Highly enantioselective synthesis of nitrocyclopropanes via organocatalytic conjugate addition of bromomalonate to αβ-unsaturated nitroalkenes

Article abstract of DOI:10.1021/ol900227j

Highly enantioselective synthesis of nitrocyclopropanes was achieved via the organocatalytic conjugate addition of dimethyl bromomalonate to nitroalkenes and the consequent intramolecular cyclopropanation. 6'-Demethyl quinine was found to be the efficient

Full text of DOI:10.1021/ol900227j

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1583-1586
Highly Enantioselective Synthesis of
Nitrocyclopropanes via Organocatalytic
Conjugate Addition of Bromomalonate
to r,ꢀ-Unsaturated Nitroalkenes
Yi-ning Xuan, Shao-zhen Nie, Li-ting Dong, Jun-min Zhang, and Ming Yan*
Industrial Institute of Fine Chemicals and Synthetic Drugs, School of Pharmaceutical
Sciences, Sun Yat-sen UniVersity, Guangzhou 510006, China
yanming@mail.sysu.edu.cn
Received February 2, 2009
ABSTRACT
Highly enantioselective synthesis of nitrocyclopropanes was achieved via the organocatalytic conjugate addition of dimethyl bromomalonate
to nitroalkenes and the consequent intramolecular cyclopropanation. 6′-Demethyl quinine was found to be the efficient catalyst. Excellent
enantioselectivities, diastereoselectivities, and good yields were obtained for a variety of aryl or heteroaryl nitroethylenes.
Chiral cyclopropanes are important structural motifs in a
great number of drugs and natural products.1 In addition,
chiral cyclopropanes are useful synthetic intermediates in
organic synthesis.2 The high strain of the cyclopropane ring
makes them susceptible to ring opening reaction with many
nucleophilic reagents. Great efforts have been made to
develop efficient synthetic methods of chiral cyclopropanes.3
Nitrocyclopropanes are a class of special cyclopropane
compounds, which are presented in some natural products
such as the peptidolactone hormaomycin4 and are also used
as the precursor of the broad-spectrum antibiotic Trova-
floxacin.5 Furthermore, nitrocyclopropanes can be converted
into a wide range of useful compounds.6 The asymmetric
synthesis of nitrocyclopropanes had been developed via the
reaction of nitroalkyl carbenes with alkenes.7 Asymmetric
conjugate addition and consequent intramolecular alkylation
are extremely powerful and general methods for the synthesis
of chiral cyclopropanes.3a,8 In recent years, asymmetric
organocatalysis has emerged as a powerful tool for the
(4) (a) Zlatopolskiy, B. D.; Loscha, K.; Alvermann, P.; Kozhushkov,
S. I.; Nikolaev, S. V.; Zeeck, A.; de Meijere, A. Chem. Eur. J. 2004, 10,
4708. (b) Zindel, J.; de Meijere, A. J. Org. Chem. 1995, 60, 2968. (c)
Andres, N.; Wolf, H.; Zaehner, H.; Roessner, E.; Zeeck, A.; Koenig, W. A.;
Sinnwell, V. HelV. Chim. Acta 1989, 72, 426.
(5) (a) Gootz, T. D.; Brighty, K. E. Med. Res. ReV. 1996, 16, 433. (b)
Brighty, K. E.; Castaldi, M. J. Synlett 1996, 1097.
(1) For the reviews of cyclopropanes as the structure motif in drugs
and natural products, see: (a) Donaldson, W. A. Tetrahedron 2001, 57, 8589.
(b) Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2251. (c) Wessjohann, L. A.;
Brandt, W.; Thiemann, T. Chem. ReV. 2003, 103, 1625.
(6) For the reactions of nitrocyclopropanes, see: (a) Lifchits, O.; Alberico,
D.; Zakharian, I.; Charette, A. B. J. Org. Chem. 2008, 73, 6838. (b) Wurz,
R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262. (c) Larionov, O. V.;
Savel’eva, T. F.; Kochetkov, K. A.; Ikonnokov, N. S.; Kozhushkov, S. I.;
Yufit, D. S.; Howard, J. A. K.; Khrustalev, V. N.; Belokon, Y. N.; de
Meijere, A. Eur. J. Org. Chem. 2003, 869. (d) Hubner, J.; Liebscher, J.;
Patzel, M. Tetrahedron 2002, 58, 10485. (e) Cao, W.; Erden, I.; Keeffe,
J. R. Angew. Chem., Int. Ed. 1995, 34, 1091. (f) Zindel, J.; Zeeck, A.; Konig,
W. A.; de Meijere, A. Tetrahedron Lett. 1993, 34, 1917. (g) Baer, H. H.;
Williams, U.; Radatus, B. Carbohydr. Res. 1988, 174, 291. (h) Seebach,
D.; Haener, R.; Vettiger, T. HelV. Chim. Acta 1987, 70, 1507.
(2) For the reviews of cyclopropanes as useful synthetic intermediates,
see: (a) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanitroalkeneo,
J.; Hudlicky, T. Chem. ReV. 1989, 89, 165. (b) Reissig, H. U.; Zimmer, R.
Chem. ReV. 2003, 103, 1151.
(3) For the reviews of asymmetric synthesis of cyclopropanes, see: (a)
Pellissier, H. Tetrahedron 2008, 64, 7041. (b) Lebel, H.; Marcoux, J. F.;
Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977. (c) Hartley, R. C.;
Caldwell, S. T. J. Chem. Soc., Perkin Trans. 1 2000, 477.
10.1021/ol900227j CCC: $40.75
Published on Web 03/04/2009
2009 American Chemical Society

synthesis of valuable chiral compounds.9 Conjugate addition
of 1-bromonitroalkanes to unsaturated aldehydes10 and
ketones11 catalyzed by chiral amines was developed by us
and other research groups. The corresponding nitrocyclo-
propanes were obtained in good yields and with excellent
enantioselectivities. On the other hand, the asymmetric
synthesis of nitrocyclopropanes via the addition of chloro-
malonates to nitroalkenes was also reported by Connon and
co-workers in 2006.12 The reaction provided the nitrocyclo-
propanes in moderate yield and with low enantioselectivity
using cinchona alkaloid derived thioureas as the catalysts.
Very recently, Fan and co-workers reported the asymmetric
synthesis of nitrocyclopropanes via oxidative cyclization of
the Michael adducts of nitroalkenes with malonates.13 Good
enantioselectivities were achieved using a chiral thiourea
catalyst derived from cyclohexanediamine. Cinchona alkaoids
are highly useful organocatalysts for a large number of
asymmetric transformations.14 Among the various derivatives
of cinchona alkaoids, 6′-demethyl cinchona alkaoids (cu-
preines and cupreidines) showed great advantages in a variety
of reactions. These catalysts feature simultaneous activation
of both nucleophile and electrophile.15 Deng and co-workers
reported a highly enantioselective addition of malonates to
nitroalkenes catalyzed by 6′-demethyl cinchona alkaoids.16
The reaction was also catalyzed by cinchona alkaloid based
urea and thiourea organocatalysts with excellent enantiose-
lectivities.17 Herein we report a highly enantioselective
conjugate addition of dimethyl bromomalonate to nitroalk-
enes catalyzed by 6′-demethyl quinine. The consequent
intramolecular cyclopropanation provided nitrocyclopropanes
in good yields and with excellent enantioselectivities.
The reaction of dimethyl bromomalonate and ꢀ-nitrosty-
rene was studied using cinchona alkaloids and its derivatives
as the catalysts (Scheme 1). Natural cinchona alkaloids
Scheme 1
.
Catalytic Addition of Dimethyl Bromomalonate to
ꢀ-Nitrostyrene
3a-3d were inefficient, and no reaction occurred after 48 h
at room temperature. Chiral amino alcohol 3e also did not
show any catalytic activity. In contrast, 6′-demethyl quinine
3f afforded the adduct in good yield and with excellent
enantioselectivity. The product 2a was deposited from the
reaction solution and easily separated by the centrifuge. The
result confirms the importance of free phenolic hydroxyl
group for the catalytic activity of cinchona alkaloids. The
similar phenomenon was also observed by Deng and co-
workers.16
Encouraged by the preliminary result, further optimization
of reaction conditions was carried out and the results are
summarized in Table 1. Lower reaction temperature signifi-
(7) Asymmetric synthesis of nitrocyclopropanes via the reaction of
nitroalkyl carbenes with alkenes, see: (a) Zhu, S.; Perman, J. A.; Zhang,
X. P. Angew. Chem., Int. Ed. 2008, 47, 8460. (b) Moreau, B.; Charette,
A. B. J. Am. Chem. Soc. 2005, 127, 18014. (c) Charette, A. B.; Wurz, R. P.
J. Mol. Catal. A 2003, 196, 83. (d) Wurz, R. P.; Charette, A. B. Org. Lett.
2003, 5, 2327.
Table 1. Optimization of Reaction Conditionsa
(8) (a) Ibrahem, I.; Zhao, G. L.; Rios, R.; Vesely, J.; Sunden, H.;
Dziedzic, P.; Cordova, A. Chem. Eur. J. 2008, 14, 7867. (b) Xie, H.; Zu,
L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886.
(9) For the general reviews on asymmetric organocatalysis, see: (a)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (b) Guillena, G.; Najera,
C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249. (c) Dalko, P. I.
EnantioselectiVe Organocatalysis; Wiley-VCH: Weinheim, Germany, 2007.
(d) The special issue devoted to “Asymmetric Organocatalysis”: List, B.
Chem. ReV. 2007, 107, 5413. (e) Yu, X. H.; Wang, W. Chem. Asian J.
2008, 3, 516.
entry
t (°C)
3f (mol %)
yield (%)b
ee (%)c
1
2
3
4
5
rt
0
-20
-20
-20
5
5
5
2
1
81
90
95
88
80
98
98
>99
99
99
(10) (a) Zhang, J. M.; Hu, Z. P.; Dong, L. T.; Xuan, Y. N.; Yan, M.
Tetrahedron: Asymmetry 2009, in press. (b) Vesely, J.; Zhao, G. L.;
Bartoszewicz, A.; Cordova, A. Tetrahedron Lett. 2008, 49, 4209.
(11) (a) Lv, j.; Zhang, J. M.; Lin, Z.; Wang, Y. M. Chem. Eur. J. 2009,
15, 972. (b) Hansen, H. M.; Longbottom, D. A.; Ley, S. V. Chem. Commun.
2006, 4838.
a Reactions were carried out for 24 h with 1a (0.5 mmol), dimethyl
bromomalonate (0.55 mmol), 3f (0.025 mmol) in THF (0.5 mL). b Isolated
yield. c Enantiomeric excess values were determined by chiral HPLC after
transformation to 4a.
(12) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006,
71, 7494.
cantly improved the yield, probably due to reduced side
reactions. In addition, the enantioselectivity could be im-
proved furthermore. Over 99% ee and excellent chemical
yield were achieved at -20 °C (Table 1, entry 3). The
decrease of catalyst loading resulted in lower chemical yield,
but the enantioselectivity of the reaction was not influenced
(Table 1, entries 3-5).
(13) Fan, R. H.; Ye, Y.; Li, W. X.; Wang, L. F. AdV. Synth. Catal.
2008, 350, 2488.
(14) For the review of cinchona alkaloids as organocatalysts, see: Tian,
S. K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res.
2004, 37, 621.
(15) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem.,
Int. Ed. 2006, 45, 7496.
(16) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004,
126, 9906.
(17) (a) Connon, S. J. Chem. Commun. 2008, 2499. (b) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (c) Ye, J. X.; Dixon,
D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
The intramolecular cyclopropanation of the product 2a was
further studied. A number of bases and solvents were
1584
Org. Lett., Vol. 11, No. 7, 2009

examined. The experiment results are listed in Table 2. The
choice of the appropriate base and solvent was important
Table 3. Synthesis of Chiral Nitrocyclopropanes from a Variety
of Nitroalkenesa
Table 2. Effect of Bases and Solvents on the Intramolecular
Cyclopropanation of 2aa
entry
R
time (h)b product, yield (%)c ee (%)d
1e
2
Ph, 1a
24
24
34
24
24
66
72
12
66
94
24
24
48
48
4a, 78
4b, 69
4c, 70
4d, 72
4e, 68
4f, 63
4g, 67
4h, 58
4i, 73
4j, 75
4k, 69
4l, 47
-
>99
96
97
>99
94
97
94
96
95
75
98
99
-
4-Cl-C6H4, 1b
2-Cl-C6H4, 1c
3-Cl-C6H4, 1d
4-Br-C6H4, 1e
4-Me-C6H4, 1f
4-MeO-C6H4, 1g
4-NO2-C6H4, 1h
2-NO2-C6H4, 1i
entry
solvent
base
Et3N
K2CO3
Et3N
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
time (h)
yield (%)b
3
4e
5
1
2
3
4
5
6
7
8
9
DCM
DMF
THF
120
120
72
38
3
3
3
2
3
trace
-
trace
32
-
trace
82
6f
7f
8
THF
MeOH
EtOAc
DMF
DMSO
NMPc
9
10 1-naphthyl, 1j
11 2-thienyl, 1k
12 2-furyl, 1l
13 pentyl, 1m
14 cyclohexyl, 1n
a Asymmetric conjugate additions were carried out with 1 (0.5 mmol),
dimethyl bromomalonate (0.55 mmol), 3f (0.025 mmol) in THF (0.5 mL).
Unless otherwise stated, adducts 2 were separated by flash column
chromatography. The intramolecular cyclopropanations were carried out
with 2 (0.1 mmol) and DABCO (0.105 mmol) in DMF (1 mL). b The
reaction time of the first step. c The combined yield of two steps. Only
trans-isomer was observed. d Determined by chiral HPLC. e Adducts of
the first reaction were separated by centrifugation. f The first step was
conducted in THF (1 mL) due to low solubility of the substrate.
64
79
a Reactions were carried out at room temperature with 2a (0.1 mmol),
base (0.105 mmol) and solvent (1 mL). b Isolated yield. Only trans-isomer
wasobserved.>99%eevalueswereobtainedinallcases.c N-Methylpyrrolidin-
2-one.
-
-
for the success of the transformation. The combination of
DABCO and DMF provided nitrocyclopropane 4a in good
yield (Table 2, entry 7). The relative configuration of 4a was
determined to be trans based on NOE analysis. No cis-isomer
was observed by NMR analysis.
The asymmetric conjugate addition of dimethyl bromo-
malonate to a number of nitroalkenes catalyzed by 3f and
consequent intramolecular cyclopropanation were studied.
The results are summarized in Table 3. Various substituted
ꢀ-phenyl nitroethylenes provided nitrocyclopropanes in good
yields and with excellent enantioselectivities (Table 3, entries
1-9). The ortho-, meta-, and para-substituents on the phenyl
ring were tolerated very well. The electronic property of the
substituent seemed to have a slight effect on the yield and
enantioselectivity. The reaction of ꢀ-naphthyl nitroethylene
required extended reaction time and provided the nitrocy-
clopropane product with moderate enantioselectivity (Table
3, entry 10). The result could be ascribed to the bigger steric
hindrance of the naphthyl group. ꢀ-Heteroaryl nitroethylenes
provided nitrocyclopropanes with excellent enantioselectivi-
ties, however, in low to moderate chemical yields (Table 3,
entries 11 and 12). ꢀ-Alkyl nitroethylenes were also exam-
ined, but no conjugate adducts were observed.
Figure 1. X-ray structure of 4h.
The asymmetric conjugate addition of dimethyl chloro-
malonate to ꢀ-nitrostyrene and the consequent intramolecular
cyclopropanation were also studied (Scheme 2). The con-
jugate addition was achieved in good yield, but the intramo-
lecular cyclopropanation of adduct 5 was found to be more
difficult than cyclopropanation of 2a. Only a trace amount
of 4a was observed after 48 h with the DABCO/DMF
system. The DBU/HMPA system adopted by Connon and
co-workers12 provided 4a in better yield, but the enantiose-
lectivity was rather poor (39% ee).
A single crystal of nitrocyclopropane 4h was obtained.
The absolute configuration of 4h was determined as (2S,3R)-
dimethyl 2-nitro-3-(4-nitrophenyl)cyclopropane-1,1-dicar-
boxylate by X-ray diffraction analysis (Figure 1).18 Analo-
gously, the other nitrocyclopropane products were proposed
to have the same absolute configurations.
(18) CCDC 718886 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
In summary, we have developed a convenient and efficient
method for the asymmetric synthesis of nitrocyclopropanes
via the organocatalytic conjugate addition of dimethyl bro-
Org. Lett., Vol. 11, No. 7, 2009
1585

the method attractive for the practical synthesis of chiral
nitrocyclopropanes. Further applications of the nitrocyclo-
propane products in organic synthesis are currently under
investigation.
Scheme 2
.
Asymmetric Cyclopropanation of ꢀ-Nitrostyrene with
Dimethyl Chloromomalonate
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20772160), NCET plan of the
Ministry of Education of China, Guangzhou Bureau of
Science and Technology for the financial support of this
study. We also thank Professor Xiao-peng Hu for performing
the X-ray diffraction analysis.
Supporting Information Available: Experimental pro-
cedures, NMR spectra, and HPLC chromatograms. This
material is available free of charge via the Internet at
http://pubs.acs.org.
momalonate to nitroalkenes and the consequent intramo-
lecular cyclopropanation. Excellent enantioselectivities, di-
astereoselectivities, and good chemical yields were achieved.
The readily available catalyst and the simple procedure make
OL900227J
1586
Org. Lett., Vol. 11, No. 7, 2009