1000801-26-2|4-(Difluoromethoxy)-2-iodoaniline| Ambeed

Yield	Reaction Conditions	Operation in experiment
53%	With sodium carbonate; lithium chloride;palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 6.0h;	INTERMEDIATE 7 (METHOD H)fert-Butyl (35)-3-[3-(trimethylsilv?prop-2-vn- 1 -yllmophiholine-4-carboxylateTo a solution of Intermediate 6 (8.05 g, 35.7 mmol) dissolved in anhydrous THF (250 mL) at 00C was added n-butyllithium (15.7 mL, 39.3 mmol, 2.5 M in hexanes) dropwise over 15 minutes. After stirring for 30 minutes, chlorotrimethylsilane was added slowly over 5 minutes and the reaction mixture stirred for 45 minutes and then allowed to warm to r.t. After stirring at r.t. for 18 h, the reaction mixture was quenched by the addition of water (ca 1 mL) and the solvent was removed in vacuo. The crude mixture was dissolved in DCM and washed with water, the aqueous phase was extracted with further DCM (500 mL) and the combined organic fractions were dried using an Isolute phase separator cartridge and concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 5-20% EtOAc/hexanes) gave the title compound (8.1 g, 76%) as a colourless oil and recovered starting material (1.25 g, 15%). delta? (CD3OD) 3.91 (IH, m), 3.82 (IH, d, J 11.7 Hz), 3.70 (IH, dd, J 3.6 and J 11.4 Hz), 3.58 (IH, dd, J 2.9 and J 13.7 Hz), 3.40-3.20 (2H, m), 2.95 (IH, m), 2.60 (IH, dd, J9.1 and J 16.7 Hz), 2.38 (IH, dd, J6.4 and J 16.7 Hz), 1.35 (9H, s), 0.00 (9H, s).
53%	With sodium carbonate; lithium chloride;palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 6.0h;Inert atmosphere;	To a solution of Intermediate 7 (0.571 g, 1.93 mmol) dissolved in DMF (23 mL) was added Intermediate 20 (0.55 g, 1.93 mmol), LiCl (0.082 g, 1.93 mmol), Na2CO3 (0.409 g, 3.86 mmol) and Pd(OAc)2 (0.017 g, 0.08 mmol) and the reaction mixture was degassed under vacuum and then purged with nitrogen. The reaction mixture was then heated at 100 C. for 6 h. The crude reaction mixture was cooled to r.t. and the solvent removed in vacuo to give a brown oil. Purification by column chromatography (SiO2, 10-30% EtOAc/hexanes; followed by SiO2, DCM) gave the title compound (0.462 g, 53%) as a yellow oil. LCMS (ES+) 399.0 ((M-tBu)+H)+, RT 3.95 minutes (Method 5).

Yield	Reaction Conditions	Operation in experiment
22%	With Iodine monochloride; In acetic acid; at 60 - 85℃; for 1.5h;	INTERMEDIATE 202-Iodo-4-difluoromethoxyanilineA solution of 4-(difluoromethoxy)aniline (1.0 g, 6.30 mmol) in AcOH (6 mL) was heated to 600C and iodine monochloride (1.07 g, 6.6 mmol) in AcOH (15 mL) was added dropwise. The reaction mixture was then heated to 85C and stirred for 1.5 h. The reaction mixture was cooled to r.t. and poured into cold water and the resulting suspension filtered. The filtrate was concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10-20% EtOAc/hexanes) gave the title compound (0.40 g, 22%) as a dark brown oil. deltaH (DMSO-d6) 7.38 (IH, d, J 2.7 Hz), 6.98- 6.94 (IH, m), 6.97 (IH, t, J74.8 Hz), 6.75 (IH, d, J 8.8 Hz), 5.20 (2H, br. s). LCMS (ES+) 286.0 (M+H)+, RT 3.28 minutes (Method 5).
22%	With Iodine monochloride; acetic acid; at 60 - 85℃;	A solution of 4-(difluoromethoxy)aniline (1.0 g, 6.30 mmol) in AcOH (6 mL) was heated to 60 C. and iodine monochloride (1.07 g, 6.6 mmol) in AcOH (15 mL) was added dropwise. The reaction mixture was then heated to 85 C. and stirred for 1.5 h. The reaction mixture was cooled to r.t. and poured into cold water and the resulting suspension filtered. The filtrate was concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10-20% EtOAc/hexanes) gave the title compound (0.40 g, 22%) as a dark brown oil. deltaH (DMSO-d6) 7.38 (1H, d, J 2.7 Hz), 6.98-6.94 (1H, m), 6.97 (1H, t, J 74.8 Hz), 6.75 (1H, d, J 8.8 Hz), 5.20 (2H, br. s). LCMS (ES+) 286.0 (M+H)+, RT 3.28 minutes (Method 5).

4-(Difluoromethoxy)-2-iodoaniline

CAS No.: 1000801-26-2

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