Merging C–H Activation and Strain–Release in Ruthenium-Catalyzed Isoindolinone Synthesis

Abstract

The merger of strain–release of 1,2-oxazetidines with carboxylic acid directed C–H activation in catalytic synthesis of isoindolinones is reported for the first time. This reaction opens a new and sustainable avenue to prepare a range of structurally diverse isoindolinone skeletons from readily available benzoic acids. The success of late-stage functionalization of some bioactive acids, and concise synthesis of biologically important skeletons demonstrated its great synthetic potential in drug discovery. Mechanistic studies indicated a plausible C–H activation/β-carbon elimination/intramolecular cyclization cascade pathway.

Merging strain-release and copper catalysis: the selective ring-opening cross-coupling of 1,2-oxazetidines with boronic acids

“…On the basis of these preliminary observations and our previous works on 1,2-oxazetidines, 15 ArB(OH) 2 followed by protonolysis gives the aminomethylation products and active Ar-Cu species for the next catalytic cycle.…”

“…On the basis of these preliminary observations and our previous works on 1,2-oxazetidines, 15 a plausible catalytic pathway is proposed in Scheme 5. The reaction begins with a transmetalation between the copper catalyst and aryboronic acid to give a reactive Ar–Cu species 1-A .…”

“…14 b Very recently, by employing 1,2-oxazetidines as formaldimine precursors, our group reported a Ru-catalysed C–H/C–N bond activation and subsequent annulation of benzoic acids for the assembly of isoindolinones (Scheme 1c). 15…”

“…Other bidentate ligands were subsequently tested. As a result, 3,4,7,8-tetramethyl-1,10phenanthroline (L 2 ), 4,7-dichloro-1,10-phenanthroline (L 3 ) and 4,4 0 -bis(1,1-dimethylethyl)-2,2 0 -bipyridine (L 5 ) gave 3aa in satisfactory yields, while N,N 0 -dimethylethylenediamine (L 4 ) resulted in a low yield (entries [15][16][17][18]. A dramatically decreased yield was observed when the reaction was conducted at 100 1C (entry 19, 56%).…”

A New Approach to Isoindolinones: Rhodium(III)‐Catalyzed [3+2] Annulation Reactions of N‐Methoxybenzamides with Bis(tosylamido)methane

“…[12] In a way, these two kinds of pathways involve [4 + 1] cyclization. In particular, in 2021, Hu [13] reported the construction of isoquinoline structure using [Ru] as a catalyst with 1,2-oxazetidine or bis(tosylamido)methane as a nitrogen source. However, when the para position of benzoic acid is substituted, the yield of the product is usually poor.…”