Highly enantioselective cyanation of aldehydes catalyzed by a multicomponent titanium complex

Article abstract of DOI:10.1021/jo060772z

A new multicomponent bifunctional catalytic system based on a titanium complex was used for the efficient enantioselective cyanation of aldehydes. The catalyst was readily prepared from tetraisopropyl titanate (Ti(Oi-Pr) ₄), (S)-6,6′-dibromo-1,

Full text of DOI:10.1021/jo060772z

Highly Enantioselective Cyanation of Aldehydes Catalyzed by a
Multicomponent Titanium Complex
†
†
†
,†,‡
Shaohua Gou, Xiaohong Chen, Yan Xiong, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Sichuan UniVersity, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, China, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan UniVersity, Chengdu 610041, China
xmfeng@scu.edu.cn
ReceiVed April 12, 2006
A new multicomponent bifunctional catalytic system based on a titanium complex was used for the
efficient enantioselective cyanation of aldehydes. The catalyst was readily prepared from tetraisopropyl
titanate (Ti(Oi-Pr) ), (S)-6,6′-dibromo-1,1′-bi-2-naphthol (1e), cinchonine (2a), and (1R,2S)-(-)-N-
4
methylephedrine (3b). It was revealed that the combination of 1e, 2a, 3b, and Ti(IV) was essential in
this cyanation. The reaction proceeded smoothly in the presence of a catalytic amount of the
multicomponent catalyst to afford the desired cyanohydrins ethyl carbonates in moderate to excellent
isolated yields (up to 95%) with high enantioselectivities (up to 94% ee). A catalytic cycle based on
experimental phenomena was proposed to explain the origin of the asymmetric induction.
Introduction
compounds using trimethylsilyl cyanide (TMSCN) or hydrogen
cyanide (HCN) as the cyanide source to react with carbonyl
compounds over the last two decades. Recently, asymmetric
Optically active cyanohydrins serve as important precursors
for many useful organic intermediates and chiral starting
materials for synthesis of several natural products. Various
2,3
cyanations employing cyanoformate ester (ROCOCN), acetyl
1
(2) For recent reviews on cyanation reactions, see: (a) Thierry, R. J. A.;
types of catalyst systems have been applied to prepare these
Lisa, A. C.; Michael, N. Synlett 2005, 125, 1828-1847. (b) Kanai, M.;
Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 125, 1491-1508. (c)
Chen, F.-X.; Feng, X.-M. Synlett 2005, 125, 892-899. (d) Brunel, J. M.;
Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752-2778. (e) Michael,
N. Tetrahedron: Asymmetry 2003, 14, 147-176. (f) Gregory, R. J. H. Chem.
ReV. 1999, 99, 3649-3682.
(3) (a) Xiong, Y.; Huang, X.; Gou, S.-H.; Huang, J.-L.; Wen, Y.-H.;
Feng, X.-M. AdV. Synth. Catal. 2006, 348, 538-544. (b) Liu, X.-H.; Qin,
B.; Zhou, X.; He, B.; Feng, X.-M. J. Am. Chem. Soc. 2005, 127, 12224-
12225. (c) Ryu, H.-D.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384-
5387. (d) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964-
8965. (e) Wen, Y.-H.; Huang, X.; Hang, J.-L.; Xiong, Y.; Qin, B.; Feng,
X.-M. Synlett 2005, 125, 2445-2447. (f) Qin, Y. C.; Liu, L.; Pu, L. Org.
Lett. 2005, 7, 2381-2383. (g) Li, Y.; He, B.; Qin, B.; Feng, X.-M.; Zhang,
G- L. J. Org. Chem. 2004, 69, 7910-7913. (h) Tian, S.-K.; Hong, R.; Deng,
L. J. Am. Chem. Soc. 2003, 125, 9901-9901.
†
Key Laboratory of Green Chemistry & Technology.
State Key Laboratory of Biotherapy, West China Hospital.
‡
(
1) For reviews on the synthesis and applications of cyanohydrins, see:
(
a) North, M. In Science of Synthesis; Murahashi, S.-I., Ed.; Thieme:
Stuttgart, 2004; Vol. 19, pp 235-284. (b) Shibasaki, M.; Kanai, M.;
Funabashi, K. J. Chem. Soc., Chem. Commun. 2002, 1989-1999. (c) Smith,
M. B.; March, J.; March’s AdVanced Organic Chemistry, 5th ed.; John Wiley
&
Sons: New York, 2001; pp 1239-1240. (d) Ojima, I. Catalytic
Asymmetric Synthesis; Wiley: New York, 2000; pp, 235-284. (e) Gregory,
R. J. H. Chem. ReV. 1999, 99, 3649-3682. (f) Mori, A.; Inoue, S. Cyanation
of Carbonyl and Amino Groups. In ComprehensiVe Asymmetric Synthesis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidel-
berg, 1999; pp 983-992. (g) Effenberger, F. Angew. Chem. 1994, 106,
1
609-1619; Angew. Chem., Int. Ed. Engl. 1994, 33, 1555-1564.
10.1021/jo060772z CCC: $33.50 © 2006 American Chemical Society
5
732
J. Org. Chem. 2006, 71, 5732-5736
Published on Web 06/27/2006

Cyanation of Aldehydes Catalyzed by a Ti Complex
cyanide, diethyl cyanophosphonate, or benzoyl cyanide as the
cyanide source to afford corresponding functionalized cyano-
TABLE 1. Asymmetric Cyanation of Benzaldehyde Catalyzed by
the Combination of Mono-Ligand and Ti(IV)
4
5
hydrins have been reported by Deng, Shibasaki, Sansano,
6
7
8
N a´ jera and Sa a´ , Belokon and North, and Moberg. Among
these precedents, a number of bifunctional chiral catalysts that
are based on BINOL and natural glucose have been successfully
applied in many asymmetric reactions.3
f,g,6,9
Triggered by the
bifunctional catalysts’ methods, we wish to explore whether the
combination of BINOL derivatives 1 with chiral amine 2 and 3
would improve enantioselectivity and reactivity. We assume that
the metallic reagent (titanium) would work as a Lewis acid to
activate the substrates (carbonyl group), meanwhile the nitrogen
entrya
ligand
time (h)
yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
2a
2b
2c
2d
3a
3b
3c
96
96
96
96
96
48
40
24
24
24
24
24
24
24
0
0
0
0
0
85
87
99
99
99
99
99
99
99
atom of the amine would work as a Lewis base to activate the
nucleophile (EtOCOCN).4
,5,9f
We report herein an efficient
14(R)
27(R)
11(R)
10(R)
9(S)
10(S)
4(R)
8(R)
multicomponent bifunctional catalyst (the combination of 1e,
a, 3b, and Ti(IV)) for the cyanation of aldehydes with ethyl
2
cyanoformate, and each component of the catalyst is com-
mercially available or easily prepared.
10
11
12
13
14
Results and Discussion
3(R)
Initially, we wish to promote the reaction of benzaldehyde
a
Conditions: 1igand/Ti(IV) ) 1/1, concentration of benzaldehyde: 0.25
with ethyl cyanoformate (EtOCOCN) in dichloromethane at -20
M, EtOCOCN: 1.2 equiv, -20 °C. Isolated yield. c Determined by HPLC
on a Chiralcel OD column. d The absolute configuration of the major product
was determined by comparison with the reported value of optical rotation
(ref 5a).
b
°
C in the presence of 10 mol % mono-ligand with Ti(IV)
complexes (Table 1). The data indicated that the BINOL
derivatives 1f,g, chiral amine 2 and 3 complexes with Ti(IV)
were able to catalyze the reaction in excellent yields (Table 1,
entries 6-14) except for BINOL derivatives 1a-e (Table 1,
entries 1-5, no reactions were observed); however, the highest
enantioselectivity was only 27% (Table 1, entry 7). Herein, we
assumed that the nitrogen atoms of these ligands (chiral amine
TABLE 2. Asymmetric Cyanation of Benzaldehyde Catalyzed by
the Combination of Double-Ligand and Ti(IV)
entrya
yield (%)b
ee (%)c,d
combined ligands
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1e
1e
1f
1g
1h
1e
1e
1e
1e
1e
1e
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
3a
3b
3c
99
99
95
99
99
60
48
99
99
99
93
94
95
90
80
90
42(R)
13(R)
12(R)
46(R)
69(R)
2
and 3, BINOL derivatives 1f,g) might act as a Lewis base to
activate the EtOCOCN in the reaction (Table 1, entries
4,6,8,9
6
-14).
On the basis of bifunctional conception,6,8,9 we expected that
e
59(R)
bifunctional catalysts could be realized by the complexes of
BINOL derivative 1 with a metallic reagent as Lewis acid
52(R)f
13(R)
26(R)
31(S)
68(R)
40(S)
20(R)
20(R)
37(R)
12(R)
10
11
12
13
14
15
16
(
(
4) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195-6196.
5) (a) Yamagiwa, N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 3413-3422. (b) Tian, J.; Yamagiwa, N.; Matsunaga,
S.; Shibasaki, M. Org. Lett. 2003, 5, 3021-3024. (c) Tian, J.; Yamagiwa,
N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2002, 41, 3636-
3
638.
(6) (a) Baeza, A.; Casas, J.; N a´ jera, C.; Sansano, J.; Sa a´ , J. M. Eur. J.
Org. Chem. 2006, 1949-1958. (b) Baeza, A.; N a´ jera, C.; Sansano, J. M.;
Sa a´ , J. M. Tetrahedron: Asymmetry 2005, 16, 2385-2389. (c) Casas, J.;
Baeza, A.; Sansano, J. M.; N a´ jera, C.; Sa a´ , J. M. Tetrahedron: Asymmetry
a
Conditions: 10 mol % of catalyst (1/Ti(IV)/2 or 3 ) 1/1/1), concentra-
tion of benzaldehyde: 0.25 M in CH2Cl2, -20 °C, 48 h, EtOCOCN: 1.2
equiv. Isolated yield. c Determined by HPLC on a Chiralcel OD column.
b
2
003, 14, 197-200. (d) Baeza, A.; Casas, J.; N a´ jera, C.; Sansano, J.; Sa a´ ,
J. M. Angew. Chem., Int. Ed. 2003, 42, 3143-3146.
7) (a) Belokon’, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; Michael, N.
d
The absolute configuration of the major product was determined by
comparison with the reported value of optical rotation (ref 5a). Add 2a to
the complex of 1e with Ti(IV), 168 h. At -45 °C, for 96 h.
e
(
f
Tetrahedron 2004, 60, 10433-10447. (b) Belokon’, Y. N.; Blacker, A. J.;
Clutterbuck, L. A.; Michael, N. Org. Lett. 2003, 5, 4505-4508.
(8) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am. Chem.
moieties to activate the carbonyl group, while chiral amine 2
or 3 acts as Lewis base moieties to activate EtOCOCN
simultaneously through a combination approach. Then, some
combinations of BINOL derivatives 1 with chiral amine 2 or 3
were investigated (Table 2, entries 1-16).
The data indicated that the combination of 1e (6,6′-Br2-
BINOL), 2a, and Ti(IV) was the best one (Table 2, entry 5).
Other combinations could catalyze the reaction in excellent
yields with 12-68% ee (Table 2, entries 1-4, 8-16). Moreover,
the absolute configuration of BINOL, its derivatives, and chiral
tertiary amines could affect the face selectivity of the reactions.
When fixing tertiary amine 2a, BINOL derivatives 1e (S) and
1h (R) led to Si face and Re face attack, respectively (Table 2,
Soc. 2005, 127, 11592-11593.
(9) (a) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 11808-11809. (b) Masumoto,
S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2
003, 125, 5634-5635. (c) Takamura, M; Fuunabashi, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801-6808. (d) Hamashima,
Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412-7413.
(e) Takamura, M. Y.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652. (f) Hamashima, Y.;
Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 2641-
2
642. (g) Hamashima, Y.; Sawada, D.; Nogami, M.; Kanai, M.; Shibasaki,
M. Tetrahedron 2001, 57, 805-814. (h) Qin, Y. C.; Pu, L. Angew. Chem.,
Int. Ed. 2006, 118, 279-283. (i) Kato, N.; Tomita, D.; Maki, K.; Kanai,
M.; Shibasaki, M. J. Org. Chem. 2004, 69, 6128-6130. (j) Casas, J.; Baeza,
A.; Sansano, J. M.; N a´ jera, C.; Sa a´ , J. M. Org. Lett. 2002, 4, 2589-2592.
(k) Gr o¨ ger, H. Chem.sEur. J. 2001, 7, 5246-5251.
J. Org. Chem, Vol. 71, No. 15, 2006 5733

Gou et al.
TABLE 3. Asymmetric Cyanation of Benzaldehyde Catalyzed by
the Combination of Three-Ligand and Ti(IV)
entrya
third ligand
time (h)
yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
48
40
40
10
10
30
10
99
99
99
99
99
99
99
69
68
65
58
74
2a
2b
3a
3b
3b
3c
e
65
47
a
Conditions: 10 mol % of catalyst (1e/2a/indicated ligand/Ti(IV) ) 1/1/
1
/1, concentration of benzaldehyde: 0.25 M in CH2Cl2, -20 °C, EtO-
COCN: 1.2 equiv. Isolated yield. c Determined by HPLC on a Chiralcel
OD column. d The absolute configuration of the major product (R) was
determined by comparison with the reported value of optical rotation (ref
b
5
a). e Add 3b to the complex of 1e, 2a, and Ti(IV).
TABLE 4. Lewis Acid and Solvent Effect
entrya
metals
solvent
time (h) yield (%)b ee (%)c,d
1
2
3
4
5
6
7
8
Ti(Oi-Pr)4
Al(Oi-Pr)3
Zn(OTf)2
Zr(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
CH2Cl2
10
10
72
10
24
10
15
10
99
99
0
99
95
99
99
99
74
11
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
toluene
THF
19
2
69
19
20
Cl(CH2)2Cl
a
Conditions: 10 mol % of catalyst (1e/2a/3b/Ti(IV) ) 1/1/1/1),
concentration of benzaldehyde: 0.25 M, -20 °C, EtOCOCN: 1.2 equiv.
b
Isolated yield. c Determined by HPLC on a Chiralcel OD column. The
d
absolute configuration of the major product (R) was determined by
comparison with the reported value of optical rotation (ref 5a).
TABLE 5. Benzaldehyde Concentration and Temperature Effect
benzaldehyde
concn (mol/L)
entrya
T (°C)
time (h)
yield (%) b
ee (%)c,d
FIGURE 1. The screened ligands.
1
2
3
4
5
6
7
8
9
0.125
0.15
0.25
0.5
1.0
0.5
0.5
0.5
0.5
0.5
-20
-20
-20
-20
-20
0
-45
-45
-78
-78
60
20
10
10
9
90
99
99
99
99
99
95
57
83
57
65
74
79
71
56
90
51
88
34
entry 5 vs 10), and vice versa (Table 2, entry 12 vs 5). Notably,
when the procedure of preparing the catalyst was changed, 2a
was added to the complex of 1e with Ti(IV), and the reactivity
and enantioselectivity were dramatically decreased (Table 2,
entry 6).
Then, we selected the combination of 1e, 2a, and Ti(IV) to
investigate other parameters. However, the enantioselectivity
was not further improved. When the reaction temperature was
decreased to -45 °C, the reactivity and enantioselectivity were
decreased to 48% yield and 52% ee, respectively (Table 2, entry
5
48
96
96
100
e
e
10
trace
a
EtOCOCN: 1.3 equiv. b Isolated yield. c Determined by HPLC on a
Chiralcel OD column. d The absolute configuration of the major product
(
(
R) was determined by comparison with the reported value of optical rotation
ref 5a). e No 3b.
7
).
So, we tried to introduce a third component which might
coordinate with the titanium to improve the ability of chiral
induction (Table 3, entries 2-7). Fortunately, when 3b was
additionally combined in the reaction system, with the time
shortened, yield remained and higher enantioselectivity was
obtained than that only using 1e, 2a, and Ti(IV) (Table 3, entry
enantioselectivities were very unsatisfactory (Table 4, entries
2 and 4). Among the solvent examination, ether solvents (THF
or Et2O) worked well but provided low enantioselectivities
(Table 4, entries 5 and 7), which might be attributed to the
coordination with the titanium of the complex. Toluene gave
the moderate enantioselectivity (Table 4, entry 6). The inferior
data employing ClCH2CH2Cl might be a result of its greater
polarity than that of CH2Cl2 (Table 4, entry 8). The best result
was obtained in CH2Cl2 (Table 4, entry 1).
5
vs 1). Under the same conditions, the combination of 1e, 2a,
3
b, and Ti(IV) afforded better results than other combinations
(
Table 3, entries 2-4, 7). It was noteworthy that, when 3b was
added to the complex of 1e, 2a, and Ti(IV), the reactivity and
enantioselectivity were slightly decreased (Table 3, entry 6 vs
Lowering the concentration of benzaldehyde led to a dramatic
drop in reactivity (Table 5, entries 1 and 2). When the
concentration of benzaldehyde was increased to 0.5 M from
0.25 M, better enantioselectivity could be obtained (Table 5,
entry 4 vs 3). Further increase of the concentration of benz-
aldehyde led to less satisfying enantioselectivity (Table 5, entry
5). It suggested that there might involve dimeric or polymeric
5
).
Then, other reaction factors were examined. It was found that
benzaldehyde could not be converted into the corresponding
product when Ti(Oi-Pr)4 was replaced by Zn(OTf)2 (Table 4,
entry 3). Although the combination of 1e, 2a, 3b, and Al(Oi-
Pr)3 or 1e, 2a, 3b, and Zr(Oi-Pr)4 had excellent reactivity, the
5734 J. Org. Chem., Vol. 71, No. 15, 2006

Cyanation of Aldehydes Catalyzed by a Ti Complex
TABLE 6. Substrate Scope
SCHEME 1. Proposed Catalytic Cycle
entrya
aldehydes
time (h) yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
benzaldehyde (4a)
48
50
72
55
72
72
90
72
50
55
100
96
48
80
72
72
95
78
82
81
75
81
88
85
83
82
78
81
87
83
88
75
90(R)
83
90
93(R)
74(R)
82(R)
93(R)
87
84(R)
94
82
58(R)
76
2-methylbenzaldehyde (4b)
3-methylbenzaldehyde (4c)
4-methylbenzaldehyde (4d)
2-methoxybenzaldehyde (4e)
3-methoxybenzaldehyde (4f)
4-methoxybenzaldehyde (4g)
3-phenoxybenzaldehyde (4h)
1-naphthaldehyde (4i)
1
1
1
1
1
1
1
2-naphthaldehyde (4j)
4-fluorobenzaldehyde (4k)
4-chlorobenzaldehyde (4l)
heliotropin (4m)
(E)-cinnamaldehyde (4n)
hexanal (4o)
6
, entry 14). Cyclohexanecarbaldehyde gave the corresponding
product with moderate enantioselectivity and yield (Table 6,
entry 16). However, the hexanal gave a poor result (Table 6,
entry 15), in contrast to Shibasaki and co-workers’ result.5a
These results showed that the multicomponent catalyst was
effective for the asymmetric cyanation of a wide range of
aldehydes.
Mechanism: On the basis of Shibasaki and other work
groups’ reports on the cyanation of carbonyl compounds with
a bifunctional catalyst,
82(R)
45(R)
d
cyclohexanecarbaldehyde (4p)
70(R)d
a
Conditions: concentration of aldehydes ) 0.5 M, EtOCOCN: 1.3
b
c
equiv. Isolated yield. Determined by HPLC on Chiralcel OD or OD-H
column; the absolute configuration of the major product was compared with
the reported value of optical rotation (refs 5a and 7a). d Determined by GC
on Chirasil DEX CB; the absolute configuration of the major product was
compared with the reported value of optical rotation (refs 5a and 7a).
3
f,6,9d,f,g,j
we considered that the complex
of (S)-6,6′-Br2-BINOL (1e) with Ti(IV) might act as the Lewis
Ti(IV) species which was attributed to the effect of concentration
of catalyst. To our delight, the enantioselectivity was increased
to 90% ee when the three-ligand system was used at -45 °C
3
e,8,9
acid to activate electrophiles (carbonyl group),
while the
tertiary amine of ligands 2a and 3b might play Lewis base to
4
,6,8,9
activate the nucleophiles (EtOCOCN).
Herein, a possible
(Table 5, entry 7). However, lowering the reaction temperature
catalytic cycle consisting of three steps was proposed (Scheme
to -78 °C led to a decrease in reactivity and slightly affected
enantioselectivity (Table 5, entry 9). In contrast, when the
double-ligand system was used under the same conditions, the
enantioselectivity was only 51 and 34% ee, respectively (Table
1
7
). Step I: The aldehyde coordinated with the titanium complex
5
,6,8
to form a catalytically active species 8.
Step II: The
EtOCOCN was activated by the Lewis base to generate complex
4
,6,8
9
.
Step III: The cyanide would react with the aldehydes to
5, entries 8 and 10). Additionally, when the reaction temperature
provide the product 6 and accomplish one catalytic cycle.
In conclusion, we have developed a novel multicomponent
bifunctional titanium complex to catalyze the enantioselective
cyanation of aldehydes. Under the optimized conditions, excel-
lent reactivity and enantioselectivity could be generated (up to
was increased to 0 °C from -20 °C, the enantioselectivity
decreased from 79 to 56% ee (Table 5, entry 6).
Moreover, the percent molar ratio of the component, catalyst
loading, and the amount of EtOCOCN were investigated, but
the enantioselectivity could not be improved (see Supporting
Information for details). Hence, the optimal conditions were 10
mol % multicomponent catalyst (1e/2a/3b/Ti(IV) ) 1/1/1/1),
9
5% yield and up to 94% ee). The strategy described in the
present work demonstrated the ability of a multicomponent
catalyst to promote an enantioselective cyanation of aldehydes,
which might provide a new direction to the design of chiral
catalysts for asymmetric catalysis. Investigations of the scope
of these applications are currently underway.
0
.5 M, CH2Cl2, -45 °C.
Substrate Generality: Encouraged by the results obtained
from benzaldehyde under the optimized conditions, a series of
aldehydes were evaluated (Table 6). Most of the aromatic, R,â-
unsaturated, aliphatic aldehydes could be converted into the
corresponding cyanohydrin carbonates in moderate to high yields
with up to 94% ee. para-Substituted benzaldehydes led to higher
enantioselectivities than benzaldehyde (Table 6, entries 4 and
Experimental Section
2-Ethoxycarbonyl-(R)-2-hydroxy-2-phenyl acetonitrile (6a):
Ti(Oi-Pr)
solution of 1e (11.1 mg, 0.025 mmol), 2a (7.35 mg, 0.025 mmol),
and 3b (4.48 mg, 0.025 mmol) in CH Cl , and the mixture was
stirred at 35 °C for 1 h under N . This was followed by the addition
of benzaldehyde (0.25 mmol) and EtOCOCN (0.325 mmol) at -45
C. The contents were stirred for 48 h, and then the solution was
4
(1.0 M in toluene, 25 µL, 0.025 mmol) was added to a
7
vs entry 1), ortho- and/or meta-substituted benzaldehydes
generally gave low enantioselectivity values than did the para-
isomers (Table 6, entries 2, 3, 5, 6, 8, and 13). 2-Naphthaldehyde
provided the highest enantioselectivity (up to 94% ee) with good
yield (Table 6, entry 10), but the 1-naphthaldehyde afforded
unsatisfactory results (Table 6, entry 9). Halogen-substituted
benzaldehydes gave lower enantioselectivity values and required
longer reaction time (Table 6, entries 11 and 12). When (E)-
cinnamaldehyde was subjected to the reaction, only the 1,2-
addition product was afforded in 83% yield with 82% ee (Table
2
2
2
°
concentrated and the residue was purified by silica gel column
chromatography (petroleum ether/diethyl ether, 10:1) to afford the
23.4
product. Colorless oil; yield 95%; [R]
D
3
+16.0 (c 2.0, CHCl )
(
90% ee). HPLC (DAICEL CHIRALCEL OD, 2-propanol/hexane
1/99, flow 1.0 mL/min, detection at 254 nm) t 13.4 and 17.5 min,
R
5
a,c
21.7
lit. [R]
D
+16.2 (c 2.8, CHCl
3
) for the R enantiomer in 94%
J. Org. Chem, Vol. 71, No. 15, 2006 5735

Gou et al.
1
ee. H NMR (CDCl
2
3
): δ 1.34 (t, J ) 7.2 Hz, 3H), 4.26-4.32 (m,
Supporting Information Available: Investigation of the percent
H), 6.27 (s, 1H), 7.45-7.49 (m, 3H), 7.53-7.56 (m, 2H).
molar ratio of the component, catalyst loading, and the amount of
1
13
EtOCOCN, characterization of products, including H and
C
Acknowledgment. We thank the National Natural Science
NMR, HRMS data, HPLC, and GC conditions, etc. This material
is available free of charge via the Internet at http://pubs.acs.org.
Foundation of China (Nos. 20390055, 20225206, and 20502019)
and the Ministry of Education, P. R. China (No. 104209 and
others) for financial support.
JO060772Z
5736 J. Org. Chem., Vol. 71, No. 15, 2006