Synthesis of α-amino nitriles from carbonyl compounds, amines, and trimethylsilyl cyanide: comparison between catalyst-free conditions and the presence of tin ion-exchanged montmorillonite

Article abstract of DOI:10.1002/ejoc.200901323

In the absence of catalysts, the three-component, one-pot synthesis of α-amino nitriles proceeded using various aldehydes and ketones together with amines and trimethylsilyl cyanide (TMSCN) in high yields under neat conditions at room temperature. The addition order of the reagents had a significant influence on the yields of the desired α-amino nitriles. In contrast, when tin ion-exchanged montmorillonite (Sn-Mont), prepared by the ion-exchange of sodium, montmorillonite (Na-Mont) with a tin tetrachloride solution, was used as a catalyst, the reaction rates significantly increased compared with those without catalysts, and the range of the applicable carbonyl compounds was also extended: structurally diverse aromatic, aliphatic and heteroatom-containing carbonyl compounds, including sterically hindered ketones as well as aliphatic and aromatic amines, were converted into the desired α-amino nitriles in good to excellent yields with short reaction times under mild conditions. Sn-Mont showed a better catalytic activity than proton or other metal ion-exchanged montmorillonites, supported SnO₂ catalysts and the previously reported homogeneous or heterogeneous catalysts. The recovered catalyst was reused several times without loss of catalytic performance. Along with the expansion of the interlayer space of Sn-Mont, the strong Bransted acid and Lewis acid nature of Sn-Mont derived from protons and SnO₂ nanoparticles present in the interlayers of Sn-Mont likely played important and cooperative roles in the high catalytic activity.

Full text of DOI:10.1002/ejoc.200901323

FULL PAPER
DOI: 10.1002/ejoc.200901323
Synthesis of α-Amino Nitriles from Carbonyl Compounds, Amines, and
Trimethylsilyl Cyanide: Comparison between Catalyst-Free Conditions and the
Presence of Tin Ion-Exchanged Montmorillonite
Jiacheng Wang,[a] Yoichi Masui,[a] and Makoto Onaka*[a]
Keywords: Heterogeneous catalysis / Clays / Tin ion exchanged montmorillonite / Strecker synthesis / Catalyst-free condi-
tions
In the absence of catalysts, the three-component, one-pot
synthesis of α-amino nitriles proceeded using various alde-
hydes and ketones together with amines and trimethylsilyl
cyanide (TMSCN) in high yields under neat conditions at
room temperature. The addition order of the reagents had a
significant influence on the yields of the desired α-amino ni-
triles. In contrast, when tin ion-exchanged montmorillonite
(Sn-Mont), prepared by the ion-exchange of sodium mont-
morillonite (Na-Mont) with a tin tetrachloride solution, was
used as a catalyst, the reaction rates significantly increased
compared with those without catalysts, and the range of the
applicable carbonyl compounds was also extended: structur-
ally diverse aromatic, aliphatic and heteroatom-containing
carbonyl compounds, including sterically hindered ketones
as well as aliphatic and aromatic amines, were converted into
the desired α-amino nitriles in good to excellent yields with
short reaction times under mild conditions. Sn-Mont showed
a better catalytic activity than proton or other metal ion-ex-
changed montmorillonites, supported SnO2 catalysts and the
previously reported homogeneous or heterogeneous cata-
lysts. The recovered catalyst was reused several times with-
out loss of catalytic performance. Along with the expansion
of the interlayer space of Sn-Mont, the strong Brønsted acid
and Lewis acid nature of Sn-Mont derived from protons and
SnO2 nanoparticles present in the interlayers of Sn-Mont
likely played important and cooperative roles in the high
catalytic activity.
tion times and tedious workup procedures. Moreover, Lewis
acid catalysts such as nickel,[4] thallium,[5] copper,[6] rho-
dium,[7] niobium,[8] indium,[9] and zinc[10] salts are prone
to rapid hydrolysis and consequent deactivation by water
released during the course of the reaction and hence are not
reusable, resulting in the production of large quantities of
inorganic waste. To overcome these disadvantages, the de-
velopment of heterogeneous catalyst systems has been fo-
cused on. However, in spite of the evident advantages of
catalyst recovery and recycling, there have been only a few
heterogeneous catalysts reported, these include: montmoril-
lonite KSF,[12] supported heteropolyacids,[13] Fe3O4 nano-
particles,[18] H2SO4/silica gel,[14] Nafion SAC-13,[19] and
PVP-SO2 complex.[20] Although effective, these systems
have drawbacks such as low activity or require large
amounts of catalyst. Moreover, these catalytic systems (and
catalyst-free[21] conditions) are only efficient for the synthe-
sis of α-amino nitriles from active aldehydes, and are not
suitable for ketone substrates. Thus, an improvement in the
catalytic activity and a reduction in the amount of hetero-
geneous catalyst required, is still highly desirable.
Introduction
There is growing interest in the one-pot Strecker synthe-
sis of α-amino nitriles from carbonyl compounds, amines
and trimethylsilyl cyanide (TMSCN) [Equation (1)], be-
cause of the significant importance of α-amino nitriles in
preparing a wide variety of amino acids, amides, diamines,
and nitrogen-containing heterocycles.[1]
(1)
A broad spectrum of catalysts has been developed to
promote the Strecker reactions, such as: metal complexes,[2]
Lewis acids,[3–11] solid acids,[12–14] base catalysts,[15] and or-
ganic catalysts,[16] etc.[17] These protocols often require not
only the use of valuable reagents, but also involve long reac-
[a] Department of Chemistry, Graduate School of Arts and Sci-
ences, The University of Tokyo,
Most three-component Strecker reactions have been per-
formed with aldehydes. In contrast, successful examples
with ketones are very few and are normally carried out
either in two steps involving initial imine formation, fol-
Meguro-ku, Tokyo 153-8902, Japan
E-mail: conaka@mail.ecc.u-tokyo.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901323.
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J. Wang, Y. Masui, M. Onaka
FULL PAPER
lowed by cyanide addition,[22] or are performed in a one-
pot synthesis under high-pressure conditions.[23] Recently
Khan[24] reported Fe(Cp)2PF6 as a homogeneous catalyst
for the reaction with ketones, whereas Olah used Ga(III)
triflate and (CH3)3SiOSO2CF3 in dichloromethane.[11,25]
More recently, Jung and coworkers reported using the
Strecker reactions with ketones; in this case the reaction
was catalyzed by palladium(II) complex and required
24 hours.[26] Thus, the aim of this study was to develop a
mild, efficient, heterogeneous catalytic system for per-
forming Strecker reactions that is particularly suitable for
ketones.
Montmorillonite, a naturally occurring clay, is composed
of stacked, negatively charged two-dimensional aluminosili-
cate layers that hold exchangeable cationic species – mostly
sodium ions – in the interlayers.[27] After either multivalent
metal cations or protons are substituted for the sodium ions
in the montmorillonite, which is designated as M-Mont (M
= metal or H) in this paper,[28–32] the clay becomes acidic
and has been utilized in various acid-catalyzed organic reac-
tions.[33] We recently found that Sn-Mont, prepared by the
ion-exchange of Na-Mont with aqueous SnCl4, contained
nanoparticles of SnO2 intercalated between the silicate lay-
ers.[34] It has also been found that Sn-Mont worked as an
effective acidic catalyst for the Michael reaction,[29] the
cyanosilylation of carbonyl compounds,[35] and for the re-
duction of carbonyl compounds with hydrosilanes.[36]
Among the various metal ion-exchanged montmorillonites,
Sn-Mont was considered to be the most acidic and thus
most suitable for the silylation of alcohols.[37] Very recently,
we reported that a very small amount of Sn-Mont could be
used as a highly active catalyst for the cyanosilylation of
sterically congested ketones.[38] To further determine the
scope and limitations of Sn-Mont for acid catalysis, it is
important to examine the catalytic potential of Sn-Mont
for organic reactions involving basic substrates such as
amines that, unsurprisingly, decrease the intrinsic acidity of
the catalyst. Therefore, we extended our studies to the one-
pot, three-component Strecker synthesis of α-amino nitriles
from carbonyl compounds, amines, and TMSCN using Sn-
Mont.
Results and Discussion
One-Pot, Three-Component Synthesis of α-Amino Nitriles
without Catalyst
Before starting the one-pot reactions using Sn-Mont as
a catalyst, we first investigated the reactions of aldehydes
without acidic catalysts under neat conditions. We observed
a very interesting phenomenon that the addition order of
the reagents directly influenced the yields. The reaction of
o-tolualdehyde (1d), aniline (2a) and TMSCN in a 1:1:1.2
molar ratio was selected as a model reaction. As shown in
Figure 1, when TMSCN was added to a mixture of 1d and
2a, the reaction proceeded very rapidly (15 min) and the
yield of 2-(2-methylphenyl)-2-(phenylamino)acetonitrile
(3d) was as high as 98% (Figure 1a). This addition process,
in which TMSCN was added to a mixture of aldehyde and
amine, was found to be the optimal procedure. Interestingly,
when 2a was added to a mixture of 1d and TMSCN, the
reaction proceeded relatively slowly and only half the start-
ing reagents were transformed into 3d after 150 min (Fig-
ure 1b). The reaction concurrently gave the corresponding
cyanohydrin trimethylsilyl ether (adduct of TMSCN to 1d)
1
in about 8% yield based on H NMR analysis, along with
a trace amount of imine from the condensation of 1d and
2a.
In the present study, we systematically investigated the
one-pot synthesis of α-amino nitriles using carbonyl com-
pounds (aldehydes and ketones), aromatic and aliphatic
amines, and TMSCN, both in the presence of Sn-Mont and
under catalyst-free conditions. In the absence of catalyst, a
broad range of aldehydes, as well as a limited number of
Figure 1. Effects of the addition order of the reagents on the yield
of the reaction of o-tolualdehyde (1d), aniline (2a), and TMSCN
in the absence of catalyst at room temperature. (a) An optimal pro-
cedure: TMSCN was added to a mixture of 1d and 2a. (b) A sub-
optimal procedure: 2a was added to a mixture of 1d and TMSCN.
The optimal and sub-optimal procedures for the one-pot
ketones, were successfully used. The reaction rates in the synthesis of α-amino nitriles were compared using a series
presence of Sn-Mont increased compared with those with- of aldehydes and amines under catalyst-free conditions at
out the catalyst. Especially, it is striking that various types room temperature; the results are shown in Table 1. Accord-
of ketones readily reacted with amines and TMSCN to give ing to the optimal addition, all the reactions rapidly pro-
the α-amino nitriles. In addition, it was revealed that Sn- ceeded, and α-amino nitriles were isolated in 89 to 99%
Mont showed a better catalytic performance when com- yields (odd entry numbers) except for entry 13 in which ra-
pared with the previously reported homogeneous and pid condensation between tolualdehyde (1c) and p-bromo-
heterogeneous catalysts and, furthermore, Sn-Mont could aniline (2c) produced a solid imine, followed by the rela-
be reused without loss of catalytic performance and simpli- tively slow addition of TMSCN to the imine. Aromatic,
fied the workup procedure (no tedious chromatographic pu- benzylic and aliphatic amines were all suitable substrates
rification was needed in most cases).
for the reaction and gave good yields. Not only did the reac-
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α-Amino Nitriles from Carbonyls, Amines, and Trimethylsilyl Cyanide
tions proceed smoothly to afforded good conversions, but (entry 4). Notably, for the reactions with n-butylamine (2d),
the product isolation did not require any tedious chromato- no corresponding α-amino nitriles were produced and the
graphic purification. Moreover, by using the optimal ad- cyanohydrin trimethylsilyl ethers were formed exclusively
dition procedure, no cyanohydrin trimethylsilyl ether by- (entries 16 and 18). For the one-pot reactions with benzyla-
products were detected.
mine (2e), α-amino nitriles were produced in low yields, and
the remaining aldehydes were completely transformed into
the corresponding cyanohydrin trimethylsilyl ethers (entries
20 and 22).
Table 1. Comparison of the addition procedures for the one-pot
synthesis of α-amino nitriles by the Strecker reactions of aldehydes,
amines, and TMSCN in the absence of catalyst under neat condi-
tions at room temperature.[a]
For such simple three-component, one-pot reactions in
the absence of catalysts, we wanted to address the question
of why the order of addition of the starting reagents had
such a significant impact on the yields of the target α-
amino nitriles shown in Figure 1 and Table 1. Scheme 1
shows the plausible reaction pathways that can be followed
when adopting different orders of reagent addition. Follow-
ing the optimal procedure, as soon as the aldehyde and
amine are mixed, prompt condensation reactions of the al-
dehyde with the amine takes place to produce the corre-
sponding imines, releasing H2O.[39] TMSCN addition to the
imines can then occur, which is catalyzed by a trace amount
of hydrogen cyanide included in the TMSCN or derived
from the hydrolysis of TMSCN and water,[40] followed by
hydrolysis with water to give the α-amino nitriles
(Scheme 1a).[41] However, when amines, and especially ani-
lines, are added to a mixture of aldehyde and TMSCN in
the sub-optimal procedure, weakly basic anilines could co-
ordinate to TMSCN to form hypervalent silicate intermedi-
ates,[42,43] giving rise to significantly reduced levels of con-
densation with the aldehyde and leading to reduced yields
of α-amino nitriles (Scheme 1b). Instead, the hypervalent
silicate intermediates could react with aldehydes to give
cyanohydrin trimethylsilyl ethers, though in poor yields.[42]
When primary aliphatic amines, which are more basic than
anilines, are used, they may actually promote the nucleo-
philic addition of TMSCN to aldehydes through the for-
mation of reactive hypervalent silicate intermediates
(Scheme 1c) to predominantly give cyanohydrin trimethyl-
silyl ethers; this is similar to the catalytic use of tertiary or
secondary amines such as Et3N, or iPr2NH.[42]
[a] Aldehydes (1 mmol), amines (1 mmol), TMSCN (1.2 mmol),
neat, room temperature. [b] A: optimal procedure; B: sub-optimal
procedure (see the Experimental Section). [c] Isolated yields for the
1
optimal procedure and H NMR-based yields for the sub-optimal
procedure. [d] The remaining aldehyde completely reacted with
TMSCN to give the corresponding cyanohydrin trimethylsilyl
ethers.
Following the sub-optimal procedure, however, the yields
of the corresponding α-amino nitriles significantly de-
creased (Table 1, even entry numbers). For example, the
one-pot reactions of benzaldehyde (1a) or its methyl-substi-
tuted analogues, aniline or its halogenated equivalent, and
TMSCN proceeded very slowly (Table 1) and the yields
were as low as 4–6%, with the exception that 4-methoxy-
Scheme 1. Plausible reaction pathways for the three-component
Strecker reactions in the absence of catalysts: (a) The optimal ad-
dition order; (b) the sub-optimal addition of anilines, and (c) the
benzaldehyde (1b), which gave a slightly better yield of 28% sub-optimal addition of aliphatic amines.
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One-Pot Strecker Synthesis of α-Amino Nitriles with Sn-
Mont Catalyst
Table 2. One-pot synthesis of α-amino nitriles by the Strecker reac-
tion of aldehydes, amines, and TMSCN in the presence of Sn-Mont
under neat conditions.[a]
The reaction of benzaldehyde (1a) and aniline (2a) with
TMSCN in the presence of Sn-Mont was selected as a
model. First, the reaction was performed in a range of sol-
vents, as summarized in Figure 2. Among the solvents
tested, dimethylformamide (DMF), toluene, and dichloro-
methane gave the product in poor yields of only 10–42%,
whereas moderate yields were obtained when the reaction
was performed in acetonitrile or even in water. More inter-
estingly, when the reaction was performed with no solvent,
the liquid substrate mixture suddenly solidified within
6 min, indicating the rapid formation of 2-phenyl-2-(phen-
ylamino)acetonitrile (3a) in an extremely high yield of 96%
(Table 2, entry 1). This indicated that the use of a solvent
significantly retarded the Strecker reaction with Sn-Mont.
Compared with the same reaction under catalyst-free condi-
tions (Table 1, entry 1), the reaction with Sn-Mont was
complete in less than half the time. Thus, neat conditions
and a small amount of Sn-Mont (10 mg; Sn: 1.9 mol-%) are
optimal for the synthesis of α-amino nitriles.[44]
[a] Aldehydes (1 mmol), amines (1 mmol), TMSCN (1.2 mmol), Sn-
Mont (10 mg; Sn: 1.9 mol-%), neat, room temperature. [b] Isolated
yields; the yields in brackets were obtained in the absence of Sn-
Mont.
The Sn-Mont-catalyzed system was also applicable to acid-
sensitive heterocyclic aldehydes such as furfuraldehyde (1g),
thiophenaldehyde (1h), and 4-pyridinecarboxaldehyde (1i)
(entries 14–16). The results in Table 2 thus show that the
present protocol has wide applicability for a range of alde-
hydes and amines.
Figure 2. Solvent effects on the Strecker reactions catalyzed by Sn-
Mont: benzaldehyde (1a; 1 mmol), aniline (2a; 1 mmol), TMSCN
(1.2 mmol), Sn-Mont (10 mg; Sn: 1.9 mol-%), room temperature,
30 min for the reactions in various solvents, and 6 min under neat
conditions.
Encouraged by these results, we continued to investigate
Conventional heterogeneous and homogeneous catalysts
the Strecker reactions with a wider variety of aldehydes and such as metal salts, supported acids, montmorillonite KSF,
amines under neat conditions at room temperature. As and iodine are all effective in the one-pot reaction of 1a, 2a
shown in Table 2, a variety of aldehydes were condensed at and TMSCN. However, these systems normally require
room temperature with amines and TMSCN in a one-pot large amounts of catalysts, long reaction times, and/or high
operation in the presence of a catalytic amount of Sn-Mont reaction temperatures to obtain 3a (see Table S1 in the Sup-
(10 mg; Sn: 1.9 mol-%) to afford the corresponding α- porting Information). In contrast, the Sn-Mont-catalyzed
amino nitriles in excellent yields. All the reactions pro- Strecker reactions smoothly proceeded at room temperature
ceeded faster than those without catalysts to give the ex- with a very small amount of Sn-Mont (10 mg; Sn: 1.9 mol-
pected products within very short reaction times (2–6 min). %) in only 6 min. The turnover frequency (TOF) of 505 h–1
For comparison, the reactions reported in entries 1, 5, 7 was clearly higher than those of the previously reported cat-
and 8, which were conducted without Sn-Mont for 6 min, alysts (1.1–376 h–1) (see Table S1 in the Supporting Infor-
gave yields (in brackets) that were far lower than those ob- mation). At the same time, the reaction rate (960 mmolh–1
tained from reactions catalyzed by Sn-Mont. The present gcat–1), based on the weight of Sn-Mont, was also far higher
method works very effectively regardless of the electronic than those (0.2–450 mmolh–1 gcat–1) for the previously re-
nature of the substituents on the benzene ring. Reactions ported catalysts (See Table S1 in the Supporting Infor-
with aliphatic amines also gave good results (entries 8–13). mation).
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α-Amino Nitriles from Carbonyls, Amines, and Trimethylsilyl Cyanide
Inspired by the results obtained with aldehydes, we then acid catalysis were also observed for the silylation of
investigated whether these simple protocols were also valid alcohols[37] and the cyanosilylation of ketones[38] using vari-
for the Strecker reaction with ketones. To reveal any differ- ous heterogeneous catalysts.
ences in the catalytic activity among the heterogeneous cat-
To demonstrate the practical applicability of Sn-Mont, a
alysts, the one-pot reaction of propiophenone (4a), 2a, and series of Strecker reactions was performed with different
TMSCN was used as a model, and the reaction was con- ketones at room temperature. For comparison, the reactions
ducted under neat conditions as shown in Table 3. No for- were also conducted without catalyst; the results are listed
mation of 2-phenyl-2-(phenylamino)butyronitrile (5a) was
observed even when the reaction time was extended to 15 h
in the absence of a catalyst (entry 1), indicating that ketones
Table 4. One-pot synthesis of α-amino nitriles from various
ketones, amines, and TMSCN under neat conditions, either cata-
lyzed by Sn-Mont or performed without catalyst.[a]
were much less reactive than aldehydes under these condi-
tions. Sn-Mont (10 mg; Sn: 1.9 mol-%), however, gave 5a in
an 84% isolated yield within three hours (entry 2). The
TOF reached 67.4 h–1, which is higher than that obtained
with Ga(OTf)3 (3.92 h–1)[25] and comparable to that using
Fe(Cp)2PF6 (57 h–1)[24] as homogeneous catalysts.
Table 3. Strecker reaction of propiophenone (4a), 2a, and TMSCN
with various catalysts under neat conditions.[a]
Entry Catalyst
Time (h)
Yield (%)[b]
1
2
3
4
No catalyst
Sn-Mont
Na-Mont
Sn(OH)4
SnO2
Sn-MCM-41
Al-MCM-41
SnO2/silica
SnO2/MCM-41
SnO2/SiO2–Al2O3
Al-Mont
15
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
0
84
0
0
0
0
0
7.2
22
37
62
50
51
39
26
12
5
6[c]
7[d]
8
9
10
11
12
13
14
15
16
H-Mont
K-10
Ti-Mont
Fe-Mont
Cu-Mont
[a] 4a (1 mmol), 2a (1 mmol), TMSCN (1.2 mmol), catalyst
(10 mg), neat, room temperature. [b] Isolated yields. [c] Si/Sn = 20.
[d] Si/Al = 20.
In contrast, when the reaction was performed with pris-
tine Na-Mont, Sn(OH)4 prepared from SnCl4 with aqueous
NH3, or crystalline SnO2, almost no reaction occurred
(Table 3, entries 3–5). The Sn- and Al-doped MCM-41 ma-
terials with high specific surface areas and ordered meso-
pores (entries 6 and 7), which have been applied in a diverse
range of reactions,[45] also had no catalytic activity. Use of
various supported SnO2 catalysts, such as SnO2/SiO2, SnO2/
MCM-41 and SnO2/SiO2–Al2O3, also resulted in very poor
yields (7.2–37%, entries 8–10). Al-Mont (62%) and H-
Mont (50%), as well as commercially available montmoril-
lonite K-10[46] (51%), were effective for this reaction and
gave the expected product in moderate yields (entries 11–
13). The catalytic activities of Ti-Mont[47,48] (39%), Fe-
Mont[31] (26%) and Cu-Mont[32] (12%) under the same
[a] Ketones (1 mmol), amines (1 mmol), TMSCN (1.2 mmol), neat,
room temperature. [b] A: use of Sn-Mont (10 mg; Sn: 1.9 mol-%),
B: without catalyst. [c] Isolated yield. [d] Ketone (1 mmol), 2a
(1.5 equiv.), TMSCN (3 equiv.), 60 °C. [e] Sn-Mont (20 mg; Sn:
3.8 mol-%). [f] The main by-products were cyanohydrin trimethyl-
silyl ethers. [g] Ketone (1 mmol), 2a (2 equiv.), TMSCN (4 equiv.),
conditions were low (entries 14–16). Similar trends in the 80 °C.
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in Table 4. Interestingly, even in the absence of catalyst, on the relative rates of the two pathways; the addition of
several reactions with the cyclic ketones 4d and 4e, aceto- amines to ketones (hemiaminal/imine formation) or
phenone (4f), 4-methoxypropiophenone (4j) (entries 6, 8, 10 TMSCN addition to ketones (cyanohydrin formation).[25]
and 20), and the halogen-substituted anilines (entries 24 With aromatic amines such as aniline, in the presence of
and 26) proceeded smoothly, although they required rela- Sn-Mont, the imine formation is far faster than that of cya-
tively long reaction times of 15 h to reach completion. In nohydrin, preferentially producing α-amino nitrile. How-
other cases, poor yields (9–30%) were observed for the reac- ever, with aliphatic amines and aromatic ketones, the more
tion with linear aliphatic ketones (entries 2 and 4), 4-meth- basic aliphatic amines act as homogeneous base catalysts to
ylpropiophenone (4k; entry 22), and chalcone (4l; entry 28) promote the nucleophilic addition of TMSCN to ketones
under catalyst-free conditions. Moreover, bromoacetophe- to provide the cyanohydrin derivatives,[42] the formation
nones 4h and 4i (entries 14 and 16), 4a (entry 18), and the rate of which is much higher than that of the corresponding
more sterically bulky ketones such as 4m, 4n, and 4o, gave imine from ketones and aliphatic amines catalyzed by Sn-
no products in the absence of catalyst even after 15 h (en- Mont.
tries 30, 32, and 34).
In the Sn-Mont-catalyzed Strecker reactions, the solid
In the presence of Sn-Mont, the reaction outcomes were catalysts were easily recovered from the reaction mixture by
greatly improved compared to those without catalysts. Vari- filtration and could be reused at least four times without
ous aliphatic and aromatic ketones, regardless of differences any obvious loss of catalytic activity in the reaction with 4f,
in the electronic characters and steric bulk, smoothly re- 2a and TMSCN (Figure 3). In addition, Sn-Mont can be
acted with aniline and TMSCN to give the corresponding stored in a glass vial under ambient conditions for six
products in fair to excellent yields after short reaction times months without any decrease in catalytic activity.
(0.2–4 h). For instance, linear aliphatic ketones [5-nonanone
(4b) and 3,3-dimethylbutan-2-one (4c)] were selectively con-
verted into the corresponding α-amino nitriles with good
yields of 84% and 83% in 3 h and 1 h, respectively (Table 4,
entries 1 and 3). Cyclopentanone (4d) and cyclohexanone
(4e) both rapidly underwent the condensation within 0.2 h
in almost quantitative yields (entries 5 and 7). The reaction
rates were far higher than those observed in reactions per-
formed without catalyst. The introduction of a methoxy
group to the para-position of 4f did not significantly change
the reaction rate (entries 9 and 11), whereas a bromo-sub-
stituent at either the meta or para position resulted in the
poorer yields of 63 and 66% yields of the α-amino nitriles,
Figure 3. Reusability of Sn-Mont for the reaction with 4f, 2a, and
respectively, along with concurrent ketimine formation (en-
tries 13 and 15). The Strecker reactions with halogenated
anilines catalyzed by Sn-Mont were also accelerated when
compared with those in the absence of catalyst (entries 23–
26). Chalcone (4l) was also suitable for the reaction, and
afforded the product in 78% yield (entry 27). Sterically hin-
dered ketones, such as benzophenone (4m), 9-fluorenone
TMSCN.
Reaction Mechanism for the One-Pot Strecker Reactions in
the Presence of Sn-Mont
One of the important characteristics of montmorillonites
(4n) and 2-benzoylnaphthalene (4o), also reacted with 2a is the ability to intercalate various organic molecules into
and TMSCN to give the corresponding products in good the interlayer spaces, resulting in an increase in the inter-
yields, although the reactions proceeded relatively slowly layer distance (see the Supporting Information). Indeed, the
(entries 29, 31, and 33). In entries 27, 29, 31, and 33, the basal spacing of Sn-Mont expanded from 1.30 to 2.51 nm
main side products were the cyanohydrin trimethylsilyl when Sn-Mont was soaked with acetophenone (4f) for
ethers, i.e. the adducts of TMSCN to the ketones. Except 10 min, as confirmed by XRD analysis (Figures 4a and b).
for these cases, no cyanohydrins were produced in any of The total expansion was about 1.21 nm, which confirms the
the other reactions reported in Table 2 and Table 4. It can intercalation of 4f into the layered Sn-Mont. The possibility
be concluded that Sn-Mont provides the best catalytic ac- that Sn-Mont-intercalated 4f could react with 2a and
tivity for the one-pot Strecker reactions and that this cata- TMSCN was supported by the observation that the mixture
lyst can be applied in the reaction of a broad range of alde- completely solidified after stirring for 20 min, which implies
hydes, ketones and aromatic amines.
the formation of 5f. Also, the basal spacing of Sn-Mont was
In contrast to the reactions with aromatic amines, the found to decrease to 2.04 nm compared with that of the 4f-
products of reactions of ketones with TMSCN and ali- intercalated Sn-Mont (Figure 4c). 4f was completely con-
phatic amines, such as n-butylamine (2d), benzylamine (2e) sumed and not included in the final product. Moreover, me-
and piperidine, were exclusively cyanohydrin trimethylsilyl chanical mixing of the product 5f and Sn-Mont by grinding
ethers (TMSCN addition products to ketones) instead of α- with a mortar did not increase the basal spacing of Sn-
amino nitriles. The direction of the overall reaction depends Mont, as shown in Figure 4d. After the reaction, the basal
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α-Amino Nitriles from Carbonyls, Amines, and Trimethylsilyl Cyanide
spacing of the recovered Sn-Mont readily reverted to that
of the original Sn-Mont by washing with dichloromethane,
which removed the products, indicating that the layered
structure of Sn-Mont was maintained during the reaction
(Figure 4f). Together, these results support the proposal
that 4f intercalates into the interlayers of Sn-Mont during
the reaction with amine and TMSCN. The finding also in-
dicates that the catalytically active sites of Sn-Mont exist in
the interlayers. Similar observations concerning expanded
basal spacing of Sn-Mont upon one-pot Strecker reactions
were also observed with other ketones (see Figure S3 in the
Supporting Information).
Figure 5. FTIR spectra of (a) Sn-Mont and (b) Sn-Mont after pyr-
idine adsorption.
and enable the iminium intermediate to be generated by
attack of an amine. The intermediate then undergoes attack
by TMSCN at the carbon–nitrogen double bond, which is
followed by hydrolysis with water to afford the α-amino ni-
trile (Scheme 2).
Scheme 2. Proposed mechanism for the one-pot synthesis of α-
amino nitriles in the presence of Sn-Mont.
Figure 4. XRD patterns of (a) Sn-Mont, (b) Sn-Mont intercalating
4f, (c) Sn-Mont after one-pot reaction of 4f, 2a, and TMSCN, (d)
a mechanically mixed sample of Sn-Mont and α-amino nitrile 5f,
(e) α-amino nitrile 5f, and (f) the recovered Sn-Mont.
Conclusions
The presence of the Brønsted and Lewis sites in Sn-Mont
was confirmed by FTIR spectroscopy after pyridine ad-
On the basis of the observations and results described
sorption. As shown in Figure 5a, fresh Sn-Mont showed above, α-amino nitriles can be easily obtained in excellent
no absorption peaks between 1400 and 1600 cm–1. Upon yields by simply mixing aldehydes as well as some ketones,
contact with pyridine (Figure 5b), Sn-Mont exhibited a amines, and TMSCN without acidic catalysts under neat
band at 1548 cm–1, which is clearly due to the pyridinium conditions. The order of addition of the reagents, however,
ions, showing that Sn-Mont has Brønsted acid sites that are strongly affects the one-pot condensation.
strong enough to protonate pyridine. Treatment of Na-
The addition of Sn-Mont results not only in significant
Mont with pyridine did not gave rise to any adsorption increases in reaction rates, especially in the case of ketones,
band at 1548 cm–1.[49] Besides the Brønsted acidity, the for- but also extends the applicability of the reaction to a wide
mation of a Lewis acid-type adduct with pyridine was ob- range of substrates, including several sterically hindered
served at 1455 cm–1.[50,51] A stronger adsorption band at ketones. Compared with the previously reported protocols,
1490 cm–1 may result from the interaction of both Lewis the Sn-Mont catalyst system has several merits, such as: (1)
and Brønsted acid sites on Sn-Mont with pyridine.[50]
operational simplicity, (2) short reaction times, and (3) the
Considering the XRD and IR findings described above, very small amount of catalyst required. Furthermore, Sn-
the efficient catalysis by Sn-Mont of the one-pot Strecker Mont is easy to prepare, environmentally sound, nontoxic,
reactions can be related to the facile and reversible expan- noncorrosive, water-tolerant, and reusable. Our method
sion of the interlayer spaces and to the strong Brønsted and avoids not only the use of easily hydrolyzed, expensive, or
Lewis acid sites in the montmorillonite interlayers. The toxic Lewis acids, but also eliminates the need for tedious
strong acid sites interact and activate carbonyl compounds, chromatographic separation and consequent loss of prod-
Eur. J. Org. Chem. 2010, 1763–1771
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1769

J. Wang, Y. Masui, M. Onaka
FULL PAPER
the water was completely evaporated to afford a white solid, which
was then dried under vacuum for 6 h to give SnO2/MCM-41 (Sn,
22.9 wt.-%). The same treatment using SiO2 (Q-3) and SiO2–Al2O3
(JRC-SAL-2) afforded SnO2/SiO2 (Sn, 22.9 wt.-%) and SnO2/SiO2–
Al2O3 (Sn, 22.9 wt.-%), respectively.
Preparation of Other Control Catalysts: Fe-Mont,[30,36,37] Sn-
MCM-41 (Si/Sn = 20)[38] and Al-MCM-41 (Si/Al = 20)[38] were
prepared according to our previous procedures. H-Mont,[52] Al-
Mont,[52] Ti-Mont,[47] and Cu-Mont[32] were synthesized according
to the ion-exchange methods reported by Prof. Kaneda.
ucts during the purification. In most cases, the products are
obtained in excellent yields with high purity.
Experimental Section
1
Instruments: H and 13C NMR spectra were recorded at 500 MHz
and 126 MHz, respectively, with a JEOL α500 NMR spectrometer;
samples were dissolved in CDCl3. The 1H NMR chemical shifts
were determined relative to the internal tetramethylsilane (δ =
0.0 ppm). The 13C NMR chemical shifts were determined relative
to the internal tetramethylsilane (δ = 0.0 ppm) or to the 13C NMR
signal of CDCl3 (δ = 77.0 ppm). The coupling constants (J) are
given in Hz. Software used to processes the NMR data was from
MestRenova (Mestrelab Research S. L.). X-ray powder diffraction
patterns were collected with a Rigaku Multiflex instrument using
Cu-Kα (λ = 0.15406 nm) radiation at 40 kV and 40 mA. The BET
surface area, pore diameter, and pore volume of the materials were
determined by a multi-point N2 adsorption–desorption method at
liquid N2 temperature (77 K) with a Belsorp-mini instrument (BEL
JAPAN, Inc). The IR spectra were measured with a JASCO IR-
630 spectrophotometer (NaCl, film). High-resolution mass spectra
were obtained with a JEOL GCmate (EI) mass spectrometer. Melt-
ing points were measured in open capillaries with an electrothermal
model IA 9100 digital melting point apparatus. Thin-layer
chromatography (TLC) was performed using commercially pre-
pared 60 mesh silica gel; plates were visualized under short-wave-
length UV light (254 nm).
IR Measurements of Sn-Mont with Pyridine Adsorption: The IR
spectra of the pyridine-adsorbed Sn-Mont were obtained at r.t. in
the transmission mode with a JASCO IR-630 spectrophotometer.
Sn-Mont (0.1 g) was treated with pyridine (1 mmol) for 1 h. The
excess pyridine was removed by heating the sample at 150 °C in
vacuo for 5 h. The pyridine-adsorbing Sn-Mont was mixed with
KBr (3 mg Sn-Mont and 100 mg KBr) and then pressed into a disc
(10 mm diameter). The IR spectrum of Sn-Mont after heating in
vacuo at 150 °C for 5 h was also obtained using a KBr pellet.
One-Pot Synthesis of α-Amino Nitriles under Catalyst-Free Condi-
tions: (a) Optimal Procedure: 1a (1 mmol) and 2a (1 mmol) were
added to a flask and the mixture was stirred at r.t. for 5 min.
TMSCN (1.2 mmol) was then added to the mixture, which was
vigorously stirred. After 15 min, the stirring bar was removed and
the mixture was washed with dichloromethane. The combined solu-
tion was evaporated under reduced pressure to give the crude prod-
ucts. Further purification was carried out by rinsing the products
with excess hexane, followed by evaporation of the residual hex-
ane[25] to afford 2-phenyl-2-(phenylamino)acetonitrile 3a (206 mg,
99%) as a white solid.
Reagents: Sodium montmorillonite (Na-Mont) was supplied by
Kunimine Industry Co., Ltd., as Kunipia F (Na, 2.69; Al, 11.8; Fe,
1.46; Mg, 1.97%. Cation-exchange capacity = 1.19 mequiv g–1).
Na-Y (Si/Al = 3.5), SiO2 (CARiACT Q-3) and SiO2–Al2O3 (JRC-
SAL-2, Al2O3 = 13.75%) as catalyst supports were supplied by
Tosoh Corporation, Fuji Silysia Chemical, Ltd., and the Catalysis
Society of Japan, respectively. All organic chemicals were pur-
chased from commercial sources [Toyko Chemical Industry or
Kanto Chemical (reagent grade)] and used without purification,
except for benzaldehyde, which was purified by distillation. Silica
gel 60 (70–230 mesh, ASTM) was used for column chromatography
and was obtained from Merck Japan Limited.
(b) Alternative Procedure: 2a (1 mmol) and TMSCN (1.2 mmol)
were added to a flask and the mixture was stirred at r.t. for 5 min.
1a (1 mmol) was then added to the mixture, which was vigorously
stirred for 15 min. The yield (4%) was determined by 1H NMR
spectroscopy.
Typical Procedure for the One-Pot Synthesis of α-Amino Nitriles
Catalyzed by Sn-Mont: 4a (0.103 mL, 1 mmol) and 2a (0.091 mL,
1 mmol) were added to a 30-mL flask containing Sn-Mont (10 mg;
Sn: 1.9 mol-%) that had been heated in vacuo at 120 °C for 1 h.
The mixture was vigorously stirred and TMSCN (0.160 mL,
1.2 mmol) was added to the mixture at 25 °C in a thermocontrolled
water bath. After completion of the reaction (monitored by TLC),
the catalyst was removed by filtration through a Celite plug, which
was washed with dichloromethane, and the combined solution was
evaporated under reduced pressure to obtain the crude product.
Further purification was carried out by rinsing the products with
excess hexane,[25] followed by evaporation of the hexane to afford 2-
phenyl-2-(phenylamino)butyronitrile (5a; 199 mg, 84%) as a white
solid. Products in entries 1 and 30 of Table 4 were purified by silica
chromatography (hexane/ethyl acetate). The products were iden-
tified by comparison with reported IR, MS, melting points, and
1H and 13C NMR spectroscopic data as shown in the Supporting
Information.
Preparation of Sn-Mont: Sn-Mont was prepared according to our
previously reported protocol;[36] Na-Mont (8 g) was ion-exchanged
with aq. SnCl4·5H2O (0.3 , 80 mL) at r.t. for 2 h, and the exchange
process was repeated. The collected clay was then washed with H2O
(2 ϫ 80 mL), with a mixture of H2O (40 mL) and MeOH (40 mL)
6 times, and with absolute methanol (80 mL). Finally Sn-Mont was
dried in vacuo (0.5 Torr) at r.t. for 12 h, followed by grinding in a
mortar with a pestle. The powder was passed through a 60-mesh
screen and stored in a general glass bottle under ambient condi-
tions. XRD analysis of Sn-Mont showed that the layered structure
was maintained after the ion-exchange, with a basal spacing of
0.34 nm (see Figure S1 in the Supporting Information). According
to the nitrogen sorption data, the specific surface area significantly
increased from 12 m2 g–1 for Na-Mont to 280 m2 g–1 for Sn-Mont
(see Figure S2 in the Supporting Information). Elemental analysis
of Sn-Mont by inductively coupled plasma (ICP) showed the de-
gree of exchange for the Na cations in Sn-Mont was 97.1%. The
Sn content of Sn-Mont is 22.9 wt.-%.
Supporting Information (see footnote on the first page of this arti-
cle): Additional experimental procedures, spectroscopic data of all
1
compounds and copies of H NMR and 13C NMR spectra.
Acknowledgments
Preparation of SnO2/MCM-41, SnO2/SiO2 and SnO2/SiO2–Al2O3:
These composite catalysts were prepared by the direct impregnation
method. MCM-41 (1 g) was added to aq. SnCl4·5H2O
We are grateful for a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and Technology,
(8.2ϫ10–2 , 30 mL). The obtained slurry was stirred at r.t. until Japan.
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Received: November 18, 2009
Published Online: February 3, 2010
Eur. J. Org. Chem. 2010, 1763–1771
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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