Catalytic asymmetric cyanoethoxycarbonylation of aldehydes using self-assembled titanium catalysts

Article abstract of DOI:10.1055/s-2007-991089

A new self-assembled titanium catalyst system has been developed for the asymmetric cyanoethoxycarbonylation of aldehydes which produced the desired products in moderate to excellent yields (up to 99%) with high enantioselectivities (up to 94% ee) under m

Full text of DOI:10.1055/s-2007-991089

LETTER
2875
Catalytic Asymmetric Cyanoethoxycarbonylation of Aldehydes Using
Self-Assembled Titanium Catalysts
C
yanoethoxycarbonylati
e
on of Aldeh
n
ydes with S
t
elf-Ass
a
embled Tit
o
a
nium Catalysts Wang,a Shaohua Gou,a Xiaohua Liu,a Xiaoming Feng*a,b
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, P. R. of China
b
State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, P. R. of China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
Received 18 August 2007
cyanoethoxycarbonylation of aldehydes under mild con-
ditions, and each component of the catalyst is commer-
cially available or easily prepared.
Abstract: A new self-assembled titanium catalyst system has been
developed for the asymmetric cyanoethoxycarbonylation of alde-
hydes which produced the desired products in moderate to excellent
yields (up to 99%) with high enantioselectivities (up to 94% ee) un-
der mild conditions. The catalyst was readily prepared from tetra-
isopropyl titanate [Ti(Oi-Pr)4], a Schiff base, and cinchonine.
Previously, our group investigated the multicomponent ti-
tanium complex4h and a self-assembled titanium catalyst4j
in the cyanation of aldehydes, and good yields and enan-
tioselectivities were obtained. However, these systems
have the limitations such as requirement for high catalyst
loading and long reaction time, which intrigued us to
search for a new highly efficient catalyst system for the
cyanoethoxycarbonylation of aldehydes.
Key words: asymmetric catalysis, cyanation, aldehydes, self-
assembly, titanium
The asymmetric cyanation of carbonyl compounds is a
useful method for the synthesis of chiral enantioenriched
cyanohydrins, which are versatile building blocks for
asymmetric synthesis.1 Intensive studies on the enantio-
selective cyanation of aldehydes and ketones using HCN,
K(Na)CN, TMSCN as the cyanide source have been re-
ported.2,3 Due to their volatility and high toxicity, access
to alternative cyanation reagent is desirable. Much effort
has therefore been devoted to the development of catalytic
systems for the one-pot catalytic asymmetric cyanation–
O-protection reaction.4–7 Recently, several successful cat-
alytic systems have been developed for the direct prepara-
tion of cyanohydrin esters by the reaction of carbonyl
compounds with cyanoformate ester (ROCOCN),4 acetyl
cyanide,5 diethylcyanophosphonate,6 or benzoyl cyanide.7
Among these precedents, Deng demonstrated the utility of
dimeric cinchona alkaloid derivatives catalysts in the
asymmetric cyanation of aliphatic ketones.4a On the other
hand, Shibasaki et al. disclosed a widely applicable,
R1
N
OH
N
HO
H
R3
OH
R
R2
N
2a: R = H
2b: R = OMe
1a: R1 = Me, R2 = t-Bu, R3 = t-Bu
1b: R1 = i-Pr, R2 = t-Bu, R3 = t-Bu
1c: R1 = Bn, R2 = t-Bu, R3 = t-Bu
1d: R1 = Ph, R2 = t-Bu, R3 = t-Bu
1e: R1 = H, R2 = t-Bu, R3 = t-Bu
H
N
HO
R
1f: R1 = i-Pr, R2 = H, R3 = H
1g: R1 = i-Pr, R2 = H, R3 = NO2
1h: R1 = i-Pr, R2 = H, R3 = t-Bu
1i: R1 = i-Pr, R2 = adamantanyl, R3 = t-Bu
N
2c: R = H
2d: R = OMe
Figure 1 The screened ligands
highly
enantioselective
cyanoethoxycarbonylation
reaction of aldehydes using a [YLi3{tris(binaphthoxide)}]
catalyst.4b,c,f Nájera and Saá reported the first enantio-
selective cyanophosphorylation of aldehydes using a 3,3'-
bis(diethylaminomethyl)-1,1¢-binaphthol (BINOLAM)–
AlCl complex.6a Belokon and North’s group found that
titanium(salen) bimetallic catalysts are highly efficient for
the cyanoethoxycarbonylation reaction of aldehydes.4d,e
Application of a new dual Lewis acid–Lewis base activa-
tion catalyst in the cyanation of aldehydes using cyanofor-
mate and acetyl cyanide as cyanide sources was also
demonstrated by Moberg et al.5 Herein, we wish to report
a new efficient self-assembled titanium catalyst for the
Initially, we tested the reaction of ethyl cyanoformate
with benzaldehyde in CH2Cl2 at –20 °C in the presence of
1b–Ti(IV) complex (5 mol%). No reaction was observed
after 48 hours (Table 1, entry 1). However, in the presence
of 2a–Ti(IV) complex (5 mol%), the reaction proceeded
smoothly to give the product in 19% ee (Table 1, entry 2).
Inspired by the self-assembly concept,4j,8 we expected that
bifunctional catalysts could be realized by the complexes
of tridentate Schiff base 1 with metallic reagent as Lewis
acid moieties to activate the electrophile, while amine 2
acted as Lewis base moieties to activate the nucleophile
simultaneously through self-assembly approach. There-
fore several tridentate Schiff base ligands 1a–i (Figure 1)
were prepared from salicylaldehyde derivatives and
various b-amino alcohols as described in the literature.9
With these ligands in hand, we tested the efficiency of
SYNLETT 2007, No. 18, pp 2875–2878
x
x
.x
x
.2
0
0
7
Advanced online publication: 12.10.2007
DOI: 10.1055/s-2007-991089; Art ID: W15007ST
© Georg Thieme Verlag Stuttgart · New York

2876
W. Wang et al.
LETTER
Table 2 Concentration and Temperature Effect on Asymmetric
Cyanoethoxycarbonylation of Benzaldehyde
Table 1 Asymmetric Cyanation of Benzaldehyde under Various
Conditionsa
OEt CN
O
Entrya
Benzaldehyde Temp
conc. (mol/L) (°C)
Time
(h)
Yield
(%)b
ee
5 mol% Ti(IV) catalyst
CH2Cl2, –20 °C
(%)c,d
PhCHO
+
*
O
O
Ph
NC
OEt
3a
4a
1
2
3
4
5
6
7
0.25
0.5
1.0
2.0
2.5
2.0
2.0
–20
–20
–20
–20
–20
0
8.5
6
97
99
97
99
99
99
15
76
80
85
90
87
70
94
Entry Ti(Oi-Pr)4 1a–i
2a–d
Time
Yield
ee
(mol%)
(mol%)
(mol%)
(h)
48
36
12
6
(%)b
(%)c,d
2.5
2.5
2.5
1.5
50
1
2
5
5
1b (5)
none
none
0
–
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2a (5)
2b (5)
2c (5)
2d (5)
2a (10)
2a (2.5)
2a (5)
2a (5)
79
90
99
92
93
99
99
89
99
99
99
99
99
99
99
99
99
19
3
5
1a (5)
1b (5)
1c (5)
1d (5)
1e (5)
1f (5)
47
4
5
80
–45
5
5
8.5
35
a Reactions were carried out on a 0.25 mmol scale of benzaldehyde in
CH2Cl2 with catalyst (5 mol%) [1b/2a/Ti(IV) = 1:1:1] and EtOCOCN
(1.5 equiv).
6
5
24
6
11
7
5
20
b Isolated yield.
c Determined by HPLC analysis on a Chiralcel OD-H column.
d The absolute configuration was R, determined by comparison with
the reported value of optical rotation.4b
8
5
7
33
9
5
1g (5)
1h (5)
1i (5)
7
23
10
11
12
13
14
15
16
17
18
5
9
37
1b–Ti(IV) complex, the reaction could be catalyzed in ex-
cellent yields, but the ee values were not superior to those
of 2a (Table 1, entries 12–14). These results showed that
the right combination of Lewis acid moieties and Lewis
base moieties was a key point for high reactivity and enan-
tioselectivity of the cyanoethoxycarbonylation of benz-
aldehyde. In our further studies, it was found that the
optimal ratio of chiral ligands to Ti(Oi-Pr)4 was 5:5:5, and
the catalyst loading was 5 mol% (Table 1, entry 4 vs.
entries 15–18). Other reaction conditions such as
solvents11 and metallic centers12 were also examined;
however, the enantiomeric excesses of the products were
not satisfactory.
5
9
16
5
1b (5)
1b (5)
1b (5)
1b (10)
1b (2.5)
1b (6)
1b (4)
5
15
5
5
37 (S)
11
5
5
10
2.5
5
20
6
49
57
6
77
5
7
73
a Reactions were carried out on a 0.25 mmol scale of benzaldehyde in
CH2Cl2 (0.5 mL) with EtOCOCN (1.5 equiv) at –20 °C.
b Isolated yield.
Further studies revealed that the concentration of benz-
aldehyde had an important effect on the reaction rate and
enantioselectivity. When the concentration of benz-
aldehyde was increased to 2.0 M, the enantioselectivity
increased up to 90% ee (Table 2, entry 4), further in-
creasing or decreasing the concentration led to a lower ee
value (Table 2, entries 1–3 and 5). The temperature effect
was also obvious. Reaction temperature that deviated
from –20 °C showed either poor yield or low enantio-
selectivity (Table 2, entry 4 vs. entries 6 and 7).
c Determined by HPLC analysis on a Chiralcel OD-H column.
d The absolute configuration was R, determined by comparison with
the reported value of optical rotation,4b unless otherwise specified.
self-assembled system of Schiff base 1, amine 2 and
Ti(Oi-Pr)4 in the cyanoethoxycarbonylation of benzalde-
hyde, and the results are summarized in Table 1.
We found that the combination of 1b, 2a and Ti(IV) could
promote the reaction smoothly to give product 4a in 80%
ee after six hours at –20 °C (Table 1, entry 4).10 Other
combinations could also catalyze the reaction in excellent
yields in 11–47% ee (Table 1, entries 3 and 5–11). Other
substituted salicylaldehydes gave products in decreased
enantioselectivity (Table 1, entry 4 vs. entries 10 and 11).
Study of the electronic effect of substituents on ligand 1
showed that electron-withdrawing group in the para posi-
tion to the OH group decreased the enantioselectivity
(Table 1, entry 9), while an electron-donating group such
as tert-butyl gave a slightly positive effect (Table 1, entry
10). When other cinchona alkaloids were combined with
Under the optimal conditions [1b (5 mol%), 2a (5 mol%),
and Ti(Oi-Pr)4 (5 mol%), 2.0 M aldehydes, at –20 °C in
CH2Cl2],13 a variety of aldehydes were evaluated and the
results are summarized in Table 3. It could be found that
most of the aromatic, a,b-unsaturated, and aliphatic alde-
hydes could be converted into the desired products in
moderate to high yields with up to 94% ee. Aromatic al-
dehydes with an electron-donating group gave similar ee
values compared to that obtained from benzaldehyde. On
the other hand, halogen-substituted benzaldehydes gave
lower ee value (Table 3, entries 8 and 9). a- or b-Naph-
thaldehydes gave good ee values (Table 3, entries 10 and
Synlett 2007, No. 18, 2875–2878 © Thieme Stuttgart · New York

LETTER
Cyanoethoxycarbonylation of Aldehydes with Self-Assembled Titanium Catalysts
2877
Table 3 Asymmetric Cyanoethoxycarbonylation of Aldehydes
Catalyzed by the Self-Assembled Titanium Catalyst
References and Notes
(1) For reviews on the synthesis and applications of
OEt CN
O
cyanohydrins, see: (a) Effenberger, F. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1555. (b) Gregory, R. J. H. Chem. Rev.
1999, 99, 3649. (c) Mori, A.; Inoue, S. Cyanation of
Carbonyl and Amino Groups, In Comprehensive
L*, 5 mol% Ti(Oi-Pr)4
+
RCHO
*
R
NC
OEt
O
O
CH2Cl2, –20 °C, 2.5 h
3a–n
4a–n
L* = 5 mol% 1b + 5 mol% 2a
Asymmetric Synthesis; Jacobsen, E. N.; Pfaltz, A.;
Entrya Aldehydes
Yield (%)b ee (%)c,d
Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999,
983. (d) Ojima, I. In Catalytic Asymmetric Synthesis; John
Wiley & Sons: Chichester, 2000, 235. (e) Smith, M. B.;
March, J. In March’s Advanced Organic Chemistry, 5th ed.;
John Wiley & Sons: New York, 2001, 1239. (f) Shibasaki,
M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989.
(g) North, M. In Science of Synthesis, Vol. 19; Murahashi, S.
I., Ed.; Thieme: Stuttgart, 2004, 235.
1
2
Benzaldehyde (3a)
99
99
96
87
99
99
89
80
83
99
99
99
73
82
90 (R)
87
2-Methylbenzaldehyde (3b)
3-Methylbenzaldehyde (3c)
4-Methylbenzaldehyde (3d)
2-Methoxybenzaldehyde (3e)
3-Methoxybenzaldehyde (3f)
4-Methoxybenzaldehyde (3g)
4-Fluorobenzaldehyde (3h)
4-Chlorobenzaldehyde (3i)
1-Naphthaldehyde (3j)
2-Naphthaldehyde (3k)
Heliotropin (3l)
3
84
4
91 (R)
83 (R)
94 (R)
94 (R)
79
(2) For recent reviews on cyanation reactions, see: (a) North,
M. Tetrahedron: Asymmetry 2003, 14, 147. (b) Brunel, J.
M.; Holmes, I. P. Angew. Chem. Int. Ed. 2004, 43, 2752.
(c) Thierry, R. J. A.; Clutterbuck, L. A.; Michael, N. Synlett
2005, 1828. (d) Kanai, M.; Kato, N.; Ichikawa, E.;
Shibasaki, M. Synlett 2005, 1491. (e) Chen, F. X.; Feng, X.
M. Synlett 2005, 892. (f) Chen, F. X.; Feng, X. M. Curr.
Org. Synth. 2006, 3, 77.
5
6
7
8
9
66 (R)
82 (R)
81
(3) For selected recent examples, see: (a) Nitta, H.; Yu, D.;
Kudo, M.; Mori, A.; Inoie, S. J. Am. Chem. Soc. 1992, 114,
7969. (b) Casas, J.; Nájera, C.; Sansano, J. M.; Saá, J. M.
Org. Lett. 2002, 4, 2589. (c) Tian, S. K.; Hong, R.; Deng, L.
J. Am. Chem. Soc. 2003, 125, 9900. (d) Li, Y.; He, B.; Qin,
B.; Feng, X. M.; Zhang, G. L. J. Org. Chem. 2004, 69, 7910.
(e) Liu, X. H.; Qin, B.; Zhou, X.; He, B.; Feng, X. M. J. Am.
Chem. Soc. 2005, 127, 12224. (f) Ryu, D. H.; Corey, E. J. J.
Am. Chem. Soc. 2005, 127, 5384. (g) Fuerst, D. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964.
(h) Wen, Y. H.; Huang, X.; Hang, J. L.; Xiong, Y.; Qin, B.;
Feng, X. M. Synlett 2005, 2445. (i) Qin, Y. C.; Liu, L.; Pu,
L. Org. Lett. 2005, 7, 2381. (j) Xiong, Y.; Huang, X.; Gou,
S. H.; Huang, J. L.; Wen, Y. H.; Feng, X. M. Adv. Synth.
Catal. 2006, 348, 538. (k) Belokon, Y. N.; Ishibashi, E.;
Nomura, H.; North, M. Chem. Commun. 2006, 16, 1775.
(4) (a) Tian, S. K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195.
(b) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem. Int. Ed. 2002, 41, 3636. (c) Tian, J.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2003, 5, 3021. (d) Belokon, Y. N.; Blacker, A. J.;
Clutterbuck, L. A.; North, M. Org. Lett. 2003, 5, 4505.
(e) Belokon, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L.
A.; North, M. Tetrahedron 2004, 60, 10433. (f) Yamagiwa,
N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 3413. (g) Li, Q. H.; Chang, L.; Liu, X. H.; Feng,
X. M. Synlett 2006, 1675. (h) Gou, S. H.; Chen, X. H.;
Xiong, Y.; Feng, X. M. J. Org. Chem. 2006, 71, 5732.
(i) Gou, S. H.; Wang, J.; Liu, X. H.; Wang, W. T.; Chen, F.
X.; Feng, X. M. Adv. Synth. Catal. 2007, 349, 343. (j) Gou,
S. H.; Liu, X. H.; Zhou, X.; Feng, X. M. Tetrahedron 2007,
63, 7935. (k) Chen, S. K.; Peng, D.; Zhou, H.; Wang, L. W.;
Chen, F. X.; Feng, X. M. Eur. J. Org. Chem. 2007, 639.
(5) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C. J.
Am. Chem. Soc. 2005, 127, 11592.
10
11
12
13
14
85
(E)-But-2-enal (3m)
91 (R)
68 (R)
Hexanal (3n)
a Reactions were carried out on a 0.25 mmol scale of the correspond-
ing aldehyde in CH2Cl2 (125 mL) with EtOCOCN (1.5 equiv).
b Isolated yield.
c Determined by HPLC analysis on a Chiralcel OD-H column or GC
on a Chiralcel DEX CB column.
d The absolute configuration of the major product was determined by
comparison with the reported value of optical rotation.3k,4b,e
11). However, when (E)-but-2-enal was subjected to the
reaction, only the 1,2-addition product was afforded in
73% yield with 91% ee (Table 3, entry 13). Hexanal also
gave the moderate enantioselectivity and yield (Table 3,
entry 14).
In conclusion, a new self-assembled catalyst system ob-
tained readily from tetraisopropyl titanate Ti(Oi-Pr)4,
Schiff base 1b and cinchonine (2a), for the cyanoethoxy-
carbonylation of aldehydes has been developed. Under
mild conditions, excellent reactivity and enantioselectivi-
ty could be generated (up to 99% yield and up to 94% ee)
in 2.5 hours. Further investigations to broaden the scope
and synthetic applications of this efficient self-assembled
catalyst are underway in our laboratory.
(6) (a) Baeza, A.; Nájera, C.; Sansano, J. M.; Saá, J. M. Angew.
Chem. Int. Ed. 2003, 42, 3143. (b) Abiko, Y.; Yamagiwa,
N.; Sugita, M.; Tian, J.; Matsunaga, S.; Shibasaki, M. Synlett
2004, 2434.
(7) Baeza, A.; Nájera, C.; Sansano, J. M.; Saá, J. M.
Tetrahedron: Asymmetry 2005, 16, 2385.
Acknowledgment
The authors thank the National Nature Science Foundation of China
(No. 20602025) for financial support. We also thank Sichuan Uni-
versity Analytical & Testing Center for NMR spectral analysis.
Synlett 2007, No. 18, 2875–2878 © Thieme Stuttgart · New York

2878
W. Wang et al.
LETTER
(8) (a) Mikami, K.; Matasukawa, S.; Volk, T.; Terada, M.
Angew. Chem. Int. Ed. 1997, 36, 2768. (b) Mikami, K.;
Terada, M.; Korenage, T.; Matsumoto, Y.; Ueki, M.;
Angelaud, R. Angew. Chem. Int. Ed. 2000, 39, 3532. (c) Li,
X. S.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem.
Soc. 2002, 124, 12636.
(9) (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Org.
Chem. 1993, 58, 1515. (b) Belokon, Y. N.; Chusov, D.;
Borkin, D. A.; Yashkina, L. V.; Dmitriev, A. V.; Katayeva,
D.; North, M. Tetrahedron: Asymmetry 2006, 17, 2328.
(10) The result of hydrogenated tridentate Schiff base 1b was
only 50% ee, maybe due to its more flexible framework.
(11) THF: 35 h, 83% yield, 35% ee; Et2O: 48 h, 70% yield, 76%
ee; toluene: 30 h, 90% yield, 31% ee; CHCl3: 15 h, 90%
yield, 52% ee; ClCH2CH2Cl: 15 h, 84% yield, 23% ee.
(12) Zr(Oi-Pr)4: 24 h, 80% yield, 72% ee; Al(Oi-Pr)3: 10 h, 90%
yield, 7% ee; Zr(OEt)4: 48 h, 84% yield, 30% ee; Cu(OTf)2,
48 h, no reaction.
(13) General Procedure for the Asymmetric Cyanoethoxy-
carbonylation of Aldehydes:
To a solution of 1b (0.0125 mmol, 4.0 mg) and 2a (0.0125
mmol, 3.7 mg) in CH2Cl2 (125 mL) was added Ti(Oi-Pr)4
(1.0 M in toluene, 0.0125 mmol, 12.5 mL) at r.t., and then the
mixture was stirred at 30 °C for 0.3 h under an argon
atmosphere. To this solution, the corresponding aldehyde
(0.25 mmol) was added, and then EtOCOCN (1.5 equiv) was
added after 10 min at –20 °C under the argon atmosphere.
After stirring for another 2.5 h, the crude product was
purified by column chromatography on silica gel (PE–Et2O,
10:1) to give the corresponding cyanohydrin carbonates.
Synlett 2007, No. 18, 2875–2878 © Thieme Stuttgart · New York

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