0.23 mmol) were added to the crude acid 81 (1.09 g, 2.98 mmol)
in N,N-dimethylformamide (6.5 cm3) and the reaction mixture
was stirred for 15 min. The amine 119 (497 mg, 2.29 mmol)
in N,N-dimethylformamide (4.5 cm3) was then added and the
mixture was stirred for 16 h at room temperature before aqueous
hydrogen chloride (1 M, 90 cm3) and dichloromethane (200 cm3)
were added. The organic layer was washed with aqueous hydrogen
chloride (1 M, 90 cm3) and saturated aqueous sodium hydrogen
carbonate (90 cm3), dried (MgSO4) and concentrated under
reduced pressure to give the crude amide 120 (936 mg, 73%)
(found: M+ + H, 564.1969. C30H31FN3O5S requires M, 564.1963)
as an oil used without further purification; m/z (ES) 602 (M+ +
39, 16%), 593 (100), 586 (15) and 564 (5).
acetate–light petroleum (50 : 50) containing triethylamine (1%)
gave the hydroxy-amide 121 (104 mg, 95%) as a white foam.
(4RS,5SR)-5-Cyclobutyl-4,5-dihydroxy-8-fluoro-2-[3-(N-
phenylmethyl)aminopropanoyl]-2,3,4,5-tetrahydro-[1H]-2-
benzazepine 122
Thiophenol (125 lL, 1.22 mmol) was added to the amide
121 (560 mg, 0.94 mmol) and potassium carbonate (453 mg,
3.28 mmol) in N,N-dimethylformamide (19 cm3) and the mixture
was stirred at room temperature for 16 h. Water (90 cm3) was then
added and the aqueous phase was extracted with ethyl acetate
(4 × 140 cm3). The organic extracts were dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the
residue using methanol–dichloromethane (up to 5% methanol)
containing triethylamine (1%) as eluent gave the title compound
122 (336 mg, 87%) as a pale yellow foam (found: M+ + H, 413.2229.
C24H30FN2O3 requires M, 413.2235); mmax 3402, 1631, 1590, 1490,
1455, 1372, 1302, 1267, 1240, 1142, 1092, 1003, 980, 816, 736 and
700 cm−1; dH (500 MHz, CDCl3) 1.13–2.92 (11 H, m, cyclobutyl-H,
5-CH, 2ꢀ-H2 and 3-H2), 3.10 (0.33 H, d, J 14.5, 3-H), 3.31 (3 H,
br s, 2 × OH and NH), 3.36–3.52 (2.67 H, m, 3-H and NCH2Ph),
3.60 (0.67 H, d, J 3, 4-H), 3.70 (0.33 H, d, J 4, 4-H), 3.94 (0.67 H,
d, J 15, 1-H), 3.99 (0.67 H, dd, J 15.5, 2, 3-Hꢀ), 4.39 and 4.48 (each
0.33 H, d, J 16.5, 1-H), 4.70 (0.33 H, d, J 14, 3-Hꢀ), 5.10 (0.67 H, d,
J 15, 1-Hꢀ), 6.74 (1 H, m, 9-H and 7-H), 6.80 (0.33 H, td, J 8.5, 2.5,
7-H), 6.95 (0.67 H, dd, J 9, 2.5, 9-H), 7.03 (1.33 H, d, J 7, ArH),
7.06 (0.67 H, d, J 7, ArH), 7.15–7.28 (3 H, m, ArH) and 7.56 (1 H,
m, 6-H); dC (125 MHz, CDCl3) 17.51, 17.53, 21.69, 21.72, 21.98,
22.01, 31.40, 33.00, 39.63, 40.22, 44.75, 45.70, 48.29, 51.44, 51.81,
53.46, 54.00, 54.18, 73.16, 73.85, 78.87, 79.19, 113.65 and 113.81
(d, 2JC-F 20), 114.19 and 114.35 (d, 2JC-F 19), 115.72 and 115.89 (d,
2JC-F 22), 117.56 and 117.73 (d, 2JC-F 21), 127.29, 127.55, 128.4,0
128.57, 128.62, 131.02, 131.08, 132.08, 132.15, 135.65, 135.71,
137.04, 137.07, 137.63, 160.16, 160.20, 162.16, 171.80 and 173.63;
m/z (ES) 435 (M+ + Na, 35%) and 413 (M+ + 1, 100).
N-Methylmorpholine-N-oxide (214 mg, 1.83 mmol) and os-
mium tetraoxide (42 mg, 0.17 mmol) were added to the crude
amide 120 (936 mg, 1.66 mmol) in acetone (26 cm3), tert-butanol
(26 cm3) and water (13 cm3). The reaction mixture was stirred
for 16 h at room temperature then saturated aqueous sodium
sulfite (140 cm3) was added. The mixture was then stirred for a
further 30 min before extracting with ethyl acetate (4 × 180 cm3).
The organic layers were dried (Na2SO4) and concentrated under
reduced pressure. Chromatography of the residue using ethyl
acetate–light petroleum (50 : 50) containing triethylamine (1%)
as eluent gave the title compound 121 (936 mg, 94%), a 50 : 50
mixture of rotamers, as a white foam (found: M+ + Na, 620.1837.
C30H32FN3NaO7S requires M, 620.1837); mmax 3430, 1633, 1590,
1543, 1493, 1455, 1371, 1346, 1267, 1239, 1163, 1126, 1095, 999,
982, 939, 852, 816, 776, 735 and 703 cm−1; dH (500 MHz, CDCl3–
D2O) 1.22 (1 H, m), 1.58–1.80 (2.5 H, m), 1.94–2.06 (2 H, m),
2.06–2.20 (1.5 H, m), 2.33 (0.5 H, m), 2.47–2.62 (1.5 H, m), 2.77
(0.5 H, m), 3.04 (0.5 H, d, J 15), 3.31–3.48 (2 H, m), 3.53 (0.5 H,
m), 3.62 (0.5 H, d, J 3.5), 3.72 (0.5 H, dd, J 15.5, 3.5), 3.75 (0.5 H,
d, J 3), 3.87 (0.5 H, d, J 15), 4.23 (1 H, s), 4.33 (0.5 H, d, J 15.5),
4.38 (0.5 H, d, J 15.5), 4.43 (0.5 H, d, J 15.5), 4.50 (0.5 H, d, J
15.5), 4.95 (0.5 H, d, 15), 6.43 (0.5 H, dd, J 8.5, 2.5, 9-H), 6.82
(0.5 H, td, J 8.5, 2.5, 7-H), 6.85–6.91 (1 H, m, 7-H and 9-H),
7.15–7.28 (5 H, m, ArH), 7.47 (0.5 H, t, J 7.5, ArH), 7.53–7.64
(3 H, m, 6-H and ArH), 7.69 (0.5 H, dd, J 8.5, 6, 6-H), 7.78 and
7.87 (each 0.5 H, d, J 8, ArH); dC (125 MHz, CDCl3) 16.50, 20.60,
20.66, 20.86, 20.99, 31.22, 31.77, 38.52, 39.09, 43.56, 43.58, 46.92,
49.77, 49.84, 51.85, 52.38, 52.45, 72.16, 72.63, 77.89, 78.08, 112.85
(4RS,5SR)-5-Cyclobutyl-4,5-dihydroxy-8-fluoro-2-[3-(N-phenyl-
methyl)aminopropyl]-2,3,4,5-tetrahydro-[1H]-2-benzazepine 123
A solution of the amide 122 (319 mg, 0.77 mmol) and lithium
aluminium hydride (235 mg, 6.19 mmol) in terahydrofuran (7 cm3)
was h◦eated under reflux for 4 h. The mixture was then cooled
to 0 C and aqueous sodium hydroxide (2 M, 30 cm3) was
added cautiously followed by ethyl acetate (25 cm3). The aqueous
phase was extracted with ethyl acetate (2 × 25 cm3) and the
organic extracts were washed with water, brine and dried (MgSO4).
Concentration under reduced pressure gave the title compound 123
(327 mg) as a pale yellow oil used without further purification
(found: M+ + H, 399.2445. C24H32FN2O2 requires M, 399.2442);
mmax 3435, 1610, 1590, 1492, 1454, 1242, 1144, 1077, 1005, 845,
814, 735 and 699 cm−1; dH (500 MHz, CDCl3) 1.20–1.29 (2 H, m),
1.60–1.77 (5 H, m, 2ꢀ-H2, cyclobutyl-H and NH), 2.01–2.18 (2 H,
m), 2.54–2.73 (5 H, m, 5-CH, 1ꢀ-H2 and 3ꢀ-H2), 2.80 (1 H, d, J 13,
3-H), 2.99–3.08 (2 H, m, 3-Hꢀ and OH), 3.47 (1 H, dd, J 14.5, 2,
1-H), 3.59–3.72 (4 H, m, 1-Hꢀ, 4-H and NCH2Ph), 6.66 (1 H, dd, J
9, 3, 9-H), 6.86 (1 H, td, J 8.5, 2.5, 7-H), 7.10–7.24 (5 H, m, ArH)
and 7.70 (1 H, dd, J 8.5, 6, 6-H); dC (75 MHz, CDCl3) 17.91, 21.87,
22.04, 27.92, 39.99, 47.63, 54.06, 58.43, 59.48, 63.38, 73.06, 79.43,
113.52 and 113.78 (d, 2JC-F 19.5), 116.66 and 116.95 (d, 2JC-F 21.5),
2
2
and 113.01 (d, JC-F 20), 113.17 and 113.32 (d, JC-F 19), 115.04
2
2
and 115.21 (d, JC-F 22), 116.61 and 116.78 (d, JC-F 22), 123.22,
123.24, 127.00, 127.23, 127.43, 127.70, 127.85, 129.75, 129.91,
129.98, 130.04, 130.58, 130.64, 130.82, 130.84, 131.78, 131.95,
132.50, 132.68, 133.50, 133.56, 134.64, 134.70, 134.90, 135.03,
135.13, 136.47, 136.49, 146.93, 146.98, 159.24 and 161.26 (d, 1JC-F
1
246.5), 159.50 and 161.46 (d, JC-F 245), 169.43 and 170.77; m/z
(ES) 620 (M+ + 23, 100%) and 598 (M+ + 1, 4).
TBTU (65 mg, 0.20 mmol) was added to the acid 81
(67 mg, 0.18 mmol) and Hu¨nig’s base (64 lL, 0.37 mmol)
in dichloromethane (1.0 cm3) and the mixture was stirred for
15 min. The amine 117 (46 mg, 0.18 mmol) in dichloromethane
(0.7 cm3) was then added and the mixture was stirred for 16 h at
room temperature. Saturated aqueous sodium hydrogen carbonate
(20 cm3) and dichloromethane (20 cm3) were added. The aqueous
layer was washed with dichloromethane (3 × 20 cm3) and the
organic extracts were dried (Na2SO4) and concentrated under
reduced pressure. Chromatography of the residue using ethyl
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2138–2157 | 2155
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