1-broMo-4-fluoro-2-Methyl-3-nitrobenzene

l-Bromo-4-fluoro-2-methyl-3-nitrobenzene (C)(C) [00170] A 250 mL single neck flask equipped with magnetic stirrer was charged with 3-fluoro-2-nitrotoluene (4.75 g, 30.6 mmol) and trifluoroacetic acid (20 mL). Sulfuric acid (96percent, 10 mL) was added dropwise over 10 minutes at 0 To 1-fluoro-3-methyl-2-nitrobenzene 8-1 (5 g, 32.25 mmol) at 0 °C under argonatmosphere was added concentrated sulfuric acid: trifluoroacetic acid (1: 2, 45 mL). To thiswas added N-bromosuccinimide (8.61 g, 48.37 mmol) portion wise for 15 mm; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (200 mL), the precipitated solid was filtered, washed with water (100 mL) and dried in vacuo to afford the crude. The crude waspurified through silica gel flash column chromatography using 1-2percent EtOAc/ hexanes to afford compound 8-2 (5.1 g, 68percent). TLC: 5percent EtOAc/ hexanes (Rj: 0.8); TLC: 30percent EtOAc/ hexanes (Rf: 0.3). 1H NMR (DMSO-d6, 400 MHz): 7.96 (dd, J = 8.9, 5.2 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 22.35 (m, 3H)To a solution of l-fluoro-3-methyl-2-nitro-benzene (5 g, 32.24 mmol, 1.0 eq) in TFA (25 mL) and conc.HTo a stirred solution of compound 12 (25 g, 161.2 mmol) in TFA: conc. H2S04 (150 mL: 75 mL) at 0 °C, under argon atmosphere, NBS (43 g, 241.9 mmol) was added portion wiseand stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured in to ice cold water (700 mL); the precipitated solid was collected by filtration and washed with water. The residue was purified by silica gel column chromatography using 2percent EtOAc/ hexane to afford the title compound 13 (21 g, 56percent) as a light yellow solid. TLC: 10percent EtOAc/ hexane (R 0.6); ‘H NMR (400 MHz, DMSO-d6): ö 7.89 —7.86 (m, 1H), 7.48 (t, J = 9.6 Hz, 1H), 2.36 (s, 3H).[00220] 1-Fluoro-3-methyl-2-nitro-benzene (5 g, 32.2 mmol) was mixed withtrifluoroacetic acid (21 mL, 274.2 mmol) and cooled to 0 °C in a salt/ice bath. Sulphuric acid(10.5 mL, 32.2 mmol) was added portionwise over 10 minutes - the reaction mixture exothermed to 1 °C. The reaction was allowed to cool back to 0 °C and N-bromosuccinimide (8.5 g, 47.8 mmol) was added portionwise over approximately 10 minutes - maintaining the temperature below 2 00. The mixture was stirred overnight - the ice bath was not removed sothe reaction was allowed to slowly warm to ambient temperature. The reaction was poured into ice/water (500mls) - a solid precipitate could be seen on the top of the ice. The mixture was stirred vigorously for 5 minutes then a mixture of isohexane (230m1s) and DCM (2Omls) was added and the mixture stirred vigorously for 10 minutes - the layers were separated and the aqueous further extracted with a mixture of isohexane (230m1s) and DCM (2Omls). The twoorganic phases were washed separately with 2 x Dl water, 1 x saturated sodium bicarbonate, 1x brine and then combined and dried over anhydrous sodium sulphate. The organic solutionwas concentrated down to give crude material, roughly 3:1 ratio of desired product: dibromo HbO 8.38 (d) F 6.6Hz, (TLC 4:1 isohexane/DOM showed no starting material and two spots.)[00221] The crude material was crystallised from isohexane (lOOmis) - stirring used oncooling, then cooling and stirring in ice bath. A white solid was filtered off (0.53g).[00222] 1H NMR (DMSO-d6): 07.99 (dd, J=5.1 and 8.9Hz, 1H), 7.49 (t, J= 9.2 Hz, 1H), 2.37 (5, 3H).[00223] A second crop was obtained on standing, together yielding 2.17g, 27percent.General procedure: A mixed solution of sulfuric acid (10 mL) and trifluoroacetic acid (50 mL) was prepared under ice bath conditions.Add 2, 6-difluoronitrobenzene (5.0 g, 31.4 mmol), N-bromosuccinimide (6.15 g, 34.5 mmol) was added slowly in portions.The reaction solution was stirred at room temperature for 18 h, and then poured into ice water (100 mL).Ethyl acetate (3 x 50 mL) was extracted and the organic layer was washed with 2M sodium hydroxide.Dry over anhydrous sodium sulfate, filter, spin dry, Made a red oil (6.6g), Yield 90.0%To a solution of Na2S.9H2O (16.42 g, 68.37 mmol, 11.48 mL, 2 eq) in EtOH (80 mL) was dropwise added Compound 1 (8 g, 34.18 mmol, 1 eq). The mixture was stirred at 50 C. for 2 hr. The reaction was quenched by HCl to pH=5 slowly and then extracted with Ethyl acetate (80 mL*2). The combined organic phase was washed with water (80 mL*2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. Compound 2 (2.5 g, crude) as a green solid. 1H NMR (400 MHz, CDCl3) S=7.21 (d, J=8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 4.53 (br s, 1H), 2.32-2.29 (m, 3H).To a solution of 1 -bromo-4-fluoro-2-methyl-3-nitrobenzene (1 g, 4.27 mmol) in DMF (20 ml_) were added 2-ethoxyethan-1 -amine (0.381 g, 4.27 mmol) and K2C03 (0.591 g, 4.27 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified using column chromatography (silica gel, 0 to 60% EtOAc/hexanes) to give the desired product (760 mg) as a pale brown oil. LC-MS (ES) m/z =303, 305 [M+H]+. NMR (400 MHz, CDCI3): delta 1 .27 (t, J = 7.1 Hz, 3H), 2.47 (s, 3H), 3.36 (t, J = 5.3 Hz, 2H), 3.58 (q, J = 7.1 Hz, 2H), 3.65 - 3.72 (m, 2H), 6.61 (d, J = 9.1 Hz, 1 H), 7.51 (d, J =9.1 Hz, 1 H).

Molecular Weight:234.02
XLogP3:2.9
Hydrogen Bond Acceptor Count:3
Exact Mass:232.94877
Monoisotopic Mass:232.94877
Topological Polar Surface Area:45.8
Heavy Atom Count:12
Complexity:185
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes