Highly enantioselective cyanoformylation of aldehydes catalyzed by a mononuclear salen-Ti(OiPr)4 complex produced in situ

Article abstract of DOI:10.1002/ejoc.200600795

An efficient enantioselective cyanoformylation of aldehydes with ethyl cyanoformate, catalyzed by a salen-Ti(OiPr)₄ complex generated in situ, has been developed. Studies of non-linear effects indicated that the mononuclear salen-titanium compl

Full text of DOI:10.1002/ejoc.200600795

FULL PAPER
DOI: 10.1002/ejoc.200600795
Highly Enantioselective Cyanoformylation of Aldehydes Catalyzed by a
Mononuclear Salen-Ti(OiPr) Complex Produced In Situ
4
[a]
[a]
[a]
[a]
[a]
Shi-Kui Chen, Dan Peng, Hui Zhou, Li-Wei Wang, Fu-Xue Chen, and
Xiao-Ming Feng*[
a,b]
Keywords: Asymmetric catalysis / Cyanohydrin / In situ preparation / Solvent effects / Titanium
An efficient enantioselective cyanoformylation of aldehydes
In the presence of 5 mol-% catalyst, the reaction can be car-
with ethyl cyanoformate, catalyzed by a salen-Ti(OiPr) com- ried out in excellent yields (up to 99%) and with high
4
plex generated in situ, has been developed. Studies of non-
linear effects indicated that the mononuclear salen-titanium
complex, and not a heterochiral complex, played a key role
in the stereodiscriminating step of the reaction. During the
preparation of the catalyst, the addition of isopropyl alcohol
was shown to avoid the formation of a heterochiral complex.
enantioselectivities (up to 91% ee). From preliminary stud-
ies, a transition state to explain the origin of the asymmetric
induction has been proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
with acetyl cyanide and cyanoformate as cyanide sources,[6]
Introduction
Shibasaki’s group demonstrated the utility of
a
Optically active cyanohydrins are of great interest for a
series of chiral, nonracemic compounds, such as β-amino
alcohols and α-hydroxy carbonyl compounds,[ many of
them serving as highly versatile building blocks in the syn-
thesis of biologically active products and chiral medicinal
agents. The last two decades have witnessed the study of a
variety of chiral catalyst systems using hydrogen cyanide
{
YLi [tris(binaphthoxide)]} single catalyst in asymmetric
3
[7]
cyanoethoxycarbonylation reactions of aldehydes, and
Sansano et al. first reported the use of BINOLAM-Ti
complexes in asymmetric cyanobenzoylations of aldehydes
at room temperature and without additives. Very recently,
our group has presented multicomponent titanium and
N,N-dioxide titanium catalysts in cyanoformylations of al-
dehydes, with good yields and enantioselectivities being ob-
1]
IV
[8]
(
HCN) or trimethylsilyl cyanide (TMSCN) as the cyanide
[2,3]
source in reactions with carbonyl compounds.
Because
[9]
tained, while in our previous study the mononuclear
of the volatile and hence hazardous natures of these rea-
gents, however, cyanoformate esters (ROCOCN), acetyl cy-
anide, or diethyl cyanophosphonate have been investigated
as alternatives, and several successful catalytic systems for
the cyanation of aldehydes and ketones with the aid of these
new cyanide sources have been developed. Deng’s group
found that a chiral tertiary amine catalyst gave excellent
yields and good enantioselectivities for cyanations of
ketones, Belokon’ and North’s group developed salen-tita-
nium bimetallic catalyst 1, which was found to be efficient
for additions of ethyl cyanoformate to aldehydes,[5] Moberg
and coworkers described the crucial importance of dual
Lewis acid/Lewis base activation in cyanations of aldehydes
salen-Ti(OiPr) complex was successfully utilized in cyano-
silylations of carbonyl compounds. Combining these pre-
cedents, we now wish to report the use of the salen-Ti-
4
[10]
(
OiPr) mononuclear complex generated in situ in catalytic
4
asymmetric additions of ethyl cyanoformate to aldehydes,
providing very stable enantiomerically enriched O-protected
cyanohydrins – very interesting from the general synthetic
point of view – in only one step.
[
4]
[
a] Key Laboratory of Green Chemistry and Technology (Sichuan
University), Ministry of Education, College of Chemistry,
Sichuan University,
Chengdu 610064, China
Fax: +86-28-85418249
E-mail: xmfeng@scu.edu.cn
[b] State Key Laboratory of Biotherapy, West China Hospital,
Sichuan University,
Chengdu 610041, China
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 639–644
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
639

X.-M. Feng et al.
FULL PAPER
Results and Discussion
Encouraged by these results, we next studied the volume
ratio of the isopropyl alcohol/chloroform mixture (En-
tries 5–8). The best ratio should be 1:4 (Entry 6, up to
The Effect of Isopropyl Alcohol
91% ee). If the ratio is decreased to 1:9, the reaction pro-
ceeds slowly and affords the product in a lower isolated
yield (Entry 5), whereas at a higher volume ratio (Entries 7
and 8) the yield and the enantioselectivity scarcely changed.
If isopropyl alcohol is used as the solvent, however, no reac-
tion was observed, which might be explained by the low
solubility of ligand 2e in it (Entry 9). The best result (99%
yield, 91% ee, Entry 6) was obtained with the optimal ratio
between iPrOH and CHCl (1:4 v/v, 0.8 mL). If CH Cl or
In the preliminary study, (1R,2R)-2e-Ti(OiPr) complex
4
was used as the catalyst and chloroform as the solvent to
perform the asymmetric addition of ethyl cyanoformate (4)
to benzaldehyde (3a) [Equation (1)], but only a 19% iso-
lated yield and a 72% ee were obtained (Table 1, Entry 1),
perhaps because of the formation of a multinuclear com-
[
11]
plex. With reference to Carreira’s previous study,
we
3
2
2
speculated that the addition of isopropyl alcohol might pre-
vent multinuclear complex formation, so isopropyl alcohol
was added to enhance the reactivity and enantioselectivity.
As shown in Table 1, the enantioselectivity improved
slightly as the molar ratio of isopropyl alcohol to benzalde-
hyde was increased from 10 to 100 mol-% (Entries 1–4).
CH CN mixed with isopropyl alcohol is used as the solvent,
3
the enantioselectivity decreases appreciably (Entries 10, 14),
whereas poor yields are obtained when toluene, THF, and
CH ClCH Cl are employed (Entries 11–13).
2
2
To gain some insight into the effect of isopropyl alcohol,
the nonlinear effect was studied. As shown in Figure 1,
when a mixture of iPrOH/CHCl (1:4 v/v, 0.8 mL) was used
3
as the solvent, the ee values between ligand 2e and product
5
a were perfectly linear (Figure 1, ᭡), while without the ad-
Table 1. Effects of solvents in the asymmetric cyanoformylation of
benzaldehyde with ethyl cyanoformate.[
a]
dition of isopropyl alcohol a multishaped nonlinear effect
was observed (Figure 1, ᭿), which indicated that a small
quantity of heterochiral complex might be being formed:
that is, that the presence of isopropyl alcohol did suppress
the formation of heterochiral complex in the catalyst prepa-
ration step. It also demonstrated that homochiral complex
2
e-Ti(OiPr) (1:1) played a key role in the stereodiscriminat-
4
[
12]
ing step of the reaction.
Entry
Solvent
iPrOH/Solvent[b] Yield
ee
[%]
%][
d]
[e]
[
1
2
3
4
5
6
7
8
9
1
1
1
1
1
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
3
3
3
–
19
21
22
24
77
99
99
99
trace
99
20
42
48
99
72
73
76
78
88
91
89
87
–
89
84
90
90
84
10 mol-%[
50 mol-%[
c]
c]
100 mol-%[
c]
1:9
1:4
3:7
1:1
–
1:4
1:4
1:4
iPrOH
CH Cl
0
1
2
3
4
2
2
toluene
THF
CH
CH
2
ClCH
CN
2
Cl 1:4
1:4
Figure 1. Studies of the nonlinear effect in the reaction between
benzaldehyde and ethyl cyanoformate in an iPrOH/CHCl mixture
1:4 v/v, 0.8 mL) as solvent (᭡), and in chloroform as solvent (᭿).
3
3
(
[
4
a] All reactions were performed with benzaldehyde (0.4 mmol) and
(0.6 mmol) in solvent (0.8 mL) at –20 °C over 16 h. Catalyst con-
sisted of a 1:1 molar ratio of ligand 2e to Ti(OiPr) ; catalyst loading
4
was 5 mol-%. [b] The volume ratio relative to the solvent (0.8 mL
in all), unless otherwise indicated. [c] The molar ratio relative to
benzaldehyde. [d] Isolated yield. [e] The ee values were determined
by HPLC with a Chiralcel OD-H column. The absolute configura-
tion was (S), by comparison with the sign of the reported optical
Catalyst Optimization
To obtain higher enantioselectivities, some mono com-
plexes of easily accessible ligands (as shown in Figure 2)
[
5a]
rotation value.
with Ti(OiPr) were tested in the reaction between benzal-
4
640
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 639–644

Highly Enantioselective Cyanoformylation of Aldehydes
FULL PAPER
dehyde and ethyl cyanoformate. These tests showed that the
Subsequently, the molar ratio of ligand 2e to Ti(OiPr)4
yield and enantiomeric excess of product 5a were greatly was surveyed, and, as shown in Table 3 (Entries 1–5), the
affected by the substituents on the salen ligands: as shown enantioselectivity hardly varied with changes in this molar
in Table 2, the best ligand was 2e, derived from the ligand ratio, which might be an indication that with the addition
bearing tBu groups at the 3Ј- and the 5Ј-positions in the of no isopropyl alcohol a multinuclear complex was formed
salicylidene phenolic rings (99% yield, 91% ee, Entry 5), in the reaction. Accordingly, the optimal molar ratio should
whereas the presence of smaller substituents at the 3Ј- and be 1:1 (Entry 1). The effect of catalyst loading was also
5Ј-positions decreased the enantioselectivity considerably studied, but, unfortunately, when the catalyst loading was
(Entries 1–4). However, the presence of the much bulkier 1- 2.5 mol-%, almost no adduct was detected (Entry 6) and
adamantanyl group at the 3Ј-position resulted in the aboli- the optimal catalyst loading should therefore be 5 mol-%.
tion of catalytic activity (Entry 6). In addition, ligands with
electron-donating or -withdrawing substituents showed
Table 3. Effects of the ligand/metal ratio and the catalyst loading
considerable decreases in both reactivity and enantio- on the enantioselectivity.[
a]
selectivity (Entries 7–9). A series of metals were then
screened in combination with ligand 2e (Entries 10–12),
Entry
Ligand 2e
mol-%]
Ti(OiPr)
[mol-%]
4
Yield
[%]
ee
[%]
[b]
[d]
[
but, unfortunately, no adduct was detected when TiCl4,
1
2
3
4
5
6
5
5
5
5
6.25
7.5
2.5
99
99
99
99
99
91
90
88
89
88
–
Al(OiPr) , or Zr(OiPr) were used as metal salts (En-
4
4
6.25
7.5
5
5
2.5
tries 10–12).
N.D.[
c]
[
4
–
a] All reactions were performed with benzaldehyde (0.4 mmol) and
(0.6 mmol) in an iPrOH/CHCl
3
mixture (1:4 v/v, 0.8 mL) at
20 °C over 16 h. [b] Isolated yield. [c] N.D. = Not detected. [d] The
ee values were determined by HPLC with a Chiralcel OD–H col-
umn. The absolute configuration was (S) by comparison with the
sign of a reported optical rotation value.[
5a]
Effect of the Amount of EtOCOCN
Furthermore, the effect of the amount of EtOCOCN was
studied and, as shown in Table 4, the reactivity and enantio-
selectivity hardly changed with a variation of the amount
of ethyl cyanoformate from 1.25 to 1.75 equiv. However, a
decrease in the amount to 1.0 equiv. or an increase to
Figure 2. Ligands assessed in this study.
2
.0 equiv. was capable of reducing the isolated yield dramat-
ically, so the optimal conditions involved the use of ligand
e (5 mol-%) and Ti(OiPr) (5 mol-%) as the catalyst, with
2
4
Table 2. Effects of ligands and metal compounds in this catalysis.[a]
ethyl cyanoformate (1.5 equiv.) and benzaldehyde (0.5 ) in
Entry
Ligand
Metal
compound [h]
Time
Yield
[%][
ee
[%]
an iPrOH/CHCl mixture (1:4 v/v, 0.8 mL) at –20 °C.
3
b]
[d]
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
4
4
4
4
4
4
4
4
4
22
22
20
20
16
40
40
40
40
40
40
40
99
94
92
90
99
0
99
20
43
N.D.[
57
44
46
62
91
–
50
47
46
–
Table 4. Effects of the amount of ethyl cyanoformate in this cataly-
sis.[
a]
Entry
EtOCOCN
equiv.]
Yield
[%][
ee
[%]
b]
[c]
[
1
2
3
4
5
1.0
1.25
1.5
1.75
2.0
50
96
99
89
82
90
87
91
89
89
c]
c]
c]
10
11
12
2e
2e
2e
TiCl
4
Al(OiPr)
Zr(OiPr)
[
3
N.D.
–
–
N.D.[
4
[
4
–
a] All reactions were performed with benzaldehyde (0.4 mmol) and
[a] All reactions were performed with benzaldehyde (0.4 mmol) and
(1:4 v/v, 0.8 mL) mixture at 4 in an iPrOH/CHCl mixture (1:4 v/v, 0.8 mL) at –20 °C over 16 h.
20 °C. Catalyst consisted of a 1:1 molar ratio of ligands to Catalyst consisted of a 1:1 molar ratio of ligand 2e to Ti(OiPr)
; catalyst loading was 5 mol-%. [b] Isolated yield. [c] N.D.
Not detected. [d] The ee values were determined by HPLC with
(0.6 mmol) in an iPrOH/CHCl
3
3
4
;
Ti(OiPr)
4
catalyst loading was 5 mol-%. [b] Isolated yield. [c] The ee values
were determined by HPLC with a Chiralcel OD-H column. The
absolute configuration was (S), by comparison with the sign of a
=
a Chiralcel OD-H column. The absolute configuration was (S), by
comparison with the sign of a reported optical rotation value.[
5a]
reported optical rotation value.
[5a]
Eur. J. Org. Chem. 2007, 639–644
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
641

X.-M. Feng et al.
FULL PAPER
Substrate Generality
Transition State Considerations
According to the X-ray structure of titanium complex
,[ the potential transition state shown in Figure 3 was
Encouraged by the results obtained from benzaldehyde,
we subjected a variety of aldehydes to cyanoformylation
with ethyl cyanoformate under the optimized conditions. As
shown in Table 5, good to excellent enantioselectivities of
13]
1
proposed. To minimize the interactions between benzalde-
hyde and the substituent on the phenyl ring of the ligand,
transition state A versus B may be favored. It also results
in an orientation in which the re-face of benzaldehyde is
exposed to the cyanide group for the nucleophilic attack,
producing the (S) enantiomer of the O-protected cyanohyd-
rin.
76–91% ee and high to excellent isolated yields were ob-
tained in the presence of 5 mol-% catalyst with aromatic,
α,β-unsaturated, and aliphatic aldehydes.
Table 5. Asymmetric cyanoformylations of aldehydes with ethyl cy-
anoformate catalyzed by (1R,2R)-salen-Ti(OiPr)
4
complex.[
a]
Entry Aldehydes 3a–l
Time
h]
Yield
[%]
ee
[%]
[
b]
[c]
[
[
d]
1
2
3
4
5
6
7
8
9
1
1
1
Benzaldehyde
16
40
55
14
92
16
10
40
114
10
54
60
99
99
99
99
89
91
90
87
93
85
92
59
91 (S)
91
87 (S)
91 (S)
88 (S)
90
[
e]
3-Methylbenzaldehyde
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
2-Naphthaldehyde
3-Phenoxybenzaldehyde
(E)-Cinnamaldehyde
4-Fluorobenzaldehyde
Heliotropin
[d]
[d]
[d]
90
[
d]
d]
81 (S)
87 (S)
86
[
0
1
2
[
f]
n-Hexanal
2-Butyraldehyde
86
76 (S)
[
d,f]
[
(
a] All reactions were performed with aldehydes (0.4 mmol) and 4
0.6 mmol) in an iPrOH/CHCl mixture (1:4 v/v, 0.8 mL) at –20 °C;
catalyst consisted of a 1:1 molar ratio of ligand 2e to Ti(OiPr)
3
4
;
catalyst loading was 5 mol-%. [b] Isolated yield. [c] Determined by
HPLC on a Chiralcel OD-H column (unless otherwise indicated).
[
d] The absolute configuration of the major product was deter-
mined by comparison with the sign of the reported optical rotation
value.
[
5a,7c]
Figure 3. The potential transition states.
[e] Determined by HPLC with a Chiralcel OD column.
[f] Determined by GC with a Chirasil DEX CB column.
In these cases, the presence of 3- and 4-substituents on
benzaldehyde had a slight effect on the enantioselectivities
Entries 1–3): 3-methylbenzaldehyde afforded the corre-
Conclusions
(
In conclusion, a mononuclear salen-Ti(OiPr) complex
4
sponding product with 91% ee (Entry 2), whereas 4-methyl- has been used to catalyze asymmetric cyanoformylations of
benzaldehyde gave the adduct with 87% ee (Entry 3). In aldehydes with ethyl cyanoformate. The addition of isopro-
comparison, electron-rich aromatic aldehydes such as he- pyl alcohol to chloroform in the reaction has been demon-
liotropin yielded the cyanohydrin ethyl carbonate in 86% ee strated to avoid the formation of the multinuclear complex
(Entry 10), 4-methoxybenzaldehyde gave the O-protected in the catalyst preparation step and optimal results were
cyanohydrin with 91% ee (Entry 4), and 3-phenoxybenzal- obtained with only 5 mol-% catalyst in an iPrOH/CHCl3
dehyde – the cyanohydrin ethyl carbonate, which might be mixture (1:4 v/v) at –20 °C, under which conditions a vari-
applied in the synthesis of the insecticide fenvaler- ety of aldehydes including aromatic, α,β-unsaturated, and
[
1a]
ate Aα
– provided the adduct with 90% ee (Entry 7). aliphatic aldehydes were converted into the corresponding
Among electron-withdrawing aromatic aldehydes, mean- cyanohydrin ethyl carbonates in 76–91% enantiomeric ex-
while, 4-chlorobenzaldehyde afforded the product in 88% ee cesses. A potential transition state based on the experimen-
(Entry 5) and 4-fluorobenzaldehyde gave its corresponding tal results, which explains the origin of the asymmetric in-
adduct in 87% ee (Entry 9). Significantly, α,β-unsaturated, duction, has been presented. Meanwhile, since optically
aliphatic, and condensed cyclic aldehydes also provided active salen is easily available on a large scale, this asymmet-
their corresponding products with good to excellent ric cyanoformylation, catalyzed by the mononuclear salen-
enantioselectivities (Entries 6, 8, 11, 12).
Ti(OiPr) complex, might be expected to have excellent po-
4
642
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 639–644

Highly Enantioselective Cyanoformylation of Aldehydes
tential for practical applications. Further efforts might be (s, 1 H, O-CH-CN), 7.25 (d, J = 7.9 Hz, 2 H, Ar-H), 7.43 (d, J =
FULL PAPER
8
.1 Hz, 2 H, Ar-H) ppm.
S)-2-Ethoxycarbonyloxy-2-(4-methoxylphenyl)acetonitrile (5d):[9b]
This compound was purified by FC with silica gel (petroleum/Et
0:1) to afford title compound 5d as a colorless oil in 99% yield
and with 91% ee as determined by HPLC analysis with a Chi-
devoted to application of this reaction in the pharmaceuti-
cal chemistry and other fields.
(
2
O
1
Experimental Section
–1
ralcel OD-H column [hexane/2-propanol 99:1, 1.0 mLmin , t
r
2
5
(
minor) = 13.8 min, t
r
(major) = 17.7 min]. [α]
D
= +3.00 (c 0.100,
General Methods: All reactions were carried out with anhydrous
solvents and under a nitrogen atmosphere in oven-dried tubes. Tol-
CHCl
3
); {ref.[ [α]
5a]
20
D
= +1.8 (c 1.8, CHCl
3
) for the (S) enantiomer
): δ = 1.30 (t, J = 7.2 Hz,
), 4.19–4.30 (m, 2 H, OCH ),
.19 (s, 1 H, O-CH-CN), 6.93 (d, J = 8.8 Hz, 2 H, Ar-H), 7.46 (d,
1
with 95% ee}. H NMR (300 MHz, CDCl
3
uene, CH
benzophenone under a nitrogen atmosphere prior to use. CH
CHCl , and CH ClCH Cl were dried with powdered CaH
distilled under a nitrogen atmosphere prior to use. (CH CHOH
was purchased from Fisher. Ti(OiPr) (from Acros) was distilled
3
CN, and THF were dried and distilled from sodium/
Cl
and
3
6
H, OCH
2
CH
3
), 3.81 (s, 3 H, OCH
3
2
2
2
,
3
2
2
2
J = 8.8 Hz, 2 H, Ar-H) ppm.
3 2
)
(5e):[9b]
4
(
S)-2-Ethoxycarbonyloxy-2-(4-chlorophenyl)acetonitrile
and diluted to 1.0  in toluene and stored under a nitrogen atmo-
sphere. HG/T2354-92 silica gel (Qingdao Haiyang Chemi-
cal Co., Ltd.) was used for flash chromatography (FC). Enantio-
meric excesses (ee’s) were determined by HPLC on the correspond-
ing commercial chiral column as stated in the experimental pro-
cedures at 23 °C with UV detection at 254 nm or GC. Specific op-
This compound was purified by FC with silica gel (petroleum/Et
0:1) to afford title compound 5e as a colorless oil in 89% yield
and with 88% ee as determined by HPLC analysis with a Chi-
2
O
1
–1
ralcel OD-H column [hexane/2-propanol 99:1, 1.0 mLmin , t
r
25
(
0
minor) = 11.248 min, t
r
20
(major) = 14.553 min]. [α]
D
= –4.95 (c
) for the (S) enanti-
omer with 94% ee}. H NMR (300 MHz, CDCl ): δ = 1.33 (t, J =
.2 Hz, 3 H, OCH CH ), 4.23–4.34 (m, 2 H, OCH ), 6.23 (s, 1 H,
O-CH-CN), 7.41–7.51 (m, 4 H, Ar-H) ppm.
-Ethoxycarbonyloxy-2-(2-naphthyl)acetonitrile (5f):[9b] This com-
pound was purified by FC with silica gel (petroleum/Et O 10:1) to
afford title compound 5f as a white solid in 91% yield and with
0% ee as determined by HPLC analysis with a Chiralcel OD-H
[5a]
3 D 3
.101, CHCl ); {ref. [α] = –2.9 (c 1.3, CHCl
tical rotations are reported as follows: [α]T
(c g/100 mL, solvent).
1
D
3
7
2
3
2
Materials: The ligands were prepared as described in the litera-
[
14]
ture.
All aldehydes, 1,2-diaminocyclohexane, and NCCOOEt
were purchased from Acros or Aldrich and used directly without
further purification.
2
2
Typical Procedure for the Asymmetric Synthesis of Optically Active
Cyanohydrin Ethyl Carbonates. (S)-2-Ethoxycarbonyloxy-2-phenyl-
9
–
1
[
9b]
column [hexane/2-propanol 90:10, 1.0 mLmin , t
r
(minor) =
= +6.25 (c 0.096, CHCl ).
): δ = 1.35 (t, J = 7.1 Hz, 3 H,
), 4.25–4.37 (m, 2 H, OCH ), 6.44 (s, 1 H, O-CH-CN),
.55–7.61 (m, 3 H, Ar-H), 7.89–8.05 (m, 3 H, Ar-H), 8.04–8.05 (m,
H; Ar-H) ppm.
acetonitrile (5a):
was added under an N
tion of (1R,2R)-salen (10.9 mg, 0.02 mmol) in mixed solvents
CHCl /(CH CHOH 4:1, 0.8 mL], followed by the addition at
20 °C of benzaldehyde (0.4 mmol) and EtOCOCN (59.3 µL,
.6 mmol). The contents were stirred for 16 h, and the residue was
Ti(OiPr)
4
(1.0  in toluene, 20 µL, 0.02 mmol)
2
5
1
0.3 min, t
r
(major) = 11.0 min]. [α]
H NMR (300 MHz, CDCl
OCH CH
2
D
3
2
atmosphere at room temperature to a solu-
1
3
2
3
[
–
0
3
3 2
)
7
1
2-Ethoxycarbonyloxy-2-(3-phenoxyphenyl)acetonitrile (5g):[9b] This
purified by silica gel column chromatography (petroleum ether/di-
ethyl ether 10:1) to afford title compound 5a as a colorless oil in
compound was purified by FC with silica gel (petroleum/Et O 10:1)
2
9
9% yield and with 91% ee as determined by HPLC analysis with
to afford title compound 5g as a colorless oil in 90% yield and with
–
1
a Chiralcel OD-H column [hexane/2-propanol 99:1, 1.0 mLmin ,
90% ee as determined by HPLC analysis with a Chiralcel OD-H
(major) = 9.9 min]. [α]2
= –20.1 (c 1.8, CHCl ) for the (S) enantiomer
with 95% ee}. H NMR (300 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, NMR (300 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 3 H, OCH CH ),
H, OCH CH ), 4.26–4.32 (m, 2 H, OCH
CN), 7.45–7.49 (m, 3 H, Ar-H), 7.53–7.56 (m, 2 H, Ar-H) ppm.
5
= –15.6 (c 0.109,
–1
t
r
(minor) = 8.4 min, t
r
D
column [hexane/2-propanol 99:1, 1.0 mLmin , tr (major) =
[
5a]
20
25
1
CHCl
3
); {ref. [α]
D
3
r 3
17.1 min, t (minor) = 26.3 min]. [α]D = –2.75 (c 0.109, CHCl ). H
1
3
3
2
3
3
2
3
2
), 6.27 (s, 1 H, O-CH- 4.24–4.35 (m, 2 H, OCH ), 6.22 (s, 1 H, O-CH-CN), 7.02–7.05 (m,
2
1 H, Ar-H), 7.17–7.19 (m, 2 H, Ar-H), 7.28–7.35 (m, 3 H, Ar-H),
7.38 (m, 3 H, Ar-H) ppm.
2
-Ethoxycarbonyloxy-2-(3-methylphenyl)acetonitrile (5b):[9b] This
compound was purified by FC with silica gel (petroleum/Et O 10:1)
(S)-2-Ethoxycarbonyloxy-4-phenylbut-3-enonitrile (5h):[9b] This
2
to afford title compound 5b as a colorless oil in 99% yield and
with 91% ee as determined by HPLC analysis with a Chiralcel OD
compound was purified by FC with silica gel (petroleum/Et O 10:1)
to afford title compound 5h as a colorless oil in 87% yield and with
2
–1
column [hexane/2-propanol 99:1, 1.0 mLmin , t
r
(minor) =
= –14.43 (c 0.097, CHCl ).
): δ = 1.33 (t, J = 7.1 Hz, 3 H,
), 4.25–4.33 (m, 2 H, OCH ), 6.39 (s,
81% ee as determined by HPLC analysis with a Chiralcel OD-H
(major) = 12.5 min]. [α]2
H NMR (300 MHz, CDCl
OCH CH ), 2.5 (s, 3 H, CH
5
–1
1
0.6 min, t
r
D
3
column [hexane/2-propanol 90:10, 1.0 mLmin , t (major) =
r
1
25
3
11.8 min, t (minor) = 13.2 min]. [α] = +10.78 (c 0.102, CHCl3);
r
20
D
{ref.[ [α] = –17.2 (c 1.9, CHCl ) for the (R) enantiomer with
7c]
2
3
3
2
D 3
1
1
H, O-CH-CN), 7.24–7.39 (m, 3 H, Ar-H), 7.58 (d, J = 6.4 Hz, 1 88% ee}. H NMR (300 MHz, CDCl ): δ = 1.36 (t, J = 7.1 Hz, 3
3
H, Ar-H) ppm.
2 3 2
H, OCH CH ), 4.27–4.34 (m, 2 H, OCH ), 5.89 (d, J = 6.8 Hz, 1
H, O-CH-CN), 6.26 (dd, J = 15.8, 6.8, Hz, 1 H, =CH), 7.02 (d, J
15.8 Hz, 1 H, Ph-CH=), 7.34–7.45 (m, 5 H, Ar-H) ppm.
(
S)-2-Ethoxycarbonyloxy-2-(4-methylphenyl)acetonitrile
(5c):[9b]
=
This compound was purified by FC with silica gel (petroleum/Et
0:1) to afford title compound 5c as a colorless oil in 99% yield and
with 87% ee as determined by HPLC analysis on a Chiralcel OD-H
2
O
1
2-Ethoxycarbonyloxy-2-(4-fluorophenyl)acetonitrile (5i):[9b] This
compound was purified by FC with silica gel (petroleum/Et O 10:1)
2
–1
column [hexane/2-propanol 99:1, 1.0 mLmin , t
r
(minor) =
= –6.19 (c 0.097, CHCl );
) for the (S) enantiomer with (minor) =
4% ee}. H NMR (300 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 10.4 min, t ).
3
CH ), 2.39 (s, 3 H, CH ), 4.22–4.33 (m, 2 H, OCH ): δ = 1.33 (t, J = 7.2 Hz, 3 H,
), 6.22 1H NMR (300 MHz, CDCl
to afford title compound 5i as a colorless oil in 93% yield and with
8
{
9
.6 min, t
r
(major) = 9.7 min]. [α]2
D
5
3
87% ee as determined by HPLC analysis with a Chiralcel OD-H
[
5a]
20
–1
ref.
[α]
D
= –5.1 (c 2.0, CHCl
3
column [hexane/2-propanol 99:1, 1.0 mLmin , t
r
1
25
3
r D 3
(major) = 12.4 min]. [α] = –19.35 (c 0.062, CHCl
H, OCH
2
3
3
2
Eur. J. Org. Chem. 2007, 639–644
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
643

X.-M. Feng et al.
FULL PAPER
OCH
2
CH
3
), 4.24–4.33 (m, 2 H, OCH
2
), 6.24 (s, 1 H, O-CH-CN),
Asymmetry 2003, 14, 147–176; c) J. M. Brunel, I. P. Holmes,
Angew. Chem. Int. Ed. 2004, 43, 2752–2778; d) F.-X. Chen, X.-
M. Feng, Synlett 2005, 892–899; e) M. Kanai, N. Kato, E.
Ichikawa, M. Shibasaki, Synlett 2005, 1491–1508; f) T. R. J.
Achard, L. A. Clutterbuck, M. North, Synlett 2005, 1828–
1847; g) F.-X. Chen, X.-M. Feng, Curr. Org. Synth. 2006, 3,
77–97.
7.11–7.17 (m, 2 H, Ar-H), 7.52–7.57 (m, 2 H, Ar-H) ppm.
2
-Ethoxycarbonyloxy-2-(benzo[d][1,3]dioxol-5-yl)acetonitrile (5j):[9b]
This compound was purified by FC with silica gel (petroleum/Et
0:1) to afford title compound 5j as a colorless oil in 85% yield
and with 86% ee as determined by HPLC analysis with a Chi-
2
O
1
–
1
ralcel OD-H column [hexane/2-propanol 90:10, 1.0 mLmin , t
r
[3] a) S.-K. Tian, R. Hong, L. Deng, J. Am. Chem. Soc. 2003, 125,
9900–9901; b) Y. Li, B. He, B. Qin, X.-M. Feng, G.-L. Zhang,
J. Org. Chem. 2004, 69, 7910–7913; c) Y.-H. Wen, X. Huang,
J.-L. Hang, Y. Xiong, B. Qin, X.-M. Feng, Synlett 2005, 2445–
(major) = 12.5 min]. [α]2
5
(minor) = 8.9 min, t
r
D
= +2.17 (c 0.092,
1
CHCl
3
). H NMR (300 MHz, CDCl
3
): δ = 1.33 (t, J = 7.2 Hz, 3
), 6.02 (s, 2 H, O-CH
O), 6.16 (s, 1 H, O-CH-CN), 6.82–6.85 (d, J = 7.8 Hz, 1 H, Ar-H),
H, OCH
2
CH
3
), 4.22–4.33 (m, 2 H, OCH
2
2
-
2
2
5
448; d) Y.-C. Qin, L. Liu, L. Pu, Org. Lett. 2005, 7, 2381–
383; e) D.-H. Ryu, E. J. Corey, J. Am. Chem. Soc. 2005, 127,
384–5387; f) D. E. Fuerst, E. N. Jacobsen, J. Am. Chem. Soc.
6.99–7.04 (m, 2 H, Ar-H) ppm.
2
-Ethoxycarboxyheptanenitrile (5k):[9b] This compound was puri-
2005, 127, 8964–8965; g) X.-H. Liu, B. Qin, X. Zhou, B. He,
X.-M. Feng, J. Am. Chem. Soc. 2005, 127, 12224–12225; h) Y.
Xiong, X. Huang, S.-H. Gou, J.-L. Huang, Y.-H. Wen, X.-M.
Feng, Adv. Synth. Catal. 2006, 348, 538–544.
2
fied by FC with silica gel (petroleum/Et O 10:1) to afford title com-
pound 5k as a colorless oil in 92% yield and with 86% ee as deter-
mined by GC analysis with a Varian Chirasil DEXCB column
[
[
4] S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2001, 123, 6195–6196.
5] a) Y. N. Belokon’, A. J. Blacker, L. A. Clutterbuck, M. North,
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P. Carta, L. A. Clutterbuck, M. North, Tetrahedron 2004, 60,
(0.25 mmϫ25 m) [column temp. 130 °C; inject temp. 250 °C; detec-
tion temp. 250 °C; inlet pressure 8 psi; t (minor) = 12.5 min, t
r
r
2
5
1
(
(
major) = 13.0 min]. [α]
300 MHz, CDCl ): δ = 0.87–0.90 (m, 3 H, CH
CH , OCH CH ), 1.46–1.54 (m, 2 H, CH
m, 2 H, CH CH), 4.23–4.32 (m, 2 H, OCH ), 5.19 (t, J = 6.7 Hz,
H, O-CH-CN) ppm.
D
= –55.65 (c 0.115, CHCl
), 1.31–1.32 (m, 7
CH ), 1.89–1.94
3
). H NMR
3
3
10433–10447.
H, CH
(
1
2
2
2
3
2
3
[6]
S. Lundgren, E. Wingstrand, M. Penhoat, C. Moberg, J. Am.
Chem. Soc. 2005, 127, 11592–11593.
2
2
[7] a) J. Tian, N. Yamagiwa, S. Matsunaga, M. Shibasaki, Angew.
Chem. Int. Ed. 2002, 41, 3636–3638; b) J. Tian, N. Yamagiwa,
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J. Org. Chem. 2006, 1949–1958.
S)-2-Ethoxycarbonyloxy-3-methylbutyronitrile (5l):[5a] This com-
pound was purified by FC with silica gel (petroleum/Et O 10:1) to
afford title compound 5l as a colorless oil in 59% yield and with
6% ee as determined by GC analysis with a Varian Chira-
sil DEXCB column (0.25 mmϫ25 m), [column temp. 130 °C; inject
temp. 200 °C; detection temp. 250 °C; inlet pressure 8 psi; t (minor)
= –82.76 (c 0.058, CHCl );
) for the (S) enantiomer with
(
2
7
[
r
(major) = 28.4 min]. [α]2
= –59.8 (c 1.2, CHCl
5
=
24.9 min, t
r
D
3
[
5a]
20
{
ref.
[α]
D
3
9% ee}. 1H NMR (400 MHz, CDCl
): δ = 0.86–1.15 (m, 6 H,
, CH ), 1.34–1.37 (m, 3 H, OCH CH ), 2.18–2.24 (m, 1 H,
), 5.04 (t, J = 5.6 Hz, 1 H, O-CH-
7
CH
3
3
3
2
3
[
9] a) Q.-H. Li, L. Chang, X.-H. Liu, X.-M. Feng, Synlett 2006,
CH), 4.25–4.31 (m, 2 H, OCH
2
1
675–1678; b) S.-H. Gou, X.-H. Chen, Y. Xiong, X.-M. Feng,
CN) ppm.
J. Org. Chem. 2006, 71, 5732–5736.
Supporting Information (see footnote on the first page of this arti-
cle): Details of the HPLC and GC analyses.
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Synlett 2003, 558–560; b) B. He, F.-X. Chen, Y. Li, X.-M. Feng,
G.-L. Zhang, Eur. J. Org. Chem. 2004, 4657–4666; c) F.-X.
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Y.-Z. Jiang, Chem. Eur. J. 2004, 10, 4790–4797; d) B. He, F.-X.
Chen, Y. Li, X.-M. Feng, G.-L. Zhang, Tetrahedron Lett. 2004,
Acknowledgments
4
5, 5465–5467; e) F.-X. Chen, B. Qin, X.-M. Feng, G.-L.
The authors thank the National Natural Science Foundation of
China(20390055, 20225206, 20502019) and the Ministry of Educa-
tion, P. R. China (104209, 20030610021 for financial support.
Zhang, Y.-Z. Jiang, Tetrahedron 2004, 60, 10449–10460.
[
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Received: September 13, 2006
[
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Published Online: November 27, 2006
644
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 639–644