Asymmetric cyanosilylation of α-keto esters catalyzed by the [Ru(phgly)2(binap)]-C6H5OLi system

Article abstract of DOI:10.1002/ejoc.200901501

The asymmetric reaction of α-keto esters and (CH₃) ₃SiCN, catalyzed by a combined system of [Ru{(S)-phgly} ₂{(S)-binap}] and C₆H₅OLi with a substrate-to-catalyst molar ratio (S/C) of 1000 at -60 °C, affords silylated cyanohydrins in up to 99% ee. Cyanosilylation smoothly proceeds with an S/C of 10,000 at -50 °C. The use of Xyl-Binap instead of Binap as a ligand provides better enantioselectivity in some cases. A series of aromatic, hetero-aromatic, aliphatic, and α,β-unsaturated keto esters are converted into the desired products.

Full text of DOI:10.1002/ejoc.200901501

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901501
Asymmetric Cyanosilylation of α-Keto Esters Catalyzed by the
[Ru(phgly)2(binap)]–C6H5OLi System
Nobuhito Kurono,[a] Masato Uemura,[a] and Takeshi Ohkuma*[a]
Keywords: Asymmetric catalysis / Lithium / Ruthenium / Cyanosilylation
The asymmetric reaction of α-keto esters and (CH3)3SiCN,
catalyzed by combined system of [Ru{(S)-phgly}2{(S)-
binap}] and C6H5OLi with a substrate-to-catalyst molar ratio
(S/C) of 1000 at –60 °C, affords silylated cyanohydrins in up
to 99% ee. Cyanosilylation smoothly proceeds with an S/C
of 10,000 at –50 °C. The use of Xyl-Binap instead of Binap as
a ligand provides better enantioselectivity in some cases. A
series of aromatic, hetero-aromatic, aliphatic, and α,β-unsat-
urated keto esters are converted into the desired products.
a
Introduction
Results and Discussion
[Ru{(S)-phgly}2{(S)-binap}] [(S,S,S)-3a] (Scheme 1) was
prepared according to the method described in our previous
report.[10] We selected methyl benzoylformate (1a) as the
standard substrate to optimize the reaction conditions. The
reaction of 1a (0.82 g, 5.0 mmol, 0.1 ) and (CH3)3SiCN
(0.99 g, 10.0 mmol) with (S,S,S)-3a (5.1 mg, 5.0 µmol, S/C
= 1000) and C6H5OLi (100 m in THF, 50 µL, 5.0 µmol)
in tC4H9OCH3 at –40 °C was completed in 3 h to afford the
R cyanation product, (R)-2a, in 97% ee (Table 1, Entry 1).
Excellent enantioselectivity of 99% was achieved at –60 °C
under otherwise identical conditions, although the reaction
rate was slower at the lower temperature (Entry 2). Cyan-
ation at –70 °C was not completed within 24 h without an
increase in enantioselectivity (Entry 3). Use of 2 equiv. of
(CH3)3SiCN to 1a was required for completion of the reac-
tion at –60 °C within 18 h (Entry 2). The yield of 2a was
decreased with decreasing amounts of reagent (Entries 4
and 5). The initial concentration of 1a affected the enantio-
The development of effective methods for the synthesis
of optically active compounds with a multi-functionalized
carbon center is highly desirable in the field of modern or-
ganic synthesis. To this end, the asymmetric cyanosilylation
of ketones is among the most reliable and versatile pro-
cedures.[1–6] In the presence of the appropriate chiral cata-
lysts, the tertiary cyanohydrin derivatives are obtained in
high enantiomeric excess (ee). However, to the best of our
knowledge, this asymmetric reaction of α-keto esters, a typi-
cal class of functionalized ketones, has not been reported
to date.[7–9] The presence of an ester moiety, which can in-
teract with the metal of catalysts, adjacent to the reaction
center may introduce difficulty into enantioface selection.
We recently reported the asymmetric cyanosilylation of
aldehydes with a novel combined catalyst of [Ru(phgly)2(bi-
nap)] and a Li salt.[10,11] The cooperation of a Lewis acidic
Li cation and the chiral Ru complex enables this asymmet-
ric transformation to proceed with high catalytic efficiency.
Herein we report for the first time the highly enantioselec-
tive cyanosilylation of α-keto esters with a catalyst system
consisting of the Binap–Ru(phgly)2 complex and C6H5OLi.
The reaction is conducted with a substrate-to-catalyst mo-
lar ratio (S/C) of 1000 at –60 °C, and 10,000 at –50 °C. A
series of aromatic, hetero-aromatic, aliphatic, and α,β-un-
saturated α-keto esters are converted into the silylated
cyanohydrins with an ee of up to 99%.
[a] Division of Chemical Process Engineering, Graduate School of
Engineering,
Hokkaido University, Japan
Fax: +81-11-706-6598
E-mail: ohkuma@eng.hokudai.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901501.
Scheme 1. Asymmetric cyanosilylation of methyl benzoylformate
(1a) with 3a and C6H5OLi.
Eur. J. Org. Chem. 2010, 1455–1459
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1455

N. Kurono, M. Uemura, T. Ohkuma
selectivity of this reaction. The ee value of 99% with 0.1  Table 2. Asymmetric cyanosilylation of α-keto esters 1.[a]
SHORT COMMUNICATION
of 1a decreased to 97% when the concentration of 1a was
increased to 0.8  (Entries 2, 6, and 7).
Entry
1
[1]0 [M][b]
3
S/C[c] T [°C] t [h] Yield [%][d] ee [%][e]
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1e
1e
1f
0.1
0.3
0.3
0.3
0.3
0.1
0.1
0.1
0.3
0.1
0.1
0.1
0.1
0.1
0.1
0.3
0.1
0.1
0.1
0.1
0.1
0.1
3a 1000
3a 10000
3a 10000
3a 10000
3a 10000
3a 1000
3b 1000
3a 1000
3a 10000
3a 1000
3a 1000
3a 1000
3a 1000
3a 1000
3a 1000
3a 10000
3a 1000
3a 1000
3a 1000
3b 1000
3a 1000
3a 1000
–60
–50
–50
–50
–50
–60
–60
–60
–50
–60
–60
–60
–60
–60
–60
–50
–50
–60
–60
–60
–60
–60
18
18
36
18
24
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
97
98
97
94
97
98
98
97
95
92
97
98
92
96
97
96
94
99
92
94
98
98
99
98
87
49
53
90
94
97
98
95
98
98
92
95
98
97
92
91
88
94
85
97
Table 1. Asymmetric cyanosilylation of methyl benzoylformate
(1a).[a]
Entry [1a]0 [M][b] CN/S[c] S/C[d] T [°C] t [h] Yield [%][e] ee [%][e]
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
0.3
0.8
0.1
0.3
0.3
0.3
0.8
2.0
2.0
2.0
1.5
1.2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1000
1000
1000
1000
1000
–40
–60
–70
–60
–60
–60
–60
–40
–40
–50
–60
–50
3
Ͼ99
Ͼ99
97
91
65
Ͼ99
99
Ͼ99
Ͼ99
Ͼ99
69
97
99
99
99
98
98
97
97
97
98
98
96
18
24
18
18
18
18
36
18
18
18
18
9
1f
10
11
12
13
14
15
16
17
18
19
20
21
22
1g
1h
1i
1j
1k
1l
1000
1000
10000
10000
10000
10000
10000
9
10
11
12
1l
1m
1n
1o
1o
1p
1q
Ͼ99
[a] Unless otherwise stated, reactions were carried out using 1a (5–
10 mmol) and (CH3)3SiCN in tert-C4H9OCH3 with a Ru complex
(S,S,S)-3a (1–5 µmol) and C6H5OLi. 3a:C6H5OLi = 1:1. [b] Initial
concentration of 1a. [c] Molar ratio of (CH3)3SiCN to substrate
(1a). [d] Substrate-to-catalyst (3a) molar ratio. [e] Data for (R)-2a
determined by chiral GC analysis.
[a] Unless otherwise stated, reactions were conducted using 1 (5–
10 mmol) and 2 equiv. of (CH3)3SiCN in tC4H9OCH3 with a Ru
complex (S,S,S)-3 (1–5 µmol) and C6H5OLi. 3:C6H5OLi = 1:1. [b]
Initial concentration of 1. [c] Substrate (1)-to-catalyst (3) molar
ratio. [d] Yield of isolated (R)-2. Yields determined by GC analysis
were Ͼ99% in all cases. [e] Data for (R)-2 determined by chiral GC
or HPLC analysis.
The cyanation of 1a (0.1 ) in the presence of (S,S,S)-3a
and C6H5OLi with an S/C of 10,000 at –40 °C for 36 h af-
forded (R)-2a in 97% ee quantitatively (Table 1, Entry 8).
The reaction rate was increased without loss of the enantio-
selectivity when a concentration of 0.3  1a was used (Entry
9). A higher ee value of 98% was attained when cyanation
was conducted at –50 °C (Entry 10). The reaction rate was
markedly reduced at –60 °C (Entry 11). Cyanation with
0.8  of 1a at –50 °C gave 2a in 96% ee (Entry 12).
Thus, we selected the reaction conditions using 1a (0.1 )
and 2 equiv. of (CH3)3SiCN in tC4H9OCH3 with (S,S,S)-3a
and C6H5OLi (3a:C6H5OLi = 1:1) at an S/C of 1000 at
–60 °C to afford (R)-2a in 99% ee quantitatively (Table 2,
Entry 1; see also Table 1, Entry 2). The desired product was
readily isolated in 97% yield by bulb-to-bulb distillation af-
ter removal of the metal compounds and excess (CH3)3-
SiCN (See the Experimental Section). When an even higher
turnover number (i.e., close to 10,000) is required, we
recommend the following conditions: 1a (0.3 ) in
tC4H9OCH3, (CH3)3SiCN (2 equiv.), (S,S,S)-3a with
C6H5OLi (S/C = 10,000), –50 °C (Table 2, Entry 2; see also
Table 1, Entry 10).
Enantioselectivity was notably influenced by the size of
the ester moieties of the substrates (Scheme 2). Methyl ester
1a was converted to 2a in 98% ee at –50 °C with the 3a– Scheme 2. Asymmetric cyanosilylation of α-keto esters 1 with 3 and
C6H5OLi.
C6H5OLi system (S/C = 10,000) (Table 2, Entry 2). The
cyanation of the ethyl ester 1b, isopropyl ester 1c, and tert-
butyl ester 1d under the same conditions gave 2b, 2c, and (Scheme 2)[12] instead of 3a (Entry 7). Stereo-demanding
2d in 87%, 49%, and 53% ee, respectively (Entries 3–5).
3,5-xylyl groups on the phosphorus atoms contributed to
When methyl 2Ј-methylbenzoate (1e) was treated with form the more suitable chiral enviraonment for this sub-
(CH3)3SiCN catalyzed by the (S,S,S)-3a–C6H5OLi system strate. The reaction of sterically less crowded 3Ј-methyl- and
with an S/C of 1000 at –60 °C, the R cyanohydrin product, 4Ј-methylbenzoylformates, 1f and 1g, with the 3a–C6H5OLi
(R)-2e, was obtained in 90% ee (Scheme 2 and Table 2, En- catalyst gave the chiral products, 2f and 2g, in 97% and
try 6). Fortunately, the ee value was increased to 94% 95% ee, respectively (Entries 8 and 10). The keto ester 1f
by using [Ru{(S)-phgly}2{(S)-xyl-binap}] [(S,S,S)-3b] (0.3 ) and (CH3)3SiCN were smoothly reacted with an
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Eur. J. Org. Chem. 2010, 1455–1459

Asymmetric Cyanosilylation of α-Keto Esters
S/C of 10,000 at –50 °C to afford 2f in 98% ee (Entry 9). The signal of (CH3)3SiOC6H5 remained unaltered during
The chlorinated keto esters at the 3Ј or 4Ј position, 1h and this procedure. Based on these data, a plausible reaction
1i, were quantitatively cyanated with the 3a–C6H5OLi sys- pathway is depicted in Scheme 3 (nonproductive and minor
tem (S/C = 1000) at –60 °C for 18 h to give 2h and 2i in pathways were not considered in this depiction). The reac-
98% ee in both cases (Entries 11 and 12). Substitution of a tion of 3, C6H5OLi, and (CH3)3SiCN gives [3·Li]CN and
strongly electron-attracting CF3 group at the 4Ј position (1j) (CH3)3SiOC6H5.[14] Keto ester 1 smoothly reacts with
decreased the ee value of product to 92%, while reactivity [3·Li]CN (in which [3·Li]+ acts as an efficient chiral Lewis
was only slightly influenced by this change in the electronic acid) to give the cyanohydrin anion with [3·Li]+.[15] This
condition (Entry 13). On the other hand, the cyanation of intermediate is silylated spontaneously with (CH3)3SiCN,
the aromatic ketone bearing an electron-donating CH3O resulting in the formation of product, 2, and the regenera-
group at the 4Ј position, 1k, catalyzed by the 3a–C6H5OLi tion of [3·Li]CN.
system quantitatively gave 2k in 95% ee under the typical
conditions (Entry 14). Methyl 2Ј-naphthoylformate (1l) was
found to be a good substrate for this asymmetric reaction,
affording the cyantion product 2l in 98% ee quantitatively
(Entry 15). High reactivity and enantioselectivity were
maintained in the cyanation of 1l with an S/C of 10,000 at
–50 °C (Entry 16).
A 3Ј-furyl ketone, 1m, was treated with the 3a–C6H5OLi
catalyst (S/C = 1000) at –50 °C due to its low solubility in
tC4H9OCH3, resulting in the product 2m in 92% ee quanti-
tatively (Entry 17). The hetero-aromatic ring was left intact.
The reaction of 2Ј-thienyl ketone 1n at –60 °C gave 2n in
91% ee (Entry 18).
Scheme 3. Proposed mechanism for cyanosilylation of α-keto esters
1.
Conclusions
The cyanation of methyl pivaloylformate (1o), a sterically
hindered aliphatic keto ester, smoothly proceeded with the
(S,S,S)-3a–C6H5OLi catalyst (S/C = 1000) at –60 °C to give
(R)-2o in 88% ee (Table 2, Entry 19). The sense of enantio-
face selection was the same as that in the reaction of benzo-
ylformate 1a. The ee value was increased to 94% when the
reaction was carried out with the 3b–C6H5OLi catalyst (En-
try 20). A secondary alkyl ketone, 1p, was cyanated with
the 3a–C6H5OLi system to give 2p in 85% ee (Entry 21).
The reaction of a 1-cyclohexenyl ketone, 1q, catalyzed by
the 3a–C6H5OLi system, afforded 2q in 97% ee quantita-
tively (Entry 22). No conjugated-addition product was ob-
served.
We report here the first example of the highly reactive
and enantioselective cyanosilylation of α-keto esters with a
unique [Ru(phgly)2(binap)]–C6H5OLi catalyst system. The
cyanation smoothly proceeds with an S/C of 1000 at –60 °C
and 10,000 at –50 °C. The use of stereo-demanding Xyl-
Binap ligand in place of Binap achieves better stereoselecti-
vity in some cases. A series of aromatic, hetero-aromatic,
aliphatic, and α,β-unsaturated α-keto esters are converted
into the cyanohydrin products in up to 99% ee. Spectro-
scopic analysis suggests that [Li·{Ru(phgly)2(binap)}]CN is
a plausible reactive species. Thus, this finding provides an
efficient procedure for the constructing of multi-function-
alized chiral carbon centers.
Comparison of enantioselectivity in the reaction of 1a
(phenyl ketone), 1p (cyclohexyl ketone), and 1q (cyclohex-
enyl ketone) with the 3a–C6H5OLi system (Table 2, Entries
1, 21, and 22) suggested that this catalyst prefers aryl and
alkenyl groups (Csp2 groups) to alkyl groups (Csp3 groups)
from CO2CH3 group (Csp2 group), although the mode of
enantioface-selection is unclear.
Experimental Section
General Procedure for the Cyanosilylation of α-Keto Esters: The
cyanosilylation of 1a illustrates the typical reaction procedure. Cau-
tion: (CH3)3SiCN must be used in a well-ventilated hood due to its
high toxicity. Ruthenium complex (S,S,S)-3a (5.1 mg, 5.0 µmol)[10]
was placed in a 500-mL Schlenk flask, and the air present in this
apparatus was replaced by argon. Anhydrous tert-C4H9OCH3
(50 mL), 1a (0.82 g, 5.0 mmol), and C6H5OLi (100 m in THF,
Here, ESI mass-spectrometric measurement of a 1:1:10
mixture of Ru complex 3a (m/z 1024), C6H5OLi, and (CH3)3-
SiCN showed prominent signals corresponding to the Ru–
Li combined species [3a·Li]+ (m/z 1031) (see the Supporting 50 µL, 5.0 µmol) were added to this flask, and the mixture was
stirred for 30 min. The resulting yellow solution was cooled down
to –60 °C. Then (CH3)3SiCN (0.99 g, 10.0 mmol) was added to the
solution in a dropwise manner for 15 min, and the reaction mixture
was stirred for 18 h. After the solvent and the volatile compounds
were evaporated under reduced pressure at ambient temperature,
the residue was suspended in hexane (100 mL). The mixture was
filtered through a celite pad, and the filtrate was concentrated un-
der reduced pressure. The crude product was purified by short-path
distillation to give (R)-2a (colorless oil, 1.27 g, 97% yield, 99% ee);
Information). The same signals were also observed in the
measurement of a 3a–Li2CO3–catalyst system.[10] 1H and
13C NMR analyses of this mixture suggested that C6H5O–
quantitatively reacted with (CH3)3SiCN to form CN– and
(CH3)3SiOC6H5 (see the Supporting Information). No
pentacoordinate Si species [(CH3)3Si(NC)2]– was observed,
although an excess amount of (CH3)3SiCN was present.[13]
The addition of sufficient amount of keto ester 1a to this
mixture resulted in the disappearance of the (CH3)3SiCN
b.p. 116–119 °C/1.0 Torr. [α]2D4
= =
+24.0 degcm3 g–1 dm–1 (c
signal, together with the appearance of the 2a product peak. 1.13 gcm–3, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.26 [s, 9
Eur. J. Org. Chem. 2010, 1455–1459
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Kurono, M. Uemura, T. Ohkuma
SHORT COMMUNICATION
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For reactions using Gd and Sm-based catalysts, see: a) K.
Yabu, S. Masumoto, S. Yamasaki, Y. Hamashima, M. Kanai,
W. Du, D. P. Curran, M. Shibasaki, J. Am. Chem. Soc. 2001,
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114, 1051–1054; Angew. Chem. Int. Ed. 2002, 41, 1009–1012;
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H, Si(CH3)3], 3.79 (s, 3 H, OCH3), 7.40–7.45 (m, 3 H, aromatic H),
7.63–7.67 ppm (m, 2 H, aromatic H). 13C NMR (100 MHz,
CDCl3): δ = 0.7 (CH3), 54.0 (CH3), 74.8 (C), 117.9 (C), 125.5 (CH),
128.8 (CH), 129.8 (CH), 136.4 (C), 167.5 ppm (C). C13H17NO3Si
(263.10): calcd. C 59.29, H 6.51, N 5.32; found C 59.23, H 6.45, N
5.25. HRMS (EI): m/z calcd: 263.0978 [M]+, obsd. 263.0970. The
ee of 2a was determined by chiral GC analysis: column, InertCap
CHIRAMIX (0.25 mmϫ30 m, depth of film = 0.25 µm, GL Sci-
ence); carrier gas: helium (100 kPa); column temp.: 70 °C heating
to 135 °C at a rate of 0.5 °C min–1; injection temp.: 220 °C; reten-
tion time (tR) of (R)-2a: 134.7 min (99.5%), tR of (S)-2a: 133.5 min
(0.5%). The absolute configuration was determined after conver-
[3]
sion to 3-hydroxy-3-phenylazetidin-2-one. [α]2D6
=
+113
degcm3 g–1 dm–1 (c = 0.612 gcm–3, CHCl3); ref.[9] [α]2D5 = –57.4
degcm3 g–1 dm–1 (c = 0.25 gcm–3, CHCl3), 80% ee (S).
Supporting Information (see also the footnote on the first page of
this article): Preparative method and properties of complex 3b, pro-
cedure for asymmetric cyanosilylation of α-keto esters, analytical
data and absolute configuration determination procedure of prod-
ucts 2, and MS and NMR behavior of catalytic species.
[4]
Acknowledgments
This work was supported by a Grant-in-Aid from the Japan Society
for the Promotion of Science (No. 21350048) and the Innovation
Plaza Hokkaido in the Japan Science and Technology Agency.
N. K. and M. U. are grateful for fellowships from the Global COE
Program, “Catalysis as the Basis for Innovation in Materials Sci-
ence” from the Ministry of Education, Culture, Sports, Science and
Technology (Japan). We would also like to thank Ms. Seiko Oka
and Ms. Ai Tokumitsu for mass-spectroscopic measurements, as
well as Ms. Miwa Kiuchi and Ms. Nao Saito for elementary analy-
sis at Instrumental Analysis Division, Equipment Management
Center, Creative Research Instruction Sosei, Hokkaido University.
[5]
[6]
For reaction using Na- and Li-based catalysts, see: a) X. Liu,
B. Qin, X. Zhou, B. He, X. Feng, J. Am. Chem. Soc. 2005, 127,
12224–12225; b) M. Hatano, T. Ikeno, T. Matsumura, S. Torii,
K. Ishihara, Adv. Synth. Catal. 2008, 350, 1776–1780.
For reactions using organocatalysts, see: a) S.-K. Tian, R.
Hong, L. Deng, J. Am. Chem. Soc. 2003, 125, 9900–9901; b)
D. E. Fuerst, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127,
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Feng, J. Org. Chem. 2007, 72, 2374–2378; d) S. J. Zuend, E. N.
Jacobsen, J. Am. Chem. Soc. 2007, 129, 15872–15883.
Examples for achiral catalytic cyanosilylation of α-keto esters,
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1297; c) H. S. Wilkinson, P. T. Grover, C. P. Vandenbossche,
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1455–1459

Asymmetric Cyanosilylation of α-Keto Esters
G. A. Olah, J. Org. Chem. 1990, 55, 2016–2018. See also: D. A.
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Li[(CH3)3Si(NC)Cl] was predominantly obtained by using
LiCl; see ref.[11]
[15] There remains the possibility that [3·Li][(CH3)3Si(NC)2],
formed reversibly, acts as an active species.
Received: December 24, 2009
[14] The reaction of (CH3)3SiCN and a Li salt depends on the na-
ture of this salt. For example, a pentavalent Si compound
Published Online: February 2, 2010
Eur. J. Org. Chem. 2010, 1455–1459
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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