3376
R.R.R. Taylor et al. / Tetrahedron 66 (2010) 3370–3377
room temperature, diluted with dichloromethane and washed with
saturated sodium bicarbonate, water and brine. Purification by col-
umn chromatography eluting with 10% ethyl acetate in hexanes
afforded 5.41 g (17.0 mmol, 63%) of 14 as a colourless oil. IR (thin
film): 3139, 3033, 2977, 2891, 1707, 1451,1416,1376,1348,1279, 1224,
1176, 1117, 996, 867, 759, 728, 696 cmꢁ1. 1H NMR (400 MHz, CDCl3):
0.002 mmol), BINAP (0.0020 g, 0.004 mmol) and 1.0 mL DMF was
placed in a recovery flask fitted with a reflux condenser and purged
with argon. The reaction mixture was heated to 115 ꢂC for 16 h
under a nitrogen atmosphere. The reaction mixture was cooled to
room temperature, and DMF removed at reduced pressure. The
residue was taken up in dichloromethane, and filtered over Celite.
Evaporation of the solvent and purification by column chroma-
tography eluting with 20% ethyl acetate in hexanes afforded 0.035 g
(0.073 mmol, 57%) of 20 as a white solid: mp¼205–210 ꢂC from
ethyl acetate/methanol. IR (chloroform): 3084, 2978, 1721, 1619,
1508, 1366, 1238, 1163, 1062, 895, 827, 800, 775, 732 cmꢁ1. 1H NMR
d
7.38–7.31 (5H, m), 6.41–6.13 (2H, br m), 5.19 (2H, s), 3.72–3.68 (4H,
br m), 1.49 (9H, s). 13C NMR (100 MHz, CDCl3):
d
152.5, 151.6, 136.2,
128.7, 128.4, 128.2, 109.8, 109.0, 107.8, 107.0, 81.4, 67.9, 41.8, 41.3, 41.0,
40.5, 40.3, 28.5. MS (ESI) m/z 341 (84 (MþNa)þ), 319 (55 (MþH)þ),
285 (16), 263 (81), 219 (56), 175 (23), 128 (5), 91 (100) HRMS (ESI)
calculated for [M]þ C17H23N2O4 319.1652; observed 319.1650.
(400 MHz, CDCl3):
d
8.49 (1H, s), 7.99 (1H, d, J¼14.5 Hz), 7.39 (1H, br
m), 4.38 (2H, q, J¼7.0 Hz), 3.77–3.05 (7H, br m), 1.50 (9H, s), 1.41
(3H, t, J¼7.0 Hz),1.29–1.28 (2H, m),1.16–1.19 (3H, m), 0.66–0.54 (1H,
4.12. ( )-2-Benzyl 5-tert-butyl 2,5-diazabicyclo[4.1.0]heptane-
2,5-dicarboxylate 15
br m). 13C NMR (100 MHz, CDCl3):
d 173.1, 166.0, 156.2, 152.7, 152.5,
150.3, 150.0, 148.1, 141.9, 141.6, 138.2, 121.2, 113.9, 113.6, 110.3, 102.4,
80.5, 80.2, 60.8, 45.9, 43.3, 41.6, 34.4, 33.4, 33.2, 29.5, 28.5,14.5,14.0,
8.2, 8.0. MS (EI) m/z 471 (3, Mþ), 414 (100), 398 (3), 370 (9), 343
(24), 324 (12), 303 (8), 257 (6), 243 (2), 229 (2), 202 (2); HRMS (EI)
calculated for [M]þ C25H30FN3O5 471.2169; observed 471.2168.
A solution of 14 (2.52 g, 7.95 mmol) in 60 mL of dry ether was
added slowly via cannula to a solution of diethylzinc (32.6 mmol,
1.0 M in hexanes) in 50 mL ether under nitrogen. The reaction
mixture was stirred at room temperature for 10 min, and diiodo-
methane (7.65 g, 28.6 mmol) was added. The reaction mixture was
stirred at room temperature for 18 h, and then cooled to 0 ꢂC.
Saturated ammonium chloride was added, and the resulting mix-
ture was filtered over Celite. The Celite pad was washed with water
and ether. After extraction with ether, the combined organic ex-
tracts were washed with water and brine, and then dried over
magnesium sulfate. Evaporation of the solvent and purification by
column chromatography eluting with 20% ethyl acetate in hexanes
afforded 2.02 g (6.07 mmol, 76%) of 15 as a colourless oil. IR (thin
film): 3588, 3518, 3387, 2978, 2932, 2878, 1702, 1454, 1399, 1354,
1295, 1237, 1178, 1119, 1057, 1003, 964, 866, 772, 702 cmꢁ1. 1H NMR
4.15. ( )-7-(2,5-Diazabicyclo[4.1.0]heptan-2-yl)-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid hydrochloride salt 17
A mixture of 20 (0.018 g, 0.038 mmol) in 1 mL of 2 M HCl was
heated to reflux for 2 h under a nitrogen atmosphere. The reaction
mixture was cooled to room temperature a small amount of ethanol
was added. The mixture was allowed to crystallize at ꢁ12 ꢂC. The
solid was filtered and washed with dichloromethane and ice cold
ethanol to afford 0.011 g (0.030 mmol, 80%) of 17 as a white solid:
mp¼241–242 ꢂC (decomp.). IR (KBr disc): 3413, 3038, 2916, 2759,
2653, 1714, 1628, 1507, 1378, 1307, 1274, 1113, 1034, 958, 893, 827,
(400 MHz, CDCl3):
2.99 (6H, br m), 1.48 (9H, s), 1.18–0.96 (1H, br m), 0.54 (1H, br s). 13C
NMR (100 MHz, CDCl3): 156.9, 156.2, 136.9, 136.6, 128.7, 128.2,
d 7.37–7.31 (5H, m), 5.20–5.12 (2H, br m), 3.53–
802, 766, 741 cmꢁ1 1H NMR (400 MHz, D2O):
. d 8.41 (1H, s), 7.41
d
127.8, 80.6, 80.3, 67.4, 42.3, 41.9, 40.9, 40.7, 28.9, 28.6, 28.3, 14.0. MS
(ESI) m/z 355 (100 (MþNa)þ), 333 (5), 315 (4), 299 (22), 277 (12),
255 (10), 233 (15); HRMS (ESI) calculated for [M]þ C18H24N2O4Na
355.1628; observed 355.1629.
(1H, br d, J¼6.5 Hz), 7.26 (1H, d, J¼14.5 Hz), 4.00 (1H, m), 3.98–3.14
(6H, br m),1.59 (1H, m),1.41–1.18 (5H, m). 13C NMR (100 MHz, D2O):
d
177.8, 171.8, 155.3, 152.8, 150.6, 145.7, 141.8, 118.4, 113.7, 113.5,
108.0, 105.9, 44.5, 43.3, 38.8, 33.1, 32.1, 12.3, 10.4, 10.2. MS (ESI) m/z
366 (5 (MþNa)þ), 344 (100 (MꢁClꢁ)þ), 326 (15), 306 (5), 285 (6),
215 (3),197 (3),179 (4), 158 (5), 149 (25), 141 (5), 113 (19),105 (8), 95
(7); HRMS (ESI) calculated for [MꢁClꢁ]þ C18H19FN3O3 344.1404;
observed 344.1417.
4.13. ( )-5-(Benzyloxycarbonyl)-2,5-
diazabicyclo[4.1.0]heptane hydrochloride 16
Anhydrous hydrochloric acid (29.1 mmol, 4.0 M in dioxane) was
added to a solution of 15 (1.61 g, 4.86 mmol) in 20 mL of ether. The
reaction mixture was stirred at room temperature for 18 h, and the
resulting white precipitate was collected by filtration and rinsed
with ether. The combined ether rinses were concentrated to dry-
ness, and the residue triturated with ethyl acetate. The combined
solids were recrystallized from ethyl acetate/methanol to afford
1.19 g (4.42 mmol, 94%) of 16 as a white solid: mp¼165–167 ꢂC
(decomp.). IR (KBr disc): 3384, 2857, 2672, 2420, 2258, 2028, 1975,
1706, 1582, 1413, 1359, 1331, 1200, 1152, 1074, 1029, 951, 827, 766,
Acknowledgements
The Natural Science and Engineering Research Council (NSERC)
of Canada and a CIHR operating grant MOP-15499 funded this
research. R.R.R.T. acknowledges receipt of an NSERC PGS M schol-
arship. R.J.M. acknowledges receipt of an OHTN fellowship. We
thank Dr. Alex Young for obtaining high-resolution mass spectra.
We also acknowledge Arlette Darfeuille-Michaud of Clermont-
Ferrand, France and Dylan Pillai of the Ontario Agency for Health
Protection and Promotion for providing bacterial strains.
741, 697, 677, 607 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d 10.24 (2H,
br s), 7.36–7.29 (5H, m), 5.15–5.10 (2H, m), 3.73–3.55 (1H, m), 3.22–
2.97 (5H, m), 1.21–1.07 (2H, m). 13C NMR (100 MHz, DMSO-d6):
Supplementary data
d
155.6, 155.1, 136.7, 136.4, 128.4, 128.2, 127.8, 127.6, 127.3, 66.5, 37.6,
37.1, 27.0, 26.9, 26.1, 25.7, 9.0, 8.6. MS (ESI) m/z 233 (15 (M)þ), 189
(26), 142 (19), 91 (100); HRMS (ESI) calculated for [M]þ C13H17N2O2
233.1284; observed 233.1296.
Additional experimental data, synthetic procedures, NMR
titration procedures, copies of 1H and 13C NMR spectra for all new
compounds, crystallographic information file (CIF) for compound
17. Supplementary data associated with this article can be found in
4.14. ( )-Ethyl 7-(5-(tert-butoxycarbonyl)-2,5-diazabicyclo-
[4.1.0]heptan-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylate 20
References and notes
A
mixture of 19 (0.040 g, 0.130 mmol), Cs2CO3 (0.084 g,
1. Pitt, W. R.; Parry, D. M.; Perry, D. G.; Groom, C. R. J. Med. Chem. 2009, 52,
0.260 mmol), (0.031 g, 0.160 mmol), Pd2(dba)3 (0.0020 g,
5
2952–2963.