tert-butyl (2S)-2-methylpiperazine-1-carboxylate;hydrochloride

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

Procedure: N-(4-Formyl-3-methylphenyl)acetamide (D52) (326 mg, 1.8 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (436 mg, 1.8 mmol), triethylamine (0.282 ml, 2 mmol) and sodium tri(acetoxy)borohydride (781 mg, 3.7 mmol) were stirred together in 1,2-DCE (15 ml) for 17 h. Saturated aqueous NaHCO3 was added and the reaction mixture stirred for 1 h. The organic layer was separated and washed with water and brine, then dried and concentrated to give the crude product which was purified by chromatography. Elution with 0-100% EtOAc/petroleum ether yielded the title compound as a colourless oil (573 mg). δH (CDCl3, 400 MHz) 7.27 (2H, m), 7.16 (1H, d), 7.11 (1H, br.s), 4.17 (1H, m), 3.78 (1H, m), 3.36 (2H, s), 3.02 (1H, m), 2.70 (1H, m), 2.56 (1H, m), 2.36 (3H, s), 2.17 (4H, m), 1.95 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MH+ 362.3. The organic layer was separated washed with water and brine dried concentrated to give the crude product which was purified by chromatography Elution with 0-100% EtOAc/petroleum ether

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

Procedure: A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (21.3 g, 0.09 mol), triethylamine (15 ml, 0.108 mol) and sodium tri(acetoxy)borohydride (42.4 g, 0.2 mol) in 1,2-DCE (500 ml) was stirred at room temperature overnight. Saturated aqueous NaHCO3 solution (200 ml) was added and the mixture stirred for 20-30 minutes. The phases were separated and the aqueous phase was washed with DCM. The combined organics were washed with brine, dried and concentrated. Column chromatography eluting with 0-20% EtOAc/hexane gave the title compound as a yellow oil which crystallized on standing (25.61 g). δH (CDCl3, 400 MHz) 8.19 (2H, d), 7.53 (2H, d), 4.21 (1H, br.s), 3.83 (1H, d), 3.62 (1H, d), 3.50 (1H, d), 3.13 (1H, td), 2.74 (1H, m), 2.54 (1H, m), 2.20 (1H, dd), 2.08 (1H, m), 1.46 (9H, s), 1.25 (3H, d). the mixture stirred for 20-30 minutes The phases were separated the aqueous phase was washed with DCM The combined organics were washed with brine dried concentrated Column chromatography eluting with 0-20% EtOAc/hexane

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

Procedure: N-(4-Formyl-3-methylphenyl)acetamide (D52) (326 mg, 1.8 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (436 mg, 1.8 mmol), triethylamine (0.282 ml, 2 mmol) and sodium tri(acetoxy)borohydride (781 mg, 3.7 mmol) were stirred together in 1,2-DCE (15 ml) for 17 h. Saturated aqueous NaHCO3 was added and the reaction mixture stirred for 1 h. The organic layer was separated and washed with water and brine, then dried and concentrated to give the crude product which was purified by chromatography. Elution with 0-100% EtOAc/petroleum ether yielded the title compound as a colourless oil (573 mg). δH (CDCl3, 400 MHz) 7.27 (2H, m), 7.16 (1H, d), 7.11 (1H, br.s), 4.17 (1H, m), 3.78 (1H, m), 3.36 (2H, s), 3.02 (1H, m), 2.70 (1H, m), 2.56 (1H, m), 2.36 (3H, s), 2.17 (4H, m), 1.95 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MH+ 362.3. The organic layer was separated washed with water and brine dried concentrated to give the crude product which was purified by chromatography Elution with 0-100% EtOAc/petroleum ether

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

Procedure: A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (21.3 g, 0.09 mol), triethylamine (15 ml, 0.108 mol) and sodium tri(acetoxy)borohydride (42.4 g, 0.2 mol) in 1,2-DCE (500 ml) was stirred at room temperature overnight. Saturated aqueous NaHCO3 solution (200 ml) was added and the mixture stirred for 20-30 minutes. The phases were separated and the aqueous phase was washed with DCM. The combined organics were washed with brine, dried and concentrated. Column chromatography eluting with 0-20% EtOAc/hexane gave the title compound as a yellow oil which crystallized on standing (25.61 g). δH (CDCl3, 400 MHz) 8.19 (2H, d), 7.53 (2H, d), 4.21 (1H, br.s), 3.83 (1H, d), 3.62 (1H, d), 3.50 (1H, d), 3.13 (1H, td), 2.74 (1H, m), 2.54 (1H, m), 2.20 (1H, dd), 2.08 (1H, m), 1.46 (9H, s), 1.25 (3H, d). the mixture stirred for 20-30 minutes The phases were separated the aqueous phase was washed with DCM The combined organics were washed with brine dried concentrated Column chromatography eluting with 0-20% EtOAc/hexane

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

Procedure: A mixture of crude 1-(bromomethyl)-2-chloro-4-nitrobenzene (D102) (0.391 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (0.407 g, 1.72 mmol) and Hunig's base (0.625 mL, 3.59 mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give an orange oil which was dissolved in DCM and washed with water (33 2) and brine, then dried and concentrated to give an orange oil. Purification by column chromatography eluting with 0-30% EtOAc/pentane gave the title compound as a yellow oil (0.199 g). δH (CDCl3, 400 MHz) 8.24 (1H, d), 8.12 (1H, dd), 7.77 (1H, d), 4.24 (1H, br.s), 3.85 (1H, d), 3.63 (2H, s), 3.14 (1H, td), 2.76 (1H, m), 2.59 (1H, m), 2.33 (1H, dd), 2.18 (1H, m), 1.47 (9H, s), 1.28 (3H, d). MS (ES): MH+ 370/372, The reaction mixture was concentrated to give an orange oil which washed with water (33 2) and brine dried concentrated to give an orange oil Purification by column chromatography eluting with 0-30% EtOAc/pentane

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

Procedure: A mixture of crude 1-(bromomethyl)-2-chloro-4-nitrobenzene (D102) (0.391 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (0.407 g, 1.72 mmol) and Hunig's base (0.625 mL, 3.59 mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give an orange oil which was dissolved in DCM and washed with water (33 2) and brine, then dried and concentrated to give an orange oil. Purification by column chromatography eluting with 0-30% EtOAc/pentane gave the title compound as a yellow oil (0.199 g). δH (CDCl3, 400 MHz) 8.24 (1H, d), 8.12 (1H, dd), 7.77 (1H, d), 4.24 (1H, br.s), 3.85 (1H, d), 3.63 (2H, s), 3.14 (1H, td), 2.76 (1H, m), 2.59 (1H, m), 2.33 (1H, dd), 2.18 (1H, m), 1.47 (9H, s), 1.28 (3H, d). MS (ES): MH+ 370/372, The reaction mixture was concentrated to give an orange oil which washed with water (33 2) and brine dried concentrated to give an orange oil Purification by column chromatography eluting with 0-30% EtOAc/pentane

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

Procedure: N-(4-Formyl-3-methylphenyl)acetamide (D78) (326 mg, 1.8 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (436 mg, 1.8 mmol), triethylamine (0.282 mL, 2 mmol) and sodium tri(acetoxy)borohydride (781 mg, 3.7 mmol) were stirred together in DCE (15 mL) for 17 h. Saturated aqueous NaHCO3 (15 mL) was added and the reaction mixture stirred for 1 h. The organic layer was separated and washed with water and brine, then dried and concentrated to give the crude product which was purified by chromatography. Elution with 0-100% ethyl acetate/petroleum ether yielded the title compound as a colourless oil (573 mg). δH (CDCl3, 400 MHz) 7.27 (2H, m), 7.16 (1H, d), 7.11 (1H, br.s), 4.17 (1H, m), 3.78 (1H, m), 3.36 (2H, s), 3.02 (1H, m), 2.70 (1H, m), 2.56 (1H, m), 2.36 (3H, s), 2.17 (4H, m), 1.95 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MS (ES): MH+ 362.3. The organic layer was separated washed with water and brine dried concentrated to give the crude product which was purified by chromatography Elution with 0-100% ethyl acetate/petroleum ether

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

Procedure: A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (21.3 g, 0.09 mol), triethylamine (15 mL, 0.108 mol) and sodium tri(acetoxy)borohydride (42.4 g, 0.2 mol) in 1,2-DCE (500 mL) was stirred at room temperature overnight. Saturated aqueous NaHCO3 solution (200 mL) was added and the mixture stirred for 20-30 minutes. The phases were separated and the aqueous phase was washed with DCM. The combined organics were washed with brine, dried and concentrated. Column chromatography eluting with 0-20% EtOAc/hexane gave the title compound as a pale yellow oil which crystallized on standing (25.61 g). δH (CDCl3, 400 MHz) 8.19 (2H, d), 7.53 (2H, d), 4.21 (1H, br.s), 3.83 (1H, d), 3.62 (1H, d), 3.50 (1H, d), 3.13 (1H, td), 2.74 (1H, m), 2.54 (1H, m), 2.20 (1H, dd), 2.08 (1H, m), 1.46 (9H, s), 1.25 (3H, d). the mixture stirred for 20-30 minutes The phases were separated the aqueous phase was washed with DCM The combined organics were washed with brine dried concentrated Column chromatography eluting with 0-20% EtOAc/hexane

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

Procedure: A mixture of crude 1-(bromomethyl)-2-chloro-4-nitrobenzene (D102) (0.391 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (0.407 g, 1.72 mmol) and Hunig's base (0.625 mL, 3.59 mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give an orange oil which was dissolved in DCM and washed with water (×2) and brine, then dried and concentrated to give an orange oil. Purification by column chromatography eluting with 0-30% EtOAc/pentane gave the title compound as a yellow oil (0.199 g). δH (CDCl3, 400 MHz) 8.24 (1H, d), 8.12 (1H, dd), 7.77 (1H, d), 4.24 (1H, br.s), 3.85 (1H, d), 3.63 (2H, s), 3.14 (1H, td), 2.76 (1H, m), 2.59 (1H, m), 2.33 (1H, dd), 2.18 (1H, m), 1.47 (9H, s), 1.28 (3H, d). MS (ES): MH+ 370/372, The reaction mixture was concentrated to give an orange oil which washed with water (×2) and brine dried concentrated to give an orange oil Purification by column chromatography eluting with 0-30% EtOAc/pentane

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

Procedure: A mixture of crude 1-(bromomethyl)-2-chloro-4-nitrobenzene (D102) (0.391 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (0.407 g, 1.72 mmol) and Hunig's base (0.625 mL, 3.59 mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give an orange oil which was dissolved in DCM and washed with water (×2) and brine, then dried and concentrated to give an orange oil. Purification by column chromatography eluting with 0-30% EtOAc/pentane gave the title compound as a yellow oil (0.199 g). δH (CDCl3, 400 MHz) 8.24 (1H, d), 8.12 (1H, dd), 7.77 (1H, d), 4.24 (1H, br.s), 3.85 (1H, d), 3.63 (2H, s), 3.14 (1H, td), 2.76 (1H, m), 2.59 (1H, m), 2.33 (1H, dd), 2.18 (1H, m), 1.47 (9H, s), 1.28 (3H, d). MS (ES): MH+ 370/372, The reaction mixture was concentrated to give an orange oil which washed with water (×2) and brine dried concentrated to give an orange oil Purification by column chromatography eluting with 0-30% EtOAc/pentane

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

Procedure: N-(4-Formyl-3-methylphenyl)acetamide (D78) (326 mg, 1.8 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (436 mg, 1.8 mmol), triethylamine (0.282 mL, 2 mmol) and sodium tri(acetoxy)borohydride (781 mg, 3.7 mmol) were stirred together in DCE (15 mL) for 17 h. Saturated aqueous NaHCO3 (15 mL) was added and the reaction mixture stirred for 1 h. The organic layer was separated and washed with water and brine, then dried and concentrated to give the crude product which was purified by chromatography. Elution with 0-100% ethyl acetate/petroleum ether yielded the title compound as a colourless oil (573 mg). δH (CDCl3, 400 MHz) 7.27 (2H, m), 7.16 (1H, d), 7.11 (1H, br.s), 4.17 (1H, m), 3.78 (1H, m), 3.36 (2H, s), 3.02 (1H, m), 2.70 (1H, m), 2.56 (1H, m), 2.36 (3H, s), 2.17 (4H, m), 1.95 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MS (ES): MH+ 362.3. The organic layer was separated washed with water and brine dried concentrated to give the crude product which was purified by chromatography Elution with 0-100% ethyl acetate/petroleum ether

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

Procedure: N-(4-Formyl-3-methylphenyl)acetamide (D78) (326 mg, 1.8 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (436 mg, 1.8 mmol), triethylamine (0.282 mL, 2 mmol) and sodium tri(acetoxy)borohydride (781 mg, 3.7 mmol) were stirred together in DCE (15 mL) for 17 h. Saturated aqueous NaHCO3 (15 mL) was added and the reaction mixture stirred for 1 h. The organic layer was separated and washed with water and brine, then dried and concentrated to give the crude product which was purified by chromatography. Elution with 0-100% ethyl acetate/petroleum ether yielded the title compound as a colourless oil (573 mg). δH (CDCl3, 400 MHz) 7.27 (2H, m), 7.16 (1H, d), 7.11 (1H, br.s), 4.17 (1H, m), 3.78 (1H, m), 3.36 (2H, s), 3.02 (1H, m), 2.70 (1H, m), 2.56 (1H, m), 2.36 (3H, s), 2.17 (4H, m), 1.95 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MS (ES): MH+ 362.3. The organic layer was separated washed with water and brine dried concentrated to give the crude product which was purified by chromatography Elution with 0-100% ethyl acetate/petroleum ether