Reactions of 3-chloro-6-hydrazinopyridazine with michael-retro-michael reagents

Although pyrazole formation results from treatment of 3-chloro-6-hydrazinopyridazine ( 2 ) with both ethoxymethylenemalononitrile and ethyl (ethoxymethylene)cyanoacetate, 6-chlorotriazolo[4,3-b]pyridazine ( 5 ) was produced (75% yield) when 2 was treated with diethyl ethoxymethylenemalonate. Treatment of 2 with diethyl acetylmalonate ( 8 ) gave both 6-chloro-3-methyltriazolo[4,3-b]pyridazine ( 10 ) and 5-hydroxy-3-methyl-1-(6-chloro-3-pyridazinyl)-1H-pyrazole-4-carboxylic acid ethyl ester ( 12 ). Pyrazole 12 was initially isolated as a salt of triazolopyridazine 10 .     

Synthese neuer Aryl-(3,-dichloro-4-pyridazinly)-ketone und ihre Reaktion mit N,N-Dinucleophilen

Synthesis of New Aryl (3,6-Dichloro-4-pyridazinyl) Ketones and their Reaction with N,N-Dinucleophiles The synthesis of the new aryl (3,6-dichloro-4-pyridazinyl) ketones 3a–e vïa Friedel-Crafts acylation of the aromatic compounds 2a–e with 3,6-dichloro-4-pyridazincarbonyl chloride (1) is described. The ketones 3a–e cyclized with N,N-dinucleophilic reagents to the 3-aryl-5-chloro-l H -pyrazolo[3,4-c]pyridazines 4a–d , and 3a–c are converted into the 3-aryl-5-chloro-l H -pyrazolo[3,4-c]pyridazin - l -ethanols 5a–c and to the hitherto unknown ring system of the 5-aryl-3-chloro-7,8-dihydro-9 H -pyridazino[3,4-e][1,4]diazepines ( 6a-c ).     

Nucleophilic substitution in 1-alkyl-4,5-dichloro-3-nitropyridazin-6-ones

Treatment of 1-alkyl-4,5-dichloro-3-nitropyridazin-6-one with C-nucleophiles and with ambident nucleophiles (2-azahetarylacetonitriles) leads to a selective substitution of a chorine atom by the quaternary carbon atom of the carbanion formed from a substituted acetonitrile. The pK_a of the CH-acid 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)malononitrile was determined by potentiometric titration. Reaction of 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)-2-hetarylacetonitriles with primary amines gives 6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-7-ones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 556–564, April, 2006.     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

Quinazolines and 1,4-benzodiazepines. XLVI. Photochemistry of nitrones and oxaziridines

The cyclic nitrones 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5a ) and 1,3-dihydro-7-methylthio-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5b ) are photoisomerized to readily isolable oxaziridines, 7-chloro-4,5-epoxy-5-phenyl-1,3,4–5-tetrahydro-2H-1,4-benzodiazepin-2-one ( 6a ) and 4,5-epoxy-5-phenyl-1,3,4,5-tetrahydro-7-methylthio-2H-1,4-benzo-diazepin-2-one ( 6b ). Oxaziridine 6b upon further irradiation gave ring expansion and ring contraction products, 4,6-dihydro-2-phenyl-9-methylthio-5H-1,3,6-benzoxadiazocin-5-one ( 7b ) and 4-benzoyl-3,4-dihydro-6-methylthioquinoxalin-2(1H)-one ( 8b ) respectively. The ring contraction product, 4-benzoyl-6-chloro-3,4-dihydroquinoxalin-2(1H)-one ( 8a ), was obtained from irradiation of oxaziridine 6a .     

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 .     

Über die Einwirkung von Ammoniak auf 5-Chlor-2-(N-methyl-jodmethansulfonamido)-benzophenon

Zusammenfassung 5-Chlor-2-(N-methyl-jodmethansulfonamido)-benzophenon (6 b) reagiert mit flüss. NH₃ zu 6-Chlor-4-hydroxy-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazin-2,2-dioxid (7), mit NH₃ in absol. Alkohol zu 6-Chlor-4-hydroxy-3-jod-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazin-2,2-dioxid (9). Der Mechanismus dieser Reaktionen wird diskutiert.

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The reaction of ammonia with 5-Chloro-2-(N-methyl-iodo-methanesulfonamido)-benzophenone

The reaction of 5-chloro-2-(N-methyl-jodomethanesulfon-amido)-benzophenone (6b) with liquid or absol. alcoholic ammonia leads to 6-chloro-4-hydroxy-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazine-2,2-dioxid (7) and 6-chloro-4-hydroxy-3-jodo-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazine-2,2-dioxid (9) resp. The mechanism of these reactions is discussed.

     

Synthesis of nucleoside analogs of 1,4-oxathiane, 1,4-dithiane,and 1,4-dioxane

The two regioisomers 6-chloro-9-(1, 4-oxathian-3-yl)-9H-purine ( 5 ) and 6-chloro-9-(1,4-oxathian-2-yl)-9H-purine ( 6 ) were obtained when 3-acetoxy-1,4-oxathiane ( 3 ) was subjected to the acid-catalyzed fusion procedure; compound 3 was prepared by a Pummerer reaction with 1,4-oxathiane 4-oxide ( 2 ). The nucleoside analog 6 could he converted into the adenine derivative 7 and 9-(1,4-oxathian-2-yl)-9H-purine-6(1H)thione ( 8 ). The following nucleoside analogs have also been synthesized: 6-chloro-9-(1,4-dithian-2-yl)-9H-purine ( 13 ), 9-(1,4-dithian-2-yl)adenine ( 14 ), 9-(1,4-dithian-2-yl)-9H-purine-6(1H)thione ( 15 ), and 6-chloro-9-(1,4-dioxan-2-yl)-9H-purine ( 18 ).     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

NMR study on the tautomeric equilibria between the hydrazone imine and diazenyl enamine forms in side chained quinoxalines: Solvent effects and temperature dependence

The reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoxaline 6 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazonium chloride gave 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)-ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8b , respectively, while the reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydrotetrazolo[1,5-a]quinoxaline 7 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazomum chloride provided 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9b , respectively. Compounds 8a,b and 9a,b showed the tautomeric equilibria between the hydrazone imine C and diazenyl enamine D forms in dimethyl sulfoxide and/or trifluoroacetic acid, and the effects of solvent and temperature on the tautomer ratios of C to D were studied by the nmr measurements in a series of mixed trifluoroacetic acid/dimethyl sulfoxide media (compounds 8a,b and 9a,b ) and at various temperatures (compounds 8a,b ).     

Synthesis of 4H-1,3,4-oxadiazino[5,6-b]quinoxalines from 2-substituted quinoxaline 4-oxides

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with acetic anhydride resulted in the intramolecular cyclization to give 8-chloro-2,4-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7a , while the reaction of compound 8 with acetic anhydride/pyridine or acetic anhydride/acetic acid afforded 3-(2,2-diacetyl-1-memymydrazmo)-7-chloro-2-oxo-1,2-dihydroquinoxaline 9 , effecting no intramolecular cyclization. The reaction of 2-(2-acetyl-1-methylhydrazino)-6-chloroquinoxaline 4-oxide 10a or 6-chloro-2-(1-methyl-2-trifluoroacetylhydrazino)quinoxaline 4-oxide 10b with phosphoryl chloride provided compound 7a or 8-chloro-4-memyl-2-trifluoromethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7b , respectively. The reaction of compound 7b with phosphorus pentasulfide gave 7-chloro-3-(1-methyl-2-trifluoroacetylhydrazino)-2-thioxo-1,2-dihydroquinoxaline 11 , whose dehydration with sulfuric acid in acetic acid afforded 8-chloro-4-methyl-2-trifluoromemyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 12 .     

Reaction of Polyhalo Semiquinoid Structures Originating from 4-Aroyl(arylsulfonyl)oximino-2,5-cyclohexadiene-1-ones with Arylsulfinic Acids

Stable semiquinoid structures, 4-aroyl(arylsulfonyl)oximino-2,6-dimethyl-5,6-dichloro-2-cyclohexen-1-ones, do not react with dialkyl phosphites, alcohols, tosylhydrazine, p-toluidine, and hydrazoic acid. In reactions with arylsulfinic acids occurs a nucleophilic substitution of chlorine at the sp ³-hybridized C⁵ carbon in the minor Z-isomer yielding 4-aroyl(arylsulfonyl)oximino-5-arylsulfonyl-2,6-dimethyl-6-chloro-2-cyclohexen-1-ones.     

Synthesis and structure determination of isomeric 7- and 8-chloro-1,5-benzodiazepine derivatives

Reaction of 4-chloro-1,2-benzenediamine with 3,3-dimercapto-1-phenyl-2-propen-1-one afforded, as expected, a mixture of 7-chloro and 8-chloro-1,3-dihydro-4-phenyl-2H-1,5-benzodiazepine-2-thione. After separation of the two components and further reaction, their structure was established by chemical degradation of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine to 5-chloro-1,3-dihydro-1-methyl-2H-benzimidazol-2-one. The structure was also confirmed by single X-ray analysis of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine.     

Unequivocal syntheses of 6-methyl- and 6-phenylisoxanthopterin

Although 6-methyl- ( 1 ) and 6-phenylisoxanthopterin ( 2 ) have previously been synthesized, the requirement of high purity necessary for immunological testing has necessitated our development of the first reported synthesis of these compounds by unequivocal methods. In the process of so doing four new pyrazines, ethyl 3-amino-5-chloro-6-methyl-2-pyrazinecarboxylate ( 11 ), N,N-dimethyl-N'-(6-chloro-3-cyano-5-phenylpyrazin-2-yl)methanimidamide ( 16 ), 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide ( 19 ), and ethyl 3-amino-5-chloro-6-phenyl-2-pyrazinecarboxylate ( 20 ) were synthesized. Four new pteridines, 7-methoxy-6-methyl-2,4-pteridinediamine ( 7 ), 7-methoxy-6-phenyl-2,4-pteridinediamine ( 17 ), 2-amino-7-ethoxy-6-methyl-4(3H)-pteridinone ( 12 ), and 2-amino-7-ethoxy-6-phenyl-4(3H)-pteridinone ( 21 ) have also been synthesized enroute to these isoxanthopterins.     

A convenient synthesis of novel pyridazino[3,4-b]quinoxaline and pyrazolo[3,4-b]quinoxaline utilizing 1,3-dipolar cycloaddition reaction

The reaction of 2,6-dichloroquinoxaline 4-oxide 4 with methylhydrazine gave 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5, whose reaction with dimethyl acetylenedicarboxylate or 2-chloroacrylonitrile resulted in the 1,3-dipolar cycloaddition reaction to afford 7-chloro-3,4-bismethoxycarbonyl-1-methyl-1,2-dihydropyridazino[3,4-b]quinoxaline 6 or 6-chloro-3-hydroxymethylene-1-methyl-2,3-dihydro-1H-pyrazolo[3,4-b] quinoxaline hydrochloride 7, respectively.     

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.     

Synthesis of 2′-deoxyribofuranosyl indole nucleosides related to the antibiotics SF-2140 and neosidomycin

The 2′-deoxyribofuranose analog of the naturally occurring antibiotics SF-2140 and neosidomycin were prepared by the direct glycosylation of the sodium salts of the appropriate indole derivatives, with 1-chloro-2- deoxy-3,5-di-O-p-toluoyl-α-D-erythropentofuranose ( 5 ). Thus, treatment of the sodium salt of 4-methoxy-1H- indol-3-ylacetonitrile ( 4a ) with 5 provided the blocked nucleoside, 4-methoxy-1-(2-deoxy-3,5-di-O-p-toluoyl-β- D-erythropentofuranosyl)-1H-indol-3-ylacetonitrile ( 6a ), which was treated with sodium methoxide to yield the SF-2140 analog, 4-methoxy-1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indol-3- ylacetonitrile ( 7a ). The neosidomycin analog ( 8 ) was prepared by treatment of the sodium salt of 1H-indol-3-ylacetonitrile ( 4b ) with 5 to obtain the blocked intermediate 1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythropentofuranosyl) ?1H-indol-3-ylace-tonitrile ( 6b ) followed by sodium methoxide treatment to give 1-(2-deoxy-β-D-erythropentofuranosyl)-1H- indol-3-ylacetonitrile ( 7b ) and finally conversion of the nitrile function of 7b to provide 1-(2-deoxy-β-D- erythropentofuranosyl)-1H-indol-3-ylacetamide ( 8 ). In a similar manner, indole ( 9a ) and several other substituted indoles including 1H-indole-4-carbonitrile ( 9b ), 4-nitro-1H-indole ( 9c ), 4-chloro-1H-indole-2-carboxamide ( 9d ) and 4-chloro-1H-indole-2-carbonitrile ( 9e ) were each glycosylated and deprotected to provide 1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole ( 11a ), 1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole-4- carbonitrile ( 11b ), 4-nitro-1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole ( 11c ), 4-chloro-1-(2-deoxy-β-D- erythropentofuranosyl)-1H-indole-2-carboxamide ( 11d ) and 4-chloro-1-(2-deoxy-β-D-erythropentofuranosyl)- 1H-indole-2-carbonitrile ( 11e ), respectively. The 2′-deoxyadenosine analog in the indole ring system was prepared for the first time by reduction of the nitro group of 11c using palladium on carbon thus providing 4-amino-1-(2-deoxy-β-D-erythropentofuranosyl)- 1H-indole ( 16 , 1,3,7-trideaza-2′-deoxyadenosine).     

Synthesis of NSC-341,964: An unexpected study on the stability of 2-aryl-4H-3,1-benzoxazin-4-ones

Resynthesis of NSC 341,964, which had been assigned structure 1 (1-[[3-(7-chloro-4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]methyl]pyridinium chloride) was approached via 7-chloro-2-(3-methylphenyl)-4H-3,1-benzoxazin-4-one ( 5 ) obtained from 3-methylbenzoyl chloride ( 2 ) and 2-amino-4-chlorobenzoic acid ( 3 ) followed by dehydration in acetic anhydride. Radical bromination provided 6 which with pyridine afforded the bromide analog 7 of 1 . Ion exchange, however, gave ring-opened benzoic acid 8 rather than 1 . The original sample of NSC 341,964 also proved to be ring-opened material. However, 7 upon standing exhibited slow hydrolysis to 8 so that the structure of the original NSC 341,964 remains uncertain. A more direct route to compound 8 is also described.     

Novel,racemic or nearly-racemic antibacterial bromo- and chloroquinols and γ-lactams of the verongiaquinol and the cavernicolin type from the marine sponge Aplysina (= Verongia) cavernicola

Butanolic extracts of the Mediterranean sponge Aplysina (= Verongia) cavernicola have given, by reverse-phase HPLC, the antibacterial quinols (±)-3-bromoverongiaquinol (= (±)-3-bromo-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1d) and (±)-3-bromo-5-chloroverongiaquinol (= (±)-3-bromo-5-chloro-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorohexadiene-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorocavernicolin (= 5-cloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 6) , the C(7)-epimerizing 7β-bromo-5-chlorocavernicolin (=7 β-bromo-5-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 4a and 7α-bromo-5-chlorocavernicolin (4b) , and the C(7)-epimerizing 5-bromo-7β-chlorocavernicolin ( = 5-bromo-7β-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 5a) and 5-bromo-7α-chlorocavernicolin (5b) . The latter four were isolated as mixtures of C(7)-epimerizing monoacetates 4a′/4b′ and 5a′/5b′. Both 1 and 1c proved to be racemic from NMR examination of their esterification products with (–)-methyl-oxyacetic acid, whilst 6 had a ca. 6% enantiomeric purity as shown by a ¹H-NMR study of its monoacetate 6′ in the presence of a chiral shift reagent. These chiroptical data of the first chiral quinols from the Verongida and of 6 suggest phenol oxidative routes from tyrosine precursors for their formation. In view of their bioactivities, 1d and 1c have been synthesized from (p-hydroxyphenyl)acetic acid byt phenol oxidative routes.     

Synthesis of 1, 5- and 1, 7-dichloro-9H-thioxanthen-9-ones

1, 5-Dichloro-9H-thioxanthen-9-one ( 2 ) was prepared by cyclization of 2-chloro-6-[(2-chlorophenyl)thio]-benzoic acid ( 10 ) obtained from 2-chloro-6-iodobenzoic acid ( 9 ) and 2-chlorobenzenethiol. Similarly, 1, 7-di-chloro-9H-thioxanthen-9-one ( 6 ) was prepared from 9 via 2-chloro-6-[(4-chlorophenyl)thio]benzoic acid ( 11 ). Compound 6 was also obtained by condensation of 2-chloro-6-mercaptobenzoic acid ( 12 ) with chlorobenzene in the presence of sulfuric acid.