The effect of hydrogen bond donors in asymmetric organocatalytic conjugate additions

Article abstract of DOI:10.1016/j.tetasy.2009.11.029

A series of primary amine organocatalysts with various hydrogen bond donors were prepared and examined in the conjugate addition of isobutyraldehyde and acetone to trans-β-nitrostyrene and (E)-methyl 2-oxo-4-phenylbut-3-enoate. The effect of N-H acidity a

Full text of DOI:10.1016/j.tetasy.2009.11.029

Tetrahedron: Asymmetry 20 (2009) 2818–2822
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The effect of hydrogen bond donors in asymmetric organocatalytic
conjugate additions
*
Jin-hua Lao, Xue-jing Zhang, Jin-jia Wang, Xue-ming Li, Ming Yan , Hai-bin Luo
Industrial Institute of Fine Chemicals and Synthetic Drugs, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of primary amine organocatalysts with various hydrogen bond donors were prepared and exam-
ined in the conjugate addition of isobutyraldehyde and acetone to trans-b-nitrostyrene and (E)-methyl
2-oxo-4-phenylbut-3-enoate. The effect of N–H acidity and hydrogen-bonding modes of the catalysts
on the catalytic activity and enantioselectivity was studied. The experimental results did not support a
general correlation of N–H acidity and hydrogen-bonding modes with catalytic activity and enantioselec-
tivity. The catalysts with double hydrogen-bonding interactions provided better catalytic activities and
enantioselectivities than the catalysts with single hydrogen-bonding interactions for the reaction of
trans-b-nitrostyrene. The catalyst with the most acidic N–H bond showed the best catalytic activity
and enantioselectivity for the reaction of (E)-methyl 2-oxo-4-phenylbut-3-enoate. These results suggest
that the effect of hydrogen bond donors in organocatalytic reactions may be highly dependent on the
substrates and the reaction conditions.
Received 14 October 2009
Accepted 27 November 2009
Available online 5 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
alysts and found that they are highly efficient for the conjugate
addition of aldehydes and ketones to nitroalkenes.3 In a subse-
Asymmetric catalysis through explicit hydrogen-bonding inter-
actions has been proved to be a highly successful strategy.1 Ureas,
thioureas, guanidinium and amidinium ions, sulfamides, and sul-
fonamides are privileged hydrogen bond donors. The hydrogen-
bonding interactions with carbonyl groups, imines, and nitro
groups of the substrates increase their electrophilic reactivity. Fur-
thermore, the hydrogen-bonding interactions also help to provide
pre-organized transition states and to control the stereoselectivity
efficiently. As a generally accepted opinion, the more acidic is the
involving heteroatom–hydrogen bond the stronger is the resulting
hydrogen-bonding interaction. In addition, double hydrogen bond
donors or multiple hydrogen bond donors are thought to be more
efficient than single hydrogen bond donors. For example, ureas,
thioureas, and guandinium ions are expected to provide better
catalytic activity than sulfonamides or amides. However, the effect
of the different hydrogen bond donors on catalytic activity and
stereoselectivity has rarely been studied in detail. Such knowledge
should be highly useful for the design of more efficient organo-
catalysts.
quent study, we also found that the structurally related thioureas
are also good catalysts for the reaction.4 Although we expected
that the more acidic N–H bond in the sulfamides could provide
better catalytic efficiency than in the corresponding thioureas, a
reliable conclusion could not be achieved by the present experi-
ment results. We become interested in the effect of the acidity
of the N–H bond and the hydrogen-bonding modes on the cata-
lytic activity and stereoselectivity of bifunctional primary amine
organocatalysts. To this end, a series of chiral bifunctional pri-
mary amines with various hydrogen bond donors were designed
and prepared. These catalysts were examined in the asymmetric
conjugate addition of aldehydes and ketones to nitroalkenes and
a,b-unsaturated ketoesters. The experimental results are reported
herein.
2. Results and discussion
Primary amines 1a–1i with a chiral cyclohexane-1,2-diamine
backbone were prepared (Scheme 1). Several kinds of hydrogen
bond donors were selected, including urea, thiourea, sulfamide,
sulfonamide, and amide. The pKa values of the selected N–H bonds
were calculated with a ACD/Lab 11 program.5 For the sake of com-
parison, the phthalimide derivative 1j was also prepared, which is
unable to provide the hydrogen-bonding interaction. Initially the
conjugate addition of isobutyraldehyde to trans-b-nitrostyrene
was explored using 1a–1j as the catalysts.6 Since the reaction
was found to be rather slow in the absence of base additives, DMAP
The combination of hydrogen bond donors and amines has led
to extremely efficient bifunctional organocatalysts for many
asymmetric transformations.2 These catalysts feature the simulta-
neous activation of both nucleophiles and electrophiles. Recently
we developed a new class of sulfamide-primary amine organocat-
* Corresponding author. Tel./fax: +86 20 39943049.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.029

J. Lao et al. / Tetrahedron: Asymmetry 20 (2009) 2818–2822
2819
O
O
O
O
O
O
S
S
S
Ph
N
H
N
F3C
N
N
H
H
H
NH2
NH2
NH2
pKa = 6.5
11.2
11.7
CF3
1c
1b
1a
O
O
S
t-Bu
Ph
O
N
H
N
H
N
F3C
N
N
H
H
NH2
NH2
H
NH2
12.0
12.3
13.1
1d
1e
1f
O
O
O
S
N
Ph
Ph
N
H
H3C
15.8
N
H
N
N
NH2
H
H
NH2
NH2
NH2
O
14.1
14.2
1g
1j
1i
1h
Scheme 1. Chiral primary amine organocatalysts 1a–1j.
was used as the selected additive based on the previous study.3a
The results are summarized in Table 1.
The reaction of acetone and trans-b-nitrostyrene was also stud-
ied using 1a–1j as the catalysts. Since both acid and base additives
were found to promote the reaction previously,3b the reaction was
examined in the presence of benzoic acid and imidazole, respec-
tively. The experimental results are summarized in Table 2.
The reaction did not occur when only a base additive (DMAP)
was used (Table 1, entry 1). Catalysts 1a–1j accelerated the reac-
tion and provided good to excellent enantioselectivities. Catalyst
1j, which is free of the hydrogen bond donor, gave the product in
low yield and moderate enantioselectivity. In addition the enantio-
facial selectivity was reversed (Table 1, entry 11). The results
clearly demonstrate the importance of the hydrogen-bonding
interaction for the catalytic behaviors of 1a–1j. However the acid-
ity of the N–H bond in the catalysts is not proportional to the cat-
alytic activity (Table 1, 1a vs 1b, 1d, 1f, and 1g). Catalyst 1f with a
more acidic N–H bond did not afford a higher reaction rate than the
structurally similar 1g (Table 1, entry 7 vs entry 8). It is obvious
that the double hydrogen-bonding interaction leads to a higher
reaction rate and enantioselectivity than the single hydrogen-
bonding interaction (1b, 1d, 1f, and 1g vs the other catalysts).
Table 2
The reaction of acetone and trans-b-nitrostyrene catalyzed by 1a–1ja
O
cat* (20 mol%)
O
additive (20 mol%)
NO2
+
Ph
NO2
Et2O, rt, 72 h
*
Ph
3
Entry
Cat
PhCOOH
Imidazole
Yieldb (%)
eec (%)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
51
74
62
87
56
95
93
55
60
19
56
74
61
58
58
64
74
64
60
22
88
54
69
63
55
82
58
66
66
40
39
70
55
50
45
67
65
49
46
ꢀ7
Table 1
The reaction of isobutyraldehyde and trans-b-nitrostyrene catalyzed by 1a–1ja
Cat
* (20 mol%)
CHO
NO2
DMAP (20 mol%)
NO2
+
CHO
Ph
CHCl3, rt
*
Ph
10
1j
2
a
The reactions were carried out with nitrostyrene (0.15 mmol), acetone (0.2 mL),
b
Entry
Cat
pKa
Time (h)
Yieldc (%)
eed (%)
catalyst (0.03 mmol), and additive (0.03 mmol) in ether (0.4 mL) at room
temperature.
1
2
3
4
5
6
7
8
9
—
—
24
6
2
24
2
24
2
2
24
6
—
87
83
44
88
52
92
89
49
85
23
—
92
99
99
98
83
97
98
93
b
Isolated yield.
Ee values were determined by chiral HPLC analysis.
1a
1b
1c
1d
1e
1f
1g
1h
1i
6.5
11.2
11.7
12.0
12.3
13.1
14.1
14.2
15.8
—
c
Generally, catalysts 1b, 1d, 1f, and 1g, which are able to exert
double hydrogen-bonding interactions, provided better enantiose-
lectivities and yields than catalysts 1c, 1e, 1h, and 1i (Table 2, en-
tries 2, 4, 6, and 7 vs entries 3, 5, 8, and 9). However catalyst 1a,
which exerts a single hydrogen-bonding interaction, provided the
best yield amongst the tested catalysts while imidazole was used
as the additive (Table 2, entry 1). Its extremely strong acidic N–H
bond may account for this result. The different dependence of addi-
tives was also observed for these two classes of catalysts. For the
former class, benzoic acid gave better enantioselectivities and
yields than imidazole (Table 2, entries 2, 4, 6, and 7). For the second
10
11
95
ꢀ64
1j
24
a
The reactions were carried out with nitrostyrene (0.20 mmol), isobutyralde-
hyde (0.05 mL), catalyst (0.04 mmol), and DMAP (0.04 mmol) in chloroform
(0.3 mL) at room temperature.
b
The pKa values were calculated with an ACD/Lab 11 program.
Isolated yield.
Ee values were determined by chiral HPLC analysis.
c
d

2820
J. Lao et al. / Tetrahedron: Asymmetry 20 (2009) 2818–2822
Table 3
The reaction of isobutyraldehyde and (E)-methyl 2-oxo-4-phenylbut-3-enoate catalyzed by 1a–1ja
OH
O
cat* (20 mol%)
additive (20 mol%)
O
O
O
PCC
CH2Cl2
O
CHO
+
Ph
O
∗
O
∗
CHCl3, rt
Ph
Ph
O
O
O
4
5
En
Cat
DMAP
PhCOOH
Yield (%)
Time (h)
Yieldb (%)
eec (%)
Time (h)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
24
24
24
24
72
24
24
30
24
72
54
66
72
67
54
58
56
69
59
44
75
0
0
24
ꢀ29
63
51
54
44
60
30
30
30
24
48
48
48
48
48
72
85
60
67
57
46
82
71
83
69
51
76
0
5
41
ꢀ5
71
58
73
59
51
10
1j
a
The reactions were carried out with (E)-methyl 2-oxo-4-phenylbut-3-enoate (0.2 mmol), isobutyraldehyde (50 lL), catalyst (0.04 mmol), and additive (0.04 mmol) in
chloroform (0.3 mL) at room temperature.
b
Isolated yield.
Ee values were determined by chiral HPLC analysis.
c
class, benzoic acid gave better enantioselectivities, but imidazole
gave better yields (Table 2, entries 1, 3, 5, 8, and 9). For catalyst
1j, both benzoic acid and imidazole provided the product in low
yields and enantioselectivities (Table 2, entry 10). Again, the acid-
ity of the N–H bond in the catalysts 1a–1i did not show a reliable
correlation between the catalytic activity and enantioselectivity.
Two bifunctional catalytic mechanisms could be suggested for
catalysts 1a–1i (Scheme 2).3a,7 The catalysts provide the primary
amine group to generate the enamine intermediates with isobutyr-
aldehyde or acetone, and at the same time exert hydrogen-bonding
interactions with trans-b-nitrostyrene. While the hydrogen bond
donors are ureas, thioureas and sulfamides, double hydrogen-
bonding interactions are proposed. For the other hydrogen bond
donors, only single hydrogen-bonding interactions are possible.
The hydrogen-bonding interactions affect the reaction in two
ways: (1) increasing the electrophilicity of nitrostyrene; and (2)
pre-organizing the reaction substrates and controlling the enanti-
oselectivity. It is expected that the double hydrogen-bonding inter-
actions provide a better acceleration effect and enantiocontrol
ability.
For this reaction the best catalyst was found to be 1a, which
possesses the most acidic N–H bond among the catalysts 1a–1i
(Table 3, entry 1). Sulfamide 1b and sulfonamide 1c provided race-
mic products (Table 3, entries 2 and 3). t-Butoxycarbamide 1e pro-
vided the product with reverse enantiofacial selectivity (Table 3,
entry 5). Catalysts 1f and 1h provided comparable yields and
enantioselectivities with 1a (Table 3, entries 6 and 8 vs entry 1),
although 1a (pKa = 6.5), 1f (pKa = 13.1), and 1h (pKa = 14.2) have
quite different pKa values. Catalysts 1a and 1h can only provide a
single hydrogen-bonding interaction, but 1f exerts a double hydro-
gen-bonding interaction. These results are different from those
obtained in the reaction of trans-b-nitrostyrene. Although a reliable
explanation could not be presented, the different hydrogen-bond-
ing modes are speculated for the reaction of (E)-methyl 2-oxo-
4-phenylbut-3-enoate (Scheme 3). Among the four possible
hydrogen-bonding modes, C and D are thought to be unfavorable
because two vicinal carbonyl groups take an approximately
parallel arrangement. In modes A and B, two carbonyl groups are
antiparallel. In the case of trans-b-nitrostyrene, the two N–O bonds
are at an angle of about 120° (Scheme 2). This structural difference
may account partially for the different catalytic behavior of 1a–1j.
Y
X
Y
X
R
N
H
N
H
R'
N
H
3. Conclusion
NH
NH
R2
R2
In conclusion, a series of primary amine organocatalysts with
various hydrogen bond donors were prepared and studied for the
conjugate addition of butyraldehyde and acetone to trans-b-nitro-
styrene and (E)-methyl 2-oxo-4-phenylbut-3-enoate. For the
reaction of trans-b-nitrostyrene, the catalysts with double hydro-
gen-bonding interactions are more efficient than the catalysts with
single hydrogen-bonding interactions concerning both the
catalytic activity and enantioselectivity. The acidity of N–H bond
of the catalysts is not proportional to the catalytic activity. How-
ever for the reaction of (E)-methyl 2-oxo-4-phenylbut-3-enoate,
the catalyst with the most acidic N–H bond showed the best cata-
lytic activity and enantioselectivity. The present experimental re-
sults cannot support a general correlation of the acidity of N–H
bond and hydrogen-bonding modes with the catalytic activity
and enantioselectivity of the catalysts. The catalytic behavior of
the catalysts seems to be highly dependent on the reaction sub-
R1
R1
O
O
O
O
N
N
R3
R3
H
H
Ph
double hydrogen-bonding interaction
Ph
single hydrogen-bonding interaction
Scheme 2. Proposed catalytic mechanism of 1a–1i for the reaction of trans-b-
nitrostyrene with isobutyraldehyde and acetone.
The reaction of isobutyraldehyde and (E)-methyl 2-oxo-4-phe-
nylbut-3-enoate was further studied using 1a–1j as catalysts.8
The primary product was a hemiacetal 4, which was oxidized by
PCC to give 5. The reaction was found to be accelerated by both
acid and base additives. Generally the acid additives provided bet-
ter yields and enantioselectivities. The experimental results are
summarized in Table 3.

J. Lao et al. / Tetrahedron: Asymmetry 20 (2009) 2818–2822
2821
Y
X
Y
X
Y
X
Y
X
R
R
R'
N
H
N
H
N
H
N
H
N
H
R'
N
H
NH
NH
Ph
NH
NH
O
O
O
O
O
O
MeO
MeO
Ph
MeO
MeO
Ph
Ph
O
O
D
C
B
A
Scheme 3. Possible hydrogen-bonding modes for the reaction of (E)-methyl 2-oxo-4-phenylbut-3-enoate.
strates and conditions. These observations should be taken into ac-
count during the design of new organocatalysts with hydrogen-
bonding interactions.
1622(m), 1453(w), 1365(m), 1267(s), 1202(s), 1092(m), 968(m);
MS (ESI, M++1): 247.1.
4.2.2. N-((1R,2R)-2-Aminocyclohexyl)benzamide 1h14
To
10 mmol) in CH2Cl2 (15 mL) was added dropwise a solution of ben-
zoyl chloride (231
a solution of (1R,2R)-cyclohexane-1,2-diamine (1.14 g,
4. Experimental
lL, 2 mmol) in 5 mL CH2Cl2 at ꢀ20 °C over
4.1. General method
30 min. The reaction mixture was stirred overnight at room tem-
perature. Then water (20 mL) was added. The organic layer was
separated and dried over Na2SO4. After the evaporation of the sol-
vent in vacuo, the residue was purified by column chromatography
over silica gel (ethyl acetate/methanol = 10/1) to provide 1h as a
1H NMR and 13C NMR spectra were recorded on Bruker AVANCE
400 spectrometer. Chemical shifts of protons are reported in parts
per million downfield from tetramethylsilane and are referenced to
residual protium in the NMR solvent (CHCl3: d 7.26 and CH3OH: d
4.84, 3.31). Chemical shifts of carbon are referenced to the carbon
resonances of the solvent (CHCl3: d 77.0 and CH3OH: d 46.0). Peaks
are labeled as singlet (s), doublet (d), triplet (t), quartet (q), and
multiplet (m). Optical rotations were measured on a Perkin Elmer
digital polarimeter. Melting points were measured on a WRS-2A
melting point apparatus and are uncorrected. The mass spectro-
scopic data were obtained at the Thermo DSQII and Agilent 6120
mass spectrometer. The high resolution mass spectroscopic data
were obtained at the Shimadzu IT-TOF mass spectrometer. Infrared
(IR) spectra were recorded on a Bruker Tensor 37 spectrophotom-
eter. The data are represented as follows: frequency of absorption
(cmꢀ1) and intensity of absorption (vs = very strong, s = strong,
m = medium, and w = weak). Enantiomeric excesses were deter-
mined by HPLC using a Daicel Chiralpak AD-H, AS-H column and
eluting with a hexane/i-PrOH solution.
white solid (150 mg, 34%). Mp 176.5–179.8 °C; ½a D20
¼ ꢀ49:0 (c
ꢂ
1.0, CH3OH); 1H NMR (400 MHz, CD3OD) d: 7.86 (d, J = 7.6 Hz,
2H), 7.53 (t, J = 7.0 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 3.75–3.69(m,
1H), 2.68–2.62 (m, 1H), 2.02–1.99 (m, 2H), 1.78–1.77 (m, 2H),
1.38–1.24 (m, 4H); 13C NMR (100 MHz, CD3OD) d: 170.6, 136.0,
132.6, 129.5, 128.4, 57.5, 55.2, 35.3, 33.1, 26.3, 26.1; IR (thin film)
m
/cmꢀ1: 3342(m), 3047(m), 2926(s), 2858(m), 1649(s), 1602(w),
1532(m), 1445(m), 1328(m), 1141(m), 1086(w); MS (ESI, M++1):
219.2.
4.3. Typical procedure for the conjugate addition of isobutyr-
aldehyde to trans-b-nitrostyrene catalyzed by 1a–1j
A mixture of trans-b-nitrostyrene (0.2 mmol), 1g (0.04 mmol),
DMAP (0.04 mmol), isobutyraldehyde (50 lL), and chloroform
(0.3 mL) was stirred at room temperature for 2 h. After the evapo-
ration of the solvent in vacuo, the residue was separated by flash
chromatography over silica gel (petroleum ether/ethyl ace-
tate = 10/1) to give 2,2-dimethyl-4-nitro-3-phenyl-butanal 2 as a
4.2. Synthesis of catalysts
Catalysts 1b,3a 1c,9 1d,10 1f, 1g,11 1i,12 and 1j13 were prepared
according to the reported procedures.
colorless oil (39 mg, 89%). ½a D20
ꢂ
¼ þ7:0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3) d: 9.51 (s, 1H), 7.31–7.24 (m, 5H), 4.85 (dd,
J = 12.9, 11.1 Hz, 1H), 4.68 (dd, J = 12.9, 4.2 Hz, 1H), 3.78 (dd,
J = 11.1, 4.2 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H); 13C NMR (75 MHz,
CDCl3) d: 204.0, 135.2, 129.0, 128.6, 128.0, 76.3, 48.5, 48.2, 21.7,
19.0; MS (EI): m/z = 221 (M+), 187, 170, 159, 145, 117, 105, 91,
4.2.1. N-((1R,2R)-2-Aminocyclohexyl)-1,1,1-trifluoromethane-
6h
sulfonamide 1a
To a solution of catalyst 1j (488 mg, 2.0 mmol) in 15 mL of dried
CH2Cl2 was added dropwise a solution of Tf2O (0.4 mL, 2.40 mmol)
in 5 mL of dried CH2Cl2 at 0 °C under N2 atmosphere over 1 h. The
resulting mixture was stirred overnight. Then CH2Cl2 (50 mL) and
HCl (l mol/L, 20 mL) were added. After the separation of the organ-
ic layer, the aqueous layer was extracted with CH2Cl2 (3 ꢁ 10 mL)
and the combined organic layer was washed with brine. The organ-
ic phase was dried over Na2SO4 and concentrated in vacuo to pro-
vide a white solid, which was refluxed with hydrazine hydrate
(0.4 mL) in ethanol (15 mL) for 2 h. The reaction solution was di-
luted with diethyl ether to precipitate phthaloyl hydrazide. The
insoluble solid was filtered and the filtrate was evaporated in va-
cuo. The crude product was purified by column chromatography
over silica gel (ethyl acetate/methanol = 15/1) to provide a white
77, 72; IR (thin film)
m : 2925(w), 1726(m), 1638(m),
/cmꢀ1
1556(s), 1456(w), 1380(m), 705(m); The enantiomeric excess
was determined by HPLC with Chiralpak AD-H column at 208 nm
(hexane/i-PrOH = 98/2, 0.5 mL/min; tR(major) = 24.9 min, tR(minor)
=
25.9 min).
4.4. Typical procedure for the conjugate addition of acetone to
trans-b-nitrostyrene catalyzed by 1a–1j
A solution of trans-b-nitrostyrene (0.15 mmol), 1g (0.03 mmol),
PhCOOH (0.03 mmol), and acetone (0.2 mL) in ether (0.4 mL) was
stirred at room temperature for 72 h. The reaction solution was
concentrated in vacuo. The residue was purified by flash column
chromatography over silica gel (petroleum ether/ethyl ace-
tate = 6/1) to give 5-nitro-4-phenylpentan-2-one 3 as a white solid
solid (160 mg, 31%).
½
a 2D0
ꢂ
¼ ꢀ7:2 (c 1.06, CH3OH); 1H NMR
(400 MHz, CD3OD) d: 3.08–3.02 (m, 1H), 2.68–2.62 (m, 1H,),
2.03–1.97 (m, 2H), 1.78–1.73 (m, 2H), 1.42–1.29 (m, 4H); 13C
(29 mg, 93%). Mp 114 ꢀ116 °C; ½a D20
ꢂ
¼ þ5:3 (c 1.06, CHCl3); 1H
1
NMR (100 MHz, CD3OD) d: 123.1 (d, JCF = 323.8 Hz), 59.4, 57.9,
35.4, 31.1, 25.8, 25.4; IR (thin film) m
/cmꢀ1: 2943(m), 2863(m),
NMR (400 MHz, CDCl3) d: 7.35–7.20 (m, 5H), 4.70 (dd, J = 12.2,

2822
J. Lao et al. / Tetrahedron: Asymmetry 20 (2009) 2818–2822
6.8 Hz, 1H), 4.60 (dd, J = 12.2, 7.8 Hz, 1H), 4.01 (m, 1H), 2.92 (d,
J = 7.0 Hz, 2H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) d: 205.4,
138.8, 129.1, 127.9, 127.4), 79.5, 46.1, 39.0, 30.4; MS (EI): m/
References
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4. Zhang, X. J.; Liu, S. P.; Lao, J. H.; Du, G. J.; Yan, M.; Chan, A. S. C. Tetrahedron:
Asymmetry 2009, 20, 1451.
5. pKa Values of the selected N–H bonds were calculated with the program ACD/
pKa DB (version 11, Advanced Chemistry Development, Inc., Toronto, Canada,
2008). The other calculation methods were also used to obtain the pKa values of
organocatalysts, see: (a) Chen, J. R.; Lu, H. H.; Li, X. Y.; Cheng, L.; Wan, J.; Xiao,
W. J. Org. Lett. 2005, 7, 4543; (b) Pansare, S. V.; Kirby, R. L. Tetrahedron 2009, 65,
4557.
6. For selected publications on the conjugate addition of aldehydes and ketones to
nitroalkenes catalyzed by chiral primary amines, see: (a) Xu, L. W.; Luo, J.; Lu, Y.
X. Chem. Commun. 2009, 1807; (b) Rasappan, R.; Reiser, O. Eur. J. Org. Chem.
2009, 1305; (c) Liu, J.; Yang, Z. G.; Liu, X. H.; Wang, Z.; Liu, Y. L.; Bai, S.; Lin, L. L.;
Feng, X. M. Org. Biomol. Chem. 2009, 7, 4120; (d) Kokotos, C. G.; Kokotos, G. Adv.
Synth. Catal. 2009, 351, 1355; (e) Gu, Q.; Guo, X. T.; Wu, X. Y. Tetrahedron 2009,
65, 5265; (f) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009,
351, 33; (g) Yang, Z. G.; Liu, J.; Liu, X. H.; Wang, Z.; Feng, X. M.; Su, Z. S.; Hu, C.
W. Adv. Synth. Catal. 2008, 350, 2001; (h) Xue, F.; Zhang, S. L.; Duan, W. H.;
Wang, W. Adv. Synth. Catal. 2008, 350, 2194; (i) Peng, F. Z.; Shao, Z. H. J. Mol.
Catal. A: Chem. 2008, 285, 1; (j) Xiong, Y.; Wen, Y. H.; Wang, F.; Gao, B.; Liu, X.
H.; Huang, X.; Feng, X. M. Adv. Synth. Catal. 2007, 349, 2156; (k) Wei, S. W.;
Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Catal. Today 2007, 121, 151; (l)
McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599; (m) Liu, K.; Cui, H. F.; Nie, J.;
Dong, K. Y.; Li, X. J.; Ma, J. A. Org. Lett. 2007, 9, 923; (n) Yalalov, D. A.; Tsogoeva,
S. B.; Schmatz, S. Adv. Synth. Catal. 2006, 348, 826; (o) Xu, Y. M.; Cordova, A.
Chem. Commun. 2006, 460; (p) Xu, Y.; Zou, W.; Sundé, H.; Ibrahem, I.; Códova,
A. Adv. Synth. Catal. 2006, 348, 418; (q) Tsogoeva, S. B.; Wei, S. W. Chem.
Commun. 2006, 1451.
z = 207 (M+), 191, 167, 133, 91, 84; IR (thin film)
m :
/cmꢀ1
3040(w), 2950(w), 1715(s), 1546(vs), 1384(s), 1362(m), 758(w),
696(w); The enantiomeric excess was determined by HPLC with
an AS-H column at 208 nm (hexane/i-PrOH = 75/25, 1.0 mL/min;
tR(major) = 10.1 min, tR(minor) = 13.1 min).
4.5. Typical procedure for the conjugate addition of isobutyr-
aldehyde to (E)-methyl 2-oxo-4-phenylbut-3-enoate catalyzed
by catalysts 1a–1j
A
mixture of (E)-methyl 2-oxo-4-phenylbut-3-enoate
(0.2 mmol), 1a (0.04 mmol), PhCOOH (0.04 mmol), and isobutyral-
dehyde (50 L) in chloroform (0.3 mL) was stirred at room temper-
l
ature for 30 h. After the evaporation of the solvent in vacuo, the
residue was separated by flash chromatography over silica gel
(petroleum ether/ethyl acetate = 8/1) to give the cyclic semi-acetal
4 as a white solid (45 mg, 85%). Oxidation of the cyclic hemiacetal
was performed in CH2Cl2 by adding 5 equiv of PCC at room temper-
ature. After stirring for 24 h, the reaction mixture was partitioned
between ethyl acetate and saturated NaHCO3. The EtOAc layer was
concentrated in vacuo and the residue was purified by column
chromatography over silica gel (petroleum ether/ethyl ace-
tate = 8/1) to afford methyl 3,3-dimethyl-2-oxo-4-phenyl-3,4-
dihydro-2H-pyran-6-carboxylate 5 as a white solid. Mp 77.5–
79.2 °C; ½a 2D0
ꢂ
¼ ꢀ19:2 (c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 7.35–7.29 (m, 3H,), 7.11–7.09 (m, 2H), 6.62 (d, J = 5.4 Hz, 1H),
3.87 (s, 3H), 3.49 (d, J = 5.4 Hz), 1.41 (s, 3H), 1.01 (s, 3H,); 13C
NMR (100 MHz, CDCl3) d: 171.8, 160.9, 141.1, 136.9, 128.8, 128.5,
7. (a) Huang, H. B.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170; (b)
Lalonde, M. P.; Chen, Y. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 6366.
128.1, 117.6, 52.65, 50.1, 40.9, 25.9, 21.5; IR (thin film) m :
/cmꢀ1
8. For asymmetric conjugate addition of aldehydes to
a,b-unsaturated
2924(s), 2853(m), 1742(s), 1696(s), 1496(w), 1469(w), 1456(m),
1387(w), 1312(m), 1254(s), 1112(m), 1068(s), 950(m), 806(m),
760(m), 702(m); MS (ESI, M++1): 261.1; HRMS (ESI) calcd for
C15H15O4 (MꢀH)ꢀ: 259.0970, found: 259.0966. The enantiomeric
excess was determined by HPLC with Chiralpak AD-H column at
208 nm (hexane/i-PrOH = 95/5, 1.0 mL/min; tR(minor) = 9.2 min,
tR(major) = 10.2 min).
ketoesters, see: (a) Wang, J.; Yu, F.; Zhang, X. J.; Ma, D. W. Org. Lett.
2008, 10, 2561; (b) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003,
42, 1498.
9. Balsells, J.; Mejorado, L.; Phillips, M.; Ortega, F.; Aguirre, G.; Somanathan, R.;
Walsh, P. J. Tetrahedron: Asymmetry 1998, 9, 4135.
10. Bied, C.; Moreau, J. J. E.; Man, M. W. C. Tetrahedron: Asymmetry 2001, 12,
329.
11. Kim, Y. K.; Lee, S. J.; Ahn, K. H. J. Org. Chem. 2000, 65, 7807.
12. Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.; Yamaguchi, K.; Ishikawa, T. J. Org.
Chem. 2000, 65, 7774.
13. Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431.
14. Kaik, M.; Gawronski, J. Tetrahedron: Asymmetry 2003, 14, 1559.
Acknowledgments
We thank National Natural Science Foundation of China (Nos.
20772160, 20972195) and Zhuhai Bureau of Science and Technol-
ogy for financial support of this study.