Pd-catalyzed C-H activation of aliphatic molecules

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The evolution of C-H activation/functionalization strategies has significantly expedited the synthesis of target molecules by introducing new disconnections in retrosynthetic analysis. The greatest challenge in this field remains the regioselective functionalization of specific sp3 C-H bonds in alkanes. The minimal reactivity differences among numerous inert C-H bonds and the fluxionality of aliphatic chains complicate selective transformations at core sites within complex molecules. Therefore, incorporating functionality at an sp3 carbon of an aliphatic motif often relies on traditional electrophilic addition or radical-based reactions.

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Although traditional directing group-assisted approaches aid in functionalizing inert C-H bonds in aliphatic molecules, they have drawbacks, such as the use of stoichiometric directing groups and multiple steps under harsh conditions, compromising step and atom economy. Strategies without directing groups are more appealing and practical. Utilizing a native carboxylate group for C-H activation is a superior alternative, as it requires no exogenous directing group. The weak coordination of carboxylate, combined with bis-coordinating ligands that occupy the empty coordination sites of the Pd complex, is advantageous. The intact carboxylic group in the substrate can be further transformed into various functional moieties, enhancing the diversity of such reactions. The developed protocols will enable step-economic synthesis of drugs, natural products, and agrochemicals by regioselectively modifying different molecules, making it a versatile tool for chemists.

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Representative publications

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1. Pd-Catalyzed Dual-γ-1,1-C(sp3)-H Activation of Free Aliphatic Acids With Allyl-O Moieties

Das, J.; Pal, T.; Ali, W.; Sahoo, S.; Maiti, D. ACS Catal., 2022, 12, 11169.

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2. Access to Unsaturated Bicyclic Lactones by Overriding Conventional C(sp3)-H Site Selectivity

Das, J.; Ali, W.; Ghosh, A.;† Pal, T.;† Mandal, A.;† Teja, C.; Dutta, S.; Pothikumar, R.; Ge, H.; Zhang, X.; Maiti, D. Nat. Chem., 2023, 15, 1626.

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3. Tandem Dehydrogenation-Olefination-Decarboxylation of Cycloalkyl Carboxylic Acids via Multifold C-H Activation

Pal, T.; Ghosh, P.; Islam, M., Guin, S.; Maji, S.; Dutta, S.; Das, J.; Ge, H.; Maiti, D. Nat. Commun., 2024 (ASAP)

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