Cooperative catalysis in highly enantioselective Mannich-type three-component reaction of a diazoacetophenone with an alcohol and an imine

Article abstract of DOI:10.1039/c0cc03024d

A highly enantioselective three-component reaction of a diazoacetophenone, an alcohol, and an imine catalyzed cooperatively by Rh₂(OAc) ₄ and BINOL-derived chiral phosphoric acid has been developed for the synthesis of chiral β-amino

Full text of DOI:10.1039/c0cc03024d

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Cooperative catalysis in highly enantioselective Mannich-type
three-component reaction of a diazoacetophenone with an alcohol
and an iminew
Xinfang Xu, Yu Qian, Liping Yang and Wenhao Hu*
Received 4th August 2010, Accepted 5th November 2010
DOI: 10.1039/c0cc03024d
A
highly enantioselective three-component reaction of
a
of diazoacetophenones. A cooperative catalysis strategy9 is
applied to achieve high-level control of the reaction selectivity.
A diazoacetophenone and an alcohol served as the enol
equivalent of an a-alkoxyl aryl ketone10 by forming an
oxonium ylide in the presence of an Rh2(OAc)4 catalyst
diazoacetophenone, an alcohol, and an imine catalyzed
cooperatively by Rh2(OAc)4 and BINOL-derived chiral
phosphoric acid has been developed for the synthesis of chiral
b-amino-a-hydroxyl ketones in good yield with excellent
diastereo and enantio selectivity.
(eqn (1)), and
a chiral Brønsted acid co-catalyst was
introduced to control the reaction selectivity by activating an
imine component. Because of the ‘‘buffered’’ reactivity of the
acceptor carbenoid as a result of ylide formation, high
enantioselectivity can be achieved in the subsequent imine
addition. The advantage of the three-component reaction
suggests that a considerable variety of optically active
a-alkoxyl-b-amino ketones bearing two adjacent chiral centers
can be assembled from three simple materials (Scheme 1).
At the outset, we were aware of some potential difficulties
that we might encounter in using a Brønsted acid as the
co-catalyst in this Mannich-type addition of oxonium ylides
to imines. In addition to the O–H insertion side reaction, other
two-component side reactions such as aziridination,11 and
Mannich-type addition of diazo compounds to imines12 may
compete with the desired three-component reaction. Despite
these concerns, we carried out the three-component reaction in
the presence of an Rh2(OAc)4 catalyst and a chiral Brønsted
acid co-catalyst, in the hope that the co-catalytic system
would help the intrinsic reaction kinetics, leading to the
desired three-component pathway.
The development of efficient methods for building poly-
functional chiral molecules from simple, readily available
starting materials continues to be a challenge for organic
chemists.1 Enantioselective multicomponent reactions (MCRs)
have received considerable attention because of the advantages
of constructing chiral compounds from three or more
precursors in one step in an efficient and atom-economic
way, and much progress has been made in recent years.2
Management of the reaction selectivity, especially the enantio-
selectivity, of MCRs is quite challenging because of the
increased number of possible conformations in transition
states that contain three or more precursors.3
Transition metal catalyzed diazo decomposition reactions
via metal carbenoid intermediates have a broad range of uses
in organic synthesis,4 including their recent application to
asymmetric MCRs.5 Davies and Beckwith classified carbenoid
intermediates into three major groups according to the carbenoid
functionality.6 It has been shown that donor/acceptor carbenoids
offer many synthetic advantages over conventional carbenoids
because of the balanced reactivity and selectivity of these
carbenoids. Excellent enantioselective control has been achieved
in a number of catalytic reactions using donor/acceptor
carbenoids.,5a–c,7 However, because of the high reactivity
of acceptor carbenoids such as those derived from
diazoacetophenone, it has been extremely difficult to achieve
high levels of enantioselective control in transition metal
catalyzed asymmetric reactions.8
We first investigated a model reaction using a diazoaceto-
phenone 1a, 9-anthryl alcohol 2a, and N-phenylbenzaldehyde
imine 3a at 0 1C with a variety of chiral phosphoric acids as
co-catalyst. As shown in Table 1, the reaction gave a low yield
of the desired coupling product with an excellent diastereo-
meric ratio (dr) and moderate enantiomeric excess (ee)
(entries 1–10). No side products derived from two-component
aziridination or Mannich reactions were observed. Instead, the
major byproduct was derived from O–H insertion to give
a-(9-anthracenylmethoxy)-acetophenone (6).13 By extensive
ð1Þ
In this study, we report a highly enantioselective Mannich-
type three-component reaction involving diazo decomposition
East China Normal University, Institute of Drug Discovery and
Development, Department of Chemistry, Shanghai 200062, China.
E-mail: whu@chem.ecnu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details and characterisation of new compounds. See DOI: 10.1039/
c0cc03024d
Scheme 1 Three-component reaction of a diazoacetophenone with an
alcohol and an imine.
c
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Chem. Commun., 2011, 47, 797–799 797

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Table 1 Catalyst screening and reaction condition optimization for the three-component Mannich-type reactiona
Entry
Cat. 5 (mol%)
Additive
Solvent
T/1C
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
5a (2)
5b (2)
5c (2)
5d (2)
5e (2)
5f (2)
5g (2)
5h (2)
5i (2)
5j (2)
5f (5)
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
4 A MS
5 A MS
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
0
0
0
0
0
0
0
0
0
25
30
26
15
23
47
29
38
33
27
85
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
52
70
61
57
60
82
47
41
55
61
90
9
10
11
0
25
a
b
c
Unless otherwise noted, the reaction was carried out on a 0.2 mmol scale and 1a : 2a : 3a = 1.2 : 1.0 : 1.0. Isolated yield of 4a. The dr ratio
1
was determined by H NMR spectroscopy from a crude reaction mixture. The ee value was determined by chiral HPLC.
d
reaction condition optimization, we found that the best result
was achieved under the following reaction conditions: 5 mol%
of 5f as the co-catalyst, 5 A molecular sieve (MS) as an
additive, toluene as the solvent, and a reaction temperature
of 25 1C; these conditions gave the desired product 4a in 85%
yield with greater than 20 : 1 dr and 90% ee (entry 11).
Once we had obtained this preliminary result, the effect of
N-substitution (N-Ar) of the imine 3 on the reaction was
evaluated. There was no significant effect on the ee with
electron-donating imines. Thus, the generality of the protocol
was investigated in detail for various diazo compounds and
imines derived from p-MeO-aniline (Table 2). With both
electron-rich and electron-poor imines, the reactions generally
proceeded smoothly, furnishing the corresponding syn-b-
amino-a-hydroxyl ketones with excellent dr and ee (entries 1–6).
The reaction is a little sensitive to the steric effects of the
imine used. When imines derived from ortho-substituted
aromatic aldehydes were used, the diastereoselectivity decreased
significantly (entries 8 and 9). It is worth mentioning that the
imine 3n generated in situ from a cyclohexyl aldehyde was
equally effective, providing the desired product syn-4p in 68%
yield with 93% ee (entry 11); this demonstrates that the
reaction scope can be extended to alkylimines. In the case
of diazo compounds 1b–1d, the reaction with imine 3h
proceeded smoothly, affording the corresponding product in
good yield and with a high level of stereoselective control
(entries 12–14).
A control experiment was carried out to exclude the
possibility that the coupling products 4 were formed from the
O–H insertion product 6 via a stepwise reaction pathway. The
reaction of imine 3b with 6 resulted no trace amount of the
three-component coupling product 4b under the same reaction
conditions as that of the three-component reaction.13 In the
current three-component reaction, the desired products 4 can
only be formed when the three precursors are concurrent, and in
the presence of the two catalysts operated cooperatively.
Table 2 Enantioselective three-component reaction of 9-anthryl alcohol (2a) with various diazo compounds 1 and imines 3a
Entry
1 (Ar1)
3 (R4)
4
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1b (p-ClC6H4)
1c (m-BrC6H4)
1d (o-BrC6H4)
3b (Ph)
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
88
83
78
73
70
75
76
82
73
71
68
67
77
74
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
80 : 20
91
92
92
98
93
90
92
90/63
80/75
93
93
94
3e (p-MeC6H4)
3f (p-FC6H4)
3g (p-ClC6H4)
3h (p-BrC6H4)
3i (p-CF3C6H4)
3j (m-BrC6H4)
3k (o-BrC6H4)
3l (o-CF3C6H4)
3m (3,4-Cl2C6H3)
3n (cyclohexyl)
3h (p-BrC6H4)
3h (p-BrC6H4)
3h (p-BrC6H4)
9
83 : 17
10
11e
12
13
14
>97 : 3
>97 : 3
>97 : 3
>97 : 3
>97 : 3
92
87
a
b
c
d
For conditions, see ESI.w Isolated yield of 4. The dr ratio was determined by 1H NMR spectroscopy from a crude reaction mixture. The ee
value was determined by chiral HPLC. Imine 3n was formed in situ from the corresponding amine and aldehyde.
e
c
798 Chem. Commun., 2011, 47, 797–799
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Mannich-type adducts are valuable synthetic intermediates.
Cleavage of the 9-anthryl auxiliary from the ketone product 4b
was accomplished using an optimized oxidation process with
NaI/TMSCl, providing the free O–H compound 7 in 68%
yield.14 The relative and absolute stereochemistry of 7 was
determined as (2S,3R) in agreement with data previously
reported in the literature.15 Oxidation with m-CPBA generated
b-amino-a-hydroxyl ester 8 in 53% yield with 35% starting
material 4b recovered (eqn (2)).13,16
Compounds, John Wiley
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Soc., 2010, 132, 440; Cyclopropanation: (b) J. L. Thompson and
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C. Venkataramani, T. Hansen and D. W. Hopper, J. Am. Chem.
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2001, 3, 3317; (b) I. Nicolas, T. Roisnel, P. L. Maux and
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reviews: (a) H. Yamamoto and K. Futatsugi, Angew. Chem., Int.
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and C. Jun, Acc. Chem. Res., 2008, 41, 222; (d) Z.-H. Shao and
H.-B. Zhang, Chem. Soc. Rev., 2009, 38, 2745; (e) J. Zhou,
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and B. List, J. Am. Chem. Soc., 2007, 129, 11336; (g) T. Yang,
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(2)
In summary, we have developed a novel enantioselective
three-component Mannich-type reaction of a diazoacetophenone,
an alcohol, and an imine co-catalyzed by Rh2(OAc)4 and a
chiral Brønsted acid. Optically active b-amino-a-hydroxyl
ketones have been prepared with excellent diastereoselectivity
and enantioselectivity from three simple starting materials in
one reaction. Successful use of acceptor carbenoids derived
from diazoacetophenones in the coupling reaction indicates
that the cooperative catalysis strategy may be applicable
to other acceptor diazo compounds to achieve a high level
of control of the reaction selectivity. Research is currently
underway to further expand the reaction scope, as well as to
demonstrate the use of this methodology in the synthesis of
biologically active compounds.
We are grateful for financial support from National Natural
Science Foundation of China (Grant No. 20772033,
20932088), Shanghai Municipal Education Commission
(09ZZ45) and Science and Technology Commission of
Shanghai Municipality (09JC1404900, 10XD1401700).
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 797–799 799