Enantioselective organocatalytic michael addition of nitroalkanes and other nucleophiles to β-trifluoromethylated acrylamides

Article abstract of DOI:10.1021/cs300806w

An organocatalytic asymmetric Michael addition of nitroalkanes to trifluoromethylated acrylamides in good yields and with good to excellent diastereoselectivities and excellent enantioselectivities is described. The Michael adducts could be readily transf

Full text of DOI:10.1021/cs300806w

Research Article
pubs.acs.org/acscatalysis
Enantioselective Organocatalytic Michael Addition of Nitroalkanes
and Other Nucleophiles to β‑Trifluoromethylated Acrylamides
Lele Wen, Liang Yin, Qilong Shen,* and Long Lu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: An organocatalytic asymmetric Michael addi-
tion of nitroalkanes to trifluoromethylated acrylamides in good
yields and with good to excellent diastereoselectivities and
excellent enantioselectivities is described. The Michael adducts
could be readily transformed into optically pure trifluorome-
thylated γ-aminobutyric acid 7 in high yields without loss in
enantioselectivities.
KEYWORDS: trifluoromethyl, organocatalyst, Michael addition, fluorine, asymmetric
conjugated addition of nitroalkanes to β-trifluoromethylated
acrylamides in good to excellent yields with high enantiose-
lectivities up to 96% ee.
INTRODUCTION
■
In recent years, the stereoselective introduction of fluorine into
druglike molecules has attracted great attention in the field of
medicinal and agricultural chemistry because of the unique
physical properties of organofluorine compounds and the huge
demands for chiral drugs.1 Consequently, development of
catalytic enantioselective methods for the construction of
trifluoromethyl-containing stereogenicity has become a synthetic
challenge.2,3 More specifically, incorporation of fluorine into γ-
aminobutyric acid and its derivatives is of great interest because
of their important role in the central nervous system.4 For
example, Pregabalin, Baclofen, and Gabapentin are important
medicines for relieving neuropathic pain.5 One general route for
the preparation of optically pure γ-aminobutyric acid is direct
asymmetric Michael addition of nitroalkanes to α, β-unsaturated
carbonyl compounds, followed by reduction of the nitro group.6
In the past 10 years, various catalysts, including chiral Lewis
acids,7 phase-transfer catalysts,8 and organocatalysts9 based on
thiourea, have been shown to be efficient for these reactions. In
contrast, Michael additions of nitroalkanes to electron-deficient
alkenes bearing a trifluoromethyl group as a Michael acceptor
have rarely been reported.4 We recently reported trifluoroethy-
lidene malonate is a good Michael receptor when it is reacted
with aldehydes using prolinol silyl ether as a catalyst to give the
addition products with high enantioselectivity.10 As part of our
ongoing programs with the aim to develop high regio- and
enantioselective methods for the construction of a chiral center
containing a trifluoromethyl group,11 we wondered if it could be
possible to realize highly enantioselective Michael additions of
nitroalkanes to trifluoroethylidene malonate, trifluoromethylated
acrylates, or acrylamides to give trifluoromethylated γ-nitro-
butyric acid derivatives that are precursors of trifluoromethylated
γ-aminobutyric acid, a potential drug candidate. Herein, we
report a Cinchona-alkaloid-thiourea-catalyzed enantioselective
RESULTS AND DISCUSSIONS
■
We initially examined quinine (2a), quinidine (2b), 9-amino-9-
deoxyquinidine (2c), Cinchona-alkaloid-thiourea9b (2d) and
Takemoto’s catalyst12 (2e) (5−15 mol %) as potential catalysts
for reaction of nitromethane and diethyl 2,2,2-trifluoroethyli-
dene malonate 1a, (E)-ethyl-4,4,4-trifluorobut-2-enoate 1b, or β-
trifluoromethylated acrylamide 1c (Table 1). Reactions of
nitromethane and diethyl 2,2,2-trifluoroethylidene malonate 1a
using quinine 2a or quinidine 2b as the catalyst occurred with
over 90% conversion after 7 h at room temperature; however,
these reactions formed the desired products in 3−5% ee (Table
1, entries 1 and 2). Reactions in the presence of quinidine
derivatives 2c occurred much more slowly, and only 31%
conversion was observed after 72 h at room temperature (Table
1, entry 3). When Cinchona-alkaloid-thiourea 2d was used as the
catalyst, the enantioselectivity was improved to 43% ee (Table 1,
entry 4). When Takemoto’s catalyst 2e was used as the catalyst,
reaction was much faster. Only 5 mol % of the catalyst was
required for the reaction to occur to full conversion after 12 h at
room temperature. However, only 44% ee was observed (Table
1, entry 5). Lowering the reaction temperature to 0 °C resulted in
only slightly improved enantioselectivity (Table 1, entry 6).
Switching the substrate to the less reactive (E)-ethyl-4,4,4-
trifluorobut-2-enoate 1b led to much slower reactions. Less then
10% conversion of the starting material was observed after 24 h at
room temperature (Table 1, entry 7). When β-trifluoromethy-
Received: December 12, 2012
Revised: January 30, 2013
Published: February 5, 2013
© 2013 American Chemical Society
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Research Article
Table 1. Optimization of Reaction Conditionsa
acrylamide 1c was faster than pentafluoroethyl-substituted
acrylamide 1c′, which required 48 h to result in full conversion.
Both of them afforded the desired Michael adducts in excellent
enentioselectivities (Table 2, 3a and 3b). Both methyl and ethyl
nitropropanoate or nitrobutanoate reacted with trifluoromethy-
lated acrylamide 1c or 1c′ with excellent diastereo- and
enantioselectivities (Table 2, 3c−f). The diastereoselectivity
was determined by 19F NMR spectroscopy of the crude reaction
mixture. Excellent diastereoselectivity in a ratio of 31:1 was
achieved for the reaction of trifluoromethylated acrylamide
derived from Evan’s auxiliary catalyzed by Cinchona-alkaloid-
thiourea 2d, whereas reaction using triethylamine as the base
gave the corresponding product in a 1.1:1 ratio of diaster-
eoselectivity (Table 2, 3g). Reaction of malononitrile with
trifluoromethylated acrylamide 1c occurred with excellent yield
but moderate enantioselectivity (Table 2, 3h).
Reactions of other nucleophiles such as malonate or β-
ketoester occurred much more slowly and in low enantiose-
lectivity. For example, reaction of β-ketoester required 96 h to
reach full conversion to give the desired product in 54% ee with a
1.4/1 ratio of diastereoselectivity, but reaction of malonate was
much slower and required 8 days to reach full conversion to give
the product in 39% yield in 77% ee (Table 2, 3i, j). In general,
reactions of trifluoromethylated acrylamide 1c were much faster
than those of trifluoromethylated acrylamide 1d and 1d′ derived
from imidazolidin-2-one, which occurred with good enantiose-
lectivity but typically required being heated to 60 °C for 24 h for
full conversion (Table 2, 3k and 3l).
Reactions of trifluoromethylated acrylamide 1e derived from
imidazole were only slightly slower, but occurred with lower
diastereo- and enantioselectivity than those of trifluoromethy-
lated acrylamide 1c (Table 3m-r). For example, reaction of
methyl nitro-2-propanoate with trifluoromethylated acrylamide
1e afforded the Michael adduct in 75% yield in 88% ee and 4.4/1
diastereoselectivity after 48 h at room temperature (Table 2, 3n).
Interestingly, when methyl or ethyl acetyl acetate was used as the
nucleophile, a cascade Michael addition, followed by intra-
molecular cyclization, proceeded to give trifluoromethylated
lactone 4a, b in good yields and with moderate enantioselectivity
(eq 1). The absolute configuration of the product was
determined by X-ray crystallographic analysis of a single crystal
of 4b.
a
Reaction conditions: 1a−c (0.1 mmol), nitromethane (0.5 mmol),
and catalyst (5−15 mol %) in solvent (0.5 mL) at indicated
b
temperature. The conversion of starting material was determined
c
by 19F NMR analysis of the crude reaction mixture. The ee value was
d
determined by chiral-phase HPLC analysis. The reaction was
conducted at 0 °C.
lated acrylamide 1c was used as the substrate and 2d was used as
the catalyst, to our delight, excellent conversion (99%) and
enantioselectivity (94%) were observed (Table 1, entry 8).
Interestingly, when 2e was used as the catalyst for the same
transformation, slightly lower enantioselectivity (91%) but in
opposite rotation was observed (Table 1, entry 9). Different
solvents were then examined to improve the yield and
enantioselectivity. It was found that reactions in dichloro-
methane occurred with full conversion after 24 h at room
temperature to give the desired product 3a in slightly lower
enentioselectivity, whereas reactions in acetonitrile or ethyl
acetate occurred much more slowly (Table 1, entries 10−12).
Less than 10% conversion was observed when the reaction was
conducted in THF at room temprature (Table 1, entry 13).
On the basis of the results summarized in Table 1, the reaction
conditions of entry 8 were chosen to study the scope of the
Michael reactions of nitroalkanes or other nucheophiles with
trifluoromethylated acrylamides, and the results are summarized
in Table 2. Reaction of nitromethane with trifluoromethylated
The absolute configuration of the stereogenic center (R) in
compound 3 was determined by X-ray crystallographic analysis
of a single crystal of 3c (Figure 1). The absolute configurations of
the Michael adducts 3p and 3q obtained from reaction of methyl
and ethyl nitropropanoate or nitrobutanoate with trifluorome-
thylated acrylamide 1e derived from imidazole were determined
by their reduced derivatives 5a and 5b (eq 2). The configurations
of the rest of the products were assigned on the assumption of a
uniform mechanistic pathway.
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a,b,c
Table 2. Enantioselective Michael Addition of Nitroalkanes and Other Nucleophiles to Trifluoromethylated Acrylamides
a
b
c
Isolated yield. Diastereoselectivity was determined by 19F NMR of the crude adducts. The ee value was determined by chiral-phase HPLC
d
e
f
g
h
i
j
analysis. 5 mol % catalyst was used. 15 mol % catalyst was used. 48 h. 96 h. 8 days. 60 °C. 1.1/1 dr for reaction using Et3N as the base.
Figure 1. The ORTEP view of compound 3c.
As a demonstration of the synthetic utility of this catalytic
spectroscopies and further confirmed by X-ray diffraction
analysis of its single crystal. Compound 6b can be easily
converted to trifluoromethylated γ-aminobutyric acid 7 in
refluxed 6 N hydrochloric acid in quantitative yield.
approach, the adduct 3a was further converted into trifluor-
omethylated γ-aminobutyric acid 7 (Scheme 1). Hydrogenation
of compound 3a using Raney Ni as the catalyst in a mixed EtOH/
EtOAc solvent at room temparature gave an inseparable mixture
of trifluoromethylated γ-lactam and 2-oxazolidone, which was
further reacted with TsCl or (Boc)2O to give compound 6a and
6b in 57% and 82% yield, respectively. The structure of the
compound 6a was characterized by 1H, 13C, 19F NMR
CONCLUSION
■
In summary, we have developed a new protocol for the
asymmetric Michael addition of nitroalkanes to trifluoromethy-
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Scheme 1. Preparation of Trifluoromethylated γ-Aminobutyric Acid 7 from Compound 3a
Tetrahedron Lett. 2008, 49, 2106. (d) Nagib, D. A.; Scott, M. E.;
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MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986. (f) Blay, G.;
lated acrylamides in good yields and with good to excellent
diastereoselectivities and excellent enantioselectivities. The
Michael adducts could be readily transformed into optically
pure trifluoromethylated γ-aminobutyric acid 7 in high yields
without loss in enantioselectivities. Mechanistic studies,
synthetic applications of these transformations, and development
of other organocatalytic enantioselective conjugate addition
reactions are ongoing in our laboratory.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: lulong@mail.sioc.ac.cn or shenql@mail.sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support from the
National Basic Research Program of China (2012CB821600,
2010CB126103), the Key Program of National Natural Science
Foundation of China (21032006), the National Natural Science
Foundation of China (21172244/21172245/B020304), Agro-
scientific Research in the Public Interest (201103007), the
National Key Technologies R&D Program (2011BAE06B05),
and the Shanghai Scientific Research Program (10XD1405200)
and the Shanghai Pujiang program (11PJ1412200) for financial
support.
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