2-position to form the intermediate disulfide.18 Thioether
7c was generated by exhaustive reduction, followed by
direct S-alkylation with 2-bromobenzyl bromide to give
7c in a good overall yield. The palladium-catalyzed
cycloamination was performed on substrate 7c on a 44-g
scale, providing efficient access to the desired ring system
4c. The overall yield from 9 to cyclic 4c on this scale was
competitive with the yield reported by Yale et al. through
the copper bronze route, thereby shortening the synthesis
of 4c by two steps.19
In summary, an alternative synthesis of heterobenz-
azepine ring systems is disclosed. The key step in this
synthesis exploits recent advancements in palladium
catalysis to form oxazepine or thiazepine ring systems.
Overall, the best conditions for this reaction were Pd2-
dba3 as a palladium source, P(t-Bu)3 as the ligand, NaO-
t-Bu alone or with K2CO3, in toluene. This reaction
worked on a variety of substrates as shown in Table 2,
and is scalable as demonstrated by the cyclization of 7c
on a 44-g scale.
d6) δ 144.2, 142.8, 131.9, 128.8, 128.3, 127.6, 127.4, 122.5, 119.7,
119.0, 118.3, 118.2, 38.4. Anal. Calcd for C13H11NS: C, 73.20;
H, 5.20; N, 6.57. Found: C, 72.83; H, 5.35; N, 6.28.
Gen er a l P r oced u r e for P r ep a r a tion of Nitr o Eth er s:
2-Br om oben zyl 2-Nitr op h en yl Eth er .6c To a flask containing
2-bromobenzyl bromide (10.0 g, 40 mmol), 2-nitrophenol (5.3 g,
38 mmol), and K2CO3 (13.1 g, 95 mmol) was added CH3CN (75
mL). The solution was heated to 70 °C with an oil bath for 2 h,
at which time the reaction was complete as shown by HPLC.
The reaction was quenched with H2O and extracted with EtOAc.
The combined organics were washed with brine and dried with
Na2SO4, and the solvent was removed under vacuum. The
resulting solid was crystallized from hexanes and EtOAc to
1
afford an off-white solid (11.2 g, 96%): mp 92-93 °C; H NMR
(300 MHz, CDCl3) δ 7.90 (dd, J ) 2, 8 Hz, 1 H), 7.69 (d, J ) 7
Hz, 1 H), 7.57 (dd, J ) 1, 8 Hz, 1 H), 7.55 (m, 1 H), 7.37 (t, J )
8 Hz, 1 H), 7.20 (ddd, J ) 1, 8, 9 Hz, 1 H), 7.17 (t, J ) 9 Hz, 1
H), 7.07 (m, 1 H), 5.27 (s, 2 H); 13C NMR (100 MHz, CDCl3) δ
151.6, 139.9, 134.9, 134.3, 132.8, 129.5, 128.5, 127.9, 125.9, 121.4,
120.9, 114.9, 70.3. Anal. Calcd for C13H10BrNO3: C, 50.67; H,
3.27; N, 4.55. Found: C, 50.64; H, 3.11; N, 4.54.
Gen er a l P r oced u r e for th e Syn th esis of Eth er -Lin k ed
Acyclic P r ecu r sor s: 2-[(2-Br om oben zyl)oxy]a n ilin e Hy-
d r och lor id e (7h ).6c 2-Bromobenzyl 2-nitrophenyl ether (5.0 g,
16.2 mmol) was dissolved in IPA (100 mL) and heated to 60 °C
with an oil bath. To this solution was added HCl (2.5 mL, 12 N)
followed by Fe (13.5 g, 242 mmol). The reaction was allowed to
stir for 17 h at 60 °C, at which time it was filtered hot through
a pad of Celite. The solution was reduced to about 20 mL under
vacuum at which time HCl/Et2O was added until a ppt formed.
The resulting off-white solid was recrystallized from MeOH and
EtOAc to afford a white solid (4.4 g, 80%): mp 194-196 °C; 1H
NMR (400 MHz, CD3OD) δ 7.68 (t, J ) 10 Hz, 2 H), 7.46 (m, 3
Exp er im en ta l Section 20
Gen er a l P r oced u r e for th e Syn th esis of Th ioeth er -
Lin k ed Acyclic P r ecu r sor s: 2-[(2-Br om oben zyl)th io]a -
n ilin e Hyd r och lor id e (7a ).6a To 2-nitrophenyl disulfide (6.0
g, 19.5 mmol) was added a solution of sodium sulfide nonahy-
drate (15.0 g, 62 mmol) in H2O (200 mL). The resulting yellow
suspension was heated at reflux for 1 h, and then cooled in an
ice bath. A solution of 2-bromobenzyl bromide (10.2 g, 41 mmol)
in THF (150 mL) was slowly added, and the resulting biphasic
mixture was heated at reflux for 1 h. The mixture was cooled
and diluted with EtOAc, and the phases were separated. The
basic aqueous phase was extracted with EtOAc, and the
combined organic phases were dried over Na2SO4, filtered, and
concentrated to give an oil that was taken-up in MeOH and Et2O.
The hydrochloride salt was prepared by treatment with 2.0 N
HCl in Et2O followed by crystallization from MeOH and Et2O
to give a white solid (6.6 g, 51%): mp 189-193 °C; 1H NMR
(400 MHz, DMSO-d6) δ 7.61 (dd, J ) 1, 8 Hz, 1 H), 7.26-7.09
H), 7.30 (m, 2 H), 7.13 (dt, J ) 2, 10 Hz, 1 H), 5.37 (s, 2 H); 13
C
NMR (100 MHz, CD3OD) δ 152.9, 136.5, 134.0, 131.7, 131.2,
130.8, 129.0, 125.2, 123.9, 122.8, 120.8, 114.6, 71.5; % water (KF)
4.93. Anal. Calcd for C13H12BrNO‚HCl‚H2O: C, 46.94; H, 4.55;
N, 4.21. Found: C, 46.89; H, 4.57; N, 4.16.
Gen er a l P r oced u r e for th e Cycloa m in a tion of Cth er s:
5,11-Dih yd r od iben zo[b,e][1,4]oxa zep in e (4h ).6c An argon-
purged vial was charged with 7h (345 mg, 1.1 mmol), NaO-t-Bu
(192 mg, 2.0 mmol), K2CO3 (276 mg, 2.0 mmol), and Pd2(dba)3
(92 mg, 0.1 mmol). Toluene (10 mL) was added followed by P(t-
Bu)3 (10 mg, 0.05 mmol). The reaction vessel was again purged
with argon, and heated to 95 °C. After 2.5 h, the reaction was
cooled, concentrated, absorbed onto silica gel, and purified using
silica gel chromatography to give an off-white solid (186 mg,
(m, 5 H), 6.99 (d, J ) 8 Hz, 1 H), 6.64 (m, 1 H), 4.07 (s, 2 H); 13
C
NMR (100 MHz, DMSO-d6) δ 137.6, 137.2, 134.3, 134.2, 132.6,
131.2, 130.7, 130.5, 130.3, 128.9, 125.7, 124.7, 41.4. Anal. Calcd
for C13H12BrNS‚HCl: C, 47.22; H, 3.96; N, 4.24. Found: C, 47.03;
H, 4.00; N, 4.17.
1
86%): mp 122-123 °C; H NMR (400 MHz, CDCl3) δ 7.18 (t, J
) 7 Hz, 1 H), 7.08 (d, J ) 7 Hz, 1 H), 6.96 (dd, J ) 1, 8 Hz, 1 H),
6.90 (t, J ) 7 Hz, 1 H), 6.75 (m, 4 H), 5.95 (br s, 1 H), 5.03 (s, 2
H); 13C NMR (100 MHz, CDCl3) δ 149.3, 143.7, 134.9, 129.5,
129.2, 126.0, 123.8, 121.9, 119.9, 119.6, 118.8, 117.1, 74.7. Anal.
Calcd for C13H11NO: C, 79.16; H, 5.62; N, 7.10. Found: C, 78.94;
H, 5.63; N, 7.10.
Gen er a l P r oced u r e for th e Cycloa m in a tion of Th io-
eth er s: 5,11-Dih yd r od iben zo[b,e][1,4]th ia zep in e (4a ).6a An
oven-dried 40-mL vial containing two 6-mm glass beads was
charged with a mixture of 7a (250 mg, 0.76 mmol), NaO-t-Bu
(163 mg, 1.7 mmol), K2CO3 (235 mg, 1.7 mmol), and Pd(dba)2
(49 mg, 8.5 µmol). After the air atomosphere was replaced with
argon, toluene (9 mL) was added, followed by P(t-Bu)3 (20 mg,
9.8 µmol). The resulting purple mixture was capped and placed
on a shaker block heated to 95 °C. After 1 h, the reaction mixture
was concentrated to dryness and absorbed to silica gel. Purifica-
tion was carried out using silica gel chromatography and
afforded the product as a pale brown solid (108 mg, 67%): 1H
NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1 H), 7.15-7.01 (m, 6 H),
6.69-6.65 (m, 2 H), 3.98 (s, 2 H); 13C NMR (100 MHz, DMSO-
Ackn owledgm en t. We acknowledge the many people
in our SAMCHEM unit’s analytical labs for data gen-
eration on compounds (IR, NMR, MS, and CHN data).
We also thank Atli Thorarensen, Michael Ennis, J on
J acobsen, and J ed Fisher for helpful advice on prepara-
tion of this manuscript.
Su p p or tin g In for m a tion Ava ila ble: Expanded version
of Table 1 for the optimization of the reaction including all
examples mentioned in the related text; experimental proce-
dures and characterization for the preparation of all examples
listed in Table 2 (7a -m and 4a -m ). This material is available
(18) Bogert, M. T.; Stull, A. Organic Syntheses; Wiley & Sons: New
York, 1941; Collect. Vol. I, pp 220-1.
(19) The yield for the transformation of 7c to 4c by the 3-step
method of Yale (see the tables for yields in ref 6a) was 40%.
(20) For general experimental considerations see the Supporting
Information.
J O026546G
J . Org. Chem, Vol. 68, No. 2, 2003 647