Asymmetric cyano-ethoxycarbonylation of aldehydes catalyzed by self-assembled titanium catalyst

Article abstract of DOI:10.1016/j.tet.2007.05.060

A new self-assembled catalyst based on titanium complex has been developed for the effective enantioselective cyano-ethoxycarbonylation of aldehydes. The self-assembled catalyst was readily prepared from (R)-3,3′-bis((methyl((S)-1-phenylethyl)amino)methyl

Full text of DOI:10.1016/j.tet.2007.05.060

Tetrahedron 63 (2007) 7935–7941
Asymmetric cyano-ethoxycarbonylation of aldehydes
catalyzed by self-assembled titanium catalyst
a
Shaohua Gou, Xiaohua Liu, Xin Zhou and Xiaoming Feng
a
a
a,b,*
a
Key Laboratory of Green Chemistry and Technology (Sichuan University), Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, China
b
State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
Received 26 March 2007; revised 16 May 2007; accepted 17 May 2007
Available online 21 May 2007
Abstract—A new self-assembled catalyst based on titanium complex has been developed for the effective enantioselective cyano-ethoxycar-
0
0
bonylation of aldehydes. The self-assembled catalyst was readily prepared from (R)-3,3 -bis((methyl((S)-1-phenylethyl)amino)methyl)-1,1 -
0
binaphthyl-2,2 -diol (1h), N-((1S,2R)-2-hydroxy-1,2-diphenylethyl)acetamide (2b), and tetraisopropyl titanate (Ti(OiPr)
4
). A variety of
aromatic aldehydes, aliphatic aldehydes, and a,b-unsaturated aldehydes were found to be suitable substrates in the presence of the self-assembled
titanium catalyst (5 mol % 1h, 5 mol % 2b, and 5 mol % Ti(OiPr)
lated yields (up to 95%) and moderate to good enantioselectivities (up to 92% ee) under mild conditions (at ꢀ15 C). A possible catalytic cycle
4
). The desired cyanohydrin ethyl carbonates were afforded with high iso-
ꢁ
based on the experimental observation was proposed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
in cyano-ethoxycarbonylation of aldehydes, with good yields
and enantioselectivities.
7
The asymmetric cyanation of carbonyl compounds is a useful
synthetic method to prepare optically active cyanohydrins,
which are versatile building blocks for the synthesis of natu-
ral products and biologically active compounds. However,
in contrast to the cyanation of aldehydes and ketones employ-
ing trimethylsilyl cyanide (TMSCN) or hydrogen cyanide
In a different reaction, Mikami and Chan et al. reported self-
assembly of two different chiral ligand components into
a highly enantioselective titanium catalyst for carbonyl-ene
1
8
reaction and addition of alkynylzinc to aldehydes. Inspired
by this method, we continued to search for a new highly
efficient catalyst system using BINOL derivatives in combi-
nation with amino alcohol to achieve structural diversity.
Thus, a set of BINOL derivatives 1a–i and some chiral amino
alcohol ligands 2a–i were investigated (synthesis for ligands:
see Section 4 for details). Herein, we wish to report these
ligands that engender a more effective catalyst by self-assem-
bly for the cyano-ethoxycarbonylation of aldehydes.
(
HCN) as the cyanide source in which considerable progress
2
,3
has been made, the one-pot catalytic asymmetric cyana-
tion-O-protection reaction is still less developed. Recently,
several successful catalyst systems employing cyanoformate
(ROCOCN), acetyl cyanide or diethyl cyanophosphonate
have been studied.
4–7
Among these precedents, Deng
reported a dimeric cinchona alkaloid derivative for the one-
4
pot enantioselective cyanation of aliphatic ketones. Shiba-
saki and Sansano et al. reported heterobimetallic complex
{
complex for the addition of cyanoformate (ROCOCN) to
YLi [tris(binaphthoxide)]} and BINOLAM–Al or –Ti(IV)
2. Results and discussion
2.1. Catalyst precursor screening
3
5
aldehydes. Belokon’, North, and Moberg developed a bime-
tallic titanium complex, and obtained the desired O-alkoxy-
carbonyl cyanohydrins with excellent results. Very recently,
6
In the preliminary studies, 10 mol % complexes of 1-
Ti(OiPr) were evaluated for the addition of ethyl cyanofor-
our group investigated multicomponent titanium complex,
N,N-dioxide titanium complex, mononuclear salen titanium,
and heterobimetallic aluminum lithium bis(binaphthoxide)
4
ꢁ
entries 1–10). It was found that the complex of 1h-Ti(OiPr)
mate to benzaldehyde in dry CH Cl at ꢀ15 C (Table 1,
2
2
4
gave the best result (55% ee and 96% yield after 24 h, Table
, entry 8). The reaction with complex of 1g-Ti(OiPr) was
slower, although it showed comparable enantioselectivity
with 1h-Ti(OiPr) (Table 1, entry 7). In contrast, the titanium
4
complexes of binol (1a), phosphorus-containing 1b or
1
4
Keywords: Asymmetric catalysis; Binol; Cyanation; Self-assembly;
Titanium.
*
Corresponding author. Fax: +86 28 85418249; e-mail: xmfeng@scu.
edu.cn
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.060

7
936
S. Gou et al. / Tetrahedron 63 (2007) 7935–7941
Table 2. Chiral activator screening
Table 1. Catalyst precursor screening
O
O
O
O
O
O
Ti(IV) catalyst
CH2Cl2, -15 °C
O
OEt
CN
Ti(IV) catalyst
CH2Cl2, -15 °C
O
OEt
CN
+
+
Ph
H
NC
OEt
Ph
H
NC
OEt
Ph
Ph
3a
4
5a
3a
4
5a
a
b
c
ee (%)
a
b
c
Entry
Ti(OiPr)
mol %)
4
1a–i (mol %)
Time (h)
Yield
(%)
Entry
1h or 1a
(5 mol %)
2a–i
(5 mol %)
Time (h)
Yield
(%)
ee
(%)
(
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
5
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
1g (10)
1h (10)
1i (10)
1h (5)
48
48
48
48
48
48
48
24
40
48
0
0
0
0
0
85
95
96
87
87
—
—
—
—
1
2
3
4
5
6
7
8
9
10
1h
1h
1h
1a
1h
1h
1h
1h
1h
1h
1h
None
2a
2b
2b
2c
2d
2e
2f
48
20
24
48
24
24
30
15
20
15
24
87
99
88
0
97
99
99
99
90
99
90
87(S)
17(S)
91(S)
—
60(S)
65(S)
63(S)
7(S)
—
14(S)
53(S)
55(S)
27(S)
87(S)
2g
2h
2i
15(S)
26(S)
3(S)
10
1
1
a
b
c
Concentration of benzaldehyde: 0.5 M; EtOCOCN: 1.5 equiv.
Isolated yield.
Determined by HPLC on Chiral OD-H column analysis, the absolute
configuration of the major product was S compared with the reported value
of optical rotation (Ref. 5a).
a
4
Concentration of benzaldehyde: 0.5 M; Ti(OiPr) : 5 mol %, EtOCOCN:
1.5 equiv.
Isolated yield.
Determined by HPLC on Chiral OD-H column analysis, the absolute
configuration of the major product was S compared with the reported value
of optical rotation (Ref. 5a).
b
c
silicon-containing 1c, nitrogen-containing BINOL deriva-
tives 1d and 1e, did not catalyze the reaction under same re-
action conditions (Table 1, entries 1–5). Gratifyingly, when
the loading of 1h-Ti(OiPr) complex was decreased from 10
4
to 5 mol %, higher enantioselectivity was achieved, although
longer reaction time was required (87% ee after 48 h, Table
Ph
R1
Ph
R1
Ph
OH
N
R
N
R
2
2
OH
1
, entry 10) (Fig. 1).
2a-c
2d-e
1
2
1
2
2
2
2
a: R = R = CH3
2d: R =H, R = CH
3
2
.2. Chiral activator screening
1
2
1
2
b: R = H, R = CH3CO
2e: R = R = CH3
1
2
c: R = H, R = Ts
8a,b
To gain higher reactivity, some chiral activators 2a–i
were investigated fixing 5 mol % 1h-Ti(OiPr) complex as
the catalyst precursor (Table 2, entries 2 and 3, and 5–11).
To our delight, when 5 mol % chiral acetamide 2b was added
4
HO
H
N
HO
H
N
R
R
together with 5 mol % 1h-Ti(OiPr) complex, higher enan-
4
tioselectivity was obtained and the reactivity was increased
dramatically (Table 2, entry 3 vs 1), which might be attrib-
uted to the hydrogen bonding between the N–H moiety of
acetamide with the oxygen atom of ethyl cyanoformate.
Other combinations of chiral ligand with 1h-Ti(OiPr)4
complex gave lower ee’s, although higher reactivity was
observed (Table 2, entries 2, 5–11). The combination of tita-
nium binol complex with acetamide 2b was also tested, but
no product was detected (Table 2, entry 4). Therefore, 2b
was selected as the best chiral activator in the self-assembled
catalytic system (Fig. 2).
N
N
2
f-g
2h-i
2
f: R = H
g: R = OMe
2h:R = H
2i: R = OMe
2
Figure 2. Structures of the chiral activators evaluated in this study.
2.3. Catalyst system optimization
In the further studies, we found that the optimum ratio of chi-
ral ligands (1h and 2b) to Ti(OiPr) was 5/5/5 (Table 3, entry
4
1
tivity and reactivity (Table 3, entries 3 and 4, and 6–8).
vs entries 2–8). Other ratios gave moderate enantioselec-
R2
N
R3(S)Ph
N
R1
Bn
Changing the ratio of chiral ligands 1h, 2b, and Ti(OiPr)4
to 2.5/5/2.5 greatly decreased the reactivity (Table 3, entry
OH
OH
(
R)
OH
OH
OH
OH
(
R)
(R)
5). We also found that the desired product could not be ob-
tained when titanium chiral acetamide 2b was used as the
catalyst (Table 3, entry 2).
R1
N
R
N
(S)
R
Bn
2
3
Ph
(
R)-1a-e
(
R)-1f-i
1f: R2 = H
1g: R2 = CH3
1h-i
Reaction solvent and other metal reagents were also exam-
ined (Table 4, entries 1–10). Among the investigated sol-
vents, ether solvents (THF or Et O) were found to afford
the product in very low yields (Table 4, entries 2 and 3).
Toluene gave moderate enantioselectivity and reactivity
1
1d: R1
N
O
1
a: R = H
=
=
1h: R3 = CH3
1i: R3 = H
1
1
b: R = P(O)Ph2
c: R1 = SiPh3 1e: R1
2
1
N
Figure 1. Structures of the ligands evaluated in this study.

S. Gou et al. / Tetrahedron 63 (2007) 7935–7941
7937
ꢁ
Table 3. Optimized ratios of chiral ligands 1h, 2b, and Ti(OiPr)
4
reaction temperature to 0 C had little effect on the reactiv-
ity, but the enantioselectivity suffered (Table 5, entry 5). No
product was observed after 48 h when the reaction tempera-
a
b
c
Entry
Ti(OiPr)
(mol %)
4
1h 2b
(mol %) (mol %)
Time (h) Yield
(%)
ee
(%)
ꢁ
ture was lowered to ꢀ45 C (Table 5, entry 6).
1
2
5
5
1h (5)
None
2b (5)
2b (5)
24
48
88
0
91(S)
—
d
3
4
5
6
7
8
2.5
5
2.5
5
10
2.5
1h (2.5) 2b (2.5)
1h (5) 2b (10)
1h (2.5) 2b (5)
72
48
150
48
120
20
77
76
Trace
83
70
81(S)
89(S)
—
85(S)
79(S)
77(S)
2.4. Substrate generality
To probe the generality of the self-assembled titanium cata-
lyst in the one-pot catalytic asymmetric cyano-ethoxycarbo-
nylation of aldehydes, a variety of aldehydes were tested
under the optimal conditions (5 mol % 1h, 5 mol % 2b, and
1h (5)
1h (5)
1h (5)
2b (2.5)
2b (5)
2b (5)
91
a
Concentration of benzaldehyde: 0.5 M in CH
Isolated yield.
Determined by HPLC on Chiral OD-H column analysis, the absolute
configuration of the major product was S compared with the reported value
of optical rotation (Ref. 5a).
2 2
Cl ; EtOCOCN: 1.5 equiv.
5
mol % Ti(OiPr) , concentration of aldehydes: 0.5 M in
4
b
c
ꢁ
CH Cl , ꢀ15 C), and the results are summarized in Table 6.
2
2
Moderate to good ee’s were obtained in each case. 4-Methyl
substituted benzaldehyde gave lower ee (Table 6, entry 2 vs
d
No product was obtained when employing 5 mol % of 2c-Ti(IV) complex
after 48 h, for the outcome of titanium 2a and titanium 2d–i, see Ref. 7b.
1), while methoxy or phenoxy substituted benzaldehyde was
highly reactive and gave good ee (Table 6, entries 3–6). The
product of 3-phenoxybenzaldehyde 5f has been employed as
a key intermediate in the synthesis of the insecticide fenval-
Table 4. The effect of reaction solvent and Lewis acid
a
b
Yield (%)
c
ee (%)
Entry
Solvent
CH Cl
Metal
Time (h)
1e
erate Aa. 4-Fluorobenzaldehyde gave 92% ee after 48 h
1
2
3
4
5
6
7
8
9
2
2
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Ti(OiPr)
Al(OiPr)
Zr(OiPr)
Sm(OiPr)
Yb(TfO)
Cu(TfO)
4
4
4
4
24
60
96
60
48
48
48
48
48
88
10
Trace
45
12
10
0
91(S)
78(S)
—
82(S)
54(S)
85(S)
—
(Table 6, entry 8). 2-Naphthaldehyde gave lower ee value
(Table 6, entry 7), which might be attributed to the steric hin-
drance. The trans-cinnamaldehyde gave 91% ee after 48 h
THF
Et
PhCH
2
O
3
(
Table 6, entry 9). It was noteworthy that the enantioselectiv-
CH
CH
CH
CH
CH
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
3
7
b
ity of hexanal was greatly increased from 45 to 78% ee
employing this self-assembled catalyst (Table 6, entry 10).
4
3
2
0
0
—
—
When the temperature was lowered to ꢀ45 C, better enan-
ꢁ
2
tioselectivity of hexanal was afforded, but longer reaction
time was required (Table 6, entry 11). Cyclohexanecarbalde-
hyde and propionaldehyde gave 75% ee and 76% ee after
a
Concentration of benzaldehyde: 0.5 M; 5 mol % 1h+5 mol %
2b+5 mol % corresponding metal reagent; EtOCOCN: 1.5 equiv;
ꢁ
ꢀ15 C.
Isolated yield.
Determined by HPLC on Chiral OD-H column analysis.
b
c
Table 6. Asymmetric cyano-ethoxycarbonylation of aldehydes catalyzed by
self-assembled titanium complex
(
(
Table 4, entry 4). The best result was obtained with CH Cl
2 2
Table 4, entry 1). When other metal reagents were employed
O
O
O
O
*
OEt
L*, 5 mol% Ti(OiPr)4
CH2Cl2, -15 °C
in the reaction, such as Al(OiPr) , Zr(OiPr) , Sm(OiPr) ,
3
Yb(TfO) , and Cu(TfO) , dissatisfactory results were ob-
2
tained (Table 4, entries 5–9).
4
3
+
R
H
NC
OEt
Ph
CN
5a-n
2
3a-n
4
L* = 5 mol % 1h + 5 mol % 2b
Lowering the concentration of benzaldehyde from 0.5 to
a
Entry Aldehydes
b
c
Time (h) Yield (%) ee (%)
0
5
.25 resulted in lower yield and enantioselectivity (Table
, entry 2). In contrast, the higher yields were obtained
1
2
3
4
5
6
7
8
9
1
Benzaldehyde (3a)
4-Methylbenzaldehyde (3b)
2-Methoxybenzaldehyde (3c) 48
3-Methoxybenzaldehyde (3d) 48
4-Methoxybenzaldehyde (3e) 60
3-Phenoxybenzaldehyde (3f) 24
2-Naphthaldehyde (3g)
4-Fluorobenzaldehyde (3h)
(E)-Cinnamaldehyde (3i)
Hexanal (3j)
Hexanal (3j)
Cyclohexanecarbaldehyde
24
96
88
76
82
84
81
95
91
81
83
88
64
86
91(S)
83(S)
92(S)
90(S)
91(S)
89
81
92
91(S)
78(S)
85(S)
75(S)
when the concentration of benzaldehyde was increased
from 0.5 to 0.75 or 1.0, but the enantioselectivity was
slightly decreased (Table 5, entries 3 and 4). Increasing the
24
48
48
24
96
24
Table 5. The effect of concentration of benzaldehyde and reaction temper-
ature
d
d
d
0e
a
Entry Solvent Concentration Temp Time (h) Yield
b
c
11
12
ee
(%)
ꢁ
(M)
( C)
(%)
(
3k)
d
d
d
1
2
3
4
5
6
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
0.5
ꢀ15
ꢀ15
ꢀ15
ꢀ15
0
24
48
20
18
18
48
88
83
91
95
93
91(S)
84(S)
88(S)
85(S)
78(S)
—
13
14
15
Propionaldehyde (3l)
Isobutyraldehyde (3m)
Pivalaldehyde (3n)
24
24
24
84
81
83
76(S)
62(S)
74(S)
0.25
0.75
1.0
0.5
0.5
a
Concentration of aldehyde: 0.5 M; EtOCOCN: 1.5 equiv.
Isolated yield.
Determined by HPLC on Chiral OD-H column analysis, the absolute
configuration of the major product was S compared with the reported value
of optical rotation (Refs. 5a and 6b).
Determined by GC analysis.
The reaction performed at ꢀ45 C.
b
c
ꢀ45
Trace
a
Conditions: 5 mol % 1h+5 mol % 2b+5 mol % Ti(IV); EtOCOCN:
.5 equiv.
Isolated yield.
1
b
c
d
e
ꢁ
Determined by HPLC on Chiral OD-H column analysis.

7938
S. Gou et al. / Tetrahedron 63 (2007) 7935–7941
Table 7. Asymmetric cyano-ethoxycarbonylation of aldehydes catalyzed by
1h-Ti(IV) complex
entries 1–13). These results revealed that the self-assembled
titanium catalyst was effective for the addition of ethyl
cyanoformate to aldehydes.
a
b
c
Entry
Aldehydes
Time (h) Yield
%)
ee
(%)
(
2
.5. Catalytic cycle considerations
1
2
3
4
5
6
7
8
9
4-Methylbenzaldehyde (3b)
2-Methoxybenzaldehyde (3c)
3-Methoxybenzaldehyde (3d)
168
96
96
68
71
70
65
77
78
73
70
76
79
75(S)
87(S)
83(S)
84(S)
81
76
83
84(S)
67(S)
70(S)
According to the previous work in the field of cyano-ethoxy-
carbonylation of aldehyde and ketone, the self-assembled
4-Methoxybenzaldehyde (3e) 120
4–6
3-Phenoxybenzaldehyde (3f)
2-Naphthaldehyde (3g)
4-Fluorobenzaldehyde (3h)
(E)-Cinnamaldehyde (3i)
Hexanal (3j)
48
48
90
96
48
48
titanium catalyst might play a multifunctional role in this
reaction (see Fig. 3). The metal moiety of complex I might
act as Lewis acid to activate the aldehyde and engender
the species II. On the other hand, the tertiary amine moiety
of complex I might act as Lewis base to activate the ethyl
d
d
1
0
Cyclohexanecarbaldehyde
(
3k)
4
,5c,d
d
d
d
cyanoformate (EtOCOCN),
and the hydrogen of acet-
1
1
1
1
2
3
Propionaldehyde (3l)
Isobutyraldehyde (3m)
Pivalaldehyde (3n)
48
48
48
74
70
76
61(S)
58(S)
69(S)
amide (2b) might coordinate weakly to the oxygen atom of
ethyl cyanoformate, simultaneously. Then, the activated ethyl
cyanoformate transfer the cyanide to the activated aldehyde
and afford the corresponding product. At the same time,
a catalytic cycle was completed.
a
Concentration of aldehyde: 0.5 M; 5 mol % 1h-Ti(IV), EtOCOCN:
ꢁ
1
.5 equiv, ꢀ15 C.
b
c
Isolated yield.
Determined by HPLC on Chiral OD-H column, the absolute configuration
of the major product was S compared with the reported value of optical
rotation (Refs. 5a and 6b).
d
3. Conclusions
Determined by GC analysis.
In conclusion, a new enantioselective catalyst for the synthe-
sis of optically active cyanohydrins via ethyl cyanoformate
addition to aldehydes has been developed. This study
showed that a combination of two kinds of chiral ligands
such as nitrogen-containing BINOL derivatives (1h) and
2
4 h, respectively (Table 6, entries 12 and 13). Isobutyralde-
hyde and pivalaldehyde gave the corresponding products
with 62% ee and 74% ee after 24 h (Table 6, entries 14
and 15).
acetamide (2b) with Ti(OiPr) generated an effective enan-
4
We also investigated the corresponding aldehydes with 1h-
Ti(OiPr) complex as catalyst under the same conditions
tioselective catalyst. Compared with the multicomponent
titanium catalyst, which we previously developed, the most
remarkable features of this catalyst system include: (a) low
amount of catalyst loading, (b) more effective for aliphatic
aldehydes, (c) the mild reaction conditions, and (d) provid-
ing a different enantiomer of the cyanohydrin ethyl
4
(
see Table 7, entries 1–10). It was found that the reaction
time was longer compared with the self-assembled system
48–168 h). And the enantioselectivities were lower than
(
the self-assembled catalyst system (58–87% ee; Table 7,
Ph
N
N
OPri
O
O
Ti
AcHN
O
Ph
Ph
O
Ph
O
I
O
OEt
R
H
R
CN
3
5
Ph
Ph
N
N
OPri Ac
OPri Ac
O
O
O
O
Ti
N
Ti
N
H
H
O
Ph
O
Ph
N+
N
Ph
Ph
O
Ph
Ph
O
EtO
O
_
O
II
R
H
R
H
III
CN
CN
OEt
4
Figure 3. The proposed catalytic cycle.

S. Gou et al. / Tetrahedron 63 (2007) 7935–7941
7939
0
4.2.1.1.1. (R)-3,3 -Bis((benzyl(methyl)amino)methyl)-
1,1 -binaphthyl-2,2 -diol (1g). Yield 87%; lightly yellow
solid, mp 128–130 C, [a]D +50.52 (c 2.0 in CHCl ). H
3
carbonates. The applications of the self-assembled titanium
catalyst system in other asymmetric catalytic reactions are
currently underway.
0
0
ꢁ
23
1
NMR (CDCl ), d¼2.28 (s, 6H), 3.60 (d, J¼12.9 Hz, 2H),
3
3
.72 (d, J¼13.1 Hz, 2H), 3.94 (d, J¼13.7 Hz, 2H), 4.12–
4
. Experimental section
4.22 (m, 2H), 5.06 (s, 2H), 7.17–7.29 (m, 16H), 7.96 (s,
1
3
2
H), 7.80 (d, J¼8.0 Hz, 2H) ppm. C NMR (CDCl3),
41.02, 61.30, 61.75, 116.72, 122.93, 124.66, 124.85,
26.03, 127.52, 127.65, 127.89, 128.28, 128.43, 129.61,
4
.1. General methods
1
1
H NMR spectra were recorded with 300 MHz spectrometer.
Chemical shifts are reported in parts per million relative to
tetramethylsilane with the solvent resonance as the internal
133.96, 136.62, 153.62. HRMS (ESI, CH OH) calcd for
3
C H N O (M) : requires 552.2777, found: 552.2709.
38 36 2 2
+
0
4.2.1.1.2. (R)-3,3 -Bis((methyl((S)-1-phenylethyl)ami-
standard (CDCl , d¼7.26 ppm). Data are reported as fol-
3
0 0
no)methyl)-1,1 -binaphthyl-2,2 -diol (1h). Yield 89%;
lightly yellow solid, mp 244–246 C, [a] +17.86 (c 2.0
lows: chemical shift, multiplicity (s-singlet, d-doublet, t-triplet,
and m-multiplet), coupling constants (Hz), and integration.
ꢁ
23
D
1
3
1
C NMR spectroscopic data were collected with a
5 MHz spectrometer with complete proton decoupling.
in CHCl ). H NMR (CDCl ), d¼1.50 (d, J¼6.9 Hz, 6H),
3
3
7
2.24 (s, 6H), 3.83–3.91 (m, 4H), 4.13 (d, J¼13.9 Hz, 2H),
Chemical shifts are reported in parts per million relative to
tetramethylsilane with the solvent resonance as internal
5.23 (s, 2H), 7.18–7.34 (m, 16H), 7.62 (s, 2H), 7.77 (d,
1
3
J¼7.9 Hz, 2H) ppm. C NMR (CDCl ), 17.40, 29.69,
3
standard (CDCl , d¼77.0 ppm). Enantiomeric excesses were
37.02, 58.76, 62.22, 116.51, 122.82, 124.75, 125.90,
127.56, 127.73, 128.26, 128.40, 129.61, 133.79, 139.94,
153.93. HRMS (ESI, CH OH) calcd for C H N O
40 40 2 2
3
determined by chiral HPLC analysis on a Daicel Chiralcel
OD-H column or chiral GC analysis on a Varian Chirasil
DEX CB instrument in comparison with authentic race-
3
+
(M) : requires 580.3156, found: 580.3090.
T
D
mates. Optical rotations were recorded as follows: [a]
(c, g/100 mL in solvent). HRMS was recorded with ESI
source (in CH OH).
4.2.1.2. Typical procedure for optically active cyano-
hydrin ethyl carbonates. Ti(OiPr) (1.0 M in toluene,
3
4
12.5 mL, 0.0125 mmol) was added to a solution of 1h
(7.25 mg, 0.0125 mmol) and 2b (3.18 mg, 0.0125 mmol) in
4
.2. Materials
ꢁ
N . Followed by the addition of the corresponding aldehyde
CH Cl , and the mixture was stirred at 30 C for 1.0 h under
2
2
All liquid aldehydes were used after distilled; EtOCOCN
was used directly without further purification. Solvents
were purified by the usual methods. Binol and ligands 2d–i
2
ꢁ
(0.25 mmol, Table 6, entries 1–15) and EtOCOCN at ꢀ15 C
after 30 min, the contents were stirred for the indicated time
in tables, and the residue was purified by silica gel column
chromatography (petroleum ether/diethyl ether, 10/1, v/v)
to afford the corresponding cyanohydrin carbonates.
9
3e
10
were commercially available. Ligands 1b–c, 1d, 1e,
(
1
1
12
1f and 1i), and 2a–c were synthesized according to the
literature procedure. Other reagents were commercially
available (Scheme 1).
4
.2.1.2.1. 2-Ethoxycarbonyl (S)-2-hydroxy-2-phenyl-ace-
2
3
4
.2.1. Synthesis of ligands 1f–h.
.2.1.1. Typical procedure for the preparation of 1g
and 1h. To a solution of 25 mmol formic acid (HCOOH)
tonitrile (5a). Yield 88%; colorless oil, [a]D ꢀ17.8 (c 2.0 in
4
CHCl ) (91% ee). HPLC (OD-H column), 2-propanol/hex-
3
ane 1/99, flow 1.0 mL/min, detection at 254 nm. t (minor)¼
R
1
1
ꢁ
5a
21.7
D
was slowly added 5.0 mmol of 2 (1f or 1i) at 0 C. The re-
action mixture was allowed to warm to room temperature
and stirred for 1.0 h. Then the solution was refluxed for
8.9 min and t (major)¼10.6 min. {Lit. [a]
+16.2 (c 2.8
in CHCl ) for R enantiomer in 94% ee}. H NMR (300 MHz,
R
1
3
CDCl ), d¼1.34 (t, J¼7.1 Hz, 3H), 4.26–4.32 (m, 2H), 6.27
3
1
0 h under N atmosphere after 5.0 mmol of HCHO (37%
2
(s, 1H), 7.45–7.49 (m, 3H), 7.53–7.56 (m, 2H) ppm.
aqueous) was added. The mixture was cooled to room tem-
perature, and adjusted to pH 9–10 with K CO . The resulting
4.2.1.2.2. 2-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methyl-
phenyl)-acetonitrile (5b). Yield 76%; colorless oil, [a]D
2
3
2
3
mixture was extracted by CH Cl (3ꢂ20 mL) and the com-
2
2
bined organic phases were dried over MgSO . After removal
4
ꢀ4.5 (c 2.0 in CHCl ) (83% ee). HPLC (OD-H column),
3
of the solvent, the residue was purified by silica gel column
chromatography with petroleum ether/ethyl acetate (3/1, v/v)
as an eluent to give BINOL derivatives 1g and 1h.
2-propanol/hexane 1/99, flow 1.0 mL/min, detection at
254 nm. t (minor)¼8.26 min and t (major)¼9.24 min.
R
R
6
b
16
{Lit. [a]D ꢀ5.1(c 2.0 in CHCl ) for S enantiomer in
3
R
R
R
CHO
N
H
N
OH
OH
1
) NH2R
2) NaBH4
OH
OH
HCOOH, HCHO
Reflux, 10 h
OH
OH
C2H5OH
Reflux
C2H5OH
Reflux
H
N
N
CHO
R
1
2 (1f or 1i)
1g: R = Bn
Ph
1h: R =
Scheme 1. The route for preparation of 1f–i.

7940
S. Gou et al. / Tetrahedron 63 (2007) 7935–7941
1
9
(
2
4% ee}. H NMR (CDCl ), d¼1.33 (t, J¼7.1 Hz, 3H), 2.39
in CHCl ) (91% ee). HPLC (OD-H column), 2-propanol/
3
hexane 10/90, flow 1.0 mL/min, detection at 254 nm. t (ma-
R
3
s, 3H), 4.22–4.33 (m, 2H), 6.22 (s, 1H), 7.25 (d, J¼7.9 Hz,
5
a
20
D
H), 7.43 (d, J¼8.1 Hz, 2H) ppm.
jor)¼11.93 min and t (minor)¼12.15 min {Lit. [a]
R
1
ꢀ
17.2 (c 0.9 in CHCl ) for R enantiomer in 88% ee}. H
3
4
.2.1.2.3. 2-Ethoxycarbonyl (S)-2-hydroxy-2-(2-methoxyl-
phenyl)-acetonitrile (5c). Yield 82%; colorless oil, [a]D
51.7 (c 2.0 in CHCl ) (92% ee). HPLC (OD-H column),
NMR (CDCl ), d¼1.36 (t, J¼7.1 Hz, 3H), 4.27–4.34 (m,
3
2
3
2H), 5.89 (d, J¼6.8 Hz, 1H), 6.26 (dd, J¼15.8, 6.8 Hz,
1H), 7.02 (d, J¼15.8 Hz, 1H), 7.34–7.45 (m, 5H) ppm.
+
3
2
2
{
9
3
-propanol/hexane 10/90, flow 1.0 mL/min, detection at
54 nm. t (minor)¼6.3 min and t (major)¼8.8 min.
4.2.1.2.10. (S)-2-Ethoxycarboxyheptanenitrile (5j). Yield
88%; colorless oil, [a]D ꢀ53.6 (c 2.0 in CHCl ) (78% ee).
R
20
R
6
b
23
Lit. [a] +57.0 (c 1.4 in CHCl ) for S enantiomer in
D
3
3
1
8% ee}. H NMR (CDCl ), d¼1.30 (t, J¼7.1 Hz, 3H),
GC [Varian Chirasil DEXCB (0.25 mmꢂ25 m), detection
3
ꢁ
ꢁ
.87 (s, 3H), 4.24–4.32 (m, 2H), 6.58 (s, 1H), 6.93 (dd,
temp 110 C; initial column temp 230 C; injection temp
ꢁ
J¼8.3, 1.6 Hz, 1H), 7.05 (dt, J¼8.2, 1.6 Hz, 1H), 7.42 (dt,
250 C; t (minor)¼30.4 min and t (major)¼32.2 min.
R
R
5
b
23
D
J¼8.2, 1.6 Hz, 1H), 7.58 (dd, J¼8.2, 1.6 Hz, 1H) ppm.
{Lit. [a] +61.7 (c 2.21 in CHCl ) for R enantiomer in
3
1
9
1.32 (m, 7H), 1.46–1.54 (m, 2H), 1.89–1.94 (m, 2H),
4% ee}. H NMR (CDCl ), d¼0.87–0.90 (m, 3H), 1.31–
3
4
.2.1.2.4. 2-Ethoxycarbonyl (S)-2-hydroxy-2-(3-methoxyl-
phenyl)-acetonitrile (5d). Yield 84%; colorless oil, [a]D
10.4 (c 2.0 in CHCl ) (90% ee). HPLC (OD-H column),
2
3
4.23–4.32 (m, 2H), 5.19 (t, J¼6.7 Hz, 1H) ppm.
ꢀ
3
2
2
-propanol/hexane 1/99, flow 1.0 mL/min, detection at
54 nm. t (minor)¼11.92 min and t (major)¼15.77 min.
4.2.1.2.11. 2-Ethoxycarbonyl (S)-2-hydroxy-2-cyclohexyl-
ethanonitrile (5k). Yield 86%; colorless oil, [a]D ꢀ49.7
2
3
R
20
R
6
b
Lit. [a] ꢀ11.3 (c 1.2 in CHCl ) for S enantiomer in
(c 2.0 in CHCl ) (75% ee). GC [Varian Chirasil DEXCB
3
D
3
1
ꢁ
9
3
(
9% ee. H NMR (CDCl ), d¼1.33 (t, J¼7.1 Hz, 3H),
(0.25 mmꢂ25 m), detection temp 130 C; initial column
3
ꢁ
ꢁ
.81 (s, 3H), 4.23–4.31 (m, 2H), 6.22 (s, 1H), 6.96–7.11
temp 250 C; injection temp 250 C; t (minor)¼29.1 min
R
5
b
27.4
D
1
m, 3H), 7.31–7.34 (t, J¼7.9 Hz, 1H) ppm.
.2.1.2.5. 2-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methoxyl-
phenyl)-acetonitrile (5e). Yield 81%; colorless oil, [a]D
2.2 (c 2.0 in CHCl ) (91% ee). HPLC (OD-H column),
and t (major)¼29.7 min. {Lit. [a]
+53.4 (c 2.21,
CHCl ) for R enantiomer in 96% ee}. H NMR (CDCl ),
R
3
3
4
d¼1.21–1.32 (m, 6H), 1.33 (t, J¼7.2 Hz, 3H), 1.73–2.05
2
3
(m, 5H), 4.21–4.33 (m, 2H), 5.14 (d, J¼5.8 Hz, 1H) ppm.
+
3
2
2
{
9
3
-propanol/hexane 1/99, flow 1.0 mL/min, detection at
54 nm. t (minor)¼13.5 min and t (major)¼16.9 min.
4.2.1.2.12. 2-Ethoxycarbonyl (S)-2-hydroxy-butanitrile
(5l). Yield 76%, [a]D ꢀ77.1 (c 2.0 in CHCl ) (76% ee).
2
5
R
R
3
6
b
20
Lit. [a] +1.8 (c 1.8 in CHCl ) for S enantiomer in
3
GC [Varian Chirasil DEXCB (0.25 mmꢂ25 m), detection
D
1
ꢁ
ꢁ
5% ee}. H NMR (CDCl ), d¼1.30 (t, J¼7.2 Hz, 3H),
temp 80 C; initial column temp 200 C; injection temp
3
ꢁ
.81 (s, 3H), 4.19–4.30 (m, 2H), 6.19 (s, 1H), 6.93 (d,
250 C; t (minor)¼20.01 min and t (major)¼24.17 min.
R
R
5
b
23
J¼8.8 Hz, 2H), 7.46 (d, J¼8.8 Hz, 2H) ppm.
{Lit. [a] +87.0 (c 1.0 in CHCl ) for R enantiomer in
D 3
1
9
2% ee}. H NMR (300 MHz, CDCl ), d¼1.12 (dd,
3
4
.2.1.2.6. 2-Ethoxycarbonyl 2-hydroxy-2-(3-phenoxy-
J¼7.2 Hz, 3H), 1.34 (dd, J¼7.1 Hz, 3H), 1.90–2.10 (m,
2H), 4.25–4.30 (m, 2H), 5.14 (dd, J¼6.7 Hz, 1H) ppm.
7
b
23
phenyl)-acetonitrile (5f). Yield 95%; colorless oil, [a]D
2.9 (c 2.0 in CHCl ) (89% ee). HPLC (OD-H column),
ꢀ
3
2
2
-propanol/hexane 10/90, flow 1.0 mL/min, detection at
54 nm. tR (major)¼7.8 min and t (minor)¼9.8 min. H
4.2.1.2.13. 2-Ethoxycarbonyl (S)-3-methylbutanenitrile
(5m). Yield 81%, [a]D ꢀ50.2 (c 2.0 in CHCl ) (62% ee).
1
25
R
3
NMR (CDCl ), d¼1.34 (t, J¼7.1 Hz, 3H), 4.24–4.35 (m,
GC [Varian Chirasil DEXCB (0.25 mmꢂ25 m), detection
3
ꢁ
ꢁ
2
7
H), 6.22 (s, 1H), 7.02–7.05 (m, 1H), 7.17–7.19 (m, 2H),
.28–7.35 (m, 3H), 7.38 (m, 3H) ppm.
temp 80 C; initial column temp 200 C; injection temp
ꢁ
250 C; t (minor)¼24.973 min and t (major)¼28.307 min.
R
R
6
b
20
D
{
Lit. [a] ꢀ59.8 (c 1.0 in CHCl ) for S enantiomer in 79%
3
1
4
.2.1.2.7. 2-Ethoxycarbonyl (S)-2-hydroxy-2-(2-naph-
ee}. H NMR (300 MHz, CDCl ), d¼1.1–1.2 (m, 6H), 1.34
3
7
b
23
thyl)-acetonitrile (5g). Yield 91%; white solid, [a]D
6.1(c 2.0 in CHCl ) (81% ee). HPLC (OD-H column),
(t, J¼7.1 Hz, 3H), 2.1–2.2 (m, 1H), 4.3–4.4 (m, 2H), 5.1 (d,
+
J¼5.8 Hz, 1H) ppm.
3
2
2
-propanol/hexane 10/90, flow 1.0 mL/min, detection at
54 nm. t (minor)¼9.6 min and t (major)¼10.3 min. H
1
0
4.2.1.2.14. 2-Ethoxycarbonyl (S)-3,3 -dimethylbutaneni-
R
R
2
5
NMR (CDCl ), d¼1.35 (t, J¼7.1 Hz, 3H), 4.25–4.37 (m,
trile (5n). Yield 83%, [a]D ꢀ49.7 (c 2.0 in CHCl ) (74%
3
3
2
8
H), 6.44 (s, 1H), 7.55–7.61 (m, 3H), 7.89–8.05 (m, 3H),
.04–8.05 (m, 1H) ppm.
ee). GC [Varian Chirasil DEXCB (0.25 mmꢂ25 m), detec-
ꢁ
ꢁ
tion temp 80 C; initial column temp 200 C; injection
ꢁ
temp 250 C; t (minor)¼30.798 min and t (major)¼
R
R
6
b
20
D
4
.2.1.2.8. 2-Ethoxycarbonyl 2-hydroxy-2-(4-fluoro-
32.798 min. {Lit. [a] ꢀ48.5 (c 1.0 in CHCl ) for S
3
7
b
23
1
phenyl)-acetonitrile (5h). Yield 81%; colorless oil, [a]D
20.1 (c 2.0 in CHCl ) (92% ee). HPLC (OD-H column), 2-
propanol/hexane 1/99, flow 1.0 mL/min, detection at 254 nm.
enantiomer in 73% ee}. H NMR (300 MHz, CDCl ),
3
ꢀ
d¼1.08 (s, 9H), 1.32 (dd, J¼7.2 Hz, 3H), 4.25 (m, 2H),
3
4.89 (s, 1H) ppm.
1
tR (minor)¼10.0 min and t (major)¼11.8 min. H NMR
R
(
(
CDCl ), d¼1.33 (t, J¼7.2 Hz, 3H), 4.24–4.33 (m, 2H), 6.24
3
s, 1H), 7.11–7.17 (m, 2H; Ar–H), 7.52–7.57 (m, 2H) ppm.
Acknowledgements
4.2.1.2.9. 2-Ethoxycarbonyl (S)-2-hydroxy-4-phenyl-but-
-enonitrile (5i). Yield 83%; colorless oil, [a]D +24.0 (c 2.0
The authors thank the National Natural Science Foundation
of China (Nos. 20390055, 20225206, and 20502019) and
2
3
3

S. Gou et al. / Tetrahedron 63 (2007) 7935–7941
7941
Sichuan University for financial support. We also thank
Sichuan University Analytical and Testing Center for
NMR Spectra Analysis.
4. Tian, S. K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195–6196.
5. (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2002, 41, 3636–3638; (b) Yamagiwa,
N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2
005, 127, 3413–3422; (c) Baeza, A.; N ꢀa jera, C.; Sansano,
J. M.; Sa ꢀa , J. M. Tetrahedron: Asymmetry 2005, 16, 2385–
389; (d) Casas, J.; Baeza, A.; Sansano, J. M.; N ꢀa jera, C.;
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