Mechanochemical C−X/C−H Functionalization: An Alternative Strategic Access to Pharmaceuticals

Abstract

In the pursuit of clean pharmaceutical production, chemists in medicinal industry require access to new sustainable methodologies to reduce and even eliminate pollution, which is mainly produced by the overuse of organic solvents during chemical synthesis of active pharmaceutical ingredients (APIs). In this context, the solvent-free/less mechanochemical functionalization of small molecules has gradually emerged as a powerful strategy for the green synthesis and modification of APIs, bioactive compounds, and functional materials. In this review, we present an overview of mechanochemical CÀ X/CÀ H functionalization applications to medicinal chemistry, involving cross-coupling, cross-dehydrogenative coupling, oxidative coupling (via CÀ H activation pathway), and direct coupling (via radical pathway) as key steps for the preparation of APIs and bioactive compounds.

Recent Advances in Alkenyl sp2 C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

“…Nevertheless, many solutions have been successfully established such as the design of metal ligands with steric constraints. It shoud be mentioned that this review focuses on alkenyl sp 2 C–F bond functionalization of gem -difluoroalkenes and their analogues, methods of C–X bond functionalization of other gem -dihalovinyl systems or aryl halides will not be covered. − …”

Force-Modulated Selectivity of the Rhodium-Catalyzed Hydroformylation of 1-Alkenes

“…In contrast to this diverse range of reaction outcomes, applications of mechanochemistry to organometallic complexes has focused primarily on force-induced metal–ligand bond scission as a means to, e.g., activate a latent homogeneous catalyst . Bulk mechanochemistry in the form of grinding and ball milling has also been used to activate metal complexes and catalysts in the solid phase, either by facilitating bond cleavage or intimate mixing of reagents . A relatively unexplored opportunity is the use of external force to modulate the reactivity of a transition metal complex that remains intact while force is applied to its ligands.…”

Mechanoenzymology in the Kinetic Resolution of β-Blockers: Propranolol as a Case Study

“…Significantly, synthetic properties of lipases, such as high chemo-, regio-, and enantioselectivity, which are observed using immobilized lipases under conventional heating and stirring conditions, , are retained when non-conventional sources of energy, such as sonochemistry, − microwaves, or mechanical activation, are used. − Indeed, the mechanochemical activation of free and immobilized enzymes corresponds to a recently created area in mechanochemistry that has been called mechanoenzymology, , whose application in the kinetic resolution of chiral compounds has led to the synthesis of active pharmaceutical ingredients (APIs) with high enantiopurity. Mechanoenzymatic and mechanochemical methods on API’s synthesis have been recently reviewed. − …”

“…Mechanoenzymatic and mechanochemical methods on API’s synthesis have been recently reviewed. 18 − 21 …”