Rhodium(III) iodide hydrate catalyzed three-component coupling reaction: synthesis of α-aminonitriles from aldehydes, amines, and trimethylsilyl cyanide

Article abstract of DOI:10.1016/j.tet.2008.03.106

Aryl imines formed from aldehydes and amines undergo smoothly in situ nucleophilic addition with trimethylsilyl cyanide (TMSCN) in the presence of catalytic amount of hydrated rhodium(III) iodide to?afford the corresponding α-aminonitriles in excellent yield. The low catalytic loading (2 mol %), mild experimental conditions, and short reaction time (mostly within 13 min) represent the key features of this novel catalytic system.

Full text of DOI:10.1016/j.tet.2008.03.106

Tetrahedron 64 (2008) 5509–5514
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rhodium(III) iodide hydrate catalyzed three-component coupling reaction:
synthesis of
a-aminonitriles from aldehydes, amines, and trimethylsilyl cyanide
*
Anjoy Majhi, Sung Soo Kim , Santosh T. Kadam
Department of Chemistry, Inha University, Incheon 402-751, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl imines formed from aldehydes and amines undergo smoothly in situ nucleophilic addition with
trimethylsilyl cyanide (TMSCN) in the presence of catalytic amount of hydrated rhodium(III) iodide
to afford the corresponding a-aminonitriles in excellent yield. The low catalytic loading (2 mol %), mild
experimental conditions, and short reaction time (mostly within 13 min) represent the key features of
this novel catalytic system.
Received 18 February 2008
Received in revised form 28 March 2008
Accepted 28 March 2008
Available online 3 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Strecker reaction
Rhodium(III) iodide hydrate
Aldehydes
Amines
Trimethylsilyl cyanide
a
-Aminonitriles
1. Introduction
reports using without catalyst.7 But their reaction time lies in the
range of hours. Solid catalysts such as heteropoly acids8 and gua-
The Strecker reaction is one of the most efficient and straight-
forward methods for the synthesis of
-aminonitriles,1 which
are very useful precursors for the synthesis of -amino acids and
various nitrogen containing heterocycles such as imidazoles and
thiadiazoles, etc.2
-Amino acids are in turn of great biological
and economical importance due to their significance in chemistry
and biology, and are useful as chiral building blocks.3 The classical
Strecker reaction is generally carried out by the nucleophilic
addition of cyanide ion to the imines using different Lewis acid or
Lewis base catalysts.4 Subsequently, several modifications of the
Strecker reaction have been reported using a variety of cyanating
nidine hydrochloride9 have been employed for the synthesis of
a-
a
aminonitriles. Most recently, a method utilizing 5 mol % Fe(Cp)2PF6
a
was reported for the synthesis of a-aminonitriles of ketones and
aldehydes.10 However, many methods involve the use of strong
acidic conditions, extended reaction time, and tedious work up
leading to the generation of a large amount of toxic waste. There-
fore, there is a need of an efficient method for the synthesis of
a
a-aminonitriles in terms of shorter reaction time and in excellent
yield.
In light of our success in developing several catalytic systems for
the synthesis of chiral11 and achiral cyanosilylether,12 we extend
them to the Strecker reaction. We wish to herein report a simple
agents such as
a-trimethylsiloxynitriles and diethylphosphor-
ocyanidate under various reaction conditions.5 The use of TMSCN
is a safer and more effective cyanide anion source for the nucleo-
philic addition reactions compared to hydrogen cyanide, sodium
cyanide, or potassium cyanide.
method for the synthesis of a-aminonitriles in the presence of
a catalytic amount (2 mol %) of rhodium(III) iodide hydrate in ace-
tonitrile at rt (Scheme 1).
Me3SiCN
Recently, numerous methods have also been developed for the
synthesis of a-aminonitriles from aldehydes, amines, and TMSCN or
tributyltincyanide catalyzed by various Lewis acids such as lithium
perchlorate, polymeric scandium triflamide, vanadyl triflate, NiCl2,
BiCl3, zinc halides, RuCl3, ytterbium triflate, montmorillonite, io-
dine, and La(NO3)3$6H2O or GdCl3$6H2O, etc.6 There are also a few
NHR'
CN
O
RhI3 H O (2 mol%)
.
2
R'-NH2
+
H
R
R
CH3CN, r.t.
Scheme 1.
2. Results and discussions
The Strecker reaction of 4-chlorobenzaldehyde, benzyl amine,
and TMSCN in various solvents is examined in the presence of
* Corresponding author. Fax: þ82 32 867 5604.
E-mail address: sungsoo@inha.ac.kr (S.S. Kim).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.106

5510
A. Majhi et al. / Tetrahedron 64 (2008) 5509–5514
catalytic amount of rhodium(III) iodide hydrate at rt. As shown
in Table 1, 1 mol % RhI3$H2O gives -aminonitriles with 85% yield
aldehydes such as 2-furaldehyde and cinnamaldehyde both form the
aminocyano compound in good yield. This may indicate that the
catalyticsystemselectivelyactivates thecarbonylfunctionandkeeps
the furan ring and double bond of cinnamaldehyde intact.
a
in 10 min in CH3CN (entry 2), while decreasing the catalyst loading
up to 0.5 mol % it gives lower yield of 70% in 10 min (entry 1). With
2 mol % catalyst the yield is increased that affords the corre-
sponding 2-(benzylamino)-2-(4-chlorophenyl)acetonitrile in 99%
yield within 10 min (entry 3). RhI3$H2O (5 mol %) also gives 99%
yield in 10 min. The solvents examined were dichloromethane,
chloroform, benzene, tetrahydrofuran, and acetonitrile. Among
these solvents tested, acetonitrile is shown to be the best (Table 1).
Accordingly, 2 mol % RhI3$H2O catalyst loading in CH3CN as a sol-
This method requires no additives to promote the reaction. No
cyanohydrin trimethylsilyl ethers (an adduct between aldehyde
and trimethylsilylcyanide) were obtained under these reaction
conditions probably because of the rapid formation of the imine
intermediate by rhodium(III) iodide hydrate. It is noteworthy that
when carrying out the reaction with acetophenone, 65% of Strecker
product and 30% cyanohydrin trimethylsilyl ethers are obtained.
This means that ketones undergo mixed reactions of both Strecker
reaction and cyanosilylation. The imine prepared from acetophe-
none and benzylamine undergoes reaction in the presence of
vent is considered optimal for the synthesis of
A variety of aldehydes including aromatic, aliphatic as well
-unsaturated ones and different amines were coupled with
a-aminonitriles.
as a,b
TMSCN under these conditions at rt (Table 2). Only 50–60% reaction
conversion was observed without catalyst in acetonitrile at rt even
after 1 h. The reaction of benzaldehyde with benzyl amine or aniline
is completed within 10 min with 97 and 95% yield, respectively
(entries 1 and 2). Similar reaction of benzaldehyde with p-methyl
benzyl amine takes place in 12 min with 95% yield (entry 3). The
p-methoxybenzaldehyde or p-tolualdehyde with benzyl amine also
proceeds nicely within 12 min with 92 and 93% yield, respectively
(entries5and6). Benzaldehydeor4-chlorobenzaldehydereactswith
cyclohexylamine to give ‘relatively’ reduced yield of the products
(entries 4 and 9). 4-Methoxy benzyl amine, 4-chlorobenzaldehyde,
and TMSCN give 97% yield in 10 min (entry 10). The reaction of
3-fluoro or 3-phenoxy benzaldehyde with benzyl amine produces
the corresponding products in excellent yield of 98 and 99% in 10 and
12 min, respectively (entries 11 and 13). m-Phenoxybenzaldehyde
reacts with aniline or p-methyl benzyl amine so as to give 96% yield
within10 min(entries12and14). Itshouldbenotedthatthereaction
of 4-nitrobenzaldehyde and benzyl amine gave no reaction product
at all. This indicates that strongly electron-withdrawing substituent
such as p-nitro may not induce the Strecker reaction (entry 15).
2 mol % RhI3$H2O with TMSCN to give 70%
The reaction of ammonia as an amine source with acetophenone
yields no product of -aminonitriles in presence of 2 mol %
a-aminonitriles in 1 h.
a
RhI3$H2O even after 2 h. Instead 60% cyanosilylation product was
isolated after overnight stirring. In contrast to our reaction time and
low catalyst loading (2 mol %), 5–10 h is required in the presence of
10 mol % of BiCl3.6e With montmorillonite KSF clay as a catalyst,6i
3.0–5.5 h is consumed for completion of the reaction in the pres-
6j
ence of 1.0 g clay; 1–8 h of reaction time and 20 mol % I2 is nec-
essary for completion of the reaction. Recently, a method utilizing
5 mol % Fe(Cp)2PF6 is reported where 20 min is needed for the
synthesis of
2 mol % RhI3$H2O is a very efficient catalyst in terms of reaction
a
-aminonitriles.10 From these result, it is evident that
time and yield for the synthesis of a-aminonitriles.
3. Summary
In conclusion, we have described a very simple, convenient, and
practical method for the synthesis of -aminonitriles through three-
a
component coupling reaction of aldehydes, amines, and TMSCN
using rhodium(III) iodide hydrate. The reaction with acetophenone
gives 65% of Strecker product and 30% of cyanohydrin trimethylsilyl
ether. The major advantage of this method is that operational sim-
plicity at rt within a short reaction time and low catalyst loading
(2 mol %). This reaction may require the shortest reaction time and
the lowest catalyst quantity of all the previous studies in recent
years. Excellent yield is obtained for both aromatic and aliphatic
aldehydes. Studies concerning the asymmetric reaction as well as
the application of the rhodium(III) iodide hydrate in the synthesis of
a,b-Unsaturated cinnamaldehyde offers 99% yield of the corre-
sponding aminocyano compound in 8 min (entry 16), whereas
hydrocinnamaldehyde produces 91% yield in 12 min (entry 17). The
reaction of hexanal and heptaldehyde gives the corresponding
products in 88 and 91% yield, respectively (entries 18 and 19). This
indicates that aliphatic aldehydes entail ‘comparatively’ lower yield
with ‘longer’ reaction time (20 min). 2-Furaldehyde (entries 20 and
21) creates the corresponding aminonitrile compound in good yield
again in longer reaction time (18 and 25 min). The acid sensitive
chiral a-aminonitriles are in progress.
Table 1
4. Experimental section
4.1. General
Three-component synthesis of
a
-aminonitriles under various conditionsa
Me3SiCN
HN
CHO
RhI3 H O
NH2
.
2
+
CN
In all cases the 1H NMR (200 MHz) spectra were recorded with
Varian Gemini 2000 spectrometer. Chemical shifts are reported in
parts per million in CDCl3 with tetramethylsilane as internal stan-
dard. 13C NMR data were collected on a Varian Gemini 2000 spec-
trometer (100 MHz). GC–MS were recorded with 1200L Single
Quadrupole GC/MS System with 3800GC/Varian.
All the chemicals were purchased from Aldrich and Fluka.
Solvents were obtained from commercial sources and purified us-
ing standard methods if necessary. Flash chromatography silica gel
(230–400 mesh) was used for column chromatography and thin-
layer chromatography was performed on Merck-precoated Silica
gel 60-F254 plates.
CH3CN, r.t.
Cl
Cl
Entry
Catalyst (mol %)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
0.5
1.0
2.0
5.0
2.0
2.0
2.0
2.0
10
10
10
10
15
15
25
30
70
85
99
99
92c
86d
90e
66f
a
RhI3$H2O was added to a mixture of 1 mmol of benzaldehyde, 1 mmol of benzyl
amine, and 1.2 mmol of TMSCN.
b
Isolated yield.
In the presence of CH2Cl2.
In the presence of CHCl3.
In the presence of THF.
4.2. General procedure for the synthesis of a-aminonitriles
c
d
e
To a mixture of aldehyde (1 mmol) and amine (1 mmol) in
acetonitrile (1 ml) were added TMSCN (1.2 mmol) and rhodium(III)
f
In the presence of benzene.

A. Majhi et al. / Tetrahedron 64 (2008) 5509–5514
5511
Table 2
Rhodium(III) iodide hydrate catalyzed three-component synthesis of
a
-aminonitrilesa
Entry
Aldehyde
Amine
Product
Time (min)
10
Yield (%)
97
HN
CN
1
C6H5CHO
Ph
NH2
NHPh
CN
2
3
C6H5CHO
C6H5CHO
C6H5NH2
10
12
95
95
HN
NH2
4-MeC6H4
CN
HN
Me
4
5
C6H5CHO
C6H11NH2
13
12
90
92
CN
HN
4-MeOC6H4CHO
Ph
NH2
NH2
CN
CN
MeO
Me
HN
6
7
4-MeOC6H4CHO
4-ClC6H4CHO
12
10
93
96
Ph
NHPh
CN
C6H5NH2
Cl
HN
8
9
4-ClC6H4CHO
4-ClC6H4CHO
10
17
99
89
Ph
NH2
CN
Cl
HN
C6H11NH2
CN
Cl
HN
10
11
4-ClC6H4CHO
3-FC6H4CHO
10
10
97
98
NH2
CN
OMe
4-MeOC6H4
Cl
HN
F
Ph
NH2
CN
NHPh
CN
PhO
12
13
3-PhOC6H4CHO
3-PhOC6H4CHO
C6H5NH2
10
12
96
99
HN
PhO
Ph
NH2
CN
CN
HN
PhO
14
15
3-PhOC6H4CHO
4-NO2C6H4CHO
10
96
NH2
4-MeC6H4
CN
Me
HN
1 h
N.R.
Ph
NH2
O2N
(continued on next page)

5512
A. Majhi et al. / Tetrahedron 64 (2008) 5509–5514
Table 2 (continued )
Entry
Aldehyde
Amine
Product
Time (min)
8
Yield (%)
99
HN
CHO
CHO
16
17
18
19
Ph
NH2
NH2
NH2
NH2
Ph
Ph
Ph
CN
HN
12
20
20
91
88
91
Ph
Ph
Ph
Ph
CN
HN
CHO
CN
HN
CHO
CN
NHPh
20
21
C6H5NH2
18
25
93
90
CHO
CHO
O
O
O
CN
H
N
Ph
Ph
NH2
NH2
O
CN
HN
22
C6H5COCH3
C6H5COCH3
1 h
2 h
65b
CN
CH3
NH2
CN
23
NH3
N.Rc
CH3
a
The structures of the products were settled from spectral (IR, 1H, 13C NMR, and GC–MS) data. The spectral data (IR, 1H, and 13C NMR) of the compounds are compared with
the literature values.6d,e,i,7,10,13
b
Reaction of acetophenone, benzyl amine, and TMSCN gives 65% of Strecker product and 30% of cyanohydrin trimethylsilyl ether in 1 h.
Cyanosilylation product (60%) was isolated after overnight stirring.
c
ꢀ
iodide hydrate (9.5 mg, 2 mol %) at rt. The completion of the
reaction was monitored with TLC and then reaction mixture was
filtered. The filtrate was concentrated and the viscous mass was
subjected to silica gel flash column chromatography (silica gel, 4%
137.08; GC–MS, m/z: 236 [Mþ ], 104; HRMS calcd for C16H16N2:
236.1313, found: 236.1315.
4.2.4. 2-(N-Cyclohexylamino)-2-phenylacetonitrile (entry 4)
Yield 192 mg; colorless crystal, mp 56–58 ꢁC; IR (KBr) 3316,
2928, 2226, 1472, 1119, 926, 757, 696; 1H NMR (CDCl3, 200 MHz):
EtOAc in hexane) to obtain pure a-aminonitrile compounds.
The spectral (IR, 1H, 13C NMR, GC–MS, and HRMS) data of some
representative products are given below. Our IR values are com-
pared with the literature values. Entries 3, 9, 10, and 14 are newly
prepared compounds.
d
1.24–1.38 (m, 4H), 1.66–1.80 (m, 6H), 2.04 (br s, 1H), 2.88 (q,
J¼6 Hz, 1H), 4.84 (s, 1H), 7.38–7.56 (m, 5H); 13C NMR (CDCl3,
100 MHz):
d
24.08, 25.77, 33.65, 51.45, 54.63, 119.16, 127.10, 128.76,
ꢀ
130.11, 135.46; GC–MS, m/z: 214 [Mþ ].
4.2.1. 2-(N-Benzylamino)-2-phenylacetonitrile (entry 1)
Yield 215 mg; colorless oil; IR (KBr): 3321, 3030, 2227, 1641,
4.2.5. 2-(N-Benzylamino)-2-(4-methoxyphenyl)acetonitrile
(entry 5)
1544, 1419, 1267, 1105, 1027, 921, 825, 749; 1H NMR (CDCl3,
200 MHz):
d
4.02 (q, J¼13.5 Hz), 4.76 (s, 1H), 7.32–7.46 (m, 8H), 7.59
50.91, 53.14, 118.54, 127.06,
Yield 232 mg; yellow oil; IR (KBr): 3332, 2930, 2221, 1600, 1503,
(m, 2H); 13C NMR (CDCl3, 100 MHz):
d
1431, 1240, 1018, 930, 754; 1H NMR (CDCl3, 200 MHz):
d
1.8 (br s,
1H), 3.83 (s, 3H), 4.01 (q, J¼13.2 Hz, 2H), 4.72 (s, 1H), 6.92–6.96 (m,
2H), 7.49–7.28 (m, 7H); 13C NMR (CDCl3, 100 MHz):
51.8, 53.4,
127.32, 128.38, 128.69, 128.74, 129.44, 134.55, 137.94; GC–MS: m/z:
ꢀ
222 [Mþ ], 195, 106, 91.
d
55.4,114.9,119.4, 127.4, 128.2,128.9,129.5, 132.5,138.9,145.2,159.8;
ꢀ
4.2.2. 2-(N-Anilino)-2-phenylacetonitrile (entry 2)
GC–MS, m/z: 252 [Mþ ].
Yield 197 mg; white solid, mp 75–76 ꢁC; IR (KBr): 3365, 3032,
2950, 2235, 1602, 1501, 1451, 1316, 1267, 933, 752, 693; 1H NMR
4.2.6. 2-(N-Benzylamino)-2-tolylacetonitrile (entry 6)
(CDCl3, 200 MHz):
J¼7.8 Hz, 1H), 7.31 (t, J¼7.8 Hz, 2H), 7.46–7.51 (m, 3H), 7.60–7.64 (m,
2H); 13C NMR (CDCl3, 100 MHz):
49.88, 114.0, 118.16, 119.95,
d
5.42 (s, 1H), 6.81 (d, J¼8.0 Hz, 2H), 6.98 (t,
Yield 219 mg; colorless oil; IR (KBr): 3324, 3029, 2227, 1580,
1495, 1219, 1022, 919, 772, 696; 1H NMR (CDCl3, 200 MHz):
d 1.82
d
(br s, 1H), 2.38 (s, 3H), 4.01 (q, J¼13.2 Hz, 2H), 4.72 (s, 1H), 7.21 (d,
127.04, 128.30, 129.34, 129.97, 133.75, 144.54; GC–MS, m/z: 208
J¼8.0 Hz, 2H), 7.28–7.45 (m, 7H); 13C NMR (CDCl3, 100 MHz):
ꢀ
[Mþ ], 181, 92.
d
21.12, 51.21, 53.19, 118.86, 127.19, 127.59, 128.39, 128.60, 129.60,
ꢀ
138.97; GC–MS, m/z: 236 [Mþ ], 209 [ꢂHCN], 91.
4.2.3. 2-(4-Methylbenzylamino)-2-phenylacetonitrile (entry 3)
Yield 224 mg; colorless oil; IR (KBr): 3340, 3030, 2912, 2225,
1610, 1505, 1457, 1220, 1090, 930, 825, 750, 696; 1H NMR (CDCl3,
4.2.7. 2-(Anilino)-2-(4-chlorophenyl)acetonitrile (entry 7)
Yield 233 mg; white solid, mp 108–110 ꢁC; IR (KBr): 3405, 2928,
200 MHz):
(s, 1H), 7.20–7.60 (m, 9H); 13C NMR (CDCl3, 100 MHz):
53.24, 118.62, 127.11, 128.19, 128.78, 129.12, 129.54, 134.65, 134.86,
d
2.02 (br s,1H), 2.40 (s, 3H), 4.03 (q, J¼13.2 Hz, 2H), 4.77
2232, 1609, 1522, 1458, 1260, 1080, 782; 1H NMR (CDCl3, 200 MHz):
d
21.10, 50.90,
d
4.09 (br s, 1H), 5.41 (s, 1H), 6.76 (d, J¼8.0 Hz, 2H), 6.93 (t, J¼7.8 Hz,
1H), 7.26–7.30 (m, 2H), 7.42 (d, J¼8.0 Hz, 2H), 7.54 (d, J¼8.0 Hz, 2H);

A. Majhi et al. / Tetrahedron 64 (2008) 5509–5514
5513
13C NMR (CDCl3, 100 MHz):
d
49.54, 114.25, 117.81, 120.47, 128.51,
4.2.15. (E)-2-(Benzylamino)-4-phenylbut-3-enenitrile (entry 16)
ꢀ
129.24, 129.54, 132.90, 135.49, 144.32; GC–MS, m/z: 242 [Mþ ].
Yield 244.8 mg; brown oil; IR (KBr): 3260, 3010, 2220, 1600,
1499, 1219, 772; 1H NMR (200 MHz, CDCl3):
d 2.70 (br s, 1H, NH),
4.2.8. 2-(Benzylamino)-2-(4-chlorophenyl)acetonitrile (entry 8)
Yield 252.8 mg; light yellow oil; IR (KBr): 3340, 2929, 2227,
1598, 1490, 1221, 1067, 919, 770, 691; 1H NMR (CDCl3, 200 MHz):
4.08 (q, J¼13.5 Hz, 2H), 4.40 (m, 1H), 6.28 (dd, J¼6.0, 17.0 Hz, 1H),
6.93 (d, J¼2.0, 16.8 Hz, 1H), 7.30–7.44 (m, 10H); 13C NMR (CDCl3,
100 MHz):
d 49.8, 50.9, 118.0, 122.3, 127.0, 127.3, 127.9, 128.3, 128.5,
d
1.97 (br s, 1H), 4.02 (q, J¼13.3 Hz, 2H), 4.75 (s, 1H), 7.54–7.34 (m,
129.0, 133.8, 135.1, 138.0; GC–MS, m/z: 248 [Mþ], 157, 90.
9H); 13C NMR (CDCl3, 100 MHz):
d
51.47, 53.0, 118.52, 127.91, 128.56,
ꢀ
128.85, 129.30, 133.39, 135.18, 138.02; GC–MS, m/z: 256 [Mþ ].
4.2.16. 2-(Benzylamino)-4-phenylbutanenitrile (entry 17)
Yield 227 mg; colorless oil; IR (KBr): 3318, 2225, 1736, 1496,
4.2.9. 2-(4-Chlorophenyl)-2-(cyclohexylamino)acetonitrile
(entry 9)
1454, 1244; 1H NMR (CDCl3, 200 MHz):
d
2.06–2.19 (m, 3H), 2.88 (t,
J¼2.0 Hz), 3.47–3.54 (m, 1H), 3.97 (q, J¼13.2 Hz, 2H), 7.19–7.41 (m,
10H); 13C NMR (CDCl3,100 MHz):
31.65, 35.05, 48.90, 51.56,119.97,
Yield 219.5 mg; yellow oil; IR (KBr): 3320, 2226, 1219, 772, 673;
d
1H NMR (CDCl3, 200 MHz):
d
1.19–1.32 (m, 6H), 1.72–1.78 (m, 4H),
126.25, 127.40,128.11, 128.22,128.41, 128.45, 138.15,139.74; GC–MS,
1.98 (br s, 1H), 2.83 (m, 1H), 4.80 (s, 1H), 7.36 (d, J¼8.0 Hz, 2H), 7.45
m/z: 250 [Mþ], 160.
(d, J¼8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
d 25.87, 31.91, 3385,
51.03, 54.82, 118.94, 128.63, 129.02, 134.05, 134.86; GC–MS, m/z:
4.2.17. 2-(Benzylamino)heptanenitrile (entry 18)
ꢀ
248 [Mþ ].
Yield 190 mg; colorless liquid; IR (KBr): 3340, 2930, 2846, 1490,
1102, 750, 678; 1H NMR (CDCl3, 200 MHz):
d
0.8–1.0 (m, 3H), 1.1–1.4
(m, 6H),1.65 (m, 2H), 3.39 (m,1H), 3.70 (q, J¼13.0 Hz, 2H), 7.22–7.33
(m, 5H); 13C NMR (CDCl3, 100 MHz):
14.10, 22.67, 23.23, 31.67,
4.2.10. 2-(4-Chlorophenyl)-2-(4-methoxylbenzylamino)acetonitrile
(entry 10)
d
Yield 277.7 mg; light yellow oil; IR (KBr): 3322, 2932, 2228, 1611,
34.37, 51.75, 53.06, 119.05, 127.46, 128.03, 128.60, 140.31; GC–MS,
1491, 1248, 1219, 1093, 1033, 920, 772; 1H NMR (CDCl3, 200 MHz):
m/z: 216 [Mþ], 92.
d
2.06 (br s, 1H), 3.82 (s, 3H), 3.91 (q, J¼13.2 Hz, 2H), 4.72 (s, 1H),
6.89–6.94 (m, 2H), 7.28–7.51 (m, 6H); 13C NMR (CDCl3, 100 MHz):
4.2.18. 2-(Benzylamino)octanenitrile (entry 19)
d
50.50, 52.50, 55.17, 113.86, 118.21, 128.45, 128.97, 129.44, 129.67,
Yield 208.5 mg; brown oil; IR (KBr): 3321, 3030, 2928, 2857,
ꢀ
133.12, 134.70, 158.91; GC–MS, m/z: 286 [Mþ ], 120.
2220, 1453, 1219, 1132, 1028, 772, 698; 1H NMR (CDCl3, 200 MHz):
d
0.84 (t, J¼7.8 Hz, 3H), 1.21–1.44 (m, 8H), 1.66 (q, J¼7.1 Hz, 2H), 2.04
(br s, 1H), 3.40 (t, J¼7.8 Hz, 1H), 3.77 (q, J¼13.2 Hz, 2H), 7.20–7.28
(m, 5H); 13C NMR (CDCl3, 100 MHz):
13.97, 22.38, 25.47, 28.57,
4.2.11. 2-(Benzylamino)-2-(3-fluorophenyl)acetonitrile (entry 11)
Yield 235.5 mg; colorless oil; IR (KBr): 3325, 3030, 2230, 1614,
1592, 1487, 1243, 1139, 1075, 964, 771, 699; 1H NMR (200 MHz,
d
31.41, 33.42, 49.65, 51.53, 120.21, 127.10, 127.66, 128.24, 138.32; GC–
ꢀ
CDCl3):
d
4.02 (q, J¼13.0 Hz, 2H), 4.77 (s, 1H), 7.11 (d, J¼8.0 Hz, 1H),
MS, m/z: 230 [Mþ ], 203.
7.30–7.46 (m, 8H); 13C NMR (CDCl3, 100 MHz):
d
51.0, 52.7, 114.5,
116.0, 118.1, 122.7, 127.6, 128.2, 128.5, 130.3, 137.0, 137.7, 164.0; GC–
4.2.19. 2-(N-Anilino)-2-furfurylacetonitrile (entry 20)
ꢀ
MS, m/z: 240 [Mþ ], 107, 105, 91; HRMS calcd for C15H13FN2:
Yield 183.6 mg; brown solid, mp 67–69 ꢁC; IR (KBr): 3360, 2923,
240.1063, found: 240.1062.
2229, 1680, 1599, 1509, 1440, 1228, 1167, 1014, 880, 751; 1H NMR
(CDCl3, 200 MHz):
d
4.14 (d, J¼8.0 Hz, 1H), 5.36 (d, J¼8.0 Hz, 1H),
4.2.12. 2-(3-Phenoxyphenyl)-2-(phenylamino)acetonitrile
(entry 12)
6.38 (m, 1H), 6.51 (m, 1H), 6.80–6.92 (m, 3H), 7.23–7.45 (m, 3H); 13
C
NMR (CDCl3, 100 MHz):
d 48.22, 111.10, 111.93, 116.35, 122.40,
ꢀ
Yield 287.8 mg; yellow solid, mp 64–66 ꢁC; IR (KBr): 3375, 3037,
2923, 2230, 1602, 1499, 1456, 1250, 1219, 1163, 1023, 967, 751, 692;
129.97, 134.42, 137.20, 146.15; GC–MS, m/z: 198 [Mþ ].
1H NMR (200 MHz, CDCl3):
d
3.79 (br s, 1H), 5.39 (s, 1H), 6.68–6.84
4.2.20. 2-(N-Benzylamino)-2-furfurylacetonitrile (entry 21)
Yield 190 mg; colorless oil; IR (KBr): 3325, 2928, 2223, 1590,
1500, 1432, 1250, 1130, 1057, 880, 751; 1H NMR (CDCl3, 200 MHz):
(m, 2H), 6.92 (t, J¼7.6 Hz, 1H), 7.06–7.48 (m, 11H); 13C NMR (CDCl3,
100 MHz):
d 49.75, 114.14, 115.06, 117.25, 118.48, 118.98, 120.20,
121.49, 123.86, 129.42, 129.87, 130.57, 135.74, 144.39, 156.15, 158.11;
d
1.98 (br s, 1H), 3.97 (q, J¼13.0 Hz, 2H), 4.76 (s, 1H), 6.27–6.30 (m,
ꢀ
GC–MS, m/z: 300 [Mþ ], 273.
1H), 7.18–7.50 (m, 7H); 13C NMR (CDCl3, 100 MHz):
d
47.78, 51.37,
109.2, 111.50, 127.67, 127.84, 128.52, 128.96, 138.22, 143.80, 147.90;
ꢀ
4.2.13. 2-(Benzylamino)-2-(3-phenoxyphenyl)acetonitrile
(entry 13)
GC–MS, m/z: 212 [Mþ ].
Yield 310.5 mg; light yellow oil; IR (KBr): 3365, 3029, 2925,
4.2.21. 2-Benzylamino-2-phenylpropionitrile (entry 22)
2226, 1580, 1440, 1106, 1019, 825, 753, 692; 1H NMR (200 MHz,
Yield 153 mg; colorless liquid; IR (KBr): 3320, 3063, 3030, 2984,
2849, 2223, 1958, 1897, 1811, 1603, 1494, 1447, 1372, 1214, 1152,
CDCl3):
7.05–7.13 (m, 2H), 7.22–7.47 (m, 12H); 13C NMR (CDCl3, 100 MHz):
50.8, 52.8, 117.3, 118.2, 118.7, 118.9, 121.5, 123.4, 127.3, 128.0, 128.0,
d
2.3 (br s, 1H, NH), 4.03 (q, J¼13.4 Hz, 2H), 4.76 (s, 1H),
1075, 1037, 863, 765, 700 cmꢂ1 1H NMR (200 MHz, CDCl3):
; d 1.83
d
(s, 3H), 3.82 (q, J¼13.0 Hz, 2H), 7.28–7.68 (m, 10H); 13C NMR
129.6, 129.9, 136.4, 137.7, 156.2, 157.5; GC–MS, m/z: 315 [MþH], 314
(100 MHz, CDCl3):
d
31.5, 49.9, 60.5, 121.1, 125.3, 127.3, 127.9, 128.2,
ꢀ
ꢀ
[Mþ ]; HRMS calcd for C21H18N2O: 314.1419, found: 314.1418.
128.5, 129.0, 138.7, 139.5; GC–MS, m/z: 236 [Mþ ].
4.2.14. 2-(4-Methylbenzylamino)-2-(3-phenoxyphenyl)acetonitrile
(entry 14)
Acknowledgements
Yield 315 mg; colorless oil; IR (KBr): 3330, 3035, 2925, 2220,
The authors thank the Centre for Biological Modulators for the fi-
nancial support. Authors also thank BK21 provided to Inha University.
1584, 1485, 1219, 1163, 772, 692; 1H NMR (CDCl3, 200 MHz):
d
2.14
(br s, 1H), 2.42(s, 1H), 4.00 (q, J¼13.4 Hz, 2H), 4.75 (s, 1H), 7.07–7.46
(m, 13H); 13C NMR (CDCl3, 100 MHz):
21.06, 50.74, 52.83, 117.40,
d
References and notes
118.35, 118.88, 118.95, 121.59, 123.52, 128.15, 129.07, 129.66, 129.82,
ꢀ
134.70, 136.55, 137.03,156.33, 157.63; GC–MS, m/z: 328 [Mþ ], 104;
1. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
HRMS calcd for C22H20N2O: 328.1576, found: 328.1573.
2. Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ. Chem. Rev.1989, 58,148–162.

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