Highly active water-soluble and recyclable organocatalyst for the asymmetric 1,4-conjugate addition of nitroalkanes to α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/adsc.201000344

A novel strategy for the catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated aldehydes in aqueous media has been developed by using diarylprolinol silyl ether in combination with benzoic acid as a water-soluble organocatalyst provid

Full text of DOI:10.1002/adsc.201000344

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DOI: 10.1002/adsc.201000344
Highly Active Water-Soluble and Recyclable Organocatalyst for
the Asymmetric 1,4-Conjugate Addition of Nitroalkanes to a,b-
Unsaturated Aldehydes
Subrata K. Ghosh,a Zilong Zheng,a and Bukuo Nia,*
a
Department of Chemistry, Texas A&M University – Commerce, Commerce, Texas 75429-3011, USA
Fax : (+1)-903-468-6020; e-mail: Bukuo_Ni@tamu-commerce.edu
Received: May 3, 2010; Revised: August 19, 2010; Published online: October 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000344.
Abstract: A novel strategy for the catalytic asym-
metric conjugate addition of nitroalkanes to a,b-un-
saturated aldehydes in aqueous media has been de-
veloped by using diarylprolinol silyl ether in combi-
nation with benzoic acid as a water-soluble organo-
catalyst providing the desired adducts in good to
excellent enantioselectivities (up to 95% ee). This
catalyst can be recycled at least five times with only
a slight reduction in activity and selectivity. In addi-
tion, the synthetic procedure presented is simple,
practical and environmentally benign.
vents. Moreover, when a water-soluble organocatalyst
is used, the water-insoluble products can be isolated
easily by simple separation and the catalytic system
can be recycled. Therefore, development of an orga-
nocatalyst that is not only active in aqueous media
but also stable and completely soluble in this solvent
would be highly desirable.
Recently, much effort has been devoted to the de-
velopment of water-compatible organocatalysts for
performing organic transformations in aqueous
media. Significant progress has been made for conju-
gate addition of aldehydes and ketones to a,b-unsatu-
rated carbonyl compounds by activating the carbonyl
compounds through a nucleophilic enamine mecha-
nism.[6] However, limited success has been achieved
so far for the conjugate addition of carbanions to a,b-
unsaturated aldehydes in aqueous systems through
electrophilic iminium ion mechanism.[7,8] This is prob-
Keywords: aldehydes; asymmetric catalysis; catalyst
À
recycling; C C bond formation; Michael addition
Asymmetric organocatalysis has attracted great inter- ably due to the lower stability of iminium ion inter-
est over the past decade.[1] Within this category, the mediate in the presence of water. Furthermore, the
organocatalyzed conjugate addition reaction is a par- high reactivity of a,b-unsaturated aldehydes undergo-
ticularly interesting and powerful synthetic method ing 1,2-addition reaction in competition with the 1,4-
À
for the construction of C C bonds in modern chemis- conjugate addition could be another reason. To the
try because it provides chiral functionalized products. best of our knowledge, there is only one report in the
These compounds can be used as versatile synthetic literature using dialkylprolinol silyl ether as an effi-
building blocks for the synthesis of biologically active cient organocatalyst for the 1,4-conjugate addition of
compounds and natural products.[2] Thus, it is not sur- nitromethane to a,b-unsaturated aldehydes in water
prising that many organocatalysts have been devel- to give excellent enantioselectivity.[6d] It should be
oped for this cornerstone reaction.[3] Among these or- noted that all organocatalysts reported so far for
ganocatalysts, chiral secondary amines, which stand asymmetric reactions in aqueous media have a
out as one of the most active and enantioselective cat- common feature that the catalysts were specifically
alysts with broad substrate generality, have expanded designed to contain large hydrophobic groups, which
the scope of organocatalysis.[4] However, performing accurately serve as a “concentrated organic phase”.
organocatalysis in aqueous media is still challenging The hydrophobicity of catalysts causes them to assem-
due to the fact that water often inhibits the catalystꢀs ble with hydrophobic reactants in water and sequester
activity and disrupts hydrogen bonds and other polar the formation of enamine or iminium transition state
interactions.[5] On the other hand, aqueous organoca- from water. As a result, the reaction is not really pro-
talysis has economic, environmental, and processing ceeding in water and is more likely performed in “or-
benefits compared to its use in typical organic sol- ganic solvent”.[9] Thus, a special design of water-solu-
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Adv. Synth. Catal. 2010, 352, 2378 – 2382

Highly Active Water-Soluble and Recyclable Organocatalyst for the Asymmetric 1,4-Conjugate Addition
ble organocatalyst is required for performing these re- kanes to a,b-unsaturated aldehydes in the presence of
actions in aqueous media with good stereoselec- water with i-PrOH as cosolvent [Scheme 1, Eq.
tion.[10]
(2)].[13] Furthermore, we found that the catalytic
With the goal of developing a recyclable catalyst system can be easily recovered and reused at least 5
that displays high activity and enantioselectivity in times with only a slightly decreased enantioselectivity.
aqueous media, our group has reported a water-solu-
To examine the performance of catalyst 1, the 1,4-
ble and recyclable catalyst, diarylprolinol silyl ether 1 conjugate addition reaction of nitromethane and cin-
in combination with Brønsted acid, which catalyzed namaldehyde to afford g-nitroaldehyde 2a was per-
the asymmetric Michael addition of aldehydes to ni- formed using benzoic acid as an additive. Screening
troolefins in aqueous media with excellent diastereo- of solvents and the ratio of benzoic acid to catalyst
and enantioselectivities through activation of alde- was investigated to optimize the reaction conditions.
hydes by an enamine mechanism [Scheme 1, Eq. The results are summarized in Table 1. Initially, the
(1)].[11,12] To further develop our catalytic system, we reaction was performed in water with 7 mol% of cata-
evaluated the iminium ion-based, organocatalytic lyst 1 in the absence of benzoic acid as additive.
direct asymmetric 1,4-conjugate addition of nitroal- There was no product 2a observed after 72 h
(entry 1). However, the reaction proceeded to afford
the product 2a in 84% yield at room temperature
after 72 h when 28 mol% of benzoic acid was added
(entry 2). When the amount of benzoic acid was in-
creased to 42 mol%, the reaction time decreased to
48 h with comparable enantioselectivity (entry 3).
However, further increases of the benzoic acid load-
ing did not improve the yield and selectivity (entry 4).
When the amount of donor CH3NO2 was reduced to
2 equivalents, the enantioselectivity was increased
from 88% to 93%; but the yield was decreased and a
longer reaction period was needed (entry 5). Lower-
ing the temperature to 48C further improved the
enantioselectivity to 95% (entry 6). Different water/
alcohol solvent systems were examined that resulted
in the desired product 2a in similarly high enantiose-
lectivities (entries 7–10). The optimal result was ob-
tained by using a solvent mixture of water:i-PrOH in
a ratio of 3:1 affording product 2a in 80% yield with
94% ee (entry 11). The absolute stereochemistry of
Scheme 1.
Table 1. Optimization of the reaction conditions of nitromethane with cinnamaldehyde.[a]
Entry
Solvent
T [oC]
PhCO2H [mol%]
CH3NO2 [equiv]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
H2O
H2O
H2O
H2O
H2O
H2O
H2O:MeOH 3:2
H2O:EtOH 3:2
H2O:i-PrOH 3:2
H2O:i-PrOH 2:1
H2O:i-PrOH 3:1
r.t.
r.t.
r.t.
r.t.
r.t.
4
4
4
4
4
0
4
4
4
4
2
2
2
2
2
2
2
72
72
48
48
60
60
48
48
48
48
48
0
–
28
42
70
42
42
42
42
42
42
42
84
80
80
50
51
78
80
82
77
80
87
87
88
93
95
90
91
94
93
94
9
10
11
4
[a]
Reactions performed on a 0.4-mmol scale using catalyst 1, benzoic acid, and solvent (0.5 mL).
Isolated yield.
Determined by chiral HPLC of the product.
[b]
[c]
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Subrata K. Ghosh et al.
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Table 3. Reaction of nitromethane with a,b-unsaturated al-
dehydes catalyzed by 1.[a]
product 2a was determined to be (S) by comparing its
optical rotation with literature values by using (S)-di-
phenylprolinol silyl ether as catalyst.[8b]
Next, the recyclability of the catalytic system
(10 mol% of catalyst 1 was used) was studied in a re-
action of nitromethane with cinnamaldehyde under
standard reaction conditions. Upon completion of the
reaction, we found that the aqueous catalytic system
was easily recovered after extraction of the product
2a by addition of a solvent mixture of hexane:Et2O
(4:1). The recovered aqueous phase was reused for
the next cycle directly by addition of fresh portions of
benzoic acid, nitromethane, cinnamaldehyde, and co-
solvent i-PrOH. The performace of the recycled cata-
lyt 1 was evaluated by prolonged and identical reac-
tion times, respectively (Table 2). As shown in
Table 2, the reactivity and enantioselectivity of the re-
covered catalyst 1 system dropped gradually after the
first cycle with prolonged reaction time (Table 2, left
column). However, the enantioselectivity was retained
in high levels and only slightly decreased in cycles 3–5
with identical reaction times (Table 2, right column).
These results demonstrate that catalyst 1 is the first
effective recyclable organocatalyst for the asymmetric
Entry
R
Product t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
Ph
2a
2b
2c
2d
46
55
55
55
48
68
48
64
53
20
82
68
66
65
48
74
70
70
73
62
93
91
94
93
94
89
91
94
87
84
4-FC6H4
2-ClC6H4
4-BrC6H4
2-NO2C6H4 2e
4-NO2C6H4 2f
2-MeOC6H4 2g
4-MeOC6H4 2h
2-furanyl
Me
2i
2j
10
[a]
Reactions performed on a 0.4-mmol scale using catalyst
1, benzoic acid, nitromethane (2 equiv.), H2O:i-PrOH
(0.5 mL).
Isolated yield.
Determined by chiral HPLC of the product.
[b]
[c]
conjugate addition reactions between nitroalkanes ing products 2b–h in moderate to good yields (48–
and a,b-unsaturated aldehydes in aqueous media with 74%) with high enantioselectivities (89–94% ee) (en-
excellent stereoselectivities. It is also amendable to a tries 2–8). The heteroaromatic a,b-unsaturated alde-
very simple, practical and green procedure for catalyt hyde was also a suitable substrate affording the prod-
recovery.
uct 2i in good enantioselectivity and yield (entry 9).
Encouraged by these results, we next probed the Furthermore, catalyst 1 is also highly effective for
scope of this asymmetric conjugate reaction with ni- conjugate addition of nitromethane to an aliphatic
tromethane and a variety of a,b-unsaturated alde- a,b-unsaturated aldehyde providing the desired prod-
hydes in a solvent mixture of H2O:i-PrOH (3:1) at uct 2j in good yield (62%) and enantioselectivity
48C (Table 3). The results show that the reaction pro- (84% ee) (entry 10).
ceeds efficiently for all cinnamaldehyde derivates
Finally, the structural effect of nitroalkanes on the
bearing both electron-deficient and electron-rich sub- conjugate addition was also investigated, and the re-
stituents on the phenyl ring affording the correspond- sults are summarized in Table 4. The reactions
worked well with nitroethane and nitropropane to
give the desired products 2k–n in 73–95% yields with
Table 2. Recycling studies of water-soluble 1-catalyzed reac-
high enantioselectivities (89–94% ee) for both syn and
anti diastereomers. However, the dr selectivities were
poor.
tion of nitromethane with cinnamaldehyde.[a]
The large-scale 1,4-conjugate addition was carried
out, in which 10 mmol of cinnamaldehyde reacted
with nitromethane under standard reaction condi-
tions. After the reaction was completed, the reaction
mixture was separated into two phases. The aqueous
phase was removed by simple separation and the or-
ganic phase was purified by flash chromatography on
silica gel to give the desired product 2a in 82% yield
with high enantioselectivity (94% ee). Notably, the
procedure is green and practical, and no organic sol-
vent is required for the work-up step.
Cycle t
Yield
ee
t
Yield
ee
[h] [%][b]
[%][c]
[h] [%][b]
[%][c]
1
2
3
4
5
37 84
48 76
53 70
84 73
120 64
93
92
92
89
84
40 86
40 75
40 67
40 58
40 45
93
93
92
91
89
[a]
Reactions performed on a 0.5-mmol scale using catalyst
1, benzoic acid, nitromethane (2 equiv.), H2O:i-PrOH
(0.5 mL).
Isolated yield.
Determined by chiral HPLC of the product.
In conclusion, a new, highly efficient, asymmetric
conjugate addition of nitroalkanes with a,b-unsaturat-
ed aldehydes catalyzed by a novel water-soluble orga-
nocatalyst, diarylprolinol silyl ether 1 in combination
[b]
[c]
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Highly Active Water-Soluble and Recyclable Organocatalyst for the Asymmetric 1,4-Conjugate Addition
Table 4. Reaction of itroalkane with a,b-unsaturated aldehydes catalyzed by 1.[a]
Entry
R1
R2
Product
t [h]
Yield [%][b]
syn/anti[c]
ee [%][d]
1
2
3
4
Ph
Me
Me
Me
Et
2k
2l
2m
2n
50
50
48
60
83
88
95
73
2/3
2/1
1/2
3/2
90/93
92/91
89/91
94/94
2-NO2C6H4
2-MeOC6H4
2-NO2C6H4
[a]
Reactions performed on a 0.4-mmol scale using catalyst 1, benzoic acid, nitroalkane (2 equiv.), and H2O:i-PrOH
(0.5 mL).
Isolated yield.
Determined by H NMR.
Determined by chiral HPLC of the product.
[b]
[c]
[d]
1
with benzoic acid, in aqueous media has been devel-
oped. The main advantages of this catalyst are the
low donor nitroalkane loading (2 equiv.), the use of
aqueous media, and the recyclable catalytic nature of
the system with high enantioselectivities (84–94% ee).
These remarkable advantages make this approach
very suitable for practical use. Further studies focus-
ing on the scope of this unique organocatalyst to cata-
lyze asymmetric transformations and the modification
of the dimethylamine moiety by synthesis of ammoni-
um ionic liquid-supported catalysts are currently
under investigation and will be reported in due
course.
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General Procedure for 1,4-Conjugate Addition of
Nitroalkanes to a,b-Unsaturated Aldehydes (Table 3
and Table 4)
To a mixed solution of H2O:i-PrOH=3:1(v/v, 0.5 mL) was
added an a,b-unsaturated aldehyde (0.4 mmol), nitroalkane
(0.8 mmol), catalyst (0.028 mmol) and benzoic acid
(0.168 mmol). The reaction mixture was stirred at 48C for
the time indicated in the Table 3. The products were extract-
ed with Et2O:hexane=1:3 (v/v). The combined organic
phase was evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel to
yield the desired addition product 2.
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We are grateful to the Robert A. Welch Foundation (T-0014)
and Office of Graduate Studies & Research at Texas A&M
University – Commerce for financial support of this research.
We are grateful to Martha Clevenger for her assistance.
Adv. Synth. Catal. 2010, 352, 2378 – 2382
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Adv. Synth. Catal. 2010, 352, 2378 – 2382