Reactions ofN-methoxydiazen-N′-oxidoacetic acid derivatives with electrophilic reagents

Bromination, methylation, and nitration ofN-methoxydiazen-N′-oxidoacetic acid derivatives were investigated. The results of the reactions depended significantly on both the type of the starting compound and the electrophilic reagent.     

Synthesis and properties of water-soluble 2-aminomethylidene derivatives of 1,3-dicarbonyl compounds

A series of [(2-dimethylamino)ethylamino]methylidene-1,3-dicarbonyl compounds was synthesized for the first time starting from the corresponding 2-ethoxymethylidene derivatives and N,N-dimethylethylenediamine. It was shown that further alkylation of aminomethylidene derivatives with methyl iodide occurs regioselectively at the tertiary nitrogen atom. Quaternization products obtained exhibit high corrosion inhibition of mild steel in hydrochloric acid medium.     

Progress in intermolecular and intramolecular reactions of thioamides with diazo compounds and azides

Reactions of thioamides with nitrogen-rich 1,3-dipoles, diazo compounds and azides, have been known for long time already. However in recent years introduction of catalysts of different types (rhodium-, ruthenium- and copper-containing and Lewis acids) as well as highly electrophilic sulfonyl azides, allowed the development of new methods for the synthesis of heterocycles, enamines and N-sulfonyl amidines. Moreover, a new methodology in organic synthesis, based on generation and subsequent transformations of α-diazocarbonyl compounds was created. Reactions of sulfonyl azides with thioamides undergo readily in mild conditions to produce different sorts of N-sulfonyl amidines and represent a new type of click-type processes. Most of the cited works were published in the current decade. Earlier seminal papers are also reviewed when they constitute the background for new synthetic methods which were developed further.     

N-amination of amino acids and its derivatives using N-Boc-O-tosyl hydroxylamine as an efficient NH-Boc transfer reagent: electrophilic amination

Terminal tert-butyloxycarbonyl (Boc) protected hydrazino acids, useful intermediates for modified peptides and biologically active heterocyclic derivatives, were synthesized by electrophilic amination methodology using N-Boc-O-tosyl hydroxylamine as an efficient NH-Boc transfer reagent. Also, we have demonstrated the conversion of other amino acid derivatives such as amino esters and amino alcohols into β-Boc-hydrazino derivatives using this reagent.     

Nucleophilic and electrophilic substitutions of difluoropropargyl bromides

Fundamental organic reactions like nucleophilic and electrophilic substitutions have seldom been studied on fluorinated propargyl or allenyl modules, when the carbon atom undergoing substitution is bonded to two fluorine atoms. Herein we report a practical synthesis of difluoropropargyl bromides from substituted acetylenes and dibromodifluorometane using a wide variety of alkyl, aryl or silyl substrates. The synthesis of O-, S- and carboxylic acid derivatives of difluoropropargyl bromide is also described. These compounds are suitable starting materials for the synthesis of electrophilically substituted difluoropropargyl derivatives via magnesium and fluoride promoted reactions. An indium-mediated reaction of silyldifluoropropargyl bromide, followed by electrophilic trapping with bromine led to a very useful bromoallene, which was then used in reactions with nucleophiles (C, O, N, P, S, Hal) to yield a de facto bimolecular nucleophilic substitution of a difluoropropargyl bromide.     

Antianexiety activity of pyridine derivatives synthesized from 2-chloro-6-hydrazino-isonicotinic acid hydrazide

A series of oxadiazole pyridine derivatives were synthesized by using 2-chloro-6-hydrazinoisonicotinic acid hydrazide as starting material. Treatment of the hydrazide with carbon disulfide to afford the oxadiazole derivative, which was treated with 5-methyl-2-furancarbaldehyde, formic acid, acetic acid/acetic anhydride, or phthalic anhydride to yield the corresponding pyridinodiazoles and on imide. Condensation of the hydrazide with p-fluorobenzaldehyde in ethanol or acetic acid in the presence of sodium acetate afforded hydrazone and oxadiazole derivatives, which were acetylated and cyclized with acetic anhydride to N-acetyloxadiazole derivatives. The hydrazone was treated with acetic acid in the presence of sodium acetate, or bromine water/sodium acetate to give on oxadiazole, while it was cyclized with chloroacetyl chloride in the presence of TEA to oxoazetidinaminoisonicotinamide. Finally, condensation of the hydrazide with acid anhydrides in refluxing glacial acetic acid afforded the corresponding bisimide derivatives. The pharmacological screening showed that many of these obtained compounds have good antianexiety activity comparable to diazepam^® as positive control.     

Catalyst-free Mannich-type reaction of 1-(N-acylamino)alkyltriphenylphosphonium salts with silyl enolates

A catalyst-free reaction of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates with silyl enolates was developed to prepare β-amino carbonyl compounds. The reported method is a useful approach for the preparation of N-protected β-amino esters as well as N-protected β-amino ketones. The starting 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates are readily available from N-protected α-amino acids. Therefore, the presented approach can be considered a new method for the α-homologation of N-protected α-amino acids to prepare β-amino acid derivatives.     

Synthesis of chiral linear and macrocyclic candidates: VI. Synthesis and antibacterial activity of some macrocyclic tripeptides and linear dipeptide Schiff bases

A series of macrocyclic tripeptides and linear dipeptide Schiff base derivatives has been synthesized using pyridine-3,5-dicarboxylic acid and L-phenyalanine methyl ester as starting materials. Treatment of pyridine-3,5-dicarbonyl dichloride with L-phenylalanine methyl ester gave N,N′-(pyridine-3,5-diyldicarbonyl)bis(L-phenyalanine methyl ester) which was hydrolyzed with 1N sodium hydroxide to the corresponding bis-acid, and the latter was cyclized with diamino acids to afford macrocyclic tripeptide derivatives. The reaction of the bis ester with hydrazine hydrate gave bis-hydrazide, which was condensed with aldehydes to obtain the corresponding Schiff base derivatives. The structures of the newly synthesized compounds were confirmed by IR, ¹H and ¹³C NMR, and MS spectral data and elemental analyses. The antimicrobial activities of some of the newly synthesized compounds were comparable with that of Streptomycin used as control.     

Dibutylphosphate (DBP) mediated synthesis of cyclic N,N′-disubstituted urea derivatives from amino esters: a comparative study

The N,N′-disubstituted urea derivatives such as amino acid hydantoins and dihydrouracil derivatives were prepared starting from natural and unnatural amino acid esters using dibutylphosphate (DBP). During the attempted synthesis of N-heterocycles with larger than six-membered rings containing the N,N′-disubstituted urea functionalities, three unexpected products namely squamolone, N-methyl pyrrolidine-2-one, and diketopiperazine were isolated.     

Synthesis and reactivity of 5-methylenehydantoins

5-Methylenehydantoin, as well as the N-mono- and N,N-di-protected derivatives, can be obtained by different synthetic routes. These compounds can undergo a large variety of reactions, such as Diels-Alder, epoxidation, methanol addition and conjugate addition reactions of different types of nucleophiles, including carbon (cyanide), nitrogen (piperidine) and sulfur (thiols, thioacetate) nucleophiles. The reactivity with electrophilic reagents, such as m-CPBA or methanol in acidic medium, and the need for Lewis acids to promote the conjugate addition reactions indicate that hydantoin is a poor electron-withdrawing group.     

Synthesis of adamantane functional derivatives basing on <Emphasis Type="Italic">N</Emphasis>-[(adamantan-1-yl)alkyl]acetamides

A series of new polyfunctional derivatives was synthesized with use of N-[(adamantan-1-yl)alkyl]-acetamides as a starting material. The reactions were carried out in acid media. The obtained compounds could be considered as a building blocks for the synthesis of conformationally restricted peptidomimetics.     

Microwave-mediated intramolecular Diels-Alder cyclization of biodihydroxylated benzoic acid derivatives

The synthetic utility of biodihydroxylated benzoic acid derivatives for the construction of bridge bicyclo scaffolds was investigated. Biodihydroxylation of benzoic acid using Ralstonia eutropha B9 gave (1S,2R)-1,2-dihydroxycyclohexa-3,5-diene-1-carboxylic acid (DCD) in high optical purity (>95% ee). Protection of the intermediate and subsequent functional group transformation gave the required cyclization precursors in moderate to excellent overall yields. Subsequent intramolecular Diels-Alder cyclization of biodihydroxylated benzoic acid derivatives was carried out using either thermal or microwave conditions. Enantiomerically pure products with five chiral centers were obtained in 4-6 steps from achiral starting material.     

Superactivity and dual reactivity of the system N-iodosuccinimide-H2SO4 in the iodination of deactivated arenes

Dissolution of N-iodosuccinimide in sulfuric acid gives rise to electrophilic iodine-containing species which are capable of successfully iodinating aromatic compounds with electron-withdrawing substituents in the temperature range from 0 to 20°C. The iodination in sulfuric acid is effected by both protonated N-iodosuccinimide and IOS(O)(OH⁺)OH intermediate.     

Poly(N-bromoacrylamide): an efficient and useful catalyst for the protection of carbonyl compounds as dithiolanes, dithianes and oxathiolanes under solvent-free and microwave conditions

Poly(N-bromoacrylamide) (PNBA) was prepared and used as a heterogeneous electrophilic catalyst under solvent-free and microwave conditions for the mild and efficient protection of carbonyl compounds as their dithiolane, dithiane and oxathiolane derivatives with 1,2-ethanedithiol, 1,3-propanedithiol and 2-mercaptoethanol, respectively in good to excellent yields. This method is simple, efficient and straightforward for synthesis of 1,3-oxathiolanes, 1,3-dithiolanes and 1,3-dithianes from carbonyl compounds. The catalyst is recoverable and reusable.     

Alkenylation of arylamines and <Emphasis Type="Italic">N</Emphasis>-arylacetamides with acetylene compounds in superacids

Vinyl type cations generated in superacid HSO₃F by the protonation of the triple bond of acetylene compounds efficiently react with arylammonium ions and N-arylacetamides yielding alkenylation products of the aromatic rings in the given amino derivatives. The regio-and stereoselectivity of electrophilic aromatic substitution was investigated involving vinyl type cations and arylammonium ions or N-arylacetamides in HSO₃F.     

High regioselectivity in electrochemical α-methoxylation of N-protected cyclic amines

N-Protecting groups of α-substituted cyclic amines strongly affected the regioselectivity in electrochemical methoxylation of these compounds. Namely, N-acyl derivatives were transformed into α′-methoxylated compounds, while N-cyano derivatives changed into α-methoxylated derivatives. Furthermore, Lewis acid catalyzed nucleophilic substitution of the α-methoxylated compounds protected with cyano group afforded α,α-disubstituted cyclic amines.     

Mechanism of the NCA polymerization. VI. Investigations on cocatalysts of the base-initiated NCA polymerization

The triethylamine-initiated polymerization of glycine-NCA [N-carboxylic acid anhydrides (oxazolidine-2,5-diones)], L -alanine-NCA, and sarcosine-NCA, as well as the pyridine-initiated polymerization of sarcosine-NCA, were carried out in the presence of potential cocatalysts. The 11 electrophilic reagents tested in this work can be divided into two classes: N-acyllactams and similar compounds, which are less reactive than the monomers and have no influence on the polymerization; and isocyanates and N-acyl-NCAs or -NTAs [N-thiocarboxylic acid anhydrides (thiazolldine-2,5-diones)], which are more electrophilic than the monomers and behave as cocatalysts in the case of glycine-NCA and alanine-NCA, since their base-initiated polymerization proceeds via the attack of NCA anions on the electrophilic N-acyl NCA chain and (“activated monomer mechanism”). In the case of sarcosine-NCA, however, the propagation involves a nucleophilic chain end (“carbamate mechanism”) and the strong electrophilic reagents behave as inhibitors.     

Synthesis of (S)-5,6-dibromo-tryptophan derivatives as building blocks for peptide chemistry

5,6-Dibromo-tryptophan is an interesting amino acid whose derivatives and analogues are found in a variety of highly bioactive natural compounds. Notwithstanding its relevance no data concerning this compound are found in the literature. Here an efficient pathway for the synthesis of 5,6-dibromo-tryptophan derivatives is reported. The reaction is performed by using 6-Br-isatin as starting material. Selective bromination at position 5 was followed by BH₃ reduction of the intermediate α-keto-amide and alkylation with Ser-OH in Ac₂O/AcOH. Optical resolution was effected by enzymatic de-acetylation of the obtained racemic mixture. Finally, in situ N^α-Boc protection of the optically pure S form yielded the desired N^α-Boc-(S)-5,6-dibromo-tryptophan.     

Synthesis of N,N′-bis[4-(1H-1,2,3-triazol-1-yl)furazan-3-yl]-methylenediamine derivatives

[3+2] Cycloaddition of azide groups of N,N′-bis(4-azidofurazan-3-yl)methylenediamine to 1,3-dicarbonyl compounds and malonodinitrile was shown to proceed regioselectively with the formation of the corresponding N,N′-bis[4-(1H-1,2,3-triazol-1-yl)furazan-3-yl]methylenediamine derivatives. The reactions of N,N′-bis(4-azidofurazan-3-yl)methylenediamine with cyanoacetic acid ethyl ester and amide led to the formation of the product of transformation of the azide group in the starting compound to the amino groups.     

Trifluoromethyl-containing N-acylmethylenequinone imines as novel highly electrophilic agents

The strategy of searching for highly electrophilic agents in a class of chemically inert compounds - methylenequinone imines - was developed and successfully performed. The first representative of such electrophiles - N-acyl-α-methoxycarbonyl-α-trifluoromethyl-p-methylenequinone imine 6 - was synthesized. Its reactions with N-, O- and C-nucleophiles were investigated that gave various derivatives of α-trifluoromethyl-α-amino(oxy) acids as well as ß,ß,ß-trifluoropropionic acids. 3-Chloro-3-trifluoro-1,3-dihydroindol-2-ones were first obtained and their reactions with nucleophiles were studied with 1-aza-3-trifluoroindene-2-ones being formed as intermediates.