Asymmetric cyanosilylation of ketones catalyzed by novel chiral N,N′-dioxide titanium complexes

Article abstract of DOI:10.1016/j.tetlet.2006.04.003

A novel C₂-symmetric chiral N,N′-dioxide titanium complex was described, which could efficiently catalyze the asymmetric cyanosilylation of ketones in high yields with up to 92% ee under mild conditions. In addition, the catalyst system was sim

Full text of DOI:10.1016/j.tetlet.2006.04.003

Tetrahedron Letters 47 (2006) 4011–4014
Asymmetric cyanosilylation of ketones catalyzed by novel chiral
0
N,N -dioxide titanium complexes
a
a
a
a
a,b,
*
Qinghan Li, Xiaohua Liu, Jun Wang, Ke Shen and Xiaoming Feng
a
Key Laboratory of Green Chemistry and Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
b
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Received 13 February 2006; revised 4 April 2006; accepted 6 April 2006
Available online 27 April 2006
0
Abstract—A novel C
2
-symmetric chiral N,N -dioxide titanium complex was described, which could efficiently catalyze the asymmetric
cyanosilylation of ketones in high yields with up to 92% ee under mild conditions. In addition, the catalyst system was simple and the
ligands could be easily prepared from commercially available chiral amino acid.
ꢀ
2006 Elsevier Ltd. All rights reserved.
0
Asymmetric cyanosilylation of ketones is intensively
studied due to the importance of cyanohydrins as the
versatile synthons. Although several outstanding cata-
ketones catalyzed by novel chiral proline-based N,N -
dioxides titanium complexes.
1
lyst systems have been identified for cyanation of car-
bonyl compounds,2 the development of asymmetric
cyanosilylation of ketones is still a challenge in terms
of their low reactivity and the difficulty in controlling
facial stereoselectivity in state-of-the-art asymmetric
synthetic methodologies. At present, the majority of
chiral catalysts used for this goal are chiral metal
Ligands 1, 2a–h, and achiral phenolic N-oxide 3 were
synthesized according to the literature (Fig. 1).
3j,9
Our studies were started with acetophenone as a model
substrate. In preliminary study, the catalytic activity of
different ligands was examined with different metal
sources for the catalytic cyanosilylation of acetophenone
at ꢀ20 ꢁC with 1.5 equiv of trimethylsilyl cyanide
3
4
complexes, cinchona alkaloids, chiral oxazoborolidin-
5
6
7
iumions, thiourea catalysts, and amino acid salts.
(TMSCN). We found that 2e–Ti(Oi-Pr) complex had
4
the highest capability of asymmetric induction among
In recent years, chiral N-oxide has played an important
ligands 1, 2a–g (Fig. 1), while the alternative enantiomer
role in efficiently promoting several synthetically useful
2h–Ti(Oi-Pr) promoted the same selective transforma-
tion to afford the alternative product, the antipode
(ꢀ54% ee).
4
8
transformations. Our group has reported the asymmet-
0
ric cyanosilylation of aldehydes by proline-based N,N -
9
dioxide, as well as enantioselective cyanosilylation of
ketones catalyzed by bifunctional N-monoxide titanium
A study on the solvent effect showed that THF provided
the best enantioselectivity (Table 1, entry 2). Effects of
the concentration showed that the optimum concentra-
tion of acetophenone was 0.5 M (Table 1, entry 5).
Further searching for the suitable additive revealed that
phenolic N-oxide 3 was the most promising one in this
catalytic system (Table 1, entry 7). We also found that
several parameters were important for both the reactivity
and enantioselectivity. Lowering the reaction tempera-
ture resulted in a remarkable enhancement in enantio-
selectivity (Table 1, entry 11, 92% yield with 86% ee at
ꢀ45 ꢁC). While further lowering the reaction temperature
led to a dramatic decrease in reactivity without any
complex only with moderate enantiomeric excess (up to
6
9% ee) of the desired product.10 In order to enhance the
activity and enantioselectivity, we designed a new class
0
of proline-based N,N -dioxides (Fig. 1), which could
be easily prepared from L-proline and amines. The reac-
0
tivity was greatly improved when N,N -dioxides were
used compared with N-monoxides. Herein, we wish to
report the results on the asymmetric cyanosilylation of
*
Corresponding author. Tel./fax: +86 28 8541 8249; e-mail:
xmfeng@scu.edu.cn
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.003

4012
Q. Li et al. / Tetrahedron Letters 47 (2006) 4011–4014
Ph Ph
NH
Ph Ph
NH
OH
O C
C O
O
O
adam
HN
O C
NH
C O
N
O
N
OH
N
O
O
tBu
3
N
N
1
2
h
R1
R1
NH
C O
NH
O C
O
O
a. R1 = cyclohexyl, R2 = CH3
b. R1 = 2-t-butylphenyl, R2 = CH3
Me
d. R1 = 1-adamantylphenyl, R2 = CH
e. R1 = diphenylmethyl, R2 = CH
3
N
OH
N
3
f. R1 = diphenylmethyl, R2 = t-Bu
g. R1 = diphenylmethyl, R2 = Cl
R2
c. R1
Ph, R2 = CH
=
3
2a-g
Figure 1. Screening of ligands and achiral phenolic N-oxide.
4
Table 1. Asymmetric cyanosilylation of acetophenone catalyzed by chiral ligand 2e–Ti(Oi-Pr) complex under various conditions
O
OTMS
2
e-Ti(OiPr)4
+
TMSCN
CH3
Ph
CH3
additive,solvent
Ph
CN
5a
4
a
a
b
c,d
Entry
2e (mol %)
Solvent
CH Cl
THF
Toluene
Et
Additive
Amount of additive (%)
Time (h)
Temp (ꢁC)
Yield (%)
ee (%)
e
1
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
10
2.5
2
2
—
—
—
—
—
—
3
—
—
—
—
—
—
5
5 mg
5
5
5
5
5
10
2.5
1.25
5
48
48
48
48
48
48
48
48
48
48
64
72
25
64
64
64
48
67
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ45
ꢀ78
rt
ꢀ45
ꢀ45
ꢀ45
ꢀ45
ꢀ45
89
95
95
94
92
94
93
51
58
67
92
81
80
90
88
85
89
82
55
58
48
48
59
52
67
52
53
56
86
86
40
86
85
80
86
86
e
2
e
3
e
4
2
O
f
5
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
g
6
7
8
9
˚
4 A MS
i-PrOH
10
11
12
13
14
15
16
17
18
Ph
3
3
P@O
3
3
3
3
3
3
3
5
a
b
c
d
e
f
Conditions: 2e–metal (1:1), concentration of acetophenone = 0.5 M, TMSCN 1.5 equiv.
Isolated yield.
Determined by GC on Chirasil DEX CB.
The absolute configuration of the major product was R, determined by the comparison with the reported values of optical rotation (Ref. 3c).
Concentration of acetophenone = 0.25 M.
Concentration of acetophenone = 0.5 M.
Concentration of acetophenone = 1.0 M.
g
improvement in enantioselectivity (Table 1, entry 12, 81%
yield with 86% ee at ꢀ78 ꢁC). When the reaction was car-
ried out at room temperature, enantioselectivity suffered
different ketones under the current catalytic conditions.11
As shown in Table 2, most of the aromatic, a,b-unsatu-
rated, heterocyclic and aliphatic ketones could be
converted into the corresponding cyanohydrin trimethyl-
silyl ethers in 62–91% yields with 78–92% ee. The para-
substituents (methyl, chloro, fluoro) on the aromatic ring
led to poorer enantioselectivities than acetophenone
(Table 2, entries 1–4), whereas the meta-chloro and
ortho-fluoro substituted ketone gave higher enantioselec-
(
Table 1, entry 13). Interestingly, the catalyst loading
had no effect on the enantioselectivity, but had only a
slight impact on the yield (Table 1, entries 11, 17, and 18).
Encouraged by the result obtained from acetophenone,
the scope of the reaction was then investigated with

Q. Li et al. / Tetrahedron Letters 47 (2006) 4011–4014
Table 2. Asymmetric cyanosilylation of ketones catalyzed by 2e–
4013
References and notes
Ti(Oi-Pr)
4
in the presence of 3
1
. For reviews on the synthesis and applications of cyano-
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O
OTMS
5
mol% 2e-Ti(OiPr)4
+
TMSCN
CH3
R
CH3
5 mol% 3,THF, -45 °C
R
CN
1
564; (c) North, M. Synlett 1993, 807–820; (d) North, M.
4
a-k
5a-k
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Time Yield ee
b
c
(
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(
f) North, M. In Science of Synthesis; Murahashi, S.-I.,
1
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4 -Methylacetophenone (4b)
72
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45
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36
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81
86
90
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90
91
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82
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90
0
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Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989–
0
0
0
0
4 -Chloroacetophenone (4c)
4 -Fluoroacetophenone (4d)
3 -Chloroacetophenone (4e)
2 -Fluoroacetophenone (4f)
88
d,f
b-Acetonaphthone (4g)
trans-4-Phenyl-3-buten-2-one (4h) 45
Benzylacetone (4i)
2-Acetylthiophene (4j)
2-Heptanone (4k)
92
e
92
1
999; (j) Special symposium for the synthesis of nonrace-
mic cyanohydrins, see: Tetrahedron 2004, 60, 10371–
0568.
36
72
36
78
83
79 (R)
1
0
1
1
1
2
. For an excellent recent review on the catalytic asymmetric
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a
Conditions: 5 mol % 2e–Ti(Oi-Pr)
concentration of acetophenone = 0.5 M in THF, TMSCN 1.5 equiv,
4
(1:1), 5 mol % additive N-oxide 3,
ꢀ
45 ꢁC.
(
b) Chen, F.-X.; Feng, X.-M. Synlett 2005, 892–899; (c)
Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett
005, 1491–1508; (d) Achard, T. R. J.; Clutterbuck, L. A.;
b
c
Isolated yield.
Determined by GC on Chirasil DEX CB. The absolute configurations
were determined by the comparison with the reported values of
optical rotation (Ref. 3c).
Determined by HPLC on Chiralcel OJ.
Determined by HPLC on Chiralcel OD.
mol % 2e–Ti(Oi-Pr)
tion of acetophenone = 0.5 M in THF, TMSCN 1.5 equiv, ꢀ78 ꢁC.
2
North, M. Synlett 2005, 1828–1847.
3
. (a) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H.
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hedron Lett. 1999, 40, 8147–8150; (c) Hamashima, Y.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
d
e
f
5
4
(1:1), 5 mol % additive N-oxide 3, concentra-
7
412–7413; (d) Hamashima, Y.; Kanai, M.; Shibasaki, M.
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tivity and yield than acetophenone (Table 2, entries 5 and
). trans-Cinnamophenone only gave 1,2-addition prod-
6
uct in 90% yield with 92% ee (Table 2, entry 8), while
benzylacetone gave poor result (Table 2, entry 9). b-Aceto-
naphthone afforded higher enantioselectivity than
acetophenone (Table 2, entry 7). The heterocyclic ketone
gave the corresponding product with good enantioselec-
tivity and moderate yield (Table 2, entry 10). Simple
aliphatic ketone provided the corresponding product with
moderate enantioselectivity and good yield (Table 2,
entry 11).
2
002, 43, 2923–2926; (g) Masumoto, S.; Suzuki, M.;
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8
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6
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In conclusion, asymmetric cyanosilylation of ketones
was achieved using 5 mol % of the chiral N,N -dioxide
0
Chem. Soc. 2003, 125, 9900–9901.
. Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127,
5
6
titanium complex and good yields of the corresponding
OTMS ethers of cyanohydrins were obtained with high
enantioselectivities (up to 92% ee) under mild reaction
conditions. Further investigations are planned to pro-
vide additional information with regard to the scope
and precise mechanism of the reaction.
5
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. Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
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Acknowledgments
2
004, 4, 2799–2801; (e) Malkov, A. V.; Orsini, M.;
We thank the National Natural Science Foundation of
China (Nos. 20225206, 20390055, and 20372050) and
the Ministry of Education, PR China (No. 104209 and
others), and Sichuan University (No. 2004CF07) for
financial support.
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2
at 35 ꢁC for 1 h under N . After the addition of aceto-
4
phenone (0.5 mmol), the reaction was cooled to ꢀ45 ꢁC.
Subsequently, TMSCN was added (161 lL, 4M in THF,
0.75 mmol) in one portion. After 72 h, the solution was
concentrated and the residue was purified by silica gel
column chromatography (petroleum ether/diethyl ether,
100:1) to afford the corresponding cyanohydrin trimethyl-
silyl ethers as colorless oil (86.4 mg, 81% yield, 86% ee).
The enantioselectivity was determined by GC [Varian, CP-
Chirasil DEX determined by Chiral GC analysis on
Chirasil DEX CB (0.25 mm · 25 m), column tempera-
ture: 105 ꢁC (isothermal), injection temperature: 250 ꢁC,
(
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L. Org. Lett. 2005, 7, 3151–3154; (k) Malkov, A. V.; Bell,
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. Wen, Y.-H.; Huang, X.; Hang, J.-L.; Xiong, Y.; Qin, B.;
Feng, X.-M. Synlett 2005, 2445–2448.
9
detector temperature: 250 ꢁC, inlet pressure: 8 psi]: t
R
1
1
0. Shen, Y.-C.; Feng, X.-M.; Zhang, G.-L.; Jiang, Y. Z.
(minor, (S)) = 21.5 min,
t
(major, (R)) = 22.1 min.
R
2
D
5
22
D
Synlett 2002, 1353–1355.
½aꢁ +7.03 (c 1.92, CH
2
Cl
2
, 86% ee) {Ref. 3k ½aꢁ
1
1. A representative procedure: Ti(Oi-Pr)
5 lL, 0.025 mmol) was stirred with 2e (18.1 mg, 0.025
mmol) and N-oxide 3 (9.5 mg, 0.025 mmol) in THF (1 mL)
4
(1 M in toluene,
2 2
+16.9 (c 2.58, CH Cl , 94% ee)}. H NMR (300
2
MHz, CDCl
5H).
3
): d 0.19 (s, 9H), 1.87 (s, 3H), 7.38–7.58 (m,