N-Heterocyclic carbene-catalyzed cyanomethylation of aldehydes with TMSAN

Article abstract of DOI:10.1016/j.tetlet.2012.02.080

N-Heterocyclic carbenes (NHCs) have been served as efficient catalysts for cyanomethylation of carbonyl compounds. In the presence of 5 mol % NHC, various aldehydes and 2,2,2-trifluoroacetophenone reacted with trimethylsilylacetonitrile (TMSAN) to give β-hydroxynitriles in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2012.02.080

Tetrahedron Letters 53 (2012) 2231–2233
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N-Heterocyclic carbene-catalyzed cyanomethylation of aldehydes with TMSAN
Ye-Cheng Fan a, Guang-Fen Du a, , Wan-Fu Sun b, Wei Kang a, Lin He a,
⇑
⇑
a Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang 832003, PR China
b Center for Physical and Chemical analysis, Xinjiang University, Urumqi, Xinjiang 830046, 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 carbenes (NHCs) have been served as efficient catalysts for cyanomethylation of carbonyl
compounds. In the presence of 5 mol % NHC, various aldehydes and 2,2,2-trifluoroacetophenone reacted
with trimethylsilylacetonitrile (TMSAN) to give b-hydroxynitriles in moderate to high yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 December 2011
Revised 9 February 2012
Accepted 17 February 2012
Available online 25 February 2012
Keywords:
N-Heterocyclic carbene
Cyanomethylation
Carbonyl compounds
Trimethylsilylacetonitrile
b-Hydroxynitriles
b-Hydroxynitriles are useful building blocks for the synthesis of
b-hydroxycarboxylic acids and their derivatives, -amino alcohols
reaction,13 Mukaiyama aldol reaction,14 Pudovik type reaction,15
and other reactions.16 In this Letter, we would like to disclose
our preliminary results on NHCs-catalyzed addition of TMSAN with
carbonyl compounds, giving b-hydroxynitriles in high yields.
At the onset of this study, the reaction of TMSAN and p-chloro-
benzaldehyde was selected as a model and various NHCs were
examined. When 1,3-bis (2,6-diisopropylphenyl) imidazol-2-yli-
dene (IPr)17 was employed, the addition proceeded smoothly in
tetrahydrofuran and afforded b-hydroxynitrile in 72% isolated
yield (Table 1, entry 1). NHC generated from imidazolium salt 2
and different bases, can also catalyze the reaction efficiently (Table
1, entries 2–4). Whereas NHCs generated from precursors 3 or 4
promoted the addition in low efficiency (Table 1, entries 5–7). To
our surprise, NHC generated from triazolium salt 5 did not catalyze
the reaction at all (Table 1, entry 8). Other reaction media, such as
toluene, DCM, ether, dichloroethane, acetonitrile, DMSO, and DMF
were also surveyed and the results indicated that DMF was the best
choice with respect to yield (Table 1, entries 9–15).18 Lowered the
catalyst loading to 5 mol %, higher yield was obtained (Table 1, en-
try 16). However, further decreased the catalyst loading to 1 mol %
led to a dramatic decrease of the yield (Table 1, entry 17). And fi-
nally, control experiment showed that the reaction cannot occur
in the absence of NHC catalyst (Table 1, entry 18).
c
as well as other important functionalities.1 Typically, the addition
of acetonitrile to carbonyl compounds under the assistance of
strong alkali metal base is the most straightforward method to pre-
pare b-hydroxynitriles.2 However, the reversibility of the reaction
and the facile dehydration of b-hydroxynitriles usually give the de-
sired products in unsatisfactory yields.3 To overcome the above
problems, great efforts have been made to improve the reaction
yields.4 Among them, the commercially available trimethylsilyl-
acetonitrile (TMSAN) was found to be a valid alternative nucleo-
phile for the cyanomethylation, it is considered that the
formation of the O-silyl ether inhibits the reversibility and there-
fore, high yields can be obtained.5 Several fluorides such as TASF,6
KF,7 CuF,8 and alkali-metal acetate9 have been utilized successfully
to promote the reaction. Strong basic proazaphosphatrane5 and tris
(2,4,6-trimethoxyphenyl) phosphine (TTMPP),10 are also used as
highly efficient organocatalysts to mediate the addition reaction.
However, catalytic methods for cyanomethylation reaction are still
scarce and efficiently organocatalytic approach for the preparation
of b-hydroxynitriles is extremely desirable.
As an important type of organocatalysts, N-Heterocyclic carb-
enes (NHCs)11 have attracted considerable attention in recent
years. We and others have illustrated the remarkable ability of
NHCs to activate the silylated reagents in a series of important
transformations, such as trifluoromethylation reaction,12 cyanation
After the optimal reaction conditions were established (DMF,
5 mol % IPr), the generality of the cyanomethylation was evaluated
and the results were summarized in Table 2. Both aromatic and
aliphatic aldehydes were suitable electrophiles. For aromatic
aldehydes, substitution of an electron-withdrawing group on the
aromatic ring resulted in higher yield than those bearing
electron-donating groups (Table 2, entries 1–6). However, strong
⇑
Corresponding authors. Tel.: +86 993 2057213; fax: +86 993 2057270.
E-mail addresses: duguangfen@shzu.edu.cn (G.-F. Du), helin@shzu.edu.cn (L. He).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.080

2232
Y.-C. Fan et al. / Tetrahedron Letters 53 (2012) 2231–2233
Table 1
Table 2 (continued)
NHCs catalyzed cyanomethylation of p-chlorobenzaldehyde with TMSANa
Entry Carbonyl compounds Time Product
(h)
Yield
(%)b
OH
CHO
+
CN
1) NHC, solvent
2) HCl, 0.5 h
CHO
OH
Me3SiCH2CN
CN
Cl
Cl
4
5
6
45
30
45
84
83
80
F
6a
8d
7
8a
F
CHO
CHO
OH
Cl-
Ar
Cl-
CN
N
N
N
N
N
N
Ar
Ar
Ar
Ar
Ar
Cl
8e
2
Cl
1
3
Ar=2,6-(i-Pr) C H
OH
2
6
3
Ar=1,3,5-Me C H
Ar=2,6-(i-Pr) C H
3
6
2
2
6
3
CN
F3C
Cl
N Ph
N
X-
R
8f
F3C
OH S
N
N
CHO
CHO
OH
OH
5
4a: R = Bn ,X = Cl
4b: R = Me, X = I
CN
7d
30
65
O2N
8g
8h
Yield (%)b
O2N
Entry
NHC
Solvent
Time (h)
MeO
1
1, (10 mol %)
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
DCM
Et2O
DMF
DCE
CH3CN
DMSO
DMF
DMF
DMF
20
20
20
20
20
20
20
20
20
20
20
20
20
30
30
30
30
30
72
70
44
66
33
6
16
NR
42
73
49
76
52
14
72
83
53
2c
3c
4c
5c
6c
7c
8
2, KOt-Bu (10 mol %)
2, Cs2CO3 (10 mol %)
2, DBU (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, (10 mol %)
1, (10 mol %)
MeO
CN
8
9
40
30
80
76
CHO
Cl
OH
CN
Cl
8i
Cl
Cl
9
10
11
12
13
14
15
16
17
18
CHO
OH
Cl
CN
10
45
65
Cl
8j
1, (10 mol %)
1, (10 mol %)
1, (5 mol %)
1, (1 mol %)
Br
CHO
OH
Br
CN 8k
11
12
45
45
82
71
No catalyst
a
b
c
O2N
CHO
OH
7 (1.5 equiv), 6a (1.0 equiv), solvent: 2.0 mL rt.
Isolated yields.
Using 12 mol % NHC-precursors and 10 mol % base.
O2N
CN
8l
CHO
OH
CN
13
45
40
68
63
8m
Table 2
NHCs catalyzed cyanomethylation of aldehydes with TMSANa
OH
14c
CN
OH
CHO
1) IPr (5 mol%)
O
O
CN
DMF, rt
OH
8n
Me3SiCH2CN
R
RCHO
+
2) HCl, 0.5 h
CHO
CHO
8
6
7
CN
15
30
63
Entry Carbonyl compounds Time Product
(h)
Yield
(%)b
8o
OH
CN
CHO
OH
CN
OH
CN
1
2
40
40
70
61
16
17
40
45
65
89
8a
8p
CHO
O
OH
CN
CF3
Me
CF3
8b
8q
Me
CHO
OH
a
b
c
7 (1.5 equiv), 6 (1.0 equiv), IPr 5 mol %, solvent: 2.0 mL, rt.
Isolated yields.
CN
3c
40
66
Using 10 mol % IPr.
MeO
d
Performed the reaction at À50 oC-rt.
8c
MeO

Y.-C. Fan et al. / Tetrahedron Letters 53 (2012) 2231–2233
2233
Supplementary data
N
N
Ar
Ar
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.080.
Me
Me
Me
DMF
Si
Me3SiCH2CN
DMF
RCHO
NCH2C
(I)
References and notes
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(Table 2, entry 7). Additionally, different positions of the substi-
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b-hydroxynitriles in good yields (Table 2, entries 15, 16). It is
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none and TMSAN proceeds smoothly to give 8q in 89% yield, which
contains a quaternary carbon center (Table 2, entry 17).
A plausible reaction mechanism was proposed and illustrated in
Scheme 1. NHC attacks the silicon atom of TMSAN to form a possi-
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bond was activated, which might trigger the following addition
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Acknowledgment
This work was supported by the Team Innovation Project of
Shihezi University.