N-Heterocyclic Carbene-Catalysed Direct Synthesis of Cyano Esters via Cyanation-Esterification Reaction of α-Keto Esters

Article abstract of DOI:10.1002/cjoc.201500399

The cyanation-esterification reaction of α-keto esters catalysed by N-heterocyclic carbenes (NHCs) is developed. Under the catalysis of 10 mol% 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, aromatic and aliphatic α-keto esters reacted with ethyl cyanoformate or acetyl cyanide to produce the corresponding cyano esters with a tetrasubstituted carbon center in high yields.

Full text of DOI:10.1002/cjoc.201500399

NOTE
DOI: 10.1002/cjoc.201500399
N-Heterocyclic Carbene-Catalysed Direct Synthesis of Cyano
Esters via Cyanation-Esterification Reaction of α-Keto Esters
Jie Zhang, Ying Wang, Guangfen Du, Cheng-Zhi Gu,* and Bin Dai
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and
Chemical Engineering, Shihezi University, Shihezi, Xinjiang 832000, China
The cyanation-esterification reaction of α-keto esters catalysed by N-heterocyclic carbenes (NHCs) is developed.
Under the catalysis of 10 mol% 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, aromatic and aliphatic α-keto
esters reacted with ethyl cyanoformate or acetyl cyanide to produce the corresponding cyano esters with a tetra-
substituted carbon center in high yields.
Keywords N-heterocyclic carbene, cyanation reaction, cyano ester, ethyl cyanoformate, acetyl cyanide
Introduction
Inova-400 spectrometer in CDCl3, with tetramethylsi-
lane as an internal standard. High-resolution mass spec-
tra (HRMS) were obtained on a micrOTOF-QII HRMS/
MS instrument (Bruker) and methanol or chloroform
was used to dissolve the sample. All starting materials
were obtained from commercial supplies and used as
received. Anhydrous THF, toluene and Et2O were dis-
tilled from sodium and benzophenone. Ethyl cyanofor-
mate (99%), acetyl cyanide (97%) and all keto esters
were obtained commercially and used directly without
further purification.
Cyanohydrins and their derivatives are ubiquitous
building blocks in the synthesis of biologically active
molecules.[1] Over the past decades, great efforts have
been devoted to developing efficient methods for the
synthesis of these important type of compounds.[2]
Recently using trimethylsilyl cyanide as cyanation
reagent, Aoyama,[3c-3e] Song,[3f] Maruoka,[3g] Suzuki[3h]
and Zhang[3i] independently developed N-heterocyclic
carbene[4] (NHC)-catalysed cyanation of aldehydes,
ketones and imines. As an important type of derivatives
of cyanohydrins, cyano esters have been widely utilized
in bioactive compounds synthesis.[5] However, to the
best of our knowledge, the direct cyano ester formation
reactions of ketones were farless examined.[6] Recenly,
our group developed NHCs-catalysed cyanation-
esterification reaction of aldehydes and cyanation-
phosphorylation reaction of ketones.[7] These studies
prompt us to further explore the similar reaction of keto
esters, which will directly construct cyano esters with a
cyanated quaternary carbon center. Herein, we would
like to report this interesting results.
Typical procedure for NHC-catalysed cyanation re-
action of keto esters with ethyl cyanoformate
IPr (19 mg, 10 mol%) was added to a solution of
keto ester 2a (0.5 mmol) and ethyl cyanoformate 1 (0.75
mmol) in dry THF (2.0 mL) under nitrogen, and the
resulting mixture was stirred at room temperature until
full consumption of the starting ketone indicated by
TLC. The solvent was removed under reduced pressure
and the crude material was purified by column chroma-
tography (PE-EtOAc, 15∶1－10∶1) to afford the pure
cyano carbonate.
Ethyl 2-cyano-2-(ethoxycarbonyloxy)-2-phenyl-
acetate (3a) Colorless oil (94% yield). 1H NMR (400
MHz, CDCl3) δ: 7.74－7.72 (m, 2H), 7.47－7.45 (m,
3H), 4.41－4.23 (m, 4H), 1.39 (t, J＝7.2 Hz, 3H), 1.28
(t, J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
163.76, 152.90, 130.76, 130.71, 129.12, 126.05, 114.89,
76.47, 66.03, 64.19, 14.09, 13.74. HRMS (ESI) calcd
for C14H15NNaO5: 300.0848; found 300.0848.
Experimental
General Information
Unless otherwise indicated, all reactions were con-
ducted under nitrogen atmosphere in oven-dried glass-
ware with magnetic stirring bar. Column chromatogra-
phy was performed with silica gel (300－400 mesh) and
analytical TLC on silica gel GF254 was detected by UV
Ethyl 2-cyano-2-(ethoxycarbonyloxy)-2-p-tolyl-
acetate (3b) Colorless oil (73% yield). 1H NMR (400
MHz, CDCl3) δ: 7.62－7.59 (m, 2H), 7.26－7.24 (m,
light or KMnO4 staining. H NMR (400 MHz), 13C
1
NMR (100 MHz) spectra were recorded on a Varian
*
E-mail: gcz_tea@shzu.edu.cn; Fax: 0086-0993-2057270
Received May 25, 2015; accepted July 14, 2015; published online September 29, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500399 or from the author.
Chin. J. Chem. 2015, 33, 1211—1215
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zhang et al.
NOTE
2H), 4.38－4.27 (m, 4H), 2.38 (s, 3H), 1.38 (t, J＝7.2
Hz, 3H), 1.28 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 163.89, 152.96, 141.02, 129.89, 129.77,
127.90, 127.82, 125.98, 114.98, 76.46, 66.28, 65.96,
65.52, 64.09, 21.21, 14.09, 13.76. HRMS (ESI) calcd
for C15H17NNaO5: 314.1004; found 314.1005.
127.80, 127.16, 126.10, 114.29, 73.59, 66.19, 64.53,
14.07, 13.77. HRMS (ESI) calcd for C12H13NNaO5S:
306.0412; found 306.0408.
Ethyl 2-cyano-2-(ethoxycarbonyloxy)-2-(furan-2-
1
yl)acetate (3i) Colorless oil (80% yield). H NMR
(400 MHz, CDCl3) δ: 7.53 (dd, J＝2.0, 0.8 Hz, 1H),
6.79 (dd, J＝3.6, 0.8 Hz, 1H), 6.48 (dd, J＝3.6, 2.0 Hz,
1H), 4.43－4.31 (m, 4H), 1.39－1.33 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ: 161.46, 152.57, 149.78,
149.50, 145.60, 142.37, 124.71, 113.01, 111.35, 71.01,
66.14, 64.63, 62.72, 14.02. HRMS (ESI) calcd for
C12H13NNaO6: 290.0641; found 290.0641.
Ethyl 2-cyano-2-(ethoxycarbonyloxy)propanoate
(3j)[2] Colorless oil (84% yield). 1H NMR (400 MHz,
CDCl3) δ: 4.38－4.27 (m, 4H), 1.90 (s, 3H), 1.37－1.33
(m, 6H); 13C NMR (100 MHz, CDCl3) δ: 165.10, 152.75,
115.58, 71.45, 65.85, 63.90, 23.91, 14.04, 13.87.
Methyl 2-cyano-2-(ethoxycarbonyloxy)-2-phenyl-
acetate (3k) Colorless oil (88% yield). 1H NMR (400
MHz, CDCl3) δ: 7.75－7.70 (m, 2H), 7.50－7.43 (m,
3H), 4.36 (q, J＝7.2 Hz, 2H), 3.86 (s, 3H), 1.39 (t, J＝
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 164.35,
152.90, 130.80, 130.71, 129.18, 126.09, 114.89, 76.33,
66.11, 64.19, 56.25, 54.58, 14.08. HRMS (ESI) calcd
for C13H13NNaO5: 286.0691; found 286.0699.
Ethyl
2-cyano-2-(ethoxycarbonyloxy)-2-(4-
fluorophenyl)acetate (3c) Colorless oil (92% yield).
1H NMR (400 MHz, CDCl3) δ: 7.76－7.70 (m, 2H),
7.18－7.12 (m, 2H), 4.38－4.28 (m, 4H), 1.39 (t, J＝7.2
Hz, 3H), 1.29 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 165.22, 163.64, 162.72, 152.78, 128.36,
128.27, 126.68, 126.65, 116.40, 116.18, 114.73, 75.88,
66.14, 64.33, 14.08, 13.74. HRMS (ESI) calcd for
C14H14FNNaO5: 318.0754; found 318.0756.
Ethyl
2-(4-chlorophenyl)-2-cyano-2-(ethoxy-
carbonyloxy)acetate (3d) Colorless oil (81% yield).
1H NMR (400 MHz, CDCl3) δ: 7.69－7.65 (m, 2H),
7.45－7.42 (m, 2H), 4.38－4.29 (m, 4H), 1.39 (t, J＝7.2
Hz, 3H), 1.28 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 163.48, 152.73, 137.10, 129.39, 129.31,
127.50, 114.59, 75.88, 66.19, 64.41, 14.08, 13.75.
HRMS (ESI) calcd for C14H14ClNNaO5: 334.0458;
found 334.0464.
Ethyl
2-(4-bromophenyl)-2-cyano-2-(ethoxy-
carbonyloxy)acetate (3e) Colorless oil (83% yield).
1H NMR (400 MHz, CDCl3) δ: 7.76－7.41 (m, 4H),
4.38－4.27 (m, 4H), 1.39 (t, J＝7.2 Hz, 3H), 1.28 (t,
J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.41,
152.72, 132.36, 129.87, 127.70, 125.36, 114.54, 75.93,
66.20, 64.43, 14.08, 13.75. HRMS (ESI) calcd for
C14H14BrNNaO5: 377.9953; found 377.9965.
Ethyl 2-cyano-2-(ethoxycarbonyloxy)-2-(2-meth-
oxyphenyl)acetate (3f) Colorless oil (78% yield). 1H
NMR (400 MHz, CDCl3) δ: 7.57 (dd, J＝8.0, 1.6 Hz,
1H), 7.46－7.42 (m, 1H), 7.06－7.01 (m, 1H), 6.98 (dd,
J＝8.4, 1.2 Hz, 1H), 4.41－4.29 (m, 4H), 3.89 (s, 3H),
1.38－1.33 (m, 6H); 13C NMR (100 MHz, CDCl3) δ:
163.73, 156.89, 152.57, 132.18, 128.36, 120.97, 120.06,
114.51, 112.20, 74.11, 65.71, 63.79, 55.92, 14.09, 13.87.
HRMS (ESI) calcd for C15H17NNaO6: 330.0954; found
330.0961.
Typical procedure for NHC-catalysed cyanation re-
action of keto esters with acetyl cyanide
IPr (19 mg, 10 mol%) was added to a solution of
keto ester 2a (0.5 mmol) and acetyl cyanide 9 (0.75
mmol) in dry DCE (2.0 mL) under nitrogen, and the
resulting mixture was stirred at room temperature until
full consumption of the starting ketone indicated by
TLC. The solvent was removed under reduced pressure
and the crude material was purified by column chroma-
tography (PE-EtOAc, 15∶1－10∶∶1) to afford the
pure cyano ester.
Ethyl 2-acetoxy-2-cyano-2-phenylacetate (10a)[6c]
Colorless oil (82% yield). 1H NMR (400 MHz, CDCl3)
δ: 7.75－7.70 (m, 2H), 7.50－7.44 (m, 3H), 4.33－4.22
(m, 2H), 2.30 (s, 3H), 1.27 (t, J＝7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 169.05, 163.82, 131.00, 130.60,
129.11, 126.06, 114.92, 74.57, 64.06, 20.35, 13.73.
Methyl 2-acetoxy-2-cyano-2-phenylacetate (10b)
Colorless oil (74% yield). 1H NMR (400 MHz, CDCl3)
δ: 7.73－7.71 (m, 2H), 7.49－7.44 (m, 3H), 3.84 (s, 3H),
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.08,
164.41, 130.84, 130.69, 129.16, 126.11, 114.81, 74.40,
54.48, 20.34. HRMS (ESI) calcd for C12H11NNaO4:
256.0586; found 256.0584.
Ethyl 2-acetoxy-2-cyano-2-p-tolylacetate (10c)
Colorless oil (43% yield). 1H NMR (400 MHz, CDCl3)
δ: 7.61－7.59 (m, 2H), 7.26－7.24 (m, 2H), 4.36 (q, J＝
7.2 Hz, 2H), 2.38 (s, 3H), 1.38 (t, J＝7.2 Hz, 3H), 1.28
(t, J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
169.12, 163.93, 140.91, 129.77, 128.05, 126.00, 115.00,
74.52, 63.96, 21.21, 20.36, 13.74. HRMS (ESI) calcd
for C14H15NNaO4: 284.0899; found 284.0900.
Ethyl
2-cyano-2-(ethoxycarbonyloxy)-2-(naph-
thalen-2-yl)acetate (3g) Colorless oil (77% yield). 1H
NMR (400 MHz, CDCl3) δ: 8.11 (d, J＝8.4 Hz, 1H),
7.98 (dd, J＝7.2, 1.2 Hz, 1H), 7.93－7.87 (m, 2H), 7.70
－7.66 (m, 1H), 7.60－7.52 (m, 2H), 4.53－4.45 (m,
4H), 1.47－1.42 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ: 163.52, 152.61, 134.41, 132.17, 129.17, 127.72,
127.38, 126.91, 124.69, 124.55, 122.30, 114.97, 66.01,
64.37, 14.11, 13.77. HRMS (ESI) calcd for C18H17N-
NaO5: 350.1004; found 350.1006.
Ethyl
2-cyano-2-(ethoxycarbonyloxy)-2-(thio-
phen-2-yl)acetate (3h) Colorless oil (71% yield). 1H
NMR (400 MHz, CDCl3) δ: 7.50－7.47 (m, 2H), 7.06
(dd, J＝5.2, 3.6 Hz, 1H) , 4.39－4.32 (m, 4H), 1.38 (t,
J＝7.2 Hz, 3H), 1.33 (t, J＝7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 163.18, 152.64, 132.37, 129.43, 129.20,
1212
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Chin. J. Chem. 2015, 33, 1211—1215

N-Heterocyclic Carbene-Catalysed Direct Synthesis of Cyano Esters
Ethyl
2-acetoxy-2-cyano-2-(4-fluorophenyl)-
113.07, 111.34, 69.31, 64.49, 20.19, 13.80. HRMS (ESI)
calcd for C11H11NNaO5: 260.0535; found 260.0528.
Ethyl 2-acetoxy-2-methyl-2-cyanoacetate (10k)[6c]
Colorless oil (43% yield). 1H NMR (400 MHz, CDCl3)
δ: 4.37－4.29 (m, 2H), 2.20 (s, 3H), 1.88 (s, 3H), 1.35 (t,
J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.91,
165.30, 123.79, 115.75, 69.35, 63.74, 28.78, 23.69,
20.11, 13.86.
acetate (10d) Colorless oil (71% yield). 1H NMR (400
MHz, CDCl3) δ: 7.75－7.70 (m, 2H), 7.18－7.13 (m,
2H), 4.34－4.21 (m, 2H), 2.30 (s, 3H), 1.28 (t, J＝7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.94, 165.15,
163.70, 162.65, 128.34, 128.25, 126.91, 126.88, 116.37,
116.15, 114.76, 74.00, 64.19, 20.30, 13.72. HRMS (ESI)
calcd for C13H12FNNaO4: 288.0648; found 288.0651.
Ethyl
2-acetoxy-2-(4-chlorophenyl)-2-cyano-
acetate (10e) Colorless oil (76% yield). 1H NMR (400
MHz, CDCl3) δ: 7.68－7.64 (m, 2H), 7.46－7.43 (m,
2H), 4.34－4.23 (m, 2H), 2.30 (s, 2H), 1.28 (t, J＝7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.88, 163.54,
136.97, 129.55, 129.38, 127.51, 114.61, 74.00, 64.28,
20.30, 13.73. HRMS (ESI) calcd for C13H12ClNNaO4:
304.0353; found 304.0349.
Results and Discussion
Our study commenced with the reaction of ethyl
cyanoformate 1 and ethyl phenylglyoxylate 2a. To our
delight, under the catalysis of 10 mol% 1,3-bis(2,6-
diisopropylphenyl)imidazole-2-ylidene (NHC 4, IPr),[8]
the reaction proceeded smoothly in THF to produce the
desired cyano ester 3a in 95% yield (Table 1, Entry 1).
NHCs derived from imidazolium salt 5 and imidazo-
linium 6 can also catalyse the reaction efficiently (Table
1, Entries 2 and 3). However, NHCs derived from
Ethyl
2-acetoxy-2-(4-bromophenyl)-2-cyano-
acetate (10f) Colorless oil (74% yield). 1H NMR (400
MHz, CDCl3) δ: 7.61－7.59 (m, 4H), 4.35－4.20 (m,
2H), 2.29 (s, 3H), 1.28 (t, J＝7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 168.86, 163.47, 132.35, 130.09,
129.11, 127.73, 126.07, 125.23, 114.55, 74.06, 64.30,
20.31, 13.74. HRMS (ESI) calcd for C13H12BrNNaO4:
347.9847; found 347.9825.
Table 1 Evaluation of reaction conditionsa
O
O
EtO
NC
O
OEt
O
NHC (10 mol%)
THF, r.t.
NC
Ar
+
Ethyl
2-acetoxy-2-cyano-2-(2-methoxyphenyl)-
OEt
OEt
O
N
acetate (10g)[6c] Colorless oil (57% yield). 1H NMR
(400 MHz, CDCl3) δ: 7.53 (dd, J＝8.0, 1.6 Hz, 1H),
7.47－7.42 (m, 1H), 7.06－7.02 (m, 1H), 7.00 (dd, J＝
8.4, 1.2 Hz, 1H), 4.37 (q, J＝7.2 Hz, 2H), 3.90 (s, 3H),
2.25 (s, 3H), 1.34 (t, J＝7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 168.68, 163.98, 156.94, 131.97, 128.05,
120.97, 120.33, 114.60, 112.27, 72.21, 63.65, 55.90,
20.55, 13.87. HRMS (ESI) calcd for C14H15NNaO5:
300.0848; found 300.0838.
1
2a
O
3a
Cl
Cl
N
N
N
N
N
Ar
Ar
Ar
Ar
Ar
4
6
5
Ar = 2,6-(i-Pr)2C6H3
Ar = 2,4,6-Me3C6H2
Ar = 2,6-(i-Pr)2C6H3
Cl
N
N Ph
X
OH
S
N
R
N
Ethyl
2-acetoxy-2-cyano-2-(naphthalen-2-yl)-
7a: R = Bn, X = Cl
7b: R = Me, X = I
acetate (10h) Colorless oil (59% yield). 1H NMR (400
MHz, CDCl3) δ: 8.47 (d, J＝7.6 Hz, 1H), 7.98－7.91 (m,
2H), 7.76－7.74 (m, 1H), 7.63－7.50 (m, 3H), 4.36 (q,
J＝7.2 Hz, 2H), 2.31 (s, 3H), 1.28 (t, J＝7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 168.66, 163.60, 132.03,
129.24, 128.66, 127.72, 127.21, 126.76, 126.44, 124.75,
124.55, 122.38, 114.98, 74.81, 64.25, 20.54, 13.77.
HRMS (ESI) calcd for C17H15NNaO4: 320.0899; found
320.0894.
8
Entry
NHC
Solvent
Time/h Yieldb/%
1
4, (10 mol%)
THF
THF
THF
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
95
89
85
15
18
17
94
78
78
78
63
88
53
82
38
2
3
4
5
6
5, KOt-Bu (10 mol%)
6, KOt-Bu (10 mol%)
7a, KOt-Bu (10 mol%) THF
7b, KOt-Bu (10 mol%) THF
Ethyl 2-acetoxy-2-cyano-2-(thiophen-2-yl)acetate
(10i) Colorless oil (63% yield). 1H NMR (400 MHz,
CDCl3) δ: 7.48－7.47 (m, 2H), 7.06 (dd, J＝4.8, 4.0 Hz,
1H), 4.38－4.28 (m, 2H), 2.26 (s, 3H), 1.32 (t, J＝7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.94, 163.26,
132.78, 129.19, 128.91, 127.79, 127.18, 125.89, 125.26,
114.34, 71.77, 64.39, 64.12, 20.23, 13.75. HRMS (ESI)
calcd for C11H11NNaO4S: 276.0306; found 276.0311.
8, KOt-Bu (10 mol%)
THF
7c 4 (10 mol%)
8d 4 (10 mol%)
THF
THF
9
4 (10 mol%)
DCM
DCE
Et2O
Toluene
DMF
THF
10 4 (10 mol%)
11 4 (10 mol%)
12 4 (10 mol%)
13 4 (10 mol%)
14 4 ( 5 mol%)
15 4 (1 mol%)
Ethyl
2-acetoxy-2-cyano-2-(furan-2-yl)acetate
(10j) Colorless oil (73% yield). 1H NMR (400 MHz,
CDCl3) δ: 7.53 (dd, J＝2.0, 0.8 Hz, 1H), 6.79 (dd, J＝
3.6, 0.8 Hz, 1H), 6.47 (dd, J＝3.6, 2.0 Hz, 1H), 4.33 (q,
J＝7.2 Hz, 2H), 1.39－1.33 (m, 6H); 13C NMR (100
MHz, CDCl3) δ: 168.88, 161.55, 149.51, 145.53, 124.73,
THF
a 1 (2.0 equiv.), 2a (1.0 equiv.), solvent: 2.0 mL, r.t. b Isolated
yields. c 1 (1.5 equiv.). d 1 (1.0 equiv.).
Chin. J. Chem. 2015, 33, 1211—1215
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Zhang et al.
NOTE
precursors thiazolium salts 7 and triazolium salt 8 only
catalyse the reaction in low efficiency (Table 1, Entries
4 and 6). After evaluation of other reaction parameters,
including solvent, molar ratio of reactants, and catalyst
loading (Table 1, Entries 7－15), the optimal reaction
conditions were established: 10 mol% IPr, 1.5 equiv.
α-keto ester, conduct the reaction in THF at room
temperature (Table 1, Entry 7).
The scope of α-keto esters was next examined under
the optimal reaction conditions and the results are sum-
marized in Table 2. Both aromatic and aliphatic α-keto
esters were suitable substrates for these cyanation addi-
tion. Aromatic α-keto esters bearing electron-neutral,
-donating and -withdrawing substituents can participate
in the reaction in high yields (Table 2, Entries 1－6).
Interestingly, ethyl naphthylglyoxylate and heteroaro-
matic α-keto esters were also proved to be good reac-
tants, producing the desired products in high yields (Ta-
ble 2, Entries 7－9). Methyl phenylglyoxylate and ethyl
pyruvate were also competent candidates for the addi-
tion, producing the corresponding products in 84% and
88% yields, respectively (Table 2, Entries 10 and 11).
Notably, the reaction could be conveniently conducted
on gram-scale and high yield was still maintained (Ta-
ble 2, Entry 12).
eloctron-neutral, and -withdrawing groups gave higher
yields than those bearing electron-donating substituents
(Table 3, Entries 1－7). Ethyl naphthylglyoxylate and
heteroaromatic α-keto esters smoothly underwent the
cyanation reaction to produce the corresponding
products in good yields (Table 2, Entries 8－10). To our
surprise, ethyl pyruvate, which was proved to be
suitable reactant for cyanoethoxycarbonylation with
ethyl cyanoformate, reacted with acetyl cyanide in
relatively low efficiency, producing the desired product
in 43% yield (Table 2, Entry 11).
Table 3 NHCs-catalysed acylcyanation reaction of α-keto
estersa
O
O
OCOCH3
R'
NC
R
4 (10 mol%)
NC
CH3
R
R'
DCE, r.t.
10
2
9
Entry
R
R'
CO2Et
CO2Me 10b
Product Time/h Yieldb/%
1
2
3
4
5
6
7
8
9
C6H5
C6H5
10a
24
24
48
48
48
48
48
48
48
48
24
82
74
43
71
76
74
57
59
63
73
43
4-CH3-C6H4
4-F-C6H4
CO2Et
CO2Et
CO2Et
CO2Et
10c
10d
10e
10f
10g
10h
10i
4-Cl-C6H4
4-Br-C6H4
Acetyl cyanide 9,[6] another cyanation reagent that
was used successfully in NHC-catalysed acylcyanation
reaction of aldehydes,[7a] was also tested for the cyana-
tion reaction of α-keto esters and the results were sum-
marized in Table 3. This time, DCE was found to be the
best choice with respect of reaction yields. Most tested
α-keto esters can react with acetyl cyanide to produce
the desired products. Aromatic α-keto esters bearing
2-CH3O-C6H4 CO2Et
α-Naphthyl
CO2Et
CO2Et
CO2Et
CO2Et
2-Thienyl
10 2-Furyl
11 CH3
10j
10k
a Reaction conditions: 9 (1.5 equiv.), 2 (1.0 equiv.), 4 (10 mol%),
ClCH2CH2Cl 2.0 mL, r.t. b Isolated yields.
Table 2 NHCs-catalysed cyanation-esterification reaction of
α-keto esters with ethyl cyanoformatea
Based on the previous study of NHC-catalysed cy-
anation of aldehydes,[7] a plausible mechanism is pro-
posed and depicted in Scheme 1.[9] The attack of NHC
on cyanation reagent might trigger the cyanation reac-
tion of keto esters and lead to the formation of the final
product.
O
O
OCOCEt
NC
R
4 (10 mol %)
NC
OEt
R
R'
R'
THF, r.t.
3
2
1
Entry
R
R'
Product Time/h Yieldb/%
1
2
C6H5
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
3a
3b
3c
3d
3e
3f
24
48
24
48
48
48
48
48
48
48
24
24
94
73
92
81
83
78
77
71
80
84
88
89c
4-CH3-C6H4
4-F-C6H4
Scheme 1 Proposed mechanism
3
O
NC
4
4-Cl-C6H4
4-Br-C6H4
R
5
+
N
N
Ar
Ar
6
2-CH3O-C6H4 CO2Et
-
CN COR
7
α-Naphthyl
2-Thienyl
2-Furyl
CH3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2Et
3g
3h
3i
O
8
N
N
R2
Ar
R1
Ar
9
R1
10
11
12
3j
R2
CN
C6H5
3k
3a
-
O
C6H5
a Reaction conditions: 1 (1.5 equiv.), 2 (1.0 equiv), 4 (10 mol%),
THF 2.0 mL, r.t. b Isolated yields. c 1 (6 mmol), 2 (4 mmol), 4 (10
mol% ), THF 8.0 mL.
COR
N
OCOR
+
N
R1
CN
R2
Ar
Ar
1214
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 1211—1215

N-Heterocyclic Carbene-Catalysed Direct Synthesis of Cyano Esters
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Conclusions
In summary, we have developed a new methodology
for the cyanation-esterification reaction of α-keto esters.
The mild conditions, simple procedure provide a novel
protocol for direct synthesis of cyano esters from ke-
tones.
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Acknowledgement
We are grateful to the National Natural Science
Foundation of China (Nos. 21262027, 21162023) and
the Natural Science Foundation of Shihezi University
(Nos. gxjs2013-zdgg02, 2012ZRKXJQ06) for financial
support of this work. We also thank Dr. L. He of Shi-
hezi University for helpful discussions.
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Demir, A. S.; Aybey, A.; Emrullahoglu, M. Synthesis 2009, 1655; (f)
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Chin. J. Chem. 2015, 33, 1211—1215
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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