Construction of Spiropyrido[2, 1‐a]isoquinoline via Tandem Reactions of Huisgen's 1,4‐Dipoles with Various Alkene Dipolarophiles

Abstract

The three‐component reaction of isoquinoline, dimethyl acetylenedicarboxylate and arylidene pivaloylacetonitrile in acetonitrile at room temperature afforded pyrido[2, 1‐a]isoquinolines 1 a‐1 j in good yields and with high diastereoselectivity. When arylidene‐substituted 1,3‐indanediones, Meldrum acids, and N,N’‐dimethylbarbituric acids were employed in the reaction, the novel functionalized spiro[indene‐2, 1′‐pyrido[2, 1‐a]isoquinolines] 2 a‐2 j, spiro[pyrido[2, 1‐a]isoquinoline‐1,5′‐[1, 3]dioxanes] 3 a‐3 h and spiro[pyrido[2, 1‐a]isoquinoline‐1,5′‐pyrimidines] 4 a‐4 e were also efficiently synthesized in satisfactory yields. The reaction mechanism included domino formation of Huisgen's 1,4‐dipole, Michael addition and cyclization processes.

Selective Construction of Spiro[indene‐2,4′‐pyrido[1,2‐a]quinolines] and Dihydroindeno[1,2‐b]pyrene via Domino Reactions of Huisgen's 1,4‐Dipoles

“…According to our previously established reaction conditions for the similar three‐component reaction containing isoquinoline, an equal amount of quinoline, dimethyl acetylenedicarboxylate (DMAD) and 2‐benzalidene‐1,3‐indanedione in dry acetonitrile was stirred at room temperature. TLC monitoring indicated that the expected spiro[indene‐2,4′‐pyrido[1,2‐ a ]quinoline] 1 a can be obtained in 54% yield.…”

“…On the basis of 1 H NMR and single crystal structures, it can be concluded that the obtained compounds all have this kind of configuration. By comparing the configuration of the spiro[indene‐2,4′‐pyrido[1,2‐ a ]quinolines] 1 a‐1 j with that of the previously prepared spiro[indene‐2,1′‐pyrido[2,1‐ a ]isoquinolines] derived from the three‐component reaction containing isoquinoline, the same cis‐ configuration of the products were obtained in the two reactions. These results showed that the domino reaction of Huisgen's 1,4‐dipoles have similar outcome of stereochemistry.…”

“…Among the various synthetic methodologies, the domino reactions with the readily available 2‐arylidene‐1,3‐indanediones have been proven to be one of the most convenient synthetic protocol for the indenone‐fused heterocycles ,. Recently, we have successfully founded that Huisgen's 1,4‐dipoles generated from the reaction of isoquinoline and dimethyl acetylenedicarboxylate reacted with various arylidene 1,3‐dicarbonyl compounds resulted in novel spiro‐pyrido[2,1‐ a ]isoquinoline in high yields . In order to further demonstrate the potential synthetic values of Huisgen's 1,4‐dipoles for construction of versatile heterocyclic compounds, herein we wish to report the selective synthesis of spiro[indene‐2,4′‐pyrido[1,2‐ a ]quinoline], dihydroindeno[1,2‐ b ]pyrene and spiro[pyrido[1,2‐ a ]quinoline‐4,5′‐pyrimidine] derivatives via domino reaction of different Huisgen's 1,4‐dipoles with 2‐arylidene‐1,3‐indanediones and 5‐arylidene‐N,N’‐dimethylbarbituric acids.…”

Stereoselective synthesis of fused-, spiro- and bridged heterocycles via cyclization of isoquinolinium salts: a recent update

“…In 2017, Yan's group developed the three component reaction of isoquinoline 11, DMAD 19 and arylidene pivaloylacetonitrile (alkene dipolarophile) 85 to obtain pyrido[2,1-a]isoquinolines 87 under ambient conditions (Scheme 24). 41 The formation of only diastereoisomer 87 was confirmed with the help of NMR spectra. X-ray crystallographic studies reveal that the aryl group and the cyano group exist in the cis-orientation.…”

Sequential and direct multicomponent reaction (MCR)-based dearomatization strategies

“…successfully provided a convenient method for the synthesis of functionalized spirocyclic derivatives (107,108,110,111) under mild reaction conditions (Scheme 21B and C). 82,83 Zhang, Cao and co-workers have reported a copper-catalyzed sequential one-pot two-step threecomponent reaction of a substituted isoquinoline, a terminal alkyne, and methyl 4,4,4trifluorobut-2-ynoate for the synthesis of 3-(trifluoromethyl)pyrrolo[2,1-a]isoquinolines 112 with air as an oxygen source (Scheme 22). 84 This oxidative cyclization proceeds through an initial copper(I)-catalyzed C-H alkynylation to give alkynyl-1,2-dihydroisoquinoline B, which subsequently undergo a copper(II)-assisted intramolecular cyclization to give the desired product.…”