Late‐Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis

Abstract

The direct CH functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible-light photoredox catalysis to achieve the direct methyl-, ethyl-, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.

Advances in Photocatalysis: A Microreview of Visible Light Mediated Ruthenium and Iridium Catalyzed Organic Transformations

“…51 Established methods such as Minisci’s persulfate mediated decarboxylation required high temperatures 52 and are often too harsh for large, complex molecules. While increases to the scope have been made, 53 DiRocco’s method to overcome these issues represents a significant advancement in LSF, in part, because the catalyst can help regulate the concentration of the reactive species.…”

DFT as a Powerful Predictive Tool in Photoredox Catalysis: Redox Potentials and Mechanistic Analysis

“…PC9 (with only fluoride substituents but different positions than those of PC8) has the largest excited-state reduction potential, E 0 (Ir 3+ * /2+ ) 0.48 V. On the other hand, the excited-state oxidation potential of PC10 (with only methyl substituents) is larger than the other two as well as PC2, being E 0 (Ir 4+/3+ *) −1.93 V. These results Table 5. Comparison of Experimental and Calculated S1 → S0 and T1 → S0 Transition Energies for the Ru 2+ Complexes (eV) and Excited-State Redox Potentials (Volts) for all Ruthenium Complexes Using SC-ZORA/PBE-D3/TZ2P and SC-ZORA/ B3LYP-D3/TZ2P in Acetonitrile 15 Therefore, late-stage C−H functionalization chemistry of heterocycles has become a mainstream area of investigation in recent years. Photoredox catalysis offers unprecedented opportunities for developing new strategies in this area.…”

“…15,16,18−21 Particularly common are complexes of ruthenium and iridium. 15,18,19 The choice of the ligand−metal combination will govern the redox potentials (E 0 ) in both the ground and excited states. For example, the ground-state reduction potentials for tris-(bipyridine)ruthenium(II) (Ru(bpy) 3 2+ ) and tris(2,2′-bipyrazyl)ruthenium(II) (Ru(bpz) 3…”

Visible-Light Photocatalytic Double C–H Functionalization of Indoles: A Synergistic Experimental and Computational Study

“…5,7,10,12,13 Visible-light photocatalysis (VLPC) has recently emerged as a powerful manifold for late-stage C-H functionalization. [1][2][3][4]7,8,14 An excellent example is the recent protocol reported by DiRocco and co-workers, 6 exemplified by the selective methylation of the antifungal agent voriconazole (Scheme 1), which was achieved in overall 75% yield to produce a mixture of mono-and dimethylated products via iridium photocatalysis. Considering the number of C-H sites available for functionalization, and the presence of other potentially interfering functional groups, this is an impressive achievement.…”