Azetidines are valuable motifs that readily access under explored chemical space for drug discovery. 3,3-Diarylazetidines are prepared in high yield from N-Cbz azetidinols in a calcium(II)-catalyzed Friedel-Crafts alkylation of (hetero)aromatics and phenols, including complex phenols such as b-estradiol. Electron poor phenols undergo O-alkylation. The product azetidines can be derivatized to drug-like compounds through the azetidine nitrogen and the aromatic groups. The N-Cbz group is crucial to reactivity by providing stabilization of an intermediate carbocation on the 4-membered ring.

4-Membered rings remain under explored motifs despite offering attractive physicochemical properties for medicinal chemistry. Arylacetic acids bearing oxetanes, azetidines and cyclobutanes are prepared in two steps: a catalytic Friedel-Crafts reaction from 4-membered ring alcohol substrates, followed by mild oxidative cleavage. The suitability of the products as building blocks is reflected in their facile purification and amenability to derivatization. Examples include heteroaromatics and aryltriflates, as well as oxetane-derived profen drug analogues and a new endomorphin derivative containing an azetidine amino acid residue.

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.

New small ring derivatives can provide valuable motifs in new chemical space for drug design. 3-Aryl-3-sulfanyl azetidines are synthesized directly from azetidine-3-ols in excellent yield by a mild Fe-catalyzed thiol alkylation. A broad range of thiols and azetidinols bearing electron donating aromatics are successful, proceeding via an azetidine carbocation. The N-Cbz group is a requirement for good reactivity, and enables the NH-azetidine to be revealed. Further reactions of the azetidine sulfides demonstrate their potential for incorporation in drug discovery programs. New chemical motifs with appropriate physicochemical properties offer valuable opportunities in drug design. 1,2 As a result, there has been significant recent attention on the synthesis of new modules that may be readily incorporated in medicinal chemistry, as fragments, building blocks or isosteres. 3 Small heterocyclic rings are attractive in this context due to low molecular weight and defined exit vectors. 4,5 Small rings readily access new chemical and IP space, particularly when combined with medicinally relevant substituents, which is partly due to their limited synthetic accessibility preventing their investigation. Sulfur functional groups are prevalent in pharmaceuticals and agrochemicals, 6 with thioethers being important in their own right and as intermediates to access sulfoxide, sulfone and sulfoximine moieties. There are examples of azetidine thioethers in biologically active compounds in the literature with the majority 3-monosubstituted, including compounds having RBP4-lowering activity and antibacterial activity (Figure 1A). 7,8 3,3-Disubstituted azetidine sulfides, without additional C2 or C4 1 2a 5 a Isolated yields quoted. Alternative 3-aryl-azetidin-3-ol substrates (3-8) were prepared by the addition of Grignard reagents to commercially available N-Cbz azetidine-3-one (Scheme 2). 16 Preinstalled benzyl-and TIPS-protected phenols were tolerated under the reaction conditions producing 9 and 10 in excellent yield. Increasing the steric demands of the azetidinol with ortho-substituted aromatics gave azetidine 11 in 92% yield. Benzodioxole and trimethoxybenzene azetidinols reacted similarly well giving products 12 to 14 in good yield using benzylic, aryl or alkyl thiols respectively as nucleophiles. Importantly, indole containing sulfanylazetidine 15 was formed in 97% yield. As such, a range of 3-sulfanyl azetidines can be readily prepared with appealing functionalities of interest to medicinal chemists, varying both the thiol and preinstalled aryl group. 3-Phenylazetidin-3-ol returned starting material, even increasing the temperature to 80 °C, indicating the need for electron-rich aromatics to stabilize the postulated azetidine carbocation intermediate. The reaction could be extended to the 5 and 6-membered N-heterocycles giving piperidine 16 and pyrrolidine 17 in 95% and 93% yield respectively using benzylmercaptan. 6 Scheme 2. Scope of azetidinols. a a Isolated yields quoted. The derivatization of various 3-sulfanyl azetidi...