2-Difluoromethyl-1H-benzoimidazole

General procedure: In a screw-cap vial, the diamine or aminothiophenol (1 mmol) was dissolved in fluorinated carboxylic acid (2 mL, 0.5 M) and the reaction was stirred at 70 °C for 16 hours. The fluorinated carboxylic acid was then evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to yield the corresponding product.After a mixture of o-phenylenediamine (51.9 g, 480 mmol), difluoroacetic acid (50.7 g, 528 mmol) and 4N HCl (500 mL) was refluxed for 2 hours, the reaction mixture was neutralized by the careful addition of anhydrous sodium carbonate. 28.8 g (0.6 mol) DFA (2, 2-difluoroacetic acid) was added to 10.8 g (0.2 mol) benzene-1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98°C) and maintained for 3 h under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene- 1 , 2-diamine was >99percent (GC). The mixture was cooled down to room temperature, and neutralized by NaHC028.8 g (0.6 mol) DFA (2, 2-difluoroacetic acid) was added to 10.8 g (0.2 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98° C.) and maintained for 3 h under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1, 2-diamine was >99percent (GC). The mixture was cooled down to room temperature, and neutralized by NaHCOPreparation 8: 2-(Difluoromethyl)-lH-benzo[d]imidazoleTo a stirred solution of O-phenylenediamine (1 g, 0.00925 mol) in 4N HCI (10 mL) was added difluoroacetic acid (0.977 g, 0.01018 mol) and the resulting mixture was heated at reflux for 2 h . The reaction mixture was cooled to room temperature, neutralized with sodium carbonate and the solid obtained was collected by filtration and washed with water (30 mL), then dried under vacuum to afford the title compound ( 1 g, 64percent) . *H NMR (400 MHz, CDCI71.4 g DFAE (recycled from example 2) was added to 21.6 g (0.2 mol) benzene- 1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98- 100 °C) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene- 1 , 2-diamine was >99percent (GC). The mixture was cooled down to 0 °C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAE (17.4 g *3) and dried under vacuum. 30.37 g light green solid was obtained in 90.36percent yield with 99percent GC purity. Total 68.3 g filtrate (DFAE) was recycled. [0026] In examples 1 -3, total 85.57 g product was obtained in above 3 batches reactions and average yield for each experiment was 85.0percent. Each product has a melting point of 162-163 °C. The product was analyzed by 1 H NM and the spectrum was as follows: 1 H NMR (300 MHz, DMSO-d6) δ: 7.16-7.42 (m, 3H), 7.68 (m, 2H), 13.3 (s, 1H). 19F NMR (282 MHz, DMSO-d6) δ: - 115.98.74.4 (0.6 mol) DFAE (ethyl 2, 2-difluoroacetate) was added to 21.6 g (0.2 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98° C.) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 5 hours the conversion of benzene-1, 2-diamine was >99percent (determined by Gas Chromatography (GC)). The mixture was cooled down to 0° C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAE (17.4 g*3), and dried under vacuum. 18 g light green solid was obtained in 53.56percent yield with 99percent GC purity. Total 70 g filtrate (DFAE) and DFMB solubilized within DFAE were recycled and used in example 2.27.84 g (0.294 mol) DFAN (2, 2-difluoroacetamide) was added to 10.8 g (0.1 mol) benzene- 1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (120 °C) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1 , 2-diamine was 87.23percent (GC). The mixture was cooled down to 0°C, and 300 ml EA was added. The organic phase was washed with 100 ml *4 water, and then with brine 50 ml * 2. Dried with Na27.84 g (0.294 mol) DFAN (2, 2-difluoroacetamide) was added to 10.8 g (0.1 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (120° C.) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1, 2-diamine was 87.23percent (GC). The mixture was cooled down to 0° C., and 300 ml EA was added. The organic phase was washed with 100 ml*4 water, and then with brine 50 ml*2. Dried with Na15.3 g (0.1 1 mol) DFAipr (isopropyl 2, 2-difluoroacetate) was added to 4.0 g (0.037 mol) benzene- 1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 °C) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 19 hrs the conversion of benzene- 1, 2-diamine was >99percent (GC). The mixture was cooled down to 0 °C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAipr for 3 times and dried under vacuum. 4 g light blue solid was obtained in 64.3percent isolated yield.15.3 g (0.11 mol) DFAipr (isopropyl 2, 2-difluoroacetate) was added to 4.0 g (0.037 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100° C.) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually.After 19 hrs the conversion of benzene-1, 2-diamine was >99percent (GC). The mixture was cooled down to 0° C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAipr for 3 times and dried under vacuum. 4 g light blue solid was obtained in 64.3percent isolated yield.33.0 g (0.294 mol) DFAMe (methyl 2, 2-difluoroacetate) was added to 10.8 g (0.1 mol) benzene- 1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 °C) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene-1 , 2-diamine was >99percent (GC). The mixture was cooled down to 0 °C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAMe for 3 times and dried under vacuum. 8, 3 g light green solid was obtained in 50.3percent isolated yield.33.0 g (0.294 mol) DFAMe (methyl 2, 2-difluoroacetate) was added to 10.8 g (0.1 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100° C.) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene-1, 2-diamine was >99percent (GC). The mixture was to cooled down to 0° C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAMe for 3 times and dried under vacuum. 8.3 g light green solid was obtained in 50.3percent isolated yield.

Molecular Weight:168.14
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:168.04990452
Monoisotopic Mass:168.04990452
Topological Polar Surface Area:28.7
Heavy Atom Count:12
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes