2-methyl-2-[(2-methylpropan-2-yl)oxy]propane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a procedure analogous to (3b), the phenol from (3a) (270 mg, 0.97 mmol) was reacted with N,N′-dimethyl-O-t-butylisourea. Silica gel chromatography (ethyl acetate-hexane, 20:80) gave the t-butyl ether (50.2 mg, 15%) as a 1:1 mixture of two isomers. MS found: (M+H)+=334.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: HClO4 (1.17 mL, 13.6 mmol) is added to a suspension of 48k (3.40 g, 9.06 mmol) in t-butyl acetate (100 mL) and DCM (150 mL). The reaction mixture is stirred at RT overnight then is diluted with EtOAc (150 mL). The solution is washed twice with aqueous 5% NaHCO3 solution, dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (Combi-Flash; EtOAc/hexane) to give t-butylether 481 (2.76 g, 71% yield) as a white solid. The solution is washed twice with aqueous 5% NaHCO3 solution dried (MgSO4) filtered concentrated under reduced pressure The residue is purified by flash chromatography (Combi-Flash; EtOAc/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The (4-(1,1-dimethylethyl)oxyphenyl)tributyltin (27) is synthesized as set forth in Scheme 3. The commercially available 4-bromophenol is reacted with isobutylene in the presence of an acid catalyst such as, for example, trifluoroacetic acid (TFA)/triethylamine (TEA), boron trifluoride-etherate (BF3.OEt2), and the like in a suitable solvent such as, for example, dichloromethane and the like to give the t-butyl ether (26). The t-butyl ether (26) is reacted with a suitable organolithium such as, for example, n-butyl lithium and the like in tetrahydrofuran (THF) at low temperature followed by tri-n-butyltin chloride to give the (4-(1,1-dimethylethyl)oxyphenyl)tributyltin (27). The (4-(1,1-dimethylethyl)oxyphenyl)tributyltin (27) is reacted with the acid chloride (25) in the presence of a suitable catalyst such as, for example, tetrakis(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II)chloride, and the like with or without sodium bicarbonate in a solvent such as, for example, THF, dioxane, and the like at temperatures between about −20° C. and about reflux to give the keto-ester (28). The keto-ester (28) is deprotected by reacting with TFA in the presence of a suitable carbonium ion scavenger such as, for example, anisole, thioanisole, triethylsilane, and the like in a solvent such as, for example, dichloromethane, chloroform, and the like, and the resulting phenol is reacted with trifluoromethanesulfonic anhydride to give the triflate (29). The triflate (29) is reacted with the phenylboric acid (30), prepared by reacting the bromobenzene (31) first with n-butyl lithium or t-butyl lithium in tetrahydrofuran at low temperatures followed by trimethylborate and acid hydrolysis, in the presence of a suitable catalyst such as, for example, tetrakis(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II)chloride, and the like with or without sodium bicarbonate in a solvent such as, for example, THF, dioxane, and the like at temperatures between about −20° C. and about reflux to give the keto-ester (32). Alternatively, the triflate (29) can be reacted with the phenyltributyltin (33), prepared by reacting the bromobenzene (31) first with n-butyl lithium or t-butyl lithium in tetrahydrofuran at low temperatures followed by tri-n-butyltin chloride, in the presence of a suitable catalyst such as, for example, tetrakis(triphenylphosphine)palladium(O), bis(triphenylphosphine)palladium(II)chloride with or without sodium bicarbonate in a solvent such as, for example, THF, dioxane, and the like at temperatures between about −20° C. and about reflux to give the keto-ester (32). The keto-ester (32) can be hydrolyzed to the corresponding keto-acid by stirring in aqueous hydrochloric acid at a concentration between about 2 M and about 6 M and at temperatures between about 25° C. and about reflux or by reacting with an alkali metal hydroxide such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in a suitable solvent such as, for example, methanol, ethanol, aqueous tetrahydrofuran, and the like at temperatures between about 0° C. and about reflux, and the keto-acid can be reacted with a compound of Formula (8) with or without a suitable base such as, for example, lithium carbonate, sodium carbonate, potassium carbonate, and the like in a suitable solvent such as, for example, ethanol, methanol, isopropanol, and the like at temperatures between about 25° C. and about reflux to give the carboxylic acid (34). Alternatively, the keto-ester (32) can be hydrolyzed to the corresponding keto-acid by stirring in aqueous hydrochloric acid at a concentration between about 2 M and about 6 M and at temperatures between about 25° C. and about reflux or by reacting with an alkali meal hydroxide such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like in a suitable solvent such as, for example, methanol, ethanol, aqueous tetrahydrofuran, and the like at temperatures between about 0° C. and about reflux, and the keto-acid can be reacted with a suitable coupling agent such as, for example, CDI, DCC, i-C4H9OCOCl, and the like followed by hydrogen sulfide to give the keto-thioacid, which in turn can be reacted with a compound of Formula (8) with or without a suitable base such as, for example, lithium carbonate, sodium carbonate, potassium carbonate and the like in a suitable solvent such as, for example, ethanol, methanol, isopropanol and the like at temperatures between about 25° C. and about reflux to give the thioacid (35). The (4-(1,1-dimethylethyl)oxyphenyl)tributyltin (27) is synthesized

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 300 mmoles of t-butanol, 100 mmoles of 1-hexanol and 2.5 g of Ti-Si-catalyst powder are stirred in a 100 ml autoclave at a pressure of 40 bar N2 and a temperature of 150° C. over a period of 17 h, 17% of n hexanol were converted into hexyl t-butyl ether with a selectivity of 90%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 300 mmoles of i-butene, 100 mmoles of 1-hexanol and 2.5 g of Ti-Si-catalyst powder are stirred in a 100 ml autoclave at a pressure of 40 bar N2 and a temperature of 150° C. over a period of 18 h, 62% of n-hexanol were converted into hexyl-t-butyl ether with a selectivity of 92%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a procedure analogous to (3b), the phenol from (3a) (270 mg, 0.97 mmol) was reacted with N,N'-dimethyl-O-t-butylisourea. Silica gel chromatography (ethyl acetate-hexane, 20:80) gave the t-butyl ether (50.2 mg, 15%) as a 1:1 mixture of two isomers. MS found: (M+H)+ =334.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Part 1. 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate: Isobutylene (2.96 mL, 0.0313 mol) was collected at −78 Celsius. To the cold isobutylene was added 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60 g, 0.0016 mol) tetrahydrofuran (3.00 mL, 0.0370 mol), sulfuric acid (0.021 mL, 0.00039 mol). The reaction was sealed and allowed to warm up to rt and stirred at rt overnight. The mixture was cooled to −78 Celsius again. The seal was replaced with a septa connecting with a balloon. The reaction was then allowed to warm up to rt gradually to allow the evaporating of excess isobutylene. The residue was diluted with EtOAc, neutralized with aq. sodium hydroxide. The organic layers were washed with brine, dried. The residue was purified on silica gel, eluting with 0 to 30% EtOAc in hexane, to afford the tert-butyl ether (0.35 g, 51%). MS (ESI): (M+H)+=440.25. The reaction was sealed The mixture was cooled to −78 Celsius again to warm up to rt gradually evaporating of excess isobutylene The residue was diluted with EtOAc The organic layers were washed with brine dried The residue was purified on silica gel eluting with 0 to 30% EtOAc in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Part 1. 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate: Isobutylene (2.96 mL, 0.0313 mol) was collected at −78 Celsius. To the cold isobutylene was added 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60 g, 0.0016 mol) tetrahydrofuran (3.00 mL, 0.0370 mol), sulfuric acid (0.021 mL, 0.00039 mol). The reaction was sealed and allowed to warm up to rt and stirred at rt overnight. The mixture was cooled to −78 Celsius again. The seal was replaced with a septa connecting with a balloon. The reaction was then allowed to warm up to rt gradually to allow the evaporating of excess isobutylene. The residue was diluted with EtOAc, neutralized with aq. sodium hydroxide. The organic layers were washed with brine, dried. The residue was purified on silica gel, eluting with 0 to 30% EtOAc in hexane, to afford the tert-butyl ether (0.35 g, 51%). MS (ESI): (M+H)+=440.25. The reaction was sealed The mixture was cooled to −78 Celsius again to warm up to rt gradually evaporating of excess isobutylene The residue was diluted with EtOAc The organic layers were washed with brine dried The residue was purified on silica gel eluting with 0 to 30% EtOAc in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure and workup in Example 14: step f, the 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step c) 1.48 g, 3.1 mmol) was converted to the amidine (40 mL of dimethylaluminum amide reagent) with concomitant removal of the tert-butyl ether. A portion of the crude amidine (800 mg) was dissolved in DMF and di-tert-butyl dicarbonate (436 mg, 2 mmol), diisopropylethylamine (350 μL, 2 mmol), and DMAP (50 mg) were added. After stirring for 16 h, the solution was poured into EtOAc (60 mL) and citric acid (20 mL). The layers were separated and the organic layer was further extracted with citric acid (10 mL), NaHCO3 (2×20 mL), water (5×10 mL), and brine (30 mL). After drying over sodium sulfate and removal of solvent in vacuo, the residue was dissolved in MeOH and solid K2CO3 was added. The mixture was stirred overnight, the solution was filtered, and the solvent was removed in vacuo. Purification of the residue by SiO2 flash chromatography yielded the title compound (80 mg, 0.158 mmol). The layers were separated the organic layer was further extracted with citric acid (10 mL), NaHCO3 (2×20 mL), water (5×10 mL), and brine (30 mL) After drying over sodium sulfate and removal of solvent in vacuo the residue was dissolved in MeOH solid K2CO3 was added The mixture was stirred overnight the solution was filtered the solvent was removed in vacuo Purification of the residue by SiO2 flash chromatography