Highly enantioselective nitro-mannich reaction catalyzed by cinchona alkaloids and N-benzotriazole derived ammonium salts

Article abstract of DOI:10.1021/ol203170x

The catalytic enantio- and diastereoselective nitro-Mannich reaction of α-amido sulfones in the mixed solvent of toluene/H₂O has been realized using a phase-transfer catalyst (PTC) derived from cinchona alkaloids and N-benzotriazole. It performed well over a wide range of substrates to give the desired products in good yields (up to 94%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1).

Full text of DOI:10.1021/ol203170x

ORGANIC
LETTERS
2012
Vol. 14, No. 3
704–707
Highly Enantioselective Nitro-Mannich
Reaction Catalyzed by Cinchona Alkaloids
and N-Benzotriazole Derived Ammonium
Salts
Yu Wei, Wei He,* Yulong Liu, Peng Liu, and Shengyong Zhang
Department of Chemistry, School of Pharmacy, Fourth Military Medical University,
Shaanxi Province, Xi’an 710032, P.R. China
weihechem@fmmu.edu.cn
Received November 27, 2011
ABSTRACT
The catalytic enantio- and diastereoselective nitro-Mannich reaction of R-amido sulfones in the mixed solvent of toluene/H2O has been realized
using a phase-transfer catalyst (PTC) derived from cinchona alkaloids and N-benzotriazole. It performed well over a wide range of substrates to
give the desired products in good yields (up to 94%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1).
The enantioselective catalytic nitro-Mannich (or aza-
Henry) reaction,1 nucleophilic addition of nitroalkanes to
imines, has emerged as a powerful tool for the preparation
of some important building blocks since the resulting
β-nitroamines adducts can either be reduced, producing
vicinal diamines, or oxidized, affording R-amino carbonyl
compounds.2 Thefirst asymmetricnitro-Mannich reaction
was reported by Shibasaki using a heterobimetallic Yb-
K-binaphthol complex as a catalyst in 1999.3 Since then,
several other groups have reported enantioselective nitro-
Mannich protocols involving metallic3,4 as well as purely
organic catalysts.5 In 2004, Takemoto reported the
first organocatalytic nitro-Mannich reaction using chiral
thiourea as a bifunctional catalyst.5a Afterward, other
thiourea catalysts, bisamidine triflate salts, ammonium
(1) For a review about the asymmetric nitro-Mannich reactions, see:
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Chem. 2009, 2401.
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Marques-Lopez, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org.
(4) (a) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. (b) Knudsen, K. R.;
Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am.
Chem. Soc. 2001, 123, 5843. (c) Anderson, J. C.; Howell, G. P.;
Lawrence, R. M.; Wilson, C. S. J. Org. Chem. 2005, 70, 5665.
(d) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3,
1362. (e) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed.
2005, 44, 3881. (f) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.;
(2) For a review about the application and preparation of vicinal
diamines and R-amino acids, see: (a) Lucet, D.; Le Gall, T.; Mioskowski,
C. Angew. Chem., Int. Ed. 1998, 37, 2580. (b) Knudsen, K. R.; Risgaard,
T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc.
2001, 123, 5843. (c) Handa, S.; Gnanadesikan, V.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900. (d) Chen, Z.-H.;
Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008,
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Lopez, R. Angew. Chem., Int. Ed. 2006, 45, 117. (g) Zhou, H.; Peng, D.;
Qin, B.; Hou, Z.; Liu, X.; Feng, X. J. Org. Chem. 2007, 72, 10302.
(h) Tan, C.; Liu, X.; Wang, L.; Wang, J.; Feng, X. Org. Lett. 2008, 10,
5305. (i) Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9, 2023. (j) Gao, F.;
Zhu, J.; Tang, Y.; Deng, M.; Qian, C. Chirality 2006, 18, 741.
€
(3) (a) Yamada, K. I.; Harwood, S. J.; Groger, H.; Shibasaki, M.
Angew. Chem., Int. Ed. 1999, 38, 3504. (b) Yamada, K.; Moll, G.;
Shibasaki, M. Synlett 2001, 980.
r
10.1021/ol203170x
Published on Web 01/18/2012
2012 American Chemical Society

betaines, and Brønsted acids have been succefully devel-
oped for this transformation in recent years.5bÀp However,
most of the substrates, N-protected imines, are unstable,
and aliphatic enolizable aldehyde derived imines are even
hard to isolate, thus resulting in a considerable limitation
to the generality of their applications.6
operational simplicity, the use of PTCs as a tool for the
catalytic asymmetric nitro-Mannich reaction is still rela-
tively undeveloped.
In 2009, we developed a series of quaternary ammonium
salts 1À2 (Figure 1), prepared simply by a reaction of
cinchona alkaloids with 1-chloromethyl benzotriazole,
which exhibits excellent enantioselectivity in the asym-
metric alkylation of glycine imines.8 Herein we report the
highly enantioselective nitro-Mannich reaction between
nitroalkane and R-amido sulfones catalyzed by ammo-
nium salts 1À5 (Figure1). Underthe optimized conditions,
the new catalytic system is valid for both aromatic and
aliphtic aldehyde derivatives, giving excellent enantioselec-
tivities and high yields. More importantly, compared with
the Palomo’s work, we obtained a complete reversal of
enantioselectivity of the products from the nitro-Mannich
reaction by changing the N-benzyl group to a N-benzo-
triazole derivative even using the same chiral source
quinine. As we know, it is very challenging in asymmetric
catalysis to obtain both enantiomers of a given reaction in
excellent enantioselectivity by using the same chiral source.
Subtle modification of the catalyst structure, using the
same chiral source, is an effective method for this purpose.9
Our work added a nice contribution to this area.
Figure 1. Phase-transfer catalysts evaluated.
Table 1. Screening of the Reaction Conditions in Asymmetric
Nitro-Mannich Reaction
Recently, Palomo’s and Herrera’s groups independently
reported the nitro-Mannich reaction between bench stable
R-amido sulfones, which generate reactive N-carbamoyl
imines in situ by inorganic base, and nitromethane using
N-benzyl quininium chloride as a phase-transfer catalyst
(PTC).7 This method successfully expanded the substrate
scope to both aromatic and aliphtic aldehyde derived azo-
methines. Although the phase-transfer catalysis appears
highly attractive considering the mild conditions and the
(5) (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625. (b) Xu, X.; Furukawa, T.; Okino, T.; Miyabe,
H.; Takemoto, Y. Chem.;Eur. J. 2006, 12, 466. (c) Yoon, T. P.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 466. (d) Rampala-
kos, C.; Wulff, W. D. Adv. Synth. Catal. 2008, 350, 1785. (e) Bernardi,
L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006,
62, 375. (f) Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron 2006, 62,
11499. (g) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem.
Soc. 2007, 129, 15110. (h) Chang, Y.-W.; Yang, J.-J.; Dang, J.-N.;
Xue, Y.-X. Synlett 2007, 2283. (i) Wang, C.; Zhou, Z.; Tang, C. Org.
Lett. 2008, 10, 1707. (j) Han, B.; Liu, Q.-P.; Li, R.; Tian, X.; Xiong,
X.-F.; Deng, J.-G.; Chen, Y.-C. Chem.;Eur. J. 2008, 14, 8094. (k)
Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J.
Am. Chem. Soc. 2008, 130, 8606. (l) Rampalakos, C.; Wulff, W. D.
Adv. Synth. Catal. 2008, 350, 1785. (m) Nugent, B. M.; Yoder, R. A.;
Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418. (n) Singh, A.;
Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866. (o) Uraguchi, D.;
Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878. (p)
Rueping, M.; Antonchick, A. P. Org. Lett. 2008, 10, 1731.
a All reactions were carried out with 0.1 mmol of R-amido sulfone
and 0.5 mmol of nitromethane in solvent (1 mL) in the presence of
0.01 mmol of catalyst and 0.13 mmol of CsOH H2O as the basic addi-
3
tive, at À50 °C for 24 h. b Isolated yield. c Determined by chiral HPLC
analysis using Chiralpak AD-H column. d The absolute configuration
of the products was assigned by comparison optical rotation and HPLC
result with the literature. e Not determined. f N-Boc benzaldimine was
used instead of R-amido sulfones 6a as substrate. g organic solvent/
H2O = 9:1. h 0.1 mmol of basic additive.
(6) (a) Yang, J. W.; Pan, S. C.; List., B. Org. Synth. 2009, 86, 11.
(b) Petrini, M.; Torregiani, E. Synthesis 2007, 2, 159. (c) Yin, B.; Zhang,
Y.; Xu, L.-W. Synthesis 2010, 21, 3583. (d) Mecozzi, T.; Petrini, M.
Synlett 2000, 73.
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(7) (a) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. J. Am. Chem.
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Soc. 2005, 127, 17622. (b) Gomez-Bengoa, E.; Linde, A.; Lopez, R.;
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Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008,
130, 7955. (c) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.;
Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975.
(8) He, W.; Wang, Q.-J.; Wang, Q.-F.; Zhang, B.-L.; Sun, X.-L.;
Zhang, S.-Y. Synlett 2009, 1311.
Org. Lett., Vol. 14, No. 3, 2012
705

Initially, the reaction between R-amido sulfones 6a and
nitromethane 7a was selected as the model reaction and the
catalysts 1À5 were screened (Table 1, entries 1À7). Inter-
estingly, the pseudoenantiomeric catalyst pairs (1a vs 2a,
1b vs 2b) give opposite enantioselectivities in the nitro-
Mannich reaction with different reactivity and stereocon-
trol. Among them, the catalyst 2b, readily prepared from
quinine and 1-chloromethylbenzotriazole, results in an
84% yield and 87% ee in the presence of 130 mol % of
Table 2. PTC Catalyzed Enantio- and Diastereoselective Nitro-
Mannich Reactions
CsOH H2O as the basic additive and toluene/H2O (9:1) -
3
as the mixed solvent at À50 °C. Notably, the abolute con-
figuration of the product catalyzed by 2b is S, which is
opposite to Palomo’s results using the same chiral source
quinine derived catalyst.7 Moreover, N-Boc benzaldimine
was directly treated with nitromethane in the presence
of 2b (entry 8), the S-product was also observed in high
yield and moderate ee value. These results indicate the
triazole moiety in the catalyst may play a crucial role in the
chiral discrimination. Catalyst 3, which has a hydroxyl on
the quinoline ring of quinine results in poor reactivities and
enantioselectivities (entry 5). The catalysts 4 and 5 with
O-alkylated or O-arylated protected C-9 hydroxyl groups
are significantly less reactive than the one containing a
free hydroxyl group, which is consistent with the experi-
mental work by Palomo and co-workers, suggesting the
possibility of H-bonding as a mechanism of activation
(entries 6À7).7b
As it can be seen from entries 4, 9À13, water has a
positive impact on the reactivities and enantioselectivities.
Especially, using toluene/H2O as a cosolvent, both yield
and ee value increased significantly (entry 4 vs 11). The
presence of water in the reaction makes product isolation
relatively easy and increases the yields and chemical purity
with no extra expenditure.10 Furthermore, in this reaction,
a basic additive is needed to help the formation of imines
by R-amido sulfones. Thus, several different bases have
been examined (entries 14À19). It seems that a stronger
base gives better results, e.g., DBU is better than DABCO
(67% yield vs 8% yield, 64% ee vs 14% ee, entries 14, 15).
All other tested inorganic bases, such as CsCO3, NaOH,
LiOH, and KOH, give good results but are still inferior to
those when using CsOH H2O as a basic additive (entries
3
16À19 vs entry 4).
After further systematic optimization of the reaction
parameters,11 the scope ofthe nitro-Mannichreaction with
nitroalkanes is explored (Table 2). The R-amido sulfones
are derived from different kinds of aldehydes, including
aromatic and aliphatic aldehydes. In general, excellent
enantioselectivities and good yields are achieved for all
a All the reactions were carried out with 0.1 mmol of R-amido sulfone
and 0.5 mmol of nitroalkanes in toluene/H2O = 9:1 (1 mL) in the
presence of 10 mol % catalyst 2b, 130 mol % CsOH H2O, reacted at
3
intended temperature for 24 h. b Isolated yield. c Assigned by HPLC data
combination with 1H NMR data and comparison with literature report.
d Determined by HPLC analysis. e Reaction time was 50 h. f After a
single crystallization.
(9) (a) Clyne, D. S.; Mermet-Bouvier, Y. C.; Nomura, N.; RajanBabu,
T. V. J. Org. Chem. 1999, 64, 7601. (b) Franzen, J.; Marigo, M.;
Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 18296. (c) Yan, X.-X.; Peng, Q.; Zhang,
Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed.
2006, 45, 1979. (d) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am.
Chem. Soc. 2007, 129, 750–751.
(10) (a) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103. (b) Brogan,
A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45,
8100. (c) Blackmond, D. G; Armstrong, A.; Coombe, V.; Wells, A.
Angew. Chem., Int. Ed. 2007, 46, 3798.
the substrates. Compared to Herrera’s and Palomo’s
research,7 we not only expanded the substrate’s scope to
6cÀf, 6n but also improved the results of R-amido sulfone
6a, 6hÀi, 6kÀl successfully. Overall, aromatic aldehyde
derived substrates, regardless of possessing an electron-
donating or -accepting group, react smoothly with nitro-
methane (entries 1À12, 72%À94% yield, 83%À99% ee).
Essentially, enantiopure 8ba (entry 3) and 8ja (entry 6) can
(11) See Supporting Information for details of condition screening.
706
Org. Lett., Vol. 14, No. 3, 2012

be obtained by direct crystallization of the crude products.
In particular, enolizable aliphatic aldehyde drived sub-
strates, such as 3-phenylpropionaldehyde derived 6m,
3-phenyl-2-propenal derived 6n, cyclohexanecarbaldehyde
derived 6o, branched or unbranched aldehyde derived
6pÀ6t, also are suited to this reaction to afford the corre-
sponding adducts in good yields and excellent enantios-
electivities (entries 13À20). Moreover, nitroethane 7b has
been proven to be a good substrate in this new catalytic
system. All the aromatic compounds with either an electron-
donating or -withdrawing group, heterocyclic compounds,
and aliphatic compounds reacted well with nitroethane 7b,
forming two stereocenters simultaneously, affording the
products with high diastereomeric ratios and enantiomeric
excess (entries 21À26).
Scheme 1. Conversion of the Product to 1,2-Diamine and
R-Amino Acid
aliphatic aldehyde derivatives to give the desired products
in good yields (up to 94%) with excellent enantioselectiv-
ities (up to 99% ee) and diastereoselectivities (up to 99:1).
By changing the N-benzyl group to a N-benzotriazole
derivative of quinine, opposite enantiomers of β-nitroa-
mines were obtained, which is a valuable supplement to
the reported method. Moreover, the optically active prod-
ucts can be easily converted into chiral vicinal diamines or
R-amino acids, which demonstrates the practicability of
this methodology. Further investigation into the mechan-
ism and applications of this methodology is ongoing in our
laboratory.
The β-nitroamines obtained in the nitro-Mannich reac-
tionare valuableintermediatesforthesynthesisofavariety
of enantioenriched compounds. To indicate this, here we
demonstrate two transformations (Scheme 1). First, the
NO2 moiety in product 8aa is readily reduced withNaBH4/
NiCl2 at 0 °C, followed by acetylation of 9 to give the
known compound R,β-diamino ester 10, allowing the ab-
solute configuration of the adducts to be confirmed. Sec-
ond, the products are used for the Nef oxidation,12 followed
by methylation, directly to afford the N-Boc-protected-(R)-
phenylglycine methyl ester 12 without loss of optical integ-
rity. In particular, our new catalytic system which catalyzes
the reaction of enolizable aldehyde-derived R-amido sul-
fone with nitroalkanes provides a new access to a wide
range of important building blocks in organic synthesis.
In conclusion, the highly enantio- and diastereoselective
nitro-Mannich reaction of R-amido sulfones and nitroalk-
anes in the mixed solvent of toluene/H2O has been realized
using a PTC derived from cinchona alkaloids and N-
benzotriazole. It performed well over both aromatic and
Acknowledgment. The financial support of the National
Natural Science Foundation of China (21072228, 20702063)
and the Young Scholar Foundation of the Fourth Military
Medical University is gratefully acknowledged. We also
would like to express our great thanks to Professor Weip-
ing Chen for valuable discussions and kind help.
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(12) (a) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62,
234. (b) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861.
Org. Lett., Vol. 14, No. 3, 2012
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