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In this paper, we describe a four step synthesis of 1,3-dioxo-1,3-dihydroisobenzofuran-4-carboxamides starting from (hetero)arylcarboxamides. These are first transformed to the corresponding acetamidines followed by condensation to substituted [(oxazol-4(5H)-ylidene)ethyl]benzamides, which are further derivatized to substituted [(oxazol-4(5H)-ylidene)allyl]benzamides. The latter compounds undergo a supposed [4 + 2] cycloaddition with maleic anhydride, leading to the final products.

Lipoxygenases metabolize polyunsaturated fatty acids into signalling molecules such as leukotrienes and lipoxins, which play a regulatory role in several inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and chronic bronchitis. Human 15-lipoxygenase-1 (15-LOX-1) is an important mammalian lipoxygenase and plays a crucial role in the biosynthesis of these inflammatory signalling molecules. New classes of inhibitors are needed to explore the lipoxygenases as therapeutic targets. Here, we present the first study that identifies ruthenium(II) (Ru(II)) complexes as novel inhibitors of 15-LOX-1. Our study includes two novel Ru(II) complexes (C1a and C1b), bearing the sulfur macrocycle [9]aneS3, S-bonded dimethylsulfoxide (dmso-S), and chelate N,N- or N,O-donor ligands which were characterised by high-resolution NMR spectroscopy, X-ray crystallography and other standard physicochemical methods. These novel complexes and previously described Ru(II) complexes with the general formula [(η6-p-cymene)RuCl(O,O-ligand)]Cl were tested for inhibition of 15-LOX-1. This enabled identification of Ru(II) complexes that inhibit 15-LOX-1 with a potency in low micromolar range. Enzyme kinetic analysis was also performed, suggesting uncompetitive inhibition.

Reactions of cyclic enaminones, derived from cyclic five- and six-membered 1,3-diones, and dimethyl acetylenedicarboxylate (DMAD) under microwave irradiation produced a mixture of two products: ring-expansion products as a result of a [2+2] cycloaddition and Michael adducts. Reaction between 4-(dimethylamino)-2H-chromen-2-one and DMAD leads to three products: 2-(4-(dimethylamino)-2-oxo-2H-chromen-3-yl)maleate as a Michael adduct, dimethyl 1-(dimethylamino)naphthalene-2,3-dicarboxylate as the product of the [2+2] cycloaddition followed by 6π disrotatory electrocyclization and elimination of CO2 and 4-(dimethylamino)naphthalene-1,2-dicarboxylate as the product of the [4+2] cycloaddition followed by elimination of CO2.

The human aldo–keto reductases (AKRs) from the 1C subfamily are important targets for the development of new drugs. In this study, we have investigated the possible interactions between the recombinant AKR1C enzymes AKR1C1–AKR1C3 and ruthenium(II) complexes; in particular, we were interested in the potential inhibitory actions. Five novel ruthenium complexes (1a, 1b, 2a, 2b, 2c), two precursor ruthenium compounds (P1, P2), and three ligands (a, b, c) were prepared and included in this study. Two different types of novel ruthenium(II) complexes were synthesized. First, bearing the sulphur macrocycle [9]aneS3, S-bonded dimethylsulphoxide (dmso-S), and an N,N-donor ligand, with the general formula of [Ru([9]aneS3)(dmso)(N,N-ligand)](PF6)2 (1a, 1b), and second, with the general formula of [(η6-p-cymene)RuCl(N,N-ligand)]Cl (2a, 2b, 2c). All of these synthesized compounds were characterized by high-resolution NMR spectroscopy, X-ray crystallography (compounds a, b, c, 1a, 1b) and other standard physicochemical methods. To evaluate the potential inhibitory actions of these compounds on the AKR1C enzymes, we followed enzymatically catalyzed oxidation of the substrate 1-acenaphthenol by NAD+ in the absence and presence of various micromolar concentrations of the individual compounds. Among 10 compounds, one ruthenium complex (2b) and two precursor ruthenium compounds (P1, P2) inhibited all three AKR1C enzymes, and one ruthenium complex (2a) inhibited only AKR1C3. Ligands a, b and c revealed no inhibition of the AKR1C enzymes. All four of the active compounds showed multiple binding with the AKR1C enzymes that was characterized by an initial instantaneous inhibition followed by a slow quasi-irreversible step. To the best of our knowledge, this is the first study that has examined interactions between these AKR1C enzymes and ruthenium(II) complexes.

Herein a simple one-pot metal-free synthesis of 2,4,5-trisubstituted pyridines and pyridine Noxides by [2+2] cycloaddition of enaminones, which are prepared in situ from alkyl, aryl and heteroaryl methyl ketones using N,N-dimethylformamide dimethyl acetal (DMFDMA), and propyne iminium salts as electron-poor acetylenes, is described.

Herein a simple one-pot metal-free synthesis of alkyl-, aryl-, heteroaryl- and alkoxycarbonyl substituted 1,3-bis(dimethylamino)benzene derivatives is described. The products were prepared from the corresponding methyl ketones or compounds with an α-methylene group in regard to the carbonyl group, using N,N-dimethylacetamide dimethyl acetal (DMADMA) as the reagent.

Replacement of the cis-Me group by CH2F in the imidazolidinone organocatalyst specified in the title (so-called McMillan generation-I catalyst) leads to reversal of the product configuration in the title reaction. The topicity reversal in the nucleophilic addition step must arise either from cis-addition with respect to the benzylic substituent of an (E)-iminium ion intermediate or from trans-addition to the corresponding (Z)-iminium ion. Mechanistic investigations have not provided evidence for either one of these two possibilities, so far.

The synthesis of U-shaped conformationally constrained analogues of peptides based on the 3-amino-2-oxo-1,5-diazabicyclo[3.3.0]octane-8-carboxylic acid scaffold was developed. [3+2] Cycloadditions of (1Z,4R*,5R*)-1-arylmethylidene-4-benzyloxycarbonylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to tert-butyl acrylate and tert-butyl methacrylate gave the corresponding racemic cycloadducts, in most cases as mixtures of isomers, which were separated by preparative chromatography. Selective deprotection of the C- and the N-terminal of these heterocyclic dipeptides followed by coupling with (S)-alanine derivatives and chromatographic separation furnished the non-racemic tripeptides as target compounds. The structures of racemic cycloadducts and non-racemic final products were determined by NMR spectroscopy and X-ray diffraction. The synthesized compounds were also evaluated for inhibition of MurD ligase and d -alanine: d -alanine ligase.

Substituted benzocyclobutenes were isolated from the reaction of substituted oxocycloocta-2,8-diene-1,2-dicarboxylates with DMAD which were themselves formed by the microwave assisted [2+2] cycloaddition of cyclic enaminones to dimethyl acetylenedicarboxylate. The high pressure hydrogenation of (1E,2Z)-dimethyl 3-(dimethylamino)-7-oxocycloocta-2,8-diene-1,2-dicarboxylate gave oxabicyclo[3.3.1]non-3-ene-2,3-dicarboxylates, while use of low pressure hydrogenation resulted in only the carbonyl group being reduced to give the corresponding hydroxyl derivative which was proposed as an intermediate of the oxabicyclo[3.3.1]nonanes formed using high pressure hydrogenation.

Herein a simple, metal-free synthesis of 2-alkyl-, 2-cycloalkyl-, 2-aryl-, and 2-heteroaryl-substituted pyridine 3,4-dicarboxylates and their N-oxides from the corresponding methyl ketones in good to excellent yield, demonstrated with 22 examples in each case, is described. The method complements the current coupling reactions of 2-heterocyclic organometallic reagents.

Ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl)carbamates 7 were prepared by the Michael addition of diethyl azodicarboxylate (3) to (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2) followed by substitution of the dimethylamino group with primary amines 5a–n to afford a mixture of (E) and (Z) diethyl 1-(1-(substituted)amino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxylates (6a–n), followed by cyclization to give final products 7a–n. The intermediate 6i was isolated and characterized and transformed into 7i. All imidazolones 7a–n were synthesized in one pot reaction sequences with individual reactions being very clean.

[3+2] Cycloadditions of (1Z,4R∗,5R∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a–e to methyl methacrylate gave the 1-CO2Me regioisomers 3/3′, exclusively, in 1–67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a–c gave the major (1R∗,3R∗,5R∗,6R∗)-isomers 3a–c, whilst ortho-disubstituted dipoles gave the major (1R∗,3S∗,5R∗,6R∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.

Microwave-assisted [2+2] cycloaddition of (E)-3-dimethylamino-1-heteroaryl-prop-2-en-1-ones to dimethyl acetylenedicarboxylates gives (2E,3E)-dimethyl-2-[(dimethylamino)methylene]-3-(substituted)succinates in 8–91% yield. In the case of a 4,5-dihydrothiazoline derivative, cycloaddition also took place at the endocyclic CN double bond.

Reactions of cyclic enaminones, derived from cyclic five- and six-membered 1,3-diones, and dimethyl acetylenedicarboxylate (DMAD) under microwave irradiation produced a mixture of two products: ring-expansion products as a result of a [2+2] cycloaddition and Michael adducts. Reaction between 4-(dimethylamino)-2H-chromen-2-one and DMAD leads to three products: 2-(4-(dimethylamino)-2-oxo-2H-chromen-3-yl)maleate as a Michael adduct, dimethyl 1-(dimethylamino)naphthalene-2,3-dicarboxylate as the product of the [2+2] cycloaddition followed by 6π disrotatory electrocyclization and elimination of CO2 and 4-(dimethylamino)naphthalene-1,2-dicarboxylate as the product of the [4+2] cycloaddition followed by elimination of CO2.

A simple, metal-free method for the synthesis of the title pyridines is developed, which complements the existing methods of 2-pyridine synthesis by coupling reactions of organometallic reagents.

The lithiation of 2-bromophenyloxiranes (I) followed by a reaction with enaminones (II) leads to diastereomeric isochromanes (III) and (IV), which are readily separable by column chromatography.

The reaction of ortho-lithiated aryloxiranes with various enaminones straightforwardly affords new functionalized isochromanes as mixtures of two epimeric stereoisomers in reasonable to very good yields (50–90%). The two diastereomers, which show a high structural variability, can be easily separated by column chromatography.

Herein a simple, metal-free synthesis of 2-alkyl-, 2-cycloalkyl-, 2-aryl-, and 2-heteroaryl-substituted pyridine 3,4-dicarboxylates and their N-oxides from the corresponding methyl ketones in good to excellent yield, demonstrated with 22 examples in each case, is described. The method complements the current coupling reactions of 2-heterocyclic organometallic reagents.

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.

Substrates (I) undergo a microwave-promoted cycloaddition with DMAD to give cyclobutene intermediates which afford the desired functionalized 1,3-dienones after ring opening.

Two new imidazo[1,2-a]pyridines, 8-hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid (4) and ethyl 8-hydroxyimidazo[1,2-a]pyridine-2-carboxylate (6) were prepared via cyclization of 2-aminopyridin-3-ol (1) with bromopyruvic acid (2) and ethyl bromopyruvate (3), respectively. 8-Hydroxyimidazo[l,2-a]-pyridine-2-carboxylic acid (4) was successfully coupled with various amino acid derivatives via its active ester intermediate into the corresponding amides 22-27. O-protected ethyl 8-hydroxyimidazo[l,2-a]pyridine-2-carboxylate 11 was transformed into its hydrazide 13, acyl azide 14, and amide 15 derivatives.