4-Fluoro-2-methylbenzonitrile

White to light yellow crystalline powder

General procedure: To a 25-mL Schlenk tube equipped with a magnetic stirrer, CuCl (0.05 mol, 5 molpercent), DABCO (0.10 mol, 10 molpercent), 4-HO-TEMPO (0.05 mmol, 5 molpercent) were added. Substrates 1 (1 mmol) and NHA mixture of 2-bromo-5fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 31 (yield 60percent). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).A mixture of 2-bromo-5fluorotoluene ( 2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was re fluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSOA. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)[0215] Compound B was prepared by re fluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO1. 4-Fluoro-2-methylbenzonitrile (31). A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSOA mixture of 2-bromo-5-fluorotoluene (35 g, 185 mmol) and CuCN (20 g, 220 mmol) in DMF (500 mL) was refluxedAfter 24 hours, the reaction was diluted with water and extracted with hexane. The organic phase was dried over MgS04 and the solvent removed to give the product 2 (60percent yield)The 2- Bromo-5-fluorotoluene(compoundA)(3.5g, 18.5mmol) and CuCN (2g, 22mol) in DMF (100ml) and heated to reflux for24h. The reaction solution was diluted with water, extracted with n-hexane, Theorganic layer was dried over MgSO1.35 g Preparation 7; 2-(bromomethyl)-4-fluorobenzonitrile; A solution of A solution of 18A (4.8 g, 25.4 mmol), NBS (4.5 g, 25.4 mmol) and 100 mg AIBN was refluxed for 2 hours under nitrogen. After cooling to room temperature, the solvent was removed and the residue was purified by column chromatography. 1H NMR (400 MHz, CDCl3): 7.68 (d, J = 5.2, 8.4 Hz, 1H), 7.28 (d, J = 2.4, 8.8 Hz, 1H), 7.10-7.6 (m, 1H), 4.60 (s, 2H).A mixture of A mixture of 2-Bromomethyl-4-fluorobenzonitrile (32). A mixture of B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)[0216] Compound C was prepared by refluxing a mixture of 4-fluoro-2- methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl4 under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): delta 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).2-Bromomethyl-4-fluorobenzonitrile (4) A mixture of 2-methyl-4-fluorophenyl-carbonitrile (2g, 14.8mM, 1.0equiv) in carbon tetrachloride (24mL) was added N- bromosuccinimide (2.64g, 14.8mM, 1.0equiv ), benzoyl peroxide (BPO, 179mg, 0.74mM, 0.05equiv), and heated to reflux for 3h under nitrogen. The reaction was complete by TLC, cooled to room temperature, filtered, washed with carbon tetrachloride, the solvent was concentrated under reduced pressure to give the crude product as a white solid. It was used directly in the next reaction without purification.A solution of compound 2 (20 g, 148 mmol), NBS (26.4 g, 150 mmol) and AIBN (1 g) in CCl4 under nitrogenThe mixture was refluxed for 2 hours and the reaction was cooled to room temperature. The solid was removed by filtration and the organic solution was concentrated to give the crude product as an oilWhich was used in the next step without further purification3.0 g of The 4- Fluoro-2-methylbenzonitrile (compound B)(2g, 14.8mmol) , N-Bromosuccinimide(NBS) (2.64g, 15mmol) , AzobisisobutyronitrileAIBN(100mg) dissolved in CCl4 , Under theprotection of nitrogen gas it was heated to reflux for 2 h. Cooled toroom temperature, filtered to remove solids, concentrated to obtain crude oil, Which was used directly in the nextstep without purification.General procedure: 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-carbamoyl-3-isobutoxyphenyl)-4H-thieno[3, 2- ]pyrrole-2-carboxylic acid Method-A Step- 1 : Preparation of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4-(4-cyano-3- isobutoxyphenyl)-4H-thieno[3, 2- ]pyrrole-2-carboxylate To a solution of methyl 5-(4-(lH-imidazol-l-yl)-2-methylphenyl)-4H-thieno[3, 2-^]pyrrole-2- carboxylate (Intermediate- 3, 300 mg, 0.89 mmol) in DMF (3.0 mL) were added K2C03 (184 mg, 1.30 mmol) and 4-fluoro-2-isobutoxybenzonitrile (700 mg, 3.62 mmol) and the reaction mixture was heated at 130°C for 5-6 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 364 mg of the title product. 1H NMR (300 MHz, DMSO d6) delta 8.42 (s, 1H), 7.82-7.79 (m, 3H), 7.64 (s, 1H), 7.57 (d, 1H), 7.42-7.39 (d, = 7.8 Hz, 1H), 7.17 (t, 2H), 6.91 (s, 1H), 6.86 (s, 1H), 3.83 (s, 3H), 3.60-3.57 (d, J = 6.3 Hz, 2H), 2.12 (s, 3H), 1.80 (m, 1H), 0.79-0.76 (d, J = 6.3 Hz, 6H); MS (m z): 511 (M+H)+.

Molecular Weight:135.14
XLogP3:2.1
Hydrogen Bond Acceptor Count:2
Exact Mass:135.048427358
Monoisotopic Mass:135.048427358
Topological Polar Surface Area:23.8
Heavy Atom Count:10
Complexity:158
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes