5-bromo-2,3-dichlorobenzaldehyde

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 5:1 (v/v) MeOH:THF solution (0.38 M) of 5-bromo-2,3-dichlorobenzaldehyde (1 eq.) from Step 1, Amine 5 was added at 0° C. sodium borohydride (1.1 eq.) portionwise over 45 min. The reaction solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was then partitioned between ether and 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid. were removed in vacuo The resulting residue was then partitioned between ether and 10% aq. HCl The aqueous layer was separated back-extracted with ether The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc)

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

Procedure: 5-Bromo-2,3-dichlorobenzaldehyde (1 eq.) from the previous step and cyclopropylamine (2 eq.) were combined in CH2Cl2 (0.1 M). To this was then added MgSO4 (1 eq.) and the resulting suspension was stirred at RT for 18 h. The insolubles were then removed via filtration through a pad of celite and the filtrate was concentrated in vacuo. The crude imine thus obtained was then re-taken up in a 2:1 (v/v) mixture of THF:MeOH (0.17 M). To this solution was added sodium borohydride (10 eq.) portionwise and the resulting mixture was stirred at RT for 48 h. The reaction was quenched with 1 N aq. HCl, neutralized with 1 N aq. NaOH and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil. The insolubles were then removed via filtration through a pad of celite the filtrate was concentrated in vacuo The crude imine thus obtained The reaction was quenched with 1 N aq. HCl extracted with ether The combined organic extracts were then washed with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc)

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

Procedure: To a TFA solution (0.38 M) of 2,3-dichlorobenzaldehyde (1 eq.) was added sulfuric acid (5 eq.). Over a period of 3 h, N-bromosuccinimide (1.5 eq.) was added portionwise at RT to afford, in the end, a yellow-orange solution. After 72 h, the crude reaction mixture was diluted with 9:1 (v/v) hexanes:ether and then washed sequentially with water, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a white solid. to afford, in the end After 72 h the crude reaction mixture ether and then washed sequentially with water, 1 N aq. NaOH, water and brine The organic extract was dried over Na2SO4 filtered the filtrate concentrated in vacuo

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

Procedure: A mixture of 5-bromo-2,3-dichlorobenzaldehyde from the previous step (1 eq.), cyclopropylamine (1 eq.) and sodium cyanoborohydride (1.5 eq.) were combined in MeOH (0.2 M). At 0° C., acetic acid (3 eq.) was added dropwise and the reaction mixture was slowly warmed to RT over 16 h. The reaction mixture was then diluted with ether and quenched with 1N aq. NaHCO3. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→80:20 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil. quenched with 1N aq. NaHCO3 The aqueous layer was separated back-extracted with ether The combined organic extracts were then washed with brine dried over MgSO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→80:20 (v/v) Hex:EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 5:1 (v/v) MeOH:THF solution (0.38 M) of 5-bromo-2,3-dichlorobenzaldehyde (1 eq.) from Step 1, Amine 5 was added at 0° C. sodium borohydride (1.1 eq.) portionwise over 45 min. The reaction solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was then partitioned between ether and 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid. were removed in vacuo The resulting residue was then partitioned between ether and 10% aq. HCl The aqueous layer was separated back-extracted with ether The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 5:1 (v/v) MeOH:THF solution (0.38 M) of 5-bromo-2,3-dichlorobenzaldehyde (1 eq.) from Step 1, Amine 5 was added at 0° C. sodium borohydride (1.1 eq.) portionwise over 45 min. The reaction solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was then partitioned between ether and 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid. were removed in vacuo The resulting residue was then partitioned between ether and 10% aq. HCl The aqueous layer was separated back-extracted with ether The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc)

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

Procedure: 5-Bromo-2,3-dichlorobenzaldehyde (1 eq.) from the previous step and cyclopropylamine (2 eq.) were combined in CH2Cl2 (0.1 M). To this was then added MgSO4 (1 eq.) and the resulting suspension was stirred at RT for 18 h. The insolubles were then removed via filtration through a pad of celite and the filtrate was concentrated in vacuo. The crude imine thus obtained was then re-taken up in a 2:1 (v/v) mixture of THF:MeOH (0.17 M). To this solution was added sodium borohydride (10 eq.) portionwise and the resulting mixture was stirred at RT for 48 h. The reaction was quenched with 1 N aq. HCl, neutralized with 1 N aq. NaOH and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil. The insolubles were then removed via filtration through a pad of celite the filtrate was concentrated in vacuo The crude imine thus obtained The reaction was quenched with 1 N aq. HCl extracted with ether The combined organic extracts were then washed with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc)

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

Procedure: To a TFA solution (0.38 M) of 2,3-dichlorobenzaldehyde (1 eq.) was added sulfuric acid (5 eq.). Over a period of 3 h, N-bromosuccinimide (1.5 eq.) was added portionwise at RT to afford, in the end, a yellow-orange solution. After 72 h, the crude reaction mixture was diluted with 9:1 (v/v) hexanes:ether and then washed sequentially with water, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a white solid. to afford, in the end After 72 h the crude reaction mixture ether and then washed sequentially with water, 1 N aq. NaOH, water and brine The organic extract was dried over Na2SO4 filtered the filtrate concentrated in vacuo

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

Procedure: A mixture of 5-bromo-2,3-dichlorobenzaldehyde from the previous step (1 eq.), cyclopropylamine (1 eq.) and sodium cyanoborohydride (1.5 eq.) were combined in MeOH (0.2 M). At 0° C., acetic acid (3 eq.) was added dropwise and the reaction mixture was slowly warmed to RT over 16 h. The reaction mixture was then diluted with ether and quenched with 1N aq. NaHCO3. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→80:20 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil. quenched with 1N aq. NaHCO3 The aqueous layer was separated back-extracted with ether The combined organic extracts were then washed with brine dried over MgSO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→80:20 (v/v) Hex:EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 5:1 (v/v) MeOH:THF solution (0.38 M) of 5-bromo-2,3-dichlorobenzaldehyde (1 eq.) from Step 1, Amine 5 was added at 0° C. sodium borohydride (1.1 eq.) portionwise over 45 min. The reaction solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was then partitioned between ether and 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid. were removed in vacuo The resulting residue was then partitioned between ether and 10% aq. HCl The aqueous layer was separated back-extracted with ether The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc)

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

Procedure: 5-Bromo-2,3-dichlorobenzaldehyde (1 eq.) from the previous step and cyclopropylamine (2 eq.) were combined in CH2Cl2 (0.1 M). To this was then added MgSO4 (1 eq.) and the resulting suspension was stirred at RT for 18 h. The insolubles were then removed via filtration through a pad of celite and the filtrate was concentrated in vacuo. The crude imine thus obtained was then re-taken up in a 2:1 (v/v) mixture of THF:MeOH (0.17 M). To this solution was added sodium borohydride (10 eq.) portionwise and the resulting mixture was stirred at RT for 48 h. The reaction was quenched with 1 N aq. HCl, neutralized with 1 N aq. NaOH and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil. The insolubles were then removed via filtration through a pad of celite the filtrate was concentrated in vacuo The crude imine thus obtained The reaction was quenched with 1 N aq. HCl extracted with ether The combined organic extracts were then washed with water and brine dried over Na2SO4 filtered the filtrate concentrated in vacuo Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc)

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

Procedure: To a TFA solution (0.38 M) of 2,3-dichlorobenzaldehyde (1 eq.) was added sulfuric acid (5 eq.). Over a period of 3 h, N-bromosuccinimide (1.5 eq.) was added portionwise at RT to afford, in the end, a yellow-orange solution. After 72 h, the crude reaction mixture was diluted with 9:1 (v/v) hexanes:ether and then washed sequentially with water, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a white solid. to afford, in the end After 72 h the crude reaction mixture ether and then washed sequentially with water, 1 N aq. NaOH, water and brine The organic extract was dried over Na2SO4 filtered the filtrate concentrated in vacuo