Enantioselective cyanosilylation of ketones with amino acid/BINAP/ ruthenium(II)-lithium phenoxide catalyst systems

Article abstract of DOI:10.1002/adsc.201200027

Enantioselective reactions of simple ketones, α,α- and β,β-dialkoxy ketones, and α-alkoxy ketones with trimethylsilyl cyanide catalyzed by the bimetallic systems of amino acid/BINAP/ruthenium(II) complexes and lithium phenoxide have been studied [BINAP=2,

Full text of DOI:10.1002/adsc.201200027

FULL PAPERS
DOI: 10.1002/adsc.201200027
Enantioselective Cyanosilylation of Ketones with Amino Acid/
BINAP/Ruthenium(II)-Lithium Phenoxide Catalyst Systems
Masato Uemura,a Nobuhito Kurono,a Yusuke Sakai,a and Takeshi Ohkumaa,*
a
Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628,
Japan
Fax : (+81)-11-706-6598; e-mail: ohkuma@eng.hokudai.ac.jp
Received: January 10, 2012; Revised: April 6, 2012; Published online: July 2, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200027.
Abstract: Enantioselective reactions of simple ke-
ACHTUNGTREN(NUNG BINAP)-lithium phenoxide system exhibited the
tones, a,a- and b,b-dialkoxy ketones, and a-alkoxy best catalyst performance to produce the cyanohy-
ketones with trimethylsilyl cyanide catalyzed by the drin derivatives in up to 99% ee and 98% ee, respec-
bimetallic systems of amino acid/BINAP/rutheni- tively [t-Leu=tert-leucinate]. The excellent catalytic
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
oxide system showed high enantioselectivity for the
reaction of acetophenone derivatives to afford the
cyanated products in up to 90% ee [PhGly=phenyl- Keywords: asymmetric catalysis; bimetallic catalysts;
glycinate]. For the cyanosilylation of dialkoxy ke- cyanosilylation; enantioselectivity; ketones; lithium;
tones and a-alkoxy ketones, the RuACTHNUTRGNEN(UG t-Leu)2 ruthenium
Introduction
99% yield) and 3-methyl-2-butanone (S/C=1000,
À208C, 36 h, 80% yield) to afford the chiral products
The enantioselective reaction of prochiral ketones in 94% ee and 90% ee, respectively.[4b]
and (CH3)3SiCN (cyanosilylation) is among the most
With respect to the second requirement, several
direct and reliable methods to produce optically catalysts with well-designed chiral structures have
active tertiary cyanohydrin derivatives, which are ver- achieved high enantioselectivity in recent years.[1–6]
satile intermediates for the synthesis of both natural The enantioselectivity of 98% obtained in the cyana-
and artificial biologically active compounds.[1] Many tion of 2’-methylacetophenone with a chiral thiourea
chiral organometallic catalysts and organocatalysts catalyst (S/C=20, À788C, 36 h, 96% yield)[6d] and the
have been applied to this important transforma- reaction of phenylglyoxal diethyl acetal catalyzed by
tion.[2–6]
a Cinchona alkaloid derivative (S/C=50, À508C,
Three major requirements for the development of 18 h, 96% yield)[6a] are noteworthy.
an efficient asymmetric cyanosilylation of ketones are
Concerning the third requirement, ketone com-
as follows: (i) high catalytic activity (low catalyst load- pounds are roughly classified into simple (unfunction-
ing), (ii) high enantioselectivity, and (iii) a wide range alized) ketones and functionalized ones. Alkyl aryl
of applications for substrates. Regarding the first ketones and dialkyl ketones are typical examples of
item, the substrate-to-catalyst molar ratio (S/C), an simple ketones. Functionalized ketones have a wide
indication of catalytic activity, of the reported reac- variation in their structures. Among them, a-hetero-
tions was usually in the range of 5–200. An exception substituted ketones have features significantly differ-
was the use of the chiral salen/Ti(IV) complex, which ent from those of simple ketones with respect to
realized the reaction of 4’-methylacetophenone with enantioselectivity, because a-heterosubstituted ke-
an S/C of 1000 (room temperature, 4 days) to give the tones tend to behave as bidentate ligands, forming
silylated cyanohydrin in 52% ee.[2d] A salen/Al
ACTHNUTRGNEUNG(III) five-membered chelate structures with catalyst metals
complex and an N-oxide (co-catalyst) system also cya- or metal cations. This behavior notably influences the
nated acetophenone (S/C=1000, À208C, 16 days, reaction mechanism and the mode of enantioface se-
Adv. Synth. Catal. 2012, 354, 2023 – 2030
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Masato Uemura et al.
FULL PAPERS
Table 1. Asymmetric cyanosilylation of acetophenone (1a).[a]
cases.[8] A series of aromatic, hetero-aromatic, aliphat-
ic, and a,b-unsaturated a-keto esters was converted
to the silylated cyanohydrins in up to 99% ee. The
spectroscopic studies suggested that a novel bimetallic
species [Li{Ru
ACHTUGTNREN(NUG PhGly)2ACHTUGNTREN(NUGN BINAP)}]CN, in which
[Li{Ru(PhGly)2A
A
CHTUNGTRENNUNG
acid, efficiently catalyzes the reaction. We herein de-
scribe our studies on the enantioselective cyanosilyla-
tion of several simple and heterosubstituted ketones
catalyzed by bimetallic systems consisting of amino
acid/BINAP/Ru(II) complexes and C6H5OLi for ach-
ieving high catalytic activity, enantioselectivity, and
amenable to a wider range of substrates.
Results and Discussion
Simple Ketones
Entry
3
1a:3:Li[b]
Temp.
[8C]
Time
[h]
Yield
[%][c]
ee
We selected acetophenone (1a), a simple aromatic
ketone, as the standard substrate to optimize the cata-
lyst structure and the reaction conditions (Table 1).
[Ru{(S)-PhGly}2{(S)-BINAP}] [(S,S,S)-3a] was pre-
[%][c]
1
2
3
4
5
6
7
8
9
3a 1000:1:1
3a 1000:1:0.5
3a 1000:1:2
3a 1000:1:3
3a 1000:1:1
3a 1000:1:1
3a 1000:1:1
3a 3000:1:1
3b 1000:1:1
3c 1000:1:1
À40
À40
À40
À40
À20
0
À60
À40
À40
À40
À40
6
6
6
6
2
>99
97
>99
93
>99
>99
97
99
98
92
36
86
86
85
73
80
69
90
84
89
51
1
pared in two steps from commercial [RuCl2ACHTUNGTRENNUNG
(h6-
C6H6)]2 according to the method described in our pre-
vious report.[7] Ru complexes 3b–3d were prepared
with basically the same methods (see the Experimen-
tal Section). The reaction of 1a (620 mg, 5.2 mmol,
0.42M) and 1.2 equiv. of (CH3)3SiCN with (S,S,S)-3a
(5,1 mg, 5.0 mmol, S/C=1000) and C6H5OLi (100 mM
in THF, 50 mL, 5.0 mmol) in tert-C4H9OCH3 at À408C
was carried out for 6 h to produce the R silylated cya-
nohydrin, (R)-2a, in 86% ee quantitatively (Table 1,
entry 1). A 1:1 ratio of 3a and C6H5OLi gave the best
result in terms of reactivity and enantioselectivity.
When a 2:1 3a-C6H5OLi system was used as a catalyst,
the reaction rate was slightly slowed (entry 2). The
enantioselectivity was decreased with an increase in
1
18
18
6
6
6
10
11 3d 1000:1:1
[a]
The reactions were conducted using 1a (5.0 mmol,
0.42M) and 1.2 equiv. of (CH3)3SiCN in t-C4H9OCH3
with Ru complex (S,S,S)-3 and C6H5OLi.
1a:3:C6H5OLi molar ratio.
[b]
[c]
Determined by chiral GC analysis.
lection. Therefore, only a limited number of chiral the proportion of C6H5OLi in the catalyst system (en-
catalysts has achieved high enantioselectivity in the tries 3 and 4). The higher ee value of 2a was obtained
cyanosilylation of both simple and functionalized ke- in the reaction at lower temperature, but a longer re-
tones. Catalyst systems combining a chiral oxazaboro- action period was required (entries 1, 5–7). The high
lidinium ion and a phosphine oxide are representative catalytic activity of the 3a-C6H5OLi system allowed
examples that catalyze the cyanosilylation of 4’-nitro- quantitative conversion in the reaction with an S/C of
acetophenone (S/C=10, 458C, 10 days, 83% yield) 3000 at À408C in 18 h (entry 8). The highest turnover
and methylglyoxal dimethyl acetal (S/C=10, 258C, number for this reaction so far reported was achieved.
2 days, 92% yield) to give both cyanated products in Use of 3b with
a sterically more demanding
96% ee.[4c] XylBINAP[9] instead of BINAP slightly increased the
We recently reported the asymmetric cyanosilyla- enantioselectivity at the cost of the reactivity (en-
tion of aldehydes[7] and a-keto esters[8] with our origi- tries 1 and 9). The structure of the amino acid moiety
nal [Ru
lyst system [PhGly=phenylglycinate, BINAP=2,2’- tioselectivity as well as the catalytic activity. Thus,
bis(diphenylphosphino)-1,1’-binaphthyl: the structures Ru(Leu)2A(BINAP) (3c) and Ru(t-Leu)2A(BINAP) (3d)
ACHTUNGTRENNUNG(PhGly)2ACHTUNGTRENNUNG(BINAP)]-Li2CO3 or C6H5OLi cata- in the Ru complex 3 significantly influenced the enan-
A
N
G
CHTUNGTRENNUNG
are given in the Scheme of Table 1]. For example, the coupled with C6H5OLi catalyzed the cyanation of 1a
reaction of a-keto esters, a class of functionalized ke- under the typical conditions to give 2a in only 51% ee
tones, was completed with an S/C of 1000 at À608C, (92% yield) and 1% ee (36% yield), respectively (en-
and with an S/C of 10,000 at À508C in 18 h in both tries 10 and 11).[9]
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Enantioselective Cyanosilylation of Ketones with Amino Acid/BINAP/Ruthenium(II)-Lithium Phenoxide
Table 2. Asymmetric cyanosilylation of simple ketones 1.[a]
88% ee (entries 3, 4, 8, and 9). The reactions of 2’-,
3’-, and 4’-chloroacetophenones, 1d–1f, at À608C
were completed in 4–7 h to give the products in 82–
87% ee (entries 5–7). The enantioselectivity of the cy-
anation of sterically hindered isobutyrophenone (1i)
with the 3a-C6H5OLi catalyst system was significantly
lower than that of the reaction of 1a (entries 1 and
10). Use of the 3b-C6H5OLi system slightly increased
the ee value of 2i to 60%, but the number was down
to 15% with the 3d-C6H5OLi system (entries 11 and
12).
Simple aliphatic ketones are difficult substrates to
cyanate with high enantioselectivity, because the two
similar alkyl groups connected at each side of the car-
bonyl moiety are hard to differentiate. Thus, the ee
value of 63% obtained in the reaction of cyclohexyl
methyl ketone (1j) with the 3b-C6H5OLi catalyst
system was the highest (Table 2, entries 13–15).
2-Heptanone (1k), a primary alkyl ketone, was con-
verted with the 3a-C6H5OLi and 3b-C6H5OLi systems
to 2k in 32% ee and 40% ee, respectively (entries 16
and 17). The sense of enantioselection was reversed
in the reaction by using the 3d-C6H5OLi system
(entry 18). The bifunctional chiral Ti(IV) complexes
Entry
1
3
Temp. [8C] Time [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1a 3a
1a 3a
1b 3a
1c 3a
1d 3a
1e 3a
1f 3a
1g 3a
1h 3a
1i 3a
1i 3b
1i 3d
1j 3a
1j 3b
1j 3d
1k 3a
1k 3b
1k 3d
À40
À60
À40
À40
À60
À60
À60
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
6
18
8
24
4
4
7
6
6
18
18
18
24
24
24
10
10
10
99
97
91
97
99
99
99
93
92
99
96
85
97
91
89
99
99
99
86
90
88
83
82
87
86
83
80
53
60
15
50
63
7
and a chiral salen/AlACTHNUTRGNEU(GN III)-N-oxide system were re-
ported to catalyze the cyanation of secondary alkyl
methyl ketones with ꢀ90% enantioselectivity.[2c,4b]
32
40
À18[d]
a,a- and b,b-Dialkoxy Ketones
[a]
The reactions were conducted using 1 (5.0 mmol, 0.42M)
and 1.2 equiv. of (CH3)3SiCN in t-C4H9OCH3 with Ru
complex (S,S,S)-3 and C6H5OLi. 1:3:C6H5OLi=1000:1:1.
Isolated yield.
Determined by chiral GC analysis.
(S)-2a was the major product.
We applied the 3-C6H5OLi catalyst systems to the
asymmetric cyanosilylation of a,a-dialkoxy ketones,
which are one of the representative classes of a-
[b]
[c]
[d]
heteroACHTNUTRGNEsUNG ubstituted ketones. Phenylglyoxal diethyl
acetal (4a), an aromatic a,a-dialkoxy ketone, was the
substrate of choice to examine the cyanation condi-
tions (Table 3). The reaction of 4a (624 mg, 3.0 mmol,
We have previously reported that the 3a-Li com- 0.3M) and a 2 equiv. of (CH3)3SiCN with (S,S,S)-3a
pound systems efficiently catalyze the asymmetric hy- (3.0 mmol, S/C=1000) and C6H5OLi (3.0 mmol) in tert-
drocyanation of aldehydes,[10] a,b-unsaturated ketones C4H9OCH3 at À408C was completed in 1 h to produce
(conjugate addition),[11] and N-protected aldimines.[12] the silylated cyanohydrin (R)-5a in 92% ee (entry 1).
However, the reaction of 1a and 3 equiv. of HCN pre- The sense of enantioselection was the same as that in
pared in situ by mixing (CH3)3SiCN and CH3OH with the reaction of aromatic simple ketones (see Table 2).
the 3a-C6H5OLi catalyst system (S/C=1000, 08C, The ee value of product 5a was much higher than that
48 h) gave the cyanohydrin in only 59% yield and 2% of the unfunctionalized silylated cyanohydrin 2i,
ee.
which has structural similarity to 5a (see Table 2,
The 3-C6H5OLi catalyst system was applied to the entry 10). The bulkiness of the substituents (R) of the
asymmetric cyanosilylation of a series of simple ke- amino acid ligands on 3 seemed to significantly affect
tones. The results are summarized in Table 2. All re- the enantioselectivity. Thus, the reactions with the
actions were conducted at À608C to À408C with an Ru
C
ACHTUGNTRNEN(UNG CH3)2] and the
S/C of 1000. The highest ee value of 90% was ob- Ru
ACHTUNGTRENNUNG
tained in the cyanation of 1a at À608C catalyzed by product 5a in 85% ee and 93% ee, respectively (en-
the 3a-C6H5OLi system (entry 2). Acetophenones tries 2 and 3). Interestingly, the excellent ee value of
with electron-donating CH3 and CH3O groups at the 98% was achieved when a 2.5:1 3d-C6H5OLi system
3’ and 4’ positions, 1b, 1c, 1g, and 1h, were converted was used as catalyst (entry 4). In the absence of the
to the corresponding silylated cyanohydrins in 80– Li compound, little conversion was observed
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Masato Uemura et al.
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Table 3. Asymmetric cyanosilylation of phenylglyoxal dieth-
yl acetal (4a).[a]
Table 4. Asymmetric cyanosilylation of a,a-dialkoxy ketones
4.[a]
Entry
3
4a:3:Li[b] Temp. [8C] Yield [%][c] ee [%][c]
1
2
3
3a
3c
3d
1000:1:1
1000:1:1
1000:1:1
À40
À40
À40
À40
À40
À40
À40
0
>99
>99
>99
>99
<1
92
85
93
4
3d 1000:1:0.4
3d 1000:1:0
3d 5000:1:0.4
98
5
nd[d]
98
6[e]
>99[f]
>99[h]
>99
7[e,g] 3d 10000:1:0.4
97
95
8
3d 1000:1:0.4
[a]
Unless otherwise stated, the reactions were carried out
using 4a (2.1–3.0 mmol, 0.3M) and 2 equiv. of
(CH3)3SiCN in t-C4H9OCH3 with Ru complex (S,S,S)-3
(2.1–3.0 mmol) and C6H5OLi for 1 h.
1a:3:C6H5OLi molar ratio.
Determined by chiral GC analysis.
Not determined.
15.6 mmol of 4a was used.
The isolated yield was 98%.
Entry
4
Temp. [8C] Time [h] Yield [%][b] ee [%][c]
[b]
[c]
[d]
[e]
[f]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4d[d]
4d
4e
4f
À40
À40
À40
À40
À40
0
À40
À40
À40
À40
À20
À40
1
2
6
1
1
1
1
2
4
>99 (95)
>99 (99)
>99 (96)
>99 (97)
>99 (99)
>99 (100)
>99 (99)
>99 (99)
>99 (95)
>99 (96)
>99 (96)
>99 (98)
98
98
99
98
97
90
91
99
98
74
90
98
[g]
[h]
The reaction was conducted using 0.8M of 4a for 2 h.
The isolated yield was 99%.
4g
4h
4i
10
11
12
31
30
2
(entry 5). The cyanations with an S/C of 5000 and
10,000 were completed in 1 h and 2 h, respectively, to
yield 5a without loss of enantioselectivity (entries 6
and 7). It was noteworthy that a high level of enantio-
selectivity was also observed in the reaction at 08C
(entry 8). This is the most active and enantioselective
catalyst for cyanosilylation of a,a-dialkoxy ketones so
far reported.[13,14] Hydrocyanation of 4a catalyzed by
the 3d-C6H5OLi system (3 equiv. of HCN, S/C=1000,
À408C, 48 h) afforded the cyanohydrin in 92% yield
and 51% ee.
4j
[a]
Unless otherwise stated, the reactions were conducted
using (2.9–3.1 mmol, 0.3M) and 2 equiv. of
(CH3)3SiCN in t-C4H9OCH3 with Ru complex (S,S,S)-3d
(3.0–3.1 mmol) and C6H5OLi. 4:3d:C6H5OLi=1000:1:0.4.
Determined by chiral GC analysis. The isolated yield is
given in parenthesis.
4
a
[b]
[c]
[d]
Determined by chiral GC or HPLC analysis.
4d:3d=5000:1.
A series of a,a-dialkoxy ketones 4 was cyanated by
using the 2.5:1 3d-C6H5OLi catalyst system (Table 4). tion of 4-chlorophenyl ketone 4e was somewhat
The reaction of 3-methylphenyl ketone 4b with an lower, but the reaction rate was also high (entry 7).
S/C of 1000 at À408C proceeded smoothly to give The 2-furyl ketone 4f was among the best substrates
quantitatively the cyanated product 5b in the same ee for this transformation (entry 8). The desired product
as that of 5a (entries 1 and 2). The excellent ee value 5f in 99% ee was quantitatively obtained in 2 h. It is
of 99% was achieved in the cyanation of the electron- worth noting that the cyanation of methylglyoxal di-
rich 4-methoxyphenyl ketone 4c, although the reac- methyl acetal (4g), a primary alkyl a,a-dialkoxy
tion rate was relatively slow (entry 3). The phenyl ketone, with the 3d-C6H5OLi-system under the typical
ketone bearing an electron-withdrawing Cl at the 3’ conditions afforded quantitatively the desired product
position (4d) was quantitatively converted to 5d in 5g in 98% ee (entry 9).[14] The reactivity and enantio-
98% ee within 1 h under the regular conditions selectivity were significantly decreased in the cyana-
(entry 4). The high reactivity of 4d allowed complete tion of the cyclohexyl ketone 4h (entry 10). A sterical-
conversion in the cyanation with an S/C of 5000 in 1 h ly hindered a,a-dialkoxy-a-phenyl ketone 4i was also
(entry 5). The ee value of 5d in the reaction at 08C quantitatively cyanated at À208C in 30 h to give 5i in
was 90% (entry 6). The enantioselectivity in the reac- 90% ee (entry 11). Notably, high reactivity and enan-
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Enantioselective Cyanosilylation of Ketones with Amino Acid/BINAP/Ruthenium(II)-Lithium Phenoxide
Table 5. Asymmetric cyanosilylation of a-alkoxy and a-
amino ketones 8.[a]
Scheme 1. Asymmetric cyanosilylation of
ketone 6.
a b,b-dialkoxy
Entry
8
Temp. [8C] Time [h] Yield [%][b] ee [%][c]
tioselectivity were achieved in the cyanation of 2,2-di-
ethoxycyclohexanone (4j), a cyclic ketonic substrate
(entry 12).
The 3d-C6H5OLi catalyst system was also effective
for the asymmetric cyanosilylation of a b,b-dialkoxy
ketone 6 (Scheme 1). The functionalized silylated cya-
nohydrin 7 in 92% ee was quantitatively obtained
under the typical conditions.
1
2
3
4
5
8a
8a[d]
8a[e]
8a
8b
8c
8d
8e
8f
À40
À40
À40
0
2
3
17
1
95
96
92
98
97
94
58
87
76
97
98
95
86
À40
À40
À40
À40
À40
2
2
5
20
20
96
6
98
7[f]
8
97[g]
91
9
69
[a]
Unless otherwise stated, the reactions were conducted
using 8 (2.7–3.3 mmol, 0.1M) and 2 equiv. of (CH3)3SiCN
in t-C4H9OCH3 with Ru complex (S,S,S)-3d (2.9–
3.3 mmol) and C6H5OLi. 8:3d:C6H5OLi=930–1000:1:1.
Isolated yield. The yields determined by GC analysis
were >99% except in the case of entries 7 and 8.
Determined chiral GC or HPLC analysis.
8a:3d:C6H5OLi=1000:1:0.4.
8a:3d:C6H5OLi=3000:1:1.
(R,R,R)-3d and 3 equiv. of (CH3)3SiCN to 8d were used.
(S)-9d was obtained.
a-Alkoxy and a-Amino Ketones
2-Methoxyacetophenone (8a), an a-alkoxy ketone, is
also an appropriate ketonic substrate for this asym-
metric cyanosilylation (Table 5). The feature of react-
ing with high enantioselectivity under catalysis with
[b]
[c]
[d]
[e]
[f]
the combined system of the RuACHTNURGTNEUNG(t-Leu)2 complex 3d
and C6H5OLi is similar to that of the reaction of phe-
nylglyoxal diethyl acetal (4a: see Table 3). Thus, 8a
(410 mg, 2.7 mmol, 0.1M) and 2 equiv. of (CH3)3SiCN
reacted with (S,S,S)-3d (2.9 mmol, S/C=930) and
C6H5OLi (3.0 mmol) in tert-C4H9OCH3 at À408C for
2 h to afford the cyanated product (R)-9a in 97% ee
[g]
quantitatively (entry 1). This is the first example of no)acetone (8f), an a-amino ketone, showed medium
enantioselective cyanosilylation of a-alkoxy aromatic enantioselectivity (entry 9).
ketones to the best of our knowledge. Use of the
2.5:1 3d-C6H5OLi system, which gives the highest
enantioselectivity for the reaction of 4a (Table 3, Conclusions
entry 4), resulted in a somewhat slower reaction rate,
although the product 9a in 98% ee was obtained The bimetallic catalyst systems of amino acid/BINAP/
quantitatively (entry 2). The reaction with an S/C of Ru(II) complexes and C6H5OLi achieve highly reac-
3000 was completed in 17 h with maintenance of tive and enantioselective cyanosilylation of a wide
a high level of enantioselectivity (entry 3). The cya- range of ketones. The selection of amino acid ligand
nated product 9a in an acceptable ee of 86% was ob- is crucial to achieve high enantioselectivity and ap-
tained at 08C (entry 4). The ketonic substrates with plicability for substrates. Thus, the system
an electron-donating CH3O and an electron-with- RuACTHNUTRGENN(GU PhGly)2CAHTUNGTREN(NGUN BINAP)-C6H5OLi catalyzes the reaction
drawing Cl at the 4’ position, 8b and 8c, were cyanat- of acetophenone derivatives to afford the silylated
ed with the same level of reactivity and stereoselectiv- tertiary cyanohydrins in up to 90% ee. When the
ity (entries 5 and 6). Notably, methoxyacetone (8d), RuACTHNUGTRENN(UG t-Leu)2ACHTUNGTREN(NUGN BINAP)-C6H5OLi catalyst is used for the
an aliphatic ketone, was quantitatively converted to cyanation of a,a- and b,b-dialkoxy ketones as well as
the cyanohydrin derivative 9d in 97% ee with the a-alkoxy ketones, the cyanated products are obtained
same catalyst (entry 7).[15] The low isolated yield was in up to 99% ee. The excellent catalytic activity of the
due to the volatility of 9d. The reaction of the methyl bimetallic systems is reflected in turnover numbers of
ketone with a methoxymethyl ether moiety 8e was 10,000, 3000, and 3000 in the cyanation of dialkoxy
relatively slow, but a high ee value of the product was ketones, simple ketones, and a-alkoxy ketones, re-
attained (entry 8). The reaction of 1-(dimethylami- spectively, in the best cases.
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Masato Uemura et al.
FULL PAPERS
8.8 Hz, aromatic H), 6.67–6.82 (m, 10H, aromatic H), 7.11–
7.23 (m, 10H, aromatic H), 7.51–7.81 (m, 8H, aromatic H),
8.10–8.15 (m, 2H, aromatic H); 31P NMR (161.7 MHz,
CDCl3): d=52.3 (s); HR-MS (ESI): m/z=1136.3376, calcd
for C68H64N2O4P2Ru [M]+: 1136.3404.
Experimental Section
General
The commercially available substrates 1a–k, 4a, 4g, 4i, 8a,
8d and 8f were used after distillation. The substrates 4b–f,
4h,[6a] 4j,[16] 6,[17] 8b, 8c, and 8e[18] were prepared in accord-
ance with the procedures in the literature. (CH3)3SiCN was
purchased from Wako Chemical Industries, Ltd. and dis-
tilled before use. Anhydrous t-C4H9OCH3, THF, DMF, pen-
tane, CH2Cl2, and methanol were purchased from Kanto
Chemical Co., Inc. and used without further purification.
The ruthenium complexes (S,S,S)-3b–d were synthesized
with the same procedure as used for (S,S,S)-3a.[7] C6H5OLi
(1.0M in THF) was purchased from Aldrich Co. and diluted
with anhydrous THF before use. NMR spectra were record-
ed on a JEOL JNM-ECS400 or LA400 (400 MHz for
1H NMR, 100 MHz for 13C NMR, 161.7 MHz for 31P NMR)
spectrometer. The chemical shifts are reported downfield
from TMS (d=0 ppm) for 1H NMR. For 13C NMR, the
chemical shifts are reported in a scale relative to the solvent
used as an internal reference. Carbon multiplicity was as-
signed by DEPT experiments. 31P NMR was carried out with
phosphoric acid as an external standard.
Ru[(S)-Leu]2[(S)-BINAP] [(S,S,S)-3c]
This complex was prepared by the same procedure as used
for 3a. The reaction of [RuCl2ACTHNUTRGNEUNG
(h6-C6H6)]2 (250 mg,
0.50 mmol), (S)-BINAP (633 mg, 1.02 mmol), and sodium
(S)-leucinate (475 mg, 3.10 mmol) gave (S,S,S)-3c; yield:
1
0.75 g (0.76 mmol, 76%). H NMR (400 MHz, CDCl3): d=
0.29 (d, 6H, J=6.6 Hz, CH3), 0.66 (d, 6H, J=6.3 Hz, CH3),
1.03–1.13 (m, 4H, (CH3)2CH & CHH), 1.81–1.89 (m, 2H,
CHH), 2.38–2.41 (m, 4H, NHH and COCH), 3.25–3.29 (m,
2H, NHH), 6.25 (d, 2H, J=8.5 Hz, aromatic H), 6.43–6.52
(m, 6H, aromatic H), 6.72 (t, 2H, J=7.6 Hz, aromatic H),
7.02–7.06 (m, 4H, aromatic H), 7.15 (t, 2H, J=7.6 Hz, aro-
matic H), 7.47–7.61 (m, 10H, aromatic H), 7.78–8.23 ppm
(m, 6H, aromatic H); 31P NMR (161.7 MHz, CDCl3): d=
52.0 (s); HR-MS (ESI): m/z=984.2771, calcd. for
C56H56N2O4P2Ru [M]+: 984.2774.
Ru[(S)-t-Leu]2[(S)-BINAP] [(S,S,S)-3d]
Preparation of Ruthenium Complex 3[7]
This complex was prepared by the same procedure as used
for 3a. The reaction of [RuCl2ACTHNUTRGNEUNG
(h6-C6H6)]2 (251 mg,
The preparation of (S,S,S)-3a illustrates the typical reaction
procedure. [RuCl2ACHTUNGTRENNUNG
(h6-C6H6)]2 (258 mg, 0.52 mmol) and (S)-
0.50 mmol), (S)-BINAP (643 mg, 1.03 mmol), and sodium
(S)-tert-leucinate (475 mg, 3.10 mmol) gave (S,S,S)-3c; yield:
0.72 g (0.73 mmol, 73%). H NMR (400 MHz, CDCl3): d=
BINAP (661 mg, 1.06 mmol) were placed in a 100-mL
Schlenk flask. After the air in the flask had been replaced
with argon, degassed DMF (15 mL) was added, and the mix-
ture was heated at 1008C for 10 min with stirring to give
a reddish brown solution. After the solution had cooled to
258C, a degassed methanol solution (30 mL) of sodium (S)-
phenylglycinate (533 mg, 3.08 mmol) was added and the
mixture was stirred for 12 h. Water (50 mL) was added to
the solution to precipitate a yellowish orange solid. The col-
lected precipitates were dissolved in CH2Cl2 (40 mL),
washed with water (50 mLꢁ3), and dried over MgSO4.
After filtration and removal of the solvent, the residue was
purified by preparative TLC (silica gel; eluent: ethyl ace-
tate; Rf =0.45–0.61). Reprecipitation with a mixture of
CH2Cl2 (10 mL) and pentane (100 mL) afforded (S,S,S)-3 as
a light yellow powder; yield: 787 mg (74%); mp (decomp)
2238C. 1H NMR (400 MHz, CDCl3): d=2.45 (br s, 2H,
NHH), 3.23 (brs, 2H, NHH), 3.63 (t, 2H, J=8.3 Hz,
2PhCH), 6.24 (d, 2H, J=9.3 Hz, aromatic H), 6.50 (m, 6H,
aromatic H), 6.71 (m, 6H, aromatic H), 7.07–7.67 (m, 24H,
aromatic H), 8.06 (m, 4H, aromatic H); 31P NMR
(161.7 MHz, CDCl3): d=52.3 (s); HR-MS (ESI): m/z=
1024.2123, calcd. for C60H48N2O4P2Ru [M]+: 1024.2149.
1
0.65 (s, 18H, CH3), 1.88–2.18 (m, 4H, NH2), 3.03 (m, 2H,
CHCH3), 6.27 (d, 2H, J=8.8 Hz, aromatic H), 6.49 (m, 6H,
aromatic H), 6.73 (m, 2H, aromatic H), 7.02 (brm, 4H, aro-
matic H), 7.16 (m, 2H, aromatic H), 7.47–7.61 (m, 10H, aro-
matic H), 7.93 (m, 2H, aromatic H), 8.03 (br, 4H, aromatic
H); 31P NMR (161.7 MHz, CDCl3): d=52.6 (s); HR-MS
(ESI): m/z=984.2772, calcd. for C56H56N2O4P2Ru [M]+:
984.2774.
General Procedure for Asymmetric Cyanosilylation
of Ketones
Caution: (CH3)3SiCN must be handled with utmost care: it is
highly flammable, and causes death by inhalation, by contact
with the skin, or if swallowed. It produces HCN gas on con-
tact with water.[19]
The cyanosilylation of 1a illustrates the typical reaction
procedure. The ruthenium complex (S,S,S)-3a (5.1 mg, 5.0
mmol) was placed in a 50-mL Schlenk flask, and the air pres-
ent in this apparatus was replaced by argon. Anhydrous t-
C4H9OCH3 (10 mL), (CH3)3SiCN (0.75 mL, 6.0 mmol), and
C6H5OLi (100 mm in THF, 50 mL, 5.0 mmol, S/C=1000) were
added to this flask, and the mixture was stirred at À408C
for 30 min. Then 1a (0.62 g, 5.2 mmol) was added to the so-
lution, and the reaction mixture was stirred for 6 h. After
the solvent and the volatile compounds were evaporated
under reduced pressure at ambient temperature, the residue
was suspended in pentane (40 mL).[20] The mixture was fil-
tered through a celite pad,[21] and the filtrate was concentrat-
ed under reduced pressure. The crude product was purified
by short-path distillation to give (R)-2a as a colorless oil;
yield: 1.13 g (5.16 mmol, 99%); 86% ee; bp 658C/20 Pa;
Ru[(S)-PhGly]2[(S)-XylBINAP] [(S,S,S)-3b]
This complex was prepared by the same procedure as used
for 3a. The reaction of [RuCl2ACTHNUTRGNEUNG
(h6-C6H6)]2 (76 mg,
0.15 mmol), (S)-XylBINAP (250 mg, 0.34 mmol), and
sodium (S)-phenylglycinate (101 mg, 0.58 mmol) gave
(S,S,S)-3b; yield: 0.18 g (0.16 mmol, 53%). 1H NMR
(400 MHz, CDCl3): d=1.67 (s, 12H, CH3), 2.27 (br. t, 2H,
NHH), 2.42 (s, 12H, CH3), 3.18 (br, dd, 2H, NHH), 3.70
(br. t, 2H, PhCH), 5.96 (s, 2H, aromatic H), 6.24 (d, 2H, J=
2028
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Adv. Synth. Catal. 2012, 354, 2023 – 2030

Enantioselective Cyanosilylation of Ketones with Amino Acid/BINAP/Ruthenium(II)-Lithium Phenoxide
[a]2D4: +20.6 degcm3 gÀ1 dmÀ1 (c 1.02, CHCl3), {lit.[2m] [a]D28:
À19.0 degcm3 gÀ1 dmÀ1 (c 1.01, CHCl3, R enantiomer in 88%
ee)}; EI-MS: m/z (relative intensity)=219.17 (0.4), 204.14
[2] For reactions using Ti-based catalysts, see: a) Y. N. Be-
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1
(96), 177.12 (100), 105.06 (56); H NMR (400 MHz, CDCl3):
d=0.18 [s, 9H, SiACHTUNGTRENNUNG(CH3)3], 1.86 (s, 3H, CH3), 7.35–7.42 (m,
3H, aromatic H), 7.54–7.56 (m, 2H, aromatic H); 13C NMR
(100 MHz, CDCl3): d=1.0 (CH3), 33.5 (CH3), 71.6 (C),
121.6 (C), 124.6 (CH), 128.6 (CH), 142.0 (C); chiral GC
analysis [Chirasil Dex (0.32 mmꢁ25 m); carrier gas: helium
(114 kPa); column temp: 1108C; injection temp: 1808C]: tR
of (S)-2a=10.6 min (7.0%), tR of (R)-2a=11.0 min (93.0%).
Supporting Information
Procedures for the asymmetric cyanosilylation of ketones,
the NMR, GC, and HPLC behavior, [a]D values and the de-
termination of the absolute configuration of products are
available in the Supporting Information.
Acknowledgements
[3] 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, 123, 9908–9909; b) K. Yabu, S. Masu-
moto, M. Kanai, D. P. Curran, M. Shibasaki, Tetrahe-
dron Lett. 2002, 43, 2923–2925; c) S. Masumoto, M.
Suzuki, M. Kanai, M. Shibasaki, Tetrahedron Lett.
2002, 43, 8647–8651; d) K. Yabu, S. Masumoto, M.
Kanai, W. Du, D. P. Curran, M. Shibasaki, Heterocycles
2003, 59, 369–385; e) S. Masumoto, M. Suzuki, M.
Kanai, M. Shibasaki, Tetrahedron 2004, 60, 10497–
10504.
This work was supported by a Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS: No. 21350048)
and the Innovation Plaza Hokkaido in the Japan Society and
Technology Agency. M.U. is the grateful recipient of a JSPS
Research Fellowship for Young Scientists. N.K. is the grateful
recipient of a fellowship from the Global COE Program,
“Catalysis as the Basis for Innovation in Materials Science”
from the Ministry of Education, Culture, Sports, Science and
Technology (Japan).
[4] For reactions using Al- and B-based catalysts, see:
a) H. Deng, M. P. Isler, M. L. Snapper, A. H. Hoveyda,
Angew. Chem. 2002, 114, 1051–1054; Angew. Chem.
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[5] For reactions 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.
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Masato Uemura et al.
FULL PAPERS
[8] N. Kurono, M. Uemura, T. Ohkuma, Eur. J. Org.
Chem. 2010, 1455–1459.
[9] Leu=leucinate, t-Leu=tert-leucinate, XylBINAP=
[15] Cyanosilylation of methoxy acetone (8d) with a chiral
thiourea catalyst (S/C=20, À788C, 8 h) gave the prod-
uct in 81% yield and 88% ee, see ref.[6d]
2,2’-bis(di-3,5-xylylphosphanyl)-1,1’-binaphthyl.
[16] For the preparation of 4j, see: S.-K. Tian, L. Deng, J.
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[18] For the preparation of 8a–c, see: R. B. Moffett, R. L.
Shriner, Org. Syntheses, Coll. Vol. 3, pp. 562–563. For
the preparation of 8e, see: A. Mordini, S. Pecchi, G.
Capozzi, A. Capperucci, A. Degl’Innocenti, G. Regina-
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[19] We recommend the use of (CH3)3SiCN under the guid-
ance of the appropriate literature. For example, see the
Safety Data Sheet, Sigma–Aldrich for Product Num-
ber 212849 (http://www.sigmaaldrich.com/safety-cen-
ter.html).
[20] Alternatively, hexane could be used to make a suspen-
sion of the ruthenium complex (S,S,S)-3a and the lithi-
um salt.
[21] Since (S,S,S)-3b–d show some solubility to pentane or
hexane, removal of the ruthenium and/or the lithium
components was carried out by a silica gel short-path
column (30 mmꢁ100 mm).
[10] For asymmetric hydrocyanation of aldehydes catalyzed
by the PhGly/BINAP/Ru(II)-LiX (X=Cl, Br) system,
see: N. Kurono, T. Yoshikawa, M. Yamasaki, T.
Ohkuma, Org. Lett. 2011, 13, 1254–1257.
[11] For asymmetric hydrocyanation of a,b-unsaturated ke-
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[12] For asymmetric hydrocyanation of N-protected aldi-
mines to the amino nitriles catalyzed by the PhGly/
BINAP/Ru(II)-C6H5OLi system, see: M. Uemura, N.
Kurono, T. Ohkuma, Org. Lett. 2012, 14, 882–885.
[13] Asymmetric cyanosilylations of arylglyoxal dialkylace-
tals catalyzed by a Cinchona alkaloid derivative (S/C=
50, À508C, 18 h, 96% yield, 98% ee) and a proline-de-
rived N-oxide (S/C=10, À458C, 10 h, 99% yield, 93%
ee) are representative examples. See: refs.[6a,6c]
[14] A chiral oxazabororidinium ion-phosphine oxide
system-catalyzed cyanosilylation of methylglyoxal di-
methyl acetal (4g: S/C=10, 258C, 2 days) to give the
product in 92% yield and 96% ee. See: ref.[4c]
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Adv. Synth. Catal. 2012, 354, 2023 – 2030