Study on Pyridine-Boryl Radical-Promoted Carbon–Carbon Bond-Forming Reactions

Abstract

Part Ⅰ. Vicinal diol is an important structural motif in synthetic and medicinal chemistry. The pinacol coupling is a common method for the preparation of vicinal diols from carbonyl compounds. Recently, our group reported a metal-free pinacol coupling method that employs persistent pyridine-boryl radical for the ketyl radical generation. This method exhibited excellent efficiency in the coupling of diaryl ketones. However, moderate yield and low diastereoselectivity were obtained with aromatic aldehydes. Reaction condition optimization of the coupling of aromatic aldehydes was conducted. Increasing the reaction temperature was the most effective solution for improving the yield. In situ generated 1,2-bonded diboron was employed for a stereoselective reaction. However, because of the fast background reaction, no significant improvement in er or dr was observed. Preformed 1,2-bonded chiral diboron was employed to impede background reaction, but the yield was significantly low. Part Ⅱ. Compared to the boryl radical-promoted pinacol coupling of benzophenones, the coupling of aromatic aldehydes was less effective presumably because of the low concentration of ketyl radical in the reaction mixture. Therefore, stoichiometric radical acceptors were employed as the coupling partner of the ketyl radical. Oxime ether, hydrazone, and imines were examined, and the desired 1,2-aminoalcohol was obtained with N-phenylbezaldimines. However, the coupling of benzaldehyde and aldimine gave unsatisfactory results because the dimerization of imines proceeded predominantly. Thus, benzophenone was employed instead of benzaldehyde for fast ketyl radical generation, but 1,2-diol was obtained as a major product. Part Ⅲ. For chemoselective coupling of ketyl radical and radical acceptor, substrates bearing both carbonyl group and radical acceptor were employed. 2-Allylbenzaldehyde gave both cyclized and dimerized products. With 2-prenylbenzaldehyde, the cyclized product was obtained in moderate yield and low diastereoselectivity. Ester-containing 2-allylic benzaldehyde and 2-cinnamylbenzaldehyde both gave notable dr. Optimization of reaction conditions was conducted with 2-cinnamylbenzaldehyde. The use of an excess amount of effective hydrogen source was a key for improving the yield, and the size of the boronic ester ring was significant for diastereoselectivy control.