Synthesis of 3-Substituted 4-Aroylisoquinolines via Pd-Catalyzed Carbonylative Cyclization of 2-(1-Alkynyl)benzaldimines

Abstract

A number of 3-substituted 4-aroylisoquinolines have been prepared in good yields by treating N-tert-butyl-2-(1-alkynyl)benzaldimines with aryl halides in the presence of CO and a palladium catalyst. Synthetically the methodology provides a simple and convenient route to isoquinolines containing an aryl, alkyl, or vinylic group at C-3 and an aroyl group at C-4 of the isoquinoline ring. The reaction is believed to proceed via cyclization of the alkyne containing a proximate nucleophilic center promoted by an acylpalladium complex.

Six‐Membered Heterocycles: Quinoline and Isoquinoline

“…The former methodology was subsequently expanded to the synthesis of 3-substituted-4-aroylisoquinolines 184 by palladium-catalyzed carbonylative cyclization of 2-(1-alkynyl)benzaldimines 185 and aryl halides (Scheme 17.112) [314,315]. The reaction is useful for both electron-rich and electron-poor aryl halides.…”

“…Dihydroisoquinolines can be produced using either sodium in liquid ammonia (3,4-dihydro, 319) [427] or lithium aluminum hydride (1,2-dihydro, 320) [427][428][429]. The dihydroisoquinolines can be oxidized back to 116 with chloranil or disproportionate in acid solution to give a mixture of 1,2,3,4-tetrahydroisoquinoline (315) and 116. Tetrahydroisoquinoline 315 can be obtained directly from 116 by reduction with sodium in a non-protic solvent or from 319 using sodium in liquid ammonia (Scheme 17.161).…”

Palladium-Catalyzed Carbonylative Synthesis of Six-Membered Heterocycles from Aryl Halides

“…The above strategy was also employed in the carbonylative synthesis of 3-substituted 4-aroylisoquinolines by Dai and Larock [66]. In the presence of Scheme 32 Regio-switchable procedure toward linear and angular fused quinazolinones 5 mol% of Pd(PPh 3 ) 4 as the catalyst and 5 equiv.…”

Coenzyme Q and mitochondrial disease

“…More directly, 3,4‐disubstituted products can be formed by the Pd‐catalyzed cross‐coupling of N ‐ tert ‐butyl‐ ortho ‐(1‐alkynyl) benzaldimines with aryl, allylic, and alkynyl halides 50b. c Similarly, the 3‐substituted 4‐aroylisoquinolines can be prepared by treating N ‐ tert ‐butyl‐2‐(1‐alkynyl) benzaldimines with aryl halides in the presence of CO and a Pd catalyst 50d. However, this method is not useful to obtain products that contain substituents at the C1 position because of the inherent structural defect of iminoalkynes.…”