Simple One-Pot Three-Component Synthesis of 2-Oxo-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinolines

Abstract

O n e -P o t S y n t h e s i s o f 2 -O x o -1 , 1 1 b -d i h y d r o -2 H -p y r i m i d o [ 2 , 1 -a ] i s o q u i n o l i n e sAbstract: Isoquinoline reacts smoothly with dialkyl acetylenedicarboxylates in the presence of isocyanates to produce dialkyl 2-oxo-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinoline-3,4-dicarboxylates in good yields.The development of simple synthetic routes for widely used organic compounds from readily available reagents is one of the major tasks in organic synthesis. 1 Bridgehead nitrogen heterocycles are of interest because they constitute an important class of natural and unnatural products, many of which exhibit useful biological activity. 2,3 The interest in fused bicyclic 6-6 systems with one ring junction and one extra nitrogen atom, stems from the appearance of saturated and partially saturated pyrido[1,2-a]pyrimidine ring systems and their 8,9-benzo analogues (pyrimido[2,1-a]isoquinolines) in many biologically active compounds and natural products, 3-10 some of which are key intermediates for the synthesis of rutaecarpine alkaloids, some have characteristic pharmacological properties such as analgesic, antiallergic, antiasthmatic, and antipsychotic agents, and some are neutral hydrogen chloride acceptors in organic synthesis. 3 As part of our current studies on the development of new routes in heterocyclic synthesis, 11 in this paper, we wish to report a simple synthesis of functionalized pyrimido[2,1-a]isoquinolines.The reaction of isoquinoline (1) and dialkyl acetylenedicarboxylates (2) in the presence of isocyanates (3) proceeds smoothly in dichloromethane at ambient temperature to produce dialkyl 2-oxo-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinoline-3,4-dicarboxylates (4) in 75-99% yields (Scheme 1).The reactions were carried out by first mixing isoquinoline and the isocyanate and then the acetylenic ester was added slowly, proceeding spontaneously in CH 2 Cl 2 , and were complete within an hour (see experimental).The structures of compounds 4a-g were deduced from their elemental analyses and their IR, 1 H NMR and 13 C NMR spectra. The mass spectrum of 4a displayed the molecular ion (M + ) peak at m/z = 390, which is consistent with the 1:1:1 adduct of isoquinoline, dimethyl acetylenedicarboxylate (DMAD) and phenyl isocyanate. The 1 H NMR spectrum of 4a exhibited three singlets readily recognized as arising from two methoxy (d = 3.87 and 3.98) and the methine (d = 6.55) protons, an AB quartet system for two vinylic protons of the enamine moiety of isoquinoline ring (d = 6.01 and 6.56, J = 7.8 Hz), and the characteristic multiplets for the aromatic protons (d = 6.6-7.2). Scheme 1Downloaded by: University of British Columbia. Copyrighted material.

Cyclative MCRs of Azines and Azinium Salts

“…Adib et al demonstrated the convenient synthesis of heterocomulunes using MCRs. [ 130 ] They reported the one‐pot synthesis of dialkyl 2‐oxo‐1,11b‐dihydro‐2 H ‐pyrimido[2,1‐ a ]isoquinoline‐3,4‐dicarboxylatesin ( 190 ) using isoquinoline ( 187 ), dialkyl acetylene dicarboxylates ( 188 ), and isocyanates ( 189 ) with good to excellent yield. Several advantages of the reaction have been demonstrated including mild and catalyst‐free conditions as well as high tolerance toward to diverse starting material mixtures (Scheme 36).…”

“…The reaction takes place via cycloaddition\dearmomatization followed by air oxygen oxidation. The synthesis were completed by using refluxing acetonitrile mixture of pyridines (129), phenacyl bromide (130), and ethyl glyoxalate (131) in the presence of excess sodium carbonate. The reaction gave polysubstituted indolizine derivatives in moderate to good yield.…”

“…Adib et al demonstrated the convenient synthesis of heterocomulunes using MCRs. [130] They reported the one-pot synthesis of dialkyl 2-oxo-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinoline-3,4-dicarboxylatesin (190) Expanding the scope of the combinatorial method in MCR, Mironov [131] et al reported the reaction of isoquinoline (191) Review doi.org/10.1002/ejoc.202001048…”

Six‐Membered Heterocycles: Quinoline and Isoquinoline

“…Isoquinoline reacts with dimethyl acetylenedicarboxylate to give quinolizinetetracarboxylate 327 [440]. When isocyanate is present in the reaction mixture, pyrimidoisoquinoline 328 is obtained [441]. A four-component reaction with dibenzoylacetylene, diketene, and amines to give pyrroloisoquinolines 329 [442], or water to give 1,2-dihydroisoquinolines [443], has been reported.…”

Isoquinoline-catalyzed reaction between 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one and dialkyl acetylene dicarboxylates: synthesis of coumarin and pyranopyrane derivatives

“…[5][6][7][8][9][10][11] These zwitterions intermediate can be trapped with a variety of electrophiles and proton donors, which is a novel protocol for the synthesis of heterocyclic compounds. [5][6][7][8][9][10][11][12][13] Trapping of the zwitterion formed by the addition of isoquinoline to dimethyl acetylenedicarboxylate (DMAD) with electrophiles such as isocyanates, 14 N-tosylimines, 15 quinines 16 and electrophilic styrenes, 17 has been recently used for the synthesis of different isoquinoline-fuzed heterocyclic systems. Reaction of electron-deficient acetylene esters with isoquinoline or quinoline has been also studied in the presence of organic acidic compounds.…”