Sulfamic acid catalyzed direct condensation of aldehydes, amines, and TMSCN to α-aminonitriles at ambient temperature

Article abstract of DOI:10.1055/s-2007-970752

A simple and efficient method has been developed for the synthesis of α-aminonitriles by a one-pot three-component condensation of aldehydes, amines, and trimethylsilyl cyanide in the presence of a catalytic amount of sulfamic acid at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970752

LETTER
803
Sulfamic Acid Catalyzed Direct Condensation of Aldehydes, Amines, and
TMSCN to a-Aminonitriles at Ambient Temperature
R
oom-Tempera
h
ture
C
onden
e
sation to Fo
n
rm
a
-Amino
jnitrilesiang Li,* Yingjie Sun, Xinghua Ren, Ping Wei, Yuhu Shi, Pingkai Ouyang
College of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 210009, P. R. of China
Fax +86(25)83479464; E-mail: zjli@njut.edu.cn
Received 8 December 2006
were decomposed9a,g or deactivated9e in the preparations
or the subsequent work-up steps, and heavy metals9c,e as
toxic waste will be an impressive negative factor especial-
ly for larger-scale preparation. Therefore, an efficient
preparation of a-aminonitriles by direct three-component
condensation catalyzed by inexpensive reagent under
mild conditions is needed.
Abstract: A simple and efficient method has been developed for
the synthesis of a-aminonitriles by a one-pot three-component
condensation of aldehydes, amines, and trimethylsilyl cyanide in
the presence of a catalytic amount of sulfamic acid at room temper-
ature.
Key words: aldehyde, amine, a-aminonitrile, sulfamic acid, three-
component reaction
NHR2
Lewis acid
R1CHO
R2NH2
+
Me3SiOH
+
+
Me3SiCN
Since Strecker’s original work in the three-component
reaction between aldehydes, ammonia and hydrocyanic
R1
CN
acid in aqueous solution, a-aminonitriles have occupied Scheme 1
an important position in organic chemistry.1 There is con-
tinuous interest in this class of compounds because they
In continuation of our work in the three-component con-
densations to afford a-amidosulfones16 and condensations
to nitrogen-containing heterocycles17 mediated by sulf-
amic acid, we have envisioned broader applications of this
solid acid in other condensations. NH2SO3H as a powerful
solid catalyst has been used in many organic prepara-
tions.18 It has a unique structure19 and prominent proper-
ties, such as, it has outstanding physical stability, is
insoluble in common organic solvents, is inexpensive, and
readily available.20 As part of our ongoing interest in
using economical reagents for organic transformations,
we had the opportunity to look into the synthesis of a-ami-
nonitriles via simple three-component reactions using
NH2SO3H as solid catalyst at ambient temperature.
are useful intermediates for the synthesis of amino acids2
and nitrogen-containing heterocycles.3 In addition, a-ami-
nonitriles have attracted much interest for their role in
interstellar chemistry and prebiotic evolution of a-amino
acids.4 The Strecker reaction in a broad sense has been
considerably extended by employment of various cata-
lysts in different solvents and sources of amino and cyano
groups.5 Among cyanide ion equivalents, trimethylsilyl
cyanide (TMSCN) is more efficient in preparations and
safer in handling.6 The synthetic routes to a-aminonitriles
using TMSCN are divided into two categories: the
reaction of imines with TMSCN,7 and the reaction of
aldehydes, amines, and TMSCN in one pot.8 In these
Strecker-type reactions, Lewis acids,9 Lewis bases,10
Lewis acid–Lewis base bifunctional catalysts,11 and most
recently, nucleophilic N-heterocyclic carbenes12 have
been employed to promote the transformations, although
uncatalyzed Strecker reactions were claimed to be viable
occasionally.13 Uncatalyzed Strecker-type reactions under
high pressure14 and in ionic liquids15 have also been re-
ported. Many types of Lewis acids are effective in the
direct three-component condensations (Scheme 1) under
various reaction conditions by simply mixing aldehydes,
amines, TMSCN and the catalyst, in which (bromodime-
thyl)sulfonium bromide,9a molecular iodine,9b lanthanoid
triflates,9c montmorillonite clay,9d indium chloride,9e
lithium perchlorate,9f and zinc iodide9g were useful ones.
However, some of these preparations require relatively
expensive reagents,9c harsh reaction conditions,9e and
sometimes tedious work-up.9g Some of the Lewis acids
Initially, the catalytic activity of sulfamic acid and the in-
fluence of solvents on the condensation of benzaldehyde,
aniline, and TMSCN at room temperature as a model
reaction were explored (Table 1). In several common
solvents, benzaldehyde (1 equiv), aniline (1 equiv),
TMSCN (1.25 equiv) and sulfamic acid (15 mol%) were
simply mixed and stirred for four hours at room tempera-
ture. Polar solvents are appropriate for this type of reac-
tion (entries 2 and 4) and acetonitrile gave excellent yield.
To justify the effectiveness of sulfamic acid as promoter
in this condensation, the loading of the catalyst was ad-
justed from the original 15 mol% to 10 mol% and 5 mol%,
the yields decreased slightly (entries 6 and 7). Blank
control without catalyst (entry 8) showed no product
formed under the same reaction conditions. Another
purpose of the blank test was to confirm the reported
results,13a in which an array of a-aminonitriles were suc-
cessfully prepared in MeCN and other solvents, and it
is emphasized that no catalyst is necessary. We have
also observed that if the preparation under conditions
SYNLETT 2007, No. 5, pp 0803–0805
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970752; Art ID: W25106ST
© Georg Thieme Verlag Stuttgart · New York

804
Z. Li et al.
LETTER
comparable to those of entry 8 (Table 1) was carried out bond, and the a-aminonitrile was formed by the two-step
in acetonitrile but the solvent was not pretreated by process.
drying, or the reaction vessel was not secured from air
moisture carefully and the reaction lasted for quite a long
time, varied amount of a-aminonitrile was formed. Water,
In summary, we have developed a convenient and effi-
cient one-pot synthesis of a-aminonitriles by a three-com-
ponent condensation of aldehydes, amines and
formed in situ or as trace residue in solvent, may exert
trimethylsilyl cyanide in the presence of solid sulfamic
pivotal influence on this ‘uncatalyzed’ reaction.13b Indeed,
acid as a catalyst. The simple experimental procedure,
a small amount of water was added in a similar prepara-
mild reaction conditions, inexpensive catalyst, short reac-
tion times and high yields are the advantages of the
tion to facilitate the condensations.13c
present procedure.
Table 1 Sulfamic Acid Catalyzed Direct Reaction of Benzalde-
hyde, Aniline, and TMSCN to a-Aminonitrile in Different Solvents at
Table 2 Sulfamic Acid Catalyzed Direct Reactions of Aldehydes,
Room Temperaturea
Amines, and TMSCN to a-Aminonitrile at Room Temperaturea
NH2SO3H
NH2SO3H
NHPh
CN
(0–15 mol%)
NHR2
(10 mol%)
PhCHO
+
PhNH2
+
Me3SiCN
R1CHO + R2NH2 + Me3SiCN
r.t., solvent
Ph
(2 mmol) (2 mmol)
(2.5 mmol)
R1
CN
r.t., MeCN
1
2
3a–v
Entry
NH2SO3H
(mol%)
Solvent
Time
(h)
Yield
(%)b
Entry R1
R2 or 2
Compd 3c Time Yield
(h)
(%)b
90
91
94
90
89
92
84
80
89
87
85
86
74
88
82
87
89
96
92
91
82
83
1
2
3
4
5
6
7
8
15
15
15
15
15
10
5
CH2Cl2
MeCN
THF
4
19
90
42
76
55
89
81
–
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a9a
3b9d
3c13a
3d9d
3e9a
4
4
2-MeC6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
4-ClC6H4
Ph
4
4
3
4
MeOH
Dioxane
MeCN
MeCN
MeCN
4
4
4
4
5
4
4
6
3f13a
3g9a
3h9d
3i10a
3j9a
4
4
7
4-FC6H4
4-FC6H4
4-NO2C6H4
Ph
4
0
48
a Conditions: 5 mL of solvent, ratio of catalyst based on benzalde-
8
4-ClC6H4
4-MeOC6H4
PhCH2
4
hyde.
9
4
b Isolated yields.
10
11
12
13
14
15
16
17
4
Ph
Piperidinyl
Pyrrolidinyl
Morpholinyl
Ph
3k10b
3l9e
8
Encouraged by these promising results, we expanded the
preparation to an array of aldehydes and an array of
amines (Table 2). Aromatic (entries 1–18, R1), hetero-
cyclic (entries 19 and 20, R1), and aliphatic (entries 21 and
22, R1) aldehydes worked well in the condensations.
Acid- or heat-sensitive aldehydes such as furfural and
isobutyraldehyde afforded the desired products in high
yields. On the other hand, aromatic (entries 1–9, 14, 16,
17, 19, and 21, R2), benzyl (entries 10, 15, 18, 20, and 22,
R2), and cyclic aliphatic secondary (entries 11–13, 2)
amines gave satisfactory results. As indicated in Table 2,
Ph
4
Ph
3m10b
3n10b
3o9e
3p9d
3q9e
3r9e
8
Piperonyl
Piperonyl
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
2-Furyl
2-Furyl
i-Pr
12
4
PhCH2
Ph
4
Ph
4
both electron-donating and electron-withdrawing substi- 18
PhCH2
4
tutions on phenyl groups of aromatic aldehydes (entries 1,
19
Ph
3s9a
4
7, and 14, R1) or aromatic amines (entries 1, 3, and 6, R2)
20
21
22
PhCH2
3t13a
3u13a
3v9e
4
showed slight influences on the reactions.
The three-component condensation most probably pro-
ceeded via two-step reactions.8,13 Firstly, sulfamic acid
promoted the formation of imine from condensation of
Ph
4
i-Pr
PhCH2
4
aldehyde and amine, the imine was protonated in some a Conditions: aldehyde (2.0 mmol), amine (2.0 mmol), TMSCN
(2.4 mmol), NH2SO3H (10 mol%) and MeCN (5 mL).21
degree to produce a small amount of iminium ion as more
electrophilic intermediate, then TMSCN interacted with
the water formed in situ to liberate or transfer the cyano
group as nucleophile to attack the carbon–nitrogen double
b Isolated yields of 3a–v.
c Each product 3 gave satisfactory spectral data that were in good
accordance with the structure and agreed with those of the literature.
Synlett 2007, No. 5, 803–805 © Thieme Stuttgart · New York

LETTER
Room-Temperature Condensation to Form a-Aminonitriles
805
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Acknowledgment
We are grateful to Basic Sciences Research Program (No.
06KJB530035) of Universities of Jiangsu Province, China, and the
Major Basic R&D Program of China (No. 2003CB716004) for
financial support.
References and Notes
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A mixture of aldehyde (2.0 mmol), amine (2.0 mmol) and
sulfamic acid (20 mg) in MeCN (5.0 mL) was stirred at r.t.
for 20 min and then trimethylsilyl cyanide (1.6 mL, 2.4
mmol) was added. The resulting reaction mixture was stirred
at r.t. for the appropriate time. After completion of the
reaction (TLC, hexane–EtOAc = 1:5), sulfamic acid was
filtered off, the filtrate was extracted with EtOAc (3 × 10
mL), the combined organic phase was washed with H2O (20
mL) and sat. aq NH4Cl (20 mL), dried over anhyd MgSO4
and concentrated in vacuo to give the crude product, which
was purified by silica gel column chromatography (hexane–
EtOAc = 1: 3) to afford the pure 3a–v, all of which were
thoroughly characterized.
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Spectral Data of Representative Compounds.
2-(o-Toluidino)-2-phenylacetonitrile (3b): pale yellow solid;
mp 71–72 [lit.9e 72–73] °C. IR (KBr): 3365, 2237 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.20 (s, 3 H), 3.38 (br d,
J = 8.1 Hz,1 H, NH), 5.45 (d, J = 8.1 Hz, 1 H), 6.80 (t, J =
7.9 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 7.9 Hz, 1
H), 7.40–7.50 (m, 3 H), 7.50 (d, J = 8.0 Hz, 2 H). ESI-
HRMS: m/z calcd for C15H15N2+ [M + H]+: 223.1235; found:
223.1231.
2-Phenyl-2-(pyrrolidin-1-yl)acetonitrile (3l): colorless oil.
IR (neat): 2223 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.75
(m, 4 H), 2.71–2.58 (m, 4 H), 5.03 (s, 1 H), 7.43–7.31 (m, 3
+
H), 7.53–7.49 (m, 2 H). ESI-HRMS: m/z calcd for C12H15N2
[M+H]+: 187.1235; found: 187.1237.
2-(Benzylamino)-2-(3-methoxyphenyl)acetonitrile (3r):
colorless oil. IR (neat): 3323, 2243 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.84 (br s, 1 H), 3.77 (s, 3 H), 3.94 (q,
J = 13.0 Hz, 2 H), 4.66 (s, 1 H), 6.86 (dd, J = 2.5, 9.4 Hz, 1
H), 7.23 (m, 2H), 7.83–7.29 (m, 6 H). ESI-HRMS: m/z calcd
for C16H17N2O+ [M + H]+: 253.1341; found: 253.1338.
2-(Benzylamino)-3-methylbutanenitrile (3v): colorless oil.
IR (neat): 3347, 2228 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.07 (d, J = 6.7 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.55
(br s, 1 H), 1.98 (m, 1 H), 3.25 (d, J = 6.0 Hz, 1 H), 3.79 (d,
J = 13.0 Hz, 1 H), 4.06 (d, J = 13.0 Hz, 1 H), 7.36–7.23 (m,
5 H). ESI-HRMS: m/z calcd for C12H17N2+ [M + H]+:
189.1392; found: 189.1390.
(c) Matsumoto, K.; Kim, J. C.; Hayashi, N.; Jenner, G.
Tetrahedron Lett. 2002, 43, 9167.
Synlett 2007, No. 5, 803–805 © Thieme Stuttgart · New York

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