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S. Zeimyte and S. Stoncius
Tetrahedron 78 (2021) 131831
solution of 2-acetylpyridine N-oxide (6) (274 mg, 2 mmol) and
4.4.3. (6R,12R)-4,10-bis(4-methoxyphenyl)-2,8-di(pyridin-2-yl)-
5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-b’]dipyridine
(8b)
corresponding aromatic aldehyde (2.8 mmol) in MeOH (10 mL) at
0
ꢀC. The mixture was warmed to room temperature and stirred
until the completion of the reaction (TLC). The solution was then
neutralized with 2 M NH4Cl (pH ~ 7), diluted with water and
extracted with DCM (3 ꢂ 20 mL). The organic phase was washed
with brine, dried (Na2SO4) and evaporated. The obtained residue
was purified by column chromatography on silica gel to yield
enones 4 as yellow solids.
Purified by column chromatography (PE/EtOAc/TEA 65:45:3.5)
to give 8b (34%), m.p. 162 ꢀC (dec.). [a]2D0 ¼ þ150 (c ¼ 0.51). 1H NMR:
d
2.40 (br s, 2H), 3.10 (d, J ¼ 17.3 Hz, 2H), 3.30 (dd, J ¼ 17.3, 5.9 Hz,
2H), 3.66 (br s, 2H), 3.84 (s, 6H), 6.88e6.94 (m, 4H), 7.20e7.27 (m,
6H), 7.76 (td, J ¼ 7.9, 1.8 Hz, 2H), 7.99 (s, 2H), 8.36 (dt, J ¼ 7.9, 1.0 Hz,
2H), 8.60 (ddd, J ¼ 4.7, 1.8, 1.0 Hz, 2H). 13C NMR:
d 28.4 (CH2), 36.3
(CH2), 36.4 (CH), 55.3 (CH3), 113.6 (CH), 120.3 (CH), 121.1 (CH), 123.2
(CH), 128.3 (C), 129.9 (CH), 131.7 (C), 136.7 (CH), 149.0 (CH), 150.6
(C), 153.5 (C), 156.7 (C), 159.2 (C), 159.7 (C). IR: 2926, 1610, 1582,
1513, 1435, 1250, 833, 793 cmꢁ1. HRMS: calcd. for C39H32N4O2
([MþH]þ) 589.2598, found 589.2598.
4.3.1. (E)-2-(3-(2,4,6-trimethoxyphenyl)acryloyl)pyridine 1-oxide
(4g)
Purified by column chromatography (DCM/MeOH 95:5) to give
4g (71%), m.p. 157e158 ꢀC. 1H NMR:
d 3.84 (s, 3H), 3.85 (s, 6H), 6.08
(s, 2H), 7.27e7.35 (m, 2H), 7.54e7.60 (m, 1H), 7.84 (d, J ¼ 16.1 Hz,
1H), 8.19 (d, J ¼ 16.1 Hz, 1H), 8.17e8.24 (m, 1H). 13C NMR:
d
55.4
4.4.4. (6R,12R)-4,10-bis(4-fluorophenyl)-2,8-di(pyridin-2-yl)-
5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-b’]dipyridine
(8c)
(CH3), 55.8 (CH3), 90.4 (CH), 106.4 (C), 124.1 (CH), 125.2 (CH), 126.7
(CH), 137.0 (CH), 140.3 (CH), 148.3 (C), 162.0 (C), 163.7 (C), 188.3 (C]
O). IR: 1626, 1588 cmꢁ1. HRMS: calcd. for C17H17NO5 ([MþH]þ)
316.1179, found 316.1173.
Purified by column chromatography (PE/EtOAc/TEA 80:20:3) to
give 8c (34%), m.p. 220 ꢀC (dec.). [a]2D0 ¼ þ236 (c ¼ 0.33). 1H NMR:
d
2.40 (br s, 2H), 3.04 (d, J ¼ 17.3 Hz, 2H), 3.27 (dd, J ¼ 17.3, 6.0 Hz,
4.4. General procedure for the synthesis of 2,20-bipyridine
derivatives 2a and 8a-f
2H), 3.67 (br s, 2H), 7.04e7.10 (m, 4H), 7.22e7.29 (m, 6H), 7.78 (td,
J ¼ 7.8, 1.8 Hz, 2H), 7.98 (s, 2H), 8.36 (dt, J ¼ 7.8, 1.0 Hz, 2H), 8.60
(ddd, J ¼ 4.8, 1.8, 1.0 Hz, 2H). 13C NMR:
d 28.3 (CH2), 36.2 (CH2), 36.3
A solution of NaOH (240 mg, 6 mmol) in H2O/MeOH (4 mL, 1:1)
was added dropwise to a solution of diketone 7 (152 mg, 1 mmol)
and corresponding enone (2 mmol) in MeOH (32 mL) at 36 ꢀC. The
mixture was stirred at this temperature until the completion (TLC),
then quenched with 2 M NH4Cl, diluted with water (20 mL) and
extracted with DCM (3 ꢂ 25 mL). Organic phase was dried (Na2SO4)
and evaporated. The obtained residue was dissolved in EtOH
(12 mL) and NH2OH$HCl (348 mg, 5 mmol) was added. Reaction
mixture was refluxed under argon atmosphere overnight, cooled
down to rt, neutralized with saturated NaHCO3 solution, extracted
with DCM (3 ꢂ 30 mL), the organic phase was dried (Na2SO4) and
evaporated. The obtained brown oily residue was purified by col-
umn chromatography on silica gel to afford bipyridine derivatives
2a and 8a-f as off-white solids.
(CH), 115.2 (d, J ¼ 21.4 Hz, CH), 120.2 (CH), 121.1 (CH), 123.4 (CH),
128.1 (C), 130.4 (d, J ¼ 8.1 Hz, CH), 135.2 (d, J ¼ 3.4 Hz, C), 136.8 (CH),
149.1 (CH), 150.0 (C), 153.7 (C), 156.4 (C), 159.7 (C), 162.4 (d, J ¼
247.0 Hz, C). IR: 3436, 2925, 1582, 1510, 1436, 1226, 838, 795 cmꢁ1
.
HRMS: calcd. for C37H26F2N4 ([MþH]þ) 565.2198, found 565.2199.
4.4.5. (6R,12R)-4,10-bis(3,5-dimethoxyphenyl)-2,8-di(pyridin-2-
yl)-5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-b’]
dipyridine (8d)
Purified by column chromatography (PE/EtOAc/TEA 50:50:3) to
give 8d (50%), m.p. 150 ꢀC (dec.). [a]2D0 ¼ þ228 (c ¼ 0.09). 1H NMR:
d
2.40 (br s, 2H), 3.16 (d, J ¼ 17.5 Hz, 2H), 3.26 (dd, J ¼ 17.5, 5.7 Hz,
2H), 3.66 (br s, 2H), 3.72 (s, 12H), 6.38 (d, J ¼ 2.3 Hz, 4H), 6.45 (t, J ¼
2.3 Hz, 2H), 7.25 (ddd, J ¼ 7.8, 4.7, 1.0 Hz, 2H), 7.77 (td, J ¼ 7.8, 1.7 Hz,
2H), 8.01 (s, 2H), 8.38 (dt, J ¼ 7.8, 1.0 Hz, 2H), 8.60 (ddd, J ¼ 4.7, 1.7,
4.4.1. 2,2’-((6R,12R)-4,10-diphenyl-5,6,11,12-tetrahydro-6,12-
methanocycloocta[1,2-b:5,6-b’]dipyridine-2,8-diyl)bis(pyridine 1-
oxide) (2a)
1.0 Hz, 2H). 13C NMR:
d 28.5 (CH2), 36.1 (CH2), 36.3 (CH), 55.3 (CH3),
100.1 (CH), 106.6 (CH), 119.8 (CH), 121.1 (CH), 123.3 (CH), 128.1 (C),
136.7 (CH), 141.2 (C), 149.0 (CH), 151.0 (C), 153.5 (C), 156.5 (C), 159.8
Purified by column chromatography (DCM/MeOH 95:5) to give
(C), 160.5 (C). IR: 2930, 1593, 1582, 1421, 1205, 1156, 835, 793 cmꢁ1
.
2a (36%), m.p. 161 ꢀC (dec.). [a]2D0 ¼ þ106 (c ¼ 0.29). 1H NMR:
d
2.40
HRMS: calcd. for C41H36N4O4 ([MþH]þ) 649.2809, found 649.2808.
(br s, 2H), 3.06 (d, J ¼ 17.6 Hz, 2H), 3.32 (dd, J ¼ 17.6, 5.9 Hz, 2H),
3.63 (br s, 2H), 7.21 (ddd, J ¼ 7.5, 6.5, 2.0 Hz, 2H), 7.27e7.41 (m,12H),
8.02 (dd, J ¼ 8.0, 2.0 Hz, 2H), 8.27 (dd, J ¼ 6.5, 1.0 Hz, 2H), 8.45 (s,
4.4.6. (6R,12R)-4,10-bis(3,5-dimethylphenyl)-2,8-di(pyridin-2-yl)-
5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-b:5,6-b’]dipyridine
(8e)
2H). 13C NMR:
d 28.2 (CH2), 36.1 (CH), 36.4 (CH2), 124.4 (CH), 124.8
(CH), 125.6 (CH), 127.7 (CH), 127.8 (CH), 128.2 (CH), 128.7 (CH), 129.0
(C), 138.8 (C), 140.5 (CH), 147.2 (C), 147.6 (C), 150.2 (C), 159.8 (C). IR:
2926, 1578, 1542, 1437, 1420, 1269, 1221, 768, 702 cmꢁ1. HRMS:
calcd. for C37H28N4O2 ([MþH]þ) 561.2285, found 561.2278.
Purified by column chromatography with hexane/EtOAc (9:1),
followed by elution with hexane/EtOAc/TEA (90:10:3) to give 8e
(45%), m.p. 186 ꢀC (dec.). [a]2D0 ¼ þ190 (c ¼ 0.80). 1H NMR:
d 2.30 (s,
12H), 2.41 (br s, 2H), 3.12 (d, J ¼ 17.5 Hz, 2H), 3.29 (dd, J ¼ 17.5,
5.8 Hz, 2H), 3.66 (br s, 2H), 6.89 (s, 4H), 6.98 (s, 2H), 7.24 (dd, J ¼ 7.9,
5.4 Hz, 2H), 7.76 (td, J ¼ 7.9, 1.7 Hz, 2H), 7.97 (s, 2H), 8.37 (d,
4.4.2. (6R,12R)-4,10-diphenyl-2,8-di(pyridin-2-yl)-5,6,11,12-
tetrahydro-6,12-methanocycloocta[1,2-b:5,6-b’]dipyridine (8a)
Purified by column chromatography (DCM/MeOH 95:5) to give
J ¼ 7.9 Hz, 2H), 8.58e8.63 (m, 2H). 13C NMR:
d 21.3 (CH3), 28.5 (CH2),
36.3 (CH2), 36.4 (CH), 120.2 (CH), 121.1 (CH), 123.2 (CH), 126.4 (CH),
128.2 (C), 129.2 (CH), 136.6 (CH), 137.6 (C), 139.3 (C), 149.1 (CH),
151.3 (C), 153.5 (C), 156.8 (C), 159.7 (C). IR: 2918, 1582, 1542, 1438,
794 cmꢁ1. HRMS: calcd. for C41H36N4 ([MþH]þ) 585.3013, found
585.3033.
8a (56%), m.p. 175 ꢀC (dec.). [a]2D0 ¼ þ280 (c ¼ 0.97). 1H NMR:
d 2.41
(br s, 2H), 3.09 (d, J ¼ 17.4 Hz, 2H), 3.30 (dd, J ¼ 17.4, 5.9 Hz, 2H), 3.67
(br s, 2H), 7.23e7.42 (m,12H), 7.76 (td, J ¼ 7.9,1.8 Hz, 2H), 8.0 (s, 2H),
8.35 (dt, J ¼ 7.9, 0.9 Hz, 2H), 8.60 (ddd, J ¼ 4.8, 1.8, 0.9 Hz, 2H). 13
C
NMR:
d 28.3 (CH2), 36.2 (CH2), 36.3 (CH), 120.2 (CH), 121.1 (CH),
123.3 (CH), 127.7 (CH), 128.1 (C), 128.2 (CH), 136.7 (CH), 139.3 (C),
149.0 (CH), 151.0 (C), 153.5 (C), 156.5 (C), 159.7 (C). IR: 3057, 2925,
1583, 1542, 1435, 770, 702 cmꢁ1. HRMS: calcd. for C37H28N4
([MþH]þ) 529.2387, found 529.2391.
4.4.7. (6R,12R)-4,10-bis(3,5-bis(trifluoromethyl)phenyl)-2,8-
di(pyridin-2-yl)-5,6,11,12-tetrahydro-6,12-methanocycloocta[1,2-
b:5,6-b’]dipyridine (8f)
Purified by column chromatography (PE/EtOAc/TEA 95:5:3) to
6