Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

Abstract

The significant number of papers and reviews published in this last decade testifies to the utility of the transition-metal-catalyzed direct C–H (hetero)arylation reactions of (hetero)arenes as efficient and powerful tools for the step- and atom-economical, regio- and chemoselective synthesis of natural and unnatural compounds. However, no review has so far been devoted to summarizing the application of these reactions in the synthesis of biologically active compounds. This review with 341 references aims to fill this gap, providing a comprehensive picture of the transition-metal-catalyzed intra- and intermolecular direct C–H (hetero)arylation reactions of (hetero)arenes with (hetero)aryl halides or pseudohalides that have been used as key steps of syntheses of unnatural biologically relevant compounds including pharmaceutical targets, up to the end of September 2015. Attention has also been directed to provide a brief description of the biological properties of the synthesized compounds.

1 Introduction

2 Syntheses via Intramolecular Direct (Hetero)arylation of (Hetero)arene Derivatives

3 Syntheses via Intermolecular Direct (Hetero)arylation Reactions

3.1 Of Arenes

3.2 Of Five-Membered Heteroarenes with One Heteroatom

3.3 Of Five-Membered Heteroarenes with Two Heteroatoms

3.4 Of Five-Membered Heteroarenes with Three and Four Heteroatoms

3.5 Of Five-Membered Heteroarenes Fused to a Six-Membered Heteroarene

3.6 Of Five-Membered Heteroarene Moieties of Tricyclic Heteroarenes

3.7 Of Six-Membered Heteroarenes

4 Syntheses of Nitrogen-Containing Polycyclic Heteroarene via One-Pot Palladium-Catalyzed Domino Direct Arylation/N-Arylation Reactions

5 Conclusions

Key words

(hetero)arenes - transition-metal catalyst - direct (hetero)arylation - C–C bond formation - biological activity - drugs

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For additional examples of ligand-free palladium-catalyzed direct C5-arylation reactions of thiazole derivatives, see:
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For protocols on the palladium-catalyzed direct C5-arylation of imidazole derivatives that have been developed by research groups other than ours, see:
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For palladium-catalyzed direct C2-arylation reactions of 1-substituted imidazoles that have been reported by research groups other than ours, see:
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For directed ortho-arylation of benzamides in an acidic solvent, see:
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For recent examples of direct arylation reaction which have been carried out using a low catalyst loading, see ref. 60d and:
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For recent examples of direct arylation reactions carried out using new catalyst systems, see ref. 127c and:
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For typical examples, see:
• 180a (Poly)halobenzenesulfonyl chlorides: Skhiri A, Beladhria A, Yuan K, Soulé J.-F, Bensalem R, Doucet H. Eur. J. Org. Chem. 2015; 4428
• 180b Arylsulfonyl chlorides: Zhang W, Liu F, Zhao B. Appl. Organomet. Chem. 2015; 29: 524
• 180c Sodium arenesulfinates: Zhu J, Chen Y, Lin F, Wang B, Huang Q, Liu L. Synlett 2015; 26: 1124
• 180d Aryldiazonium salts: Shin K, Park S.-W, Chang S. J. Am. Chem. Soc. 2015; 137: 8584
• 180e Aryltrimethylammonium triflates: Zhu F, Tao J.-L, Wang Z.-X. Org. Lett. 2015; 17: 4926
• 180f Benzenesulfonyl chlorides: Hfaiedh A, Yuan K, Ben Ammar H, Ben Hassine B, Soulé F, Doucet H. ChemSusChem 2015; 8: 1794
• 180g 2-Thiophenecarboxylic acids: Zhao S, Liu Y.-J, Yan S.-Y, Chen F.-J, Zhang Z.-Z, Shi B.-F. Org. Lett. 2015; 17: 3338
• 180h 2-Methoxybenzoic acids: Zhang Y, Zhao H, Zhang M, Su W. Angew. Chem. Int. Ed. 2015; 54: 3817
• 180i Diversely substituted aryl carboxylic acids: Zhang L, Xue X, Xu C, Pan Y, Zhang G, Xu L, Li H, Shi Z. ChemCatChem 2014; 6: 3069

For recent examples of C–H direct (hetero)arylation reactions carried out in or on water, see refs. 88a–d,f,g and:
• 181a Zhu Y, Bauer M, Ackermann L. Chem. Eur. J. 2015; 21: 9980
• 181b Singh KS, Dixneuf PH. ChemCatChem 2013; 5: 1313
• 181c Ackermann L, Mulzer M. Org. Lett. 2008; 10: 5043