Copper-Catalyzed Domino Three-Component Benzannulation: Access to Isoquinolines

Abstract

We report herein the synthesis of isoquinolines through a copper(I)-catalyzed domino reaction. During this transformation, three molecules of terminal alkynes, 2-bromoaryl aldehydes (ketones), and acetamide react together, in a sequence including Sonogashira coupling, condensation, 6-endo-dig cyclization, elimination of acetic acid, and hydrolysis. In this reaction, isoquinolines with broad functional group tolerance were successfully obtained by using acetamide as nitrogen source, which provides an alternative to odorous and toxic amines.

LiN(SiMe3)2/KOtBu-Promoted Synthesis of Isoquinolone Derivatives from 2-Methylaryl Aldehydes and Nitriles

“…In 2023, Frantz et al described an effective site-selective allylic C­(sp 3 )–H functionalization protocol with KTMP for the total synthesis of (+)-artemisinin from amorphadiene. In continuation with our previous work on the synthesis of N -heterocyclic compounds, we herein report the LiN­(SiMe 3 ) 2 /KO t Bu-promoted formal [4 + 2] cycloaddition reaction for the one-pot synthesis of isoquinolones via C­(sp 3 )–H bond activation (Scheme d). Notably, compared with reported synthetic procedures, this method does not require the preinstallation of amides and low temperature condition.…”

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

“…In 2022, Wang and coworkers [98] demonstrated a Cu‐catalyzed three‐component domino reaction of 2‐bromoryl‐aldehydes/ketones 176 , terminal alkynes 175 , and acetamide 177 to synthesize highly substituted isoquinolines 178 (Scheme 61). The reactants reacted using CuI and NaOH in water as a reaction medium.…”

“…Li and coworkers [97] used calcium carbide 173 as an alkyne source for constructing benzo [4,5] In 2022, Wang and coworkers [98] EDGs and EWGs have been well accommodated under the copper reaction conditions and various desired isoquinolines 178 were generated in good yields. Estrone containing the alkyne group was also successfully transformed into the desired product, which displayed the significance of the protocol in late-stage alteration of the drug molecules.…”