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Synthesis of Benzo[3,4-h][1,6]naphthyridines via Friedlander Condensation with
Active Methylenes
March 2011
305
9-Chloro-3-methyl-2-phenylbenzo[h][1,6]naphthyridine
(3c). Pale yellow solid; (0.164 g, 80%); mp 294–295ꢀC; ir
(potassium bromide): 3093(w), 2973(w), 1643(s), 1631(m),
9-Chloro-2-(3,4-dimethoxyphenyl)benzo[h][1,6]naphthyri-
dine (3h). Pale yellow solid; (0.154 g, 75%); mp 294–295ꢀC;
ir (potassium bromide): 3018(m), 2963(w), 1683(w), 1669(m)
1
1612(m), 1582(m), 1567(m) cmꢂ1
;
1H NMR (DMSO-d6): d
cmꢂ1; H NMR (DMSO-d6): d 3.67 (s, 6H), 7.06 (d, J ¼ 7.5
2.31 (s, 3H), 7.22–7.56 (m, 5H), 7.84 (d, J ¼ 7.4 Hz, 1H),
8.01 (d, J ¼ 7.4 Hz, 1H), 8.37 (s, 1H), 8.82 (s, 1H), 9.15 (s,
1H); 13C NMR (DMSO-d6): d 14.5, 121.7, 124.0, 126.9,
128.6, 129.1, 129.7, 130.1, 130.3, 132.0, 132.4, 132.9, 133.1,
135.2, 135.3, 137.3, 146.6, 150.1, 160.8; ms: m/z (%) 304
(Mþ, 100), 306 (Mþ2, 32); Anal. Calcd. For C19H13ClN2
(304.77): C, 74.88; H, 4.30; N, 9.19. Found. C, 74.91; H, 4.43;
N, 9.24.
9-Chloro-2-(2-chlorophenyl)benzo[h][1,6]naphthyridine
(3d). Colorless solid; (0.140 g, 68%); mp 276–277ꢀC; ir (po-
tassium bromide): 2985(m), 2822(w), 2818(m), 1691(m),
1637(w), 1583(w), 1501(w) cmꢂ1 1H NMR (DMSO-d6): d
;
7.44 (m, 2H), 7.51 (d, J ¼ 8.2 Hz, 1H), 7.63 (d, J ¼ 8.2 Hz,
1H), 7.93 (d, J ¼ 7.5 Hz, 1H, ), 8.12 (d, J ¼ 7.5 Hz, 1H),
8.24 (d, J ¼ 6.7 Hz, 1H), 8.42 (d, J ¼ 6.7 Hz, 1H), 9.27
(s, 1H), 9.33 (s, 1H); 13C NMR (DMSO-d6): d 120.5, 123.3,
124.9, 126.8, 127.5, 127.9, 128.2, 129.1, 130.3, 131.1, 131.9,
132.4, 132.7, 134.0, 134.7, 145.1, 149.1, 152.7; ms: m/z (%)
324 (Mþ, 100), 326 (Mþ2, 31), 328 (Mþ4, 18); Anal. Calcd.
For C18H10Cl2N2 (325.19): C, 66.48; H, 3.10; N, 8.16. Found.
C, 66.52; H, 3.19; N, 8.27.
Hz, 1H), 7.30 (dd, J ¼ 7.2,2.2 Hz, 1H), 7.35 (d, J ¼ 2.2 Hz,
1H), 8.23 (d, J ¼ 8.4 Hz, 1H), 8.35 (d, J ¼ 7.4 Hz, 1H), 8.50
(d, J ¼ 8.4 Hz, 1H), 8.75 (d, J ¼ 7.4 Hz, 1H), 9.11 (s, 1H),
9.23 (s, 1H); ms: m/z (%) 350 (Mþ, 100), 352 (Mþ2, 34);
Anal. Calcd. For C20H15ClN2O2 (350.80): C, 68.48; H, 4.31;
N, 7.99. Found. C, 68.53; H, 4.42; N, 8.1.
9-Chloro-2-(2,6-dimethoxyphenyl)benzo[h][1,6]naphthyri-
dine (3i). Colorless solid; (0.158 g, 77%); mp 297–298ꢀC; ir
(potassium bromide): 2981(m), 2897(w), 1676(m), 1632(m),
1
1548(w) cmꢂ1; H NMR (DMSO-d6): d 3.79 (s, 6H), 7.43 (m,
3H, ArAH), 8.3 1(d, J ¼ 8.2 Hz, 1H), 8.42 (d, J ¼ 7.8 Hz,
1H), 8.45 (d, J ¼ 8.2 Hz, 1H), 8.73 (d, J ¼ 7.8 Hz, 1H), 9.10
(s, 1H), 9.17 (s, 1H); ms: m/z (%) 350 (Mþ, 100), 352 (Mþ2,
36); Anal. Calcd. For C20H15ClN2O2 (350.80): C, 68.48; H,
4.31; N, 7.99. Found. C, 68.50; H, 4.37; N, 8.2.
9-Chloro-2-p-tolylbenzo[h][1,6]naphthyridine (3j). Colorless
solid; (0.156 g, 76%); mp 297–298ꢀC; ir (potassium bromide):
2981(m), 2978(w), 2896(m), 1635(m), 1618(m), 1512(w)
1
cmꢂ1; H NMR (DMSO-d6): d 2.43 (s, 3H, CH3), 7.37 (d, J ¼
8.4 Hz, 2H), 7.51 (d, J ¼ 8.4 Hz, 2H), 8.10 (d, J ¼ 8.5 Hz,
1H), 8.23 (d, J ¼ 8.2 Hz, 1H), 8.27 (d, J ¼ 8.5 Hz, 1H), 8.44
(d, J ¼ 8.2 Hz, 1H), 8.91 (s, 1H), 9.13 (s, 1H); ms: m/z (%)
304 (Mþ, 100), 306 (Mþ2, 31); Anal. Calcd. For C19H13ClN2
(304.77): C, 74.88; H, 4.30; N, 9.19. Found. C, 74.91; H, 4.33;
N, 9.27.
9-Chloro-2-(4-chlorophenyl)benzo[h][1,6]naphthyridine
(3e). Pale yellow solid; (0.142 g, 69%); mp 269–270ꢀC; ir (po-
tassium bromide): 3012(m), 2921(m), 2817(w), 1658(m), 1649(s),
1
1486(m), 1422(w), 1583(w) cmꢂ1; H NMR (DMSO-d6): d 7.37
(d, J ¼ 7.9 Hz, 2H), 7.91 (d, J ¼ 8.3 Hz, 1H), 8.14 (d, J ¼ 8.3
Hz, 1H), 8.36 (d, J ¼ 7.2 Hz, 1H, ), 8.52 (d, J ¼ 7.9 Hz, 2H),
8.65 (d, J ¼ 7.2 Hz, 1H), 9.00 (s, 1H), 9.24 (s, 1H); 13C NMR
(DMSO-d6): d 118.3, 123.0, 127.2, 127.9, 128.9 (2 C’s) 130.0,
130.7, 130.9, 131.2, 133.3, 134.1, 134.7, 143.8 (2 C’s) 147.2,
154.0, 157.1; ms: m/z (%) 324 (Mþ,100), 326 (Mþ2, 36), 328
(Mþ4, 13); Anal. Calcd. For C18H10Cl2N2 (325.19): C, 66.48; H,
3.10; N, 8.16. Found. C, 66.49; H, 3.21; N, 8.29.
2-(3,5-Bis(trifluoromethyl)phenyl)-9-chlorobenzo[h][1,6]-
naphthyridine (3k). Colorless solid; (0.154 g, 75%); mp 283–
284ꢀC; ir (potassium bromide): 3012(m), 2937(m), 1683(w),
1662(s), 1544(m), 1537(w); 1H NMR (DMSO-d6): d 7.87 (m,
1H), 8.16 (m, 2H), 8.65 (dd, J ¼ 2.7,8.4 Hz, 1H), 8.80 (dd,
J ¼ 2.7,8.4 Hz,1H), 8.93 (s,2H), 9.01 (s, 1H), 9.44 (s, 1H);
ms: m/z (%) 426 (Mþ, 100), 428 (Mþ2, 33); Anal. Calcd. For
C20H9ClF6N2 (426.74): C, 56.33; H, 2.11; N, 6.57. Found. C,
56.31; H, 2.17; N, 6.56.
General procedure for the synthesis of compounds 5a
and b. A mixture of 1b (0.206 g, 1 mmol) and corresponding
ketones 4a–b (1 mmol) in DMF with catalytic amount of
KOH was heated under reflux for 3 h. After completion of the
reaction (TLC check), solvent was evaporated under reduced
pressure, the crude solid was washed with methanol, filtered,
dried under high vacuum, and recrystallized from ethanol:
DMF (6:4) to furnish 5a–b in 76–79% yield.
9-Chloro-2-(4-fluorophenyl)benzo[h][1,6]naphthyridine
(3f). Colorless solid; (0.150 g, 73%); mp 297–298ꢀC; ir (po-
tassium bromide): 2989(m), 2817(w), 1631(m), 1604(m),
1
1588(m), 1563(m) cmꢂ1; H NMR (DMSO-d6): d 7.55 (d, J ¼
8.4 Hz, 2H), 7.71 (d, J ¼ 7.4 Hz, 1H), 7.93 (d, J ¼ 7.4 Hz,
1H), 8.06 (d, J ¼ 7.5 Hz, 1H), 8.19 (d, J ¼ 7.5 Hz, 1H), 8.58
(d, J ¼ 8.4 Hz, 2H), 8.90 (s, 1H), 9.26 (s, 1H ); 13C NMR
(DMSO-d6): d 113.4 (2 C’s), 120.7, 122.9, 125.6, 125.8,
129.1(2 C’s), 129.9, 131.1, 131.9, 132.0, 133.7, 135.1, 144.6,
147.9, 154.1, 159.3; ms: m/z (%) 308 (Mþ, 100), 310 (Mþ2,
33); Anal. Calcd. For C18H10ClFN2 (308.74): C, 70.03; H,
3.26; N, 9.07. Found. C, 70.11; H, 3.37; N, 9.19.
9-Chloro-2,3-dimethylbenzo[h][1,6]naphthyridine (5a). Pale
yellow solid; (0.160 g, 78%); mp 302–303ꢀC; ir (potassium
bromide): 3012(w), 2982(m), 2811(m), 1683(m), 1661(w),
1
2-(4-Bromophenyl)-9-chlorobenzo[h][1,6]naphthyridine
(3g). Pale yellow solid; (0.150 g, 73%); mp 267–268ꢀC; ir
(potassium bromide): 3005(w), 2918(m), 1645(m), 1623(w),
1537(m), 1518(s) cmꢂ1; H NMR (DMSO-d6): d 2.55 (s, 3H),
2.71 (s, 3H), 7.86 (d, J ¼ 6.6 Hz, 1H), 8.10 (d, J ¼ 6.6 Hz,
1H), 8.32 (s, 1H) 8.96 (s, 1H), 9.30 (s, 1H); 13C NMR
(DMSO-d6): d 16.3, 18.1, 120.7, 126.6, 127.8, 130.1, 131.3,
132.6, 133.1, 133.2, 135.0, 145.7, 150.0, 159.1; ms: m/z (%)
242 (Mþ, 100), 244 (Mþ2, 37); Anal. Calcd. For C14H11ClN2
(242.70): C, 69.28; H, 4.57; N, 11.54. Found. C, 69.37; H,
4.58; N, 11.63.
9-Chloro-2-methyl-3-phenylbenzo[h][1,6]naphthyridine
(5b). Pale yellow solid; (0.156 g, 76%); mp 291–292ꢀC; ir
(potassium bromide): 3314(m), 3017(m), 2983(w), 1683(m),
1676(w), 1560(w), 1553(w) cmꢂ1 1H NMR (DMSO-d6): d
;
1
1522(m) cmꢂ1; H NMR (DMSO-d6): d 7.25 (d, J ¼ 7.5 Hz,
2H), 7.81 (d, J ¼ 8.5 Hz, 1H), 8.23 (d, J ¼ 8.5 Hz, 1H), 8.37
(d, J ¼ 7.6 Hz, 1H, ), 8.56 (d, J ¼ 7.5 Hz, 2H), 8.53 (d, J ¼
7.6 Hz, 1H), 9.08 (s, 1H), 9.31 (s, 1H); 13C NMR (DMSO-d6):
d 117.7, 123.5, 126.9, 128.0, 129.0 (2 C’s) 131.0, 131.2,
131.3, 131.4, 134.0, 134.2, 134.6, 144 (2 C’s) 147.0, 154.4,
159.8; ms: m/z (%) 368 (Mþ, 78), 370 (Mþ2, 95), 372 (Mþ4,
19); Anal. Calcd. For C18H10BrClN2 (369.64): C, 58.49; H,
2.73; N, 7.58. Found. C, 58.58; H, 2.75; N, 7.69.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet