Table 4: Sequential hydrocyanation of different substrates.[a]
ketones, 1q and 1r, were converted into the 1,4-adducts, 2q
and 2r, with 95% ee in both cases (Table 2, entries 22 and 23).
The reaction of 3-hepten-2-one (1s), an aliphatic enone, with
the 3a/C6H5OLi system was slow, but the cyanation with an
S/C of 200 at 08C for 24 hours afforded 2s in 99% yield and
93% ee when 3b was used instead of 3a (Table 2, entry 24).[11]
The chiral Gd and Sr catalysts reported by Shibasaki exhibit
wider applicability to the reaction of aliphatic and b,b-
disubstituted enones.[2]
The 3b/C6H5OLi catalyst was applied to the regioselective
cyanation of a dialkenyl ketone. When cyclohexenyl pentenyl
ketone 4 was subjected to the cyanation conditions, the
monocyanated product 5 (at the pentenyl group) was
obtained in 96% ee (Scheme 3). The regioselectivity was
estimated to be greater than 99%.
Run number[b]
1
t [h]
Yield [%][c]
ee [%][d]
1
2
3
4
5
1n
1p
1j
3
12
5
3
12
96
96
98
95
99
93
90
96
95
96
1l
1k[e]
[a] Reactions were conducted using 1 (8.2 mmol) and HCN (11.8 mmol)
in tert-C4H9OCH3 (48 mL) at 08C with a solid (S,S,S)-3a and C6H5OLi
(50 mm in THF). 1/3a/C6H5OLi=500:1:1 (initial). HCN was prepared in
situ from (CH3)3SiCN and CH3OH in a 1:1 ratio. [b] Number of times the
catalyst was used. [c] Yield of isolated 2. [d] Determined by GC or HPLC
on a chiral stationary phase. [e] Reaction using 1k (3.2 mmol) and HCN
(4.8 mmol) in tert-C4H9OCH3 (19 mL).
original [Ru(phgly)2(binap)]/C6H5OLi system. The reaction
was carried out with an S/C in the range of 200–1000 at
ꢀ208C!08C. A series of aryl-, hetero-aryl-, and alkyl-
substituted enones was converted into the 1,4-addition
products in up to 98% ee without formation of a detectable
amount of the 1,2-adducts. The reaction of cyclohexenyl
pentenyl ketone afforded the monocyanated product at the
less-hindered site in high regio- and enantioselectivity. The
robust [Ru(phgly)2(binap)] complex can be reused with
addition of fresh C6H5OLi without loss of the stereoselectiv-
ity. We hope these findings will contribute to the progress of
synthetic organic chemistry.
Scheme 3. Regioselective cyanation of dienone 4.
The Ru complex 3a was so robust that it was recovered by
column chromatography on silica gel from the reaction
mixture in the open air, and was reusable as a cyanation
catalyst with the addition of fresh C6H5OLi. As shown in
Table 3, 3a could be used five times in the cyanation of 1a
Experimental Section
The typical procedure for the hydrocyanation of 1-phenyl-2-buten-1-
one (1a): Caution: (CH3)3SiCN and HCN that is formed in situ must
be used in a well-ventilated fume hood owing to their high toxicity.
Ruthenium complex (S,S,S)-3a (6.2 mg, 6.1 mmol)[7,8] was placed in a
50 mL Schlenk flask, and the air present in this apparatus was
replaced by argon. Anhydrous CH3OH (146 mg, 4.6 mmol) was
added to this flask, and the mixture was cooled to 08C. Then
(CH3)3SiCN (445 mg, 4.5 mmol) was added in a dropwise manner,
and the mixture was stirred for 15 min. To the solution containing
HCN, anhydrous tert-C4H9OCH3 (18 mL) and C6H5OLi (60 mm in
THF, 100 mL, 6.0 mmol) were added at 08C, and the mixture was
stirred for 30 min. Then 1a (447 mg, 3.1 mmol) was added to this
solution in a dropwise manner over 5 min, and the reaction mixture
was stirred for 5 h. After the solvent and the volatile compounds were
evaporated under reduced pressure, the residue was purified by
column chromatography on silica gel to give (S)-2a (colorless oil,
Table 3: Recycled use of 3a in the hydrocyanation of 1a.[a]
Run number[b]
Conversion [%][c]
Yield [%][d]
ee [%][c]
1
2
3
4
5
>99
>99
>99
>99
>99
97
93
99
99
99
93
94
93
93
92
[a] Reactions were conducted using 1a (10 mmol) and HCN (15 mmol)
in tert-C4H9OCH3 (60 mL) at 08C for 5 h with a solid (S,S,S)-3a and
C6H5OLi (50 mm in THF). 1a/3a/C6H5OLi=500:1:1 (initial). HCN was
prepared in situ from (CH3)3SiCN and CH3OH in a 1:1 ratio. [b] Number
of times the catalyst was used. [c] Determined by GC on a chiral
stationary phase. [d] Yield of isolated 2a.
24
531 mg, 99% yield, 94% ee). ½aꢁD ¼ꢀ6.7 degcm3 gꢀ1 dmꢀ1 (c =
25
1.07 gcmꢀ3, CHCl3); literature[2a] ½aꢁD ¼ꢀ6.2 degcm3 gꢀ1 dmꢀ1 (c =
0.6 gcmꢀ3, CHCl3), 88% ee (absolute configuration was unreported);
1H NMR (400 MHz, CDCl3): d = 1.43 (d, 3H, J = 6.8 Hz, CH3), 3.23
(dd, 1H, J = 6.5, 17.0 Hz, CHH), 3.31–3.40 (m, 1H, CHCN), 3.43 (dd,
1H, J = 6.2, 17.0 Hz, CHH), 7.48–7.51 (m, 2H, aromatic H), 7.60–7.63
(m, 1H, aromatic H), 7.95–7.97 ppm (m, 2H, aromatic H); 13C NMR
(67.7 MHz, CDCl3): d = 17.8 (CH3), 20.5 (CH), 42.2 (CH2), 122.6 (C),
128.0 (CH), 128.8 (CH), 133.8 (CH), 135.8 (C), 195.1 ppm (C); HRMS
(ESI): m/z calcd for C11H11ClNO: 208.05292 [M+Cl]ꢀ; found:
208.05292. The ee value of 2a was determined by GC on a chiral
stationary phase using an InertCap CHIRAMIX column (0.25 mm ꢁ
30 m, depth of film = 0.25 mm, GL Science); carrier gas: helium
(217 kPa); column temp: 1708C heating to 1798C at a rate of
0.58Cminꢀ1; injection temp; 2508C; retention time (tR) of (R)-2a:
17.5 min (3.1%), tR of (S)-2a: 16.5 min (96.9%). The ee value was not
changed by purification with column chromatography. The absolute
with an initial S/C of 500 at 08C with maintaining high
enantioselectivity. The total turnover number was about 2500.
The notable robustness and reusability of 3a make it suitable
for practical use.
In addition, different a,b-unsaturated ketones 1 were
cyanated sequentially with this catalyst-reuse procedure.
Table 4 lists the results. The catalyst efficiency and enantio-
selectivity for all runs were comparable to those of the regular
single-run reactions shown in Table 2.
In summary, we have reported here the efficient enantio-
selective conjugate addition of HCN into the a,b-unsaturated
ketones to afford the b-cyano ketones catalyzed by our
Angew. Chem. Int. Ed. 2011, 50, 5541 –5544
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5543