Highly efficient Cs2CO3-catalyzed 1,4-addition of Me3SiCN to enones with water as the additive

Article abstract of DOI:10.1055/s-0029-1218653

A facile and efficient 1,4-addition of Me₃SiCN to enones has been achieved with perfect regioselectivity using Cs₂CO₃ as catalyst. Thus, with 0.5 mol% of Cs₂CO₃ and 4 equivalents of H₂O as the additive excellent yields (81-99%) of -cyanoketones are obtained within one to five hours. Both aromatic and aliphatic enones are found suitable substrates for this protocol. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218653

PAPER
1325
Highly Efficient Cs2CO3-Catalyzed 1,4-Addition of Me3SiCN to Enones with
Water as the Additive
C
s
CO3-Ci
a
talyze
n
d
1,4-Additio
g
n of Me3SiCyN to Enonesa Yang,a,b Yongbin Shen,a Fu-Xue Chen*a
2
a
Department of Applied Chemistry, School of Chemical Engineering & the Environment, Beijing Institute of Technology, 5 South
Zhongguancun Street, Haidian District, Beijing 100081, P. R. of China
b
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China
Fax +86(10)68918296; E-mail: fuxue.chen@bit.edu.cn
Received 25 November 2009; revised 15 December 2009
selective conjugate addition of cyanide to enones is also
disclosed by Shibasaki.14 Though these significant
achievements have been made, 1,4-additon of Me3SiCN
to a broad scope of enones is still demanding.15
Abstract: A facile and efficient 1,4-addition of Me3SiCN to enones
has been achieved with perfect regioselectivity using Cs2CO3 as cat-
alyst. Thus, with 0.5 mol% of Cs2CO3 and 4 equivalents of H2O as
the additive excellent yields (81–99%) of b-cyanoketones are ob-
tained within one to five hours. Both aromatic and aliphatic enones
are found suitable substrates for this protocol.
Previously, we presented a CsF-catalyzed 1,4-addition of
Me3SiCN to aromatic enones with excellent yield and re-
gioselectivity (Scheme 2).16 Unfortunately, aliphatic
enones are not suitable substrates. Although CsF has good
solubility in dioxane and catalytic activity, it is relatively
expensive and much hygroscopic. Moreover, fluoride ion
is harmful to the environment. Compared to CsF, Cs2CO3
is inexpensive and stable to moisture, which is widely
used as catalyst or base in organic synthesis,17 but only in
few examples of conjugate addition reactions.18 To the
best our knowledge, Cs2CO3 is scarcely applied to the 1,4-
addition of cyanide to a,b-unsaturated carbonyl com-
pounds. Herein, we report an efficient Cs2CO3-catalyzed
1,4-addition of Me3SiCN to both aromatic and aliphatic
enones.
Key words: 1,4-addition, catalysis, enones, nitriles, regioselectivi-
ty
As one of the most general and versatile methods for C–C
bond formation, the conjugate addition to a,b-unsaturated
carbonyl compounds has received much attention.1 In this
context, the transition-metal-catalyzed 1,4-additions of
aryl2 and alkyl reagents have been well developed,3 yet
the 1,4-addition of weak nucleophile cyanide to a,b-un-
saturated carbonyl compounds with high regioselectivity
remains challenging (Scheme 1).
OSiMe3
1,2-addition
CsF (1 mol%)
Me3SiCN (2.2 equiv)
R1
R2
NC
O
O
CN
O
H2O (4 equiv)
+ Me3SiCN
R1
R2
dioxane, reflux, 1–7 h
R1
R1
CN OSiMe3
R2
1,4-addition
R2
R2
R1
91–99%
Scheme 1 Additions of Me3SiCN to enones
Scheme 2 CsF-catalyzed 1,4-addition of Me3SiCN to aromatic
enones
On the other hand, 1,4-addition of cyanide to enones has
been extensively utilized in syntheses of biologically ac-
tive molecules4 and complex natural products.5 In the lit-
erature, frequently employed methods involve Me3SiCN6
and Et2AlCN7 as the cyanide sources and Et3Al6,8a and
Model reaction is conducted with chalcone (1a) and
Me3SiCN. Initially, the effect of solvent is evaluated with
Cs2CO3 (10 mol%) as the catalyst at different reflux tem-
perature (Table 1). The yields of the 1,4-addition product
2a differ significantly based on the solvent used. When
CH2Cl2 is used as the solvent, no conversion occurs
(Table 1, entry 1). However, poor yield is obtained in
THF (Table 1, entry 2) as well as trace product in toluene
(Table 1, entry 3). Although with similar boiling point to
toluene, dioxane gives excellent yield of 92% (Table 1,
entry 4). However, when more polar solvents such as
DMF and DMSO with higher boiling point are used, the
isolated yields decrease sharply (Table 1, entries 5, 6).
9
Pd(OAc)2 as Lewis acid catalysts.8 Ionic liquid and mi-
crowave also have been applied to this transformation in
line with the concept of green chemistry.10,11 Recently,
Shibasaki and co-workers reported an entirely distinct
nickel(0)–cyclooctadiene (COD) complex toward the ele-
gant synthesis of Tamiflu,12 an important anti-influenza
drug, and subsequent Ni(0) and Gd(OTf)3 cooperative cat-
alyst in the 1,4-addition of Me3SiCN to a wide variety of
aliphatic enones.13 The first example of catalytic enantio-
With dioxane as the solvent, the effects of reaction tem-
perature and time on the model reaction are investigated
(Table 2). When increasing the temperature from 40 °C to
SYNTHESIS 2010, No. 8, pp 1325–1333
Advanced online publication: 29.01.2010
DOI: 10.1055/s-0029-1218653; Art ID: F22209SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

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J. Yang et al.
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results of Na2CO3, K2CO3, and Cs2CO3, the possible ‘ce-
sium effect’ can not be ruled out.19 Nevertheless, control
experiment using more basic CsOH gives inferior result
(Table 3, entry 4). CsCl yields the product in only 10%
(Table 3, entry 5). At present reaction conditions, CsF
gives less amount of 2a (Table 3, entry 6). Hence, Cs2CO3
shows the best catalytic activity.
Table 1 Effect of Solvent on the Cs2CO3-Catalyzed 1,4-Addition of
Me3SiCN to Chalcone (1a)a
1) Cs2CO3 (10 mol%)
Me3SiCN (2.2 equiv)
solvent, reflux, 4.5 h
CN
O
O
Ph
Ph
Ph
Ph
2) 1 M HCl, r.t.
2a
1a
Entry
Solventb
CH2Cl2
THF
Yield (%)c
Table 3 Catalyst Screening in the Model Reactiona
1
2
3
4
5
6
0
1) catalyst (10 mol%)
Me3SiCN (2.2 equiv)
dioxane, reflux, 4.5 h
CN
O
O
10
trace
92
34
27
Ph
Ph
Ph
Ph
toluene
dioxane
DMF
2) 1 M HCl, r.t.
2a
1a
Entry
Catalyst
Na2CO3
K2CO3
Cs2CO3
CsOH
CsCl
Yield (%)b
1
2
3
4
5
6
24
40
92
77
10
72
DMSO
a Reaction conditions: chalcone (1a; 0.15 mmol), Me3SiCN (0.33
mmol, 2.2 equiv), Cs2CO3 (10 mol%), solvent (1.5 mL), reflux, 4.5 h.
b Anhydrous solvent.
c Isolated yield.
reflux temperature, the yield increases stepwise (Table 2,
entries 1–3). However, overheated dioxane is unfavorable
to the yield (Table 2, entry 4). A reaction time of 4.5 hours
is necessary for good conversion; otherwise gradually de-
creased yield is obtained with relatively shorter reaction
time (Table 2, entries 5, 6).
CsF
a Reaction conditions: chalcone (1a; 0.15 mmol), Me3SiCN (0.33
mmol, 2.2 equiv), catalyst (10 mol%), dioxane (1.5 mL), reflux, 4.5 h.
b Isolated yield.
Subsequently, effects of catalyst loading and additives are
investigated with results listed in Table 4. Reasonably, as
reducing the catalyst loading from 10 mol% to 1 mol% the
yield of product 2a decreases gradually from 92% to 64%
(Table 4, entries 1–3). Considering that proton is needed
to complete the reaction sequence and the significant im-
provement by protic additives in the conjugate addition of
Me3SiCN to a,b-unsaturated carbonyl compounds in re-
cent years,14,15 the effect of protonic additive is studied
with 1 mol% of Cs2CO3 (Table 4, entries 4–9). Thus, al-
cohol and phenol (2,6-dimethylphenol, DMP) are intro-
duced into the reaction mixture giving moderate increase
of the yield of 2a (Table 4, entries 4 and 5 vs. entry 3). An
encouraging result is obtained when H2O is added
(Table 4, entries 6–8). The reaction proceeds cleanly and
gives the highest yield with 4 equivalents of water
(Table 4, entry 8). However, much excessive amount of
H2O reduces the yield of 2a (Table 4, entry 9). In addition,
as an adequate amount of water has been introduced into
the reaction resulting in no formation of O-trimethylsilyl
1,4-adduct enolate in the reaction mixture, the subsequent
quenching with 1 M HCl is not needed anymore (Table 4,
entry 8).
Table 2 Effects of Temperature and Time on the Cs2CO3-Catalyzed
1,4-Addition of Me3SiCN to Chalcone (1a)a
1) Cs2CO3 (10 mol%)
Me3SiCN (2.2 equiv)
dioxane
O
CN
O
Ph
Ph
Ph
Ph
2) 1 M HCl, r.t.
1a
2a
Entry
Temp (°C)
40
Time (h)
4.5
Yield (%)b
1
2
3
4c
5
6
trace
31
80
4.5
reflux
120
4.5
92
4.5
76
reflux
reflux
2.5
61
1
33
a Reaction conditions: chalcone (1a; 0.15 mmol), Me3SiCN (0.33
mmol, 2.2 equiv), Cs2CO3 (10 mol%), dioxane (1.5 mL).
b Isolated yield.
c In a sealed tube.
Water is frequently used in modern organic synthesis and
has been comprehensively reviewed.20 From the results in
Table 4, it implies that H2O is not only used to provide
proton (Table 4, entry 7 vs. entries 4 and 5). In this case,
H2O probably facilitates the reversion of possible 1,2-ad-
dition followed by a fast irreversible 1,4-addition.14 Side
evidence comes from the fact that neither 1,4-adduct silyl
On the basis of above results, various catalysts are
screened in the model reaction in dioxane at reflux tem-
perature (Table 3). A yield of 24% is obtained with 10
mol% of Na2CO3 (Table 3, entry 1). K2CO3 gives yet un-
satisfactory 40% yield (Table 3, entry 2). Delightedly,
Cs2CO3 makes the reaction proceed smoothly to afford the
product 2a in 92% yield (Table 3, entry 3). Comparing the
Synthesis 2010, No. 8, 1325–1333 © Thieme Stuttgart · New York

PAPER
Cs2CO3-Catalyzed 1,4-Addition of Me3SiCN to Enones
1327
Table 4 Effects of Catalyst Loading and Additive on the Cs2CO3-
Catalyzed 1,4-Addition of Me3SiCN to Chalcone (1a)a
Table 5 Effect of Cyanide Source on the Cs2CO3-Catalyzed 1,4-
Addition of Me3SiCN to Chalcone (1a)a
1) Cs2CO3
Me3SiCN (2.2 equiv)
additive
Cs2CO3 (1 mol%)
cyanide (2.2 equiv)
H2O (4 equiv)
O
O
CN
O
CN
O
dioxane, reflux, 4.5 h
dioxane, reflux, 4.5 h
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2) 1 M HCl, r.t.
1a
1a
2a
2a
Entry
Cs2CO3 (mol%)
Additive (equiv)b
–
Yield (%)c
Entry
Cyanide source
Me3SiCN
Yield (%)b
1
2
3
4
5
6
7
8d
9
10
5
92
71
64
79
75
84
87
92
29
1
2
3
4
92
66
0
–
t-Bu(Me)2SiCN
K3Fe(CN)6
CuCN
1
–
1
i-PrOH (1)
DMP (1)
H2O (0.3)
H2O (1)
H2O (4)
H2O (1:5)e
0
a Reaction conditions: chalcone (1a; 0.15 mmol), cyanide (0.33
mmol, 2.2 equiv), catalyst (1 mol%), dioxane (1.5 mL), reflux, 4.5 h.
b Isolated yield.
1
1
1
Table 6 Effects of Catalyst Loading and Concentration of Chalcone
(1a) on the Cs2CO3-Catalyzed 1,4-Addition of Me3SiCNa
1
1
Cs2CO3 (x mol%)
Me3SiCN (y equiv)
a Reaction conditions: chalcone (1a; 0.15 mmol), Me3SiCN (0.33
mmol, 2.2 equiv), dioxane (1.5 mL), reflux, 4.5 h.
b Relative to 1a.
O
CN
O
H2O (4 equiv)
dioxane, reflux
Ph
Ph
Ph
Ph
c Isolated yield.
1a
2a
d Comparable yield is obtained without quencher (1 M HCl).
e Volume ratio of H2O to dioxane. DMP = 2,6-dimethylphenol.
Entry
Cs2CO3
(mol%)b
Me3SiCN
Concn
(M)c
Time Yield
(equiv)b
(h)
4.5
4.5
3
(%)d
59
92
99
99
95
97
88
99
99
99
95
36
93
enolate nor 1,2-adduct silyl ether is detected by TLC mon-
itoring during the course of the reaction in the presence of
water (Table 4, entries 7 and 8), though alkali carbonate
has been used to catalyze the 1,2-addition of Me3SiCN to
ketones in the literature.21
1
2
1
2.2
0.05
0.1
0.3
0.6
1
1
2.2
3
1
2.2
4
1
2.2
3
Further, several cyanide sources involving inorganic cya-
nides are examined referring to the above conditions
(Table 5). Compared to Me3SiCN, tert-butyldimethylsilyl
cyanide (TBSCN) gives inferior yield (entry 2 vs. 1),
which is not in line with Shibasaki’s observation.14 With
inorganic cyanides such as K3Fe(CN)6 and CuCN, no re-
action takes place at all (entries 3 and 4).
5
1
2.2
4.5
3
6
1
1.5
0.3
0.3
0.3
0.6
0.6
1
7
1
1.2
3
8
0.5
0.5
0.5
0.3
0.1
0.5
2.2
3.5
3
9
2.2
To obtain the best catalyst efficiency, subsequent optimi-
zation focusing on concentration of chalcone (1a) and
equivalent of Me3SiCN is carried out (Table 6). First, con-
centration of chalcone is changed from 0.05 M to 1 M
stepwise with 1 mol% of Cs2CO3 and 2.2 equivalents of
Me3SiCN in the presence of 4 equivalents of H2O
(Table 6, entries 1–5). Reaction at low concentration leads
to a slow reaction rate and thus a low yield (Table 6, entry
1). As increasing the concentration, the reactions afford
10
11
12
13e
1.5
3
1.5
5.5
7
2.2
1
1.5
0.6
4.5
a Reaction conditions: dioxane, reflux.
b Relative to 1a.
almost stoichiometric product 2a at 0.3 M and 0.6 M with- c Concentration of 1a.
in a shorter reaction time (Table 6, entries 3 and 4 vs. en-
d Isolated yield.
e Performed on gram scale, see experimental section.
try 2). However, at much higher concentration (1 M) the
model reaction produces lower yield even with a longer
reaction time (Table 6, entry 5). Second, lowering the
equivalent of Me3SiCN shows that 1.5 equivalents of
Me3SiCN are enough for a comparative yield at 0.3 M
(Table 6, entry 6 vs. entries 5 and 7). Encouraged by these
results, further decrease of the catalyst loading to 0.5
mol% is performed at 0.3 M and 0.6 M also giving excel-
lent yields (Table 6, entries 8–10). Furthermore, the satis-
factory result is retained even with much low catalyst
Synthesis 2010, No. 8, 1325–1333 © Thieme Stuttgart · New York

1328
J. Yang et al.
PAPER
loading at 0.3 mol% of Cs2CO3 and 1.5 equivalents of temperature – the substrate generality is evaluated
Me3SiCN at much concentrated of chalcone (1a) (Table 6, (Table 7). In general, the chalcone derivatives give excel-
entry 11). However, further decrease of catalyst loading to lent yields (90–99%) at varying reaction rate (Table 7,
0.1 mol% results in either longer reaction time or low entries 1–9). With electron-donating substituents the reac-
yield (Table 6, entry 12). For considerable reaction rate, tions proceed slowly than chalcone (Table 7, entries 2–5
the catalyst loading is determined to be 0.5 mol% at 0.6 M vs. entry 1). On the other hand, electron-deficient a,b-un-
of chalcone (1a) (Table 6, entry 10). This protocol is such saturated enones are converted into b-cyanoketones much
practical that it can be easily scaled up to gram scale in quickly (Table 7, entries 6–9). b-Alkyl substituted enone
93% isolated yield of 2a (Table 6, entry 13).
1j also gives excellent yield under these conditions
(Table 7, entry 10). Most excitingly, the present protocol
can be applied to aliphatic enones with excellent yields
(Table 7, entries 11–13).
With the optimal reaction conditions at hand – enones (0.3
mol, 0.6 M), Me3SiCN (1.5 equiv), Cs2CO3 (0.5 mol%),
H2O (4 equiv to enones) in dioxane (0.5 mL) at reflux
Table 7 Substrate Generality of Cs2CO3-Catalyzed 1,4-Addition of Me3SiCN to Enonesa
Cs2CO3 (0.5 mol%)
Me3SiCN (1.5 equiv)
H2O (4 equiv)
dioxane, reflux
O
CN
O
R1
R2
R1
R2
1a–m
2a–m
Entry
1
Product
Time (h)
3
Yield (%)b
99c
CN
O
O
2a
2b
OMe CN
2
3
5
4
97
99
CN
O
O
MeO
2c
CN
4
5
98
MeO
2d
CN
O
5
6
7
5
1
1
99
99
98
Me
2e
Cl
CN
O
2f
Cl
CN
O
Cl
2g
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PAPER
Cs2CO3-Catalyzed 1,4-Addition of Me3SiCN to Enones
1329
Table 7 Substrate Generality of Cs2CO3-Catalyzed 1,4-Addition of Me3SiCN to Enonesa (continued)
Cs2CO3 (0.5 mol%)
Me3SiCN (1.5 equiv)
H2O (4 equiv)
dioxane, reflux
O
CN
O
R1
R2
R1
R2
1a–m
2a–m
Entry
8
Product
Time (h)
1
Yield (%)b
90
CN
O
O2N
2h
Cl
CN
O
9
1
1
94
99
NO2
2i
CN
O
10
2j
CN
O
11
12
13
3
3
3
81
98
99
2k
2l
CN
O
CN
O
2m
a Reaction conditions: enones (0.3 mmol, 0.6 M), Me3SiCN (0.45 mmol, 1.5 equiv), Cs2CO3 (0.5 mol%), H2O (4 equiv), dioxane (0.5 mL),
reflux for indicated reaction times.
b Isolated yield.
c Performed on gram scale, 93% yield (see experimental section).
Table 8 Control Experimentsa
To shed light on the possible origin of the remarkable per-
formance of the 1,4-addition reaction catalyzed by
CN
O
O
HCN
or
Me3SiCN
Cs2CO3 (0.5 mol%)
dioxane, reflux, 3 h
+
Cs2CO3 with H2O as additive, several control experiments
are performed (Table 8). Considering possible generation
of HCN in situ from Me3SiCN and H2O to participate in
the reaction, HCN is investigated as another cyanide
source. As expected, the yield is considerably lower either
with or without H2O (Table 8, entries 1 and 2). However,
excellent yield can be obtained when Me3SiCN is em-
ployed (Table 8, entry 3). These phenomena indicate that
HCN generated in situ from Me3SiCN and H2O does not
account for the perfect 1,4-addition efficiency while
Ph
Ph
Ph
Ph
2a
1a
Entry
Cyanide source
HCNd
H2O (equiv)b
Yield (%)c
1
2
3
–
4
4
52
61
99
HCNd
Me3SiCN
a Reaction conditions: chalcone (1a; 0.3 mmol, 0.6 M), cyanide
Me3SiCN is likely to be the real cyanating reagent,22 or at source (0.45 mmol, 1.5 equiv), Cs2CO3 (0.5 mol%), dioxane (0.5
mL), reflux for 3 h.
least that HCN as the only cyanide source makes the reac-
b Relative to 1a.
tion inferior to the combined use of Me3SiCN and H2O.15f
c Isolated yield.
In our opinion, as shown in Scheme 3, water here is main-
ly used to fasten the catalytic cycle by protonation of the
O-trimethylsilyl 1,4-adduct enolate affording the b-cy-
anoketone and in part to suppress the possible 1,2-addi-
tion as well.21a,b
d HCN solution was generated prior to use from equal molar ratio of
Me3SiCN and MeOH.
Hypervalent silicon species must be involved in the tran-
sition state (Scheme 3). It is a general known chemistry
Synthesis 2010, No. 8, 1325–1333 © Thieme Stuttgart · New York

1330
J. Yang et al.
PAPER
Me3SiCN
Cs2CO3
CN
Si
CN
Si
Cs
Cs
O
O
O
O
O
R1
R2
OCs
OCs
3a
1
3b
SiMe3
R2
CN
O
O
O
Cs
Cs
R1
5
O
O
O
O
Cs
Si
Cs
O
Me3SiCN
H2O
CN
Si
CN
CN
O
O
R1
R2
R1
R2
R1
R2
4a
4b
2
Scheme 3 Proposed catalytic cycle
vents were dried under argon prior to use. Enones 1a–j were synthe-
sized according to reported procedure.26 Enones 1k–m were
purchased from Alfa Aesar and used directly.
that the reactions of silicon reagents usually involve hy-
pervalent silicon through nucleophilic activation.21a,23 In
the present less strong dipolar dioxane, we proposed pen-
tacoordinated silicate 3a,b as the real cyanide reagent
formed by the interaction between Me3SiCN and the par-
tially dissociated carbonate anion of Cs2CO3.19,21a Subse-
quently, the silicate species 3 undergoes conjugate
addition through a dual activation transition state 424 af-
fording silyl enolate 5 and regeneration of 3a,b, in which
5 is immediately hydrolyzed by water into 2.
1,4-Addition of Me3SiCN to Enones 1a–m; General Procedure
After Cs2CO3 (0.5 mg, 0.0015 mmol, 0.5 mol%), enone 1 (0.3
mmol), and dioxane (0.5 mL) were charged into a dry Schlenk tube
equipped with cold finger under argon, Me3SiCN (57 mL, 0.45
mmol, 1.5 equiv) and H2O (22 mL, 1.2 mmol, 4 equiv) were added.
The reaction mixture was stirred at reflux temperature until the re-
action was complete (monitored by TLC). Then, H2O (2 mL) was
added at r.t. and the resulting mixture was extracted with EtOAc (5
mL) (Caution! HCN generated in the reaction mixture is highly
toxic. Those operations should be conducted in a well-ventilated
hood). The extract was washed with H2O (2 mL), brine (3 mL),
dried (Na2SO4), and concentrated. The crude product was purified
by flash column chromatography on silica gel (PE–EtOAc, 20:1,
unless otherwise noted) to afford pure products 2 (Table 7).
In conclusion, a successful Cs2CO3-catalyzed 1,4-addi-
tion of Me3SiCN to both aromatic and aliphatic enones
has been achieved. The 1,4-adducts are obtained in excel-
lent yields with 0.5 mol% of Cs2CO3 and 4 equivalents of
H2O as the additive within one to five hours. The facile
availability of the catalyst and high regioselectivity of the
reaction make it much more practical. It can be easily
scaled up to gram scale with excellent yield. Further
mechanistic elucidation and extension to asymmetric ver-
sion of this protocol are under way in our group.25
1,4-Addition of Me3SiCN to Chalcone (1a) on Gram Scale;
4-Oxo-2,4-diphenylbutanenitrile (2a)
To a suspension of Cs2CO3 (7.8 mg, 0.024 mmol, 0.5 mol%) and
chalcone (1a; 1 g, 4.8 mmol) in anhyd dioxane (8.0 mL) in a 50 mL
Schlenk tube equipped with cold finger under argon were added
Me3SiCN (0.91 mL, 7.2 mmol, 1.5 equiv) and H2O (0.34 mL, 19.2
mmol, 4 equiv) sequentially. The reaction mixture was stirred at re-
flux temperature for 4.5 h. Upon completion of the reaction as noted
by TLC monitoring, H2O (5 mL) was added to quench the reaction
at r.t. The resulting mixture was extracted with EtOAc (20 mL)
(Caution! HCN generated in the reaction mixture is highly toxic.
Those operations should be conducted in a well-ventilated hood).
The extract was washed with H2O (3 × 4 mL), brine (5 mL), dried
(Na2SO4), and concentrated. The crude solid was washed with hot
PE–EtOAc (20:1, 2 × 5 mL) to afford pure 2a (1054 mg, 93%) as a
yellowish brown solid.
NMR spectra were recorded on a Bruker AVIII 400 spectrometer,
1
operating at 400 MHz for H NMR, and 100 MHz for 13C NMR.
Chemical shifts for 1H NMR and 13C NMR spectra are reported as
d in units of parts per million (ppm) downfield from Me4Si and rel-
ative to the signal of CDCl3. The IR spectra were recorded on a
Perkin-Elmer Spectrum One with KBr pellets for solids and as films
for liquids. The elemental analyses were performed on an Elemen-
tar Vario MICRO CUBE instrument. All melting points were deter-
mined on a XT4A melting point apparatus and uncorrected.
Analytical TLC was performed using F254 precoated silica gel
plate. Column chromatography was performed with silica gel (200–
300 mesh). Petroleum ether (PE) used had a boiling point range of
60–90 °C.
When performed on 0.3 mmol scale (optimized general procedure),
yield: 99%; white solid; mp 120–122 °C (Lit.11 mp 122–125 °C).
IR (KBr): 1681, 2236 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.52 (dd, J = 6.0, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.74 (dd, J = 8.0, 18.0 Hz, 1 H, NCCHCHAHB-
All reactions were carried out under argon atmosphere using typical
vacuum-line techniques unless otherwise noted. Me3SiCN and
Cs2CO3 were purchased from Alfa Aesar and used directly. All sol-
Synthesis 2010, No. 8, 1325–1333 © Thieme Stuttgart · New York

PAPER
Cs2CO3-Catalyzed 1,4-Addition of Me3SiCN to Enones
1331
CO), 4.57 (dd, J = 6.0, 8.0 Hz, 1 H, NCCHCHAHBCO), 7.34–7.49
(m, 7 H, ArH), 7.58–7.62 (m, 1 H, ArH), 7.92–7.94 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 30.1, 42.4, 119.7, 127.8, 128.1,
128.8, 129.5, 129.9, 130.3, 132.7, 133.9, 135.6, 194.4.
13C NMR (100 MHz, CDCl3): d = 31.9, 44.5, 120.6, 127.5, 128.1,
128.4, 128.8, 129.3, 133.9, 135.3, 135.8, 194.6.
2-(2,4-Dichlorophenyl)-4-oxo-4-phenylbutanenitrile (2g)
Yield: 98%; white solid; mp 90–91 °C.
2-(2-Methoxyphenyl)-4-oxo-4-phenylbutanenitrile (2b)
IR (KBr): 1682, 2247 cm–1.
Yield: 97%; white solid; mp 84–86 °C.
IR (KBr): 1685, 2245 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.52 (dd, J = 4.8, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.67 (dd, J = 9.2, 18.0 Hz, 1 H, NCCHCHAHB-
CO), 4.88 (dd, J = 4.8, 9.2 Hz, 1 H, NCCHCHAHBCO), 7.33–7.36
(m, 1 H, ArH), 7.45–7.50 (m, 3 H, ArH), 7.59–7.63 (m, 2 H, ArH),
7.93–7.95 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 29.7, 42.2, 119.3, 128.08, 128.11,
128.9, 130.1, 130.5, 131.3, 133.5, 134.0, 135.3, 135.5, 194.1.
1H NMR (400 MHz, CDCl3): d = 3.50 (dd, J = 4.8, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.65 (dd, J = 8.8, 18.0 Hz, 1 H, NCCHCHAHB-
CO), 3.87 (s, 3 H, OCH3), 4.78 (dd, J = 4.8, 8.8 Hz, 1 H, NCCH-
CHAHBCO), 6.91–7.02 (m, 2 H, ArH), 7.31–7.35 (m, 1 H, ArH),
7.45–7.51 (m, 3 H, ArH), 7.56–7.61 (m, 1 H, ArH), 7.93–7.95 (m,
2 H, ArH).
Anal. Calcd for C16H11Cl2NO: C, 63.18; H, 3.65; N, 4.60. Found: C,
63.06; H, 3.73; N, 4.65.
13C NMR (100 MHz, CDCl3): d = 27.5, 42.2, 55.6, 111.0, 120.5,
121.1, 123.2, 128.1, 128.7, 129.0, 129.8, 133.6, 136.0, 156.3, 195.3.
2-(3-Nitrophenyl)-4-oxo-4-phenylbutanenitrile (2h)
The purification of 2h was performed by column chromatography
with PE–EtOAc (10:1) as the eluent; yield: 90%; yellowish solid;
mp 132–133 °C.
2-(3-Methoxyphenyl)-4-oxo-4-phenylbutanenitrile (2c)
Yield: 99%; white solid; mp 106–108 °C.
IR (KBr): 1678, 2236 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.50 (dd, J = 6.0, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.72 (dd, J = 8.0, 18.0 Hz, 1 H, NCCHCHAHB-
CO), 3.82 (s, 3 H, OCH3), 4.55 (dd, J = 6.0, 8.0 Hz, 1 H, NCCH-
CHAHBCO), 6.86–6.88 (m, 1 H, ArH), 6.96–7.02 (m, 2 H, ArH),
7.28–7.32 (m, 1 H, ArH), 7.45–7.49 (m, 2 H, ArH), 7.58–7.62 (m,
1 H, ArH), 7.92–7.94 (m, 2 H, ArH).
IR (KBr): 1680, 2245 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.61 (dd, J = 6.8, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.80 (dd, J = 6.8, 18.0 Hz, 1 H, NCCHCHAHB-
CO), 4.72 (dd, J = 6.8, 6.8 Hz, 1 H, NCCHCHAHBCO), 7.47–7.51
(m, 2 H, ArH), 7.59–7.64 (m, 2 H, ArH), 7.83–7.85 (m, 1 H, ArH),
7.92–7.94 (m, 2 H, ArH), 8.20–8.23 (m, 1 H, ArH), 8.33–8.34 (m,
1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 31.9, 44.5, 55.4, 113.3, 113.8,
119.6, 120.5, 128.1, 128.8, 130.4, 133.9, 135.8, 136.7, 160.2, 194.6.
13C NMR (100 MHz, CDCl3): d = 31.6, 43.9, 119.5, 122.8, 123.6,
128.1, 129.0, 130.4, 133.9, 134.2, 135.3, 137.4, 148.7, 193.8.
2-(4-Methoxyphenyl)-4-oxo-4-phenylbutanenitrile (2d)
Anal. Calcd for C16H12N2O3: C, 68.56; H, 4.32; N, 9.99. Found: C,
68.41; H, 4.45; N, 10.09.
Yield: 98%; white solid; mp 111–113 °C (Lit.11 mp 113–114 °C).
IR (KBr): 1677, 2234 cm–1.
2-(2-Chlorophenyl)-4-(4-nitrophenyl)-4-oxobutanenitrile (2i)
The purification of 2i was performed by column chromatography
with PE–EtOAc (10:1) as the eluent; yield: 94%; white solid; mp
126–127 °C.
1H NMR (400 MHz, CDCl3): d = 3.49 (dd, J = 6.4, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.73 (dd, J = 7.6, 18.0 Hz, 1 H, NCCHCHAHB-
CO), 3.80 (s, 3 H, OCH3), 4.53 (dd, J = 6.4, 7.6 Hz, 1 H, NCCH-
CHAHBCO), 6.89–6.92 (m, 2 H, ArH), 7.33–7.36 (m, 2 H, ArH),
7.45–7.49 (m, 2 H, ArH), 7.57–7.61 (m, 1 H, ArH), 7.91–7.93 (m,
2 H, ArH).
IR (KBr): 1691, 2252 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.57 (dd, J = 4.4, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.71 (dd, J = 9.6, 18.0 Hz, 1 H, NCCHCHAHB-
CO), 4.93 (dd, J = 4.4, 9.6 Hz, 1 H, NCCHCHAHBCO), 7.33–7.40
(m, 2 H, ArH), 7.44–7.46 (m, 1 H, ArH), 7.69–7.71 (m, 1 H, ArH),
8.10–8.13 (m, 2 H, ArH), 8.32–8.35 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 30.0, 42.9, 119.2, 124.1, 127.9,
129.2, 129.5, 130.2, 130.4, 132.1, 132.6, 139.9, 150.8, 193.1.
13C NMR (100 MHz, CDCl3): d = 31.2, 44.6, 55.4, 114.6, 120.9,
127.2, 128.1, 128.7, 128.8, 133.8, 135.8, 159.6, 194.7.
4-Oxo-4-phenyl-2-p-tolylbutanenitrile (2e)
Yield: 99%; white solid; mp 129–131 °C (Lit.11 135–137 °C).
IR (KBr): 1674, 2239 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 3.49 (dd,
J = 6.4, 18.0 Hz, 1 H, NCCHCHAHBCO), 3.70 (dd, J = 8.0, 18.0 Hz,
1 H, NCCHCHAHBCO), 4.53 (dd, J = 6.4, 8.0 Hz, 1 H, NCCH-
CHAHBCO), 7.19 (d, J = 8.0 Hz, 2 H, ArH), 7.31 (d, J = 8.0 Hz, 2
H, ArH), 7.45–7.48 (m, 2 H, ArH), 7.57–7.61 (m, 1 H, ArH), 7.91–
7.93 (m, 2 H, ArH).
Anal. Calcd for C16H11ClN2O3: C, 61.06; H, 3.52; N, 8.90. Found:
C, 61.88; H, 3.84; N, 8.87.
2-Methyl-4-oxo-4-phenylbutanenitrile (2j)
Yield: 99%; colorless oil.
IR (film): 1686, 2236 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 6.8 Hz, 3 H, CH3),
3.14 (dd, J = 6.4, 17.2 Hz, 1 H, NCCHCHAHBCO), 3.27 (dd,
J = 6.4, 13.2 Hz, 1 H, NC-CHCHAHBCO), 3.24–3.37 (m, 1 H, NC-
CHCHAHBCO), 7.40–7.44 (m, 2 H, ArH), 7.52–7.55 (m, 1 H, ArH),
7.87–7.89 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 17.9, 20.5, 42.2, 122.6, 128.0,
128.8, 133.8, 135.9, 195.1.
13C NMR (100 MHz, CDCl3): d = 21.0, 31.5, 44.6, 120.8, 127.4,
128.1, 128.8, 129.9, 132.3, 133.8, 135.8, 138.3, 194.7.
2-(2-Chlorophenyl)-4-oxo-4-phenylbutanenitrile (2f)
Yield: 99%; white solid; mp 100–102 °C (Lit.27 mp 106–108 °C).
IR (KBr): 1686, 2247 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.53 (dd, J = 4.8, 18.0 Hz, 1 H,
NCCHCHAHBCO), 3.68 (dd, J = 9.2, 18.0 Hz, 1 H, NCCHCHAHB-
CO), 4.93 (dd, J = 4.8, 9.2 Hz, 1 H, NCCHCHAHBCO), 7.29–7.38
(m, 2 H, ArH), 7.42–7.50 (m, 3 H, ArH), 7.58–7.62 (m, 1 H, ArH),
7.67–7.69 (m, 1 H, ArH), 7.94–7.96 (m, 2 H, ArH).
4-Oxo-2-propylpentanenitrile (2k)
The purification of 2k was performed by column chromatography
with PE–EtOAc (10:1) as the eluent; yield: 81%; yellowish oil.
Synthesis 2010, No. 8, 1325–1333 © Thieme Stuttgart · New York

1332
J. Yang et al.
PAPER
IR (film): 1721, 2241 cm–1.
J. Org. Chem. 2007, 72, 7423. (d) Hegedus, L. S.; Cross, J.
J. Org. Chem. 2004, 69, 8492.
1H NMR (500 MHz, CDCl3): d = 0.98 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.50–1.61 (m, 4 H, CH3CH2CH2CHCN), 2.23 (s, 3 H, COCH3),
2.70 (dd, J = 6.5, 18.0 Hz, 1 H, NCCHCHAHBCO), 2.86 (dd,
J = 7.0, 18.0 Hz, 1 H, NCCHCHAHBCO), 3.07–3.10 (m, 1 H, NC-
CHCHAHBCO).
13C NMR (125 MHz, CDCl3): d = 13.5, 20.4, 25.8, 30.0, 33.8, 45.4,
121.6, 203.8.
(5) For recent examples involving conjugate hydrocyanation of
enones in the syntheses of natural products, see:
(a) Siwicka, A.; Cuperly, D.; Tedeschi, L.; Le Vézouët, R.;
White, A. J. P.; Barrett, A. G. M. Tetrahedron 2007, 63,
5903. (b) Muratake, H.; Natsume, M. Tetrahedron 2006, 62,
7071. (c) Mander, L. N.; Thomson, R. J. J. Org. Chem. 2005,
70, 1654. (d) Rahman, S. M. A.; Ohno, H.; Yoshino, H.;
Satoh, N.; Tsukaguchi, M.; Murakami, K.; Iwata, C.;
Maezaki, N.; Tanaka, T. Tetrahedron 2001, 57, 127.
(e) Rahman, S. M. A.; Ohno, H.; Maezaki, N.; Iwata, C.;
Tanaka, T. Org. Lett. 2000, 2, 2893.
2-(2-Oxopropyl)hexanenitrile (2l)
The purification of 2l was performed by column chromatography
with PE–EtOAc (10:1) as the eluent; yield: 98%; yellowish oil.
IR (film): 1721, 2241 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H, CH3CH2),
1.22–1.61 (m, 6 H, CH3CH2CH2 CH2CHCN), 2.20 (s, 3 H, COCH3),
2.67 (dd, J = 6.8, 18.0 Hz, 1 H, NCCHCHAHBCO), 2.87 (dd,
J = 7.2, 18.0 Hz, 1 H, NCCHCHAHBCO), 3.03–3.07 (m, 1 H, NC-
CHCHAHBCO).
13C NMR (100 MHz, CDCl3): d = 13.7, 22.1, 25.9, 29.1, 30.0, 31.5,
45.4, 121.6, 203.7.
(6) Utimoto, K.; Obayashi, M.; Shishiyama, Y.; Inoue, M.;
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Shishiyama, Y.; Obayashi, M.; Nozaki, H. Tetrahedron
1983, 39, 967. (b) Gerus, I. I.; Kruchok, I. S.; Kukhar, V. P.
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Tetrahedron Lett. 2000, 41, 2591.
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2008, 49, 6360.
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Tetrahedron Lett. 2007, 48, 2037.
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Shibasaki, M. Tetrahedron Lett. 2007, 48, 1403. (b)Fukuta,
Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 6312.
(13) Tanaka, Y.; Kanai, M.; Shibasaki, M. Synlett 2008, 2295.
(14) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2008, 130, 6072.
(15) For examples of asymmetric addition of Me3SiCN to a,b-
unsaturated imides, see: (a) Mazet, C.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2008, 47, 1762. (b) Madhavan, N.;
Weck, M. Adv. Synth. Catal. 2008, 350, 419. (c) Fujimori,
I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.;
Kanai, M.; Shibasaki, M. Tetrahedron 2007, 63, 5820.
(d) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 514. (e) Sammis, G. M.; Danjo, H.;
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125, 4442.
2-(2-Oxopropyl)heptanenitrile (2m)
The purification of 2m was performed by column chromatography
with PE–EtOAc (10:1) as the eluent; yield: 99%; yellowish oil.
IR (film): 1721, 2241 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.2 Hz, 3 H, CH3CH2),
1.25–1.36 (m,
4 H, CH3CH2CH2), 1.41–1.62 (m, 4 H,
CH2CH2CHCN), 2.19 (s, 3 H, COCH3), 2.66 (dd, J = 6.8, 18.0 Hz,
1 H, NCCHCHAHBCO), 2.86 (dd, J = 7.2, 18.0 Hz, 1 H, NCCH-
CHAHBCO), 3.00–3.06 (m, 1 H, NCCHCHAHBCO).
13C NMR (100 MHz, CDCl3): d = 13.9, 22.4, 26.0, 26.7, 30.0, 31.1,
31.8, 45.4, 121.7, 203.7.
Acknowledgment
The authors thank Beijing Institute of Technology and NSFC
(20972016) for financial support.
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