Direct Benzylic C-H Etherification Enabled by Base-Promoted Halogen Transfer.

We disclose a benzylic C-H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence. The combination of tert-butoxide bases with 2-halothiophene halogen oxidants enables the first general protocol for generating and using benzyl halides through a deprotonative pathway. In contrast to existing radical-based methods for C-H functionalization, this process is guided by C-H acidity trends.

Mild Darzens Annulations for the Assembly of Trifluoromethylthiolated (SCF) Aziridine and Cyclopropane Structures.

We report mild new annulation approaches to trisubstituted trifluoromethylthiolated (SCF) aziridines and cyclopropanes via Darzens inspired protocols. The products of these anionic annulations, rarely studied previously, possess attractive features rendering them valuable building blocks for synthesis platforms. In this study, trisubstituted acetophenone nucleophiles bearing SCF and bromine substituents in their α position were shown to undergo [2 + 1] annulations with vinyl ketones and tosyl-protected imines under mild reaction conditions.

Dienolate Annulation Approach for Assembly of Densely Substituted Aromatic Architectures.

The efficient assembly of complex aromatic structures from simple acyclic building blocks is reported. An anion-cascade union of an enoate and a conjugated imine affords cyclohexenone products, which are readily aromatized to phenols. By engaging the intermediate cyclohexenones with Grignard reagents, a facile addition/elimination proceeds yielding chiral cyclohexadienes, which are then aromatized.

Dramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades.

We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an -relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a -relationship.

Strategic Vinyl Sulfone Nucleophile β-Substitution Significantly Impacts Selectivity in Vinylogous Darzens and Aza-Darzens Reactions.

Vinylogous Darzens and aza-Darzens reactions employing a benzothiophene 1,1-dioxide nucleophile are reported. These new [2 + 1] annulation reactions, which proceed under mild reaction conditions, are γ-selective, affording -epoxides selectively and favoring -aziridines. The reactions are base-dependent, with KOtBu and CsCO being optimal for aldehyde and imine annulations, respectively.

A Survey of the Structures of US FDA Approved Combination Drugs.

Combination drugs are an important class of US FDA approved pharmaceuticals. These drugs have been on a continuous growth trajectory since the first combination drugs were approved in the 1940s. In this Perspective, we report the first comprehensive compilation and analysis of US FDA approved combination drugs, from the first approval in 1943 through 2018.

Asymmetric Vinylogous Aza-Darzens Approach to Vinyl Aziridines.

A new asymmetric approach to assemble cis-vinyl aziridines is reported. A reaction of strategically substituted dienolates, decorated with a γ-leaving group, with chiral sulfinimines afforded chiral vinyl aziridine products in good to excellent yields. This is the first systematic study toward the realization of a useful asymmetric vinylogous aza-Darzens reaction.

From Oxiranes to Oligomers: Architectures of U.S. FDA Approved Pharmaceuticals Containing Oxygen Heterocycles.

Oxygen heterocycles are the second most common type of heterocycles that appear as structural components of U.S. Food and Drug Administration (FDA) approved pharmaceuticals.