Phenol → (2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine

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A mixture of [(2S)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.26 g, 9.20 mmol), phenol (0.87 g, 9.2 mmol), triphenylphosphine (2.42 g, 9.20 mmol) and THF (80 mL) is cooled in a 0° C. bath under N2. Diethylazodicarboxylate (1.50 ml, 9.5 mmol) is added, and the mixture is allowed to warm to rt overnight. The mixture is adsorbed onto SiO2 and chromatographed (Biotage 40S+SIM, (1:19) EtOAc:hexane). The product fractions are pooled and concentrated to afford 1.45 g (49%) of (2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine as a clear oil. A mixture of this oil (14, 0.472 g, 1.47 mmol), (R)-3-aminoquinuclidine (0.557 g, 4.41 mmol), palladium acetate (0.083 g, 0.37 mmol), 1,3-bis(diphenylphosphino)propane (0.153 g, 0.370 mmol), and toluene (20 ml) are stirred under CO (g) in a 97° C. oil bath. The mixture is allowed to cool to rt and after 1.5 h is concentrated. The residue is partitioned between NaOH (aq) and EtOAc. The organic layer is separated, washed with brine, dried (MgSO4), filtered, and concentrated. The residue is chromatographed (Biotage 40 S, (1:10:190) NH4OH—MeOH—CHCl3). The product fractions are pooled and concentrated affording the product as a foam. The foam is taken up in EtOH, treated with fumaric acid (1.0 eq) and water (1 drop), and partially concentrated. Et2O is added and the resulting solid filtered and dried to provide 0.310 g (53%) of Example 11 as a monohydrate solid: 1H NMR (400 MHz, CD3OD) δ 7.49, 7.43, 7.25-7.35, 6.90-7.05, 6.70, 4.55-4.65, 4.45-4.55, 4.35-4.45, 4.20-4.35, 3.75-3.85, 3.20-3.50, 2.30-2.40, 2.15-2.30, 2.00-2.15, 1.85-2.00.

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