Supporting Information for

An expeditious and efficient synthesis of highly

functionalized [1,6]-naphthyridines under catalyst-free
conditions in aqueous medium

Chhanda Mukhopadhyaya*, Paramita Dasa and Ray J. Butcherb

a: Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata-700009, India

b: Department of Chemistry, Howard University, Washington DC 20059, USA
cmukhop@yahoo.co.in

Table of Contents
General Methods . S2
Experimental Procedures for 4aa-4fh ..S3-S18
Experimental Procedures for intermediate 5 and 7...S18-S19
1

H NMR and 13C NMR spectra for 4aa-4fh.S20-S39

2D NMR spectra for 4aa..S40-S41

1

H NMR and 13C NMR spectra for 5 and 7..S42-S43

CIF FILE for 4ae..S44-S53

S1

General Methods
All solvents were dried by standard methods. Chemicals were purchased from Aldrich and Spectrochem
and used without further purification. Column chromatography was performed on silica gel (60-120 mesh).
TLC was done on glass sheets pre-coated with silica gel (with binder, 300 mesh, Spectrochem). The 1Hand 13C-NMR spectra were taken in d6 - DMSO with TMS as an internal reference and in one case CDCl3.
The chemical shifts were reported as values (ppm) relative to TMS. IR spectra were recorded in KBr
pellets. Ion cyclotron resonance Fourier transform HRMS was performed on a Micromass ZQ instrument
(Waters) (location: Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata-700032).

The C-H-N-analyses were carried out on a 2400 Series II CHNS Analyzer, Perkin Elmer USA.

Experimental Procedures
General procedure for preparation of [1,6]-naphthyridines 4aa-4fh
A mixture of ketone 1 (2 mmol), malononitrile 2 (2 mmol) and amine 3 (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography using ethylacetate-petrolium ether as
eluent.
5-Amino-2-methyl-2,4-diphenyl-7-piperidin-1-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4aa):

NH2
H
N
H3C

N
H

N
CN

A mixture of ketone 1a (2 mmol), malononitrile 2 (2 mmol) and amine 3a (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
S2

the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (5:95
v/v) as eluent to give [1,6]naphthyridine 4aa (392 mg, 0.93 mmol, 93%) as white solid. Mp 207-209 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.55 (br s, 6H), 1.65 (s, 3H), 3.44
(s, 4H), 4.92 (br s, 2H), 5.57 (s, 1H), 6.74 (s, 1H), 7.14-7.23 (m, 3H), 7.27-7.38 (m, 4H), 7.43 (d, J = 7.5
Hz, 2H); 13C NMR (75 MHz, DMSO-D6) 24.3, 25.7, 30.9, 48.7, 56.5, 68.6, 90.6, 118.7, 124.7, 126.6,
126.9, 127.8, 127.9, 128.2, 128.5, 132.6, 138.8, 148.7, 154.7, 154.8, 161.6; IR (KBr) 3516, 3392, 3307,
2931, 2835, 2193, 1585, 1536, 1498, 1439, 1373, 1287, 1196, 1125, 1029, 763, 697, 569, 513 cm-1; Anal.
Calcd: C, 76.93; H, 6.46; N, 16.61. Found: C, 77.15, H, 6.52, N, 76.31. HRMS (m/z) Calcd for C27H27N5:
421.2266. Found 421.2244.
5-Amino-2-methyl-2,4-diphenyl-7-pyrrolidin-1-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4ab):

NH2

H3C
N
H

N
CN

A mixture of ketone 1a (2 mmol), malononitrile 2 (2 mmol) and amine 3b (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (12:88
v/v) as eluent to give [1,6]naphthyridine 4ab (379 mg, 0.93 mmol, 93%) as light yellow solid. Mp 179-181
C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.65 (s, 3H), 1.77-1.86 (m, 4H),
3.46-3.49 (m, 2H), 3.58-3.61 (m, 2H), 4.83 (br s, 2H), 5.52 (s, 1H), 6.40 (s, 1H), 7.14-7.23 (m, 3H), 7.277.36 (m, 5H), 7.44 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, DMSO-D6) 25.1, 31.0, 48.6, 56.5, 66.0, 89.7,
S3

119.4, 124.8, 126.0, 127.9, 128.0, 128.3, 128.5, 132.8, 139.2, 148.8, 155.0, 157.4; IR (KBr) 3492, 3355,
3310, 2969, 2863, 2178, 1625, 1572, 1533, 1443, 1341, 1292, 764, 698, 654 cm-1; Anal. Calcd: C, 76.63;
H, 6.18; N, 17.19. Found: C, 76.86, H, 6.22, N, 17.33.
5-Amino-2-methyl-7-morpholin-4-yl-2,4-diphenyl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4ac):

NH2
H
N
H3C

N
H

N
CN

A mixture of ketone 1a (2 mmol), malononitrile 2 (2 mmol) and amine 3c (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (15:85
v/v) as eluent to give [1,6]naphthyridine 4ac (385 mg, 0.91 mmol, 91%) as cream coloured solid. Mp 217219 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.66 (s, 3H), 3.34-3.37 (m,
2H), 3.47-3.52 (m, 2H), 3.62 (br s, 4H), 5.02 (br s, 2H), 5.60 (s, 1H), 6.88 (s, 1H), 7.14-7.23 (m, 3H), 7.277.35 (m, 5H), 7.43 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, DMSO-D6) 30.9, 48.2, 56.5, 66.1, 69.2, 91.0,
124.7, 126.6, 127.4, 128.0, 128.3, 128.5, 132.4, 154.7, 154.8, 161.6; IR (KBr) 3517, 3396, 3311, 2947,
2838, 2193, 1584, 1538, 1497, 1439, 1336, 1274, 1196, 1113, 1030, 762, 697, 595, 558 cm-1; Anal. Calcd:
C, 73.74; H, 5.95; N, 16.54. Found: C, 73.95, H, 5.99, N, 16.68.
5-Amino-7-dimethylamino-2-methyl-2,4-diphenyl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4ae):

S4

NH2
H

H3C
N
H

CH3
N
CH3

CN

A mixture of ketone 1a (2 mmol), malononitrile 2 (2 mmol) and amine 3e (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (20:80
v/v) as eluent to give [1,6]naphthyridine 4ae (343 mg, 0.90 mmol, 90%) as cream coloured solid. Mp 161163 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) ) 1.65 (s, 3H), 3.04 (s,
6H), 4.92 (br s, 2H), 5.56 (s, 1H), 6.62 (s, 1H), 7.14-7.23 (m, 3H), 7.27-7.34 (m, 5H), 7.44 (d, J = 7.5 Hz,
2H); 13C NMR (75 MHz, DMSO-D6) 31.0, 56.5, 66.7, 90.1, 117.8, 119.2, 124.8, 126.4, 126.6, 127.9,
128.0, 128.3, 128.5, 132.7, 138.9, 148.8, 154.6, 155.0, 160.7, 162.0; IR (KBr) 3512, 3389, 337, 2934, 2187,
1581, 1531, 409, 1304, 1187, 1117, 1070, 762, 694 cm-1; Anal. Calcd: C, 75.56; H, 6.08; N, 18.36. Found:
C, 75.71, H, 6.1, N, 18.46.
5-Amino-2,4-bis-(4-chloro-phenyl)-2-methyl-7-pyrrolidin-1-yl-1,2-dihydro[1,6]naphthyridine-8-carbonitrile (4bb):

Cl

NH2
H
N
H3C

N
H

N
CN

Cl
A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3b (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
S5

the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (12:88
v/v) as eluent to give [1,6]naphthyridine 4bb (437 mg, 0.92 mmol, 92%) as white solid. Mp 159-161 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.64 (s, 3H), 1.79-1.85 (m, 4H),
3.49 (br s, 2H), 3.58 (br s, 2H), 4.95 (br s, 2H), 5.54 (s, 1H), 6.57 (s, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.35 (t,
J = 8.1 Hz, 4H), 7.43 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, DMSO-D6) 25.1, 30.5, 48.5, 56.1, 65.9,
89.5, 119.2, 126.8, 128.1, 128.2, 129.8, 131.2, 132.3, 137.5, 147.5, 154.8, 154.9, 157.5; IR (KBr) 3493,
3302, 3234, 2966, 2864, 2190, 1621, 1576, 1534, 1491, 1440, 1345, 1090, 1011, 828, 668, 524 cm-1; Anal.
Calcd: C, 65.55; H, 4.87; N, 14.70. Found: C, 65.80, H, 4.85, N, 14.83.
5-Amino-2,4-bis-(4-chloro-phenyl)-2-methyl-7-morpholin-4-yl-1,2-dihydro[1,6]naphthyridine-8-carbonitrile (4bc):

Cl

NH2
H
N
H3C

N
H

N
CN

Cl
A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3c (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (15:85
v/v) as eluent to give [1,6]naphthyridine 4bc (458 mg, 0.93 mmol, 93%) as cream coloured solid. Mp 205207 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.65 (s, 3H), 3.35-3.39 (m,
2H), 3.49-3.55 (m, 2H), 3.58-3.64 (m, 4H), 5.18 (br s, 2H), 5.63 (s, 1H), 7.00 (s, 1H), 7.22 (d, J = 8.1 Hz,
S6

2H), 7.36 (t, J = 7.6 Hz, 4H), 7.44 (d, J = 8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-D6) 30.4, 48.1, 56.2,
66.1, 68.9, 98.8, 117.7, 118.4, 126.8, 127.1, 128.0, 128.1, 129.8, 121.2, 132.0, 132.3, 137.0, 147.4, 154.7,
161.6; IR (KBr) 3493, 3371, 3300, 2964, 2900, 2856, 2185, 1582, 1528, 1438, 1275, 1197, 1104, 1014,
825, 607, 556, 432 cm-1; Anal. Calcd: C, 63.42; H, 4.71; N, 14.22. Found: C, 63.53, H, 4.74, N, 14.35.
5-Amino-2,4-bis-(4-chloro-phenyl)-2-methyl-7-(4-methyl-piperazin-1-yl)-1,2-dihydro[1,6]naphthyridine-8-carbonitrile (4bd):

Cl

NH2
H
N
H3C

N
H

N
CN

CH3

Cl
A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3d (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (25:75
v/v) as eluent to give [1,6]naphthyridine 4bd (489 mg, 0.89 mmol, 89%) as cream coloured solid. Mp 191193 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.64 (s, 3H), 2.16 (s, 3H),
2.35 (br s, 4H), 3.41 (br s, 2H), 3.48 (br s, 2H), 5.14 (br s, 2H), 5.61 (s, 1H), 6.96 (s, 1H), 7.21 (d, J = 7.8
Hz, 2H), 7.35 (t, J = 7.5 Hz, 4H), 7.43 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, DMSO-D6) 30.6, 45.8,
47.5, 54.7, 56.2, 68.8, 90.7, 118.6, 126.8, 127.0, 128.2, 129.9, 131.3, 132.1, 132.3, 137.1, 147.5, 154.7,
161.6; IR (KBr) 3473, 3319, 2974, 2972, 2190, 1580, 1538, 1495, 1434, 1290, 1199, 1093, 1010, 926, 825,
707, 636, 554 cm-1; Anal. Calcd: C, 64.16; H, 5.18; N, 16.63. Found: C, 64.35, H, 5.21, N, 16.80.

S7

5-Amino-2,4-bis-(4-chloro-phenyl)-7-dimethylamino-2-methyl-1,2-dihydro[1,6]naphthyridine-8-carbonitrile (4be):

Cl

NH2
H
N
H3C

N
H

CN

CH3
N
CH3

Cl
A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3e (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (20:80
v/v) as eluent to give [1,6]naphthyridine 4be (404 mg, 0.90 mmol, 90%) as white solid. Mp 150-152 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.64 (s, 3H, CH3), 3.04 (s, 6H), 5.06
(br s, 2H), 5.58 (s, 1H), 6.76 (s, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 8.4 Hz, 4H), 7.44 (d, J = 8.4 Hz,
2H);

13

C NMR (75 MHz, DMSO-D6) 30.6, 56.2, 66.5, 89.9, 119.1, 126.2, 126.8, 128.1, 128.2, 129.8,

131.3, 132.3, 137.3, 147.6, 154.6, 154.9, 160.8, 161.9; IR (KBr) 3511, 3406, 3310, 2970, 2933, 2882, 2188,
1583, 1533, 1438, 1406, 1089, 1010, 827, 627, 550 cm-1; Anal. Calcd: C, 64.01; H, 4.70; N, 15.55. Found:
C, 64.10, H, 4.71, N, 15.65.
5-Amino-2,4-bis-(4-chloro-phenyl)-7-diallylamino-2-methyl-1,2-dihydro-[1,6]naphthyridine8-carbonitrile (4bf):

S8

Cl

NH2
H
N
H3C

N
H

N
CN

Cl
A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3f (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (20:80
v/v) as eluent to give [1,6]naphthyridine 4bf (441 mg, 0.92 mmol, 92%) as cream coloured solid. Mp 104106 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.64 (s, 3H), 4.05 (br s,
4H), 5.14 (d, J = 13.5 Hz, 6H), 5.58 (s, 1H), 5.85 (br s, 2H), 6.78 (s, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.367.45 (m, 4H), 7.55 (d, J = 7.2 Hz, 2H);

13

C NMR (75 MHz, DMSO-D6) 30.6, 50.7, 55.2, 66.9, 90.1,

117.4, 118.8, 126.4, 126.6, 126.8, 128.2, 129.8, 131.3, 132.1, 132.3, 134.7, 137.3, 147.5, 154.6, 154.8,
159.5, 161.9; IR (KBr) 3478, 3374, 3287, 2197, 1610, 1578, 1531,1431, 1341, 1287, 1194, 1105, 997, 927,
828, 699 cm-1; Anal. Calcd: C, 66.93; H, 5.02; N, 13.94. Found: C, 67.13, H, 5.04, N, 14.06.
5-Amino-2,4-bis-(4-chloro-phenyl)-7-cyclohexylamino-2-methyl-1,2-dihydro[1,6]naphthyridine-8-carbonitrile (4bg):

Cl

NH2
H
N
H3C

Cl

N
H

CN

N
H
S9

A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3g (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (15:85
v/v) as eluent to give [1,6]naphthyridine 4bg (463 mg, 0.92 mmol, 92%) as white solid. Mp 179-181 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.04-1.32 (m, 5H), 1.51-1.75 (m,
8H), 3.83-3.85 (m, 1H), 4.97 (br s, 2H), 5.46 (s, 1H), 5.78 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 7.21 (d, J = 7.8
Hz, 2H), 7.35 (t, J = 7.5 Hz, 4H), 7.43 (d, J = 8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-D6) 25.1, 25.3,
30.4, 32.6, 32.7, 48.6, 56.0, 65.2, 88.8, 117.7, 125.6, 126.9, 128.1, 128.2, 129.9, 131.2, 132.2, 137.8, 147.6,
154.0, 155.7, 158.0, 161.9; IR (KBr) 3522, 3404, 3309, 2924, 2190, 1571, 1518, 1444, 1351, 1092, 822,
778, 582 cm-1; Anal. Calcd: C, 66.67; H, 5.39; N, 13.88. Found: C, 66.66, H, 5.41, N, 13.97.
5-Amino-2,4-bis-(4-methoxy-phenyl)-2-methyl-7-piperidin-1-yl-1,2-dihydro[1,6]naphthyridine-8-carbonitrile (4ca):

OCH3

NH2

H3C
N
H

N
CN

H3CO
A mixture of ketone 1c (2 mmol), malononitrile 2 (2 mmol) and amine 3a (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (10:90
v/v) as eluent to give [1,6]naphthyridine 4ca (433 mg, 0.92 mmol, 92%) as cream coloured solid. Mp 124S10

126 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.54 (br s, 6H), 1.62 (s, 3H,
CH3), 3.43 (s, 4H), 3.67 (s, 3H), 3.73 (s, 3H), 4.97 (br s, 2H), 5.46 (s, 1H), 6.61 (s, 1H), 6.84 (d, J = 8.7
Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H); 13C NMR (75 MHz,
DMSO-D6) 24.4, 25.7, 30.9, 48.8, 55.1, 55.2, 56.0, 68.7, 90.8, 113.6, 113.9, 117.8, 118.8, 126.0, 126.4,
129.2, 131.0, 131.9, 140.7, 154.8, 158.0, 159.0, 161.6, 162.0; IR (KBr) 3503, 3389, 3307, 2929, 2849,
2189, 1579, 1538, 1504, 1444, 1376, 1292, 1244, 1176, 1120, 1028, 828 cm-1; Anal. Calcd: C, 72.33; H,
6.49; N, 14.54. Found: C, 72.48, H, 6.52, N, 14.65.
5-Amino-2,4-bis-(4-methoxy-phenyl)-2-methyl-7-morpholin-4-yl-1,2-dihydro[1,6]naphthyridine-8-carbonitrile (4cc):

OCH3

NH2

H3C
N
H

N
CN

H3CO
A mixture of ketone 1c (2 mmol), malononitrile 2 (2 mmol) and amine 3c (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (20:80
v/v) as eluent to give [1,6]naphthyridine 4cc (450 mg, 0.93 mmol, 93%) as yellow solid. Mp 149-151 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.63 (s, 3H), 3.23-3.37 (m, 2H),
3.46-3.52 (m, 2H), 3.58-3.62 (m, 4H), 3.68 (s, 3H), 3.73 (s, 3H), 5.04 (br s, 2H), 5.48 (s, 1H), 6.71 (s, 1H),
6.85 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H); 13C
NMR (75 MHz, DMSO-D6) 30.8, 48.2, 55.1, 55.2, 56.0, 66.2, 69.3, 91.2, 113.6, 113.9, 117.8, 118.5,
125.9, 126.8, 129.2, 130.8, 131.7, 140.6, 154.7, 158.0, 159.0, 161.5; IR (KBr) 3462, 3359, 3295, 2953,
S11

2840, 2190, 1623, 1579, 1537, 1508, 1455, 1296, 1241, 1179, 1108, 1030, 829 cm-1; Anal. Calcd: C,
69.55; H, 6.04; N, 14.48. Found: C, 69.77, H, 6.07, N, 14.60.
5-Amino-2,4-diisobutyl-2-methyl-7-piperidin-1-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4da):

H3C

CH3
H
CH2 NH2

H
N
H3C
N
H2C
H
H3C
H
H3C

N
CN

A mixture of ketone 1d (2 mmol), malononitrile 2 (2 mmol) and amine 3a (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (5:95
v/v) as eluent to give [1,6]naphthyridine 4da (343 mg, 0.90 mmol, 90%) as white solid. Mp 124-126 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 0.84-0.88 (m, 6H), 0.91-0.99 (m,
6H), 1.08 (s, 3H, CH3), 1.41-1.43 (m, 2H), 1.51 (s, 6H), 1.68-1.76 (m, 1H), 2.13 (d, J = 12.9 Hz, 1H), 2.26
(d, J = 13.2 Hz, 1H), 2.59-2.66 (m, 1H), 3.36 (s, 4H), 5.54 (s, 1H), 5.57 (s, 1H), 5.73 (s, 2H, NH2); 13C
NMR (75 MHz, DMSO-D6) 23.5, 23.7, 23.8, 24.4, 24.6, 24.8, 25.7, 26.5, 27.4, 35.8, 49.0, 49.2, 53.5,
68.3, 90.5, 117.8, 125.8, 132.1, 152.3, 155.8, 160.8; IR (KBr) 3440, 3333, 2934, 2861, 2196, 1581, 1546,
1445, 1370, 1196, 1225, 1021, 899, 782, 599, 528 cm-1; Anal. Calcd: C, 72.40; H, 9.25; N, 18.35. Found:
C, 72.60, H, 9.31, N, 18.47.

S12

5-Amino-2,4-bis-(9H-fluoren-2-yl)-2-methyl-7-piperidin-1-yl-1,2-dihydro-[1,6]naphthyridine8-carbonitrile (4ea):

NH2
H
N

H3C
N
H

N
CN

A mixture of ketone 1e (2 mmol), malononitrile 2 (2 mmol) and amine 3a (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (5:95
v/v) as eluent to give [1,6]naphthyridine 4ea (538 mg, 0.90 mmol, 90%) as light yellow solid. Mp 109-111
C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.56 (br s, 6H), 1.72 (s, 3H),
3.46 (s, 4H), 3.89 (s, 4H), 4.99 (br s, 2H), 5.69 (s, 1H), 6.80 (s, 1H), 7.25-7.38 (m, 5H), 7.48-7.58 (m, 4H),
7.69 (s, 1H), 7.81-7.89 (m, 4H); 13C NMR (75 MHz, DMSO-D6) 24.4, 25.7, 31.1, 36.5, 36.6, 48.8, 56.8,
68.7, 90.8, 118.8, 119.7, 120.0, 120.2, 121.7, 123.6, 124.7, 125.2, 125.3, 127.0, 132.7, 137.3, 139.8, 140.8,
140.9, 143.1, 143.2, 143.3, 147.7, 154.8, 154.9, 161.7; IR (KBr) 3497, 3391, 2927, 2851, 2185, 1578, 1537,
1438, 1370, 1289, 1199, 1120, 1019, 830, 769, 735 cm-1; Anal. Calcd: C, 82.38; H, 5.90; N, 11.72. Found:
C, 82.61, H, 5.92, N, 11.85.
5-Amino-2-methyl-7-piperidin-1-yl-1,2-di-thiophen-2-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4fa):

S13

NH2

H3C
S

N
H

N
CN

A mixture of ketone 1f (2 mmol), malononitrile 2 (2 mmol) and amine 3a (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (7:93
v/v) as eluent to give [1,6]naphthyridine 4fa (398 mg, 0.92 mmol, 92%) as cream coloured solid. Mp 151153 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.54 (br s, 6H), 1.76 (s, 3H),
3.44 (s, 4H), 5.27 (br s, 2H), 5.54 (s, 1H), 6.76 (s, 1H), 6.90-6.95 (m, 2H), 6.99 (d, J = 1.8 Hz), 7.02-7.05
(m, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H); 13C NMR (75 MHz, DMSO-D6) 24.3, 25.7,
30.4, 48.6, 54.6, 68.5, 90.3, 117.8, 118.4, 122.7, 124.8, 126.2. 126.4, 126.7, 126.9, 127.4, 140.2, 152.9,
154.1, 154.9; IR (KBr) 3493, 3384, 3299, 2928, 2846, 2190, 1580, 1536, 1434, 1364, 1194, 1015, 830, 781,
693 cm-1; Anal. Calcd: C, 63.71; H, 5.35; N, 16.15. Found: C, 63.81, H, 5.37, N, 16.28.
5-Amino-2-methyl-7-pyrrolidin-1-yl-2,4-di-thiophen-2-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4fb):

S
H

NH2
N

H3C

N
S H

N
CN

A mixture of ketone 1f (2 mmol), malononitrile 2 (2 mmol) and amine 3b (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
S14

extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (12:88
v/v) as eluent to give [1,6]naphthyridine 4fb (386 mg, 0.92 mmol, 92%) as white solid. Mp 173-175 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.76-1.85 (m, 7H), 3.46-3.49 (m,
2H), 3.56-3.59 (m, 2H), 5.17 (br s, 2H), 5.50 (s, 1H), 6.42 (s, 1H), 6.90-6.96 (m, 2H), 6.90-6.99 (m, 1H),
7.02-7.04 (m, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 5.1 Hz, 1H); 13C NMR (75 MHz, DMSO-D6)
25.1, 30.38, 48.6, 54.6, 66.0, 89.5, 119.0, 122.7, 124.8, 126.1, 126.4, 126.6, 126.9, 127.5, 140.5, 143.1,
152.9, 154.3, 155.1, 157.4, 162.0; IR (KBr) 3493, 3381, 3308, 2968, 2869, 2188, 1578, 1530, 1433, 1342,
1298, 1218, 1169, 696 cm-1; Anal. Calcd: C, 62.98; H, 5.04; N, 16.69. Found: C, 63.14, H, 5.07, N, 16.82.
5-Amino-2-methyl-7-morpholin-4-yl-2,4-di-thiophen-2-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4fc):

S
H
H3C
S

NH2
N

N
H

N
CN

A mixture of ketone 1f (2 mmol), malononitrile 2 (2 mmol) and amine 3c (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (15:85
v/v) as eluent to give [1,6]naphthyridine 4fc (396 mg, 0.91 mmol, 91%) as cream coloured solid. Mp 173175 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.77 (s, 3H, CH3), 3.36-3.40
(m, 2H), 3.48-3.54 (m, 2H), 3.58-3.62 (m, 4H), 5.35 (br s, 2H), 5.58 (s, 1H), 6.89-6.94 (m, 3H), 6.99-7.05
(m, 2H), 7.34 (d, J = 4.8 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H); 13C NMR (75 MHz, DMSO-D6) 30.3, 48.2,
54.7, 66.1, 69.1, 90.7, 117.8, 118.2. 122.8, 124.8, 126.0, 126.5, 126.8, 126.9, 127.4, 140.0, 152.8, 154.1,
S15

154.9, 161.6, 161.9; IR (KBr) 3491, 3337, 3277, 2965, 2895, 2856, 2197, 1583, 1538, 1438, 1376, 1290,
1255, 1198, 1108, 1031, 906, 849, 772, 697, 635 cm-1; Anal. Calcd: C, 60.66; H, 4.86; N, 16.08. Found: C,
60.76, H, 4.88, N, 16.19.
5-Amino-7-dimethylamino-2-methyl-2,4-di-thiophen-2-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4fe):
S
H
H3C
S

NH2
N

N
H

CN

CH3
N
CH3

A mixture of ketone 1f (2 mmol), malononitrile 2 (2 mmol) and amine 3e (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (20:80
v/v) as eluent to give [1,6]naphthyridine 4fe (354 mg, 0.90 mmol, 90%) as white solid. Mp 153-155 C
(recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.76 (s, 3H), 3.03 (s, 6H), 5.26 (br
s, 2H), 5.56 (s, 1H), 6.62 (s, 1H), 6.90-6.95 (m, 2H), 6.98-6.99 (m, 1H), 7.02-7.05 (m, 1H), 7.34 (d, J = 4.8
Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H); 13C NMR (75 MHz, DMSO-D6) 30.4, 54.6, 66.6, 89.8, 117.8, 118.8.
122.7, 124.8, 126.3, 126.4, 126.6, 126.9, 127.4, 140.3, 142.8, 152.9, 154.3, 154.8, 160.6, 162.0; IR (KBr)
3460, 3303, 3204, 2935, 182, 1630, 1575, 1534, 1442, 1404, 1301, 1225, 712 cm-1; Anal. Calcd: C, 61.04;
H, 4.87; N, 17.80. Found: C, 60.16, H, 4.89, N, 17.92.
5-Amino-7-diallylamino-2-methyl-2,4-di-thiophen-2-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4ff):

S16

S
H

NH2
N

H3C

N
S H

N
CN

A mixture of ketone 1f (2 mmol), malononitrile 2 (2 mmol) and amine 3f (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the disappearance of
the starting material in thin layer chromatography. After completion of the reaction the crude product was
extracted from water in DCM using separating funnel. The solvents were evaporated in a rotary evaporator
and the residue was subjected to silica gel column chromatography with ethylacetate-petrolium ether (15:85
v/v) as eluent to give [1,6]naphthyridine 4ff (401 mg, 0.90 mmol, 90%) as cream coloured solid. Mp 169161 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.76 (s, 3H), 4.05 (br s, 4H),
5.12-5.27 (m, 6H), 5.53 9s, 1H), 5.84 (br s, 2H), 6.58 (s, 1H), 6.94-7.12 (m, 4H), 7.35 (br s, 1H), 7.53 (br s,
13

1H);

C NMR (75 MHz, DMSO-D6) 30.4, 50.7, 54.7, 66.8, 90.0, 117.4, 118.6, 122.8, 124.9, 126.1,

124.4, 126.7, 126.9, 127.4, 134.6, 140.2, 152.8, 154.2, 154.8, 159.3, 161.9; IR (KBr) 3478, 3375, 3287,
2194, 1609, 1578, 1531, 1431, 1341, 1287, 1194, 1106, 927, 699 cm-1; Anal. Calcd: C, 64.69; H, 5.20; N,
15.72. Found: C, 64.81, H, 5.23, N, 15.83.
5-Amino-7-benzylamino-2-methyl-2,4-di-thiophen-2-yl-1,2-dihydro-[1,6]naphthyridine-8carbonitrile (4fh):

S
H

H3C
S

NH2

N
H

CN

N
H

CH2

A mixture of ketone 1f (2 mmol), malononitrile 2 (2 mmol) and amine 3h (1 mmol) in water (2

mL) were heated under reflux at 100 C for 3 h. The completion of the reaction is indicated by the
disappearance of the starting material in thin layer chromatography. After completion of the reaction the
S17

crude product was extracted from water in DCM using separating funnel. The solvents were evaporated in a
rotary evaporator and the residue was subjected to silica gel column chromatography with ethylacetatepetrolium ether (20:80 v/v) as eluent to give [1,6]naphthyridine 4fh (360 mg, 0.79 mmol, 79%) as yellow
solid. Mp 170-172 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.75 (s, 3H),
4.41-4.54 (m, 2H), 5.19 (br s, 2H), 5.43 (s, 1H), 6.85 (s, 1H), 6.91-7.04 (m, 4H), 7.16-7.27 (m, 6H), 7.33
(d, J = 4.8 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H); 13C NMR (75 MHz, DMSO-D6) 30.2, 43.4, 54.5, 65.4, 88.9,
117.4, 122.8, 124.8, 126.0, 126.2, 126.4, 126.5, 126.7, 126.9, 127.4, 127.5, 128.2, 140.7, 140.8, 153.1,
153.3, 155.8, 158.6, 162.0; IR (KBr) 3478, 3315, 2927, 2192, 1621, 1574, 1514, 1439, 1335, 1221, 1109,
840, 701 cm-1; Anal. Calcd: C, 65.91; H, 4.65; N, 15.37. Found: C, 66.14, H, 4.70, N, 15.50.
Experimental procedure for preparation of intermediate 5
2-[1-(4-Chloro-phenyl)-ethylidene]-malononitrile (5):
NC

CN
CH3

Cl

A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3c (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 0.5 h. The reaction mixture was cooled rapidly by placing it on ice. The
crude product was extracted from water in DCM using separating funnel. The solvents were evaporated in a
rotary evaporator and the residue was subjected to silica gel column chromatography with ethylacetatepetrolium ether (3:97 v/v) as eluent to give Knoevenagel product 5 (385 mg, 1.90 mmol, 95%) as light
yellow solid. Mp 79-81 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, CDCl3) 2.63 (s, 3H),
7.50 (s, 4H);

13

C NMR (75 MHz, CDCl3) 24.1, 85.1, 112.4, 112.5, 128.7, 129.4, 134.1, 138.6, 162.2,

173.8; IR (KBr) 2225, 1580, 1487, 1403, 1301, 1094, 1010, 838, 717, 478 cm-1; Anal. Calcd: C, 65.20; H,
3.48; N, 13.82. Found: C, 65.31, H, 3.50, N, 13.91.
Experimental procedure for preparation of intermediate 7
2-[4,6-Bis-(4-chloro-phenyl)-3-iminomethylene-6-methyl-3,6-dihydro-pyridin-2-yl]malononitrile (7):
S18

Cl

C
H

H3C

NH
CN

CN

Cl

A mixture of ketone 1b (2 mmol), malononitrile 2 (2 mmol) and amine 3c (1 mmol) in water (2 mL) were
heated under reflux at 100 C for 2 h. The reaction mixture was cooled rapidly by placing it on ice. The
crude product was extracted from water in DCM using separating funnel. The solvents were evaporated in a
rotary evaporator and the residue was subjected to silica gel column chromatography with ethylacetatepetrolium ether (20:80 v/v) as eluent to give intermediate 7 (381 mg, 0.94 mmol, 94%) as yellow solid. Mp
174-176 C (recrystallized from EtOAc/ DCM); 1H NMR (300 MHz, DMSO-D6) 1.87(s, 3H), 3.45 (s,
1H), 7.43 (s, 1H), 7.52 (s, 8H), 10.10 (br s, 1H); 13C NMR (75 MHz, DMSO-D6) 24.9, 26.4, 34.3, 66.7,
117.8, 128.3, 128.4, 129.7, 130.5, 133.5, 135.4, 139.2, 162.0, 184.9; IR (KBr) 3463, 3248, 3156, 2934,
2225, 1747, 1603, 1453, 1400, 1096, 1010, 900, 833, 729, 534 cm-1; Anal. Calcd: C, 65.20; H, 3.48; N,
13.82. Found: C, 65.32, H, 3.50, N, 13.92.

S19

Spectral Data of [1,6]-naphthyridines 4aa-4fh

S20

S21

S22

S23

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S25

S26

S27

S28

S29