Phosphoryl-substituted azaheterocycles are a highly important class of organophosphorus compounds due to their biological activities and applications in medicinal chemistry, material sciences, and organic synthesis.[1] The development of novel efficient synthesis of these molecular targets remains an currently central area of organic chemistry research.
Herein, we report a previously unknown, convenient and highly reactive hydrazides of phosphoryl thioformic acid as advanced reagents in the concise synthesis of five- and six-membered P,N-heterocycles. Based on our previous results [2] and the chemistry of thiohydrozones, we have elaborated flexible synthetic approaches towards unknown POR2 functionalysed pyridazines and 1,3,4-thiadiazoles with chemoselective control of heterocyclization patterns (Scheme 1).
Phosphamide and phosphine oxide derivatives of pyridazines were exclusively synthesized via condensation of β-chlorovinyl aldehydes with hydrazides of phosphoryl thioformic acid. The method was found quite general since both aliphatic and aromatic aldehydes and steroid derivatives reacted smoothly providing diverse pyridazines. Using saturated aldehydes as a substrate in one-pot oxidation protocol 2-phosphoryl substituted 1,3,4-thiodiazoles were obtained in high yields and minimum synthetic steps. This transformation was performed with different aryl, hetaryl or aliphatic aldehydes. A number of compounds obtained were discovered as inhibitors of AKT kinases.
The reported study was funded by RFBR and Moscow city Government according to the research project № 15-34-70030 «mol_а_mos».
References
[1] (a) Lysakowska, M. et al., Arch. Pharm. Chem. Life Sci. 2011, 11, 301–310. (b) Kokosza, K. et al., Bioorg. Med. Chem. 2015, 23, 3135–3146.
[2] (a) Komkov, A.V. et al., Org. Lett., 2015, 17 (15), 3734–3737. (b) Volkova, Y.A. et al., RSC Adv., 2016, 6, 42863-42868. (c) Yarovenko, V.N. et al., Russ. J. Org. Chem., 2003, 39 (8), 1133-1139.
