Oxetanes: Recent Advances in Synthesis, Reactivity and Medicinal Chemistry

The 4-membered oxetane ring has been increasingly exploited for its behaviors, i.e. influence on physicochemical properties as a stable motif in medicinal chemistry, and propensity to undergo ring opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last 5 years up to the end of 2015. These methods are clustered by strategy for preparation of the ring (Sections 3 and 4), and further derivatisation of preformed oxetane-containing building blocks (Sections 5-7). Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally examples of oxetane derivatives in ring opening and ring expansion reactions are described

Regio- and stereoselective palladium catalyzed C(sp3)–H arylation of pyrrolidines and piperidines with C(3) directing groups

The selective synthesis of cis-3,4-disubstituted pyrrolidines and piperidines is achieved by a Pd-catalyzed C–H arylation with excellent regio- and stereo-selectivity using an aminoquinoline auxiliary at C(3). The arylation conditions are silver free, use a low catalyst loading, and employ inexpensive K2CO3 as a base. Directing group removal is accomplished under new, mild conditions to access amide, acid, ester and alcohol containing fragments and building blocks. This C–H arylation protocol enabled a short and stereocontrolled formal synthesis of (–)-paroxetine

Straightforward Strategies for the Preparation of NH-Sulfoximines: A Serendipitous Story

Sulfoximines are emerging as valuable new isosteres for use in medicinal chemistry, with the potential to modulate physicochemical properties. Recent developments in synthetic strategy have made the unprotected ‘free’ NH-sulfoximine group more readily available, facilitating further study. This account reviews approaches to NH-sulfoximines, with a focus on our contribution to the field. Starting from the development of catalytic strategies involving transition metals, more sustainable metal-free processes has been discovered. In particular, the use of hypervalent iodine reagents to mediate NH transfer to sulfoxides is described, along with assessment of the substrate scope. Furthermore, a one pot strategy to convert sulfides directly to NH-sulfoximines is discussed, with N and O transfer occurring under the reaction conditions. Mechanistic evidence for the new procedures is included as well as relevant synthetic applications that further exemplify the potential of these approaches. 1. Introduction 2. Strategies to form NH-sulfoximines involving transition metal catalysts 3. Metal-free strategies to prepare NH-sulfoximines 4. Mechanistic evidence for the direct synthesis of NH-sulfoximines from sulfoxides and sulfides. 5. Further applications 6. Conclusion

Search for novel order in URu2Si2 by neutron scattering

We have made extensive reciprocal space maps in the heavy-fermion superconductor URu2Si2 using high-resolution time-of-flight single-crystal neutron diffraction to search for signs of a hidden order parameter related to the 17.5 K phase transition. Within the present sensitivity of the experiment (0.007 mu(B)/U-ion for sharp peaks), no additional features such as incommensurate structures or short-range order have been found in the (hOl) or (hhl) scattering planes. The only additional low-temperature scattering observed was the well-known tiny antiferromagnetic moment of 0.03 mu(B)/U-ion

Oxetane ethers are formed reversibly in the lithium-catalyzed Friedel-Crafts alkylation of phenols with oxetanols: synthesis of dihydrobenzofurans, diaryloxetanes, and oxetane ethers

Studies on the mechanism and intermediate products in the Friedel–Crafts reaction between oxetanols and phenols are presented. Formation of O-alkylated intermediates is identified using 1H NMR spectroscopy, in a reversible formation of the kinetic oxetane ether products. An interesting relationship between the electronic nature of the nucleophile and the degree of O-alkylation is uncovered. For phenols substituted with an electron withdrawing group such as CN, oxetane ethers are the only products isolated regardless of reaction time. Increasing the electron rich nature of the phenol leads to an increased proportion of the thermodynamic C-alkylated Friedel–Crafts products after just one hour and as the sole product/s after extended reaction times. These studies have enabled a more complete catalytic cycle to be proposed. Using the same lithium catalyst and carefully selected reaction times, several examples of oxetane ethers are successfully isolated as novel bioisosteres for ester groups