T.S. Banerjee et al. / Bioorg. Med. Chem. 22 (2014) 6062–6070
6067
153.2, 154.7; HRMS (ESI) (M+Na)+ calculated for C17H16O4SNa+
= 339.0667, found 339.0665.
4.1.1.10. exo-Methyl 2-(2-(benzofuran-2-yl)ethyl)-2-azabicy-
clo[2.2.2]oct-5-ene-7-carboxylate (12b). Title compound
(12b) was synthesized in 75% yield from 9 and 4b. IR (neat, CHCl3):
2947, 1735, 1454, 1253, 1197, 742 cmꢂ1 1H NMR (500 MHz,
4.1.1.6. 3-(Benzofuran-2-yl)propyl 4-methylbenzenesulfonate
m
.
(10).
Compound (10) was prepared following similar proce-
CDCl3) d 1.36–1.42 (1H, m), 1.91 (1H, dt, J = 9.0, 2.5 Hz), 2.17 (1H,
ddd, J = 12.5, 4.3, 2.6 Hz), 2.41–2.45 (1H, m), 2.48–2.52 (1H, m),
2.58 (1H, br s), 2.75–2.99 (3H, m), 3.20 (1H, dd, J = 9.0, 2.0 Hz),
3.55 (3H, s), 3.83–3.85 (1H, m), 6.26 (1H, dd, J = 7.5, 6.5 Hz), 6.40
(1H, s), 6.48 (1H, t, J = 7.5 Hz), 7.14–7.21 (2H, m), 7.36–7.40 (1H,
m), 7.45–7.48 (1H, m). 13C NMR (125 MHz, CDCl3) d 24.4, 27.8,
31.1, 45.4, 51.8, 54.9, 55.2, 55.9, 56.06, 102.51, 102.55, 110.8,
120.31, 120.51, 122.5, 123.14, 123.57, 129.18, 129.94, 135.4,
154.6, 158.1, 174.9. HRMS (ESI) (M+H)+ calculated for C19H21NO3H+
312.1600, found 312.1595.
dure as (8) and was obtained as colorless solid. Melting point:
74 °C. Yield: 70%. Rf (4:1, petroleum ether/EtOAc) = 0.49. IR (neat,
CHCl3):
NMR (300 MHz, CDCl3): d 1.96–2.05 (2H, m), 2.34 (3H, s), 2.72–
2.77 (2H, t, J = 7.2 Hz), 3.99–4.03 (2H, t, J = 6.1 Hz), 6.20 (1H, s),
7.08–7.13 (3H, m), 7.21–7.24 (2H, m), 7.35 (1H, m), 7.68–7.71
(2H, d, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3): d 21.6, 24.3, 26.9,
69.2, 102.8, 110.7, 120.3, 122.5, 123.4, 127.9, 128.6, 129.8, 132.9,
144.8, 154.6, 156.9.
m .
1928, 1593, 1450, 1348, 1172, 923, 742, 549 cmꢂ1 1H
4.1.1.7. endo-Methyl-2-(benzofuran-2-ylmethyl)-2-azabicy-
4.1.1.11. endo-Methyl 2-(3-(benzofuran-2-yl)propyl)-2-azabicy-
clo[2.2.2]oct-5-ene-7 carboxylate (11a).
A
suspension of
clo[2.2.2]oct-5-ene-7-carboxylate (13a).
13a was prepared in 79% yield from 10 and 4a. IR (neat, CHCl3):
2949, 1735, 1454, 1253, 1197, 1172, 750 cmꢂ1 1H NMR
Title compound
K2CO3 (500 mg, 3.16 mmol) in anhydrous CH3CN (5.0 mL) contain-
ing the isoquinuclidine salt 4a (230 mg, 1.4 mmol) and chloro com-
pound 8 (210 mg, 1.26 mmol) was refluxed for 14 h then cooled to
rt and filtered through a pad of Celite, washed with EtOAc
(2 ꢁ 7 mL). The combined organic extracts were concentrated in
vacuo and purified by column chromatography (100–200 mesh sil-
ica gel) using EtOAc in petroleum ether (PE) as eluent to obtain the
m
.
(500 MHz, CDCl3) d 1.67–1.78 (2H, m), 1.84–1.95 (3H, m), 2.29–
2.34 (1H, m), 2.55–2.61 (2H, m), 2.73–2.83 (2H, m), 2.92 (1H, dd,
J = 9.5, 2.0 Hz), 3.07–3.11 (1H, m), 3.63 (3H, s), 3.77 (1H, br s),
6.13–6.16 (1H, m), 6.33 (1H, s), 6.42 (1H, t, J = 7.5 Hz), 7.14–7.22
(2H, m), 7.38 (1H,), 7.45–7.47 (1H, m). 13C NMR (125 MHz, CDCl3)
d 26.16, 26.33, 26.39, 30.9, 43.98 51.8, 54.4, 54.6, 57.2, 102.1, 110.8,
120.3, 122.5, 123.2, 129.11, 129.62, 134.8, 154.8, 159.4, 174.6.
HRMS (ESI) (M+H)+ calculated for C20H23NO3H+ 326.1756, found
326.1751.
compound 11a in 71% yield. IR (neat, CHCl3):
m 2949, 1736, 1454,
1194, 1167, 749 cmꢂ1 1H NMR (500 MHz, CDCl3) d 1.69–1.72
.
(1H, m), 1.81–1.86 (1H, t, J = 11.0 Hz), 2.07–2.09 (1H, d,
J = 9.5 Hz), 2.61 (1H, br s), 3.05–3.07 (1H, d, J = 10.0 Hz),
3.17–3.19 (1H, br s), 3.56–3.59 (1H, d, J = 14.0 Hz), 3.62 (3H, s),
3.76–3.79 (1H, d, J = 14.5 Hz), 3.89 (1H, br s), 6.20–6.22 (1H, t,
J = 5.5 Hz), 6.47–6.50 (1H, t, J = 7.0 Hz), 6.57 (1H, s), 7.18–7.26
(2H, m), 7.47–7.48 (1H, d, J = 7.5 Hz), 7.51–7.53 (1H, d, J = 7.0 Hz).
13C NMR (125 MHz, CDCl3) d 26.2, 30.9, 44.2, 51.9, 53.7, 54.13,
54.34, 105.1, 111.4, 120.8, 122.7, 123.9, 128.5, 129.4, 135.1,
155.2, 155.8, 174.4. HRMS (ESI) (M+H)+ calculated for C18H19NO3H+
298.1443 found 298.1436.
4.1.1.12. exo-Methyl-2-(3-(benzofuran-2-yl)propyl)-2-azabicy-
clo[2.2.2]oct-5-ene-7-carboxylate (13b).
was synthesized in 74% yield from 10 and 4b. IR (neat, CHCl3):
2947, 1737, 1600, 1454, 1251, 1197, 750 cmꢂ1 1H NMR
Title compound
m
.
(500 MHz, CDCl3) d 1.38–1.42 (1H, m), 1.73–1.79 (2H, m), 1.82
(1H, dt, J = 9.0, 2.5 Hz), 2.16–2.21 (2H, m), 2.43–2.56 (3H, m),
2.73–2.79 (2H, m), 3.15 (1H, dd, J = 9.0, 2.0 Hz), 3.73 (3H, s), 3.80
(1H, br s), 6.21 (1H, m), 6.36 (1H, s), 6.44-6.47 (1H, t, J = 7.2 Hz),
7.15–7.21 (2H, m), 7.39–7.41 (1H, d, J = 8.0 Hz), 7.46–7.48 (1H,
m). 13C NMR (125 MHz, CDCl3) d 24.5, 25.8, 26.3, 31.1, 45.5, 51.9,
55.01, 55.14, 56.9, 101.9, 110.8, 120.2, 122.4, 123.1, 129.2, 129.9,
135.3, 154.8, 159.9, 175.1. HRMS (ESI) (M+H)+ calculated for
4.1.1.8.
[2.2.2]oct-5-ene-7-carboxylate (11b).
synthesized in 64% yield from compounds 8 and 4b. IR (neat,
CHCl3):
2943, 1742, 1450, 1193, 1167, 746 cmꢂ1 1H NMR
exo-Methyl-2-(benzofuran-2-ylmethyl)-2-azabicyclo-
Compound 11b was
m
.
(500 MHz, CDCl3) d 1.30–1.35 (1H, t, J = 11.5 Hz), 1.92–1.94 (1H,
d, J = 9.0 Hz), 2.10–2.15 (1H, d, J = 12.5 Hz), 2.34–2.36 (1H, d,
J = 11.0 Hz), 2.52 (1H, br s), 3.20–3.21 (1H, d, J = 9.0 Hz),
3.40–3.45 (1H, d, J = 14.5 Hz), 3.55–3.57 (4H, m), 3.79 (1H, br s),
6.16–6.19 (1H, t, J = 6.5 Hz), 6.40–6.45 (2H, m), 7.09–7.17 (2H,
m), 7.29 (1H, d, J = 8.0 Hz), 7.33–7.36 (1H, d, J = 7.5 Hz). 13C NMR
(125 MHz, CDCl3) d 24.2, 31.1, 45.2, 51.8, 54.02, 54.26, 54.83,
104.4, 110.97, 120.6, 122.5, 123.6, 128.6, 129.7, 135.6, 154.9,
156.4, 174.8. HRMS (ESI) (M+H)+ calculated for C18H19NO3H+
298.1443 found 298.1436.
C
20H23NO3H+ 326.1756, found 326.1749.
4.1.1.13. endo-Methyl 2-(benzofuran-2-ylmethyl)-2-azabicy-
clo[2.2.2]octane-7-carboxylate (14). To a stirred solution of
compound 11a (84 mg, 0.28 mmol) in dry methanol (5.0 mL) was
added Pd-C (10%) and stirred overnight under hydrogen atmo-
sphere using a hydrogen balloon. Reaction mixture was filtered
through a pad of Celite, concentrated in vacuo and purified by silica
gel column chromatography (100–200 mesh silica gel) using EtOAc
in petroleum ether (PE) as eluent to obtain the compound 14
(79 mg, 93%), (Rf = 0.52, PE/EtOAc, 4:1) as a pale yellow oil. IR (neat,
4.1.1.9. endo-Methyl 2-(2-(benzofuran-2-yl)ethyl)-2-azabicy-
CHCl3): m .
2947, 1736, 1454, 1171, 750 cmꢂ1 1H NMR (500 MHz,
clo[2.2.2]oct-5-ene-carboxylate (12a).
synthesized in 83% yield (326 mg), (Rf = 0.44, PE/EtOAc, 4:1) as a
pale yellow oil from 9 and 4a. IR (neat, CHCl3): 3407, 2949,
1732, 1602, 1454, 1251 cmꢂ1 1H NMR (500 MHz, CDCl3) d 1.68–
1.80 (2H, m), 2.01–2.05 (1H, dt, J = 9.5, 2.5 Hz), 2.59 (1H, br s),
2.63–2.66 (1H, m), 2.86–2.95 (3H, m), 2.97 (1H, dd, J = 9.7, 2.0 Hz),
3.08–3.11 (1H, m), 3.62 (3H, s), 3.82–3.83 (1H, m), 6.18 (1H, dt,
J = 6.5 Hz), 6.40 (1H, s), 6.44 (1H, t, J = 7.25 Hz), 7.15–7.21 (2H, m),
7.39 (1H, d, J = 9.0 Hz), 7.45–7.47 (1H, dd, J = 7.0,1.5 Hz). 13C NMR
(125 MHz, CDCl3) d 26.0, 28.1, 30.8, 44.0, 51.8, 54.26, 54.66, 55.97,
56.03, 102.5, 110.77, 110.89, 120.3, 122.49, 122.69, 123.25,
123.66, 128.9, 129.6, 134.8, 154.7, 157.6, 174.4. HRMS (ESI)
(M+H)+ calculated for C19H21NO3H+ 312.1600, found 312.1592.
Compound 12a was
CDCl3) d 1.53–1.68 (3H, m), 1.77–1.87 (3H, m), 2.03–2.08 (1H,
m), 2.63–2.64 (1H, dd, J = 8.0, 1.5 Hz), 2.95–2.96 (1H, dd, J = 8.0,
1.5 Hz), 3.01 (1H, s), 3.02–3.06 (2H, m), 3.66 (3H, s), 3.80–3.88
(3H, m), 6.61 (1H, s), 7.18–7.25 (2H, m), 7.46–7.48 (1H, d,
J = 8.0 Hz), 7.52–7.53 (1H, dd, J = 8.0 Hz). 13C NMR (125 MHz,
CDCl3) d 22.3, 24.2, 25.8, 27.2, 39.5, 51.8, 51.9, 52.8, 55.7, 104.9,
111.4, 120.8, 122.7, 123.9, 128.6, 155.2, 155.9, 175.4. HRMS (ESI)
(M+H)+ calculated for C18H21NO3H+ 300.1600 found 300.1604.
m
.
4.1.1.14.
endo-Methyl
2-((1H-indol-2-yl)methyl)-2-azbicy-
suspension of
clo[2.2.2]oct-5-ene-7-carboxylate (15).
A
K2CO3 (2.0 g, 14.4 mmol) in anhydrous CH3CN (10 mL) containing
the compound 4a (1.8 g, 7.2 mmol) and propargyl bromide (80%