Lithium tetrafluoroborate-catalyzed solventless synthesis of α-aminonitriles

Article abstract of DOI:10.1007/s00706-007-0675-5

Lithium tetrafluoroborate-catalyzed one-pot, highly efficient, and solvent-free protocol has been developed for the synthesis of α-aminonitriles from aldehydes/ketones, amines, and trimethylsilyl cyanide.

Full text of DOI:10.1007/s00706-007-0675-5

Monatshefte fu¨r Chemie 138, 759–762 (2007)
DOI 10.1007/s00706-007-0675-5
Printed in The Netherlands
Lithium Tetrafluoroborate–Catalyzed Solventless Synthesis
of a-Aminonitriles
Uday V. Desai1;ꢀ, Satish D. Mitragotri1, Takaram S. Thopate1, Dattaprasad M. Pore1,
and Prakash P. Wadgaonkar2
1
Department of Chemistry, Shivaji University, Kolhapur, India
2
National Chemical Laboratory, Polymer Science and Engineering Division, Pune, India
Received November 3, 2006; accepted March 2, 2007; published online May 31, 2007
# Springer-Verlag 2007
Summary. Lithium tetrafluoroborate-catalyzed one-pot,
easily handled reagent. The nucleophilic addition of
highly efficient, and solvent-free protocol has been developed
for the synthesis of ꢀ-aminonitriles from aldehydes=ketones,
amines, and trimethylsilyl cyanide.
cyanide ion to imines is carried out in the presence
of either a base or an acid. However, the use of a
Lewis acid catalyst is one of the keys to performing
this reaction efficiently. Many Lewis acid catalysts
like the triflates of Sc [5a], Yb [5b], V [5c], and Cu
[5d], lithium perchlorate=diethylether [6], iodine [7],
and the halides of Ru [8a], Bi [8b], Co [8c], and In
[8d] have been successfully used. Quite recently
copper triflate [5d] as well as bromodimethylsulfo-
nium bromide [9] have also been reported for the
synthesis of ꢀ-aminonitriles. However, many Lewis
acids are prone to undergo decomposition in the pre-
sence of nitrogen containing reactants and this some-
times necessitates the use of more than stoichiometric
amounts of a Lewis acid catalyst [10]. Furthermore,
some of these catalysts are expensive [5a–d, 8a, d],
toxic [8a, c], need longer reaction time, and are not
environmentally benign. Thus, the development of a
new, highly rapid, and efficient protocol for the syn-
thesis of ꢀ-aminonitriles is desirable.
Keywords. Aldehydes; Amines; Trimethylsilyl cyanide; ꢀ-
Aminonitriles; Lithium tetrafluoroborate.
Introduction
ꢀ-Aminonitriles are useful intermediates for the syn-
thesis of aminoacids [1] as well as nitrogen contain-
ing heterocycles such as thiadiazoles, imidazoles, etc.
[2], and they possess a wide range of biological and
biochemical properties. As such, they act as enzyme
inhibitors, have an effect on the contraction of mus-
cles, are known to inhibit the introduction of gallium
into tissues, and are reported to serve as antitumor
agents. Some compounds of this class have been
proved to be highly effective towards carcinoma and
seminoma in clinical experiments and a number of ꢀ-
aminonitriles do exhibit fungicidal and herbicidal
activity [3].
Lithium tetrafluoroborate is a well-known mild
Lewis acid catalyst which has received much attention
these days. Unlike lithium perchlorate-diethyl ether
it is a non-explosive, non oxidizing, as well as non
nucleophilic agent and serves as a slow release source
of BF3 [11]. Thus, it provides a convenient procedure
to carry out reactions under neutral conditions. It has
been used earlier in many organic transformations,
ꢀ-Aminonitriles are generally prepared by the nu-
cleophilic addition of cyanide ion to imines (Strecker
synthesis). Amongst various cyanide ion sources [4]
trimethylsilyl cyanide (TMSCN) is a safer and more
ꢀ
com
Corresponding author. E-mail: uprabhu_desai@rediffmail.

760
U. V. Desai et al.
the desired product in the absence of catalyst and the
necessity of 10 mol% catalyst for the completion of
the reaction at room temperature. The use of com-
mon organic solvents was not found to be beneficial
and the best results were obtained under solvent-free
conditions.
Scheme 1
To explore scope and limitations of the catalyst, the
protocol was extended towards a variety of aldehydes
including an aliphatic aldehyde (4a), aromatic alde-
hydes possessing electron donating groups (4c, 4e, 4f,
4j), acid sensitive aldehydes like cinnamaldehyde (4l),
furfuraldehyde (4g), as well as with a range of amines
including aliphatic (4p), aromatic, aralkyl (4h, 4i), and
a secondary amine like morpholine (4k, 4m). In all
these cases, the reactions proceeded satisfactorily to
furnish corresponding ꢀ-aminonitriles in acceptable
yields and purity. The protocol was then extended to-
wards ketones as the source of carbonyl compounds.
Interestingly, with acetophenone as well as cyclo-
hexanone, although desired ꢀ-aminonitriles were
obtained with an aromatic amine, they failed to react
with benzyl amine, morpholine, as well as piperidine
(4q, 4r, 4s). The results are summarized in Table 1.
In conclusion we have demonstrated that lithium
tetrafluoroborate is a highly efficient catalyst for the
synthesis of ꢀ-aminonitriles in short time under sol-
vent-free conditions.
including the cyanosilylation of ketones [12]. How-
ever, to the best of our knowledge it has not been used
so far for the synthesis of ꢀ-aminonitriles and herein
we report the use of lithium tetrafluoroborate as a mild
Lewis acid catalyst for the synthesis of ꢀ-aminonitriles
under solvent-free conditions (Scheme 1).
Results and Discussion
A mixture of benzaldehyde (1 equiv.), aniline
(1equiv.), TMSCN (1.1 equiv.), and LiBF4 (0.1 equiv.)
was stirred at room temperature, when corresponding
ꢀ-aminonitrile resulted (TLC, IR) in a short reaction
time. The structure of the resultant ꢀ-aminonitrile was
confirmed by spectral studies. The appearance of two
1
singlets in the H NMR spectrum at ꢁ ¼ 4.03 and
5.26ppm clearly indicated the formation of the ex-
pected ꢀ-aminonitrile 4b. The reaction conditions
were then optimized with respect to the amount of
catalyst used, which revealed the non-formation of
Table 1. Lithium tetrafluoroborate-catalyzed synthesis of ꢀ-aminonitriles
ꢀ-Aminonitriles 4
Aldehyde=ketone 1
Amine 2
Time=min
Yielda=%
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
Isobutyraldehyde
Benzaldehyde
4-Methylbenzaldehyde
Benzaldehyde
3,4-Dimethoxybenzaldehyde
4-Chlorobenzaldehyde
2-Furaldehyde
Aniline
Aniline
Aniline
4-methylaniline
Aniline
Aniline
20
12
15
15
20
10
15
15
20
15
20
20
20
20
25
25
NR
NR
NR
86
90
82
87
79
94
93
91
95
84
96
86
85
91
88
72
–
Aniline
Benzaldehyde
Benzylamine
Benzylamine
Aniline
Morpholine
Aniline
Morpholine
Aniline
Aniline
Isopropyl amine
Benzylamine
Morpholine
Piperidine
4-Chlorobenzaldehyde
4-Isopropylbenzaldehyde
Benzaldehyde
Cinnamaldehyde
4-Chlorobenzaldehyde
Acetophenone
Cyclohexanone
Benzaldehyde
Acetophenone=cyclohexanone
Acetophenone=cyclohexanone
Acetophenone=cyclohexanone
–
–
a
Yields refer to pure, isolated products; NR no reaction

Solventless Synthesis of ꢀ-Aminonitriles
761
J ¼ 8 Hz), 7.05 (2H, d, J ¼ 8 Hz), 7.42 (3H, m), 7.57 (2H, t)
ppm; 13C NMR (CDCl3): ꢁ ¼ 20.56 (CH3), 50.59 (CH), 114.33
(CN), 118.23, 127.08, 129.10, 129.26, 129.52, 129.87, 133.92,
142.19 (Ar–Cs) ppm.
Experimental
All the aldehydes, TMSCN, and various amines were ob-
tained from Lancaster or Acros and were used without puri-
fication. The melting points reported were recorded on a
KUMAR melting point apparatus. IR spectra were recorded
on a Perkin Elmer-793 instrument. 1H and 13C NMR spectra
were recorded as CDCl3 solutions on a Bruker AC-200
spectrometer at 200 and 50 MHz, respectively, using TMS
as an internal standard. Chemical shifts are expressed in ꢁ
units.
2-(3,4-Dimethoxyphenyl)-2-(phenylamino)acetonitrile
(4e, C16H16N2O2)
Liquid; IR (neat): ꢂꢀ¼ 3419, 3020, 2966, 2236 (weak), 1607,
1504, 1373, 929, 757 cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 3.91 (1H,
s), 3.95 (6H, s), 5.37 (1H, brs), 6.77 (2H, d, J ¼ 8 Hz), 6.92 (1H,
t, J ¼ 8 Hz), 7.06–7.15 (2H, m), 7.26 (1H, d), 7.41 (2H, d, J ¼
8 Hz) ppm; 13C NMR (CDCl3): ꢁ ¼ 49.70 (CH), 55.80 (OCH3),
109.86 (CN), 110.98, 113.84, 118.23, 119.44, 119.82, 125.96,
128.86, 129.25, 144.52, 149.45 (Ar–Cs) ppm.
Representative Procedure
A mixture of 2 mmol benzaldehyde (2a), 2 mmol aniline
(2b), 2.2mmol TMSCN and 20mg lithium tetrafluoroborate
(0.20 mmol) was stirred at room temperature for an appropri-
ate time (Table 1). On completion of the reaction (TLC),
20cm3 water were added, and the reaction mixture was ex-
tracted with ether. The ether extract was washed with water,
dried over anhydrous sodium sulfate, and ether was removed.
The residue obtained was filtered through a short column of
silica gel to afford pure ꢀ-aminonitrile 4b, which was char-
acterized by spectral methods.
2-(4-Chlorophenyl)-2-(phenylamino)acetonitrile (4f)
Mp 109–110ꢂC (Ref. [13] 109–112ꢂC); IR (KBr):
ꢂꢀ¼ 3369, 2924, 2854, 2238 (weak), 1603, 1502, 1385,
1218, 1094, 770 cmꢁ1
;
1H NMR (CDCl3): ꢁ ¼ 4.03 (1H,
d, J ¼ 6 Hz), 5.33 (1H, d, J ¼ 6 Hz), 6.69 (2H, d, J ¼ 7 Hz),
Hz), 6.87 (1H, t, J ¼ 7 Hz), 7.22 (2H, t, J ¼ 7 Hz), 7.37 (2H,
d, J ¼ 7 Hz), 7.48 (2H, d, J ¼ 7 Hz) ppm; 13C NMR
(CDCl3): ꢁ ¼ 49.60 (CH), 114.36 (CN), 117.63, 128.61,
129.53, 132.64, 132.58, 135.64, 144.41 (Ar–Cs) ppm.
The spectral data of some of the ꢀ-aminonitriles are sum-
marized below.
2-Furyl-2-(phenylamino)acetonitrile (4g)
2-Isopropyl-2-(phenylamino)acetonitrile (4a, C11H14N2)
Liquid; IR (neat): ꢂꢀ¼ 3419, 3020, 2227 (weak), 1760, 1513,
1373, 1216, 1009, 759 cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 1.17 (3H,
d, J ¼ 6 Hz), 1.18 (3H, d, J ¼ 6 Hz), 2.16 (1H, septet, J ¼
6 Hz), 4.03 (1H, d, J ¼ 6 Hz), 5.26 (1H, brs, J ¼ 6 Hz), 6.69
(2H, d, J ¼ 8 Hz), 6.84 (1H, t, J ¼ 8 Hz), 7.21 (2H, d, J ¼ 8 Hz)
ppm; 13C NMR (CDCl3): ꢁ ¼ 18.32 (CH3), 19.24 (CH3), 31.64
[CH(CH3)2], 52.47 (CH), 113.95 (CN), 118.42, 119.80, 129.39,
144.93 (Ar–Cs) ppm.
Mp 67–69ꢂC (Ref. [13] 68–70ꢂC); IR (KBr): ꢂꢀ¼ 3393, 3020,
2236 (weak), 1738, 1603, 1523, 1424, 1217, 1018, 770,
670 cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 4.13 (1H, brs), 5.44 (1H, d,
J ¼ 6 Hz), 6.41 (1H, d, J ¼ 3 Hz), 6.57 (1H, d, J ¼ 4 Hz), 6.72
(2H, d, J ¼ 8 Hz), 6.88 (1H, t, J ¼ 8 Hz), 7.25 (2H, t, J ¼ 8 Hz),
7.46(1H, d, J ¼ 3 Hz) ppm;13C NMR(CDCl3):ꢁ ¼ 52.90 (CH),
114.42 (CN), 105.02, 110.52, 142.10, 152.50 (furan ring Cs),
117.82, 118.65, 129.44, 147.60 (Ar–Cs) ppm.
2-(Benzylamino)-2-phenylacetonitrile (4h, C15H14N2)
Liquid; IR (neat): ꢂꢀ¼ 3397, 3020, 2229 (weak), 1661, 1531,
1261, 1216, 1095, 759, 669cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 2.18
(1H, brs), 3.94 (2H, AB quartet), 4.71 (1H, s), 7.19–7.82
(10H, m) ppm; 13C NMR (CDCl3): ꢁ ¼ 51.90 (CH), 54.92
(CH2), 114.75 (CN), 120.36, 127.63, 128.91, 129.36, 131.51,
135.70, 138.50, 142.90 (Ar–Cs) ppm.
2-Phenyl-2-(phenylamino)acetonitrile (4b)
Mp 71–73ꢂC (Ref. [13] 73–74ꢂC); IR (KBr): ꢂꢀ¼ 3419, 3020,
1H NMR (CDCl3): ꢁ ¼ 4.03 (1H, d, J ¼ 6 Hz), 5.26 (1H, d,
J ¼ 6 Hz), 6.72 (2H, d, J ¼ 6 Hz), 6.86 (1H, t, J ¼ 6 Hz), 7.23
(2H, d), 7.41 (3H, brs) 7.56 (2H, brs) ppm; 13C NMR (CDCl3):
ꢁ ¼ 50.36 (CH), 114.36 (CN), 117.90, 120.46, 127.30, 129.34,
129.62, 134.35, 144.81 (Ar–Cs) ppm.
2741, 2237 (weak), 1602, 1503, 1311, 1217, 757, 669 cmꢁ1
;
2-(Benzylamino)-2-(4-chlorophenyl)acetonitrile
(4i, C15H13ClN2)
2-(4-Methylphenyl)-2-(phenylamino)acetonitrile (4c)
Mp 76–78ꢂC (Ref. [13] 76–78ꢂC); IR (KBr): ꢂꢀ¼ 3418, 3020,
1H NMR (CDCl3): ꢁ ¼ 2.32 (3H, s), 3.87 (1H, brs), 5.26 (1H,
brs), 6.65 (2H, d, J ¼ 8 Hz), 6.79 (1H, t, J ¼ 8 Hz), 7.12–7.20
(4H, m), 7.36 (2H, d, J ¼ 8 Hz) ppm; 13C NMR (CDCl3):
ꢁ ¼ 20.54 (CH3), 50.59 (CH), 114.31 (CN), 118.32, 127.08,
129.11, 129.27, 129.53, 129.88, 133.91, 142.19 (Ar–Cs) ppm.
Liquid; IR (neat): ꢂꢀ¼ 3401, 3020, 2229 (weak), 1635, 1553,
1422, 1219, 1994, 772, 669cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 1.98
(1H, brs), 3.94 (2H, AB quartet), 4.74 (1H, s), 7.14–7.89 (9H,
m) ppm; 13C NMR (CDCl3): ꢁ ¼ 48.60 (CH), 52.10 (CH2),
117.26 (CN), 127.32, 128.29, 129.16, 129.79, 130.82,
132.16, 134.13, 138.75 (Ar–Cs) ppm.
2927, 2232 (weak), 1605, 1503, 1216, 1098, 757, 669 cmꢁ1
;
2-(4-Isopropylphenyl)-2-(phenylamino)acetonitrile
2-(4-Methylphenylamino)-2-phenylacetonitrile (4d, C15H14N2)
Mp 81–83ꢂC; IR (KBr): ꢂꢀ¼ 3394, 3020, 2741, 2232 (weak),
1519, 1215, 759, 669 cmꢁ1; 1H NMR (CDCl3):ꢁ ¼ 2.28 (3H, s),
3.84 (1H, d, J ¼ 10Hz), 5.35 (1H, d, J ¼ 10 Hz), 6.66 (2H, d,
(4j, C17H18N2)
Liquid; IR (neat): ꢂ ¼ 3420, 3020, 2966, 2236 (weak), 1607,
1504, 1373, 1219, 929, 757 cmꢁ1; 1H NMR (CDCl3): ꢁ ¼ 1.31
(6H, d, J ¼ 8 Hz), 2.99 (1H, septet, J ¼ 8 Hz), 5.41 (1H, s), 6.81
ꢀ

762
U. V. Desai et al.: Solventless Synthesis of ꢀ-Aminonitriles
(2H,d, J ¼ 8 Hz),6.93(1H,t,J ¼ 8 Hz), 7.29–7.37(5H,m),7.55
(2H, d, J ¼ 8 Hz) ppm; 13C NMR (CDCl3): ꢁ ¼ 28.87 (CH3),
33.83 [CH(CH3)2], 49.79 (CH), 113.87 (CN), 118.23, 119.86,
127.10, 127.15, 129.31, 131.08, 144.55, 150.18 (Ar–Cs) ppm.
Acknowledgements
One of the authors (UVD) thanks UGC, New Delhi for finan-
cial assistance [F.30-72=2004(SR)]. TST and SDM thank UGC
authorities for the research Fellowships.
2-(Morpholino)-2-phenylacetonitrile (4k)
Mp 69–71ꢂC (Ref. [8a] 69–71ꢂC); 1H NMR (CDCl3):
ꢁ ¼ 2.50–2.65 (4H, m), 3.60–3.80 (4H, m), 4.81 (1H, s),
7.30–7.70 (5H, m) ppm; 13C NMR (CDCl3): ꢁ ¼ 50.22 (CH),
61.80 (2ꢃN–CH2), 66.38 (2ꢃO–CH2), 114.92 (CN), 128.24,
129.63, 130.10, 132.90 (Ar–Cs) ppm.
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Mp 114–116ꢂC (Ref. [13] 117–119ꢂC), IR (KBr): ꢂꢀ¼ 3419,
3019, 2232 (weak), 1602, 1501, 1217, 928, 770 cmꢁ1; 1H NMR
(CDCl3): ꢁ ¼ 3.86 (1H, brs), 5.33 (1H, s), 6.74 (2H, d, J ¼
8 Hz), 6.93 (1H, dd, J ¼ 16, 2 Hz), 7.21–7.50 (10H, m) ppm;
13C NMR (CDCl3): ꢁ ¼ 47.72 (CH), 114.24 (CN), 117.56,
120.23, 120.81, 1226.80, 128.70, 129.45, 130.15, 133.178,
134.90, 144.27 (¼CH, Ar–Cs) ppm.
2-Phenyl-2-(phenylamino)propionitrile (4n, C15H14N2)
Mp 146–148ꢂC; 1H NMR (CDCl3): ꢁ ¼ 1.98 (3H, s), 4.3 (1H,
bs), 6.7 (2H, d, J ¼ 8 Hz), 6.79 (1H, t, J ¼ 8 Hz), 7.15 (2H, t,
J ¼ 8 Hz), 7.38 (3H, m), 7.62 (2H, d, J ¼ 8 Hz) ppm; 13C
NMR (CDCl3): ꢁ ¼ 33.38 (CH3), 57.07 (C–CH3), 115.58
(CN), 119.76, 120.61, 124.71, 128.41, 128.85, 129.07,
139.71, 143.30 (Ar–Cs) ppm.
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1419
2-Cyclohexyl-2-(phenylamino)acetonitrile (4o, C13H16N2)
1H NMR (CDCl3): ꢁ ¼ 1.28–1.36 (1H, bs), 1.60–1.74 (6H,
m), 1.76–1.82 (2H, m), 2.28–2.38 (2H, m), 6.86–6.96 (3H,
m, J ¼ 8 Hz), 7.4 (2H, t, J ¼ 8 Hz) ppm; 13C NMR (CDCl3):
ꢁ ¼ 22.22 (CH2), 24.88 (CH2), 36.57 (CH2), 54.32 (C–NH),
117.35 (CN), 120.34, 121.08, 129.03, 143.35 (Ar–Cs) ppm.
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2-(Isopropylamino)-2-phenylacetonitrile (4p, C11H14N2)
1H NMR (CDCl3): ꢁ ¼ 1.21 (6H, d, J ¼ 7 Hz), 3.27 (1H, m),
4.64 (1H, s), 7.30–7.50 (5H, m) ppm; 13C NMR (CDCl3): ꢁ ¼
20.82 (CH3), 21.70 (CH3), 47.52 [CH(CH3)2], 52.63 (CH),
119.43 (CN), 127.81, 129.31, 129.43, 136.10 (Ar–Cs) ppm.
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