Selective Mechanochemical Monoarylation of Unbiased Dibromoarenes by in Situ Crystallization

Abstract

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of liquid, unbiased dibromoarenes under mechanochemical conditions selectively afford the monoarylated products. The lower reactivity of the crystalline monoarylated products relative to the liquid starting materials should be attributed predominantly to the low diffusion efficiency of the former in the reaction mixture, which results in a selective monoarylation. The present study sheds light on a novel approach using in-situ phase transitions in solids to design selective organic transformations that are difficult to achieve via conventional solution-based synthesis.

Desymmetrization of pibrentasvir for efficient prodrug synthesis

“…Since mono-Boc regioisomers 11 and 12 showed favorable solubility differences in MTBE ( vide supra ), and it was anticipated that a primary aliphatic amine may deprotect the benzimidazoles at a slow enough rate that mono-Boc 11 could be protected from further de-Boc to PIB by crystallization, 18 the reaction solvent was switched from THF to MTBE and n -butylamine was added to the reaction mixture ( Scheme 3 ). Much to our delight, under these conditions, up-Boc cleaved significantly faster than down-Boc, with 14 converting to 11 and 15 converting to 12 quite rapidly over the first 2.5 h while 13 converted more slowly to 11 .…”

Sustainability Assessment of Mechanochemistry by Using the Twelve Principles of Green Chemistry

“…[25][26][27] Complementarily, mechanochemical multicomponent reactions, [28] and multistep mechanosyntheses have also become a recurrent synthetic practice to limit waste production by reducing the number of intermediary separation and purification steps. [21,[29][30][31][32][33][34][35] In this context, a recent study on the synthesis of the biologically active compound PZ-1361 clearly illustrates the benefits of applying ball milling techniques in organic synthesis (Scheme 1). [36] Compared with the classical protocol in solution to access PZ-1361, the mechanochemical route afforded the product faster, in higher yield, and with better green chemistry metrics (Scheme 1).…”

“…In addition to sublimation, the use of other less energy consuming purification strategies such as filtration has enabled the isolation of products after mechanochemical reactions using a minimal amount of organic solvents or water [25–27] . Complementarily, mechanochemical multicomponent reactions, [28] and multistep mechanosyntheses have also become a recurrent synthetic practice to limit waste production by reducing the number of intermediary separation and purification steps [21,29–35] . In this context, a recent study on the synthesis of the biologically active compound PZ‐1361 clearly illustrates the benefits of applying ball milling techniques in organic synthesis (Scheme 1).…”

Desymmetrization of Pibrentasvir for Efficient Prodrug Synthesis

“…17 However, while both 13 and 14 contain at least one down-Boc benzimidazole, their simultaneous selective conversion to down-mono-Boc 11 without further de-Boc to PIB remained a significant hurdle to accomplishing PIB desymmetrization. anticipated that a primary aliphatic amine may deprotect the benzimidazoles at a slow enough rate that mono-Boc 11 could be protected from further de-Boc to PIB by crystallization, 18 the reaction solvent was switched from THF to MTBE and n-butylamine was added to the reaction mixture (Scheme 3). Much to our delight, under these conditions, up-Boc cleaved significantly faster than down-Boc, with 14 converting to 11 and 15 converting to 12 quite rapidly over the first 2.5 h while 13 converted more slowly to 11.…”