A new and efficient multicomponent solid-phase synthesis of 2-acylaminomethylthiazoles

A new multicomponent reaction (MCR) for the preparation of 2-substituted thiazole libraries using Rink amide resin is described. Thiazoles are assembled in a one-pot MCR of a thiocarboxylic acid, aldehyde, 3-(N,N-dimethylamino)-2-isocyanoacrylate with a resin-bound primary amine. Aliphatic and aromatic thiocarboxylic acids as well as aliphatic and (hetero-) aromatic aldehydes work in the reaction. Cleavage of the product yields the substituted thiazoles in reasonable to good purity.     

Facile acid-catalyzed condensation of 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone with phenols, methoxyaromatic systems and enols

Various phenols, methoxy aromatic compounds, 3- and 4-hydroxycoumarins and enols smoothly condense with 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone 1 in an acid medium producing 2-aryl/alkyl-2,2′-biindan-1,1′,3,3′-tetrones in high yields. The adducts of resorcinol, 1,3,5-trihydroxybenzene and α- and β-naphthols of 1 preferably remain in the intramolecular hemi-ketal form, confirmed by X-ray diffraction studies. On the other hand para and meta substituted phenols condense with 1 in an acid medium to produce 6 or 7 substituted 2′,4-spiro(1′,3′-indanedion)-indeno[3,2-b]chromenes in good yields.     

Influence of an ortho-sulfinyl group on the configurational stability of α-lithiated aryloxiranes: deuteration of tolylsulfinyl styrene oxides

The influence of the p-tolylsulfinyl group, located at ortho-, meta-, and para-position, on the regio- and stereoselectivity of the deuteration reactions of substituted styrene oxides has been investigated. The sulfinyl group at an ortho-position reduces the configurational stability of α-lithiated styrene oxides, whereas meta- and para-sulfinyl derivatives completely control the regioselectivity only yielding deuterated products at the aromatic ring due to its strong ortho-director effect.     

KMnO4-mediated direct C2-selective C−H arylation of quinoline N-oxides with aromatic hydrazines

An efficient protocol for the synthesis of 2-arylquinoline N-oxides has been developed via KMnO₄-mediated cross-coupling reaction of quinoline N-oxides with aromatic hydrazines in moderated to good yields. The reactions proceeded efficiently over a broad range of substrates with excellent regioselectivity and functional group tolerance.     

Lithiation of 2-(chloroaryl)-2-aryl-1,3-dioxolanes with butyllithium activated by N,N,N′,N″,N″-pentamethyldiethylenetriamine

Intramolecular competition of variously substituted phenyl rings of benzophenone ketals in lithiation reactions proved to be a useful tool to study both ortho-directing ability and long-range effects of the substituents. The regioselectivities observed in the reaction of benzophenone ketals having one or two chloro substituents in one of the aryl rings with butyllithium complexed to N,N,N′,N″,N″-pentamethyldiethylenetriamine demonstrate the significance of both ortho- and meta-acidifying effect of the chloro substituents. The lithio species thus generated were carboxylated resulting in new polysubstituted benzoic acids.     

Structure-property relationships for novel wholly aromatic polyamide-hydrazides containing various proportions of para-phenylene and meta-phenylene units: I. Synthesis and characterization

A series of novel wholly aromatic polyamide-hydrazides was synthesized by a low temperature solution polycondensation reaction of either 4-amino-3-hydroxybenzhydrazide or 3-amino-4-hydroxybenzhydrazide with an equimolar amount of either terephthaloyl chloride (TCl), isophthaloyl chloride (ICl), or mixtures of various molar ratios of TCl and ICl in anhydrous N,N-dimethylacetamide (DMAc) as a solvent. Polymer structures were identified by elemental analysis and infrared spectroscopy. All the polymers have the same structural formula except the way of linking phenylene units inside the polymer chain. The content of para- and meta-phenylene moieties was varied within this series so that the changes in the latter were 10 mol % from polymer to polymer, starting from an overall content of 0-100 mol %. The prepared polymers were characterized for their properties in order to acquire clear understanding of the influence exerted by controlled structural variations in these polymers upon some of important properties, such as solubility, intrinsic viscosity, moisture regain, mechanical properties and thermal as well as thermo-oxidative stability. The polymers were readily soluble in several organic polar solvents such as DMAc, N,N-dimethylformamide, dimethyl sulphoxide, N-methyl-2-pyrrolidone and hexamethyl phosphoramide and could be cast into flexible films. Their solubilities were found to increase remarkably with introduction of meta-phenylene moieties into the polymer chains. Their intrinsic viscosities ranged from 0.73 to 4.83 dl g⁻¹ in DMAc at 30 °C and increased with the increase of para-phenylene units content. Mechanical properties of the films produced from these polymers are improved markedly by substitution of para-phenylene units for meta-phenylene units. Thermogravimetric studies revealed that the completely para-oriented type of polymer has better thermal and thermo-oxidative stability relative to that of the other polymers. Moreover, the results reveal that the prepared polymers have a great affinity to water sorption. The hydrophilic character increases as a function of meta-oriented phenylene rings incorporated into the polymer chains.     

Synthesis of О-2-(acyl)vinylketoximes and their unusual rearrangements into 2- and 3-acyl-substituted pyrroles

О-2-(Acyl)vinylketoximes (freshly prepared from ketoximes and acylacetylenes in the presence of Ph₃P as catalyst in up to 83% yields) rearrange upon heating (125-150 °C) to give 2- or 3-acylpyrroles, wherein the positions of the acyl substituents do not correspond to known O-vinyloxime rearrangements; the chemo- and regioselectivity of the rearrangements depend on the reaction conditions. The described rearrangement enables syntheses of previously inaccessible substituted 2- or 3-acylpyrroles.     

Practical and regioselective brominations of aromatic compounds using tetrabutylammonium peroxydisulfate

Direct bromination of wide range of aromatic compounds substituted with electron donating groups such as methoxy, hydroxy, or amino groups have been achieved with high regioselectivity by the reaction with Br₂ in the presence of tetrabutylammonium peroxydisulfate 1 under mild conditions in acetonitrile in excellent yields. The use of lithium bromide as a bromination reagent afforded high yields of monobromo compounds with complete regioselectivity under neutral and mild reaction conditions in acetonitrile.     

Synthesis of optically active cyanohydrins from aromatic ketones: evidence of an increased substrate range and inverted stereoselectivity for the hydroxynitrile lyase from Linum usitatissimum

The synthesis of (R)- and (S)-cyanohydrins from a range of aromatic methyl and ethyl ketones, including the first examples from substituted variants of phenylacetone, benzylacetone and propiophenone, is described. Commercially available hydroxynitrile lyase (HNL) enzymes were used to catalyze the asymmetric addition of cyanide to the ketones, including the first successful application of the flax HNL (LuHNL) to the synthesis of any aromatic (S)-cyanohydrin. Both reaction yields and stereoselectivities were shown to be influenced by the carbon chain length between the ketone and phenyl functional groups, and the type of aromatic substitution present on the starting material. Substrates converted with the greatest degree of productivity and selectivity were phenylacetones with large, electron withdrawing meta-substituents, such as 3-Cl, 3-Br and 3-CF₃ phenylacetones, from which cyanohydrins are formed with 93–99% ee and 61–71% yield.     

A convenient and efficient ring-opening reaction of aziridines with acetylenes and synthesis of dihydropyrroles

In the presence of ^tBuOK, reaction of acetylenes with N-Ts substituted aziridines derived from both cyclic and acyclic alkenes at room temperature gave rise to homopropargylamines in good to high yields and in high regioselectivity. Not only Ph- and Me₃Si-substituted acetylenes but also acetylene itself was suitable reagents. Treatment of ring-opening products with I₂ and AgOAc in the presence of K₂CO₃ provided dihydropyrroles in high yields. One-pot synthesis of dihydropyrroles was also realized by the reaction of aziridines and phenylacetylene in the presence of NaH followed by the treatment with I₂ and AgOAc.     

Metal-free and highly regioselective synthesis of N-heteroaryl substituted pyrazoles from α,β-unsaturated N-tosylhydrazones and heteroaryl chlorides

A cascade cyclization/nucleophilic aromatic substitution (S_NAr) reaction of α,β-unsaturated N-tosylhydrazones with N-heteroaryl chlorides was developed for the synthesis of N-heteroaryl pyrazole derivatives. This one-pot reaction provided bi(heteroaryl) derivatives in good to excellent yields and with excellent regioselectivity. The procedure is operationally simple and applicable to large-scale synthesis.     

Simple and Highly Efficient Catalytic Thiocyanation of Aromatic Compounds in Aqueous Media

Two simple, mild, and efficient procedures for the thiocyanation of N‐heterocycles, substituted anilines (electron‐rich and electron‐deficient), and N‐substituted aromatic amines at room temperature are reported (Table 3). The first uses H₂O₂ as pollution‐free oxidant and the second H₅IO₆; both with the reagent potassium thiocyanate in H₂O as solvent. These procedures provided the target thiocyanates after a short reaction time in good to excellent yields and high regioselectivity.     

A simple,efficient, regioselective and one-pot preparation of N-hydroxy- and N–O-protected hydroxyindoles via cycloaddition of nitrosoarenes with alkynes. Synthetic scope,applications and novel by-products

The thermal reaction between nitrosoarenes and alkynes under alkylating conditions produces N-alkoxyindoles as the major products in moderate to good yields and excellent regioselectivity. Various electrophiles are used affording different N–O-protected hydroxyindoles in a multi-component fashion. Privileged acetylenic substrates used in reactions with substituted nitrosoarenes are arylalkynes or propiolates. Potentially bioactive compounds and other classes of highly functionalizable indole products were prepared. Reactions between o-carbomethoxy-nitrosoarenes and arylacetylenes provided tricyclic compounds containing an acylaziridine indoline skeleton.     

Direct alkenylation of arylamines at the ortho-position with magnesium alkylidene carbenoids and some theoretical studies of the reactions

1-Chlorovinyl p-tolyl sulfoxides were synthesized from ketones and chloromethyl p-tolyl sulfoxide in high yields. Treatment of the sulfoxides with isopropylmagnesium chloride at −78 °C in toluene gave magnesium alkylidene carbenoids (α-chloro alkenylmagnesium chlorides), which were treated with N-lithio arylamines to afford ortho-alkenylated arylamines in moderate yields. The reaction, in some cases, proceeded in a highly stereospecific manner at the carbon bearing the chlorine and the sulfinyl group. The structures of the α-chloro alkenylmagnesium chlorides and the reactivity of the N-lithio meta-substituted anilines were studied at the B3LYP and MP2 levels of theory with the 6-31(+)G* basis set. This reaction offers a quite novel and direct alkenylation of arylamines at the ortho-position of the aromatic ring.     

Silylamines in organic synthesis: preparation and some reactions of N,C-dilithiosilylamines

The dimetallation of some olefinic and aromatic N-trimethylsilylamines has been examined. Treatment with a two molar proportion of n-butyllithium gives organodimetallic reagents, which react with trimethylchlorosilane to give N,N,C-tris(trimethylsilyl)amines in 45 to 65% yields. The dianonic reagent obtained from (trimethylsilyl)(allyl)amine reacts with benzoyl chloride, N,N-dimethylformamide, ethyl-2-furylcarboxylate, and benzil to give substituted pyrroles and pyridines.     

Yb(OTf)3: an efficient catalyst for the synthesis of 3-arylbenzo [f]quinoline-1,2-dicarboxylate derivatives via imino-Diels-Alder reaction

A mild and facile method for the synthesis of 3-arylbenzo[f]quinoline-1,2-dicarboxylate derivatives is reported by an imino-Diels-Alder reaction in high yields (76-92%). This procedure includes a novel three-component reaction of aromatic aldehyde, naphthalen-2-amine, and but-2-ynedioate catalyzed by Yb(OTf)₃ in toluene. The results are obviously different from those of the simple substituted aniline-involved reactions catalyzed by ZnCl₂ or KOH in the literature.     

Zinc chloride catalyzed three-component Ugi reaction: synthesis of N-cyclohexyl-2-(2-hydroxyphenylamino)acetamide derivatives

The ability of zinc chloride as a catalyst to promote the three-component Ugi reaction of 2-aminophenols, aliphatic or aromatic aldehydes, and cyclohexyl isocyanide in methanol at room temperature is described. The N-cyclohexyl-2-(2-hydroxyphenylamino) amide products are obtained in high yields. When N,N-dimethylformamide dimethyl acetal and triethyl orthoformate, as two new components of the three-component Ugi reaction are used instead of the aldehyde the reaction gives N-cyclohexyl-2-(dimethylamino)-2-(2-hydroxyphenylamino)acetamide and N-cyclohexyl-2-(2-hydroxyphenylamino)-2-ethoxyacetamide derivatives, respectively.     

Regioselectivity of the acidolysis of 2-(chloromethyl)oxirane with aromatic acids in the presence of organic bases

Regioselectivity of the reaction of 2-(chloromethyl)oxirane with aromatic acids in the presence of tertiary amines and tetraalkylammonium halides has been studied. Opening of the oxirane ring follows simultaneously S_N2 and borderline S_N2 mechanisms. The regioselectivity of the acidolysis of substituted oxiranes is determined by acid-base properties of the reactants and catalysts and steric factor. The regioselectivity increases as the contribution of the S_N2 mechanism increases.     

Thiocyanation of N-arenesulfonyl-N′-aroyl-1,4-benzoquinone diimines

The reaction of N-arenesulfonyl-N′-aroyl-1,4-benzoquinone diimines with potassium thiocyanate in glacial acetic acid occurs as 1,4-addition of thiocyanate ion by the sulfur atom to the quinoid ring in the meta position with respect to the aroyl group. The addition products, N-[4-(arenesulfonamido)-3-thiocyanatophenyl]-benzamides, partially undergo intramolecular cyclization to N-(2-imino-3-arenesulfonyl-2,3-dihydro-1,3-benzothiazol-6-yl)benzamides whose hydrolysis yields 2-amino-6-benzamido-1,3-benzothiazol-3-ium arenesulfonates. The latter lose arenesulfonic acid with formation of N-(2-amino-1,3-benzothiazol-6-yl)benzamides on treatment with a mixture of methanol with water and acetic acid.     

Stereoisomerism in the series of isoindole-based quaternary salts

Steric structure of quaternary ammonium salts of the 3-[alkyl(aryl)amino]-1-[alkyl(aryl)iminio]-1H-isoindole series was studied by ¹H NMR spectroscopy and X-ray analysis. The examined salts are characterized by E,E configuration of substituents with respect to the exocyclic C-N bonds, and the presence of ortho- and meta-substituents in the benzene rings on the nitrogen atoms gives rise to atropisomers. Sterically hindered N-(2,4,6-trimethylphenyl) derivative was found to exist as Z,Z isomer which undergoes irreversible thermal isomerization into the more stable E,E isomer through intermediate Z,E structure. The reactions of 1,1,3-trichloro-1H-isoindole with secondary aromatic amines having an electron-withdrawing substituent in the ortho position in the presence of organic bases (triethylamine, N,N-dimethylbenzylamine) are accompanied by decomposition of the latter and formation of unsymmetrically substituted salts of the 3-[alkyl(aryl)amino]-1-(dialkyliminio)-1H-isoindole series, which contain both arylamine residue and dialkylamino group and are also characterized by atropisomerism.