A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

Intramolecular 4+2 cycloaddition of thieno[2,3-e][1,2,4]triazines: routes towards condensed thieno[2,3-b]pyridines

Synthetic approaches towards new condensed thienopyridine ring systems including furo[2,3-b]thieno[3,2-e]pyridines, bisthieno[2,3-b:3′,2′-e]pyridines, 5H-chromeno[2,3-b]thieno[3,2-e]pyridines, 5H-benzo(f)chromeno[2,3-b]thieno[3,2-e]pyridines have been achieved by application of intramolecular 4+2 cycloaddition reactions of suitably designed thieno[2,3-e][1,2,4]triazines tethered with alkene or alkyne terminals.     

Cycloalkano[1″,2″:4,5;4″,3″:4′,5′]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines): synthesis, structure and mechanism of their formation

Reactions of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with cyclohexyl- and cycloheptylamines in the presence of AgPy₂MnO₄ produce novel cycloalkano[1″,2″:4,5;4″,3″:4′,5′]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines). Detailed information concerning the scope and mechanism of these transformations is discussed.     

Synthesis of dihydrochromeno[4,3-b]pyrrolo[3,2-f]quinolines via intramolecular aza Diels-Alder reaction

An efficient and convenient one-pot intramolecular aza Diels-Alder approach for the synthesis of dihydrochromeno[4,3-b]pyrrolo[3,2-f]quinolines has been reported. Particularly valuable features of this methodology include simple execution, inexpensive catalyst, and good product yields.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Grignard reagent-promoted 6-endo-dig cyclization: instantaneous synthesis of original dipyrido[1,2-a:3′,4′-d]imidazole

Dipyrido[1,2-a:3′,4′-d]imidazole derivatives can be readily synthetized from various 3-alkyne-2-cyanoimidazo[1,2-a]pyridines via an efficient Grignard reagent-promoted 6-endo-dig cyclization of nitrile to alkynes. A previous optimization of the Sonogashira coupling reaction at C(3) of the 2-cyanoimidazo[1,2-a]pyridine was necessary as this coupling reaction is known to be largely influenced by the nature of the 2-substituent.     

Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines as synthons for the preparation of polycondensed heterocycles: reaction with chlorocarboxylic acid chlorides

Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines and 2-amino[1,2,4]triazolo[5,1-b]quinazolines react with the chlorides of chloroacetic, 3-chloropropanoic, and 4-chlorobutanoic acids at 0–5 °C to give amides through acylation of the 2-amino group. Heating the corresponding 3-chloropropanoyl derivatives at 80–90 °C in DMF leads to selective intramolecular alkylation at N-3 to form the chlorides of partially hydrogenated [1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ones and pyrimido[2′,1′:3,4][1,2,4]triazolo[5,1-b]quinazolin-12-ones. It may be more convenient to prepare such compounds through one-pot processes. Some reactions of the synthesized chlorides of polycondensed heterocycles have been studied. Conditions have been found to effect the selective synthesis of free bases, oxidative aromatization or hydrolysis of the dihydropyrimidine cycle, and the selective hydrolytic cleavage or elimination of the pyrimidone ring. Some of the resulting compounds represent new mesoionic heterocycles.     

One-pot two-step tandem reactions for selective synthesis of pyrrolo[2,1-a]isoquinolines and dihydro-, tetrahydro-derivatives

A sequential one-pot two-step tandem reaction for selective and efficient synthesis of pyrrolo[2,1-a]isoquinoline and its dihydro- and tetrahydro-derivatives has been developed. The tandem reactions of isoquinoline, α-halogenated methylene compounds, aromatic aldehydes, and cyanoacetamide firstly give tetrahydropyrrolo[2,1-a]isoquinolines as main products. The corresponding pyrrolo[2,1-a]isoquinolines and dihydropyrrolo[2,1-a]isoquinolines can be obtained directly by controlling oxidation with DDQ. The mechanism of this tandem reaction involved the 1,3-dipolar cycloaddition of isoquinolinium ylide as the key step. A unique elimination of the amido group preferring to the cyano group has been observed.     

Pyrazolo[2′,3′:3,4][1,3]oxazino[5,6-b]quinoxaline, a novel tetracyclic ring system

Reaction of 2-chloro-3-(3-chloro-1H-pyrazol-5-yl)quinoxaline and aldehydes does not afford the corresponding N-(α-hydroxyalkylated) derivatives but results in a cyclisation reaction to give a derivative bearing the hitherto undescribed pyrazolo[2′,3′:3,4][1,3]oxazino[5,6-b]quinoxaline system.     

A rapid access to indolo[2,1-a]pyrrolo[4′,3′:4,5]pyrano[5,6-c]coumarin/[6,5-c]chromone derivatives by domino Knoevenagal intramolecular hetero Diels-Alder reactions

Knoevenagal condensation of indole-2-carbaldehyde containing an internal dienophile with coumarins, followed by domino intramolecular hetero Diels-Alder reaction, provides polycyclic heterocycles. Different approaches for stereo- and chemoselective synthesis of indolo[2,1-a]pyrrolo[4′,3′:4,5]pyrano[5,6-c]coumarin and indolo[2,1-a]pyrrolo[4′,3′:4,5]pyrano[6,5-c]chromone derivatives are described.     

First synthesis of 4-aminopyrido[2′,3′:4,5]furo[3,2-d]pyrimidines

This Letter describes for the first time the synthesis of pyrido[2′,3′:4,5]furo[3,2-d]pyrimidines substituted by a primary or secondary amino group on position 4 of the pyrimidine ring. Application of microwave irradiation technology allowed fast and convenient procedures.     

A novel one-pot and efficient procedure for the synthesis of 3H-spiro[isobenzofuran-1,6′-pyrrolo[2,3-d]pyrimidine]-2′,3,4′,5′-tetraones

A novel and practical one-pot procedure is described for the preparation of several new of 3H-spiro[isobenzofuran-1,6′-pyrrolo[2,3-d]pyrimidine]-2′,3,4′,5′-tetraones based on the addition reaction of ninhydrin and 6-aminouracils followed by oxidative cleavage of their corresponding dihydroxyindenopyrrolopyrimidines.     

Substituted chromones in [3+2] cycloadditions with nonstabilized azomethine ylides: synthesis of 1-benzopyrano[2,3-c]pyrrolidines and 1-benzopyrano[2,3-c:3,4-c′]dipyrrolidines

Chromones bearing electron-withdrawing substituents at the 2- or 3-position react with nonstabilized azomethine ylides to produce 1-benzopyrano[2,3-c]pyrrolidines in good yields. Reactions of 3-cyanochromones proceed diastereoselectively to give 1-benzopyrano[2,3-c]pyrrolidines and tetrahydro-1H-spiro[chromeno[2,3-c]pyrrol-9,5′-oxazolidine]-9a-carbonitriles, depending on the reactant ratio, as a result of a 1,3-dipolar cycloaddition of the azomethine ylide at the double bond and carbonyl group of the chromone system. The latter undergoes demethylenation and recyclization into a novel hexahydrochromeno[2,3-c:3,4-c′]dipyrrole tetracyclic system on heating with hydrochloric acid.     

Iron(III) chloride catalysed three-component Grieco condensation: Synthesis of tetrahydropyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines

Three-component Grieco condensation reaction of 3-aminopyrazolo[3,4-b]pyridine, formaldehyde/benzaldehyde and electron rich alkenes in presence of iron(III) chloride gave tetrahydropyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines in single pot. The sequence of reactions is formation of di-azadiene in situ and the subsequent regioselective addition of alkenes in aza-Diels Alder type reaction. The structure and stereochemistry of the products were confirmed by spectral data and single crystal X-ray crystallography.     

Diels-Alder reactions of pyrrolo[3,4-b]porphyrins

In the presence of excess dimethylacetylene dicarboxylate (DMAD), nickel(II) pyrrolo[3,4-b]porphyrins undergo both Diels-Alder cycloaddition and Michael addition in toluene to give two bis-adducts, identified as compounds 4 and 5; the reaction can be accelerated by the addition of Lewis or Brønsted-Lowry acids. Refluxing the reaction mixture in 1,2,4-trichlorobenzene (220 °C) leads to a nickel(II) monobenzoporphyrin 2 as the main product. The structure of compound 4 was confirmed by X-ray crystallography.     

Diversity-oriented decoration of pyrrolo[1,2-a]pyrazines

Diversity-oriented synthesis of a chemical library based on a pyrrolo[1,2-a]pyrazine core is described by using palladium-catalyzed direct C6 arylation of pyrrolo[1,2-a]pyrazines with various aryl bromides. The starting materials, pyrrolo[1,2-a]pyrazines, were easily synthesized by the base-mediated N-alkylation of pyrrole-2-carboxaldehyde with several 2-bromoacetophenones followed by dehydrative cyclization with incorporation of nitrogen by the action of ammonium acetate. Introduction of other functional groups on this chemical scaffold is also discussed herein.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

2-Amidinylindole-3-carbaldehydes: synthesis of new tetracyclic compounds containing the pyrrolo[1,2-c]1,4-diazepine ring

2-Amidinylindol-3-carbaldehydes bearing an α-alkoxycarbonyl substituent on the cyclic-tertiary amine moiety were prepared. Pyrolysis of these amidines in diethylenglycol-monoethyl ether produced mainly a pyrrolo[1′,2′-1,2]-1,4-diazepino[5,6-b]indol-7,11-dione. A similar result was obtained starting from 2-amidinylbenzofuran-3-carbaldehyde.     

Synthesis of pyrrolo[2,3-c]2,7-naphthyridine derivatives by cascade heterocyclization reaction of 2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles

Alkylation of the title pyridinedicarbonitriles with N-substituted chloroacetamides was found to give 5,6-diamino-8-dialkylamino-2,3-dihydro-2-oxo-1H-pyrrolo[2,3-c]2,7-naphthyridine-9-carbonitriles. The structure of obtained compounds was unambiguously confirmed by X-ray crystallographic study. The heterocyclization reaction proceeded regioselectively involving 3-CN group of the starting pyridines without participation of 5-CN. The reasons of the selectivity were discussed. An interaction of prepared naphthyridine derivatives with acetic acid anhydride and cyclohexanone yielded 2-dialkylamino-6,8,9,10-tetrahydro-5-methyl-9-oxopyrimido[4,5,6-ij]pyrrolo[2,3-c]2,7-naphthyridine-1-carbonitriles and 2-dialkylamino-4,5,6,8,9,10-hexahydro-9-oxospiro{pyrimido[4,5,6-ij]pyrrolo[2,3-c]2,7-naphthyridine-5,1′-cyclohexane}-1-carbonitriles, respectively. All fused 2,7-naphthyridines obtained were derivatives of novel heterocyclic systems.     

Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh₃)₂] or [Cu(Phen)(PPh₃)₂]NO₃.