The First and Second Cinchona Rearrangement
chonine 4-OMs (437 mg, 1.17 mmol) was allowed to react
according to general procedure A with n-Bu4NSCN (706 mg,
2.35 mmol) to afford 6-SCN (342 mg, 89%). 1H NMR (400 MHz,
CDCl3): δ 8.91 (d, J ) 4.5 Hz, H-2′), 8.20-8.06 (m, H-8′, H-5′),
7.77-7.69 (m, H-7′), 7.68-7.60 (m, H-6′), 7.31 (d, J ) 4.6 Hz,
H-3′), 5.99 (ddd, J ) 6.9, 10.4, 17.2 Hz, H-10), 5.23-5.01 (m,
H-11, H-11), 4.71 (d, J ) 11.4 Hz, H-2), 4.08-3.98 (m, H-3),
3.65 (dd, J ) 9.6, 15.0 Hz, H-7), 3.27-3.20 (m, H-8), 2.93-
2.83 (m, H-7), 2.63-2.41 (m, H-8. H-4, H-4), 2.33-2.26 (m,
H-6), 1.98-1.88 (m, H-5, H-9), 1.82-1.71 (m, H-9). 13C NMR
(100 MHz, CDCl3): δ 149.3 (CH, C-2′), 149.2 (C, C-10′), 144.4
(C, C-4′), 139.5 (CH, C-10), 130.5 (CH, C-8′), 129.3 (CH, C-7′),
127.4 (C, C-9′), 127.2 (CH, C-5′), 123.6 (CH, C-6′), 116.8 (CH,
C-3′), 115.9 (CH2, C-11), 110.4 (C, C-12, SCN), 69.6 (CH, C-3),
56.5 (CH2, C-7), 44.5 (CH, C-2), 42.9 (CH, C-6), 39.1 (CH2, C-8),
34.1 (CH2, C-4), 32.2 (CH, C-5), 27.8 (CH2, C-9). IR (Golden
Gate ATR) υ 2961 m, 2873 m, 2147 w, 2052 s, 1593 w, 1507
w, 1464 m, 1381 m, 1162 w, 995 w, 881 w, 733 m. MS-MAT
(160 °C): m/z 337 (M+ + 2, 11.86), 335 (M+, 38), 309 (6), 302
(100), 295 (47), 278 (66), 250 (19), 236 (17), 222 (24), 210 (11),
195 (24), 183 (33), 167 (42), 155 (20), 136 (24), 115 (15), 108
(8), 95 (6), 81 (19), 67 (11). HRMS (C20H21N3S) calcd 335.1456,
found 335.1454.
Exp er im en ta l Section
Gen er a l. The atom numbering follows the Cinchona alka-
loid convention. The new ring expanded Cinchona alkaloids
are numbered according to the Beilstein AutoNom.
1H NMR and 13C NMR spectra (peaks assigned by DEPT,
HMQC, HMBC, H, H-COSY) were recorded at 400 and 500
MHz in deuterated chloroform unless otherwise stated, with
tetramethylsilane as internal standard. Mass spectra were
recorded at 70 eV. Preparative column chromatography was
performed on silica gel (particle size 30-60 µm). Analytical
TLC was carried out on aluminum-backed 0.2-mm silica gel
60 F254 plates. Petrol ether (PE) and methyl tert-butyl ether
(MTBE) were distilled before use. Methanol was dried over
calcium hydride and citric acid and distilled over magnesium
before use. The quality of the Cinchona alkaloids may vary
from batch to batch. Usually, the cinch bases (6′-R ) H) are
accompanied by 10,11-dihydro and 6′-OMe derivatives (<10%).
Gen er a l P r oced u r e A for P r ep a r a tion of Rin g-Ex-
p a n d ed 1-Aza bicyclo[3.2.2]n on a n es w ith C3 Su bstitu -
en ts. To a solution of O-mesylated cinchonine or cinchonidine
in trifluoroethanol (5 mL/mmol) was added the nucleophile
(2-3 equiv) and the reaction mixture was refluxed at 80-90
°C for 4-8 h. Progress of the reaction was monitored by thin-
layer chromatography (TLC). Saturated aq NaHCO3 was
added and the aqueous layer was extracted with CH2Cl2. The
combined organic layer was dried (Na2SO4) and the solvent
was removed in vacuo. The crude product was purified by
column chromatography (MTBE-MTBE/MeOH 5:1) to furnish
the ring-expanded products and products with intact cage.
Illu str a tive Solvolysis w ith Th iocya n a te a s Nu cleo-
p h ile: (1S,2R,3S,5S,6R)-2-Qu in olin -4-yl-3-th iocya n a to-6-
vin yl-1-a za -bicyclo[3.2.2]n on a n e 6-SCN. O-Mesylated cin-
Ack n ow led gm en t. We thank Buchler GmbH for
Cinchona alkaloids, InnoChemTech Braunschweig and
the Fonds der Chemischen Industrie for support, Amy
Stockwell for experimental assistance, Dr. E. Hofer for
NMR assistance, and Ulrike Eggert and Lars Ole
Haustedt for their help.
Su p p or tin g In for m a tion Ava ila ble: General procedures
and spectroscopic data for 23 azabicycles with expanded and
intact cage; crystallographic data for 3-Br, 5a -Cl, 6-OH, and
E-cinchene as CIF files. This material is available free of
J O030363S
J . Org. Chem, Vol. 69, No. 9, 2004 2991