Highly active bifunctional salenTi(IV) catalysts for asymmetric cyanosilylation of aldehydes and TMSCN

Article abstract of DOI:10.1016/j.cclet.2011.06.016

A novel enantiopure salen ligand bearing a diphenylphosphine oxide on the 3-position of one aromatic ring was synthesized and combined with Ti(Oi-Pr) ₄ as a monometallic bifunctional catalyst for asymmetric cyanosilylation reaction of aldehydes with trimethylsilyl cyanide (TMSCN). The catalyst system exhibited excellent activity and moderate enantioselectivity. The addition of TMSCN to 4-nitrobenzaldehyde in the presence of 1 mol% catalyst loading could complete within 10 min at ambient temperature. An intramolecularly cooperative catalysis was observed in this system wherein the central metal Ti(IV) is suggested to play a role of Lewis acid to activate aldehydes while the appended diphenylphosphine oxide worked as Lewis base to activate TMSCN.

Full text of DOI:10.1016/j.cclet.2011.06.016

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1285–1288
www.elsevier.com/locate/cclet
Highly active bifunctional salenTi(IV) catalysts for asymmetric
cyanosilylation of aldehydes and TMSCN
*
Ye Qian Wen, Wei Min Ren, Xiao Bing Lu
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
Received 15 March 2011
Available online 30 July 2011
Abstract
A novel enantiopure salen ligand bearing a diphenylphosphine oxide on the 3-position of one aromatic ring was synthesized and
combined with Ti(Oi-Pr)4 as a monometallic bifunctional catalyst for asymmetric cyanosilylation reaction of aldehydes with
trimethylsilyl cyanide (TMSCN). The catalyst system exhibited excellent activity and moderate enantioselectivity. The addition of
TMSCN to 4-nitrobenzaldehyde in the presence of 1 mol% catalyst loading could complete within 10 min at ambient temperature.
An intramolecularly cooperative catalysis was observed in this system wherein the central metal Ti(IV) is suggested to play a role of
Lewis acid to activate aldehydes while the appended diphenylphosphine oxide worked as Lewis base to activate TMSCN.
# 2011 Xiao Bing Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Cyanohydrin; Bifunctional catalyst; Salen; TMSCN; Diphenylphosphine oxide
Asymmetric catalytic formation of C–C bonds is a basic and vital method in organic synthesis [1]. Cyanosilylation
reaction of carbonyl compounds with TMSCN has attracted much attention due to the easy construction of new chiral
center. Numerous catalyst systems including Lewis acids [2], Lewis bases [3], N-heterocyclic carbenes [4], metal
complexes [5], inorganic salts [6] and bifunctional catalysts [7–11] have been developed for the reaction of carbonyl
compounds with trimethylsilyl cyanide (TMSCN). Among them bifunctional catalysts are more fascinating. Shibasaki
and co-workers first reported the use of BINOL-based Lewis acid–Lewis base bifunctional catalyst 1 for
cyanosilylation of aldehydes [7]. In this system, activation of both substrates and nucleophiles occurs simultaneously
´
at the Lewis acid and the Lewis base moiety in the catalyst 1 (Fig. 1). Following this study, Najera et al. designed a
monometallic bifunctional catalyst BINOLAM-AlCl 2 for this reaction [8]. Other backbones, such as PyBOX
derivatives [9], and N-oxide containing ligand [10], were also used as ligands for catalyzing asymmetric
cyanosilylation reaction to afford cyanohydrins with high enantiomeric excess.
Salen ligands based on diimine-diphenolate bearing a linkage between two imine donors have emerged as one of
the most versatile synthetic ligands [11]. SalenTi(IV) complexes were reported as active catalyst for asymmetric
addition of TMSCN to aldehydes [2,10,12]. Recently, we have reported bifunctional metal-salen catalysts for the
coupling reaction of CO2 and epoxides to yield the corresponding organic carbonates with excellent activity [13,14].
Herein, we designed a new salen ligand L3 in which a phosphine oxide was attached on the 3-position of one aromatic
* Corresponding author.
E-mail address: lxb-1999@163.com (X.B. Lu).
1001-8417/$ – see front matter # 2011 Xiao Bing Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.06.016

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Y.Q. Wen et al. / Chinese Chemical Letters 22 (2011) 1285–1288
Fig. 1. Design of Lewis acid–base bifunctional catalyst.
ring through a methylene. The ligand, in combination with Ti(Oi-Pr)4, proved to be effective in catalyzing the addition
of TMSCN to aldehydes. In this catalyst system, the phosphine oxide is suggested to play a role of Lewis base to
activate nucleophile, while the central metal ion acted as Lewis acid to activate electrophile (Fig. 1).
1. Results and discussion
The chiral ligand L3 bearing a phosphine oxide on the 3-position of one aromatic ring was first synthesized. In order
to illustrate our speculation, symmetrical ligand L4 that possessed phosphine oxide groups on both 3- and 30-position
and ligand L5 in which the phosphine oxide group was appended on the 5-position of one aromatic ring have also been
synthesized (Fig. 2).
We delightedly found that the catalyst system based on L3 showed excellent activity and moderate
enantioselectivity, and up to 98% yield was achieved at 4 h with 1 mol% catalyst loading (Table 1, entry 1).
Interestingly, the catalyst system with regard to L4 also exhibited very high activity for this reaction, but the
enantioselectivity of the resulting cyanosilylation product is only 48% ee (entry 2). It is tentatively ascribed to the
attack of TMSCN at both Re- and Si-faces of the coordinated benzaldehyde, owing to the symmetrical structure of
the ligand.
For demonstrating the intramolecularly cooperative catalysis of the catalyst system of L3 in conjunction with
Ti(Oi-Pr)4, we also set out some control experiments. Firstly, ligand L5 in which diphenylphosphine oxide was
connected on 5-position of one aromatic ring was chosen for a comparison purpose. Under the same condition,
cyanosilylation product was obtained in 70% yield and 37% ee after 24 h (entry 3), whereas 70% ee was obtained with
the catalyst system regarding L3. It is tentatively ascribed to the far distance between the Lewis acid and Lewis base in
the system concerning L5, which is unfavourable to bring the activated TMSCN into appropriate position for attacking
aldehyde coordinating to titanium. Interestingly, when 1 mol% Ph3PO was added to the system of L3/Ti(Oi-Pr)4, lower
enantioselectivity was observed in the resultant product (entry 4).
Although the catalyst system consisting of cyclohexane-1,2-diamine derived salen ligand and Ti(Oi-Pr)4 had
been reported to be active on the asymmetric cyanosilylation of carbonyl compounds with TMSCN in 1996 [15],
further mechanistic investigation demonstrated that the actual catalytic species was dinuclear (salen)titanium
N
N
N
N
R4
OH HO
R3
OH HO
R1
R2
L3: R1=t-Bu; R2=CH2P(O)Ph2; R3=t-Bu; R4=t-Bu
L4: R1=CH2P(O)Ph2; R2=CH2P(O)Ph2; R3=t-Bu; R4=t-Bu
L5: R1=t-Bu; R2=t-Bu; R3=CH2P(O)Ph2; R4=t-Bu
L6
Fig. 2. Chiral ligands used for asymmetric cyanosilylation.

Y.Q. Wen et al. / Chinese Chemical Letters 22 (2011) 1285–1288
1287
Table 1
Cyanosilylation of aldehydes under selected condition
i
(1)1 mol% L-Ti(O Pr)
4
OH
*
O
CH Cl , rt
2
2
(CH ) SiCN
+
3 3
R
CN
R
H
2 mol/L HCl
2.0 eq
.
Entry
Ligand (Ln)
R
Time (h)
Yield(%)a
ee (%)b
1
2
3
4
5
3
6
6
3
3
3
3
3
3
Ph
4
3
98
70
48
37
59
–
Ph
99
3
4c
Ph
24
5
70
Ph
72
5
Ph
24
24
20
24
7
Trace
70
6c
7
Ph
51
69
69
60d
<1
26
52
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-NO2C6H4
(CH3)2CH
99
8
93
9
99
10
11
12
0.15
99
3
95
24
97
O
a
Isolated yields.
b
c
d
Determined by HPLC on a Chiralcel column (OD-H, OJ-H and AS-H), after conversion to the corresponding acetate.
1 mol% Ph3PO was added.
Determined of cynosilylation product straightforward by HPLC.
rather than the corresponding monometallic complex, due to the presence of the adventitious water in the system
[5a,16]. For a comparison purpose, the catalyst system consisting of L6 in conjunction with Ti(Oi-Pr)4 was tested
for this reaction under rigorously anhydrous conditions, but unfortunately only trace quantities of cyanosilylation
product was obtained (entry 5). Similar result was also observed with the use of titanium dichloride complex of
L6 as catalyst at the same conditions [17]. Interestingly, when 1 mol% Ph3PO was added, the above two catalyst
system all showed certain activity and moderate enantioselectivity (entry 6), though the activity is significantly
lower than that of the catalyst system regarding L3 and L4. This result also indicates that the appended phosphine
oxide on the salen ligand is more beneficial to cooperatively catalyse this reaction than free Ph3PO.
Furthermore, the catalytic system consisted of L3 in conjunction with Ti(Oi-Pr)4 was successfully applied to the
cyanosilylation of other aromatic aldehydes with TMSCN (entries 7ꢀ10). In the presence of 1 mol% catalyst at
ambient temperature, substituted benzaldehydes with an electron-donating group exhibited significantly low
reactivity in comparison with benzaldehyde. The resulting cyanosilylation products have moderate enantioselec-
tivity. On the contrary, 4-nitrobenzaldehyde showed excellent reactivity in the cyanosilylation with TMSCN and was
completely transformed into the corresponding product within 10 min. Surprisingly, the resulting cyanosilylation
product has no enantioselectivity (entry 10). Furthermore, the catalytic system was compatible with aliphatic
aldehyde (entry 11) and a,b-unsaturated aldehyde (entry 12), but relatively low enantioselectivities were observed in
the resultant products.
2. Conclusion
We have developed a novel bifunctional Ti(IV)-salen catalyst with a diphenylphosphine oxide on the 3-position of
one aromatic ring for the cyanosilylation of various aldehydes with TMSCN. This catalyst exhibits high activity in
comparison with binary catalyst systems concerning free Ph3PO. The appended phosphine oxide on the ligand plays a
role of Lewis base to activate TMSCN, and cooperatively catalyzes the cyanosilylation reaction with the central Ti(IV)
ion as Lewis acid.

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Y.Q. Wen et al. / Chinese Chemical Letters 22 (2011) 1285–1288
Acknowledgments
This work was support by a Foundation for the Author of National Excellent Doctoral Dissertation of China (No.
FANEDD, 200759).
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