Iron-Catalyzed Alkane's Sp3 Carbon-Hydrogen Borylation, Thioetherification and Sulfoxideation

The general formula for alkanes is C_nH_2n+2 and the direct activation and functionalization of aliphatic carbon-hydrogen bonds has always been considered an important research in the field of alkanes in organic chemistry. This process can directly synthesize high value-added functional products from common alkanes. Compared with the functionalization of aromatic sp² carbon-hydrogen bonds, the sp³ carbon-hydrogen bonds of ordinary alkanes are difficult to control due to their low reactivity and selectivity, so direct activation and functionalization are extremely difficult. The current common strategy is to use directing groups or noble metal catalysis to achieve such transformations. In recent years, light-induced radical-mediated hydrogen atom transfer (HAT) has emerged as an attractive strategy to directly activate the carbon-hydrogen bonds of alkanes without prefunctionalization or installation of directing groups. . In this field of research, a much-concerned issue is the regioselectivity of hydrogen atom transfer, which largely depends on factors such as bond dissociation energy, bond strength, and steric effects of C-H bonds.

Recently, light-induced ligand-to-metal charge transfer (LMCT) has been shown to be an effective synthetic tool for building organic molecules. Using cheap 3d transition metals (iron, copper, nickel, cobalt, etc.) as catalysts, high-valent metal-ligand complexes are directly excited by visible light irradiation to generate active free radical species. These free radical intermediate can be used as a HAT reagent to carry out the intermolecular hydrogen atom transfer process with the sp³ carbon-hydrogen bond of the aliphatic compound and trigger a series of sp³ carbon-hydrogen bond functionalization reactions. Among them, photoinduced chlorine radical species have been identified as key intermediates in the LMCT method, which are involved in reactions such as C(sp³)–H arylation, alkylation, amination, and alkynylation as HAT reagents. It is worth pondering whether this light-induced LMCT strategy can be used to realize the construction of valuable carbon-boron bonds and carbon-sulfur bonds? Besides the HAT species, are there other key factors affecting the regioselectivity of sp³ hydrocarbon functionalization?

Focusing on this key issue, some researchers have achieved sp³ carbon-hydrogen bond borylation, thioetherification, and sulfoxide reactions of unguided alkane and other aliphatic molecules through the light-induced LMCT process and using cheap metallic iron as a catalyst. It is worth noting that all three reactions exhibit good regioselectivity. The method exhibits a very broad substrate scope (>150 examples), not only containing simple alkanes molecules, but also can be extended to other molecules containing aliphatic C-H bonds, including ketones, esters, ethers, nitriles, amides, sulfonamides, halides and silanes, etc., and can be applied to the post-modification of some drug molecules and natural products.

According to the results of the mechanistic study, the researchers proposed a possible mechanism: photoexcitation of the iron complex (A) will generate its excited state (B), and intramolecular LMCT will occur to generate iron (II) complex (C) and chlorine free radical species.

The chlorine radical undergoes rapid hydrogen atom transfer (HAT) with the C–H compound, releasing a key carbon-centered radical intermediate (D). In one aspect, a carbon-centered radical (D) reacts with a ligand-stabilized B₂(cat)₂ to generate an alkylboronate (E) and a boron radical (F). A one-electron transfer between the oxidizing agent (NFSI) and the iron(II) species produces the iron(III) species (A) and simultaneously generates the reduced NFSI species, which can quench the boron radical (F). On the other hand, acetyl chloride activates sulfinates in situ to generate sulfone sulfides (in the presence of H₂O) or sulfone sulfoxides (under anhydrous conditions), it will capture carbon center radicals (D) and release sulfhydryl or sulfinated products, while generating sulfonyl radicals, which can oxidize iron (II) to iron (III), realizing the catalytic cycle of iron.

Reference

1. Iron-Catalyzed C(sp³)–H Borylation, Thiolation, and Sulfinylation Enabled by Photoinduced Ligand-to-Metal Charge Transfer
   J. Am. Chem. Soc., 2023, 145, 7600–7611