Rearrangement of 1,4-benzodiazepin-2,4-diones to 3,l-benzoxazin-4-ones

Treatment of 7-chloro-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (Ia) with refluxing acetic anhydride in the presence of pyridine afforded 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (IIa). A plausible reaction path for this novel rearrangement reaction is described: Ia → 4-acetyl-7-chloro-3,4-dihydro-lH-1,4-benzodiazepin-2,5-dione → 7-chloro-1,4-diacetyl-3,4-dihydro-lH-1,4-benzodiazepin-2,4-dione → IIa. When 7-chloro-3,4-dihydro-4-methyl-lH-1,4-benzodiazepin-2,5-dione (Ib), 3,4-dihydro-4-methyl-1H-1,4-benzodiazepin-2,5-dione (Id) and 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Ie) were allowed to react with acetic anhydride under conditions similar to those used for the rearrangement reaction, only acetylation occurred.     

Mechanism of the condensation reaction between 1-aryl- and heteroaryl-1,4-dihydro-3(2H)-isoquinolinones and aldehydes

4-Benzylidene-1-phenyl-1,4-dihydro-3(2H)-isoquinolinone, the intermediary product of the carbonyl condensation reaction between 1-phenyl-1,4-dihydro-3(2H)-isoquinolinone and benzaldehyde, rearranges in the presence of an equivalent quantity of sodium hydride into 4-benzyl-1-phenyl-3(2H)-isoquinolinone. As the possibility of the migration of the hydrogen at C-1 in the form of a proton or a hydrogen atom (radical reaction) was excluded, the mechanism of the rearrangement could be depicted as an intermolecular hydride anion migration. In case of the 1-(4-pyridyl)- and 1-(3-pyridyl)-1,4-dihydro-3(2H)-isoquinolinones, however, the rearrangement can be carried out also in polyphosphoric acid and in this case a proton loss-proton gain mechanism was proved.     

Drug-induced modifications of the immune response part 94-(Arylamino)-2,5-dihydro-2-oxo-N-(trans-2-phenylcycolopropyl)furan-3-carboxamides as Novel Antiallergic Compounds

The synthesis and antiallergic activity of a series of 4-(arylamino)-2,5-dihydro-2-oxo-N-(trans-2-phenyl-cyclopropyl)furan-3-carboxamides 10 are described. Treatment of N-substituted 2-amino-4,5-dihydro-4-oxofuran-3-carboxylic acids 9 with chlorooxobis(2-oxo-1,3-oxazolidin-3-yl)phosphorus ( 2 ) and an appropriate aromatic amine in the presence of Et₃N, resulted in a novel 3(2H)-furanone-→2(5H)-furanone rearrangement that led to the facile preparation of the new amides 10 . The latter exerted a potent antiallergic activity when tested in the dermal vascular permeability and active anaphylaxis assays in rats. The most active compound 10b inhibited the action of serotonin, histamine, and bradykinin by 94, 92, and 100%, respectively, when administered intraperitoneally to rats at doses of 100 mg/kg. The present series of 10 represents a novel class of antiallergic agents.     

A study of the synthesis and some reactions of 3-phenyl-1,4-benzothiazines

Condensation of o-aminothiophenol with 2-bromoacetophenone yields 3-phenyI-1,4-benzo-thiazine hydrobromide, which upon treatment with alkali gave a mixture of 3-phenyl-2H-1,4-benzothiazine (VIIa) and 3-phenyl-4H-1,4-benzothiazine (VIIb). Catalytic hydrogenation led to rearrangement of the benzothiazine (VIIa) to 2-phenyl-2-methyl-2,3-dihydrobenzothiazole (X), while reduction with lithium aluminium hydride resulted in 3-phenyl-2,3-dihydro-4H-1,4-benzothiazine (XVI). The latter was transferred to 3-phenyl-4-aminoalkyl-2,3-dihydro-4H-1,4-benzothiazines (XVII and XVIII).     

On the reaction of 3-nitro-1,2-phenylenediamine with ethyl acetoacetate. Condensed dihydrodiazepinones

Condensation of 3-nitro-1,2-phenylenediamine with ethyl acetoacetate in boiling xylene gave two isomeric 2,3-dihydro-4-methyl-9-nitro- and 2,5-dihydro-4-methyl-6-nitro-1H-1,5-benzodiazepin-2-ones, the 9-nitro derivative thermal rearrangement product N-isopropenyl-4-nitrobenzimidazolone and a non cyclic acetoacetamide derivative. At room temperature these reactants afforded 2,3-dihydro-2-ethoxycarbonyl-methyl-2-methyl-4-nitrobenzimidazole.     

Acid catalyzed rearrangements in the arylimino indoline series. Part IV . Reactions of 1,2-dihydro-2-phenyl-2-(indol-3-yl-derivatives)-3-phenylimino-3H-indole with trichloroacetic and hydrochloric acids. Crystal structure of 1,2-dihydro-2-phenyl-2-(indol-3-yl)-3-phenylimino-3H-indole

2-Phenyl-3-phenylimino-3H-indole reacts with indole, 2-methylindole and 1,2-dimethylindole in the presence of stoichiometric trichloroacetic acid to form 1,2-dihydro-2-phenyl-2-(indol-3-yl-derivatives)-3-phenylimino-3H-indole, which during a longer period of time (16 hours) undergoes indolyl transposition to carbon-3 and elimination of aniline affording the 3,3′-bis-indolyls. In the case of 1,2-dimethylindole the intermediate coming from the indolyl migration may undergo a nucleophilic addition to carbon-2 of another molecule of indole; the new intermediate leads to the formation of 2-phenyl-3,3′-di-(1,2-dimethylindol-3-yl)-3H-indole by elimination of aniline and migration to carbon-3 of the second molecule of indole. By treatment with hydrochloric acid in refluxing ethanol, 1,2-dihydro-2-phenyl-2-(indol-3-yl-derivatives)-3-phenylimino-3H-indole afford to 3,3′-bis-indolyls and 1,2-dihydro-2-phenyl-2-(indol-3-yl-derivatives)-3H-indol-3-one (indoxyls). The crystal structure of 1,2-dihydro-2-phenyl-2-(indol-3-yl)-3-phenylimino-3H-indole is also reported. The latter compound does not give rearrangement products by acid treatment, only untreatable tarry material.     

Curtius rearrangement in the 5-phenyl-1,4-benzodiazepine series. Unprecedented participation by an imine nitrogen

The previously unknown 3-aminomethyl-1,3-dihydro-5-(2′-fluorophenyl)-2H,4-benzodiazepin-2-one, 3a, was synthesized in two steps as a racemate. In the chiral series, 3(S)-azidocarbonylmethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 12b, was prepared from Nα-Cbz-β-methylaspartate in five synthetic operations and subjected to Curtius rearrangement. The intermediate isocyanate was trapped intramolecularly by the 5-imine nitrogen of the benzodiazepine ring in 12b. This unanticipated result runs counter to the generally held dictum that the isocyanate group has a strictly linear shape.     

Synthesis of 2,3-dihydro-5H-oxazolo[2,3-B]quinazolin-5-ones

Iodide-catalyzed ring expansion of 2-[(1-aziridinylcarbonyl)amino]benzoic acid methyl ester (2) gave 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one (3) in quantitative yield. Treatment of the dimethyl analog of 2 (9) with sodium iodide in acetone gave a mixture of the 2,3-dihydro-2,2-dimethyl- (10) and 2,3-dihydro-3,3-dimethyl-5H-oxazolo[2,3-b]quinazolin-5-ones (11). However, rearrangement of 9 with sulfuric acid produced only 10. Synthesis of 11 by another route for comparison is described, and the known syntheses of 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-ones are reviewed.     

Unusual rearrangement of (cyclopropylmethoxy)benzene and its derivatives in the presence of BF<Subscript>3</Subscript>·Et<Subscript>2</Subscript>O

(Cyclopropylmethoxy)benzene and its ortho- and para-bromo-substituted analogs in the presence of BF₃ · Et₂O undergo rearrangement with formation of (cyclobutyloxy)benzene and 2-ethyl-2,3-dihydro-1-benzofuran.     

Studies on the benzo[1,2]cyclohepta[3,4,5-d,e]isoquinoline ring system

The syntheses of various oxidation states of the novel benzo[1, 2]cyclohepta[3, 4, 5-d, e]-isoquinoline ring system is described. The ring system was obtained by the Schmidt rearrangement, with exclusive alkyl migration, of 1, 6, 7, 11b-tetrahydro - 2H - dibenz-[cd,h]azulen-2-one and by a Bischler-Napieralski reaction of suitable derivatives of 10, 11-dihydro-5H-dibenzo[a, d]cycloheptene - 5 - methylamine. 4, 5, 10, 11 - Tetramethoxy derivatives of the new ring system were best prepared by a Pictet-Spengler reaction of the appropriate amine.     

Rearrangements of the aminoalkylation products of tetrahydro-2H-1,3-oxazine-2-thione

The nature of the compounds afforded by the rearrangement of the aminopropylation and aminoethylation products of tetrahydro-2H-1,3-oxazine-2-thione (I) has been investigated. In both instances compounds that can be considered to result from ring opening at either the C-O or C-S bond of a hypothetical bicyclic intermediate of structure IV were obtained. The compounds required for identification of the rearrangement products have been prepared by the reaction of the 2-methylthio derivatives of 2-thiazoline, 5,6-dihydro-4H-1,3-thiazine, and 5,6-dihydro-4H-1,3-oxazine with the appropriate hydroxyalkylamine or mercaptoalkylamine.     

Reduction products of 3(2H)-cinnolinones

Reduction of 3(2H)-cinnolinone with zinc and ammonium hydroxide forms 1,4-dihydro-3(2H)-cinnolinone which rapidly rearranges to 1-amino-2-indolinone (1-aminooxindole) in acid solution. 1,4-Dihydro-2-methyl-3(2H)-cinnolinone is formed from 2-methyl-3(2H)-cinnolinone under the same conditions, but its rearrangement to 1-(N-methylamino)-2-indolinone (1-(N-methylamino)oxindole) in acid solution is much slower.     

Synthesis of phenyl-substituted 2H-3,4-dihydro-3-aminomethyl-1,4-benzoxazines. Intermediates for 1H-2,3,3a,4-tetrahydroimidazo[5,1-c][1,4]benzoxazin-1-one derivatives. Part II

The synthesis of 2H-3, 4-dihydro-3-aminomethyl-1, 4-benzoxazines substituted by one phenyl group in the 2, 3 or α-position is reported. The two diastereoisomers of the 2-phenyl-derivative were independently synthesized from ethyl trans-3-phenylglycidate by a stereospecific route. A previous attempt at the synthesis of these same compounds gave rise to an unexpected aliphatic-aromatic ketone rearrangement.     

Stereospecific synthesis of new 5-substituted 6-methyl-4,5-dihydro-2H-pyridazin-3-ones. X-ray assignment study

Reaction of hydrazine hydrate with 4,5-dihydro-3H-4-acetyl furan-2-ones I led to ring opening and rearrangement into 6-methyl-4,5-dihydro-2H-pyridazin-3-ones II ( 1–20 ), the structure of which was determined by spectroscopic methods (ir, ¹H and ¹³C nmr). An X-ray crystal structure study of compound 2 supports the assignment of configuration erythro (5RS, 7SR) for pyridazinones II. Stereochemical courses of this new synthetic route are discussed.     

Reaction of 4,5-diaminopyrimidine and ethyl acetoacetate: Synthesis and chemistry of isomeric dihydropyrimido[4,5-b][1,4] diazepinones

Depending upon reaction conditions, 4,5-diaminopyrimidine and acetoacetic ester gave a variety of condensation products, including the two isomeric dihydropyrimido[4,5-b][1,4]-diazepinones. Under conditions leading to bicyclic products, the formation of 1,5-dihydro-4-methyl-2H-pyrimido[4,5-b][1,4]diazepin-2-one ( 2 ) was strongly favored. The isomeric 3,5-dihydro-2-methyl-4H-4-one compound ( 4 ) was best obtained by cyclization of ethyl 3-(4-amino-5-pyrimidylamino)crotonate ( 3 ) under base catalysis. Thermal rearrangement of 2 and 4 proceeded, in each instance, with loss of the isopropenyl moiety and gave 8-purinone. Compound 4 underwent ring contraction under the influence of alkoxide to yield a product which was shown to be the 7-isopropenyl-8-purinone ( 6 ).     

A facile and novel synthesis of 1,6-naphthyridin-2(1H)-ones

A new and convenient procedure for the synthesis of 1,6-naphthyridin-2(1H)-ones and their derivatives is described. In the first scheme 5-acetyl-6-[2-(dimethylamino)ethenyl]-1,2-dihydro-2-oxo-3-pyridinecarbonitrile ( 4 ) obtained by the reaction of N,N-dimethylformamide dimethyl acetal with 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile ( 3 ) was cyclized to 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile ( 5 ) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5-methyl-1,6-naphthyridin-2(1H)-one ( 8 ) and its dimer 9 . Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one ( 12 ) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one ( 13 ). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5-acyl(aroyl)-6-methyl-2(1H)-pyridinones ( 21 ) which in turn were treated with Bredereck's reagent to produce 5-acyl(aroyl)-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinones ( 22 ). Treatment of 22 with ammonium acetate led to the formation of 1,6-naphthyridin-2(1H)-ones 23 .     

Ring-transformation reactions of 5-hydroxy-2-oxabicyclo[3.2.0]-heptan-4-ones and 5-hydroxy-2-oxabicyclo[3.2.0]hept-6-en-4-ones

Dehydrochlorination of chlorinated 5-hydroxy-2-oxabicyclo[3.2.0]heptan-4-ones, 3a-c, which were obtained from the photo[2+2]cycloadditions between 4-hydroxy-3(2H)-furanone 1 and chloroethylenes, with triethylamine gave 2-ethenyl-3(2H)-furanones 4a,b or 2-(2-cyanoethyl)-3(2H)-furanone 4c. 2-Oxa-bicyclo[3.2.0]hept-6-en-4-ones 7 being [2+2]cycloadducts between 1 and acetylenes gave 2,3-dihydro-3-oxooxepin derivatives 8 by electrocyclic rearrangement.     

2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones

A novel method for synthesis of 2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones by condensation of 3-R-4,5-dihydro-1H-1,2,4-triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl chlorides is proposed.     

A Novel Approach to 2,2-Disubstituted 1,2-Dihydro-4-phenylquinolines

The reaction of 2-(1-phenylvinyl)aniline and 4-chloro-2-(1-phenylvinyl)aniline with acetophenone derivatives, 1-(naphthalen-1-yl)ethanone and 1-(furan-2-yl)ethanone in toluene at 110–115° with toluene-4-sulfonic acid as a catalyst leads in good-to-excellent yields to the 2,2-disubstituted 1,2-dihydro-4-phenyl-quinolines 1–18 (Scheme 1, Table). The structure of the new racemic 1,2-dihydroquinolines 1–18 is determined by NMR spectroscopy. A reaction mechanism proceeding via a 6π-electrocyclic rearrangement of 2-(1-phenylvinyl)anils 19 as the key step is proposed for the formation of these compounds (Scheme 1). The scope and limitations of the novel methods are discussed (Scheme 2).     

Fries rearrangement of methoxyphenyl 3-methylbut-2-enoates

Fries rearrangement of 2-, 3- and 4-methoxyphenyl 3-methylbut-2-enoates 3-5 in methanesulfonic acid, polyphosphoric acid, aluminum chloride and under photochemical conditions have been studied. The outcome of the reactions was determined by the substitution pattern in the starting products and the reaction conditions used. Under Lewis acid catalysis, acylation accounted for the major components of the reaction mixtures, leading to the formation of indanones and 2,3-dihydro-4H-1-benzopyran-4-ones respectively in the case of o- and m-esters 3 and 5 , whereas alkylation to afford dihydrocoumarins was the favored path for p-ester 5. On the other hand, o-acylation was in all cases the major reaction course in the photochemical rearrangement.