1-(bromomethyl)-2-(difluoromethyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure as described in EXAMPLE 8 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-(difluoromethyl)benzene to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 3′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one was obtained (52%) as a colorless solid: mp 191-193° C.; 1H NMR (300 MHz, DMSO-d6) δ7.67 (d, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 7.37 (s, 1H), 7.26-7.20 (m, 3H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.24 (s, 1H), 5.17-5.04 (m, 2H), 4.77 (ABq, 2H), 4.20-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ177.4, 155.3, 144.7, 142.6, 138.3, 134.5 (t, JC-F=3.8 Hz), 132.1, 131.9, 131.8 (t, JC-F=21.3 Hz), 129.3, 128.3, 127.4, 127.0 (t, JC-F=7.7 Hz), 124.3, 123.7, 121.5, 114.9 (t, JC-F=236.0 Hz), 111.8, 109.8, 99.3, 80.1, 64.7, 64.1, 57.8; MS (ES+) m/z 435.7 (M+1).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(difluoromethyl)-2-methylbenzene (2.90 g, 20.4 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.63 g, 20.4 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol). The mixture was heated at reflux for 16 h. Further 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol) was added, the mixture was heated at reflux for 4 h, allowed to cool to ambient temperature, diluted with dichloromethane (175 mL) and washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane to afford 1-(bromomethyl)-2-(difluoromethyl)benzene as a yellow solid: 1H NMR (300 MHz, CDCl3) δ7.58-7.56 (m, 1H), 7.43-7.37 (m, 3H), 6.95 (t, 55.2 Hz, 1H), 4.59 (s, 2H). The mixture was heated at reflux for 16 h the mixture was heated at reflux for 4 h washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL) The organic phase was dried over sodium sulfate filtered concentrated in vacuo The resultant residue was purified by column chromatography eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(difluoromethyl)-2-methylbenzene (2.90 g, 20.4 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.63 g, 20.4 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol). The mixture was heated at reflux for 16 h. Further 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol) was added, the mixture was heated at reflux for 4 h, allowed to cool to ambient temperature, diluted with dichloromethane (175 mL) and washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane to afford 1-(bromomethyl)-2-(difluoromethyl)benzene as a yellow solid: 1H NMR (300 MHz, CDCl3) δ7.58-7.56 (m, 1H), 7.43-7.37 (m, 3H), 6.95 (t, 55.2 Hz, 1H), 4.59 (s, 2H). The mixture was heated at reflux for 16 h the mixture was heated at reflux for 4 h washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL) The organic phase was dried over sodium sulfate filtered concentrated in vacuo The resultant residue was purified by column chromatography eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(difluoromethyl)-2-methylbenzene (2.90 g, 20.4 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.63 g, 20.4 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol). The mixture was heated at reflux for 16 h. Further 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol) was added, the mixture was heated at reflux for 4 h, allowed to cool to ambient temperature, diluted with dichloromethane (175 mL) and washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane to afford 1-(bromomethyl)-2-(difluoromethyl)benzene as a yellow solid: 1H NMR (300 MHz, CDCl3) δ7.58-7.56 (m, 1H), 7.43-7.37 (m, 3H), 6.95 (t, 55.2 Hz, 1H), 4.59 (s, 2H). The mixture was heated at reflux for 16 h the mixture was heated at reflux for 4 h washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL) The organic phase was dried over sodium sulfate filtered concentrated in vacuo The resultant residue was purified by column chromatography eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure as described in EXAMPLE 8 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-(difluoromethyl)benzene to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 3′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one was obtained (52%) as a colorless solid: mp 191-193° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 7.37 (s, 1H), 7.26-7.20 (m, 3H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.24 (s, 1H), 5.17-5.04 (m, 2H), 4.77 (ABq, 2H), 4.20-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.3, 144.7, 142.6, 138.3, 134.5 (t, JC-F=3.8 Hz), 132.1, 131.9, 131.8 (t, JC-F=21.3 Hz), 129.3, 128.3, 127.4, 127.0 (t, JC-F=7.7 Hz), 124.3, 123.7, 121.5, 114.9 (t, JC-F=236.0 Hz), 111.8, 109.8, 99.3, 80.1, 64.7, 64.1, 57.8; MS (ES+) m/z 435.7 (M+1).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(difluoromethyl)-2-methylbenzene (2.90 g, 20.4 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.63 g, 20.4 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol). The mixture was heated at reflux for 16 h. Further 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol) was added, the mixture was heated at reflux for 4 h, allowed to cool to ambient temperature, diluted with dichloromethane (175 mL) and washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane to afford 1-(bromomethyl)-2-(difluoromethyl)benzene as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.58-7.56 (m, 1H), 7.43-7.37 (m, 3H), 6.95 (t, JH-F=55.2 Hz, 1H), 4.59 (s, 2H). The mixture was heated at reflux for 16 h the mixture was heated at reflux for 4 h washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL) The organic phase was dried over sodium sulfate filtered concentrated in vacuo The resultant residue was purified by column chromatography eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane