Carbon nitrogen construction is a classic reaction in organic synthesis, with various construction methods such as Buchwald coupling, Ullman coupling, substitution reactions of amines with fatty halogenated hydrocarbons or aromatic halogenated hydrocarbons, and so on. When it comes to the construction of carbon and nitrogen, one type of reaction that cannot be ignored is reductive amination, which is one of the most commonly used methods for carbon and nitrogen construction. Reductive amination usually involves the reaction of amines with aldehydes and ketones in the presence of reducing agents, and aldehydes and ketones will not be further elaborated here. In addition to common fatty amines and aromatic amines, such as sulfonamides and carboxylic acid amides, amines can also undergo reductive amination reactions very well. However, these reactions are relatively not widely used. Many times, when we need to use esters to construct saturated C-N bonds, we first need to reduce the esters to aldehydes, and then carry out reductive amination after obtaining the aldehydes. If esters are directly converted into saturated amines through a one pot method, it is still very attractive.
Today, I would like to share with you a report from the Pei Qiang Huang team at Xiamen University in December 2024 (10.1002/anie. 2022422742). Esters can be efficiently synthesized into saturated amines through a one pot method, which involves reduction followed by either reductive amination or 1,2-addition. We focus on the reductive amination part. Meanwhile, it is worth noting that the two key reagents involved in the reaction: one Ir catalyst and the other B reagent, are commercially available. Among them, when the reaction scale reaches 15g, the catalyst dosage is as low as 0.001 mol%.
Let's take a look at the specific experimental operation process. Primary amines and secondary amines are slightly different, but both are very convenient to operate:
General Procedure A: Catalytic reductive amination of esters with secondary amines.To a 10 mL dried round bottom-flask containing an ester (1.0 mmol, 1.0 equiv) and[Ir(COD)2]BArF (1.3 mg, 0.1 mol%) in toluene (2.0 mL) was added EtzSiH2 (0.19 mL, 1.5 equiv)under stirring. The solution was stirred at 40 °C for 5 h. After being cooled to RT, amine (1.5mmol, 1.5 equiv) and AcOH (68 uL, 1.2 equiv) were added, the reaction mixture was stirred for30 min before addition of 1,1,3,3-tetramethyldisiloxane (TMDS, 0.28 mL, 1.5 equiv) withB(CsFs)3 (20.0 mg, 4 mol%), the reaction mixture was stirred at RT for 2 h. The reaction wasquenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethylacetate (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered,and concentrated under reduced pressure. The residue was purified by flash columnchromatography (FC) on silica gel to afford the desired N-alkylated amine.
General Procedure B: Catalytic reductive amination of esters with primary amines.To a 10 mL dried round bottom-flask containing an ester (1.0 mmol, 1.0 equiv) and[Ir(COD)2]BArF (1.3 mg, 0.1 mol%) in toluene (2.0 mL) was added Et2SiH2 (0.19 mL, 1.5 equiv)under stirring. The solution was stirred at 40 °℃ for 5 h. After being cooled to rt, an amine (1.5mmol, 1.5 equiv) and AcOH (68 uL, 1.2 equiv) were added, the reaction mixture was stirred for30 min before addition of PhSiH3 (324.0 mg, 3.0 equiv) with B(CsFs)3 (25.0 mg, 5 mol%), thereaction mixture was stirred at 80 °℃ for 8 h. The reaction was quenched with a saturatedaqueous solution of sodium bicarbonate and extracted with ethyl acetate (3 × 5 mL). Thecombined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated underreduced pressure. The residue was purified by flash column chromatography (FC) on silica gelto afford the desired N-alkylated amine.
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