* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With iodine; silver trifluoroacetate In chloroform at 20℃; for 62 h;
Add a fine suspension of iodine (25.4 g, 100 mmol) in CHCl3 (700 mL) dropwise to a stirred mixture of 3-methoxyphenol (10.8 mL, 100 mmol), silver trifluoroacetate (22.1 g, 100 mmol), and CHC13 (100 mL) over 2h under N2 at room temperature. Stir at room temperature under N2 for 60h then filter mixture over Celite0 and rinse pad with CHCL3. WASH solution with aqueous 0.1 N NA2S204 solution, saturated NAHCO3 solution and backextract from aqueous with CHCl3. Dry combined organic layers over NA2SO4 and concentrate to get 26.6 g brown oil. Purify the residue by flash chromatography on silica gel eluting with CHCl3 to afford 2-iodo-5-methoxy-phenol (18.4 g, 74percent). MS (IS) 249 (M-1)-. Add copper (1) iodide (0.28 g, 1.5 mmol) to a stirred solution of 2-iodo-5- methoxy-phenol (18.4 g, 73.6 mmol) and trimethylsilyl acetylene (15.6 mL, 110.4 mmol) in THF (225 mL, anhydrous) in a dry RB flask. Add dichlorobis (triphenylphosphine) palladium (II) (1.55 g, 2.2 mmol) and diisopropylamine (21.7 mL, 154.5 mmol) and stir the mixture at room temperature under N2 overnight Quench reaction with water and extract with EtOAc (x3). Dry combined organic layers over MGS04 and concentrate to get 29 g black oil. Adsorb on SI02 and purify the residue by flash chromatography on silica gel eluting with 0-15percent EtOAc/hexanes to afford 5-methoxy-2- trimethylsilanylethynyl-phenol (11.5 g, 71percent). MS (IS) 221 (M+1) +. Add diisopropylamine (11.0 mL, 78.3 mmol) to a rapidly stirred solution OF 5- methoxy-2-trimethylsilanylethynyl-phenol (11.5 g, 52. 2 mmol) in CHZCLZ at room temperature under N2. Add 2- (trimethylsilyl) ethoxymethyl chloride (13.9 mL, 78.3 mmol) dropwise over 5 minutes and stir at room temperature under N2 overnight Acidify with aqueous 1N HCl solution, add water, separate layers. Extract from aqueous layer with CH2C12 (x2), dry combined organic layers over MgS04 and concentrate. Adsorb on SI02 and purify the residue by flash chromatography on silica gel eluting with 0-5percent ETOAC/HEXANES to afford 4-methoxy-2- (2-trimethylsilanyl-ethoxymethoxy)-l- trimethylsilanylethynyl-benzene (13.5 g, 74percent). MS (IS) 351 (M+1) . Add a solution of potassium hydroxide (2.3 g, 40.4 mmol) in water (20 ML) dropwise to a rapidly stirred solution of 4-METHOXY-2- (2-TRIMETHYLSILANYL- ETHOXYMETHOXY)-L-TRIMETHYLSILANYLETHYNYL-BENZENE (13.5 g, 38. 5 mmol) in methanol (200 ML) and stir at room temperature for 1 hour. Concentrate, add brine to residue and extract with EtOAc (x2). Dry combined organic layers over MGS04 and concentrate to get 11.7 g brown oil. Adsorb on Si02 and purify the residue by flash chromatography on silica gel eluting with 0-10percent EtOAc/hexanes to afford [2- (2-ethynyl-5-methoxy- PHENOXYMETHOXY)-ETHYL]-TRIMETHYL-SILANE (10.0 g, 93percent). MS (IS) 279 (M+1) +. Add 1,4-phenylenediisocyanate (6.41 g, 40. 0 mmol) to a stirred solution of [2- (2- ETHYNYL-5-METHOXY-PHENOXYMETHOXY)-ETHYL]-TRIMETHYL-SILANE (5.57 g, 20.0 mmol) and 6- nitro-hexanoic acid ethyl ester (7.56 g, 40.0 mmol) in toluene (150 mL, anhydrous) and stir under N2. Add triethylamine (5.6 ML, 40.0 mmol) and heat to reflux under N2. After 2 hours add additional toluene (150 mL, anhydrous) and continue refluxing overnight. Filter mixture through a pad of CELITE#x0;COMMAT; and rinse with toluene. Concentrate to get 8.7 g yellow oil. Purify the residue by flash chromatography on silica gel eluting with 0-20percent EtOAc/hexanes then 0-30percent ET20/HEXANES to afford the title compound (5.20 g, 58percent). Correct regioisomer is confirmed by NOESY. MS (IS) 450 (M+1) +.
69%
With N-iodo-succinimide; trifluoroacetic acid In acetonitrile at 20℃; for 0.833333 h; Inert atmosphere
To a solution of 3-methoxyphenol (10, 517.7 mg, 96 percent, 4.0 mmol) in MeCN (16 mL) were added trifluoroacetic acid (0.09 mL, 1.2 mmol) and N-iodosuccinimide (1.424 g, 8.0 mmol). The solution was stirred at ambient temperature for 50 min and quenched with saturated aqueous Na2S2O3 solution. The mixture was extracted three times with EtOAc, and the combined organic layers were dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by flash chromatography (isohexane/DCM/EtOAc 10:2:1) to afford phenol 7 (687.6 mg, 69 percent) as an off-white solid.
52.87%
With iodine; silver trifluoroacetate In chloroform at 20℃; for 24 h;
(1) 250 mL of a round bottomed flask,I2 (5.1 g, 20.0 mmol) was dissolved in chloroform (150 mL)And stirred for more than 1.5 hours. another,Compound No. 1 (R1 = H) (20.0 mmol) was placed in 250 mL of a round bottomed flask,Silver trifluoroacetate AgOTFA (4.5 g, 20.0 mmol) was added.The chloroform solution was slowly added (about 2-3 hours) into a tin foil-wrapped flask,The reaction was stirred at room temperature for 24 hours. filter,And the residue was washed with chloroform. Then with saturated Na2S2O3 solution,Saturated NaHCO3 solution,Saturated brine, and the resulting organic phase was dried over anhydrous Na2SO4.Filtered and concentrated under reduced pressure and subjected to column chromatography (using CH2Cl2 as eluent and column chromatography).To obtain the product,2-iodo-5-methoxyphenol (Formula 2, R1 = H).The white solid was 52.87percent yield.
Reference：
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[2] Chemical Communications, 2016, vol. 52, # 29, p. 5152 - 5155
[3] Organic and Biomolecular Chemistry, 2017, vol. 15, # 9, p. 1956 - 1960
[4] Chemical Communications, 2018, vol. 54, # 39, p. 4935 - 4938
[5] Patent: WO2005/19184, 2005, A1, . Location in patent: Page/Page column 65-66
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[15] Patent: WO2005/63739, 2005, A1, . Location in patent: Page/Page column 50-51
3
[ 150-19-6 ]
[ 7440-44-0 ]
[ 41046-70-2 ]
Yield
Reaction Conditions
Operation in experiment
55%
With NaH In methanol; iodine; methyl cyclohexane; toluene
a. 2-Iodo-5-methoxyphenol To a round bottom flask under nitrogen was added 8.4 g (0.174 mole) of 50percent NaH in oil. The NaH was washed twice with hexane, cooled to 0° C. in ice, and 20.0 g (0.161 mole) of m-methoxyphenol in 200 ml of toluene was added with stirring. After the evolution of hydrogen was complete 34.1 g (0.134 mole) of iodine dissolved in 600 ml of toluene was added over 30 minutes. A 100 ml portion of toluene was used to wash in the remaining iodine. The reaction was stirred for 11/2 hrs., ether was added and the organic layer washed with 3N HCl, water, sodium thiosulfate, brine and dried with MgSO4. The solvent was evaporated in vacuo and the residue crystallized from 1:1 toluene:methylcyclohexane to give 24.1 g of green solid. The green solid was stirred with charcoal in methanol for 1/2 hr., the solution filtered, and evaporated in vacuo, and the resulting residue recrystallized in 1:1 toluene:methylcyclohexane to give 19.8 g (55percent yield) of 2-iodo-5-methoxyphenol, mp 70°-72.5° C.
With copper(l) iodide; N,N,N',N'-tetramethylguanidine;bis-triphenylphosphine-palladium(II) chloride; In DMF (N,N-dimethyl-formamide); at -78 - 20℃; for 18h;
A pressure tube was charged with a stir bar 2-lodo-5-methoxyphenol (500mg, 2. 0mmol) (prepared according to Heterocycles 45, (6), 1997,1137), Cl2Pd (PPh3) 2 (70mg, [0.] 1mmol), Cul (19mg, [0.] [1MMOL),] 1,1, 3, [3-TETRAMETHYLGUANIDINE] (2. 5ml, 20. 0mmol) and DMF (10 [ML),] then cooled [TO-78] while propyne gas was condensed. The tube was sealed and allowed to warm to room temperature. After 18 hours, the contents of the tube were poured into sat NaCI solution and extracted with EtOAc (2x). The combined organic layers were washed with brine (3x), dried [(MGS04)] and concentrated under reduced pressure. The residue was flash chromatographed on silica gel eluting 3: 1 (hexanes/ethyl acetate) to give 239mg (74%) of an amber [LIQUID.'H] NMR [(DMSO-D6) No. ]7.31 [(1 H,] d, J = 8.3 Hz), 6.95 [(1 H,] [D,] J = 2.2 Hz), 6.80 (1 H, dd, J = 2.2, 8.3 Hz), 6.27 (1 H, s), 3.85 (3H, s), 2.40 (3H, s). AnaL Calcd for [C10H1002 ]0.05 hexanes: [C,] 74.30 ; H, 6.48. Found: [C,] [74. 63] ; H, 6.48.
69%
With copper(l) iodide; N,N,N',N'-tetramethylguanidine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at -78 - 20℃; for 55h;
Step 1 6-methoxy-2-methyl-benzofuranA solution of <strong>[41046-70-2]2-iodo-5-methoxy-phenol</strong> (39 g, 156 mmol) in dimethylformamide (300 mL) and N,N,N',N'-tetramethylguanidine (150 mL) is treated with copper(I) Iodide (1.89 g, 9.82 mmol) and bis(triphcnylphosphinc)palladium(II) chloride (1.9 g; 2.71 mmol; 1.900 g). The mixture is cooled to -78 0C. Propyne (100 g; 2.50 moles) is bubbled through the mixture for 1 hour. The reaction mixture is stirred <n="28"/>and allowed to warm to room temperature gradually over 6 hours and stirred for 2 days. The reaction mixture is quenched with water (800 mL) and extracted with EtOAc (500 mL). The organic layers are dried over Na2 SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are concentrated. The material is dried in vacuo to afford the title compound (17.5 g, 69%). 1H NMR (400 MHz, CDCl3): delta 7.31- 7.29 (d, IH), 6.95 (s, IH), 6.81-6.79 (d, IH), 6.26 (s, IH), 3.81 (s, 3H), 2.40 (s, 3H).
46%
With copper(l) iodide; N,N,N',N'-tetramethylguanidine;bis-triphenylphosphine-palladium(II) chloride; In DMF (N,N-dimethyl-formamide); at -78℃; for 17h;
A solution of compound 5-B (14.6 g, 58.5 mmol), Cul (0.56 g, 2.9 mmol), NN, IV, IV- tetramethylguanidine (74 mL, 585 mmol) and dichlorobis (triphenyl phosphine) palladium (II) (3.9 g, 5.5 mmol) in 200 mL anhydrous DMF was cooled to-78 C. Propyne gas was bubbled in for 25 minutes. A balloon was placed to catch propyne. The reaction mixture was stirred for 17 hours, allowing temperature to go from-78 C to room temperature. The solution was poured into 200 mL water and extracted with EtOAc, washed with water, brine and dried over MgS04. Silica gel column chromatography eluted with hexane/ethyl acetate (9: 1) gave 6-methoxy-2-methyl-1- benzofuran 5-C (4.4 g, 46% yield).
Add a fine suspension of iodine (25.4 g, 100 mmol) in CHCl3 (700 mL) dropwise to a stirred mixture of 3-methoxyphenol (10.8 mL, 100 mmol), silver trifluoroacetate (22.1 g, 100 mmol), and CHC13 (100 mL) over 2h under N2 at room temperature. Stir at room temperature under N2 for 60h then filter mixture over Celite0 and rinse pad with CHCL3. WASH solution with aqueous 0.1 N NA2S204 solution, saturated NAHCO3 solution and backextract from aqueous with CHCl3. Dry combined organic layers over NA2SO4 and concentrate to get 26.6 g brown oil. Purify the residue by flash chromatography on silica gel eluting with CHCl3 to afford <strong>[41046-70-2]2-iodo-5-methoxy-phenol</strong> (18.4 g, 74%). MS (IS) 249 (M-1)-. Add copper (1) iodide (0.28 g, 1.5 mmol) to a stirred solution of 2-iodo-5- methoxy-phenol (18.4 g, 73.6 mmol) and trimethylsilyl acetylene (15.6 mL, 110.4 mmol) in THF (225 mL, anhydrous) in a dry RB flask. Add dichlorobis (triphenylphosphine) palladium (II) (1.55 g, 2.2 mmol) and diisopropylamine (21.7 mL, 154.5 mmol) and stir the mixture at room temperature under N2 overnight Quench reaction with water and extract with EtOAc (x3). Dry combined organic layers over MGS04 and concentrate to get 29 g black oil. Adsorb on SI02 and purify the residue by flash chromatography on silica gel eluting with 0-15% EtOAc/hexanes to afford 5-methoxy-2- trimethylsilanylethynyl-phenol (11.5 g, 71%). MS (IS) 221 (M+1) +. Add diisopropylamine (11.0 mL, 78.3 mmol) to a rapidly stirred solution OF 5- methoxy-2-trimethylsilanylethynyl-phenol (11.5 g, 52. 2 mmol) in CHZCLZ at room temperature under N2. Add 2- (trimethylsilyl) ethoxymethyl chloride (13.9 mL, 78.3 mmol) dropwise over 5 minutes and stir at room temperature under N2 overnight Acidify with aqueous 1N HCl solution, add water, separate layers. Extract from aqueous layer with CH2C12 (x2), dry combined organic layers over MgS04 and concentrate. Adsorb on SI02 and purify the residue by flash chromatography on silica gel eluting with 0-5% ETOAC/HEXANES to afford 4-methoxy-2- (2-trimethylsilanyl-ethoxymethoxy)-l- trimethylsilanylethynyl-benzene (13.5 g, 74%). MS (IS) 351 (M+1) . Add a solution of potassium hydroxide (2.3 g, 40.4 mmol) in water (20 ML) dropwise to a rapidly stirred solution of 4-METHOXY-2- (2-TRIMETHYLSILANYL- ETHOXYMETHOXY)-L-TRIMETHYLSILANYLETHYNYL-BENZENE (13.5 g, 38. 5 mmol) in methanol (200 ML) and stir at room temperature for 1 hour. Concentrate, add brine to residue and extract with EtOAc (x2). Dry combined organic layers over MGS04 and concentrate to get 11.7 g brown oil. Adsorb on Si02 and purify the residue by flash chromatography on silica gel eluting with 0-10% EtOAc/hexanes to afford [2- (2-ethynyl-5-methoxy- PHENOXYMETHOXY)-ETHYL]-TRIMETHYL-SILANE (10.0 g, 93%). MS (IS) 279 (M+1) +. Add 1,4-phenylenediisocyanate (6.41 g, 40. 0 mmol) to a stirred solution of [2- (2- ETHYNYL-5-METHOXY-PHENOXYMETHOXY)-ETHYL]-TRIMETHYL-SILANE (5.57 g, 20.0 mmol) and 6- nitro-hexanoic acid ethyl ester (7.56 g, 40.0 mmol) in toluene (150 mL, anhydrous) and stir under N2. Add triethylamine (5.6 ML, 40.0 mmol) and heat to reflux under N2. After 2 hours add additional toluene (150 mL, anhydrous) and continue refluxing overnight. Filter mixture through a pad of CELITE COMMAT; and rinse with toluene. Concentrate to get 8.7 g yellow oil. Purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes then 0-30% ET20/HEXANES to afford the title compound (5.20 g, 58%). Correct regioisomer is confirmed by NOESY. MS (IS) 450 (M+1) +.
With sodium carbonate; lithium chloride;palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 4h;
A suspension of <strong>[41046-70-2]2-<strong>[41046-70-2]iodo-5-methoxyphenol</strong></strong> (1.1 g, 4.41 mmol), -(tert-buty- dimethylsilanyl)-3-(tert-butyl-dimethyl-silanyloxy)-propyne (1.5 g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100 0C was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (tic) and the solvent was removed by distillation under vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl ether/triethylamine; 95:5:1%) to give the title compound as a yellow oil; (1.09 g, 87 %); 1H NMR (300 MHz, CDCl3) delta 7.52(d, IH, J= 8.57 Hz), 6.97(d, IH5 J = 2.15 Hz), 6.83(dd, IH, J = 8.54, 2.18 Hz), 4.81(s, 2H, CH2), 3.83(s, 3H, OMe), 0.93(s, 9H), 0.91(s, 9H), 0.34(s, 6H), 0.11(S, 6H).
87%
With sodium carbonate; lithium chloride;palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 4h;
Step 1 : te/'/-Butyldimethylsilyl-3-(^buty IdimethylsilyIoxymethyIene)-6- methoxybenzofuran (Larock coupling) A suspension of <strong>[41046-70-2]2-<strong>[41046-70-2]iodo-5-methoxyphenol</strong></strong> (1.1 g, 4.41 mmol), 1 -(t°/Y-butyldimethylsilyl)- 3-(te7'/-butyldimethylsilyloxy)propyne (1.5 g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100 0C was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (monitored by tic) and the solvent was removed by distillation under vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl ether/tiethylamine; 95:5:1%) to give the title compound as a yellow oil (1.09 g, 87 %); 1H NMR (300 MHz, CDCl3) delta 7.52(d, IH, J= 8.57 Hz), 6.97(d, IH, J = 2.15 Hz), 6.83(dd, IH, J = 8.54, 2.18 Hz), 4.81(s, 2H, CH2), 3.83(s, 3H, OMe), 0.93(s, 9H), 0.91(s, 9H), 0.34(s, 6H), 0.1 l(s, 6H).
2-(2-furyl)-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzo[6]furan[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With sodium carbonate; lithium chloride;palladium diacetate; In N,N-dimethyl-formamide; at 100 - 105℃; for 6h;
5-Iodo-5-methoxyphenol (125mg, 0.5 mmol), 3-(2-furyl)-l-(3,455-trimethoxyphenyl)- prop-2-yn-l-one (172 mg, 0.6 mmol), LiCl (21.2 mg, 0.5 mmol) and Na2CO3 (265 mg, 2.5 mmol) were added to anhydrous DMF (3 ml) and flushed with N2 three times. Pd(OAc)2 was added to the reaction mixture and again flushed with N2. The reaction mixture was heated to 100-105 0C for 6 h and then reaction was cooled to room temp. Quenched by addition of aqueous NH4Cl solution and extracted with EtOAc. 2-(2-Furyl)-6-methoxy-3- (3,4,5-trimethoxybenzoyl)benzo[Z>]ruran was isolated in 12% yield by silica gel column chromatography using 20 to 40% EtOAc in hexane. 1H NMR (300MHz5 CDCl3) delta: 3.75(s,6H5 OMe)5 3.86(s, 3H5 OMe), 3.90(s, 3H5 OMe)5 6.44-6.46(m, IH), 6.87(dd, J=2.1, 8.7, EPO <DP n="115"/>U2006/000192- 114 -IH)5 6.97(d, J=3.6, IH), 7.07(d, J=2.1, IH), 7.15(s, 2H)5 7.36(d, J=SJ, IH), 7.41(d, J=I.2, IH). MS (ES) m/z: 408.9(M+H)+
This compound was prepared by application of the general procedure to 2-iodo-5- methoxy-phenol, 4-ethynyl-l-(4-methoxy-benzyl)-lH-pyrazole and 3,4,5-trimethoxy-iodo- benzene. The crude product was stirred with potassium carbonate (excess) in methanol for3 h to hydrolyse ester by-products and submitted to silica-gel flash chromatography (eluent= 2:1 hexanes: ethyl acetate) to afford a mixture of the title compound and the corresponding non-carbonyl inserted derivative. This mixture was used directly in the subsequent deprotection. An analytical sample was purified by recrystallisation from dichloromethane/hexane. 1H-NMR (CDCl3) delta 8.03 (s, IH), 8.01 (s, IH), 7.18 (d, J = 8.6Hz, 2H), 7.14 (d, J = 8.7 Hz, IH), 7.10 (s, 2H), 7.02 (d, J = 2.2 Hz, IH), 6.86 (d, J = 8.6Hz, 2H), 6.79 (dd, J = 8.7, 2.2 Hz, IH), 5.22 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.78 (s,3H), 3.75 (s, 6H). 13C-NMR (CDCl3) delta 190.2, 159.5, 158.1, 154.2, 153.3, 152.9, 142.3, 139.1, 133.6, 129.8, 129.3, 127.6, 121.7, 120.9, 114.2, 113.8, 112.9, 112.2, 107.0, 95.5,60.9, 56.1, 55.8, 55.6, 55.2.; General Procedure for Carbonylative Multicomponent CouplingTo a solution of iodophenol (1 eq) and alkyne (1.2 eq) in dry THF (5 niL/mmol) under nitrogen at 0C was added methyl magnesium chloride (solution in THF, 2.5 eq) and the reaction allowed to warm to room temperature. After stirring for 10 minutes, Pd(Ph3P)2Cl2 (5 mol%) was added and the reaction heated to 650C for 4-8 h (tic). The THF was removed under vacuum and replaced with DMSO (12 mL/mmol) and the nitrogen atmosphere was replaced with carbon monoxide. The aryl iodide (1.05 eq) was added and the reaction heated to 90-100C overnight then quenched with 10% NH4Cl (aq> and extracted with ethyl acetate. The organic layer was washed with brine and the solvent removed under vacuum. The residue was concentrated onto silica gel and purified by flash column chromatography.
b. [(2-Iodo-5-methoxyphenoxy)methyl]oxirane A 5.0 g (0.02 mole) sample of <strong>[41046-70-2]2-<strong>[41046-70-2]iodo-5-methoxyphenol</strong></strong> was added in portions to a suspension of 1.01 g (0.021 mole) of 50% sodium hydride (from which the oil had been removed by washing with hexane) in 40 ml of dry DMF. The resulting solution was cooled to 5 C. and 9.14 g (0.099 mole) of epichlorohydrin was added. The mixture was heated at 60 C. for 15 minutes. The mixture was cooled and filtered through diatomaceous earth. The solvent was evaporated in vacuo from the filtrate. The residue was taken up in ether, the ether washed with water and brine, dried (MgSO4) and the solvent evaporated in vacuo to give 5.72 g (93% yield) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane as a brown oil.
With caesium carbonate; In N,N-dimethyl-formamide; for 60h;
Synthesis of (R,S)-(6-methoxy-2,3-dihvdro-benzofuran-3-yl)-methanol (23):(1) Step A: (R,S)-2-(2-lodo-5-methoxy-phenoxymethyl)-oxirane (19); 2-lodo-5-methoxy-phenol (2 g, 8 mmol) is dissolved in 15 ml of DMF. Caesium carbonate (3.9 g, 12 mmol) and 2-chloromethyl-oxirane (0.94 ml, 12 mmol) is added and the mixture is stirred for 60 hours. The reaction is then treated with 10 ml of 2N NaOH and extracted with diethyl ether. The ether layer is washed with 1 N-NaOH, water and brine, dried over sodium sulfate and evaporated. The crude oil is used without further purification in the next step. MS (ESI): 306.8 [M+H]+, 1 H-NMR (CDCI3): delta (ppm) 7.56 (d, 1H), 6.4 (d, 1H), 6.28 (dd, 1H), 4.2 (dd, 1 H), 3.97 (dd, 1 H), 3.72 (s, 3H), 3.33 (m, 1 H), 2.85 (m, 2H).
With NaH; In methanol; iodine; methyl cyclohexane; toluene;
a. 2-Iodo-5-methoxyphenol To a round bottom flask under nitrogen was added 8.4 g (0.174 mole) of 50% NaH in oil. The NaH was washed twice with hexane, cooled to 0 C. in ice, and 20.0 g (0.161 mole) of m-methoxyphenol in 200 ml of toluene was added with stirring. After the evolution of hydrogen was complete 34.1 g (0.134 mole) of iodine dissolved in 600 ml of toluene was added over 30 minutes. A 100 ml portion of toluene was used to wash in the remaining iodine. The reaction was stirred for 11/2 hrs., ether was added and the organic layer washed with 3N HCl, water, sodium thiosulfate, brine and dried with MgSO4. The solvent was evaporated in vacuo and the residue crystallized from 1:1 toluene:methylcyclohexane to give 24.1 g of green solid. The green solid was stirred with charcoal in methanol for 1/2 hr., the solution filtered, and evaporated in vacuo, and the resulting residue recrystallized in 1:1 toluene:methylcyclohexane to give 19.8 g (55% yield) of 2-iodo-5-methoxyphenol, mp 70-72.5 C.
Example 14(a) 6-methoxy-2-ethylbenzofuran This material was prepared from <strong>[41046-70-2]2-<strong>[41046-70-2]iodo-5-methoxyphenol</strong></strong> (1 g, 4 mmole) and 1-butyne in a manner as previously described for example 12a to give 570 mg (81%) of a brown oil. 1H NMR (CDCl3) delta7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.04 (2H, q, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz).
Example 15(a) 6-methoxy-2-(1-methylethyl)benzofuran Example 15(a) was prepared from <strong>[41046-70-2]2-<strong>[41046-70-2]iodo-5-methoxyphenol</strong></strong> (896 mg, 3.6 mmole) and 3-methyl-1-butyne in a manner as previously described for example 12a to give 265 mg (38%) of an amber oil. 1H NMR (CDCl3) delta7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.07-3.01 (1H, m), 1.31 (6H, d, J=7.1 Hz).
cis-10-methoxy-7,7a-dihydro-5H-benzo[g]benzofuro[3,2-c]chromene-5,13(12aH)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With palladium diacetate; silver carbonate; In acetone; for 8h;Reflux;
General procedure: To a stirred solution of 9 (0.5 mmol), 13a (0,5 mmol) or 13b (0.5 mmol) in acetone (10 mL), 2-iodophenols 10 (0.6 mmol), silver carbonate (1.5 mmol) and Pd(OAc)2 (10 mol%) were added. This experimental procedure was accomplished in presence (20 mol %) or in absence of PPh3. The reaction mixture was refluxed for 8 h and filtered in celite with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was washed in n-hexane and purified by flash chromatography on silica.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 60℃; for 5h;Inert atmosphere;
General procedure: To a soln of 12 or 13 (0.114 mmol) in DMF (340 muL) was added PdCl2(PPh3)2 (4.0 mg, 5.7 mumol), CuI (5.0 mg, 23 mumol), Ph3P (2.0 mg, 5.7 mumol), Et3N (32 muL, 0.23 mmol) and alkyne 2 or 18 (0.228 mmol), and the resulting mixture was stirred at 50 C for 0.5 h (5 h at 60 C for 19 d). Air was allowed to enter the system and the mixture was stirred for a further 20 h at 50 C (3 h at 60 C for 19 d).The work-up procedure described above was then followed. Products 19 were characterized by comparison of their spectroscopic data with those previously reported for the same compounds.
With potassium carbonate; In acetone; at 20℃; for 6h;Reflux;
General procedure: To a stirred solution of ortho halophenol derivative 4 (1.0 equiv) and potassium carbonate (K2CO3) (1.0 equiv) in acetone (4 mL/mmol of substrate) was added ethyl-2-bromoacetate (1.02 equiv) at room temperature. The reaction mixture was stirred at reflux until complete conversion as indicated by TLC. The resulting mixture was allowed to cool to room temperature, filtered through Celite, washed with excess EtOAc (three times), and concentrated under reduced pressure. Unless otherwise noted, the crude residue was purified to obtain the pure product.
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