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 and biological evaluation of 5-substituted-4-nitroimidazole ribonucleosides

The imidazole nucleosides, 4(5)-bromo-5(4)-nitro-1-β-D-ribofuranosylimidazoles, have been prepared via glycosylation of the trimethylsilylated aglycone, 4(5)-bromo-5(4)-nitroimidazole, with tetra-O-acetyl-β-D-ribo-furanose followed by removal of the acetyl protecting groups. The 5-bromo-4-nitro-1-β-D-ribofuranosylimidazole nucleoside was acetonated to produce 5-bromo-4-nitro-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-imidazole which was cyclized to provide the corresponding anhydronucleoside 5,5′-anhydro-4-nitro-5-oxo-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole. Sodium hydrosulfide treatment of 5-bromo-4-nitroimidazole nucleoside provided 5-mercapto-4-nitro-1-β-D-ribofuranosylimidazole 5-sodium salt which was alkylated with E-1,5-diiodopent-1-ene to yield 5-(E-1-iodo-1-penten-5-yl)thio-4-nitro-1-β-D-ribofuranosylimidazole. The corresponding iodine-125-labeled compound was prepared similarly using radiolabeled diiodopentene. The 5-bromo-4-nitroimidazole, 5-mercapto-4-nitroimidazole, and 5-iodopentenylthio-4-nitroimidazole nucleosides were cytotoxic to Molt-3 cells in vitro at concentrations higher than 10 μg/mL. The radiolabeled 5-iodopentenylthio-4-nitroimidazole nucleoside showed 2-fold higher uptake in a rapidly growing tumor as compared to uptake in a relatively slower growing tumor in mice.     

Pyrimidine derivatives. VI. Synthesis of mono-, di-, tri-, and tetrabromo-substituted pyrimidine derivatives

The following bromo-2,4(1H,3H)-pyrimidinediones possessing a bromo substituent at the 5-position and side chains at the 1- and 6-positions were prepared. The three types of mono-bromo derivatives are: 1-(bromoalkyl)-3,6-dimethyl- 3a-d , 5-bromo-3,6-dimethyl-1-(hydroxyalkyl)- 4a-d , and 1-(acetoxyalkyl)-5-bromo-3,6-dimethyl-2,4(1H,3H)-pyrimidinediones 11a-d . The three types of dibromo derivatives are: 5-bromo-1-(bromoalkyl)-3,6-dimethyl- Sa-d , 1-(acetoxyalkyl)-5-bromo-6-bromomethyl- 8a, 8c , and 8d , and 5-bromo-6-bromomethyl 1-(hydroxyalkyl)-2,4(1H,3H)-pyrimidinediones 9a, 9c , and 9d . Likewise one group of tribromo and one group of tetrabromo derivatives are: 5-bromo-1-(bromoalkyl)-6-bromomethyl -7a-d and 5-bromo-1-(bromoalkyl)-6-dibromomethyl-2,4(1H,3H)-pyrimidinediones 6a-d .     

Effect of methyl substituents on the NMR spectra of aromatic protons of some nitrobenzene derivatives

Proton NMR spectra were recorded and analysed for 1-bromo-4-nitrobenzene, 2-bromo-5-nitroluene, 3-bromo-6-nitrotoluene and 2-bromo-5-nitro-p-xylene, as well as for the corresponding compounds having p-CH₃C₆H₄S in place of Br. Chemical shifts and coupling constants generally agree with expected values; however, a deshielding effect of the methyl group on aromatic protons was observed in one case.     

Brominated trimetrexate analogues as inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase

Five previously undescribed trimetrexate analogues with bulky 2′-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,l-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile ( 15 ) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile ( 16 ). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine ( 8a ) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2,3-d]pyrimidine ( 12 ) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)-5-chloro-quinazoline ( 9a ), 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 10 ), and 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 11 ). Enzyme inhibition assays revealed that space-filling 2′-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3′,4′,5′-trimethoxyphenyl side chain and a CH₂, CH₂CH₂, or CH₂NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.     

Regioselective arylation of 3-bromopyridine

The addition of aryl Grignard reagents to the 1-phenoxycarbonyl salt of 3-bromopyridine affords 2-aryl-5-bromo-1-phenoxycarbonyl-1,2-dihydropyridines and 4-aryl-3-bromo-1-phenoxycarbonyl-1,4-dihydropyridines. The crude dihydropyridines were aromatized with o-chloranil in refluxing toluene to give 4- and 6-aryl-3-bromopyridines. The regioselectivity of this two-step process, 6- vs. 4-substitution, was examined and found to be dependent upon the structure of the Grignard reagent. Unhindered aryl Grignard reagents, e.g., phenyl and 2-naphthyl, gave mainly 6-aryl-3-bromopyridines (49-52%) along with 9% of the 4-substituted isomer and less than 4% of the 2-aryl-3-bromopyridine. Hindered aryl Grignard reagents, e.g., o-tolyl and 1-naphthyl, are less regioselective. When a catalytic amount of cuprous iodide is present during the Grignard reaction, nearly exclusive 1,4-addition results. The crude 4-aryl-3-bromo-1,4-dihydropyridines were aromatized with p-chloranil to provide 4-aryl-3-bromopyridines in good yield and high isomeric purity. The sequential use of the cuprous iodide-catalyzed Grignard reaction and the “normal” Grignard reaction provided a regiospeci-fic synthesis of 3-bromo-6-(p-methoxyphenyl)-4-phenylpyridine from 3-bromopyridine.     

Synthesis of 1-{4a,6-dimethyl-4a,9a-dihydropyrano-[3,4-<Emphasis Type="Italic">b</Emphasis>]indol-9(1<Emphasis Type="Italic">H</Emphasis>)-yl}ethanone

Heating of the bromination product of 4-methyl-3,6-dihydro-2H-pyran with 4-toluidine or 2-bromo-4-methylamiline in triethylamine gave 4-methyl-N-(4-methylphenyl)- and N-(2-bromo-4-methylphenyl)-4-methyl-3,6-dihydro-2H-pyran-3-amines which were converted into the corresponding amides by reaction with bromo- or chloroacetyl chloride. 1-{4a,6-Dimethyl-4a,9a-dihydropyrano[3,4-b]indol-9(1H)-yl} ethanone was synthesized in good yield by heating N-(2-bromo-4-methylphenyl)-N-(4-methyl-3,6-dihydro-2Hpyran-3-yl)acetamide in boiling toluene in the presence of palladium(II) acetate, triphenylphosphine, copper(II) acetate, triethylamine, and potassium carbonate.     

Reactions of 3-isopropenyltropolones with bromine and N-bromosuccinimide: Formation of 8H-cyclohepta[b]furan-8-one derivatives

3-Isopropenyltropolones 1a-c were treated with bromine in carbon tetrachloride to give 3-methyl-8H-cyclohepta[b]furan-8-ones 2a-c and their corresponding 7-bromo-substituted compounds 3a-c , while reactions in acetic acid gave the bromo-substituted compounds 3a-c . On the other hand, bromination of 1a-c with N-bromosuccinimide afforded 7-bromo-3-(2-bromo-1-methylethenyl)tropolones 5a-c . The compound 2a was treated with bromine to give 2-bromo-3-methyl-8H-cyclohepta[b]furan-8-one ( 4 ). The tropolones 5a-c were heated in the presence of potassium carbonate to give the cyclized compounds 3a-c .     

Novel Copolymers of Styrene. 17. Ring-Trisubstituted Methyl 2-Cyano-3-Phenyl-2-Propenoates

Electrophilic trisubstituted ethylenes, ring-trisubstituted methyl 2-cyano-3-phenyl-2-propenoates, RPhCH = C(CN)CO₂CH₃ (where R is 2,4,6-trimethyl, 3,5-dimethoxy-4-hydroxy, 3,5-dimethyl-4-hydoxy, 3,4,5-trimethoxy, 2-bromo-3-hydroxy-4-methoxy, 5-bromo-2,3-dimethoxy, 5-bromo-2,4-dimethoxy, 6-bromo-3,4-dimethoxy were prepared and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-trisubstituted benzaldehydes and methyl cyanoacetate, and characterized by CHN analysis, IR, ¹H and ¹³C-NMR. All the ethylenes were copolymerized with styrene (M₁) in solution with radical initiation (ABCN) at 70°C. The compositions of the copolymers were calculated from nitrogen analysis and the structures were analyzed by IR, ¹H and ¹³C-NMR. The order of relative reactivity (1/r₁) for the monomers is 5-bromo-2,3-dimethoxy (2.69) > 3,4,5-trimethoxy (1.86) > 6-bromo-3,4-dimethoxy (0.84) > 5-bromo-2,4-dimethoxy (0.39) > 4-hydoxy-3,5-dimethyl (0.31) = 2-bromo-3-hydroxy-4-methoxy (0.31) > 3,5-dimethoxy-4-hydroxy (0.24) > 2,4,6-trimethyl (0.22). Relatively high T_g of the copolymers in comparison with that of polystyrene indicates a decrease in chain mobility of the copolymer due to the high dipolar character of the trisubstituted ethylene monomer unit. Decomposition of the copolymers in nitrogen occurred in two steps, first in the 200–500ºC range with residue (1–6% wt), which then decomposed in the 500–800ºC range.     

A reaction of 6-bromo-1,2-naphthoquinone with tri(<Emphasis Type="Italic">n</Emphasis>-butyl)phosphine: A convenient route to phosphorus-containing 1,2-naphthoquinones and 1,2-dihydroxynaphthalenes

A reaction of 6-bromo-1,2-naphthoquinone with tri(n-butyl)phosphine gave 2-hydroxy-4-tri(n-butyl)phosphonionaphth-1-olate (betaine with the P—C bond). When treated with bromine, this betaine changed into (6-bromo-1,2-dihydroxy-4-naphthyl)tri(n-butyl)phosphonium bromide and (6-bromo-1,2-dioxo-1,2-dihydro-4-naphthyl)tri(n-butyl)phosphonium bromide in the ratio ∼1: 1. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 534–536, March, 2007.     

Synthesis in the phenothiazine series

The corresponding amines were obtained by reduction of 1-nitro-3-bromophenothiazine and 2-bromo-4-nitrophenothiazine. 1-Amino-3-bromophenothiazine reacts with formic acid to give 4-bromoimidazo[4,5,1-k, l ]phenothiazine and with carbon disulfide to give 4-bromo-1,2-dihydroimidazo [4,5,1-k, l ]phenothiazine-1-thione. 4-Aminophenothiazine reacts with sulfur and carbon disulfide to give 2, 3-dihydrothiazolo[5,4-c]phenothiazine-2-thione.See [1] for communication XXXIV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 202–203, February, 1974.     

The syntheses and NMR spectra of the twelve isomeric thieno[b]fused naphthyridines

Through the use of Pd(0)-catalyzed couplings between 2-(2-trimethylstannyl-3-pyridyl)-1,3-dioxolane, 3-trimethylstannyl-2-pyridine carboxaldehyde, 3-trimethylstannyl-4-pyridine carboxaldehyde and 4-trimethyl-stannyl-3-pyridine carboxaldehyde with t-butyl-N-(3-bromo-2-thienyl)carbamate, t-butyl-N-(2-bromo-3-thienyl)carbamate and t-butyl-N-(4-bromo-3-thienyl)carbamate in N,N-dimethylformamide at 100°, using cupric oxide as a coreagent, all twelve isomeric thieno[b]naphthyridines have been synthesized in an one-pot procedure. A detailed study of the ¹H and ¹³C nmr spectra of these isomers has been undertaken.     

Benzofurans. Improved syntheses of bufuralol, 7-ethyl-2-(2-tert-butylamino-1-hydroxyethyl)benzofuran,and 1″-oxobufuralol, 7-acetyl-2-(2-tert-butylamino-1-hydroxyethyl)benzofuran

An improved laboratory scale synthesis of bufuralol ( 1 ) and 1″-oxobufuralol ( 4 ) was accomplished. The intermediate benzofurans were prepared via aromatization of 2,3-dihydrobenzofurans or by a one-step acidcatalyzed cyclization from 2,2-diethoxyethyl 4-bromo-6-ethyl-2-formylphenyl ether ( 23 ). Base-catalyzed cyclization of 3-(5-bromo-3-ethyl-2-hydroxyphenyl)-1.2-epoxypropane ( 16 ) provided the key intermediate, 5-bromo-7-ethyl-2-hydroxymethyl-2,3-dihydrobenzofuran ( 17 ). Selective functionalization of the C-2 and C-7 positions of the benzofuran ring system was accomplished to afford both 1 and 4 .     

Studies on Pyrimidines: Synthesis of Pyrimidine-Annelated Heterocycles from 5-Amino-6-cyclohex-2-enyl-1, 3-dimethyl-uracil

Summary.  Treatment of 5-amino-6-cyclohex-2-enyl-1, 3-dimethyl-uracil with pyridinium hydrotribromide or hexamethylenetetrammonium hydrotribromide furnished the corresponding linear heterocyclic 6-bromo-1, 3-dimethylhexahydroindolo[3,2-d]pyrimidine-2, 4-diones in 90% yield. Reaction of the same educt with molecular bromine in chloroform afforded the bicyclic 9-bromo-1, 3-dimethylhexahydrobicyclo[3.3.1]indolo[3,2-d]pyrimidine-2, 4-diones in 85% yield. Upon treatment of the above substrate with cold concentrated sulfuric acid, a mixture of 1, 3-dimethylhexahydro-indolo[3, 2-d]pyrimidine-2, 4-dione (28%) and 1, 3-dimethylhexahydrobicyclo[3.3.1]indolo[3, 2-d]pyrimidine-2, 4-dione (60%) was obtained. Received August 4, 2000. Accepted (revised) November 15, 2000     

Improved syntheses of thieno[2,3-b]- and [3,2-b]-fused naphthyridines

The preparation of eight isomeric thieno[2,3-b]- and [3,2-b]-fused naphthyridines [1] was improved through the Pd(0) catalyzed cross-coupling of 3-formyl-4-iodopyridine, 2-formyl-3-iodopyridine, 3-bromo-4-formylpyridine and 2-bromo-3-formylpyridine with t-butyl N-(2-trimethylstannyl-3-thienyl)car-bamate and t-butyl N-(3-trimethylstanny-2-thienyl)carbamate.     

Zur Synthese sulfonierter Derivate von 2-Fluoranilin

Syntheses of Sulfonated Derivatives of 2-Fluoroaniline Synthesis of 4-amino-3-fluorobenzenesulfonic acid ( 3 ) was achieved in two ways: reaction of 2-fluoroaniline ( 1 ) with amidosulfonic acid and by first conventionally converting 4-nitro-3-fluoroaniline ( 8 ) to 4-nitro-3-fluorobenzenesulfonyl chloride ( 9 ) followed subsequently by hydrolysis to 3-fluoro-4-nitrobenzenesulfonic acid ( 10 ) and reduction. Hydrogenolysis of 3 gave sulfanilic acid ( 7 ). Both, sulfonation of fluorobenzene ( 6 ) to 4-fluorobenzenesulfonic acid ( 11 ) followed by nitration and sulfonation of 1-fluoro-2-nitrobenzene ( 12 ) led to 4-fluoro-3-nitrobenzenesulfonic acid ( 13 ). Reduction of 13 gave the isomeric 3-amino-4-fluorobenzenesulfonic acid ( 4 ), which was also obtained both by sulfonation of 1 and by sulfonation of o-fluoroacetanilide ( 14 ) followed by hydrolysis. Selective hydrogenolyses of 2-amino-5-bromo-3-fluorobenzenesulfonic acid ( 15 ), prepared by reaction of 4-bromo-2-fluoroaniline ( 16 ) with amidosulfonic acid, and of 4-amino-2-bromo-5-fluorobenzenesulfonic acid ( 20 ), obtained by sulfonation of 5-bromo-2-fluoroaniline ( 19 ) yielded the isomers 2-amino-3-fluorobenzenesulfonic acid ( 5 ) and 3 , respectively. The fourth isomer, 3-amino-2-fluorobenzenesulfonic acid ( 2 ), was synthesized by sulfur dioxide treatment of the diazonium chloride derived from 2-fluoro-3-nitroaniline ( 21 ) to 2-fluoro-3-nitrobenzenesulfonyl chloride ( 22 ), followed by hydrolysis to 2-fluoro-3-nitrobenzenesulfonic acid ( 23 ) and final Béchamp-reduction.     

Reaction of Zinc Enolates of Alkyl Esters of Substituted 4-Bromo-3-Oxoalkanoic Acids with Aldehydes

Zinc enolates formed from ethyl 4-bromo-2,2,4-trimethyl-3-oxopentanoate react under the conditions of one- of two-stage synthesis with aliphatic, unsaturated, or aromatic aldehydes to form 6-R-2,2,4,4-tetramethyl-2,3,5,6-tetrahydropyran-2,4-diones. Zinc enolates obtained from ethyl 4-bromo-2,2-dimethyl-3-oxopentanoate, -hexanoate, and -2,2,5-trimethyl-3-oxohexanoate under the similar conditions react with aliphatic or aromatic aldehydes to give mainly 5-R¹-6-R²-3,3-dimethyl-2,3,5,6-tetrahydropyran-2,4-diones as E or Z isomers or their mixtures. Zinc enolates generated from the ethyl 4-bromo-2,2-diethyl- or 2-benzyl-2-ethyl-3-oxobutanoates react with aromatic aldehydes to give ethyl 5-R-2-R-2-ethyl-3-oxo-4-pentenoates as E isomers.     

Cinnoline chemistry. XIV. 3-cyclohexylcinnolines

The synthesis of 3-cyclohexyl-6,7-dimethoxy-1H-4-cinnolone ( 4 ), 4-chloro-3-cyclohexyl-6,7-dimethoxycinnoline ( 5 ) and 8-bromo-3-cyclohexyl-6,7-dimethoxy-1H-4-cinnolone ( 6 ) are reported.     

Investigations in the field of benzoxa- zines. 15*. Tandem heterocyclizations with the participion of 2-formylbenzoic acid. The synthesis of isoindolo[1,2-<Emphasis Type="Italic">b</Emphasis>][1, 3]- and -[2,1-<Emphasis Type="Italic">a</Emphasis>][1, 3]benzoxazinones

Single stage reactions of 2-formylbenzoic acids with substituted 2-(1-aminoalkyl)phenols and 2-amino-phenylcarbinols give a novel series of isomeric isoindolobenzoxazinones. X-ray analysis was used to study the molecular structure of 9-bromo-5,5-diphenyl-5H-isoindolo[2,1-a][1, 3]benzoxazin-11(6aH)-one and 2-bromo-8,10-dimethyl-10H-isoindolo[1,2-b][1, 3]-benzoxazin-12(4bH)-one.     

Syntheses of various 5-(bromoaryl)-substituted uracils

The Suzuki Pd(0)-catalyzed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium, previously further developed by us, has been used for regioselective preparation of 5-(2′-bromo-5′-furyl)-, 5-(2′-bromo-4′-furyl)-, 5-(2′-bromo-5′-thienyl)-, 5-(2′-bromo-4′-thienyl)-, 5-(4′-bromo-2′-thiazolyl)-, 5-(3′-bromophenyl)-, 5-(6′-bromo-2′-pyridyl)- and 5-(4′-bromo-2′-pyrimidyl)-substituted 2,4-di-t-butoxypyrimidines. In the coupling between 2,4-di-t-butoxy-5-pyrimidineboronic acid and the nine different aryl dibromides that were tried as coupling partners, only the 2,4- and 2,5-dibromothiazoles did not give satisfactory yields, 15% and 0%, respectively. The other seven aryl dibromides gave the desired 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 58-89% yield. Attempts to synthesise 2,4-di-t-butoxy-5-(2′-bromo-4′-thienyl)pyrimidine from 2-bromo-4-iodothiophene failed. Dealkylation of the 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 2.5 M hydrochloric acid gave the corresponding 5-(bromoaryl)uracils in almost quantitative yields.