2-Chloro-3-nitrophenol

Synthesis of [2-CHLORO-3- (2, 2-DIMETHYL-4-PHENETHYLSULFANYLMETHYL-1, ] 2- dihydroquinoline-6-yl) phenol OH z O < \ CI 8r OrB/ H H Suzuki OH OH ci ci \I \I I/ \ \ I \ N N H H 10 To a suspension of 2-amino-3-nitrophenol (10 g, 65 mmol) in concentrated [HC1] (10 mL) at [0°C, ] sodium nitrite (5.1 g, 73.3 mmol) in water (60 [ML)] was added dropwise. After stirring for 30 minutes at [0°C, ] CuCl (12.8 g, [130] mmol) in 10percent [H2SO4] (3 mL) was added and the reaction was stirred for 18 hours. The heterogeneous mixture was filtered and washed with water. The filtrate was extracted three times with 70 mL portions of EtOAc. Evaporation of EtOAc extractions afforded 7 grams (62percent yield) of pure [2-CHLORO-3-NITROPHENOL, ] 2-Chloro-3- nitrophenol (6 g, 35 mmol) was dissolved in methanol (100 [ML)] and treated with ammonium chloride (9.4 g, 175.7 mmol) and zinc dust (46 g, 702.8 mmol). The resulting mixture was refluxed for one hour. After filtration and evaporation, 2-chloro-3-aminophenol was collected (4.5 g, 90percent yield) as a purple solid. To a suspension of 2-chloro-3-aminophenol (4.5 g, 31 mmol) in concentrated [HCI] (10 mL) at [0°C] was added dropwise sodium nitrite (2.5 g, 35 mmol) in water (50 mL). After stirring for 30 minutes at [0°C, ] [I (I] (10.4 g, 63 mmol) in 10percent [H2SO4] (3 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours, then filtered, extracted with EtOAc, and concentrated in vacuo to afford 2-chloro-3-iodophenol as a dark purple solid (6 g, 75percent yield). 6-Bromo-2, 2, [4-TRIMETHYL-1, ] 2-dihydroquinoline (2.3 g, 9.2 mmol) (Example 8) and bis (pinacol) diborane (4.2 g, 16.5 mmol) were combined in DMSO (2 mL). [KOAC] (2.7 g, 27.4 mmol) was added, followed by [PDCL2] (dppf) (100 mg). The contents were placed into a microwave reaction vessel assembly and irradiated at [120°C] for 15 minutes. After cooling to room temperature, purification by chromatography afforded 2, 2, [4-TRIMETHYL-6- (4, ] 4, 5, 5- tetramethyl- [1, 3, 2] [DIOXABOROLAN-2-YL)-1, ] 2-dihydroquinoline (2.3 g, [84percent] yield) as a white crystalline solid. 2, 2, [4-TRIMETHYL-6- (4, ] 4, 5, [5-TETRAMETHYL- [1, ] 3, 2] [DIOXABOROLAN-2-YL)-1, ] 2-dihydroquinoline [(308] mg) and 393 mg of 2-chloro-3-iodophenol were coupled using of 100 mg [OF PDCL2 (DPPF)] and [300 MG OF KOAC TO GIVE 250 MG OF 2-CHLORO-3- (2, 2, 4-TRIMETHYL-1, 2-DIHYDROQUINOLIN-6-YL) -] phenol. Using the procedures described in Example 7, this (85 mg) was reacted with NBS to give 56 mg [OF 3- (4-BROMOMETHYL-2, 2-DIMETHYL-1, 2-DIHYDROQUINOLIN-6-YL)-2-CHLOROPHENOL.] The product (50 mg) was coupled with 0.04 mL of 2-phenylethanethiol to give 40 mg of the title compound as an oil.2-Amino-3-nitrophenol B1 (5 g; 32.4 MMOL) was dissolved in concentrated HCI (75 ML) and 1, 4-dioxane (14. 7 mL). The mixture was heated to 70 C UNTIL most of the solids were in solution. The reaction mixture was cooled to 0 C (ice bath), and sodium nitrite (2.23 g; 32.3 MMOL) in H20 (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained BELOW 10 C during the addition and the stirring was continued for an additional 15 min at 0°C. This diazonium intermediate was poured into a solution of Cu (I) CI (3.8 g; 38.9 MMOL) in H20 (18. 5 mL) and conc. HCI (18.5 mL) at 0 C. The reaction was stirred for 15 min at 0 C, WARMED TO 60 C, and stirred for an additional 15 min The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3X 150 mL). The organic layers were combined, washed with brine (1X), dried (NA2SO4), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil. The crude material was purified by flash column chromatography (1 : 25 ultra pure silica gel, 230-400 mesh, 40-60 MM, 60 angstroms; 3: 1 hexane/EtOAcas the solvent) to afford pure 2-chloro-3-nitrophenol C2 (48percent; 2.7 g) as an orange solid. MS 171. 8 (MH)- : Homogeneity by HPLC (TFA) 220 nm: 96percent. Relevant literature for the Sandmeyer Reaction: J. Med. Chem, 1982, 25 (4), 446- 451.Step A:; 2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in concentratedHCI (75 ml) and 1, 4-dioxane (14.7 ml). The mixture was heated to 70°C until most ofthe solids were in solution. The reaction mixture was cooled to 0°C (ice bath), andsodium nitrite (2.23 g; 32.3 mmol) in H2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in concentratedHCI (75 ml) and 1, 4-dioxane (14.7 ml_). The mixture was heated to 70°C until most ofthe solids were in solution. The reaction mixture was cooled to 0°C (ice bath), andsodium nitrite (2.23 g; 32.3 mmol) in HINTERMEDIATE PREPARATION 152-chloro-3-[ 1-methylethyl)oxy]aniline2-chloro-3-nitrophenolA mixture of 2-amino-3-nitrophenol (23.7 g, 154 mmol) was dissolved in concentrated HCI (356 mL, 4.27 mol) and 1 , 4-dioxane (70 mL) and heated to 70°C until most of the solids were in solution. The reaction mixture was cooled to 0°C and sodium nitrite (10.61 g, 154 mmol) in water (26.0 mL) was added over a period of 3 h. The temperature was maintained below 10°C during the addition and stirring was continued for an additional 15 min at 0°C. This diazonium intermediate was poured into a solution of copper(l) chloride (18.27 g, 185 mmol) in water (90 mL) and concentrated HCI (90 mL) at 0°C. The reaction was stirred for 15 min at 0°C, warmed to 60°C, and stirred for an additional 15 min. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was transferred to a separatory funnel and extracted with Et1.1. The nitrophenol starting material C2 (1.3 g; 7.49 MMOL) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 MMOL), followed by Mel (1. 4 mL; 22. 5 MMOL). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 ML), washed with water (150 mL), brine (4x 100 mL), and then dried(MGSO4) THE organic phase was filtered and evaporated to afford the crude 2- CHLORO-3-NITROANISOLE C3 (98%; 1.38 g) as an orange solid. Homogeneity by HPLC (TFA) 220 nm: 93%.Step B:; The nitrophenol starting material 1c1 (1.3 g; 7.49 mmol) was dissolved inDMF (10 ml) and to this solution was added ground cesium carbonate (2.92 g; 8.96mmol), followed by Mel (1.4 ml; 22.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated in vacuo and the residue taken upin ether (150 ml), washed with water (150 ml), brine (4 X 100 mL), and then driedover (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 1c2 (98%; 1.38 g) as an orange solid.The nitrophenol starting material 1c1 (1.3 g; 7.49 mmol) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 mmol), followed by MeI (1.4 mL; 22.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 mL), washed with water (150 mL), brine (4×100 mL), and then dried(MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 1c2 (98%; 1.38 g) as an orange solid.The nitrophenol starting material 2c1 (1.3 g; 7.49 mmol) was dissolved inDMF (10 ml) and to this solution was added ground cesium carbonate (2.92 g; 8.96mmol), followed by Mel (1.4 ml; 22.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated in vacua and the residue taken upin ether (150 ml), washed with water (150 ml), brine (4 X 100 ml), and then driedover (MgSO4). The organic phase was filtered and evaporated to afford the crude 2-chloro-3-nitroanisole 2c2 (98%; 1.38 g) as an orange solid.Homogeneity by HPLC (TFA) (at) 220nm: 93%.3-Nitrophenol (10 g, 72 mmol) was dissolved in hot concentrated hydrochloric acid (100 ml) and cooled rapidly (ice-brine bath) to give a fine suspension. Potassium chlorate (8.8 g, 72 mmol) was dissolved in water (100 ml) and added to the mixture and stirring continued at 0C for 2 hours. The reaction mixture was extracted with ethyl acetate (2X100 ml) and the combined organic extracts washed with water (100 ml), brine (100 ml), dried over sodium sulfate and evaporated in vacuo (water bath temp <45C) to give (ii) Examples of the hydroxyaryl compound (formula 2): ... nitrophenol, cyanophenol, chlorophenol, fluorophenol,

Molecular Weight:173.55
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:172.9879707
Monoisotopic Mass:172.9879707
Topological Polar Surface Area:66
Heavy Atom Count:11
Complexity:158
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes