ethyl 5-bromo-2-chlorobenzoate

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 5-bromo-2-chlorobenzoate (1 eq.) in THF (0.03 M) was added, at −78° C., DIBAL (2.5 eq). The reaction was stirred at −78° C. for 1 h and then warmed slowly to RT over 1 h. The reaction mixture was then diluted with ether and carefully quenched with aq. 6 M HCl. The organic layer was separated and the aqueous layer was back extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a white semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil. warmed slowly to RT over 1 h carefully quenched with aq. 6 M HCl The organic layer was separated the aqueous layer was back extracted with ether The combined organic extracts were washed with sat. aq. NaHCO3 and brine dried over MgSO4 filtered Concentration of the filtrate in vacuo afforded a white semi-solid Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc)

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

Procedure: In a schlenck tube, a mixture of ethyl 5-bromo-2-chlorobenzoate (7.60 mmol, 2 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.59 mmol, 1.3 g), Cs2CO3 (18.97 mmol, 6.18 g), PdCl2dppf.CH2Cl2 (0.76 mmol, 0.620 g) in dioxane (70 ml) and water (15 ml) was heated for 2 hours at 110° C., under argon atmosphere. The solvent was evaporated and the mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting hexane/ethyl acetate mixtures and affording 1.5 g (yield 92%) of the expected product. The solvent was evaporated the mixture was extracted between ethyl acetate and water The crude mixture was purified by chromatography over SiO2 eluting hexane/ethyl acetate mixtures

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

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

Procedure: In a schlenck tube, a mixture of ethyl 5-bromo-2-chlorobenzoate (7.60 mmol, 2 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.59 mmol, 1.3 g), Cs2CO3 (18.97 mmol, 6.18 g), PdCl2dppf.CH2Cl2 (0.76 mmol, 0.620 g) in dioxane (70 ml) and water (15 ml) was heated for 2 hours at 110° C., under argon atmosphere. The solvent was evaporated and the mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting hexane/ethyl acetate mixtures and affording 1.5 g (yield 92%) of the expected product. The solvent was evaporated the mixture was extracted between ethyl acetate and water The crude mixture was purified by chromatography over SiO2 eluting hexane/ethyl acetate mixtures

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

Procedure: Prepared as described in Example 5a) using 5-bromo-2-chloro-benzoic acid, ethyl ester (0.50 g), 3-pyrrolidinyl-carbamic acid 1,1-dimethylethyl ester (0.42 g), cesium carbonate (0.86 g), palladium (II) acetate (21 mg) and (R)-BINAP (88 mg) and toluene (3 ml) to afford the subtitle compound as an oil (0.25 g). Prepared

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2-chloro-benzoic acid, ethyl ester (0.50 g), hexahydro-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (0.46 g), cesium carbonate (0.86 g), palladium (II) acetate (8.5 mg) and (R)-BINAP (35 mg) in toluene (3 ml) was heated at 100° C. for 14 h in a pressure vessel flushed with nitrogen. The cooled reaction mixture was poured into water and extracted (3 times) with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and then dried over magnesium sulfate. Evaporation under reduced pressure gave an oil which was purified by chromatography over silica gel, eluting with 20% ethyl acetate in iso-hexane to yield the subtitle compound as an oil (0.21 g). flushed with nitrogen The cooled reaction mixture extracted (3 times) with ethyl acetate The combined organic extracts were washed with saturated sodium chloride solution dried over magnesium sulfate Evaporation under reduced pressure gave an oil which was purified by chromatography over silica gel eluting with 20% ethyl acetate in iso-hexane

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

Procedure: Ethyl 5-bromo-2-chlorobenzoate (0.80 g, 3.04 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.19 g, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.28 g, 0.30 mmol) and cesium carbonate (Cs2CO3) (1.39 g, 4.26 mmol) were placed in a Schlenk tube and purged by repeated nitrogen/vacuum cycles for 30 minutes. Dry toluene (6 mL) and 1-(2-dimethylaminoethyl)piperazine (0.55 mL, 3.65 mmol) were then added. The reaction mixture was stirred for 10 min at room temperature, heated at 85° C. overnight and then cooled to room temperature. The solution was diluted with EtOAc (30 mL), the insoluble material was filtered off and the filtrate was washed with saturated brine (15 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue that was purified by flash chromatography (eluent gradient: EtOAc, EtOAc:MeOH/1:1, EtOAc:MeOH:NH3 in MeOH (2M)/1:1:0.2) to afford 0.30 g of the title compound (30%). 1H-NMR (400 MHz, DMSO): δ 1.28 (3H, t), 2.12 (6H, s), 2.32-2.42 (4H, m), 2.47-2.51 (4H, m), 3.11-3.14 (4H, m), 4.27 (2H, q), 7.06-7.09 (1H, m), 7.18-7.19 (1H, m), 7.30-7.32 (1H, m). purged by repeated nitrogen/vacuum cycles for 30 minutes heated at 85° C. overnight cooled to room temperature the insoluble material was filtered off the filtrate was washed with saturated brine (15 mL) The organic phase was dried over Na2SO4 filtered concentrated under reduced pressure to obtain a residue that was purified by flash chromatography (eluent gradient: EtOAc, EtOAc:MeOH/1:1, EtOAc:MeOH:NH3 in MeOH (2M)/1:1:0.2)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 5-bromo-2-chlorobenzoate (1.9 g) in DMF (12 mL), toluene (0.3 mL), cyclopropylacetylene (714 mg), copper iodide (275 mg), dichloro bis(triphenylphosphine)palladium (1.01 g) and triethylamine (20.1 mL) were added, and the mixture was degassed, stirred at 100° C. under argon atmosphere for 8 hours, and then the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble material was filtered off on celite. The mother liquor was washed with brine, dried over magnesium sulfate and concentrated. By purification on column chromatography, ethyl 2-chloro-5-(cyclopropylethynyl)benzoate (1.86 g) was obtained as brown oil. the mixture was degassed the reaction mixture was cooled to room temperature diluted with ethyl acetate The insoluble material was filtered off on celite The mother liquor was washed with brine dried over magnesium sulfate concentrated By purification on column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Piperazine-1-carboxylic acid tert-butyl ester (106 mg), 3-bromo-6-chlorobenzoic acid ethyl ester (125 mg), cesium carbonate (220 mg), palladium acetate (5 mg) and R-BINAP (22 mg) were combined in toluene (2 ml) and heated at 100° C. in a sealed vessel for 48 hr. The cooled reaction was loaded onto a silica column and eluted with iso-hexane/ethyl acetate (4:1) to give the subtitle product (170 mg). The cooled reaction eluted with iso-hexane/ethyl acetate (4:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 5-bromo-2-chlorobenzoate (1 eq.) in THF (0.03 M) was added, at −78° C., DIBAL (2.5 eq). The reaction was stirred at −78° C. for 1 h and then warmed slowly to RT over 1 h. The reaction mixture was then diluted with ether and carefully quenched with aq. 6 M HCl. The organic layer was separated and the aqueous layer was back extracted with ether. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a white semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil. warmed slowly to RT over 1 h carefully quenched with aq. 6 M HCl The organic layer was separated the aqueous layer was back extracted with ether The combined organic extracts were washed with sat. aq. NaHCO3 and brine dried over MgSO4 filtered Concentration of the filtrate in vacuo afforded a white semi-solid Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc)

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