Fine modification of salen ligands - Effects on the salen-Ti-catalyzed asymmetric cyanosilylation of aldehydes

Article abstract of DOI:10.1002/ejoc.201100319

New bifunctional N-oxide salen-Ti^IV complexes and a pyrrolidine salen-Ti^IV complex in combination with achiral N-oxide were developed and applied to the asymmetric addition of trimethylsilyl cyanide to aldehydes. Notably, both enanti

Full text of DOI:10.1002/ejoc.201100319

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100319
Fine Modification of Salen Ligands – Effects on the Salen–Ti-Catalyzed
Asymmetric Cyanosilylation of Aldehydes
Chengwei Lv,[a,b] Qigan Cheng,[a] Daqian Xu,[a,b] Shoufeng Wang,[a] Chungu Xia,[a] and
Wei Sun*[a]
Keywords: Asymmetric catalysis / Dual activation / Ligand design / N-Oxide / Cyanosilylation
New bifunctional N-oxide salen–TiIV complexes and a pyr- reaction, which are based on the same chiral diamine collar
rolidine salen–TiIV complex in combination with achiral N-
oxide were developed and applied to the asymmetric ad-
dition of trimethylsilyl cyanide to aldehydes. Notably, both
enantiomers of trimethylsilyl ethers of cyanohydrins could be
easily prepared by modifying the catalysts employed in this
derived from L-tartaric acid. The products were obtained
generally with moderate to good enantiomeric excesses and
excellent yields by using relatively low catalyst loadings and
only 1.05 equivalents of trimethylsilylcyanide (TMSCN).
vated substrate.[8] Based on the above dual activation phe-
nomenon, the “two-center catalysis” following the pioneer-
ing work of Shibasaki and co-workers[9] is a conceptually
new strategy for enantioselective synthesis. This strategy has
led many researchers to fabricate single-component bifunc-
tional catalysts to facilitate the reaction in a synergistic
manner similar to enzymatic processes.[8] Generally, the cat-
alysts consist of LALB (Lewis acid/Lewis base) or LABB
(Lewis acid/Brønsted base) moieties capable of simulta-
neously activating both electrophiles and nucleophiles. This
synergistic function makes the two substrates more reactive
and controls their orientation to improve the enantio-
selectivity.[8,10] So it is no surprise that this type of catalysts
have achieved a pinnacle in asymmetric cyanation.
Introduction
Chiral cyanohydrins are versatile building blocks, be-
cause their two functional groups can be readily manipu-
lated to produce a large range of biologically important
compounds including α-hydroxy acids and esters, α-hydroxy
aldehydes and ketones, α-amino acids, and β-amino
alcohols, which have been widely used as the components
of industrially valuable products such as pharmaceuticals,
agrochemicals, flavorings, and fragrances.[1,2] For this
reason, design and synthesis of chiral catalysts for asym-
metric addition of cyanide to carbonyl compounds to form
cyanohydrins is of current interest in synthetic chemis-
try.[2e,3] A variety of enantioselective catalytic systems have
been employed for these additions, providing enantiomer-
ically enriched products in many cases.[2,4] The majority of
Although impressive enantiomeric excesses have been ob-
the catalysts are chiral transition metal complexes, which tained in some cases, these reactions are still a great chal-
are generated from TiIV, AlIII, VIV, MnIII, some lanthanides, lenge in terms of the efficiency, cost, and adaptability of the
and chiral ligands.[2c,5] Prominent amongst the most effec- catalysis,[11] and it is highly desired to develop more efficient
tive catalysts for these reactions are metal–salen com- and adaptable catalysts that have the ability to efficiently
plexes,[6] especially those of titanium.[2] Meanwhile, adding enhance the reactivity and to regulate its orientation in an
a base in a metal–salen catalytic system to construct a two- asymmetric atmosphere. In recent years, metal complexes
component (dual activation) catalytic system is well known, of chiral N-oxide have been disclosed as highly effective bi-
and this strategy has been used for the asymmetric cyan- functional catalysts in many asymmetric procedures.[12] For
ation of aldehydes[2d] and ketones with trimethylsilyl cyan- example, Feng and co-workers reported that chiral N-oxide
ide,[7] in which process the base additive activates the cyano- complexes can efficiently catalyze the asymmetric cyano-
silylation agent and facilitates cyanide delivery to the acti- silylation of imines,[13] aldehydes,[14] and ketones.[15] In-
spired by the above pioneering studies using chiral N-oxide
complexes as efficient bifunctional catalysts and our early
[a] State Key Laboratory for Oxo Synthesis and Selective
work in asymmetric reactions with salen-type com-
plexes,[16–19] we initiated a study to synthesize some new
bifunctional N-oxide salen–Ti catalysts and provide a com-
parison of the catalytic activity and the asymmetric induc-
tion ability of N-oxide salen–Ti catalysts and a pyrrolidine
salen TiIV complex with achiral N-oxide for the cyano-
silylation of aldehydes.
Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences,
Lanzhou 730000, China
Fax: +86-931-827-7088
E-mail: wsun@licp.cas.cn
[b] Graduate School of the Chinese Academy of Sciences,
Beijing 100039, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100319.
Eur. J. Org. Chem. 2011, 3407–3411
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Lv, Q. Cheng, D. Xu, S. Wang, C. Xia, W. Sun
SHORT COMMUNICATION
Table 1. The screening of reaction conditions for the addition of
TMSCN to benzaldehyde.[a]
Results and Discussion
The N-oxide salen-type ligands 1a–1c (Figure 1) were
synthesized from the corresponding salen ligands and m-
chloroperoxybenzoic acid (m-CPBA). With the above bi-
functional ligands in hand, we first examined the asymmet-
ric cyanosilylation of benzaldehyde with trimethylsilylcyan-
ide (TMSCN). The catalysts were first prepared in situ by
stirring the N-oxide salen ligands with Ti(OiPr)4 at ambient
temperature for 2 h in dichloromethane, then the experi-
ments were carried out at 0 °C using 2 mol-% catalyst load-
ing for 15 h. The data indicated that the N-oxide salen–Ti
complexes were able to catalyze the reaction in good yields;
however, the enantioselectivity was very poor; the 3,5-di-
tert-butyl-substituted ligand gave the highest enantio-
selectivity (Table 1, entries 1–3). For comparison, the con-
ventional 3,5-di-tert-butyl-substituted ligand 2a was also
tested in the same reaction, and an 81% ee was observed
under the same conditions (Table 1, entry 4). The prepared
Ti complexes 4 and 5 (Figure 2) derived from ligands 1a
and 2a, respectively, were directly employed as catalysts,
achieving similar results with those of catalysts prepared in
Entry Catalyst (mol-%) Solvent
Conv.[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
1a + Ti(OiPr)4 (2) CH2Cl2
1b + Ti(OiPr)4 (2) CH2Cl2
1c + Ti(OiPr)4 (2) CH2Cl2
2a + Ti(OiPr)4 (2) CH2Cl2
99
90
75
94
99
98
99
98
98
98
31
35
69
74
24 (R)
10 (R)
11 (R)
81 (S)
25 (R)
85 (S)
29 (R)
32 (R)
11 (R)
24 (R)
57 (S)
84 (S)
77 (S)
27 (S)
84 (S)
4 (2)
5 (2)
4 (2)
4 (2)
4 (2)
4 (2)
5 (2)
5 (2)
5 (2)
5 (2)
5 (2)
CH2Cl2
CH2Cl2
Et2O
toluene
THF
iPr2O
Et2O
THF
toluene
CHCl3
9
10
11
12
13
14
15
ClCH2CH2Cl 93
[a] All reactions are carried out at 0 °C for 15 h. [b] Determined by
GC with nonane as internal standard. [c] The enantiomeric excess
situ (Table 1, entries 1, 4–6). On the basis of the above re- of silyl ether is determined by chiral GC with a CP-Chirasil-Dex
CB column. The absolute configuration is based on the known
order of elution of the two enantiomers.
sults, N-oxide salen–Ti complex 4 and salen complex 5 were
employed as catalysts for evaluating the effects of the sol-
vents. Complex 4 promoted the reaction well in all tested
solvents. Toluene gave the highest enantioselectivity
(Table 1, entry 8). The effect of the solvents was obvious for
salen complex 5, and the best result was obtained in
CH2Cl2 (Table 1, entry 6). Reaction in ClCH2CH2Cl re-
sulted in a comparable outcome both in yield and ee
(Table 1, entry 15).
Figure 2. Ti complexes 4 and 5 derived from ligands 1a and 2a,
respectively.
In order to determine the importance of the role played
by the N-oxide group of the salen unit in enhancing the
reactivity and nucleophilicity of TMSCN, control experi-
Figure 1. Achiral N-oxide and chiral ligands used in this study.
ments were carried out with benzaldehyde as substrate and
Compared with the structure of complex 5, 4 possessed ligand 1a or 2a alone as catalyst. As shown in Table 2 (entry
an N-oxide group in the pyrrolidine ring (Figure 2). The 9), ligand 2a could not promote the addition reaction. In-
difference led to a great diversity in the enantioselectivity deed, the addition reaction occurred in the presence of the
(Table 1, entries 5, 6). A possible explanation for this re- N-oxide salen ligand 1a (Table 2, entry 1). A new signal that
1
duced asymmetric induction ability of 4 is that there may appeared at 0.17 ppm in the H NMR spectrum, between
be interaction between the N-oxide group and the titanium the N-oxide salen ligand 1a and TMSCN, was in agreement
center of the complex. The other reason is that the N-oxide with Feng’s[7a,7b] reports and could also reveal that coordi-
group of the salen unit could activate TMSCN and acceler- nation existed in the N-oxide group and TMSCN (see Sup-
ate the reaction. So, the catalytic effect of the N-oxide group porting Information, Figure S1).
is predominant when utilizing a high loading of N-oxide
Encouraged by the above findings, we set out to examine
salen–Ti catalyst. An interesting observation is that both Ti other reaction factors. Generally, the enantioselectivity
complexes derived from the same chiral diamine could give could be improved by lowering the temperature of the reac-
rise to different enantiomers of products. The phenomenon tion. When the temperature was lowered to –20 °C, catalyst
is evidently caused by the N-oxide group.
4 gave the product quantitatively in a 41% ee (Table 2, entry
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Eur. J. Org. Chem. 2011, 3407–3411

Salen–Ti-Catalyzed Asymmetric Cyanosilylation of Aldehydes
Table 2. The screening of reaction conditions for the addition of oxide salen–Ti complex 4 or salen–Ti complex 5 together
TMSCN to benzaldehyde.[a]
with N-oxide 3 as catalysts. The results are summarized in
Table 3.
Table 3. Cyanation of aldehydes with TMSCN.
Entry
TMSCN
[equiv.]
T
[°C]
Catalyst
(mol-%)
Conv.[b] ee[c]
[%]
[%]
1
2
3
4
5
6
7
8
2
2
2
0
1a (2)
36
98
97
98
97
95
98
69
0
0
Catalyst 4[a]
Yield[c] ee[d]
Catalyst 5[b]
Yield[c] ee[d]
–20
–40
–20
–20
–20
–20
–20
0
0
0
0
0
4 (2)
41 (R)
39 (R)
70 (R)
71 (R)
70 (R)
78 (R)
65 (R)
0
85 (S)
82 (S)
86 (S)
67 (S)
87 (S)
86 (S)
90 (S)
86 (S)
Entry Aldehyde
4 (2)
1.5
1.2
1.05
1.05
1.05
2
1.5
1.5
1.5
1.5
1.2
1.05
1.05
1.05
4 (1)
[%]
[%]
[%]
[%]
4 (1)
1
2
benzaldehyde
4-methyl-
benzaldehyde
3-methyl-
95
94
78 (R)
68 (R)
96
60
90 (S)
86 (S)
4 (1)
4 (0.5)
4 (0.2)
2a (2)
3
92
90
94
91
85
93
92
91
95
70 (R)
58 (R)
88 (R)
79 (R)
71 (R)
69 (R)
42 (R)
9
98
93
56
98
85
95
96
97
96
93
87 (S)
67 (S)
87 (S)
84 (S)
82 (S)
89 (S)
51 (S)
39
9
benzaldehyde
2-methyl-
10
11
12
13
14
15
16
17
5 (2)
5 (2) + 3 (2)
5 (1) + 3 (1)
87
99
99
4
benzaldehyde
4-methoxy-
benzaldehyde
3-methoxy-
benzaldehyde
2-methoxy-
benzaldehyde
4-chloro-
5
5 (0.5) + 3 (0.5) 73
0
0
–10
–20
5 (1) + 3 (1)
5 (1) + 3 (1)
5 (1) + 3 (1)
5 (1) + 3 (1)
99
99
98
89
6
7
[a] Conditions: runs in entries 1–8 were carried out in toluene for
20 h, runs in entries 9–15 were carried out in CH2Cl2 for 15 h,
and runs in entries 16–17 were carried out in CH2Cl2 for 24 h.
[b] Determined by GC with nonane as internal standard. [c] The
enantiomeric excess of silyl ether was determined by chiral GC with
a CP-Chirasil-Dex CB column. The absolute configuration is based
on the known order of elution of the two enantiomers.
8
benzaldehyde
2-chloro-
9
benzaldehyde
2,6-dichloro-
benzaldehyde
2-bromo-
10
11
12
13
38
27
benzaldehyde
4-trifluoromethyl- 98
benzaldehyde
56 (R)
35 (S)
2). Continuously lowering the temperature led to a slight
decrease of the enantioselectivity. It is well known that 14
enantioselectivity could be increased by reducing the cata-
furfural
91
97
46 (R)
59 (R)
80
70
69 (S)
61 (S)
cinnamaldehyde
trimethyl-
acetaldehyde
heptaldehyde
15
86
93
21 (R)
34 (R)
88
90
48 (S)
78 (S)
lyst loading in the asymmetric addition of TMSCN to alde-
16
hydes.[5b,5c] In this regard, the effect of varying the ratio of
catalyst and substrate was also investigated. As shown in
Table 2, the enantiomeric excess of product could be im-
proved significantly from 41% to 78% when the catalyst
loading was reduced to 0.5 mol-% (Table 2, entry 7). The
parameters of this reaction promoted by complex 5 were
also screened. As a control experiment, an achiral N-oxide
3 was introduced to the reaction.[7a] By the aid of the N-
oxide 3, the amount of TMSCN could also be reduced to
1.05 equiv. compared to the amount of aldehyde. At –10 °C,
[a] All reactions were carried out in the present of 0.5 mol-% of 4
in toluene for 20 h at –20 °C. [b] All reactions were catalyzed by
1 mol-% of 5 in combination with 1 mol-% of 3 in CH2Cl2 for 24 h
at –10 °C. [c] Isolated yield. [d] The enantiomeric excess of silyl
ether was determined by chiral GC with a CP-Chirasil-Dex CB
column. The absolute configurations were determined by compari-
son the known order of elution of the two enantiomers or the sign
of the optical rotation with literature data.
The data shown in Table 3 indicated that higher enantio-
silyl ether could be formed in 98% yield and 90% ee with meric excesses were obtained with electron-rich aromatic al-
1.0 mol-% 5 and 1.0 mol-% N-oxide 3 (Table 2, entry 16). dehydes, while electron-deficient aromatic aldehydes gave
Further lowering of the temperature resulted in a decrease lower enantiomeric excesses for both catalyst systems. It is
both in yield and enantioselectivity (Table 2, entry 17). evident that the steric properties of the aromatic aldehydes
Hence, the optimal conditions were 1.0 mol-% 5 and have a great effect on the ee values of the products in this
1.0 mol-% achiral N-oxide 3 (TMSCN/aldehyde = 1.05), reaction. The ortho-substituted aromatic aldehydes gave
CH2Cl2, –10 °C.
lower ee than the meta-substituted and para-substituted
The purpose of this work is to compare the catalytic ac- aromatic aldehydes. In terms of chemical yield, para-substi-
tivity and the asymmetric induction ability of the two cata- tuted aromatic aldehydes were superior to meta- or ortho-
lytic systems. After screening the reaction conditions, the substituted ones. Curiously, the electron-rich 4-methyl benz-
reactions of various aldehydes, including aromatic, olefinic, aldehyde and 4-methoxybenzaldehyde were converted with
and aliphatic derivatives, with TMSCN were carried out moderate yields and better enantioselectivities when em-
under the optimal conditions, by employing bifunctional N- ploying complex 5 and N-oxide 3 as catalyst. For these two
Eur. J. Org. Chem. 2011, 3407–3411
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3409

C. Lv, Q. Cheng, D. Xu, S. Wang, C. Xia, W. Sun
SHORT COMMUNICATION
substrates, using complex 4 as catalyst led to excellent yields
(Table 3, entries 2, 5). Moderate enantioselectivities were
achieved in the cyanation of furfural and cinnamaldehyde
with the two catalyst systems; a better yield was observed
by using complex 4 (Table 3, entries 13, 14). The reactions
of n-heptaldehyde and trimethylacetaldehyde gave a high
catalytic activity and low asymmetric induction ability
(Table 3, entries 15, 16).
Acknowledgments
We are grateful for financial support from the Chinese Academy
of Sciences and National Natural Science Foundation of China
(21073210, 20873166).
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Conclusions
Two catalytic systems based on the same chiral diamine
derived from l-tartaric acid have been developed for the
addition of TMSCN to aldehydes by employing relatively
low catalyst loading and 1.05 equiv. of TMSCN. The per-
formance of bifunctional catalyst 4 and catalyst 5 in combi-
nation with 3 is compared. A variety of aldehydes were con-
verted into the corresponding trimethylsilyl ether of
cyanohydrins in good yields with moderate to excellent
enantioselectivities. Bifunctional catalyst 4, bearing an N-
oxide group in the ligand, shows better catalytic activity
than complex 5 even at low catalyst loading. However, the
asymmetric induction ability of catalyst 4 is inferior to 5
together with N-oxide compound 3. These studies also indi-
cated that an entire reversal of enantioselectivity was
achieved by adding an N-oxide group onto the ligand. Fur-
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efforts to extend the use of the present catalytic system in
other asymmetric reactions are currently in progress.
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Experimental Section
General Procedure for the Asymmetric Addition of Trimethylsilylcy-
anide to Aldehydes with Complex 4 as Catalyst: Complex 4 (1.6 mg,
0.002 mmol, 0.5 mol-%) and substrate (0.4 mmol) were added to
the solvent toluene (3 mL) under an Ar atmosphere in a test tube,
and the solution was stirred for 10 min at –20 °C. Then, TMSCN
(1.05 equiv., 0.42 mmol) was added to the solution, and the reac-
tion mixture was kept at –20 °C for 20 h. After that, the ee was
analyzed by GC (CP-Chirasil-Dex CB column). The desired prod-
ucts were obtained by short silica gel column chromatography
(200–300 mesh, 5:1 petroleum ether/ethyl acetate as eluent).
General Procedure for the Asymmetric Addition of Trimethylsilylcy-
anide to Aldehydes with Complex 5 and N-Oxide 3 as Catalyst:
Complex
5 (3.1 mg, 0.004 mmol, 1 mol-%) and N-oxide 3
(0.004 mmol, 1 mol-%) were added to the solvent CH2Cl2 (1 mL)
under an Ar atmosphere in a test tube, and the solution was stirred
for 40 min at –10 °C. Then, the substrate (0.4 mmol) was added to
this solution, and the mixture was stirred for 30 min. Finally,
TMSCN (1.05 equiv., 0.42 mmol) was added to the solution, and
the reaction mixture was kept at –10 °C for 24 h. After that, the ee
was analyzed by GC (CP-Chirasil-Dex CB column). The desired
products were obtained by short silica gel column chromatography
(200–300 mesh, 5:1 petroleum ether/ethyl acetate as eluent).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data for products, cop-
ies of NMR spectra of the products, and copies of GC spectra.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3407–3411

Salen–Ti-Catalyzed Asymmetric Cyanosilylation of Aldehydes
[10]
[11]
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Received: March 6, 2011
Published Online: May 19, 2011
Eur. J. Org. Chem. 2011, 3407–3411
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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