New Routes to Fused Isoquinolines

Abstract

Treatment of 6,7-diethoxy-3,4-dihydroisoquinoline (8) and its 1-methyl derivative 12 with hydrazonoyl halides 10 in the presence of Et 3 N in THF under reflux afforded the corresponding 5,6-dihydro-1,2,4-triazolo[3,4-a]isoquinolines 11 and 13, respectively, in high yield (Schemes 2 and 3). The products are formed via regioselective 1,3-dipolar cycloaddition of the intermediate nitrilimines 9 with the isoquinoline CN bond. Reaction of 6,7-diethoxy-3,4-dihydroisoquinoline-1-acetonitrile (4a) with ethyl a-cyanocinnamates 15 in the presence of piperidine in refluxing MeCN yielded benzo[a]quinolizin-4-ones 16 (Scheme 4). Under the same conditions, 12 and arylidene malononitriles 19 reacted to give benzo[a]quinolizin-4-imines 20 (Scheme 5). Instead of 15 and 19, mixtures of an aromatic aldehyde, and ethyl cyanoacetate or malononitrile, respectively, can be used in a one-pot reaction. Introduction. ± Within the class of fused isoquinolines with their cardiovascular [1], anti-inflammatory [2], and antidepressant [3] activities, [1,2,4]triazolo[3,4-a]isoquinolines are of considerable pharmaceutical and agricultural interest [4 ± 7]. Therefore, the synthesis of this ring system is an attractive goal. A convenient approach is the 1,3-dipolar cycloaddition of nitrilimines [8 ± 10], generated by elimination of HX from corresponding hydrazonoyl halides [11 ± 13], to the CN bond of 3,4-dihydroisoquinolines [12] [14]. It has been shown that derivatives of type 1 can be obtained in high yields with R 1 H or alkyl [5] [6] [15] [16]. On the other hand, 3,4-dihydroisoquinolin-1-acetonitriles and hydrazonoyl halides in refluxing THF in the presence of Et 3 N reacted to give pyrrolo[2,1-a]isoquinoline derivatives of type 2 via a cyclocondensation reaction [15] [17]. Spirocyclic adducts of type 3, which could have been formed by 1,3-dipolar cycloaddition with the enamine tautomer of 3,4-dihydroisoquinolin-1-acetamide, have never been observed [6] [15] [17] 3 ).The recently reported results of the reaction of hydrazonoyl halides with 3,4-dihydroisoquinolin-1-acetamide 4 in the presence of Et 3 N [17] are in pronounced contrast to those published earlier [6]. Whereas the reaction of 5 in refluxing THF yielded only the cyclocondensation product 6, the structure of the product obtained from the reaction in CH 2 Cl 2 at room temperature was described as the cycloadduct 1a

Reactivity of 1-methylisoquinoline synthesis of pyrazolyl triazoloisoquinoline and thia-diazolyl isoquinoline derivatives

“…Therefore, the synthesis of this ring system is an attractive goal. We have previously reported the syntheses of triazoloisoquinoline and fused isoquinoline compounds via reaction of 3,4-dihydro-6,7-dimethoxyisoquinoline derivatives with hydrazonoyl halides in chloroform in the presence of triethylamine or in pyridine as catalyst and solvent [8][9][10][11][12]. The aim of the present study is to introduce a new synthetic method by replacing triethylamine in chloroform by the ecologically more acceptable catalyst chitosan [13,14] and under microwave irradiation to enhance reaction rates [15][16][17][18][19] for the synthesis of [1,2,4]triazolo [3,4-a]isoquinolines which were found to be useful precursors for the synthesis of new enaminones 7.…”

Synthesis and Reactivity of 2-Chloro-3-formylpyrido[2,1-a]isoquinoline Derivative. A Novel Routes to Pyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline and Isoquinolino[2,1-g][1,6]naphthyridines

“…[24][25][26][27][28][29] In conjunction with this work we report here the synthesis of the starting 2-chloro-3-formyl-9,10-dimethoxy-4-oxo-6,7dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (3) (Scheme 1). Treatment of 1-cyanomethylisoquinoline 1 with diethyl malonate in nitrobenzene and refluxed for 30 min gave 2-hydroxy-9,10dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (2) in 92% yield.…”

“…[5][6][7][8][9][10][11][12][13][14][15][16][17] Recently, we have been involved in the synthesis and chemistry of several fused isoqinoline derivatives. [18][19][20][21][22][23][24][25][26][27][28][29] In the present paper, we introduce a new and general route to pyrido[2,1-a]isoquinoline containing many reactive sites. The aim of this study, on one hand is to prepare a novel tetracyclic compounds starting from readily obtainable materials in good yields and on the other hand, to prepare compounds that might have pharmacological activity.…”

Synthesis and Reactions of Pyrido[2,1‐a]isoquinolin‐4‐yl Formimidate Derivatives and Antimicrobial Activities of Isolated Products

“…Also, benzo[a]isoquinolines have been associated with a variety of interesting pharmacological properties, among which chemotherapeutic , neuroleptic , anticonvulsant , and anti‐inflammatory . Our research group for 15 years has been focusing on the synthesis of isoquinoline‐containing compounds, and a variety of chemically diverse structures with biological and antitumor activity were obtained . In addition, we have also been interested in the search of new compounds with antitumor properties.…”