Reaction of 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline with diethyl fumarate

The reaction of 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline with diethyl fumarate goes by two possible paths, to form a mixture of 3-carbethoxymethyl-4-oxo-1,2,3,6, 7,IIb-hexahydro-4H-pyrazino[2,1-a]isoquinoline and its isomer 4-carboxymethyl-3-oxo-1,2,3,6,7-llb-hexahydro-4H-pyrazino[2,1-a]isoquinoline.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 798–800, June, 1985.     

Synthesis and acylation of 1,2,3,4-tetrahydroisoquinoline derivatives

1,2,3,4-Tetrahydroisoquinolines were synthesized, and their acylation was studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 780–783, June, 1993.     

Azocoupling reactions of enaminocarbonyl derivatives of 1,2,3,4-tetrahydroisoquinoline with diazonium salts

It has been shown that enamino amide and enamino ketone derivatives of 1,2,3,4-tetrahydroisoquinoline react with diazonium salts to form azo compounds. Depending on the enamine structure they can exist just as azo dyes or as azohydrazone tautomers. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1382–1387, September, 2006.     

Synthesis and acylation of tertiary enamines: 1,2,3,4-tetrahydroisoquinoline derivatives

N-methyl-3,3-R¹R²-1-(R³-methylene)-1,2,3,4-tetrahydroisoquinolines were obtained; they react with acylating agents forming enaminocarbonyl derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 939–942, July, 1988.     

Cyclodehydration of N-(2-nitroaryl)-1,2,3,4-tetrahydroisoquinoline derivatives

Compounds 1a-1g gave the corresponding N-oxide derivatives 3a-3g when heated with acetic or propionic acid.     

Reaction of ninhydrin with enamino amides of the 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline series and drotaverine

“Push–pull” enamines of the 1,2,3,4-tetrahydroisoquinoline series, 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin- 1-ylidene)acetamides, reacted as 1,3-binucleophiles with ninhydrin to form tricyclic tetrahydroindeno[1,2-b]pyrrole system. The nucleophilic centers in the enamines were the amide NH₂ group and ß-carbon atom of the enamine fragment. The reaction of ninhydrin with 2-[2,2-dimethyl-2,3-dihydrobenzo[f]-isoquinolin-1(4H)-ylidene]-1-(pyrrolidin-1-yl)ethanone involved only addition to the ß-carbon atom of the enamine fragment. The different reaction directions were rationalized by steric effect of two methyl groups in position 3 of the isoquinoline ring. The Knoevenagel condensation product was obtained by the reaction of ninhydrin with drotaverine (base). The structure of the 1,3-addition product, (3aS,8bS,Z)-{2,2-dimethyl-2,3- dihydrobenzo[f]isoquinolin-4(1H)-ylidene}-3a,8b-dihydroxy-1,3,3a,8b-tetrahydroindeno[1,2-b]pyrrole-2,4-dione, was confirmed by X-ray analysis.     

Thiocarbamoylation of 1,2,3,4-tetrahydroisoquinoline enamines with phenyl isothiocyanate

Reactions of 1,3,3-trimethyl-3,4-dihydroisoquinoline and its benzo[f] derivative with phenyl isothiocyanate gave the corresponding enamino thioamides. Enamino ester, enamino amides, and enamino nitriles of the 1,2,3,4-tetrahydroisoquinoline series reacted with phenyl isothiocyanate in a similar way. The resulting enamino thioamides underwent acylation with acid chlorides at the β-carbon atom of the enamino fragment. The structure of the obtained enamino thioamides is stabilized by intramolecular H-bonding.     

Solid-phase synthesis of 1,2,3,4-tetrahydroisoquinoline derivatives employing support-bound tyrosine esters in the Pictet-Spengler reaction

The solid-phase synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxamides employing carboxyl-supported, o-alkylated tyrosine esters in a Pictet-Spengler reaction is described. Esterification of [4-(hydroxyphenyl)thiomethyl]polystyrene (Marshall resin) with ethers of N-BOC-L-tyrosine using diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (4-DMAP) afforded the solid-supported ester derivatives. Removal of the BOC group with trifluoroacetic acid (TFA) afforded the carboxyl-supported tyrosine ester, which was then treated with paraformaldehyde and TFA to afford the desired solid-supported counterpart. Acylation of the secondary amine with arylsulfonyl chlorides followed by reaction with amines resulted in the formation of the desired 2-arylsulfonyl-7-alkoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamides. Alternatively, the support-bound tetrahydroisoquinoline-3-carboxylate derivatives could be treated with an aldehyde and a reducing agent to give the corresponding support-bound tertiary amine. Exposure of these resin-bound products to amines afforded the corresponding 2-alkyl-7-alkoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamides after cleavage from the resin. Alternative routes to the desired chemotypes, as well optimization of the conditions for the Pictet-Spengler reaction and the conditions for the acylation and reductive amination of the support-bound secondary amines, are also described.     

Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents

A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca2? channel blockers.     

Ring-opening reactions of halogenated N-aryl-1,2,3,4-tetrahydroisoquinoline and 2,3,4,5-tetrahydro-1H-2-benzazepine derivatives

Compounds 4a-4d, 4f and 10 were prepared and their ring-opening reactions with N-bromosuccinimide (NBS) investigated. Compounds 4a and 4b gave a mixture of products which did not contain any significant quantity of the corresponding aldehydes 5a and 5b whereas compounds 4c, 4d and 4f gave exclusively the aldehydes 5c, 5d and 5f respectively. Compound 10 similarly gave the aldehyde 11 when treated with NBS.     

Synthesis of enaminoamides of the 1,2,3,4-tetrahydroisoquinoline series

Enaminoamides of the 1,2,3,4-tetrahydroisoquinoline series having the Z-configuration were synthesized by the reaction of dialkylbenzylcarbinols cyanaceamides.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1239–1242, September, 1989.     

Reactions of enamino keto esters of 1,2,3,4-tetrahydroisoquinoline series with nucleophiles

It has been shown that the reaction of the methyl ester of 3-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-idene)pyruvic acid with thiosemicarbazide in glacial acetic acid leads to heterocyclization with the formation of 3,3-dimethyl-1-(5-thioxo-1,5-dihydro-1,2,4-triazol-3-ylmethylidenecarbonyl)-1,2,3,4-tetra-hydroisoquinoline, but the interaction with semicarbazide under the same conditions leads to annelation of the pyrrole ring. On condensation of the enamino keto ester with malonodinitrile, the nitrile of 2-cyano-4-dicyanomethylidene-5-(3,3-dimethyl-1,2,3.4-tetrahydroisoquinolin-1-idene)-3-oxo-pentanoic acid is formed.     

Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4-tetrahydroisoquinoline analogs

An operationally simple and eco-friendly protocol has been developed for the synthesis of N-sulfonyl-1,2,3,4-tetrahydroisoquinolines 3 using the modified Pictet-Spengler reaction of N-sulfonylphenylethylamines 1 and various aldehydes 2 in the presence of tungstophosphoric acid hydrate.     

Synthesis and biological evaluation of 1,2,3,4-tetrahydroisoquinoline derivatives as potent and selective M2 muscarinic receptor antagonists.

A series of 1,2,3,4-tetrahydroisoquinoline derivatives containing the 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton were prepared and evaluated for their in vitro binding affinities to muscarinic receptors and for antagonism of bradycardia in vivo. Among them, compound 3f had the highest affinity for M2 muscarinic receptors in the heart (pKi = 9.1) with low affinity for M3 muscarinic receptors in the submandibular gland. A structure-activity relationship (SAR) study suggested that the benzene ring fused piperidine and the alkyl linker chain length are crucially important for increased M2 affinity.     

Synthesis and properties of enaminoketohydrazides of the 1,2,3,4-tetrahydroisoquinoline series

It has been established that the reaction of 2,3-dioxopyrrolo[2,1-a]isoquinolines with hydrazine occurs at the lactam carbonyl with fission of the pyrroledione ring and the formation of enaminoketohydrazides, the structure of which was confirmed by x-ray crystallographic and spectral data on these compounds and their derivatives (hydrazones).Institute of Technical Chemistry, Urals Branch, Russian Academy of Sciences, Perm 614000, Russia. N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1111–1117, August, 1998.     

Synthesis of Pyrimido[6,1-a]isoquinolines by the Reaction of Thriethyl Orthoformate with Enamines of 3,3-dialkyl-1,2,3,4-tetrahydroisoquinoline series

Russian Journal of Organic Chemistry - Boiling (Z)-2-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]acetamides in AcOEt/Ac2O leads involves annelation of the pyrimidine ring to form...     

Synthesis and pharmacological evaluation of 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives as specific bradycardic agents

Novel 1,2,3,4-tetrahydroisoquinoline derivatives bearing directly a cyclic amine at the 2-position were prepared and examined for their bradycardic activities in isolated right atria and in anesthetized rats. The structure-activity relationships (SAR) study revealed that the 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline skeleton is essential for the appearance of potent in vitro activity, and that the presence of at least one methoxy group at the 6- or 7-position of the 1,2,3,4-tetrahydroisoquinoline ring is important to exert potent in vitro activity. In vivo tests of selected compounds demonstrated that 2-(1-benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6c) exhibited potent bradycardic activity with negligible influence on mean blood pressure in rats, although its potency is a half of that of Zatebradine.