Amy T. Bellinghiere, Erin E. Doherty, W. Pistel
May 4, 2015
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Organic Preparations and Procedures International
Abstract
Since the first report of its preparation in 1878, oxetane has been widely used in polymer synthesis. Of particular note, C(3)-substituted oxetanes readily deliver polyether glycols with the C(3)-pendant substituents on their surfaces upon polymerization. The oxetane moiety is also present in various natural products of pharmaceutical importance (e. g. the anti-cancer drug, Taxol). Recently, oxetanes have emerged as versatile, liponeutral surrogates for structural motifs such as gem-dimethyl or carbonyl groups in drug discovery and synthesis. In the pharmaceutical field, C(3)-substituted oxetanes are particularly useful as they are achiral and do not introduce a new stereocenter on the drug analog. Molecular incorporation of the oxetane typically involves the coupling of a reactive group on the oxetane with a reactive site on the polymer or the pharmaceutical drug and it is crucial that this ‘coupling’ reaction be selective and proceed in high yield. Thus, we envision that C(3)-alkoxyamine oxetane 3 (Scheme 1) could serve for the facile incorporation of the oxetane moiety via formation of the oxime ether bond with aldehydes or ketones. We became interested in C(3)-alkoxyamine oxetane 3 as part of a separate study on polymers bearing alkoxyamine side-chains. Although oxetanes containing various reactive C(3)-substituents (e. g. halides, amines, azides, etc.) are known, we are unaware of any literature report for the synthesis of oxetane 3 bearing an alkoxyamine at the C(3)-position or its phthalimide precursor 2 (Scheme 1). Herein, we report a straightforward synthesis of the title compound 3 from the commercially available 3-bromomethyl-3-methyloxetane (1) in two steps. Treatment of 1 with N-hydroxyphthalimide and K2CO3 in DMF gave a 75% yield of oxetane 2 which was used in the next step without any purification. However, residual DMF during the work-up was detrimental to the yield. Complete removal of DMF could