T. Cailly, M. Begtrup / Tetrahedron 66 (2010) 1299–1307
1305
J¼8.2 Hz, 1H), 7.90 (d, 3J¼8.8 Hz, 1H), 8.30–8.33 (m, 2H), 8.59 (d,
3J¼8.8 Hz, 1H), 9.06 (dd, J¼8.0 and 1.6 Hz, 1H) ppm. 13C NMR
105 ꢁC. 1H NMR (300 MHz, CDCl3):
d
¼1.75 (m, 4H), 2.82 (m, 4H),
6.82 (dd, J¼8.2 and 1.2 Hz, 1H), 7.06–7.17 (m, 2H), 7.38 (dd, 3J¼8.0
and 4.8 Hz, 1H), 8.02 (dd, 3J¼8.0 Hz, 4J¼1.6 Hz, 1H), 8.87 (dd,
(75 MHz, CDCl3):
d¼26.4, 51.7, 115.0, 117.6, 122.9, 124.3, 126.7, 127.9,
129.6, 130.2, 130.8, 135.6, 139.2, 147.2, 148.4, 151.4, 156.3, 158.2 ppm.
HRMS (ESI) calcd for C22H20N3 326.1657, found 326.1653. 6-Phenyl-
3J¼4.8 Hz, 4J¼1.6 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3):
¼26.0,
d
50.9, 113.3, 114.6, 116.7, 122.31, 122.36, 124.9, 125.0, 131.3, 140.4,
149.3, 152.4, 163.4 ppm. HRMS (ESI) calcd for C16H15BrN3 328.0449,
found 328.0457.
2-(2-pyrrolidin-1-ylphenyl)nicotinonitrile
2s:
white
powder
¼1.81
(0.059 g, 50%). Mp 110–111 ꢁC. 1H NMR (300 MHz, CDCl3):
d
(m, 4H), 2.98 (m, 4H), 6.87–6.96 (m, 2H), 7.31–7.41 (m, 2H), 7.47–
7.52 (m, 3H), 7.73 (d, 3J¼8.2 Hz, 1H), 8.02 (d, 3J¼8.2 Hz, 1H), 8.10–
4.13.6. 2-(2-Fluorophenyl)-4-pyrrolidin-1-ylnicotinonitrile
2y. Following the general procedure, using 2-(2-fluorophenyl)-4-
iodonicotinonitrile 2e (0.100 g, 0.31 mmol), LiCl (0.065 g,
1.54 mmol), pyrrolidine (0.030 mL, 0.37 mmol) and n-butyllithium
(0.230 mL, 0.37 mmol, 1.6 M in n-hexane). EtOAc/n-heptane (1/9
and 1/4) was used as the eluents for the chromatography giving 2y
as a white powder (0.073 g, 89%). Mp 140–140.5 ꢁC. 1H NMR
8.13 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼26.2, 51.2, 108.4,
115.1, 117.4, 117.7, 118.1, 125.5, 127.9, 129.3, 130.71, 130.74, 132.4,
138.1, 141.3, 148.0, 159.6, 164.1 ppm. HRMS (ESI) calcd for C22H20N3
326.1657, found 326.1657.
4.13.3. 3-Phenyl-5-pyrrolidin-1-ylbenzo[h]-1,6-naphthyridine
3e. Following the general procedure, using 2-(2-fluorophenyl)-5-
phenylnicotinonitrile 2q (0.44 g, 1.60 mmol), LiCl (0.34 g,
8.02 mmol), pyrrolidine (0.16 mL, 1.92 mmol) and n-butyllithium
(1.20 mL, 1.92 mmol, 1.6 M in n-hexane). EtOAc/n-heptane (1/9)
was used as the eluent for the chromatography giving 3e as a yel-
low powder (0.28 g, 53%). Mp 170–172 ꢁC. 1H NMR (300 MHz,
(300 MHz, CDCl3):
d
¼2.05 (m, 4H), 3.72 (m, 4H), 6.48 (d, 3J¼6.1 Hz,
1H), 7.14–7.26 (m, 2H), 7.40–7.53 (m, 2H), 8.27 (d, 3J¼6.1 Hz, 1H)
ppm. 13C NMR (75 MHz, CDCl3):
d¼26.0, 50.3, 93.3, 107.9, 116.3 (d,
2J¼22 Hz), 119.2, 124.6 (d, J¼3 Hz), 127.6 (d, 2J¼14 Hz), 131.4 (d,
J¼2 Hz), 131.6 (d, 3J¼8 Hz), 150.9, 154.1, 160.1 (d, 1J¼247 Hz),
161.0 ppm. HRMS (ESI) calcd for C16H15FN3 268.1250, found
268.1250.
CDCl3):
d
¼2.06 (m, 4H), 3.96 (m, 4H), 7.40 (m, 1H), 7.46 (m, 1H), 7.54
(m, 2H), 7.64 (m, 1H), 7.70 (m, 2H), 7.77 (m, 1H), 8.70 (d, 4J¼2.1 Hz,
1H), 8.87 (dd, J¼8.6 and 1.5 Hz, 1H), 9.26 (d, 4J¼2.1 Hz, 1H) ppm. 13
C
NMR (75 MHz, CDCl3):
d¼26.5, 51.9, 116.3, 122.5, 123.3, 124.0, 126.9,
4.14. General procedure for KOH mediated anionic ring
closure 5a–k
127.6, 128.6, 129.7, 130.8, 132.6, 1337, 138.1, 146.9, 150.5, 150.7,
156.5 ppm. HRMS (ESI) calcd for C22H20N3 326.1657, found
326.1669.
A microwave tube was charged with: starting material (1 equiv),
KOH (5 equiv) and MeOH (5 mL for 0.1 g of starting material). The
tube was sealed and heated at 150 ꢁC using microwave for the in-
dicated time. After cooling to room temperature, water (15 mL) was
added and the mixture was filtrated. The solid was then washed
several times with Et2O.
4.13.4. 10-Chloro-5-pyrrolidin-1-ylbenzo[h]-1,6-naphthyridine
3f. Following the general procedure, using 2-(2-chloro-6-fluoro-
phenyl)nicotinonitrile 2l (0.100 g, 0.43 mmol), LiCl (0.091 g,
2.15 mmol), pyrrolidine (0.040 mL, 0.52 mmol) and n-butyllithium
(0.320 mL, 0.52 mmol, 1.6 M in n-hexane). EtOAc/n-heptane (1/9
and 1/4) was used as the eluents for the chromatography giving 3f
as a yellow powder (0.046 g, 38%). Mp 99–101 ꢁC. 1H NMR
4.14.1. 2-Butylbenzo[h]-1,6-naphthyridin-5(6H)-one 5b. Following the
general procedure, using 6-butyl-2-(2-fluorophenyl)nicotinonitrile
2b (0.100 g, 0.39 mmol), KOH (0.110 g, 1.95 mmol) and heating for
10 min, giving 5b as a white powder (0.059 g, 65%). Mp 196–198 ꢁC.
(300 MHz, CDCl3):
d
¼2.03 (m, 4H), 3.88 (m, 4H), 7.40–7.79 (m, 2H),
7.50 (dd, 3J¼8.5 and 4.4 Hz, 1H), 7.68 (dd, J¼7.6 and 1.7 Hz, 1H), 8.53
(dd, 3J¼8.5 Hz, 4J¼1.7 Hz, 1H), 9.11 (dd, 3J¼4.4 Hz, 4J¼1.7 Hz, 1H)
1H NMR (300 MHz, DMSO-d6):
d
¼0.96 (t, J¼7.3 Hz, 3H), 1.37 (st,
ppm. 13C NMR (75 MHz, CDCl3):
d¼26.4, 51.6, 116.7, 119.6, 120.8,
J¼7.5 Hz, 2H), 1.77 (qt, J¼7.5 Hz, 2H), 2.93 (t, J¼7.7 Hz, 2H), 7.27 (t,
J¼7.5 Hz, 1H), 7.34 (d, J¼7.9 Hz, 1H), 7.48–7.56 (m; 2H), 8.45 (d,
J¼8.2 Hz, 1H), 8.58 (d, J¼7.0 Hz, 1H) 11.78 (br s, 1H) ppm. 13C NMR
126.4, 126.8, 129.9, 131.4, 134.2, 149.0, 150.7, 151.3, 156.5 ppm.
C16H14ClN3 (283.76): calcd C, 67.72; H, 4.97; N, 14.81, found C, 67.47;
H, 4.97; N, 14.53. 2-(2-Chloro-6-pyrrolidin-1-ylphenyl)nicotinonitrile
2v: yellow powder (0.052 g, 43%). Mp 117.5–118 ꢁC. 1H NMR
(75 MHz, DMSO-d6):
123.1, 123.6, 124.8, 131.8, 136.7, 138.8, 150.8, 161.8, 167.6 ppm. HRMS
(ESI) calcd for C16H17N2O 253.1341, found 253.1334.
d
¼14.7, 22.7, 31.8, 38.6, 116.7, 119.7, 119.9,
(300 MHz, CDCl3):
d
¼1.76 (m, 4H), 2.82 (m, 4H), 6.77 (d, J¼8.5 Hz,
1H), 6.89 (d, J¼7.9 Hz, 1H), 7.19–7.25 (m, 1H), 7.39 (dd, 3J¼7.9 and
5.0 Hz, 1H), 8.03 (dd, 3J¼7.9 Hz, 4J¼1.6 Hz, 1H), 8.87 (dd, 3J¼5.0 Hz,
4.14.2. 2-Phenylbenzo[h]-1,6-naphthyridin-5(6H)-one 5c. Following
the general procedure, using 2-(2-fluorophenyl)-6-phenyl-
nicotinonitrile 2d (0.128 g, 0.46 mmol), KOH (0.130 g, 2.31 mmol)
and heating for 10 min, giving 5c as a white powder (0.110 g, 91%).
4J¼1.6 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3):
¼26.0, 50.9, 113.43,
d
113.9, 116.8, 118.9, 122.2, 123.2, 131.0, 134.8, 140.4, 149.3, 152.4,
162.1 ppm. HRMS (ESI) calcd for C16H15ClN3 328.0955, found
328.0947.
Mp 286–289 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d¼7.29–7.36 (m,
1H), 7.39 (d, J¼8.3 Hz, 1H), 7.53–7.64 (m, 4H), 8.24 (d, 3J¼8.5 Hz,
1H), 8.37–8.37 (m, 2H), 8.64 (d, 3J¼8.5 Hz, 1H), 8.78 (dd, J¼8.0 and
0.9 Hz, 1H), 11.72 (br s, 1H) ppm. 13C NMR (75 MHz, DMSO-d6):
4.13.5. 10-Bromo-5-pyrrolidin-1-ylbenzo[h]-1,6-naphthyridine
3g. Following the general procedure, using 2-(2-bromo-6-fluo-
rophenyl)nicotinonitrile 2m (0.100 g, 0.43 mmol), LiCl (0.076 g,
1.80 mmol), pyrrolidine (0.030 mL, 0.36 mmol) and n-butyllithium
(0.270 mL, 0.36 mmol, 1.6 M in n-hexane). EtOAc/n-heptane (1/9
and 1/4) were used as the eluents for the chromatography giving 3g
as a white powder (0.052 g, 43%). Mp 94–96 ꢁC. 1H NMR (300 MHz,
d
¼115.9, 118.9, 119.7, 122.4, 124.3, 127.4, 129.0, 130.4, 131.3, 136.9,
137.7, 138.2, 150.4, 159.4, 160.8 ppm. HRMS (ESI) calcd for
C18H13N2O 273.1028, found 273.1027.
4.14.3. 3-Phenylbenzo[h]-1,6-naphthyridin-5(6H)-one 5e. Following
the general procedure, using 2-(2-fluorophenyl)-5-phenyl-
nicotinonitrile 2q (0.066 g, 0.24 mmol), KOH (0.067 g, 1.2 mmol)
and heating for 10 min giving 5e as a white powder (0.049 g, 76%).
CDCl3):
d
¼2.01 (m, 4H), 3.86 (m, 4H), 7.34–7.39 (m, 1H), 7.47 (dd,
3J¼8.2 and 4.4 Hz, 1H), 7.66–7.72 (m, 2H), 8.48 (dd, 3J¼8.2 Hz,
4J¼1.7 Hz, 1H), 9.09 (dd, 3J¼4.4 Hz, 4J¼1.7 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3):
d
¼26.3, 51.6, 116.4, 118.7, 120.9, 127.1, 130.3, 130.7,
Mp 280–282 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.28–7.59 (m,
6H), 7.87 (d, J¼7.3 Hz, 2H), 8.60 (d, J¼7.6 Hz,1H), 8.74 (s, 1H), 9.37 (s,
1H), 11.93 (br s, 1H) ppm. 13C NMR (75 MHz, DMSO-d6):
¼116.8,
119.6, 122.0, 123.3, 124.8, 127.8, 129.4, 130.1, 131.9, 133.4, 135.7, 137.1,
134.2, 147.8, 149.0, 150.2, 150.9, 156.4 ppm. HRMS (ESI) calcd for
C16H15BrN3 328.0449, found 328.0483. 2-(2-Bromo-6-pyrrolidin-1-
ylphenyl)nicotinonitrile 2x: white powder (0.034 g, 29%). Mp 104–
d