Competitive thermal ene reaction and Diels-Alder reactions of 2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1,2-a]pyrimidin-4(4H)-ones

Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-3-(2-substituted and 2,2-disubstituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-ones gave azepine, the desired ene products, and/or pyran derivatives. The formation of the latter was responsible for the [4+2] cycloaddition reaction between the α,β-unsaturated ester carbonyl moiety as a diene part and the alkenylamino moiety as an ene one. The reaction features depended upon the kinds of substituents both on the vinyl and alkenyl counterparts; strongly electron-withdrawing substituents on the vinyl moiety or an electron-donating substituent on the alkenyl one changed the reaction feature from the ene reaction to the hetero Diels-Alder reaction.     

Substituent-controlled domino-Knoevenagel-hetero Diels-Alder reaction—a one-pot synthesis of polycyclic heterocycles

The reaction of 2-(N-alkenyl-N-aryl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde with dimedone/Meldrum’s acid/4-hydroxycoumarin by heating in ethanol in the presence of pyridine produces polycyclic heterocycles bearing pyridine and pyran rings in a one-pot reaction. The effect of substituents on N-atom of the amino function controls the mode of reaction. Terminal alkenes prefer intramolecular Michael type reaction, but non-terminal alkenes favour Diels-Alder reaction, whereas, under similar condition, 2-(N-alkyl-N-allyl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde undergoes domino-Knoevenagel-hetero Diels-Alder reaction.     

A method for the synthesis of cyclopropanes by regiospecific and regioselective magnesium carbenoid 1,3-CH insertion as the key reactions

Addition reaction of two geometrical isomers of 1-chlorovinyl p-tolyl sulfoxides, derived from unsymmetrical ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of tert-butyl acetate gave single diastereomers of the adduct, respectively. Treatment of each diastereomer with i-PrMgCl resulted in the formation of magnesium carbenoid. Highly regiospecific 1,3-CH insertion reaction was found to take place from each magnesium carbenoid to afford cyclopropanes. On the other hand, when the unsymmetrical ketones bearing an oxygen- or a nitrogen-functional group on the α-carbon were used in this procedure, the regioselective 1,3-CH insertion reaction proceeded mainly. Stereochemistry of the adducts, reaction mechanism, and essence of the specificity and the selectivity are discussed.     

Novel and efficient synthesis of triazolobenzodiazepine analogues through the sequential Ugi 4CR-click-N-arylation reactions

An efficient approach for the synthesis of N-alkyl-2-aryl-2-(6-oxo-4H-benzo[f][1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)acetamides is described. The protocol involves Ugi four-component reaction of 2-bromobenzoic acid, propargylamine, aldehydes and isocyanides followed by in situ sequential click reaction of azide ion with triple bond and N-arylation reaction to afford desired products in good to excellent yields.     

An easy and general protocol for multicomponent coupling reactions of aldehydes, amides, and dienophiles

An improved procedure for the three-component coupling reaction of aldehydes, amides, and dienophiles (AAD-reaction) has been developed. The use of microwave technology enables the endo-selective synthesis of N-acyl cyclohexenylamines via condensation of readily available aldehydes and amides, and subsequent Diels-Alder reaction with electron-deficient dienophiles in significantly improved yields. Advantageously, there is no need of employing additional solvents and reaction times are drastically reduced compared to similar thermal reactions.     

Domino synthesis of fused hexacyclic imidazoquinolinoacridinones catalyzed by CuI/l-proline

A three-component reaction of 2-halogenated aromatic aldehydes, 1H-benzo[d]imidazol-5-amine and cyclohexane-1,3-diones is described, and gives imidazoquinolinoacridinone derivatives in good yields catalyzed by CuI/l-proline. This Domino reaction constructs a fused hexacyclic skeleton in one-pot containing two new rings, six new bonds and an Ullmann-type C–N bond coupling reaction.     

Towards synthesis of kavalactone derivatives

Kavalactone derivatives were synthesized using a Heck reaction of the 4-methoxy-6-vinyl-5,6-dihydropyran-2-one with aryl iodides. The Suzuki-Miyaura reaction of an aryl boronic acid and (Z)-4-methoxy-6-(2-iodovinyl)-5,6-dihydropyran-2-one has also been successfully used to produce both Z and E isomers of lactones.     

Iodine-catalyzed tandem oxidative coupling reaction: A one-pot strategy for the synthesis of new coumarin-fused pyrroles

The simple and facile strategy for the synthesis of 2,3-disubstituted-chromeno[4,3-b]pyrrole-4(1H)-ones has been established. This method describes the Kornblum oxidation reaction of acetophenones, followed by the Knoevenagle treatment of the resulted (het)arylglyoxals with active methylene compounds and consequently iodine-activated Michael type reaction with 4-amino coumarin in a one-pot manner to afford disubstituted chromeno[4,3-b]pyrrole-4(1H)-one derivatives.     

Regioselective synthesis of 2,3-disubstituted 1-alkyl pyrrolo[2,3-b] quinoxalines through palladium-catalyzed Heck reaction of chalcones and evaluation of their anti-bacterial activities

The regioselective synthesis of 1-alkyl-2-aryl-3-acyl pyrrolo[2,3-b]quinoxalines through palladium-catalyzed Heck coupling reaction/heteroannulation was reported. The reaction of N-alkyl/benzyl-3-chloroquinoxaline-2-amines with chalcones catalyzed by Pd(OAc)₂ in the presence of KO^tBu, as the base, in DMSO afforded the desired products in good-to-high yields. The MIC and MBC determinations revealed that these compounds could be used in the future research works for the development of antibiotics.     

Microwave-induced domino-Knoevenagel-hetero Diels–Alder reaction—an easy route to di[1]benzopyrano[2,3-b:4′,3′-d]pyridine

MW-irradiation of a well-ground equimolar mixture of 2-(N-alkynyl-N-aryl)aminochromone-3-carbaldehyde and dimedone underwent domino-Knoevenagel-hetero Diels–Alder (DKHDA) reaction for nonterminal alkynes, whereas conventional heating of the above reaction mixture in ethanol in the presence of pyridine accomplished alkyne-carbonyl metathesis (ACM) reaction or both ACM and DKHDA reaction. Here is the first example of an organo-catalyzed ACM reaction.     

Convergent multicomponent assembly of 2-acyloxymethyl thiazoles

Diverse substituted 2-acyloxymethyl thiazoles can be assembled by a new multicomponent reaction (MCR) of methyl 3-(N,N-dimethylamino)-2-isocyanoacrylate, aldehydes and thiocarboxylic acid under Lewis acid catalysis. The reaction is performed under mild conditions and is compatible with a wide range of functionalized starting materials. 13 examples are given.     

One-pot facile synthesis of polysubstituted pyridines via tandem reaction of the Blaise reaction intermediates and 3-formylchromones

A novel tandem one-pot method for the synthesis of polysubstituted pyridine derivatives has been developed via Knoevenagel-type reaction and subsequent 6π electrocyclization of the Blaise reaction intermediates and 3-formylchromones. Short reaction time, moderate to good yields and excellent functional group tolerance have been accomplished in this protocol.     

Investigations of the stereoselectivity of the intramolecular Diels-Alder reaction of a spiculoic acid model system

Model linear precursors to the spiculoic acids were prepared and underwent thermally induced IMDA reactions. The configuration of C5 in the stereotriad was found to dominate any inherent endo/exo selectivity of the IMDA reaction. The isomer (2E,5S)-20 underwent the IMDA to give the spiculoic acid stereochemistry in 84% yield and 94% ds. The required stereotriads were synthesised using stereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the π-facial preference of (S)-2-benzoyloxypentan-3-one ((S)-27) led to (5R)-(22) and a syn-titanium aldol reaction, under the stereocontrol of a chiral N-acylthiazolidinethione (42) led to (5S)-(22). Chain extension using standard Wittig, HWE and ‘modified’ Julia olefinations installed the diene and dienophile components giving the linear precursors to the IMDA reactions.     

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction is described. The sequence of hydroboration of ω-alkenyl thiol ester with 9-BBN and the Liebeskind-Srogl reaction results in the formation of medium-sized carbocyclic ketones with good yield.     

Convenient synthesis of 1a,1b,2,5-tetrahydro-1H-5a-aza-cyclopropa[a]indenes by base promoted cyclodimerization of 1,1-dicyano-2-aryl-3-benzoylcyclopropanes

1,1-Dicyano-2-aryl-3-benzoylcyclopropanes in acetonitrile in the presence of triethylamine underwent cyclodimerization reaction to afford the novel polyfunctionalized 1a,1b,2,5-tetrahydro-1H-5a-aza-cyclopropa[a]indenes in moderate yields. These polycyclic compounds can be more conveniently synthesized by the one-pot domino reaction of N-phenacylpyridinium bromides with arylidene malononitriles.     

The first example of regiospecific magnesium carbenoid 1,3-CH insertion: its mechanism and stereochemistry

Addition reaction of two geometrical isomers of 1-chlorovinyl p-tolyl sulfoxides, derived from unsymmetrical ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of tert-butyl acetate gave single isomers of the adduct, respectively. Treatment of each diastereomer with i-PrMgCl resulted in the formation of magnesium carbenoids. Highly regiospecific 1,3-CH insertion reaction was found to take place from the magnesium carbenoids to afford cyclopropanes in high yields. Stereochemistry of the adducts, reaction mechanism, and origin of the regiospecificity are discussed.     

A novel enzymatic tandem process: utilization of biocatalytic promiscuity for high stereoselective synthesis of 5-hydroxyimino-4,5-dihydrofurans

A lipase-catalyzed protocol for the synthesis of 5-hydroxyimino-4,5-dihydrofurans via tandem coupling between β-nitrostyrenes and 1,3-dicarbonyl compounds was developed in a ‘one-pot’ strategy. A series of β-nitrostyrenes were employed to expand the scope of this new biocatalytic promiscuity with high stereoselectivity (Z/E up to 99:1) and moderate to good yields. The reaction activity of 1,3-cyclohexanedione was found to be better than linear 2,4-pentanedione, while ethyl acetoacetate and diethylmalonate were not suitable for this reaction under the same conditions. Single-crystal X-ray diffraction analysis indicated that the reaction was stereoselective and Z-stereomer was found to be the major product. A reaction mechanism was supposed to elucidate the biocatalytic process.     

A facile one-pot regioselective synthesis of functionalized novel benzo[f]chromeno[4,3-b][1,7]naphthyridines and benzo[f][1,7]naphthyridines via an imino Diels-Alder reaction

A novel series of functionalized 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 1,3-diphenylbenzo[f][1,7]naphthyridines have been synthesized by an efficient regioselective one-pot multicomponent synthesis through intra and intermolecular imino Diels-Alder reaction. In this method, we have achieved complete regioselectivity and atom economy with polysubstituted core motifs in moderate to good yields. The proposed mechanism of this reaction has also discussed.     

Development of an unexpected reaction pathway for the synthesis of 1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines through palladium-catalyzed cascade reactions

1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines are synthesized through the multi-component reaction of 3-substituted 2-chloroquinoxalines, propargyl bromide, and excess secondary amines in the presence of a palladium copper catalytic system. This one-pot process provides an unexpected synthesis of new trisubstituted pyrrolo[1,2-a]quinoxalines by the introduction of two amine substituents onto the fused pyrrole rings in a single reaction procedure. The compounds formed are fully characterized by the analytical spectral data and X-ray analysis. A number of synthesized pyrrolo[1,2-a]quinoxaline derivatives are also screened against the three bacterial strains Micrococcus luteus, Pseudomonas aeruginos, and Bacillus subtilis. According to the results obtained, compounds 3b, 3c, and 3e are active against M. luteus, compounds 3b and 3e are active against Ps. Aeruginos, and only compound 3f is active against all the three bacterial strains.     

Synthesis and utility of new amine/nucleobase addition products of allenylphosphonates

In the reaction of allenylphosphonates with amines/nucleobases, depending on the amine and the allenylphosphonate, either Z- or E-vinylphosphonate or allylphosphonate as a single isomer with a β-amino functionality was isolated. A simple route to phosphonates with a β-NH₂ group is developed by direct reaction with ammonia. In reactions with adenine, three different modes of reaction, with one of them involving an unusual cyclisation, are observed. The utility of (enamino)allyl phosphonate products thus obtained in the synthesis of (enamino)-1,3-butadienes via Horner-Wadsworth-Emmons (HWE) reaction is also demonstrated.