New trans/cis tetrahydroisoquinolines. 2. trans‐ and cis‐3‐(1‐methyl‐1h‐pyrrol‐2‐yl)‐1‐(2H)‐oxo‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquino‐lin‐4‐carboxylic acids and subsequent transformations

Abstract

Stereochemical course of the reaction of homophthalic anhydride and N-(1-methyl-1H-pyrrol-2-ylmethylidene)-phenethylamine was studied. Mixtures of the expected trans-and cis-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids trans-4 and cis-4 were obtained along with by-products 5 and 6. The ratios of all products and the diastereomers, obtained under different reaction conditions, were established by pmr. THF as a solvent and ultrasonic treatment are applied for the first time in the reaction of this type. The reaction was made diastereoselective towards any isomer. The carboxylic group of trans-4 was transformed in four steps into various cyclic amino-methyl groups yielding numerous new tetrahydroisoquinolinones trans-10a-i incorporating a given fragment of pharmacological interest. Reduction of 10a-i was studied.J. Heterocyclic Chem., 40, 795 (2003). 2,3,4-Trisubstituted 1,2,3,4-tetrahydroisoquinolines 1 are important from synthetic and pharmacological point of view [1][2][3][4][5][6][7][8][9]. Some of them have cis and trans forms if C 3 and C 4 are stereogenic centres. The synthesis of such tetrahydroisoquinolines is possible by reactions of different types where one or two bonds of piperidine ring are formed [10][11][12][13][14][15][16][17][18][19]. Compounds of type 1a are prepared in one step, with the formation of b and d bonds, by a new reaction from homophthalic anhydride and an imine [20,21]. Haimova et al. [22,23] assume that bond d is formed before bond b. Chushman and Madaj [24] discuss this mechanism of the reaction, the alternative mechanism (b formed before d) and the concerted mechanism (b and d are formed simultaneously). On the basis of data from Hammett equation, they give preference of the alternative mechanism. In the first paper of this series [1], we have pointed out that some of the data of ref. 24 are in agreement with the concerted mechanism. Thus, this mechanism should be not excluded from consideration. A specific concerted mechanism being 2π + 4 σ has been proposed [1]. Recently, a modification of this mechanism has been supported [25] by a MO and DFT theoretical study.Since 1977, the reaction between a homophthalic anhydride and an imine has been widely applied [1,2,[20][21][22][23][24][26][27][28][29][30][31][32][33][34][35][36][37][38] for preparation of substituted tetrahydroisoquinolinones and polycyclic heterocycles containing isoquinoline moiety. Although the reaction is of great synthetic importance, its stereochemical course varies from case to case and thus predictions are difficult to make.The present paper deals with the chemical and stereochemical course of the reaction between homophathalic anhydride (2) and the acyclic imine 3 aiming at selection of conditions leading predominantly to either trans-4 or cis-4 (see Scheme 1). In general, trans and cis diastereomers, as racemates, have different properties including pharmacological activity. Thus, making a specific reaction diastereoselective is important. Compounds 2 and 3 have enantiotopic faces (re/si) as shown in ...

(3RS,4RS)-3-(2-Furyl)-2-phenethyl-4-(pyrrolidin-1-ylcarbonyl)-3,4-dihydroisoquinolin-1(2H)-one

“…Compound (I) was synthesized by the well known reaction between homophthalic anhydride and imine (Haimova et al, 1977;Kozekov et al, 2002;Stoyanova et al, 2003), leading to the corresponding transand cis-carboxylic acids and their subsequent transformations by analogy to Haimova et al (1984). The product was characterized by IR, 1 H and 13 C NMR spectra.…”

Novel isoquinoline derivatives from isochromen-1,3-dione

“…In this context, chromene derivatives are a class of natural products that often occurs as microbial metabolites and that have been found to exhibit interesting biological properties, [1][2][3][4][5][6][7] including antifungal, anti-inflammatory, anti-allergic, narcotic, anti-angiogenic, anti-malarial, [8] anti-bacterial, [9] anti-cancer, anti-virus [10] and anti-microbial activities [11,12]. In view of their natural occurrence, biological activities and utility as synthetic intermediates, [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] we report here the synthesis of novel isochromene and isoquinoline derivatives starting from the readily obtainable Z-2-[1-carboxy-2-(3,4-dimethoxy phenyl)vinyl]-benzoic acid, 1 [28].…”

Solution-Phase Parallel Synthesis of Novel 1,2,3,4-Tetrahydroisoquinolin-1-ones as Anticonvulsant Agents

“…and the nature of reagents employed influence their stereochemistry. [10][11][12][13][14][15] We report here a simple methodology for the solutionphase parallel synthesis (SPPS) of PD00735 and its analogues with the aim to obtain a small library of isoquinolinonic acids for the evaluation in audiogenic seizure test and draw structure-activity relationship (SAR) considerations for this class of compounds. …”

“…isoquinoline-4-carboxylic Acid(13): 57% yield as yellow crystals, mp 234-236°C 1. H-NMR (DMSO-d 6 ) d: 4.06 and 5.15 (2H, 2d, Jϭ15.11, Jϭ8.51, ArH), 12.50 (1H, bs, COOH).…”

“…1H, s, ArH, H-2Љ), 7.98-8.04 (2H, m, ArH), 12.50 (1H, bs, COOH) 13. C-NMR (DMSO-d 6 ) d: 49.22 (CH 2 ), 50.38 and 60.88 (C-3 and C-4), 121.34, 122.64, 127.25, 128.14, 128.36, 128.75, 129.83, 130.27, 130.52, 131.96, 132.90, 133.31, 136.34, 141.80, 147.89, 163.00 (CO), 169.03 (COOH).…”