Studies on quinoline derivatives and related compounds. 1. A new synthesis of 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids

A novel preparative method for 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was developed. The key process is the cyclization of N-alkylanilinomethylenemalonales, which was effected successfully in the presence of polyphosphoric acid, polyphosphate ester, boron tri-fluoride or a mixture of acetic anhydride and sulfuric acid. With phosphorus oxychloride, N-alkylanilinomethylenemalonates yielded 1-alkyl-4-chloro-3-carbethoxyquinolinium salts which were hydrolyzed readily to ethyl 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylates or their acids. By means of this novel method several new 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylic acids were prepared.     

The reaction of 4-alkyl-3-thiosemicarbazides with β-haloketones

The reactions of 4-alkyl-3-thiosemicarbazides with β-halophenones and o-halophenones gave 4,5-dihydro-N-alkyl-3-phenyl-1H-pyrazole-1-carbothioaraides and 3-phenyl-1H-indazoles, respectively.     

Heterocyclic compounds from 3,3-dimercapto-1-aryl-2-propen-1-ones. Note 3. Condensation with N-methyl-o-phenylenediamine and N-benzyl-o-phenylenediamine

Two seven-membered ring compounds and three five-membered ring compounds were obtained by reaction in hot xylene of 3,3-dimercapto-l-phenyl-2-propen-1-one (1) with N-alkyl-o-phenylenediamines (2) . Compounds isolated were the 4-phenyl-5-alkyl-1,5-dihydro-2H-1,5-benzodiazepine-2-thiones (3) the 1-alkyl-4-phenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thiones (4) , the 1-alkyl-2-phenacylbenzimidazoles (5) , the 1-alkyl-2-phenylbenzimidazoles (6) and the 1-alkyl-2-methylbenzimidazoles (7) . The structures of these compounds were elucidated from their chemical reactivity and their nmr and ir spectra.     

A convenient synthesis of 3-alkyl-2,3-dihydro-2,4-dioxo-6-phenyl-, 3-alkyl-2,3-dihydro-4-oxo-6-phenyl-2-thioxo-, and 3-alkyl-2-arylimino-2,3-dihydro-4-oxo-6-phenyl-4H-1,3-thiazines

The reactions of 1-alkylamino-1-alkylthio-3-phenylpropene-3-thiones 3 with thiophosgene and phosgene in toluene, followed by treatment of the reaction mixture with triethylamine gave 3-alkyl-2,3-dihydro-4-oxo-6-phenyl-2-thioxo- 4 , 3-alkyl-2,3-dihydro-2,4-dioxo-6-phenyl-4H-1,3-thiazines 5 , respectively in good to excellent yields. Similarly treatment of compounds 3 with N-arylimidoyl dichloride in benzene at room temperature gave 3-alkyl-2-arylimino-2,3-dihydro-4-oxo-6-phenyl-4H-1,3-thiazines 6 in excellent yields. The reactions of compounds 3 with oxalyl chloride in toluene gave also 5 in good yields.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. X. Synthesis of N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones and of 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted 1-amino-4-methyl-1-penten-3-ones and 1-amino-4,4-dimethyl-1-penten-3-ones occurred in moderate to fair yield only in the case of aromatic N-substitution to give N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution, cyclo-addition led directly to 6-alkyl-4-dialkylamino-3-chloro-2H-pyran-2-ones only for N,N-disubstituted 1-amino-4,4-dimethyl-1-penten-3-ones. The reaction between 1-dimethylamino-4-methyl-1-penten-3-one and dichloroketene gave 3-chloro-4-dimethylamino-3,6-dihydro-6-isopropylidene-2H-pyran-2-one in low yield.     

Synthesis of 3-Acyl-1,2-benzisoxazoles

A convenient method for the synthesis of 3-acyl-1,2-benzisoxazoles, which are unstable toward bases, is described. Base-catalyzed cyclization of 2-alkyl- and aryl-1,3-dithian-2-yl o-chlorophenylketoximes 4a-1 gave 3-(2-alkyl- and aryl-1,3-dithian-2-yl)-1,2-benzisoxazoles 8a-1 , which were converted into the corresponding 3-acyl-1,2-benzisoxazoles 1a-1.     

Syntheses of 2-acetyl-3-hydroxy-1-n-propylpyrrole from isomaltol and 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones from maltol

2-Acetyl-3-hydroxyfuran (2) reacts with n-propylamine affording 2-acetyl-3-hydroxy-1-n-propylpyrrole (3) in 63% yield. The transformation of 2-methyl-3-hydroxy-4-pyrone (4) into 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones is achieved by benzylation of the 3-hydroxyl group whereupon the product reacts with ammonia and the corresponding pyridone is obtained. The pyridone is alkylated with alkyl bromides and after hydrobromic acid in acetic acid cleavage of the 3-position ether function, 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones are obtained in 48% overall yield.     

A study on ester formylhydrazones

A series of ester formylhydrazones 2 were synthesized from the reaction of alkyl imidate hydrochlorides 1 with formylhydrazine. Treatment of 2 with hydrazine hydrate, ethyl carbazate and tert-butyl carbazate led to the formation of 3-alkyl-4-amino-, 3-alkyl-4-ethoxycarbonylamino- and 3-alkyl-4-tert-butoxycar-bonylamino-4H-1,2,4-triazoles 3–5 , respectively. Reaction of compounds 2 with formylhydrazine gave N,N'-diformylhydrazine 6 . Compounds 2 were reacted with 2,5-dimethoxytetrahydrofuran to afford 3-alkyl-4-(1H-pyrrol-1-yl)-4H-1,2,4-triazoles 8 .     

Synthesis of 3-Alkyl-6-aryl(arylamino)-7H-[1,2,4]triazolo- [3,4-b][1,3,4]thiadiazines

Starting from 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols and substituted chloroacetanilides, the corresponding (5-alkyl-4-amino-4H-1,2,4-triazol-3-ylsulfanyl)acetanilides were synthesized. The products underwent intramolecular cyclization in boiling phosphoryl chloride to afford 3-alkyl-6-arylamino-7H-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines. 3-Alkyl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hydrobromides were obtained by reaction of 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols with substituted phenacyl bromides.     

3-(4-Hydroxyphenylthio)pyrrolidine-2,5-diones

3-(4-Hydroxyphenylthio)pyrrolidine-2,5-diones were prepared by the conjugate addition of substituted 4-hydroxybenzenethiols to 1-alkyl-1H-pyrrole-2,5-diones. The analytical and spectral data are reported.     

4-Substituted-3-alkyl-3,4-dihydro-2H-1,3-benzoxazin-2-ones. IV (2-4). Keto-Enol tautomerism of β-keto ester derivatives. Reaction of β-dicarbonyl compounds with diamines

A series of α-[3-alkyl-3,4-dihydro-2-oxo-2H-1,3-benzoxazin-4-yl]-β-keto ester derivatives 1 (Table I) were synthesized by the condensation of 3-alkyl-3,4-dihydro-4-hydroxy-2H-1,3-benzoxazine-2-ones 3 (2) with β-keto esters 4 in the presence of traces of mineral acids under azeotropic conditions. Condensation of 1 with hydrazines 5 gave pyrazolone derivatives 2 (Table II). Condensation of β-diketone derivatives 6 with hydrazines 5 and with 1,2-benzenediamine ( 8 ) resulted in the formation of pyrazoles ( 7a-c ) and diazepine derivatives 12 (Table III) and 13 , respectively.     

Synthesis of azolo[a]pyridines from 5-(bromomethyl)hept-4-en-3-one and 5-bromopent-3-en-2-one derivatives

Alkyl derivatives of 1H-imidazo[1,2-a]pyridin-4-ium, 5H-pyrido[1,2-a]benzimidazol-10-ium, 1H-[1,2,4]-triazolo[4,3-a]pyridin-4-ium, and 3-methylthiazolo[3,2-a]pyridin-4-ium bromides were obtained in two stages from (4Z)-5-(bromomethyl)-2,2,6,6-tetramethylhept-4-en-3-one, 5-bromo-4-methylpent-3-en-2-one, or (3E)-5-bromopent-3-en-2-one by alkylation of 1-alkyl-1H-imidazoles, 1-alkyl-1H-benz-imidazoles, 1-methyl-1H-1,2,4-triazole, and 4-methylthiazole and subsequent cyclization of the quaternary azolium salts in the presence of bases.     

The chemistry of coumarin derivatives. Part 3. Synthesis of 3-alkyl-4-hydroxycoumarins by reductive fragmentation of 3,3′-alkyiidene-4,4′-dihydroxybis[coumarins]

Treatment of 3,3′-alkylidene-4,4′-dihydroxybis[coumarins] 1 with NaBH₃CN in refluxing MeOH affords 3-alkyl-4-hydroxycoumarins 2 and 4-hydroxycoumarin ( 3 ; Scheme 1). The reaction might take place via hydride trapping of alkylidenechromandiones C formed from 1 in a retro-Michael reaction. Such a retro-Michael reaction of 1 might be biologically relevant. The presence of C during the reductive fragmentation 1 → 2 is suggested by Diels-Alder and nucleophilic trapping of the alkylidenechromandiones C as well as from cross-over experiments with coumarins other than 3 (see Scheme 2). The reductive fragmentation of 1 allows the chemo- and regioselective synthesis of a variety of 3-alkyl-4-hydroxycoumarins 2 (see Table).     

The alkylation of 3H-phenoxazin-3-one derivatives

2-Alkyl-, 4-alkyl-, and 2,4-dialkyl-3H-phenoxazin-3-ones were prepared by reacting 3H-phenoxazin-3-one with alkyl radicals in aqueous acetonitrile at 70–75°. The alkyl radicals were generated from the silver catalysed oxidative decarboxylation of acids with peroxydisulphate.     

1-Ethyl-1,4-dihydro-4-oxo-7-(pyridinyl)-3-quinolinecarboxylic acids. I. Synthesis of 3- and 4-(3-aminophenyl)pyridine intermediates

A series of substituted 3- and 4-(3-aminophenyl)pyridines has been prepared as intermediates for the synthesis of some 1-alkyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The Hantzsch, Hauser and other pyridine syntheses were used. 4-(3-Aminophenyl)pyridine was prepared via 3-(4-pyridinyl)-2-cyclohexen-1-one using the Semmler-Wolff reaction.     

Convenient preparation of N-substituted 2-amino-4H-3,l-benzoxazin-4-ones and 3-substituted 2,4(1H,3H)-quinazolinediones

Room temperature treatment of 2-(3-arylureido)benzoic acids ( 1 ) and methyl 2-(3-alkyl-, or 3-arylureido)- benzoates ( 2 ) with concentrated sulfuric acid leads to N-substituted 2-amino-4H-3,l-benzoxazin-4-ones ( 3 ) in generally very good yields. The isomeric 3-substituted 2,4(1H,3H)-quinazolinediones ( 4 ) are conveniently made in high yield by the action of aqueous-ethanolic sodium hydoxide on 2.     

Reductive ring cleavage of 1-alkyl-4-benzoylamino-5-phenyl-3-pyrazolidinones with raney-nickel alloy. Synthesis of N-benzoyl-3-alkylamino-3-phenylalanine amides from rel-(4R,5R)-4-benzoylamino-5-phenyl-3-pyrazolidinone

rel-(4R,5R)-4-Benzoylamino-5-phenyl-3-pyrazolidinone ( 1 ) was alkylated at position 1 with carbonyl compounds 2a-g . The corresponding rel-(4R,5R)-4-benzoylamino-5-phenyl-3-pyrazolidinone-1-azomethine imines 3a-g , were treated with sodium borohydride to give rel-(4R,5R)-1-alkyl-4-benzoylamino-5-phenyl-3-pyrazolidinones 4a-g . Reduction of pyrazolidinones 4a-g with Raney-nickel alloy in methanolic potassium hydroxide furnished rel-(4R,5R)-N-benzoyl-3-alkylamino-3-phenylalanine amides 5a-f .     

Naphth[1,2-d]oxazole intermediates in the preparation of 3-hydroxy-4-(1-alkyl-3-methyl-5-hydroxy-4-pyrazolyl)-azo-1-naphthalenesulfonamide dyes

Acylation of 4-amino-3-hydroxy-1-naphthalenesulfonic acid ( 3 ) with benzoyl chloride in pyridine gave pyridinium 3-hydroxy-4-(N-benzoylamino)-1-naphthalenesulfonate ( 12 ) which was converted by thionyl chloride followed by diethylamine into N,N-diethyl-2-phenylnaphth[1,2-d]oxazole-5-sulfonamide ( 14 ). The naphthoxazole moiety was hydrolyzed with potassium hydroxide and the resulting N,N-diethyl-4-amino-3-hydroxy-1-naphthalenesulfonamide ( 11 ) coupled with 1-alkyl-3-methyl-5-pyrazolones. The 2-phenylnaphth[1,2-d]oxazole intermediates and various by-products were investigated.     

A Convenient Synthesis of 2-Acyl-2-alkyl-3-nitro-2H-chromenes

Treatment of 2-hydroxybenzaldehydes by potassium t-butoxide in THF at 0°C, followed by addition of β-nitroenones 1 affords 2-acyl-2-alkyl-4-hydroxy-3-nitrochromanes 3. Subsequent treatment of these nitro alcohols by silica gel at 50°C leads to the desired 2-acyl-2-alkyl-3-nitro-2H-chromenes 4 in good yields.     

Substituted Quinolinones. Part 19. New and Unexpected Results from Oxidation of 3-Acetyl-1-Alkyl- 4-Hydroxyquinolin-2(1H)-Ones Using Selenium Dioxide

Abstract

Oxidation of 3-acetyl-1-alkyl-4-hydroxyquinolin-2(1H)-ones using selenium dioxide under Riley conditions was described. The oxidation reaction produced a mixture of 2 unexpected α-keto acid and its dehydrated dimer derivatives. The oxidation reaction was studied under different reaction conditions in order to maximize the yields and optimize reaction conditions. Also, 1-alkyl-4-hydroxy-3-(2-nitroacetyl)quinolin-2(1H)-one and/or 3-acetyl-1-alkyl-4-diflouro-boryloxyquinolin-2(1H)-one derivatives were subjected to the same oxidation reaction giving rise improved reaction yields and selectivity in case of the boron-complex. Alkaline degradation of the dehydrated dimers led to formation of the 4-hydroxy-2-oxoquinoline-3-carboxylic acids while under the same conditions the α-keto acids underwent deoxalylation.

[Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the following free supplemental files: Additional figures].