02241nas a2200217 4500008004100000022001400041245015800055210006900213260000800282300001400290490000700304520143800311100001701749700002101766700003001787700002801817700001701845700001601862700001801878856012701896 2025 eng d a2041-652000aPhosphite mediated molecular editing via switch to meta-C-H alkylation of isoquinolines: emergence of a distinct photochemical [1,3] N to C rearrangement0 aPhosphite mediated molecular editing via switch to metaCH alkyla cJAN a1809-18180 v163 a

The isoquinoline core is present in one of the largest subsets of bioactive natural products. The multifunctional isoquinoline core exerts diverse bioactivity, resulting in the development of numerous isoquinoline-based drugs and molecules that are currently under clinical trials. We developed a new approach for phosphite-mediated [1,2] alkyl migration for an overall ortho-C-H alkylation via N-alkylation of isoquinoline. Tuning the phosphite-mediated protocol to switch the site selectivity would expedite direct and diverse multi-C-H bond functionalization. We report a new approach starting with a simple N-alkylation of isoquinoline with sterically and electronically diverse alkyl bromides for their phosphite-mediated photochemical [1,3] N to C rearrangement followed by a rearomatization sequence that leads to meta-C-H (C4) alkylation. Combined experimental and computational studies unveiled the emergence of an unprecedented C-N bond cleavage pathway from the singlet excited state of the enamine-type intermediate. Our radical bond-cleavage pathway favors substituted alkyl group migration that complements the recently successful meta-alkylation methods with smaller and more reactive electrophiles. This switch in site selectivity via tuning the phosphite-mediated protocol resulted in sequential C-H difunctionalization of isoquinoline including regiodivergent ortho, meta-dialkylations of isoquinolines.

1 aRani, Soniya1 aRay, Anuj, Kumar1 aDewangan, Devendra, Kumar1 aPatil, Nita, Aruna Ramc1 aAarthika, M.1 aPaul, Ankan1 aMaity, Pradip uhttps://library.ncl.res.in/content/phosphite-mediated-molecular-editing-switch-meta-c-h-alkylation-isoquinolines-emergence