Diphenylprolinol silyl ether as catalyst of an asymmetric, catalytic, and direct Michael reaction of nitroalkanes with α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol702545z

(Chemical Equation Presented) A catalytic enantioselective direct conjugate addition of nitroalkanes to α,β-unsaturated aldehydes using diphenylprolinol silyl ether as an organocatalyst has been developed. Using this methodology as a key step, short syntheses of therapeutically useful compounds have also been accomplished.

Full text of DOI:10.1021/ol702545z

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5307-5309
Diphenylprolinol Silyl Ether as Catalyst
of an Asymmetric, Catalytic, and Direct
Michael Reaction of Nitroalkanes with
r,â-Unsaturated Aldehydes
Hiroaki Gotoh, Hayato Ishikawa, and Yujiro Hayashi*
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received October 19, 2007
ABSTRACT
A catalytic enantioselective direct conjugate addition of nitroalkanes to
r,â-unsaturated aldehydes using diphenylprolinol silyl ether as an
organocatalyst has been developed. Using this methodology as a key step, short syntheses of therapeutically useful compounds have also
been accomplished.
The conjugate addition of carbanions to R,â-unsaturated
carbonyl compounds is one of the most fundamental carbon-
carbon bond-forming reactions in organic synthesis.1 We
have reported a highly syn- and enantioselective Michael
reaction catalyzed by diphenylprolinol silyl ether (1), in
which aldehyde and nitroalkene act as Michael donor and
acceptor, respectively (eq 1).2 The Michael reaction of the
reverse combination, in which nitroalkane and R,â-unsatur-
ated aldehyde act as donor and acceptor, respectively (eq
2), is also synthetically important, as it too can provide
versatile synthetic intermediates such as amino carbonyl
compounds and amino alkanes. Hence, the catalytic asym-
metric Michael reaction of nitroalkanes has been intensively
investigated.3 In spite of considerable effort, most of the
Michael reactions of nitroalkanes that have been devised are
limited to R,â-unsaturated ketones, esters, or amides. Achiev-
ing the Michael reaction of R,â-unsaturated aldehydes is
thought to be difficult because the competitive 1,2-addition
reaction occurs readily due to the highly reactive aldehyde.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992. For recent reviews on the catalytic
asymmetric Michael reaction, see: (b) Krause, N.; Hoffman-Roder, A.
Synthesis 2001, 171. (c) Sibi, M.; Manyem, S. Tetrahedron 2000, 56, 8033.
(d) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley: New York, 2000; p 569. (e) Tomioka, K.; Nagaoka,
Y. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, Chapter 31.1. For
review of the organocatalytic 1,4-conjugate addition, see: (f) Tsogoeva, S.
B. Eur. J. Org. Chem. 2007, 1701.
Recently the field of organocatalysis has been developing
rapidly,4 and several organocatalysts have been successfully
applied to the Michael reaction of nitroalkanes via the
iminium activation strategy, although these have been limited
to R,â-unsaturated ketones.5 For R,â-unsaturated aldehydes,
Maruoka and co-workers have developed an elegant chiral
phase transfer Michael reaction, in which the silyl nitronates
(2) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int.
Ed. 2005, 44, 4212.
10.1021/ol702545z CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/13/2007

prepared from nitroethane and nitropropane were employed
instead of the nitroalkanes, but they reported no results for
nitromethane.6 Arvidsson and co-workers recently reported
the Michael reaction of R,â-unsaturated aldehydes with
nitroalkanes catalyzed by imidazole-containing organocata-
lyst. The reaction had limited success with nitroethane and
nitropropane, but only moderate enantioselectivity (47% ee)
with nitromethane.7 However, no widely applicable, direct
Michael reactions of simple nitroalkanes, and inclusive of
nitromethane, with R,â-unsaturated aldehydes have been
described, in spite of the synthetic potential of such reac-
tions.8 In this communication, we disclose such a reaction.
The Michael reaction of nitromethane and cinnamaldehyde
was selected as a model (eq 3). First silyl ethers of
diarylprolinols,9,10,11 independently developed by Jørgensen’s9
and our2,10 groups, were used as catalyst. When diphenyl-
prolinol silyl ether 1 was employed, the desired product was
obtained with excellent enantioselectivity (98% ee), in spite
of the low yield which is caused by over-reaction of the
initially generated product with a second nitromethane via
the Henry reaction. To improve the yield, the reaction
conditions were examined in detail. It was found that both
the additive and solvent used in the reaction are important.
After screening of additives such as p-nitrophenol,10a PhCO2H,
CF3CO2H, NaHCO3, and AcONa, the reaction was found to
be accelerated in the presence of PhCO2H. After screening
the solvent, we found that excellent yield and enantioselec-
tivity were achieved when MeOH10a was employed (Table
1). It should be noted that the bis(trifluoromethyl) substi-
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
solvent
time/h
yield/%b
ee/%c
d
1
2
3
4
5
6
7
1
1
1
1
1
2
3
-
28
8
31e
56
56
63
90
57
52
98
96
93
97
95
82
77
CH3CN
DMF
CH2Cl2
MeOH
MeOH
MeOH
24
16
16
16
16
(3) (a) Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki,
M. Tetrahedron Lett. 1998, 39, 7557. (b) Itoh, K.; Kanemasa, S. J. Am.
Chem. Soc. 2002, 124, 13394. (c) Sammis, G. M.; Jacobsen, E. N. J. Am.
Chem. Soc. 2003, 125, 4442. (d) Choudary, B. M.; Ranganath, K. V. S.;
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Today 2007, 12, 8. (g) Dalko, P. I., Ed. EnantioselectiVe Organocatalysis;
Wiley-VCH: Weinheim, 2007.
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61, 3520. (b) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (c) Corey.
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S. E.; Ley, S. V. Chem. Commun. 2005, 5346. (h) Mitchell, C. E. T.;
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4, 2039. (i) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2006, 128, 9413.
a Unless otherwise shown, the reaction was performed employing
cinnamaldehyde (0.6 mmol), nitromethane (1.8 mmol), catalyst (0.06 mmol),
PhCO2H (0.12 mmol), and solvent (1.2 mL) at rt. b Isolated yield. c Optical
purity was determined by the chiral GC analysis. d Neat reaction conditions
without PhCO2H. e 1,5-Dinitro-4-phenyl-1-pentene was obtained in 22%
yield.
tuted catalyst 2 and diphenylprolinol 3 were ineffective
(entries 6, 7).
(6) (a) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
9022. (b) Ooi, T.; Motimoto, K.; Doda, K.; Maruoka, K. Chem. Lett. 2004,
33, 824. (c) Ooi, T.; Doda, K.; Takeda, S.; Maruoka, K. Tetrahedron Lett.
2006, 47, 145.
(7) Hojabri, L.; Hartikka, A.; Moghaddam, F. M.; Arvidsson, P. I. AdV.
Synth. Catal. 2007, 349, 740.
(8) During the preparation of this manuscript, Palomo reported the similar
reaction using dialkylprolinol silyl ether as an organocatalyst in the presence
of water. Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.;
Vera, S. Angew. Chem., Int. Ed. 2007, 48. DOI: 10.1002/anie.200703261.
(9) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Marigo, M.; Fielenbach, D.;
Braunton, A.; Kjasgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005,
44, 3703. (c) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (d) Marigo, M.;
Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
15710. (e) Zhuang, W.; Marigo, M.; Jørgensen, K. A. Org. Biomol. Chem.
2005, 3, 3883. (f) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjasgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (g)
Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2006, 45, 4305. (h) Brandau, S.; Maerten, E.; Jørgensen,
K. A. J. Am. Chem. Soc. 2006, 128, 14986. (i) Carlone, A.; Marigo, M.;
North, C.; Landa, A.; Jørgensen, K. A. Chem. Commun. 2006, 4928. (j)
Bertelsen, S.; Marigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 12973. (k) Bertelsen, S.; Diner, P.; Johansen, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536. (l) Aleman, J.; Cabrera,
S.; Maerten, E.; Overgaard, J.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2007, 46, 5520.
Figure 1. Organocatalysts examined in this study.
As the best conditions had been found, the generality of
the reaction was investigated, with the results summarized
in Table 2. Not only phenyl, but also a 2-naphthyl-substi-
tuted acrolein derivative gave an excellent result (entry 2).
The reaction proceeds efficiently for acrolein derivatives not
only with electron-rich aromatic substituents such as 3,4-
methylenedioxyphenyl and p-methoxyphenyl (entries 3, 4),
but also with electron-deficient substituents such as p-bro-
mophenyl, p-chlorophenyl, and p-nitrophenyl (entries 5-8),
(10) (a) Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.; Hayashi, Y. Angew.
Chem., Int. Ed. 2006, 45, 6853. (b) Hayashi, Y.; Okano, T.; Aratake, S.;
Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922. (c) Gotoh, H.; Hayashi,
Y. Org. Lett. 2007, 9, 2859.
5308
Org. Lett., Vol. 9, No. 25, 2007

a similar two-step sequence from ent-5j, which had been
prepared using ent-1 (eq 8).
Table 2. Catalytic Asymmetric Michael Reaction of CH3NO2
and R,â-Unsaturated Aldehydesa
entry
R
time/h yield/%b ee/%c
1
2
3
4
5
6
7d
8e
9
10
11f
12f
13f
Ph 4a
2-naph 4b
3,4-methylenedioxyphenyl 4c
p-MeOPh 4d
p-BrPh 4e
p-ClPh 4f
p-ClPh 4f
p-NO2Ph 4g
2-furyl 4h
n-Bu 4i
16
16
17
16
17
17
40
48
24
42
96
120
96
90
94
80
88
87
83
80
76
82
53
77
68
76
95
93
93
95
95
94
92
95
93
90
91
91
92
In summary, we have developed a catalytic, enantiose-
lective, direct conjugate addition of nitroalkanes to R,â-
unsaturated aldehydes using diphenylprolinol silyl ether as
an organocatalyst. This reaction expands the previous sub-
strate scope significantly and is the successful reaction using
nitromethane directly with R,â-unsaturated aldehydes. Using
this methodology as a key step, short syntheses of therapeuti-
cally useful compounds can be realized. It is interesting to
note that the same catalyst 1 is effective in the enantiose-
lective Michael reaction of both the R,â-unsaturated alde-
hyde/nitroalkane and the inverse nitroalkene/aldehyde sub-
strate pairs.
n-Bu 4i
i-Bu 4j
PhCH2CH2 4k
a Unless otherwise shown, the reaction was performed employing R,â-
unsaturated aldehyde (0.6 mmol), nitromethane (1.8 mmol), 1 (0.06 mmol),
PhCO2H (0.12 mmol) and MeOH (1.2 mL) at rt. b Isolated yield. c Optical
purity was determined by chiral GC or HPLC analysis, see Supporting
Information for details. d Catalyst loading is 2 mol %. e The reaction was
performed at 4 °C. f The reaction was performed without PhCO2H.
Acknowledgment. This work was partially supported by
the Toray Science Foundation and a Grand-in-Aid for
Scientific Research from The Ministry of Education, Culture,
Sports, Science, and Technology (MEXT).
to afford excellent enantioselectivities in all the cases
examined. Heteroaromatic groups such as furyl are suitable
substituents (entry 9). In the case of alkyl group-substituted
acrolein, good yield and excellent enantioselectivities were
obtained without addition of PhCO2H (entries 11-13). The
loading of the catalyst can be reduced to 2 mol % (entry 7).
Supporting Information Available: Detailed experi-
1
mental procedures, full characterization, copies of H- and
13C NMR and IR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL702545Z
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Not only nitromethane but also other nitroalkanes can be
used successfully. Nitroethane reacts with cinnamaldehyde
in MeOH to afford the adduct in 95% yield with excellent
enantioselectivity, while the diastereoselectivity was 1:1 (eq
5). Though the reactivity of a â,â-disubstituted nitroalkane
was low, 2-nitropropane reacts with cinnamaldehyde under
neat conditions to afford the Michael adduct in moderate
yield with high enantioselectivity (eq 6).
Because of the synthetic versatility of the nitro and
aldehyde groups, short syntheses of a broad range of chiral
pharmaceuticals would be possible by employing the pres-
ent Michael reaction as a key step. Baclofen5c,12 is a thera-
peutically useful GABAB receptor agonist, which was synthe-
sized in only two steps, an oxidation and a reduction (eq 7),
from 5f, prepared by the current Michael reaction using 2
mol % of the catalyst (Table 2, entry 7). Pregabalin,3c,12c,13
an important anticonvulsant drug, was also synthesized via
(12) Recent synthesis of baclofen, see: (a) Camps, P.; Munoz-Torrero,
D.; Sanchez, L. Tetrahedron: Asymmetry 2004, 15, 2039. (b) Felluga, F.;
Gombac, V.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2005, 16,
1341. (c) Armstrong, A.; Convine, N. J.; Popkin, M. E. Synlett 2006, 1589
and references therein.
(13) Recent synthesis of pregabalin, see: Mita, T.; Sasaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514 and the references
therein.
Org. Lett., Vol. 9, No. 25, 2007
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