Benzylic C–H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

Abstract

C(sp3)–H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp3)–H isocyanation protocol that enables...

Cu-Catalyzed Site-Selective Benzylic Chlorination Enabling Net C–H Coupling with Oxidatively Sensitive Nucleophiles

“…However, radical-chain chlorination methods that involve chlorine radical (Cl · ) as the hydrogen-atom transfer (HAT) reagent, often exhibit poor C–H site selectivity. Consequently, benzylic chlorides are commonly prepared by the reaction of benzylic alcohols with SOCl 2 or via other functional-group interconversion methods. ,,,, C–H chlorination methods that employ species other than Cl · for the HAT step can show improved selectivity. − In this context, Cu catalysts, in combination with N -fluorobenzenesulfonimide as the oxidant (Cu/NFSI), promote diverse C–H functionalization and oxidative cross-coupling reactions (e.g., Figure B) − that exhibit high benzylic site selectivity. These methods involve a radical-relay mechanism, in which HAT generates a diffusible benzylic radical that undergoes subsequent functionalization by Cu II and a nucleophilic coupling partner.…”

Copper-Catalyzed Cross-Coupling of Benzylic C–H Bonds and Azoles with Controlled N-Site Selectivity

“…Investigation of oxidative cross-coupling of benzylic C−H substrates and N−H azoles started with ethylbenzene (1a) and ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2a), a pyrazole featured in previous drug discovery efforts. 17 reactions, including pseudohalides (cyanide, 18 azide, 8d isocyanate 19 ), alcohols, 20 carbamates, 21 and carbon-based nucleophiles ((bpy)Zn(CF 3 ) 2 , 22 ArB(OH) 2 , 23 alkynes 24 ). 19,20,27 The above mechanistic considerations guided a survey of reaction conditions.…”

“…17 reactions, including pseudohalides (cyanide, 18 azide, 8d isocyanate 19 ), alcohols, 20 carbamates, 21 and carbon-based nucleophiles ((bpy)Zn(CF 3 ) 2 , 22 ArB(OH) 2 , 23 alkynes 24 ). 19,20,27 The above mechanistic considerations guided a survey of reaction conditions. Initial screening data showed that Cu/ NFSI-catalyzed oxidative coupling of 1a and 2a favors the N 2 isomeric product 3aa when the reaction is conducted in chlorinated solvents PhCl and dichloromethane (DCM) (Figure 2A, entries 1 and 2; see Supporting Information for full screening details).…”

“…Potential reaction conditions were inspired by recent studies involving the use of copper catalysts in combination with N -fluorobenzenesulfonimide (NFSI) as the oxidant. Diverse nucleophilic coupling partners have been used in these reactions, including pseudohalides (cyanide, azide, isocyanate), alcohols, carbamates, and carbon-based nucleophiles ((bpy)­Zn­(CF 3 ) 2 , ArB­(OH) 2 , alkynes). , Cu I -mediated activation of NFSI generates an N -centered radical that promotes selective HAT from benzylic C–H bonds, and subsequent coupling with heteroatom nucleophiles appears to favor a radical–polar crossover pathway involving formation of a benzylic cation intermediate. ,, Complementary studies have shown that mild reductants, such as dialkylphosphites, can promote these reactions by buffering the redox state of the Cu catalyst and ensuring that both Cu I and Cu II are present in the reaction. ,, …”

Multidimensional Screening Accelerates the Discovery of Rhodium Catalyst Systems for Selective Intra- and Intermolecular C–H Amidations

“…Recent advances in high-throughput experimentation (HTE) enabled the fast examination of multiple reactions with minimum resources in a relatively short period of time. − Thus, the HTE approach has been successfully applied to pharmaceutical synthesis − and catalyst design. − Benefitting from the HTE logic and known accessibility to both Cp X - and LX-type compounds, we envisaged generating a wide array of Cp X M­(LX) complexes in situ by simple premixing of [Cp X MCl 2 ] 2 and LX co-ligands. Moreover, we also envisioned additionally screening the metal centers and nitrenoid precursors (Scheme b, right).…”