1
066
A. G. Katsifis et al.
(1H, m); 6.87 (1H, m). Mass spectrum m/z: 227 (M , 81Br, 51%), 225
+
with a solution of potassium t-butoxide (200 mg, 1.78 mmol), dimethyl-
formamide (20 ml) and ethyl isocyanoacetate (0.20 ml, 1.8 mmol). The
yellow oil obtained upon workup as described above was purified by
flash chromatography (100% ethyl acetate) to afford a white solid.
Recrystallization from ethyl acetate gave the ethyl tetracyclic ester (14)
as colourless crystals (0.17 g, 27%), m.p. 234–235° (Found: C, 46.9; H,
+
79
(M , Br, 57), 199 (98), 197 (100), 172 (42), 170 (53), 63 (43).
1
H n.m.r. analysis of the original mixture indicated that 40% was the
6-bromoisatin (27) and 60% the desired 4-bromoisatin (26).
5-Bromo-2 H-3,1-benzoxazine-2,4(1H)-dione (28)
3
.6; N, 9.4. C17H16IN
3
3
O requires C, 46.7; H, 3.7; N, 9.6%). max
The mixture of bromoisatins (26) and (27) (1.0 g, 4.4 mmol) was
added to a solution of acetic acid (5 ml) and acetic anhydride (5 ml), and
the mixture was warmed to 60°. Chromium trioxide (0.74 g, 7.4 mmol)
was added slowly to ensure that the temperature remained between 80
and 90°. After the final addition the mixture was stirred for 10 min at
(
CHCl
3
) 1720s, 1633s, 1547w, 1495m, 1442s, 1370m, 1323m, 1301w,
1
1
278w, 1253s, 1187m, 1120m, 961m. H n.m.r. (CDCl
3
): ␦ 8.45 (1H,
d, J 2.1 Hz, H 8); 7.95 (1H, dd, J 2.1, 8.4 Hz, H6); 7.83 (1H, s,
H3); 7.14 (1H, d, J 8.4 Hz, H 5); 4.75 (1H, m); 4.42 (2H, q, J 7.1 Hz,
CH
2
); 3.72–3.86 (1H, m); 3.40–3.65 (2H, m); 2.11–2.41 (3H, m); 1.44
8
0°, cooled, and the precipitate collected by filtration. The precipitate
+
(
3H, t, J 7.1 Hz, CH
3
). Mass spectrum m/z: 437 (M , 19%), 391 (68),
was washed with water, and dried to a constant weight under high
vacuum, to give the product as a pale yellow solid (0.90 g, 84%). A
small sample was purified by flash chromatography (40% ethyl
acetate/light petroleum); in order of elution the products were as
follows.
3
63 (100).
Ethyl (13aS)-9-Oxo-7-tributylstannyl-11,12,13,13a-tetrahydro-
9
1
H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-
-carboxylate (16)
(
A) 7-Bromo-2H-3,1-benzoxazine-2,4(1H)-dione (29), m.p.
23 1
Asolution of the 7-iodo ethyl ester (14) (50 mg, 0.11 mmol), toluene
252–253° (lit. 256°). H n.m.r. ((CD ) SO): ␦ 7.80 (1H, d, J 8.4 Hz,
3
2
(
10 ml), bis(tributyltin) (0.13 ml, 0.26 mmol) and tetrakis(triph-
H5); 7.39 (1H, dd, J 1.8, 8.4 Hz, H6); 7.26 (1H, d, J 1.8 Hz, H 8).
enylphosphine)palladium(0) (10 mg, 0.01 mmol) was heated at reflux
for 20 h. The oil obtained upon workup was purified by flash chro-
matography (40% ethyl acetate/light petroleum) and gave the 7-trib-
(B) The 5-bromo dione (28), a white solid. Recrystallization from
2
2
ethyl acetate gave colourless microcrystals, m.p. 260–261° (lit.
1
260–262°). H n.m.r. ((CD ) SO): ␦ 11.82 (1H, s, NH); 7.46–7.59 (2H,
3
2
utylstannyl ethyl ester (16) as a colourless oil (46 mg, 70%) (Found:
m); 7.13 (1H, dd, J 1.9, 7.3 Hz). Mass spectrum (electrospray) m/z: 242
1
+
C, 58.2; H, 7.4. C29
H
43
N
3
O
3
Sn requires C, 58.1; H, 7.2%). H n.m.r.
(M ), 241, 240, 198, 197, 195, 127, 126.
(
CDCl
J 0.9, 7.8 Hz, H 6); 7.33 (1H, d, J 7.8 Hz, H 5); 4.72–4.80 (1H, m); 4.41
2H, q, 7.1 Hz, CH CH ); 3.71–3.87 (1H, m); 3.43–3.67 (2H, m);
.10–2.40 (3H, m); 1.04–1.80 (21H, m); 0.89 (9H, t, J 7.1 Hz,
3
): ␦ 8.19 (1H, d, J 0.9 Hz, H 8); 7.85 (1H, s, H 3); 7.71 (1H, dd,
(11aS)-6-Bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzo-
diazepine-5,11(10H)-dione (30)
(
2
3
2
The mixture of the bromoisatoic anhydrides (28) and (29) (0.73 g,
+
(
CH
3
CH
2
CH
2
CH ) Sn). Mass spectrum m/z: 544(M –Bu, 100%), 430
2
3
3
.0 mmol), dimethylformamide (20 ml) and L-proline (0.50 g, 4.3
+
(
M – (3×Bu), 33), 356 (19), 57 (15).
mmol) was heated gently with stirring until gas evolution ceased. The
solution was then heated at reflux for 1 h, cooled, and poured onto water
3
-Bromo-␣-(hydroxyimino)acetanilide (25)
(
150 ml). The mixture was extracted with chloroform (3×50 ml),
Anhydrous sodium sulfate (18 g, 0.13 mol) was added over 1 min to
washed with water (3×50 ml), dried over anhydrous magnesium
sulfate, and the solvent was removed under reduced pressure to give a
yellow oil. T.l.c. analysis indicated two products (0.31 g, 35%). A
small sample was purified by flash chromatography (100% chloro-
form), and the two products, in order of elution, were as follows.
(A) The 8-bromo dione* (31), a white powder. Recrystallization
from ethyl acetate gave white microcrystals, m.p. 293–295° (Found: C,
49.1; H, 3.7; N, 9.5. C H BrN O requires C, 48.8; H, 3.7; N, 9.5%).
a stirred solution of water (150 ml) and chloral hydrate (11.6 g, 70
mmol). Separately, 3-bromoaniline (24) (10 g, 58 mmol) was added
slowly to a stirred solution of hydrochloric acid (10 M, 6 ml) and water
(
50 ml). The 3-bromoaniline solution was then added to the first solu-
tion, and a precipitate formed. A solution of hydroxylamine hydrochlo-
ride (15 g, 0.22 mol) and water (70 ml) was then added. The mixture
was heated slowly to reflux, resulting in dissolution of the precipitate,
and almost immediately another precipitate formed. The mixture was
heated at reflux for a further 10 min, cooled, filtered and the residue
washed well with water, and dried under high vacuum. The bromo
oxime (25) was obtained as a cream solid (11.76 g, 83 %), m.p.
1
2
11
2
2
1
H n.m.r (CDCl ): ␦ 8.39 (1H, s, NH); 7.88 (1H, d, J 8.4 Hz, H 9); 7.39
3
(1H, dd, J 1.7, 8.4 Hz, H7); 7.20 (1H, d, J 1.7 Hz, H 6); 3.99–4.15 (1H,
m); 3.71–3.87 (1H, m); 3.50–3.68 (1H, m); 2.64–2.88 (1H, m);
+
81
+
1.92–2.10 (3H, m). Mass spectrum m/z: 296 (M , Br, 25%), 294 (M ,
1
8
1
79
1
61–162° (lit. 165°). H n.m.r. ((CD
3
)
2
SO/CDCl
3
): ␦ 11.80 (1H, br s);
Br, 26), 238 (16), 70 (100).
8
.75 (1H, br s); 7.95 (1H, s); 7.45–7.60 (2H, m); 7.10–7.27 (2H, m).
(B) The 6-bromo dione (30), a white solid. Recrystallization from
2
4
1
ethyl acetate gave white crystals, m.p. 231–232° (lit. 221–224°). H
4
-Bromoisatin (26)
n.m.r. (CDCl ): 8.49 (1H, s, NH); 7.51 (1H, dd, J 1.0, 8.0 Hz); 7.23
3
Sulfuric acid (18 M, 10 ml) was warmed to 60° and the bromo oxime
(1H, m, H 8); 6.99 (1H, dd, J 1.0, 8.3 Hz); 4.08–4.19 (1H, m);
(
25) (2.0 g, 8.2 mmol) was added slowly to ensure that the temperature
3.86–3.98 (1H, m); 2.62–2.82 (1H, m); 1.93–2.15 (3H, m). Mass spec-
+
81
+ 79
remained between 60 and 80°. After the final addition the mixture was
stirred at 80° for 1 h. The mixture was cooled, and poured onto crushed
ice (100 g). The precipitate was collected by filtration and washed with
water, and dried to constant weight under high vacuum to give the crude
product as a bright orange solid (1.54 g, 83%). T.l.c. analysis (40%
ethyl acetate/light petroleum) indicated two products. A small sample
was purified by flash chromatography (80% ethyl acetate/light
petroleum) and the two products in order of elution were as follows.
trum m/z: 296 (M , Br, 12.5%), 294 (M , Br, 14), 70 (100).
2
-Acetamido-6-bromotoluene (34)
A solution of stannous chloride dihydrate (12.8 g, 57 mmol), 6-
bromo-2-nitrotoluene (30) (4.0 g, 18.5 mmol) and ethanol (100 ml) was
stirred at room temperature. After 24 h, t.l.c. analysis (20% ethyl
acetate/light petroleum) indicated that some starting material remained.
The solution was heated at reflux for 3 h, cooled, and concentrated to
10 ml under reduced pressure. The residue was made alkaline by the
addition of sodium hydroxide (2 M), and extracted with ethyl acetate
(3×50 ml). The organic phases were washed with water (2×40 ml),
dried over anhydrous sodium sulfate, and the solvent was removed
under reduced pressure to give the 2-amino-6-bromotoluene (33) as a
1
8
(
A) 6-Bromoisatin (27), orange crystals, m.p. 269–270° (lit. 267°).
H n.m.r. ((CD SO/CDCl ): ␦ 10.71 (1H, s, NH); 7.40 (1H, d, J 8.0
Hz, H 4); 7.20 (1H, dd, J 1.4, 7.5 Hz, H 5); 7.12 (1H, d, J 1.4 Hz, H7).
1
3
)
2
3
+
81
+ 79
Mass spectrum m/z: 227 (M , Br, 64%), 225 (M , Br, 64), 199 (100),
1
97 (99), 172 (24), 170 (41), 90 (62), 63 (43).
B) 4-Bromoisatin (26), orange crystals, m.p. 272–273° (lit. 270°).
SO/CDCl ): ␦ 10.71 (1H, s, NH); 7.32 (1H, m); 7.17
1
8
1
(
yellow oil (3.18 g, 92%). H n.m.r. (CDCl ): ␦ 6.99 (1H, dd, J 1.1, 7.9
3
1
H n.m.r. ((CD
3
)
2
3
Hz, H 5); 6.85 (1H, m, H4); 6.60 (1H, dd, J 1.1, 7.8 Hz, H3); 3.74 (2H,
*
(11aS)-8-Bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione.