Matthew Dowling

Synthesis of Highly Functionalized Oxetanes

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. CO2Bn N2 NC HO Br

Synthesis of 3-Fluoropyrazoles from 2-Trifluoromethyl-1-alkenes

Significance: Reported is the synthesis of isatoic anhydrides 2 via the carbonylation of substituted anilines 1 utilizing a C–H activation procedure. Optimization studies demonstrated the beneficial effects of potassium iodide and the importance of oxidant and solvent choice. A substrate-scope screen showed that electron-rich anilines were the most reactive (2a–c). However, electron-deficient anilines proved useful substrates with the addition of pivalic acid and increased pressure (2d–i). In the case of 2a, a catalytic procedure [with respect to Cu(OAc)2] using oxygen as the terminal oxidant was demonstrated, affording the desired isatoic anhydride in marginally reduced yield. Derivatization of 2a to the ortho-amino acid 3a, ester 3b, and primary amide 3c was reported. Comment: Isatoic anhydrides are useful reagents for the preparation of anthranilic acid derivatives and various heterocycles alike (see Review below). Traditionally these heterocycles have been prepared via various multi-step sequences, for example from the anthranilic acids themselves (E. C. Wagner, M. F. Fegley Org. Synth. 1947, 27, 45) or via oxidation of phthalimides. The current report is attractive for several reasons, including circumventing the need for regioselective prefunctionalization and employing readily available anilines 2 as starting material.