Photoredox-mediated radical functionalization of unactivated diamondoid C–H bonds
Creators: name: Dang, Hoang Thai
Publisher: name: University of Iowa
Year: 2023
Subjects: Diamondoids
Photoredox catalysis
Pyrylium photocatalysis
Radical functionalization
Regioselective synthesis
Unactivated C–H
public abstract

description: Efficient carbon-hydrogen (C–H) bond functionalization is pivotal in organic synthesis and drug development. Hydrogen atom transfer (HAT) methods (both thermal and photochemical) enable the direct transformation of a C–H bond to C–C or C–X bonds. Yet, challenges persist in reactivity and selectivity, particularly for substrates like diamondoids which have multiple types of C–H sites.
description: Diamondoids are polycyclic hydrocarbons which currently present a challenging yet promising class for functionalization. Radical C–H functionalization methods on diamondoid substrates are reviewed herein, with an emphasis on key reactions relevant to the subsequent research. From the discovery of adamantane in crude oil reserves to its efficient Lewis acid-mediated synthesis, adamantane became the first diamondoid to be popularized. Commercial accessibility and discovery of early amino-diamondoid drugs heightened interest into diamondoids, leading to diverse C–H functionalization strategies. Adamantanes are integral in pharmaceuticals and materials and inspire numerous ligands and catalysts. Radical reactions which involve the adamantyl radical include acylation, alkylation, alkenylation, alkynylation, and arylation, all of which showcase the versatility of diamondoids in C–H activation.
description: Advancements in photochemical HAT methods have modernized direct C–H functionalization, eliminating pre-functionalization steps in drug synthesis. Despite numerous advances in HAT-mediated C–H transformations, challenges persist in regioselectivity for complex substrate classes like diamondoids. Our group reports a strategy which merges HAT and photoredox to enable selective radical generation from diamondoid C–H donors. Adamantane, the simplest diamondoid and a valuable model C–H donor, demonstrated exceptional regiocontrol in aminoalkylation via photoredox and HAT dual catalysis. This approach yielded over 17 monofunctionalized adamantanes in 28-87% yields, including a key intermediate for saxagliptin. In addition to a dual catalytic system featuring an iridium complex and amine HAT catalyst, we found that a direct quinone HAT catalyst was an efficient catalyst for asymmetric aminoalkylation with chiral sulfinamines. Water, previously used as a proton shuttle agent, was found unnecessary in the aminoalkylation conditions described herein. Reductive cleavage of protecting groups led to free amino-diamondoid pharmacophores.
description: Previous group members’ attempts to apply the dual-photoredox method to diamantane, a higher diamondoid with multiple 3° C–H bonds, revealed low regioselectivity ratios with a ~1.2:1 ratio of medial:apical products. Our exploration of cationic pyrylium dyes as photoredox catalysts coupled with inorganic Brønsted bases seeks to address these challenges. Despite an unexpected average 3.4:1 medial:apical product ratio, the method stands as efficient, metal-free, and promising for higher diamondoid functionalization. Water and base were discovered to be detrimental to the reaction yield, as confirmed by optimization studies. Leveraging NMR spectroscopy for accurate yield quantification and optimizing drying agents, we obtained isolated yields up to 98%. Our proposed mechanism involves photooxidation of diamantane, proton loss, and trapping of the diamantyl radical. Stern-Volmer experiments and EPR analysis support this mechanism, corroborating diamantyl radical formation upon a photooxidation event by the pyrylium.