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.     

Synthesis of New 1,2,3,4-Tetrahydroisoquinoline Derivatives. 2-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)anilines

A four-step procedure has been developed for the synthesis of new 2-(2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)anilines by acylation of 2-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)anilines at the amino group with isobutyryl chloride, reduction of the endocyclic C=N bond in N-[2-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)phenyl]isobutyramides, N-alkylation of N-[2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl]isobutyramides to N-[2-(2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl]isobutyramides, and acid hydrolysis of the latter.     

Synthesis of isoquinoline derivatives of quinoxalin-2-one from pyrrolo[2,1-a]isoquinoline-2,3-diones and o-phenylenediamine

Reactions of 5,5-dialkyl-2,3,4,5-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-diones with o-phenylenediamine in the presence of a catalytic amount of hydrogen chloride or p-toluenesulfonic acid involved opening of the pyrrole ring with formation of 3-(3,3-dialkyl-1,2,3,4-tetrahydroisoquinolin-1-ylidenemethyl)quinoxalin-2(1H)-ones. The presence of an enamine fragment in the products was confirmed by reaction with oxalyl chloride.     

Synthesis and properties of 1-aroyl-5,5-dialkyl-2,3,5,6-tetrahydropyrrolo[ 2,1-<Emphasis Type="Italic">a</Emphasis>]isoquinoline-2,3-diones

Acylation of 1-methyl-3,3-dialkyl-3,4-dihydroisoquinolines with acid chlorides afforded enaminoketones. Enaminophenylketones from the obtained series were reacted with oxalyl chloride to provide 1-benzoyl-5,5-dialkyl-2,3,5,6- tetrahydropyrrolo[2,1-a]isoquinoline- 2,3-diones. The reaction of the latter with binucleophiles leads to the opening of the pyrrole ring and to the heterocyclization: Under the effect of o-phenyldiamine qinoxaline is formed, 1,2-cyclohexanediamine provides the hexahydro-benzimidazole system, о-aminophenol gives benzoxazole, 3-hydroxy-2-amino-pyridine furnishes oxazolo[4,5-b]pyridine. In the reaction with hydrazine hydrate the acylation occurs with hydrazide formation.     

Five-membered 2,3-dioxo heterocycles: LIII. Reaction of 3-Aroyl-1<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones with substituted 1,3,3-trimethyl-3,4-dihydroisoquinolines. A new approach to 13-aza analogs of steroids

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with substituted 1,3,3-trimethyl-3,4-dihydroisoquinolines to give the corresponding 3-aroyl-4-hydroxy-1-(2-hydroxyphenyl)-5′,5′-dimethyl-5′,6′-dihydro-1H-spiro[pyrrole-2,2′-pyrrolo[2,1-a]isoquinoline]-3′,5-diones. 7′,8′-Benzo derivatives of the latter may be regarded as 13-azagonane analogs having a spiro-fused pyrrole ring at C¹⁶.     

Reactions of <Emphasis Type="Italic">p</Emphasis>-quinone diimines of the 1,2,3,4,4a,5-hexahydro-10<Emphasis Type="Italic">H</Emphasis>-benzimidazo[2,1-<Emphasis Type="Italic">j</Emphasis>]quinolin-10-imines with some compounds having an activated methylene group

Reactions of N-(1,2,3,4,4a,5-hexahydro-10H-benzimidazo[2,1-j]quinolin-10-ylidene)amines with malononitrile and cyanoacetamide gave the corresponding 12-methylidene derivatives.     

The Annelation for Enaminoureides of 3,3-Dimethyl-1,2,3,4-tetrahydroisoquinoline Series by Action of Oxalyl Chloride and Ninhydrin

By reaction of Ritter cyclization of cyanoacetylureas with dimethylbenzylcarbinoles the corresponding enaminoureides were obtained, derivatives of 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline. The polyfunctional character of obtained compounds is confirmed by the structure of products of reaction with some electrophiles: phenyl isocyanate reacts at the γ-C atom of enamine and CONH₂ group of urea, under the action of oxalyl chloride annelation of a pyrrole cycle occurs with the formation of a derivative of 2,3-dioxopyrrolo[2,1-a]isoquinoline. Reaction with ninhydrin occurs similary with enaminoamides having hydrogen atoms at the amide nitrogen: a pyrrole ring is fused with the formation of a system of indeno[1,2-b]pyrrole.     

Transformations of 5-chloro-2-hydrazino-4-<Emphasis Type="Italic">p</Emphasis>-tolylsulfonyl-1,3-thiazole

Accessible 2,2-dichloro-1-p-tolylsulfonylethenyl isothiocyanate reacted with hydrazine hydrate to give 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole whose reactions with thiols and amines followed a complicated pattern. Treatment of 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole with acetylacetone led to the formation of previously unknown 5-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-p-tolylsulfonyl-1,3-thiazole which reacted with O-, S-, and N-centered nucleophiles at the C⁵ atom with high regioselectivity.     

Some Transformations of 2-(Chloromethyl)-5,5-dimethyl-5,6-dihydrobenzo[<Emphasis Type="Italic">h</Emphasis>]quinazolin-4(3<Emphasis Type="Italic">H</Emphasis>)-one

The condensation of 1-amino-3,3-dimethyl-3,4-dihydronaphthalene-2-carbonitrile with chloroacetyl chloride afforded chloro-N-(2-cyano-3,3-dimethyl-3,4-dihydronaphthalen-1-yl)acetamide which underwent cyclization to 2-(chloromethyl)-5,5-dimethyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one. The latter reacted with various nucleophiles (alkali metal alkoxides, piperazine, 2-sulfanylethanol) to give 2-(alkoxymethyl)-, 2-(piperazin-1-ylmethyl)-, and 2-{[(2-hydroxyethyl)sulfanyl]methyl}-5,5-dimethyl-5,6-dihydrobenzo[h]quinazolin- 4(3H)-ones. The condensation of 2-(chloromethyl)benzo[h]quinazoline with 2-thioxo derivatives of quinazoline and benzo[h]quinazolines led to the formation of bis-quinazolines in which 5,5-dimethyl-5,6- dihydrobenzo[h]quinazolin-4(3H)-one fragment is linked to quinazoline or benzo[h]quinazoline system through a CH₂S bridge.     

Reaction of dichlorocarbene with substituted 3,4-dihydroisoquinolines and 1-methylene-1,2,3,4-tetrahydroisoquinolines

Reaction of dichlorocarbene with 3,3-dialkyl-3,4-dihydroisoquinolines results in the formation of gemdichloroazirino[2,1-a]isoquinolines, which are in turn converted to 3-benzazepinones upon hydrolysis. Reaction of dichlorocarbene with the ethyl ester or amide of (3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)acetic acid is accompanied by rearrangement of the intermediate carbene adducts at the enamine C=C bond and results in the formation of a 1-azadiene, 3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-3-chloroacrylic acid ethyl ester, and a spirolactam, 3,3-dimethyl-3-chlorospiro[1,2,3,4-tetrahydroisoquinoline-1,2-pyrrole]-5(2H)-one, respectively.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1086–1091, August, 1990.     

Chemistry of Acyl(imidoyl)ketenes: IX. Synthesis and Thermolysis of 3-Aroyl-8-chloro-1,2-dihydro-4<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones

Reactions of 3-Z-aroylmethylene-6-chloro-3,4-dihydro-2H-1,4-benzoxazine-2-ones with oxalyl chloride afford 3-aroyl-8-chloro-1,2-dihydro-4H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones and Z-3-(2-aryl-2-chlorovinyl)-6-chloro-2H-1,4-benzoxazine-2-ones. Aroyl(imidoyl)ketenes generated by decarbonylation of pyrrolobenzoxazinetriones undergo dimerization through [4+2]-cycloaddition to form 4-aroyl-3-aroyloxy-2-(2-oxo-2H-1,4-benzoxazin-3-yl)-1H, 5H-pyrido[2,1-c][1,4]benzoxazine-1,5-diones.     

Synthesis of 5,8-Diamino-Substituted Pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]pyrimidines and Pyrimido[4′,5′:4,5]thieno[2,3-<Emphasis Type="Italic">c</Emphasis>]isoquinolines

Ethyl 1-amino-8,8-dimethyl-5-(piperidin-1-yl)-8,9-dihydro-6H-pyrano[4,3-d]thieno[2,3-b]pyridine-2-carboxylate and ethyl 1-amino-5-(piperidin-1-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxylate reacted with benzoyl isothiocyanate to give the corresponding 1-thioureido derivatives which underwent cyclization to 2,2-dimethyl-5-(piperidin-1-yl)-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4″,3″:4′,5′]pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidin-8(9H)-one and 5-(piperidin-1-yl)-10-thioxo-1,2,3,4,10,11-hexahydropyrimido-[4′,5′:4,5]thieno[2,3-c]isoquinolin-8(9H)-one. The cyclization products were converted into 8-chloro derivatives, and the chlorine atom therein was replaced by various amines.     

Five-membered 2,3-dioxo heterocycles: LI. Reaction of 3-aroyl-2,4-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with 3-amino-5,5-dimethylcyclohex-2-en-1-ones

3-Aroyl-2,4-dihydro-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with N-unsubstituted and N-substituted 3-amino-5,5-dimethylcyclohex-2-en-1-ones to give 3′-aroyl-4′-hydroxy-1′-(o-hydroxy-phenyl)-6,6-dimethyl-6,7-dihydrospiro[indole-3,2′-pyrrole]-2,4,5′(1H,1′H,5H)-triones. The molecular and crystalline structure of the 1-cyclohexyl-substituted derivative was studied by X-ray analysis.     

Activated sterically strained C=N bond in <Emphasis Type="Italic">N</Emphasis>-substituted <Emphasis Type="Italic">p</Emphasis>-quinone mono- and diimines: XV. Synthesis,structure, and reactions with alcohols of <Emphasis Type="Italic">N</Emphasis>-carbamoyl-1,4-benzoquinone imines

The reaction of 4-aminophenols with N-nitrourea or with sodium cyanate in acetic acid gave the corresponding 4-ureidophenols which were oxidized to N-carbamoyl-1,4-benzoquinone imines, substituted N-(4-oxocyclohexa-2,5-dien-1-ylidene)ureas. N-(2,6-Dimethyl-4-oxocyclohexa-2,5-dien-1-ylidene)urea possessing activated sterically strained C=N bond reacted with alcohols to afford N-(1-alkoxy-2,6-dimethyl-4-oxocyclohexa-2,5-dienyl)ureas.     

Thienooxazolopyrimidinium salts. Reaction of 1-bromomethyl-5-oxo-4-phenyl-1,2,4,5,6,7,8,9-octahydro[1]benzothieno-[3,2-<Emphasis Type="Italic">e</Emphasis>][1,3]oxazolo[3,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-11-ium bromide with oxygen-centered nucleophiles

Reactions of [1]benzothieno[3,2-e][1,3]oxazolo[3,2-a]pyrimidin-11-ium bromide with oxygen-containing nucleophiles involve opening of the dihydrooxazole ring and lead to the formation of new functionally substituted thieno[2,3]-d]pyrimidine derivatives.     

New Synthesis of Pyrano[4,3-<Emphasis Type="Italic">d</Emphasis>]pyrazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]pyridines

A new efficient method has been developed for the synthesis of highly biologically active pyrano-[4,3-d]pyrazolo[3,4-b]pyridines on the basis of Smiles rearrangement of ethyl [(8-alkyl(aryl)-5-cyano-3,3-dimethyl-3,4-dihydro-1H-pyrano[3,4-c]pyridin-6-yl)oxy]acetates. Intermediate acetohydrazides have also been isolated. The proposed procedure is advantageous due to the possibility of avoiding experimentally difficult chlorination stage.     

Chemistry of iminofurans: XIII. Recyclization of 4-arylamino-2-<Emphasis Type="Italic">tert</Emphasis>-butyl-5-oxo-2,5-dihydrofuran-2-yl acetates with ethyl cyanoacetate

Recyclization of 4-arylamino-2-tert-butyl-5-oxo-2,5-dihydrofuran-2-yl acetates with ethyl cyanoacetate in the presence of triethylamine afforded the corresponding ethyl 2-amino-1-aryl-5-(3,3-dimethyl-2-oxobutylidene)-4-oxo-1H-4,5-dihydropyrrole-3-carboxylates.     

1,3-dipolar cycloaddition of diazomethane to quinoid derivatives of pyrido[1,2-<Emphasis Type="Italic">a</Emphasis>]benzimidazole

Reactions of diazomethane with quinone mono(di)imines and methylidene quinone imines of pyrido[1,2-a]benzimidazole series occurs by the route of 1,3-dipolar cycloaddition and leads to the formation of quinoid compounds, in particular, previously unknown heterocyclic structures of indazolo[7',6':4,5]imidazo-[2,1-j]quinoline, indazolo[7',6':4,5]imidazo[2,1-e]acridine, indazolo[4',5':4,5]imidazo[2,1-j]quinoline, and indazolo[4',5':4,5]imidazo[2,1-e]acridine.     

Features of the reaction of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acid esters with acetone and <Emphasis Type="Italic">p</Emphasis>-toluidine

Three-component reactions of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acids with acetone and p-toluidine were studied; their specific feature was the formation of the regioisomeric esters of 4-hydroxy-2,2-dimethyl-1-(4-methylphenyl)-5-(2-oxoalkyliden)-2,5-dihydro-1H-pyrrole-3-carboxylic acids and [4-alkanoyl-3-hydroxy-5,5-dimethyl-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene]acetic acid. Structure of the synthesized compounds was discussed based on the data of IR and ¹H NMR spectroscopy and X-ray diffraction analysis.     

Alkenyl derivatives of 5-nitro-2-pyridone: Synthesis and halocyclization

Alkylation of 5-nitro-2-pyridone by alkenyl halides in acetone in the presence of K₂СО₃ proceeds with generation of a mixture of N- and О-derivatives with N-isomer prevailing. 1-Allyl- and 1-methylallyl-5-nitro-2-pyridone react with halogens with the formation of 2-halomethyl-6-nitro-2,3-dihydrooxazolo[3,2-a]-pyridinium halides. 1-Prenyl-5-nitro-2-pyridone reacts with bromine with the formation of 3-bromine-2,2-dimethyl-7-nitro-3,4-dihydro-2Н-pyrido[2,1-b][1,3]oxazinium bromide, and with iodine giving 2,2-dimethyl-7-nitro-3,4-dihydro-2Н-pyrido[2,1-b][1,3]oxazinium triiodide.