2678 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Campiani et al.
1
1725 cm-1; H NMR (CDCl3) δ 0.97 (t, 3 H, J ) 3.5 Hz), 1.97
for 16e. After flash chromatography (dichloromethane), 16a
was obtained as colorless oil: IR 1640 cm-1; 1H NMR (CDCl3)
δ 0.84 (t, 3 H, J ) 7.0 Hz), 0.94 (t, 3 H, J ) 7.2 Hz), 1.40 (m,
2 H), 1.77 (m, 4 H), 6.42 (m, 1 H), 7.16-7.37 (m, 6 H) ; 13C
NMR (CDCl3) δ 7.7, 14.3, 16.5, 29.0, 37.9, 93.6, 111.5, 120.3,
121.6, 125.2, 125.3, 125.4, 127.0, 133.8, 134.0, 146.5, 193.4.
(()-6-Allyl-6-eth ylpyr r olo[2,1-d][1,5]ben zoxazepin -7(6H)-
on e (16b). Starting from 280 mg (1.23 mmol) of 15a , the title
oxazepinone was obtained following the procedure as for 16e.
After flash chromatography, 16b was obtained as colorless
prisms: IR 1646 cm-1; 1H NMR (CDCl3) δ 0.95 (t, 3 H, J ) 7.3
Hz), 1.69-2.00 (m, 2H), 2.46-2.67 (m, 2 H), 5.07 (m, 2 H),
5.70-5.92 (m, 1 H), 6.41 (m, 1 H), 7.14-7.37 (m, 6 H).
(()-6-E t h y l-6-(2-i s o p e n t e n y l)p y r r o lo [2,1-d ][1,5]-
ben zoxa zep in -7(6H)-on e (16c). Starting from 140 mg (0.61
mmol) of 15a , the title compound was obtained following the
procedure as for 16e. After flash chromatography (dichlo-
romethane), 16c was obtained as colorless prisms: IR 1650
(m, 2 H), 4.58 (t, 1 H, J ) 5.5 Hz), 6.30 (m, 2 H), 6.87-7.35
(m, 6 H).
(()-r-[[2-(1H -P yr r ol-1-yl)p h en yl]oxy]-2-n a p h t h yla ce-
tic Acid (14c). Similarly to 14b, the acid 14c was prepared
starting from 1.6 g (4.3 mmol) of 13c (reaction time 3 h). 14c
was obtained as colorless prisms: IR (neat) 3410, 1730 cm-1
;
1H NMR (CDCl3) δ 5.50 (br s, 1 H), 6.10 (s, 1 H), 6.32 (m, 2
H), 6.92-7.15 (m, 4 H), 7.21-7.60 (m, 6 H), 7.84 (m, 2 H), 8.15
(m, 1 H).
(()-r-[[3-(1H -P yr r ol-1-yl)-2-n a p h t h yl]oxy]p h en yla ce-
tic Acid (14d ). Starting from 13d (2.65 g, 6.9 mmol), the title
compound was obtained (reaction time 4 h) following the
procedure as for 14b. After purification by flash chromatog-
raphy (benzene), 14d crystallized as colorless prisms: IR (KBr)
1734 cm-1 1H NMR (CDCl3) δ 5.20 (s, 1 H), 6.04 (m, 2 H),
;
6.90-7.60 (m, 13 H).
Gen er a l P r oced u r e for P r ep a r a t ion of Com p ou n d s
15a -d . This procedure is illustrated for the preparation of
(()-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)-one (15b).
Phosphorus pentachloride (400 mg, 1.92 mmol) was added to
a solution of acid 14b (500 mg, 1.89 mmol) in dry 1,2-
dichloroethane (8.5 mL) within 20 min. The reaction mixture
was stirred at room temperature for 5 h, and then was poured
into crushed ice, basified with 10% NaOH solution, and
extracted with chloroform. The organic layers were washed
with brine, dried, and evaporated. The residue was chromato-
graphed (dichloromethane and hexanes, 2/1) and recrystallized
to yield 300 mg of oxazepinone 15b as colorless prisms: IR
1
cm-1; H NMR (CDCl3) δ 0.94 (t, 3 H, J ) 7.3 Hz), 1.53 (s, 3
H), 1.67 (s, 3 H), 1.85 (m, 2 H), 2.48 (d, 2 H, J ) 6.9 Hz), 5.19
(t, 1 H, J ) 7.8 Hz), 6.41 (m, 1 H), 7.0-7.36 (m, 6 H); 13C NMR
(CDCl3) δ 7.8, 18.0, 25.9, 29.4, 34.2, 93.6, 111.5, 117.3, 120.5,
121.6, 125.2, 125.4, 127.1, 133.7, 134.0, 135.1, 146.5, 193.3.
(()-6-Meth yl-6-p h en ylp yr r olo[2,1-d ][1,5]ben zoxa zep in -
7(6H)-on e (16d ). Starting from 15b (300 mg, 1.1 mmol), the
title compound was prepared (reaction time 12 h) following
the procedure described for 16e and was recrystallized as
1
colorless prisms: IR (CHCl3) 1660 cm-1; H NMR (CDCl3) δ
1.91 (s, 3 H), 6.46 (m, 1 H), 6.90-7.45 (m, 11 H).
(CHCl3) 1670 cm-1; H NMR (CDCl3) δ 5.47 (s, 1 H), 6.43 (m,
1 H), 6.80-7.40 (m, 11 H).
1
(()-6-P h en yl-6-n -pr opylpyr r olo[2,1-d][1,5]ben zoxazepin -
7(6H)-on e (16f). Starting from 200 mg (0.72 mmol) of 15b,
the title compound was obtained (reaction time 12 h), following
the procedure as for 16e, as colorless prisms: IR (CHCl3) 1640
(()-6-E t h ylp yr r olo[2,1-d ][1,5]b e n zoxa ze p in -7(6H )-
on e (15a ). Similarly to 15b, the oxazepinone 15a was
prepared starting from 4.0 g (16.3 mmol) of 14a (reaction time
6 h at 80 °C). 15a was obtained as pale brown prisms: IR
1
cm-1; H NMR (CDCl3) δ 0.92 (t, 3 H, J ) 7.0 Hz), 1.61 (m, 2
H), 2.43 (m, 2 H), 6.45 (m, 1 H), 6.90-7.40 (m, 11 H); 13C NMR
(CDCl3) δ 14.3, 17.1, 41.7, 95.7, 11.6, 120.5, 121.6, 125.2, 125.5,
126.0, 126.8, 127.5, 128.0, 133.8, 134.0, 138.4, 146.7, 192.7.
(()-6-Allyl-6-p h en ylp yr r olo[2,1-d ][1,5]b en zoxa zep in -
7(6H)-on e (16g). Similarly to 16e, the ketone 16g was
prepared starting from 200 mg (0.72 mmol) of 15b (reaction
time 12h). Oxazepinone 16g was obtained as colorless
(CHCl3) 1650 cm-1; H NMR (CDCl3) δ 1.17 (t, 3 H, J ) 7.0
1
Hz), 1.89 (m, 1 H), 2.16 (m, 1 H), 4.30 (dd, 1 H, J ) 8.8, 3.9
Hz), 6.44 (m, 1 H), 7.18-7.40 (m, 6 H).
(()-6-(2-Na p h t h yl)p yr r olo[2,1-d ][1,5]b e n zoxa ze p in -
7(6H)-on e (15c). Similarly to 15b, the oxazepinone 15c was
prepared starting from 2.38 g (6.94 mmol) of 14c (reaction time
7 h at 80 °C). 15c was obtained as white prisms: IR (CHCl3)
1
prisms: IR (Nujol) 1642 cm-1; H NMR (CDCl3) δ 3.15 (m, 2
1643 cm-1
;
1H NMR (CDCl3) δ 6.27 (s, 1 H), 6.55 (m, 1 H),
H), 5.10 (dd, 1 H, J ) 10.7, 1.4 Hz), 5.20 (d, 1 H, J ) 1.6 Hz),
5.89 (m, 1 H), 6.45 (m, 1 H), 6.95-7.40 (m, 11 H); 13C NMR
(CDCl3) δ 43.4, 94.8, 111.8, 119.0, 120.7, 121.5, 125.3, 125.6,
126.3, 126.7, 127.5, 128.1, 128.3, 132.4, 133.7, 137.8, 146.4,
191.8.
6.76 (dd, 1 H, J ) 9.0 Hz), 6.95 (m, 1 H), 7.09-7.63 (m, 10 H),
8.23 (m, 1 H).
(()-5-P h en yln aph th o[2,3-b]pyr r olo[1,2-d][1,4]oxazepin -
4(5H)-on e (15d ). Similarly to 15b, the oxazepinone 15d was
prepared starting from 1.14 g (3.2 mmol) of 14d (reaction time
4 h at 80 °C). 15d was obtained as colorless prisms: IR
(()-6-(2-I s o p e n t e n y l)-6-p h e n y lp y r r o lo [2,1-d ][1,5]-
ben zoxa zep in -7(6H)-on e (16h ). Starting from 300 mg (1.09
mmol) of oxazepinone 15b, the title compound was obtained
as colorless prisms (reaction time 10 h), following the proce-
dure described for 16e. 16h was purified by flash chroma-
(CHCl3) 1645 cm-1; H NMR (CDCl3) δ 5.57 (s, 1 H), 6.56 (m,
1
1 H), 7.25-7.86 (m, 13 H).
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zep i-
n on es 16. This procedure is illustrated for the preparation
of (()-6-ethyl-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)-
one (16e). A solution of 15b (366 mg, 1.33 mmol) in anhydrous
THF (5 mL) was added to a suspension of potassium hydride
(153 mg, 1.33 mmol, 35% in oil) in anhydrous THF (2.5 mL).
The reaction mixture was stirred for 2 h at room temperature,
and then ethyl iodide (204 mg, 1.33 mmol) was added. After
an additional 30 min at room temperature the solvent was
removed, and the residue was partitioned between water and
EtOAc. The organic layer was washed with brine, dried, and
concentrated. The residue was purified by flash chromatog-
raphy (dichloromethane) to give 280 mg of ketone 16e which
tography (35% chloroform in hexanes): IR (Nujol) 1650 cm-1
;
1H NMR (CDCl3) δ 1.57 (s, 3 H), 1.66 (s, 3 H), 2.97 (m, 1 H),
3.16 (m, 1 H), 5.23 (m, 1 H), 6.44 (m, 1 H), 6.95-7.45 (m, 11
H); 13C NMR (CDCl3) δ 18.2, 25.8, 37.2, 95.2, 111.7, 118.0,
120.5, 121.5, 125.3, 125.6, 126.2, 126.8, 127.5, 128.0, 133.6,
133.9, 135.0, 138.4, 146.5, 192.5.
(()-6-(Cyclop r op ylm eth yl)-6-p h en ylp yr r olo[2,1-d ][1,5]-
ben zoxa zep in -7(6H)-on e (16i). Starting from 15b (287 mg,
1.04 mmol), the title compound was obtained (reaction time
15 h) following the procedure described for 16e. After flash
chromatography (30% dichloromethane in hexanes), 16i was
obtained as colorless prisms: IR (film) 1650 cm-1 1H NMR
;
crystallized as pale yellow prisms: IR (Nujol) 1655 cm-1; H
(CDCl3) δ 0.2 (m, 2 H), 0.46 (m, 2 H), 1.08 (m, 1 H), 2.23 (m,
1 H), 2.58 (m, 1 H), 6.46 (m, 1 H), 6.80-7.35 (m, 11 H); 13C
NMR (CDCl3) δ 5.0, 5.7, 6.2, 45.3, 96.1, 111.6, 120.5, 121.4,
125.1, 125.4, 126.2, 126.7, 127.7, 128.0, 128.3, 134.0, 134.5,
138.2, 147.0, 192.7.
(()-6 -E t h y l -6 -(2 -n a p h t h y l )p y r r o l o [2 ,1 -d ][1 ,5 ]-
ben zoxa zep in -7(6H)-on e (16j). Similarly to 16e, the oxaze-
pinone 16j was prepared starting from 120 mg (0.37 mmol) of
15c (reaction time 15 h) and, after purification by flash
chromatography (dichloromethane and hexanes, 1:1), was
obtained as colorless prisms: IR (CHCl3) 1640 cm-1; 1H NMR
(CDCl3) δ 1.17 (t, 3 H, J ) 7.0 Hz), 2.60 (m, 1 H), 3.03 (m, 1
H), 6.52 (m, 1 H), 6.73-7.88 (m, 12 H), 8.80 (d, 1 H, J ) 8.5
1
NMR (CDCl3) δ 1.06 (t, 3 H, J ) 7.2 Hz), 2.42 (m, 2 H), 6.45
(m, 1 H), 6.80-7.40 (m, 11H); 13C NMR (CDCl3) δ 18.3, 32.3,
96.0, 111.6, 120.5, 121.6, 125.2, 125.5, 126.0, 126.8, 127.5,
128.1, 133.8, 134.1, 138.2, 146.7, 192.6. The O-alkylated
regioisomer 16l was also isolated by flash chromatography and
recrystallized as colorless prisms: IR (CHCl3) 1599, 740 cm-1
;
1H NMR (CDCl3) δ 1.30 (t, 3 H, J ) 6.9 Hz), 3.88 (q, 2 H, J )
6.8 Hz), 6.45 (m, 1 H), 6.61 (m, 1 H), 7.15-7.36 (m, 9 H), 8.04
(m, 1 H).
(()-6-Eth yl-6-n -p r op ylp yr r olo[2,1-d ][1,5]ben zoxa zep in -
7(6H)-on e (16a ). Starting from 140 mg (0.61 mmol) of 15a ,
the title compound was obtained following the procedure as