5726
C. Maiereanu et al. / Bioorg. Med. Chem. 19 (2011) 5716–5733
mixture (1.63 g, 64%) after crystallisation and washing with iPr2O
at 0 °C. The isomer separation occurred by semi-preparative HPLC
HR-MS (ESI-Q-Tof) calcd for C22H26BrLiNO3 [M+Li]+: 438.1251
and 440.1233; found: 438.1237 and 440.1221.
(on C18 Kromasil 100, 5
l
m, 4.6 ꢂ 250 mm) with MeOH/H2O 75:25
cis-11d or 11d0, 1H NMR (CDCl3, 400 MHz): 7.49 (d,
J = 8.3 Hz, 1Har); 7.45–7.2 (m, 5Har); 7.00 (d, J = 8.3 Hz, 1Har);
5.03 (br s, 1H, NH); 4.24 (br s, 1H, H-6); 3.79 (br s, 2H); 3.06
(br s, 1H); 2.94 (br s, 1H); 2.50 (br s, 1H); 1.90 (br s, 1H);
1.44 (s, 10H).
as eluent, to give 11c as cis/trans mixture (250 mg, 10%) and 11c0 as
cis/trans mixture (1.10 g, 43%) as. The cis-11c isomer could be ob-
tained pure.
Isomeric mixture 11c/11c0: cream solid, mp 179–184 °C. IR
(KBr): 3358, 2978, 2934, 1681, 1667, 1523, 1446, 1367, 1248,
1166, 1043, 777 cmꢀ1. HR-MS (ESI-Q-Tof) calcd for C16H22BrLiNO3
[M+Li]+: 362.0938 and 364.0919; found: 362.0849 and 364.0829.
trans-11c: 1H NMR (CDCl3, 400 MHz): 7.44 (dd, 1H, H-3); 7.01
(br d, 1H, H-1); 6.97 (t, 1H, H-2); 4.53 (br d, 1H, NH); 3.69 (br m,
1H, H-7); 3.63 (dd, 1H, Ha-5); 3.35 (br t, 1H, H-6); 3.08 (br s, 1H,
OH); 2.95 (dd, 1H, Hb-5); 2.87 (ddd, 1H, Ha-9); 2.76 (ddd, 1H,
Hb-9); 2.21 (m, 1H, Ha-8); 1.46 (s, 9H, CMe3); 1.32 (dq, 1H, Hb-
8); J(1.2) = 7.4, J(1,3) = 1.6, J(2,3) = 8.0, J(5a,5b) = 14.2, J(5a,6) = 1.6,
J(5b,6) = 10.0, J(6,7) = 9.0, J(NH,7) = 8.2, J(7,8a) = 4.2, J(7,8b) = 11.3,
cis-11d0 or 11d, 1H NMR (CDCl3, 400 MHz): 7.51 (d, J = 8.3 Hz,
1Har); 7.45–7.2 (m, 5Har); 6.98 (d, J = 8.3 Hz, 1Har); 4.96 (br d,
J = 8.8 Hz, 1H, NH); 4.02 (br s, 1H, H-6); 3.79 (br s, 2H); 3.50 (br
s, 1H); 3.28 (br s, 1H); 2.84 (br d, J = 15 Hz, 1H); 2.04 (br s, 1H);
1.44 (br s, 10H).
trans-11d, 1H NMR (CDCl3, 400 MHz): 7.48 (d, 1H, H-3); 7.42–
7.33 (m, 3 Har); 7.19 (m, 2Har); 6.96 (d, 1H, H-2); 4.54 (br s, 1H,
NH); 3.69 (br d, 2H, H-7, Ha-5); 3.43 (br t, 1H, H-6); 3.20 (br s,
1H, OH); 3.05 (dd, 1H, Hb-5); 2.93 (dd, 1H, Ha-9); 2.61 (dd, 1H,
Hb-9); 2.10 (m, 1H, Ha-8); 1.44 (s, 9H, CMe3); 1.29 (br q, 1H,
Hb-8); J(2,3) = 8.2, J(5a,5b) = 14.2, J(5a,6) = 1.6, J(5b,6) = 10.2,
J(6,7) = 8.6, J(7,8a) = 4.4, J(7,8b) = 11.4, J(8a,8b) = 13.6, J(8a,9a) =
8.0, J(8a,9b) = 1.2, J(8b,9a) = 1.6, J(8b,9b) = 11.0, J(9a,9b) =
14.8 Hz.
J(8a,8b) = 13.8,
J(8a,9a) = 1.8,
J(8a,9b) = 7.5,
J(8b,9a) = 11.0,
J(8b,9b) = 2.0, J(9a,9b) = 14.7 Hz. 13C NMR (CDCl3, 100 MHz):
156.9 (NCO); 144.6 (C(4a)); 136.2 (C(9a)); 131.4 (C(3)); 128.2,
128.0 (C(1), C(2)), 125.7 (C(4)); 80.5 (CMe3); 73.7 (C(6)); 60.1
(C(7)); 39.7 (C(5)); 32.7 (C(8)); 28.5 (C(9)); 28.5 (CMe3).
trans-11d0: 1H NMR (CDCl3, 400 MHz): 7.47 (d, 1H, H-2); 7.44–
7.33 (m, 3Har); 7.25 (m, 2Har); 6.98 (d, 1H, H-3); 4.56 (br s, 1H,
NH); 3.70 (br q, 1H, H-7); 3.50 (dd, 1H, Ha-9); 3.40 (br t, 1H, H-
6); 3.19 (br s, 1H, OH); 3.14 (dd, 1H, Ha-5); 2.82 (dd, 1H, Hb-5);
2.78 (dd, 1H, Hb-9); 2.25 (m, 1H, Ha-8); 1.45 (s, 9H, CMe3); 1.37
(br q, 1H, Hb-8); J(2,3) = 8.2, J(5a,5b) = 14.4, J(5a,6) = 1.8, J(5b,6) =
10.2, J(6,7) = 10.8, J(7,8a) = 4.6, J(7,8b) = 11.8, J(8a,8b) = 13.6,
J(8a,9a) = 8.0, J(8a,9b) = 1.0, J(8b,9a) = 1.6, J(8b,9b) = 11.4, J(9a,9b) =
15.0 Hz.
cis-11c: colorless crystals, mp 183–184 °C. IR (KBr): 775, 1014,
1043, 1085, 1164, 1251, 1367, 1390, 1453, 1524, 1665, 2981,
2933, 3375, 3471 cmꢀ1 1H NMR (CDCl3, 400 MHz): 7.46 (d, 1H,
.
J = 8.0 Hz, H-3); 7.06 (d, 1H, J = 7.3 Hz, H-1); 7.01 (dd, 1H, J = 7.3,
8.0 Hz, H-2); 5.04 (br d, 1H, J = 8.5 Hz, NH); 4.19 (br s, 1H, H-6);
3.77 (br s, 2H, H-7, Ha-5); 2.98 (d, 1H, J = 14.3 Hz, Hb-5); 2.79
(m, 2H, CH2(9)); 1.99 (br m, 1H, Ha-8); 1.50 (br m, 1H, Hb-8);
1.45 (s, 9H, CMe3). 13C NMR (CDCl3, 100 MHz): 155.7 (NCO);
145.0 (C(4a)); 134.7 (C(9a)); 131.5 (C(3)); 128.6, 128.3
(C(1),C(2)), 127.1 (C(4)); 79.7 (CMe3); 69.1 (C(6)); 57.0 (C(7));
37.4 (C(5)); 33.2 (C(9)); 28.9 (C(8)); 28.7 (CMe3). HR-MS (ESI+)
calcd for C16H22BrNNaO3 [M+Na]+: 378.0675; found: 378.0665.
trans-11c0: 1H NMR (CDCl3, 400 MHz): 7.43 (dd, 1H, H-2); 7.14
(br d, 1H, H-4); 6.98 (t, 1H, H-3); 4.52 (br d, 1H, NH); 3.70 (br m,
1H, H-7); 3.40 (ddd, 1H, Ha-9); 3.35 (dt, 1H, H-6); 3.06, 3.02 (m,
2H, Ha-5,Hb-5); 2.71 (ddd, 1H, Hb-9); 2.20 (m, 1H, Ha-8); 1.46
(s, 9H, CMe3); 1.31 (dq, 1H, Hb-8); J(2,3) = 8.0, J(2,4) = 1.0,
J(3,4) = 7.4, J(5a,5b) = 14.0, J(5a,6) = 10,4, J(5b,6) = 3.2, J(6,7) = 9.0,
J(NH,7) = ca 7, J(7,8a) = 4.4, J(7,8b) = 11.2, J(8a,8b) = 13.8, J(8a,9a) =
8.2, J(8a,9b) = 1.6, J(8b,9a) = 1.6, J(8b,9b) = 11.2, J(9a,9b) = 15.0 Hz.
cis-11c0: 1H NMR (CDCl3, 400 MHz, 330 K): 7.47 (dd, 1H, H-2);
7.09 (br d, 1H, H-4); 6.98 (t, 1H, H-3); 4.91 (br d, 1H, NH); 4.11
(t, 1H, H-6); 3.81 (m, 1H, H-7); 3.39 (ddd, 1H, Ha-9); 3.12, 3.07
(m, 2H, Ha-5, Hb-5); 2.67 (dd, 1H, Hb-9); 2.00 (ddd, 1H, Ha-8);
1.47 (dq, 1H, Hb-8); 1.46 (s, 9H, CMe3); 1.28 (br s, 1H, OH).
J(2,3) = 8.0, J(2,4) = 1.0, J(3,4) = 7.4, J(5a,5b) = 14.4, J(5a,6) = 1.8,
J(5b,6) = 7.2, J(6,7) = 2.2, J(OH,6) = 7.6; J(NH,7) = 8.0, J(7,8a) = 4.2,
10.4. 1,4-Dibromo-7-(tert-butoxycarbonylamino)-6,7,8,9-tetra-
hydro-5H-benzocyclohepten-6-ol (cis/trans mixture, 11e)
General procedure (g) with 10e (7.75 g, 19.1 mmol) in 2 M NH3
solution in EtOH (60 mL) and with Ti(OiPr)4 (22.6 mL, g,
76.3 mmol, 4 equiv) for 6 h, then reduction with NaBH4
(1.08 g, 28.6 mmol, 1.5 equiv) for 3 h to give the crude amine
(10.3 g, quant.). Acylation with Boc2O (6.48 g, 29.7 mmol,
1.5 equiv), NaHCO3 (2.73 g, 25.7 mmol, 1.3 equiv) in MeOH
(100 mL) for 16 h gave 11e (1.20 g, 15%) after purification by flash
chromatography (cyclohexane/AcOEt 8/2). The trans-11e isomer
could be obtained pure.
cis-11e: cream resin. IR (KBr): 3450, 3355, 1667, 1529, 1367,
1168 cmꢀ1 1H NMR (CDCl3, 400 MHz): 7.32, 7.31 (2 d, J = 8.6 Hz,
.
2H, H-2,H-3); 4.92 (br s, 1H, NH); 4.22 (d, 1H, H-6); 3.75 (m, 1H,
H-7); 3.70 (m, 1H, Ha-9); 3.43 (m, 1H, Ha-5); 3.09 (m, 1H, Hb-5);
2.77 (m, 1H, Hb-9); 2.01 (m, 1H, Ha-8); 1.53 (m, 1H, Hb-8); 1.53
(s, 9H, CMe3). 13C NMR (CDCl3, 100 MHz): 27.1 (C(9)); 28.4
(CMe3); 31.2 (C(8)); 37.9 (C(5)); 56.1 (C(7)); 68.3 (C(6)); 79.6
(CMe3); 123.8, 124.6 (C(1),C(4)); 131.8, 132.4 (C(2),C(3)); 141.7,
143.3 (C(4a),C(9a)); 155.2 (NCO).
J(7,8b) = 11.6,
J(8a,8b) = 14.0,
J(8a,9a) = 8.4,
J(8a,9b) = 1.2,
J(8b,9a) = 1.5, J(8b,9b) = 11.6, J(9a,9b) = 14.8 Hz.
10.3. 4-Bromo-7-(tert-butoxycarbonylamino)-1-phenyl-6,7,8,9-
tetrahydro-5H-benzocyclohepten-6-ol (cis/trans mixture, 11d)
and 1-bromo-7-(tert-butoxycarbonylamino)-4-phenyl-6,7,8,9-
tetrahydro-5H-benzocyclohepten-6-ol (cis/trans mixture, 11d0)
trans-11e: cream crystals, mp 175–180 °C. IR (KBr): 3360, 2980,
1677, 1521, 1368, 1324, 1173, 1045 cmꢀ1 1H NMR (CDCl3,
.
400 MHz): 7.29, 7.28 (2 d, 2H, J = 8.4 Hz, H-2,H-3); 4.54 (br s, 1H,
NH); 3.70 (br s, 1H, H-7); 3.64 (dd, 1H, Ha-5); 3.42 (ddd, 1H, Ha-
9); 3.34 (ddd, IH, H-6); 3.02 (dd, 1H, Hb-5); 2.80 (ddd, 1H, Hb-9);
2.22 (dddt, 1H, Ha-8); 1.27 (dq, 1H, Hb-8); 1.45 (s, 9H, CMe3);
J(5a,5b) = 14.5, J(5a,6) = 1.8, J(5b,6) = 10.2, J(6,7) = 8.6, J(6,8a) =
1.0, J(7,8a) = 4.5, J(7,8b) = 11.0, J(8a,8b) = 13.7, J(8a,9a) = 8.0,
J(8a,9b) =1.8, J(8b,9a) = 1.0, J(8b,9b) = 11.5, J(9a,9b) = 14.8 Hz. 13C
NMR (CDCl3, 100 MHz): 28.3 (CMe3); 30.7 (C(9)); 31.3 (C(8));
40.4 (C(5)); 59.7 (C(7)); 73.5 (C(6)); 80.4 (CMe3); 122.9, 124.5
(C(4),C(1)); 131.9, 132.1 (C(2),C(3)); 138.2, 143.2 (C(4a),C(9a));
General procedure (g) with 10d/10d0 (1.52 g, 3.77 mmol) in 2 M
NH3 solution in EtOH (10 mL) and with Ti(OiPr)4 (2.3 mL,
7.54 mmol, 2 equiv) for 6 h, then reduction with NaBH4 (213 mg,
5.65 mmol, 1.5 equiv) for 3 h to give the crude amine (945 mg,
76%). Acylation with Boc2O (940 mg, 4.27 mmol, 1.5 equiv), NaH-
CO3 (392 mg, 3.70 mmol, 1.3 equiv) in MeOH (20 mL) for 16 h gave
the 60:40 mixture of 11d/11d0 (518 mg, 32%) inseparable isomers.
Isomeric mixture 11d/11d0: colorless crystals, mp 174–176 °C.
156.8 (NCO). HR-MS (ESI-Q-Tof) calcd for
C16H21Br2NNaO3
IR (KBr): 3487, 3362, 2979, 2932, 1664, 1530, 1252, 1168 cmꢀ1
.
[M+Na]+: 457.9761; found: 457.9753.