tert-butyl N-(2-fluorophenyl)carbamate

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:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−78° C.) solution of (2-fluoro-phenyl)-carbamic acid tert-butyl ester (38.0 g, 180 mmol) in THF (700 mL) under nitrogen was added tert-butyllithium (1.7 M, 240 mL, 408 mmol). The mixture was stirred for 1 h at −78° C. and then a solution of iodine (60.8 g, 240 mmol) in THF (150 mL) was added slowly. The reaction mixture was stirred for further 1 h. Saturated aqueous ammonium chloride (100 mL) was added slowly and the mixture was warmed to RT. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography (5% ethyl acetate:hexanes) to afford 39.1 g (65%) of the title compound as a while solid. 1H NMR (300 MHz, CDCl3): δ 1.50 (s, 9H), 5.98 (br. s, 1H), 6.92-6.99 (m, 1H), 7.08-7.15 (m, 1H), 7.62 (dt, J=7.8, 1.2 Hz, 1H). The reaction mixture was stirred for further 1 h the mixture was warmed to RT The layers were separated the aqueous layer was extracted with ethyl acetate (2×100 mL) The combined organic fractions were washed with brine (200 mL) dried over anhydrous sodium sulfate concentrated The residue was purified by flash chromatography (5% ethyl acetate:hexanes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2-fluorophenylcarbamate (from step 1) (1.0 eq.) in tetrahydrofuran (0.25 M) at −78° C. under N2 atmosphere was added dropwise 1.7 M tert-butyllithium (2.4 eq.). The reaction was warmed to −40° C. slowly over 2 hours, and neat trimethyl borate (3.8 eq.) was added. The reaction was warmed to room temperature over 30 minutes. An aqueous solution of 1N NaOH was slowly added to the reaction and stirred for 15 minutes. The mixture was poured into ethyl acetate and acidified with 3N HCl to dissolve the solids. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The resulting solids were stirred in 1:1 ether/hexane, filtered, and dried. The solids were carried onto the next step without further purification. The reaction was warmed to room temperature over 30 minutes to dissolve the solids The aqueous layer was extracted twice with ethyl acetate the combined organic layers were washed with brine dried over anhydrous MgSO4 concentrated en vacuo The resulting solids were stirred in 1:1 ether/hexane filtered dried The solids were carried onto the next step without further purification

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(t-butoxycarbonyl)-2-fluoroaniline (5.0 g, 24 mmoles) in anhydrous tetrahydrofuran (50 ml) was cooled to -78° C. under a nitrogen atmosphere. To this solution was added t-butyl lithium (2.0M, 57.6 mmoles, 28.8 ml) at such a rate that the temperature did not exceed -65° C. When the addition was complete, the mixture was stirred at -78° C. for an additional 15 minutes and at -20° C. for 2.5 hours. To this reaction mixture was added dimethyl disulfide (2.82 g, 30 mmoles) in 10 ml of anhydrous tetrahydrofuran while maintaining the temperature at -20° C. for an additional hour. The mixture was allowed to warm to ambient temperature and then 25 ml of 1N sodium hydroxide was added. The mixture obtained was extracted with diethyl ether (2×100 ml). The organic phase was separated and dried over magnesium sulfate and then the solvent was removed by evaporation under reduced pressure to obtain a tan solid. This was hydrolized in dilute hydrochloric acid (6N, 200 ml) by heating to reflux for three hours. The resulting solution was extracted with diethyl ether and the aqueous layer was neutralized with sodium hydroxide (6N, 200 ml), and extracted with methylene chloride, dried over magnesium sulfate and the solvent removed by evaporation under reduced pressure to obtain an amber oil. This was distilled to give 3.2 g (85% of theory) of the title compound, having a b.p. of 62°-65° C. at 0.2 mm Hg. did not exceed -65° C When the addition while maintaining the temperature at -20° C. for an additional hour to warm to ambient temperature The mixture obtained was extracted with diethyl ether (2×100 ml) The organic phase was separated dried over magnesium sulfate the solvent was removed by evaporation under reduced pressure to obtain a tan solid by heating to reflux for three hours The resulting solution was extracted with diethyl ether extracted with methylene chloride dried over magnesium sulfate the solvent removed by evaporation under reduced pressure to obtain an amber oil This was distilled

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

Procedure: This material was prepared for N-t-butoxycarbonyl-2-fluoroaniline and dimethyl disulfide following the general procedure outlined in Example 102. IR and 1H NMR spectra of the product were consistent with the assigned structure.

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

Procedure: This material was prepared for N-t-butoxycarbonyl-2-fluoroaniline and dimethyl disulfide following the general procedure outlined in Example 102. IR and 1H NMR spectra of the product were consistent with the assigned structure.

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 8.15 g (38.5 mmol) of N-t-butoxycarbonyl-2-fluoroaniline in 30 ml of dry THF was cooled to -70° C., and 46.3 ml (93 mmol) of 2.0 M t-butyllithium in pentane was added dropwise at a rate sufficient to maintain the temperature below -65° C. When the addition was complete the reaction mixture was stirred at -70° C. for 15 minutes, warmed to -20° C. and stirred for 2.5 hours. A solution of 6.8 g (30 mmol) of methyl iodide in THF was added and the reaction was allowed to warm to room temperature. The reaction mixture was partitioned between ether and water, and the organic layer was washed with saturated aqueous NaCl and dried (MgSO4). Evaporation at reduced pressure gave a yellow solid which was added to 25 ml of 3N HCl and heated at reflux for 3 hours. After cooling to room temperature the pH of the solution was adjusted to pH 7, and the solution was extracted twice with methylene chloride. The combined organic phases were washed with water and dried (MgSO4). Evaporation at reduced pressure gave a yellow oil which was Kugelrohr distilled to yield 3.8 g (80%) of the desired product as a liquid, b.p. 91°-93° C. (0.1 mm). IR and 1H NMR spectra were in agreement with the assigned structure. to maintain the temperature below -65° C When the addition warmed to -20° C. stirred for 2.5 hours to warm to room temperature The reaction mixture was partitioned between ether and water the organic layer was washed with saturated aqueous NaCl dried (MgSO4) Evaporation at reduced pressure gave a yellow solid which heated at reflux for 3 hours After cooling to room temperature the pH of the solution the solution was extracted twice with methylene chloride The combined organic phases were washed with water dried (MgSO4) Evaporation at reduced pressure gave a yellow oil which distilled

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

Procedure: This material was prepared for N-t-butoxycarbonyl-2-fluoroaniline and dimethyl disulfide following the general procedure outlined in Example 86. IR and 1H NMR spectra of the product were consistent with the assigned structure.