Asymmetric addition of KCN and Ac2O to aldehydes catalyzed by recyclable polymeric salen-Ti(IV) complexes

Article abstract of DOI:10.1016/j.tetlet.2004.04.086

Polymeric salen-Ti(IV) complexes were employed in the enantioselective O-acetyl cyanation of aldehydes with KCN and Ac₂O. The polymeric catalysts with appropriate crosslinking degree exhibited good activities and enantioselectivities, up to 94%

Full text of DOI:10.1016/j.tetlet.2004.04.086

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 4763–4767
Asymmetric addition of KCN and Ac2O to aldehydes catalyzed
by recyclable polymeric salen-Ti(IV) complexes
Wei Huang, Yuming Song, Changmin Bai, Guoying Cao and Zhuo Zheng*
Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian 116023, PR China
Received 7 January 2004; revised 7 April 2004; accepted 9 April 2004
Abstract—Polymeric salen-Ti(IV) complexes were employed in the enantioselective O-acetyl cyanation of aldehydeswith KCN and
Ac2O. The polymeric catalysts with appropriate crosslinking degree exhibited good activities and enantioselectivities, up to 94%
yield and 91% ee were obtained at )20 ꢀC with 1 mol % of catalyst (based on bimetallic catalytic unit). Moreover, the crosslinked
polymeric catalyst could be easily recovered and reused for six consecutive runs without obvious decrease in activity and enantio-
selectivity.
ꢁ 2004 Elsevier Ltd. All rights reserved.
Chiral cyanohydrinshave attracted great interetssdue
to their potential applicationsin pharmaceuticals, agro-
chemicals and other fields. Many efficient and suc-
cessful methods have been developed to synthesize the
chiral cyanohydrins. It is no doubt that the catalytic
process with metal complexes is one of the most
attractive methodsbecaues of the multiplicationsof
chirality.1;2 Among the metal-complex catalysts, chiral
salen-Ti(IV) complexes have shown excellent catalytic
efficiency in asymmetric trimethylsilylcyanation of
aldehydes.3–5 Recently, many methodshave been
developed to improve the catalytic efficiency and to re-
cycle the salen–metal complexes, such as, ionic liquids,6;7
organic or inorganic supported catalysts.8–12 However,
volatile and expensive trimethylsilyl cyanide was used in
the above-mentioned processes. Although some less
expensive cyanide sources, such as ethyl cyanoformate
and benzoyl cyanide, have been employed in synthesis of
O-protected cyanohydrins,13–18 exploring a nonvolatile
and cheap cyanide source is still interesting.
plex 1 (Fig. 1). In the past years, we have developed
some efficient chiral polymeric salen catalysts, which
were successfully employed in the enantioselective
epoxidation and hydrolytic kinetic resolution (HKR) of
epoxides, and could be easily recovered and reused.21–25
We reasoned that the Ti(IV) complexes derived from
these types of polymeric salen ligands could be used as
the catalysts for preparation of chiral O-acetyl cyano-
hydrins and kept their easily recycling properties. Con-
sidering that a bimetallic Ti–(l-O)2–Ti moiety in
complex 1 played a key role in obtaining high ee and
high activity,4;5 we estimated that linear polymeric salen
ligandswould be very difficult to form the Ti–( l-O)2–Ti
species for the spatial reason. Therefore, our research
was focused on the crosslinked polymeric salen ligands 3
Our research was inspired by the studies of Belokon and
co-workers.19;20 In their process, O-acetyl cyanohydrins
in high ee were obtained with KCN, Ac2O and alde-
hydescatalyzed by aslen bimetallic Ti–( l-O)2–Ti com-
O
O
N
N
O
O
O
O
N
N
Ti
Ti
Keywords: O-Acetyl cyanohydrins; Recyclable polymeric salen-Ti(IV)
complexes; Potassium cyanide; Aldehyde; Asymmetric cyanation.
* Corresponding author. Tel.: +86-411-8466-3087; fax: +86-411-8468-
4746; e-mail: zhengz@ms.dicp.ac.cn
1
Figure 1. The bimetallic salen-Ti(IV) complex.
0040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.086

4764
W. Huang et al. / Tetrahedron Letters 45 (2004) 4763–4767
(Scheme 1).24 We envisioned that the appropriate dis-
tance between two metal centresin the Ti(IV) complexes
of 3 wasbeneficial to form the bimetallic Ti–( l-O)2–Ti
species, a similar bimetallic structure as in complex 1. As
a result, we herein reported the efficient asymmetric
addition of KCN and Ac2O to aldehydescatalyzed by a
series of crosslinked polymeric salen-Ti(IV) complexes,
which could be easily recovered and reused without
obvious decrease in activity and enantioselectivity even
after six consecutive runs.
tion of benzaldehyde was firstly investigated, and the
results were summarized in Table 1 (entries 2–9). In
order to show the validity of the developed polymeric
catalysts, the result by salen-Ti(IV) bimetallic complex 1
was listed in entry 1 as a comparison.19;20 The cross-
linking degree of the polymeric catalysts was easily ad-
justed by the change of the proportion of
trisalicylaldehyde 5 (the crosslinking agent) and disali-
cylaldehyde 6. When the proportion of 5 and 6 was
between 0.5/100 and 2/100, the comparable results with
catalyst 1 were obtained (Table 1, entries2–4). However,
the enantioselectivities decreased gradually with the
increase of the ratio of 5 to 6 (Table 1, entries5–9).
When the completely crosslinked ligand 4 wasused, the
reactivity and enantioselectivity of the catalyst were
decreased dramatically (Table 1, entry 10). The same
trend wasobserved at both 20 and )20 ꢀC (Table 1), and
better results were obtained at )20 ꢀC. From the above
The crosslinked polymeric salen ligands 3 were prepared
according to our previousreported methods(Scheme
1).24 The preparation of the bimetallic Ti–(l-O)2–Ti
salen complexes and the subsequent O-acetyl cyanation
of aldehydeswere carried out according to the literature
4;19;20
procedures(Scheme 2). The effect of the crosslink-
ing degree of the polymeric ligandsin O-acetyl cyana-
OH
OHC
tBu
OH
OH
OH
O
OHC
tBu
O
OHC
O
tBu
OHC
O
tBu
O
O
O
O
O
O
O
O
tBu
HO
O
O
O
CHO
5
6
5
(R,R)-1,2-diaminocyclohexane THF
6
salen=
N
N
n
e
l
a
O
OH HO
But But
s
O
O
O
O
O
O
O
O
O
O
salen
O
O
salen
O
O
n
m
O
s
a
2 Tri / Di = 0 / 100,
m=0
n=0
l
e
n
3 Tri / Di = 0.5 / 100~50 /100,
4 Tri / Di = 100 / 0,
Scheme 1. Synthesis of the crosslinked salen ligands.
Salen-Ti(IV)
H
H CN
OAc
+
AcOK
+
Ac O + KCN
2
C O
R
*
R
R= Ar, Alkyl
Scheme 2. Synthesis of chiral O-acetyl cyanohydrins promoted by chiral polymeric salen-Ti(IV) complexes.

W. Huang et al. / Tetrahedron Letters 45 (2004) 4763–4767
4765
Table 1. Enantioselective synthesis of O-acetyl cyanohydrin from benzaldehyde, KCN and Ac2O catalyzed by different salen-Ti(IV) complexesa
Entry
Ligand (5/6)b
20 ꢀC
)20 ꢀC
Eed
Conf.e
Conv.c
Eed
Conv.c
1
(R)-1f
>90
83
74
78
88
89 (89)g
88
87 (87)g
85
81
S
S
S
S
S
S
S
S
S
S
S
S
S
2
(R)-3 (0.5:100)
(R)-3 (1:100)
(R)-3 (2:100)
(R)-3 (6:100)
(R)-3 (14:100)
(R)-3 (18:100)
(R)-3 (25:100)
(R)-3 (50:100)
(R)-4 (100:0)
(R)-2 (0:100)
(R)-7
91 (100)g
89
85 (99)g
84
3
88
92
78
78
4
5
95
86
75
63
6
79
60
60 (99)g
7
87
92
NDh
59
56
NDh
77
8
79 (79)g
70
55
9
39
13
58 (83)g
10
11
12
13
35
72
44
62
89 (89)g
68
86 (83)g
77
NDh
47
NDh
52
68 (96)g
(R)-8
a Reaction conditions: benzaldehyde (1 mmol), KCN, Ac2O (ratio ¼ 1:4:4) in 5 mL mixture solvents (mol ratio: CH2Cl2/tBuOH/H2O ¼ 2500:10:1) in
present of catalyst prepared from 2 mol % (R)-ligand and 2 mol % Ti(i-OPr)4, stirred for 4 h.
b The proportion of trisalicylaldehyde 5 and disalicylaldehyde 6 wasthe ratio of weight.
c Based on GC integral area.
d Determined by GC analysis using a chiral capillary column (cyclodex-b, 2,3,6-methylated, 30 m · 0.25 mm (id)).
e Absolute configurations were assigned by comparison of literature date with the Ref. 20.
f Results were obtained by catalyst 1 in the Ref. 20.
g The results in parentheses were obtained in reaction for 16 h.
h ND, not determined.
results, we could conclude that the ratio of 5 to 6 played
an important role in forming the bimetallic Ti–(l-O)2–Ti
species. When the proportion of 5 and 6 wasbetween
0.5/100 and 2/100, the species could be formed, thus a
comparable ee could be obtained. When the polymeric
N
N
O
O
OH HO
But
O
O
R
R
ligand waswith excesof
5, which had a more rigid
But
structure, it was difficult to form the key species. To
further clarify the importance of the crosslinking degree,
we used oligomeric ligand 2 without the crosslinking
agent 5 to perform the asymmetric cyanation under the
identical conditions, the results showed that ligand 2
had the same enantioselective induction as that of with
the ligand 3 (0.5/100), but the lower conversion was
observed even in prolonged reaction time (Table 1, entry
11). The dissatisfactory results obtained by linear poly-
meric salen ligand 7 (Fig. 2) could further confirm our
presumption that the crosslinking degree had the
important effect, because this more rigid polymeric salen
wasmuch more difficult to form Ti–( l-O)2–Ti species
(Table 1, entry 12). Finally, monomeric analogue salen
ligand 8 (Fig. 3) was screened, and the similar enantio-
selectivity and activity as 1 were obtained (Table 1, entry
13), which indicated that the phenolic ester group in the
8
H3CO
OCH2
R=
Figure 3. The monomeric analogue salen ligand.
ligand had little influence in the asymmetric O-acetyl
cyanation of benzaldehyde.
Under the optimized conditions, a variety of substituted
benzaldehydesaswell asseveral aliphatic aldehydesand
heteroaromatic aldehydes were used as substrates for
this O-acetyl cyanation with the catalyst prepared from
ligand 3 (5:6 ¼ 0.5/100) and Ti(i-OPr)4. The results were
listed in Table 2. The substituents of benzaldehyde had a
great influence on the reactivity and enantioselectivity.
When 4-fluorobenzaldhyde was used, the best result was
obtained as91% ee and 94% yield (Table 2, entry 5). As
for the aliphatic aldehydes, the chiral products were
obtained in 81–86% eeswith moderate to good yields
(Table 2, entries11–13), except that the chain secondary
aldehyde (isobutyraldhyde) gave 67% ee (Table 2, entry
14). The results of substituted benzaldehydes and ali-
phatic aldehydes were comparable to those with catalyst
1 at lower reaction temperature ()42 ꢀC).19;20 O-Acetyl
cyanation of heteroaromatic aldehydescould alos pro-
ceed smoothly. When 2-furaldehyde and 2-thiophene-
carboxaldehyde were used, good enantioselectivities and
activitiescould be obtained (Table 2, entries15 and 16),
N
N
OH HO
t
t
Bu
Bu
n
7
Figure 2. The linear polymeric salen ligand.

4766
W. Huang et al. / Tetrahedron Letters 45 (2004) 4763–4767
Table 2. Enantioselective synthesis of O-acetyl cyanohydrinsfrom aldehydes, KCN and Ac 2O catalyzed by crosslinked polymeric catalysta
Entry
Substrate
Time (h)
Yield (%)b
Ee (%)c (configuration)d
1
PhCHO
16
16
16
16
16
16
16
4
93
85
88
93
94
93
93
89
58
95
94
89
62
61
64
73
NDe
89 (S)
88 (S)
86 (S)
89 (S)
91 (S)
85 (S)
81 (S)
70 (S)
87 (S)
84 (S)
83 (S)
81 (S)
86 (S)
67 (S)
66 (ND)e
78 (ND)e
6.4 (ND)e
2
2-CH3C6H4CHO
3-CH3C6H4CHO
4-CH3C6H4CHO
4-FC6H4CHO
3
4
5
6
4-ClC6H4CHO
4-BrC6H4CHO
7
8
4-CF3C6H4CHO
4-MeOC6H4CHO
3-PhOC6H4CHO
PhCH2CH2CHO
Cyclohexanecarboxaldehyde
Me2CHCH2CHO
Me2CHCHO
9
40
16
16
16
20
20
16
16
16
10
11
12
13
14
15
16
17
2-Furaldehyde
2-Thiophenecarboxaldehyde
2-Pyridinecarboxaldehyde
a Reaction conditions: aldehyde (1 mmol), KCN, Ac2O (ratio ¼ 1:4:4) in 5 mL mixture solvents (mol ratio: CH2Cl2/tBuOH/H2O ¼ 2500:10:1) in
present of catalyst prepared from 2 mol % (R)-ligand 3 (5/6 ¼ 0.5:100) and 2 mol % Ti(i-OPr)4, stirred at )20 ꢀC.
b Isolated yield based on the aldehydes, after flash chromatography (silica gel).
c Determined by GC analysis using a chiral capillary column (cyclodex-b, 2,3,6-methylated, 30 m · 0.25 mm (id)).
d Absolute configurations were assigned by comparison of literature date with the Ref. 20, unless otherwise indicated.
e ND, not determined.
while only 6.4% ee wasobtained, when 2-pyridinecar-
boxaldehyde wasused (Table 2, entry 17).
degree to examine the recycling ability,26 and the results
were listed in Table 3. As expected, the higher cross-
linked polymeric catalyst showed excellent reusability in
the O-acetyl cyanation of benzaldehyde, even after seven
consecutive runs, up to 74% ee and 95% conversion was
obtained. It was the first example of asymmetric addi-
tion of KCN and Ac2O to aldehydescatalyzed by
recyclable catalysts.
In our previousresearch, we have reported that the cat-
alysts derived from polymeric ligands had the advan-
tage of easy recovery and reusable, as well as the
comparable catalytic ability in the enantioselective
epoxidation and HKR of epoxideswith monomeric sa-
len–metal catalysts.21–24 We then would like to know
whether the catalysts derived from these crosslinked
In conclusion, polymeric salen-Ti(IV) complexes were
successfully employed in the asymmetric addition of
KCN and Ac2O to aldehydes. A series of O-acetyl
cyanohydrinsin moderate to good ee were obtained
when crosslinked polymeric salen 3 (5/6 ¼ 0.5/100–2/
100) was used as ligand. Moreover, the crosslinked
polymeric salen-Ti(IV) catalysts exhibited excellent
recycling performance. The different efficienciesbetween
the crosslinked ligands 3 and the linear ligand 7 might be
meaningful for the design of the polymeric catalysts in
thisfield.
polymeric ligandscould alos be recycled in
O-acetyl
cyanation of benzaldehyde. Initially, the optimized
ligand 3 (5/6 ¼ 0.5/100) wasapplied in the recycling
experiment, however, the result was discouraged that the
recovered catalyst showed extremely low activity and
enantioselectivity, which was probably due to the
instability of the lower crosslinked ligand. We then used
the ligand 3 (5/6 ¼ 25/100) with higher crosslinking
Table 3. The recycle of crosslinked polymeric salen-Ti(IV) catalyst in
enantioselective synthesis of O-acetyl cyanohydrin from benzaldehyde,
KCN and Ac2Oa
Acknowledgements
Cycle
Time (h)
Conv. (%)b
Ee (%)c
Thiswork wassupported by the National Natural Sci-
ence Foundation of China (29933050).
Fresh
9
16
16
16
16
20
20
99
99
98
99
99
99
95
80
78
78
78
80
80
74
1
2
3
4
5
6
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be recovered efficiently.