N-heterocyclic carbene catalyzed cyanation reaction of carbonyl compounds with ethyl cyanoformate and acetyl cyanide

Article abstract of DOI:10.1016/j.tetlet.2011.10.119

N-heterocyclic carbene (NHC) has been employed as an efficient catalyst for cyanation reaction of carbonyl compounds. Under catalysis of 1 mol % NHCs, various aldehydes and 2,2,2-trifluoroacetophenone coupled with ethyl cyanoformate in THF to provide cyanohydrins ethyl carbonates in excellent yields. While in the presence of 10 mol % catalyst, different types of aldehydes and 2,2,2-trifluoroacetophenone reacted with acetyl cyanide in dichloroethane to give acylated cyanohydrins in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2011.10.119

Tetrahedron Letters 52 (2011) 7153–7156
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-heterocyclic carbene catalyzed cyanation reaction of carbonyl compounds
with ethyl cyanoformate and acetyl cyanide
Jie Zhang a, GuangFen Du b, YueKe Xu b, Lin He b, , Bin Dai b,
⇑
⇑
a School of Chemical Engineering and Technology, Tianjin University. Tianjin 300072, PR China
b Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang 832003, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
N-heterocyclic carbene (NHC) has been employed as an efficient catalyst for cyanation reaction of car-
bonyl compounds. Under catalysis of 1 mol % NHCs, various aldehydes and 2,2,2-trifluoroacetophenone
coupled with ethyl cyanoformate in THF to provide cyanohydrins ethyl carbonates in excellent yields.
While in the presence of 10 mol % catalyst, different types of aldehydes and 2,2,2-trifluoroacetophenone
reacted with acetyl cyanide in dichloroethane to give acylated cyanohydrins in moderate to high yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 20 July 2011
Revised 10 October 2011
Accepted 21 October 2011
Available online 28 October 2011
Keywords:
N-heterocyclic carbenes
Cyanation reaction
Carbonyl compounds
Ethyl cyanoformate
Acetyl cyanide
The past decade has witnessed a dramatic growth in organoca-
talysis chemistry of N-heterocyclic carbenes (NHCs).1 As one class
of versatile nucleophilic organocatalyst, NHCs have been utilized
broadly in a variety of important transformations, such as benzoin
reaction,2 Stetter reaction,3 ring-opening reaction,4 homoenolate
transformations5 and other reactions.6 Recently, NHCs were found
to be efficient catalysts for cyanosilylation of carbonyl compounds
cyanide, respectively. Herein, we would like to discourse our preli-
minary results on this topic.
Initially, the cyanoethoxycarbonylation reaction of benzalde-
hyde and ethyl cyanoformate was tested under catalysis of differ-
ent kinds of NHCs. To our delight, we found that the reaction
proceeded very smoothly in the presence of 10 mol % 1,3-bis(2,6-
diisopropylphenyl)imidazole-2-ylidene (IPr,
a
stable NHC),13
and aldimines, using trimethylsilyl cyanide as
a
cyanation
affording cyanohydrin ethyl carbonate 8a in a moderate yield after
12 h (Table 1, entry 1). Interestingly, when we increased the
amount of ethyl cyanoformate to 2.0 equiv, the reaction could be
converted quantitatively within 30 min (Table 1, entry 2). Similar
results were obtained with NHCs generated in situ from precursors
2 and 3 (Table 1, entries 3, 4), whereas NHCs derived from thiazo-
lium and triazolium salts showed low catalytic activities (Table 1,
entries 5–7). A brief survey of solvents revealed that dichlorometh-
ane, ether and toluene were all suitable reaction media (Table 1,
entries 8–10). Surprisingly, lowered catalyst loading to 1 mol %,
the excellent reaction yield can still be maintained (Table 1, entry
11). Even after decreasing catalyst loading to 0.5 mol %, the reac-
tion finished in slightly lower yield within 2 h (Table 1, entry
12). Further reduced catalyst loading to 0.1 mol % led to a dramatic
decrease of the yield (Table 1, entries 13, 14).
With the optimal reaction conditions in hand, a series of alde-
hydes were evaluated for the reaction and the results were sum-
marized in Table 2.14 It was found that both aromatic and
aliphatic aldehydes were suitable electrophiles. Aromatic alde-
hydes with either electro-donating or withdrawing groups worked
well, and the substituted groups showed a slight influence on the
reaction yield (Table 2, entries 1–7). Additionally, the position of
reagent.7
Cyanohydrins serve as essential building blocks in biologically
active compounds,8 and tremendous efforts have been devoted to
synthesizing this type of important compounds.9 Hydrogen cya-
nide and trimethylsilyl cyanide are most commonly used as the
sources of cyanide ions. However, the intrinsic high toxicity and
the instability of O-trimethylsilyl cyanohydrins restrain their po-
tential application sometimes. To overcome the unavoidable weak-
ness of hydrogen cyanide and trimethylsilyl cyanide, alkyl
cyanoformates and acyl cyanide have been applied as alternative
cyanide sources, and different catalytic systems for these types of
cyanations have been developed successfully in the recent years.10
In contrast to the extensive exploration of chiral ligand-metal
catalysis, the reactions promoted by organocatalysts were far less
examined.11 In line with our continue interest of NHCs chemis-
try,12 we found that NHCs can be used as efficient catalysts for
the cyanation of aldehydes with ethyl cyanoformate and acetyl
⇑
Corresponding authors. Tel.: +86 993 2058176; fax: +86 993 2057270.
E-mail addresses: helin@shzu.edu.cn (L. He), db_tea@shzu.edu.cn (B. Dai).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.119

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J. Zhang et al. / Tetrahedron Letters 52 (2011) 7153–7156
Table 1
Table 2
NHCs catalyzed cyanation of benzaldehyde with ethyl cyanoformatea
NHCs catalyzed cyanation of aldehydes with ethyl cyanoformatea
O
O
CHO
O
OEt
O
OEt
CN
O
6
O
IPr (1 mol%)
THF, r.t.
NHC (10 mol%)
+
CN
RCHO
7
R
NC
OEt
NC
OEt
solvent
8
Yieldb (%)
98
7a
6
8a
Entry
1
Aldehyde
CHO
Time (h)
1
Product
Cl-
Ar
Cl-
Ar
8a
N
N
N
N
N
N
Ar
Ar
Ar
Ar
CHO
2
1
3
2
3
24
24
8b
8c
90
73
Ar=2,6-(i-Pr)2C6H3
Ar=1,3,5-Me3C6H2
Ar=2,6-(i-Pr)2C6H3
CHO
Cl
N
MeO
O
X-
R
N
Ph
OH
CHO
S
N
N
4
5
6
36
2
8d
8e
8f
83
99
96
5
4a: R = Bn, X = Cl
4b: R = Me, X = I
O
MeO
CHO
Entry
NHC
Solvent
Time (h)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
1, (10 mol %)
1, (10 mol %)
THF
THF
THF
THF
THF
THF
THF
DCM
Et2O
Toluene
THF
12
0.5
1.5
2
24
24
24
1
1
1
1
2
63
99
91
90
11
18
14
95
96
85
98
89
22
—
CHO
12
2, KOt-Bu (10 mol %)
3, KOt-Bu(10 mol %)
4a, KOt-Bu(10 mol %)
4b, KOt-Bu(10 mol %)
5, KOt-Bu(10 mol %)
1, (10 mol %)
1, (10 mol %)
1, (10 mol %)
1, (1 mol %)
1, (0.5 mol %)
F
CHO
CHO
7
8
4
12
24
4
8g
8h
8i
94
94
90
97
98
Cl
Br
CHO
9
THF
THF
THF
Cl
CHO
1, (0.1 mol %)
1, (0.01 mol %)
12
12
10
11
8j
a
b
c
6 (2.0 equiv), 7a (1.0 equiv), solvent: 2.0 mL, r.t.
Isolated yields.
CHO
4
8k
6 (1.0 equiv).
OMe
CHO
12
13
24
4
8l
97
85
substituents had little effects on the reactions (Table 2, entries 8–
15). On the other hand, aliphatic aldehydes such as cyclohexane-
carboxaldehyde and 3-phenylpropionaldehyde were also good
substrates for the additions (Table 2, entries 17, 18). Interestingly,
2,2,2-trifluoroacetophenone was also proved to be an excellent
candidate, giving 8s in a 64% yield (Table 2, entry 19).
OEt
CHO
8m
OCH2Ph
CHO
14
15
4
8
8n
8o
94
91
CF3
In the view of the high reactivity of ethyl cyanoformate ob-
served, acetyl cyanide 9 was also tested.15 This time, the solvent
switched to DCE, and increasing the loading of IPr to 10 mol %
proved to be optimal.16 High yields were obtained for the most
tested aromatic as well as the aliphatic aldehydes, although rela-
tively long time was needed, presumably because of the stronger
bond between the acetyl and cyanide groups in 9. As expected,
the reaction of aromatic aldehydes with electron-donating groups
proceeded slowly and provided the desired products in moderate
yields (Table 3, entries 1–17). Also, 2,2,2-trifluoroacetophenone
was investigated, giving 10r in low yield (Table 3, entry 18).
Based on the previous work of NHCs promoted cyanosilylation
reaction of carbonyl compounds, two plausible mechanisms were
illustrated in Scheme 1. Initially, the addition of NHC to aldehyde
may initiate the following cyanation reaction (pathway I). Alterna-
tively the addition was triggered through the activation of cyana-
tion reagent by NHCs (pathway II).‘
CHO
Cl
Cl
CHO
16
17
18
2
36
12
8p
8q
8r
99
70
82
CHO
CHO
O
19
12
8s
64
CF3
a
Reaction conditions: 6 (2.0 equiv), 7 (1.0 equiv), IPr (1 mol %), THF 2.0 mL, r.t.
Isolated yields.
b
In summary, we have demonstrated a new method for NHCs-
catalyzed cyanation of aldehydes and 2,2,2-trifluoroacetophenone
with ethyl cyanoformate or acetyl cyanide. The low catalyst
loading and mild conditions provide a valuable approach for the
synthesis of O-protected cyanohydrins. Further studies toward
the expansion of the scope, and using this method to other electro-
philes are ongoing in our laboratory.

J. Zhang et al. / Tetrahedron Letters 52 (2011) 7153–7156
7155
Table 3
O
NC
NHCs catalyzed cyanation of aldehydes with acetyl cyanidea
R'
RCHO
Ar
O
N
N
N
NC
R'
Ar
Ar
O
O
N
O
O
CH3
CN
10
CN COR
Ar
H
IPr (10 mol%)
R
RCHO
NC
CH3
R
RCHO
ClCH2CH2Cl, r.t.
9
7
II
N
N
I
Ar
Ar
CN
R
Entry
1
Aldehyde
CHO
Time (h)
24
Product
Yieldb (%)
83
Ar
O
N
N
OCOR'
H
10a
OCOR'
CN
COR'
N
Ar
R
CHO
CN
R
Ar
Ar
2
3
4
5
36
36
36
24
10b
10c
10d
10e
65
62
81
78
N
CHO
CHO
Scheme 1. Proposed mechanisms.
MeO
MeO
Acknowledgments
CHO
We thank the Key Project of National Science and Technology of
China (No. 2009ZX09103-015) and Shihezi University for financial
support.
F
CHO
CHO
6
7
8
12
18
12
10f
10g
10h
82
76
78
Cl
Br
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.119.
CHO
Cl
CHO
References and notes
9
48
48
48
48
10i
10j
10k
10l
82
73
71
70
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Me
CHO
10
11
12
OMe
CHO
OEt
CHO
OCH2Ph
CHO
13
14
36
8
10m
10n
84
89
CF3
CHO
Cl
Cl
CHO
15
16
17
24
36
12
10o
10p
10q
82
90
71
CHO
CHO
O
18
36
10r
30
CF3
a
Reaction conditions: 9 (2.0 equiv), 7 (1.0 equiv), IPr (10 mol %), solvent 2.0 mL,
8. For recent reviews on synthesis and reactions of cyanohydrins, see: (a) Gregory,
R. J. H. Chem. Rev. 1999, 99, 3649; (b) Smith, M. B.; March, J. Advanced Organic
Chemistry, 5th ed.; John Wiley & Sons: New York, 2001; (c) Shan, G.; Hammock,
r.t.
b
Isolated yields.

7156
J. Zhang et al. / Tetrahedron Letters 52 (2011) 7153–7156
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14. Typical procedure for cyanation of aldehydes with ethyl cyanoformate (Table 2
R.; Stok, J. E.; Morisseau, C.; LeValley, S. E.; Green, C. E.; Hammock, B. D. Anal.
Biochem. 2003, 315, 208; (e) Brunel, J. M.; Holmes, I. P. Angew. Chem., Int. Ed.
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L.; Feng, X. M. Chem. Commun. 2009, 41, 6145.
entry 1): To a stirred solution of aldehyde 7a (48.0
lL, 0.5 mmol, 1.0 equiv) in
THF (2.0 mL) was added ethyl cyanoformate (98.0
lL, 1.0 mmol, 2.0 equiv) at
room temperature under argon atmosphere. After that the solution was then
cooled to 0 °C and IPr (2.0 mg, 1 mol %) was added. The mixture was stirred at
room temperature until the starting aldehyde was fully consumed as indicated
by TLC concentration and the crude material was purified by column
chromatography (PE-EtOAc: 9:1) to afford product 8a (100 mg, 98%) as a
colorless oil. 1H NMR (400 MHz CDCl3): d 7.59–7.53 (m, 2H), 7.49–7.44 (m, 3H),
6.27 (s, 1H), 4.37–4.23 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 13C NMR (100 MHz,
CDCl3) d 153.65, 131.45, 130.85, 129.50, 128.10, 115.96, 66.58, 65.85, 14.34;
GC–MS (EI) m/z 205.0 [M]+.
9. For reviews on cyanation reactions, see: (a) Veum, L.; Kuster, M.; Telalovic, S.;
Hanefeld, U.; Maschmeyer, T. Eur. J. Org. Chem. 2002, 1516; (b) Gröger, H. Chem.
Eur. J. 2001, 7, 5246; (c) North, M. Tetrahedron: Asymmetry 2003, 14, 147; (d)
Belokon, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M. Tetrahedron
2004, 60, 10433; (e) Yamagiwa, N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am.
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2010, 49, 6746.
15. The addition of benzaldehyde to acetyl cyanide in THF under optimal
conditions that are used for cyanation with ethyl cyanoformate, isolated only
35% yield of the product. After a brief survey of solvents, catalyst loading and
other reaction conditions, we found that in the presence of 10 mol % IPr, the
cyano-acylation of aldehydes worked well in dichloroethane and afforded
acylated cyanohydrins in high yields. See Supplementary data for details of
reaction procedure.
16. Typical procedure for cyanation reaction with acetyl cyanide (Table 3 entry 6): To
a stirred solution of aldehyde 7f (70.0 mg, 0.5 mmol, 1.0 equiv) in 1,2-DCE
(2.0 mL) was added acetyl cyanide (80.0 lL, 1.0 mmol, 2.0 equiv) at room
temperature under argon atmosphere. After that the solution was then cooled
to 0 °C and IPr (19.4 mg, 10 mol %) was added. The mixture was stirred at room
temperature until the starting aldehyde was fully consumed as indicated by
TLC concentration, the crude material was purified by column chromatography
(PE-EtOAc: 15:1) to afford product 10f (92 mg, 82%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.49–7.45 (m, 2H), 7.45–7.41 (m, 2H), 6.38 (s, 1H), 2.17 (s,
3H); 13C NMR (100 MHz, CDCl3) d 168.78, 136.64, 130.26, 129.52, 129.27,
115.77, 62.15, 20.43; GC–MS: (EI) m/z 209.0 [M]+.
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