Conformational lock in a Bronsted acid-Lewis base organocatalyst for the aza-Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetasy.2006.01.007

(S)-3-(N-Isopropyl-N-3-pyridinylaminomethyl)BINOL has been established as an efficient asymmetric bifunctional organocatalyst for the aza-MBH reaction. The acid-base functionalities cooperate in substrate activation and fixing of the organocatalyst confor

Full text of DOI:10.1016/j.tetasy.2006.01.007

Tetrahedron: Asymmetry 17 (2006) 578–583
Conformational lock in a Brønsted acid–Lewis base
organocatalyst for the aza-Morita–Baylis–Hillman reaction
Katsuya Matsui, Kouichi Tanaka, Atsushi Horii, Shinobu Takizawa and Hiroaki Sasai*
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
Received 16 November 2005; accepted 11 January 2006
Available online 20 February 2006
Abstract—(S)-3-(N-Isopropyl-N-3-pyridinylaminomethyl)BINOL has been established as an efficient asymmetric bifunctional
organocatalyst for the aza-MBH reaction. The acid–base functionalities cooperate in substrate activation and fixing of the organo-
catalyst conformation to promote the reaction with high enantiocontrol.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
The aza-MBH reaction is a C–C bond-forming reaction
of activated alkenes with imines, catalyzed by Lewis
bases such as amines or phosphines, resulting in highly
functionalized allylic amines, which are valuable build-
Asymmetric catalysis is one of the most powerful
approaches for synthesizing enantiomerically pure and
useful compounds. In particular, the design and devel-
opment of asymmetric catalysts possessing two or more
reaction-promoting functionalities are of ongoing inter-
6
,7
ing blocks in medicinal chemistry. Excellent organo-
catalytic systems using quinidine-derived catalysts have
7
b,e
7c
been independently reported by Shi,
Adolfsson,
1
–4
7d
7i
est in asymmetric synthesis.
The functionalities acti-
Hatakeyama, and Jacobsen for this asymmetric pro-
cess. Shi has also reported the use of chiral phosphinyl
BINOL to promote the aza-MBH reaction.
vate the substrates by synergistic cooperation,
affording the products in high yield and high enantio-
selectivity. Bifunctional organometallic catalysts are
representative examples of this type.
bifunctional catalysts, which can be recovered and
7
f–h
The
development of efficient catalysts for the aza-MBH reac-
tion has been a considerable challenge in organic
synthesis.
1
,2
Immobilized
3
reused have also been investigated. However, the
practical use of immobilized organometallic catalysts is
generally difficult due to leaching of the metal, which
results in deactivation of the catalyst and/or contamina-
tion of the product of the catalytic reaction. For this
reason, the development of asymmetric systems that
do not contain a metal has been of great importance
in organic chemistry. Herein, we report a new class
of bifunctional metal-free catalysts for the enantioselec-
tive aza-Morita–Baylis–Hillman (aza-MBH) reaction of
a,b-unsaturated carbonyl compounds with N-tosyl-
imines. The combination of Brønsted acid and Lewis
base units for the activation of substrates in a single chi-
ral environment results in high enantioselectivity in the
adduct.
2. Results and discussion
We designed an organic molecule, in which chiral
Brønsted acid units are connected with a Lewis base unit
via a spacer, as shown in Figure 1. Our aim was to create
a chiral molecule in which both Brønsted acid and Lewis
base units were optimally positioned for the activation
4
,5
spacer
Lewis base unit
3
LB
OH
OH
Bronsted acid units
BINOL unit
*
0
Corresponding author. Tel.: +81 6 6879 8465; fax: +81 6 6879
469; e-mail: sasai@sanken.osaka-u.ac.jp
Figure 1. Concept of chiral bifunctional organocatalyst for aza-MBH
reaction.
8
957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.007

K. Matsui et al. / Tetrahedron: Asymmetry 17 (2006) 578–583
579
of a,b-unsaturated carbonyl compounds. The acid unit
NMe2
N
Me2N
3
would activate the carbonyl group and the Lewis base
unit would subsequently react with the b-position of
the substrate in a Michael addition reaction (Scheme
Me
N
3
3
N
N
1
). The chiral Michael intermediate I, generated by
OH
OH
OH
OH
cooperative interaction between each component of
the organocatalyst, could furnish the product with high
enantioselectivity via the Mannich and retro-Michael
reactions.
OH
OH
1
a-b
1c
2a-c
1
1
1
2
a: (S)-3-[4-(dimethylamino)pyridin-2-yl]BINOL
b: (S)-3-[4-(dimethylamino)pyridin-3-yl]BINOL
c: (S)-3-[3-(dimethylamino)pyridin-5-yl]BINOL
a: (S)-3-(N-methyl-N-3-pyridinylaminomethyl)BINOL
2b: (S)-3-(N-methyl-N-2-pyridinylaminomethyl)BINOL
2c: (S)-3-(N-methyl-N-4-pyridinylaminomethyl)BINOL
NHR3
O
NR3
O
R1
+
R1
R2
R2
H
α,β-Unsaturated
Carbonyl Compound
Figure 2. Novel chiral bifunctional organocatalysts for aza-MBH
reaction.
Imine
Allyl Amine
Bifunctional Organocatalyst
retro-Michael
Michael
Reaction
Reaction
(β−Elimination)
(10 mol %) and 4-DMAP (10 mol %) promoted the reac-
tion of 3a with 4a to give product 5a (entry 7), the
organocatalysts 1a and 1b, in which the pyridine ring
is attached directly to the 3-position of BINOL, resulted
in either low activity or none at all (entries 8–9). The
organocatalyst 1c, bearing 3-dimethylaminopyridine,
was also synthesized and used in the reaction, resulting
in a slight improvement in chemical yield (entry 10).
The catalytic deficiency of 1 may be due to the inappro-
priate position of the Lewis base on the catalyst. Next,
we synthesized organocatalysts 2a–c, in which 3-, 2-,
or 4-aminopyridine derivatives are attached via a
methylene spacer. Although organocatalyst 2b, which
contains a 2-aminopyridine unit, was found to be inef-
fective (entry 12), catalyst 2a, containing a 3-aminopyri-
dine unit, afforded 5a in 41% yield with 73% ee (entry
NR3
R2
LB
LB
NR3
R2
Mannich
Reaction
OH
OH
O
H
O
OH
R1
OH
R1
I
Scheme 1. Proposed catalytic cycle for the bifunctional organocata-
lyst-mediated aza-MBH reaction.
With the aim of developing such organocatalysts, the
reaction of the prototypical substrates methyl vinyl
ketone 3a and phenyl N-tosylimine 4a was initially
attempted in the presence of 4-, 3-, and 2-dimethylamino-
pyridine (4-, 3-, and 2-DMAP). As 4-DMAP can
6
d,f
act efficiently as a Lewis base in this reaction
(Table
11). In contrast, the same reaction mediated by a mixed
1
, entries 3–5), (S)-BINOLs bearing 4-dimethylamino-
pyridine were designed first (Fig. 2, compounds 1a–b).
Although a mixed reagent consisting of (S)-BINOL
reagent, (S)-BINOL (10 mol %) and 3-DMAP (10
mol %), produced 5a in 48% yield with low enantioselec-
tivity (entry 6). The organocatalyst 2c contains a 4-
aminopyridine unit, for which intramolecular Michael
addition would be impossible, and this catalyst was
found not to promote the reaction (entry 13). These
results indicate that the exact positioning of the active
units on the catalyst can dramatically improve the effi-
ciency of bifunctional asymmetric organocatalysis.
Table 1. Enantioselective aza-MBH reaction of 3a with 4a using
organocatalysts
NTs
O
NHTs
O
catalyst
+
H
CH2Cl2, rt
3
a
4a
5a
Encouraged by these results, we went on to study the
effects of solvent and temperature on the reaction of
a
b
Entry Organocatalyst
Time (h) Yield (%) ee (%)
3a with p-chlorophenyl N-tosylimine 4b (Table 2).
1
2
3
4
5
6
7
8
9
1
1
1
1
None
48
48
48
48
NR
NR
NR
27
55
48
60
Trace
21
56
41
—
—
—
—
—
3
2
33
2
Ethereal solvents such as diethyl ether, t-BuOMe, cyclo-
pentyl methyl ether (CPME), and dimethyl ether (DME)
(entries 1–4), along with toluene (entry 6) gave relatively
good results in comparison with THF (entry 5) and
other polar, less polar, aprotic, and protic solvents,
including halogenated solvents, DMF, acetonitrile, and
methanol (entries 7–12). A mixed solvent system consist-
ing of CPME–toluene (9/1) at ꢀ15 °C afforded the best
outcome (entry 14). It was established that the most effi-
cient organocatalyst for the reaction was 6a, which bears
an i-Pr substituent on the amino group (Table 3, entry
2).
(S)-BINOL
2-DMAP
3-DMAP
4-DMAP
(S)-BINOL + 3-DMAP 168
(S)-BINOL + 4-DMAP
1a
1b
1c
2a
2b
2c
d
d
7.5
c,d
c,d
8
168
168
168
168
168
168
0
1
2
3
2
73
—
—
NR
NR
a
b
c
Isolated yield.
Determined by HPLC (Daicel Chiralpak AD-H).
0 mol % of (S)-BINOL and 10 mol % of 3- or 4-DMAP were used.
Next, we investigated the substrate scope of this bifunc-
tional asymmetric catalyst system under optimal condi-
tions (Table 4). Whether the aromatic substituent R of
1
2
d
Decomposition of 4a was observed.

5
80
K. Matsui et al. / Tetrahedron: Asymmetry 17 (2006) 578–583
Table 4. Enantioselective aza-MBH reaction of 3 with 4 catalyzed by
Table 2. Effect of solvent on aza-MBH reaction
NTs
6
a
O
NHTs
2
a (10 mol%)
O
O
NHTs
NTs
6a (10 mol%)
3
a
+
H
CH2Cl2, rt
+
1
1
2
R
R2
o
R
R
H
toluene:CPME (1:9), -15 C
Cl
Cl
4
b
5b
3
4
5
a
b
Entry Solvent
Time (h) Yield (%) ee (%)
1
2
b
Entry 3: R
4: R
Time Yield
(h)
ee
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
Et
2
O
108
72
72
60
48
24
24
24
24
48
48
60
72
74
92
97
73
71
81
72
73
78
68
59
72
59
54
57
63
67
18
83
90
(%)
(%)
t-BuOMe
CPME
DME
THF
Toluene
1
2
3
4
5
6
7
8
9
1
1
1
1
Me 3a Ph 4a
Me 3a p-Cl–C
168
60
72
5a, 93
5b, 96
5c, 95
5d, 93
87
95
93
94
91
90
93
94
86
93
6
H
4
4b
4d
Me 3a p-F–C
Me 3a p-Br–C
Me 3a p-CN–C
Me 3a p-Me–C
Me 3a p-Et–C
Me 3a p-MeO–C
Me 3a m-NO
Me 3a m-Cl–C
Me 3a 2-Furyl 4k
Me 3a 2-Naphthyl 4l
Me 3a 1-Naphthyl 4m
Me 3a o-Cl–C 4n
6
H
4
4c
6
H
4
36
6
H
4
4e
4f
4g
60
192
120
5e, quant.
5f, 90
CH
2
Cl
2
Quant.
97
6
H
4
CHCl
ClCH
DMF
3
6
H
4
6
5g, 97
5h, 93
5i, 94
2
CH
2
Cl
87
7
60
46
93
97
4
H 4h 132
0
1
2
3
4
2
–C
6
H
4
4i
24
72
MeCN
MeOH
CPME–toluene (9/1)
0
1
2
3
6
H
4
4j
5j, 93
48
5k, quant. 93
108
288
84
5l, 94
5m, 88
5n, 92
5o, 91
5p, 88
5q, 95
5r, 91
91
70
62
91
88
94
58
c
CPME–toluene (9/1) 144
a
b
c
Isolated yield.
14
15
16
6 4
H
Determined by HPLC (Daicel Chiralpak AD-H).
Me 3a p-NO
2
2
2
2
–C
–C
–C
–C
6
H
4
4
4
4
4o
4o
4o
4o
12
96
36
192
Performed at ꢀ15 °C.
Et 3b
H 3c
Ph 3d
p-NO
p-NO
p-NO
H
H
H
6
6
6
1
1
7
8
a
Isolated yield.
b
Determined by HPLC (Daicel Chiralpak AD-H or OD-H).
Table 3. Effect of N-substituent R on bifunctional organocatalysts
R
N
N
0
OH
tected catalysts 7a (2 -OMe group) and 7b (2-OMe
group), an aniline derivative 8, and pyridine derivatives
OH
(
10 mol%)
9
a and 9b, with different spacer chain lengths, and 9c,
3
a
+
4b
5b
o
which contains an oxygen atom linkage (Fig. 3).
Although catalyst 7a was found to be ineffective in pro-
moting the reaction (5a, 5% yield, 24% ee), 7b showed a
slightly decreased activity (5a, 85% yield, 79% ee) com-
pared to the parent catalyst 2a. Interestingly, it was
found that 8 and 9 did not promote the reaction. These
results and the significant enantioselectivity of 6a are
consistent with the idea that our designed organic mole-
cules can act as bifunctional catalysts, utilizing both
toluene:CPME (1:9), -15 C
a
b
Entry
R
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
Me
i-Pr
H
Et
t-Bu
Bn
2a
6a
6b
6c
6d
6e
144
60
240
132
240
72
97
96
62
90
72
Quant.
90
95
87
91
83
93
0
a
the phenolic 2 -hydroxy group and the pyridine moiety
Isolated yield.
Determined by HPLC (Daicel Chiralpak AD-H).
b
to activate the substrate. Since one acid–base pair fixes
the conformation of organocatalyst 6a, the other acid–
base unit appears able to activate substrate 3 with high
enantiocontrol, although the nucleophilicity of the
pyridinyl nitrogen of 2a (or 6a) is low compared to that
4
was electron-withdrawing or electron-donating, organ-
ocatalyst 6a efficiently promoted the reaction with high
enantioselectivity (entries 1–10, and 15). 2-Furyl and
8
of 2b or 2c. A molecular orbital calculation for 6a also
2
-naphthyl tosylimines were also found to be suitable
supported the suggested conformation (Fig. 4).
substrates (entries 11 and 12). The use of 1-naphthyl
and o-chlorophenyl tosylimines resulted in moderate
enantioselectivity (entries 13 and 14). Although the
reactions of methyl or ethyl vinyl ketone and acrolein
afforded the corresponding adducts with high enantio-
selectivity (entries 15–17), the enantioselectivity was
only moderate when phenyl vinyl ketone was used (entry
Me
N
Me
N
3
X
N
2
N
1
OR
OH
OH
OH
OH
2
OR
2'
1
8).
1
2
8
9a: X=CH2
9b: X=(CH2)2
c: X=CH O
Catalysts 2a and 6a possess two phenolic hydroxy
groups and two nitrogen atoms. In order to clarify the
role of each unit in the reaction, we examined the fol-
lowing derivatives of the parent catalysts: two monopro-
7a: R =H, R =Me
1
2
7b: R =Me, R =H
9
2
Figure 3.

K. Matsui et al. / Tetrahedron: Asymmetry 17 (2006) 578–583
581
ESI-MS). Elemental analysis was performed on
Perkin–Elmer 2400.
Adducts 5a–d, 5f–l, 5o–q are known compounds.6,7 For
organocatalysts 2a and 6a and adducts 5e, 5m, 5n, and
5r as new compounds, their spectral data are shown as
follows.
4.2. General procedure for synthesis of (S)-3-(N-methyl-
N-3-pyridinylaminomethyl)-BINOL 2a and (S)-3-(N-iso-
propyl-N-3-pyridinylaminomethyl)-BINOL 6a
Figure 4. Molecular orbital calculation for 6a: Spartan ’04, job type:
geometry optimization, method: Hartee–Fock, basis set: 6-31G**. N–
˚
Compound (S)-II: A solution of the corresponding 3-N-
H atomic distance: 2.004 A; angle between N–H–O bonds: 144.72°.
9
a
methylaminopyridine (26.0 mg, 0.24 mmol) or 3-N-
9
b,c
isopropylaminopyridine
(32.7 mg, 0.24 mmol) in
3. Conclusion
THF (0.7 mL) was added to a heterogeneous solution
of NaH (16 mg, 0.24 mmol) in THF (0.3 mL) at 0 °C.
1
0
We have discovered an efficient and novel bifunc-
tional organocatalyst for the enantioselective aza-MBH
reaction, (S)-3-(N-isopropyl-N-3-pyridinylaminomethyl)-
BINOL.
After stirring for 2 h at 60 °C, a solution of (S)-I
(0.20 mmol) in THF (1.0 mL) was combined with the
reaction mixture. The mixture was stirred for 15 min
at room temperature and then quenched with saturated
NH Cl aq at 0 °C. The organic phase was extracted with
4
The reaction was shown to be significantly influenced by
the position of the Lewis base attached to BINOL. The
acid–base functionalities harmoniously cooperate to
activate the substrate and fix the conformation of the
organocatalyst, resulting in promotion of the reaction
with high enantioselectivity.
CH Cl , dried over Na SO , filtered, and concentrated.
2
2
2
4
The residue obtained was purified by flash chromato-
graphy (SiO , CH Cl /MeOH = 19/1) to afford the title
2
2
2
compound (S)-II (IIa, R = Me, quant.; IIb, R = i-Pr,
60% yield).
Compound (S)-IIa: Colorless oil; IR (neat): m 3083,
ꢀ
1
1
2912, 2812, 1581, 1494, 1444, 1346, 1222 cm
;
H
4. Experimental
NMR (CDCl ): d 8.25 (1H, d, J = 3.0 Hz), 7.99 (2H,
3
d, J = 9.2 Hz), 7.89 (1H, d, J = 8.6 Hz), 7.75 (1H, d,
4
.1. General
J = 8.1 Hz), 7.61 (1H, s), 7.60 (1H, d, J = 8.4 Hz),
7.41–7.11 (6H, m), 7.19 (2H, d, J = 7.0 Hz), 5.16 (1H,
Commercially available organic and inorganic com-
pounds were used without further purification, except
for the solvent, which was distilled from sodium/benzo-
phenone or CaH . Column chromatography on SiO
d, J = 7.3 Hz), 5.06 (1H, d, J = 7.3 Hz), 4.91 (2H, s),
4.67 (1H, d, J = 5.9 Hz), 4.50 (1H, d, J = 5.9 Hz), 3.28
(3H, s), 3.18 (3H, s), 3.10 (3H, s); C NMR (CDCl3):
d 152.6, 152.4, 145.1, 137.6, 134.5, 133.7, 133.1, 130.7,
130.5, 129.9, 129.6, 127.8, 127.7, 126.8, 125.9, 125.8,
1
3
2
2
was performed with Kanto Silica Gel 60 (40–100 lm).
1
25.5, 125.4, 125.3, 125.0, 124.1, 123.5, 120.4, 118.2,
1
13
H and C NMR spectra were recorded with JEOL
116.4, 99.3, 94.8, 57.0, 56.1, 52.7, 38.7; HRMS (ESI)
calcd for C H N NaO , m/z = 517.2103 [(M+Na) ];
found, m/z = 517.2093. ½aꢁ ¼ ꢀ40:8 (c 1.0, CHCl3).
1
13
+
JNM-EX270 FT NMR ( H NMR 270 MHz,
C
3
1
32
2
4
20
NMR 67.7 MHz). All signals are expressed as ppm
downfield from tetramethylsilane used as an internal
standard. FT-IR spectra were recorded on a SHIMA-
DZU FTIR-8300. Optical rotations were measured with
JASCO P-1030 polarimeter. HPLC analyses were per-
formed on a JASCO HPLC system (JASCO PU 980
pump and UV-975 UV/vis detector) using a mixture of
hexane and i-PrOH as the eluent. Mass spectra were
obtained on JEOL JMS-DX300 (for EI-MS), JEOL
JMS-700 (for FAB-MS), and JMS-T100LC (for
D
Compound (S)-IIb: Brown oil; IR (neat): m 3095, 2945,
2829, 1596, 1514, 1444, 1375, 1221 cm
(CDCl ): d 8.27 (1H, br s), 7.99 (2H, d, J = 8.9 Hz),
7.89 (1H, d, J = 8.1 Hz), 7.75 (1H, d, J = 5.7 Hz), 7.74
(1H, s), 7.60 (1H, d, J = 8.4 Hz), 7.41–7.05 (8H, m),
5.15 (1H, d, J = 7.0 Hz), 5.07 (1H, d, J = 7.0 Hz), 4.74
(2H, s), 4.70 (1H, d, J = 5.7 Hz), 4.53 (1H, d,
J = 5.7 Hz), 4.48–4.36 (1H, m), 3.18 (3H, s), 3.12 (3H,
ꢀ
1
1
; H NMR
3
R
R
N
R
N
HN
Br
N
N
N
NaH
TMSBr
CH2Cl2, -10 o
OMOM
OMOM
OMOM
OMOM
OH
OH
THF, 60 o
C
C
(S)-I
(S)-IIa (R=Me)
(S)-2a (R=Me)
(S)-6a (R=i-Pr)
(S)-IIb (R=i-Pr)

582
K. Matsui et al. / Tetrahedron: Asymmetry 17 (2006) 578–583
1
3
s), 1.33 (3H, d, J = 6.7 Hz), 1.32 (3H, d, J = 6.7 Hz);
C
corresponding adduct 5 as a white solid. All products
1
13
NMR (CDCl ): d 152.7, 152.0, 145.2, 145.1, 137.4,
were characterized by H and C NMR, MS, and IR
spectroscopy. The absolute configurations of 5 were
determined by comparing the specific rotation assign-
3
1
1
1
4
33.8, 132.0, 130.9, 129.9, 129.6, 127.8, 127.7, 126.8,
26.5, 125.7, 125.5, 125.4, 125.4, 125.1, 124.9, 124.1,
23.6, 120.6, 119.3, 116.6, 99.3, 95.0, 55.9, 56.0, 48.1,
4.7, 19.8, 19.7; HRMS (ESI) calcd for C H N O ,
6
,7
ments with those in the literature.
3
3
35
2
4
+
m/z = 523.2597 [(M+H) ]; found, m/z = 523.2585.
4.4. N-[1-(4-Cyanophenyl)-2-methylene-3-oxobutyl]-4-
methylbenzenesulfonamide 5e
2
D
0
½
aꢁ ¼ ꢀ43:2 (c 1.0, CHCl3).
Compound (S)-2a: Trimethylsilyl bromide (53 lL,
.4 mmol) was added to the mixture of (S)-IIa
White solid. Mp 104–105 °C (hexane–EtOAc). IR
ꢀ
1
1
0
(neat): m 2210, 1655 cm . H NMR (CDCl ): d 7.56
3
˚
(
0.2 mmol) and MS 4 A (10 mg) in CH Cl (1 mL) at
(2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.21 (2H,
d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 6.05 (1H, s),
5.97 (1H, s), 5.20 (1H, d, J = 9.2 Hz), 2.36 (3H, s),
2
2
0
°C. After stirring for 30 min, the reaction mixture
was quenched with water. The organic phase was
extracted with CH Cl . The combined organic extracts
1
3
2.10 (3H, s). C NMR (CDCl ): d 198.3, 145.4, 144.2,
2
2
3
were then dried over Na SO and evaporated in vacuo.
143.5, 137.2, 132.0, 129.4, 129.2, 127.1, 118.3, 111.2,
2
4
The residue was purified by flash chromatography (SiO2,
58.5, 26.2, 21.5. HRMS (ESI) m/z calcd for
+
CH Cl /MeOH = 9/1) to give the title compound (S)-2a
C H N O NaS: 377.0936 [M +Na]; found, 377.0922.
2
2
19 18
2
3
2
0
(
92% yield).
½aꢁ ¼ þ2:0 (c 0.6, CHCl ). Daicel Chiralpak AD-H col-
D
3
umn, detection at 254 nm, i-PrOH–hexane = 1/4, flow
rate 0.5 mL/min, 33.2 min (minor isomer, S) and
39.6 min (major isomer, R).
Compound (S)-2a: White solid. Mp 119–120 °C (hex-
ane–CH Cl ). IR (neat): m 3389, 3012, 2933, 1284,
2
2
ꢀ
1
1
612, 1588, 1510, 1424, 1412, 1367, 1220, 1012 cm .
1
H NMR (270 MHz, CDCl ): d 8.28–8.18 (1H, br),
4.5. 4-Methyl-N-(2-methylene-1-naphthalen-1-yl-3-
oxobutyl)benzenesulfonamide 5m
3
7
.96 (2H, d, J = 9.2 Hz), 7.89 (2H, d, J = 8.4 Hz), 7.79
(
1H, d, J = 8.1 Hz), 7.70 (1H, s), 7.39 (1H, d, J =
8
.9 Hz), 7.34–7.13 (7H, m), 4.76 (2H, s), 3.18 (3H, s).
White solid. Mp 119–120 °C (hexane–EtOAc). IR
1
3
ꢀ1
1
C NMR (67.7 MHz, CDCl ): d 153.3, 151.4, 145.2,
(neat): m 1655 cm . H NMR (CDCl ): d 7.79 (2H, d,
3
3
1
1
1
36.6, 133.8, 133.0, 129.0, 128.8, 128.1, 127.8, 127.1,
26.9, 126.5, 125.6, 124.4, 124.3, 123.7, 123.3, 119.5,
J = 7.8 Hz), 7.73 (2H, d, J = 8.1 Hz), 7.64 (2H, d,
J = 7.8 Hz), 7.44 (1H, dd, J = 7.9 and 6.7 Hz), 7.36–
7.24 (3H, m), 7.20 (2H, d, J = 7.8 Hz), 6.27 (1H, s),
6.22 (1H, s), 6.20 (1H, d, J = 7.0 Hz), 5.12 (1H, d,
18.3, 113.3, 112.0, 53.0, 38.6. HRMS (ESI): m/z calcd
+
for C H N O : 407.1760 [M +H]; found: 407.1740.
2
7
23
2
2
20
13
½
aꢁ ¼ ꢀ17:8 (c 0.7, CHCl3).
J = 7.0 Hz), 2.42 (3H, s), 2.23 (3H, s). C NMR
D
(
CDCl ): d 198.2, 147.3, 143.3, 136.9, 134.5, 133.8,
3
Compound (S)-6a: Similar to the synthetic procedure
for (S)-2a, (S)-6a was prepared from (S)-IIb (0.2 mmol)
in 90% yield. Green solid. Mp 122–123 °C (hexane–
CH Cl ). IR (neat): m 3440, 3055, 2966, 2823, 1705,
130.3, 129.4, 128.7, 128.5, 127.6, 127.3, 126.4, 125.7,
124.9, 124.8, 122.9, 53.2, 26.4, 21.6. HRMS (ESI)
+
m/z calcd for C H NNaO S: 402.1140 [M +Na];
2
2
21
3
20
found, 402.1152. ½aꢁ ¼ þ18:3 (c 0.6, CHCl ). Daicel
2
2
D
3
1
1
620, 1585, 1566, 1497, 1431, 1342, 1272, 1184, 1134,
Chiralpak AD-H column, detection at 254 nm, i-
PrOH–hexane = 1/4, flow rate 0.5 mL/min, 49.5 min
(minor isomer, S) and 58.8 min (major isomer, R).
ꢀ
1 1
061 cm . H NMR (270 MHz, CDCl ): d 8.18 (1H,
3
d, J = 2.7 Hz), 7.94 (1H, dd, J = 4.0 and 0.8 Hz), 7.85
(
(
1H, d, J = 8.9 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.79–7.65
2H, m), 7.28 (1H, d, J = 8.9 Hz), 7.28–7.00 (7H, m),
4.6. N-[1-(2-Chlorophenyl)-2-methylene-3-oxobutyl]-4-
methylbenzenesulfonamide 5n
6
.96 (1H, d, J = 8.1 Hz), 4.55 (2H, s), 4.04–3.93 (1H,
m), 1.21 (3H, d, J = 6.7 Hz), 1.18 (3H, d, J = 6.7 Hz).
1
3
C NMR (67.7 MHz, CDCl ): d 152.4, 151.8, 143.8,
White solid. Mp 83–84 °C (hexane–EtOAc). IR (neat): m
3
ꢀ
1
1
1
1
1
1
4
0
40.0, 133.5, 132.9, 130.6, 129.2, 128.8, 128.3, 128.2,
28.1, 127.9, 126.9, 126.7, 126.2, 124.3, 124.3, 124.2,
23.8, 123.5, 123.4, 117.8, 112.4, 112.3, 50.8, 47.0,
9.6, 19.4. HRMS (ESI): m/z calcd for C H N O :
1670 cm
.
H NMR (CDCl ): d 7.63 (2H, d,
3
J = 8.4 Hz), 7.33–7.06 (6H, m), 6.16, (2H, s), 5.77 (1H,
d, J = 8.4 Hz), 5.69 (1H, d, J = 8.4 Hz), 2.37 (3H, s),
1
3
2.21 (3H, s). C NMR (CDCl ): d 198.5, 145.4, 143.2,
2
9
27
2
2
3
+
20
35.2073 [M +H]; found, 435.2062. ½aꢁ ¼ ꢀ28:5 (c
143.1, 137.0, 135.9, 132.6, 129.5, 129.0, 128.7, 127.1,
D
.4, CHCl ).
126.7, 126.2, 55.4, 26.4, 21.5. HRMS (ESI) m/z calcd
3
+
for C H ClNNaO S, 386.0594 [M +Na]; found,
1
8
18
3
20
4.3. Procedure for enantioselective aza-MBH reaction
catalyzed by (S)-6a (Table 4)
386.0604. ½aꢁ ¼ þ13:0 (c 0.6, CHCl ). Daicel Chiralpak
D
3
AD-H column, detection at 254 nm, i-PrOH–hex-
ane = 1/4, flow rate 0.3 mL/min, 48.6 min (minor iso-
mer, S) and 55.7 min (major isomer, R).
To a solution of organocatalyst 6a (2.2 mg, 0.005 mmol)
in a mixed solvent CPME and toluene (9/1, 0.1 mL)
were added 3 (0.15 mmol) and imine 4 (0.05 mmol) at
4.7. N-[2-Benzoyl-1-(4-nitrophenyl)allyl]-4-methyl-
benzenesulfonamide 5r
ꢀ
15 °C. The mixture was stirred until the reaction had
reached completion with monitoring with TLC analysis.
The mixture was directly purified by flash column chro-
White solid. Mp 143–144 °C (hexane–EtOAc). IR
ꢀ
1 1
matography (SiO , hexane–EtOAc = 2/1) to give the
(neat): m 1653, 1508, 1340 cm . H NMR (CDCl ): d
3
2

K. Matsui et al. / Tetrahedron: Asymmetry 17 (2006) 578–583
583
7
7
.87 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.33–
.13 (6H, m), 7.03 (1H, dd, J = 9.4 and 0.8 Hz), 7.00
Maruoka, K. J. Am. Chem. Soc. 2004, 126, 6844; (c) Ishii,
T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem.
Soc. 2004, 126, 9558; (d) Okino, T.; Hoashi, Y.; Take-
moto, Y. J. Am. Chem. Soc. 2003, 125, 12672; (e) Li, H.;
Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004,
(
2H, d, J = 7.8 Hz), 6.10 (1H, d, J = 8.9 Hz), 5.87 (1H,
s), 5.59 (1H, s), 5.31 (1H, d, J = 9.2 Hz), 2.17 (3H, s).
1
3
C NMR (CDCl ): d 196.3, 147.2, 146.0, 143.9, 143.7,
3
1
26, 9906; (f) Mermerian, A. H.; Fu, G. C. J. Am. Chem.
1
1
37.3, 136.4, 133.0, 130.3, 129.3, 128.3, 128.3, 127.4,
Soc. 2003, 125, 4050; (g) Uraguchi, D.; Sorimachi, K.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 11804; (h)
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566; (i) Wang, J.; Li, H.; Yu, X.;
Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293; (j) Wang, J.; Li,
H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713;
27.0, 123.7, 59.6, 21.6. HRMS (ESI) m/z calcd for
+
C H N NaO S: 459.0991 [M +Na]; found, 459.0990.
2
3
20
2
5
2
0
½
aꢁ ¼ ꢀ3:3 (c 0.6, CHCl ). Daicel Chiralpak OD-H col-
D
3
umn, detection at 254 nm, i-PrOH–hexane = 1/4, flow
rate 0.5 mL/min, 42.4 min (major isomer, R) and
(
k) Berkessel, A.; Cleemann, F.; Mukherjee, S.; M u¨ ller, T.
5
3.9 min (minor isomer, S).
N.; Lex, J. Angew. Chem., Int. Ed. 2005, 44, 807; (l) Ye, J.;
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Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We thank the
technical staff of the Materials Analysis Center of ISIR,
Osaka University.
5
. (a) Asymmetric Organocatalyst—From Biomimetic Con-
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7. Aza-MBH reactions are accelerated in the presence of
acidic and basic catalysts. (a) Matsui, K.; Takizawa, S.;
Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680; (b) Shi, M.;
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