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A Safer Reduction of Carboxylic Acids with Titanium Catalysis

P. Veeraraghavan Ramachandran*, Abdulkhaliq A. Alawaed and Henry J. Hamann

*Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States, Email:

P. V. Ramachandran, A. A. Alawaed, H. J. Hamann, Org. Lett., 2022, 24, 8481-8486.

DOI: 10.1021/acs.orglett.2c03326

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Ammonia-borane reduces acids to alcohols at room temperature in the presence of catalytic TiCl4. This process tolerates a variety of potentially reactive functional groups, including N-protected amino acids, nitriles and, to some extent, esters. Aliphatic acids can be selectively reduced in the presence of aromatic acids.

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General procedure for 1 mmol scale reduction

A 50 mL oven dried round bottom flask was charged with carboxylic acid (1mmol, 1eq) and a magnetic stir bar. The flask was sealed using a rubber septum, and connected to an indirect nitrogen line. After purging the flask with nitrogen, distilled diethyl ether (3 mL) was added, and the solution was cooled at 0 C with an ice bath. Subsequently, titanium tetrachloride (TiCl4) (0.1 mmol, 0.1 eq) was added dropwise to the solution through the septum using a syringe. The septum was then carefully open andsolid ammonia borane (NH3.BH3) (2.0mmol, 2.0eq) was added slowly to the reaction mixture. Upon complete addition the reaction flask was again sealed with a septum, and connected to an indirect nitrogen line. After stirring at 0 C for 1 minute, the reaction mixture was allowed to warm up to room temperature, stirred and monitored by TLC until completion.On completion of the reaction, the crude mixture was brought to 0C and quenched by slow addition of cold 1M HCl, then transferred to a separatory funnel and extracted with diethyl ether (2 3mL). The combined organic layers were washed with 1M NaOH (1 x 3 mL) and then with brine (1 x 3 mL), dried over anhydrous sodium sulfate, filtered through cotton, and concentrated under rotary evaporation and the remain solvent was removed by applying high vacuum for 30 minutes. Column chromatography was performed only if necessary to further purify the product using a hexanes : ethyl acetate (v/v = 90:10) solvent system to afford the desired product.

TiCl4-Catalyzed Hydroboration of Ketones with Ammonia Borane

P. V. Ramachandran, A. A. Alawaed, H. J. Hamann, J. Org. Chem., 2022, 87, 13259-13269.

Balancing Lewis Acidity and Carbocation Stability for the Selective Deoxyhalogenation of Aryl Carbonyls and Carbinols

P. V. Ramachandran, A. A. Alawaed, H. J. Hamann, Org. Lett., 2023, 25, 4650-4655.

Key Words

reduction of carboxylic acids, ammonia-borane

ID: J54-Y2022