Organocatalyzed enantioselective Michael additions of nitroalkanes to enones by using primary-secondary diamine catalysts

Article abstract of DOI:10.1039/c002552f

Primary-secondary diamines perform as efficient organocatalysts for the asymmetric addition of nitroalkanes to enones, giving the Michael adducts with excellent yields and enantioselectivities.

Full text of DOI:10.1039/c002552f

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Organocatalyzed enantioselective Michael additions of nitroalkanes to
enones by using primary–secondary diamine catalystsw
Ying-Quan Yang,a Xin-Kuan Chen,b Hua Xiao,a Wen Liua and Gang Zhao*ab
Received 5th February 2010, Accepted 1st April 2010
First published as an Advance Article on the web 29th April 2010
DOI: 10.1039/c002552f
Primary–secondary diamines perform as efficient organo-
catalysts for the asymmetric addition of nitroalkanes to enones,
giving the Michael adducts with excellent yields and enantio-
selectivities.
Table 1 Conjugate addition reaction of 2-nitropropane 1a to 4-(4-
chlorophenyl)but-3-en-2-one 2c catalyzed by 3a
The organocatalytic asymmetric Michael additions1 of nitro-
alkanes to a,b-unsaturated ketones, which could produce
useful products convertible to a variety of valuable structures
such as pyrrolidines,5a lactones,2 carbocycles,3 and amino
acids,4 has attracted considerable interests.5 Jørgensen5a,b
and Ley5c,d obtained modest to good enantioselectivity
(65–92% ee) for such additions between 2-nitropropane and
acyclic enones catalyzed by chiral tetrazoles. Using cinchona
alkaloid-derived thioureas, Soos et al. realized the asymmetric
addition of nitromethane to chalcones with high enantio-
selectivities,5e while Liang et al. realized the addition of
2-nitropropane to acyclic enones with moderate to good
enantioselectivity (73–86% ee). Only very recently did Wang
et al. report the highest enantioselectivity (92–99% ee) for the
reaction between nitromethane and acyclic enones using
cyclohexanediamine-derived primary amine thiourea catalysts.5g
Despite these significant advancements, present catalytic
systems more or less suffer several drawbacks such as long
reaction times (2–5 days), and costly thiourea catalysts. There-
fore, the development of cheaper and more simple organo-
catalysts6 is still highly desirable in order to make this
transformation more practical for use in organic synthesis.
With readily available and inexpensive natural amino acids
as a chiral source,7 our group have developed very simple
primary–secondary diamine organocatalysts for the asymmetric
reactions of a,b-enones.8 We now disclose herein that a similar
catalyst system could also efficiently catalyze the asymmetric
Michael reaction between nitroalkanes and a,b-unsaturated
ketones. Initially, the reaction of 2-nitropropane 1a with enone
2c was selected as a model reaction for catalyst evaluation
(Table 1). While catalyst 3a (Fig. 1) bearing two primary
amino groups derived from L-phenylalanine promoted this
reaction with moderate yield and poor enantioselectivity, its
monomethylated analogue 3b provided much better enantio-
selectivity (Table 1, entries 1 and 2). The length of the alkyl
chain connected to the nitrogen atom was found to influence
Entry
Catalyst
Solvent
Yield [%]b
ee [%]c
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Et2O
77
65
86
94
91
90
88
91
89
74
62
87
5
72
77
81
81
79
83
80
87
67
72
70
9
10
11
12
3i
3i
3i
Toluene
a
Reaction conditions: Unless specified, 2c (0.5 mmol, 1.0 equiv.) and
1a (1.0 mL) were used in solvent (1.0 mL) in the presence of 3
b
c
(20 mol%). Isolated yields. Determined by chiral HPLC analysis.
The absolute configuration was determined by comparison of the
specific optical rotation with that of the literature data.
Fig. 1 Structures of the catalysts studied.
the catalytic abilities of the catalysts and the n-propylated
catalyst 3d gave higher yield and ee value, which is in accord
with the findings from our previous studies8 (Table 1, entry 4).
Interestingly, the catalyst 3g with a bulky tert-butyl group in
the secondary amine moiety exhibited better enantioselectivity
in this reaction (Table 1, entry 7). Moreover, replacing the
benzyl group of 3g by an 3-indolyl group yielded the optimum
catalyst 3i derived from L-tryptophan, which provided the
desired product 4ac with 87% ee (Table 1, entry 9). Several
other solvents were also screened for catalyst 3i but with
inferior results (Table 1, entries 10–12).
a Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, China. E-mail: zhaog@mail.sioc.ac.cn
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experimental
details, analytical data, HPLC chromatography and NMR spectra of
products. See DOI: 10.1039/c002552f
Our further optimizing efforts were shifted to the examination
of the effect of several acid additives, which are well-documented
ꢀc
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Table 2 Effects of acid additives on the catalytic performance of
catalyst 3ia
(Table 3). Firstly, F-, Cl-, substituted enones worked well
for this reaction (Table 3, entries 2–5). For enones 2a–2g with
substituted benzene rings, both electron-donating and electron-
withdrawing substituents on different positions of the benzene
ring were well tolerated in the present system with good to
excellent enantioselectivities (86–91% ee) (Table 3, entries
1–7). Heterocyclic furyl enone 2h also performed well to
give the desired product in 90% yield and 88% ee (Table 3,
entry 8). No decrease in yield and ee value was observed for
the slightly more sterically hindered enone 2i (Table 3, entry
9). Moreover, the reaction could also be extended to the
aliphatic substrate 2j albeit with an apparent decrease in
the yield (Table 3, entry 10). Unfortunately, a sharp decrease
in enantioselectivity was observed for the cyclic substrate
2-cyclohexenone 2k (Table 3, entry 11). And good enantio-
selectivity could be realized for chalcone substrate 2l albeit
with low yield (Table 3, entry 12). Pleasingly, excellent result
was also obtained when nitromethane 1b was used in stead
of 2-nitropropane 1a as the nucleophilic reagent (Table 3,
entry 13).
Entry
Additive
Yield [%]b
ee [%]c
1d
2
3
4
5
6
7
8
none
HOAc
PhCO2H
TFA
PTSA
89
87
85
49
34
82
85
83
99
92
87
79
72
58
68
72
60
64
90
85
D-CSA
D-Boc-Phg-OH
L-Boc-Phg-OH
4-nitrophenol
4-nitrophenol
9
10e
a
Reaction conditions: Unless specified, 2c (0.5 mmol, 1.0 equiv.) and
1a (1.0 mL) were used in CH2Cl2 (1.0 mL) in the presence of 3i
Based on the extensively studied iminium catalysis of enones
using primary amine catalysts, a pretransition state I similar to
that previously proposed by us for the reaction between
malonates and enones may be invoked to explain the observed
stereochemical results (Fig. 2). In this pretransition state, the
primary amine moiety of the catalyst 3i activates the enone 2
via the formation of an iminium ion while the secondary amine
activates the nucleophile nitroalkane 1 and may also direct its
attack to the iminium ion through H-bonding interaction. The
Re face of the enone in this pretransition state assembly I is
shielded by the bulky indolyl group driving the nitroalkane to
attack the Si face of the enone 2. The acid additive may
facilitate the formation of the iminium ion and foster the
regeneration of the catalyst in the hydrolysis of the enamine
intermediate after the addition step. However, the exact existing
or functioning forms of the acid additives in the reaction
system are difficult to be determined.
b
(20 mol%) and an acid additive (20 mol%). Isolated yields.
c
d
Determined by chiral HPLC analysis. Reaction was run for
e
48 h. The reaction mixture was stirred at 0 1C.
to be beneficial for the iminium catalysis. To our delight, the
addition of an appropriate acid additive not only improved the
yield and ee values, but also decreased the reaction time
significantly from 48 to 24 h (Table 2). Thus, the reaction
was best performed using a 1 : 1 combination of 3i/4-nitrophenol
to provide the desired product with 99% yield and 90% ee
(Table 2, entry 9).
With the optimized reaction conditions in hand, the scope of
the addition of nitroalkanes 1 to enones 2 was explored
Table 3 Enantioselective Michael reaction between nitroalkanes 1
and enones 2 catalyzed by the 3i/4-nitrophenol combinationa
In summary, we have developed a novel readily available
primary–secondary diamine catalyst system for the Michael
additions of nitroalkanes to enones. High yields and enantio-
selectivities were achieved for a range of both nitroalkanes and
enones. Efforts are being focused on further application of the
catalyst system to other related reactions as well as a more
detailed mechanistic understanding of the reaction.
Entry R1
R2
Product Yield [%]b ee [%]c
1
Ph
Me, 2a 4aa
Me, 2b 4ab
Me, 2c 4ac
Me, 2d 4ad
Me, 2e 4ae
Me, 2f 4af
Me, 2g 4ag
Me, 2h 4ah
Et, 2i 4ai
Me, 2j 4aj
90
86
99
88
84
98
86
90
85
65
84
62
86
88
91
90
87
86
91
91
88
90
91
60
92
91
Research support from National Basic Research Program
of China (973 Program, 2010CB833200, 2010CB833300) the
National Natural Science Foundation of China (No.20172064,
203900502, 20532040), Shanghai Natural Science Council, and
Excellent Young Scholars Foundation of National Natural
Science Foundation of China (20525208).
2
3
4
5
6
7
8
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-MeOC6H4
4-NO2C6H4
2-furyl
9
Ph
n-C4H9
2-Cyclohexenone (2k)
Ph
Ph
10
11
12d
13e
—
4ak
Ph, 2l 4al
Me, 2a 4ba
a
Reaction conditions: Unless specified, 2 (0.5 mmol, 1.0 equiv.) and
1a (1.0 mL) were used in CH2Cl2 (1.0 mL) in the presence of
b
3i/4-nitrophenol (20 mol%). Isolated yields. Determined by chiral
c
d
e
HPLC analysis. Reaction was run for 96 h. MeNO2 (1.0 mL) was
used.
Fig. 2 Possible pretransition state I.
ꢀc
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ꢀc
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