Davis OA, Croft RA, Bull JA * Imperial College London, England
Synthesis of Diversely Functionalized 2,2-Disubstituted Oxetanes: Fragment Motifs
in New Chemical Space.
Chem. Commun. 2015;
51: 15446-15449
Key words
oxetanes - O–H insertion - rhodium - catalysis - diazomalonates
Significance
In 2014, the Bull group reported a two-step approach for preparing substituted oxetanes
through a reaction sequence involving rhodium-catalyzed O–H insertion of diazomalonates
into substituted bromohydrins and subsequent base-mediated cyclization to form the
oxetane (O. A. Davis, J. A. Bull Angew. Chem. Int. Ed. 2014, 53, 14230). In the present report, the scope of this chemistry is expanded to include
other malonate derivatives, including phosphonate, sulfone, nitrile, aryl, and amide
functionalities. The resulting products and their related derivatives constitute interesting
fragments for drug discovery research, and many would be difficult to prepare by using
more conventional approaches, such as Williamson etherification, epoxide ring expansion,
the use of sulfoxonium ylides, or photochemical methods.
Comment
Oxetanes are valuable bioisosteres for gem-dimethyl and carbonyl functionalities and they have been shown to improve aqueous
solubility markedly when applied in these and other contexts (K. Muller et al. J. Med. Chem. 2010, 53, 3227). Starting from either 3-iodooxetane or oxetane-3-one, methods for preparing
3-substituted or 3,3-disubstituted oxetanes have been well developed over the past
decade. However, available methods for preparing 2-substituted oxetanes are less well
explored. The use of dichloromethane as solvent in the O–H insertion step is important
for obtaining good yield when nitrile-containing starting materials are employed.
For aryl-substituted oxetanes, the use of LiHMDS in the cyclization step rather than
sodium hydride afforded superior yields.