2-Chloro-6-methyl-benzoic acid methyl ester

A. A suspension of 2-chloro-6-methyl-benzoic acid (7.82 g, 45.8 MMOL) in thionyl chloride (20.0 mL, 275 MMOL), was immersed in an oil bath held at 85°C, and refluxed for 16 hours. The resulting pale brown solution was concentrated under reduced pressure to afford the acid chloride as a pale brown oil. This material was carried on to the ester formation without purification. The acid chloride (45.8 mmol from previous step) was dissolved in DICHLOROMETHANE (20 mL) and the mixture cooled in an ice bath. Methanol (10 mL, 247 MMOL) was added and the ice bath was then removed. HPLC of the reaction mixture 45 minutes after removal of the ice bath showed a 4: 1 mixture of starting acid: product ester. The reaction mixture was then treated with triethylamine (15 mL, 108 MMOL) dropwise over several minutes. The triethylamine addition was exothermic and led to the production of a lot of smoke in the reaction flask. After stirring overnight at ambient temperature HPLC indicated complete conversion to product. The reaction mixture was poured into a mixture of ether (200 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The layers were separated and the basic aqueous layer was extracted with ether (3 x 50 mL). The organic layers were combined and washed with brine, then dried (NA2SO4), filtered, and concentrated under reduced pressure to afford a yellow oil. The material was purified by flash chromatography eluting with a gradient from 0percent to 10percent ethyl acetate/hexane to afford 2-chloro-6-methylbenzoic acid methyl ester (7.38 g, 87percent yield) as a clear colorless liquid :'H-NMR (400 MHz, CDCI3) : 8 7.24-7. 19 (2H, m), 7.14-7. 08 (1H, m), 3.95 (3H, s), 2.32 (3H, s) ppm.Preparation XVII: 2-chloro-6-dimethylaminomethyl-benzoic acid. Step 1. Synthesis of 2-bromomethyl-6-chloro-benzoic acid methyl ester.2-Chloro-6-methyl benzoic acid (5.8 g, 34.0 mmoles) was suspended in dichloromethane (100 ml). To the suspension was added DMF (250 mg, 3.4 mmoles) and then dropwise oxalyl chloride (3.9 ml, 44.2 mmoles). The resultant solution was stirred at ambient temperature for 24 hours. Further DMF (250 mg, 3.4 EPO A. A suspension of 2-chloro-6-methyl-benzoic acid (7.82 g, 45.8 MMOL) in thionyl chloride (20.0 mL, 275 MMOL), was immersed in an oil bath held at 85°C, and refluxed for 16 hours. The resulting pale brown solution was concentrated under reduced pressure to afford the acid chloride as a pale brown oil. This material was carried on to the ester formation without purification. The acid chloride (45.8 mmol from previous step) was dissolved in DICHLOROMETHANE (20 mL) and the mixture cooled in an ice bath. Methanol (10 mL, 247 MMOL) was added and the ice bath was then removed. HPLC of the reaction mixture 45 minutes after removal of the ice bath showed a 4: 1 mixture of starting acid: product ester. The reaction mixture was then treated with triethylamine (15 mL, 108 MMOL) dropwise over several minutes. The triethylamine addition was exothermic and led to the production of a lot of smoke in the reaction flask. After stirring overnight at ambient temperature HPLC indicated complete conversion to product. The reaction mixture was poured into a mixture of ether (200 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The layers were separated and the basic aqueous layer was extracted with ether (3 x 50 mL). The organic layers were combined and washed with brine, then dried (NA2SO4), filtered, and concentrated under reduced pressure to afford a yellow oil. The material was purified by flash chromatography eluting with a gradient from 0percent to 10percent ethyl acetate/hexane to afford 2-chloro-6-methylbenzoic acid methyl ester (7.38 g, 87percent yield) as a clear colorless liquid :'H-NMR (400 MHz, CDCI3) : 8 7.24-7. 19 (2H, m), 7.14-7. 08 (1H, m), 3.95 (3H, s), 2.32 (3H, s) ppm.Preparation XVII: 2-chloro-6-dimethylaminomethyl-benzoic acid. Step 1. Synthesis of 2-bromomethyl-6-chloro-benzoic acid methyl ester.2-Chloro-6-methyl benzoic acid (5.8 g, 34.0 mmoles) was suspended in dichloromethane (100 ml). To the suspension was added DMF (250 mg, 3.4 mmoles) and then dropwise oxalyl chloride (3.9 ml, 44.2 mmoles). The resultant solution was stirred at ambient temperature for 24 hours. Further DMF (250 mg, 3.4 EPO General procedure: In a fume hood, an oven dried Schlenk flask equipped with a magnetic stirring bar was filled with N2 and evacuated (three cycles). Under N2 atmosphere [Ir(OMe)(COD)]2 (13.3 mg, 0.01 mmol, 1 mol%), 4, 4-ditert-butyl-2, 2?-bipyridyl (10.7 mg, 0.02 mmol, 2 mol%), and pinacolborane (HBPin) (436 muL, 384 mg, 3 mmol, 1.5 equiv) were added. The appropriate arene substrate (2 mmol, 1 equiv) was added via micropipette under N2 atmosphere. The Schlenk flask was closed and the reaction mixture was heated at 80 C in an oil bath. The progress of reaction was monitored by GC-MS and TLC. Upon completion of reaction, Schlenk flask was cooled to r.t. and exposed to air. The contents of the flask were dissolved in CH2Cl2 (3-5 mL) and taken out in a round-bottomed flask. The volatile organics were removed under reduced pressure using a rotary evaporator. The crude product was purified by column chromatography (silica gel, hexanes-CH2Cl2 1:1).

Molecular Weight:184.62
XLogP3:2.6
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:184.0291072
Monoisotopic Mass:184.0291072
Topological Polar Surface Area:26.3
Heavy Atom Count:12
Complexity:170
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes