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3.6.4. [6-(2-Methoxy-1,3,3-trimethylbicyclo[2.2.1]hept-
2-yl)pyridin-2-yl](pyridin-2-yl) methyl acetate 16.
Diastereomeric mixture, 4% de (1R,2S,4S,10S) and
(1R,2S,4S,10R). Silica column chromatography eluted with
ethyl acetate/cyclohexane (40 mg, 26%, yellow oil).
HRMS found 394.2254 for M+; C24H30N2O3 requires
394.2256. 1H NMR d 8.54 (m, 2H), 7.69 (ddd, J1¼
J2¼7.71 Hz, J3¼1.75 Hz, 2H), 7.61 (dd, J1¼J2¼7.57 Hz,
2H), 7.57 (dd, J1¼J2¼8.80 Hz, 2H), 7.32 (dd, J1¼2.98 Hz,
J2¼7.64 Hz, 2H), 7.28 (d, J¼7.98 Hz, 2H), 7.17 (m, 2H),
6.91/6.89 (s, 2H), 3.12/3.11 (s, 6H), 2.51 (m, 2H), 2.21 (s,
6H), 2.05–1.96 (m, 2H), 1.83–1.73 (m, 2H), 1.54–1.36 (m,
4H), 1.18 (s, 3H), 1.15 (s, 3H), 1.12–1.07 (m, 2H), 1.00
(m, 2H), 0.92 (s, 6H), 0.08 (s, 3H), 0.05 (s, 3H). 13C NMR
d 170/169 (C), 162.3/162.2 (C), 158.5 (C), 155.6/155.5
(C), 149.9/149.0 (CH), 136.4 (CH), 136.0 (CH), 122.8/
122.7 (CH), 122.7/122.5 (CH), 122.0/121.9 (CH), 118.9/
118.7 (CH), 89.9 (C), 78.7/78.6 (CH), 54.6 (CH3), 52.4/
52.3 (C), 48.4/48.3 (C), 48.4 (CH3), 44.3/44.2 (CH2), 31.7
(CH2), 28.8/28.7 (CH3), 25.3 (CH2), 21.2/21.1 (CH3),
20.0/19.8 (CH3), 14.1 (CH). EM (EI) m/z (%) 394 (16),
380 (30), 379 (100), 319 (31), 314, (20), 313 (96).
(ddd, J1¼J2¼12.9 Hz, J3¼4.8 Hz, 2H), 1.00 (s, 3H), 0.99
(s, 3H), 0.98 (s, 6H), 0.40 (s, 3H), 0.39 (s, 3H). 13C NMR
d 162.11 (C), 161.19 (C), 136.62 (CH), 121.90/121.84
(CH), 117.71 (CH), 84.24 (C), 70.09/69.93 (CH), 52.45/
52.36 (C), 49.24 (CH), 46.47 (C), 42.39 (CH2), 32.92
(CH2), 29.55/29.52 (CH), 24.80/24.68 (CH2), 24.41 (CH3),
22.55 (CH3), 17.58 (CH3). EM (EI) m/z (%) 275 (8), 260
(12), 194 (100), 178 (71). In the first fraction 10 (10 mg,
10%) was obtained.
3.7.2. Pyridin-2-yl [6-(2,7,7-trimethyltricyclo[2,2,1,
2,6]hept-1-yl)pyridin-2-yl] methanone 18. Silica column
0
chromatography with ethyl acetate/cyclohexane as eluent.
Brown oil (17 mg, 13%). HRMS found for M+ 318.1733;
C21H22N2O requires 318.1732. 1H NMR d 8.73 (d, J¼
4.34 Hz, 1H), 8.06 (d, J¼7.82 Hz, 1H), 7.90 (dd, J1¼
7.67 Hz, J2¼0.98 Hz, 1H), 7.83 (ddd, J1¼J2¼7.71 Hz,
J3¼1.7 Hz, 1H), 7.74 (dd, J1¼J2¼7.79 Hz, 1H), 7.43 (m,
1H), 7.35 (dd, J1¼7.86 Hz, J2¼1.00 Hz, 1H), 1.82 (m,
2H), 1.53 (m, 1H), 1.40 (s, 1H), 1.32 (m, 1H), 1.22 (m, 1H),
1.07 (s, 3H), 1.00 (s, 3H), 0.86 (s, 3H). 13C NMR d 193.4
(C]O), 159.0 (C), 154.7 (C), 153.5 (C), 149.1 (CH),
136.0 (CH), 127.3 (CH), 127.2 (CH), 125.7 (CH), 125.6
(CH), 121.3 (CH), 46.8 (C), 44.1 (CH), 42.0 (C), 38.6 (CH2),
32.2 (CH2), 29.4 (C), 27.1 (CH3), 22.6 (CH3), 21.7 (CH3),
14.0 (CH). EM (EI) m/z (%) 318 (100), 303 (60), 277 (34),
212 (20), 78 (20). Further elution gave 17 (55.1 g, 38%).
3.6.5. (1R,2S,4S)-[6-(2-Methoxy-1,3,3-trimethylbicy-
clo[2.2.1]hept-2-yl)pyridin-2-yl](pyridin-2-yl) meth-
anone 17. Silica column chromatography eluted with ethyl
acetate/cyclohexane (83.1 mg, 60% colourless oil). HRMS
found for M+ 350.1995; C22H26N2O2 requires 350.1994.
1H NMR d 8.68 (m, 1H), 7.95 (dd, J1¼7.62 Hz, J2¼
1.09 Hz, 1H), 7.94–7.79 (m, 3H), 7.06 (dd, J1¼7.99 Hz,
J2¼1.10 Hz, 1H), 7.44–7.40 (m, 1H), 3.15 (s, 3H), 2.31
(m, 1H), 2.01 (m, 1H), 1.83–1.73 (m, 1H), 1.54–1.36 (m,
3H), 1.18 (s, 3H), 1.14–1.04 (m, 1H), 0.98 (s, 3H), 0.30 (s,
3H). 13C NMR d 194.4 (C]O), 162.2 (C), 155.8 (C),
152.5 (C), 148.9 (CH), 136.2 (CH), 136.1 (CH), 126.0 (CH),
125.3 (CH), 123.9 (CH), 121.6 (CH), 90.0 (C), 54.6 (CH3),
52.2 (C), 48.5 (C), 48.4 (CH3), 44.4 (CH2), 31.6 (CH2),
29.1 (CH3), 24.4 (CH2), 21.6 (CH3), 19.9 (CH3), 14.1 (CH).
EM (EI) m/z (%) 350 (13), 335 (50), 269 (100), 78 (18).
3.8. Ring opening reaction of triazolopyridines 3 and 4
with SeO2
Method A: a suspension of triazolopyridine 3 or 4 and sele-
nium dioxide (2 equiv) in sulfuric acid (10 mL, 2.5 M) was
heated (see conditions in Table 1). Method B: a suspension
of 3 and selenium dioxide (2 equiv) in p-xylene was heated
(see conditions in Table 1). Then the corresponding mixture
was filtered and the filtrate neutralized with a saturated aque-
ous solution of sodium hydrogencarbonate and extracted
with dichloromethane. The organic solvent was dried and
evaporated. The residue was purified by chromatotron to ob-
tain 12 (22%).
3.7. General procedure for ring opening reactions of
triazolopyridines 3, 4 and 15 with sulfuric acid
3.9. Synthesis of Zn(4)Cl2
A solution of the corresponding triazolopyridine in aqueous
sulfuric acid (10 mL, 2.5 M) was heated (see conditions
in Table 1). The solution was neutralized with a saturated
aqueous solution of sodium bicarbonate and extracted with
dichloromethane. The organic solvent was dried and evapo-
rated. The residue was purified by silica column chromato-
graphy or chromatotron. With 4 no reaction was observed.
The products, yields and conditions of purification are given
for each compound.
To a solution of (1R,2S,4S)-1,3,3-trimethyl-2-(6-[1,2,3]tri-
azolo[1,5-a]pyridin-3-yl-pyridin-2-yl)-bicyclo[2.2.1]hept-2-
ol 4 (50 mg, 0.14 mmol) in dichloromethane (20 mL), a solu-
tion of Cl2Zn in ether (0.15 mL, 1 M) was added. A yellow
solution was formed and was stirred (30 min) at room tem-
perature. Evaporation of the solvent gives a yellow oil that
was washed with hot ethyl acetate. The oil obtained has
1
identical H and 13C NMR in DMSO-d6 that the ligand 4.
HRMS (FAB) found for M+ 447.093; C21H24N4OClZn
requires 447.093. MS m/e (%) 454 (3), 453 (16), 452 (17),
451 (62), 450 (31), 449 (92), 448 (25), 447 (100). UV lmax
(log 3) (MeOH) 225 (2.5), 270 (2.47), 311 (2.56), 320 (2.57).
3.7.1. 2-[6-(1-Hydroxy-ethyl)-pyridin-2-yl]-1,3,3-trime-
thylbicyclo[2.2.1]hept-2-ol 9. Diastereomeric mixture 5%
de (1R,2S,4S,10S) and (1R,2S,4S,10R). Purified by chromato-
tron with ethyl acetate/hexane (52 mg, 60% colourless oil).
HRMS found for M+ 275.1889; C17H25NO2 requires
275.1885. 1H NMR d 7.65 (dd, J1¼7.8 Hz, J2¼7.5 Hz,
2H), 7.43 (d, J¼7.8 Hz, 2H), 7.18 (d, J¼7.5 Hz, 2H), 4.88
(d, J¼6.6 Hz, 2H), 3.2 (br s, 2OH), 2.28 (m, 4H), 1.87–
1.78 (m, 4H), 1.5 (d, J¼6.6 Hz, 3H), 1.49 (d, J¼6.6 Hz,
3H), 1.51–1.48 (m, 2H), 1.35 (d, J¼9.3 Hz, 2H), 1.17
Acknowledgements
ꢀ
We are much grateful to the Ministerio de Educacion y Cien-
cia (Spain) (Project CTQ2006-15672-C05-03) for its finan-
cial support, and to the SCSIE for the realization of the