Conjugate Hydrocyanation of Chalcone Derivatives Using Ethyl Cyanoacetate as an Organic Cyanide Source

Article abstract of DOI:10.1002/cjoc.201600860

The conjugate hydrocyanation of chalcone derivatives using ethyl cyanoacetate as an organic cyanide source at room temperature under open air and transition metal-free conditions was described. The protocol has advantages of using relatively cheap, less toxic, stable and easy-to-handle cyanating reagent, high yield, and mild reaction condition.

Full text of DOI:10.1002/cjoc.201600860

FULL PAPER
DOI: 10.1002/cjoc.201600860
Conjugate Hydrocyanation of Chalcone Derivatives Using Ethyl
Cyanoacetate as an Organic Cyanide Source
Zheng Li* and Junjun Yin
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
The conjugate hydrocyanation of chalcone derivatives using ethyl cyanoacetate as an organic cyanide source at
room temperature under open air and transition metal-free conditions was described. The protocol has advantages of
using relatively cheap, less toxic, stable and easy-to-handle cyanating reagent, high yield, and mild reaction condi-
tion.
Keywords hydrocyanation, chalcone derivative, ethyl cyanoacetate, organic cyanide source
Introduction
metal-free and open air conditions to conduct the con-
jugate hydrocyanation of chalcone derivatives (Scheme
1, route 4). In comparison with other organic cyanide
sources reported, such as TMSCN,[10] acetone cyanohy-
drin,[11] ethyl cyanoformate,[12] acetyl cyanide,[13]
NCTS,[14] mandelonitrile,[15] isonitrile,[16] acetonitrile,[17]
DMF-ammonia[18] and DMF,[19] ethyl cyanoacetate as a
new and alternative organic cyanide source has the dis-
tinct advantages of being relatively cheap, less toxic,
stable and easy-to-handle.
Cyanation of organic chemicals is an important way
to synthesize various compounds bearing cyano group.[1]
Conjugate addition of cyanide to chalcone derivatives
has been explored in recent years, which has been
demonstrated to be an efficient route to β-cyano ke-
tones.[2] β-Cyano ketones are valuable synthons for the
synthetic organic chemistry, and the cyano group can be
easily transformed into a variety of functional groups,
such as amides, amines, aldehydes, acids, esters, tria-
zoles, tetrazoles, oxazoles and thiazoles.[3] However, the
current existing reactions require the use of various
highly toxic cyanide sources, such as HCN,[4] KCN[5]
and Et2AlCN,[6] in super-stoichiometric amounts.
Therefore, the discovery of new sources of cyanide
generated from simple and readily available reagents is
still an extremely attractive challenging goal.
Scheme 1 The bond cleavage type of ethyl cyanoacetate
As an important reagent, the conventional reactions
of ethyl cyanoacetate are the provision of carbon anion
under basic conditions to participate in Knoevenagel
condensation etc. (Scheme 1, route 1).[7] Liu reported a
palladium-catalyzed decarboxylative coupling of ethyl
cyanoacetate with aryl halides (triflates),[8] in which

Experimental
ethyl cyanoacetate provided NCCH2 through C－C
bond cleavage (Scheme 1, route 2). Recently, Shen re-
ported ethyl cyanoacetate could be used as an organic
cyanide source to provide CN via C－C bond cleavage
of NC-CH2 moiety for the palladium-catalyzed cya-
nation of aryl halides (Scheme 1, route 3).[9] However,
in this reaction the expensive transition metal is required,
and the substrate scope only limits to aryl halides.
In this paper, we report the utilization of ethyl cy-
anoacetate as an organic cyanide source via C－CN
bond cleavage at room temperature under transition
IR spectra were recorded using KBr pellets on an
1
Alpha Centauri FTIR spectrophotometer. H NMR and
13C NMR spectra were recorded on a Mercury-400BB
instrument using CDCl3 as solvent and Me4Si as internal
standard. Melting points were observed in an electro-
thermal melting point apparatus.
Typical procedure for conjugate hydrocyanation of
chalcone derivatives with ethyl cyanoacetate
To a solution of 0.5 mmol of chalcone derivative in 5
*
E-mail: lizheng@nwnu.edu.cn
Received December 4, 2016; accepted January 31, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc. 201600860 or from the author.
Chin. J. Chem. 2017, XX, 1—6
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Li & Yin
FULL PAPER
mL of DMF was added 0.55 mmol of ethyl cyanoacetate
and 1.0 mmol of potassium hydroxide. The reaction
mixture was stirred at room temperature for 8 h under
open air. After completion of the reaction, the resulting
mixture was poured into water and extracted with
EtOAc (3×10 mL). The combined organic phase was
washed with water (3×10 mL), dried over anhydrous
magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by flash chromatog-
raphy [silica gel, V(petroleum ether)/V(ethyl acetate)＝
20∶1] to give product. The analytical data for products
are given below.
Yellow solid. M.p. 148－150 ℃. 1H NMR (CDCl3, 400
MHz) δ: 3.55 (dd, J＝5.6, 18.0 Hz, 1H, CHCHaHCO),
3.78 (dd, J＝7.6, 18.0 Hz, 1H, CHCHbHCO), 4.56 (dd,
J＝5.6, 6.8 Hz, 1H, ArCHCH2), 7.38－7.43 (m, 5H,
ArH ), 8.09 (d, J＝8.0 Hz, 2H, ArH), 8.32 (d, J＝8.0 Hz,
2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 31.8, 45.0,
120.1, 124.0, 127.4, 128.6, 129.2, 129.4, 134.6, 139.8,
150.7, 193.3. IR (KBr) ν: 1685 (C＝O), 2242 (CN) cm1.
Anal. calcd for C16H12N2O3 (280.28): C 68.56, H 4.32,
N 9.99; found C 68.67, H 4.33, N 10.01.
4-Oxo-4-phenyl-2-(4-tolyl)butanenitrile
(2f)
White solid. M.p. 132－134 ℃ (lit.[20] 129－131 ℃).
1H NMR (CDCl3, 400 MHz) δ: 2.27 (s, 3H, CH3), 3.42
(dd, J＝6.0, 18.0 Hz, 1H, CHCHaHCO), 3.63 (dd, J＝
8.0, 18.0 Hz, 1H, CHCHbHCO), 4.46 (dd, J＝6.4, 7.6
Hz, 1H, ArCHCH2), 7.11－7.54 (m, 7H, ArH), 7.85 (d,
J＝8.4 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ:
21.0, 31.5, 44.5, 120.8, 127.3, 128.0, 128.8, 129.9,
132.2, 133.8, 135.6, 138.2, 194.7. IR (KBr) ν: 1676 (C
＝O), 2239 (CN) cm1. Anal. calcd for C17H15NO
(249.31): C 81.90, H 6.06, N 5.62; found C 81.98, H
6.09, N 5.60.
4-Oxo-2,4-diphenylbutanenitrile (2a) White sol-
1
id. M.p. 120－122 ℃ (lit.[20] 120－122 ℃). H NMR
(CDCl3, 400 MHz) δ: 3.51 (dd, J＝5.6, 18.0 Hz, 1H,
CHCHaHCO), 3.74 (dd, J ＝ 7.6, 18.0 Hz, 1H,
CHCHbHCO), 4.58 (dd, J＝6.0, 6.4 Hz, 1H, ArCHCH2),
7.26－7.43 (m, 7H, ArH), 7.58－7.62 (m, 1H, ArH),
7.92－7.94 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
δ: 31.9, 44.5, 120.6, 127.5, 128.1, 128.4, 128.8, 129.3,
133.9, 135.2, 135.6 194.6. IR (KBr) ν: 1681 (C＝O),
2238 (CN) cm1. Anal. calcd for C16H13NO (235.28): C
81.68, H 5.57, N 5.95; found C 81.59, H 5.56, N 5.97.
4-Oxo-2,4-di-(4-tolyl)butanenitrile (2g)
White
1
4-Oxo-2-phenyl-4-(4-tolyl)butanenitrile
(2b)
solid. M.p. 108－110 ℃. H NMR (CDCl3, 400 MHz)
δ: 2.27 (s, 3H, CH3), 2.34 (s, 3H, CH3), 3.39 (dd, J＝6.4,
18.0 Hz, 1H, CHCHaHCO), 3.61 (dd, J＝7.2, 18.0 Hz,
1H, CHCHbHCO), 4.45 (dd, J ＝ 6.4, 7.6 Hz, 1H,
ArCHCH2), 7.12 (d, J＝7.6 Hz, 2H, ArH), 7.18－7.26
(m, 4H, ArH), 7.75 (d, J＝8.0 Hz, 2H, ArH); 13C NMR
(CDCl3, 100 MHz) δ: 21.1, 21.7, 31.5, 44.4, 120.9,
127.3, 128.2, 129.5, 129.9, 132.3, 133.2, 138.2, 144.8,
194.3. IR (KBr) ν: 1671 (C＝O), 2243 (CN) cm1. Anal.
calcd for C18H17NO (263.33): C 82.10, H 6.51, N 5.32;
found C 82.25, H 6.53, N 5.30.
1
White solid. M.p. 66－68 ℃ (lit.[21] 71－73 ℃). H
NMR (CDCl3, 400 MHz) δ: 2.34 (s, 3H, CH3) 3.41 (dd,
J＝6.4, 17.6 Hz, 1H, CHCHaHCO), 3.63 (dd, J＝8.4,
17.6 Hz, 1H, CHCHbHCO), 4.49 (dd, J＝6.0, 8.0 Hz,
1H, ArCHCH2), 7.18－7.38 (m, 7H, ArH), 7.45 (d, J＝
8.0 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 21.7,
31.9, 44.4, 120.7, 127.5, 128.2, 128.3, 129.2, 129.5,
133.2, 135.3, 144.9, 194.2. IR (KBr) ν: 1676 (C＝O),
2242 (CN) cm1. Anal. calcd for C17H15NO (249.31): C
81.90, H 6.06, N 5.62; found C 81.99, H 6.05, N 5.64.
4-(4-Methoxyphenyl)-4-oxo-2-phenylbutanenitrile
(2c) Oil (lit. Oil).[21] 1H NMR (CDCl3, 400 MHz) δ:
3.37 (dd, J＝6.0, 17.6 Hz, 1H, CHCHaHCO), 3.60 (dd,
J＝8.4, 17.6 Hz, 1H, CHCHbHCO), 3.79 (s, 3H, CH3),
4.49 (dd, J＝6.0, 8.0 Hz, 1H, ArCHCH2), 6.85 (d, J＝
6.8 Hz, 2H, ArH), 7.23－7.37 (m, 5H, ArH), 7.83 (d, J
＝6.8 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ:
31.9, 44.1, 55.5, 113.9, 120.8, 127.4, 128.3, 128.7,
129.2, 130.4, 135.4, 164.0, 193.0. IR (KBr) ν: 1676 (C
＝O), 2243 (CN) cm1. Anal. calcd for C17H15NO2
(265.31): C 76.96, H 5.70, N 5.28; found C 76.80, H
5.71, N 5.30.
4-(4-Chlorophenyl)-4-oxo-2-(4-tolyl)butanenitrile
1
(2h) White solid. M.p. 90－92 ℃. H NMR (CDCl3,
400 MHz) δ: 2.35 (s, 3H, CH3), 3.45 (dd, J＝6.0, 18.0
Hz, 1H, CHCHaHCO), 3.67 (dd, J＝8.4, 18.0 Hz, 1H,
CHCHbHCO), 4.50 (t, J＝6.8 Hz, 1H, ArCHCH2), 7.19
(d, J＝7.6 Hz, 2H, ArH), 7.31 (d, J＝8.0 Hz, 2H, ArH),
7.44 (d, J＝7.6 Hz, 2H, ArH), 7.86 (d, J＝8.0 Hz, 2H,
ArH); 13C NMR (CDCl3, 100 MHz) δ: 21.0, 31.5, 44.5,
120.6, 127.3, 129.1, 129.4, 129.9, 132.0, 133.9, 138.3,
140.4, 193.5. IR (KBr) ν: 1676 (C＝O), 2241 (CN) cm1.
Anal. calcd for C17H14ClNO (283.75): C 71.96, H 4.97,
N 4.94; found C 72.08, H 4.99, N 4.93.
4-(4-Chlorophenyl)-4-oxo-2-phenylbutanenitrile
(2d) White solid. M.p. 112 － 114 ℃ . 1H NMR
(CDCl3, 400 MHz) δ: 3.39 (dd, J＝5.6, 18.0 Hz, 1H,
CHCHaHCO), 3.63 (dd, J ＝ 8.4, 18.0 Hz, 1H,
CHCHbHCO), 4.47 (dd, J＝6.4, 7.6 Hz, 1H, ArCHCH2),
7.25－7.38 (m, 7H, ArH), 7.79 (d, J＝8.8 Hz, 2H, ArH);
13C NMR (CDCl3, 100 MHz) δ: 31.9, 44.5, 120.4, 127.4,
128.4, 129.2, 129.3, 129.5, 133.9, 135.0, 140.4, 193.5.
IR (KBr) ν: 1676 (C＝O), 2241 (CN) cm1. Anal. calcd
for C16H12ClNO (269.73): C 71.25, H 4.48, N 5.19;
found C 71.37, H 4.50, N 5.21.
2-(4-Methoxyphenyl)-4-oxo-4-phenylbutanenitrile
(2i) White solid. M.p. 112－114 ℃ (lit.[20] 111－
1
113 ℃). H NMR (CDCl3, 400 MHz) δ: 3.41 (dd, J＝
6.4, 18.0 Hz, 1H, CHCHaHCO), 3.62 (dd, J＝7.6, 18.0
Hz, 1H, CHCHbHCO), 3.74 (s, 3H, CH3), 4.43 (t, J＝
6.8 Hz, 1H, ArCHCH2), 6.83 (d, J＝9.2 Hz, 2H, ArH),
7.37－7.54 (m, 5H, ArH), 7.84 (d, J＝9.2 Hz, 2H, ArH);
13C NMR (CDCl3, 100 MHz) δ: 31.1, 44.5, 55.3, 114.5,
120.9, 127.1, 128.0, 128.6, 128.8, 133.9, 135.6, 159.5,
194.8. IR (KBr) ν: 1678 (C＝O), 2238 (CN) cm1. Anal.
calcd for C17H15NO2 (265.31): C 76.96, H 5.70, N 5.28;
found C 77.05, H 5.68, N 5.30.
4-(4-Nitrophenyl)-4-oxo-2-phenylbutanenitrile (2e)
2
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Chin. J. Chem. 2017, XX, 1—6

Conjugate Hydrocyanation of Chalcone Derivatives
2-(4-Methoxyphenyl)-4-oxo-4-(4-tolyl)butaneni-
trile(2j) White solid. M.p. 100－102 ℃. H NMR
3.64, N 4.59.
1
2-(3-Bromophenyl)-4-oxo-4-phenylbutanenitrile (2o)
White solid. M.p. 114－116 ℃. H NMR (CDCl3, 400
1
(CDCl3, 400 MHz) δ: 2.32 (s, 3H, CH3), 3.39 (dd, J＝
6.4, 18.0 Hz, 1H, CHCHaHCO), 3.58 (dd, J＝8.0, 18.0
Hz, 1H, CHCHbHCO), 3.72 (s, 3H, CH3), 4.42 (t, J＝
6.8 Hz, 1H, ArCHCH2), 6.83 (d, J＝8.8 Hz, 2H, ArH),
7.17 (d, J＝8.0 Hz, 2H, ArH), 7.29 (d, J＝8.8 Hz, 2H,
ArH), 7.73 (d, J＝8.0 Hz, 2H, ArH); 13C NMR (CDCl3,
100 MHz) δ: 21.9, 31.4, 44.7, 55.6, 114.8, 121.3, 127.5,
128.4, 128.9, 129.7, 133.5, 145.1, 159.7, 194.6. IR (KBr)
ν: 1671 (C＝O), 2242 (CN) cm1. Anal. calcd for
C18H17NO2 (279.33): C 77.40, H 6.13, N 5.01; found C
77.33, H 6.11, N 4.99.
MHz) δ: 3.52 (dd, J＝5.6, 18.0 Hz, 1H, CHCHaHCO),
3.74 (dd, J＝7.6, 18.0 Hz, 1H, CHCHbHCO), 4.55 (dd,
J＝5.6, 8.0 Hz, 1H, ArCHCH2), 7.27－7.63 (m, 7H,
ArH), 7.93 (d, J＝8.4 Hz, 2H, ArH); 13C NMR (CDCl3,
100 MHz) δ: 31.4, 44.2, 120.1, 123.1, 126.3, 128.1,
128.9, 130.6, 130.8, 131.6, 134.1, 135.4, 137.4, 194.2.
IR (KBr) ν: 1679 (C＝O), 2241 (CN) cm1. Anal. calcd
for C16H12BrNO (314.18): C 61.17, H 3.85, N 4.46;
found C 61.09, H 3.85, N 4.45.
2-(4-Nitrophenyl)-4-oxo-4-phenylbutanenitrile (2p)
Yellow solid. M.p. 152－154 ℃. 1H NMR (CDCl3, 400
MHz) δ: 3.55 (dd, J＝5.6, 18.0 Hz, 1H, CHCHaHCO)
3.78 (dd, J＝8.0, 18.0 Hz, 1H, CHCHbHCO), 4.55 (dd,
J＝6.0, 7.6 Hz, 1H, ArCHCH2), 7.36－7.45 (m, 5H,
ArH), 8.09 (d, J＝8.8 Hz, 2H, ArH), 8.19 (d, J＝8.8 Hz,
2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 31.9, 45.0,
120.1, 124.1, 127.4, 128.6, 129.2, 129.4, 134.6, 139.9,
150.7, 193.3. IR (KBr) ν: 1684 (C＝O), 2241 (CN) cm1.
Anal. calcd for C16H12N2O3 (280.28): C 68.56, H 4.32,
N 9.99; found C 68.67, H 4.33, N 9.96.
2-(4-Chlorophenyl)-4-oxo-4-phenylbutanenitrile
(2k) White solid. M.p. 112－114 ℃ (lit.[21] 112－
1
113 ℃). H NMR (CDCl3, 400 MHz) δ: 3.41 (dd, J＝
6.4, 18.0 Hz, 1H, CHCHaHCO), 3.61 (dd, J＝8.8, 18.0
Hz, 1H, CHCHbHCO), 4.46 (dd, J＝6.4, 7.2 Hz, 1H,
ArCHCH2), 7.25－7.52 (m, 7H, ArH), 7.80－7.82 (m,
2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 31.3, 44.3,
120.2, 128.1, 128.8, 128.9, 129.4, 133.7, 134.0, 134.4,
135.5, 194.3. IR (KBr) ν: 1676 (C＝O), 2242 (CN) cm1.
Anal. calcd for C16H12ClNO (269.73): C 71.25, H 4.48,
N 5.19; found C 71.37, H 4.50, N 5.20.
2-(4-Chlorophenyl)-4-oxo-4-(4-tolyl)butanenitrile
(2l) White solid. M.p. 102－104 ℃. 1H NMR (CDCl3,
400 MHz) δ: 2.36 (s, 3H, CH3), 3.43 (dd, J＝6.0, 18.0
Hz, 1H, CHCHaHCO), 3.63 (dd, J＝7.6, 18.0 Hz, 1H,
CHCHbHCO), 4.50 (t, J＝6.8 Hz, 1H, ArCHCH2), 7.22
(d, J＝8.4 Hz, 2H, ArH), 7.29－7.34 (m, 4H, ArH), 7.76
(d, J＝8.4 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
δ: 21.7, 31.4, 44.1, 120.3, 128.0, 128.9 129.2, 129.3,
129.5, 133.8, 134.3, 145.0, 193.9. IR (KBr) ν: 1669 (C
＝O), 2245 (CN) cm1. Anal. calcd for C17H14ClNO
(283.75): C 71.96, H 4.97, N 4.94; found C 71.80, H
4.96, N 4.97.
4-(Furan-2-yl)-4-oxo-2-phenylbutanenitrile (2q)
White solid. M.p. 111－113 ℃. H NMR (400 MHz,
1
CDCl3) δ: 3.38 (dd, J＝17.6, 6.0 Hz, 1H, COCHaH),
3.59 (dd, J＝17.6, 7.6 Hz, 1H, COCHHb), 4.54 (t, J＝
7.6 Hz, 1H, ArCHCH2), 6.56 (s, 1H, ArH), 7.25 (d, J＝
11.3 Hz, 1H, ArH), 7.29－7.50 (m, 5H, ArH), 7.59 (s,
1H, ArH); 13C NMR (100 MHz, CDCl3) δ: 31.5, 43.9,
112.6, 117.9, 120.3, 127.4, 128.4, 129.2, 135.0, 146.9,
151.9, 183.7. IR (KBr) ν: 1662 (C＝O), 2246 (CN) cm1.
Anal. calcd for C14H11NO2 (225.08): C 74.65, H 4.92, N
6.22; found C 74.57, H 4.93, N 6.20.
Results and Discussion
2,4-Bis-(4-chlorophenyl)-4-oxo-butanenitrile (2m)
1
Initially, the model reaction of chalcone (1a) with
ethyl cyanoacetate was examined under various condi-
tions. It was found that the reaction could be carried out
through conjugate hydrocyanation to give 2a and
through Michael addition to give 3a (Scheme 2). The
bases played a key role in the reaction. The reaction in
some organic bases like Et3N, DABCO and piperidine
only gave Michael addition product 3a (Table 1, entries
1 － 3). The reaction in some inorganic bases like
Na2CO3 and K2CO3 could afford both hydrocyanation
product 2a and Michael addition product 3a at the same
time (Table 1, entries 4, 5). However, the reaction in
NaOH and KOH could selectively produce 2a as a sole
product in high yield (Table 1, entries 6, 7). Among
them, the best yield was obtained by using KOH as a
base (Table 1, entry 7). In addition, when the amount of
KOH was decreased from 2 to 1 equiv., the selectivity
and yield for 2a was largely reduced (Table 1, entry 8).
Moreover, if the reaction was carried out under nitrogen
atmosphere, only by-product 3a was observed, which
implied that air was an indispensable condition for the
White solid. M.p. 102－104 ℃. H NMR (CDCl3, 400
MHz) δ: 3.41 (dd, J＝6.4, 18.0 Hz, 1H, CHCHaHCO),
3.61 (dd, J＝7.2, 18.0 Hz, 1H, CHCHbHCO), 4.49 (t,
J＝7.2 Hz, 1H, ArCHCH2), 7.19－7.33 (m, 6H, ArH),
7.74 (d, J＝8.4 Hz, 2H, ArH); 13C NMR (CDCl3, 100
MHz) δ: 31.3, 44.2, 120.3, 128.2, 129.0, 129.4, 129.5,
133.1, 133.8, 134.4, 145.1, 193.9. IR (KBr) ν: 1670 (C
＝O), 2246 (CN) cm1. Anal. calcd for C16H11Cl2NO
(304.17): C 63.18, H 3.65, N 4.60; found C 63.24, H
3.66, N 4.62.
2-(2,4-Dichlorophenyl)-4-oxo-4-phenylbutaneni-
trile (2n) White solid. M.p. 88－90 ℃ (lit.[20] 90－
91 ℃). 1H NMR (CDCl3, 400 MHz) δ: 3.44 (dd, J＝8.4,
18.0 Hz, 1H, CHCHaHCO), 3.59 (dd, J＝9.2, 18.0 Hz,
1H, CHCHbHCO), 4.80 (dd, J ＝ 4.8, 9.2 Hz, 1H,
ArCHCH2), 7.25－7.56 (m, 6H, ArH), 7.86 (d, J＝8.0
Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 29.6,
42.1, 119.3, 128.0, 128.1, 128.8, 130.0, 130.4, 131.2,
133.4, 133.9, 135.2, 135.3, 194.1. IR (KBr) ν: 1670 (C
＝O), 2246 (CN) cm1. Anal. calcd for C16H11Cl2NO
(304.17): C 63.18, H 3.65, N 4.60; found C 63.00, H
Chin. J. Chem. 2017, XX, 1—6
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Li & Yin
Table 2 The effect of solvents on the yield of 2aa
FULL PAPER
hydrocyantion of 1a (Table 1, entry 9).
Entry
Solvent
THF
Yield of 2ab/%
Yield of 3ab/%
Scheme 2 The reaction of 1a with ethyl cyanoacetate
1
2
－
－
－
－
14
77
92
－
19
33
70
91
86
13
－
－
1,4-dioxane
PhMe
3
4
MeCN
EtOH
5
6
DMSO
DMF
7
8c
DMF
a Reaction conditions: 1a (0.5 mmol), ethyl cyanoacetate (0.55
Table 1 The effect of the bases on the yield of 2aa
mmol) and KOH (1.0 mmol) in solvent (5 mL) at room tempera-
c
ture under air for 8 h. b Isolated yields. Without ethyl cyanoace-
Entry
Base
Et3N
Yield of 2ab/%
Yield of 3ab/%
tate.
1
2
－
－
－
43
86
81
92
24
0
81
46
95
47
9
Scheme 3 Hydrocyanation of chalcone derivatives with ethyl
cyanoacetate
DABCO
Piperidine
Na2CO3
K2CO3
NaOH
KOH
3
4
5
6
－
－
47
95
7
8c
9d
KOH
KOH
Table 3 The substrate scope for the hydrocyanation of chalcone
derivatives with ethyl cyanoacetatea
a Reaction conditions: 1a (0.5 mmol), ethyl cyanoacetate (0.55
mmol) and base (1.0 mmol) in DMF (5 mL) at room temperature
under air for 8 h. b Isolated yields. c Using 1 equiv. of KOH.
d Under N2 atmosphere.
Entry
1
R1
R2
Yieldb/%
2a 92
2b 88
2c 93
2d 90
2e 56c
2f 87
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
C6H5
The solvents also played an important role in the re-
action. It was found that the reaction in THF,
1,4-dioxane, MeCN and PhMe only gave by-product 3a
(Table 2, entries 1－4). The reaction in EtOH and
DMSO could produce 2a and 3a simultaneously in dif-
ferent yield (Table 2, entries 5, 6). However, the reac-
tion in DMF could selectively afford 2a as a sole prod-
uct in excellent yield (Table 2, entry 7). These results
indicated that the selectivity of reaction was related to
the solvent polarity, and high polar solvents were ad-
vantageous to the formation of 2a. In addition, the reac-
tion in DMF under the absence of ethyl cyanoacetate as
a cyanating agent could not give any product, which
indicated that DMF could not act as a cyanating agent in
this reaction as the literature reported (Table 2, entry
8).[19]
3
4
5
6
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
7
4-MeC6H4
4-ClC6H4
C6H5
2g 85
2h 88
2i 91
8
9
10
11
12
13
14
15
16
4-MeC6H4
C6H5
2j 89
2k 92
2l 91
4-ClC6H4
4-MeC6H4
4-ClC6H4
C6H5
4-ClC6H4
2m 88
2n 81
2o 90
2p 55d
2,4-Cl2C6H3
3-BrC6H4
C6H5
4-O2NC6H4
C6H5
Under the optimized condition, a range of chalcone
derivatives were examined for the conjugate hydrocya-
nation by employing ethyl cyanoacetate as an organic
cyanide source at room temperature under open air and
transition metal-free conditions (Scheme 3, Table 3). All
reactions proceeded smoothly to afford the correspond-
ing β-cyanoketones in moderate to excellent yield. Both
R1 and R2 could be electron-rich or electron-deficient
aromatic rings (Table 3, entries 1－16). In addition, for
heteroaromatic ring, such as furyl, the corresponding
product was also obtained in high yield (Table 3,
17
C6H5
2q 87
O
a Reaction conditions: chalcone derivative (0.5 mmol), ethyl cy-
anoacetate (0.55 mmol) and KOH (1.0 mmol) in DMF (5 mL) at
room temperature under air for 8 h. b Isolated yields. c Conven-
tional Michael additional product was observed in 26% yield.
d Conventional Michael additional product was observed in 18%
yield.
entry17). However, for the aliphatic enone, such as
4
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Conjugate Hydrocyanation of Chalcone Derivatives
Scheme 4 Proposed mechanism for the conjugate hydrocyanation of 1a with ethyl cyanoacetate
O
O
Ph
Ph
Ph
NC
NC
COOEt
COOEt
1a
KOH
COOEt
Ph
NC
3a
B
NC
COOEt
O
O
KOH
CO2Et
CN
KOH
EtO2C
CN
O2 (air)
A
O
C
Ph
Ph
Ph
1a
O
O
Ph
H2O
Ph
CN
Ph
CN
D
2a
hex-3-en-2-one, the corresponding cyanation product
was not observed, and only conventional Michael addi-
tional product was obtained in low yield. For the
β,β-disubstituted enones, such as 1,3,3-triphenylprop-
2-en-1-one, no reaction was observed under studied
conditions
In addition, we have also compared the similar or-
ganic cyanide sources containing R-CH2CN structures
(Table 4). It was found that propanenitrile and chloro-
propanenitrile as cyanating agents could not give the
expected product at all (Table 4, entries 1, 2). 3-Oxo-3-
(piperidin-1-yl)propanenitrile could give 2a in low yield
(Table 4, entry 3). Meanwhile, phenylacetonitrile could
afford 2a in moderate yield (Table 4, entry 4). However,
manolonitrile was also an excellent cyanating agent and
produced 2a in almost the same yield as ethyl cyanoac-
tate (Table 4, entries 5, 6).
rivatives with ethyl cyanoacetate is proposed (Scheme
4). Initially, aerobic C－H oxidation of ethyl cyanoace-
tate with the assistance of KOH and O2 provided ethyl
2-cyano-2-oxoacetate (A). In addition, ethyl cyanoace-
tate could also produce anion B in the presence of KOH.
Nucleophilic attack of the anion B on the carbonyl
group of A generated cyanide anion (CN) and C. Sub-
sequently, nucleophilic addition of a cyanide anion to
chalcone (1a) in the presence of KOH resulted in the
formation of the key intermediate D. D was protonated
by water to give the final product 2a. Under a certain
condition, anion B could also directly attack the chal-
cone 1a to afford 3a as a by-product.
Conclusions
In summary, a new efficient method has been devel-
oped for the conjugate hydrocyanation of chalcone de-
rivatives using ethyl cyanoacetate as an organic cyanide
source. It is the first report on the utilization of ethyl
cyanoacetate as an organic cyanating reagent via C－
CN bond cleavage under transition metal-free condition.
The new cyanating agent has the distinct advantages of
being relatively cheap, less toxic, stable and
easy-to-handle.
Table 4 The effect of similar organic cyanating agents on the
yield of 2aa
Entry
RCH2CN
CH3CH2CN
ClCH2CH2CN
Yield of 2ab/%
Yield of 3ab/%
1
2
0
0
56
63
3
8
38
Acknowledgement
4
5
6
PhCH2CN
NCCH2CN
38
91
92
49
0
The authors thank the National Natural Science
Foundation of China (Nos. 21462038, 21362034) and
Key Laboratory of Eco-Environment-Related Polymer
Materials of Ministry of Education for the financial
support of this work.
EtOOCCH2CN
0
a
Reaction conditions: 1a (0.5 mmol), cyanating agent (0.55
mmol) and KOH (1.0 mmol) in DMF (5 mL) at room temperature
under air for 8 h. b Isolated yields.
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