A novel approach to the synthesis of α-aminonitriles using triphenyl-phosphine dibromide under solvent-free conditions

Article abstract of DOI:10.1055/s-0032-1317690

A quick and highly efficient, one-pot, three-component, solvent-free method for the synthesis of α-aminonitriles starting from the corresponding carbonyl compounds, amines, and trimethylisocyanide using triphenylphosphine dibromide, has been developed. Diverse α-aminonitriles have been synthesized in good to excellent yields (80-99%) using a range of aldehydes, ketones and amines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317690

LETTER
▌33
lAetteNr ovel Approach to the Synthesis of α-Aminonitriles Using Triphenyl-
phosphine Dibromide under Solvent-Free Conditions
Synthesis of α-Aminonitriles
Devdutt Chaturvedi,*a Amit K. Chaturvedi,b Parmesh K. Dwivedi,a Nisha Mishrab
a
Laboratory of Medicinal Chemistry, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow 226028,
U. P., India
Fax +91(522)2399610; E-mail: devduttchaturvedi@gmail.com; E-mail: dchaturvedi@lko.amity.edu
b
Synthetic Research Laboratory, Department of Chemistry, B. S. A. P. G. College, Mathura 281004, U. P., India
Received: 06.08.2012; Accepted after revision: 02.11.2012
Therefore, there is continuing interest in developing new,
efficient and safer protocols employing mild reaction con-
ditions.
Abstract: A quick and highly efficient, one-pot, three-component,
solvent-free method for the synthesis of α-aminonitriles starting
from the corresponding carbonyl compounds, amines, and trimethyl-
isocyanide using triphenylphosphine dibromide, has been devel-
oped. Diverse α-aminonitriles have been synthesized in good to
excellent yields (80–99%) using a range of aldehydes, ketones and
amines.
In recent years, triphenylphosphine dibromide (Ph3PBr2)
has emerged as a versatile reagent in organic synthesis.10
Our group has been engaged in the development of novel
and efficient synthetic methodologies.11 In the present
communication, we wish to report an efficient method for
the synthesis of α-aminonitriles through reaction of the
corresponding carbonyl compounds, amines, and
TMSCN using a catalytic amount of triphenylphosphine
dibromide (TPPDB) under solvent-free conditions.12 Tri-
phenylphosphine dibromide was synthesized by the re-
ported procedure.10
Key words: multicomponent reactions, Strecker synthesis, amino-
nitriles, carbonyl compounds
α-Aminonitriles constitute a major class of naturally oc-
curring compounds that display remarkable biological
activities1 (anticancer, antibacterial, antifungal, antibiotic,
and antiviral) and also serve as efficient precursors for the
synthesis of natural and unnatural α-amino acids.2 They
have also been widely used as essential building blocks in
peptide and protein synthesis.3 Their synthetic utility has
further been applied as a versatile synthon for the synthe-
ses of amides, diamines, and various kinds of structurally
diverse nitrogen and sulfur heterocycles4 such as imidaz-
oles and thiadiazoles. Furthermore, their synthetic utility
has also been extended through carbanion-induced nu-
cleophilic attack on the α-carbon atom with a variety of
electrophiles, offering the possibility of further synthetic
transformations.5
To optimize the protocol, the reaction of an equimolar
amount of aniline, benzaldehyde, and trimethysilylcya-
nide, using a catalytic amount of TPPDB, was studied in
a range of anhydrous solvents (CH2Cl2, THF, Et2O,
MeCN, DMF, MeNO2, and MeOH) at room temperature
and the corresponding α-aminonitrile was isolated. The
best yields (99%) of the desired α-aminonitrile were
achieved using at least 10 mol% TPPDB in the absence of
solvent (Scheme 1).
CN
O
Ph3PBr2
R3NH2
+
TMSCN
+
NHR3
R1
R1
R2
solvent-free, r.t.
80–99%
Among the reported methods, nucleophilic addition of cy-
anide ion to imines (Strecker reaction) offers one of the
most direct approaches to the synthesis of α-aminoni-
triles.6 The cyanide sources used during the course of this
reaction include HCN, KCN, TMSCN, (EtO)2P(O)CN,
Et2AlCN, Bu3SnCN, MeCOCN, acetone cyanohydrin,
acyl cyanides, ethyl cyanoformate, bis(dialkyl)amino-
cyanoboranes, and K4[Fe(CN)6],7 the majority of which
are hazardous, toxic, and require harsh reaction condi-
tions. In recent years, in the search for novel and efficient
protocols for the synthesis of α-aminonitriles, a broad
spectrum of metal complexes, Lewis acids, solid acids,
bases, and organic catalysts have been developed to pro-
mote this reaction.8,9 The majority of these catalysts are
only efficient for the synthesis of α-aminonitriles from ac-
tive aldehydes and are not suitable for ketone substrates.
R2
I
R
1 = alkyl, cycloalkyl, aryl,
naphthyl, anthracenyl, heteroaryl
R2 = H, Me, Et, Ph
R3 = alkyl, Ph, aryl
Scheme 1
It was subsequently observed that the desired α-amino-
nitrile could be achieved without using TPPDB under sol-
vent-free conditions; although the reaction took longer
(4 h) and afforded a lower yield (92%). However, al-
though acetophenone reacted with aniline and TMSCN
using a catalytic amount of TPPDB to afford a high-yield
of the desired α-aminonitrile under solvent-free condi-
tions at room temperature (Table 1), when this reaction
was repeated without using TPPDB, the corresponding
α-aminonitrile could not be achieved even after extended
periods (4 h). When this reaction was repeated employing
SYNLETT 2013, 24, 0033–0036
Advanced online publication: 04.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317690; Art ID: ST-2012-D0664-L
© Georg Thieme Verlag Stuttgart · New York

34
D. Chaturvedi et al.
LETTER
Table 3 Synthesis of α-Aminonitriles of General Formula I
TPPDB without using TMSCN, the corresponding imine
was obtained; without TPPDB no imine was observed.
This implies a role for TPPDB in the generation of the cor-
responding imines in situ, particularly from ketones.
Entry R1
R2
R3
Time Yield Ref.
(min) (%)
9i
5
6
7
8
9
3,4-Cl2C6H3
H
Ph
30
35
30
35
30
60
60
25
95
91
90
91
89
80
89
95
96
98
99
92
95
93
91
90
93
94
98
96
92
88
85
84
82
80
81
83
81
80
86
83
81
83
87
82
Table 1 Effect of Triphenylphosphine Dibromide on the Formation
of α-Aminonitriles I
9b
9a
9a
8i
4-FC6H4
H
Ph
R1
R2
R3
Time
TPPDB (mol%) Yield (%)
4-MeC6H4
4-MeOC6H4
3-pyridyl
H
Ph
H
Ph
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
20 min
4 h
10
98
92
98
–
H
Ph
H
absent
10
8p
8q
8m
8p
9b
8n
8n
9b
8o
8r
10 C9H19
11 Et
H
Ph
Me
Me
25 min
4 h
H
Ph
absent
12 Ph
H
4-MeC6H4
Comparing the catalytic activity of TPPBD with some re-
ported catalysts such as I2, guanidine hydrochloride, and
cellulose sulfuric acid for the synthesis of α-aminonitriles
under solvent-free conditions, it was found that TPPDB
was superior, achieving high yields of the desired prod-
ucts in shorter reaction times (Table 2).
13 Ph
H
4-MeOC6H4 25
Ph 30
4-MeOC6H4 30
14 Ph
Me
Me
Me
H
15 Ph
16 Ph
4-ClC6H4
30
25
30
35
30
30
Ph
Ph
Ph
30
30
35
35
45
45
35
35
35
35
45
50
55
55
17 Ph
Bn
Ph
Ph
Ph
Bn
Table 2 Effect of Catalysts on the Formation of α-Aminonitriles I
18 1-naphthyl
19 9-anthryl
20 c-Pr
H
R1
R2
R3
Time (h) Catalyst (10 mol%)
Yield (%)
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4
I2
58
52
78
64
8o
9b
8n
8n
9a
9b
9b
9b
9b
9b
9b
8i
H
Me
H
8
I2
21 Ph
Me
2
GuHCl
GuHCl
22 –(CH2)4–
23 –(CH2)5–
24 –(CH2)6–
25 Ph
Me
H
4
2
cellulose sulfuric acid 66
cellulose sulfuric acid 53
Me
H
4
Et
Et
Ph
Me
Me
H
Ph
25 min
30 min
TPPBD
TPPBD
98
98
26 Ph
Bn
Ph
Me
27 Ph
28 2-naphthyl
29 i-Pr
Ph
The scope of this reaction was further explored with a
range of aliphatic and aromatic substituted aldehydes and
ketones bearing electron-releasing and electron-with-
drawing functionalities and primary aliphatic and aromat-
ic amines having electron-releasing and electron-
withdrawing functional groups. Best yields of the prod-
ucts were obtained when an electron-releasing group was
present at the para-position of the aromatic aldehydes,
ketones, and amines (Table 3).
Ph
30 PhCH=CH
31 Ph
Ph
H
n-Bu
n-Bu
Bn
Ph
–
32 4-MeC6H4
33 c-Hex
34 c-Hex
35 n-Bu
H
–
H
–
H
8r
n-Bu Ph
Table 3 Synthesis of α-Aminonitriles of General Formula I
8r
Entry R1
R2
R3
Time Yield Ref.
(min) (%)
36 2-naphthyl
37 4-O2NC6H4
38 3-Me-2-HSC6H3
39 3-pyridyl
Ph
Ph
Ph
Ph
9b
8o
8n
8n
Me
Me
Me
8d
1
2
3
4
Ph
H
H
H
H
Ph
Ph
Ph
Ph
25
25
30
30
98
97
94
94
8m
8i
4-ClC6H4
4-O2NC6H4
4-BrC6H5
4-MeOC6H4 45
4-MeOC6H4 50
40 3,4-(OCH2O)C6H3 Me
9i
Synlett 2013, 24, 33–36
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of α-Aminonitriles
35
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In conclusion, we have developed a simple and efficient
method for the synthesis of α-aminonitriles starting from
their corresponding carbonyl compounds, amines, and tri-
methylsilyl cyanide, by employing a catalytic amount of
TPPDB under solvent-free conditions.
Acknowledgment
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The authors wish to thank the Pro-Vice Chancellor, and Dean, Re-
search (Science and Technology) of Amity University, Lucknow
for his constant encouragement and support.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 33–36

36
D. Chaturvedi et al.
LETTER
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C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.80; H,
5.76; N, 13.47.
2-Anilino-2-(4-chlorophenyl)acetonitrile (Table 3, Entry
2): White solid; mp 96–98 °C; IR (CHCl3): 3365, 3055,
2235, 1603, 1504 cm–1; 1H NMR (300 MHz, CDCl3): δ =
4.02 (d, J = 6 Hz, 1 H), 5.41 (d, J = 9 Hz, 1 H), 6.75 (d, J =
9 Hz, 2 H), 6.92 (t, J = 6 Hz, 1 H), 7.28 (m, 2 H), 7.42 (d, J
= 9 Hz, 2 H), 7.53 (d, J = 6 Hz, 2 H); 13C NMR (75 MHz,
CDCl3): δ = 49.5, 114.2, 117.8, 120.4, 128.4, 129.2, 129.6,
132.8, 135.4, 144.3; MS (ESI): m/z = 242.1 [M]+; Anal.
Calcd for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54; Found:
C, 69.19; H, 4.63; N, 11.56.
2-Anilino-2-(4-nitrophenyl)acetonitrile (Table 3, Entry
3): Gummy solid; IR (CHCl3): 3381, 3063, 2225, 1601,
1550, 1502 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.08 (d,
J = 9 Hz, 1 H), 5.57 (d, J = 9 Hz, 1 H), 6.68 (d, J = 9 Hz,
2 H), 6.78 (t, J = 8 Hz, 1 H), 7.29 (t, J = 9 Hz, 2 H), 7.8 (d, J
= 9 Hz, 2 H), 8.1 (d, J = 9 Hz, 2 H); 13C NMR (75 MHz,
CDCl3): δ = 49.8, 115.3, 118.0, 127.0, 127.7, 127.8, 128.6,
129.0, 133.8, 144.1, 145.0; MS (ESI): m/z = 276.2 [M +
Na]+; Anal. Calcd for C14H11N3O2: C, 66.40; H, 4.38; N,
16.59; Found: C, 66.46; H, 4.40; N, 16.51.
(12) Synthesis of α-Aminonitriles; Typical Procedure: A
mixture of aldehyde (1 mmol), amine (1 mmol),
triphenylphosphine dibromide (10 mol%), and
trimethylsilylcyanide (1.2 mmol) was stirred at room
temperature until the reaction was complete (monitored by
TLC). The reaction mixture was then extracted with EtOAc
(×3), dried over anhydrous Na2SO4, filtered, and
concentrated. Purification of the crude product by
chromatography on silica gel (60–120 mesh; petroleum
ether–EtOAc, 5:1) gave the pure product.
2-Anilino-2-phenylacetonitrile (Table 3, Entry 1): Light-
yellow solid; mp 85–86 °C; IR (CHCl3): 3368, 3055, 2233,
1602, 1502 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.03 (d,
J = 9 Hz, 1 H), 5.41 (d, J = 9 Hz, 1 H), 6.76 (d, J = 9 Hz,
2 H), 6.90 (t, J = 6 Hz, 1 H), 7.30 (t, J = 9 Hz, 2 H), 7.44 (m,
3 H), 7.59 (m, 2 H); 13C NMR (75 MHz, CDCl3): δ = 49.8,
114.0, 118.1, 119.9, 127.0, 128.3, 129.4, 129.8, 133.6,
144.6; MS (ESI): m/z = 208.2 [M]+; Anal. Calcd for
Synlett 2013, 24, 33–36
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