Transition Metal‐Free Direct CH (Hetero)arylation of Heteroarenes: A Sustainable Methodology to Access (Hetero)aryl‐Substituted Heteroarenes

Abstract

In recent years, environmental and economic reasons have motivated the development of transition metalfree carbon-carbon bond forming reactions and some excellent reviews have covered this research area of particular interest for pharmaceutical industry. However, none of these reviews has been specifically dedicated to summarize and discuss the results achieved in the rapidly growing field of the transition metal-free direct (hetero)arylation reactions of heteroarenes. This review, which covers the literature from 2008 to 2014, aims to provide a thorough insight of the synthetic and mechanistic aspects of these atom economical and environmental benign reactions also highlighting their advantages and possible disadvantages compared to conventional methods for the synthesis of arylheteroarenes and biheteroaryls via transition metal-catalyzed reactions. 1. Introduction 2. Direct (Hetero)arylation of Heteroarenes with (Hetero)aryl Halides or Pseudohalides 3. Direct (Hetero)arylation of Heteroarenes with (Hetero)aryl Iodonium Salts 4. Direct Arylation of Heteroarenes with Anilines Nitrosated in situ or Arylhydrazines 5. Direct Arylation of Benzothiazoles with Aryl Aldehydes 6. Direct (Hetero)arylation of Heteroarenes with (Hetero)arylmetals 7. Conclusions

Visible‐Light‐Induced, Catalyst‐Free Radical Arylations of Arenes and Heteroarenes with Aryldiazonium Salts

“…Synthetic methods for the construction of aryl–aryl bonds are mainly based on transition‐metal catalysis, including Suzuki, Stille, and Ullmann couplings, and biaryls may as well be obtained through C−H activation reactions, oxidative coupling reactions, and reactions via arynes . Radical‐based transformations, which are a further alternative for biaryl synthesis, have recently received attention through new developments in the field of catalysis, particularly photocatalysis . Such photocatalyzed reactions can be conducted with a number of aryl radical precursors including diazonium and iodonium salts, diazoanhydrides, carboxylic acids, azo sulfones, and iodo‐, bromo‐, and chloroarenes .…”

Transition‐Metal‐Free Heterobiaryl Synthesis via Aryne Coupling

“…The interest for heterobiaryls and their applications is a driving force for the continuous development of new synthetic methods towards theses peculiar structures. In comparison to the classical biaryl compounds, the presence of an heterocycle in the biaryl structure can provide attractive synthetic and biologic opportunities although this often complicates the coupling between the two (hetero)aromatic partners‐ a favored synthetic methods for the construction . Indeed, the reduced reactivity of the substrate, the coordinating property of the heteroatom with the metal center of the catalyst where applicable, and the reduced configurational stability of the product usually make the access to these compounds more complicated, especially the chiral ones …”

“…Recently, the drive for sustainable alternatives avoiding the use of expensive and potentially toxic transition metals has stimulated efforts for the development of metal‐free “greener” synthetic methods, such as the direct arylation of heteroarenes . These processes often rely on radical‐type mechanisms combining for example the use of aryl halides with a diaryliodonium salt, or a metal‐alkoxide with amine bases .…”

“…In comparison to the classical biaryl compounds, the presence of an heterocycle in the biaryl structure can provide attractive synthetic and biologic opportunities although this often complicates the coupling between the two (hetero)aromatic partners-a favored synthetic methods for the construction. [5][6][7][8] Indeed, the reduced reactivity of the substrate, the coordinating property of the heteroatom with the metal center of the catalyst where applicable, and the reduced configurational stability of the product usually make the access to these compounds more complicated, especially the chiral ones. [9][10][11][12][13][14][15][16][17] Additionally, the unique reactivity of each type of heterocycles renders difficult the development of a general synthetic route compatible with a range of various heteroaryl containing compounds, and makes the simple extension of aryl-aryl coupling methods generally ineffective.…”

“…Recently, the drive for sustainable alternatives avoiding the use of expensive and potentially toxic transition metals has stimulated efforts for the development of metal-free "greener" synthetic methods, [21][22][23] such as the direct arylation of heteroarenes. [7] These processes often rely on radical-type mechanisms combining for example the use of aryl halides with a diaryliodonium salt [8,24] or a metal-alkoxide with amine bases. [25][26][27] However, these alternatives often require the use of the (hetero)arene coupling component in a very large molar excess and the regioselectivity of the arylation remains an important issue.…”