A chiral functionalized salt-catalyzed asymmetric michael addition of ketones to nitroolefins

Article abstract of DOI:10.1002/adsc.200700184

The chiral functionalized salt catalysis, which differs from the known enzyme- and transition metal-based methods, has been successfully developed to carry out the Michael addition of ketones to nitroolefins. Chiral anion salt (type I), chiral cation salt (type II), or chiral anion-chiral cation salt (type III) could be expected to be remarkably effective catalysts and afford the corresponding chemically and optically pure Michael addition adducts. A primary amine group activating the ketone during salt catalysis was their obvious and common property. Based on preliminary experimental investigations and previous reports on primary amine catalysis, a reaction pathway via imine, enamine, iminium ion to imine was proposed.

Full text of DOI:10.1002/adsc.200700184

FULL PAPERS
DOI: 10.1002/adsc.200700184
A Chiral Functionalized Salt-Catalyzed Asymmetric Michael
Addition of Ketones to Nitroolefins
Yan Xiong,a Yuehong Wen,a Fei Wang,a Bo Gao,a Xiaohua Liu,a Xiao Huang,a
and Xiaoming Fenga,b,*
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, Peopleꢀs Republic of China
State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, Peopleꢀs Repubic of China
b
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Received: April 15, 2007; Published online: September 11, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The chiral functionalized salt catalysis, mary amine group activating the ketone during salt
which differs from the known enzyme- and transition catalysis was their obvious and common property.
metal-based methods, has been successfully devel- Based on preliminary experimental investigations
oped to carry out the Michaeladdition of ketones to
nitroolefins. Chiral anion salt (type I), chiralcation
salt (type II), or chiralanion-chiralcation satl (type
III) could be expected to be remarkably effective
and previous reports on primary amine catalysis, a
reaction pathway via imine, enamine, iminium ion to
imine was proposed.
catalysts and afford the corresponding chemically Keywords: amino acids; diamines; Michaeladdition;
and optically pure Michael addition adducts. A pri- nitroolefins; salt catalysis
Introduction
tive ion quaternary ammonium salts and chiral oxaza-
borolidinium ion salts (type II) have largely emerged
Salt catalysts, especially chiral functionalized salt cata- as remarkably potent, useful and versatile chiral cata-
lysts (Figure 1, types I, II and III), have attracted lysts for asymmetric processes,[2] whereas ammonium
(NH2)+, catalysis has appeared spor-
+
À
growing attention recently, due to their tuneable fea- salt, NH3 or =
tures for various chemicaltasks, their advantages in a
adically in catalytic asymmetric reactions. There is a
convenient recovering and reusing process,[1–3] and logic in expecting catalysts (type III), whose cation
their possibilities in relation to structural modification and anion are both chiral, to effectively promote
of either the cation or anion. In developing chiral some asymmetric reactions. In this regard, Barbas III
anion amino acid salts (type I), bifunctionalsodium
used an ammonium salt (Figure 2) to catalyze aldol
(S)-aminophenylacetate has been developed for appli- reactions.[1e,f]
[4,5]
cation in the asymmetric cyanosilylation of ketones in
our previous studies.[3] As a counterpart, chiralposi-
Since the initialpioneering works,
remarkable
advances in the application of secondary amines, such
as pyrrolidine- and imidazoline-type chiral organoca-
talysts, on the Michael addition of carbonyl com-
pound to nitroalkenes have been reported,[6] in which
Figure 1. Combinations of chiralfunctionalsatls.
Figure 2. Barbas IIIꢀs ammonium salt.
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Asymmetric MichaelAddition of Ketones to Nitrooel fins
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the asymmetric enamine catalysis of carbonyltransfor-
also preliminarily demonstrates the possible efficient
mations has been commonly accepted, and initially use of a primary amine in salt catalytic systems (en-
proceeded via iminium ion formation and almost tries 1 and 2).[10]
always ultimately resulted in iminium ion formation.[7]
The substituent on the phenylgroup, sovlent, cata-
By comparison, besides effective primary amine-thio- lyst loading and the cation were all consecutively in-
urea catalysis,[8] little progress has been made via en- vestigated. At 08C, catalyst 1b only gave a trace of
amine catalysis in the development of chiral small- product under solvent-free conditions (entry 3). Al-
molecule primary amine catalysts, especially of the though the chloro-substituent on the para-position of
primary amine-salt catalyst system. Nevertheless, pri- the phenylgroup ( 1e) gave the same enantiomeric
mary amine catalysis was effectively exploited using excess (61% ee) at room temperature (entry 6), the
enzymes such as type I aldolases, decarboxylases and enantioselectivity could also be improved up to 72%
dehydratases, each of which contains catalytically ee without the loss of isolated yield and diastereose-
active lysine residues.[9] Considering the particularities lectivity after 12 h at 08C (entry 7). At room tempera-
and potentials of the primary amine-salt catalysis, we ture, a routine solvent screen established that m-
now report on the primary amine salt-catalyzed asym- xylene was the most effective in terms of the yields
metric Michaeladdition of ketones to nitrooel fins via and selectivities (entry 8 vs. 10–14). With m-xylene,
enamine catalysis, which is initiated via imine forma- decreasing the temperature to 08C was favorable and
tion and ultimately resulted in imine formation, and increased the enantioselectivity to 79% ee (entry 9 vs.
which also could deliver excellent reactivities and se- 8). Meanwhile, in the presence of lower (10 mol%)
lectivities.
or higher (30 mol%) catalyst loadings, inferior asym-
metric induction was recorded (entries 15 and 16).
Replacing cation Na+ with H+, Li+, or K+ showed
that the transition from metalto non-metaland de-
creasing effective cation size led to decreasing reactiv-
ity and enantioselectivity, with even amino acid 1c
having no reaction. The catalyst 1f afforded good
Results and Discussion
Achiral Cation-Chiral Anion Salt Catalysis
We firstly become interested in the possible use of enantioselectivities up to 84% ee at 08C and 87% ee
chiral anion salt catalysis (type I) in the asymmetric at À208C with acceptable diastereoselectivities (en-
Michaeladdition of ketones to nitrooelfins. Cataylsts
tries 17 and 18). The fluoro-substituent on the para-
1a–b and 1d–h (Figure 3) were prepared by treating position or the chloro-substituent on the ortho-posi-
the amino acid with an equivalent of MOH (M=Li, tion of the phenylgroup ( 1g or 1h) gave lowered en-
Na and K) in methanol. The Michael addition of cy- antiomeric excesses (entries 19 and 20). Therefore, we
clohexanone to nitrostyrene, as a model reaction, was found that treatment of nitrostyrene and cyclohexa-
then explored to determine the optimal conditions, none with catalyst 1f (20 mol%) in m-xylene led to
with the initial results being summarized in Table 1. the most efficient enantioselective formation of prod-
As the data show, compared to pyrrolidine-type chiral uct.
amino acid salt 1a, sodium (S)-aminophenylacaetate
1b was prominent in providing the Michaeladdition
Under the optimalconditions, the substrate gener-
ality was examined, and the results are listed in
product in 95% yield with a better enantioselectivities Table 2. Various styrene-type nitroolefins worked well
(61% ee) under the conditions of 20 mol% catalyst in this reaction to obtain good diastereoselectivities
loading, and solvent-free at room temperature, which (up to 96:4 syn/anti) and enantioselectivities (up to
95% ee). For some of the substrates, temperature ef-
fects were also examined. Decreasing the temperature
from 0 to À208C, with relatively lower reactivities,
the selectivities were all improved. The reactions of
cyclopentanone and acetone with nitrostyrene could
also give adducts in moderate yields with good selec-
tivities (entries 17 and 18).
Chiral Cation-Achiral Anion Salt Catalysis
Attempting to develop a chiral cation salt (type II)
and based on Barbas IIIꢀs ammonium salt (Figure 2),
we considered the combination of a chiralamine and
a protonated amine positive ion to activate ketones
Figure 3. The evaluated chiral anion catalysts.
via enamine formation and simultaneously activate ni-
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Table 1. Optimization studies.
Entry[a]
Catalyst
Solvent[b]
Temperature [oC]
t [h]
Yield [%][c]
dr [syn/anti][d]
ee [%][e]
1
2
1a
1b
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1f
1f
1g
1h
neat
neat
neat
m-xylene
m-xylene
neat
r.t.
r.t.
0
0
0
r.t.
0
r.t.
0
r.t.
r.t.
r.t.
r.t.
r.t.
0
4
4
12
12
12
4
12
4
12
4
4
4
4
4
12
12
12
36
12
12
96
95
trace
n.r.
11
95
95
95
93
92
92
93
94
90
23
93
98
80
82
91
96:4
90:10
–
18
61
–
–
8
3
4[f]
5
–
69:31
92:8
89:11
92:8
6
7
8
9
61
72
69
79
61
65
67
68
55
70
77
84
87
77
73
neat
m-xylene
m-xylene
CH2Cl2
toluene
o-xylene
hexane
THF
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
93:7
10
11
12
13
14
15[g]
16[h]
17
18
19
20
83:17
84:16
89:11
85:15
80:20
90:10
87:13
76:24
82:18
90:10
92:8
0
0
À20
0
0
[a]
All reactions were carried out on a scale of 0.1 mmol nitrostyrene and 0.2 mL cyclohexanone.
[b]
[c]
[d]
[e]
[f]
0.2 mL solvent.
Isolated yield.
Determined by H NMR spectroscopy.
1
Determined by HPLC analysis.
n.r.=no reaction.
10 mol% catalyst loading.
30 mol% catalyst loading.
[g]
[h]
ies[12] established that (S)-2-amino-2-phenylacetic
À
À
troalkenes via a hydrogen bond of CONH and ion
+
À
À
NHn (n=1–3) interacting with the NO2 group. acid-derived primary amine salt 5 could most effec-
This approach was also partly motivated by recent tively promote the enantioselective addition (entry 6).
successes in the application of similar diamine back- For diamine derivative 4, 4-toluenesulfonic acid addi-
bones as bifunctionalcataylsts in the asymmetric cya-
tive (5 mol%) provided relatively inferior results, and
30 mol% of the same sulfonic acid gave no reaction,
nosilylation of ketones and aldehydes.[11]
Salts 2, 3, 5 and 6 (Figure 4) were prepared in situ mainly due to no amine group activating the cyclo-
by treating diamine derivatives with an equivalent of hexanone via the enamine (entries 4 and 5).[13] Con-
4-toluenesulfonic acid (see Experimental Section). trasting salt 5 with diamine derivative 4, higher cata-
The modelreactions of cycolhexanone and nitrostyr-
ene were carried out in neat mixtures with 15 mol%
lytic efficiency and asymmetric inductivity suggested
that introduction of H+ might form a more effective
catalyst loading at room temperature for 10 h, and the hydrogen bond by avoiding elongating the O···H dis-
results are summarized in Table 3. Secondary amine tance which resulted from the quick inversion of the
salts 2 and 3 derived respectively from (R,R)- and lone electron pair on the nitrogen atom of the pri-
(S,S)-diamine gave the same configuration of products mary amine (see Figure 5). In a controlexperiment,
(see Supporting Information) and almost equal enan- catalyst 6 gave no Michaeladdition adduct (entry 7),
tioselectivity, which revealed that the absolute config- which showed that the amide unit might contribute to
uration of the chiral diamine moiety had little effect formation of a further hydrogen bond to activate the
on the asymmetric induction (entries 1 and 2). Based nitroalkene to some extent.
on the R,R-diamine moiety, systematic screening stud-
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Asymmetric MichaelAddition of Ketones to Nitrooel fins
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Table 2. The substrate generality.
Entry
Products
Temperature [oC]
t [h]
Yield [%]
dr [syn/anti]
ee [%]
1
2
0
À20
12
36
98
80
76:24
82:18
84
87
3
4
0
À20
12
36
99
53
87:13
96:4
94
95
5
6
0
0
12
12
69
40
83:17
58:42
85
78
7
8
0
À20
12
36
65
86
74:26
80:20
85
93
9
10
0
À20
12
36
82
62
88:12
96:4
92
94
11
12
0
À20
12
36
83
65
68:32
70:30
85
88
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Table 2. (Continued)
Entry
Products
Temperature [oC]
t [h]
Yield [%]
dr [syn/anti]
ee [%]
13
14
0
À20
12
36
89
68
73:27
87:13
90
95
15
16
0
0
12
12
74
87
70:30
61:39
85
61
17
18
0
0
12
12
52
57
83:17
83
69
–
Under the optimalconditions, a variety of nitrooel -
the asymmetric inductivity (Table 3, entry 1 vs. 2),
fins with different structures were investigated, with commercially cheap racemic 1,2-diphenylethane-1,2-
the results being summarized in Table 4. Various sty- diamine was directly used to synthesize the salt 7.
rene-type nitroolefins reacted smoothly with cyclo- Catalyzed by salt 7, the reaction of cyclohexanone
hexanone in good yields with excellent diastereoselec- and nitrostyrene provided almost the same yield of
tivities and enantioselectivities (entries 1–11). Gener- the product with little loss in terms of selectivities
ally, substituents on aryl groups influenced only slight- (Scheme 1). In order to explore the reason that the
ly the diastereoselectivities and enantioselectivities, as racemic diamine could not influence the reactivity
well as the yields. For example, nitroolefins bearing and selectivities, the geometries of
N
N
both electron-withdrawing and electron-donating aryl 4 were optimized by the B3LYP method using a 6-
groups gave the desired products with high selectivi- 31G* basis set (Figure 6).[14] Although the two phenyl
ties (dr up to 94/6 and ee up to 96%) in excellent groups of the diamine moieties were respectively bent
yields (up to 99%). In the presence of an additional outwards and inwards in
50 mL of water, the reactivity and selectivity of the wards in (S,S)-4, the structures of their two amino
modelreaction were maintained (entry 2). The ob- acid units remained similar and the N···N distance of
served diastereoselectivities and/or enantioselectivi- two active sites respectively remained 5.09 Š in
ties for both cyclopentanone and acetone appeared to (R,R)-4 and 5.56 Š in (S,S)-4. This approximation
A
AHCTREUNG
A
ACHTREUNG
be higher than those obtained previously with a sec- could make them provide a similarly efficient cooper-
ondary amine as the catalyst (entries 12 and 13). ation in the Michaeladdition of ketone to nitrooel fin.
While attempting to use cycloheptanone and a-tetra- Thus, differing from our previous studies using dia-
lone as the prochiral donors, very poor reaction effi- mine derivatives as catalysts, in which the spread of
ciencies were produced.
With regard to an interesting synthetic application minated the face selectivity,[11,15] the phenylgroups in
of this protocol, and considering the absolute configu- (R,R)-4 or (S,S)-4 contributed to the highly asymmet-
ration of the chiral diamine moiety has little effect on ric induction only by furnishing an appropriate chiral
the phenylgroup of the diamine moiety directyl do-
A
ACHTREUNG
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Figure 4. The evaluated chiral cation catalysts.
Table 3. Optimization studies.
A catalytic cycle consistent with our experimental
observations was proposed and is depicted in
Figure 7. The nitroalkene is activated through two
oxygen atoms binding respectively to hydrogen atoms
+
on amide and NH3 groups,[16] and the cyclohexa-
À
none condenses with the primary amine group of cat-
alyst 5 to form imine intermediate A. Isomerization
of imine A leads to the formation of active enamine
B,[7] which can react with the electrophilic nitroalkene
via nucleophilic addition to give an a-modified imini-
um ion C. After H+ transfers to form imine D, imine
D can hydrolyze to give Michael addition adduct in
the presence of water. In contrast to secondary
amine-catalyzed Michael additions of ketones to ni-
troolefins, which proceed through iminium ion, enam-
ine to iminium ion in tandem,[7] the primary amine-
catalyzed reaction proceeds via imine A, enamine B,
and iminium ion C to imine D.
Entry
Catalyst
Yield [%][a]
dr [syn/anti][b]
ee [%][c]
1
2
3
2
3
4
4
4
5
6
90
83
58
94
n.r.
91
n.r.
95:5
96:4
87:13
90:10
-
70
72
74
90
-
4[d]
5[e]
6
93:7
-
93
-
7
[a]
Isolated yield.
Determined by H NMR spectroscopy.
Determined by HPLC analysis.
4-Toluenesulfonic acid (5 mol%) was added.
4-Toluenesulfonic acid (30 mol%) was added. n. r.=no
[b]
[c]
[d]
[e]
1
reaction.
Chiral Cation-Chiral Anion Salt Catalysis
pocket with the amino acid units and an appropriate Chiralanion satl 1f and chiralcation satl 5, respec-
distance between the two active sites.
tively, have been successfully employed to the Mi-
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Yan Xiong et al.
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Scheme 1.
Figure 5. Proposed effect of the amine protonation process on the hydrogen bond.
chaeladdition of ketones to nitrooelfins, which re-
vealed that the combination[17] of a chiralcation and a
chiralanion might produce strong asymmetric induc-
Conclusions
The primary amine-salt catalysis has been applied to
tion. The 4-toluenesulfonic acid anion of catalyst 5 the asymmetric Michaeladdition of ketones to nitro-
was replaced with the chiral d-camphorsulfonic acid olefins. Chiral functionalized salts, type I, such as po-
anion to form a chiral cation-chiral anion salt catalyst tassium (S)-2-amino-2-(4-chlorophenyl)acetate 1f,
8. Catalyst 8 also afforded 2-(2-nitro-1-phenyl-ethyl)- type II, such as 5, and type III, such as 8, could effec-
cyclohexanone in 95% yield with 93:7 syn/anti and tively promote the Michael addition of ketones to ni-
93% ee (Scheme 2).
troolefins. The experimental procedures were air-tol-
erant, simple and convenient. Amino acid salt 1f pos-
sessed remarkable advantages: cheap, readily pre-
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Asymmetric MichaelAddition of Ketones to Nitrooel fins
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Table 4. The substrate generality.
Entry Product
Yield [%] dr [syn/anti] ee [%] Entry Product
Yield [%] dr [syn/anti] ee [%]
1
91
91
93:7
94:6
93
92
2[a]
8
9
99
99
91:9
95
96
3
4
95
99
91:9
92:8
91
95
90:10
10
88
94:6
95
5
6
99
99
99
90:10
91:9
94
94
96
11
12
13
88
99
99
92:8
80:20
-
96
93
73
7
94:6
[a]
Water (50 mL) was added.
pared and efficiently recovered. By dual activation These protocols provide an alternative to that of the
catalysis, chiral positive ion ammonium salt 5 gave processes with secondary amine (e.g., pyrrolidine-
the corresponding products in excellent yields and imidazoline-type) chiral organocatalysts. Further
(ꢀ88%) with selectivities (up to 94:6 syn/anti and attempts to improve the selectivity and catalytic effi-
96% ee) in no more than 10 h. Optimizing conditions ciency through modifying the catalyst and optimizing
+
À
revealed that NH3 cooperating with an amide could the reaction conditions, whilst exploring the origins of
provide more effective hydrogen bond interactions the selectivity, are underway.
than NH2 to activate the acceptor, to attain suffi-
cient proximity for carbon-carbon bond formation.
À
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Figure 6. The optimized geometries of
N
N
Figure 7. The proposed mechanism (anion TsOÀ was omitted).
the internalstandard (CDCl , d=7.26). Data are reported
3
Experimental Section
as follows: chemical shift, multiplicity (s=singlet, d=dou-
blet, t=triplet, m=multiplet), coupling constants (Hz), inte-
gration, and assignment. Enantiomer ratios were determined
by chiral HPLC analysis on Daicel Chiralcel AS-H and AD-
H.
General Remarks
Michaeladdition reactions were carried out in test tubes
with magnetic stirring and no specialprecautions were
taken to exclude water or air from the reaction vessel. Cy-
clohexanone and m-xylene were purified by the usual meth-
ods. Purification of reaction products was carried out by
flash chromatography using silica gel. Optical rotations were
measured with a sodium lamp and reported as follows: [a]TD:
Typical Procedure for the Synthesis of (2S,2’S)-N,N’-
((1R,2R)-1,2-Diphenylethane-1,2-diyl)bis(2-amino-2-
phenylacetamide)
1
(c=g/100 mL, solvent). H NMR spectra were recorded on
AHCTREUNG
instruments of 300 MHz. Chemicalshifts are reported in
ppm from tetramethylsilane with the solvent resonance as
.
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Asymmetric MichaelAddition of Ketones to Nitrooel fins
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Scheme 2.
References
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Tetrahendron Lett. 1999, 40, 8231–8234; for quaternary
ammonium salt-catalyzed nitroaldol reaction, see:
m) E. J. Corey, F. Y. Zhang, Angew. Chem. Int. Ed.
Engl 1999, 38, 1931–1934; n) T. Ooi, K. Doda, K. Mar-
Procedure for amino acid salt catalysis: To the mixture of
potassium (S)-2-amino-2-(4-chlorophenyl)acetate 1f (4.5 mg,
0.02 mmol) and (2-nitrovinyl)benzene (14.9 mg, 0.1 mmol)
in m-xylene (0.2 mL) was added cyclohexanone (0.2 mL) at
08C. The mixture was stirred for 12 h and purified by flash
chromatography using EtOAc/PE (1:10, v/v) as eluent to
afford 2-(2-nitro-1-phenylethyl)cyclohexanone as an white
solid; yield: 24.2 mg (98%, 76:24 syn/anti, 84% ee).
Procedure for ammonium salt catalysis: To the mixture of
(2S,2’S)-N,N’-((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(2-am-
G
ino-2-phenylacetamide) (7.2 mg, 0.015 mmol) and 4-toluene-
sulfonic acid (2.6 mg, 0.015 mmol) was added cyclohexanone
(0.2 mL) at room temperature. After stirring for 20 min, ni-
trostyrene (14.9 mg, 0.1 mmol) was added. The mixture was
stirred for 10 h at room temperature and purified by flash
chromatography using EtOAc/PE (1:10, v/v) as eluent to
afford 2-(2-nitro-1-phenylethyl)cyclohexanone as a white
solid; yield: 22.5 mg (91% yield, 93:7 syn/anti, 93% ee).
HPLC (Chiralcel AS-H, hexane/i-PrOH, 75:25 v/v,
1.0 mLminÀ1, 238C, UV 210 nm): tr
(minor)=9.30 min,
U
tr (major)=13.19 min; [a]2D5: À21.9o (c 0.24, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.34–7.28 (m, 3H), 7.18–
7.15 (m, 2H), 4.94 (dd, J1 =12.5 Hz, J2 =4.6 Hz, 1H), 4.63
(dd, J1 =12.5 Hz, J2 =9.9 Hz, 1H), 3.76 (dt, J1 =9.9 Hz, J2 =
4.6 Hz, 1H), 2.73–2.68 (m, 1H), 2.50–2.38 (m, 2H), 2.10–
2.05 (m, 1H), 1.81–1.53 (m, 4H), 1.25–1.20 (m, 1H).
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 20225206, 20390055 and 20602025) and Sichuan Uni-
versity for financial support. We also thank Sichuan Universi-
ty Analytical and Testing Center for NMR analysis.
Adv. Synth. Catal. 2007, 349, 2156 – 2166
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2165

Yan Xiong et al.
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Adv. Synth. Catal. 2007, 349, 2156 – 2166