An efficient enantioselective method for asymmetric Michael addition of nitroalkanes to α,β-unsaturated aldehydes

Article abstract of DOI:10.1039/b717000a

The addition of nitroalkanes to α,β-unsaturated aldehydes under the catalysis of (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine and lithium acetate as additive afforded γ-nitroaldehydes in good yield and up to 97% ee. The Royal Society of Chemistry.

Full text of DOI:10.1039/b717000a

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An efficient enantioselective method for asymmetric Michael addition of
nitroalkanes to a,b-unsaturated aldehydesw
Yongcan Wang,a Pengfei Li,a Xinmiao Liang,*ab Tony Y. Zhangc and Jinxing Ye*b
Received (in Cambridge, UK) 2nd November 2007, Accepted 11th January 2008
First published as an Advance Article on the web 31st January 2008
DOI: 10.1039/b717000a
The addition of nitroalkanes to a,b-unsaturated aldehydes under
the catalysis of (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrro-
lidine and lithium acetate as additive afforded c-nitroaldehydes
in good yield and up to 97% ee.
lytic conditions using 5 mol% of 2-(diphenyl(trimethyl-
silyloxy)methyl)pyrrolidine (4)8,9 as the organocatalyst. For
example, the reaction in methanol or dichloromethane pro-
ceeded to only 14% or 5% conversion after 12 h. A mixed
solvent of CH2Cl2–MeOH (v/v 9 : 1) improved the conversion
slightly to 25% (entries 1–3). A remarkable enhancement was
achieved when an additive base, lithium acetate (30 mol%),
was introduced to the reaction system,10 which supposedly
enhances the nucleophilicity of deprotonated nitromethane
and accelerates the formation of the iminium ion. Under these
conditions, the reaction proceeded to full conversion within
12 h in a mixed solvent of CH2Cl2–MeOH (9 : 1) with 95% ee.
The reactions in methanol or dichloromethane alone also
Asymmetric organocatalysis is one of the most rapidly grow-
ing and fruitful research areas in synthetic organic chemistry in
the past few years.1,2 Nowadays, the term asymmetric orga-
nocatalysis covers a wide range of organic processes and
methodologies, providing efficient and environmentally
friendly access to enantiomerically pure compounds including
many drugs and bioactive natural products.3
The catalytic asymmetric Michael addition is one of the
most thoroughly studied chiral bond-forming processes. Re-
cently, the field of asymmetric organocatalytic Michael addi-
tion employing chiral organocatalysts has received widespread
attention.4 Among these reactions, the conjugate additions of
nitroalkanes to a,b-unsaturated carbonyl compounds are
especially useful, because their products are precursors to a
variety of highly functionalized structures, such as aminocar-
bonyl compounds, aminoalkanes, and pyrrolidines.5 Several
organocatalytic methods via an iminium mechanism have been
developed for conjugate additions of nitroalkanes to enones,6
using L-proline and its derivatives, chiral imidazoline or chiral
diamine-dipeptides as catalysts. However, the protocol for
achieving the Michael addition of nitroalkanes to a,b-unsatu-
rated aldehydes is still somewhat cumbersome.7 The major
complication may have been the fact that a,b-unsaturated
aldehydes readily undergo 1,2-addition with nitroalkanes un-
der the reaction conditions. Herein, we would like to report a
highly efficient and enantioselective method for carrying out
this kind of Michael addition based on Lewis base–Brønsted
base bifunctional catalysis.
Table 1 Reaction conditions optimization for the enantioselective
Michael addition of cinnamaldehyde (1a) and nitromethane (2a)
Entry 4a (%) Additive base
Solventb
Conv.c (%) eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2
2
2
1
None
None
None
MeOH
CH2Cl2
14(12 h) nd
5(12 h) nd
DCM : MeOH 9 : 1 25(12 h) 94
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
PhCO2Li
4-FPhCO2Li
MeOH
CH2Cl2
76(12 h) 94
48(12 h) 95
DCM : MeOH 9 : 1 499(12 h) 95
Toluene
EtOAc
Et2O
17(12 h) nd
11(12 h) nd
17(12 h) nd
DCM : MeOH 9 : 1 499(12 h) 93
DCM : MeOH 9 : 1 499(12 h) 95
4-MeOPhCO2Li DCM : MeOH 9 : 1 499(12 h) 94
2-NO2PhCO2Li DCM : MeOH 9 : 1 499(12 h) 93
4-NO2PhCO2Li DCM : MeOH 9 : 1 499(12 h) 93
LiOH
Et3N
The Michael addition of cinnamaldehyde (1a) and nitro-
methane (2a) under various conditions was first investigated
and representative results are presented in Table 1.
DCM : MeOH 9 : 1 91(12 h) 60
DCM : MeOH 9 : 1 17(12 h) nd
DCM : MeOH 9 : 1 47(12 h) 93
DCM : MeOH 9 : 1 95(12 h) 93
The Michael addition of cinnamaldehyde (1a) and nitro-
methane (2a) gave poor results under ordinary iminium cata-
DABCO
Et3N–AcOH
DABCO–AcOH DCM : MeOH 9 : 1 96(12 h) 93
LiOAc
LiOAce
LiOAce
LiOAce
DCM : MeOH 9 : 1 90(40 h) 94
DCM : MeOH 1 : 9 499(40 h) 95
MeOH 92(40 h) 94
DCM : MeOH 1 : 9 88(72 h) 95
a Dalian Institute of Chemical Physics, Chinese Academy of Science,
457 Zhongshan Road, Dalian 116023, China. E-mail:
liangxm@dicp.ac.cn
b School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China. E-mail:
yejx@ecust.edu.cn
a
Reaction conditions: cinnamaldehyde (1.0 mmol), nitromethane (3.0 mmol), 4
b
and additive (0.3 mmol) in solvent (2.0 mL) under room temperature. The
c Eli Lilly and Company, Indianapolis, Indiana 46285, USA
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the Michael addition products. See
DOI: 10.1039/b717000a
c
solvent ratio refers to v : v. The conversion was determined by GC with area
d
percentage. The enantiomeric excess was determined via HPLC using
a
e
Chiralpaks AD-H column. Lithium acetate (0.1 mmol) was used.
ꢀc
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1232 | Chem. Commun., 2008, 1232–1234

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afforded conversions of 76% and 48%, and ee’s of 94% and
95%, respectively (entries 4–6). These encouraging results
indicated that Lewis base–Brønsted base bifunctional catalysis
might indeed be operating for this particular type of Michael
addition.
Table 2 Base–base bifunctional catalytic enantioselective Michael
addition of a,b-unsaturated aldehydes (1) and nitromethane (2a)
A series of other solvents were then investigated, but
solvents other than MeOH or CH2Cl2, such as toluene, ethyl
acetate or ether, resulted in low conversions (entries 7–9).
The effects of other additives were also investigated. It was
found that a series of lithium benzoate derivatives were also
suitable for obtaining satisfactory conversion and enantios-
electivity, and all of these salts gave results similar to that with
lithium acetate (entries 10–14). The addition of a strong base
such as lithium hydroxide afforded low enantioselectivity
(60% ee) due to the increase in background racemization
(entry 15). It is worthy of note that using an organic amine
as an additive base did not efficiently improve the reaction
outcome. For example, the reaction using triethylamine or
DABCO resulted in respectively only 17% or 47% conversion
after 12 h (entries 16–17).11 Interestingly, their acetate salts
gave satisfying results with 495% conversion. This might be
because of the existence of countercations in these salts which
favor the formation of the iminium ion (entries 18–19).
More experiments showed that the proportion of the mixed
CH2Cl2–MeOH solvent also affected the reaction perfor-
mance. An increase in the content of methanol led to increased
activity. For example, the reaction in 9 : 1 CH2Cl2–MeOH
resulted in 90% conversion and 94% ee after 40 h using 2
mol% of 4 and 30 mol% of lithium acetate, while in 1 : 9
CH2Cl2–MeOH, full conversion and 95% ee were obtained
within the same time frame even with 2 mol% of 4 and 10
mol% of lithium acetate (entries 20–21). However, the pre-
sence of dichloromethane was necessary because the reaction
in pure methanol was incomplete (entry 22). Further reduction
in catalyst loading to 1 mol% of catalyst 4 and 10 mol%
of lithium acetate resulted in 88% conversion after 72 h
(entry 23).
Entry
Ra
4 (%)
Time/h Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Ph
2-MeOC6H4
2-ClC6H4
2
2
2
5
2
2
5
5
10
10
10
2
5
5
5
5
5
40
48
84
72
33
96
96
48
60
60
40
96
96
96
72
100
72
80
63
61
73
72
66
67
65
61
67
74
67
74
76
65
60
68
95
97
95
92
93
96
93
92
90
92
92
81
88
90
92
94
93
d
2-NO2C6H4
3-ClC6H4
4-FC6H4
4-MeC6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
2-Furanyl
Me
Et
n-Pr
n-Bu
n-Hept
Hex-3-en-1-yl
10
11
12
13
14
15
16
17
a
Reaction conditions: a,b-unsaturated aldehyde (1.0 mmol), nitro-
methane (3.0 mmol), 4 and lithium acetate (0.1 mmol) in CH2Cl2
:
b
c
MeOH (1 : 9 v/v, 2.0 mL) at room temperature. Isolated yield. The
enantiomeric excess was detected using GC or HPLC. For details, see
d
ESIw. In 9 : 1 CH2Cl2 : MeOH (v/v).
This catalytic method was also proven suitable for higher
nitroalkanes. For example, Michael addition of nitroethane to
cinnamaldehyde progressed to full conversion with 2 mol% of
4 and 10 mol% of lithium acetate within 72 h. The reaction
gave two diastereoisomers with a ratio about 48 : 52 and
respective ee’s of 95% and 96% (Scheme 1).
A very important synthetic application of this kind of
Michael addition is the transformation of the addition product
to an optically active g-amino acid. For example, the addition
product 3i0, prepared from 4-chlorocinnamaldehyde and
nitromethane catalyzed by (R)-4, could be conveniently
converted to the corresponding g-nitro acid 5i0.12 The nitro
group of 5i0 was easily reduced to an amino group with the
usual hydrogenation process13 to afford the optically active
(R)-baclofen hydrochloride salt, which is an important
GABAB receptor agonist (Scheme 2).14
To demonstrate the generality of this catalytic Michael
addition, the additions of nitromethane to various a,b-unsa-
turated aldehydes were then evaluated and representative
examples are shown in Table 2.z
The addition of nitromethane to aromatic a,b-unsaturated
aldehydes afforded good results. Cinnamaldehyde derivates
with electron-withdrawing or donating group on the ortho-,
meta-, or para-position of the benzene ring all gave full
conversion and good to excellent enantioselectivity ranging
from 90% to 97%. (entries 1–10). An aromatic heterocyclic
a,b-unsaturated aldehyde such as 3-(furan-2-yl)acrylaldehyde
also resulted in 92% ee using 10 mol% of catalyst 4 and
10 mol% of lithium acetate (entry 11).
In summary, we have developed a new Lewis base–Brønsted
base bifunctional catalysis for the asymmetric catalytic
Michael addition of nitroalkanes to a,b-unsaturated aldehydes
with high efficiency and enantioselectivity, even with a
The addition of nitromethane to aliphatic a,b-unsaturated
aldehydes also exhibited promising results. A series of
alkenals, such as crotonaldehyde, pentenal, hexenal or
decenal, all achieved full conversion and good to excellent
enantioselectivity ranging from 81% to 94% ee using
2–10 mol% of catalyst 4 and 10 mol% of lithium acetate
(entries 12–16). Aliphatic a,b-unsaturated aldehydes with a
functional group such as 2-trans-6-cis-nonadienal also
behaved satisfactorily (entry 17).
Scheme 1 Enantioselective Michael addition of cinnamaldehyde and
nitroethane.
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7 For previous work on the enantioselective addition of nitroalkanes
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Scheme 2 Synthetic route for the preparation of the optically active
(R)-baclofen hydrochloride salt.
1–2 mol% loading level for the catalyst. The results indicated
that this methodology might be of practical and general utility
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results from which will be presented in due course.
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Notes and references
z General procedure for the Michael addition of nitroalkanes to a,b-
unsaturated aldehydes: to a mixed solution of 1 : 9 CH2Cl2–MeOH
(v/v, 2.0 mL) was added a,b-unsaturated aldehyde 1 (1.0 mmol),
nitroalkane 2 (3.0 mmol), catalyst 4 (6.5 mg, 0.02 mmol) and lithium
acetate (6.6 mg, 0.10 mmol). The reaction mixture was stirred at room
temperature for the time indicated in Table 2 and then the solvent was
removed under vacuum. Water (5.0 mL) was added to the residue and
it was extracted with CH2Cl2 three times. The combined organic
phases were dried over anhydrous Na2SO4, filtered and evaporated
under vacuum. The residue was purified by column chromatography
on silica gel (350–400 mesh) to yield the desired addition product.
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1234 | Chem. Commun., 2008, 1232–1234