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T. Hussenether et al. / Bioorg. Med. Chem. 12 (2004) 2625–2637
([d6]DMSO) 2.61 (t, 2H, J ¼ 6:0 Hz), 3.53–3.60 (m, 6H),
3.64 (m, 4H), 4.92 (t, br, J ¼ 2:9 Hz, exchangeable with
D2O), 6.63–6.77 (m, 4H), 6.80 (m, 1H), 6.86 (d, 1H,
J ¼ 8:5 Hz), 7.56 (m, 1H), 8.14 (dd, 1H, J ¼ 4:6, 1.1 Hz);
MS m=z 307 [Mþ]. Anal. C18H21N5 (307.40) C, H, N.
ylpiperazine (35a) (0.5 g) gave 8 (60 mg, 39%). Mp 193–
1
194 °C; H NMR ([d6]DMSO) 2.61 (t, 4H, J ¼ 4:8 Hz),
2.81 (d, 2H, J ¼ 6:9 Hz), 3.03 (t, 2H, J ¼ 6:9 Hz), 3.19
(t, 4H, J ¼ 4:8 Hz), 6.73 (s, br, 1H, exchangeable with
D2O), 6.93–6.99 (m, 2H), 7.11–7.21 (m, 3H), 7.66 (d,
1H, J ¼ 6:2 Hz), 8.83 (d, 1H, J ¼ 6:2 Hz), 9.02 (s, 1H);
MS m=z 307 [Mþ]. Anal. C18H21N5 (307.40) C, H, N.
4.34. 2-(4-Phenylpiperazin-1-yl)-4,5-dihydro-3H-pyr-
ido[2,3-b][1,4]diazepine (7a)
4.38. 1,2,3,4-Tetrahydro-5H-1,4-benzodiazepin-5-one
(34)
A mixture of 26a (82 mg, 0.5 mmol), PCl5 (105 mg,
0.5 mmol), POCl3 (5 mL) and pyridine (two drops) was
heated to 135 °C under a nitrogen atmosphere for 4 h.
After cooling to room temperature volatile components
were evaporated. The residue was dried in vacuum over
night and refluxed in EtOH. Without further purifica-
tion 1-phenylpiperazine (35a) (0.5 g) was added and the
resulting mixture was refluxed in dry EtOH (10 mL) for
another 4 h. The solvent was removed in vacuum. The
residue was purified by column chromatography
(CH2Cl2/MeOH ¼ 94:6) to obtain 7a (74 mg, 48%). Mp
176–178 °C. 1H NMR ([d6]DMSO) 2.61 (t, 4H,
J ¼ 4:6 Hz), 2.86 (t, 2H, J ¼ 7:5 Hz), 3.05 (t, 2H,
J ¼ 7:5 Hz), 3.12 (t, 4H, J ¼ 4:6 Hz), 6.76 (m, 1H, H-8),
6.89–6.95 (m, 2H), 7.13–7.23 (m, 3H), 7.88 (d, 1H,
J ¼ 7:4 Hz), 8.25 (d, 1H), 12.76 (s, br, 1H, exchangeable
with D2O); MS m=z 307 [Mþ]. Anal. C18H21N5 (307.40)
C, H, N.
3,4-Dihydro-1H-1,4-benzodiazepin-2,5-dione (33) (8.8 g,
50 mmol) was added in small portions to a slurry of
LiAlH4 (3.91 g, 115 mmol) in dry THF (100 mL) at a
rate, which causes mild reflux. Refluxing was continued
for 14 h, and then kept at room temperature over night.
The mixture was treated carefully with water (20 mL),
2 N NaOH (15%, 10 mL) and finally with water (50 mL).
The formed slurry was filtered through a Celite pad and
washed with hot THF several times. The filtrate and
washings were combined and extracted with CHCl3.
Combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuum. The residue
was purified by column chromatography (CH2Cl2/
MeOH ¼ 97:3) to yield 34 (2.98 g, 37%) as colorless
powder. Mp 143–145 °C.; IR 2924, 2852, 1660, 1631,
1
1599, 1495 cmꢀ1; H NMR ([d6]DMSO) 3.27–3.43 (m,
4H), 6.39–6.58 (m, 2H), 6.66 (d, 1H, J ¼ 8:4 Hz), 7.09–
7.17 (m, 1H), 7.68–7.75 (m, 1H), 7.93 (t, br, 1H,
J ¼ 5:2 Hz, exchangeable with D2O); MS m=z 162 [Mþ].
Anal. C9H10N2O (162.19) C, H, N.
4.35. 8-Chloro-2-(4-phenylpiperazin-1-yl)-4,5-dihydro-
3H-pyrido[2,3-b][1,4]diazepine (7b)
Preparation and purification (CH2Cl2/MeOH ¼ 97:3)
according to 7a from 26b (99 mg, 0.5 mmol) and
1-phenylpiperazine (35a) (0.5 g) gave 7b (70 mg, 41%).
Mp 153–155 °C; 1H NMR ([d6]DMSO) 2.56 (t, 2H,
J ¼ 6:8 Hz,), 2.72 (t, 4H, J ¼ 5:0 Hz), 3.16 (t, 2H,
J ¼ 6:8 Hz), 3.28 (t, 4H, J ¼ 5:0 Hz), 6.56 (s, br, 1H),
6.83–7.00 (m, 2H), 7.14 (s, 1H), 7.23–7.52 (m, 3H), 7.64
(s, 1H, exchangeable with D2O); MS m=z 341 [Mþ].
Anal. C18H20ClN5 (341.85) C, H, N.
4.39. 1-Allyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-
one (36)
To a solution of 34 (2.43 g, 15 mmol) in dry benzene
(10 mL), allyl bromide (1.82, 15 mmol) and triethyl-
amine (0.2 mL) were added and the mixture was refluxed
with stirring for 2 h and allowed to stand over night at
room temperature. The solvent and excess of allyl bro-
mide was removed in vacuum. The residue was treated
with ice water (20 mL) and extracted three times with
diethyl ether (50 mL). Combined ether layers were dried
over Na2SO4 and concentrated in vacuum. The residue
was purified by flash chromatography (cyclohexane/
EtOAc ¼ 6:4) to yield 36 (1.61 g, 53%) as colorless
4.36. 2-[(4-(4-Chlorophenyl)piperazin-1-yl]-4,5-dihydro-
3H-pyrido[2,3-b][1, 4]diazepine (7c)
Preparation and purification (CH2Cl2/MeOH ¼ 96:4)
according to 5a from 26a (82 mg, 0.5 mmol) and 1-(4-
chlorophenyl)piperazine (35d) (0.5 g) gave 7c (70 mg,
41%). Mp 196–198 °C; 1H NMR 2.59 (t, 4H,
J ¼ 4:5 Hz), 2.85 (t, 2H, J ¼ 7:5 Hz), 3.04 (t, 2H,
J ¼ 7:5 Hz), 3.12 (t, 4H, J ¼ 4:5 Hz), 6.93 (d, 2H), 7.14–
7.23 (m, 3H), 7.88 (d, 1H, J ¼ 7:6 Hz), 8.24 (d, 1H,
J ¼ 3:3 Hz), 12.78 (s, br, 1H, exchangeable with D2O);
MS m=z 341 [Mþ]. Anal. C18H20ClN5 (341.85) C, H, N.
1
powder. Mp 92–94 °C; H NMR ([d6]DMSO) 3.20 (m,
4H), 3.80 (d, 2H, J ¼ 5:7 Hz), 5.14–5.27 (m, 2H), 5.77–
5.90 (m, 1H), 6.90 (m, 1H), 7.33 (m, 1H), 7.47 (m, 1H),
8.15 (s, br, 1H, exchangeable with D2O); MS m=z 202
[Mþ]. Anal. C12H14N2O (202.26) C, H, N.
4.40. 1-Allyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-
5-thione (37)
4.37. 4-(4-Phenylpiperazin-1-yl-)-2,3-dihydro-1H-pyr-
ido[3,4-b][1,4]diazepine (8)
Compound 36 (1.52 g, 7.5 mmol) and P2S5 (2.22 g,
10 mmol) were refluxed for 2.5 h in dry pyridine. The
solvent was removed in vacuum. The brown, resinous
residue was suspended in a Na2CO3 solution (10%,
50 mL) and extracted with CH2Cl2. Combined organic
Preparation and purification (CH2Cl2/MeOH ¼ 95:5)
according to 7a from 30 (82 mg, 0.5 mmol) and 1-phen-