4,4,6-trimethylcyclohex-2-en-1-one

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

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4,4-dimethyl-cyclohex-2-en-1-one (5.00 g, 40.3 mmol, 1 equiv) in tetrahydrofuran (130 mL) was added to a solution of LHMDS (1 M in tetrahydrofuran, 58.4 mL, 58.4 mmol, 1.45 equiv) in tetrahydrofuran (60 mL) at −78° C. After stirring for 1 h, iodomethane (5.02 mL, 80.6 mmol, 2.0 equiv) was added dropwise to the flask. The cooling bath was immediately removed and the reaction mixture was allowed to warm to room temperature (23° C.). After stirring 11 h, saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask. The layers were separated and the aqueous layer was extracted with three 50-mL portions of ether. The combined organic layers were washed once with brine (10 mL) and dried over sodium sulfate (15 min). Following filtration, volatiles were removed in vacuo, leaving a brown residue which was distilled at 22 torr furnishing 4,4,6-trimethyl-cyclohex-2-en-1-one (10, 3.93 g, 72%) as a clear oil, bp 82-86° C. (Torri, J.; Azzaro, M. Bull. Soc. Chem. Fr. 1978, 283; incorporated herein by reference). The cooling bath was immediately removed After stirring 11 h saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask The layers were separated the aqueous layer was extracted with three 50-mL portions of ether The combined organic layers were washed once with brine (10 mL) dried over sodium sulfate (15 min) filtration, volatiles were removed in vacuo leaving a brown residue which was distilled at 22 torr

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4,4-dimethyl-cyclohex-2-en-1-one (5.00 g, 40.3 mmol, 1 equiv) in tetrahydrofuran (130 mL) was added to a solution of LHMDS (1 M in tetrahydrofuran, 58.4 mL, 58.4 mmol, 1.45 equiv) in tetrahydrofuran (60 mL) at −78° C. After stirring for 1 h, iodomethane (5.02 mL, 80.6 mmol, 2.0 equiv) was added dropwise to the flask. The cooling bath was immediately removed and the reaction mixture was allowed to warm to room temperature (23° C.). After stirring 11 h, saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask. The layers were separated and the aqueous layer was extracted with three 50-mL portions of ether. The combined organic layers were washed once with brine (10 mL) and dried over sodium sulfate (15 min). Following filtration, volatiles were removed in vacuo, leaving a brown residue which was distilled at 22 torr furnishing 4,4,6-trimethyl-cyclohex-2-en-1-one (10, 3.93 g, 72%) as a clear oil, bp 82-86° C. (Torri, J.; Azzaro, M. Bull. Soc. Chem. Fr. 1978, 283; incorporated herein by reference). The cooling bath was immediately removed After stirring 11 h saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask The layers were separated the aqueous layer was extracted with three 50-mL portions of ether The combined organic layers were washed once with brine (10 mL) dried over sodium sulfate (15 min) filtration, volatiles were removed in vacuo leaving a brown residue which was distilled at 22 torr

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

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

Procedure: To a slurry of magnesium turnings (66 g, 2.73 g atoms) in diethyl ether (300 ml) was added a solution of 4-chlorobenzyl chloride (418 g, 2.6 moles) in diethyl ether (1500 ml) at such a rate as to maintain gentle reflux. After a further 30 minutes, a solution of 4,4,6-trimethylcyclohex-2-en-1-one (340 g, 2.46 moles) in diethyl ether (350 ml) was added, again maintaining a gentle reflux. After 1 hour the mixture was added into saturated aqueous ammonium chloride (4 liters) and the phases separated. The ether phase was back-washed with water (1 liter) and used directly in the next reaction. A small portion of 1-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-2-en-1-ol was isolated for characterisation (gas chromatography analysis showed two isomers in approximately equal amounts). to maintain gentle reflux again maintaining a gentle reflux the phases separated The ether phase was back-washed with water (1 liter) used directly in the next reaction

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

Procedure: To a slurry of magnesium turnings (66 g, 2.73 g.atoms) in diethyl ether (300 ml) was added a solution of 4-chlorobenzyl chloride (418 g, 2.6 moles) in diethyl ether (1500 ml) at such a rate as to maintain gentle reflux. After a further 30 minutes, a solution of 4,4,6-trimethylcyclohex-2- en-1-one (340 g, 2.46 moles) in diethyl ether (350 ml) was added, again maintaining a gentle reflux. After 1 hour the mixture was added into saturated aqueous ammonium chloride (4 liters) and the phases separated. The ether phase was back-washed with water (1 liter) and used directly in the next reaction. A small portion of 1-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-2- en-1-ol was isolated for characterisation (gas chromatography analysis showed two isomers in approximately equal amounts). to maintain gentle reflux again maintaining a gentle reflux the phases separated The ether phase was back-washed with water (1 liter) used directly in the next reaction

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

Procedure: The procedure of example III was employed on 12 moles of isobutyraldehyde, 11 moles of methyl isopropenyl ketone and 800 ml of 0.8 M aqueous sodium hydroxide solution. After the reaction was completed the aqueous layer was removed. To the residual organic phase was added an equal volume of benzene and a catalytic amount (ca. 5 g) of p-toluenesulfonic acid. The reaction mixture was heated at reflux with concomitant removal of water via a Dean Stark trap. The usual workup and distillation afforded 897 g (59%) of the desired 4,4,6-trimethyl-2-cyclohexenone (II) with physical constants and spectral data identical with that isolated in Example III. Continued distillation afforded no material containing the 5-hydroxy-2,4,4-trimethylcyclohexanone isolated in Example III where the acid treatment step was omitted. was removed To the residual organic phase was added an equal volume of benzene The reaction mixture was heated at reflux with concomitant removal of water via a Dean Stark trap The usual workup and distillation

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

Procedure: To a mixture of isobutyraldehyde (382 g, 5.3 mole) in 400 ml of 0.8 M aqueous sodium hydroxide was added methyl isopropenyl ketone (420 g, 5.0 mole) over a 1 hr period at 25°. The mixture was then heated to 75° for 1 hr. The mixture was cooled, and the layers were separated. The organic phase was washed neutral with water. Distillation of this organic material afforded 297 g (2.15 mole, 43% yield) of the desired 4,4,6-trimethyl-2-cyclohexenone, bp 68°-69° at 10mm, nD20 1.4685, with an infrared and nmr spectra identical with that reported in the literature (JOC 33, 4060 (1968)). Continued distillation afforded a new material (116 g) with a boiling point of 100° to 120° at 0.5mm. This material slowly crystallized and was filtered and washed with hexane. These crystals proved to be 5-hydroxy-2,4,4-trimethylcyclohexanone and exhibited the following spectral characteristics: mp 105°-106°; ir (KBr) 3360 (OH), 1685 (C=O), 1250, 1195, 1135, 1111, 1029, 983 cm-1 ; nmr (CDCl3) 0.98 (d, J=6.5Hz, 3H), 1.04 (s, 3H), 1.22 (s, 3H), 1.53 (d,d,d, J=13, 8, 1.5 Hz, 1H), 1.90 (d, J=13 Hz, 1H), 2.35 (d,d, J=15, 3 Hz, 1H), 2.62 (d,d, J=15, 3 Hz, 1H), 3.85 (m, 1H); mass spectrum (m/e, (relative intensity) 156 (8), 138 (2), 100 (100), 72 (35), 70 (33) 68 (37), 56 (80), 43 (38), 41 (37). The mixture was then heated to 75° for 1 hr The mixture was cooled the layers were separated The organic phase was washed neutral with water Distillation of this organic material

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

Procedure: To a slurry of magnesium turnings (66 g, 2.73 g.atoms) in diethyl ether (300 ml) was added a solution of 4-chlorobenzyl chloride (418 g, 2.6 moles) in diethyl ether (1500 ml) at such a rate as to maintain gentle reflux. After a further 30 minutes, a solution of 4,4,6-trimethylcyclohex-2-en-1-one (340 g, 2.46 moles) in diethyl ether (350 ml) was added, again maintaining a gentle reflux. After 1 hour the mixture was added into saturated aqueous ammonium chloride (4 liters) and the phases separated. The ether phase was back-washed with water (1 liter) and used directly in the next reaction. A small portion of 1-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-2-en-1-ol was isolated for characterisation (gas chromatography analysis showed two isomers in approximately equal amounts). to maintain gentle reflux again maintaining a gentle reflux the phases separated The ether phase was back-washed with water (1 liter) used directly in the next reaction

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4,4-dimethyl-cyclohex-2-en-1-one (5.00 g, 40.3 mmol, 1 equiv) in tetrahydrofuran (130 mL) was added to a solution of LHMDS (1 M in tetrahydrofuran, 58.4 mL, 58.4 mmol, 1.45 equiv) in tetrahydrofuran (60 mL) at −78° C. After stirring for 1 h, iodomethane (5.02 mL, 80.6 mmol, 2.0 equiv) was added dropwise to the flask. The cooling bath was immediately removed and the reaction mixture was allowed to warm to room temperature (23° C.). After stirring 11 h, saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask. The layers were separated and the aqueous layer was extracted with three 50-mL portions of ether. The combined organic layers were washed once with brine (10 mL) and dried over sodium sulfate (15 min). Following filtration, volatiles were removed in vacuo, leaving a brown residue which was distilled at 22 torr furnishing 4,4,6-trimethyl-cyclohex-2-en-1-one (10, 3.93 g, 72%) as a clear oil, bp 82-86° C. (Torri, J.; Azzaro, M. Bull. Soc. Chem. Fr. 1978, 283; incorporated herein by reference). The cooling bath was immediately removed After stirring 11 h saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask The layers were separated the aqueous layer was extracted with three 50-mL portions of ether The combined organic layers were washed once with brine (10 mL) dried over sodium sulfate (15 min) filtration, volatiles were removed in vacuo leaving a brown residue which was distilled at 22 torr