L-Proline catalyzed one pot synthesis of α-aminonitriles

Article abstract of DOI:10.1016/j.tetlet.2013.05.025

l-Proline (20 mol %) was found to be an efficient organocatalyst for one pot synthesis of a variety of α-aminonitriles from aldehydes, amines, and trimethylsilyl cyanide (TMSCN) in acetonitrile at ambient temperature giving good to excellent yields (72-95%).

Full text of DOI:10.1016/j.tetlet.2013.05.025

Accepted Manuscript
L-Proline catalyzed one pot synthesis of α-aminonitriles
Aayesha Nasreen
PII:
S0040-4039(13)00782-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.025
TETL 42925
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 February 2013
4 May 2013
8 May 2013
Please cite this article as: Nasreen, A., L-Proline catalyzed one pot synthesis of α-aminonitriles, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.025
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1
L-Proline catalyzed one pot synthesis of α-aminonitriles
Aayesha Nasreen
Department of Chemistry, College of Sciences, Jazan University, 6811- Arroudah, Jazan, 82724-3750, K.S.A
P.O. Box No. 2097, Fax: 073227066, E-Mail: aayesha_iict@yahoo.co.in
Abstract: L-Proline (20 mol %) was found to be an efficient organocatalyst for one pot synthesis
of a variety of α-aminonitriles from aldehydes, amines and trimethylsilyl cyanide (TMSCN) in
acetonitrile at ambient temperature giving good to excellent yields (72- 95 %).
Keywords: L-proline, aldehydes, amines, trimethylsilyl cyanide, α-aminonitriles.
Bifunctional α-amino nitriles are versatile intermediates in organic synthesis. They also exhibit a
valuable dual reactivity, which has been utilized in a broad range of synthetic applications.1a The
nucleophilic additions to the nitrile group provide access to α-amino aldehydes, α-amino
ketones, α-amino alcohols, 1,2-diamines and many nitrogen containing heterocycles.1b,2 In
particular, stereodefined α-amino acid-derived amino nitriles have shown a high potential for
molecular diversity generation.3,4These are the key precursors for the synthesis of various
biologically useful molecules such as proteins, and have several applications as the chiral
building blocks in the pharmaceutical industry.5-8
Numerous methods describing the preparation of α-amino nitriles have been reported in the
literature. Among the reported methods the most important route for the synthesis of α-
aminonitriles is the Strecker reaction.9,10 Several modifications of the Strecker reaction have been
Corresponding author; Fax: 073227066, E-Mail: aayesha_iict@yahoo.co.in

2
made and a variety of cyanating agents such as α-trimethylsiloxy nitriles and diethyl
phosphorocyanidates11 and trimethylsilyl cyanide12 were used under various conditions. The
classical Strecker experimental procedure is tedious and thus, several modified methods have
been reported using a variety of catalysts,13-35 Ionic liquids like [Hbim+][Cl-],36 TSIL,37
xanthansulphuric acid as biosupported solid acid catalyst,38 β-cyclodextrin39 and oxalic acid.40
Organocatalysis41 has gained widespread attention as a result of the efficiency and selectivity of
many reactions. Novel methods employing organic molecules are advantageous from both a
practical and an environmental standpoint. Recently, the commercially available and inexpensive
amino acid L-proline has been elegantly used to catalyze many reactions such as the Mannich
reaction and the direct asymmetric aldol reaction.42 The L-proline function has been proposed to
act like a ‘microaldolase’ that facilitates each step of the mechanism including the formation of
the intermediate imine and the carbon-carbon bond. L-Proline has been exploited as an efficient
organocatalyst in the organic synthetic routes for carbon-carbon, carbon-heteroatom bonds and
heterocycles.43,44
As a continuation of our recent efforts to develop new organic transformations we would like to
report a highly efficient route for the synthesis of α-aminonitriles by one pot three-component
coupling of aldehydes, amines catalyzed by commercially available, inexpensive, mild L-proline
as organocatalyst and trimethylsilyl cyanide as a cyanide ion source, (Scheme-1) which is a safer
and more easily handled reagent compared to alkali cyanides and HCN.37
CN
O
R2
L-Proline ( 20 mol %)
R2NH2
+
R1
+
TMSCN
N
H
R1
H
RT
CH3CN ,
R1, R2 = alkyl, aryl
4a-4y
2
3
1
Scheme-1
One pot three-component synthesis of α-aminonitriles

3
In the present study we extend the scope of the L-proline catalyzed synthesis of α-aminonitriles45
and the results are presented here. In order to optimize the reaction conditions initially we
studied the efficacy of L-proline by taking catalytic amount of 20 mol % and benzaldehyde (1
mmol), aniline (1 mmol) and TMSCN (1.2 mmol), in acetonitrile (5 mL) as model reaction, the
reaction gave corresponding 2-(N-anilino)-2-phenylacetonitrile with 95% yield in 2 h (Table-1,
entry-5). In the absence of L-proline even up to 10 h (Table-1 entry-1) no reaction was observed.
Although the amount of catalyst has been optimized to 20 mol % lesser amount (10 mol %) also
worked when longer reaction times were employed. (Table-1, entry-3).
Table-1 Screening of catalyst L-proline on model reaction between benzaldehyde (1 mmol), aniline (1 mmol) and
TMSCN (1.2 mmol), in acetonitrile (5 mL)
Entry
Catalyst ( mol %)
Time ( hours ) Yieldb (% )
1
2
3
4
5
6
No catalyst
10
7
0
5
40
70
85
95
95
10
15
20
6
6
2
25
2
b
Isolated yields
The model reaction was performed in various solvents using L-proline as the catalyst to identify
the best medium for the reaction. A range of solvents such as CHCl3, DCM, THF, DMSO,
toluene, H2O, acetonitrile, were examined and acetonitrile emerged as the solvent of choice in
terms of reaction kinetics and product yield. (Table-2, entry-8).

4
Table-2 Screening of solvents for the synthesis of 2-(N-anilino)-2-phenylacetonitrile from benzaldehyde (1 mmol),
aniline(1 mmol) and TMSCN (1.2 mmol) in the presence of L-proline ( 20 mol %)
Entry
Solvent
Time ( hours) Yield(%)
1
2
3
4
5
6
7
8
CHCl3
DCM
2.5
2.5
3
70
68
THF
60
DMSO
Toluene
H2O
4
30
4.5
5
35
NR
NR
95
No Solvent
CH3CN
7
2
NR; No Reaction
Ketones largely remained inert under these reaction conditions. Longer reaction times and
greater amounts of L-proline also failed to make a significant improvement. On the other hand
aliphatic and aromatic aldehydes afforded excellent yields. Various kinds of primary and
secondary amines are readily coupled to give the desired product in good yields. Furthermore
aldehydes such as cinnamaldehyde and furfuraldehyde (Table-3 entry, 14, 15- 4n, 4o) also
worked well without any decomposition or polymerization under these reaction conditions. This
method is equally effective with aldehydes bearing electron withdrawing substituents in the
aromatic ring. No undesired side product such as cyanohydrin trimethylsilylether, an adduct
between the aldehyde and trimethylsilyl cyanide was observed because of the rapid formation of
iminium intermediate. The scope and generality of the reaction are illustrated with respect to
various amines and aldehydes including unsaturated and heterocyclic aldehydes 4a-4y (Table-3).

5
Table-3 L-Proline catalyzed synthesis of α-aminonitriles from aldehydes (1) amines (2) TMSCN (3)
Time (hours)c
Yield (%)b
Product (4a - 4m)a
Entry
Amine (2)
C6H5NH2
C6H5NH2
Aldehyde (1)
C6H5CHO
2
2
4a
4b
4c
95
90
1
3-CH3OC6H4CHO
2
3
3
4
4
83
80
2-CH3C6H4NH2
2-C2H5OC6H4CHO
CHO
O
O
4d
4e
C6H5CH2CH2NH2
4
80
4-FC6H4NH2
3,4,5-(CH3O)3C6H2CHO
CHO
5
6
7
80
85
4-FC6H4NH2
C6H5NH2
4f
5
3
4g
4-CH3C6H4CHO
3
4
4h
4i
78
75
C6H5NH2
C6H5NH2
4-ClC6H4CHO
4-CNC6H4CHO
8
9
4j
2-ClC6H4CHO
3
4
4
3
80
80
10
11
C6H5NH2
C6H5NH2
3-CH3OC6H4CHO
4k
4l
C6H5CHO
C6H5CHO
12
13
4-ClC6H4NH2
75
80
4m
4-CH3OC6H4NH2
a all the products are characterized by spectral analysis b isolated yields c room temperature

6
Table-3 continued
Amine(2)
Product(4n-4Y)a Time(hours)b
Aldehyde(1)
Yield(%)c
Entry
14
4.5
80
75
4n
C6H5NH2
C6H5NH2
C6H5NH2
C6H5CH=CHCHO
C4H3OCHO
4o
4.5
15
16
72
4p
5-CH3C4H2OCHO
C6H5CHO
4.5
75
85
75
4
17
4q
O
NH
3.5
4r
3-CH3OC6H4CHO
C6H5CH2NH2
C6H5CH2NH2
18
19
4
4s
C4H9CHO
C4H9CHO
C6H5CHO
4
78
78
4t
C6H5NH2
20
21
4u
3.5
3.5
3.5
C6H5CH2NH2
80
82
4v
C6H5CH2NH2
C6H5CH2NH2
22
23
4-CH3C6H4CHO
4w
4-ClC6H4CHO
CHO
4x
4y
75
75
4
C6H5CH2NH2
CH3(CH2)3
24
25
4.5
C6H5CHO
a all the products are characterized by spectral analysis b isolated yields c room temperature
In conclusion we have developed a clean and environmentally friendly alternative protocol for
the one pot synthesis of α-aminonitriles in good to excellent yields by using commercially
available inexpensive L-proline as an organocatalyst. The present protocol has several
advantages: mild reaction conditions, operational and experimental simplicity. We believe that
this L-proline promoted methodology will be a valuable addition for the synthesis of α-
aminonitriles which are important synthetic intermediates for the synthesis of biologically active
compounds and industrial materials.
Acknowlegdements
Dr. Aayesha Nasreen thanks the Head, Department of chemistry Dr. Rita M. Break for her
cooperation and Jazan University, for giving me an opportunity to continue research.

7
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45. Representative procedure is as follows: To a mixture of aldehyde 1 (1 mmol), amine 2 (1
mmol), and trimethylsilyl cyanide 3 (TMSCN) (1.2 mmol) in acetonitrile (5 mL) L-proline (
20 mol %) was added and the reaction mixture was stirred for the time specified in Table-3.
After completion of the reaction as indicated by TLC, the reaction mixture was quenched
with aqueous saturated NaHCO3 followed by brine solution and then extracted with
ethylacetate, dried over Na2SO4, concentrated under vacuum and the crude mixture was
purified by column chromatography on silica gel (hexane:ethylacetate 2:1) (Merck 100-200
mesh) to afford the corresponding pure α-aminonitriles 4a-4y (Table-3). All the products
are well characterized by spectral analysis (IR, 1H NMR,13C NMR, MS) elemental analysis
and were found to be identical with those reported in the literature.24, 35- 40
Spectral data for selected compounds: 2-(N-Anilino)-2-phenyl acetonitrile (4a): White
crystalline solid, m.p. 82-84oC. IR(KBr): 3369, 3025, 2955, 2229, 1604, 1517, 1480,
1
1317, 1148, 985, 769 cm-1; HNMR (500 MHz, DMSO-d6): d= 3.84 (d, 1H,J = 8.0 Hz) 5.22
(d, 1H, J= 8.4 Hz), 6.62 (d, 2H, J= 8.0 Hz), 6.76 (t,1H, J= 8.0 Hz), 7.06-7.15 (m, 2H), 7.27-
7.35 (m, 3H), 7.43-7.46 (m, 2H) ppm; 13CNMR(125 MHz, DMSO-d6) d= 50.1, 114.6,
118.3, 120.8, 127.4, 129.5, 129.3, 133.9, MS (EI): m/z (%) 208 (M+); Anal. Calcd. for
C14H12N2: C,80.77; H, 5.77; N, 13.46 %; Found: C, 80.73; H, 5.70; N, 13.42 %.
2-(N-Anilino)-2-(4-cyano phenyl) acetonitrile (4i): Pale yellow solid, m.p.116-119oC.
1
IR(KBr): 3386, 2879, 2236, 1594, 1496, 1449, 1276, 1124, 1006, 789 cm-1; HNMR (500
MHz, DMSO-d6): d= 4.17 (bs, 1H), 5.59 (s,1H), 6.82 (d, 2H, J= 7.8 Hz), 6.98 (t, 1H, J= 7.4

10
13
Hz), 7.34 (t, 2H, J =7.6 Hz), 7.82 (s, 4H) ppm; CNMR (125MHz, DMSO-d6): d= 49.7,
114.3, 118.2, 120.9, 127.2, 129.6, 133.1, 144.2 ppm;MS(EI): m/z (%) 233 (M+); Anal.Calcd.
for C15H11N3: C,77.25; H, 4.72; N, 18.03 %; Found: C, 77.37; H,4.68; N, 18.05 %.
o
2-(N-Anilino)-2-(2-chloro phenyl) acetonitrile (4j): White solid, m.p. 66-69 C. IR(KBr):
1
3401, 2903, 2239, 1603, 1507, 1459, 1294, 1146, 1007, 786 cm-1; HNMR (500 MHz,
DMSO-d6 ): d= 3.84 (d, 1H, J = 7.5 Hz), 5.56 (d, 1H, J= 8.1 Hz), 6.62 (d, 2H, J= 8.1 Hz),
6.74 (t, 1H,J= 7.7 Hz), 7.07 (t, 2H, J = 8.2 Hz), 7.20–7.24 (m, 2H), 7.28-7.30 (m, 1H),
7.54-7.57 (m, 1H) ppm; 13CNMR (125 MHz, DMSO-d6): d= 50.3, 55.7, 114.5, 118.3, 119.2,
120.4, 129.7, 130.2, 135.144.9 ppm; MS (EI): m/z (%) 243 (M+); Anal.Calcd. for
C14H11N2Cl: C, 69.28; H, 4.55; N, 11.57 %; Found: C, 69.22; H, 4.45; N, 11.46 %.
o
2-(N-4-Chloroanilino)-2-phenyl acetonitrile (4l): White solid, m.p. 109-110 C. IR (KBr):
1
3377, 2898, 2228, 1611, 1509, 1450, 1299, 1122, 1018, 781 cm-1; HNMR(500 MHz,
DMSO-d6): d= 3.83 (bs, 1H), 5.22 (d, 1H, J= 6.0 Hz), 6.58 (d, 2H, J= 7.77 Hz), 6.77 (t, 1H,
J= 7.2 Hz), 7.05 (t, 2H, J= 8.0 Hz), 7.29 (d, 2H, J= 8.77 Hz), 7.44 (d, 2H, J= 8.4 Hz) ppm;
13CNMR(125 MHz, DMSO-d6): d= 50.2, 115.5, 117.7, 124.6, 127.2, 129.3, 129.5, 130.2,
133.6, 143.4 ppm; MS (EI): m/z(%) 243 (M+); Anal.Calcd. for C14H11N2Cl: C, 69.25; H,
4.54; N, 11.53 %; Found: C, 69.29; H, 4.52; N, 11.55%.
o
2-(N-4-Methoxyanilino)-2-phenyl acetonitrile (4m): White solid, m.p. 94-97 C. IR (KBr):
1
3369, 3035, 2928, 2249, 1597, 1505, 1445, 1306, 1105, 993, 779 cm-1; HNMR(500 MHz,
DMSO-d6 ): d= 3.61(s, 3H), 3.73 (bs, 1H), 5.13 (d, 1H, J= 6.4 Hz), 6.52 (d, 2H, J= 8.0 Hz),
13
6.60 - 6.73 (m, 3H), 7.07 (d, 2H, J= 8.0 Hz), 7.45 (d, 2H, J = 8.1 Hz) ppm; CNMR(125
MHz, DMSO-d6 ): d= 48.5, 114.7, 117.9, 120.4, 121.6, 127.3, 128.7, 129.9, 132.6, 135.7,
144.4 ppm; MS (EI): m/z (%) 238 (M+); Anal. Calcd. for C15H14N2O: C, 75.63; H, 5.88; N,
11.77 %; Found: C, 75.64; H, 5.92; N, 11.78 %.
o
2-(N-Anilino)-2-cinnamyl acetonitrile (4n): Pale yellow solid, m.p. 110-112 C. IR (KBr):
1
3349, 2934, 2222, 1609, 1505, 1463, 1278, 1035, 978, 894, 778 cm-1; HNMR (500 MHz,
DMSO-d6): d= 3.94 (d, 1H,J= 9.7 Hz), 5.06 -5.10 (m, 1H), 6.34 (dd, 1H, J= 4.7, 15.9 Hz),
6.83(d, 1H, J= 8.2 Hz), 6.96 (t, 1H, J= 8.5 Hz), 7.09 (d, 1H, J= 16.4 Hz), 7.35-7.47 (m, 8H)
13
ppm; CNMR (125 MHz, DMSO-d6 ): d= 47.5, 114.7, 117.4, 120.7, 121.4, 126.6, 128.9,
128.7, 129.9, 134.7, 135.2, 144.8 ppm; MS(EI): m/z (%) 234 (M+) ; Anal. Calcd. for
C16H14N2: C, 82.05; H, 5.98; N, 11.96%; Found: C, 82.11; H, 5.97; N, 12.01%.

11
2-(N-Anilino)-2-furfuryl acetonitrile (4o): Dark brown solid, m.p. 68-70 oC. IR (KBr): 3359,
2985, 2247, 1648, 1565, 1503, 1445, 1296, 1254, 1148, 1015, 889, 754 cm-1; 1HNMR (500
MHz, DMSO-d6): d= 4.21 (bs, 1H), 5.59 (d, 1H, J= 6.9 Hz), 6.49 (t, 1H, J= 2.7 Hz), 6.68 (d,
1H, J= 3.6 Hz), 6.89 (d, 2H, J= 7.9 Hz), 6.99 (t, 1H, J= 7.6 Hz), 7.37 (t, 2H, J= 7.8 Hz), 7.56
(d, 1H, J= 1.0 Hz) ppm; 13CNMR (125 MHz, DMSO-d6): d= 48.3, 111.4, 111.6, 116. 5,
122.7, 129.8, 134.5, 137.4, 146.7 ppm; MS (EI): m/z (%) 198(M+); Anal. Calcd. for
C12H10N2O: C, 72.73; H, 5.05; N, 14.14 %; Found: C, 72.74; H,5.04; N,14.13 %.
2-(N-Benzylamino)-2-phenyl acetonitrile (4u): Colorless oil; IR (neat): 3408, 2925, 2235,
1
1649, 1518, 1409 cm-1; H NMR (300. MHz, CDCl3): d= 1.80 (brs, 1H), 3.96 (q, J= 13.5
Hz, 2H), 4.71 (s, 1H), 6.77 (d, J= 8.0 Hz, 1H), 7.14 (t, J= 7.8 Hz, 1H), 7.25-7.44 (m, 6H),
7.48-7.53 (m, 2H) ppm; 13CNMR(125 MHz, DMSO-d6): d= 51.6, 53.7, 119.2, 128.6, 128.9,
129.3, 129.4, 130.6, 135.3, 138.5, 143.9 ppm; MS (EI): m/z (%) 222 (M+), Anal.Calcd for
C15H14N2: C,81.05; H, 6.35; N,12.60 %; found: C, 80.05, H, 6.25, N, 12.36 %.
2-(N-Benzylamino)-2-isopropyl acetonitrile (4x): Colorless oil; IR (neat): 3365, 3020, 2945,
1
2862, 2234, 1506, 1465,1315cm-1; H NMR (300MHz, CDCl3): d= 1.05 (d,J= 6.6 Hz, 3H),
1.08 (d, J= 6.6 Hz, 3H), 1.55 (brs, 1H), 1.95-2.00 (m, 1H), 3.26 (d, J= 6.0 Hz, 1H), 3.84 (d,
J= 13.0 Hz, 1H), 4.08 (d, J= 13.0 Hz, 1H), 7.21-7.46 (m, 5H) ppm; 13CNMR (125MHz,
DMSO-d6): d = 17.9, 18.1, 29.3, 51.9, 53.3, 118.3, 127.5, 128.4, 128.7, 137.4 ppm; MS (EI):
m/z (%) = 188 (M+) Anal.Calcd for C12H16N2: C, 76.56; H, 8.57; N, 14.88 % Found C,
76.46; H, 8.58; N, 14.76 %.

12
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L ‐Proline catalyzed one pot synthesis of
α‐aminonitriles
Aayesha Nasreen
CN
O
R2
L-Proline ( 20 mol %)
RT
R2NH2
+
R1
+
TMSCN
N
H
R1
H
CH3CN ,
R1, R2 = alkyl, aryl
4a-4y
2
3
1
L - Proline ( 20 mol % ) was found to be an efficient organocatalyst for one pot synthesis of a variety
of α-aminonitriles from aldehydes (1), amines (2) and trimethylsilyl cyanide (TMSCN, 3) in
acetonitrile at ambient temperature giving good to excellent yields (72-95 %).