Photolyse von 3-Methyl-2, 1-benzisoxazol (3-Methylanthranil) und 2-Azido-acetophenon in Gegenwart von Schwefelsäure und Benzolderivaten

Photolysis of 3-Methyl-2, 1-benzisoxazole (3-Methylanthranil) and 2-Azido-acetophenone in the Presence of Sulfuric Acid and Benzene Derivatives Irradiation of 3-methylanthranil ( 1 ) in acetonitrile in the presence of sulfuric acid and benzene, toluene, p-xylene, mesitylene or anisole with a mercury high-pressure lamp through a pyrex filter yields beside varying amounts of 2-amino-acetophenone ( 3 ) and 2-amino-5-hydroxy- ( 4a ) and 2-amino-3-hydroxy-acetophenone ( 4b ) the corresponding diphenylamine derivatives 5 (see Table 1). In the case of toluene and anisole mixtures of the corresponding ortho- and para-substituted isomers ( 5b, 5d or 5g, 5i respectively), but no meta-substituted isomers ( 5c or 5h ) are obtained. In addition to these products, the irradiation of 1 in the presence of anisole yields also 2-amino-5-(4′-methoxyphenyl)-acetophenone ( 7 ), 2-amino-3-(4′-methoxyphenyl)-acetophenone ( 8 ) and 2-methoxy-9-methyl-acridine ( 6 ; see Scheme 1). The latter product is also formed thermally by acid catalysis from the diphenylamine derivative 5i . Irradiation of 2-azido-acetophenone ( 2 ) in acetonitrile solution in the presence of sulfuric acid and benzene leads to the formation of 1, 3, 4a, 4b, 5a and 9 (see Table 2). Compounds 3, 4a, 4b and 5a are also obtained after acid catalyzed decomposition of 2 in the presence of benzene. Thus, it is concluded that irradiation of 1 or 2 in the presence of sulfuric acid yields 2-acetyl-phenylnitrenium ions 10 in the singlet ground state which will undergo electrophilic substitution of the aromatic compounds, perhaps via the π-complex 11 (see Scheme 2).     

Synthesis of 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones

The reactions of 1-substituted 2-nitro-3-phenylaminoprop-2-en-1-ones with cyanothioacetamide afforded the corresponding 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones, which were used for the synthesis of 6-substituted 3-cyano-2-methylthio-5-nitropyridines and 7-substituted 4-hydroxy-8-nitropyrido[2",3":4,5]thieno[2,3-b]pyridin-2(1H)-ones.     

The cyelodesulfurization of thio-compounds. Part XVII. Synthesis of some novel 2-substituted amino-3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones by cyelodesulfurization of thiosemicarbazides with dicyclohexylearbodiimide (DCCD)

A simple method for the synthesis of a novel series of 2-substituted amino-3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones (11–16) has been established through two routes. The first involving the cyelodesulfurization of the thiosemicarbazides (3–8) with DCCD and the second reacting mixtures of the acid hydrazide 1 with a variety of the isothiocyanates 2 and DCCD. The structure of the cyclized products was confirmed by nmr and mass spectra.     

Deoxydative substitution of pyridine 1-oxides by thiols. Part XX. Reactions of (2, 3, and 4-phenyl)-, 3-acetamido-, 3-bromo-, 3-acetoxy-, 3-ethoxypyridine 1-oxides with 1-adamantanethiol in acetic anhydride

Substitutions of 2, 3, and 4-substituted pyridine 1-oxides by 1-adamantanethiol in acetic anhydride takes place at available α-, to a lesser degree at β-, and rarely at γ-ring carbons. It was found that 2-phenylpyridine 1-oxide produces a mixture of 5- and 6-(1-adamantylthio)-2-phenylpyridines, and 4-phenylpyridine 1-oxide a mixture of 2- and 3-isomeric sulfides. Substitutions of the 1-oxides of 3-phenyl-, 3-acetamido-, 3-acetoxy-, 3-bromo-, and 3-ethoxypyridine by 1-adamantanethiol in acetic anhydride led to mixtures consisting predominantly of 2- and 6-sulfide, and to a lesser extent, the 5-sulfide. When triethylamine is present in otherwise identical reaction mixtures, the ratio of α to β-sulfides increases. From the reactions of 3- and 4-phenylpyridine 1-oxides, there were isolated some N-acetyl hydroxy (or acetoxy) 1-adamantylthio substituted 1,2,3,4-and 1,2,3,6-tetrahydropyridines, whose structures are discussed.     

Synthesis of Diazadi(and tri)thiacrown Ethers Containing Two 5-Substituent(or 2-methyl)-8-hydroxyquinoline Side Arms

Abstract

Sixteen new diazadi(or tri)thiacrown ethers containing two 5-substituent(or 2-methyl)-8-hydroxyquino-lin-2-ylmethyl side arms have been prepared by a three-step process. First, the appropriate bis(α-chloroamide)s were treated with five dimercaptans in base to form macrocyclic di(or tri)thiadiamides. The macrocyclic diamides were reduced by BH₃-THF to form 1,7-diaza-4-oxa-10,13-dithia-cyclopentadecane (11); 1,7-diaza-4,13-dioxa-10,16-dithiacyclooctadecane (12); 1,7-diaza-4-oxa-10,13,16-trithiacyclooctadecane (13); 1,7-diaza-4,13,16-trioxa-10,19-dithiacycloheneicosane (14); and 1,10-diaza-4,7-dioxa-13,16-dithiacyclooctadecane (15). The diazadi(or tri)thiacrown ethers were then treated with 8-hydroxyquinoline, 8-hydroxy-5-methylquinoline, 5-chloro-8-hydroxyquinoline, and 8-hydroxyquinaldine in the presence of paraformal-delyde in refluxing benzene to form the bis(8-hydroxy-5-substituent(or 2-methyl)quinolin-7-ymethy)-substituted diazadi(or tri)thiacrown ethers 16-31. The crown ethers containing two 8-hydroxyquinoline or 8-hydroxyquinaldine side arms proved to be mixtures of about 90% bis(8-hydroxyquinolin-7-ylmethyl)-substituted crown ethers; 9% mixed (8-hydroxyquinolin-7-ymethyl)-substituted and (8-hydroxyquinolin-5-ylmethyl)-substituted crown ethers; and 1% bis(8-hydroxyquinolin-5-ylmethyl)-substituted crown ethers.     

Pteridines. Part XLI. Synthesis and properties of 6,7,8-trimethyl-4-thiolumazine

The first representative of the 8-substituted 4-thiolumazine series has been synthesized. In a sequence of reactions, 4,6-dichloropyrimidin-2-(1H)-one ( 1 ) is first converted into 4-chloro-6-(methylamino)pyrimidin-2(1H)-one ( 6 ), then the Cl-atom displaced by the thioxo group (→7) followed by a coupling reaction with 4-chlorophenyldiazonium chloride to introduce the necessary N-function into the 5-position (→ 9 ; Scheme 1). Reduction of the p-chlorophenylazo group leads to the 6-(methlyamino)-4-thiouracil-5-amine ( 10 ) which on condensation with diacetyl gives 6,7,8-trimethyl-4-thiolumazine ( 8 ). The physical properties of 8 are compared with the 2-thio analog and 6,7,8-trimethyllumazine indicating that 8 possesses the highest acidity and the longest UV absorption.     

The reactions of some ortho-substituted anilines with various α,β-acetylenic ketones. A route to substituted quinolines

The reactions of some ortho-substituted anilines with various α,β-acetylenic ketones were investigated as a route to 4-alkyl-, 4-aryl-, 4-hydroxy-, and 4-amino-3-quinolyl ketones. The anilines examined were 2-aminoacetophenone ( 1 ), 2-aminobenzophenone ( 2 ), anthranilonitrile ( 3 ), methyl anthranilate ( 4 ), and ethyl anthranilate ( 5 ). The acetylenic ketones used were 1,4-diphenyl-2-butyne-1,4-dione ( 6 ), 3-butyn-2-one (7), 1,3-diphenyl-2-propyn-1-one ( 8 ), and 4-phenyl-3-butyn-2-one ( 9 ). The acetylenic ketones typically reacted with the anilines to give enamines; however, exceptions were found. Acetylene 6 reacts with 3 to give the enamine ( 13 ) along with a small amount of 2,3-dibenzoyl-4-quinolamine ( 14 ). The reactions of 1 or 2 with 6 give the respective quinoline derivatives directly. Acetylene 8 reacts with 2 to give 3-benzoyl-2,4-diphenylquinoline ( 22 ) directly, whereas no reaction occurs between 8 and 1 or 3 . Acetylene 9 does not react with 1, 2 , or 3 . The enamines exist as the intramolecularly hydrogen bonded isomers and usually undergo cyclization with 5 molar equivalents of methanolic sodium methoxide to give quinoline derivatives. The 4-quinolinols exist predominantly as the 4-quinolinone tautomer.     

Synthesis of 5-substituted 1-aryl-1H-pyrazole-4-acetonitriles, 4-methyl-1-phenyl-1H-pyrazole-3-carbonitriles and pharmacologically active 1-aryl-1H-pyrazole-4-acetic acids

Lithium aluminum hydride reduction of 5-substituted or unsubstituted ethyl or methyl 1-aryl-1H-pyrazole-4-carboxylates gave, generally in excellent yields, 5-substituted or unsubstituted 1-aryl-1H-pyrazole-4-methanols which afforded the corresponding 1-aryl-4-(bromomethyl)-1H-pyrazoles with hydrobromic acid in acetic acid solution. These crude intermediates gave by reaction with potassium cyanide in dimethylsulfoxide solution 1-aryl-1H-pyrazole-4-acetonitriles only in the case of 5-unsubstituted compounds, otherwise mixtures of 5-substituted 1-aryl-1H-pyrazole-4-acetonitriles and 4-methyl-1-phenyl-1H-pyrazole-3-carbonitriles were generally obtained. Acetonitriles IIIa,b,i,l gave in excellent yields the corresponding 1-aryl-1H-pyrazole-4-acetic acids Va,b,i,l by alkaline hydrolysis. Compounds Vb,i,l showed in the writhing test appreciable analgesic properties, associated with low acute toxicity; moreover, compound VI exhibited a statistically significant antiinflammatory activity in the carrageenan-induced edema assay.     

Synthesis of pyrimidino[4,5-b][1,5]benzodiazepin-2-ones and pyrimidino[1,6-a]benzimidazol-1-ones from 4-ethoxycarbonylamino-1H-1,5-benzodiazpine-3-carbonitrile via 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles

Reactions of 4-ethoxycarbonylamino-1H-1,5-benzodiazepine-3-carbonitrile (2) with aliphatic primary amines gave 1-substituted 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles 3. Analogous reactions of 2 with aromatic primary amines afforded 2-(2′-anilino-1′-cyanovinyl)benzimidazoles 5 and 6. Upon treatment with triethylamine, 3 underwent intramolecular cyclization to give 3-substituted 5-aminopyrimidino[4,5-b]-[1,5]benzodiazepin-2(3H,11H)-ones 8 . Heating of 3 with p-toluenesulfonic acid in ethanol gave 2-substituted pyrimidino[1,6-a]benzimidazol-1(2H)one-4-carbonitriles 9 . Reactions of 2 with hydrazines were also described. Mechanistic pathways are proposed to account for the products.     

2-Imidazolines. IV . 1-Aryl-2-alkylthio-4,5- diamino-4,5-dihydroimidazoles. Synthesis and properties

1,2-Diimmonium salts ( 1 ) react with S-substituted isothioureas ( 3 ) yielding 2-alkylthio-4,5-diamino-4,5-dihydroimidazoles ( 4 ), which under mild pyrolytic conditions afforded 2-alkylthio-5-aminoimidazoles ( 7 ). Imidazolines ( 4 ) and imidazoles ( 7 ) were easily desulfurated with Raney nickel affording 4,5-diamino-4,5-dihydroimidazole ( 9 ) and 5-aminoimidazole ( 10 ), respectively.     

A Theoretical Study on the Tautomerism of C-Carboxylic and Methoxycarbonyl Substituted Azoles

DFT calculations (B3LYP/6-31+G^**) have been carried out on 106 tautomers and conformers of NH-azoles bearing CO₂H and CO₂CH₃ groups. The following azoles systems have been studied: 2-substituted pyrroles, 2-substituted indoles, 2-substituted imidazoles, 2-substituted benzimidazoles, 4(5)-substituted imidazoles, 3(5)-substituted pyrazoles, 3-substituted indazoles (1H and 2H), 3,4(5)-substituted-1,2,3(5)-triazoles, 2,3(5)-substituted-1,2(3),4-triazoles, 4(5)-1,2,3,4(5)-tetrazoles. In the case of pyrazole, 3,5-disubstituted derivatives have also been computed, including four dimers.Dedicated to our friend Professor Vladimir I. Minkin on his 70th anniversary.     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. VI. Synthesis of ethyl or methyl 1,5-disubstituted 1H-pyrazole-4-carboxylates

Reaction of ethyl or methyl 3-oxoalkanoates with N,N-dimethylformamide dimethyl acetal gave, generally in excellent yields, a series of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates II which reacted with phenylhydrazine to afford the esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids III in high yields. Esters III were hydrolyzed to the relative 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles in excellent yields. Reaction of II with methylhydrazine afforded in general a mixture of 3- and 5-substituted ethyl 1-methyl-1H-pyrazole-4-carboxylates with the exception of IIg , which gave in high yield methyl 5-benzyl-1-methyl-1H-pyrazole-4-carboxylate, which was hydrolyzed to the relative pyrazolecarboxylic acid. This afforded by heating 5-benzyl-1-methyl-1H-pyrazole in quantitative yield.     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. X. synthesis of 5-substituted ethyl or methyl 4-isoxazolecarboxylates and methyl 4-(2,2-dimethyl-1-oxopropyl)-5-isoxazolecarboxylate

Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with hydroxylamine hydrochloride in methanol solution afforded in high yields the relative esters of 5-substituted 4-isoxazolecarboxylic acids II . These esters were hydrolyzed generally with concentrated hydrochloric acid-acetic acid mixtures to the corresponding carboxylic acids in satisfactory yields. Ethyl or methyl esters II isomerized with sodium ethoxide or methoxide, respectively, to the corresponding esters or hemiesters of 2-cyano-3-oxoalkanoic acids generally in excellent to satisfactory yields. Reaction of methyl 5,5-dimethyl-3-dimethylaminomethylene-2,4-dioxohexanoate with hydroxylamine hydrochloride afforded in moderate yield methyl 4-(2,2-dimethyl-1-oxopropyl)-5-isoxazolecarboxylate, which was converted by acid hydrolysis as above to 4-t-butyl-4-hydroxyfuro[3,4-d]isoxazol-6-(4H)-one.     

Tetrazole compounds. 8. Synthesis of tetrazolylpyrimidines from tetrazolyl-substituted enamino ketones

Tetrazolyl-substituted enamino ketones 1 react with various amidines 2 to give 5-(1-phenyl-1H-tetrazol-5-yl)pyrimidines 3 . In the case of the chloroacetyl enamine 4 4-(N,N-dimethylaminomethyl)-substituted tetra-zolylpyrimidines 5 were obtained. Subsequent hydrolysis of the 4-trifluoromethyl derivatives 3b, 3d and 3g afforded the corresponding 5-(1-phenyl-1H-tetrazol-5-yl)pyrimidine-4-carboxylic acids 6 .     

Studies on quinoline derivatives and related compounds. IV. Synthesis of 4-substituted 1-alkyl-1,4-dihydro-3-quinolinecarboxylic acid

By the displacement reactions of 1-ethyl-4-chloro-3-carboethoxy-6,7-methylenedioxyquinolinium iodide ( 3a ), several 4-substituted derivatives including the 4-thioxo ( 1c ) and 4-amino derivatives ( 6 ) of oxolinic acid were prepared. The acid 1c and its N₁-substituted derivatives ( 18a-h ) were prepared alternatively by alkylation of ethyl 4-ethylmercapto-6,7-methylenedioxy-3-quinolinecarboxylate ( 15 ) followed by treatment with sodium hydrosulfide and hydrolysis.     

Potential antipsychotic agents. Part 8. Antidopaminergic properties of a potent series of 5-substituted (−)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-dimethoxybcnzaimides. Synthesis via common lithio intermediates

A series of 5-substituted (?)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-diniethoxybenzanndes were made by reaction of the corresponding benzoyl chlorides with (S)-1-ethylpyrrolidine-2-methylaruine (→ 14–16 , 18–21 ). The acids required were prepared in a regiospecific manner from 5-bromo-2,3-dimethoxybenzoic acid which was protected as dihydrooxazole (→ 4–8 ), metalated, reacted with various electrophiles (MeI, EtI, BuBr, CC1³CCl³ or MeSSMe), and hydrolyzed (→ 9–13 ). Alternatively, (-)-(S)-5-bromo-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-di-methoxybenzamide was treated with KH followed by BuLi and an electrophile (I₂ or Me³SiCl) to give the 5-iodo and 5-(trimethylsilyl) derivatives 17 and 22 , respectively. All 5-substituted amides were highly potent inhibitors of [³H]spiperone binding in rat striatal membranes with IC⁵⁰ values of 0.5 to 5 nM (Table 3). Thus, a relatively large steric bulk can be accomodated in the position para to the 2-MeO group. This work also supports the notion that a positive as well as negative electrostatic potential can be located in this position. A selected number of derivatives were also investigated in vivo and found to inhibit apomorphine-induced behavioural responses in the same dose range as haloperidol and raclopride (Table 4). This new group of benzamides is suitable for investigations of dopamine D-2 receptors in labelled or unlabelled form.     

5-Cyano-6-aryluracil and 2-thiouracil derivatives as potential chemotherapeutic agents. IV

A series of 5-cyano-6-aryluracils and 2-thiouracils 1a-h has been prepared and alkylated to 1,3-dialkyluracils 2a-d and 2-alkylthiouracils, 3, 4 and 6 , by electrophilic substitution with alkyl halides. Reaction of 1b with dibromoethane and 1,3-dibromopropane gave the corresponding bicyclic products, 7-aryl-6-cyano-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones 5a,b and 8-aryl-7-cyano-3,4-dihydro-2H-pyrimido[2,3-b][1,3]thiazin-6-ones 5c-g . Nucleophilic substitution on 6 with hydrazine led to 7 which on refluxing with formic acid gave 5-aryl-6-cyano-8-methyl-s-triazolo[3,4-b]pyrimidin-7-ones ( 9 ), while with acetic and propionic acids only 2-acylhydrazino-3-methyl-4-oxo-5-cyano-6-arylpyrimidines 8a,b were isolated. The hydrazine 7 undergoes cyclization with acetylacetone and methyl dimethylmercaptoacrylate providing 2-(pyrazol-1-yl)-3-methyl-4-oxo-5-cyano-6-substituted pyrimidines 10 , and 11 . Some of the compounds were screened for antibacterial-, antifungal- and antiviral activities and a few of them showed significant chemotherapeutical activities.     

Some aspects of the chemistry of pyrimido[1,2-B]pyridazinones

On reacting the 3-aminopyridazines 1a,d,e with dimethyl acetylenedicarboxylate (DMAD), the pyrimido[1,2-b]pyridazin-2-(2H)-ones 2e-g , whereas starting from 1f , the 4(4H)-ones 5a and 3b,d were prepared. In the 2(2H)-one series, the reactions of 2b with various amino compounds resulted in various types of products. The reaction of N-methylaminopyridazines 1g,h with DMAD led to the endo-N-substituted derivatives 8a,b , whereas 1h with diethyl ethoxymethylenemalonate (DEM) gave the exo-N-substituted compound 1k. The constitution of the compounds was proved by spectroscopic and chemical evidences.     

Stereoselective synthesis of pyrrolo[2,3-d]pyrimidine α- and β-D-ribonucleosides from anomerically pure D-ribofuranosyl chlorides: Solid-Liquid Phase-Transfer Glycosylation and 15N-NMR Spectra

Solid-liquid phase-transfer glycosylation (KOH, tris[2-(2-methoxyethoxy)ethye]amine ( = TDA-1), MeCN) of pyrrolo[2,3-d]pyrimidines such as 3a and 3b with an equimolar amount of 5-O-[(1,1 -dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribofuranosyl chloride (1) [6] gave the protected β-D -nucleosides 4a and 4b , respectively, stereoselectively (Scheme). The β-D -anomer 2 [6] yielded the corresponding α-D -nucleosides 5a and 5b with traces of the β-D -compounds. The 6-substituted 7-deazapurine nucleosides 6a , 7a , and 8 were converted into tubercidin (10) or its α-D -anomer (11) . Spin-lattice relaxation measurements of anomeric ribonucleosides revealed that T₁ values of H? C(8) in the α-D -series are significantly increased compared to H? C(8) in the β-D -series while the opposite is true for T₁ of H? C(1′). ¹⁵N-NMR data of 6-substituted 7-deazapurine D -ribofuranosides were assigned and compared with those of 2′-deoxy compounds. Furthermore, it was shown that 7-deaza-2′deoxyadenosine ( = 2′-deoxytubercidin; 12 ) is protonated at N(1), whereas the protonation site of 7-deaza-2′-deoxyguanosine ( 20 ) is N(3).     

Pteridines. Part LXXXVII. Synthesis and Properties of 8-Substituted 2-Thiolumazines

Various 8-substituted 2,8-dihydro-2-thioxopteridin-4(3H)-ones ( 14 – 21 ) and 2-(methylthio)pteridin-4(8H)-ones ( 27 – 32 ) have been synthesized by condensation of the appropriate 5-amino-6-(substituted amino)-1,2-dihydro-2-thioxopyrimidin-4(3H)-ones ( 22 – 34 ) and 5-amino-6-(substituted amino)-2-(methylthio)pyrimidin-4(3H)-ones ( 25 , 26 ), respectively, with glyoxal, biacetyl, and benzil. The presence of a quinonoid cross-conjugated π-electron system makes this type of compounds susceptible to nucleophilic additions in position 7, which leads to intramolecular ( 43 , 45 ) and intermolecular ( 44 ) covalent adducts. The newly synthesized compounds have been characterized by elemental analyses, pK_a determinations, ¹H-NMR and UV spectra. UV-Spectral changes in dependence of the pH are associated with the most appropriate molecular species including the monocations, neutral forms, covalent adducts, mono- and dianions.