A multicomponent synthesis of 2-amino-3-cyanopyridine derivatives catalyzed by heterogeneous and recyclable copper nanoparticles on charcoal

Article abstract of DOI:10.5935/0103-5053.20150327

An efficient and convenient method was developed for synthesis of 2-amino-3-cyanopyridine derivatives via the four-component coupling reaction between ketone, aldehyde, malononitrile, and ammonium acetate in the presence of 2 molpercent copper nanoparticles on charcoal (Cu/C) catalyst. A variety of ketones and aldehydes was used to afford the corresponding products in good to excellent yields. The method is applicable to large-scale operation without any problem. The catalyst could be quantitatively recovered from the reaction mixture by simple filtration and reused at least eight times with almost consistent activity.

Full text of DOI:10.5935/0103-5053.20150327

http://dx.doi.org/10.5935/0103-5053.20150327
J. Braz. Chem. Soc., Vol. 27, No. 4, 759-768, 2016.
Printed in Brazil - ©2016 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
A Multicomponent Synthesis of 2-Amino-3-cyanopyridine Derivatives Catalyzed by
Heterogeneous and Recyclable Copper Nanoparticles on Charcoal
Reza Khalifeh* and Mahdiyeh Ghamari
Department of Chemistry, Shiraz University of Technology, 71555-313 Shiraz, Iran
An efficient and convenient method was developed for synthesis of 2-amino-3-cyanopyridine
derivatives via the four-component coupling reaction between ketone, aldehyde, malononitrile, and
ammonium acetate in the presence of 2 mol% copper nanoparticles on charcoal (Cu/C) catalyst.A
variety of ketones and aldehydes was used to afford the corresponding products in good to excellent
yields. The method is applicable to large-scale operation without any problem. The catalyst could
be quantitatively recovered from the reaction mixture by simple filtration and reused at least eight
times with almost consistent activity.
Keywords: 2-amino-3-cyanopyridine, Cu/C, heterogeneous catalyst, multicomponent reaction
Introduction
condensation reaction,18 as well as via a one pot four
components reaction19,20 in conventional heating or under
microwave irradiation, and also by some other methods.21,22
In recent efforts to develop more facile methods for the
synthesis of 2-amino-3-cyanopyridines, metal-catalyzed
reactions have been developed.19
In recent years, the use of heterogeneous catalysts has
received considerable interest in organic synthesis. Using
heterogeneous catalysts in synthetic organic routes has
some advantages over their counterparts, such as great
durability toward the reaction conditions, having highly
active sites, recyclability and reusability of catalyst.23
Recently, we have reported copper nanoparticles on
charcoal (Cu/C) as an excellent heterogeneous catalyst for
synthesis of triazole, propargylamine and benzimidazole
derivatives.24-26
Basedontheabovementionedreportsandincontinuation
of our efforts to develop facile and general methods for the
preparation of 2-amino-3-cyanopyridine derivatives, and
as a part of our studies to utilize heterogeneous catalyst
for the synthesis of organic compounds,27-31 here we wish
to report a heterogeneous catalyst system based on Cu/C
and illustrate its application for the synthesis of 2-amino-
3-cyanopyridine derivatives without any cocatalyst or
activator under mild conditions.
Pyridine moieties are common substructures in
numerous natural products, pharmaceuticals, and functional
materials.1-3 Polysubstituted pyridines possess important
biological and pharmacological activities and could be used
as potential agrochemicals, for example as herbicides.4 In
addition, the molecules containing pyridine moiety are used
as non linear optical materials,5 electrical materials,6 and
chelating agents in metal ligand chemistry.7 Among them,
2-amino-3-cyanopyridines are known as IKK-β-inhibitors.8
They have been identified to possess multiple biological
activities such as antimicrobial,9 antiviral,10 antibacterial,11
antifungal,12 antitumor,13 anti-inflammatory,14 as well as
antihypertensive15 properties. Besides, they are important
and useful intermediates in preparing a variety of
heterocyclic compounds.12,16
The interesting biological properties of these
compounds have promoted a great deal of research effort
toward development of new synthetic methodologies
for the preparation of 2-amino-3-cyanopyridines and
their derivatives. Therefore, the synthesis of 2-amino-3-
cyanopyridine derivatives continues to attract much interest
in organic chemistry.
A survey of the literature shows that the major synthetic
approaches that are used to prepare various types of
2-amino-3-cyanopyridine derivatives involve utilization
of corresponding 2-chloro derivatives as substrates,17
chalcones on treatment with ammonium acetate via the
Experimental
Instrumentation, analyses and starting material
Nuclear magnetic resonance (NMR) spectra were
*e-mail: khalifeh@sutech.ac.ir

760
A Multicomponent Synthesis of 2-Amino-3-cyanopyridine Derivatives
J. Braz. Chem. Soc.
recorded on a Bruker Avance DPX-250 spectrometer
(1H NMR at 250 MHz and 13C NMR at 62.5 MHz) in
pure deuterated solvents with tetramethylsilane (TMS) as
an internal standard. Infrared (IR) spectra were obtained
using a Shimadzu FTIR 8300 spectrophotometer. Mass
spectra were determined on a Shimadzu GCMS-QP
1000 EX instrument at 70 or 20 eV. Elemental analyses
were performed with a Thermo Finnigan CHNS-O 1112
series analyzer. Melting points were determined in open
capillary tubes in a Büchi 535 circulating oil melting point
apparatus. The purity determination of the substrates and
reaction monitoring were accomplished by thin-layer
chromatography (TLC) on silica gel PolyGram SILG/
UV 254 plates. Column chromatography was carried out
on short columns of silica gel 60 (70-230 mesh) in glass
columns (2-3 cm diameter) using 15-30 g of silica gel per
g crude mixture. Chemical materials were purchased from
Fluka, Aldrich and Merck. The used activated carbon was
also purchased from Merck (Art. No. 9631, 0.3-0.05 mm).
2-Amino-4,6-diphenylnicotinonitrile (1)
White solid; m.p. 176-177 °C; IR (KBr) νmax / cm-1
3465 (w), 3379 (w), 3306 (w), 3181 (w), 2207 (s), 1641
(s), 1585 (s), 1574 (s), 1550 (m), 1497 (w), 1452 (w), 1370
(w), 1259 (w), 759 (s), 699 (s); 1H NMR (250 MHz, CDCl3)
d 5.38 (s, 2H), 7.22 (s, 1H), 7.46-7.66 (m, 7H), 7.99 (d,
13
2H, J 2.1 Hz), 8.00-8.03 (m, 1H); C NMR (62.5 MHz,
CDCl3) d 111.3, 116.0, 117.2, 127.3, 128.2, 128.4, 128.8,
128.9, 129.7, 129.8, 130.2, 136.9, 137.4, 137.9, 150.0,
155.1, 159.8, 160.3; ESI-MS (%) 273 ([M + 2]+, 0.5), 272
([M + 1]+, 4.6), 271 ([M+], 9.0), 167 (11.7), 149 (34.0), 129
(14.1), 113 (10.3), 97 (23.1), 73 (39.9), 57 (100.0); anal.
calcd. for C18H13N3 (271.316): C, 79.68; H, 4.83; found:
C, 79.81; H, 4.97.
2-Amino-4-(4-methylphenyl)-6-phenylnicotinonitrile (2)
White solid; m.p. 160-161 °C; IR (KBr) νmax / cm-1 3468
(w), 3364 (w), 3310 (w), 3237 (w), 2216 (m), 1579 (s), 1570
(s), 1548 (s), 1516 (m), 1448 (w), 1368 (w), 1284 (w), 811
(m), 766 (m), 701 (m); 1H NMR (250 MHz, CDCl3) d 2.44
(s, 3H), 5.33 (s, 2H), 7.20 (d, 1H, J 0.9 Hz), 7.26 (d, 1H,
J 0.9 Hz), 7.32 (t, 1H, J 6.9 Hz), 7.45-7.51 (m, 3H), 7.55
(d, 2H, J 8.0 Hz), 7.90-8.02 (m, 2H); 13C NMR (62.5 MHz,
CDCl3) d 21.4, 111.2, 119.9, 127.3, 128.1, 128.3, 128.4,
128.8, 128.9, 129.6, 130.1, 155.0, 160.0; ESI-MS (%) 287
([M + 2]+, 8.3), 286 ([M + 1]+, 28.8), 285 ([M+], 45.3), 233
(21.1), 206 (14.9), 149 (30.7), 133 (25.9), 111 (18.1), 91
(100.0), 69 (85.9); anal. calcd. for C19H15N3 (285.343): C,
79.98; H, 5.30; found: C, 79.85; H, 5.44.
Synthesis of copper nanoparticles on charcoal (Cu/C)
The activated carbon (1.0 g) was refluxed in nitric
acid solution (5.0 mol L-1, 30 mL) for 6 h, washed with
deionized water until pH 6-7 and finally dried in an oven
at 110 °C for 12 h under vacuum. For the synthesis of
Cu/C, CuI (100 mg) was dissolved in absolute ethanol
(30 mL), and stirred at reflux temperature for 4 h under
nitrogen atmosphere in the presence of 1.0 g of purified
activated carbon. The resulting solid was washed with
ethanol (4 × 30 mL). Finally, the copper in charcoal
was dried under vacuum in an oven overnight at
110 °C.24
2-Amino-4-(4-methoxyphenyl)-6-phenylnicotinonitrile (3)
White solid; m.p. 182-183 °C; IR (KBr) νmax / cm-1
3467 (w), 3309 (w), 3187 (w), 2350 (s), 2337 (m), 2207
(w), 1700 (w), 1636 (m), 1576 (m), 1517 (s), 1256 (m),
1
General procedure
1181 (w), 1026 (w); H NMR (250 MHz, CDCl3) d 3.87
(s, 3H), 5.34 (s, 2H), 7.04 (dd, 2H, J 6.7, 2.1 Hz), 7.19 (s,
1H), 7.46 (d, 2H, J 1.9 Hz), 7.48-7.50 (m, 1H), 7.61 (dd,
2H, J 6.7, 2.1 Hz), 7.98 (d, 1H, J 2.0 Hz), 7.99-8.01 (m,
General procedure for the synthesis of 1-17
A 25 mL flask was filled with the mixture of substituted
aldehyde (1.0 mmol), ketone (1.0 mmol), malononitrile
(1.5 mmol), ammonium acetate (2.0 mmol), Cu/C
nanocatalyst (2.0 mol%) and then stirred in acetonitrile
(2.0 mL) at 80 °C under ambient atmosphere. Progress of
the reactions was monitored with TLC using n-hexane/
ethyl acetate (10:1). After completion, the crude reaction
mixture was filtered through a pad of Celite and washed
with hot ethanol (3 × 10 mL). The recovered catalyst was
dried under vacuum at 40 °C for 5 h and stored for another
consecutive reaction run, and the combined filtrates were
concentrated in vacuo and the resulting residue was purified
by silica gel column chromatography employing n-hexane/
ethyl acetate (10:1) as eluent.
13
1H); C NMR (62.5 MHz, CDCl3) d 55.4, 110.9, 114.4,
117.5, 127.3, 128.8, 129.1, 129.6, 130.1, 138.0, 154.7,
159.7, 160.4, 160.9; ESI-MS (%) 303 ([M + 2]+, 14.5),
302 ([M + 1]+, 62.8), 301 ([M+], 100.0), 300 (21.6), 257
(13.5), 239 (14.3), 134 (19.8), 112 (17.9), 83 (86.6), 57
(92.9); anal. calcd. for C19H15N3O (301.342): C, 75.73; H,
5.02; found: C, 75.87; H, 4.87.
2-Amino-4-(4-chlorophenyl)-6-phenylnicotinonitrile (4)
White solid; m.p. 229-230 °C; IR (KBr) νmax / cm-1 3496
(w), 3363 (w), 3305 (w), 2209 (m), 1634 (s), 1596 (s),
1578 (s), 1570 (s), 1549 (s), 1493 (s), 1367 (m), 1259 (m),
1095 (m), 1015 (m), 817 (m), 797 (m), 697 (m); 1H NMR

Vol. 27, No. 4, 2016
Khalifeh and Ghamari
761
(250 MHz, CDCl3) d 5.40 (s, 2H), 6.86 (s, 1H), 7.46-7.59
(m, 9H); 13C NMR (62.5 MHz, CDCl3) d 110.9, 116.9,
119.8, 127.3, 128.4, 128.8, 129.0, 129.2, 129.5, 129.7,
129.8, 130.3, 153.8, 160.0; ESI-MS (%) 307 ([M + 2]+,
41.0), 306 ([M + 1]+, 52.2), 305 ([M+], 100.0), 271 (10.1),
227 (10.8), 202 (10.4), 140 (18.4), 104 (15.7), 83 (39.8),
57 (40.6); anal. calcd. for C18H12ClN3 (305.761): C, 70.71;
H, 3.96; found: C, 70.59; H, 4.12.
2-Amino-6-(4-chlorophenyl)-4-phenylnicotinonitrile (8)
White solid; m.p. 240-241 °C; IR (KBr) νmax / cm-1 3500
(m), 3395 (s), 2210 (s), 1660 (s), 1571 (s), 1550 (s), 1499
(w), 1458 (w), 1424 (w), 1367 (w), 1262 (m), 1088 (m),
1
1012 (w), 831 (s), 763 (s), 695 (s); H NMR (250 MHz,
CDCl3) d 5.36 (s, 2H), 7.18 (d, 1H, J 0.8 Hz), 7.44 (d,
2H, J 8.1 Hz), 7.50-7.56 (m, 3H), 7.60-7.65 (m, 2H), 7.96
(d, 2H, J 8.1 Hz); 13C NMR (62.5 MHz, CDCl3) d 110.9,
117.3, 128.1, 128.6, 129.0, 129.9, 155.0, 160.1; ESI-MS
(%) 307 ([M + 2]+, 24.2), 306 ([M + 1]+, 32.3), 305 ([M+],
64.1), 129 (17.2), 111 (25.3), 83 (46.0), 57 (100.0); anal.
calcd. for C18H12ClN3 (305.761): C, 70.71; H, 3.96; found:
C, 70.58; H, 3.87.
Methyl 4-(2-amino-3-cyano-6-phenyl-4-pyridinyl)benzoate
(5)
White solid; m.p. 204-205 °C; IR (KBr) νmax / cm-1 3468
(w), 3313 (w), 3199 (w), 2206 (m), 1735 (s), 1638 (m), 1580
(m), 1545 (m), 1429 (w), 1305 (m), 1280 (m), 1257 (w),
1120 (w), 820 (w), 760 (m); 1H NMR (250 MHz, CDCl3)
d 3.97 (s, 3H), 5.39 (s, 2H), 7.23 (dd, 2H, J 10.9, 1.8 Hz),
7.46-7.72 (m, 4H), 7.99-8.01 (m, 2H), 8.15-8.21 (m, 2H);
13C NMR (62.5 MHz, CDCl3) d 52.4, 111.1, 127.4, 128.3,
128.5, 128.9, 129.0, 130.2, 130.4, 131.3, 160.2; ESI-MS
(%) 331 ([M + 2]+, 1.4), 330 ([M + 1]+, 11.4), 329 ([M+],
22.9), 305 (10.7), 295 (14.5), 271 (34.0), 149 (16.8), 129
(14.0), 111 (14.7), 85 (29.7), 69 (100.0); anal. calcd. for
C20H15N3O2 (329.352): C, 72.94; H, 4.59; found: C, 72.79;
H, 4.72.
2-Amino-6-(4-methylphenyl)-4-phenylnicotinonitrile (9)
White solid; m.p. 165-166 °C; IR (KBr) νmax / cm-1 3473
(w), 3315 (w), 3198 (w), 2207 (s), 1625 (s), 1585 (s), 1549
(s), 1497 (w), 1454 (w), 1373 (w), 1259 (w), 825 (m), 765
(s), 699 (s); 1H NMR (250 MHz, CDCl3) d 2.42 (s, 3H), 5.37
(s, 2H), 7.19 (s, 1H), 7.28 (d, 2H, J 9.2 Hz), 7.20-7.55 (m,
3H), 7.60-7.66 (m, 2H), 7.91 (d, 2H, J 8.1 Hz); 13C NMR
(62.5 MHz, CDCl3) d 21.4, 110.9, 117.3, 127.2, 128.2,
129.6, 129.8, 135.1, 137.0, 138.6, 155.0, 159.8, 160.3;
ESI-MS (%) 287 ([M + 2]+, 8.3), 286 ([M + 1]+, 28.8), 285
([M+], 45.3), 233 (21.1), 206 (14.9), 149 (30.7), 133 (25.9),
111 (18.1), 91 (100.0), 69 (85.9); anal. calcd. for C19H15N3
(285.343): C, 79.98; H, 5.30; found: C, 79.83; H, 5.43.
2-Amino-6-phenyl-4-(3-thienyl)nicotinonitrile (6)
White solid; m.p. 213-214 °C; IR (KBr) νmax / cm-1
3478 (m), 3368 (m), 3307 (m), 3180 (m), 3101 (m), 2216
(s), 1650 (s), 1578 (s), 1559 (m), 1454 (w), 1358 (w), 1262
(w), 837 (w), 793 (s), 755 (s), 700 (s); 1H NMR (250 MHz,
CDCl3) d 5.39 (s, 2H), 6.95 (s, 1H), 7.44-7.55 (m, 7H), 7.78
(s, 1H); 13C NMR (62.5 MHz, CDCl3) d 110.4, 119.3, 126.0,
126.2, 126.9, 127.0, 127.3, 128.3, 128.8, 128.9, 129.7,
130.2, 132.2, 137.3, 153.4; ESI-MS (%) 279 ([M + 2]+, 3.3),
278 ([M + 1]+, 9.3), 277 ([M+], 14.7), 246 (5.3), 229 (3.1),
168 (2.9), 151 (2.9), 57 (3.2); anal. calcd. for C16H11N3S
(277.345): C, 69.29; H, 4.00; found: C, 69.44; H, 4.11.
2-Amino-6-(4-methoxyphenyl)-4-phenylnicotinonitrile (10)
White solid; m.p. 166-167 °C; IR (KBr) νmax / cm-1 3489
(m), 3370 (s), 2206 (s), 1617 (s), 1584 (s), 1545 (s), 1515
(s), 1428 (m), 1370 (m), 1239 (s), 1174 (s), 1031 (m), 829
1
(s), 766 (s), 702 (s); H NMR (250 MHz, CDCl3) d 3.85
(s, 3H), 5.31 (s, 2H), 7.00 (dd, 2H, J 6.8, 2.0 Hz), 7.15
(s, 1H), 7.50-7.65 (m, 5H), 7.98 (dd, 2H, J 6.8, 2.1 Hz);
13C NMR (62.5 MHz, CDCl3) d 55.4, 110.4, 114.1, 128.1,
128.4, 128.8, 128.9, 129.7, 160.2, 161.4; ESI-MS (%) 303
([M + 2]+, 5.9), 302 ([M + 1]+, 21.3), 301 ([M+], 40.9), 149
(20.0), 85 (21.3), 69 (100.0); anal. calcd. for C19H15N3O
(301.342): C, 75.73; H, 5.02; found: C, 75.69; H, 4.89.
2-Amino-4-methyl-6-phenylnicotinonitrile (7)
White solid; m.p. 121-122 °C; IR (KBr) νmax / cm-1 3470
(s), 3349 (s), 3239 (m), 3170 (m), 2208 (s), 1650 (s), 1587
(m), 1560 (m), 1454 (w), 1358 (w), 1287 (w), 1267 (w), 769
(w), 753 (w), 696 (s), 668 (m); 1H NMR (250 MHz, CDCl3)
d 2.50 (s, 3H), 5.20 (s, 2H), 7.03 (s, 1H), 7.42-7.50 (m,
3H), 7.92 (d, 1H, J 2.1 Hz), 7.93-7.95 (m, 1H); 13C NMR
(62.5 MHz, CDCl3) d 21.4, 111.9, 115.4, 119.2, 120.3,
127.2, 128.3, 128.7, 128.8, 129.6, 130.0, 135.3, 136.3,
152.6; ESI-MS (%) 211 ([M + 2]+, 14.1), 210 ([M + 1]+,
84.8), 209 ([M+], 100.0), 181 (28.2), 157 (19.1), 104 (20.2),
77 (11.6); anal. calcd. for C13H11N3 (209.247): C, 74.62; H,
5.30; found: C, 74.73; H, 5.18.
2-Amino-6-(2-naphthyl)-4-phenylnicotinonitrile (11)
White solid; m.p. 171-172 °C; IR (KBr) νmax / cm-1
3473 (w), 3304 (w), 3172 (w), 2207 (s), 1640 (s), 1585
(s), 1550 (s), 1498 (m), 1452 (m), 1435 (m), 1266 (m), 808
1
(s), 759 (s), 697 (s); H NMR (250 MHz, CDCl3) d 5.42
(s, 2H), 7.36 (s, 1H), 7.54 (dd, 4H, J 5.3, 2.0 Hz), 7.66 (d,
1H, J 1.8 Hz), 7.68-7.70 (m, 2H), 7.86-7.95 (m, 3H), 8.12
(dd, 1H, J 8.6, 1.7 Hz,), 8.52 (s, 1H); 13C NMR (62.5 MHz,
CDCl3) d 111.5, 117.2, 124.4, 126.6, 127.2, 127.4, 127.7,
128.2, 128.5, 128.9, 129.0, 129.8, 133.2, 134.2, 135.1,

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A Multicomponent Synthesis of 2-Amino-3-cyanopyridine Derivatives
J. Braz. Chem. Soc.
155.1, 159.6, 160.3; ESI-MS (%) 323 ([M + 2]+, 9.2), 322
([M + 1]+, 22.1), 321 ([M+], 46.7), 149 (15.4), 109 (11.6),
91 (23.7), 69 (100.0); anal. calcd. for C22H15N3 (321.375):
C, 82.22; H, 4.70; found: C, 82.34; H, 4.57.
21.4, 116.0, 120.3, 128.3, 128.8, 129.5, 137.4, 147.7, 152.6;
ESI-MS (%) 211 ([M + 2]+, 19.2), 210 ([M + 1]+, 61.2), 209
([M+], 100.0), 181 (24.7), 156 (50.2), 129 (32.4), 104 (27.9),
77 (17.4), 51 (17.8); anal. calcd. for C13H11N3 (209.247):
C, 74.62; H, 5.30; found: C, 74.71; H, 5.42.
2-Amino-4-phenyl-5,6,7,8-tetrahydro-3-quinolinecarbonitrile
(12)
2-Amino-6-isopropyl-4-phenylnicotinonitrile (16)
White solid; m.p. 247-248 °C; IR (KBr) νmax / cm-1 3419
(s), 3349(s), 3264 (s), 2217 (s), 1654 (s), 1560 (s), 1458 (m),
1281 (m), 1170 (w), 770 (w), 710 (m), 675 (w); 1H NMR
(250 MHz, CDCl3) d 1.55-1.83 (m, 4H), 2.16-2.30 (m, 2H),
2.92-2.97 (m, 2H), 5.00 (s, 2H), 7.18-7.25 (m, 2H), 7.42-
7.51 (m, 3H); 13C NMR (62.5 MHz, CDCl3) d 21.8, 22.5,
27.3, 29.6, 115.4, 126.2, 128.2, 128.7, 137.0, 145.7, 146.9,
149.7, 150.1, 155.0; anal. calcd. for C16H15N3 (249.311):
C, 77.08; H, 6.06; found: C, 76.93; H, 6.21.
White solid; m.p. 151-152 °C; IR (KBr) νmax / cm-1 3474
(w), 3403 (s), 3364 (m), 3321 (w), 3166 (m), 2217 (s), 1653
(s), 1575 (s), 1555 (s), 1517(s), 1447 (m), 1254 (m), 1184
(w), 1072 (m), 819 (s); 1H NMR (250 MHz, CDCl3) d 1.27
(d, 6H, J 6.9 Hz), 2.85-2.96 (m, 1H), 5.22 (s, 2H), 6.63
(s, 1H), 7.27-7.31 (m, 3H), 7.41-7.50 (m, 2H); 13C NMR
(62.5 MHz, CDCl3) d 21.4, 22.0, 36.6, 111.2, 120.3, 128.0,
128.2, 128.7, 129.5, 137.4, 154.5, 159.7, 173.3; ESI-MS
(%) 238 ([M + 1]+, 68.6), 237 ([M+], 86.3), 236 (98.0),
149 (45.1), 73 (41.2), 57 (100.0); anal. calcd. for C15H15N3
(237.300): C, 75.92; H, 6.37; found: C, 76.03; H, 6.51.
2-Amino-6-methyl-4-phenyl-5,6,7,8-tetrahydro-3-
quinolinecarbonitrile (13)
White solid; m.p. 238-239 °C; IR (KBr) νmax / cm-1 3454
(s), 3349 (s), 3234 (s), 2926 (s), 2218 (s), 1654 (s), 1565 (s),
1457 (m), 1275 (m), 1232 (w), 783 (w), 716 (s); 1H NMR
(250 MHz, CDCl3) d 0.93 (d, 3H, J 6.5 Hz), 1.32-1.40 (m,
1H), 1.65-1.68 (m, 1H), 1.86-1.97 (m, 2H), 2.28-2.36 (m,
1H), 2.89-3.14 (m, 2H), 5.05 (s, 2H), 7.17-7.26 (m, 2H),
7.45-7.50 (m, 3H); 13C NMR (62.5 MHz, CDCl3) d 21.5,
28.8, 29.2, 29.6, 29.9, 115.5, 125.9, 128.6, 129.4, 137.0,
146.6, 149.8, 150.1; ESI-MS (%) 265 ([M + 2]+, 20.3), 264
([M + 1]+, 54.1), 111 ([M+], 32.4), 83 (73.0), 55 (100.0);
anal. calcd. for C17H17N3 (263.337): C, 77.54; H, 6.51;
found: C, 77.65; H, 6.39.
Methyl 6-amino-5-cyano-2-methyl-4-phenylnicotinate (17)
White solid; m.p. 181-182 °C; IR (KBr) νmax / cm-1
3435 (s), 3355 (s), 3254 (m), 2952 (w), 2220 (s), 1725
(s), 1653 (s), 1564 (s), 1438 (m), 1301 (s), 1208 (s), 1171
(m), 1051 (m), 960 (w), 757 (w), 730 (m), 710 (m), 546
(w); 1H NMR (250 MHz, CDCl3) d 2.55 (s, 3H), 3.45 (s,
3H), 5.41 (s, 2H), 7.30-7.34 (m, 2H), 7.42-7.46 (m, 3H);
13C NMR (62.5 MHz, CDCl3) d 19.6, 52.3, 97.5, 114.8,
115.0, 128.0, 129.5, 136.2, 145.8, 152.0, 155.7, 167.2,
184.4; anal. calcd. for C15H13N3O2 (267.283): C, 67.40; H,
4.90; found: C, 67.52; H, 4.79.
Results and Discussion
2-Amino-6-tert-butyl-4-phenylnicotinonitrile (14)
White solid; m.p. 169-170 °C; IR (KBr) νmax / cm-1 3414
(m), 3363 (m), 3317 (m), 3209 (m), 2958 (w), 2209 (s),
1640 (s), 1575 (s), 1548 (s), 1497 (m), 1454 (m), 1253 (m),
1204 (w), 1151 (w), 766 (m), 698 (s); 1H NMR (250 MHz,
CDCl3) d 1.24 (s, 9H), 5.14 (s, 2H), 6.70 (s, 1H), 7.30-7.47
(m, 5H); 13C NMR (62.5 MHz, CDCl3) d 29.7, 36.3, 110.0,
116.8, 117.4, 128.5, 129.3, 137.4, 154.5, 159.7, 173.3;
ESI-MS (%) 253 ([M + 2]+, 1.6) , 252 ([M + 1]+, 27.5),
251 ([M+], 51.9), 236 (100.0), 209 (77.2), 140 (13.8), 91
(42.9), 57 (35.4); anal. calcd. for C16H17N3 (251.326): C,
76.46; H, 6.82; found: C, 76.35; H, 6.94.
The Cu/C catalyst which had been previously
synthesized and used for various organic transformations
in our published works24-26 was also used in this project.
The catalyst was synthesized in two steps. In a general
procedure the activated carbon was refluxed with a nitric
acid solution for 6 h and washed with deionized water
until pH 6-7, and then dried in an oven at 110 °C overnight
under vacuum. The oxidized activated carbon was refluxed
with a solution of CuI under a N2 atmosphere in absolute
ethanol for 4 h, washed with ethanol, and finally dried
under vacuum in an oven overnight at 110 °C (Scheme 1).
To exploit a method for the preparation of new 2-amino-
3-cyanopyridine derivatives, the reaction of acetophenone
(1 mmol), benzaldehyde (1 mmol), malononitrile
(1.5 mmol) and ammonium acetate (2 mmol) in the
presence of Cu/C under air atmosphere was chosen as
a model and its behavior was studied under a variety of
conditions (Table 1).
2-Amino-6-methyl-4-phenylnicotinonitrile (15)
White solid; m.p. 188-189 °C; IR (KBr) νmax / cm-1
3470 (s), 3347 (s), 3239 (m), 2227 (s), 1650 (s), 1585 (m),
1559 (m), 1287 (m), 859 (m), 752 (m), 696 (s); 1H NMR
(250 MHz, CDCl3) d 2.55 (s, 3H), 5.23 (s, 2H), 6.71 (s,
13
1H), 7.46-7.54 (m, 5H); C NMR (62.5 MHz, CDCl3) d

Vol. 27, No. 4, 2016
Khalifeh and Ghamari
763
HNO3 (5 mol L-1)
CuI
Charcoal
Cu/C
Oxidized charcoal
EtOH/N2
Reflux
4 h
Reflux
6 h
Scheme 1. Synthesis of copper nanoparticles on charcoal (Cu/C).
Table 1. Optimization of reaction conditions
CHO
O
CN
Solvent, T (°C)
CH3
CN
+
NH4OAc
+
+
CN
N
NH2
entry
1
Solvent
CHCl3
Catalyst (concentration / mol%)
Cu/C (2)
Temperature / °C
reflux
80
time / h
Yielda / %
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
10
45
20
70
67
20
–
2
DMF
Cu/C (2)
3
ethanol
Cu/C (2)
reflux
reflux
reflux
reflux
80
4
acetone
Cu/C (2)
5
ethyl acetate
THF
Cu/C (2)
6
Cu/C (2)
7
PEG 300
toluene
Cu/C (2)
8
Cu/C (2)
reflux
reflux
reflux
reflux
reflux
reflux
reflux
r.t.
76
91
74
92
65
60
–
9b
10
11
12
13
14
15
16
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
Cu/C (2)
Cu/C (1)
Cu/C (5)
CuI (2)
Cu(OAc)2 (2)
–
Cu/C (2)
–
Cc
reflux
–
b
c
aIsolated yield; best reaction conditions; oxidized charcoal. DMF: N,N-dimethylformamide; THF: tetrahydrofuran; PEG 300: polyethylene glycol
300 g mol-1; r.t.: room temperature.
We commenced our investigation with the reaction of
starting materials in chloroform as solvent in the presence
of Cu/C as a catalyst. Analysis of the resulting mixture
revealed that the desired product 1 was formed after 6 h
in only 10% yield (Table 1, entry 1). Yield of the reaction
increased upon using N,N-dimethylformamide (DMF)
instead of chloroform (entry 2 vs. 1). Replacement of
DMF with ethanol (entry 3) did not give an improved
outcome, while the formation of product 1 was markedly
improved when using the same catalyst in acetone at reflux
condition (entry 4). Further condition screening suggested
that when the reaction was carried out in the presence of
Cu/C, upon switching the solvents from acetone to ethyl
acetate, tetrahydrofuran (THF) or polyethylene glycol
300 g mol-1 (PEG 300), the yield of desired product
decreased (entries 5-7). However, when the reaction
was carried out in toluene at reflux condition for 6 h, the
expected product was achieved in 76% yield (entry 8).
Interestingly, when model compounds were treated with
2 mol% of Cu/C in acetonitrile at reflux for 6 h, the expected
reaction proceeded successfully to give product in 91%
yield (entry 9). A further decrease in the catalyst loading
resulted in 74% isolated yield (entry 10), but increase in
the catalyst loading did not enhance the reaction yield any
further (entry 11). Further optimization of the reaction
conditions revealed that other Cu sources regardless of their

764
A Multicomponent Synthesis of 2-Amino-3-cyanopyridine Derivatives
J. Braz. Chem. Soc.
oxidation states (either I or II) did not show better catalytic
activity (entries 12 and 13). We speculate that the observed
higher yields are probably due to the large surface area
and more stability of the formed nanoparticles of Cu/C.
In addition, CuI showed lower yield in comparison with
Cu/C under these reaction conditions. It is possibly due
to the disproportionation of this salt under optimization
reaction condition.
When this reaction was carried out in acetonitrile at
reflux condition for 6 h, without any catalyst, no desired
2-amino-3-cyanopyridine was obtained (Table 1, entry 14).
Next, experiment was carried out to distinguish the effect
of temperature on the reaction. As depicted in Table 1, the
desired product could not be detected at room temperature
(entry 15). In addition, control experiments demonstrated
that no reaction occurred in the presence of charcoal as a
catalyst (entry 16).
After the optimization reaction conditions, in order
to examine the scope of the reaction, we treated various
aldehydes and methylketones in the presence of malonitrile
and NH4OAc with Cu/C in refluxing acetonitrile, and
desired 2-amino-3-cyanopyridine derivatives were obtained
in good to high yields (Table 2).
From the results shown, aldehydes with both electron-
withdrawing and -donating substituting groups afforded
the 2-amino-3-cyanopyridine derivatives through reaction
Table 2. Substrate scope for the synthesis of 2-amino-3-cyanopyridine derivativesa
entry
Aldehyde
Ketone
Product
time / h
Yieldb / %
CHO
O
CN
1
6
91
CH3
N
NH2
1
2
3
4
CH3
CHO
O
O
O
2
3
4
6
6
8
86
83
90
CH3
CN
CH3
N
NH2
OCH3
CHO
CH3
CN
OCH3
N
NH2
Cl
CHO
CH3
CN
Cl
N
NH2

Vol. 27, No. 4, 2016
Khalifeh and Ghamari
765
Table 2. Substrate scope for the synthesis of 2-amino-3-cyanopyridine derivativesa (cont.)
entry
Aldehyde
Ketone
Product
CO2CH3
time / h
Yieldb / %
CHO
O
5
8
94
CH3
CN
CO2CH3
N
NH2
5
S
O
CHO
CN
6
7
86
CH3
S
N
NH2
6
CH3
O
CN
O
7
6
71
CH3
H3C
N
NH2
7
O
CHO
CHO
CHO
CN
CH3
8
6
7
6
90
84
90
Cl
N
NH2
Cl
8
O
CN
CH3
9
H3C
N
NH2
H3C
9
O
CN
CH3
10
H3CO
N
NH2
H3CO
10

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A Multicomponent Synthesis of 2-Amino-3-cyanopyridine Derivatives
J. Braz. Chem. Soc.
Yieldb / %
85
Table 2. Substrate scope for the synthesis of 2-amino-3-cyanopyridine derivativesa (cont.)
entry
11
Aldehyde
Ketone
Product
time / h
CHO
O
CN
6
CH3
N
NH2
11
CHO
O
12
13
8
8
84
86
CN
N
NH2
12
O
CHO
H3C
CN
CH3
N
NH2
13
CHO
CHO
CHO
CHO
O
H3C
H3C
CN
14
15
16
17
7
7
7
7
83
87
86
85
CH3
CH3
H3C
H3C
N
NH2
CH3
14
O
CN
H3C
CH3
H3C
N
NH2
15
O
H3C
CN
CH3
CH3
H3C
N
NH2
CH3
16
O
O
O
H3C
CN
O
CH3
H3CO
H3C
N
NH2
17
aReaction conditions: aldehyde (1.0 mmol), ketone (1.0 mmol), malononitrile (1.5 mmol), ammonium acetate (2.0 mmol), Cu/C (2 mol%), CH3CN and
reflux; bisolated yields.

Vol. 27, No. 4, 2016
Khalifeh and Ghamari
767
with acetophenone, malononitrile and ammonium acetate
and the isolated yields range from 86 to 94% (Table 2,
entries 2-5). In an effort to apply the present reaction
conditions to the synthesis of heterocycles related to
2-amino-3-cyanopyridines, the feasibility of the reaction
with heteroaromatic aldehyde was examined (entry 6). It is
noteworthy that the reaction of 3-thiophenecarbaldehyde as
a heterocyclic aldehyde proceeded well to give the desired
products in 86% yield. To expand the scope of the current
method, aliphatic aldehyde was also examined as a substrate.
The desired product 7 was obtained with good yields
(entry 7). We further explored the potential of the present
protocol from the standpoint of variety of ketones. As seen
from Table 2, this strategy is effective for a great diversity
of ketones such as alkylaryl (entries 8-11), cyclic (entries 12
and 13), and dialkyl ketones (entries 14-17).Acetophenone
with both electron-withdrawing and -donating substituting
groups fairly tolerate the reaction conditions and also afford
the desired products in good yields (entries 8-10), and
proves the generality of the strategy elaborated. The highly
conjugated ketone derivative was also an excellent substrate
for this reaction, and the corresponding compound 11 was
produced (entry 11). For cyclic ketones, this transformation
proceeded smoothly and afforded the products in good
yields. For example, the reaction of cyclohexanone or
4-methyl cyclohexanone led to the corresponding products
in 84 and 86% isolated yields, respectively (entries 12
and 13). To our delight, this method could be successfully
applied to dialkyl ketones. For example, the product having
t-butyl, isopropyl or methyl groups derived from the
corresponding methyl ketone was formed in satisfactory
yield (entries 14-16). Meanwhile, methyl acetoacetate also
reacted with benzaldehyde and generated the corresponding
product 17 in 85% yield (entry 17).
Conclusions
In conclusion, we have reported a direct one-pot
method for the construction of 2-amino-3-cyanopyridine
derivatives starting from aldehydes, ketones, malononitrile,
and ammonium acetate in the presence of Cu/C as a
heterogeneous catalyst system, in up to 71% isolated yield.
Various aldehydes and ketones were readily applied to this
synthetic protocol. It is noted that in the present system
the catalyst can be recycled and reused at least eight times
without significant losses of activity.
Supplementary Information
Supplementary data (1H NMR, 13C NMR, mass
spectra of compounds, X-ray diffraction (XRD) pattern
and scanning electron microscopy (SEM) image of Cu/C)
are available free of charge at http://jbcs.sbq.org.br as
PDF file.
Acknowledgements
We gratefully acknowledge the support of this work
by the Shiraz University of Technology Research Council.
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