Transition Metal-Catalysed Direct C-H Bond Functionalizations of 2-Pyridone Beyond C3-Selectivity.

2-Pyridone is a ubiquitous motif in natural products, drug molecules, ligands in catalysis and organic materials. There is a necessity of direct step-economic methods for the construction of 2-pyridone based molecules. Strategically, the primary developments have led to the C3-functionalizations due to the inherent reactivity of this center. Despite this, many elegant transition metal-catalysed methods have been established to introduce versatile functional groups at the C4, C5 and C6-position via direct C-H bond functionalizations. This minireview focuses on the categorized introduction of different functional groups at the 2-pyridone scaffolds beyond C3-selectivity and discusses substrate scope, limitations and plausible mechanistic details.

Direct Pd(II)-Catalyzed Site-Selective C5-Arylation of 2-Pyridone Using Aryl Iodides.

A straightforward Pd(II)-catalyzed general strategy was developed for the C5-selective arylation of the 2-pyridone core with easily available aryl iodides. The transformation was highly regioselective and accomplished with a wide scope and functional group tolerance. Silver nitrate played a crucial role in this direct site-selective arylation. The method was extended to synthesize biologically active molecules.

Regiocontrolled direct C4 and C2-methyl thiolation of indoles under rhodium-catalyzed mild conditions.

A straightforward Rh(iii)-catalyzed general strategy was developed for the site-selective remote C4 (sp2) and C2 (sp3)-methyl thiolation of an indole core, keeping the oxime directing group at the C3 position. The transformation was accomplished under mild conditions with a wide scope and functional group tolerance. The directing group can easily be removed after operation. Methyl substitution at the C2 position of the indole core led to C2 (sp3)-methyl thiolation.

Gold(I)-Catalyzed Cyclization for the Synthesis of 8-Hydroxy-3- substituted Isocoumarins: Total Synthesis of Exserolide F.

A highly regioselective gold(I)-catalyzed 6-endo-dig cyclization of 2,2-dimethyl-5-(alkynyl)-4H-benzo[d][1,3]dioxin-4-ones for the synthesis of 8-hydroxy-3-substituted isocoumarins is described. Key features of the reaction include the broad substrate scope, scalability, and tolerance for protecting groups. The synthetic utility of this novel method is demonstrated by the first total synthesis of exserolide F, an isocoumarin-containing polyol natural product.

Asymmetric Total Synthesis of the Putative Structure of Diplopyrone.

The first asymmetric total synthesis of the putative structure of diplopyrone was achieved in 17 linear steps starting from cis-1,4-butene-diol. The synthetic route features iodine-catalyzed tandem isomerization followed by C-O and C-C bond formation reaction strategy developed by our own group to construct the trans-2,6-disubstituted dihydropyran ring, asymmetric α-aminoxylation reaction, and Still-Gennari (Z)-selective olefination reactions. Careful comparison of 1H and 13C NMR spectroscopic data as well as investigation of the UV and circular dichroism spectrum in trifluoroethanol for compound 2 suggest that the putative structure for diplopyrone {6-[(1S)-1-hydroxyethyl]-2,4a(S),6(R),8a(S)-tetrahydropyran[3,2-b]pyran-2-one} requires revision.

Rhodium(III)-Catalyzed C6-Selective Arylation of 2-Pyridones and Related Heterocycles Using Quinone Diazides: Syntheses of Heteroarylated Phenols.

An efficient, direct C6-arylation of 2-pyridones has been successfully accomplished with quinone diazides under Rh(III)-catalyzed redox-neutral conditions. The optimized method is simple, mild, and highly regioselective with a broad substrate scope. The strict regioselectivity is guided by the pyridyl substituent attached to the nitrogen of the pyridone ring. As the directing 2-pyridyl group can easily be removed at any suitable stage after functionalization, the method provides a facile access to complex heteroarylated phenol moieties by wide-ranging heterocyclic scaffolds.