2,3-Difluoro-6-nitroaniline

light yellow powder

1, 2, 3-trifluoro-4-nitrobenzene 8.85g of (50 mmol) was dissolved in ethanol 50 ml. To this solution 25percent aqueous ammonia 13.62g (the ammonia 200mmol equivalent) was added, followed by stirring at room temperature for 8 hours. Then, the ethanol was distilled off, and filtered. The resulting crude crystals were washed with water, then dried under reduced pressure. 2, 3-difluoro-6-nitroaniline 7.94g (45.6mmol, 91.2percent yield). 1H-NMR analysis results of the resulting compound were as follows.Ten batches, each of 2.00 g (11.3 mmol) of l, 2, 3-trifluoro-4-nitrobenzene and 4.2 ml (29.6 mmol) of 7N methanolic ammonia solution, were reacted sequentially for 90 min at 70A solution of 1, 2, 3-trifluoro-4-nitrobenzene (1) (1.00 g, 5.64 mmol, 1.00 equiv) in methanolic ammonia (1.5 mL) was taken in microwave vial and heated to 70° C. for 90 min in the microwave. 2- (0257) (Aminomethyl)-5-(trifluoromethyl)pyridine hydrochloride (0.180 g, 0.804 mmol) was neutralized with 1 M NaOH (0.84 mL). The resulting aqueous solution was extracted with CH2CI2 (3 x). The combined organic layers were dried (Na2S04), and concentrated in vacuo to give a yellowish oil that was dissolved in dry DMSO (1.6 mL) and treated with To a solution of NaH (180 mg, 3.99 mmol) was added portionwise to a solution of 1-(methyl- sulfonyl)piperidin-4-ol (425 mg, 2.25 mmol) in dry THF (10 mL). After 20 minutes, 2, 3 difluoro-6-nitroaniline (200 mg, 1.13 mmol) was added portionwise. The reaction mixture was stirred at 70C overnight, then quenched with saturated aqueous NH4Cl solution (1 mL) and concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The resulting material was taken up in EtOH (10 mL), and 10% Pd/C (35 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite (1 g), washing the plug with EtOAc. The residue was concentrated in vacuo to give the title compound (150 mg, 43% overall) as a brown solid. LCMS (Method 5): [M+H]+ m/z 304, RT 0.79 minutes.To a solution of pyridin-3-ylacetonitrile (0.32 mL, 3.0 mmol) in THF (10 mL) under N2 at 0C was added potassium tert-butoxide (348 mg, 3.04 mmol) portionwise. The reaction mixture was stirred for 30 minutes, then a solution of 2, 3 difluoro-6-nitro- aniline (500 mg, 2.82 mmol) in THF (3 mL) was added. The solution was stirred for a further 30 minutes. The reaction mixture was quenched with 2M aqueous HCl (1.5 mL) and stirred for 1 h, then concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The resulting material was taken up in EtOH (5 mL), and 10% Pd/C (22 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite (1 g), washing the plug with EtOAc. The residue was concentrated in vacuo to give the title compound (325 mg, 40% overall) as a brown oil. LCMS (Method 5): [M+H]+ m/z 243, RT 0.78 minutes.To a solution of 2, 3 difluoro-6-nitroaniline (300 mg, 1.69 mmol) in NMP (1 mL) at r.t. was added morpholine (150 mL, 1.69 mmol), followed by triethylamine (710 muL, 5.1 mmol). The reaction mixture was heated under focussed microwave irradiation for 1 h at 90C, then cooled to r.t., poured onto water (80 mL) and stood at r.t. for 1 h. The mixture was cooled to 0C in an ice bath, then filtered and dried for 4 h on a sintered funnel under suction. The resulting yellow solid was taken up in EtOH (10 mL), and 10% Pd/C (35 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite (1 g). The residue was concentrated in vacuo to give the title compound as a brown solid (301 mg, 92% overall). LCMS (Method 5): [M+H]+ m/z 225, RT 0.36 minutes.A solution of 3-(aminomethyl)-6-(trifluoromethyl)pyridine 3g (0.200 g, 1.08 mmol) and 2, 3-difluoro- 6-nitroaniline 4a (0.203 g, 1.13 mmol) in dry DMSO (2 mL) was treated under N2 with Et3N (0.16 mL, 1.19 mmol) and I2 (11 mg, 0.04 mmol). The reaction mixture was heated to 120 C for 30 h, cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on Si02 (acetone/hexanes, 1:8 to 1:5 to 1:4, containing Et3N (1%)) to afford 5m (0.302 g, 85%) as a yellow solid: Mp 151.8-152.2 C; IR (ATR) 3478, 3364, 1631, 1484, 1335, 1286, 1251, 1178, 1131, 1085 cm 1; lH NMR (400 MHz, acetone-de) d 8.81 (s, 1 H), 8.08 (d, 1 H, J = 8.0 Hz), 7.82 (d, 1 H, J = (0286) 8.4 Hz), 7.78-7.75 (m, 1 H), 6.71 (brs, 3 H), 6.27-6.21 (m, 1 H), 4.80 (d, 2 H, J = 6.4 Hz); 13C NMR (100 MHz, acetone-de) d 150.2, 147.2 (q, J = 34.0 Hz), 142.0 (d, J = 9.0 Hz), 139.6, 138.6 (d, J = 228.0 Hz), 137.3, 136.7 (d, J = 13.0 Hz), 125.6 (d, J = 4.0 Hz), 123.9 (d, J = 2.0 Hz), 122.8 (q, (0287) J = 271.0 Hz), 121.2 (q, J = 2.7 Hz), 101.5 (d, J = 3.3 Hz), 44.2; 19F NMR (376 MHz, acetone-de) d -68.2 (s, 3 F), -160.3 (s, 1 F); HRMS (HESI) m/z calcd for Ci HnN402F4 [M+H]+ 331.0813, found 331.0811.

Molecular Weight:174.10
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Exact Mass:174.02408370
Monoisotopic Mass:174.02408370
Topological Polar Surface Area:71.8
Heavy Atom Count:12
Complexity:185
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes