Catalytic cyanomethylation of carbonyl compounds and imines with highly basic phosphine

Article abstract of DOI:10.1016/j.tetlet.2008.02.155

A highly basic phosphine, tris(2,4,6-trimethoxy phenyl)phosphine (TTMPP), catalyzes cyanomethylation using trimethylsilylacetonitrile (TMSCH₂CN) to give the corresponding products in good to high yields, with both carbonyl compounds and imines.

Full text of DOI:10.1016/j.tetlet.2008.02.155

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Tetrahedron Letters 49 (2008) 2982–2984
Catalytic cyanomethylation of carbonyl compounds
and imines with highly basic phosphine
Satoru Matsukawa *, Eri Kitazaki
Department of Science, Faculty of Education, Ibaraki University, Mito, Ibaraki 310-8512, Japan
Received 29 January 2008; revised 16 February 2008; accepted 28 February 2008
Available online 4 March 2008
Abstract
A highly basic phosphine, tris(2,4,6-trimethoxy phenyl)phosphine (TTMPP), catalyzes cyanomethylation using trimethylsilylaceto-
nitrile (TMSCH2CN) to give the corresponding products in good to high yields, with both carbonyl compounds and imines.
Ó 2008 Elsevier Ltd. All rights reserved.
b-Hydroxy nitriles are useful intermediates in organic
synthesis, for example, in the synthesis of c-aminoalcohols
and b-hydroxycarboxylic acids.1 Thus, several methods
have been developed for their synthesis. Generally, b-
hydroxy nitriles are prepared by reacting alkaliacetonitriles
with carbonyl compounds.2 However, the resultant
b-hydroxy nitriles are easily dehydrated to afford a,b-
unsaturated nitriles, and the yield of product is sometimes
unsatisfactory. Among several methods to overcome this
problem,3,4 cyanomethylation using trimethylsilylaceto-
nitrile (TMSCH2CN) is considered to be one of the most
efficient methods because of their low basicity and high
stability. On this basis, catalytic cyanomethylation proce-
dures using TASF,4c CuF,4d and AcOLi4e have been devel-
oped to realize high yield and selectivity. However, the
examples of the catalytic cyanomethylation are still scarce.
On the other hand, organocatalysis is currently being
vigorously pursued because of its attractive features such
as the metal-free conditions, experimental simplicity.5
we report that TTMPP catalyzes the cyanomethylation of
carbonyl compounds and imines by using TMSCH2CN
via C–Si bond activation.
Initially, cyanomethylation of benzaldehyde with
TMSCH2CN was examined in the presence of 10 mol %
TTMPP in DMF at room temperature.9 The desired prod-
uct was obtained in 92% yield in 3 h (Table 1, entry 1). The
product was obtained in moderate to low yield when other
phosphines were used instead of TTMPP (Table 1, entries 1
vs 7–10). THF, DMPU, and toluene were also effective sol-
vents in this TTMPP-catalyzed reaction. However, only
trace amounts of product were obtained using CH2Cl2,
MeOH, and acetonitrile.
In order to clarify the scope of this reaction, several alde-
hydes were examined in the presence of 10 mol % TTMPP
(Table 2). Good results were obtained for both aromatics
having an electron-donating or -withdrawing group and ali-
phatic aldehydes. Ketones also worked in the reaction,
which proceeded smoothly with various ketones in the pre-
sence of 10 mol % TTMPP. 1,2-Adducts were obtained in
good yields when a,b-unsaturated ketones were employed.
Aliphatic ketones also worked well, although longer
reaction times and 20 mol % TTMPP were required when
compared to the reaction with aromatic ketones.
Tris(2,4,6-trimethoxyphenyl)phosphine
(TTMPP)
is
known to be a highly basic phosphine owing to its multiple
methoxy substitutions.6 Many unique reactions have been
reported using TTMPP as an organocatalyst.7 We previ-
ously demonstrated that TTMPP catalyzes aldol, imine-
aldol reactions via O–Si bond activation.8 In this Letter,
Imines were also examined in this TTMPP-catalyzed
cyanomethylation.10 The resultant b-amino nitriles are use-
ful building blocks, as they are easily converted into either
b-aminocarboxylic acid or 1,3-diamino compounds.11 In
*
Corresponding author. Tel./fax: +81 29 228 8234.
E-mail address: smatsuka@mx.ibaraki.ac.jp (S. Matsukawa).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.155

S. Matsukawa, E. Kitazaki / Tetrahedron Letters 49 (2008) 2982–2984
2983
Table 1
Other phosphines, such as triphenylphosphine and tributyl-
phosphine did not catalyze this reaction. This fact clearly
shows the superiority of TTMPP. Good to high yields of
several b-amino nitriles were obtained under the same con-
ditions (Table 3, entries 5–8). Unfortunately, we had no
success with aliphatic aldimines under these conditions.
Although the mechanism of this reaction is not clear, a
possible mechanism is illustrated in Scheme 1. First,
TTMPP coordinates the silicon atom of the TMSCH2CN
to form activated penta coordinated silicon species 1
(mainly in THF, toluene) or hexa coordinated silicon spe-
cies 10 (mainly in DMF, DMPU), and the C–Si bond is
activated. Next, the nucleophilicity of the CH2CN group
is enhanced and it readily reacts with an electrophile to
produce the alkoxide or amino ion 2 and silylphosphonium
Optimization of the reaction conditions
Phosphines
OH
H+
O
(10 mol%)
+
CN
Me3Si
CN
Ph
solvent
Ph
Entry
H
H
3 h, rt
Phosphines
TTMPP
Solvent
DMF
Yield (%)
92
1
2a
DMF
THF
46
82
OMe
MeO
P
3
OMe
3
4
5
6
7
8
9
DMPUb
Toluene
CH3CN
MeOH
CH2Cl2
DMF
DMF
DMF
DMF
100
93
0
0
0
62
14
0
Table 3
TMPPc
Ph3P
nBu3P
tBu3P
TTMPP-catalyzed cyanomethylation of various imines
10
11
12
a
TTMPP
0
Ts
H
Ts
H+
N
HN
1 H
(20 mol%)
1 mol % of TTMPP was used.
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
Tris(4-methoxyphenyl)phosphine.
+
Me3Si
CN
CN
b
DMPU
R1
R
c
8 h, 50 °C
Entry
R1
Yield (%)
Table 2
1
C6H5
C6H5
C6H5
C6H5
4-CH3OC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
Furyl
80
25
0
TTMPP-catalyzed cyanomethylation of various aldehydes and ketones
2a
3b
4c
5
TTMPP
(10 mol%)
0
H+
OH
O
85
75
80
75
30
+
CN
Me3Si
CN
6
7
8
9
DMF
R
R1
1R2
R2
3 h, rt
Entry
R1
C6H5
R2
Yielda (%)
a
TMPP was used instead of TTMPP.
P(tBu)3 was used instead of TTMPP.
PPh3 was uesd instead of TTMPP.
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
92
95
97
80
99
80
98
91
85
65
80
96
69
73
81
74
66
80
68
65
56
b
c
4-CH3OC6H4
4-ClC6H4
4-CNC6H4
1-Naphtyl
2-Naphtyl
(E)-PhCH@CH
PhCH2CH2
n-C8H17
SiMe3
X
CN
R1
R2
10
11
12b
13
14
15
16
17
18
19
20b
21b
a
Furyl
C6H5
Ar3P
Me3SiCH2CN
CH3
4
(TTMPP)
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
C6H5
C2H5
4-CH3OC6H4
4-ClC6H4
4-CF3C6H4
3-CH3OC6H4
C6H5
(E)-PhCH@CH
(E)-PhCH@CH
C5H11
-
X
Ar3P
Me
Me
Ar3P
CN
R
Me
Me
Me
DMF
1R2
Si Me
Si
2
CH2CN
CH2CN
1'
Ar3P+—SiMe3
1
cyclo-C6H10
3
Isolated yield.
20 mol % of TTMPP was used.
b
X
R1
R2
the present study, we screened solvents and aldimines and
found that the corresponding b-amino nitrile was obtained
in good yield using N-tosylaldimine in DMPU at 50 °C.12
X = O, NTs
Scheme 1.

2984
S. Matsukawa, E. Kitazaki / Tetrahedron Letters 49 (2008) 2982–2984
Lett. 2001, 934; (c) Kawabata, H.; Hayashi, M. Tetrahedron Lett.
2002, 43, 5645; (d) Ro¨per, S.; Wartchow, R.; Hoffmann, M. R. Org.
Lett. 2002, 4, 3179. Catalytic cynanosilylation using phosphine or
phosphonium salt, see: (e) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama,
T. Chem. Lett. 1991, 537; (f) Cordoba, R.; Plumet, J. Tetrahedron
Lett. 2003, 44, 6157; (g) Wang, X.; Tian, S.-K. Tetrahedron Lett. 2007,
48, 6010.
salt 3. Finally, immediate silylation occurs to give the
silylated adduct 4 with regeneration of TTMPP.
In summary, we demonstrated that TTMPP catalyzes
cyanomethylation using TMSCH2CN. TTMPP effectively
activated the C–Si bond of TMSCH2CN, and the reaction
proceeded smoothly to afford the corresponding product.
This reaction can be applied to not only carbonyl com-
pounds but also imines. Further investigation along these
lines, including stereoselective reactions, is currently
underway.
8. (a) Matsukawa, S.; Okano, N.; Imamoto, T. Tetrahedron Lett. 2000,
41, 103; (b) Matsukawa, S.; Obu, K. Chem. Lett. 2004, 1626.
9. Typical experimental procedure: To a solution of TTMPP (26.6 mg,
0.05 mmol) in DMF (1 mL) was added benzaldehyde (53.1 mg,
0.5 mmol) and TMSCH2CN (105 mL, 0.75 mmol) at room temper-
ature. After stirring for 3 h, the resultant mixture was quenched with
5% HCl–MeOH (2 mL). The mixture was extracted with EtOAc and
organic layer was washed with brine and dried over anhydrous
Na2SO4, and evaporated. The crude mixture was purified by
preparative TLC to afford the desired product (67.8 mg, 92%) as
colorless oil.
References and notes
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