An efficient and chemoselective method to generate arynes.

Arynes hold immense potential as reactive intermediates in organic synthesis as they engage in a diverse range of mechanistically distinct chemical reactions. However, the poor functional group compatibility of generating arynes or their precursors has stymied their widespread use. Here, we show that generating arynes by deprotonation of an arene and elimination of an "onium" leaving group is mild, efficient and broad in scope.

Vicinal stereocenters asymmetric allylic alkylation and Cope rearrangement: a straightforward route to functionally and stereochemically rich heterocycles.

An asymmetric allylic alkylation/Cope rearrangement (AAA/[3,3]) capable of stereoselectively constructing vicinal stereocenters has been developed. Strategically integrated 4-methylation on the 3,3-dicyano-1,5-diene controls stereoselectivity and drives Cope rearrangement equilibrium in the forward direction. The AAA/[3,3] sequence rapidly converts abundant achiral and racemic starting materials into valuable (hetero)cycloalkane building blocks bearing significant functional and stereochemical complexity, highlighting the value of (hetero)cyclohexylidenemalononitriles as launching points for complex heterocycle synthesis.

Synthesis of Arynes via Formal Dehydrogenation of Arenes.

Arynes offer immense potential for diversification of benzenoid rings, which occur in pharmaceuticals, agrochemicals, and liquid crystals. However, accessing these high-energy intermediates requires synthetic precursors, which involve either harsh conditions or multistep syntheses. The development of alternative methods to access arynes using simpler substrates and milder conditions is necessary for a more streamlined approach.

Aryl(TMP)iodonium Tosylate Reagents as a Strategic Entry Point to Diverse Aryl Intermediates: Selective Access to Arynes.

Arenes are broadly found motifs in societally important molecules. Access to diverse arene chemical space is critically important, and the ability to do so from common reagents is highly desirable. Aryl(TMP)iodonium tosylates provide one such access point to arene chemical space via diverse aryl intermediates.

Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*.

Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described. In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings.

Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients.

Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution patterns of benzenoid rings in small molecule APIs approved by the FDA through 2019 and show that only a few substitution patterns (1-, 1,2-, 1,4-, and 1,2,4-) prevail, and the distribution has remained relatively constant over time. We postulate the connection between available synthetic methods and the occurrence of a few benzenoid substitution patterns by providing an overview of synthetic methods that elaborate existing substitution patterns and those that create new substitution patterns, including those of the former that are favored by medicinal chemists.

A Selective C-H Deprotonation Strategy to Access Functionalized Arynes by Using Hypervalent Iodine.

Described here is an efficient method to access highly functionalized arynes from unsymmetrical aryl(mesityl)iodonium tosylate salts. The iodonium salts are prepared in a single pot from either commercially available aryl iodides or arylboronic acids. The aryne intermediates are generated by ortho-C-H deprotonation of aryl(mesityl)iodonium salt with a commercially available amide base and trapped in a cycloaddition reaction with furan in moderate to good yields.