2-chloro-4,4-dimethylcyclohexene-1-carbaldehyde

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux overnight. The reaction mixture was quenched with a 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum to give the title compound. The solution was warmed up to room temperature The mixture was heated to reflux overnight The reaction mixture was quenched with a 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) to dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated at reflux for overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. The solution was warmed up to room temperature The mixture was heated at reflux for overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL) to give a colorless solution. The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux for overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. to give a colorless solution The solution was warmed up to room temperature The mixture was heated to reflux for overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 ml round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. The solution was warmed up to room temperature The mixture was heated to reflux overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 ml round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. The solution was warmed up to room temperature The mixture was heated to reflux overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL) to give a colorless solution. The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux for overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. to give a colorless solution The solution was warmed up to room temperature The mixture was heated to reflux for overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL). The mixture was stirred at 20° C. for 5 min. 21.0 wt % K2CO3 aq. solution (76.0 g) was added. The mixture was stirred at room temperature (rt) for NLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N2 for three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N2. The reaction mixture was evacuated and purged with N2 for three times (an orange colored mixture). The bottle was back filled with N2 and heated to ˜35° C. in an oil bath (bath temp ˜35° C.). The mixture was stirred at 30° C. overnight (15 hours). The reaction mixture was cooled to RT, and pulled IP sample from the upper organic phase for reaction completion, typically starting material <2% (orange colored mixture). Toluene (100 mL) and 5% NaHCO3-2% L-Cysteine aq. solution (100 mL) were added. The mixture was stirred at 20° C. for 60 min. The mixture was filtered through a pad of Celite to remove black solid, rinsing the flask and pad with toluene (10 mL). The upper organic phase was washed with 5% NaHCO3 aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to ˜1/3 volume (˜35 mL). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. 1HNMR (CDCl3): δ 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t, J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H). The mixture was stirred at room temperature (rt) for NLT 5 min. The mixture was evacuated purged with N2 for three times Palladium acetate (66 mg, 0.5 mol %) was added all at once under N2 The reaction mixture was evacuated purged with N2 for three times (an orange colored mixture) The bottle was back filled with N2 heated to ˜35° C. in an oil bath (bath temp ˜35° C.) The mixture was stirred at 30° C. overnight (15 hours) The reaction mixture was cooled to RT for reaction completion, typically starting material <2% (orange colored mixture) The mixture was stirred at 20° C. for 60 min The mixture was filtered through a pad of Celite to remove black solid rinsing the flask and pad with toluene (10 mL) The upper organic phase was washed with 5% NaHCO3 aq. solution-2% L-Cysteine (100 mL) once more The upper organic phase was washed with 25% brine (100 mL)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 ml round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. The solution was warmed up to room temperature The mixture was heated to reflux overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux overnight. The reaction mixture was quenched with a 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum to give the title compound. The solution was warmed up to room temperature The mixture was heated to reflux overnight The reaction mixture was quenched with a 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) to dichloromethane (30 mL). The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated at reflux for overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. The solution was warmed up to room temperature The mixture was heated at reflux for overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL) to give a colorless solution. The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux for overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. to give a colorless solution The solution was warmed up to room temperature The mixture was heated to reflux for overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL) to give a colorless solution. The mixture was cooled to −10° C., and phosphoryl trichloride (4 mL) was added dropwise. The solution was warmed up to room temperature, and 3,3-dimethylcyclohexanone (5.5 mL) was added slowly. The mixture was heated to reflux for overnight. The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water). The aqueous layer was extracted with ether (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, and dried under vacuum. to give a colorless solution The solution was warmed up to room temperature The mixture was heated to reflux for overnight The reaction mixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mL water) The aqueous layer was extracted with ether (3×200 mL) dried over Na2SO4 filtered dried under vacuum