatic Nitroalkenesa
a-d See Table 3. e Reaction run at -55 °C (24 h).
ACA reactions with high enantioselectivity (85-95% ee).
Furthermore, as shown by the examples in entries 5 and 6
of Table 4, albeit less effectively than a previous protocol
disclosed by Feringa,2h the present method can also be used
for asymmetric alkylations of acetal substrates.
It should be noted that although all catalytic ACA were
carried out with 3 equiv of alkylzincs, reactions can proceed
efficiently with only 1 equiv of alkylmetal. Moreover,
commercially available (CuOTf)2‚PhMe (Aldrich) can be
used to obtain the desired products in high yield and optical
purity. The example shown in eq 2 is illustrative. Cu-
a Times: 1 h with Et2Zn, 24 h with Me2Zn, 12 h otherwise. b Isolated
yields. c Determined by chiral GLC and HPLC (see SI for details). d 4 mol
% 9 and 2 mol % (CuOTf)2‚C6H6 was used. e Reaction run with 4 mol %
9 and 2 mol % (CuOTf)2‚C6H6 at -30 °C.
catalyzed addition to 1a is carried out in the presence of 1
Org. Lett., Vol. 6, No. 16, 2004
2831

equiv of Me2Zn, 1 mol % commercially available (CuOTf)2‚
PhMe (unpurified), and 1 mol % phosphine 9 to afford 2b
in 70% isolated yield and 90% ee.
illustrated previously,2h nitroacetals 2w and 2x (entries 5 and
6, Table 4) can be converted to the corresponding â2-amino
acids.
As mentioned before, optically enriched nitroalkanes are
precursors to a wide range of N-containing compounds. The
optically enriched amines 14-16 shown in Figure 1 can be
In summary, we present a method for catalytic enantio-
selective alkylation of acyclic nitroalkenes that allows
efficient access to â-alkylnitroalkanes and the derived amines
in high optical purity. Considering the versatility of nitro-
alkanes, the present general protocol should prove to be of
notable utility in asymmetric organic synthesis.
Design and development of new chiral catalysts and
enantioselective methods for olefin alkylation, as well as
applications to the synthesis of biologically active molecules,
are in progress in our laboratories.
Figure 1. Optically enriched amines available through reduction
of Cu-catalyzed ACA products. Conditions: 10% Pd(C), 1 atm H2,
MeOH, 22 °C, 12 h.
Acknowledgment. Financial support was provided by the
NIH (GM-47480). We are grateful to Dr. Courtney A. Cullis
for helpful discussions.
easily synthesized through Pd-catalyzed reductions of Cu-
catalyzed ACA products in high yield. Furthermore, as
Supporting Information Available: Experimental pro-
cedures and spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 4018-4019 and references therein.
(10) For example, see: (a) Reference 7d. (b) Murphy, K. E.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 4690-4691.
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