A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction

The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na₂S₂O₄ in dioxane/water at reflux.     

Parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives

The parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives is described. The key intermediate 2,6-bis-aminopyridine-4-carboxylic acid methyl ester was synthesised in a two step procedure in 64% overall yield and elaborated to a variety of triazolopyridine-5-carboxylic acid methyl ester by selective pyridine-N-amination, condensation of the adduct with a wide selection of aldehydes and subsequent cyclisation and oxidation. The desired esters were obtained in yields up to 70%. The final transformation to the amide derivatives was accomplished by application of carefully optimised reaction conditions thus giving access to a library of total 500 triazolopyridine amide derivatives. Iterative synthetic cycles (12-48 library members each) allowing for maximal flexibility in chemistry and maximal efficiency in in vitro biological activity optimisation guided by molecular modelling efforts constitute a synergistic procedure for rapid lead optimisation.     

Catalytic Friedel–Crafts allylation using Zn(II) triflimidate

The activity of various metallic triflates and triflimidates in the Friedel–Crafts allylation of activated aromatic rings was examined. Zinc bis(trifluoromethylsulfonyl)amide was proved to be a good catalyst in the model reaction with anisole and prenyl acetate. The Friedel–Crafts allylation reaction of various aryl derivatives with allyl acetates was efficiently catalysed under mild conditions, using 3 mol% of Zn(NTf₂)₂ as the catalyst, without solvent, at 100 °C. The desired ortho and para mono-allylated products were selectively obtained in good yields. The para isomer was always favoured.     

Nickel complexes of chlorophyll derivatives

Nickel complexes of certain phorbine and amide derivatives of chlorophyll a were synthesized. Most of the chlorophyll a derivatives studied form nickel complexes when boiled in toluene with an equimolar amount of nickel acetylacetonate in high yield. The yields of the nickel complexes of the chlorophyll derivatives are determined by the stability of the starting ligand under the reaction conditions.     

Photometric determination of sulfanilic amide derivatives in drug formulaions and blood plasma

2,3,5,6-Tetrachloro-p-benzoquinone (TCPBQ) generated in the oxidation of sulfanilic acid amide derivatives was found to form a colored product with sodium diethyldithiocarbamate (DEDTC). The optimal conditions for the formation of this compound are determined. A possibility of using the oxidation reaction to TCPBQ followed by interaction with DEDTC as a versatile scheme for the photometric determination of sulfanilic amide derivatives in drug formulations and blood plasma was demonstrated.     

Copper-catalyzed domino reaction of carbodiimides and benzoic acid derivatives for the synthesis of quinazolinediones

Quinazolinediones were obtained from 2-iodobenzoic acids and carbodiimide derivatives under mild reaction conditions via a copper-catalyzed domino reaction. The absence of an external base was essential to avoid the generation of amide by-products. Both alkyl- and aryl-substituted carbodiimides gave the corresponding quinazolinediones. However, the use of aryl-substituted carbodiimides resulted in low yields due to an undesired elimination process.     

A ligand-free Pd-catalyzed cascade reaction: an access to the highly diverse isoquinolin-1(2H)-one derivatives via isocyanide and Ugi-MCR synthesized amide precursors

A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a Mazurciewitcz-Ganesan type sequence to provide isoquinoline-1(2H)-one derivatives in moderate to good yields.     

Tetramic acid and imidazolidinone syntheses via unexpected base induced cyclisations of alanine derived Weinreb amides

Reactions of N-protected derivatives of Weinreb amides of alanine with strong base unexpectedly gave tetramic acid derivatives or an imidazolidinone. The tetramic acid derivatives were obtained by unusual cyclisation of N-acyl N-methoxy derivatives of alanine Weinreb amide upon treatment with potassium hexamethyldisilazide and benzyl bromide. In contrast, treatment of a bromobenzylidine alanine Weinreb amide with potassium hexamethyldisilazide gave rise to cyclisation to form an imidazolidinone.     

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. ⁶Li and ¹⁵N NMR spectroscopic studies of doubly labelled ⁶lithium (S)-¹⁵N-benzyl-¹⁵N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C₂-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.     

Synthesis and characterization of novel heat resistant poly(amide imide)s

A series of new poly(amide imide)s was prepared from new diacid containing sulfone, ether, amide and imide groups with various aromatic diamines. The diacid was synthesized via four steps, starting from reaction of 4-aminophenol with 4-nitrobenzoyl chloride in the presence of propylene oxide afforded N-(4-hydroxy phenyl)-4-nitrobenzamide. In the second step, reduction of nitro group resulted in preparation of 4-amino-N-(4-hydroxy phenyl) benzamide. In the next step for the preparation of diamine, the reaction of 4-amino-N-(4-hydroxy phenyl) benzamide with bis-(4-chlorophenyl) sulfone in the presence of K₂CO₃ was achieved. The prepared sulfone ether amide diamine was reacted with two moles of trimellitic anhydride to synthesize related sulfone ether amide imide diacid. The precursors and final monomer were characterized by FT-IR, H-NMR and elemental analysis. Direct polycondensation reaction of the sulfone ether amide imide diacid with different diamines in the presence of triphenyl phosphite afforded five different poly (sulfone ether amide imide amide)s. The obtained polymers were fully characterized and their physical properties including thermal behavior, thermal stability, solubility, and inherent viscosity were studied.     

Selective synthesis of ureas and tetrazoles from amides controlled by experimental conditions using conventional and microwave irradiation

An efficient synthetic procedure has been achieved for selective synthesis of 1,5-disubstituted tetrazoles and diaryl ureas from secondary amides in situ in the presence of NaN₃ and POCl₃ as solvent, both by conventional and microwave methods. The reaction conditions were optimized to yield selectively either tetrazoles or urea derivatives from reasonable to excellent yields. These conversions have been tested and verified with various secondary amide precursors. The synthesized compounds were characterized by ¹H NMR, ¹³C NMR and ESI-MS spectroscopic techniques.     

Synthesis of gem-diamino derivatives on solid support

Anchoring of an α-amino-acid amide residue by its amine function to a carbamate resin followed by primary amide Hofmann rearrangement led to a gem-diamino residue linked to the resin. The generated primary amine could be acylated with various carboxylic compounds offering a large variety of molecules. Furthermore, this new solid-phase strategy allowed a reliable synthesis of a gem-diamino monomeric residue which could not be easily obtained in solution due to the limited stability of monocarbamate-protected gem-diaminoalkyl derivatives.     

Synthesis and kinetic investigation of the selective acidolysis of para-substituted N-benzyl- or N-phenyl-N-phenylacetyl-α,α-dialkylglycine cyclohexylamides

Several derivatives of N-phenylacetyl-N-benzyl-α,α-dimethylglycine cyclohexylamide and their α,α-dibenzylglycine analogues were synthesised by a Ugi-Passerini reaction. In addition, a few analogues of the former but having an N-phenyl instead of a benzyl group at the nitrogen atom were synthesised. The compounds in each of these three sets differed from each other at position 4 of the N-benzyl (and N-phenyl) group. These adducts were submitted to acidolysis with TFA to obtain the corresponding free acids, the reactions being monitored by HPLC and data collected for kinetic purposes. The kinetic data were submitted to Hammett uni- and biparametric relationships and the results were analysed in terms of structure-reactivity in connection with the sensitivity of the reaction rates to the electronic contributions of the various substituents at position 4 of the aromatic rings. The results allowed comparison with information obtained in previous investigations and rationalise the contribution of the substituent at the nitrogen atom to the lability of the C-terminal amide bond.     

Chemo- and stereoselectivity in titanium-mediated regioselective ring-opening reaction of epoxides at the more substituted carbon

Chemo- and stereoselectivity in the ring-opening reaction of epoxides with a reagent prepared from allylmagnesium halide and chlorotitanium triphenoxide is described. It has been proven that the allylating reagent can also be used for the reaction of epoxides bearing a tert-butyl ester, amide, or acetal moiety, and that the epoxide cleavage regioselectively takes place at the more substituted carbon in all cases. Interestingly, while the reaction of acyclic 2,2,3-trialkyl epoxides or 3,3-disubstituted 2,3-epoxy alcohol derivatives with the allyltitanium reagent yielded the allylated products as an almost 1:1 diastereomixture, the ring-opening reaction of 2-substituted 2,3-epoxy alcohol derivatives stereospecifically proceeded through the anti pathway. The latter reaction is extremely useful for asymmetric construction of quaternary carbon centers.     

One‐pot three‐component synthesis of novel 2‐(3‐nitro‐phenyl)‐quinazoline‐4‐carboxylic acid derivatives

A simple and easy synthesis of 2‐(3‐nitro‐phenyl)‐quinazoline‐4‐carboxylic acid ( 3 ) has been successfully developed through a one‐pot three‐component condensation reaction of (2‐amino‐phenyl)‐oxo‐acetic acid sodium salt ( 1 ) obtained from the hydrolysis of isatin with ammonium acetate and 3‐nitrobenzaldehyde. Some novel quinazoline‐ester derivatives 4‐7 were then obtained by the reaction between the new compound 3 and various alcohols. Then, quinazoline‐amide derivatives 10‐14 were synthesized from the reaction of various amines and 2‐(3‐nitro‐phenyl)‐quinazoline‐4‐carbonyl chloride ( 8 ), obtained by the reaction of compound 3 with SOCl₂. Finally, some novel quinazoline‐azo derivatives 17‐19 were synthesized by the coupling reaction between β‐dicarbonyl compounds and the novel amino‐quinazoline derivative compound 15 , obtained by reduction of nitro‐quinazoline derivative compound 11 . Thus, a new series of quinazoline‐4‐carboxylic acid, ester, amide, and azo derivatives was synthesized and fully characterized by ¹H NMR, ¹³C NMR, IR, and mass spectrometry analysis.     

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.     

Isocyanide-based multicomponent reactions: synthesis of 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives

A new isocyanide-based multicomponent reaction between an aromatic aldehyde, malononitrile, an isocyanide, and acetic acid efficiently provides 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives in excellent yields in ethanol at 70 °C. This reaction led to the construction of two carbon-carbon bonds and one amide group in a single synthetic step.     

A mild, expedient, one-pot trifluoromethanesulfonic anhydride mediated synthesis of N-arylimidates

The direct transformation of various secondary amides into N-arylimidates via mild electrophilic amide activation with trifluoromethanesulfonic anhydride (Tf₂O) in the presence of 2-chloropyridine (2-ClPyr) is described. Low-temperature amide activation followed by C-O bond formation with 2-naphthol provides the desired N-arylimidates in short overall reaction times. In contrast, reaction with oxindole proceeds via formation of a C-C bond to give 1-(1H-indol-2-yl)naphthalene-2-ol.     

Enzymatic resolution of methyl N-alkyl-azetidine-2-carboxylates by Candida antarctica lipase-mediated ammoniolysis

A facile method for the synthesis of optically active azetidine-2-carboxylic acid derivatives is presented. Racemic N-alkylated azetidine esters are resolved by lipase from Candida antarctica in an ammoniolysis reaction, and both the S-amide and the R-ester are obtained with excellent stereoselectivity.     

Regioselective synthesis of 6-amino- and 6-amido-6-deoxypullulans

Hydrophobically modified polysaccharides that contain amine and amide groups possess valuable features for drug delivery and other applications. These chemical groups are known to play a fundamental role in the biological activity of important polysaccharides. Pullulan is known for its non-toxicity and biocompatibility, therefore, we have applied the versatile Staudinger reaction for the synthesis of regioselectively substituted pullulan derivatives containing amine or amide groups with promise for biomedical applications. The synthesis began with the regioselective bromination of pullulan at C-6 with N-bromosuccinimide and triphenylphosphine, providing 6-bromo-6-deoxy-pullulan, which is soluble in a range of organic solvents and therefore is a dynamic intermediate for the synthesis of other pullulan derivatives. Azide displacement of bromide from 6-bromo-6-deoxy-pullulan esters yielded the corresponding 6-azido-6-deoxy-pullulan esters. Staudinger reduction of these azides efficiently and chemoselectively afforded the corresponding amino- or amidopullulans.