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.
