Cl
2
) 0.55. IR (KBr) ν 3278, 3105, 3058, 2943, 1686, 1641,
Preparation of 3-Acetoxy-7-chloro-1,3-dihydro-5-phenyl-
2H-1,4-benzodiazepin-2-one (7) by Copper(II) Acetate/
Potassium Iodide-Mediated Acetoxylation. To a solution
of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-
one (3; 2.71 g, 0.01 mol) in glacial acetic acid (30 mL)
copper(II) acetate monohydrate (3.99 g, 0.02 mol, 2 equiv),
potassium iodide (1.83 g, 0.011 mol, 1.1 equiv), and
potassium acetate (1.96 g, 0.02 mol, 2 equiv) were added.
The resulting reaction mixture was heated at 80 °C for 5 h.
The reaction mixture was evaporated under a reduced
pressure to dryness. The residue was extracted with chlo-
roform (5 × 30 mL) and filtered to remove inorganic solids.
Combined organic extracts were washed with a 10% aqueous
-1
1
596, 1579, 1518, 1446, 1394, 1323, 1290, 1256, 1231 cm .
1
H NMR (600 MHz, CDCl
3
) δ 4.16 (s, CH Cl), 7.44-7.49
2
(
1
m, 4H), 7.56-7.64 (m, 1H), 7.67-7.70 (m, 2H), 8.54 (d,
H, arom., J ) 9.3 Hz), 11.42 (s, 1H, NH) ppm. 1 C NMR
3
(600 MHz, CDCl
3
) δ 42.74, 122.56, 125.01, 127.85, 128.19,
1
1
29.63, 132.23, 132.72, 133.35, 137.12, 137.28, 164.92,
97.26 ppm.
2
-Chloroacetamido-5,2′-dichlorobenzophenone (12):
3.61 g (98.1%) of colorless crystals, mp 160.2-162.0 °C.
(CH Cl ) 0.63. IR (KBr) ν 3183, 3007, 1690, 1645, 1600,
578, 1510, 1434, 1396, 1315, 1288, 1269, 1241 cm . H
NMR (600 MHz, CDCl ) δ 4.25 (s, 2H, CH Cl), 7.35-7.45
m, 3H), 7.48-7.75 (m, 3H), 8.77 (d, 1H, arom., J ) 9.1
3
R
f
2
2
-
1 1
1
3
2
solution of Na
S
2 2
3 2
O ‚5H O (2 × 30 mL) and water (2 × 30
(
13
mL) and evaporated to dryness. The crude product (R
f
0.45)
Hz), 12.18 (s, 1H, NH) ppm. C NMR (600 MHz, CDCl
3
)
was purified by preparative chromatography on a silica gel
column (200 g) with dichloromethane/2-propanol (9.5:0.5)
as an eluent to yield 2.40 g (73.0%) of pure 7 as colorless
crystals, mp 240-242 °C.
δ 43.00, 122.12, 126.81, 128.25, 128.71, 130.12, 130.84,
131.65, 133.25, 135.19, 137.51, 138.65, 165.60, 197.64 ppm.
Preparation of 7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-
benzodiazepin-2-one (3) and 7-Chloro-1,3-dihydro-5-(2-
chlorophenyl)-2H-1,4-benzodiazepin-2-one (4). General
Procedure. To a solution of 2-chloroacetamido-5-chloroben-
zophenone (11; 24.65 g, 0.08 mol) or 2-chloroacetamido-
IR (KBr) ν 3408, 3230, 3153, 3045, 2926, 1925, 1750,
1
1
3
9
8
1
720, 1608, 1578, 1483, 1446, 1423, 1390, 1331, 1316, 1261,
-
1 1
232, 1169 cm . H NMR (600 MHz, CDCl
H, CH COO), 5.96 (s, 1H, CHOAc), 7.24-7.59 (m, 8H),
.99 (s, 1H, NH) ppm. C NMR (600 MHz, CDCl
3
) δ 2.34 (s,
3
2′,5-dichlorobenzophenone (12; 27.41 g, 0.08 mol) in 96%
13
3
) δ 21.04,
ethanol (500 mL) hexamethylenetetramine (HMTM; 24.65
g, 0.18 mol, 2.2 equiv) and ammonium acetate (13.57 g, 0.18
mol, 2.2 equiv) were added. The reaction mixture was stirred
at reflux temperature for 6 h. Then the reaction mixture was
evaporated to dryness. Distilled water (300 mL) was added,
and the resulting suspension was stirred at 60 °C for 0.5 h.
The suspension was cooled to +15 °C and filtered. A crude
product was dried at 105 °C for 5 h. The crude product was
purified with toluene (80 mL) at 70 °C for 0.5 h. The
obtained suspension was cooled to +10 °C and filtered, and
the crystals were washed with cold toluene (3 × 10 mL).
The purified products were dried at 105 °C for 5 h.
4.39, 123.36, 128.32, 129.39, 129.80, 130.19, 131.07,
32.45, 136.02, 137.28, 165.93, 167.03, 170.24 ppm.
Preparation of 3-Acetoxy-7-chloro-1,3-dihydro-5-phenyl-
H-1,4-benzodiazepin-2-one (7) and 3-Acetoxy-7-chloro-
,3-dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-
2
1
one (8) by Iodine-Catalysed Acetoxylation with Various
Stoichiometric Oxidants. To a solution of 7-chloro-1,3-
dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (3; 2.71 g,
0
1
.01 mol) or 7-chloro-1,3-dihydro-5-(2-chlorophenyl)-2H-
,4-benzodiazepin-2-one (4; 3.05 g, 0.01 mol) in glacial
acetic acid (50 mL) potassium acetate (1.96 g, 0.02 mol, 2
equiv.), iodine (1.27 g, 5 mmol, 50 mol %), and one of the
7
-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-
-one (3): 16.50 g (76.2%) of colorless crystals, mp 217.3-
18.1 °C. R (CH Cl /2-PrOH, 9.5:0.5) 0.36. IR (KBr) ν
177, 3041, 2956, 2845, 1681, 1606, 1575, 1479, 1444, 1384,
following stoichiometric oxidants (0.02 mol, 2 equiv), MnO
2
2
2
3
1
(
(
1.74 g; at once), NaNO
2.86 g; during 5 min), (H
‚4H O (3.08 g; at once), Na
during 5 min), (NH (4.56 g; at once), or K
2
(1.38 g; during 5 min), Ca(OCl)
N) CO‚H (1.88 g; at once),
CO
2
f
2
2
2
2
2 2
O
NaBO
3
2
2
3
‚1.5H
2
O
2
(3.14 g;
(5.41
-
1 1
360, 1321, 1304, 1285, 1259, 1234, 1194 cm . H NMR
) δ 4.33 (s, 2H, COCH N), 7.18 (d,
H, arom., J ) 8.7 Hz), 7.26-7.29 (m, 1H), 7.37-7.46 (m,
H), 7.51-7.54 (m, 1H), 10.14 (s, 1H, NH) ppm. C NMR
) δ 56.48, 122.75, 128.34, 128.44,
) S
4 2 2
O
8
S O
2 2 8
(
600 MHz, DMSO-d
1
5
6
2
g; at once), were added. The reaction mixture was stirred at
5-90 °C during the time indicated in Table 1. Then the
6
13
volatiles were evaporated under a reduced pressure. The
residue was extracted with boiling chloroform (3 × 50 mL)
and filtered to remove inorganic solids. The combined
organic extracts were washed with a 10% aqueous solution
(
600 MHz, DMSO-d
6
128.72, 129.56, 129.68, 130.60, 131.80, 137.45, 138.75,
169.95, 172.25 ppm.
7
-Chloro-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4-ben-
zodiazepin-2-one (4): 21.12 g (86.5%) of colourless crystals,
mp 197.5-200.0 °C. R (CH Cl /2-PrOH, 9.5:0.5) 0.40. IR
KBr) ν 3344, 3213, 3118, 3063, 2961, 1684, 1618, 1593,
of Na
mL) and dried (Na
2
S
2
O
3
‚5H
2
O (2 × 50 mL) and distilled water (2 × 30
2
SO ), filtered, and evaporated to dryness.
4
f
2
2
The crude product 7 or 8 was purified by preparative
chromatography on a silica gel (200 g) column using
dichloromethane/2-propanol (9.5:0.5) as an eluent. The
isolated products 7 (R 0.45) or 8 (R 0.45) in all experiments
(
1
572, 1485, 1444, 1434, 1390, 1366, 1324, 1296, 1255, 1235
-
1
1
cm . H NMR (600 MHz, DMSO-d
COCH N), 7.03 (d, 1H, arom., J ) 2.2 Hz), 7.13-7.16 (m,
H), 7.19-7.52 (m, 5H), 10.31 (s, 1H, NH) ppm. C NMR
600 MHz, DMSO-d ) δ 56.34, 122.51, 126.81, 128.88,
6
) δ 4.39 (s, 2H,
f
f
1
13
2
gave the same IR, H NMR, and C NMR spectra.
13
1
(
3-Acetoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-ben-
1
13
6
zodiazepin-2-one (7): IR, H NMR, and C NMR spectra
correspond to the spectra of the product 7 obtained by Cu-
129.94, 130.82, 131.75, 132.94, 136.55, 138.06, 169.26,
171.33 ppm.
2
(OAc) /KI-mediated acetoxylation.
1196
•
Vol. 10, No. 6, 2006 / Organic Process Research & Development