S. Dey et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
7
vigorously for 36 h. P4O10 was filtered off and the filtrate was con-
centrated in vacuo. The crude product was purified by fc (d = 3 cm,
I = 20 cm, V = 20 mL, cyclohexane:EtOAc 50:50). At first compound
13, then compound 12 was eluted.
142.6 (3C, Carom-q). Exact Mass (APCI): m/z = 310.2165 (calcd.
310.2166 for C21H28NO [M+H+]). Purity (HPLC): 99.2% (tR = 18.37
min).
13 (Cyclohexane: ethyl acetate = 1:1, Rf = 0.70): Colorless oil,
4.2.6. (1RS,2RS)-2-Methyl-3-(5-phenylpentyl)-2,3,4,5-tetrahydro-1H-
3-benzazepin-1-ol (cis-4b)
yield 950 mg (44%) C11H12F3NO2S (279.2 g/mol). FT-IR (neat):
m
(cmÀ1) = 2959/2849 (CAH), 1387/1142 (S@O), 823/815 (CAHarom).
1H NMR (400 MHz, CDCl3): d (ppm) = 1.65 (d, J = 7.5 Hz, 3H, CH3),
3.01 (dd, J = 15.1/7.0 Hz, 1H, 3-H), 3.13 (ddd, J = 15.1/11.9/5.9 Hz,
1H, 4-H), 3.69 (s, broad, 1H, 3-H), 4.02 (s broad, 1H, 1-H), 4.65 (q,
J = 7.5 Hz, 1H, 2-H), 7.08–7.12 (m, 1H, Ar-H), 7.19–7.20 (m, 1H,
Ar-H), 7.22–7.26 (m, 2H, Ar-H). 13C NMR (101 MHz, CDCl3): d
(ppm) = 16.9 (1C, CH3), 28.9 (1C, C-4), 44.5 (1C, C-3), 47.7 (1C, C-
1), 120.3 (q, J = 323.5 Hz, 1C, CF3), 126.2 (1C, Carom), 127.0 (1C,
Under N2, anhydrous K2CO3 (162 mg, 1.17 mmol) was added to
a solution of ketone 12 (120 mg, 0.39 mmol) in dry CH3CN (15 mL)
and the mixture was heated to reflux for 3 h. The reaction mixture
was cooled to rt and filtered to remove K2CO3. It was concentrated
in vacuo and the residue (14) was dissolved in dry MeOH (5 mL).
After cooling to 0 °C, NaBH4 (45 mg, 1.17 mmol) was added and
the mixture was stirred for 3 h at rt. A saturated solution of
NaHCO3 was added and the reaction mixture was extracted with
CH2Cl2 (3 Â 20 mL). The CH2Cl2 layer was dried over Na2SO4, fil-
tered and the solvent was evaporated in vacuo. The residue (15)
was dissolved in dry CH3CN (3 mL). Then 1-chloro-5-phenylpen-
Carom), 127.5 (1C, Carom), 129.3 (1C, Carom), 130.9 (1C, C-qarom),
132.8 (1C, C-qarom). Exact Mass (APCI): m/z = 302.0438 (calcd.
302.0433 for C11H12F3NO2SNa [M+Na+]).
12 (Cyclohexane: ethyl acetate = 1:1, Rf = 0.50): Colorless oil,
tane (107 mg, 102 lL, 0.58 mmol), K2CO3 (155 mg, 1.17 mmol)
yield 690 mg (29%). C12H12F3NO3S (307.2 g/mol). FT-IR (neat):
m
and Bu4NI (144 mg, 0.39 mmol) were added and the mixture was
heated to reflux for 60 h. The solvent was evaporated in vacuo
and the crude product was purified by fc (d = 2 cm, I = 15 cm, V =
7 mL, cyclohexane:EtOAc 60:40 + 1% NH3, Rf = 0.30). Yellow oil,
(cmÀ1) = 2922/2843 (CAH), 1689 (C@Oketone), 1628/1614/1495
(C@Carom), 1379/1169 (S@O). 1H NMR (400 MHz, CDCl3): d (ppm)
= 1.70 (d, J = 7.5 Hz, 3H, CH3), 3.00 (dd, J = 6.7 Hz, 1H, 4-H), 3.07–
3.13 (m, 1H, 4-H), 3.72 (s broad, 1H, 5-H), 3.82 (s broad, 1H, 5-
H), 4.76 (q, J = 7.5 Hz, 1H, 2-H), 7.23 (d, J = 8.0 Hz, 1H, 6-Harom),
7.40–7.45 (m, 1H, 8-Harom), 7.52 (td, J = 7.5/1.3 Hz, 1H, 7-Harom),
7.60 (dd, J = 7.7/1.5 Hz, 1H, 9-Harom). 13C NMR (101 MHz, CDCl3):
d (ppm) = 16.9 (1C, CH3), 32.8 (1C, C-4), 47.8 (1C, C-5), 55.4 (1C,
C-2), 119.9 (q, J = 322.4 Hz, 1C, CF3), 128.5 (1C, C-6arom), 129.3
(1C, C-9arom), 129.6 (1C, C-8arom), 134.4 (1C, C-7arom), 136.2 (1C,
C-qarom), 136.3 (1C, C-qarom), 200.3 (1C, C@O). Exact Mass (APCI):
m/z = 330.0389 (calcd. 330.0382 for C12H12F3NO3SNa [M+Na+]).
Purity (HPLC): 95.2% (tR = 21.73 min).
yield 45 mg (36%). C22H29NO (323.2 g/mol). FT-IR (neat):
m
(cmÀ1) = 3388 (OH), 2938 (aliphatic CAH), 2859 (aliphatic CAH),
1433 (C@C), 877, 797, 692 (aromatic CAH). 1H NMR (400 MHz,
CDCl3): d (ppm) = 0.80 (d, J = 6.1 Hz, 3H, CH3), 1.37 (quin., J = 7.6
Hz, 2H, NCH2CH2CH2CH2CH2Ph), 1.53–1.62 (m, 2H, NCH2CH2CH2-
CH2CH2Ph), 1.63–1.69 (m, 2H, NCH2CH2CH2CH2CH2Ph), 2.57–2–
65 (m, 4H, NCH2CH2CH2CH2CH2Ph), 2.68–2.76 (m, 2H, 4-H), 2.80
(dd, J = 14.5/6.5 Hz, 1H, 5-H), 3.00 (m, 1H, 5-H), 3.13 (q, J = 5.8
Hz, 1H, 2-H), 5.05 (s-broad, 1H, 1-H), 7.05 (d, J = 7.2 Hz, 1H, Ar-
H), 7.14–7.23 (m, 5H, Ar-H, Ph-H), 7.27–7.31 (m, 2H, Ar-H, Ph-H),
7.40 (d, J = 7.3 Hz, 1H, Ar-H).The signal for the OH proton is not
seen in the spectrum. 13C NMR (101 MHz, CDCl3): d (ppm) = 10.3
(1C, CH3), 27.1 (1C, NCH2CH2CH2CH2CH2Ph), 27.2 (1C, NCH2CH2-
CH2CH2CH2Ph), 31.6 (1C, NCH2CH2CH2CH2CH2Ph), 35.9 (1C, NCH2-
CH2CH2CH2CH2Ph), 36.1 (1C, C-5), 49.1 (1C, C-4), 55.3 (1C,
NCH2CH2CH2CH2CH2Ph), 61.2 (1C, C-2), 75.6 (1C, C-1), 125.8,
125.9, 126.4, 127.1, 128.4, 128.5, 129.2 (9C, Carom), 138.4, 141.6,
142.7 (3C, Carom-q). Exact Mass (APCI): m/z = 324.2338 (calcd.
324.2322 for C22H30NO [M+H+]). Purity (HPLC): 99.6% (tR = 19.25
min).
4.2.5. (1RS,2RS)-2-Methyl-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-
3-benzazepin-1-ol (cis-4a)
Under N2, anhydrous K2CO3 (270 mg, 1.95 mmol) was added to
a solution of ketone 12 (150 mg, 0.48 mmol) in dry CH3CN (15 mL)
and the mixture was heated to reflux for 3 h. The reaction mixture
was cooled to rt and filtered to remove K2CO3. It was concentrated
in vacuo and the residue (14) was dissolved in dry MeOH (8 mL).
After cooling to 0 °C, NaBH4 (55 mg, 1.44 mmol) was added and
the mixture was stirred for 3 h at rt. A saturated solution of
NaHCO3 was added and the reaction mixture was extracted with
CH2Cl2 (3 Â 20 mL). The CH2Cl2 layer was dried over Na2SO4, fil-
tered and the solvent was evaporated in vacuo. The residue (15)
was dissolved in dry CH3CN (3 mL). Then 1-chloro-4-phenylbutane
(162 mg, 0.16 mL, 0.96 mmol), K2CO3 (266 mg, 1.92 mmol) and
Bu4NI (266 mg, 0.72 mmol) were added and the mixture was
heated to reflux for 60 h. The solvent was evaporated in vacuo
and the crude product was purified by fc (d = 2 cm, I = 15 cm, V =
7 mL, cyclohexane:EtOAc 50:50 + 1% NH3, Rf = 0.51). Yellow oil,
4.2.7. (1RS,2RS)-2-Methyl-3-(4-phenylbenzyl)-2,3,4,5-tetrahydro-1H-
3-benzazepin-1-ol (cis-4c)
Under N2, anhydrous K2CO3 (162 mg, 1.17 mmol) was added to
a solution of ketone 12 (120 mg, 0.39 mmol) in dry CH3CN (15 mL)
and the mixture was heated to reflux for 3 h. The reaction mixture
was cooled to rt and filtered to remove K2CO3. It was concentrated
in vacuo and the residue (14) was dissolved in dry MeOH (5 mL).
After cooling to 0 °C, NaBH4 (44 mg, 1.17 mmol) was added and
the mixture was stirred for 3 h at rt. A saturated solution of
NaHCO3 was added and the reaction mixture was extracted with
CH2Cl2 (3 Â 20 mL). The CH2Cl2 layer was dried over Na2SO4, fil-
tered and the solvent was evaporated in vacuo. The residue (15)
was dissolved in dry CH2Cl2 (5 mL). Then, 4-phenylbenzaldehyde
(85 mg, 0.47 mmol) was added and the mixture was stirred for
30 min. NaBH(OAc)3 (248 mg, 1.17 mmol) was added and the mix-
ture was stirred for 16 h at rt. A saturated solution of NaHCO3 was
added and mixture was extracted with CH2Cl2 (3 Â 20 mL), the
CH2Cl2 layer was dried over Na2SO4, filtered and the solvent was
evaporated in vacuo. The crude product was purified by fc (d = 2
cm, I = 15 cm, v = 7 mL, cyclohexane:EtOAc 70:30 + 1% NH3, Rf =
0.50) to obtain a pale yellow solid, yield 40 mg (30%). C24H25NO
yield 50 mg (34%).
C21H27NO (309.2 g/mol). FT-IR (neat): m
(cmÀ1) = 3390 (OH), 2940 (aliphatic CAH), 2815 (aliphatic CAH),
1450 (C@C), 840, 745, 694 (aromatic CAH). 1H NMR (400 MHz,
CDCl3): d (ppm) = 0.79 (d, J = 6.2 Hz, 3H, CH3), 1.56–1.63 (m, 2H,
NCH2CH2CH2CH2Ph), 1.67 (quint., J = 7.1 Hz, 2H, NCH2CH2CH2CH2-
Ph), 2.62–2.67 (m, 4H, NCH2CH2CH2CH2Ph), 2.68–2.74 (m, 2H, 4-
H), 2.79 (dd, J = 14.8/6.2 Hz, 1H, 5-H), 2.99 (m, 1H, 5-H), 3.11 (q,
J = 6.1 Hz, 1H, 2-H), 5.05 (broad-s, 1H, 1-H), 7.06 (d, J = 7.3 Hz,
1H, Ar-H), 7.16–7.21 (m, 5H, Ph-H), 7.20–7.23 (m, 2H, Ar-H), 7.40
(d, J = 7.5 Hz, 1H, Ar-H). A signal for the OH proton is not seen in
the spectrum. 13C NMR (101 MHz, CDCl3): d (ppm) = 9.7 (1C,
CH3), 26.9 (1C, NCH2CH2CH2CH2Ph), 29.4 (1C, NCH2CH2CH2CH2Ph),
35.7 (1C, NCH2CH2CH2CH2Ph), 35.9 (1C, C-5), 48.9 (1C, C-4), 55.2
(1C, NCH2CH2CH2CH2Ph), 61.2 (1C, C-2), 75.5 (1C, C-1), 125.7,
125.8, 126.4, 127.0, 128.4, 128.5, 129.2 (9C, Carom), 138.6, 141.7,
(343.5 g/mol). FT-IR (neat):
CAH), 2810 (aliphatic CAH), 1432 (C@C), 787, 733, 682 (aromatic
m
(cmÀ1) = 3345 (OH), 2929 (aliphatic