Synthesis and Identification of Epoxy Derivatives of 5-Methylhexahydroisoindole-1,3-dione and Biological Evaluation

Cyclic imides belong to a well-known class of organic compounds with various biological activities, promoting a great interest in compounds with this functional group. Due to the structural complexity of some molecules and their spectra, it is necessary to use several spectrometric methods associated with auxiliary tools, such as the theoretical calculation for the structural elucidation of complex structures. In this work, the synthesis of epoxy derivatives of 5-methylhexahydroisoindole-1,3-diones was carried out in five steps. Diels–Alder reaction of isoprene and maleic anhydride followed by reaction with m-anisidine afforded the amide (2). Esterification of amide (2) with methanol in the presence of sulfuric acid provided the ester (3) that cyclized in situ to give imides 4 and 4-ent. Epoxidation of 4 and 4-ent with meta-chloroperbenzoic acid (MCPBA) afforded 5a and 5b. The diastereomers were separated by silica gel flash column chromatography, and their structures were determined by analyses of the spectrometric methods. Their structures were confirmed by matching the calculated ¹H and ¹³C NMR chemical shifts of (5a and 5b) with the experimental data of the diastereomers using MAE, CP3, and DP4 statistical analyses. Biological assays were carried out to evaluate the potential herbicide activity of the imides. Compounds 5a and 5b inhibited root growth of the weed Bidens pilosa by more than 70% at all the concentrations evaluated.     

Unexpected reductive transformation of 1-substituted 5-hydroxy-4,5-diphenyl-1H-imidazol-2(5H)-ones and their cyclic analogs by the reaction with thiourea and hydrochloric acid

An unexpected reductive transformation of 1-substituted 5-hydroxy-4,5-diphenyl-1H-imidazol-2(5H)-ones (imidazolones) and their cyclic analogs to give 1-substituted 4,5-diphenyl-1H-imidazol-2(5H)-ones (imidazolinones) upon reaction with thiourea and hydrochloric acid was discovered.     

cis–trans Enantiomerism in the Diels–Alder cycloadducts of 6-arylfulvenes with maleic anhydride: resolution of the exo adducts via the N-((1S)-1-(naphth-1-yl)ethyl)imide derivatives: assignment of the absolute configurations based on the crystal structure of an imide diastereomer

A new case of the uncommon cis–trans enantiomerism is presented. The titled anhydride adducts were prepared in good yields by the known reaction of three 6-arylfulvenes with maleic anhydride (aryl = phenyl, p-tolyl and p-anisyl). The exo adducts were converted to the corresponding imides by reaction with (1S)-1-(naphth-1-yl)ethylamine in ∼80% yields, and the resulting diastereomeric imides separated by silica gel column chromatography. They were hydrolysed and recyclised to the chiral anhydrides, in ‘one-pot’ with 10% NaOH–EtOH, followed by treatment with 2 M HCl, in ∼40% yields. The titled anhydrides were thus obtained in homochiral form, in enantiomeric purities (generally) of ∼90% as indicated by chiral HPLC. The chiral anhydrides were also converted to the corresponding imides (presumably stereospecifically), by treatment with ammonia solution in excellent yields. The crystal structure of one of the above diastereomeric imides (derived from 6-phenylfulvene) was determined, and based on the known (S)-configuration of the naphthylethylamine moiety, the ‘configurations’ of the original anhydride adducts were assigned.     

Synthesis of pyridazino[4,5-b]indole derivatives from 2-(3-carboxy-1-methylindole)acetic acid anhydride

2-(3-Carboxy-1-methylindole)acetic acid anhydride ( 1 ) reacts with aryldiazonium salts to give 85–95% of the corresponding α-hydrazono anhydrides 2 . Treating 2 with boiling hydrazine hydrate in xylene, the respective 2-aryl-4-carbohydrazido-5-methyl-1-oxo-1,2-dihydro-5H/-pyridazino[4,5-b]indoles 3 were obtained (47–67%), and these compounds characterized as the respective benzylidene derivatives 4 . Compounds 2 react with amines (aniline, morpholine, piperidine) to give the respective 2-(3-carboxy-1-methylindole)aceta-mide 5 or the respective 2-aryl-4-carboxamido-5-methyl-5H-pyridazino[4,5-b]indole 6 , the product obtained depending on the structure of the aryl substituent. Boiling 2b (aryl = 4-chlorophenyl) with 5% sodium hydroxide gave (80%) 2-(3-carboxy-1-methylindole)acetic acid ( 7 ). Hydrolysis of 2b gave a mixture of 7 and 2-(3-carboxy-1-methylindolyl)-2-(4-chlorophenylhydrazono)acetic acid ( 8 ).     

Reactions of vinyl 2,3-epoxypropyl ethers with 4,5-dihydro-1H-pyrazoles

Reactions of vinyl 2,3-epoxypropyl ether and 2-(vinyloxy)ethyl 2,3-epoxypropyl ether with 4,5-dihydro-1H-pyrazoles give, respectively, 3-vinyloxy-1-(4,5-dihydro-1H-pyrazol-1-yl)propan-2-ols and 3-(2-vinyloxyethoxy)-1-(4,5-dihydro-1H-pyrazol-1-yl)propan-2-ols in 70–91% yield.     

Aza-claisen rearrangements in the 2-allyloxy substituted oxazole system

Thermolysis and photolysis of several 2-allyloxy substituted 4,5-diphenyloxazoles results in a sigmatropic reorganization to give substituted oxazolin-2-ones.     

Synthesis of some new spiroindoline derivatives incorporated with pyrazoloheterocycles

Indole-2,3-dione ( 1 ) was treated with malonic acid ( 2 ) in a mixture of ethanol/pyridine to afford 1-[3-(2-oxoindolinylidene)]acetic acid ( 3 ). Compound 3 reacted with thionyl chloride to give the corresponding acid chloride ( 4 ). The acid chloride 4 reacted with arenes in the presence of AlCl₃ to yield 3-(2-oxoindolinylidene)acetophenones 5a–c . Compounds 5a–c reacted with 3-methylpyrazolin-5-one derivatives 6a , b to give 3-aracyl-3-[4′-(3′-methylpyrazolin-5-onyl)]-indoline-2-one derivatives 7a–f . Compounds 7a–f were treated with phosphorus pentoxide in phosphoric acid, with ammonium acetate or methanolic methylamine and with phosphorus pentasulfide to give spiro[indoline-3,4′-(pyrazolo[4,5-b]pyran)]-2-ones 8a–f , spiro[indoline-3,4′-(pyrazolo[4,5-b]-dihydropyridine)]-2-ones 9a–f , 10a–f and spiro[indoline-3,4′-(pyrazolo[4,5-b]thiopyran)]-2-ones 10a–f , respectively. All of the synthesized spiroheterocycle derivatives were identified by conventional spectroscopic methods (IR, ¹H NMR) and elemental analyses. © John Wiley & Sons, Inc.     

Solid-phase synthesis of 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-thiones and 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-ones

An efficient approach for the synthesis of 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-thiones and 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-ones on solid phase has been developed. The reaction conditions were readily amenable and the products were obtained in good yields and purities after their cleavage from the resin.     

Synthesis and acid-catalyzed transformations of solvomercuration adducts of 2-nitrobenzylcyclopropane. First stable metalated 1-oxo-3,4-dihydro-1H-2,1-benzoxazinium ions

Sovomercuration adducts of 2-nitrobenzyl-, 2-nitro-4,5-(ethylenedioxy)benzyl-, and 4,5-dimethoxy-2-nitrobenzylcyclopropanes were synthesized. The adducts reacted with sulfuric, fluorosulfonic, or chlorosulfonic acid to give 3-(2-chloromercurio)ethyl-1-oxo-3,4-dihydro-1H-2,1-benzoxazinium ions whose stability depended on the nature of substituents in the aromatic ring. Unstable metalated 1-oxo-3,4-dihydro-1H-2,1-benzoxazinium ions underwent fast protodemercuration to form metal-free 3-ethyl-1-oxo-3,4-dihydro-1H-2,1-benzoxazinium ions. Stable analogs in the above acids did not change to an appreciable extent over a period of 48–72 h. Hydrolysis of stable metalated 1-oxo-1,3-dihydro-2,1-benzoxazolium ions afforded only 4-chloromercurio-1-(2-nitroaryl)butan-2-ol.     

Enzymatic resolution of (±)-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester and its transformations into polyfunctionalised amino acids and dipeptides

Enantiomerically pure (5R)-(?)-5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester was obtained via enzymatic resolution of the corresponding racemic mixture using a lipase from hog pancreas (PPL). The following reduction of the ester group to the corresponding alcohol and the oxidation of the latter led to (5R)-(?)-5-phenyl-4,5-dihydroisoxazole-3-carbaldehyde, and the reaction between this and Schöllkopf’s reagent, (2R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine, gave mixtures of adducts with a good syn/anti ratio. The steric configurations of the major diastereoisomer were assigned on the basis of spectroscopic data and X-ray analysis. The subsequent controlled hydrolysis of the pyrazine ring led to β-(5-phenyl-4,5-dihydroisoxazol-3-yl)-serine methyl esters and the corresponding dipeptides with (R)-valine. Finally, reductive cleavage of the 4,5-dihydroisoxazole ring under hydrolytic conditions made it possible to obtain the corresponding polyfunctionalised dipeptides.     

Alternate pathway for the click reaction of 2-(2-azidophenyl)-4,5-diaryloxazoles

The CuSO₄/ascorbate-mediated ‘click’ reaction of 2-(2-azidophenyl)-4,5-diaryloxazoles and arylacetylenes proceeded through an alternate pathway whereby reduction of the azide predominated over formation of the 1,2,3-triazole-forming cycloaddition. The unimolecular product, 2-(2-aminophenyl)-4,5-diphenyloxazole, was isolated which appears to be a formal reduction of the arylazide to the corresponding arylamine. A series of oxazoles which possessed various substituents (F, Cl, Br, OCH₃) on the 4,5-diaryl rings and having the 2-azido group on the 2-oxazolylphenyl position were submitted to the same ‘click’ conditions and gave the corresponding arylamine products (73–99%). The reaction appears to be specific toward the ortho-azido substitution of the polycyclic system, as the corresponding azidomethyl-substituted phenyl oxazoles do not give the ‘reduction’ products but gave the expected click products with the acetylenic co-reactants.     

Preparation of azidoaryl- and azidoalkyloxazoles for click chemistry

A series of azidoaryl- and azidoalkyl(diphenyl)oxazole scaffolds were warranted for biofilm inhibition studies. Cyclization of azidoaryl- or azidoalkyl esters of benzoin with ammonium acetate in acetic acid gives 2-azidoaryl- or 2-azidoalkyl-4,5-diphenyloxazoles. The azidoaryl esters are prepared from the corresponding azidocarboxylic acids/acid chlorides while the azidoalkyl esters are prepared from the corresponding haloalkyl esters.     

Cyclopolycondensation. XIII. New synthetic route to fully aromatic poly(heterocyclic imides) with alternating repeating units

Fully aromatic poly(heterocyclic imides) of high molecular weight were prepared by the cyclopolycondensation reactions of aromatic diamines with new monomer adducts prepared by condensing orthodisubstituted aromatic diamines with chloroformyl phthalic anhydrides. The low-temperature solution polymerization techniques yielded tractable poly(amic acid), which was converted to poly(heterocyclic imides) by heat treatment to effect cyclodehydration at 250–400°C under reduced pressure. In this way, the polyaromatic imideheterocycles such as poly(benzoxazinone imides), poly(benzoxazole imides), poly(benzimidazole imides) and poly(benzothiazole imides) were prepared, which have excellent processability and thermal stability both in nitrogen and in air. The poly(amic acids) are soluble in such organic polar solvents as N,N-dimethyl-acetamide, N-methylpyrrolidone, and dimethyl sulfoxide, and the films can be cast from the polymer solution of poly(amic acids) (η_inh = 0.8–1.8). The film is made tough by being heated in nitrogen or under reduced pressure to effect cyclodehydration at 300–400°C. The polymerization was carried out by first isolating the monomer adducts, followed by polymerization with aromatic diamines. On subsequently being heated, the open-chain precursor, poly(amic acid), undergoes cyclodehydration along the polymer chain, giving the thermally stable ordered copolymers of the corresponding heterocyclic imide structure.     

The synthesis and characterisation of N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides and related pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones as potential enantioselective organocatalysts

The acylation of substituted 2-aminopropanamides with (2S)-Boc-proline, (2S)-Cbz-proline and (2S)-Bn-proline was used to prepare substituted 1-protected N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (74-89%), whose subsequent deprotection gave N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (94-95%). The enantiomerically pure N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides obtained were tested as organocatalysts for the aldol reaction of cyclohexanone with 4-nitrobenzaldehyde, with yields ranging from 38% to 79% ee. The highest enantioselectivity (89% ee) was achieved by catalysis with N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide (methanol, l0% HCl). By the action of sodium methoxide, Boc-N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide was quantitatively cyclised to 2-(1-Boc-pyrrolidin-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one, which was accompanied by racemisation at the stereogenic centre of the proline skeleton. Alternatively, the substituted 4,4-dialkyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones were prepared by oxidation of 4,4-dialkyl-2-((2S)-1-Boc-pyrrolidin-2-yl)-4,5-dihydro-1H-imidazolidin-5-ones (54-69%). In an acid medium, 2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one and (4S)-4-isopropyl-4-methyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-one underwent racemisation. Conversely, the free base of (2S)-2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one very easily underwent oxidation to give the achiral 2-(4,5-dihydro-3H-pyrrol-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one.     

Synthesis of 2-hetarylimidazo[4,5-<Emphasis Type="Italic">d</Emphasis>]pyridazine derivatives

2-Chloropyridine-3,4-diamine reacted with hetarenecarboxylic acids (pyridine-2-, pyridine-3-, and pyridine-4-carboxylic acids and 6-oxo-1,6-dihydropyridazine-3-carboxylic acid) in polyphosphoric acid at 160–170°C to give the corresponding 2-hetarylimidazo[4,5-c]pyridin-4-ones. Nitration of the latter with a mixture of concentrated nitric and sulfuric acids led to the formation of 2-hetaryl-7-nitroimidazo[4,5-c]pyridin-4-ones which were converted into 2-hetaryl-7-methylimidazo[4,5-d]pyridazin-4-ones by the action of hydrazine hydrate at 140–150°C.     

Reaction of 3-(alken-1-yl)-4,5-dihydro-3H-pyrazoles with sodium nitrite in acetic acid

3-Vinyl-4,5-dihydro-3H-pyrazole reacted with sodium nitrite in acetic acid to give 3-vinyl-1-nitroso-4,5-dihydro-1H-pyrazole, whereas 3-isopropenyl-4,5-dihydro-3H-pyrazole under analogous conditions was unexpectedly converted into a nitro derivative, 3-(1-methyl-2-nitrovinyl)-4,5-dihydro-1H-pyrazole.     

Chemoselective ester/ether C–O cleavage of methyl anisates by aluminum triiodide

The aluminum triiodide mediated chemoselective ester/ether C–O cleavage of methyl anisates was investigated. o-Anisate undergoes ether cleavage at low temperatures in carbon disulfide, cyclohexane and acetonitrile. Further cleavage of the ester group occurs at elevated temperatures to afford salicylic acid. The cleavage of p-anisate is solvent-dependent. In cyclohexane, the ester and ether groups were cleaved non-selectively to give equimolar amounts of p-anisic acid and methyl p-hydroxybenzoate. The ester group was preferentially cleaved in acetonitrile, compared to ether group cleavage in carbon disulfide. The ester cleavage reaction was improved using pyridine as an acid scavenger additive. Reasons for the contrasting reactivity of anisates towards AlI₃ were explored, and the methods were applied to cleavage of the tert-butyl ester of acemetacin which gave different products under these conditions.     

Alkylation of 4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-2-thiol with iodomethylsilanes and -siloxanes

The alkylation of 4,5-dihydro-1H-imidazole-2-thiol with 1-iodomethyl(dimethyl)phenylsilane, 1-(iodomethyl)-1,1,3,3,3-pentamethyldisiloxane, and 1,3-bis(iodomethyl)-1,1,3,3-tetramethyldisiloxane involved iodine-catalyzed cleavage of the Si–C_sp ² and Si–O bonds with liberated (in situ) hydrogen iodide to afford 2-({[(4,5-dihydro-1H-imidazolium-2-ylsulfanyl)methyl]-1,1,3,3-tetramethyldisiloxanylmethyl}sulfanyl)-4,5-dihydro-1H-imidazolium di- and tetraiodides. Replacement of iodide ion in the products by triiodide gives new organosilicon ionic liquids with several charged fragments.     

Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acids—Scope and limitations of diazo and olefinic substrates

High enantioselectivities (94-96% ee) were obtained for the inverse electron-demand 1,3-dipolar cycloadditions between cyclohexyl vinyl ether and 2-benzopyrylium-4-olate generated via Rh₂(OAc)₄-catalyzed decomposition of o-methoxycarbonyl-α-diazoacetophenone. The reactions were effectively catalyzed by Eu(OTf)₃, Ho(OTf)₃, or Gd(OTf)₃ complexes (10 mol %) of chiral 2,6-bis[(4S,5S)-4,5-diphenyl-2-oxazolinyl]pyridine. The reactions with the other electron-rich dipolarophiles such as allyl alcohol, 2,3-dihydrofuran, and butyl-tert-butyldimethylsilylketene acetal showed moderate enanantioselectivities (60-73% ee). Good to high enantioselectivities (73-97% ee) were also obtained for the cycloadditions between 3-acyl-2-benzopyrylium-4-olates, generated from methyl 2-(2-diazo-1,3-dioxoalkyl)benzoates and butyl or cyclohexyl vinyl ethers, in the presence of binaphthyldiimine (BINIM)-Ni(II) complexes (10 mol %). Under similar conditions, the reaction between methyl 2-(2-diazo-1,3-dioxohexyl)benzoate and 2,3-dihydrofuran was highly endo-selective, and moderately enantioselective (70% ee). For the BINIM-Ni(II)-catalyzed reactions of cyclohexyl vinyl ether, the use of an epoxyindanone as the 3-acyl-2-benzopyrylium-4-olate precursor revealed that the chiral Lewis acid can function as a catalyst for asymmetric induction. The scope of the cyclic carbonyl ylides was extended to those generated from 1-diazo-2,5-pentanedione derivatives, which were reacted with butyl or TBS vinyl ether and catalyzed using the (4S,5S)-Pybox-4,5-Ph₂-Lu(OTf)₃ complex to give good levels of asymmetric inductions (75-84% ee).     

Synthesis of some new derivatives of 4-hydrazino-5H-pyridazino[4,5-b]indole

This paper describes the synthesis of 1-chloro-4-hydrazino-5H-pyridazino[4,5-b]indole ( 4 ) and some of the triazoles ( 6–8 ), tetrazoles ( 10–11 ), triazolotetrazoles ( 9 ) and bis-tetrazoles ( 12 ) derived from it. All of these were previously unknown compounds. Treating 1,4-dioxo-1,2,3,4-tetrahydro-5H-pyridazino[4,5-b]indole ( 1 ) with phosphorus oxychloride gave 1,4-dichloro-5H-pyridazino[4,5-b]indole ( 2 ), which reacts regioselectively with hydrazine to give compound 4 . The reactions of 4 with formic and acetic acids gave 6-chloro-11 H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles ( 6a-6b ), respectively. Reaction of compound 6a with hydrazine gave 6-hydrazino-11H-1,2,4-triazolo[4,3–6]-pyridazino[4,5,-b]indole ( 8 ). This with nitrous acid gave 6-azido-11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]-indole ( 9 ). Compound 4 reacted with nitrous acid to give 6-chloro-11H-tetrazolo[4,5-b]pyridazino[4,5-b]-indole ( 10 ), which gave 1,4-diazydo-5H-pyridazino[4,5-b]indole ( 12 ), through successive reactions with hydrazine and nitrous acid. All compounds were characterized by elemental analysis, ir and ¹H-nmr spectra.