The highly efficient 1,4-addition of TMSCN to aromatic enones catalyzed by CsF with water as the additive

Article abstract of DOI:10.1055/s-0029-1218376

An efficient 1,4-addition of TMSCN to aromatic enones has been achieved in excellent yields (91-99%) by CsF (1 mol%) as the catalyst and H₂O (4 equiv) as the additive in refluxing dioxane within 2-7 hours. Georg Thieme Verlag Stuttgart - New Yo

Full text of DOI:10.1055/s-0029-1218376

LETTER
3365
The Highly Efficient 1,4-Addition of TMSCN to Aromatic Enones Catalyzed
by CsF with Water as the Additive
1
, 4-Additi
i
on of
C
n
yanide gya Yang,a,b Yinxian Wang,a Shaoxiang Wu,a Fu-Xue Chen*a
a
Department of Applied Chemistry, School of Chemical Engineering & the Environment, Beijing Institute of Technology,
No. 5 South Zhongguancun Street, Haidian District, Beijing 100081, P. R. of China
Fax +86(10)68918296; E-mail: fuxue.chen@bit.edu.cn
b
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China
Received 10 September 2009
manding.15 Herein, we report an efficient CsF-catalyzed
1,4-addition of TMSCN to aromatic enones in the pres-
ence of water.
Abstract: An efficient 1,4-addition of TMSCN to aromatic enones
has been achieved in excellent yields (91–99%) by CsF (1 mol%) as
the catalyst and H2O (4 equiv) as the additive in refluxing dioxane
within 2–7 hours.
In view of high affinity of silicon for fluoride anion,16 we
Key words: 1,4-addition reaction, enones, nitriles, regioselectivity, suppose that fluoride could activate TMSCN. Model ex-
CsF
periments were conducted with chalcone (1a) and
TMSCN to optimize the reaction conditions (Table 1).
Initially, various fluorides were examined in dioxane at
refluxing temperature. Thus, 41% yield was obtained with
hydrated KF (20 mol%, entry 1). On the other hand,
Bu4NF gave an inferior 75% yield (entry 2). Surprisingly,
the reaction proceeded smoothly in the presence of CsF17
to afford the product 2a in 92% yield (entry 3). Compar-
ing the results of KF and CsF, a possible ‘cesium effect’
cannot be ruled out at present.18 Nevertheless, a control
The conjugate addition of a,b-unsaturated carbonyl com-
pounds is one of the supremely important C–C bond for-
mation reactions in organic synthesis.1 Unlike the well
developed transition metal-catalyzed 1,4-addition of aryl2
and alkyl reagents,3 the regioselective 1,4-addition of
weakly nucleophilic cyanide to a,b-unsaturated carbonyl
compounds remains challenging (Equation 1).
OSiMe3
Table 1 Optimization of Reaction Conditionsa
1,2-addition
R1
R2
1) cat.
Me3SiCN (2.2 equiv)
dioxane, reflux
NC
O
CN
O
O
+ Me3SiCN
R1
R2
Ph
Ph
Ph
Ph
CN OSiMe3
R2
2) 1 M HCl, r.t.
1a
2a
R1
1,4-addition
Entry Cat.
(mol%)
Additive
(equiv)b
Concn Time
Yield
(%)d
(M)c
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.3
0.3
(h)
5.5
5.5
5.5
5.5
5.5
5.5
4
Equation 1
1
KF·2H2O (20)
Bu4NF (20)
CsF (20)
CsCl (20)
CsF (20)
CsF (20)
CsF (20)
CsF (5)
41
75
92
16
30
7
In the literature, 1,4-addition of cyanide to enones has
been applied to syntheses of biologically active
molecules4 and complex natural products.5 In this context,
mild cyanide source such as TMSCN6 and Et2AlCN7 are
frequently employed with catalysts such as Et3Al,6,9a
Pd(OAc)2,8 and Lewis acids.9 Ionic liquid and microwave
have been utilized in this reaction in line of the concept of
green chemistry.10,11 Recently, Shibasaki and co-workers
applied an entirely distinct Ni(0)–cyclooctadiene (COD)
complex to the elegant synthesis of Tamiflu,12 an impor-
tant anti-influenza drug, and subsequent Ni(0) and
Gd(OTf)3 as the cooperative catalyst to the 1,4-addition of
TMSCN to a wide variety of aliphatic enones.13 The first
synthetically useful catalytic enantioselective conjugate
addition of cyanide to enones is also documented by
Shibasaki.14 Despite these achievements, practical regio-
selective 1,4-additon of TMSCN to enones is still de-
2
3
4
5e
6f
7
H2O (4)
H2O (4)
H2O (4)
99
99
99
8
4
9g
CsF (1)
4
a Unless otherwise noted, all reactions are conducted with 0.15 mmol
(0.1 M) or 0.3 mmol (0.3 M) of chalcone (1a) in dioxane (1.5 mL or
1.0 mL, respectively) under argon.
b Relative to 1a.
c Concentration of chalcone.
d Isolated yield.
e Performed in THF.
SYNLETT 2009, No. 20, pp 3365–3367
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218376; Art ID: W14009ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9
f Performed at 40 °C.
g Comparable results are obtained under open-air conditions.

3366
J. Yang et al.
LETTER
experiment using CsCl yielded the product in only 16% a,b-unsaturated enones were converted into b-cyano-
yield (entry 4). Subsequently, the effects of solvent and ketones much faster (entries 6–9). b-Alkyl-substituted
reaction temperature were investigated. The yield de- enone 1j also gave excellent yields under the optimal
creased sharply in THF (entry 5) and in other solvents,19 reaction conditions (entry 10). However, aliphatic enones
or at lower temperature (entry 6).
could not be converted into the product under these con-
ditions.
Considering proton might be needed to complete the reac-
tion sequence, the effect of water as an additive was stud-
ied (vide infra).20 Dramatically, the reaction proceeded
cleanly with four equivalents of water within four hours
(entry 7). Further decreasing the catalyst loading down to
5 mol% and 1 mol% gave almost quantitative yields at
slightly concentrated solutions (entries 8 and 9). Compa-
rable results were obtained when the reaction was con-
ducted under open-air conditions (entry 9).
Table 3 Scope of Substrate
O
CN
O
CsF (1 mol%)
H2O (4 equiv)
R1
R1
Me3SiCN (2.2 equiv)
dioxane, reflux
R2
R2
2a–j
1a–j
Entrya Product
Time (h) Yield (%)b
1c
2
3
4
5
6
7
8
9
2a R1 = Ph, R2 = H
4
99
99
99
99
99
99
99
91
93
97
To examine the effect of additives, water and other proton
sources were added to the reaction mixture (Table 2).
Without any proton additive, the yield was 52% (entry 1).
Increasing the amount of H2O from 0.3 to 1 equivalent,
the yield of 2a increased gradually from 59% to 70% (en-
tries 2 and 3). Other proton sources such as alcohols and
phenols (2,6-dimethylphenol) gave inferior yields (entries
4 and 5). It implied that H2O was not only used to provide
proton.20 The optimum yield was obtained with four
equivalents of water (entry 6). However, using excessive
amount of H2O reduced the product yield (entry 7).
2b R1 = 2-MeOC6H4, R2 = H
2c R1 = 3-MeOC6H4, R2 = H
2d R1 = 4-MeOC6H4, R2 = H
2e R1 = 4-MeC6H4, R2 = H
2f R1 = 2-ClC6H4, R2 = H
2g R1 = 2,4-Cl2C6H3, R2 = H
2h R1 = 3-O2NC6H4, R2 = H
2i R1 = 2-ClC6H4, R2 = O2N
2j R1 = Me, R2 = H
7
5
7
6
1.5
1.5
1.5
1
Table 2 Effect of Protonic Additive
CsF (1 mol%)
additive (x equiv)
10
1.5
Me3SiCN (2.2 equiv)
dioxane, reflux, 4 h
O
CN
O
a Conditions: enones (0.3 mmol), CsF (0.5 mg, 0.003 mmol, 1 mol%),
TMSCN (84 mL, 0.66 mmol, 2.2 equiv), H2O (22 mL, 1.2 mmol, 4
equiv), dioxane (1.0 mL), under argon.
Ph
Ph
Ph
Ph
1a
2a
b Isolated yield.
Entrya
Additive (equiv)b
none
Yield (%)c
c Comparable results are obtained under open-air conditions.
1d
2d
3
52
59
70
55
64
99
77
In conclusion, the highly regioselective 1,4-addition of
TMSCN to aromatic enones had been achieved with good
substrate generality. The 1,4-adducts were obtained in ex-
cellent yields with 1 mol% of CsF as the catalyst and four
equivalents of H2O as the additive. Further studies to elu-
cidate the reaction mechanism and extension to asymmet-
ric version of this protocol are under way in our group.
H2O (0.3)
H2O (1)
4d
5d
6
i-PrOH (1)
DMPh (1)
H2O (4)
7
H2O (0.3 mL)
Supporting Information for this article is available online at
a Conditions: 1a (62.5 mg, 0.3 mmol), CsF (0.5 mg, 0.003 mmol, 1
mol%), TMSCN (84 mL, 0.66 mmol, 2.2 equiv), dioxane (1.0 mL),
under argon, 4 h.
http://www.thieme-connect.com/ejournals/toc/synlett.
b Relative to 1a.
Acknowledgment
c Isolated yield.
d Quenched with 1 M HCl; DMPh = 2,6-dimethylphenol.
The authors thank Beijing Institute of Technology and NSFC
(20502019 & 20972016) for financial support.
Under the optimized reaction conditions, the substrate
scope of the CsF-catalyzed 1,4-addition of TMSCN to
enones was evaluated (Table 3).19,21 In general, chalcone
derivatives gave excellent yields (91–97%) at varying
reaction rate (entries 1–9). With electron-donating substit-
uents, the reactions proceeded slowly than chalcone (en-
tries 2–5 vs. entry 1). On the other hand, electron-deficient
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Synlett 2009, No. 20, 3365–3367 © Thieme Stuttgart · New York

LETTER
1,4-Addition of Cyanide
3367
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(21) Preparation of 2a
The solution of CsF (0.5 mg, 0.003 mmol, 1 mol%) and
enone (1a, 62.5 mg, 0.3 mmol) in dioxane (1 mL) is added
TMSCN (84 mL, 0.66 mmol, 2.2 equiv) and H2O (22 mL, 1.2
mmol, 4 equiv) subsequently in a dry Schlenk tube equipped
with cold finger under argon. The reaction mixture is stirred
at reflux temperature until the reaction is completed
(monitored by TLC). 1 M HCl (0.3 mL) is added to quench
the reaction with additional 20 min stirring at r.t. The
resulting mixture is 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 is washed with H2O, brine, dried over anhyd
Na2SO4, and concentrated. The crude product is purified by
flash chromatography on silica gel (PE–EtOAc, 20:1) to
afford 2a as white solid in 99% yield.
Nitrile 2a: mp 120–122 °C (lit.: 122–125 °C).11 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,
NCCHCHAHBCO), 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) ppm. 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 ppm. IR (KBr): n =
1681, 2236 cm–1.
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S.; Levacher, V. Angew. Chem. Int. Ed. 2007, 46, 7090.
(b) Yanagisawa, A.; Touge, T.; Arai, T. Angew. Chem. Int.
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