Bioisosteres provide valuable design elements for medicinal chemists to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides, an extremely common pharmacophore, but are rarely examined due to the lack of available synthetic methods. Here, we describe a new class of reactions for sulfonyl fluorides to form aminooxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. An unprecedented defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared.Kinetic and computational studies support the formation of an oxetane carbocation as the rate determining step, followed by a chemoselective nucleophile coupling step.New reaction classes have enormous potential to access underexplored chemical space and influence molecular design. 1,2 A limited set of reliable and predictable reactions continue to have a disproportionate influence on the ability to construct medicinal and agrochemical compounds. 3 Such reactions can enable rapid access to derivatives, while also influencing, and limiting, molecular design. Most notably, click reactions have had an enormous impact in the chemical and biological sciences, which proceed on complex substrates without stringent conditions. 4,5,6,7 In drug discovery, amide bond formation continues to be the most common reaction, 3 exploiting vast amine and carboxylic acid libraries available to pharmaceutical companies. Amides are therefore prevalent in marketed pharmaceutical and agrochemical compounds, and display valuable features being more stable than other carbonyl derivatives, powerful H-bond donors and acceptors, and ubiquitous as critical bonding units in natural peptides and proteins. 8 Nonetheless, the amide sub-structure will frequently not provide the subtle balance of properties that is required for a successful active ingredient. Consequently, bioisosteres of amides are also common, providing a mimic of the features of the amide and adjusting the global properties of a compound. 9,10,11 While amidation is extensively investigated, with powerful, mostly stoichiometric coupling reagents, 12 the same cannot be said for amide-isosteres, which often require bespoke synthetic efforts (Fig. 1a).3,3-Disubstituted oxetanes have garnered considerable interest as carbonyl replacements, due to the similar dipole moments, hydrogen-bonding capacity, and oxygen lone pair orientation. 13,14 Their use as a bioisostere or replacement group also introduces a more 3-dimensional element to a drug compound that can have beneficial binding and solubility effects. 15 The motif is exemplified by antiviral Ziresovir, bear...

No abstract

Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible.

Annulations that combine diacceptors with bis-nucleophiles are uncommon. Here, we report the synthesis of 1,4-dioxanes from 3-aryloxetan-3-ols, as 1,2-bis-electrophiles and 1,2-diols. Brønsted acid Tf 2 NH catalyzes both the selective activation of the oxetanol, to form an oxetane carbocation that reacts with the diol, and intramolecular ring opening of the oxetane. High regio- and diastereoselectivity are achieved with unsymmetrical diols. The substituted dioxanes and fused bicyclic products present interesting motifs for drug discovery and can be further functionalized.

No abstract