d-Fused [1]Benzazepines
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1303
7.56 (m, 2H), 7.59 (“t”, 2H, J ) 7.4/7.4 Hz), 7.63-7.68 (m, 2H),
7.89 (s, 1H), 8.16-8.23 (m, 3H), 10.38 (s, 1H). Anal. C, H, N.
4-(4-Me t h oxyp h e n yl)-2-p h e n yl-5H -p yr id o[3,2-d ][1]-
ben za zep in -6(7H)-on e (10l) was prepared following general
procedure A in 33% yield from 2a : colorless needles; mp 268
°C; IR 3190 (NH), 1670 cm-1 (CdO); 1H NMR (400 MHz) 3.45
(br s, 2H), 3.86 (s, 3H, OCH3), 7.15 (d, 2H, J ) 9.2 Hz), 7.25
(dd, 1H, J ) 7.6/1.0 Hz), 7.36 (d“t”, 1H, J ) 7.6/7.6/1.0 Hz),
7.43-7.56 (m, 4H), 7.65 (d, 2H, J ) 8.6 Hz), 7.93 (s, 1H), 8.22
(d“t”, 3H, J ) 8.4/8.4/1.5 Hz), 10.38 (s, 1H). Anal. C, H, N.
2 ,4 -B i s (4 -m e t h o x y p h e n y l )-5 H -p y r i d o [3 ,2 -d ][1 ]-
ben za zep in -6(7H)-on e (10m ) was prepared following general
procedure A in 42% yield from 2a : colorless needles; mp 234
°C; IR 3190 (NH), 1675 cm-1 (CdO); 1H NMR (400 MHz), 3.35
(br s, 2H), 3.83 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 7.06 (d, 2H,
J ) 9.2 Hz), 7.15 (d, 2H, J ) 8.7 Hz), 7.25 (d, 1H, J ) 7.6 Hz),
7.35 (“t”, 1H, J ) 7.6/7.6 Hz), 7.51 (d“t”, 1H, J ) 7.6/7.6/1.5
Hz), 7.62 (d, 2H, J ) 8.6 Hz), 7.85 (s, 1H), 8.18 (d, 3H, J ) 8.6
Hz), 10.38 (s, 1H). Anal. C, H, N.
4-(3,4-Dim eth oxyp h en yl)-2-p h en yl-5H-p yr id o[3,2-d ][1]-
ben za zep in -6(7H)-on e (10n ) was prepared following general
procedure A in 36% yield from 2a : colorless needles; mp 297-
298 °C; IR 3190 (NH), 1670 cm-1 (CdO); 1H NMR (400 MHz)
3.30 (br s, 2H), 3.86 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 7.14-
7.30 (m, 4H), 7.34-7.40 (m, 1H), 7.44-7.56 (m, 4H), 7.96 (s,
1H), 8.23 (d“t”, 3H, J ) 7.4/7.4/1.5 Hz), 10.39 (s, 1H). Anal.
C, H, N.
2-(1,3-Ben zod ioxol-5-yl)-4-p h en yl-5H-p yr id o[3,2-d ][1]-
ben za zep in -6(7H)-on e (10o) was prepared following general
procedure A in 15% yield from 2a : colorless needles; mp 235
°C; IR 3180 (NH), 1680 cm-1 (CdO); 1H NMR (400 MHz) 3.32
(br s, 2H), 6.10 (s, 2H, methylenedioxy-CH2), 7.04 (d, 1H, J )
8.1 Hz), 7.25 (dd, 1H, J ) 7.6/7.6 Hz), 7.36 (d“t”, 1H, J ) 7.6/
7.6/1.0 Hz), 7.49-7.56 (m, 2H), 7.59 (“t”, 2H, J ) 7.1/7.1 Hz),
7.66 (d, 2H, J ) 7.1 Hz), 7.79-7.83 (m, 2H), 7.89 (s, 1H), 8.19
(dd, 1H, J ) 8.1/1.5 Hz), 10.38 (s, 1H). Anal. C, H, N.
Hydr oxylated 2,4-Diar yl-5H-pyr ido[3,2-d][1]ben zazepin -
6(7H)-on es 10p -r , Gen er a l P r oced u r e B. To a solution of
the appropriate methoxy derivative 10k -m in CH2Cl2 (10 mL)
was added BBr3. After 18 h of stirring at room temperature,
water (10 mL) was added, and stirring was continued for 6 h
at room temperature. A solid was formed, which was collected
by filtration, washed with water, and recrystallized from
ethanol.
Hz), 9.72 (s, 1H, OH), 9.77 (s, 1H, OH), 10.35 (s, 1H). Anal.
(C25H18N2O3‚C2H5OH) C, H; N: calcd, 6.35; found, 6.83.
2,4-D ia r y l-5H -p y r id o [3,2-d ][1]b e n za ze p in e -6(7H )-
th ion es 11b-o, Gen er a l P r oced u r e C. A solution of the
appropriate lactam 10b-o in THF or 1,4-dioxane was stirred
at 50 °C under nitrogen. Phosphorus pentasulfide and after
1 min NaHCO3 were added to the mixture, which was then
refluxed under nitrogen, and the reaction was monitored by
TLC. If the reaction was not complete after 3 h, addition of
the indicated amounts of phosphorus pentasulfide and
NaHCO3 was repeated and refluxing was continued for 3 h.
After being cooled to room temperature, the mixture was
poured onto crushed ice (50 mL) and stirred until the ice
melted. The precipitate was filtered, washed with water, and
recrystallized from ethanol/toluene.
2-(4-C h lo r o p h e n y l)-4-p h e n y l-5H -p y r id o [3,2-d ][1]-
ben za zep in e-6(7H)-th ion e (11b) was prepared following
general procedure C from 10b (198 mg, 0.5 mmol), phosphorus
pentasulfide (200 mg, 0.9 mmol), and NaHCO3 (285 mg, 3.4
mmol) in THF (15 mL) in 67% yield: colorless crystals; mp
280 °C; IR 3150 cm-1 (NH); 1H NMR (400 MHz) 3.57 (br s,
1H), 4.19 (br s, 1H), 7.37 (d, 1H, J ) 7.6 Hz), 7.47 (d“t”, 1H, J
) 8.1/8.1/1.0 Hz), 7.51-7.61 (m, 6H), 7.80 (d, 2H, J ) 6.6 Hz),
7.99 (s, 1H), 8.19 (dd, 1H, J ) 7.6/1.3 Hz), 8.26-8.31 (m, 2H),
12.37 (s, 1H). Anal. C, H, Cl, N, S.
2-(3-C h lo r o p h e n y l)-4-p h e n y l-5H -p y r id o [3,2-d ][1]-
ben za zep in e-6(7H)-th ion e (11c) was prepared following
general procedure C from 10c (300 mg, 0.76 mmol), phospho-
rus pentasulfide (300 mg, 1.35 mmol), and NaHCO3 (430 mg,
5.1 mmol) in THF (25 mL) in 56% yield: colorless crystals;
mp 293 °C; IR 3160 cm-1 (NH); 1H NMR (400 MHz) 3.57 (br s,
1H), 4.21 (br s, 1H), 7.38 (d, 1H, J ) 8.1 Hz), 7.48 (d“t”, 1H, J
) 6.6/6.6/1.0 Hz), 7.51-7.61 (m, 6H), 7.80 (d, 2H, J ) 6.6 Hz),
8.04 (s, 1H), 8.18-8.25 (m, 2H), 8.30 (s, 1H), 12.38 (s, 1H).
Anal. C, H, Cl, N, S.
2-(2-C h lo r o p h e n y l)-4-p h e n y l-5H -p y r id o [3,2-d ][1]-
ben za zep in e-6(7H)-th ion e (11d ) was prepared following
general procedure C from 10d (396 mg, 1.0 mmol), phosphorus
pentasulfide (400 mg, 1.8 mmol), and NaHCO3 (560 mg, 6.66
mmol) in 1,4-dioxane (15 mL) in 70% yield: colorless crystals;
1
mp 320 °C dec; IR 3150 cm-1 (NH); H NMR (400 MHz) 3.59
(br s, 1H), 4.24 (br s, 1H), 7.56-7.64 (m, 9H), 7.67 (s, 1H),
7.76-7.81 (m, 3H), 8.13 (dd, 1H, J ) 8.1/1.5 Hz), 12.41 (s, 1H).
Anal. C, H, Cl, N, S.
4-(4-C h lo r o p h e n y l)-2-p h e n y l-5H -p y r id o [3,2-d ][1]-
ben za zep in e-6(7H)-th ion e (11e) was prepared following
general procedure C from 10e (298 mg, 0.75 mmol), phospho-
rus pentasulfide (294 mg, 1.32 mmol), and NaHCO3 (430 mg,
5.1 mmol) in THF (25 mL) in 77% yield: colorless crystals;
mp 270 °C; IR 3140 cm-1 (NH); 1H NMR (400 MHz) 3.59 (br s,
1H), 4.14 (br s, 1H), 7.38 (dd, 1H, J ) 8.1/1.0 Hz), 7.44-7.55
(m, 4H), 7.57 (d“t”, 1H, J ) 7.6/7.6/1.5 Hz), 7.64 (d, 2H, J )
8.7 Hz), 7.81 (d, 2H, J ) 8.7 Hz), 7.96 (s, 1H), 8.18-8.26 (m,
3H), 12.39 (s, 1H). Anal. C, H, Cl, N, S.
2-(4-H yd r oxyp h e n yl)-4-p h e n yl-5H -p yr id o[3,2-d ][1]-
b en za zep in -6(7H )-on e (10p ) was prepared following gen-
eral procedure B from 10k (425 mg, 1.08 mmol) and BBr3 (576
mg, 2.3 mmol) in 33% yield: colorless needles; mp >330 °C;
IR 3310 (OH), 3220 (NH), 1660 cm-1 (CdO); 1H NMR (400
MHz) 3.35 (br s, 2H), 6.89 (d, 2H, J ) 8.0 Hz), 7.24 (d, 1H, J
) 8.0 Hz), 7.35 (d“t”, 1H, J ) 7.6/7.6/1.0 Hz), 7.49-7.55 (m,
2H), 7.56-7.61 (m, 2H), 7.62-7.67 (m, 2H), 7.83 (s, 1H), 8.06-
8.11 (m, 2H), 8.19 (dd, 1H, J ) 8.0/1.6 Hz), 9.73 (s, 1H, OH),
10.38 (s, 1H). Anal. C, H, N.
4-(4-H yd r oxyp h e n yl)-2-p h e n yl-5H -p yr id o[3,2-d ][1]-
ben za zep in -6(7H)-on e (10q) was prepared following general
procedure B from 10l (275 mg, 0.7 mmol) and BBr3 (376 mg,
1.5 mmol) in 38% yield: colorless crystals; mp 303 °C; IR 3260
(OH, NH), 1665 cm-1 (CdO); 1H NMR 3.39 (br s, 2H), 6.96 (d,
2H, J ) 8.7 Hz), 7.25 (d, 1H, J ) 8.1 Hz), 7.36 (d“t”, 1H, J )
7.4/7.4/1.0 Hz), 7.43-7.56 (m, 6H), 7.90 (s, 1H), 8.21 (d“t”, 3H,
J ) 8.1/8.1/1.5 Hz), 9.79 (s, 1H, OH), 10.38 (s, 1H). Anal. C,
H, N.
2 ,4 -B i s (4 -h y d r o x y p h e n y l )-5 H -p y r i d o [3 ,2 -d ][1 ]-
ben za zep in -6(7H)-on e (10r ) was prepared following general
procedure B from 10m (211 mg, 0.5 mmol) and BBr3 (378 mg,
1.51 mmol) in 36% yield: colorless crystals including one C2H5-
OH per molecule; mp >330 °C; IR 3265 (OH, NH), 1660 cm-1
(CdO); 1H NMR (400 MHz) 1.06 (t, 3H, J ) 6.8 Hz, CH3CH2-
OH), 3.35 (br s, 2H), 3.44 (dq, 2H, J ) 6.8/5.1 Hz, CH3CH2-
OH), 4,34 (t, 1H, J ) 5.1 Hz, CH3CH2OH), 6.26 (d, 2H, J )
8.7 Hz), 6.95 (d, 2H, J ) 8.1 Hz), 7.24 (d, 1H, J ) 7.8 Hz),
7.35 (“t”, 1H, J ) 6.9/6.9 Hz), 7.46-7.54 (m, 3H), 7.77 (s,
1H), 8.06 (d, 2H, J ) 8.7 Hz), 8.18 (dd, 1H, J ) 7.6/1.0
4-(3-C h lo r o p h e n y l)-2-p h e n y l-5H -p y r id o [3,2-d ][1]-
ben za zep in e-6(7H)-th ion e (11f) was prepared following
general procedure C from 10f (324 mg, 0.82 mmol), phosphorus
pentasulfide (294 mg, 1.32 mmol), and NaHCO3 (430 mg, 5.1
mmol) in THF (28 mL) in 55% yield: colorless crystals; mp
281 °C; IR 3140 cm-1 (NH); 1H NMR (400 MHz) 3.57 (br s,
1H), 4.12 (br s, 1H), 7.38 (d, 1H, J ) 8.1 Hz), 7.44-7.55 (m,
4H), 7.56-7.63 (m, 3H), 7.70-7.77 (m, 1H), 7.93 (s, 1H), 7.99
(s, 1H), 8.21 (dd, 1H, J ) 8.2/1.5), 8.25 (d, 2H, J ) 7.1 Hz),
12.39 (s, 1H). Anal. C, H, Cl, N, S.
4-(4-B r o m o p h e n y l)-2-p h e n y l-5H -p y r id o [3,2-d ][1]-
ben za zep in e-6(7H)-th ion e (11g) was prepared following
general procedure C from 10g (205 mg, 0.46 mmol), phospho-
rus pentasulfide (294 mg, 1.32 mmol), and NaHCO3 (430 mg,
5.1 mmol) in THF (15 mL) in 61% yield: colorless crystals;
mp 302 °C; IR 3150 cm-1 (NH); 1H NMR (400 MHz) 3.58 (br s,
1H), 4.12 (br s, 1H), 7.38 (dd, 1H, J ) 8.8/1.1 Hz), 7.45-7.55
(m, 4H), 7.58 (d“t”, 1H, J ) 7.5/7.5/1.6 Hz), 7.71-7.80 (m, 4H),
7.96 (s, 1H), 8.22 (d“t”, 3H, J ) 9.0/9.0/1.6 Hz), 12.38 (s, 1H).
Anal. C, H, Br, N, S.