methyl 4,4-dimethyl-3-oxopentanoate

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

Procedure: Methyl-4,4-dimethyl-3-oxovalerate (15.8 g, 0.1 mol) and 2-methoxy-5-nitroaniline (16.8 g, 0.01 mol) were taken up in toluene (150 mL) in a round bottomed flask fitted with a Dean-Stark trap. The mixture was heated to a vigorous reflux while the MeOH side-product was distilled off and removed. After 4 hours, the mixture was cooled and the toluene removed in vacuo. The residue was recrystallized from acetonitrile to yield 27 g of the desired condensation product. fitted with a Dean-Stark trap The mixture was heated to was distilled off removed the mixture was cooled the toluene removed in vacuo The residue was recrystallized from acetonitrile to yield 27 g of the desired condensation product

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

Procedure: Methyl 4,4-dimethyl-3-oxopentanoate (15.82 g) and guanidine carbonate (20.0 g) were mixed in 80 mL of ethanol, and the solution refluxed for 16 hours. The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added. The remaining mixture was acidified to pH 5 with acetic acid, affording a white precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6 g), m.p. 285°-288° C. (dec.). the solution refluxed for 16 hours The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added affording a white precipitate The precipitate was collected by filtration washed with water dried in a vacuum oven

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

Procedure: 8-Hydroxyjulolidine (1.0 g, 5.29 mmol) and methyl 4,4-dimethyl-3-oxopentanoate (1.0 g, 6.32 mmol) were heated together under nitrogen at 200° C. for 4 hours, after which time more methyl 4,4-dimethyl-3-oxopentanoate (0.5 g, 3.16 mmol) was added and heating was continued for 2 hours. After cooling to room temperature, the reaction mixture was dissolved in dichloromethane and applied to a short column of silica gel (approx. 200 g). Elution with dichloromethane removed non-polar by-products, while subsequent elution with ether afforded 11-[1,1-dimethylethyl]-9-oxo-2,3,6,7-tetrahydro-1H,5H-[1]benzopyrano[6,7,8-ij]quinolizine (1.12 g, 71% yield) as a brown oil which solidified on standing. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy. heating Elution with dichloromethane removed non-polar by-products while subsequent elution with ether

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

Procedure: 8-Hydroxyjulolidine (1.0 g, 5.29 mmol) and methyl 4,4-dimethyl-3-oxopentanoate (1.0 g, 6.32 mmol) were heated together under nitrogen at 200° C. for 4 hours, after which time more methyl 4,4-dimethyl-3-oxopentanoate (0.5 g, 3.16 mmol) was added and heating was continued for 2 hours. After cooling to room temperature, the reaction mixture was dissolved in dichloromethane and applied to a short column of silica gel (approx. 200 g). Elution with dichloromethane removed non-polar by-products, while subsequent elution with ether afforded 11-[1,1-dimethylethyl]-9-oxo-2,3,6,7-tetrahydro-1H,5H-[1]benzopyrano[6,7,8-ij]quinolizine (1.12 g, 71% yield) as a brown oil which solidified on standing. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy. heating Elution with dichloromethane removed non-polar by-products while subsequent elution with ether

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

Procedure: A mixture of 2-trifluoromethylbenzamidine (1.12 g, 5 mmol), sodium ethoxide (1.02 g, 15 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid methyl ester (0.80 mL, 5 mmol) in ethanol (50 mL) and was heated at reflux for 16 hours. The reaction was cooled, concentrated, diluted with water and acidified with 2 N hydrochloric acid. This solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.48 g, 32% yield) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) δ 12.8 (br s, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.78 (m, 2H), 7.71 (d, J=7.4 Hz, 1H), 6.24 (s, 1H), 1.20 (s, 9H) ppm; LC-MS 297.03 (M+H); Rt (Method A) 3.30 minutes. was heated at reflux for 16 hours The reaction was cooled concentrated diluted with water This solution was extracted with ethyl acetate dried over sodium sulfate concentrated Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)]

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

Procedure: A mixture of 2-trifluoromethylbenzamidine (1.12 g, 5 mmol), sodium ethoxide (1.02 g, 15 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid methyl ester (0.80 mL, 5 mmol) in ethanol (50 mL) and was heated at reflux for 16 hours. The reaction was cooled, concentrated, diluted with water and acidified with 2 N hydrochloric acid. This solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.48 g, 32% yield) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) δ 12.8 (br s, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.78 (m, 2H), 7.71 (d, J=7.4 Hz, 1H), 6.24 (s, 1H), 1.20 (s, 9H) ppm; LC-MS 297.03 (M+H); Rt (Method A) 3.30 minutes. was heated at reflux for 16 hours The reaction was cooled concentrated diluted with water This solution was extracted with ethyl acetate dried over sodium sulfate concentrated Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)]

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

Procedure: In a 250 ml flask, place 16 g (0.088 m) of 3-nitrobenzamidoxime (9a), 21.3 g (0.135 m) of methyl 4,4-dimethyl-3-oxovalerate (10a; R1=t-butyl), and 120 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 23 hrs. Distill off toluene under a reduced pressure at 50-60° C. to thick oil. Add 60 ml of heptane to the oil with stirring, cool and stir at 0-5° C. for 30 min. Collect solid, wash with heptane, and dry in air to give 22.9 g (90%) of 5-(3,3-dimethyl-2-oxobutyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula I: R1=t-butyl and R2=3-nitrophenyl]. Heat under reflux with a Dean-Stark trap for 23 hrs Distill off toluene under a reduced pressure at 50-60° C. to thick oil Add 60 ml of heptane to the oil with stirring cool stir at 0-5° C. for 30 min Collect solid wash with heptane dry in air

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

Procedure: In a 250 ml flask, place 16 g (0.088 m) of 3-nitrobenzamidoxime (9a), 21.3 g (0.135 m) of methyl 4,4-dimethyl-3-oxovalerate (10a; R1=t-butyl), and 120 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 23 hrs. Distill off toluene under a reduced pressure at 50-60° C. to thick oil. Add 60 ml of heptane to the oil with stirring, cool and stir at 0-5° C. for 30 min. Collect solid, wash with heptane, and dry in air to give 22.9 g (90%) of 5-(3,3-dimethyl-2-oxobutyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula II: R1=t-butyl and R2=3-nitrophenyl]. Heat under reflux with a Dean-Stark trap for 23 hrs Distill off toluene under a reduced pressure at 50-60° C. to thick oil Add 60 ml of heptane to the oil with stirring cool stir at 0-5° C. for 30 min Collect solid wash with heptane dry in air

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

Procedure: Methyl 4,4-dimethyl-3-oxopentanoate (15.82 g) and guanidine carbonate (20.0 g) were mixed in 80 mL of ethanol, and the solution refluxed for 16 hours. The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added. The remaining mixture was acidified to pH 5 with acetic acid, affording a white precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6 g), m.p. 285-288° C. (dec.). the solution refluxed for 16 hours The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added affording a white precipitate The precipitate was collected by filtration washed with water dried in a vacuum oven

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

Procedure: Methyl 4,4-dimethyl-3-oxopentanoate (15.82 g) and guanidine carbonate (20.0 g) were mixed in 80 mL of ethanol, and the solution refluxed for 16 hours. The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added. The remaining mixture was acidified to pH 5 with acetic acid, affording a white precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6 g), m.p. 285-288° C. (dec.). the solution refluxed for 16 hours The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added affording a white precipitate The precipitate was collected by filtration washed with water dried in a vacuum oven

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

Procedure: Methyl 4,4-dimethyl-3-oxopentanoate (15.82 g) and guanidine carbonate (20.0 g) were mixed in 80 mL of ethanol, and the solution refluxed for 16 hours. The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added. The remaining mixture was acidified to pH 5 with acetic acid, affording a white precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6 g), m.p. 285-288° C. (dec.). the solution refluxed for 16 hours The reaction mixture was concentrated to 50 mL by removal of solvent under reduced pressure, and 20 mL of water was added affording a white precipitate The precipitate was collected by filtration washed with water dried in a vacuum oven

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

Procedure: 60 g of sodium hydride were suspended in 450 cc of dimethyl carbonate and 100 cc of hexamethyl phosphoric acid triamide. 100 g of pinacolone (92%) were added slowly at 45° C and on completion of the addition, the reaction mixture was processed as described in 3 above. The yield was 83.5% of pivaloyl acetic acid methyl ester.