Highly efficient amine organocatalysts based on bispidine for the asymmetric Michael addition of ketones to nitroolefins

Article abstract of DOI:10.1002/adsc.200800341

A highly diastereoselective and enantioselective Michael addition of cyclohexanone, acetone and other ketones to nitroolefins was developed by the use of an amine organocatalyst based on bispidine. Additionally, a theoretical study of transition structures revealed that this bispidinebased primary-secondary amine catalyst could serve through an enamine intermediate and H-bond interaction, which was important for the reactivity and selectivity of this reaction.

Full text of DOI:10.1002/adsc.200800341

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DOI: 10.1002/adsc.200800341
Highly Efficient Amine Organocatalysts Based on Bispidine for
the Asymmetric Michael Addition of Ketones to Nitroolefins
Zhigang Yang,a Jie Liu,a Xiaohua Liu,a Zhen Wang,a Xiaoming Feng,a,b,*
Zhishan Su,a and Changwei Hua,*
a
Key Laboratory of Green Chemistry &Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, Peopleꢀs Republic of China
State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, Peopleꢀs Republic of China
b
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Received: June 3, 2008; Published online: August 13, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800341.
Abstract: A highly diastereoselective and enantio-
selective Michael addition of cyclohexanone, ace-
tone and other ketones to nitroolefins was devel-
oped by the use of an amine organocatalyst based
on bispidine. Additionally, a theoretical study of
transition structures revealed that this bispidine-
based primary-secondary amine catalyst could serve
through an enamine intermediate and H-bond inter-
action, which was important for the reactivity and
selectivity of this reaction.
Figure 1. Chiral bispidine-based amine organocatalysts.
serve through an enamine intermediate[6] and H-bond
interaction, which might work well in the Michael re-
action of ketones with nitroolefins. Herein, we report
the asymmetric Michael addition of cyclohexanone
and acetone to nitroolefins catalyzed by chiral amine
1 to give the desired adducts in high yields with excel-
lent enantioselectivities and diastereoselectivities (up
Keywords: amine organocatalyst; asymmetric syn-
thesis; bispidine; Michael addition; nitroolefins
The Michael addition represents one of the most im- to 99% yield, 99% ee, 98/2 dr) under mild conditions.
portant reactions for the formation of carbon-carbon Initially, the catalytic asymmetric Michael reaction
bonds in organic synthesis.[1] Since the organocatalytic of cyclohexanone with trans-b-nitrostyrene was car-
asymmetric Michael addition of ketones to trans-b-ni- ried out with 20 mol% 1a derived from l-phenylala-
trostyrene was pioneered by Barbas and List inde- nine at room temperature in CH2Cl2. The reaction
pendently,[2,3] a great effort has been devoted to the gave the desired product in 16% yield with 40% ee
development of more selective and efficient catalytic (Table 1, entry 1). Poor enantioselectivity was ob-
systems for this synthetically useful transformation, tained on using the catalyst 1b derived from l-proline
such as pyrrolidine-based derivatives, chiral primary (17% ee; Table 1, entry 2). When the combined cata-
amines and thiourea-amine bifunctional catalysts.[4–7] lyst of bispidine with l-valine and l-leucine were
In spite of the excellent results have been achieved by used, the enantioselectivity was improved to 46% ee
these systems, the design and development of novel (Table 1, entries 3 and 4). Better results could be ob-
backbones and efficient chiral organocatalysts remain tained with 1e which introduced l-phenylglycine into
a major challenge in synthetic organic chemistry. Re- the bispidine (63% ee; Table 1, entry 5). To obtain
cently, we designed a kind of novel amine organocata- even higher yield and enantioselectivity, some acids
lyst 1 (Figure 1) based on bispidine which efficiently were employed as additives. Fortunately, the addition
catalyzed the asymmetric direct aldol reaction of of 20 mol% HCOOH significantly increased the reac-
functionalized ketones with excellent enantioselectivi- tivity (80% yield) as well as the enantioselectivity
ties.[8] Based on the mechanistic rational, this bispi- (78% ee; Table 1, entry 6). However, when using
dine based primary-secondary amine catalyst could AcOH or PhCOOH as additives, the enantioselectivi-
Adv. Synth. Catal. 2008, 350, 2001 – 2006
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2001

Zhigang Yang et al.
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Additive[b]
Solvent
Time [h]
Yield [%][c]
syn/anti[d]
ee [%][d]
1
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1f
1g
1f
1f
1f
1f
1f
1f
1f
none
none
none
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
10
18
26
10
10
10
10
26
26
5
16
82
25
10
20
80
75
46
trace
97
97
96
93
96
30
25
92
92
92
85/15
93/7
40
17
44
46
63
78
55
49
–
93
97
77
98
94
80
37
98
97
98
2[e]
3
80/20
83/17
83/17
86/14
83/17
82/18
–
74/26
73/27
78/22
82/18
83/17
87/13
72/28
90/10
89/11
90/10
4
5
6
7
8
9
10
11
12
13
14[f]
15
16
17
18
19[g]
none
HCO2H
AcOH
PhCO2H
TFA
TBBP
TBBP
TBBP
TBBP
TBBP
TBBP
TBBP
TBBP
TBBP
TBBP
5
12
10
6
40
12
2
–
DMSO
EtOH
water
brine
water
4
12
[a]
Unless otherwise noted, all reactions were carried out using 20 mol% 1, cyclohexanone 2 (0.1 mL, 0.96 mmol) and nitro-
olefin 3a (0.05 mmol) in 0.4 mL of the indicated solvent at room temperature.
1/additive=1/1, TBBP=3,3’,5,5’-tetrabromobiphenol.
Isolated yield.
Determined by chiral HPLC.
An opposite configuration of product was obtained as determined by HPLC.
Cyclohexanone was used as solvent.
ACHTREUNG
[b]
[c]
[d]
[e]
[f]
[g]
The reaction was carried out using cyclohexanone 2 (0.2 mL, 1.93 mmol), nitrostyrene 3a (0.1 mmol), 10 mol% 3,3’,5,5’-
tetrabromobiphenol, 0.8 mL water in the presence of 10 mol% 1f.
ty decreased (Table 1, entries 7 and 8), and the use of (90/10 dr), enantioselectivity (98% ee) and yield
TFA only afforded a trace of product (Table 1, (92%) in 2 h (Table 1, entries 17 and 18). On the
entry 9), while 93% ee and 97% yield were observed other hand, reducing the catalyst loading to 10 mol%
in the presence of 3,3’,5,5’-tetrabromobiphenol led to no loss of diastereoselectivity and enantioselec-
(TBBP) (Table 1, entry 10). Then the catalyst from tivity with water as solvent (Table 1, entry 19).
the l-phenylglycine analogue with a para-substituent
Under the optimized reaction conditions (Table 1,
was examined (Table 1, entries 11 and 12). As illus- entry 19), a series of nitroolefins derived from aro-
trated in Table 1, catalyst 1f derived from l-4-fluoro- matic aldehydes was tested with cyclohexanone as
phenylglycine in the presence of TBBP additive donor and excellent results (dr up to 98/2 and ee up
proved to be an efficient organocatalytic system for to 98%; Table 2, entries 1–12) were achieved. When a
the direct asymmetric conjugate addition of cyclohex- heterocyclic nitroolefin was used as substrate, a slight
anone to nitrostyrene with excellent selectivity (97% decrease was observed in diastereoselectivity, whereas
ee, 90/10 dr). Some solvents were evaluated to further the yield and enantioselectivity were retained
improve the diastereoselectivity and enantioselectivi- (Table 2, entry 13). Unfortunately, cyclopentanone in-
ty. High enantioselectivities were obtained in THF stead of cyclohexanone as a Michael donor provided
and cyclohexanone (Table 1, entries 13 and 14), and a poor results.[9]
significant drop of both the reactivity and enantiose-
The catalytic direct asymmetric Michael addition of
lectivity was found in DMSO, EtOH (Table 1, en- acetone to nitroolefin 3a was also explored under the
tries 15 and 16). It was noteworthy that water as well same conditions (94% ee and 82% yield in water
as brine were superior to other solvents,[7] providing within 60 h; Table 3, entry 1). When acetone was used
the Michael product with high diastereoselectivity as the solvent instead of water, 85% yield and 95% ee
2002
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Table 2. Asymmetric Michael addition of cyclohexanone to nitroalkenes catalyzed by 1f.[a]
Entry
Ar
Time [h]
Yield [%][b]
syn/anti[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
Ph (3a)
12
3
92
95
82
98
99
99
86
98
91
90
90/10
93/7
90/10
90/10
98/2
98
97
96
98
98
98
97
95
97
98
4-BrC6H4 (3b)
4-NCC6H4 (3c)
3-ClC6H4 (3d)
2-NO2C6H4 (3e)
2,4-Cl2C6H3 (3f)
4-MeOC6H4 (3g)
4-MeC6H4 (3h)
3-MeOC6H4 (3i)
3,4-(MeO)2C6H3 (3j)
120
18
12
10
40
10
20
48
96/4
89/11
90/10
91/9
10
93/7
11
60
70
88/12
96
12
13
1-naphthyl (3l)
2-furyl (3m)
48
10
94
99
95/5
78/22
98
95
[a]
Unless otherwise noted, all reactions were carried out using 10 mol% 1f, 10 mol% 3,3’,5,5’-tetrabromobiphenol, cyclohex-
anone (0.2 mL, 1.93 mmol) and nitroolefin (0.1 mmol) in water (0.8 mL) at room temperature.
Isolated yield.
Determined by chiral HPLC.
[b]
[c]
Table 3. Asymmetric addition of acyclic ketones to nitroalkenes.[a]
Entry
R1
R2
Product
Time [h]
Yield [%][b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[e]
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
Ph
6a
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
60
24
24
24
24
24
24
24
24
24
24
24
24
24
54
24
82
85
83
88
95
90
95
96
80
90
88
92
89
99
30
90 (55)
94 (R)
95 (R)
90
93 (R)
90
92
90
95
93
96 (R)
94
96
96 (R)
93
81
4-NCC6H4
4-BrC6H4
3-NO2C6H4
3-ClC6H4
2-NO2C6H4
2-ClC6H4
2,4-Cl2C6H3
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2-furyl
1-naphthyl
i-Pr
Ph
99
[a]
Unless otherwise noted, all reactions were carried out using 10 mol% 1f, 10 mol% 3,3’,5,5’-tetrabromobiphenol (TBBP),
acetone (1.0 mL, 13.5 mmol) and nitroolefin (0.1 mmol) at room temperature.
Isolated yield.
[b]
[c]
[d]
[e]
Determined by chiral HPLC, the absolute configurations were determined by comparison with literature data.[6m,10]
Water as solvent.
A mixture of regioisomers, containing 55% linear and 35% branched Michael adducts with 1.0 mL 2-butanone as solvent.
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Figure 2. The calculated transition states of the Michael reaction of a nitroalkene with acetone catalyzed by 1e-3,3’,5,5’-tetra-
bromobiphenol.[12]
were obtained (Table 3, entry 2; see Supporting Infor- the transition states, one of the hydrogen atoms of the
mation for details). Next, the substrate scope of the hydroxy group participates in an intramolecular hy-
nitroolefin with acetone as donor was probed drogen bond and the other one is free for protonating
(Table 3). It appeared that the position and the elec- the secondary amine of 1e and activates the nitroal-
tronic property of the substituents on the aromatic kene by hydrogen bonding. For working models C
rings of nitroolefins had a limited influence on the and D: on the 3,3’,5,5’-tetrabromobiphenol moiety of
stereoselectivity of conjugate additions. Electron- the transition states, one of the hydrogen atoms of the
withdrawing (Table 3, entries 3–9), or -donating hydroxy group protonates the secondary amine of 1e
(Table 3, entries 10–12) groups on the aromatic ring, and the other one forms an intermolecular hydrogen
heterocyclic and fused ring (Table 3, entries 13 and bond with an oxygen atom of the nitroalkene. Based
14) nitroolefins gave highly enantioselective adducts. on computational results, the energies of TS1 and TS2
Noticeably, an aliphatic nitroolefin as a Michael ac- were lower than those of TS3 and TS4, respectively
ceptor (Table 3, entry 15) also resulted in good enan- (see Supporting Information). So, working models A
tioselectivity (81% ee) but a dramatic drop in yield. and B are more favorable than C and D. The H-bond
When 2-butanone was employed as a Michael donor, between the nitroalkene and catalyst 1e in TS1 was
the linear Michael adduct 6o was obtained as the shorter than that in TS2, which indicated a stronger
major product in excellent enantioselectivity (99% ee) interaction to nitroalkene in TS1. Furthermore, TS1
with moderate yield (Table 3, entry 16).
was also energetically more stable than TS2 by
The mechanism of the asymmetric Michael addition ~2.2 kcalmolÀ1. Thus, TS1 was found to be the favora-
between acetone and nitroalkene catalyzed by the pri- ble transition state which led to the formation of the
mary-secondary diamine catalyst 1e[11] and TBBP as major R-enantiomer and showed good agreement
additive has been investigated by theoretical simula- with the observed experimental results.
tions. Four proposed working models for this reaction
In summary, a highly diastereoselective and enan-
are shown in Figure 2.[6n,8,13] For working models A tioselective Michael addition of cyclohexanone, ace-
and B: on the 3,3’,5,5’-tetrabromobiphenol moiety of tone and other ketones to nitroolefins was developed
2004
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References
by the use of an amine organocatalyst based on bispi-
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secondary amine catalyst could serve through an en-
amine intermediate and H-bond interaction, which
was important for the reactivity and selectivity of this
reaction. The tolerance of aqueous media of this cata-
lyst also affords a promising scan for other valuable
organic transformations and further studies are under
way.
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General Procedure for the Direct Michael Reaction
To the mixture of catalyst 1f (2.8 mg, 0.01 mmol), 3,3’,5,5’-
tetrabromobiphenol (5.0 mg, 0.01 mmol), nitroolefin 3a
(14.9 mg, 0.1 mmol) in water (0.8 mL) was added cyclohexa-
none (0.2 mL, 1.93 mmol) at room temperature. The reac-
tion mixture was stirred until the nitroolefin was consumed
(monitored by TLC). The reaction mixture was diluted with
CH2Cl2 and quenched by the addition of 1.0 N NaOH solu-
tion. The water phase was extracted three times with
CH2Cl2, and the combined organic layers were dried over
Na2SO4 and concentrated. The residue was purified by silica
gel column chromatography (eluent: petroleum ether/ethyl
acetate=4/1) to afford the desired product.
Acknowledgements
We appreciate the National Natural Science Foundation of
China (Nos. 20602025 and 20732003) and the Ministry of
Education (2007061009) for financial support. We also thank
Sichuan University Analytical & Testing Center for NMR
analysis and the State Key Laboratory of Biotherapy for HR-
MS analysis.
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2005

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