624
A. Putey et al. / European Journal of Medicinal Chemistry 83 (2014) 617e629
Recrystallization from CH2Cl2; yield: 81%; solid; mp 169 ꢁC (dec.);
IR (KBr, cmꢀ1): 3020, 2950, 1710, 1100, 750; 1H NMR (300 MHz,
CDCl3):
CH2I), 4.20 (dd, 1H, J ¼ 10.0, 12.8 Hz, NCH2), 4.83 (dd, 1H, J ¼ 3.4,
12.8 Hz, NCH2), 4.94e5.02 (m, 1H, CH), 7.27e7.67 (m, 4H, HAr); 13
NMR (75 MHz, DMSO-d6): 3.9 (CH2), 44.6 (CH2), 76.0 (CH), 97.6
(Cq), 111.6 (CH), 119.5 (Cq), 120.5 (CH), 122.1 (CH), 126.3 (C), 126.9
(CH), 135.2 (Cq), 157.1 (CO); MS (ESI): m/z MS (ESI) m/z 406 (79Br),
408 (81Br) [MþH]þ.
n
C
d
3.42 (dd, 1H, J ¼ 8.7, 10.6 Hz, CH2), 3.59 (dd, 1H, J ¼ 4.4,
d
10.6 Hz, CH2), 4.27 (dd, 1H, J ¼ 9.0, 12.8 Hz, CH2), 4.74 (dd, 1H,
J ¼ 3.3, 12.8 Hz, CH2), 4.80e4.89 (m, 1H, CH), 7.31 (t, 1H, J ¼ 8.0 Hz,
H
Ar), 7.36 (d, 1H, J ¼ 8.0 Hz, HAr), 7.50 (t, 1H, J ¼ 8.0 Hz, HAr), 7.62 (d,
1H, J ¼ 8.0 Hz, HAr); 13C NMR (75 MHz, CDCl3):
d 1.1 (CH2), 44.9
(CH2), 68.9 (Cq), 76.2 (CH), 110.4 (CH), 121.9 (Cq), 122.7 (CH), 124.2
(CH), 127.8 (CH), 131.1 (Cq), 136.8 (Cq), 157.4 (CO); MS (ESI): m/z 454
[MþH]þ.
4.1.4.7. 10-Bromo-3-(iodomethyl)-7-methoxy-3,4-dihydro-1H-[1,4]
oxazino[4,3-a]indol-1-one (4g). Starting acid ¼ 3g. Trituration with
Et2O; yield: 33%; mp 167e169 ꢁC; IR (KBr, cmꢀ1):
n 3001, 2914,
2836, 1718, 1624, 1407, 1099; 1H NMR (300 MHz, DMSO-d6):
4.1.4.2. 10-Iodo-3-(iodomethyl)-9-methoxy-3,4-dihydro-1H-[1,4]
oxazino[4,3-a]indol-1-one (4b) (CAS: 935280-31-2). Starting
acid ¼ 3b. Chromatography eluent: PE/EtOAc 3:2; yield: 96%; mp
d
3.56e3.66 (m, 2H, CH2), 3.86 (s, 3H, CH3), 4.12 (dd, 1H, J ¼ 10.0,
12.8 Hz, CH2), 4.80 (dd, 1H, J ¼ 3.2, 12.8 Hz, CH2), 4.88e4.96 (m, 1H,
CH), 6.92 (dd, 1H, J ¼ 1.9, 8.9 Hz, HAr), 7.18 (d, 1H, J ¼ 1.9 Hz, HAr),
150e151 ꢁC; IR (KBr, cmꢀ1):
n
3000, 2956, 2835, 1710, 1614, 1511,
7.48 (d, 1H, J ¼ 8.9 Hz, HAr); 13C NMR (75 MHz, DMSO-d6):
d 4.1
1455, 1263, 1129; 1H NMR (300 MHz, CDCl3):
d
3.39 (dd, 1H, J ¼ 8.6,
(CH2), 44.8 (CH2), 55.8 (CH3), 75.7 (CH), 92.9 (CH), 98.4 (Cq), 114.3
(CH), 118.3 (Cq), 120.8 (Cq), 121.5 (CH), 136.5 (Cq), 157.1 (Cq), 159.7
(Cq); MS (ESI) m/z 436 (79Br), 438 (81Br) [MþH]þ.
10.6 Hz, CH2), 3.57 (dd, 1H, J ¼ 4.4, 10.6 Hz, CH2), 3.97 (s, 3H, CH3),
4.19 (dd,1H, J ¼ 9.0,12.8 Hz, CH2), 4.66 (dd,1H, J ¼ 4.7,12.8 Hz, CH2),
4.75e4.83 (m, 1H, CH), 6.58 (d, 1H, J ¼ 7.9 Hz, HAr), 6.96 (d, 1H,
J ¼ 8.5 Hz, HAr), 7.35 (t, 1H, J ¼ 8.3 Hz, HAr); 13C NMR (75 MHz,
4.1.5. General procedure for preparation of compounds 5aeg
A solution of 4 (7.95 mmol) in anhydrous MeOH/THF (2:1)
(90 mL) was added dropwise over a period of 20 min to an ice-cold
saturated ammonia solution in MeOH (30 mL). The reaction
mixture was allowed to warm up to RT and stirred for an appro-
priate time (see reaction time below). The solvents were then
removed by evaporation and the crude residue was purified by
trituration or by column chromatography to give 5.
DMSO-d6):
d 1.3 (CH2), 45.0 (CH2), 55.4 (CH3), 62.4 (C), 75.8 (CH),
101.5 (CH), 102.8 (CH), 119.9 (C), 120.9 (C), 128.2 (CH), 138.3 (C),
155.5 (C), 157.4 (C); MS (ESI): m/z 484 [MþH]þ.
4.1.4.3. 10-Iodo-3-(iodomethyl)-8-methoxy-3,4-dihydro-1H-[1,4]
oxazino[4,3-a]indol-1-one
(4c)
(CAS:
918161-90-7). Starting
acid ¼ 3c. Trituration with EtOAc/PE, yield: 94%. mp 145e147 ꢁC; IR
(KBr, cmꢀ1):
n
3032, 3003, 2941, 2829, 1724, 1619, 1407, 1092; 1H
NMR (300 MHz, CDCl3):
d
3.41 (dd, 1H, J ¼ 8.7, 10.7 Hz, CH2), 3.58
4.1.5.1. 4-Hydroxy-11-iodo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]
indol-1-one (5a) (CAS: 918161-92-9). Starting lactone ¼ 4a. Reac-
tion time: 48 h; trituration with EtOAc/EtOH; yield: 64%; mp 199 ꢁC
(dd, 1H, J ¼ 4.3, 10.7 Hz CH2), 3.92 (s, 3H, CH3), 4.23 (dd, 1H, J ¼ 9.2,
12.3 Hz, CH2), 4.68 (dd, 1H, J ¼ 3.4, 12.3 Hz, CH2), 4.79e4.87 (m, 1H,
CH), 6.94 (d, 1H, J ¼ 2.3 Hz, HAr), 7.14 (dd, 1H, J ¼ 2.3, 8.9 Hz, HAr),
(dec.); IR (KBr, cmꢀ1):
n
3410, 3320e3200, 3060, 2920, 1635, 1515,
7.26 (d, 1H, J ¼ 8.9 Hz, HAr); 13C NMR (75 MHz, DMSO-d6):
d
4.1
1090, 745; 1H NMR (300 MHz, DMSO-d6):
d
2.73e2.80 (m, 1H, CH2),
(CH2), 44.8 (CH2), 55.4 (CH3), 66.6 (Cq), 75.7 (CH), 102.2 (CH), 112.8
(CH), 118.7 (CH), 122.2 (Cq), 130.5 (Cq), 131.6 (Cq), 155.5 (Cq), 157.5
(Cq); MS (ESI): m/z 484 [MþH]þ.
3.15e3.21 (m, 1H, CH2), 4.18e4.29 (m, 2H, CH2 þ CH), 4.43e4.49 (m,
1H, CH2), 5.38 (d, 1H, J ¼ 3.4 Hz, OH), 7.19 (t, 1H, J ¼ 7.9 Hz, HAr), 7.35
(t, 1H, J ¼ 7.9 Hz, HAr), 7.39 (d, 1H, J ¼ 7.9 Hz, HAr), 7.58 (d, 1H,
J ¼ 7.9 Hz, HAr), 8.30 (br t, 1H, J ¼ 5.5 Hz, NH); 13C NMR (75 MHz,
4.1.4.4. 10-Iodo-3-(iodomethyl)-7-methoxy-3,4-dihydro-1H-[1,4]
oxazino[4,3-a]indol-1-one (4d) (CAS: 918161-91-8). Starting
acid ¼ 3d. Trituration with Et2O/CHCl3; yield: 67%; mp 165e167 ꢁC;
DMSO-d6): d 45.3 (CH2), 48.7 (CH2), 61.3 (Cq), 69.5 (CH), 111.0 (CH),
120.8 (CH), 121.7 (CH), 124.6 (CH), 129.2 (Cq), 133.4 (Cq), 137.2 (Cq),
164.0 (CO); MS (ESI): m/z 343 [MþH]þ.
IR (KBr, cmꢀ1):
n
3014, 2957, 1730, 1620, 1405, 1090; 1H NMR
(300 MHz, DMSO-d6):
d
3.55e3.66 (m, 2H, CH2), 3.86 (s, 3H, CH3),
4.1.5.2. 4-Hydroxy-11-Iodo-10-methoxy-2,3,4,5-tetrahydro-[1,4]dia-
zepino[1,2-a]indol-1-one (5b). Starting lactone ¼ 4b. Reaction time:
24 h; trituration with CH2Cl2, yield: 83%; mp 139e141 ꢁC; IR (KBr,
4.14 (dd, 1H, J ¼ 10.2, 12.8 Hz, CH2), 4.81 (dd, 1H, J ¼ 3.3, 12.8 Hz,
CH2), 4.86e4.94 (m, 1H, CH), 6.90 (dd, 1H, J ¼ 1.9, 8.9 Hz, HAr), 7.14
(d, 1H, J ¼ 1.9 Hz, HAr), 7.35 (d, 1H, J ¼ 8.9 Hz, HAr); 13C NMR
cmꢀ1):
n
3475e3180, 3273, 3071, 2929, 2837, 1633,1515, 1450, 1095,
(75 MHz, DMSO-d6):
d
4.2 (CH2), 44.9 (CH2), 55.7 (CH3), 68.4 (C),
927; 1H NMR (300 MHz, DMSO-d6):
d
2.66e2.75 (m, 1H, CH2),
75.4 (CH), 92.8 (CH), 114.1 (CH), 121.1 (Cq), 123.7 (CH), 124.6 (Cq),
3.08e3.15 (m, 1H, CH2), 3.86 (s, 3H, CH3), 4.11e4.22 (m, 2H,
CH2 þ CH), 4.35e4.42 (m, 1H, CH2), 5.35 (d, 1H, J ¼ 2.4 Hz, OH), 6.58
(dd, 1H, J ¼ 2.3, 6.3 Hz, HAr), 7.16e7.23 (m, 2H, HAr), 8.25 (br t, 1H,
137.4 (Cq), 157.6 (Cq), 159.7 (Cq); MS (ESI): m/z 484 [MþH]þ.
4.1.4.5. 7-Benzyloxy-10-Iodo-3-(iodomethyl)-3,4-dihydro-1H-[1,4]
J ¼ 5.5 Hz, NH); 13C NMR (75 MHz, DMSO-d6):
d 45.1 (CH2), 48.5
oxazino[4,3-a]indol-1-one (4e). Starting acid ¼ 3e. Trituration with
(CH2), 54.1 (C), 55.1 (CH3), 69.3 (CH), 99.6 (CH), 102.4 (CH), 116.9 (C),
124.6 (CH), 132.7 (C), 138.5 (C), 153.5 (C), 164.0 (C); MS (ESI): m/z
373 [MþH]þ.
CH2Cl2; yield: 60%; mp 186e187 ꢁC; IR (KBr, cmꢀ1):
n 3063, 3027,
2958, 1718, 1617, 1406, 1095, 741, 698; 1H NMR (300 MHz, DMSO-
d6):
d
3.56e3.66 (m, 2H, CH2), 4.14 (dd, 1H, J ¼ 10.0, 11.5 Hz, CH2),
4.79 (dd, 1H, J ¼ 3.0, 13.0 Hz, CH2), 4.89e4.94 (m, 1H, CH), 5.20 (s,
4.1.5.3. 4-Hydroxy-11-Iodo-9-methoxy-2,3,4,5-tetrahydro-[1,4]dia-
2H, CH2), 6.99 (dd, 1H, J ¼ 2.1, 8.9 Hz, HAr), 7.29e7.51 (m, 7H, HAr);
zepino[1,2-a]indol-1-one
(5c)
(CAS:
918161e93-0). Starting
13C NMR (75 MHz, DMSO-d6):
d
4.1 (CH2), 44.9 (CH2), 68.4 (Cq), 69.8
lactone ¼ 4c. Reaction time: 24 h; chromatography eluent: CH2Cl2/
(CH2), 75.5 (CH), 94.1 (CH), 114.4 (CH), 121.2 (Cq), 123.8 (CH), 124.8
(Cq), 127.8 (2 ꢂ CH), 128.0 (CH), 128.5 (2 ꢂ CH), 136.7 (Cq), 137.3
(Cq), 157.6 (Cq), 158.7 (Cq); MS (ESI): m/z 560 [MþH]þ.
MeOH 95:5; yield: 79%; mp > 210 ꢁC (washing with CH2Cl2); IR
(KBr, cmꢀ1):
n
3405e3200, 3242, 3073, 2929, 2847, 1636, 1518, 1457,
1092, 927; 1H NMR (300 MHz, DMSO-d6):
d
2.71e2.79 (m, 1H, CH2),
3.12e3.20 (m, 1H, CH2), 3.81 (s, 3H, CH3), 4.16e4.23 (m, 2H,
CH2 þ CH), 4.39e4.46 (m, 1H, CH2), 5.37 (d, 1H, J ¼ 3.0 Hz, OH), 6.79
(d, 1H, J ¼ 2.3 Hz, HAr), 6.98 (dd, 1H, J ¼ 2.3, 8.9 Hz, HAr), 7.50 (d, 1H,
J ¼ 8.9 Hz, HAr), 8.25 (br t, 1H, J ¼ 5.5 Hz, NH); 13C NMR (75 MHz,
4.1.4.6. 10-Bromo-3-(iodomethyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]indol-1-one (4f). Starting acid ¼ 3f. Trituration with CHCl3/Et2O;
yield: 91%; mp 124e126 ꢁC; IR (KBr, cmꢀ1):
n 3058, 3018, 2978,1716,
1615, 1105, 743; 1H NMR (300 MHz, DMSO-d6):
d
3.33e3.68 (m, 2H,
DMSO-d6): d 45.4 (CH2), 48.9 (CH2), 55.4 (CH3), 60.5 (Cq), 69.6 (CH),