4-BROMO-2-IODOPHENOL

4-Bromo-2-iodophenol (4). 2-Iodophenol (11 g, 50 mmol) was dissolved in DCM (200 mL) and MeOH (100 mL). Tetrabutylammonium tribromide (TBATB) (25.31 g, 52.5 mmol) was then added portionwise over 10 min. The solution was stirred at room temperature for 2 h and then quenched with 1 N HCl (200 mL). The DCM layer was extracted and the aqueous layer was extracted another two times with DCM. The organic layers were then combined, washed with brine, dried, and concentrated. Purification of the residue with flash chromatography (silica, 50percent-100percent DCM/Hexanes) yielded 4-bromo-2-iodophenol (10.2 g, 68percent).4-Bromophenol (51.9 g, 0.30 mol) and N-iodosuccinimide (67.5 g, 0.30 mol) were combined in acetic acid (360 ML).The mixture was stirred briefly, treated with concentrated sulfuric acid (5 ML, 0.09 mol) and stirred at about 22° C. overnight.The mixture was poured into water (about 800 ML) with stirring to precipitate the product.The suspension was stirred for about 1 hour and filtered.The wet cake was washed with water (50 ML, 2*) and dried under reduced pressure at about 50° C. (80.9 g, 90percent). MS-DEI (M+H)+ m/z at 298; 1H NMR (CDCl3 at 400 MHz) δ5.28 (s, 1H), 6.86 (d, 1H), 7.33 (dd, 1H), 7.75 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ86.0, 112.8, 116.0, 132.7, 139.4, 153.7. Step A: To a solution of 4-bromophenol (25 g, 144.5 mmol) in 25percent aqueous ammonia solution (350 mL) was added a solution of potassium iodide (72 g, 433.5 mmol) and iodine (36.7 g, 144.5 mmol) in water (288 mL). The reaction mixture was stirred at ambient temperature for 2 h and quenched with 250 mL of water. The reaction was acidified by addition of concentrated HCl (350 mL) and extracted with dichloromethane. The combined organic extracts were dried over NaGeneral procedure: The general method for ultrasonically assisted brominationreaction is almost similar to conventional reaction as mentionedabove. A centimolar (0.01 mol) organic substrate (phenols, anilines, or acetanilides), 0.001 mol potassium halide(KBr), about 50 mg of dilute KHSO4, and hypervalent Cr(VI) reagent (IQCC or IQDC) were suspended in about30 mL solvent (DCE or ACN) in a previously cleaned roundbottom(R.B) flask placed in a sonicator. The reaction mixtureis sonicated at room temperature about 30–40 min. Progressof the reaction was monitored by TLC technique. Workupprocedure after completion of the reaction mixture is similarto the one described previously.To a solution of 2-amino-4-bromophenol (2 g, 8.9 mmol, 1.0 equiv) in HC1 (5 M, 12.5 mE, 7.0 equiv) was added drop-wise a solution of sodium nitrite (0.62 g, 8.9 mmol, 1.0 equiv) in water (5 mE) at 00 C. The mixture was stirred at this temperature for 30 mm afier which a cooled solution of KI (1.5 g, 8.9 mmol, 1.0 equiv) inH2O (14 mE) was slowly added at 00 C. The mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mE) and the separated aqueous phase was extracted with ethyl acetate (100 mEx3). The combined organic fraction was washed with Na2S2O3 (10percent, 40 mE), water (100 mEx2) and brine (40 mE), dried over Na2SO4 and concentrated to dryness.11219] The residue was purified by flash silica gel chromatography (ethyl acetate/hexanes) to afford 1.1 g 4-bromo-2- iodo-pheno as a yellow solid.The product from Example 3A (14.95 g, 50 mmol), palladium(II) acetate (0.11 g, 0.5 mmol), triphenylphosphine (0.26 g, 1.0 mmol), and copper(l) iodide (0.19 g, 1.0 mmol) were combined in isopropyl acetate (100 ML).nitrogen gas was bubbled through the reaction mixture for about 15 minutes.The mixture was treated with 3-butyn-1-ol (5.6 ML, 75.0 mmol) stirred briefly and then treated with diisopropylamine (42 ML, 300 mmol) slowly over about 10 minutes.After stirring for 2 hours at about 22 C., the mixture was heated at about 60 C. for about 6 hours and then cooled to about 22 C. The reaction mixture was filtered through a pad of Celite (~5 g) and the Celite was washed with isopropyl acetate (~30 ML).The filtrate was washed with saturated NaHCO3 solution (100 ML, 2*), 10% Na2S2O3 solution (100 ML, 2*), brine (50 ML), dried over Na2SO4, and distilled to dryness.The residue was purified by silica gel column chromatography to provide the title compound (8.7 g, 72% yield). MS DCl (M+NH4)+ m/z at 258, 260; 1H NMR (CDCl3 at 400 MHz) delta3.03 (m, 2H), 3.98 (m, 2H), 6.45 (m, 1 H), 7.25-7.32 (m, 2H), 7.60 (d, 1H); 13C NMR CDCl3 at 100 MHz) delta32.2, 60.6, 103.0, 112.1, 115.4, 122.8, 126.1, 130.4, 153.1, 157.0.(2R)-2-Methylpyrrolidine tartrate (1.17 g, 5.0 mmol), and potassium carbonate (1.38 g, 10.0 mmol) were combined in acetonitrile (20 ML) and heated at 60 C. for 1 hour.The mixture was treated with 3-butynyl 4-methylbenzenesulfonate (673 mg, 3.0 mmol) and heated at about 60 C. overnight.The mixture was cooled to about 5 C. and filtered.The mixture was treated with the product from Example 3A (300 mg, 1.0 mmol), diisopropylamine (1.20 g, 11.8 mmol), dichlorobis(triphenylphosphine)palladium (II) (35.1 mg, 0.05 mmol), and copper iodide (38.0 mg, 0.20 mmol).After stirring overnight at about 30 C., the mixture was concentrated to dryness.The residue in ethyl acetate (20 ML) was washed with 5% NaHCO3 (20 ML*2) and 25% brine (25 ML).The organic phase was separated, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated to dryness to provide the title compound. MS (esi): 308, 310 (M+H)+; 1H-NMR (CDCl3) delta7.58 (1H, d, J=1.7 Hz), 7.27 (2H, m), 6.38 (1 H, s), 3.20 (2H, m), 2.95 (2H, m), 2.43 (1H, m), 2.28 (1H, m), 2.19 (1H, q, J=8.8 Hz), 1.95 (1H, m), 1.75 (2H, m), 1.42 (1H, m), 1.13 (3H, d, J=6.2 Hz); 13C-NMR (CDCl3) delta158.8, 152.9, 130.6, 125.7, 122.6, 115.2, 111.9, 101.8, 60.0, 53.9, 51.9, 32.9, 28.4, 22.0, 19.3.To a solution of (F?)-methyl 2-hydroxypropanoate (1.1 ) (1 mmol), To a solution of (R)-methyl 2-hydroxypropanoate (1.1) (1 mmol),

Molecular Weight:298.90
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:297.84902
Monoisotopic Mass:297.84902
Topological Polar Surface Area:20.2
Heavy Atom Count:9
Complexity:99.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes