Mechanochemical Tandem Reactions: A Sustainable and Direct Route to 1,2-Di-Functional Indolizines via In Situ...

Herein, we report a sustainable, metal-free tandem mechanochemical strategy for the construction and C-H chalcogenocyanation of indolizines from pyridine-2-carboxaldehydes and α,β-unsaturated compounds. The method involves DABCO-catalyzed in situ formation of the Baylis-Hillman adduct followed by cyclization, delivering 2-functionalized indolizines within 30 min under solid-phase mixer-milling conditions, with yields of up to 81%. Several of these products were further subjected to mechanochemical thio- and seleno-cyanation. Notably, a combination of commercially available NaSCN/KSeCN and NCS first generates electrophilic chalcogenocyanating agents that afford the unprecedented 1-chalcogenocyanated-2-formyl-indolizine scaffold in just 15 min with up to 94% yields, in a work-up-free process. Interestingly, silica-assisted solid-phase mechanochemistry enables tandem conversion of the starting pyridine-2-carboxaldehydes and enones directly into 1,2-difunctionalized indolizines, with practically no drop in overall yields (best yield 75%). Furthermore, the dual-functional handles allow diverse post-functionalizations, including the conversion of -SCN to -SCF₃ and sulfenyl tetrazoles, and -CHO to indolizino-benzazoles, all via mixer-milling. The scalability of the tandem mechanosynthesis of 1,2-difunctionalized indolizines was established using selected examples. The time-efficient and step-economic solid-phase tandem mechanochemical method exhibits strong sustainability metrics, including low process mass intensity (PMI 9.1 g g^-1), low E-factors (4.1), good atom economy (65% AE), and a high EcoScale score (∼70).