4-Fluoro-3-methoxyaniline

To a solution of 1-fluoro-2-methoxy-4-nitrobenzene (101) (5.0 g, 29.0 mmol) in methanol (25 mL) was added 10 percent Pd/C (500 mg) at room temperature under H2 atmosphere. After reaction completion (monitored by TLC), the mixture was filtered and the filtrate was evaporated under vacuo to afford title compound 202 (4.0 g, 97 percent yield). ‘H NIVIR (400 1VIHz, DMSO-d6): 3.72 (s, 3H), 4.93 (s, 2H), 6.02-6.05 (m, 1H), 6.33 (dd, J7.6, 2.4 Hz, 1H), 6.81 (dd, J 11.6, 8.8 Hz, 1H).N-(4-fluoro-3-methoxyphenyl)pivalamide Step 1 : 4-fluoro-3-methoxyanilineNitro compound Il (6.5 g, 0.038 mol) and iron powder (10.6 g, 0.19 mol) were suspended in ethanol (90 ml) at OGeneral procedure: In a round bottom flask, PPL (20 mg) was added to a mixture of 1Hpyrazole-4-carbaldehyde derivative (1 mmol), substituted amine(1 mmol) and diethyl phosphite (1.2 mmol). The reaction mixture wasthen stirred at 45 C under solvent-free condition and the progress ofthe reaction was monitored by TLC. After completion of the reaction, enzyme was removed by filtration and the filterate was extracted withdichloromethane. Organic layer was washed with excess of brine anddried over anhydrous Na2SO4. Solvent was concentrated under reducedpressure and the crude product thus obtained was purified by crystallizationusing ethyl acetate: n-hexane (1:4) to give white solid.General procedure: In a round bottom flask, PPL (20 mg) was added to a mixture of 1Hpyrazole-4-carbaldehyde derivative (1 mmol), substituted amine(1 mmol) and diethyl phosphite (1.2 mmol). The reaction mixture wasthen stirred at 45 C under solvent-free condition and the progress ofthe reaction was monitored by TLC. After completion of the reaction, enzyme was removed by filtration and the filterate was extracted withdichloromethane. Organic layer was washed with excess of brine anddried over anhydrous Na2SO4. Solvent was concentrated under reducedpressure and the crude product thus obtained was purified by crystallizationusing ethyl acetate: n-hexane (1:4) to give white solid.General procedure: Ethyl 4-bromo-1H-indole-2-carboxylate (1 eq), Pd2(dba)3 (0.1 eq), X-phos(0.2 eq), Cs2CO3 (3 eq) and aryl amine (3 eq) was added to a microwave tube, dissolved in 1, 4-dioxane, and filled with argon gas. The microwave reaction wascarried out at 100 C for 0.5-1.5 h, and the starting material disappeared. The mixturewas cooled to room temperature and concentrated. Ethyl acetate was added todissolve the residue, and the mixture was washed with saturated brine and water, driedover anhydrous Na2SO4, and concentrated in vacuo. The crude product was purifiedby column chromatography to afford the target compound. Compounds 8m-8o, 8s, 8a-3 ~ 8a-5, 8a-13, 8a-15 ~ 8a-17, 8o-1 ~ 8o-24 were prepared with method 3.Take 6-chloro-4-bromo-1H-2-carboxylic acid ethyl ester (200mg, 0.67mmol), add toluene, add Pd2dba3 (122 mg, 0.13mmol), X-phos (127mg, 0.26mmol), Cs2CO3 (653mg, 2mmol) and compound 4-Amino-7-fluoro-1H-indole-2-carboxylic acid ethyl trifluoroacetate (140 mg, 0.44 mmol), Pd2 (dba) 3 (40 mg, 0.044 mmol), Xantphos (51 mg, 0.088 mmol) ), Cs2CO3 (429mg, 1.32mmol) and 4-bromo-6-acetylamino-1H-indole-2-carboxylic acid ethyl ester (100 mg, 0.31 mmol), Pd2 (dba) 3 (28 mg, 0.031 mmol), X-phos (30 mg, 0.062 mmol), Cs2CO3 (301 mg, 0.92 mmol) and General procedure: Ethyl 4-bromo-1H-indole-2-carboxylate (1 eq), Pd2(dba)3 (0.1 eq), X-phos(0.2 eq), Cs2CO3 (3 eq) and aryl amine (3 eq) was added to a microwave tube, dissolved in 1, 4-dioxane, and filled with argon gas. The microwave reaction wascarried out at 100 C for 0.5-1.5 h, and the starting material disappeared. The mixturewas cooled to room temperature and concentrated. Ethyl acetate was added todissolve the residue, and the mixture was washed with saturated brine and water, driedover anhydrous Na2SO4, and concentrated in vacuo. The crude product was purifiedby column chromatography to afford the target compound. Compounds 8m-8o, 8s, 8a-3 ~ 8a-5, 8a-13, 8a-15 ~ 8a-17, 8o-1 ~ 8o-24 were prepared with method 3.iii: Intermediate 3 (1.0 eq) and cesium carbonate (2.0 eq) and corresponding phenylamine (1.2 eq) were added into a dry reaction flask. Dry DMF was used as reaction solvent, N2 was used to remove water vapor and oxygen. Then catalyst and ligand Pd(AcO)2 (0.1 eq) and Xantphos (0.1 eq) were added. The reaction mixture was transferred to a 60 C oil bath, 6~7 hours. After the reaction completed, the mixture was filtered and evaporated. Intermediate 4 was gained. The yield was 50%.

Molecular Weight:141.14
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:141.058992041
Monoisotopic Mass:141.058992041
Topological Polar Surface Area:35.2
Heavy Atom Count:10
Complexity:110
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes