Solvent-free organocatalytic Michael addition of diethyl malonate to nitroalkenes: The practical synthesis of Pregabalin and γ-nitrobutyric acid derivatives

Article abstract of DOI:10.1016/j.tet.2010.11.053

A highly enantioselective synthesis of Pregabalin 1 hydrochloride with good overall yield (44%) and enantioselectivity (98% ee) was described. The key step is an asymmetric Michael addition of equivalent of diethyl malonate and nitroalkene under solvent-f

Full text of DOI:10.1016/j.tet.2010.11.053

Tetrahedron 67 (2011) 636e640
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Solvent-free organocatalytic Michael addition of diethyl malonate to nitroalkenes:
the practical synthesis of Pregabalin and
g
-nitrobutyric acid derivatives
*
Jin-ming Liu, Xin Wang, Ze-mei Ge, Qi Sun, Tie-ming Cheng, Run-tao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2010
Received in revised form 5 November 2010
Accepted 12 November 2010
Available online 18 November 2010
A highly enantioselective synthesis of Pregabalin 1 hydrochloride with good overall yield (44%) and
enantioselectivity (98% ee) was described. The key step is an asymmetric Michael addition of equivalent
of diethyl malonate and nitroalkene under solvent-free conditions using thiourea 2 as catalyst. The re-
action can be applied to a variety of aromatic and aliphatic substituted nitroalkenes affording corre-
sponding adducts in good to excellent yields (61e92%) and enantioselectivities (78e93% ee).
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pregabalin
Organocatalysis
Solvent-free
Michael addition
g-Nitrobutyric acid derivatives
1. Introduction
Pregabalin (1), an anticonvulsant drug, which is used to treat
epilepsy and neuropathic pain, is considered as one of the block-
buster drugs of the future. Thus, the development of simple and
efficient synthetic processes has become an important research
goal for medicinal and organic chemists. Though the initial in-
dustrial preparation of Pregabalin was a racemic synthesis followed
by resolution, much attention has been focused on the de-
velopment of asymmetric synthetic processes.1 Among them,
asymmetric Michael addition was considered as one of the most
effective routes for constructing the chiral center of Pregabalin.1g,2
However, most of them were catalyzed by metal complexes. Such
as, Sammins and Jacobsen2a described a highly enantioselective
Fig. 1. Structure of Pregabalin.
Although the product could be obtained in an excellent enan-
tioselectivity and yields in the cases of metal catalysis, the draw-
backs, such as the harsh reaction conditions, high toxicity or
expensive catalyst could not be avoided. Recently, some effort has
been directed toward the application of organocatalytic asymmetric
Michael addition in the preparation of Pregabalin3 because orga-
nocatalyzed reactions are always environmentally friendly pro-
cesses with the benefits of easy operation, readyavailability, and low
toxicity of catalysts. Forexamples, Pregabalin has also been obtained
by catalytic enantioselective conjugate addition of nitroalkenes to
route for 1 through conjugate addition of cyanide to
a,b-un-
saturated imide by salen Al catalysis. Shibasaki’s group1g developed
a catalytic enantioselective conjugate addition reaction of cyanide
to
a,b-unsaturated N-acylpyrrole mediated by a chiral gadoli-
a,b-unsaturated aldehydes using diphenylprolinol silyl ether as
niumcatalyst. Armstrong et al.2b described the synthesis of enan-
tiopure Pregabalin through conjugate addition of cyanide to a chiral
organocatalyst.3a Bassas et al. described a synthetic procedure of
Pregabalin, which was based on a Michael addition reaction of
Meldrum’s acid to a nitroalkene mediated by a quinidine derived
thiourea.3b Unfortunately, the use of harmful organic solvents and
an excess of Michael donors were required in most cases. Therefore,
it is still a challenge for organic chemist todevelop an environmental
protective and economic synthetic procedure of Pregabalin.
a,b
-unsaturated isobutyloxazolidinone. Poe et al.2c also synthesized
1 by a one-pot reaction of isovaleraldehyde, nitromethane, and
dimethyl malonate promoted by two microencap sulated catalysts
(Fig. 1).
In recent years, the Michael addition of malonate to nitroalkenes
promoted by organocatalysts,4 especially bifunctional thiourea
catalysts,5 have been investigated extensively and excellent
* Corresponding author. Tel.: þ8610 82801504; fax: þ8610 82716956; e-mail
address: lirt@mail.bjmu.edu.cn (R.-t. Li).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.053

J.-m. Liu et al. / Tetrahedron 67 (2011) 636e640
637
enantioselectivity and yields have been achieved. For examples,
Deng4a reported that cinchona alkaloids could catalyze this re-
action in nearly solvent-free condition with high yield and ee value;
Takemoto’s group5a,b developed a Michael addition of malonate to
nitroalkenes promoted by chiral thiourea catalysts. Enlightened by
their work, we achieved to form the stereocenter of Pregabalin via
an enantioselective Michael addition reaction catalyzed by thiourea
26 as depicted in Scheme 1. Meanwhile, the drawbacks of previous
synthetic methodology have been successfully overcome by
avoiding the use of organic solvent and reducing the amount of
Michael donors in order to meet the requirements of green
chemistry. Herein, we present a practical synthesis of Pregabalin via
solvent-free organocatalytic Michael addition of equivalent of
diethyl malonate and nitroalkene.
(73%) and moderate enantioselectivity (67% ee) were obtained in
the presence of bentonite. Much to our delight, the enantiose-
lectivity was obviously improved in the absence of solid media
(Table 1, entry 5, 74% yield, 77% ee). Accordingly, we next turned our
attention to the investigation of solvent-free reaction. Under sol-
vent-free conditions, reaction temperature, catalyst loading and
ratio of the substrates were systematically examined and the se-
lected findings were detailed in Table 1. It is clear that reaction
temperature of ꢀ20 ꢁC is more suitable (Table 1, entry 7, 71% yield,
89% ee). The catalyst loading screening revealed that 10 mol % and
20 mol % of catalyst gave the almost similar results (Table 1, entries
7 and 9). Reducing catalyst loading to 5 mol % led to a great de-
crease of yield (Table 1, entry 10). Notably, reducing the amount of
diethyl malonate from 2 to 1 equiv did not lead to any significant
influence on both the yield and enantioselectivity (Table 1, entries 9
and 11). Thus, it could be concluded that the best compromise
between reaction rate and enantioselectivity was achieved by using
equivalent mole of diethyl malonate and nitroalkene in the pres-
ence of 10 mol % of thiourea 2 at ꢀ20 ꢁC.
After established the optimal reaction conditions, we then ap-
plied this efficient enantioselective Michael reaction to the syn-
thesis of Pregabalin. As outlined in Scheme 2, the nitroalkene 3,
prepared from the condensation of isopropylaldehyde with nitro-
methane, reacted with diethyl malonate in the presence of 10 mol %
of catalyst 2 under solvent-free conditions at ꢀ20 ꢁC for 24 h
affording the key intermediate 4 in 73% yield with 88% ee. Then,
hydrogenation of 4 in the presence of Raney-Ni gave the (S)-ethyl 4-
isobutyl-2-oxopyrrolidine-3-carboxylate 5 as a white solid in 72%
yield after crystallization from hexane. Finally, 5 was refluxed for
18 h in 6 N HCl affording Pregabalin as its hydrochloric salt (1$HCl)
in 92% yield. The overall yield is 44% through four steps starting
from isopropylaldehyde. Meanwhile, the key intermediate 6 from 5
to 1$HCl was also obtained in 90% yield with 98% ee. The excellent
enantioselectivity of 6 should be attributable to the effective crys-
tallization of 5. The optical purity of Pregabalin could be indirectly
evaluated according to the enantioselectivity of 6, because the last
step did not involve the chiral center. Consequently, we succeeded
in the synthesis of Pregabalin by this simple procedure with high
enantioselectivity.
Scheme 1. Retrosynthetic analysis of Pregabalin.
2. Results and discussion
Previously, we found that the organocatalytic aldol reaction of
aldehydes and ketones could be performed in alkaline Al2O3 with
considerable satisfying results.7 This result aroused our interest to
explore the organocatalytic asymmetric Michael addition of mal-
onate to nitroalkene in solid media. Initially we screened a number
of solid media for the reaction of diethyl malonate with nitroalkene
(3) in the ratio of 2:1 using 20 mol % of thiourea 2 as catalyst at
room temperature (Table 1, entries 1e4). It showed that good yield
Table 1
Reaction conditions screeninga
Entry Media
Catalyst loading (mol %) Temp (ꢁC) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
Alkaline Al2O3 20
Neutral Al2O3 20
rt
rt
rt
rt
rt
0
ꢀ20
ꢀ30
ꢀ20
ꢀ20
ꢀ20
72
61
68
73
74
73
71
54
73
38
72
0
0
Scheme 2. Enantioselective synthetic route of Pregabalin hydrochloride. Reagents and
conditions: (i) (1) CH3NO2, NaOH, EtOH, 0 ꢁC; (2) DCC, CuCl, Et2O, rt; (ii) diethyl
malonate, 2 (10 mol %), ꢀ20 ꢁC, 24 h; (iii) Raney-Ni, H2, MeOH, rt, 24 h; (iv) 6 N HCl,
reflux for 18 h; (v) NaOH, EtOH, rt; (vi) toluene, reflux for 6 h; (vii) 6 N HCl, reflux for
10 h.
Silica gel
Bentonite
20
20
20
20
20
20
10
5
20
67
77
75
89
85
88
87
88
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
9
In order to test the versatility of the protocol, various aromatic and
aliphatic substituted nitroalkenes assubstrates were examinedunder
optimized reaction conditions (Table 2). To our pleasure, good yields
and enantioselectivities could be obtained in the cases of aliphatic
nitroalkenes as receptors (Table 2, entries 1e6), which is reluctant to
undergo Michael addition reaction according to the previous liter-
atures.5c,d The length of R groups in aliphatic nitroalkenes does not
10
11d
10
a
Unless specified, the reaction was conducted with 3 (0.1 mmol), diethyl malo-
nate (0.2 mmol), and catalyst 2 for 24 h.
b
Isolated yields.
Determined by chiral HPLC analysis.
Diethyl malonate (0.1 mmol) was used.
c
d

638
J.-m. Liu et al. / Tetrahedron 67 (2011) 636e640
Table 2
24 h, the reaction mixture was directly purified by column chro-
matography on silica gel (ethyl acetate/petroleum ether¼1:3) to
afford desired product.
Enantioselective Michael addition of diethyl malonate to substituted nitroalkenes
under solvent-free conditionsa
4.3. Total synthesis of hydrochloride of Pregabalin
4.3.1. (E)-4-Methyl-1-nitro-1-pentene (3)8. An aqueous 10 M so-
dium hydroxide solution (9 mL, 90 mmol) was added dropwise
under mechanical stirring (to prevent the formation of a solid
mass) to a solution of isovaleraldehyde (7.81 g, 90 mmol) and ni-
tromethane (5.6 g, 90 mmol) in EtOH (150 mL) at 0 ꢁC. After 10 min,
the crude mixture was warmed to room temperature and stirred
overnight. Then, acetic acid (5.2 mL, 90 mmol) was added. The
aqueous layer was extracted with diethyl ether (3ꢂ50 mL). The
extracts were washed with water until the pH of the washings was
6. The residue was dried, filtrated, and concentrated in vacuo
affording crude 3-methyl-1-(nitromethyl)butanol, which was used
without further purification. Then DCC (20.5 g, 0.1 mol) and CuCl
(200 mg, 2 mmol) were added successively to a solution of 3-
methyl-1-(nitromethyl)butanol (15.84 g, 90 mmol) in anhydrous
ether (50 mL). The reaction mixture was stirred overnight at room
temperature and cooled to 0 ꢁC. Hexane (100 mL), water (20 mL),
and acetic acid (8.2 mL) were added. The mixture was warmed to
room temperature and stirred until completion of the reaction. The
organic phase was washed with water, saturated with aqueous
ammonium chloride solution and brine, then dried. After filtration
and evaporation in vacuo, the residue was purified by column
chromatography (ethyl acetate/petroleum ether¼1:3) affording
compound 3 (6.04 g, 90%). Colorless oil; 1H NMR (400 MHz, CDCl3):
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
CH3CH2e
8a
8b
8c
8d
8e
8f
8g
8h
8i
78
77
74
71
61
76
88
86
67
92
91
78
87
87
89
83
86
90
89
85
88
93
CH3(CH2)2e
CH3(CH2)3e
CH3(CH2)4e
CH3(CH2)9e
(eCH2e)5CHe
C6H5e
4-MeeC6H4e
4-CH3OeC6H4e
4-FeC6H4e
2-Thienyle
7d
8d
9d
10d
11d
8j
8k
a
Unless specified, the reaction was conducted with 7 (0.1 mmol), diethyl malo-
nate (0.1 mmol), and catalyst 2 (0.01 mmol) under solvent-free conditions at ꢀ20 ꢁC
for 24 h.
b
Isolated yields.
Determined by chiral HPLC analysis.
Diethyl malonate (0.2 mmol) was used.
c
d
obviously influence the enantioselectivities. For the aryl-substituted
nitroalkenes, all the tested examples afforded the corresponding
Michael adducts in good to excellent yields and enantioselectivities
(Table 2, entries 7e11).
d
7.22e7.29 (m, 1H), 6.96e7.00 (m, 1H), 2.13e2.17 (m, 2H),1.81e1.87
(m, 1H), 0.97 (d, J¼7.2 Hz, 6H).
3. Conclusion
4.3.2. (S)-Diethyl-2-(4-methyl-1-nitropentan-2-yl-) malonate (4)9. Ni
troalkene 3 (2.06 g, 16 mmol) was added to a stirred solution of
diethyl malonate (2.56 g, 16 mmol) and thiourea-catalyst 2 (0.66 g,
1.6 mmol) at ꢀ20 ꢁC. After being stirred for 24 h, the reaction mixture
was directly purified by column chromatography on silica gel (ethyl
acetate/petroleum ether¼1:3) to afford desired product 4 (3.65 g,
In summary, we have developed an efficient and practical
asymmetric synthesis of (S)-3-aminomethyl-5-methylhexanoic
acid (Pregabalin) using isopropylaldehyde, nitromethane, and
diethyl malonate as starting materials in 44% overall yield and 98%
ee through four steps. The key organocatalytic Michael addition of
equivalent of diethyl malonate to nitroalkene for constructing
chiral center of Pregabalin was carried out under solvent-free
conditions. Moreover, the versatility and potent of this solvent-free
organocatalytic Michael addition have been demonstrated by
a broad scope of substrates.
73%). Yellow oil; 88% ee; 1H NMR (400 MHz, CDCl3):
d
4.65 (dd, J¼13.2,
4.8 Hz, 1H), 4.46 (dd, J¼13.2, 6.4 Hz, 1H), 4.13e4.19 (m, 4H), 3.55 (d,
J¼5.6 Hz, 1H), 2.87e2.92 (m, 1H), 1.57e1.63 (m, 1H), 1.20e1.29 (m,
8H), 0.85e0.87 (m, 6H); 13C NMR (100 MHz, CDCl3):
d 167.9, 167.7,
76.8, 61.7, 61.6, 52.6, 38.9, 34.7, 25.0, 22.2, 22.1, 13.9, 13.8; Chiral HPLC
(Daicel Chiralcel OD-H) hexanes/2-propanol¼98:2; flow rate: 1.0 mL/
4. Experimental
min;
l
¼210 nm; tminor¼6.2 min, tmajor¼8.6 min.
4.3.3. Ethyl-4-isobutyl-2-oxopyrrolidine-3-carboxylate (5)10. A so-
lution of 4 (1.59 g, 8 mmol) in 2 mL THF and 10 mL EtOH was added
4.1. General experimental
Melting point data were recorded on an X-4 micro-melting
point instrument. NMR spectra were registered on Varian Mercury-
300 and JEOL JNM-LA400 using TMS as an internal standard. High-
resolution mass spectra were recorded on a ZAB-HS instrument
using an electrospray source (ESI). Elemental analyses were per-
formed on a Vario EL III (Germany). Optical rotations were mea-
sured in H2O with an Optical Activity Ltd. AA-10R digital
polarimeter. Thin-layer chromatography (TLC) was carried out us-
ing Silica gel 60. Enantiomer ratios were determined by chiral HPLC
using an Agilent 1100 HPLC systems with column Daicel Chiralpak
to
a hydrogenation bottle containing Raney-Ni (0.16 g). The
resulting black suspension was stirred at room temperature under
H2 at 4 atm for 24 h. After completion of the reaction, the resulting
mixture was filtered and the solvent was evaporated under vac-
uum. The crude product was purified by column chromatography
(ethyl acetate/petroleum ether¼1:3 as eluent) to give colorless oil.
After crystallization from petroleum ether, white crystal (700 mg,
72%) was obtained. White crystal; mp 72e73 ꢁC; 1H NMR (400 MHz,
CDCl3):
d 6.69 (s, 1H), 4.21e4.28 (m, 2H), 3.52e3.58 (m, 1H),
2.89e2.06 (m, 3H), 1.51e1.61 (m, 1H), 1.34e1.46 (m, 2H), 1.30 (t,
J¼7.2 Hz, 3H), 0.90 (t, J¼6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3):
AD-H (5
mm 4.6ꢂ250 mm) and Daicel Chiralcel OD-H (5
mm
4.6ꢂ250 mm).
d
173.7, 169.9, 61.4, 54.9, 46.8, 43.2, 37.4, 25.8, 22.5, 22.4, 14.1.
4.2. General procedure for reaction condition screening
4.3.4. (S)-4-Isobutylpyrrolidin-2-one (6)11. NaOH (1 N, 20 mL) was
added to the solution of 5 (2.87 g, 13.5 mmol) in EtOH (60 mL) at
room temperature. After stirring for 30 min, the reaction mixture
was concentrated in vacuo. To the residue was added H2O and 5 N
HCl, and the aqueous phase was extracted with CHCl3 (3ꢂ50 mL).
Nitroalkene (12.8 mg, 0.1 mmol) was added to a stirred solution
of diethyl malonate (32 mg, 0.2 mmol) and thiourea-catalyst 2 in
1 g solid carrier or in solvent-free condition. After being stirred for

J.-m. Liu et al. / Tetrahedron 67 (2011) 636e640
639
The extract was dried over MgSO4, filtrated, and concentrated in
vacuo to afford the corresponding carboxylic acid, which was used
without further purification. After refluxing in toluene (30 mL) for
6 h, the reaction mixture was purified by column chromatography
on silica gel (ethyl acetate/petroleum ether¼1:6 as eluent) to afford
desired product 6 (1.71 g, 90%). Colorless oil; 98% ee; 1H NMR
Chiral HPLC (Daicel Chiralcel OD-H) hexanes/2-propanol¼98:2;
flow rate: 1.0 mL/min;
¼210 nm; tminor¼5.8 min, tmajor¼6.7 min.
l
4.4.4. (S)-Diethyl 2-(1-nitroheptan-2-yl)malonate (8d)5a. Colorless
oil; 89% ee; 1H NMR (300 MHz, CDCl3):
d
4.71 (dd, J¼8.4, 4.8 Hz,1H),
4.53 (dd, J¼7.2, 6.3 Hz, 1H), 4.18e4.26 (m, 4H), 3.63 (d, J¼5.7 Hz,
1H), 2.86e2.92 (m, 1H), 1.26e1.49 (m, 14H), 0.88 (t, J¼6.6 Hz, 3H);
Chiral HPLC (Daicel Chiralcel OD-H) hexanes/2-propanol¼98:2;
(400 MHz, CDCl3):
d
6.30 (s, 1H), 3.48 (dd, J¼8.8 Hz, 1H), 2.99 (dd,
J¼7.2, 2.4 Hz, 1H), 2.50e2.58 (m, 1H), 2.42 (dd, J¼8.8, 8 Hz, 1H), 1.97
(dd, J¼8.8, 8 Hz, 1H), 1.53e1.61 (m, 1H), 1.31e1.37 (m, 2H),
flow rate: 1.0 mL/min;
l¼210 nm; tminor¼7.4 min, tmajor¼11.1 min.
0.89e0.92 (m, 6H); 13C NMR (100 MHz, CDCl3):
d 178.8, 48.3, 43.8,
37.1, 32.8, 26.1, 22.6, 22.4; Chiral HPLC (Daicel Chiralpak AD-H)
4.4.5. (S)-Diethyl 2-(1-nitrododecan-2-yl)malonate (8e). Colorless
oil; 83% ee; 1H NMR (300 MHz, CDCl3):
hexanes/2-propanol¼96:4; flow rate: 1.0 mL/min;
l¼210 nm;
d
4.71 (dd, J¼8.7, 4.8 Hz, 1H),
tmajor¼12.8 min, tminor¼14.6 min.
4.53 (dd, J¼6.9, 6.3 Hz, 1H), 4.19e4.26 (m, 4H), 3.62 (d, J¼6.0 Hz,
1H), 2.86e2.92 (m, 1H), 1.25e1.45 (m, 24H), 0.88 (t, J¼6.0 Hz, 3H);
4.3.5. (S)-3-Aminomethyl-5-methyl-hexanoic acid (Pregabalin) hy-
drochloride (1$HCl)2a. Compound 5 (1.7 g, 121 mmol) and 6 N HCl
aqueous (40 mL) were heated at 100 ꢁC for 18 h. Upon cooling, the
mixture was extracted with EtOAc (4ꢂ10 mL). The aqueous layer
was concentrated in vacuo to give product 1$HCl (1.78 g, 92%).
The product could also be obtained from 6: the solution of 6
(107 mg, 0.55 mmol) in 6 N HCl (2.7 mL) was refluxed at 100 ꢁC for
13C NMR (125 MHz, CDCl3):
d 168.0, 167.8, 76.7, 61.9, 61.7, 52.6, 36.9,
31.8, 30.0, 29.5, 29.4, 29.2, 26.5, 22.6, 14.0, 14.0; HRMS (ESI): m/z
calcd for C19H35NNaO6 [MþNaþ]: 395.23566. Found: 395.23587;
Chiral HPLC (Daicel Chiralcel OD-H) hexanes/2-propanol¼98:2;
flow rate: 1.0 mL/min;
l¼210 nm; tminor¼7.0 min, tmajor¼10.7 min.
4.4.6. (S)-Diethyl 2-(1-cyclohexyl-2-nitroethyl)- malonate (8f). Color
less oil; 86% ee; 1H NMR (300 MHz, CDCl3):
10 h. The reaction mixture was concentrated in vacuo to afford
d
4.73 (dd, J¼10.5, 4.2 Hz,
20
hydrochloride of Pregabalin 1$HCl (129 mg, 95%). White solid; [
a
]
1H), 4.61 (dd, J¼8.1, 6.6 Hz, 1H), 4.17e4.25 (m, 4H), 3.71 (d, J¼5.1 Hz,
D
þ7.15(c 1.1, H2O) (Ref. 2a [
a
]
20 þ7.0(c 1.1, H2O)); 1H NMR (400 MHz,
1H), 2.85e2.93 (m, 1H), 1.66e1.74 (m, 4H), 1.41e1.50 (m, 1H), 1.28 (t,
D
CD3OD):
d
2.96e2.98 (m, 1H), 2.37e2.48 (m, 1H), 2.18e2.24 (m, 1H),
J¼6.9 Hz, 6H), 0.94e1.19 (m, 6H); 13C NMR (100 MHz, CDCl3):
d 168.5,
1.66e1.73 (m, 1H), 1.25e1.29 (m, 1H), 0.92e0.96 (m, 6H); 13C NMR
(CD3OD, 100 MHz):
¼175.7, 44.4, 41.9, 37.2,32.4, 26.0, 23.1, 22.6.
168.1, 75.4, 61.9, 61.6, 51.4, 41.9, 39.6, 30.1, 29.7, 26.2, 26.1, 25.9, 13.8;
HRMS (ESI): m/z calcd for C15H25NNaO6 [MþNaþ]: 338.15741. Found:
298.15727; Chiral HPLC (Daicel Chiralcel OD-H) hexanes/2-prop-
d
anol¼98:2; flow rate: 1.0 mL/min;
l
¼210 nm; tminor¼7.2 min,
4.4. General procedure for enantioselective Michael addition
of diethyl malonate to nitroalkenes
tmajor¼14.5 min.
4.4.7. (R)-Diethyl 2-(2-nitro-1-phenylethyl)- malonate (8g)5a
White solid; mp 43e45 ꢁC (Ref. 4a mp 45e47 ꢁC); 90% ee; 1H NMR
(300 MHz, CDCl3): 7.15e7.27 (m, 5H), 4.75e4.89 (m, 2H),
.
To a stirred solution of diethyl malonate (1.0 equiv, 0.1 mmol)
and thiourea-catalyst 2 (0.1 equiv, 0.01 mmol) was added nitro-
alkene (1.0 equiv, 0.1 mmol) at ꢀ20 ꢁC. After being stirred for 24 h,
the mixture was directly purified by column chromatography on
silica gel (ethyl acetate/petroleum ether¼1:3 as eluent) to afford
desired product.
d
4.11e4.20 (m, 3H), 3.90e3.97 (m, 2H), 3.71 (d, J¼9.3 Hz, 1H), 1.19 (t,
J¼6.9 Hz, 3H), 0.97 (t, J¼6.9 Hz, 3H); Chiral HPLC (Daicel Chiralpak
AD-H) hexanes/2-propanol¼90:10; flow rate: 1.0 mL/min;
l¼254 nm; tmajor¼8.3 min, tminor¼20.5 min.
4.4.1. (S)-Diethyl 2-(1-nitrobutan-2-yl)malonate (8a). Colorless oil;
4.4.8. (R)-Diethyl 2-(2-nitro-1-p-tolylethyl)-malonate (8h)11. Colorless
oil; 89% ee; 1H NMR (300 MHz, CDCl3):
7.11 (s, 4H), 4.79e4.91 (m,
78% ee; 1H NMR (300 MHz, CDCl3):
d
4.72 (dd, J¼8.7, 4.8 Hz, 1H),
d
4.46 (dd, J¼7.2, 6.0 Hz, 1H), 4.19e4.26 (m, 4H), 3.63 (d, J¼5.7 Hz,
1H), 2.81e2.87 (m, 1H), 1.48e1.58 (m, 2H), 1.28 (t, J¼7.2 Hz, 6H),
2H), 4.17e4.26 (m, 3H), 3.98e4.05 (m, 2H), 3.79 (d, J¼9.3 Hz, 1H), 2.30
(s, 3H), 1.26 (t, J¼6.9 Hz, 3H),1.06 (t, J¼6.9 Hz, 3H); Chiral HPLC (Daicel
Chiralpak AD-H) hexanes/2-propanol¼95:5; flow rate: 1.0 mL/min;
1.00 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 168.0, 167.7,
76.3, 61.9, 61.7, 52.4, 38.4, 29.6, 23.1, 14.0, 11.1; HRMS (ESI): m/z
calcd for C11H19NNaO6 [MþNaþ]: 284.11046. Found: 284.11055;
Chiral HPLC (Daicel Chiralpak OD-H) hexanes/2-propanol¼98:2;
l¼215 nm; tmajor¼13.57 min, tminor¼35.6 min.
4.4.9. (R)-Diethyl
2-(1-(4-methoxyphenyl)-2-nitroethyl)malonate
7.15 (d,
flow rate: 1.0 mL/min;
l
¼210 nm; tminor¼7.2 min, tmajor¼8.2 min.
(8i)11. Yellow oil; 85% ee; 1H NMR (300 MHz, CDCl3):
d
J¼8.4 Hz, 2H), 6.83 (d, J¼8.1 Hz, 2H), 4.81e4.90 (m, 3H), 4.16e4.26
(m, 2H), 3.77e3.80 (m, 4H), 1.24e1.29 (m, 3H), 1.05e1.10 (m, 3H);
Chiral HPLC (Daicel Chiralpak AD-H) hexanes/2-propanol¼70:30;
4.4.2. (S)-Diethyl 2-(1-nitropentan-2-yl)malonate (8b). Colorless
oil; 87% ee; 1H NMR (300 MHz, CDCl3):
d
4.71 (dd, J¼8.7, 4.8 Hz,1H),
4.54 (dd, J¼6.9, 6.3 Hz, 1H), 4.19e4.26 (m, 4H), 3.62 (d, J¼5.7 Hz,
1H), 2.88e2.94 (m, 1H), 1.35e1.49 (m, 4H), 1.28 (t, J¼7.2 Hz, 6H),
flow rate: 0.5 mL/min;
l¼210 nm; tmajor¼10.6 min, tminor¼36.8 min.
0.92 (t, J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d
168.0, 167.8,
4.4.10. (R)-Diethyl
2-(1-(4-fluorophenyl)-2-nitroethyl)malonate
1
76.7, 61.9, 61.7, 52.6, 36.6, 32.1, 29.6, 19.8, 14.0, 13.7; HRMS (ESI): m/z
calcd for C12H21NNaO6 [MþNaþ]: 298.12611. Found: 298.12632;
Chiral HPLC (Daicel Chiralpak OD-H) hexanes/2-propanol¼98:2;
(8j)5a. Colorless oil; 88% ee; H NMR (300 MHz, CDCl3):
d
7.21e7.27
(m, 2H), 7.01 (t, 2H), 4.78e4.94 (m, 2H), 4.17e4.26 (m, 3H), 3.98e4.05
(m, 2H), 3.79 (d, J¼9.3 Hz, 1H), 1.26 (t, J¼6.9 Hz, 3H), 1.06 (t, J¼6.9 Hz,
3H); Chiral HPLC (Daicel Chiralpak AD-H) hexanes/2-prop-
flow rate: 1.0 mL/min;
l
¼210 nm; tminor¼8.5 min, tmajor¼12.6 min.
anol¼90:10; flow rate: 1.0 mL/min;
l¼254 nm; tmajor¼8.5 min,
4.4.3. (S)-Diethyl 2-(1-nitrohexan-2-yl)malonate (8c). Colorless oil;
87% ee; 1H NMR (300 MHz, CDCl3):
tminor¼29.2 min.
d
4.71 (dd, J¼8.4, 4.8 Hz, 1H),
4.53 (dd, J¼6.9, 6.3 Hz, 1H), 4.18e4.26 (m, 4H), 3.62 (d, J¼5.7 Hz,
4.4.11. (S)-Diethyl 2-(2-nitro-1-(thiophen-2-yl)-ethyl)malonate (8k)5a
Colorless oil; 93% ee; 1H NMR (300 MHz, CDCl3):
7.22e7.26 (m, 1H),
.
1H), 2.89 (m, 1H), 1.44e1.51 (m, 2H), 1.26e1.35 (m, 10H), 0.92 (t,
d
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
167.9, 167.8, 76.7, 61.8,
6.91e6.95 (m, 2H), 4.90e4.93 (m, 2H), 4.52e4.59 (m, 1H), 4.19e4.27
(m, 2H), 4.08e4.15 (m, 2H), 3.87 (d, J¼8.1 Hz, 1H), 1.26 (t, J¼6.9 Hz,
3H), 1.16 (t, J¼6.9 Hz, 3H); Chiral HPLC (Daicel Chiralpak AD-H)
61.7, 52.6, 36.8, 29.6, 28.6, 22.3, 13.9, 13.9, 13.7; HRMS (ESI): m/z
calcd for C13H23NNaO6 [MþNaþ]: 312.14176. Found: 312.14205;

640
J.-m. Liu et al. / Tetrahedron 67 (2011) 636e640
Z.; Jiang, Y.; Hu, W. Synlett 2004, 1763e1765; (g) Mita, T.; Sasaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514e515; (i) Rodriguez, V.; Quintero, L.;
Sartillo-Piscil, F. Tetrahedron Lett. 2007, 48, 4305e4308; (k) Ok, T.; Jeon, A.; Lee, J.;
Lim, J. H.; Hong, C. S.; Lee, H.-S. J. Org. Chem. 2007, 72, 7390e7393; (l) Hamersak,
Z.; Stipetic, I.; Avdagic, A. Tetrahedron: Asymmetry 2007, 18, 1481e1485.
2. (a) Sammins, G. L.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442e4443; (b)
Armstrong, A.; Convine, N. J.; Popkin, M. E. Synlett 2006, 1589e1591; (c) Poe, S.;
Kobaslija, M.; McQuade, T. J. Am. Chem. Soc. 2007, 129, 9216e9221; (d) Carlone,
A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A. Chem. Commun. 2006,
4928e4930; (e) Rodríguez, B.; Bruckmann, A.; Bolm, C. Chem.dEur. J. 2007, 13,
4710e4722.
hexanes/2-propanol¼90:10; flow rate: 1.0 mL/min;
tmajor¼8.2 min, tminor¼15.1 min.
l
¼254 nm;
Acknowledgements
This research was supported by the funds of National Natural
Science Foundation of China (No. 20972005), and National Key
Technology R&D Program; Contract grant number: 2007BAI34B00.
3. (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307e5309; (b) Bassas,
O.; Huuskonen, J.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org. Chem. 2009,
1340e1351.
Supplementary data
4. (a) Deng, L. J. Am. Chem. Soc. 2004, 126, 9906e9907; (b) Terada, M.; Ube, H.;
Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454e1455; (c) Almasi, D.; Alonso, D. A.;
Gomez-Bengoa, E. G.; Najera, C. J. Org. Chem. 2009, 74, 6163e6168.
5. (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672e12673; (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Take-
moto, Y. J. Am. Chem. Soc. 2005, 127, 119e125; (c) McCooey, S. H.; Connon, S. T.
Angew. Chem., Int. Ed. 2005, 44, 6367e6370; (d) Ye, J.; Dixon, D. J.; Hynes, P. S.
Chem. Commun. 2005, 4481e4483; (e) Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.;
Lai, L.; Wu, L.; Zhang, J.; Wang, R. J. Org. Chem. 2009, 74, 5562e5567.
6. The general procedure for preparing catalyst 2 see Ref. 5a.
7. Lei, M.; Xia, S.; Wang, J.-F.; Ge, Z.-M.; Cheng, T.-M.; Li, R.-T. Chirality 2010, 22,
580e586.
The original spectra of 1H NMR,13C NMR, and HPLC of all products
are supplied. The supplementary data files are to be used as an aid for
the refereeing of the paper only. Supplementary data associated
with this article can be found in online version at doi:10.1016/
j.tet.2010.11.053. These data include MOL files and InChIKeys of the
most important compounds described in this article.
References and notes
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