2,2,6,6-tetramethyloxan-4-one

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

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

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

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: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 2,2,6,6-tetramethyl tetrahydropyran-4-one (WO 2005012220). 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.4 Hz), 7.98 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.34 (d, 1H, J=2.0 Hz), 5.74 (br s, 1H), 2.32 (m, 2H), 2.08 (m, 2H), 1.87 (m, 4H), 1.56-1.58 (m, 8H), 1.56 (s, 6H), 1.21 (s, 6H).

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

Procedure: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 2,2,6,6-tetramethyl tetrahydropyran-4-one (WO 2005012220). 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.4 Hz), 7.98 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.34 (d, 1H, J=2.0 Hz), 5.74 (br s, 1H), 2.32 (m, 2H), 2.08 (m, 2H), 1.87 (m, 4H), 1.56-1.58 (m, 8H), 1.56 (s, 6H), 1.21 (s, 6H).

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

Procedure: The general McMurry procedure, described for 14 was employed using (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (2.10 g, 7.58 mmol), and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (1.40 g, 8.96 g). Standard work-up followed by purification gave 2.64 g (87%) of the title compound 211 as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.37 (s, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 2.16 (s, 2H), 2.10 (s, 2H), 1.13 (s, 6H), 1.12 (s, 6H). LCMS (ESI): m/z 399 and 401 (M−H)−. Standard work-up followed by purification

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

Procedure: To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20 mL) was slowly added TiCl4 (0.45 mL, 4.07 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02 mmol) and 2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-one (0.49 g, 3.05 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.40 g (94%) of compound 136 as a yellow foam. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 6H), 1.22 (s, 6H), 2.18 (s, 2H), 2.23 (s, 2H), 5.04 (d, J=4.0 Hz, 1H), 6.80-6.88 (m, 2H), 6.93 (t, J=8.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H). LCMS (ES): m/z 417 (M−H)−. at room temperature The mixture was heated at reflux for 2 h The reaction mixture was heated at reflux The reaction mixture was filtered through a pad of Celite the pad was washed with EtOAc (100 mL) The filtrate was transferred to a separatory funnel the layers were separated The aqueous layer was further extracted with EtOAc (25 mL) The combined organic phase was washed with brine dried over Na2SO4 filtered the filtrate was concentrated to give the crude product as yellow oil The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc

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

Procedure: To a stirred suspension of zinc powder (0.59 g, 8.99 mmol) in THF (20 mL) was slowly added TiCl4 (0.50 mL, 4.50 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105) (0.35 g, 1.12 mmol) and 2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-one (0.54 g, 3.37 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow viscous oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.47 g (96%) of compound 130 as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 6H), 1.22 (s, 6H), 2.18 (s, 2H), 2.22 (s, 2H), 5.47 (s, 1H), 6.90-7.00 (m, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.09 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H). LCMS (ESI), m/z 433 (M−H)−. at room temperature The mixture was heated at reflux for 2 h The reaction mixture was heated at reflux The reaction mixture was filtered through a pad of Celite the pad was washed with EtOAc (100 mL) The filtrate was transferred to a separatory funnel the layers were separated The aqueous layer was further extracted with EtOAc (25 mL) The combined organic phase was washed with brine dried over Na2SO4 filtered the filtrate was concentrated to give the crude product as yellow viscous oil The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc

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

Procedure: The general McMurry protocol, described for 14 was followed. Thus, methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24 (0.196 g, 0.765 mmol) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.370 g, 2.37 mmol) were subjected for McMurry coupling reaction conditions. Standard work-up followed by purification by column chromatography gave 0.272 g (93%) of the title compound 101 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 3.92 (s, 3H), 2.27 (s, 2H), 2.21 (s, 2H), 1.28 (s, 6H), 1.25 (s, 6H). LCMS (ESI): m/z 379 (M−H)−. Standard work-up followed by purification by column chromatography

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

Procedure: Following the procedure described for compound 46, zinc powder (0.957 g, 14.6 mmole), TiCl4 (0.800 mL, 7.30 mmole), (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.512 g, 1.85 mmole) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.851 mL, 5.45 mmole), afforded 0.564 g (76%) of 53 as a white foamy solid. 1H NMR (CDCl3): δ 7.41 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.3 Hz, 2H), 4.99 (s, 1H), 2.24 (s, 2H), 2.20 (s, 2H), 1.22 (s, 6H), 1.21 (s, 6H).