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

Abstract

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.

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

“…Although the first observation of arynes via the ortho deprotonation of symmetrical diaryliodonium salts occurred in the 1970s, , the development of methods with synthetically useful yields has only recently emerged with aryl­(Mes)­iodonium salts (Mes = 2,4,6-trimethylphenyl; Scheme a) . These recent advances aside, some limitations exist.…”

“…These recent advances aside, some limitations exist. From a practical standpoint, the aryl scope is often rather narrow; that is, strongly electron-donating and strongly electron-withdrawing substituents are largely absent, especially in the para position , and with tert -butoxide as the base . Moreover, in some cases, the mesityl group undergoes competitive aryl transfer via ipso substitution. , Evidence of the challenges surrounding chemoselectivity have been documented by Olofsson and coworkers during their mechanistic study of hydroxide arylation (Scheme b) .…”

“…On the basis of ease-of-use and greenness, we prefer sodium tert -butoxide among the bases known to generate arynes from aryl­(Mes)­iodonium salts. , Therefore, we used sodium tert- butoxide in reactions with a series of salts having different electronic effects ( 1a – g ) and auxiliaries (Mes and TMP). The arynes were trapped with furan 2a as cycloadducts 3a – g (Table ).…”

Diaryliodonium(iii) salts in one-pot double functionalization of C–IIIIandorthoC–H bonds

“…Stuart and Cheong's group achieved the regioselective synthesis of 1,2,3,4-tetrasubstituted benzene by double functionalization via aryne formation (Scheme 43). 80 Aryl(mesityl)iodonium salts bearing multi substituents reacted with N , N -dimethylimidazolidinone 110 in the presence of NaO t Bu to afford the corresponding bicyclic product containing a 1,2,3,4-tetrasubstituted benzene moiety 111 . Various aryl(mesityl)iodonium salts and arynophiles, 112–115 , are amenable to selective transformation leading to the corresponding 1,2,3,4-tetrasubstituted benzenes, 116–119 .…”

Cyclic Diaryl λ3-Bromanes: A Rapid Access to Molecular Complexity via Cycloaddition Reactions

“…Albeit scarcely investigated, a general and straightforward alternative approach based on a modular functionalization via pericyclic reactions of a finely designed biaryl benzyne precursor represents an attractive solution to this synthetic issue (Scheme a) . However, multiple drawbacks hamper the state-of-the-art of the aryne-based approach (Scheme b): (1) lengthy synthetic routes for the preparation of aryne precursors, (2) the limited atom economy resulting from the aryne generation with the removal of leaving groups (−OTf and −TMS; −X and −OR; Aux-I) which translate into significant waste formation, and (3) the limited functional group tolerance as the base- and fluorine-sensitive moieties are generally incompatible. − Accordingly, the implementation of the pericyclic reactions to rapidly access dissymmetrical 2,3,2′,3′,4′-substituted biaryls diversity requests design of original biaryl aryne precursors, activated under mild reaction conditions and in the presence of a weak base.…”