An analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients (APIs) approved by the FDA reveals a preference for 1,4-substituted (para), 1-substituted (mono), 1,2,4-substituted, and 1,2-substituted (ortho) arenes. Notably, these substitution patterns are widely commercially available and readily accessible by electrophilic aromatic substitution (SEAr), but more highly substituted and contra-electronic substitution patterns are severely underrepresented in drug substances. Finally, structural variation decreases with increasing substitution and there is a strong reliance on natural product scaffolds in drugs with more highly substituted benzenoid rings.
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. Coupling partners for the aryne intermediates beyond furan are also described, including benzyl azide and alicyclic amine nucleophiles. The regio- and chemoselectivity of this reaction is discussed and evidence for the spectator aryl ligand of the iodonium salt as a critical control element in selectivity is presented.
An analysis of benzenoid substitution patterns in small molecule active
pharmaceutical ingredients (APIs) approved by the FDA reveals a preference for
1,4-substituted (<i>para</i>), 1-substituted
(<i>mono</i>), 1,2,4-substituted, and
1,2-substituted (<i>ortho</i>) arenes. Notably,
these substitution patterns are widely commercially available and readily
accessible by electrophilic aromatic substitution (S<sub>E</sub>Ar), but more
highly substituted and contra-electronic substitution patterns are severely
underrepresented in drug substances. Finally, structural variation decreases
with increasing substitution and there is a strong reliance on natural product
scaffolds in drugs with more highly substituted benzenoid rings.
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. Here we demonstrate that controlling reaction pathways selectively leads to arynes with a broad scope of arenes and arynophiles (24 examples, 70% average yield) and efficient access to biologically active compounds.
Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical,a grochemical, and natural products, is described. [1] In the past, the regioselective syntheses of such compounds have been as ignificant challenge. This work reports am ethod using substituted arynesd erived from aryl(Mes)iodonium salts to access ar ange of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events:1 )ortho-d eprotonation of aryl(Mes)iodonium salts to generate as ubstituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reportedr eaction conditions to generatea rynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor.Ac ompetition experiment furtherr eveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.Scheme1.Selectedexamples and retrosynthesis of 1,2,3,4-substituted benzenoid rings.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.