Alcohols as alkylating agents in heteroarene C–H functionalization

• Published in: Nature (London) 2015-09, Vol.525 (7567), p.87-90
• Main Authors: Jin, Jian, MacMillan, David W. C.
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - chemistry; 639/638/403/933; 639/638/77/890; Acids; Alcohols; Alcohols - chemistry; Alkylating Agents - chemistry; Alkylation; Biosynthesis; Carbon - chemistry; Catalysis; Chemical reactions; Deoxyribonucleic acid; DNA; Humanities and Social Sciences; Hydrocarbons; Hydrogen - chemistry; Kinases; letter; Light; Metabolism; Methods; Milrinone - chemistry; multidisciplinary; Oxidation-Reduction; Oxidizing agents; Oxygen - chemistry; Pharmaceutical sciences; Photochemical Processes; Reagents; Science; Substrate Specificity
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14885

The biochemical process of spin-centre shift is used to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors; this represents the first broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. Dual catalytic alkylation of heteroarenes A central reaction in DNA biosynthesis is ribonucleotide deoxygenation via the radical-mediated elimination of H 2 O, which is an example of 'spin-centre shift' (SCS), during which an alcohol C–O bond is cleaved to produce in a carbon-centred radical intermediate. Although SCS is a well-understood biochemical process, it is underutilized by the synthetic organic chemistry community. Here Jian Jin and David MacMillan show that it is possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylations using alcohols as radical precursors. This method represents the first broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the merger of photoredox and hydrogen atom transfer catalysis. Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage 1 . One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H 2 O to deoxygenate ribonucleotides, an example of ‘spin-centre shift’ 2 , during which an alcohol C–O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides 3 , 4 , 5 , 6 , 7 , a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox