N.A. Haverkate et al.
Bioorganic & Medicinal Chemistry 37 (2021) 116092
128.42 (C-5), 132.9 (C-4), 139.0 (C-1′), 147.0 (C-3), 158.5 (C-6), 160.0
(C-7a), 163.7 (2-CONH), 199.7 (5-COCH3); IR: νmax (film)/cmꢀ 1 3396,
3300, 2981, 1682, 1590, 1444, 1255, 1100; m/z (ESI+): 348 (MNa+,
80%), 302 (50%), 261 (25%), 227 (100%), 217 (22%); HRMS (ESI+)
found (MNa+): 348.0774 C17H15N3NaO2S requires 348.0777.
Hz, H-4′), 7.26 (2H, br s, NH2), 7.28 (2H, m, H-3′ and H-5′), 7.30–7.37
(5H, m, 5 × Ar-CH), 7.67 (2H, d, J = 7.5 Hz, H-2′ and H-6′), 8.14 (1H, s,
H-4), 9.36 (1H, br s, NH); 13C NMR (100 MHz, (CD3)2SO) 32.2 (C-8),
49.9 (C-7), 54.5 (C-5), 61.3 (C-6′’’), 96.0 (C-2), 121.1 (C-2′ and C-6′),
123.3 (C-4′), 124.2 (C-3a), 126.3 (C-4a), 127.1 (C-4′’), 128.29 (C-3′, C-5′
and 2 × Ar-C), 128.34 (2 × Ar-C), 128.8 (C-4), 138.1 (C-1′’), 139.0 (C-
1′), 146.8 (C-3), 156.6 (C-9a), 156.7 (C–8a), 164.0 (2-CONH); IR: νmax
(film)/cmꢀ 1 3441, 3332, 3027, 2814, 1606, 1587, 1254, 1106; m/z
(ESI+): 415 (MH+, 100%), 227 (10%); HRMS (ESI+) found (MH+):
415.1576 C24H23N4OS requires 415.1587.
5-Acetyl-3-amino-N-(isoquinolin-4′-yl)-6-methylthieno[2,3-b]pyridine-
2-carboxamide 4n. The reaction was carried out following general pro-
cedure A using carbonitrile 2 (44.0 mg, 0.23 mmol), acetamide 3n (50.0
mg, 0.23 mmol) and anhydrous sodium carbonate (36.0 mg, 0.34 mmol)
in absolute ethanol (3.00 mL) for 48 h to give the title compound 4n
(58.0 mg, 68%) as a mustard yellow solid. m.p. > 230 ◦C. 1H NMR (400
MHz, (CD3)2SO) 2.67 (3H, s, 5-COCH3), 2.77 (3H, s, 6-CH3), 7.45 (2H, br
s, NH2), 7.69 (1H, t, J = 7.3 Hz, H-7′), 7.79 (1H, t, J = 7.3 Hz, H-6′), 8.00
(1H, d, J = 7.3 Hz, H-5′), 8.15 (1H, d, J = 7.3 Hz, H-8′), 8.61 (1H, s, H-
3′), 9.04 (1H, s, H-4), 9.17 (1H, s, H-1′), 9.83 (1H, br s, NH); 13C NMR
(100 MHz, (CD3)2SO) 25.1 (6-CH3), 29.2 (5-COCH3), 122.9 (C-5′), 124.0
(C-3a), 127.2 (C-7′), 127.4 (C-8′), 128.3 (C-5), 128.5 (C-6′), 129.8 (C-4′
and C-8′a), 132.2 (C-4′a), 132.8 (C-4), 140.0 (C-3′), 146.2 (C-3), 148.9
(C-1′), 157.1 (C-6), 160.2 (C-7a), 165.0 (2-CONH), 199.7 (5-CO). C-2 not
observed; IR: νmax (film)/cmꢀ 1 3426, 3264, 2981, 2886, 1683, 1586,
1541, 1484, 1248, 1103; m/z (ESI+): 399 (MNa+, 100%); HRMS (ESI+)
found (MNa+): 399.0891 C20H16N4NaO2S requires 399.0886.
Benzyl 3-amino-2-(phenylcarbamoyl)-7,8-dihydrothieno[2,3-b][1,6]
naphthyridine-6(5H)-carboxylate 16a. The reaction was carried out
following general procedure A using carbonitrile 13 (0.20 g, 0.62
mmol), acetamide 3a (0.13 g, 0.62 mmol) and anhydrous sodium car-
bonate (0.13 g, 1.23 mmol) in absolute ethanol (2.50 mL) to give the title
compound 16a (0.09 g, 33%) as a light grey solid. m.p. > 230 ◦C. 1H NMR
(400 MHz, (CD3)2SO) 3.06 (2H, t, J = 5.9 Hz, H-8), 3.80 (2H, br s, H-7),
4.74 (2H, br s, H-5), 5.15 (2H, s, OCH2), 7.06 (1H, t, J = 7.5 Hz, H-4′),
7.28–7.41 (9H, m, H-3′, H-5′, H-2′’, H-3′’, H-4′’, H-5′’, H-6′’ and NH2),
7.67 (2H, d, J = 7.5 Hz, H-2′ and H-6′), 8.30 (1H, s, H-4), 9.40 (1H, br s,
NH); 13C NMR (100 MHz, (CD3)2SO) 31.8 (C-8), 44.8 (C-7), 53.2 (C-5),
66.5 (OCH2), 121.1 (C-2′, C-6′ and C-3a), 123.3 (C-4′), 124.6 (C-4a),
127.6 (C-2′’ and C-6′’), 127.9 (C-4′’), 128.3 and 128.4 (C-3′, C-5′, C-3′’
and C-5′’), 128.6 (C-4), 136.8 (C-1′’), 139.0 (C-1′), 146.6 (C-3), 154.7
5-Acetyl-3-amino-N-(2′,3′-dihydrobenzo[b][1′,4′]dioxin-5′-yl)-6-meth-
ylthieno[2,3-b]pyridine-2-carboxamide 4t. The reaction was carried out
following general procedure A using carbonitrile 2 (68.0 mg, 0.35
mmol), acetamide 3t (80.0 mg, 0.35 mmol) and anhydrous sodium
carbonate (74.0 mg, 0.70 mmol) in absolute ethanol (3.00 mL) for 48 h
to give the title compound 4t (106.0 mg, 82%) as a light brown solid. m.
p. > 230 ◦C. 1H NMR (400 MHz, (CD3)2SO) 2.66 (3H, s, 5-COCH3), 2.75
(3H, s, 6-CH3), 4.25–4.27 (2H, m, H-2′), 4.31–4.33 (2H, m, H-3′), 6.70
(1H, dd, J = 8.2, 1.5 Hz, H-8′), 6.81 (1H, t, J = 8.2 Hz, H-7′), 7.33 (1H,
dd, J = 8.2, 1.5 Hz, H-6′), 7.42 (2H, br s, NH2), 8.56 (1H, br s, NH), 9.07
(1H, s, H-4); 13C NMR (100 MHz, (CD3)2SO) 25.1 (6-CH3), 29.2 (5-
COCH3), 63.9 (C-2′), 64.4 (C-3′), 96.8 (C-2), 113.2 (C-8′), 116.1 (C-6′),
120.0 (C-7′), 124.0 (C-3a), 127.0 (C-5′), 128.5 (C-5), 133.1 (C-4), 136.0
(C-4′a), 143.5 (C-8′a), 146.6 (C-3), 158.5 (C-6), 159.6 (C-7a), 163.1 (2-
CONH), 199.7 (5-CO); IR: νmax (film)/cmꢀ 1 3414, 3298, 2893, 1687,
1611, 1586, 1446, 1286, 1077, 1088; m/z (ESI+): 406 (MNa+, 100%);
HRMS (ESI+) found (MNa+): 406.0837 C19H17N3NaO4S requires
406.0832.
–
(6-C O), 156.3 (C-8a), 156.7 (C-9a), 163.9 (2-CONH). C-2 not
–
observed; IR: νmax (film)/cmꢀ 1 3497, 3231, 3030, 2938, 1687, 1590,
1256, 1209, 1113; m/z (ESI+): 481 (MNa+, 100%), 201 (40%); HRMS
(ESI+) found (MNa+): 481.1296 C25H22N4NaO3S requires 481.1305.
3-Amino-6-methyl-N-phenyl-5,6,7,8-tetrahydrothieno[2,3-b][1,6]
naphthyridine-2-carboxamide 17a. The reaction was carried out
following general procedure A using carbonitrile 14 (0.20 g, 0.97
mmol), acetamide 3a (0.21 g, 0.97 mmol) and anhydrous sodium car-
bonate (0.21 g, 1.95 mmol) in absolute ethanol (4.00 mL) to give the title
compound 17a (0.14 g, 44%) as a brown solid. m.p. > 230 ◦C. 1H NMR
(400 MHz, (CD3)2SO) 2.40 (3H, s, NCH3), 2.75 (2H, t, J = 5.8 Hz, H-7),
3.04 (2H, t, J = 5.8 Hz, H-8), 3.63 (2H, s, H-5), 7.05 (1H, t, J = 7.5 Hz, H-
4′), 7.30 (4H, m, H-3′, H-5′ and NH2), 7.67 (2H, d, J = 7.5 Hz, H-2′ and
H-6′), 8.16 (1H, s, H-4), 9.38 (1H, br s, NH); 13C NMR (100 MHz,
(CD3)2SO) 32.3 (C-8), 45.4 (NCH3), 52.1 (C-7), 56.6 (C-5), 121.1 (C-2′
and C-6′), 123.2 (C-4′), 124.2 (C-3a), 126.4 (C-4a), 128.3 (C-3′ and C-5′),
128.4 (C-4), 139.1 (C-1′), 146.7 (C-3), 156.6 (C-8a and C-9a), 164.0 (2-
CONH). C-2 not observed; IR: νmax (film)/cmꢀ 1 3142, 3310, 2939, 1589,
1520, 1437, 1254, 1116; m/z (ESI+): 361 (MNa+, 100%); HRMS (ESI+)
found (MNa+): 361.1082 C18H18N4NaOS requires 361.1094.
5-Acetyl-3-amino-6-methyl-N-(pyridin-2′-yl)thieno[2,3-b]pyridine-2-
carboxamide 4v. The reaction was carried out following general pro-
cedure A using acetamide 3v (89.0 mg, 0.52 mmol), carbonitrile 2 (0.10
g, 0.52 mmol) and anhydrous sodium carbonate (0.11 g, 1.0 mmol) in
absolute ethanol (2.0 mL) to give the title compound 4v (0.133 g, 78%) as
a beige solid. m.p. > 230 ◦C. 1H NMR (400 MHz, (CD3)2SO) 2.66 (3H, s,
COCH3), 2.75 (3H, s, 6-CH3), 7.13 (1H, dt, J = 5.0, 1.4 Hz, H-5′), 7.57
(2H, br s, NH2), 7.81 (1H, dt, J = 8.6, 1.4 Hz, H-4′), 8.05 (1H, d, J = 8.4
Hz, H-3′), 8.36 (1H, dd, J = 5.0, 1.4 Hz, H-6′), 9.08 (1H, s, H-4), 9.77
(1H, br s, NH); 13C NMR (100 MHz, (CD3)2SO) 25.2 (6-CH3), 29.2
(COCH3), 96.4 (C-2), 114.8 (C-3′), 119.5 (C-5′), 123.7 (C-3a), 128.4 (C-
5), 133.2 (C-4), 137.9 (C-4′), 147.7 and 147.9 (C-3 and C-6′), 152.0 (C-
3-Amino-N-phenyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]pyri-
dine-2-carboxamide 19a. The reaction was carried out following general
procedure A using carbonitrile 20 (0.10 g, 0.520 mmol), acetamide 3a
(0.11 g, 0.520 mmol) and anhydrous sodium carbonate (0.11 g, 1.04
mmol) in absolute ethanol (2.00 mL) to give the title compound 19a
1
◦
(0.131 g, 77%) as a brown solid. m.p. > 230 C. H NMR (400 MHz,
(CD3)2SO) 3.04 (2H, t, J = 5.8 Hz, H-8), 4.04 (2H, t, J = 5.8 Hz, H-7),
4.85 (2H, s, H-5), 7.07 (1H, t, J = 7.5 Hz, H-4′), 7.29–7.33 (4H, m, H-3′,
H-5′ and NH2), 7.68 (2H, d, J = 7.5 Hz, H-2′ and H-6′), 8.18 (1H, s, H-4),
9.40 (1H, br s, NH); 13C NMR (100 MHz, (CD3)2SO) 31.7 (C-8), 64.7 (C-
7), 66.6 (C-5), 96.2 (C-2), 121.1 (C-2′ and C-6′), 123.3 (C-4′), 124.4 (C-
3a), 126.6 (C-4a), 126.9 (C-4), 128.4 (C-3′ and C-5′), 139.0 (C-1′), 146.8
(C-3), 155.3 (C-8a), 156.8 (C-9a), 164.0 (2-CONH); IR: νmax (film)/cmꢀ 1
3430, 3323, 2938, 1593, 1436, 1237, 1107; m/z (ESI+): 348 (MNa+,
100%), 227 (40%), 159 (20%), 101 (18%); HRMS (ESI+) found (MNa+):
348.0774 C17H15N3NaO2S requires 348.0777.
′
–
2 ), 158.8 (C-6), 160.3 (C-7a), 163.8 (C O), 199.6 (COCH ); IR:
–
νmax(film)/cmꢀ 1 3364, 3180, 2926, 1683, 1619, 1596, 1573,31456,
1428, 994, 779; m/z (ESI): 349 (MNa+, 94%), 327 (MH+, 47%), 233
(C11H9N2O2S+, 57%), 207 (C10H11N2OS+, 100%), 121 (C6H5N2O+,
82%), 95 (C5H7N+2 , 7%); HRMS (ESI+) found (MH+): 327.0908,
C16H15N4O2S requires 327.0910.
3-Amino-6-benzyl-N-phenyl-5,6,7,8-tetrahydrothieno[2,3-b][1,6]naph-
thyridine-2-carboxamide 15a. The reaction was carried out following
general procedure A using carbonitrile 12 (50.0 mg, 0.178 mmol),
acetamide 3a (38.0 mg, 0.178 mmol) and anhydrous sodium carbonate
(20.0 mg, 0.188 mmol) in absolute ethanol (2.00 mL) to give the title
compound 15a (25.0 mg, 34%) as a dark brown solid. m.p. > 230 ◦C. 1H
NMR (400 MHz, (CD3)2SO) 2.85 (2H, t, J = 5.3 Hz, H-7), 3.03 (2H, t, J =
5.3 Hz, H-8), 3.67 (2H, s, H-5), 3.72 (2H, s, H-6′’’), 7.06 (1H, t, J = 7.5
3-Amino-5-(1-hydroxyethyl)-6-methyl-N-phenylthieno[2,3-b]pyridine-
2-carboxamide 5a. The reaction was carried out following general pro-
cedure B using ketone 4a (0.05 g, 0.15 mmol), NaBH4 (6.00 mg, 0.15
mmol) and methanol (0.51 mL) in THF (7.70 mL) to give the title com-
pound 5a (32.0 mg, 64%) as a yellow solid. m.p. > 230 ◦C. 1H NMR (400
MHz, (CD3)2SO) 1.40 (3H, d, J = 6.4 Hz, CHCH3), 2.61 (3H, s, 6-CH3),
8