Efficient and highly enantioselective michael addition of aldehydes to nitroalkenes catalyzed by a surfactant-type organocatalyst in the presence of water

Article abstract of DOI:10.1246/cl.2010.412

It was found that in the presence of 20 mol % HCOOH, (S)prolinol sily1 ether organocatalyst bearing a long chain only in 2 mol % loading could catalyze the asymmetric Michael reaction of various aldehydes with irans-nitroalkenes at room temperature in the

Full text of DOI:10.1246/cl.2010.412

doi:10.1246/cl.2010.412
412
Published on the web March 20, 2010
Efficient and Highly Enantioselective Michael Addition of Aldehydes to Nitroalkenes
Catalyzed by a Surfactant-type Organocatalyst in the Presence of Water
Feng Hu,1 Chang-Shan Guo,1 Jin Xie,1 Hai-Liang Zhu,2 and Zhi-Zhen Huang*1
1College of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China
2College of Life Science, Nanjing University, Nanjing 210093, P. R. China
(Received January 22, 2010; CL-100069; E-mail: huangzz@nju.edu.cn)
It was found that in the presence of 20 mol % HCOOH, (S)-
bond-forming reactions in organic synthesis4 and there are only
a few reports3a-3d on the asymmetric Michael addition catalyzed
by chiral surfactant organocatalysts in the presence of water,
developing new chiral surfactant organocatalysts and their
highly stereoselective Michael reaction in the presence of water
is still a challenging subject. Herein we wish to present our
recent investigation on the synthesis of surfactant-type organo-
catalysts and the efficient and highly enantioselective Michael
addition of aldehydes to nitroalkenes in the presence of water.
Because many organocatalysts containing a chiral pyrrol-
idine backbone show excellent asymmetric induction, trans-4-
hydroxy-L-proline was chosen as a starting material to introduce
a hydrophobic group in the 4-position of the pyrrolidine
backbone. Initially, trans-4-hydroxy-L-proline was reacted with
(Boc2)O to give N-Boc-protected 4-hydroxyproline 5 in an
excellent yield according to a literature method (Scheme 1).5 In
the presence of potassium hydroxide, 5 could be etherified
smoothly by n-dodecyl bromide in DMSO to afford crude N-
Boc-protected 4-dodecyloxylproline, followed by the reaction
with methyl iodide in the presence of potassium carbonate,
furnishing pyrrolidine ester bearing a long chain 6 in 86% yield
for the two-step reaction.6 Ester 6 was reduced smoothly with
sodium borohydride in the presence of LiCl to give correspond-
ing prolinol, followed by tosylation in pyridine to afford desired
tosylate 7 in 88% yield for the two-step reaction.7 After the
reaction of tosylate 7 with pyrrolidine or imidazolyl sodium was
performed, the successive deprotection of Boc by TFA in
CH2Cl2 gave long chain pyrrolidines 8a in 86% yield and 8b in
88% yield respectively.7b,8 Then, ester 6 was reacted with ethyl
Grignard reagent, followed by deprotection of Boc with TFA,
giving a long chain prolinol 9 in 87% yield for the two-step
reaction.3b Finally, the reaction of prolinol 9 with TMSCl in
CH2Cl2 afforded desired prolinol silyl ether bearing a long chain
10 in 93% yield.3b
prolinol silyl ether organocatalyst bearing a long chain only in
2 mol % loading could catalyze the asymmetric Michael reaction
of various aldehydes with trans-nitroalkenes at room temper-
ature in the presence of water, giving the desired adducts in
excellent yields with high diastereoselectivities and excellent
enantioselectivities (up to >99% ee).
Presently organocatalysis is developing very rapidly and is
playing increasingly important roles in the synthesis of organic
molecules, especially in the construction of complex molecular
skeletons.1 Meanwhile, aqueous reactions have drawn much
attention because water is environmentally benign, safe, and
cheap as compared to organic solvents. Although there are
reports on successful aqueous asymmetric reactions catalyzed
by organocatalysts, the reactivities and selectivities of many
organocatalysts reduce in the presence of water.1-3 Recently, the
surfactant organocatalysts, which contain both hydrophilic and
hydrophobic moieties, proved very effective in aqueous organo-
catalytic reactions.2,3 In 2006, Takabe et al. employed 1/TFA to
catalyze the direct Michael addition of ketones with ¢-nitro-
styrene in brine, giving Michael adducts in good yields with
high enantioselectivities (up to 97% ee) (Figure 1).3a In 2007,
Palomo group found that in the presence of benzoic acid,
pyrrolidine catalyst 2, which formed emulsion easily with
reaction mixture in the presence of water, could catalyze the
Michael reaction of ¡,¢-unsaturated aldehydes with nitro-
methane or benzyl malonate to furnish desired adducts in
satisfactory yields with excellent enantioselectivities (up to 99%
ee).3b Luo, Cheng et al. revealed that under the catalysis of
surfactant imidazolium sulfate 3, the Michael addition of
cyclohexanone to ¢-nitrostyrenes was performed smoothly with
high reactivities and excellent diastereoselectivities and en-
antioselectivities (up to 98% ee) in the presence of water.3c Very
recently, Ni et al. developed a novel asymmetric Michael
addition of aldehydes to nitroolefins on water, which was
catalyzed by recyclable 4/PhCOOH with hydrophilic groups
and hydrophobic groups and provided the Michael adducts with
excellent diastereo- and enantioselectivities (up to >99% ee).3d
Because the Michael addition is one of the most important C-C
HO
O
O
O
1. CH3(CH2)11Br
KOH
11
1. NaBH4/ LiCl
2. TsCl/ Pyridine
OH
OMe
N
Boc
N
Boc
2. MeI/K2CO3
5
6
O
O
11
N
8a:
N
N
NH or
11
1.
NNa
Y =
OTs
N
Y
N
N
H
2. TFA/ CH2Cl2
8b:
OSiPh3
Boc
Y =
7
8
C[(CH2)4CH3]2
N[(CH2)9CH3]2
N
N
H
O
1
H
Et
Et
OSiMe3
O
11
2
Et
Et
11
1. EtMgBr/THF
2. TFA/CH2Cl2
Me3SiCl
Et3N
6
OH
OTMS
N
H
N
H
NBu-n
N
[
[CH
2NMe2]2
C
10
N
9
N
H
H
OSO3C12H25
3
4
Scheme 1. Synthesis of pyrrolidine organocatalysts bearing
long chain 8-10.
Figure 1.
Chem. Lett. 2010, 39, 412-414
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

413
Table 1. Optimization of the Michael reaction of n-butyralde-
Table 2. Surfactant 10/HCOOH-catalyzed Michael addition of
aldehydes to trans-nitroalkenes in the presence of watera
hyde with trans-¢-nitrostyrenea
O
O
Ar
Et
Et
10 (2mol%)
HCOOH (20mol%)
H2O
Ph
O
O
R1
8-11 (cat.)
NO2
NO2
H
NO2
H
OSiMe3
NO2
+
H
Ph
H
+
N
H
Ar
H2O
R
R1
R
12a
13a
14a
14
12
13
11
Yield/%b d.r.c ee/%d
Entry Cat.
Acid
Time/h Yield/%b d.r.c ee/%d
14 R
R1 Ar
a
b
c
d
e
CH3CH2
CH3CH2
H
H
H
H
H
H
H
H
H
H
H
C6H5
4-BrC6H4
C6H5
4-CH3OC6H4
3-CH3OC6H4
1-C10H7
4-FC6H4
C6H5
93
90
95
94
90
92
92
93
95
90
94
90
91
93
92/8
90/10
96/4
94/6
95/5
96
95
98
96
99
1
2
3
4
5
6
7
8
9
8a
8b
9
®
®
®
®
36
36
36
36
36
36
36
36
36
36
36
8
24
32
23
48
43
51
42
87
<5
10
87
95
92
93
n.d.
n.d.
n.d.
75:25
n.d.
n.d.
n.d.
81:19
n.d.
n.d.
n.d.
n.d.
87
n.d.
n.d.
n.d.
90
n.d.
n.d.
90
93
94
(CH3)2CH
(CH3)2CH
(CH3)2CH
(CH3)2CH
(CH3)2CH
CH3(CH2)2
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
CH3
10
8a
8b
9
AcOH
AcOH
AcOH
AcOH
®
AcOH
PhCO2H
HCOOH
HCOOH
HCOOH
f
96/4 >99
g
h
i
j
k
l
94/6
96/4
90/10
90/10
92/8
®
95
96
97
95
98
93
94
96
10
C6H5
4-CH3C6H4
1-C10H7
11
11
10
10
10
10
11
12
13e
n.d.
81:19
86:14
91:9
92:8
CH3 C6H5
H
H
m
n
CH3(CH2)5
CH3(CH2)5
C6H5
4-CH3OC6H4
93/7
95/5
26
16
14e,f 10
96
aThe reaction of aldehyde 12 (0.75 mmol) with nitroalkene 13
(0.5 mmol) was performed for 12-18 h at rt in water (0.5 mL).
bIsolated yields. cd.r. (syn/anti) values were determined by
1H NMR or HPLC. dDetermined by chiral HPLC using a
Chiralcel AD-H column.
aThe mixture of aldehyde 12a (0.75 mmol), nitrostyrene (0.5
mmol), organocatalyst (5 mol %), acid (5 mol %), and water
(0.5 mL) was stirred at room temperature. bIsolated yields. cd.r.
(syn/anti) values were determined by 1H NMR or HPLC.
dDetermined by chiral HPLC using a Chiralcel AD-H column.
f
e2 mol % 10. 20 mol % acid.
With the four chiral organocatalysts bearing a long chain 8a,
8b, 9, and 10 in hand, we chose the Michael addition of n-
butyraldehyde (12a) to trans-¢-nitrostyrene (13a) as a model
reaction to probe optimal reaction conditions. It was found that,
when 5 mol % of chiral organocatalysts 8a, 8b, 9, and 10 were
employed, the Michael reaction occurred in the presence of pure
water, but the yields of adduct 10a were low (Entries 1-4,
Table 1). When equimolar of acetic acid was added, which
formed surfactant with the long chain amines 8a, 8b, 9, or 10, it
was found that 10 resulted in remarkable increase of the yield up
to 87% with good diastereoselectivity and high enantioselectiv-
ity (compare Entry 4 with 8, Table 1). The experiment also
demonstrated that prolinol silyl ether without a long chain 11 led
to a very poor yield under the same conditions as its long chain
counterpart 10 (compare Entry 8 with 10, Table 1). Further
optimal investigation revealed that using 5 mol % HCOOH
instead of acetic acid resulted in the increase of enantioselec-
tivity from 87 to 93% ee (compare Entry 8 with 12). Decreasing
the amount of organocatalyst 10 from 5 to 2 mol % led to little
increase of diastereoselectivity (syn/anti) from 86/14 to 91/9
(compare Entry 12 with 13, Table 1). Moreover, when the
amount of HCOOH was increased to 20 mol %, our experiment
demonstrated that the reaction rate was accelerated and the
enantioselectivity was increased to 96% ee (compare Entry 13
with 14, Table 1).
enantioselectivities (99% ee in most cases).9a In 2008, Ma
et al. found that diphenylprolinol silyl ether also catalyzed
Michael reaction of aldehydes with nitroalkenes in the presence
of water, affording desired adducts in good yields with excellent
enantioselectivities (>99% ee).9b Our experiment indicated that
under the optimal conditions, diethylprolinol silyl ether bearing
a long chain 10 could catalyzed the Michael reaction of trans-
nitroalkenes 13 with various aldehydes 12 smoothly at room
temperature, giving the desired adducts 14a-14n in excellent
yields (90-95%) (Table 2).10,11 It was also found that for almost
all aldehydes 12, use of chiral catalyst 10 could result in high
diastereoselectivities (syn/anti = 90/10-96/4) and excellent
enantioseletivities (93- >99% ee) in the nitro-Michael reaction.
For the Michael reaction of aldehyde with alkyl-substituted
nitroalkene, the reaction of 3-methylbutanal with (E)-1-nitro-
pent-1-ene was tried and it was found that the reaction yield was
decreased dramatically. It should be noted that the physical
appearances of the reaction mixtures were emulsions under
stirring. The absolute configurations of the adducts 14a-14n
were assigned by comparison of the results of optical rotation
and chiral HPLC with those of known compounds and all
adducts 14a-14n are dextrorotatary in CHCl3.8
In conclusion, our experiments demonstrated that in the
presence of 20 mol % HCOOH, prolinol silyl ether organo-
catalyst bearing a long chain 10 only in 2 mol % loading could
efficiently catalyze the asymmetric Michael reaction of alde-
hydes 12 with trans-nitroalkenes 13 at room temperature in the
presence of water, giving the desired adducts 14a-14n in
excellent yields (90-95%) with high diastereoselectivities (syn/
anti = 90/10-96/4) and excellent enantioselectivities (93-
>99% ee).
In view of the condition experiments (Table 1), the
optimized reaction should be catalyzed by 2 mol % diethyl-
prolinol silyl ether 10 with 20 mol % HCOOH. In 2005, Hayashi
et al. successively employed diphenylprolinol silyl ether to
catalyze Michael reaction of aldehydes with nitroalkenes,
furnishing desired adducts in good yields with excellent
Chem. Lett. 2010, 39, 412-414
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

414
We thank the National Natural Science Foundation of China
for its financial support of the project No. 20872059.
b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem.
2002, 1877. c) S. B. Tsogoeva, Eur. J. Org. Chem. 2007,
1701. d) H. Kotsuki, H. Ikishima, A. Okuyama, Heterocycles
2008, 75, 757.
References and Notes
1
2
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Some Aldol reactions catalyzed by surfactant organocata-
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7
8
9
10 General procedure for Michael addition of aldehydes to
trans-nitroalkene: The mixture of aldehyde 12 (0.75 mmol),
organocatalyst 10 (4.2 mg, 0.01 mmol), and HCOOH (9 mg,
0.20 mmol) in water (0.5 mL) was stirred at room temper-
ature for 5 min. Then, powdered trans-nitroalkene 13 (0.5
mmol) was added and the reaction mixture was stirred at
room temperature. After the reaction was completed (about
12-18 h monitored by TLC), the mixture was concentrated
under reduced pressure, and the resulting residue was
purified by column chromatography (petroleum ether/
AcOEt as eluent) to give the Michael adducts 14a-14n.
11 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
3
4
a) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92, 771.
Chem. Lett. 2010, 39, 412-414
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/