Silicon-based lewis acid assisted cinchona alkaloid catalysis: Highly enantioselective aza-michael reaction under solvent-free conditions

Article abstract of DOI:10.1021/ol202803b

The study showed that a combination of an achiral silicon-based Lewis acid and chiral Lewis base, such as iodotrimethylsilane (TMSI) and cinchonine, generated a highly enantioselective catalyst system under solvent-free conditions which gave aromatic β-amino ketones with up to >99% ee. Mechanistic studies demonstrate the enhanced asymmetric induction may be due to the combined and competitive activation of acarbonyl moiety of chalcone with cinchonine and the silicon-based Lewis acid in the aza-Michael reaction.2011 American Chemical Society.

Full text of DOI:10.1021/ol202803b

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6508–6511
Silicon-Based Lewis Acid Assisted
Cinchona Alkaloid Catalysis: Highly
Enantioselective Aza-Michael Reaction
under Solvent-Free Conditions
Hua-Meng Yang, Li Li, Fei Li, Ke-Zhi Jiang, Jun-Yan Shang, Guo-Qiao Lai, and Li-Wen Xu*
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, Hangzhou Normal University, Hangzhou 310012, P. R. China
licpxulw@yahoo.com; liwenxu@hznu.edu.cn
Received October 18, 2011
ABSTRACT
The study showed that a combination of an achiral silicon-based Lewis acid and chiral Lewis base, such as iodotrimethylsilane (TMSI) and
cinchonine, generated a highly enantioselective catalyst system under solvent-free conditions which gave aromatic β-amino ketones with
up to >99% ee. Mechanistic studies demonstrate the enhanced asymmetric induction may be due to the combined and competitive activation of a
carbonyl moiety of chalcone with cinchonine and the silicon-based Lewis acid in the aza-Michael reaction.
An aza-Michael reaction of a nitrogen-centered sourceis
a convenient and important way to prepare pharmacologi-
cally and synthetically useful β-amino carbonyl compounds,
including β-amino acids, and β-lactams.1 Over the past
decade tremendous progress has been achieved by employ-
ing different nitrogen nucleophiles and new acceptors as
well as more efficient catalyst systems for this important
organic transformation.2 Especially in the past several
years, the development of novel and efficient synthetic
methods leading to chiral β-amino ketones, β-amino acids,
and their derivatives has attracted much attention in orga-
nic synthesis; however, most of asymmetric aza-Michael
reactions with high asymmetric induction or excellent
enantioselectivities rely on the use of chiral auxiliaries,
chiral starting materials, or stoichiometric amounts of
chiral ligands.1ꢀ3 Since the first example was reported by
the Jørgensen group in 1996,4 much effort has been expen-
ded on seeking both chiral transition-metal-based cata-
lysts5 and organocatalysts6 for asymmetric aza-Michael
reaction. However, the catalytic, highly enantioselective
aza-Michael reaction is still one of the major challenges in
(1) (a) Juaristi, E. Enantioselective Synthesis of β-Amino Acids; Wiley-
VCH: Weinheim, 1997. (b) Georg, G. I. The Organic Chemistry of
β-Lactams; Wiley-VCH: Weinheim, 1993. (c) Magriotis, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 4377–4379. (d) Weiner, B.; Szymanski, W.; Janssen,
D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656–
1691.
(2) Recent examples: (a) Wang, X. F.; An, J.; Zhang, X. X.; Tan, F.;
Chen, J. R.; Xiao, W. J. Org. Lett. 2011, 13, 808–811. (b) Fustero, S.;
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A.; Zanda, M.; de Arellano, C. R. J. Org. Chem. 2009, 74, 3122–3132.
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r
10.1021/ol202803b
Published on Web 11/16/2011
2011 American Chemical Society

synthetic organic chemistry and asymmetric catalysis.
Therefore, the development of new chiral catalyst systems
for aza-Michael reaction is highly desired. Combining
chiral catalysts having different or similar properties is
currently an important and promising strategy for devel-
oping highly efficient catalytic transformations.7
Scheme 1
Cooperative combined catalyst systems inspired from
metalloenzymes with multiple cooperative noncovalent
interactions is currently a popular and important research
topic in asymmetric catalysis.7e Various bifunctional metal
and organocatalysts including the strategy of combined
catalyst systems, such as Lewis acid/Brønsted acid or base,8
Lewis acid/Lewis acid or base,9 Lewis base/Brønsted acid
or base,10 and combined transition metal/organocatalysis,11,12
have been developed to provide unique catalytic activities
during the past decade. Herein, we describe a different and
idiographic class of combination catalysts for aza-Michael
reaction, in which chiral Lewis base catalysis was assisted
by an achiral silicon-based Lewis acid catalyst.
On the basis of previous results (Scheme 1)13 and studies
on silicon-based Lewis acids14 and a pioneering report by
Scettri and Acocella et al.15 for the aza-Michael reaction of
aromatic amines to chalcones, we hypothesized that the
silicon-based bulky group acts not only as a simple moiety
to provide a steric bias in the transition state (Thorpeꢀ
Ingold effect)16 but also as a Lewis acid to electronically
modify the properties of the Lewis basic cinchona alkaloid.
To test this hypothesis involving silicon-based Lewis acid
(SLA) assisted Lewis base catalysis, we decided to search
for a new catalyst system.
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Among the Lewis acids screened in combination with
cinchonine for the aza-Michael reaction aniline to chal-
cone, a catalytic amount of iodotrimethylsilane (TMSI)
and trimethylsilyl acetate (TMSOAc) were promising. The
optimization studies were summarized in Table S1 (see
Supporting Infromation, SI). Initial investigations using
different silicon-based Lewis acids (SLAs) revealed that,
while most of bulky silicon Lewis acids provided poor
enantioselectivities, the combinational use of cinchonine
and TMSI or TMSOAc was uniquely efficient in affording
completed conversion with good enantioselectivity (80% ee)
of the aza-Michael adduct 3a at room temperature. When
the SLA used is trimethylsilyl trifluoromethanesulfonate
(TMSOTf) the decrease in the asymmetric induction
(28% ee) may be due to the unfavorable functionality of
the stronger Lewis acidity. Efforts to optimize this result
led to the following observations. (1) Enantioselectivities
and conversions were independent of the silicon-based
Lewis acid catalyst loading (from 10 to 20 mol % of
TMSI). (2) Best results were obtained under solvent-free
conditions. Similar enantioselectivities were obtained in
hexamethyldisiloxane (79% ee) but at the expense of yields
for the same time. Other solvents, such as diethyl ether, resul-
ted in poorer enantioselectivity and conversion (62% ee,
91% yield). (3) Interestingly, an increase or decrease in the
reaction temperature was detrimental or unprofitable to
enantioselectivities.
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In this reaction, significant variations in the stereoselec-
tivity (0ꢀ77% ee) were observed depending on the nature
of Lewis acids. Among the metallic Lewis acids screened,
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Org. Lett., Vol. 13, No. 24, 2011
6509

Introduction of a methyl group to the para-position of
aniline also led to similarly and highly stereoselective aza-
Michael addition (entry 7). Interestingly, when the sub-
stitutents on either the anilines or chalcones were replaced
with other groups, the ee outcome was decreased drama-
tically (entries 6 and 9). Although the enantioselectivities
obtained in some cases were moderate to good (57ꢀ82%
ee), the aza-Michael reaction is an interesting reaction as it
is sensitive to an aromatic or alkyl structure for enones.
We have tried different receptors such as R,β-unsatu-
rated ester or amide and different nitrogen sources, such as
BzNH2, TsNH2, and BnONH2, for various aza-Michael
reactions. Unfortunately, it was found that trace or no aza-
Michael adducts were obtained under the reported condi-
tions. Although not perfect in broadsubstrate scopes in the
presence of this catalyst system, to the best of our knowl-
edge, it is the first example that the enantioselectivities
of aza-Michael reaction of aromatic amines to chalcones
could reach up to 99% ee easily, which provided a new direct
method for the preparation of aromatic β-amino ketones.
To explain the combined effect of a silicon-based Lewis
acid and cinchonine in this aza-Michael reaction, the
mechanism of TMSI/cinchonine-catalyzed aza-Michael
reaction was proposed in Scheme 2 on the basis of experi-
mental results and 29Si NMR analysis (see SI), in which the
Lewis acid assisted Lewis base (LLB)17 catalysis is exhib-
ited possibly in the catalytic aza-Michael reaction of ani-
line with chalcone (Route I in Scheme 2). The assisted
functionality of a silicon-based Lewis acid could also be con-
firmed because we have observed that other Lewis acids
such as Cu- or Ti-based Lewis acids also resulted in pro-
mising enantioselectivities (Table S1 of SI, entries 12ꢀ24),
and significant variations in the stereoselectivity (0ꢀ77%
ee) were observed for these Lewis acids. The origin of
higher stereoselectivity with an (R)-adduct relative to an
(S)-adduct in the presenceof a silicon-basedLewis acid can
be explained as follows: (1) the SLA could strongly acti-
vates the carbonyl substrates via a carbonyl silylation
reaction18 (I-2), and the more active silicon-based Lewis
acid/Lewis base catalyst system is in situ generated from or
interactedwith cinchonine anda trimethylsilane halide(for
example, TMSCl). (2) It would be a considerable factor for
the higher stereoselectivity that the steric bulkiness of
counterion [CN/TMS]þXꢀ (I-1) brings about effective
shielding of the activated olefin functionality with the
well-known ThorpeꢀIngold effect16 to enhance the chir-
ality transfer from cinchonine. (3) It is speculated that the
key points include that the role of the silicon element in this
catalyst system is not only as a bulky group to strengthen
the steric repulsion but also as a promoter/activator19 to
accelerate the initial step of the reaction between cincho-
nine and the substrate (chalcone). It is interesting that the
Table 1. Catalytic Aza-Michael Reaction with Various Aro-
matic Amines to Chalcones Using Silicon-Based Lewis Acid
(SLA) as Cocatalystsa
yield
(%)b
ee
(%)c
entry
R1
R2
R3
X
t/d
1
H
H
H
H
H
H
H
I
2
7
7
2
2
3
3
3
3
3
2
2
>99
80
2
2-OMe
2-OMe
4-Me
4-Me
H
H
I
>99
>99
>99
>99
>99
>99
54 (50)
>99
>99
>99
>99
>99
>99
>99
>99
57
3
H
Cl
I
4
H
5
H
Cl
I
6
4-Cl
H
H
7
H
4-Me
H
I
>99
96
8
4-Me
4-Me
4-Br
4-Me
H
4-OMe
H
I
9
3-Me
H
I
60
10
11
12
4-OMe
H
I
97
3-Me
3-Me
I
82d
71d
H
I
a Aza-Michael additions were performed under solvent-free condi-
tions similarly to that of Table 1. b NMR yield with isolated yield in
parentheses. These reactions occurred completely, and yields of isolated
products were >90%. c Enantioselectivity of aza-Michael adduct was
determined by HPLC with chiral column. d 5 mol % of catalyst systems
were used.
Ti(Oi-Pr)4, NbCl5, CuCl, and CuI gave an aza-Michael
adduct in >70% ee. It is noteworthy that lower enantios-
electivities were observed for strong Lewis acidic Bi(OTf)3 -
3
4H2O, YbCl3 7H2O, and Cu(II) salts. Therefore, the TMSI
was found tobethebestLewisacidinthe cinchonine-based
cooperative catalyst system.
3
Having successfully discovered complementary catalyst
systems for the highly efficient asymmetric aza-Michael
reaction of aniline to chalcone under solvent-free condi-
tions, the scope and generality of the aza-Michael reaction
of aromatic amines and chalcones was explored (Table 1).
The combined cinchonine/TMSI catalytic reaction condi-
tions proved general for a range of aromatic amines to
chalcones with better enantioselectivities in comparison to
previous reports. The aza-Michael reaction of aniline with
some chalcones, such as the substrates of entries 2ꢀ5,
exhibited excellent enantioselectivities (>99% ee) in com-
pleted conversions (>99%) in the presence of TMSI or
TMSCl. It should be noted that the crude mixture was
directly purified by column chromatography (silica gel,
petroleum ethyl acetate mixtures) to obtain the aza-Mi-
chael adducts without crystallization. Undoubtedly, the
combined use of a silicon-based Lewis acid and cinchonine
in this aza-Michael reaction had a very positive effect on
the enhancement of asymmetric induction in comparison
to that of only catalyst 4 under solvent-free conditions.
(17) (a) Mizutani, T.; Murakami, T.; Matsumi, N.; Ogoshi, H. J. Am.
Chem. Soc. 1997, 119, 8991–9001. (b) Shibasaki, M.; Lida, T.; Yamada,
Y. M. A. J. Synth. Org. Chem. 1998, 56, 344–356. (c) Shibasaki, M.;
Kanai, M. Chem. Pharm. Bull. 2001, 49, 511–524.
(18) (a) Mathieu, B.; de Fays, L.; Ghosez, L. Tetrahedron Lett. 2000,
41, 9561–9564. (b) Frantz, D. E.; Singleton, D. A. J. Am. Chem. Soc.
2000, 122, 3288–3295. (c) Boxer, M. B.; Yamamoto, H. J. Am. Chem.
Soc. 2006, 128, 48–49.
6510
Org. Lett., Vol. 13, No. 24, 2011

extremities (57% ee vs >99% ee) with only relatively
minor modifications in the substrates were observed, in
accordance with an earlier report on the cinchonine-
catalyzed aza-Michael reaction (11ꢀ58% ee).15 We sug-
gested that the effect of the substituent of the aromatic rings
on stereoselectivity is derived from a change in the πꢀπ
stacking interaction between the aromatic rings of aniline
and chalcones. Although several trials including kinetic
experiments to establish the true mechanism were un-
successful, on this basis, the fine-tuning of the reaction
conditions and selectivityꢀreactivity balance for the aza-
Michael reaction should be beneficial to the enantioselec-
tivity enhancement.
Scheme 2. Plausible Reaction Mechanism of Aza-Michael Re-
action
In summary, an effective protocol for the enantioselec-
tive aza-Michael addition of aromatic amines to chalcones
is disclosed. The study showed that a combination of an
achiral silicon-based Lewis acid and a chiral Lewis base,
such as TMSI and cinchonine, generated a highly enantio-
selective catalyst system under solvent-free conditions
which gave aromatic β-amino ketones with up to >99% ee.
The aza-Michael reaction was optimized for a range of
aromatic primary amines possessing both electron-defi-
cient and -rich substitution patterns. Mechanistic studies
demonstrate the enhanced asymmetric induction may be
due to the combined and competitive activation of the
carbonyl moiety of chalcone with hydrogen bonding and
the achiral silicon-based Lewis acid assisted chiral Lewis
basic cinchonine in the aza-Michael reaction. We believe
these results encourage further research efforts to develop
novel Lewis acid assisted chiral Lewis base catalyst systems
in the presence of organosilicon compounds with bulky
groups for asymmetric transformation through combined
and competitive activation. Although the present com-
bined catalyst system has some limitations in terms of
catalytic efficiency and enantioselectivities, this aza-Mi-
chael reaction constitutes a direct catalytic asymmetric
route to chiral β-amino ketones and supports that modifying
the existing and classic chiral catalysts with the introduction
of silicon-based Lewis acid to a combined catalyst system
would facilitate the enhancement of stereoselectivity in
certain asymmetric transformations and sets the basis for
further development.
Acknowledgment. Financial support by the National
Natural Science Foundation of China (NSFC, Nos.
20973051 and 21173064) and Program for Excellent Young
Teachers in Hangzhou Normal University (HNUEYT,
JTAS 2011-01-014) is appreciated. X.L.W. thank Prof.
ꢀ
Arrigo Scettri, Dipartimento di Chimica, Universita di
Salerno, for his help.
Supporting Information Available. Experimental pro-
cedures, characterization of the products, and other
detailed results and discussions. This material is available
free of charge via Internet at http://pubs.acs.org.
(19) Shi, Z. H.; Shen, H.; Yang, K. F.; Jiang, J. X.; Lai, G. Q.; Lu, Y.;
Xu, L. W. Eur. J. Org. Chem. 2011, 66–70.
Org. Lett., Vol. 13, No. 24, 2011
6511