Enantioselective cyanation of aldehydes catalyzed by bifunctional salen-aluminum complex

Article abstract of DOI:10.1016/j.catcom.2012.06.025

Chiral N-oxide salen ligands and their corresponding Al complexes were synthesized. Notably, the catalytic activity and asymmetric induction ability of the bifunctional N-oxide salen-Al for asymmetric cyanosilylation were compared with that of bi-componen

Full text of DOI:10.1016/j.catcom.2012.06.025

Catalysis Communications 27 (2012) 138–140
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Enantioselective cyanation of aldehydes catalyzed by bifunctional
salen–aluminum complex
Chengwei Lv a,b, Cheng-Xia Miao a, Daqian Xu a, Shoufeng Wang a, Chungu Xia a, Wei Sun a,
⁎
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
Chemistry and Chemical Engineering Faculty, Liaoning Normal University, Dalian 116029, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2012
Received in revised form 23 June 2012
Accepted 27 June 2012
Available online 21 July 2012
Chiral N-oxide salen ligands and their corresponding Al complexes were synthesized. Notably, the catalytic activ-
ity and asymmetric induction ability of the bifunctional N-oxide salen-Al for asymmetric cyanosilylation were
compared with that of bi-component catalyst system including chiral pyrrolidine salen–Al complex and
Ph3PO. Interestingly, introducing N-oxide group in salen unit could enhance the activity and enantioselectivity
of bifunctional catalyst without further adding Ph3PO as co-catalyst and inverse configurations were generated
from the two systems. In addition, excellent yields and high ee values could be obtained under milder conditions
in bifunctional catalyst system compared with that of bi-component catalyst system.
Keywords:
Asymmetric cyanosilylation
Bifunctional catalyst
Bi-component catalyst
Salen–Al complex
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
the addition of Et2Zn to aldehyde [23], Strecker and Aldol reaction [24]
and the reduction of ketones [25] and so on [26,27]. Especially, chiral
Catalytic enantioselective cyanation of carbonyl compound is a
pivotal process for synthesis of enantiomerically pure cyanohydrins,
which are important subunits frequently found in biologically active
compounds and versatile building blocks for pharmaceuticals, agro-
chemicals and specialty materials [1–6]. In view of their importance,
much effort has been devoted to designing and synthesizing of
more efficient chiral catalyst for the asymmetric cyanation of carbon-
yl compound [3,4,7–9]. Among the various catalysts, chiral Ti or Al–
salen complexes are the most widely used and effective ones for the
asymmetric cyanation reaction [10–16]. In the systems catalyzed by
chiral Ti-salen complexes, Ding [14], Belokoń and North [15] gained
unprecedented progress. Although significant progress has been also
made in chiral Al-salen catalyzed systems [12,17], additives such as
Ph3PO or derivatives are essential to achieve high efficiency and
enantioselectivity. That's to say, it was necessary to additionally add
some additives to activate the cyanosilylation agent and facilitate cy-
anide delivery to the activated substrate. Recently, it is popular to de-
sign bifunctional asymmetric catalysts consisting of Lewis acid and
Lewis base/Brønsted base moieties, which activate both electrophiles
and nucleophiles at defined positions simultaneously, to avoid the
N-oxide compounds have been relative systemically investigated for
the asymmetric cyanosilylation and Feng et al. have made a signifi-
cant progress in this respect [4].
In conjunction with the project on developing new tetradentate
complexes as catalysts for asymmetric reactions [28–33], we wanted
to apply the N-oxide salen ligands which have been used in the asym-
metric cyanosilylation by our group (Fig. 1), and their corresponding
Aluminum complexes (Fig. 2, 4) as bifunctional catalysts to asymmetric
addition of trimethylsilyl cyanide (TMSCN) to benzaldehyde. Herein,
the catalytic activity and the asymmetric induction ability of the bifunc-
tional catalysts were compared with that of the bi-component system
including simple pyrrolidine salen-Al (Fig. 2, 3) in combination with
Ph3PO. To be delighted, introducing N-oxide group in salen unit really
enhanced the activity and enantioselectivity of bifunctional catalyst
without further adding Ph3PO as co-catalyst and inverse configurations
were generated from the two systems [29].
2. Experimental
2.1. Preparation of the corresponding Al complexes 3 or 4
use of additives. Interestingly,
a number of 1,1′-bi-2-naphthol
(BINOL)-based bifunctional chiral catalysts have been successfully ap-
plied in asymmetric cyanation of carbonyl compound [18–20].
On the other hand, chiral N-oxides have been extensively used in
asymmetric reactions, such as the allylation of aldehydes [21,22],
Chiral N-oxide salen and chiral pyrrolidine salen ligands were pre-
pared as we described before [29]. The corresponding Al complex
were synthesized by the reaction of equimolar amounts of ligand 1b
or 2a and AlEt2Cl (25% w/w in heptane) in dry CH2Cl2 under an argon
atmosphere stirring for 10 h at room temperature. Then the solvent
was evaporated under vacuum and the crude product was washed
with hexane to give the salen-Al 3 or 4 as a brown solid. Compound 3:
⁎
Corresponding author. Tel.: +86 931 496 8278; fax: +86 931 827 7088.
E-mail address: wsun@licp.cas.cn (W. Sun).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2012.06.025

C. Lv et al. / Catalysis Communications 27 (2012) 138–140
139
Fig. 1. Chiral ligands used in the study.
IR (KBr): 2958, 2906, 1623, 1555, 1540, 1466, 1438, 1391. HRMS
(ESI-MS) calcd. for 648.4110, found:
41H55N3O2Al: [M-Cl-O]+
yield and ee employing 4 as the catalyst neither in the presence or ab-
sence of Ph3PO (entries 8 vs 9).
C
:
648.4099. Compound 4: IR (KBr): 2957, 2906, 2868, 2796, 1626, 1469,
1440. HRMS (ESI-MS) calcd. for C53H67N3O2Al: [M-Cl]+: 804.5049,
found: 804.5029.
Subsequently, the parameters of the reaction conditions were sys-
tematically optimized employing 3 or 4 as the catalyst respectively
(see Supporting Information, Table S1 and Table S2). After rough op-
timization, the reaction conditions for 3 were 1 mol% catalyst,
10 mol% Ph3PO and 2 equiv. of TMSCN in CHCl3 at −10 °C for 24 h
(Table 1, entry 5); on the other hand, 1 mol% catalyst and 1.2 equiv.
of TMSCN in toluene at 0 °C for 10 h were the optimized conditions
by employing 4 as the catalyst (Table 1, entry 10). As a whole, excel-
lent yields and high ee values could be obtained under milder condi-
tions in bifunctional catalyst system compared with that of
bi-component catalyst system. Interestingly, inverse configurations
were generated from the two systems.
Encouraged by the results, we further examined the utility and
generality of the approach for the asymmetric addition of
trimethylsilylcyanide to different aldehydes including aromatic, allyl-
ic and aliphatic derivatives catalyzed by the bifunctional N-oxide cat-
alyst 4 and the data were summarized in Table 2. Most aromatic
aldehydes could be transformed into the desired product with mod-
erate to excellent ees and good yields (Table 2, entries 1–12). Obvi-
ously, the results indicated that the steric hindrance had great
impact on the ees and had no significant influence on yields. The ees
were lower for most ortho-substituted benzaldehyde than others
with meta- or para-substitute (entries 2, 9, 10 and 11), especially
for 2,6-dichloro benzaldehyde. However, unexpected phenomena
that 4-methoxybenzaldehyde was converted with high yield in com-
bination with low enantioselectivities and 2-methoxybenzaldehyde
gave good yield and selectivity were observed (entries 5 and 7). On
the other hand, the ees and yields have slightly relationship with
the electronic effect. Particularly, 92% ee could be acquired employing
4-tri-fluoromethyl benzaldehyde as the substrate (entry 12). Addi-
tionally, furfural gave approximate ee and yield with benzaldehyde
(entry 13). Furthermore, allylic aldehyde also afforded 68% ee with
good yields (entry 14). Aliphatic aldehydes, such as heptaldehyde,
reacted smoothly with TMSCN and gave a high catalytic activity
with moderate asymmetric induction ability (entry 16). Unfortunate-
ly, trimethylacetaldehyde did not furnish a satisfactory result due to
the influence of the corresponding tBu group (entry 15). Besides,
2.2. General procedure for the asymmetric addition of trimethylsilylcyanide
to aldehydes employing complex 4 as catalyst
To a solution of complex 4 (2.8 mg, 0.004 mmol, 1 mol%) and sub-
strate (0.4 mmol) in toluene (1 mL) under Ar atmosphere stirred for
10 min at 0 °C, 1.2 equiv. of TMSCN (0.48 mmol) was added and the
reaction mixture was kept at 0 °C for 10 h. After that the ee was ana-
lyzed by GC (CP-Chirasil-Dex CB column). The yields were obtained
by short silica gel column chromatograph (200–300 mesh, 5:1 petro-
leum ether/ethyl acetate as eluent). Absolute configurations were de-
termined by comparison the known order of elution of the two
enantiomers or the sign of optical rotation with literature data
[34,35].
3. Results and discussion
In the preliminary experiments, the asymmetric addition of
TMSCN to benzaldehyde was chosen as the model reaction to evalu-
ate the activity and enantioselectivity of the catalyst systems. Firstly,
the activities of the catalysts prepared in situ by stirring ligands
with AlEt2Cl at room temperature for 2 h in dichloromethane were
investigated (Table 1, entries 1, 2, 6 and 7). Interestingly, substituents
at 3, 3′-position of salen ligands 1 had some effect on the ee values
and had no influence on the yields. It was shown that adamantly larg-
er group was beneficial to the enantioselectivity and tBu group even
abolished the asymmetric inductivity completely. On the other
hand, the yields and the ees had almost no relationship with the sub-
stituents of ligand 2. Additionally, there is only slightly increase in
enantioselectivity directly employing Al-complex 3 or 4 as catalyst
(entries 2 vs 3, and 6 vs 8). Obviously, Ph3PO was important for 3
and the enantioselectivity or yield of mandelonitrile was dramatically
decreased without it (entries 3 vs 4). However, there is no change in
Fig. 2. The corresponding Al-complexes derived from ligands 1b and 2a.

140
C. Lv et al. / Catalysis Communications 27 (2012) 138–140
Table 1
employing bifunctional N-oxide salen-Al complex as catalyst could pro-
mote the reaction smoothly without adding Ph3PO as co-catalyst and
give excellent yields and high ee values under milder conditions (0 °C,
1.2 equiv. TMSCN and 10 h) than bi-component catalyst system. Fur-
thermore, inverse configurations were generated from the two systems.
Developing new, efficient and highly enantioselective ligands and fur-
ther studies on asymmetric catalysis are currently underway in our
laboratory.
The screening of reaction conditions for the addition of TMSCN to benzaldehyde.a
Entry
Cat. (mol%)
TMSCN
(equiv)
Ph3PO (mol%)
Conv.b (%)
Eec (%)
1
2
3
1a+AlEt2Cl (2)
1b+AlEt2Cl (2)
3 (2)
3 (2)
3 (1)
2a+AlEt2Cl (2)
2b+AlEt2Cl (2)
4 (2)
4 (2)
4 (1)
1.5
1.5
1.5
1.5
2.0
1.5
1.5
1.5
1.5
1.2
10
10
10
0
10
0
0
0
10
0
93
92
96
16
99
99
99
99
99
99
rac
9 (S)
13 (S)
8 (R)
82 (S)
23 (R)
25 (R)
30 (R)
30 (R)
80 (R)
Acknowledgement
4
We are grateful for financial support from the Chinese Academy of
Sciences and the National Natural Science Foundation of China
(21073210, 20873166).
5d
6
7
8
9
Appendix A. Supplementary data
10e
a
Conditions: entries 1–4 are carried out at rt for 20 h, entries 6–9 are carried out for
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.06.025.
10 h.
b
c
GC yield, n-nonane as internal standard.
Enantiomeric excess of silyl ether is determined by chiral GC with
a
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Cyanation of aldehydes with TMSCN catalyzed by catalyst 4.a
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Entry
Aldehyde
Cat. 4
Yieldb
(%)
Eec
(%)
1
2
3
4
5
6
7
8
Benzaldehyde
97
93
93
89
95
96
93
96
88
90
85
98
94
91
9
80 (R)
76 (R)
80 (R)
67 (R)
45 (R)
86 (R)
84 (R)
82 (R)
54 (R)
12
4-Methyl benzaldehyde
3-Methyl benzaldehyde
2-Methyl benzaldehyde
4-Methoxy benzaldehyde
3-Methoxy benzaldehyde
2-Methoxy benzaldehyde
4-Chloro benzaldehyde
2-chloro benzaldehyde
2,6-Dichloro benzaldehyde
2-Bromo benzaldehyde
4-Tri-fluoromethyl benzaldehyde
Furfural
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9
10
11
12
13
14
15
16
72
92 (R)
76 (R)
68 (R)
54 (R)
76 (R)
Cinnamaldehyde
Trimethyl acetaldehyde
Heptaldehyde
90
a
All reactions are carried out in the present of 1 mol% of 4 in toluene at 0 °C for 10 h
with 1.2 equiv TMSCN.
b
Isolated yield.
c
Enantiomeric excess of silyl ether is determined by chiral GC with a CP-Chirasil-Dex
CB column. Absolute configurations were determined by comparison the known order
of elution of the two enantiomers.