7852 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Frost (ne´e Pace) et al.
reduced pressure to give a quantitative amount of the intermediate
(1S,6R)-3-(2,2,2-trifluoro-acetyl)-3,8-diaza-bicyclo[4.2.0]octane-8-
carboxylic acid tert-butyl ester, which was used directly below (MS
(DCI/NH3) m/z 326 (M + NH4)+).
NH3) m/z 448 (M + H)+). This material was deprotected and its
fumarate salt formed as described for 25 to give 31 (0.107 g, 0.22
mmol, 43% yield). 1H NMR (300 MHz, CD3OD) δ 2.02 (m, 1H),
2.22 (m, 1H), 3.18 (m, 1H), 3.33 (m, 1H), 3.54 (dd, J ) 14.6, 3.1
Hz, 1H), 3.88 (m, 3H), 4.17 (dd, J ) 11.0, 9.0 Hz, 1H), 4.79 (dt,
J ) 9.1, 2.7 Hz, 1H), 6.68 (s, 2H), 7.60 (d, J ) 3.1 Hz, 1H), 7.98
(d, J ) 3.1 Hz, 1H); MS (DCI/NH3) m/z 348 (M + H)+; Anal.
(C11H13Br2N3‚C4H4O4‚H2O) C, H, N.
To a solution of the (1S,6R)-3-(2,2,2-trifluoro-acetyl)-3,8-diaza-
bicyclo[4.2.0]octane-8-carboxylic acid tert-butyl ester (31.6 mmol)
in 150 mL of CH3OH and 30 mL of H2O was added K2CO3 (5.1
g, 37.2 mmol). This mixture was stirred at ambient temperature
for 16 h and then concentrated under reduced pressure. The crude
material was filtered through a plug of Celite and silica gel with
9:1:0.1 CH2Cl2/CH3OH/NH4OH. The still crude material was
purified via column chromatography (9:1:0.1 CH2Cl2/CH3OH/
NH4OH) to give 6.6 g of the title compound 7 (31 mmol, 98%
yield). 1H NMR (300 MHz, CD3OD) δ 1.45 (s, 9H), 1.81 (m, 1H),
2.15 (m, 1H), 2.65 (m, 1H), 2.91 (ddd, J ) 13.0, 8.6, 4.2 Hz, 1H),
3.09 (dd, J ) 14.2, 3.4 Hz, 1H), 3.28 (m, 1H), 3.39 (dd, J ) 14.2,
2.0 Hz, 1H), 3.49 (dd, J ) 8.1, 3.1 Hz, 1H), 4.01 (t, J ) 7.8 Hz,
1H), 4.33 (m, 1H); MS (DCI/NH3) m/z 213 (M + H)+.
Acknowledgment. The authors would like to thank John
Malysz and Michael Dart for assistance with the preparation of
this manuscript.
Supporting Information Available: Elemental analysis for all
final compounds, experimental information and data for compounds
1
22-26, 28-30, and 32-71, X-ray data for ent-14, and H NMR
spectra for representative compounds. This material is available
Representative Procedures: (1S,6R)-3-(5-Bromo-pyridin-3-
yl)-3,8-diaza-bicyclo[4.2.0]octane Fumarate (27). Buchwald-
Hartwig Coupling: A mixture of tris(dibenzylideneacetone)-
dipalladium (Pd2(dba)3, 65 mg, 0.071 mmol; Strem) and 2,2′-
bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 73 mg, 0.12 mmol;
Strem) in 5 mL of PhCH3 was warmed to 85 °C for 15 min. This
mixture was added via cannula to a solution of 7 (0.50 g, 2.4 mmol)
and 3,5-dibromopyridine (0.73 g, 3.1 mmol) in 30 mL of PhCH3
at ambient temperature. NaOt-Bu (0.34 g, 3.53 mmol) was added,
and the mixture was warmed to 80 °C and allowed to stir for 16 h.
The reaction mixture was then concentrated under reduced pressure
and purified via column chromatography (50% hexanes/EtOAc) to
give (1S,6R)-3-(5-bromo-pyridin-3-yl)-3,8-diaza-bicyclo[4.2.0]-
octane-8-carboxylic acid tert-butyl ester (0.55 g, 1.5 mmol, 63%
yield). Data for intermediate: 1H NMR (300 MHz, CD3OD) δ 1.31
(s, 9H), 1.95 (m, 1H), 2.21 (m, 1H), 2.83 (m, 1H), 3.39 (m, 2H),
3.71 (dt, J ) 12.9, 4.4 Hz, 1H), 3.76 (m, 1H), 3.95 (t, J ) 8.5 Hz,
1H), 4.03 (m, 1H), 4.52 (m, 1H), 7.34 (s, 1H), 7.85 (s, 1H), 8.04
(s, 1H); MS (DCI/NH3) m/z 190 (M + H)+.
Removal of t-Butylcarbamate Group: To the coupled product
(1S,6R)-3-(5-bromo-pyridin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane-8-
carboxylic acid tert-butyl ester (0.26 g, 0.71 mmol) in 6 mL of
CH2Cl2 at 0 °C was added 4 mL of trifluoroacetic acid. The mixture
was allowed to warm to ambient temperature. After stirring for 2
h, the mixture was concentrated under reduced pressure and was
purified via column chromatography (9:1:0.1 CH2Cl2/CH3OH/
NH4OH) to give the free amine, (1S,6R)-3-(5-bromo-pyridin-3-yl)-
3,8-diaza-bicyclo[4.2.0]octane, which was directly converted to the
corresponding salt.
Salt Formation: To the free amine (0.71 mmol) in 5 mL of
10% CH3OH in Et2O was added fumaric acid (82 mg, 0.71 mmol)
in 2 mL of 10% CH3OH in Et2O. The resulting precipitate was
isolated via filtration to give 27 (0.12 g, 0.31 mmol, 44% yield).
1H NMR (300 MHz, CD3OD) δ 2.02 (m, 1H), 2.21 (m, 1H), 3.16
(m, 1H), 3.35 (m, 1H), 3.55 (dd, J ) 14.7, 3.2 Hz, 1H), 3.91 (m,
3H), 4.17 (dd, J ) 11.0, 9.0 Hz, 1H), 4.80 (dt, J ) 9.2, 3.1 Hz,
1H), 6.64 (s, 2H), 7.49 (dd, J ) 2.7 Hz, 1H), 7.99 (d, J ) 1.7 Hz,
1H), 8.15 (d, J ) 2.7 Hz, 1H); MS (DCI/NH3) m/z 268, 270 (M +
H)+; Anal. (C11H14BrN3‚C4H4O4‚0.25H2O) C, H, N.
(1S,6R)-3-(5,6-Dibromo-pyridin-3-yl)-3,8-diaza-bicyclo[4.2.0]-
octane Fumarate (31). The intermediate from the coupling of 7
with dibromopyridine, (1S,6R)-3-(5-bromo-pyridin-3-yl)-3,8-diaza-
bicyclo[4.2.0]octane-8-carboxylic acid tert-butyl ester (0.20 g, 0.54
mmol) in 20 mL of CH3CN at -40 °C was treated with
N-bromosuccinimide (NBS, 96 mg, 0.54 mmol). This mixture was
stirred at -40 °C for 1.5 h, then quenched with 5 mL of H2O, and
allowed to warm to ambient temperature. The layers were separated,
and the aqueous layer was extracted with 3 × 5 mL of CH2Cl2.
The combined organics were dried over anhydrous Na2SO4, filtered,
concentrated under reduced pressure, and purified via column
chromatography (50% hexanes/EtOAc) to give 0.23 g (1S,6R)-3-
(5,6-dibromo-pyridin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane-8-car-
boxylic acid tert-butyl ester (0.51 mmol, 95% yield, MS (DCI/
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