Al-MCM-41 catalyzed three-component Strecker-type synthesis of α-aminonitriles

Article abstract of DOI:10.1016/j.tet.2010.01.001

Mesoporous aluminosilicate (Al-MCM-41) efficiently catalyzed the three-component Strecker-type reaction of benzylacetone and aniline with trimethylsilyl cyanide in CH₂Cl₂ at room temperature to afford the corresponding α-aminonitrile in excellent yields (up to 97%). Mesoporous silica (MCM-41), amorphous SiO₂-Al₂O₃, and H-Y and H-ZSM-5 zeolites also catalyzed this reaction, but gave the desired product in lower yields. The Al-MCM-41 catalyzed three-component Strecker-type reaction was applicable to a wide range of ketones, aldehydes, and amines. Furthermore, the Al-MCM-41 catalyst could be applied to a fixed-bed flow reactor: The desired α-aminonitrile derivative was constantly produced in nearly 80% yields for 48 h.

Full text of DOI:10.1016/j.tet.2010.01.001

Tetrahedron 66 (2010) 1898–1901
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Al-MCM-41 catalyzed three-component Strecker-type synthesis
of a-aminonitriles
*
Katsuyuki Iwanami, Hana Seo, Jun-Chul Choi, Toshiyasu Sakakura, Hiroyuki Yasuda
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2009
Received in revised form 25 December 2009
Accepted 4 January 2010
Available online 11 January 2010
Mesoporous aluminosilicate (Al-MCM-41) efficiently catalyzed the three-component Strecker-type re-
action of benzylacetone and aniline with trimethylsilyl cyanide in CH2Cl2 at room temperature to afford
the corresponding a-aminonitrile in excellent yields (up to 97%). Mesoporous silica (MCM-41), amor-
phous SiO2–Al2O3, and H-Y and H-ZSM-5 zeolites also catalyzed this reaction, but gave the desired
product in lower yields. The Al-MCM-41 catalyzed three-component Strecker-type reaction was appli-
cable to a wide range of ketones, aldehydes, and amines. Furthermore, the Al-MCM-41 catalyst could be
Keywords:
applied to a fixed-bed flow reactor: The desired
nearly 80% yields for 48 h.
a
-aminonitrile derivative was constantly produced in
Three-component Strecker-type reaction
a
-Aminonitriles
Ó 2010 Elsevier Ltd. All rights reserved.
Heterogeneous catalysis
Mesoporous materials
Al-MCM-41
1. Introduction
efficient Fe(Cp)2PF6 catalyzed Strecker-type reaction from ketones
as well as aldehydes under solvent-free conditions.8 In both
cases, however, the reactions are promoted by homogeneous
catalytic systems. Therefore, there is still scope to develop an
efficient heterogeneous catalyst for preparing a wide range of
Three-component Strecker-type reaction from carbonyl com-
pounds, amines, and trimethylsilyl cyanide (TMSCN) is an important
reaction in organic synthesis because the products,
derivatives, are versatile intermediates, which can be transformed
into various building blocks, including -amino acids, 1,2-diamines,
a-aminonitrile
a-aminonitriles.
a
Ordered mesoporous materials are very attractive as hetero-
and nitrogen-containing heterocycles.1 Various Lewis acids such as
Yb(OTf)3,2a Pr(OTf)3,2b Cu(OTf)2,2c LiClO4,2d BiCl3,2e NiCl2,2f RuCl3,2g
CeCl3,2h InI3,2i RhI3,2j La(NO3)3$6H2O or GdCl3$6H2O,2k iodine,2l and
(bromodimethyl)sulfonium bromide,2m homogeneously catalyze
the Strecker-type reaction. On the other hand, several heteroge-
neous catalysts, which are more advantageous in terms of catalyst/
product separation and continuous production, have been proposed
for the reaction. The examples include polymer-supported scandium
triflate,3a montmorillonite,3b sulfuric acid on silica,3c,d heteropoly
acid,3e–g sulfamic acid,3h,i and poly(4-vinyl pyridine)–SO2 complex.3j
A few catalyst-free methods are also known.4 However, the
starting carbonyl compounds are mostly limited to aldehydes;
there are few examples on the successful three-component re-
action starting from ketones. Matsumoto et al. performed the
three-component reaction using ketones under extremely high
pressure conditions (600 MPa).5 Olah et al. have reported this
type of reaction from fluorinated ketones using Ga(OTf)3 or
TMSOTf as a catalyst.6,7 Khan et al. have also reported the
geneous solid catalysts for fine chemicals synthesis because their
large pore sizes and pore volumes allow facile diffusion of bulky
reactants and products that are often involved in such a re-
action.9 The additional attractive feature of mesoporous materials
is their high surface areas, which provide a high concentration of
active sites often introduced by incorporating metal ions into the
siliceous framework. For instance, aluminum substituted meso-
porous silicas show acid catalysis for numerous fine chemicals
syntheses.10 Recent examples include acetalization,11 esterifica-
tion,12 -keto ester synthesis,13 cyanosilylation,14 allylation,15 and
b
Mukaiyama aldol reaction.16 Herein, we report that mesoporous
aluminosilicate (Al-MCM-41) is a highly efficient heterogeneous
catalyst for the three-component Strecker-type reaction of vari-
ous ketones including less reactive acyclic ketones with amines
and TMSCN. Using the catalyst in a flow reactor, a-aminonitriles
can be continuously produced without catalyst separation from
the products.
2. Results and discussion
We initially used benzylacetone and aniline (1.2 equiv) as sub-
strates to investigate the effect of catalysts on the three-component
* Corresponding author. Tel.: þ81 29 861 9399; fax: þ81 29 861 4580.
E-mail address: h.yasuda@aist.go.jp (H. Yasuda).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.001

K. Iwanami et al. / Tetrahedron 66 (2010) 1898–1901
1899
Strecker-type reaction with TMSCN (1.2 equiv) in CH2Cl2. The re-
sults are summarized in Table 1. It is noteworthy that the reaction
hardly proceeded in the absence of a catalyst (Table 1, entry 1).
Silica gel was not effective for the reaction, whereas mesoporous
Table 2 summarizes the scope of amines as well as carbonyl
compounds. Depending on the combination of ketone and amine,
the reaction proceeded fairly well even in the absence of the cat-
alyst. In each case, however, the use of Al-MCM-41 gave the product
in a higher yield. When benzylamine and p-anisidine were used,
silica (MCM-41) afforded the desired a-aminonitrile in a 61% yield
(Table 1, entries 2 and 3). Additionally, substitution of a part of
silicon in MCM-41 with aluminum improved the yield, and the
desired product was obtained in 97% yield when Al-MCM-41 with
a Si/Al ratio of 20 (denoted by Al-MCM-41 (20)) was used (Table 1,
entry 6). On the other hand, amorphous silica/alumina (SiO2–Al2O3;
Si/Al¼20) and zeolites such as H-Y and H-ZSM-5 gave moderate
yields (Table 1, entries 7–9). If one considers the specific surface
the corresponding a-aminonitrile derivatives, in which the amino
groups were protected with N-benzyl and N-PMP (p-methoxy-
phenyl) groups, respectively, were obtained in excellent yields
(Table 2, entries 2 and 3). In contrast, the use of pyrrolidine as an
amine did not give the desired a-aminonitrile, but produced the
corresponding cyanohydrin trimethylsilyl ether quantitatively
(Table 2, entry 4). Cyclic ketones such as cyclohexanone, 2-meth-
ylcyclohexanone, and cyclopentanone afforded the desired prod-
ucts in good to high yields within 3 h (Table 2, entries 5–7). In the
areas of Al-MCM-41 (20) and SiO2–Al2O3 being 993 and 157 m2 gꢀ1
,
respectively, one can see that the high yield produced by Al-MCM-
41 (20) is primarily due to its high surface area. For the Al-MCM-41
(20) catalyst, the yield increased with the amount of catalyst, but
the use of 50 mg was enough to obtain the best result (Table 1,
entries 10–13). Among the solvents tested in the Al-MCM-41 cat-
alyzed reaction, CH2Cl2 was the most suitable. Toluene and aceto-
nitrile17 were also a good solvent, but DMF and THF gave somewhat
lower yields (Table 1, entries 14–17).
case of sterically hindered pinacolin, aromatic ketone, and
a,b-un-
saturated ketone, the yields of the corresponding -aminonitriles
a
were moderate (Table 2, entries 8–10). On the other hand, the re-
action starting from benzophenone did not proceed at all (entry
11). On the contrary, the three-component reaction of aldehydes
such as n-hexanal, cyclohexanecarbaldehyde, and benzaldehyde
with benzylamine and TMSCN proceeded sufficiently without cat-
alyst, although the use of the Al-MCM-41 catalyst improved the
yields of the desired aminonitriles (Table 2, entries 12–17).
To obtain insights into the reaction mechanism, we carried out
two experiments shown in Scheme 1. First, we performed the re-
action between cyanohydrin trimethylsilyl ether derived from
benzylacetone and aniline in the presence of the Al-MCM-41 cat-
Table 1
Three-component Strecker-type reaction of benzylacetone with aniline and TMSCN
by various catalystsa
O
+
PhNH2
+
TMSCN
Ph
alyst (Eq. 1). However, the corresponding a-aminonitrile was not
formed at all. Therefore, it is unlikely that the present three-com-
ponent reaction proceeds via cyanohydrin silyl ethers. Second, the
reaction between imine derived from benzylacetone and TMSCN in
Catalyst
NC
NHPh
Ph
the presence of Al-MCM-41 produced
the reaction was much slower than the three-component reaction;
the yield of -aminonitrile was only 29% in 24 h. Therefore, it is also
a-aminonitrile (Eq. 2), but
Entry
Catalystb
Amount of
catalyst (mg)
Solvent
Yieldc (%)
a
1
2
3
4
5
6
7
8
None
SiO2
MCM-41
Al-MCM-41 (100)
Al-MCM-41 (50)
Al-MCM-41 (20)
SiO2–Al2O3
H-Y
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH3CN
DMF
2
5
unlikely that the three-component reaction proceeds via imine
although the intermediacy of imine has been assumed, for instance
in the homogeneous Fe(Cp)2PF6 catalyzed reaction.8 If these results
are taken into account, it is reasonable to assume that the three-
component reaction over the Al-MCM-41 catalyst proceeds by way
of an N,O-acetal intermediate,18 which is formed from ketones and
amines (Scheme 2). Ketones activated by the acidic proton of Al-
MCM-41 react with amines to form N,O-acetals, which undergo
nucleophilic attack by TMSCN, as the case of ring opening reactions
of semicyclic N,O-acetals with silicon-based nucleophiles,19 leading
50
50
50
50
50
50
50
50
100
20
10
5
61
82
89
97 (95)d
40
64
28
92
82
79
74
94
87
71
71
e
9
H-ZSM-5
10
11
12
13
14
15
16
17
Al-MCM-41 (20)
Al-MCM-41 (20)
Al-MCM-41 (20)
Al-MCM-41 (20)
Al-MCM-41 (20)
Al-MCM-41 (20)
Al-MCM-41 (20)
Al-MCM-41 (20)
to a-aminonitriles. Since MCM-41 showed appreciable catalysis for
50
50
50
50
this three-component reaction (Table 1, entry 3), the weak acid site
like the surface silanol group (pKa¼7.2)20 should be sufficient to
activate ketones.
THF
a
Finally, we performed the continuous Strecker-type reaction of
benzylacetone, aniline, and TMSCN using a fixed-bed flow reactor
in order to demonstrate the merit of Al-MCM-41 as a solid catalyst,
as well as examine the catalytic stability. The catalytic activity was
Reaction conditions: benzylacetone (1 mmol), aniline (1.2 mmol), TMSCN
(1.2 mmol), catalyst, solvent (2 mL), room temperature, under an argon atmosphere,
24 h.
b
Figures in parentheses are the molar ratio of Si/Al (input).
c
Each yield was determined by 1H NMR using 1,1,2,2-tetrachloroethane as an
maintained for at least 48 h, and the desired
a-aminonitrile de-
internal standard, unless otherwise noted.
d
rivative was constantly produced in nearly 80% yields (Fig. 1). This
proves that Al-MCM-41 is stable enough to serve as a solid catalyst
under the present reaction conditions.
Isolated yield after gel permeation chromatography (GPC).
Amorphous silica–alumina.
e
To verify whether the catalysis of Al-MCM-41 in this reaction is
heterogeneous or not, we conducted the following experiment. A
mixture of benzylacetone (1.0 mmol), aniline (1.2 mmol), TMSCN
(1.2 mmol), triphenylmethane (internal standard), and Al-MCM-41
(20) (50 mg) in CH2Cl2 (3.0 mL) was stirred at room temperature.
After 1 h, Al-MCM-41 (20) was filtered off, and the filtrate was
stirred again under the same conditions for 23 h. However, the
increase in the yield was negligible (32% at 1 h and 33% at 24 h),
In conclusion, we have demonstrated that Al-MCM-41 is
a highly active heterogeneous solid catalyst for the three-compo-
nent Strecker-type reaction. Using the Al-MCM-41 catalyst and
TMSCN as a cyanide source, various a-aminonitriles are obtained
from a wide range of ketones and amines in high yields under mild
reaction conditions. The merit of the Al-MCM-41 catalyst is the
presence of a high concentration of the acid sites easily accessible to
large molecules per weight of the catalyst. This report extends the
application range of mesoporous aluminosilicates as heteroge-
neous catalysts in organic synthesis, especially for fine chemicals.
indicating that Al-MCM-41 truly works as
catalyst.
a heterogeneous

1900
K. Iwanami et al. / Tetrahedron 66 (2010) 1898–1901
Table 2
Three-component Strecker-type reaction of various carbonyl compounds and amines catalyzed by Al-MCM-41a
Al-MCM-41
NR3R4
R2
O
NC
R1
R3R4NH
+
+
TMSCN
R1
R2
CH2Cl2
Entry
R1
R2
R3
R4
Time (h)
Yieldb (%)
Yieldc (%)
1
2
3
4
5
6
7
8
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
–(CH2)5–
–CHMe(CH2)4–
–(CH2)4–
t-Bu
Me
Me
Me
Me
Ph
PhCH2
4-MeOC6H4
–(CH2)4–
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
–(CH2)4–
H
H
H
24
24
24
24
3
97 (95)d
98 (97)d
95 (93)d
0
2
25
6
0
H
H
H
H
H
H
H
H
H
H
H
H
91e
74
55
df
4
5
8
3
3
78
76
48
73
Me
Me
Me
Ph
H
H
H
H
H
24
24
24
24
0.25
0.25
0.25
2
9
Ph
10
11
12
13
14
15
16
17
PhCH¼CH
40
Ph
0g
df
df
84
85
75
93
79
PhCH2CH2
n-C6H13
cyclo-C6H11
t-Bu
96e
90e
91e
84e
Ph
0.5
3
100
100
PhCH2CH2
H
a
Reaction conditions: carbonyl compound (1 mmol), amine (1.2 mmol), TMSCN (1.2 mmol), CH2Cl2 (2 mL), room temperature, under an argon atmosphere.
b
Yields in the presence of Al-MCM-41 (20) (50 mg for ketones and 10 mg for aldehydes). Each yield was determined by 1H NMR spectroscopy using 1,1,2,2-tetra-
chloroethane as an internal standard, unless otherwise noted.
c
Yields in the absence of Al-MCM-41 (20). Each yield was determined in the same manner as footnote [b].
Isolated yield after gel permeation chromatography (GPC).
Isolated yield after silica gel column chromatography.
Not determined.
d
e
f
g
No reaction.
Al-MCM-41
NC
OTMS
NC
NHPh
NHPh
+
+
PhNH2
(1)
(2)
Ph
Ph
Ph
CH2Cl2, rt, 24 h
0%
NPh
Al-MCM-41
NC
TMSCN
Ph
CH2Cl2, rt, 24 h
29%
a-aminonitriles from cyanohydrin trimethylsilyl ether (Eq. 1: cyanohydrin TMS ether (1 mmol), aniline (1.2 mmol), Al-MCM-41 (50 mg)) and from imine
Scheme 1. Preparation of
(Eq. 2: imine (1 mmol), TMSCN (1.2 mmol), Al-MCM-41 (50 mg)).
Al
Si
O
Al
Si
O
O
H
O
O
O
H
O
H
N+
H
H+
NC
NHR
HO
NHR
HO
R
+
Me3SiOH
Me3Si CN
RNH2
Al
Si
Al
Si
Al
Si
O
O
O
O
O
H
O
O
O
H+
O
H
Scheme 2. Possible reaction mechanism of the three-component Strecker-type reaction catalyzed by Al-MCM-41.

K. Iwanami et al. / Tetrahedron 66 (2010) 1898–1901
1901
benzylacetone:aniline:TMSCN¼1.0:1.05:1.1), triphenylmethane as
an internal standard (2.5 wt %), and CH2Cl2 (for balance), was
continuously introduced into the reactor at room temperature with
a syringe pump (Harvard type 55-1111, Harvard Apparatus Inc.) at
a flow rate of 1.25 g hꢀ1. The weight hourly space velocity (WHSV)
was 12.5 hꢀ1. The liquid products were collected for 10 min every
6 h and analyzed by 1H NMR.
100
80
60
40
20
0
Acknowledgements
This research was financially supported by the Project of ‘De-
velopment of Microspace and Nanospace Reaction Environment
Technology for Functional Materials’ of New Energy and Industrial
Technology Development Organization (NEDO), Japan.
0
6
12 18 24 30 36 42 48
Time on stream (h)
Figure 1.
a-Aminonitrile yield during a continuous flow reaction. Reaction conditions:
benzylacetone (7.4 wt %), aniline (1.05 equiv), and TMSCN (1.1 equiv) in CH2Cl2. Al-
MCM-41 (20) (100 mg, loaded in a 4 mm I.D.ꢂ30 mm Pylex glass tube), flow rate
(1.25 g hꢀ1), room temperature.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.001.
3. Experimental section
3.1. Preparation of catalysts
References and notes
Al-MCM-41 (Si/Al¼20) was prepared by a direct hydrothermal
synthesis method according to the literature21 using cetyl-
trimethylammonium bromide (CTMABr) as a template. The Si and
Al sources were colloidal silica and sodium aluminate, respectively.
The molar ratio of CTMABr:SiO2:NaAlO4:NaOH:NH3:H2O was
1.1:20:1.0:5.5:1.1:940. The gel mixture was initially stirred for 1 h at
room temperature, and then heated to 97 ꢁC. After 1 day, the
mixture was cooled to room temperature and the pH of the reaction
mixture was adjusted to 10.2 by adding 30 wt % acetic acid. The
heating and pH adjustment procedures were repeated twice. The
resulting solid was filtered, washed with deionized water, dried at
97 ꢁC, and then calcined in air at 550 ꢁC for 18 h. The BET surface
area and the pore volume were 993 m2 gꢀ1 and 1.08 cm3 gꢀ1, re-
spectively. The preparation and characterization of Al-MCM-41 (Si/
Al¼50 and 100), MCM-41, amorphous SiO2–Al2O3, H-Y, and H-ZSM-
5 are shown in the Supplementary data.
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Dichloromethane was distilled from calcium hydride. TMSCN
was purchased from Tokyo Chemical Industry Co., Ltd. and distilled
prior to use. Benzaldehyde, cyclohexanone, and aniline were used
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3.2.1. The reaction procedure in entry 1 in Table 2. To a suspension
of Al-MCM-41 (20) (50 mg), which was pretreated in vacuo at
120 ꢁC for 1 h, benzylacetone (148 mg, 1.0 mmol), and aniline
(110 mL, 1.2 mmol) in CH2Cl2 (2 mL) was added TMSCN (160 mL,
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1.2 mmol). The reaction mixture was stirred at room temperature
under an argon atmosphere. After 24 h, the catalyst was removed
via filtration and the solvent was evaporated in vacuo. 1H NMR
analysis (400 MHz) of the product using 1,1,2,2-tetrachloroethane
as an internal standard showed that 2-methyl-2-phenylamino-4-
phenylbutanenitrile was obtained in 97% yield. The product was
isolated by GPC (238 mg, 95%) and gave satisfactory 1H NMR, 13C
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17. Yus et al. have reported that acetonitrile itself highly promotes the three-
component Strecker-type reaction.4b In our examination, when the reaction
starting from benzylacetone was performed in acetonitrile in the absence of the
Al-MCM-41 catalyst, the desired product was obtained in 1% yield in 24 h.
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12510.
NMR, and IR spectra. The spectral data for new
included in the Supplementary data.
a-aminonitriles are
3.2.2. The reaction procedure in Figure 1. The reactor was a Pyrex
glass tube (4 mm inner diameter and 30 mm long), which was
loaded with Al-MCM-41 (20) (100 mg) pretreated in vacuo at
120 ꢁC for 1 h. The liquid feed, which contained benzylacetone
(7.4 wt %), aniline (4.9 wt %), TMSCN (5.4 wt %) (molar ratio of
20. Gru¨n, M.; Kurganov, A. A.; Schacht, S.; Schu¨th, F.; Unger, K. K. J. Chromatogr., A
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