Expedient N-arylation for the synthesis of 2-arylamino-3-cyanopyridines using ionic copper(I) complex as a catalyst

Article abstract of DOI:10.3987/COM-12-12461

The N-arylation of 2-amino-3-cyanopyridines is firstly described by using ionic copper(I) complex (Phen)₂Cu⁺BF₄ ^- (phen = 1,10-phenanthroline) as an efficient catalyst. The synthetic protocol can be applied to synthesize a wide range of 2-arylamino-3-cyanopyridine products in good to excellent isolated yields. The resulted products are potentially building blocks for further preparation of biologically interesting products or useful ligands for metal catalysis.

Full text of DOI:10.3987/COM-12-12461

HETEROCYCLES, Vol. 85, No. 6, 2012
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HETEROCYCLES, Vol. 85, No. 6, 2012, pp. 1393 - 1404. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 12th March, 2012, Accepted, 16th April, 2012, Published online, 27th April, 2012
DOI: 10.3987/COM-12-12461
EXPEDIENT
N-ARYLATION
FOR
THE
SYNTHESIS
OF
2-ARYLAMINO-3-CYANOPYRIDINES USING IONIC COPPER(I)
COMPLEX AS A CATALYST
Min Zhang,* Biao Xiong, Ting Wang, Xiaoting Wang, Fengxia Yan, and
Yuqiang Ding*
1School of Chemical and Material Engineering and the Key Laboratory of Food
Colloids and Biotechnology, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi 214122, China (email:
zm31289@yahoo.com.cn)
Abstract — The N-arylation of 2-amino-3-cyanopyridines is firstly described by
-
using ionic copper(I) complex (Phen)2Cu+BF4 (phen = 1,10-phenanthroline) as an
efficient catalyst. The synthetic protocol can be applied to synthesize a wide range
of 2-arylamino-3-cyanopyridine products in good to excellent isolated yields. The
resulted products are potentially building blocks for further preparation of
biologically interesting products or useful ligands for metal catalysis.
INTRODUCTION
2-Arylamino-3-cyanopyridines constitute significant important structural units found in numerous
bioactive products,1 pigments2 and functional materials.3 Additionally, such a class of compounds can
serve as synthetically interesting building blocks for preparation of bioactive heterocycles4 or
nitrogen-containing ligands for metal catalysis.5 Generally, 2-arylamino-3-cyanopyridines can be
prepared by multicomponent reactions.6 In spite of these elegant contributions, to the best of our
knowledge,
copper-catalyzed
N-arylation
(or
so-called
Ullmann-type
coupling)
of
2-amino-3-cyanopyridines with aryl halides has not been performed yet, such a strategy can provide an
alternative pathway for the synthesis of 2-arylamino-3-cyanopyridines. However, the challenging points
for such a transformation are associated with the steric hindrance of ortho-cyano group on pyridine
skeleton, or the nitrogen atoms in substrates may competitively occupy the coordination sites of copper
catalysts that could decrease the catalyst activity.7

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HETEROCYCLES, Vol. 85, No. 6, 2012
Owing to the economic attractiveness and excellent functional tolerance of copper catalysis, copper is
considered as a desired alternative for toxic or expensive transition-metal catalysts (i.e. palladium,
rhodium) in some aspects.8 Notably, the application of copper-catalyzed Ullmann-type coupling reactions
has regained considerable attention during the past decade since the breakthrough was achieved by the
group of Buchwald and others.9 Generally, the related catalytic systems were formed by in situ generation
of active copper species in the presence of suitable copper precursors and ligands. However, the
development of efficient and well-defined copper complexes as the catalysts for C-N coupling reactions
still remains an interesting and demanding goal.
Drawing from the significant importance of 2-arylamino-3-cyanopyridines and our continuous interest in
developing efficient methodologies for the synthesis of pyridine-based products10 and finding their
applications in organometallic chemistry,11 we became interested in establishing a copper-catalyzed
N-arylation of 2-amino-3-cyanopyridines. Herein, we present our new protocol for realizing such a goal
-
by using ionic copper(I) complex (Phen)2Cu+BF4 as an efficient catalyst without introduction of
additional ligands (Scheme 1).
R1
R1
I
(Phen)2CuBF4 (5 mol%)
R2
CN
CN
+
R3
R3
N
NH2
N
3
N
H
R2
1
2
Scheme 1. N-Arylation of 2-amino-3-cyano-pyridines using ionic copper(I) complex as a catalyst
RESULTS AND DISCUSSION
In order to determine an efficient catalytic system, our investigation was initiated by using a
CuI/L-proline system which was developed by Ma and co-workers,12 and the synthesis of 2-N-arylated
product 3a from 2-amino-4,6-diphenylnicotinonitrile 1a and iodobenzene 2a was chosen as a model
reaction and conducted at 120 °C for 24 hours to evaluate the influence of different solvents on the
reaction efficiency. Among the solvents tested (Table 1, entries 1-4), DMSO showed the best reactivity
and resulted in 3a in 48% yield. Under the same reaction conditions, CuI in combination with
1,10-phenanthroline improved the product yield to 66% (Table 1, entry 5). However, the absence of
1,10-phenanthroline resulted in a low yield (Table 1, entry 6), which indicates that the nitrogen-ligand is
essential to promote such an arylation reaction. Subsequently, a variety of copper(I) and copper(II)
catalyst precursors in combination with 1,10-phenanthroline were explored for the model reaction (Table
1, entries 7-10). The obtained results showed that (MeCN)4CuBF4 exhibited excellent activity in the
formation of product 3a while 10 mol% of catalyst was used (Table 1, entry 10).

HETEROCYCLES, Vol. 85, No. 6, 2012
1395
Table 1. Screening catalytic system for the synthesis of 3aa
Ph
Ph
N
I
CN
CN
DMSO, K2CO3
cat, N2, 120 °C
Ph
N
NH2
Ph
NHPh
1a
2a
3a
Entry
Catalyst/Ligand
Base
Solvent Yield% of 3ab
1
2
CuI/L-proline
CuI/L-proline
CuI/L-proline
CuI/L-Proline
CuI/Phen
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
toluene
dioxane
DMF
<10
12
36
48
66
38
42
40
69
3
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
5
6
CuI/-
7
Cu(OAc)2/Phen
Cu(OTf)2/Phen
CuCl/Phen
8
9
10
Cu(MeCN)4BF4/
Phen
K2CO3
DMSO
(78, 72, 50)c
complex A
complex Ad
complex Ad
complex Ad
K2CO3
NaOH
NEt3
DMSO
DMSO
DMSO
DMSO
(80, 80, 58)c
11
12
13
14
52
21
78
Cs2CO3
a Reaction conditions: unless otherwise stated, the mixture of 1a (0.5 mmol, 135 mg), 2a (0.5 mmol, 102 mg), base
(1 mmol), solvent (1 mL), catalyst (10 mol%) and ligand (20 mol%) were stirred under N2 atmosphere in a schlenk
tube at 120 °C for 24 h.
b Isolated yields.
c Yields are with respect to 10 mol%, 5 mol% and 1 mol% of catalyst used, respectively.
d Catalyst loading: 5 mol%.
+
CH2Cl2, MeOH,
40 oC, 3 h
N
N
N
N
-
Cu
BF4
+ 2 Phen
Cu(MeCN)4BF4
-
Complex A: (Phen)2Cu+BF4 , 80%
Scheme 2. Synthesis of ionic copper(I) complex A
With the above-mentioned effective catalytic system in hand, we then tried to obtain a copper catalyst that
can catalyze the N-arylation of 2-amino-3-cyanopyridines in an efficient manner. Ionic copper(I) complex
featuring two bidentate ligand (phen = 1,10-phenanthroline) was prepared according to reported protocols
(Scheme 2).13 And further investigations showed that only 5 mol% of this complex were sufficient to

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HETEROCYCLES, Vol. 85, No. 6, 2012
result in a desired product yield without introduction of additional ligands (Table 1, entries 11). The
-
-
results clearly indicates that (Phen)2Cu+BF4 has better catalytic activity than that of (MeCN)4Cu+BF4 in
-
combination with 1,10-phenanthroline. The presence of (Phen)2Cu+BF4 also other inorganic and organic
bases can be used, although the product yields were relatively lower (Table 1, entries 12-14). Thus, the
-
use of 5 mol% of (Phen)2Cu+BF4 (complex A), 2 equivalent of K2CO3 in DMSO and at 120 °C was
chosen as the optimal conditions for our N-arylation.
R1
R1
CN
I
DMSO, K2CO3, N2, 120 °C
CN
R3
R3
Complex A (5 mol%)
N
NH2
R2
N
N
H
2
R2
1
3
1
2
2a
: R = H
2b: R3 = 4-Me
2c: R3 = 4-Br
1a
: R = H, R = H
3, yielda
OMe
1b: R1 = 4-OMe, R2 = H
1c: R1 = H, R2 = 4-Cl
1d: R1 = 4-OMe, R2 = 4-Cl
1
2
1e
: R = 2-Cl, R = H
: R = 2-Cl, R = 4-Cl
Ph
1
2
Ph
N
1f
Ph
CN
CN
NHPh
CN
N
CN
NHPh
N
Ph
N
Ph
N
NHPh
H
Cl
Cl
3a, (80%, 42%, trace)b
3b, 81%
3c, 72%
3d, 65%
OMe
OMe
OMe
Ph
CN
CN
N
N
CN
CN
H
Cl
N
N
H
Ph
N
N
H
Ph
Cl
N
NHPh
Cl
3e, 78%
3f, 71%
3g 69%
3h, 78%
Cl
Cl
CN
CN
Cl
CN
CN
N
NHPh
N
N
H
Ph
N
NHPh
Ph
N
N
Cl
Cl
H
3i, 72%
3j, 70%
3k, 83%
3l, 72%
Ph
CN
NH
Ph
Cl
CN
Br
CN
Br
Cl
Ph
N
CN
Br
N
N
H
N
N
H
Ph
N
N
H
Cl
Cl
NO2
3m, 61%
3n 60%
3o, 65%
3p, trace
Scheme 3.c N-Arylation of 2-amino-3-cyanopyridines with aryl halides
a Isolated yields are with respect to substrate 1 used.
b Yields are with respect to iodobenzene, bromobenzene and chlorobenzene used, respectively.
c Reaction conditions: the mixture of 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1 mmol), DMSO (1 mL) and complex
A (0.025 mmol) were stirred at 120 °C for 24 h under N2 atmosphere in schlenk tube.

HETEROCYCLES, Vol. 85, No. 6, 2012
1397
Subsequently, we examined the scope of this ionic copper(I) complex-catalyzed protocol by using a
variety combination of 2-amino-3-cyanopyridines 1 with aryl halides 2. As shown in Scheme 3, aryl
iodides were proven to be effective coupling partners, while aryl bromide and aryl chloride have low
reactivity in the formation of expected products (Scheme 3, see 3a). So we then focused on the
N-arylation reactions by using different aryl iodide reagents. All the reactions proceeded smoothly and
resulted in desired products in good to excellent yields (Scheme 3, 3a-3o). The electronic properties of
different aryl substituents on the pyridine skeleton have little influence on the formation of 2-N-arylated
products. However, the substituents on the aryl iodides have significant influence on the product yields.
Specifically, electron-rich aryl iodides favored the formation of 2-N-arylated products and gave relatively
higher product yields (Scheme 3, compared 3a-3l with 3m-3p). While aryl iodide bearing a strong
electron-withdrawing group (i. e. 1-iodo-4-nitrobenzene) gave only a trace amount of expected product
(Scheme 3, see 3p). The appeared phenomenon is in marked contrast to most Ullmann coupling systems
reported. It might be attributed to the reductive elimination step can significantly influence the product
formation in the catalytic cycle,14 and the discoveries will benefit the design of novel and efficient copper
catalysts for C-N coupling reactions of electron-rich halogenated substrates.
Scheme 4. N-Arylation by using pyridyl haldes as coupling partner
Furthermore, our protocol was tested by applying 3-bromopyridine 2d and 2-bromopyridine 2e as the
coupling partners. As described in Scheme 4, the reaction of 1b and 2d resulted in expected
mono-arylated product 4a in 60% yields (Scheme 2, eq. 1). Interestingly, diarylated product 4b and 4c
were obtained exclusively even using equimolar of 2-bromopyridine 2e with 1b or 1c. The N-diarylation
can be explained as the mono-arylated product arising from 2e can serve as a tridentate ligand by
replacing 1,10-phenanthroline ligand in complex A, and forming an active species that favor a second

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HETEROCYCLES, Vol. 85, No. 6, 2012
N-arylation. Notably, the diarylated products may serve as potentially valuable ligands for metal
catalysis,5 metal-based photosensitiser,15 and etc.
In conclusion, the N-arylation of 2-amino-3-cyano-pyridines was firstly established by using ionic
-
copper(I) complex (Phen)2Cu+BF4 as an efficient catalyst. This copper-catalyzed intermolecular
Ullmann-type coupling reaction can be applied for the synthesis of a wide range of
2-arylamino-3-cyano-pyridine products in good to excellent isolated yields. Diarylated products can also
be obtained while 2-bromopyridine was employed as a coupling reagent. We are convinced this synthetic
protocol is of general interest for preparation of 2-arylamino-3-cyano-pyridines and pyridine-based
ligands.
EXPERIMENTAL
All the obtained products (except 3a, 3d and 3f, all other products are new ones) were characterized by
1
13
melting points (mp), H-NMR, C-NMR, Low-resolution mass spectra (LRMS), and infrared spectra
(IR). Melting points were measured on an Electrothemal SGW-X4 microscopy digital melting point
apparatus and are uncorrected; IR spectra were recorded on a FTLA2000 spectrometer; 1H-NMR spectra
were obtained on Bruker-400. Chemical shifts were reported in parts per million (ppm, δ) downfield from
tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), and broad (br); MS was measured on ZMD-4000 spectrometer; TLC was performed using
commercially prepared 100-400 mesh silica gel plates (GF254), and visualization was effected at 254 nm;
All the reagents were purchased from commercial sources (Alfa, Acros, Aldrich), and used without
further purification.
Typical procedure for synthesis of polyfunctional 4,6-diphenyl-2-(phenylamino)nicotinonitrile (3a).
2-Amino-4,6-diphenylnicotinonitrile 1a (0.5 mmol, 135 mg), iodobenzene 2a (0.5 mmol, 102 mg),
-
K2CO3 (1 mmol, 138 mg) and (Phen)2Cu+BF4 (0.025 mmol, 13.7 mg) were added in a Schlenk tube, then
1 mL DMSO was added successively under N2 atmosphere, the resulting mixture was stirred at 120 °C
for 24 hours, after cooling to room temperature, the reaction mixture was filtered, then it was purified by
preparative TLC on silica, eluting with petroleum ether: EtOAc (10: 1) to provide desired products 3a.
-
Synthesis of complex (Phen)2Cu+BF4
-
Complex (Phen)2Cu+BF4 was synthesized following a similar procedure reported in the literature.13 To a
25 mL Schlenk tube was added (MeCN)4CuBF4 (0.2 mmol, 62.0 mg), Phen (0.4 mmol, 79.2 mg), then 5
mL methanol and 2 mL CH2Cl2 were added successively under N2 atmosphere, the resulting mixture was
stirred at 40 °C for 3 h. After the evaporation of solvent, the product was obtained as black brown powder.

HETEROCYCLES, Vol. 85, No. 6, 2012
1399
Yield: 80%; 1H NMR (400 MHz, CD2Cl2): δ 7.94-8.18 (m, 8H), 8.67-8.93 (m, 8H); IR (KBr, cm-1): νmax
=
1625, 1591, 1522, 1427, 1066, 842, 722.
Analytical Data of all obtained compounds
(1) 4,6-Diphenyl-2-(phenylamino)nicotinonitrile (3a)
Yield: 80%; yellow solid; mp 215-217 °C; 1H NMR (400 MHz, CDCl3): δ 7.17 (t, J = 7.2 Hz, 1H), 7.37
(br, 1H), 7.36 (s, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.50-7.52 (m, 3H), 7.55-7.60 (m, 3H), 7.68-7.70 (m, 2H),
13
7.79 (d, J = 7.6 Hz, 2H), 8.09-8.11 (m, 2H); C NMR (100 MHz, CDCl3): δ 158.99, 156.61, 155.49,
139.01, 137.95, 137.05, 130.36, 129.95, 129.04, 128.98, 128.89, 128.26, 127.48, 123.61, 120.67, 117.09,
111.54, 90.10; IR (KBr, cm-1): νmax = 3335, 2215, 1602, 1582, 1548, 1497, 1446, 1376, 1260, 1098, 1025,
802, 732, 684; MS (EI, m/z): 347 [M]+.
(2) 4,6-Diphenyl-2-(p-tolylamino)nicotinonitrile (3b)
Yield: 81%; yellow solid; mp 195-197 °C; 1H NMR (400 MHz, CDCl3): δ 2.40 (s, 3H), 7.24 (s, 2H), 7.26
13
(br, 1H), 7.33 (s, 1H), 7.49-7.58 (m, 6H), 7.64-7.70 (m, 4H), 8.08-8.10 (m, 2H); C NMR (100 MHz,
CDCl3): δ 158.97, 156.75, 155.43, 138.01, 137.12, 136.37, 133.27, 130.31, 129.90, 129.47, 129.01,
128.85, 128.25, 127.48, 120.89, 117.18, 111.22, 89.81, 20.91; IR (KBr, cm-1): νmax = 3329, 2928, 2215,
1608, 1577, 1550, 1513, 1524, 1492, 1458, 1408, 1256, 814, 757, 699; MS (EI, m/z): 361 [M]+.
(3) 6-(4-Chlorophenyl)-4-phenyl-2-(phenylamino)nicotinonitrile (3c)
Yield: 72%; yellow solid; mp 207-209 °C; 1H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 7.2 Hz, 1H), 7.32 (s,
1H), 7.42-7.49 (m, 4H), 7.57-7.60 (m, 3H), 7.67-7.69 (m, 2H), 7.73 (d, J = 8.0 Hz, 2H), 8.02-8.05 (m,
13
2H); C NMR (100 MHz, CDCl3): δ 157.69, 156.69, 155.74, 138.81, 136.87, 136.58, 136.33, 130.06,
129.13, 129.08, 129.00, 128.72, 128.22, 123.84, 120.84, 116.90, 111.29, 90.38; IR (KBr, cm-1): νmax
=
3328, 2214, 1614, 1584, 1541, 1498, 1432, 1375, 1094, 1164, 1129, 835, 766, 698; MS (EI, m/z): 382
[M]+.
(4) 6-(4-Chlorophenyl)-4-(4-methoxyphenyl)-2-(phenylamino)nicotinonitrile (3d)
Yield: 65%; yellow solid; mp 217-220 °C; 1H NMR (400 MHz, CDCl3): δ 3.92 (s, 3H), 7.17 (t, J = 7.2 Hz,
1H), 7.25 (s, 2H), 7.29 (br, 1H), 7.38 (s, 1H), 7.46-7.49 (m, 2H), 7.65 (t, J = 8.4 Hz, 2H), 7.73-7.78 (m,
4H), 8.00-8.04 (m, 2H); IR (KBr, cm-1): νmax = 3332, 2949, 2217, 1608, 1580, 1541, 1513, 1491, 1434,
1370, 1030, 826, 756, 693; MS (EI, m/z): 412 [M]+.
(5) 6-(4-Chlorophenyl)-4-phenyl-2-(p-tolylamino)nicotinonitrile (3e)
Yield: 78%; yellow solid; mp 216-218 °C; 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 7.23 (s, 2H), 7.25

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HETEROCYCLES, Vol. 85, No. 6, 2012
13
(s, 1H), 7.45-7.49 (m, 2H), 7.55-7.62 (m, 5H), 7.66-7.69 (m, 2H), 8.00-8.04 (m, 2H); C NMR (100
MHz, CDCl3): δ 157.69, 156.75, 155.63, 136.96, 136.50, 136.41, 136.18, 133.52, 130.00, 129.50, 129.07,
129.05, 128.71, 128.21, 121.07, 117.00, 110.96, 90.08, 20.92; IR (KBr, cm-1): νmax = 3328, 2945, 2216,
1610, 1580, 1546, 1513, 1490, 1449, 1410, 1397, 1364, 1253, 1091, 1013, 824, 762, 699; MS (EI, m/z):
396 [M]+.
(6) 6-(4-Chlorophenyl)-4-(4-methoxyphenyl)-2-(p-tolylamino)nicotinonitrile (3f)
Yield: 71%; yellow solid; mp 218-220 °C; IR (KBr, cm-1): νmax = 3324, 2921, 2217, 1609, 1580, 1546,
1511, 1491, 1448, 1418, 1368, 1255, 1092, 1029, 820, 790; MS (EI, m/z): 426 [M]+.
(7) 4-(4-Methoxyphenyl)-6-phenyl-2-(phenylamino)nicotinonitrile (3g)
Yield: 71%; yellow solid; mp 189-191 °C; 1H NMR (400 MHz, CDCl3): δ 3.92 (s, 3H), 7.07-7.11 (m, 2H),
7.16 (t, J = 7.2 Hz, 1H), 7.34 (s, 1H), 7.40-7.46 (m, 2H), 7.50-7.54 (m, 3H), 7.65-7.68 (m, 2H), 7.78 (dd,
13
J = 8.8 Hz, 2H), 8.08-8.11 (m, 2H); C NMR (100 MHz, CDCl3): δ 161.09, 158.83, 156.69, 155.07,
139.09, 138.07, 130.27, 129.71, 128.96, 128.86, 127.45, 125.68, 123.51, 120.61, 117.44, 114.48, 111.32,
89.79, 55.47; IR (KBr, cm-1): νmax = 3309, 2919, 2215, 1605, 1572, 1536, 1511, 1497, 1459, 1446, 1424,
1374, 1298, 1255, 1234, 1180, 1038, 832, 763, 732, 694; MS (EI, m/z): 377 [M]+.
(8) 4-(4-Methoxyphenyl)-6-phenyl-2-(p-tolylamino)nicotinonitrile (3h)
1
Yield: 78%; yellow solid; mp 229-231 °C; H NMR (400 MHz, CDCl3): δ 2.40 (s, 3H), 3.92 (s, 3H),
7.07-7.11 (m, 2H), 7.22 (br, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.31 (s, 1H), 7.48-7.53 (m, 3H), 7.64-7.67 (m,
4H), 8.07-8.10 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.04, 158.82, 156.84, 155.03, 138.12, 136.45,
133.16, 130.20, 129.70, 129.45, 129.35, 128.82, 127.44, 120.84, 117.53, 114.45, 111.01, 89.49, 55.46,
20.90; IR (KBr, cm-1): νmax = 3321, 2923, 2216, 1608, 1574, 1534, 1496, 1458, 1419, 1350, 1263, 1164,
1029, 829, 757, 696; MS (EI, m/z): 391 [M]+.
(9) 4-(2-Chlorophenyl)-6-phenyl-2-(p-tolylamino)nicotinonitrile (3i)
1
Yield: 72%; yellow solid; mp 187-188 °C; H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 7.12 (br, 1H),
7.25 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.43-7.52 (m, 6H), 7.58-7.61 (m, 1H), 7.65 (d, J = 8.4 Hz, 2H),
13
8.07-8.09 (m, 2H); C NMR (100 MHz, CDCl3): δ 158.86, 156.20, 153.27, 137.85, 136.24, 136.02,
133.36, 132.38, 130.75, 130.39, 130.31, 129.50, 128.86, 127.52, 127.18, 120.88, 116.25, 112.09, 91.53,
20.92; IR (KBr, cm-1): νmax = 3341, 2949, 2215, 1602, 1578, 1547, 1474, 1456, 1431, 1406, 1374, 1252,
1233, 1053, 963, 813, 755, 697; MS (EI, m/z): 396 [M]+.
(10) 4-(2-Chlorophenyl)-6-phenyl-2-(phenylamino)nicotinonitrile (3j)

HETEROCYCLES, Vol. 85, No. 6, 2012
1401
Yield: 75%; yellow solid; mp 167-168 °C; 1H NMR (400 MHz, CDCl3): δ 7.02 (t, J = 7.2 Hz, 1H), 7.22
(br, 1H), 7.28 (s, 1H), 7.40-7.50 (m, 8H), 7.56-7.58 (m, 1H), 7.76 (d, J = 7.6 Hz, 2H), 8.05-8.07 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 158.88, 156.06, 153.33, 138.90, 137.80, 135.96, 132.39, 130.81, 130.46,
130.39, 130.33, 129.00, 128.91, 127.54, 127.21, 123.70, 120.67, 116.16, 112.41, 91.85; IR (KBr, cm-1):
νmax = 3347, 2211, 1602, 1579, 1541, 1497, 1445, 1420, 1376, 1253, 1175, 1053, 1029, 961, 856, 761,
694; MS (EI, m/z): 382 [M]+.
(11) 4-(2-Chlorophenyl)-6-(4-chlorophenyl)-2-(p-tolylamino)nicotinonitrile (3k)
1
Yield: 83%; yellow solid; mp 205-206 °C; H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 7.18 (br, 1H),
7.23 (s, 1H), 7.22-7.27 (d, J = 8.4 Hz, 2H), 7.43-7.48 (m, 5H), 7.58-7.62 (m, 3H), 8.00 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3): δ 157.59, 156.21, 153.47, 136.59, 136.27, 136.05, 135.85, 133.62, 132.34,
130.85, 130.34, 129.52, 129.09, 128.76, 127.23, 121.07, 116.09, 111.83, 91.82, 20.93; IR (KBr, cm-1):
νmax = 3349, 2939, 2212, 1604, 1573, 1548, 1486, 1456, 1433, 1407, 1376, 1164, 1034, 961, 849, 757,
698; MS (EI, m/z): 430 [M]+.
(12) 4-(2-Chlorophenyl)-6-(4-chlorophenyl)-2-(phenylamino)nicotinonitrile (3l)
Yield: 72%; yellow solid; mp 200-201 °C; 1H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 8.4 Hz, 1H), 7.24
(br, 1H), 7.26 (s, 1H), 7.42-7.50 (m, 7H), 7.59-7.61 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 8.01 (dd, J = 6.8
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 157.61, 156.05, 153.52, 138.70, 136.67, 136.21, 135.77, 132.34,
130.90, 130.35, 129.14, 129.02, 128.77, 127.25, 123.90, 120.81, 115.99, 112.16, 92.12; IR (KBr, cm-1):
νmax = 3341, 2221, 1611, 1576, 1542, 1507, 1497, 1474, 1457, 1435, 1385, 1363, 1252, 1092, 1012, 961,
828, 757, 745, 691; MS (EI, m/z): 416 [M]+.
(13) 2-(4-Bromophenylamino)-4-(2-chlorophenyl)-6-phenylnicotinonitrile (3m)
1
Yield: 61%; yellow solid; mp 201-203 °C; H NMR (400 MHz, CDCl3): δ 7.22 (br, 1H), 7.33 (s, 1H),
7.42-7.49 (m, 3H), 7.50-7.57 (m, 5H), 7.59-7.61 (m, 1H), 7.68 (dd, J = 6.8 Hz, 2H), 8.05-8.07 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 158.90, 155.72, 153.43, 137.99, 137.62, 135.79, 132.35, 131.92, 130.89,
130.60, 130.36, 128.98, 127.49, 127.24, 122.23, 116.12, 116.00, 112.80, 92.09; IR (KBr, cm-1): νmax
=
3342, 2211, 1600, 1574, 1548, 1524, 1489, 1456, 1428, 1397, 1366, 1253, 1073, 1050, 1015, 961, 855,
811, 759, 703; MS (EI, m/z): 461 [M]+.
(14) 2-(4-Bromophenylamino)-6-(4-chlorophenyl)-4-phenylnicotinonitrile (3n)
Yield: 60%; yellow solid; mp 237-240 °C; 1H NMR (400 MHz, CDCl3): δ 7.06-7.10 (m, 3H), 7.42 (dd, J
13
= 8.8 Hz, 2H), 7.50 (s, 1H), 7.51-7.59 (m, 6H), 7.69 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H); C
NMR (100 MHz, CDCl3): δ 157.75, 155.77, 153.00, 137.88, 136.91, 132.65, 131.94, 130.16, 129.23,

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HETEROCYCLES, Vol. 85, No. 6, 2012
129.01, 128.51, 127.28, 127.09, 122.38, 118.43, 114.9, 111.67, 92.71; IR (KBr, cm-1): νmax = 3341, 2212,
1602, 1573, 1543, 1522, 1487, 1455, 1428, 1396, 1356, 1254, 1078, 1052, 1016, 961, 855, 813, 761, 702;
MS (EI, m/z): 461 [M]+.
(15) 2-(4-Bromophenylamino)-4-(2-chlorophenyl)-6-(4-chlorophenyl)nicotinonitrile (3o)
Yield: 65%; yellow solid; mp 197-199 °C; 1H NMR (400 MHz, CDCl3): δ 7.09 (dd, J = 6.8 Hz, 1H), 7.21
(br, 1H), 7.40-7.44 (m, 2H), 7.45-7.50 (m, 4H), 7.55 (dd, J = 6.8 Hz, 2H ), 7.64 (d, J = 8.8 Hz, 2H), 7.98
13
(d, J = 6.8 Hz, 2H); C NMR (100 MHz, CDCl3): δ 157.64, 155.72, 153.61, 137.79, 136.84, 136.04,
135.61, 132.65, 131.97, 130.98, 130.39, 129.22, 128.72, 127.28, 127.18, 122.36, 116.37, 115.82, 111.57,
92.38; IR (KBr, cm-1): νmax = 3343, 2922, 2209, 1596, 1577, 1546, 1488, 1401, 1367, 1256, 1093, 1071,
1012, 830, 809, 759, 735; MS (EI, m/z): 495 [M]+.
(16) 4-(4-Methoxyphenyl)-6-phenyl-2-(pyridin-3-ylamino)nicotinonitrile (4a)
1
Yield: 60%; yellow solid; mp 211-213 °C; H NMR (400 MHz, CDCl3): δ 3.93 (s, 3H), 7.10 (d, J = 8.8
Hz, 2H), 7.25 (br, 1H), 7.37 (m, 1H), 7.40 (s, 1H), 7.51-7.54 (m, 3H), 7.67 (d, J = 8.8 Hz, 2H), 8.06-8.08
13
(m, 2H), 8.20-8.22 (m, 1H), 8.41 (d, J = 4.4 Hz, 1H), 9.03 (d, J = 2.4 Hz, 1H); C NMR (100 MHz,
CDCl3): δ 161.22, 158.96, 156.35, 155.26, 142.40, 137.77, 135.92, 132.44, 130.50, 130.11, 129.74,
128.98, 127.43, 124.16, 123.48, 115.66, 114.54, 112.11, 90.22, 55.48; IR (KBr, cm-1): νmax = 3297, 2923,
2215, 1605, 1570, 1536, 1513, 1483, 1457, 1422, 1403, 1372, 1264, 1235, 1185, 1026, 832, 765, 695; MS
(EI, m/z): 378 [M]+.
(17) 2-(Dipyridin-2-ylamino)-4-(4-methoxyphenyl)-6-phenylnicotinonitrile (4b)
1
Yield: 69%; yellow solid; mp 171-172 °C; H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H), 7.02 (d, J = 8.8
Hz, 2H), 7.08-7.11 (m, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.37-7.39 (m, 3H), 7.60 (d, J = 8.8 Hz, 2H), 7.64 (s,
13
1H), 7.68-7.70 (m, 2H), 7.83-7.85 (m, 2H), 7.19 (dd, J = 4.8 Hz, 2H); C NMR (100 MHz, CDCl3): δ
158.90, 157.18, 155.72, 153.43, 148.67, 137.99, 135.79, 131.92, 130.89, 130.60, 130.36, 128.98, 127.49,
127.24, 122.23, 116.12, 116.00, 112.80, 92.09, 55.43; IR (KBr, cm-1): νmax = 2929, 2853, 2221, 1608,
1586, 1532, 1513, 1468, 1429, 1375, 1278, 1255, 1180, 1029, 835, 770, 741, 693; MS (EI, m/z): 455
[M]+.
(18) 4-(2-Chlorophenyl)-2-(dipyridin-2-ylamino)-6-phenylnicotinonitrile (4c)
Yield: 53%; yellow solid; mp 154-156 °C; 1H NMR (400 MHz, CDCl3): δ 7.13 (dd, J = 7.2 Hz, 2H), 7.22
(d, J = 8.0 Hz, 2H), 7.39-7.47 (m, 6H), 7.54-7.57 (m, 1H), 7.63 (s, 1H), 7.71-7.75 (m, 2H), 7.71 (dd, J =
8.0 Hz, 2H), 8.45 (dd, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 158.19, 157.92, 155.98, 153.04,
147.69, 136.92, 136.10, 134.58, 131.59, 129.78, 129.66, 129.31, 129.20, 127.71, 126.37, 126.12, 119.10,

HETEROCYCLES, Vol. 85, No. 6, 2012
1403
117.83, 116.32, 113.84, 102.69; IR (KBr, cm-1): νmax = 3056, 2963, 2854, 2225, 1577, 1538, 1469, 1430,
1376, 1312, 1240, 1150, 1056, 995, 891, 769, 738, 696; MS (EI, m/z): 460 [M]+.
ACKNOWLEDGEMENT
The authors are grateful to the funds of the National Natural Science Foundation of China (21101080),
Fundamental Research Funds for the Central Universities of China (JUSRP10905, JUSRP211A07 and
1045210372090460), Natural Science Foundation of Jiangsu Province (SBK201122766), and “333 Talent
Project of Jiangsu Province”.
REFERENCES AND NOTES
1
(a) J. L. Bolliger, M. Oberholzer, and C. M. Frech, Adv. Synth. Catal., 2011, 353, 945; (b) V. Onnis,
M. T. Cocco, R. Fadda, and C. Congiu, Bioorg. Med. Chem., 2009, 17, 6158.
2
3
M. L. H. Mantel, A. T. Lindhardt, D. Lupp, and T. Skrydstrup, Chem. Eur. J., 2010, 16, 5437.
(a) M. K. Leung, A. B. Mandal, C. C. Wang, G. H. Lee, S. M. Peng, H. L. Cheng, G. R. Her, I. Chao,
H. F. Lu, Y. C. Sun, M. Y. Shiao, and P. T. Chou, J. Am. Chem. Soc., 2002, 124, 4287; (b) M. Xue
and C. F. Chen, Chem. Commun., 2011, 47, 2318.
4
5
6
(a) X. P. Wang, L. J. Ma, and W. Yu, Synthesis, 2011, 2445; (b) S. Mishra and R. Ghosh, Synthesis,
2011, 21, 3463; (c) O. R. Thiel, M. M. Achmatowicz, A. Reichelt, and R. D. Larsen, Angew. Chem.
Int. Ed., 2010, 49, 8395; (d) H. Wang, Y. Wang, C. Peng, J. Zhang, and Q. Zhu, J. Am. Chem. Soc.,
2010, 132, 13217.
(a) C. Romain, S. Gaillard, M. K. Elmkaddem, L. Toupet, C. Fischmeister, C. M. Tomas, and J. L.
Renaud, Organometallics, 2010, 29, 1992; (b) E. Ruba, A. Hummel, K. Mereiter, R. Schmid, and K.
Kirchner, Organometallics, 2002, 21, 4955; (c) T. Gosavi, C. Wagner, K. H. Merzweiler, H. Schmidt,
and D. Steinborn, Organometallics, 2005, 24, 533.
(a) B. Jiang, C. Li, S. J. Tu, and F. Shi, J. Comb. Chem., 2010, 12, 482; (b) Z. G. Han, C. B. Miao, F.
Shi, N. Ma, G. Zhang, and S. J. Tu, J. Comb. Chem., 2010, 12, 16; (c) Y. Wan, R. Yuan, F. R. Zhang,
L. L. Pang, R. Ma, C. H. Yue, W. Lin, W. Yin, R. C. Bo, and H. Wu, Synth. Commun., 2011, 41, 2997;
(d) S. J. Tu, B. Jiang, Y. Zhang, R. H. Jia, J. Y. Zhang, C. S. Yao, and F. Shi, Org. Biomol. Chem.,
2007, 5, 355.
7
8
M. Zhang, S. Imm, S. Baehn, H. Neumann, and M. Beller, Angew. Chem. Int. Ed., 2011, 50, 11197.
(a) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, and M. Lemaire, Chem. Rev., 2002, 102, 1359; (b) T.
Schulz, C. Torborg, S. Enthaler, B. Schaffner, A. Dumrath, A. Spannenberg, H. Neumann, A. Borner,
and M. Beller, Chem. Eur. J., 2009, 15, 4528.

1404
HETEROCYCLES, Vol. 85, No. 6, 2012
9
(a) F. Monnier and M. Taillefer, Angew. Chem. Int. Ed., 2009, 48, 6954; (b) M. Carril, R. SanMartin,
and E. Dominguez, Chem. Soc. Rev., 2008, 37, 639; (c) A. Klapars, J. C. Antilla, X. Huang, and S. L.
Buchwald, J. Am. Chem. Soc., 2001, 123, 7727.
10 (a) M. Zhang, T. Roisnel, and P. H. Dixneuf, Adv. Synth. Catal., 2010, 352, 1896; (b) M. Zhang, B.
Xiong, T. Wang, Y. Q. Ding, and L. Wang, Heterocycles, 2011, 83, 2289; (c) M. Zhang, B. Xiong, W.
Yang, D. N. T. Kumar, and Y. Q. Ding, Monatsh. Chem., 2012, 143, 471.
11 W. Yang, H. Fu, Q. J. Song, M. Zhang, and Y. Q. Ding, Organometallics, 2011, 30, 77.
12 (a) L. T. Xu, Y. W. Jiang, and D. W. Ma, Synlett, 2010, 15, 2285; (b) X. Lu, L. Shi, H. Zhang, and D.
W. Ma, Tetrahedron, 2010, 66, 5714; (c) L. Guo, B. Li, W. L. Huang, G. Pei, and D. W. Ma, Synlett,
2008, 12, 1833; (d) B. L.Zou, Q. L. Yuan, and D. W. Ma, Angew. Chem. Int. Ed., 2007, 46, 2598.
13 (a) K. Moriwaki, K. Satoh, T. Takada, Masahiro, Y. Ishino, and T. Ohno, Tetrahedron Lett., 2005, 46,
7559; (b) A. A. Schilt and R. C. J. Taylor, Inorg. Nucl. Chem., 1959, 9, 211.
14 S. L. Zhang and Y. Q. Ding, Organometallics, 2011, 30, 633.
15 (a) A. Hagfeldt, G. Boschloo, L. C. Sun, L. Kloo, and H. Pettersson, Chem. Rev., 2010, 110, 6595;
(b) F. Gartner, A. Boddien, E. Barsch, K. Fumino, S. Losse, H. Junge, D. Hollmann, A. Bruckner, R.
Ludwig, and M. Beller, Chem. Eur. J., 2011, 17, 6425.