A Modular Flow Design for the meta‐Selective C−H Arylation of Anilines

Abstract

Described herein is an effective and practical modular flow design for the meta-selective CÀHa rylation of anilines.T he design consists of four continuous-flowm odules (i.e., diaryliodonium salt synthesis,m eta-selective CÀHa rylation, inline copper extraction, and aniline deprotection) which can be operated either individually or consecutively to provide direct access to meta-arylated anilines.W ith at otal residence time of 1hour,t he desired product could be obtained in high yield and excellent purity without the need for column chromatography,a nd the residual copper content meets the standards for parenterally administered pharmaceutical substances.Site-selective C À Hb ond functionalization strategies are of paramount importance in modern organic synthesis.[1] However,b ecause of the ubiquitous presence of CÀHb onds in organic molecules,the regioselective assembly of substituted arenes remains am ajor challenge.T raditionally,t he ortho and, to some extent, the para substitution of arenes have been thoroughly explored with the use of Friedel-Crafts chemistry. More recently,m uch work has been carried out on the transition metal catalyzed ortho-functionalization of arenes, and it proceeds by ac yclometalation strategy.[2] In contrast, the development of meta-selective transformations has required much more scientific investigation. Besides traditional approaches which rely on tuning steric and electronic properties of aromatic substrates,n ovel robust catalytic strategies have emerged.[3] Fore xample,t he incorporation of directing-group templates [4] or the use of transient ligand mediators [5] (e.g.,P d/norbornene) have been exploited to carefully navigate transition metals to the meta-position.Among the reported meta-selective C À Hf unctionalization strategies,the meta-arylation of electron-rich arenes is of high interest to access novel biaryl motifs,w hich represent ac ommon moiety within medicines,a grochemicals,a nd functional materials.[6] In particular, Gaunt and co-workers first reported the meta-selective C À Ha rylation of protected anilines. [7] This transformation was believed to proceed via ah ighly electrophilic Cu III

Synthesis of 4‐Methylbenzoate(2′,4′,6′‐Trimethoxy‐Phenyl)Iodonium Tosylate

“…Based on limited safety information on hypervalent iodine in the literature 11 and the potential for exothermic events that have been suggested in a related diaryliodonium salt synthesis, 12 we conducted a safety evaluation during the development of this procedure. We specifically focused on the potential thermal hazards of I-oxidation with m-CPBA and the thermal stability of the hypervalent iodine species (intermediate 1 and product 2).…”

Electrocatalytic oxidation of 5‐hydroxymethylfurfural for sustainable 2,5‐furandicarboxylic acid production—From mechanism to catalysts design

“…More importantly, isotopic labeling and 1 H‐NMR results confirmed that the H* species used for 4‐NBA ERR were derived from water (Figure 9I). 135,136 The OH* radical generated in the first step of water dissociation was identified as the active species of HMFOR by electron spin resonance (Figure 9J). 137 The enhanced electronic conductivity and electron transfer in heterojunctions, as well as the well‐defined reaction pathways and their pairing advantages, provide guidance for the sustainable synthesis of various value‐added chemicals via paired electrocatalysis.…”

Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites

“…With mono-substituted arenes, a high degree of regioselectivity was observed irrespective of their electronic nature (Scheme 1b). While toluene (14), anisole (15), and chlorobenzene (16) provided high para-selectivity, nitrobenzene (18), trifluoromethylbenzene (19), and benzaldehyde (20) gave high metaselectivity, and with fluorobenzene (21) ortho-selectivity was observed. The intriguing aspects continued with paraolefination of free phenol (17) obviating the prior protection protocol.…”