Copper‐Catalyzed C(sp³)− Functionalization and Annulation of 2‐Bromoaryl Oximes with Active Methylene Compounds towards Synthesis of Isoquinoline N‐Oxides

Abstract

The established process proceeds through copper (II)‐catalyzed C(sp3)− functionalization of β‐diketones/β‐ketoesters with 2‐bromobenzaldehyde oximes followed by the intramolecular cyclization of in situ generated acylated intermediates to deliver isoquinoline N‐oxides. The copper(II) acetate catalyzed C−H functionalization showed maximum efficacy at 60 °C in methanol/toluene as solvent. The described reaction conditions were applicable over a wide range of substrates with a variety of functional groups to yield isoquinoline N‐oxides in yields up to 85%. The developed approach was further elucidated by means of control experiments and DFT calculations.

Iodine and DMSO as Surrogate of Hazardous Metal and Non‐Metal Reagents in Organic Synthesis

“…The N-oxide and sulfoxide compounds are widely used in organic synthesis and have significant biological importance, leading to considerable research on their chemistry and applications. [834][835][836] Various methods have been developed to convert N-oxides into amines, using reagents such as Cu (Scheme 83 (a)), Zn (Scheme 83 (b) and (d)), [837][838][839] In (Scheme 83 (c)), NaHSO 3 (Scheme 83 (f)), silane (Scheme 83 (g)), SOCl 2 (Scheme 83 (h)), and AuHAP (Scheme 83 (i)). [840][841][842][843][844] However, these methods have limitations such as narrow substrate coverage, the use of expensive and moisture-sensitive reagents, and the use of transition metals in challenging reaction conditions.…”

“…The N‐oxide and sulfoxide compounds are widely used in organic synthesis and have significant biological importance, leading to considerable research on their chemistry and applications [834–836] . Various methods have been developed to convert N‐oxides into amines, using reagents such as Cu (Scheme 83 (a)), Zn (Scheme 83 (b) and (d)), [837–839] In (Scheme 83 (c)), NaHSO 3 (Scheme 83 (f)), silane (Scheme 83 (g)), SOCl 2 (Scheme 83 (h)), and AuHAP (Scheme 83 (i)) [840–844] .…”

Recent Advances in the 3 d‐Transition‐Metal‐Catalyzed Synthesis of Isoquinolines and its Derivatives

“…In 2023, Malakar and coworkers [109] demonstrated a Cu‐catalyzed ( sp 3 ) functionalization and annulation reaction between 2‐bromoaryl oximes 210 and active methylene compounds 211 to furnish various isoquinolines N ‐oxides 212 (Scheme 72). The reaction was performed using 20 mol % copper(II)acetate and 2.5 equiv.…”

“…In 2023, Liang and Wang [108] reported a Cucatalyzed domino reaction between o-halobenzoates 207 and enaminones 208 to furnish various isoquinolinones 209 (Scheme 71). Various substituted isoquinolinones 209 were obtained in good yields using In 2023, Malakar and coworkers [109] demonstrated a Cu-catalyzed (sp 3 ) functionalization and annulation reaction between 2-bromoaryl oximes 210 and active methylene compounds 211 to furnish various isoquinolines N-oxides 212 (Scheme 72). The reaction was performed using 20 mol % copper(II)acetate and 2.5 equiv.…”

Oxidative Cyclization of Oximes with Propargyl Alcohols toward Functionalized Isoquinoline N‐Oxides Synthesis

“…[5] Very recently, Malakar and co-workers reported a Cu(II)-catalyzed C(sp 3 )À H functionalization and annulation of 2-bromoaryl oximes with active methylene compounds to afford various structurally diverse isoquinoline N-oxides. [6] Although these synthetic methods can provide efficient approaches to build the core isoquinoline N-oxides, some drawbacks, such as harsh reaction conditions, narrow substrate scope, and the requirement of highly functionalized starting materials, limit their synthetic usage. Therefore, the development of mild and straightforward processes to access various multifunctionalized isoquinoline N-oxides from readily available starting materials is of great significance.…”