The general procedure for the synthesis of 4,5-difluoro-1-indanone from 2,3-difluorophenylpropionic acid is as follows:
1. Hydrogenation reaction: 2,3-difluorocinnamic acid (2.8 g, 15.2 mmol) was dissolved in ethanol (100 mL) and hydrogenated for 16 h at room temperature using H2 (balloon) and 10% Pd/C (0.3 g) as catalyst. Upon completion of the reaction, it was filtered through diatomaceous earth (Celite) and the solvent was evaporated to give 3-(2,3-difluorophenyl)propionic acid as a solid in 98% yield.
2. Acylation reaction: 3-(2,3-difluorophenyl)propionic acid (2.7 g, 14.4 mmol) was dissolved in CH2Cl2, oxalyl chloride (8.7 mL, 2M in CH2Cl2) and a few drops of DMF were added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. A dark colored residue was precipitated. A dark colored residue was decanted and the solvent was removed in vacuum. The residue was dissolved in CH2Cl2 (20 mL) and added to a mixture of AlCl3 (1.92 g, 14.4 mmol) in CH2Cl2 (25 mL). The mixture was heated at 50 °C for 16 hours. After completion of the reaction, it was poured into ice water, the aqueous phase was separated and extracted with CH2Cl2. The organic layers were combined, washed sequentially with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 20% EtOAc:hexane to afford 4,5-difluoro-1-indanone (intermediate TWENTY-2) in 68% yield.
3. Reformatsky reaction: 4,5-difluoro-1-indanone (intermediate TWENTY-2) (1.36 g, 8.10 mmol) was dissolved in benzene (20 mL) and ether (20 mL), and a small amount of iodine crystals, ethyl bromoacetate (1.4 mL, 12.3 mmol) and zinc powder (1.60 g, 24.4 mmol) were added. The mixture was heated at room temperature to 70 °C for 16 hours of reaction. After cooling, it was filtered through diatomaceous earth (Celite) and the filtrate was evaporated. The residue ((4,5-difluoro-1-hydroxy-indan-1-yl)ethyl acetate) was dissolved in benzene, a catalytic amount of p-toluenesulfonic acid (pTsOH) was added, and the mixture was heated to reflux for 16 hr in a Dean-Stark manifold. After cooling, the aqueous layer was diluted with aqueous acid and ethyl acetate and extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, evaporated, and purified by silica gel chromatography with 10 to 15% ether:hexanes to afford a mixture of E- and Z-(4,5-difluoro-1-indenylidene)ethyl acetate (intermediate TWENTY-3) as a solid.
4. Hydrogenation reaction: E- and Z-(4,5-difluoro-1-indenylidene)ethyl acetate (Intermediate TWENTY-3) (1.1 g) were dissolved in EtOAc (25 mL) and hydrogenated using 10% Pd/C (0.16 g) and H2 (balloon) for 16 h at room temperature. Filtration and evaporation of the filtrate gave ethyl (4,5-difluoro-1-indenyl)acetate.
5. Reduction reaction: Ethyl (4,5-difluoro-1-indenyl)acetate (1.1 g, 4.58 mmol) was dissolved in THF (60 mL) and MeOH (1 mL), LiBH4 (0.21 g, 8.5 mmol) was added, and the reaction was carried out for 5 h at 65 °C. The reaction was carried out at 65 °C for 2 h. After cooling, THF was removed in vacuo, and the reaction was carried out in vacuo. After cooling, THF was removed in vacuum and the layers were separated by dilution with EtOAc and saturated NaHCO3. The organic layer was dried with MgSO4, filtered, and evaporated to give 2-(4,5-difluoro-1-indenyl)ethanol (Intermediate TWENTY-4) as a clear colorless oil in 88% yield.
6. Final step: 4-(4,5-Difluoro-1-indenylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 156) was synthesized using 2-(4,5-difluoro-1-indenyl)ethanol (Intermediate TWENTY-4) according to method SEVENTEEN.
