Catalytic asymmetric conjugate addition of nitroalkanes to cycloalkenones

Article abstract of DOI:10.1021/ol000170g

Nitroalkanes add to cyclic and acyclic enones in an enantioselective manner in the presence of catalytic quantities of L-proline and trans2,5-dimethylpiperazine as excess additive.

Full text of DOI:10.1021/ol000170g

ORGANIC
LETTERS
2000
Vol. 2, No. 19
2975-2978
Catalytic Asymmetric Conjugate
Addition of Nitroalkanes to
Cycloalkenones
Stephen Hanessian* and Vinh Pham
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128,
Succ. Centre-Ville, Montre´al, QC, H3C 3J7, Canada
hanessia@ere.umontreal.ca
Received June 29, 2000
ABSTRACT
Nitroalkanes add to cyclic and acyclic enones in an enantioselective manner in the presence of catalytic quantities of L-proline and trans-
2,5-dimethylpiperazine as excess additive.
The formation of C-C bonds by conjugate addition of
appropriate carbanionic reagents to R,â-unsaturated carbonyl
compounds (Michael reaction) is one of the most useful
methods of remote functionalization in organic synthesis.1
In the case of nitroalkanes, the products of 1,4-addition to
enones are also useful as precursors to aminoalkanes2 through
reduction and to other functionality that can be derived from
the venerable nitro group.3
Efforts toward achieving asymmetric conjugate addition
of nitroalkanes to R,â-unsaturated ketones in the presence
of catalytic quantities of chiral bases have been the subject
of several reports. For example, the reaction of nitroalkanes
with chalcone catalyzed by chiral ammonium salts4 (20%
ee), Ni(II) or Co(II) complexes5 (38% ee), quinine6 (∼60%
ee), azacrown ethers7 (∼90% ee), and La-BINOL complex8
(>95% ee) are known.
To the best of our knowledge, there is one definitive report
describing catalytic asymmetric additions of nitroalkanes to
cyclic enones. Yamaguchi and co-workers9 found that
rubidium prolinate was an effective catalyst in the addition
of 2-nitropropane to cyclohexenone (59% ee) and cyclohep-
tenone (79% ee). An attempt to use metal complexes of
(4) Colonna, S.; Hiemstra, H.; Wynberg, H. J. Chem. Soc., Chem.
Commun. 1978, 238; Colonna, S.; Re, A.; Wynberg, H. J. Chem. Soc.,
Perkin Trans. 1 1981, 547.
(5) Botteghi, C.; Paganelli, S.; Shionato, A.; Boga, C.; Fava, A. J. Mol.
Catal. 1991, 66, 7.
(6) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.; Matsumoto, K. J.
Org. Chem. 1988, 53, 1157. See also ref 4.
(7) Bako´, P.; To¨ke, L. Tetrahedron Lett. 1997, 38, 7259. For related
work, see: Bako´, P.; Nova´k, T.; Luda´nyi, K.; Pete, B.; To¨ke, L.; Keglevich,
G. Tetrahedron: Asymmetry 1999, 10, 2373.
(8) Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki,
M. Tetrahedron Lett. 1998, 39, 7557.
(9) a. Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama,
M. Tetrahedron 1997, 53, 11223. (b) Yamaguchi, M.; Shiraishi, T.; Igarashi,
Y.; Hirama, M. Tetrahedron Lett. 1994, 35, 8233.
(10) Schionato, A.; Paganelli, S.; Botteghi, C.; Chelucci, G. J. Mol. Catal.
1989, 50, 11.
(11) For a review on additives and cocatalysts in asymmetric reactions,
see: Vogel, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 1570.
(1) For recent reviews and monographs, see: (a) Leonard, J. Contemp.
Org. Synth. 1994, 1, 387. (b) Perlmutter, P. Conjugate Addition Reactions
in Organic Synthesis; Pergamon: Oxford, 1992. (c) Rossiter, B. E.; Swingle,
N. M. Chem. ReV. 1992, 92, 771.
(2) For examples of conjugate addition of R-amino alkyl moieties to
enones, see: (a) Dieter, R. K.; Alexander, C. W.; Nice, L. E. Tetrahedron
2000, 56, 2767. (b) Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem.
Soc. 1997, 119, 10537. For R-aminoalkyl carbanions, see: (c) Shawe, T.
T.; Meyers, A. I. J. Org. Chem. 1991, 56, 2751. (d) Beak, P.; Lee, W. K.
J. Org. Chem. 1993, 58, 1109 and previous papers. For diastereoselective
Michael additions of nitromethane to chiral nonracemic enoates, see: (e)
Patrocinio, V. L.; Costa, P. R. R.; Correia, C. R. D. Synthesis 1994, 474.
(3) For reviews, see: Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991,
423. Rosini, G.; Ballini, R. Synthesis 1988, 833.
10.1021/ol000170g CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/19/2000

pyrrolidine derivatives as catalysts in the conjugate addition
of nitromethane to cyclohexenone resulted in a product with
7% ee.10
2-one. Definitive confirmation of absolute or relative ster-
eochemistry was obtained by spectroscopic and X-ray crystal
structural analysis.12
We then extended our studies to the addition of ni-
tromethane, nitroethane, and 1-nitro-4-butene in the presence
of L-proline as catalyst and trans-2,5-dimethylpiperazine as
additive. Our results are shown in Table 2, where the
We report herein on the catalytic asymmetric conjugate
addition of various nitroalkanes to cyclic enones such as
cyclopentenone, cyclohexenone, and cycloheptenone with
hitherto unprecedented enantiomeric excesses. Promising
results were also observed with some acyclic R,â-unsaturated
ketones.
Utilizing L-proline as catalyst in the presence of trans-
2,5-dimethylpiperazine as an additive11 resulted in substan-
tially improved enantioselectivities for the addition of
2-nitropropane, nitrocyclopentane, and nitrocyclohexane to
cyclic enones compared to those of rubidium prolinate as
shown in Table 1. Addition of 2-nitropropane to chalcone
afforded the dextrorotary isomer with 68% ee, compared to
rubidium prolinate (31% ee). Similar results were obtained
in additions to (E)-3-nonen-2-one and (E)-3-phenyl-buten-
Table 2. Conjugate Addition with Nitroalkanes Catalyzed by
L-Proline and trans-2,5-Dimethylpiperazinea-c
Table 1. Conjugate Addition with Nitroalkanes Catalyzed by
L-Proline and trans-2,5-Dimethylpiperazinea-c
enantioselectives are also compared to those of rubidium
prolinate. Thus, with nitromethane in particular, significant
enantioenrichment of the dextrorotatory isomer was observed
in all cases (Table 2). When a 2-substituted nitroalkane was
used, the high stereoselectivity at the â-position of the enone
was maintained. However, the products were mixtures of
diastereomers arising from the nitroalkyl side chain. Nev-
ertheless, the isomers could be separated chromatographically
and analyzed for their respective enantiopurities as shown
in Table 2. In these cases, the ee values of each isomer were
mediocre when using rubidium prolinate as catalyst. The
(12) Experimental conditions and pertinent details provided as Supporting
Information.
(13) For an example of catalytic enantioselective conjugate additions of
R-nitro esters, see: Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L.
Tetrahedron: Asymmetry 1997, 8, 3403.
2976
Org. Lett., Vol. 2, No. 19, 2000

adduct of methyl 3-nitro-1-propionate to cyclohexenone
showed 29% ee after removal of the nitro group by
elimination and catalytic hydrogenation. No asymmetric
induction was observed with methyl 2-nitroacetate.13
It is evident from the above results that the highest levels
of asymmetric induction in the addition of nitroalkanes are
observed with cyclohexenone. Although somewhat lower,
the enantioselectivities with cyclopentenone are encouraging
in view of the conspicuous absence of related examples in
the literature. Indeed, the majority of catalytic conjugate
additions of nitroalkanes have utilized cyclohexenone as a
model cyclic enone and chalcone as an acyclic analogue.
Yamaguchi and co-workers9 had established strict steric
and functional requirements for their amino acid catalyst.
We investigated a variety of substituted and conformationally
biased derivatives of proline and L-azetidine carboxylic acid
in conjunction with various additives for the addition of
2-nitropropane to cyclohexenone.12 Proline proved to be the
best catalyst as observed by Yamaguchi also.9
We then launched a systematic search for a basic additive
in order to find an optimal combination for the addition of
2-nitropropane to cyclohexenone.14 While the relationship
between the structure of the additive and the resulting ee
values are not evident, it appears that the combination of
basicity15 and structure plays a stereodifferentiating role in
the reaction. We also studied the possible effects of matched
and mismatched pairs as in the case of the ephedrines, N,N-
dimethyl-trans-1,2-diaminocyclohexanes, and R-methylben-
zylamines. The results, however, were not particularly
different within each pair. With the exception of quinine and
quinidine, the need for a secondary amine became evident
in comparing N,N-tetramethylethylenediamine (4% ee) with
N,N-dimethylethylenediamine (75% ee) among other related
examples.14
nitroalkanes, shown in Tables 1 and 2. The proportion of
additive seemed to affect the time of the reaction but not
the yield or enantiopurity of the product. Chloroform was
the best solvent, although mixtures of chloroform and toluene
were also acceptable except that reaction was incomplete
after 66 h. The presence of alcohols (for example, CHCl3:
2-PrOH 3:1) diminished the enantioselectively. Rigorous
drying of the solvent resulted in recovery of the enone,
emphasizing the intervention of a hydrolytic step in the
catalytic cycle due to traces of water.
In view of the enhancing effect of the additives, it was
interesting to study the nonlinear effect16 as a mechanistic
probe, particularly since Yamaguchi had observed a linear
relationship of the ee of rubidium prolinate with the ee of
the adduct of diisopropyl malonate to cycloheptenone in
CHCl3 containing 30 mol % of water (59% ee).17
We observed a linear effect for the reaction of 2-nitro-
propane with cyclohexenone catalyzed by rubidium proli-
nate,9 or by L-proline in the presence of piperidine (Figure
1). However, in the presence of trans-2,5-dimethylpiperazine
Consistently high ee values were observed within the
group of piperazines studied, although piperidine itself
proved to be beneficial as well. The choice of trans-2,5-
dimethylpiperazine as the best additive in this study was
based on its performance with the three enones with
(14) Effect of the bases in the Michael addition: metals salts, CsF, 66%
ee; LiOH, 50% ee; RbOH, 59% ee; RbOH and crown 18-6, 9% ee (S);
secondary amines, piperidine, 86% ee; pyrrolidine, 4% ee; morpholine,
85% ee; 2,2,6,6-tetramethylpiperidine, 76% ee; 3,5-dimethylpiperidine, 87%
ee; 2,6-dimethylpiperidine, 72% ee; 4-(N-piperidinyl)piperidine, 80% ee;
2-(2-methylaminoethyl)pyridine, 66% ee; diethylamine (or triethylamine)
and RbOH, 45% ee; (+)- or (-)-methylbenzylamine, 10-17% ee; 1,2-
diamines, (1R,2R)-(-)-diaminocyclohexane, 66% ee; (2R,3R)-(+)-diphen-
ylethylenediamine and CsF, 58% ee; 1,2-dialkylamines, N,N′-dimethyl-
ethylenediamine or N,N′-dimethylpropylenediamine, 70-75% ee; (R,R)- or
(S,S)-N,N′-dimethyl-1,2-diaminocyclohexane, 48-58% ee; tertiary amines,
DABCO, 15% ee; (-)-spartein, 12% ee (S); N,N′-tetramethylethylenedi-
amine, 4% ee (with RbOH, 64% ee); DBU, 18% ee (S); DBN, 19% ee (S);
1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine, 27% ee in CHCl3 (S),
19% ee (R) in benzene; 1,2-amino alcohols, (1R,2S)- or (1S,2R)-ephedrine,
74% ee; N-methylethanolamine, 71% ee; L-prolinol, 16% ee (S); quinine
and quinidine, quinine, 76% ee (in toluene, 63% ee); quinine and RbOH,
77% ee; quinine and alumina, 62% ee; quinidine, 62% ee; piperazines,
trans-2,5-dimethylpiperazine, 93% ee; 2,6-dimethylpiperazine (cis), 86%
ee; piperazine, 88% ee; piperazine and RbOH, 72% ee; N-methylpiperazine,
78% ee. (a) Percent enantioselectivity determined by conversion to the
corresponding ketal with (2R,3R)-2,3-butanediol and recording 13C NMR.
(b) For ratios of additives and additional information, see Suppporting
Information.
Figure 1. Nonlinear effects in the addition of 2-nitropropane to
2-cyclohexenone.
we observed a pronounced nonlinear effect. The ee of the
product remained almost constant with increasing levels of
ee of L-proline over the range 20-80% enantiopurity, only
(16) For an excellent review, see: Girard, C.; Kagan, H. Angew. Chem.,
Int. Ed. 1998, 37, 2923.
(17) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61,
3520.
(15) For a discussion of basicities of piperazines and related secondary
amines, see: Keyworth, D. A. J. Org. Chem. 1959, 24, 1355.
Org. Lett., Vol. 2, No. 19, 2000
2977

to rise sharply to a maximum value of 93% ee for the final
product. The effect of quinine was not as pronounced,
although a deviation from linearity was also clear.
While it is not possible to derive clear mechanistic
conclusions in a complex system that comprises a catalyst
and an additive, in addition to the nitroalkane and the enone,
the results are reminiscent of MLx systems where NLE
curves show a similar trend.16
In conclusion, we have shown the first examples of
catalytic asymmetric conjugate addition of nitroalkanes to
cyclic enones in the presence of L-proline with high enan-
tioselectivities and trans-2,5-dimethylpiperazine. The pro-
nounced nonlinear effect indicates a complex multicompo-
nent chiral catalytic system which reaches its maximum
efficiency of 93% ee for (S)-3-(2-nitropropyl)cyclohexane.
Acknowledgment. We thank NSERCC and the Medicinal
Chemistry Chair Program for generous financial assistance.
Supporting Information Available: Experimental pro-
1
cedures, X-ray structures, and H and 13C NMR spectra for
compounds reported in Tables 1 and 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL000170G
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