Primary amine/(+)-CSA salt-promoted organocatalytic conjugate addition of nitro esters to enones

Article abstract of DOI:10.1021/ol1006407

The combination of 9-amino-9-deoxy-epi-cinchonine and (+)-CSA resulted in a novel primary amine-based organocatalyst for effective iminium activation of α,β-unsaturated ketones. Such a catalytic system could catalyze the conjugate addition of nitroacetate

Full text of DOI:10.1021/ol1006407

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2278-2281
Primary Amine/(+)-CSA Salt-Promoted
Organocatalytic Conjugate Addition of
Nitro Esters to Enones
Chen Liu and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National UniVersity of Singapore, 3 Science DriVe 3, Republic of Singapore, 117543
chmlyx@nus.edu.sg
Received March 18, 2010
ABSTRACT
The combination of 9-amino-9-deoxy-epi-cinchonine and (+)-CSA resulted in a novel primary amine-based organocatalyst for effective iminium
activation of r,ꢀ-unsaturated ketones. Such a catalytic system could catalyze the conjugate addition of nitroacetate to enones in a highly
enantioselective manner, affording the desired adducts in high yields and with up to 99% ee.
The conjugate addition of the stabilized carbanions to R,ꢀ-
unsaturated carbonyl compounds represents one fundamental
carbon-carbon bond-forming reaction in organic synthesis,
and the development of chiral catalysts for the asymmetric
version of this reaction constitutes an important research field
and has been well-explored in recent years.1 In particular,
small organic molecules have been found to be extremely
useful in promoting asymmetric conjugate addition reac-
tions.2 Since MacMillan’s introduction of iminium catalysis
as a general mode of activation in asymmetric catalysis,3
this LUMO-lowering strategy has been firmly established
and has found wide applications in asymmetric synthesis.4
It should be noted that catalysts used for the iminium
activations in the early days are mostly chiral secondary
amines and have been utilized mainly for the activation of
R,ꢀ-unsaturated aldehydes. Primary amine-based organo-
catalytic synthetic methods have emerged as powerful and
versatile tools in asymmetric synthesis recently.5 In particular,
chiral primary amines are extremely useful in iminium
catalysis, and reactions catalyzed by primary amines in many
cases are better than or complementary to those achieved
with reactions promoted by pyrrolidine-based secondary
amine catalysts.6 As part of our research program toward
the development of primary amine-based asymmetric syn-
thetic methods,7 we became interested in the design of novel
organocatalytic reactions utilizing primary amine-induced
iminium activation.
(4) For selected reviews, see: (a) Erkkila, A.; Majander, I.; Pihko, P. M.
Chem. ReV. 2007, 107, 5416. (b) Lelais, G.; MacMillan, D. W. C.
Aldrichimica Acta 2006, 39, 79. For selected examples, see: (c) Austin,
J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (d) Austin,
J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5482.
(1) For reviews, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033. (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171. (c)
Berner, O. E.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1788. (d)
Yamaguchi, M. ComprehensiVe Asymmetric Catalysis I -III; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999.
(2) For recent reviews on organocatalytic conjugate additions, see: (a)
Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18,
299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(5) For reviews on primary amino acids and primary amines in
asymmetric catalysis, see: (a) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun.
2009, 1807. (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047. (c)
Peng, F.; Shao, Z. J. Mol. Catal. A 2008, 285, 1. (d) Chen, Y.-C. Synlett
2008, 1919. (e) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759.
(3) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243.
10.1021/ol1006407  2010 American Chemical Society
Published on Web 04/22/2010

Nitro esters are valuable sources of stabilized carbanions
in organic synthesis, and they have been used as masked
amino acids in various organic transformations.8 However,
enantioselective reactions employing nitro esters are currently
very limited.9 In this context, we were intrigued to develop
an organocatalytic asymmetric addition of nitro esters to R,ꢀ-
unsaturated ketones, as examples of this type of enantiose-
lective conjugate additions are scarce in the literature. Ikariya
and co-workers reported enantioselective addition of ethyl
nitroacetate to cyclopentenone, catalyzed by a chiral ruthe-
nium complex.10 Jørgensen et al. prepared a number of novel
secondary amine organocatalysts and applied them in the
Michael addition of nitroacetate to R,ꢀ-unsaturated ketones.
The products were formed with good enantioselectivities,
and no diastereoselectivity was observed.11 Although very
interesting, those reported reactions suffered from very low
reaction rates, and virtually no reaction scope was explored
in these studies. We envisaged that an enantioselective
conjugate addition of nitro esters to enones may be achieved
via efficient iminium activation of enones by primary amine-
based organocatalysts. Herein, we show that the combination
of (+)-camphorsulfonic acid (CSA) with cinchonidine results
in an effective organic catalyst, which catalyzed the enan-
tioselective conjugate addition of nitroacetate to R,ꢀ-unsatur-
ated ketones, affording the desired adducts with excellent
enantiomeric excesses.
The reaction between ethyl nitroacetate 1a and trans-4-
phenyl-3-buten-2-one 2a was chosen as a model reaction,
and the catalytic effects of various primary amine catalysts
were examined. The results are summarized in Table 1.
Table 1. Screening of Organocatalysts for the Conjugate Addition
of Ethyl R-Nitro Acetate to trans-4-Phenyl-3-buten-2-onea
eed (%)
entry cat.
additive
t (h) yieldb (%) drc syn/anti
1
2
3
4
5
6
7
8
4
5
6
7
8
8
8
8
9
p-NO2PhCO2H
p-NO2PhCO2H
p-NO2PhCO2H
p-NO2PhCO2H
p-NO2PhCO2H
TsOH
24
9
74
91
97
99
39
59
89
94
80
80
89
87
1:1 77/80
1:1 66/65
1:1 83/83
1:1 0/13
1:1 98/98
1:1 91/90
1:1 94/93
1:1 99/99
1:1 -77/-86
1:1 -77/-84
1:1 99/99
1:1 97/86
(6) For selected excellent examples, see: (a) Chen, W.; Du, W.; Yue,
L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2007, 5,
816. (b) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.;
Melchiorre, P. Org. Lett. 2007, 9, 1403. (c) Kim, H.; Yen, C.; Preston, P.;
Chin, J. Org. Lett. 2006, 8, 5239. (d) Xie, J.-W.; Yue, L.; Chen, W.; Du,
W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413. (e) Xie,
J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.;
Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389. (f) Li, P.; Wang,
Y.; Liang, X.; Ye, J. Chem. Commun. 2008, 3302. (g) Ricci, P.; Carlone,
A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. AdV. Synth. Catal.
2008, 350, 49. (h) Lu, X.; Deng, L. Angew. Chem., Int. Ed. 2008, 47, 7710.
(i) Carlone, A.; Bartoli, G.; Bosco, M.; Pesciaioli, F.; Ricci, P.; Sambri, L.;
Melchiorre, P. Eur. J. Org. Chem. 2007, 5492. (j) Ishihara, K.; Nakano, K.
J. Am. Chem. Soc. 2005, 127, 10504. (k) Singh, R. P.; Bartelson, K.; Wang,
Y.; Su, H.; Lu, X.; Deng, L. J. Am. Chem. Soc. 2008, 130, 2422. (l) Chen,
W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.; Chen, Y.-C. Angew. Chem.,
Int. Ed. 2007, 46, 7667. (m) Martin, N. J. A.; List, B. J. Am. Chem. Soc.
2006, 128, 13368. (n) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem.
Soc. 2008, 130, 6070. (o) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L.
J. Am. Chem. Soc. 2008, 130, 8134. (p) Reisinger, C. M.; Wang, X.; List,
B. Angew. Chem., Int. Ed. 2008, 47, 8112.
48
14
24
24
24
24
24
24
24
20
(-)-CSA
(+)-CSA
9
(+)-CSAe
10
11
12
10 (+)-CSA
11 (+)-CSA
12 (+)-CSA
a Reactions were performed with 4-phenyl-but-3-en-2-one (0.1 mmol),
ethyl nitroacetate (0.2 mmol), and primary amine (0.01 mmol) in xylene
c
(0.1 mL) at room temperature. b Isolated yield. Determined by H NMR
analysis of the products. d The ee value was determined by chiral HPLC
analysis. e 20 mol % additive.
1
(7) For our work on primary amino acid/amine mediated organocatalysis,
see: (a) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801.
(b) Cheng, L.; Han, X.; Huang, H.; Wong, M. W.; Lu, Y. Chem. Commun.
2007, 4143. (c) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5,
1018. (d) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007,
349, 812. (e) Zhu, Q.; Lu, Y. Chem. Commun. 2008, 6315. (f) Han, X.;
Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed.
2009, 48, 7604. (g) Zhu, Q.; Lu, Y. Chem. Commun. 2010, 46, 2235. (h)
Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong, M. W.; Lu, Y. Org. Biomol.
Chem. 2010, 8, 1368. (i) Jiang, Z.; Lu, Y. Tetrahedron Lett. 2010, 51, 1884.
(8) (a) Rosini, G.; Ballini, R. Synthesis 1988, 833. (b) Charette, A. B.;
Wurz, R. P.; Ollevier, T. HelV. Chim. Acta 2002, 85, 4468. (c) Fornicola,
R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998, 63, 3528. (d)
Shen, B.; Johnston, J. N. Org. Lett. 2008, 10, 4397.
(1S,2S)-1,2-Diphenylethane-1,2-diamine-derived primary amine
catalysts containing thiourea (4) and sulfonamides (5 and
6), in combination with p-nitrobenzoic acid, were found to
be effective, affording the desired products in excellent yields
and with moderate to good enantioselectivities (entries 1-3).
O-TBS-L-Threonine 7 gave almost racemic products (entry
4). Cinchona alkaloids are privileged chrial structural scaf-
folds in asymmetric catalysis,12 and various cinchona
alkaloids were next investigated. 9-Amino-9-deoxy-epi-
cinchonine (8), combining with p-nitrobenzoic acid or
p-toluenesulfonic acid, afforded the products in low yields
(entries 5 and 6). We reasoned the nature of the counteranion
might be important in the asymmetric induction.13 We thus
(9) For enantioselective Mannich reactions of nitroesters, see: (a) Singh,
A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129,
3466. (b) Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866.
(c) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362.
(10) Ikariya, T.; Wang, H.; Watanabe, M.; Murata, K. J. Organomet.
Chem. 2004, 689, 1377.
(11) (a) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
2002, 67, 8331. (b) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett.
2005, 7, 3897.
(12) For a recent book, see: Song, C. E., Ed. Cinchoan Alkaloids in
Synthesis & Catalysis: Ligands, Immobilization and Organocatalysis; Wiley-
VCH: Weinheim, 2009.
Org. Lett., Vol. 12, No. 10, 2010
2279

decided to introduce chiral acid to the catalytic system, and
camphorsulfonic acid (CSA) was selected. While (-)-CSA
salt of 8 gave very good results, (+)-CSA salt of 8 turned
out to be an even better catalyst, affording the desired adducts
in excellent yield and with 99% ee, although little diaste-
reoselectivity was observed (entry 8). Primary amines derived
from cinchonidine (9) and quinine (10) were less effective
(entries 9 and 10), and quinidine or 6′-demethylated quinidine
(11)-based primary amine was equally effective (entries 11
and 12). A catalytic system comprising 8 and (+)-CSA was
chosen as the catalyst for the further reactions since such a
system gave marginally higher yield of the product.
Table 2. Conjugate Addition of Ethyl Nitroacetate to
R,ꢀ-Unsaturated Ketonesa
The influence of ester moieties of different nitro esters on
the reactions was next examined (Scheme 1). tert-Butyl
Scheme 1
.
Conjugate Addition of Various Nitro Esters to
trans-4-Phenyl-3-buten-2-one
nitroacetate offered slightly improved diastereoselectivity;
however, the chemical yield dropped significantly. Benzyl
nitroacetate turned out to be completely ineffective, affording
the adducts in nearly racemic form. In contrast to unbranched
nitro esters, R-substituted ethyl nitroacetate was unsuitable
for the conjugate addition reaction, and no desired product
was obtained. We previously employed fluorinated nucleo-
philes14 for the asymmetric generation of fluorinated qua-
ternary chiral centers, and when R-fluorinated nitroacetate
was employed, the conjugate addition also could not proceed.
To establish the reaction scope, a number of enones were
employed as acceptors, and the results are summarized in
Table 2. Reactions are applicable to various ꢀ-aryl-substituted
butenones, and conjugate addition products were obtained
with very high enantioselectivity; however, virtually no
diastereoselectivities were observed (entries 1-7). Cyclic
enones, such as cyclohexenone and cycloheptenone, were
also excellent acceptors for the conjugation additions,
affording the desired products in high yields and with
excellent enantioselectivity (entries 8 and 9).
(13) (a) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (b)
Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
(14) (a) Han, X.; Luo, J.; Liu, C.; Lu, Y. Chem. Commun. 2009, 2044.
(b) Ding, C.; Mauroka, K. Synlett 2009, 664. (c) Jiang, Z.; Pan, Y.; Zhao,
Y.; Ma, T.; Lee, R.; Yang, Y.; Huang, K.-W.; Wong, M. W.; Tan, C.-H.
Angew. Chem., Int. Ed. 2009, 48, 3627. (d) Pan, Y.; Zhao, Y.; Ma, T.;
Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem.sEur. J. 2010, 16, 779. (e)
Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W. Chem. Commun. 2009,
2136. (f) Prakash, G. K. S.; Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A.
Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4090.
a Reactions were performed with enone (0.1 mmol), ethyl nitroacetate
(0.2 mmol), 8 (0.01 mmol), and (+)-CSA (0.01 mmol) in xylene (0.1 mL)
c
at room temperature. b Isolated yield. Determined by H NMR analysis
1
of the products. d The ee value was determined by chiral HPLC analysis.
2280
Org. Lett., Vol. 12, No. 10, 2010

The Michael adducts obtained from the catalytic enanti-
oselective conjugate addition of ethyl nitroacetate to R,ꢀ-
unsaturated ketones are rich in functionality and ready to be
converted into useful chiral building blocks (Scheme 2). The
separated by column chromatographic purification, which can
be further converted to optically pure R-fluorinated ester 15
or R-fluorinated nitro compound 16 following the procedures
reported in the literature.15
In summary, we discovered that a combination of 9-amino-
9-deoxy-epi-cinchonine 8 and (+)-CSA resulted in a novel
primary amine-based catalyst for efficient activation of R,ꢀ-
unsaturated ketones via iminium intermediates. The CSA salt
of 8 was capable of catalyzing the conjugate addition of nitro
acetate to enones in a highly enantioselective manner,
affording the desired adducts in excellent yields and with
up to 99% ee. Extension of this useful iminium catalyst to
other catalytic asymmetric reactions, particularly those
involving enone substrates, is under investigation in our
laboratory.
Scheme 2. Synthetic Manipulations of Adduct 3a
Acknowledgment. We thank the National University of
Singapore and the Ministry of Education (MOE) of Sin-
gapore (R-143-000-362-112) for the generous financial
support.
Supporting Information Available: Representative ex-
perimental procedures, HPLC chromatogram, and NMR
spectra of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
facile reduction of the nitro group, followed by in situ
reductive amination, afforded chiral pyrrolidine 13 as a single
stereoisomer.11a To partially circumvent the low diastereo-
selectivities of our reactions, adduct 3a was subjected to
electrophilic fluorination reaction to yield 14 with fluorinated
quaternary centers. The two diastereomers of 14 can be easily
OL1006407
(15) Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1989, 54,
5453.
Org. Lett., Vol. 12, No. 10, 2010
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