New routes to aroylthiadiazolines and arylazothiazoles from phenylglyoxalyl bromide arylhydrazones and phenacyl thiocyanate

Reaction of phenylglyoxalyl bromide arylhydrazones (III) with thiourea in ethanol produces 2-amino-4-phenyl-5-arylazothiazoles (XI) instead of the expected 2-benzoyl-4-aryl-5-imino-Δ^2?1,3,4-thiadiazolines (V) obtained from III and potassium thiocyanate. Phenacyl thiocyanate (IV) couples with diazotized anilines to give V. The mechanisms of formation of V and XI from VI and III, respectively, are postulated. Nitrosation of V gives the corresponding N-nitroso derivatives (VII), which decompose upon refluxing in xylene to give 2,4-disubstituted Δ² ?1,3,4-thiadiazolin-5-ones (VIII). The thiadiazolines V give the respective N-aeyl derivatives IX and X with acetic anhydride and benzoyl chloride in pyridine.     

Studies on the syntheses of azole derivatives. Part VII. Syntheses of 1 -phenyl-Δ2-1,2,4-triazolin-5-one derivatives [studies on the syntheses of heteroeyclic compounds. CD XI]

Bromination of 3-methyl-1-phenyl-Δ²-1,2,3-lriazolin-5-one (II) and its 4-phenyl derivative III afforded the corresponding I-(p-Bromophenyl) derivatives IV and V, respectively. (Chlorination of the 4-phenyl derivative III gave I-(P-chlorophenyl) derivative VI. In addition, 3-N-subsuituted-carhamoyl-1,2,4-triazolin-5-ones(XII, XIII, and XIV) were synthesized by the Schotten-Baumann reaction of 3-carboxy-1-phenyl-Δ²-1,2,4-triazolin-5-one (XI) with various amines.     

Hydrazidoyl halides in synthesis of Δ2-1,3,4-selenadiazolin-5-ones

Reaction of hydrazidoyl halides 1-5 with potassium selenocyanate in ethanol produces the corresponding 2,4-disubstituted-5-iminoδ²-1,3,4-selenadiazolines, 9-13 respectively. Nitrosation of the latter yields the N-nitroso derivatives 14-17 , which decompose upon refluxing in xylene to give 2,4-disubstituted Δ²-1,3,4-selenadiazolin-5-ones in good yield. Compounds 9-13 give the respective N-acetyl derivatives 22-26 and N-benzoyl derivatives 27-31 with acetic anhydride and benzoyl chloride in pyridine.     

Benzomorphan related compounds. IV. The stevens rearrangement of a trimethoxybenzyl-1,2,5,6-tetrahydropyridinium salt

The potassium hydroxide-induced (Stevens) rearrangement of 1,3,4-trimethyl-1-(3,4,5-trimethoxybenzyl)-1,2,5,6-tetrahydropyridinium chloride (I) gives the desired 1,3,4-trimethyl-2-(3,4,5-trimethoxybenzyl)-1,2,5,6-tetrahydropyridine (III) and the Hofmann elimination product, N-methyl-N-(3,4,5-trimethoxybenzyl)-2,3-dimethyl-2,4-pentadienamine (II). In the presence of ethereal phenyllithium, the salt I undergoes rearrangement giving the expected tetrahydropyridine III in about 17% yield and four other products, N-(3,4,5-trimethoxybenzyl)methylamine (VI), 1,3,4-trimethyl-2-(6-methyl-2,3,4-trimethoxyphenyl)-1,2,5,6-tetrahydropyridine (IV), 1,3,3-trirnethyl-2-(3,4,5-trimethoxyphenyl)-4-rnethylenepiperidine (V) and 1,3,4-trimethyl-4-(3,4,5-trimethoxybenzyl)-1,4,5,6-tetrahydropyridine (VII), the latter being the 1,4-Stevens rearrangement product which cyclizes easily to β-2′,3′,4′-trimethoxy-2,5,9-trimethyl-7,8-benzomorphan (VIII). Their structures have been proved both by analytical and spectral data. A possible route for VIII and its stereochemical aspects are discussed.     

Acetylenic ketones. Part VI. Reaction of aroylphenylacetylenes with hydrazine derivatives

The reaction of aroylphenylacetylenes (I) with acyl- or aroylhydrazines (II) gave ω-aroyl-acetophenone-N-acyl or N-aroylhydrazones (IV). The latter gave upon treatment with methanolic potassium hydroxide and with acetic anhydride in the presence of sodium acetate, the corresponding pyrazoles (V) and the N-acetylpyrazoles (VII and VIII), respectively. The acetylenic ketones ( 1 ) also reacted with methylhydrazine and 1,1-dimethylhydrazine to give 5-aryl-1-methyl-3-phenylpyrazoles (XII), and 1,1-dimethylhydrazine derivatives (XIII), respectively. When the latter compounds were heated with acetic anhydride, they gave the N-methylpyrazoles (XII).     

New tetracyclic compounds containing the β-carboline moiety

Oxidation of 1-methyl-3-methoxycarbonyl-β-carboline with selenium dioxide gave 1-formyl-3-methoxycarbonyl-β-carboline II . Compound II reacted with acetic or propionic anhydride to give easily the 2-methoxycarbonyl-6H-indolo[3,2,1-d,e][1,5]naphthyridin-6-ones III ; reaction of II with some primary amines led to the formation of the Schiff bases IV , which were reduced to the 1-aminomethyl-3-methoxycarbonyl-β-carbolines V with sodium borohydride. Cyclization of V with aqueous formaldehyde led to the pyrimido[3,4,5-lm]pyrido[3,4-b]indoles VI . Analogously, cyclization with formaldehyde, acetone or 1,1′-carbonyldiimidazole of the 3-aminomethyl- 1,2,3,4-tetrahydro-β-carbolines VIII , obtained by reaction of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline VII with amines followed by lithium aluminium hydride reduction of the resulting amides, gave the imidazo[1′,5′-1,6]pyrido[3,4-b]indoles IX and X . Dieckmann cyclization of 3-methoxycarbonyl-2-[(3-ethoxycarbonyl)-1-propyl]-1,2,3,4-tetrahydro-β-carboline XI led to a 1:1 mixture of the β-ketoesters XII and XIII , which underwent deethoxycarbonylation to 5,6,8,9,10,11,11a,12-octahydroindolo[3,2-b]quinolizin-11-one XIV . Finally, the polyphosphoric acid (or esters) catalyzed cyclization of the N-acyl derivatives XVI of 3-hydrazinocarbonyl-β-carboline XV led smoothly to the 3-(1,3,4-oxadiazol-2-yl)-β-carbolines XVII .     

Reactions with 2-mercaptopyrimidines. Synthesis of some new thiazolo[3,2-a]- and triazolo[4,3-a]pyrimidines

Alkylation of 5-cyano-4-oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine I with methyl iodide, chloroacetic acid or 3-chloro-2,4-pentanedione, afforded the S-alkyl derivatives IIa-c. 2-Carboxymethylthio and 2-(2′,4′-dioxopentan-3-ylthio) derivatives IIb and IIc could be cyclised by acetic anhydride or polyphosphoric acid to give 6-cyano-3,5-dioxo-5H-7-phenylthiazolo[3,2-a]pyrimidine III and 2-acetyl-6-carboxamido-5H-3-methyl-7-phenylthiazolo[3,2-a]pyrimidine-5-one IX , respectively. Benzoylation of 2-hydrazinopyrimidine derivative XII , in anhydrous dioxan, afforded the N-benzoyl derivative XIII , which could be cyclised by heating in dimethylformamide to give 5-amino-6-cyano-3,7-diphenyl-s-triazolo[4,3-a]pyrimidine ( XIV ). The 2-hydrazinopyrimidine derivatives XII and XV reacted with benzoyl isothiocyanate in dioxane to yield 4-benzoylthiosemicarbazide derivatives XVI and XVII , which were converted into the 2-s-trizolopyrimidine derivatives XVIII and XIX , respectively. Also, XVI and XVII reacted with 2,4-pentanedione and 3-chloro-2,4-pentanedione to yield 2-pyrazolopyrimidine derivatives XX and XXI , respectively.     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.     

Syntheses and reactions of optically active polymers. II. Preparations of optically active polymers containing quinine,L-ephedrine,and L-histidine residues and their reactions with α-cyanoethylaquocobaloxime

Preparations of polymers with bis(dimethylglyoximato)cobalt (cobaloxime) were investigated. 4-Vinylpyridine was reacted with α-cyanoethylaquocobaloxime to produce α-cyanoethyl-4-vinylpyridinatocobaloxime (I) in 72% yield. It did not, however, polymerize by the use of azobisisobutyronitrile (AIBN) as an initiator. Polymers containing α-cyanoethylcobaloxime were obtained by reactions of polymers with α-cyanoethylaquocobaloxime (II). Poly(9-O-methacryloylquinine) (III), poly(O-methacryloyl-N-methyl-L -ephedrine) (IV), poly[N^α-(o-vinylbenzyl)-L -histidine] (V), and poly(4-vinylpyridine) (VI) were prepared and used in these reactions. Polymers V and VI were reacted with II to give polymers X, XI, XII, and XIII containing α-cyanoethylcobaloxime.     

Acetylenic ketones. Part V. Reaction of acetylenic ketones with thiourea and some of its derivatives

Aroylphenylacetylenes (I) reacted with thiourea and S-benzylisothiourea to give 4,6-diaryl-pyrimidine-2(1H)thiones (IV) and α-aroyl-β-benzylmercaptostyrenes (X), respectively. Methyla-tion and acetylation of the thiones (IV) gave the corresponding S-methyl- (V) and S-acetyl- (VI) derivatives, respectively. The oxidation of these thiones gave the corresponding disulfide derivatives (VII). Reaction of α-aroyl-β-benzylmercaptostyrenes (X) with hydrazine hydrate and phenylhydrazine gave 3(5)-aryl-5(3)-phenylpyrazoles (XI) and 3-aryl-1,5-diphenylpyrazoles (XIII), respectively. Reaction of aroylphenylacetylenes (1) with N-allylthiourea gave 1-allyl-4,6-diaryl-pyrimidine-2-thiones (XVI).     

Acetylinic ketones. Part II.. Reaction of acetylenic ketones with nucleophilic nitrogen compounds

Aroylphenylacetylenes (I) reacted with ethyl and phenyl hydrazinecarboxylates (II) to give ω-aroylacetophenone-N-ethoxycarbonyl-(Vla-f) and N-phenoxycarbonyl-(VIg-l) hydrazones, respectively. When these were healed with acetic anhydride they were converted to 5-aryl-1-ethoxycarbonyl-and 1-phenoxycarbonyl-3-phenylpyrazoles (VII), respectively, which on hydrolysis with rnethanolic potassium hydroxide gave the corresponding 5(3)aryl-3(5)phenylpyrazoles (VIII). Reaction of the above acetylenic ketones with guanidine hydrochloride in the presence of sodium carbonate gave the corresponding 2-amino-6-aryl-4-phenylpyrimidines (XII). Similarly, reaction of benzoylphenylacetylene with thiourea and with urea in the presence of sodium ethoxide gave rise to 2,4-diphenylpyrimidine-2-thione (XVIII) and 2,4-diphenyl-2(1H)pyrimidin-one (XV), respectively.     

Thermische Umwandlung von Phenyl-penta-2,4-dienyläthern in 4-[Penta-2,4-dienyl]-phenole als Beispiel für [5,5]-sigmatropische Umlagerungen. Vorläufige Mitteilung

The reaction between phenol and trans penta-2,4-dienyl chloride gave trans penta-2,4-dienyl Phenyl ether (I), whereas with a mixture of sorbyl chloride and 1-methylpenta-2,4-dienyl chloride, pure trans, trans hexa-2,4-dienyl phenyl ether (IV) and trans 1-methylpenta-2,4-dienyl phenyl ether (V) were obtained. The ether I gave, on heating in dilute solution at 185°, 4-(penta-2,4-dienyl)-phenol (III) as the main product, and also some 2-(2-vinylallyl)-phenol (II). The ether IV provided, on heating at 165°, in addition to the ortho CLAISEN rearrangement product VI, mainly a mixture consisting of 94% 4-(1-methylpenta-2,4-dienyl)-phenol (VIII) and only 6% 4-(hexa-2,4-dineyl)-phenol(IX). The latter product (IX) was the only para isomer produced on heating ether V, but in addition 22% of the ortho rearrangement product VII was formed. The migrations I → III, IV → VIII, and V → IX, proceeding through a ten membered transition state, are the first [5,5] sigmatropic rearrangements described.     

Studies on the syntheses of analgesics. Part XXXII. An alternative synthesis of 1,2,3,4,5,6-Hexahydro-8-hydroxy-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazoeine [Studies on the syntheses of heterocyclic compounds. Part CDLXXX]

Bischler-Napieralski reaction of the amides (VIII and IX), derived from the 3-methyl-3-pentenylamine (III) with the phenylacetic acid derivatives (V ～ VII), gave the 5,6-dihydropyridines (XII and XIII), which were reduced, followed by N-benzylation, to afford the 1,2,5,6-tetrahydropyridines (XIX ～ XXI). Grewe-type cyclization of these compounds gave 3-benzyl-3-benzazocine (II), which was already converted into pentazocine (Ic). Moreover, the 1,2,5,6-tetrahydropyridines (XIX ～ XXI) were also obtained from the 2-benzylidene-1,2,5,6-tetrahydropyridine (XVII ～ XVIII) from the N-benzylamine (IV) of III via the amides (X and XI).     

1-(Aziridine) carbonyl chlorides and 1-(aziridine) carbonyl quaternary ammonium chlorides. Rearrangement to 2-(chloroalkyl) isocyanates

Aziridine reacted with phosgene in the presence of an acid acceptor or with 1,1′-carbonylbis(pyridinium) chloride to produce 1-(aziridine)carbonyl chloride (XII) or 1-(aziridine)carbonyl pyridinium chloride (XIII), respectively, as transient intermediates. Attempts to trap and observe (XII) and (XIII) at -10° were unsuccessful. These elusive materials underwent facile rearrangements to 2 - chloroethyl isocyanate under these conditions. Aziridine reacted with 1,1′-carbonylbis(triethylammonium)chloride (VII) at -20° to give 1-(aziridine) carbonyl triethylammonium chloride (X) as a transient intermediate which proceeded to 2-chloroethyl isocyanate. At -10° this reaction produced N,N-diethyl-1-aziridinecarboxamide. Aziridine reacted with a large excess of phosgene in the absence of an acid acceptor to give N-2-(chloroethyl) carbamoyl chloride (III), 1,1′-bis(2-chloroethyl) urea (IV) and 2-(β-chloroethylamino)-2-oxazoline hydrochloride (V). Possible mechanisms for these reactions are discussed.     

Metallacycloalkanes : II. Reactions of α,α′-bipyridyl-5-nickela-3,3,7,7-tetramethyl-trans-tricyclo[4.1.0.02,4]heptane

The title compound (II) underwent reductive elimination on treatment with maleic anhydride, tetracyanoethylene or triphenylphosphite to give 3,3,6,6,-tetramethyl-trans-tricyclo[3.1.0.0^2,4]hexane (III). With triphenylphosphite bi(2,2-dimethylcyclopropyl) (V) and 1-(2,2-dimethylcyclopropyl)-3-methyl-1,3-butadiene (VI) were also formed. Acidolysis of II with either HCl, malonic acid or methanol gave V. An intermediate complex α,α′-bipyridyl(phenoxy)-3-nickel-1,1′-bi-(2,2′-dimethylcyclopropyl) (VIII) was isolated by reaction of II with phenol. Methylene dibromide reacts with II to give III and 3,3,7,7-tetramethyl-trans-tricyclo[4.1.0.0^2,4]heptane (IV). With triethylaluminum and II complete exchange of the alkyl groups occurred and V was released on hydrolysis. Trifluoroborane diethyl ether and II gave 3,3,6,6-tetramethylcyclohexa-1,4-diene in a rearrangement-displacement reaction. The cyclodimerisation of 3,3-dimethylcyclopropene (I) to III catalysed by II and the fact that II can be recovered from the reaction mixture provides strong evidence for the intermediacy of metallacyclopentanes in these transition-metal-catalysed [2π + 2π] cyclo-additions.     

7-Deazapurines II. Syntheses and reactions of 5-aminopyrrolo[2,3-d] pyrimidine-6-carbonitrile and related compounds

The reaction of 4-chloro-2-phenyl-5-pyrimidinecarbonitrile (III) with N-methylglycinonitrile gave 4-[(eyanomethyl)methylamino]-2-phenyl-5-pyrimidinecarbonitrile (VIa), which upon cycli-zation under Dieckmann conditions afforded 5-amino-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]-pyrimidine-6-carbonitrile (VIIa). Other examples (VIIb and VIIc) were prepared similarly from the reactions of III with glycinamide and ethyl glycinate, respectively. The preparation of simple 5-amino derivatives of the pyrrolo[2,3-d] pyrimidines thus synthesized is described. The alkyla-tion of VIIc with N-cyeloheptylchloroacetamide took place at the ring nitrogen, giving XII. The reaction of VIIa with formamide gave 4-amino-5-methyl-7-phenyl-5H-pyrrolo[2,3-d:4,5-d′ ]-dipyrimidine (XIII), the first member of a new ring system. Treatment of VIIa with carbon disulfide and pyridine afforded another example of this new ring system, 1,5-dihydro-5-methyl-7-phenyl-2H-pyrrolo[2,3-d:4,5-d′] dipyrimidine-2,4-(3H)dithione (XIV).     

Synthesis of certain metabolites and analogs of vitamin B6 and their ring-chain tautomerism

Pyridoxol and pyridoxal on benzylation with dimethylphenylbenzylammonium hydroxide (“leucotrope”) gave 3-O-benzylpyridoxol (IV) and 3-O-benzylpyridoxal (V), respectively. As a possible mechanism of this reaction an ion pair intermediate has been postulated. Oxidation of IV and V with chromic oxide-pyridine-acetic acid complex gave 3-O-benzyl-4-pyridoxic acid lactone (VI), which could also be obtained by benzylation of 4-pyridoxic acid. Treatment of VI with dimethylamine gave 2-methyl-3-benzyloxy-5-hydroxymethylpyridine-4-N,N-dimethylcarbox-amide (X) which oxidized to form the 5-formyl derivative (XI). The latter on hydrolysis yielded the metabolite, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylic acid (I). When reacted with liquid ammonia, VI gave 3-O-benzyl-4-pyridoxamide (VII) which was then oxidized to give 2-methyl-3-benzyloxypyridine-4,5-dicarboxylic acid cyclicimide(IX). Acid hydrolysis of IX gave another metabolite, 2-methyl-3-hydroxypyridine-4,5-dicarboxylic acid (XIII), which could also be obtained by oxidizing XI with potassium permanganate in water to yield 2-methyl-3-benzyloxy-5-carboxypyridine-4-N,N-dimethylcarboxamide (XII) and subsequent hydrolysis with hydrochloric acid. A positional isomer of I, 2-methyl-3-hydroxy-4-formylpyridine-5-carboxylic acid (XVII) was synthesized starting from 3-O-benzyl-5-pyridoxic acid lactone (XIV) following similar reaction sequences used for the preparation of I. Ring-chain tautomerism has been studied in I, XVII, opianic acid (XVIII), phthalaldehydic acid (XIX) and (2-carboxy-4,5-dimethoxy)-phenylacetaldehyde (XX) in different solvents by nmr and in the solid state by ir spectroscopy. A direct and reliable differentiation between the open form (aldehyde proton in low field) and the ring form (lactol proton in the intermediate field) has been obtained by nmr spectroscopy. In sodium deuteroxide and pyridine-d₅ the open chain form existed exclusively (except for homolog (XX) which is in cyclic form in pyridine-d₅), whereas in 18% hydrogen chloride in deuterium oxide all the compounds are completely in the cyclic form. In hexafluoroacetone hydrate-d₂, XVIII, XIX, and XX exist in the cyclic form whereas I is in the open form. In DMS0-d₆ both cyclic and open-chain forms have been observed in XVIII, XIX and XX. Definite peak assignment for the two forms could not be made in I due to broadening or superimposition with C₆-H. The metabolite I, isometabolite (XVII) and opianic acid (XVIII) form cyclic acetyl derivatives which give a sharp lactol peak. In the solid state XVIII, XIX are in the cyclic form and I and XX in the open-chain form as observed by ir spectroscopy.     

Synthesis of heterocycles. Part VII Synthesis and antimicrobial activity of some 7H-s-triazolo[3,4-b][1,3,4]thiadiazine and s-triazolo[3,4-b][1,3,4]thiadiazole derivatives

The cyclization of 4-amino-5-aryl-3-cyanomethylthio-1,2,4-triazoles II in the presence of concentrated sulfuric acid yields 7H-6-amino-s-triazolo[3,4-b][1,3,4]thiadiazines III . Cyclization of 4-amino-5-aryl-1,2,4-tria-zole-3-thiones I with phenacyl chloride yields 7H-3-aryl-6-phenyl-s-triazolo[3,4-b][1,3,4]thiadiazines IV . Similarly, compounds I condensed with cyanogen bromide, phenyl isothiocyanate and carbon disulfide to give the corresponding cyclized products 6-amino-3-aryl-s-triazolo[3,4-b][1,3,4]thiadiazoles V , 3-aryl-6-phenyl-amino-s-triazolo[3,4-b][1,3,4]thiadiazoles VI and 3-aryl-striazolo[3,4-b][1,3,4]thiadiazol-6(5H)thiones VII , respectively. Also in the presence of phosphoryl chloride, compounds I underwent cyclization with monocarbo-xylic acids and oxalic acid to 3,6-diaryl-s-triazolo[3,4-b][1,3,4]thiadiazole VIII and 6,6′-bis(3-aryl-s-triazolo-[3,4-b][1,3,4]thiadiazoles) IX . The above compounds were screened for their antimicrobial activity.     

Heterocycles. Part VIII. Synthesis of new substituted benz[g]indazoles

Aryl aldehydes I reacted with α-tetralone to give the corresponding 2-arylidene-1-tetralone II. Condensation of the latter chalcones with hydrazine, methylhydrazine and phenylhydrazine produced the corresponding benzo[g]indazoles III, V and VI respectively. Acetylation of the 2H-benz[g]indazole derivatives III gave the corresponding 2-acetylated compounds IV. The structure of all products was elucidated by chemical and spectroscopic methods.     

Studies on the syntheses of azole derivatives. Part IX. Formation of 2,4-disubstituted δ2 -1,3,4-oxadiazolin-5-one and 4-substituted 1,2,4-triazolidin-3,5-dione derivatives by thermal reaetion of N-aryl-N-benzylearbamoyl azides

The structure of the novel produets, 2,4-ltis-(N-benzy1-4-nitroanilino)-Δ²-1,3,4-oxadiazolin-5-one (VII), 2-benzy1-1-(N-benzy1-4-chloroanilino)-4-(4-chlorophenyl)-1,2,4-triazolidin-3,5-dione (XIVa), and 2-benzy1-1-(N-benzylanilino)-4-pheny1-1,2,4-triazolidin-3,5-dione (XIVb), obtained upon thermal reaction of N-bcnzyl-N-(4-nitrophenyl)carbamoyl azide (la), N-benzyl-N-(4-chloro-phenyl)carbamoyl azide (Ib) and N-benzyl-N-phcnylcarbamoyl azide (le), respectively, were determined.