Palladium-catalyzed reductive N-heterocyclization of alkenyl-substituted nitroarenes as a viable method for the preparation of bicyclic pyrrolo-fused heteroaromatic compounds

Palladium-catalyzed, carbon monoxide-mediated reductive N-heterocyclization of nitro-heteroaromatic compounds having an alkene adjacent to the nitro-group affords bicyclic pyrrolo-fused heteroaromatic molecules. This type of reaction was used to prepare the fused bicyclo[3.3.0] ring-system: thieno[3,2-b]pyrrole, thieno[2,3-b]pyrrole, furo[2,3-b]pyrrole, pyrrolo[3,2-d]thiazole, and pyrrolo[2,3-d]imidazole and the bicyclo[4.3.0] ring-systems: pyrrolo[3,2-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridazine, and pyrrolo[3,2-d]pyrimidine in 32-94% yield.     

Electrophilic heterocyclization of 6-alken(yn)ylsulfanyl-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(5<Emphasis Type="Italic">H</Emphasis>)-ones

6-Allylsulfanyl-1-arylpyrazolo[3,4-d]pyrimidin-4(5H)-ones react with iodine and sulfuric acid to give angular pyrazolothiazolopyrimidine derivatives. The reaction of 6-(prop-2-yn-1-ylsulfanyl)-1-(4-tolyl)-pyrazolo[3,4-d]pyrimidin-4(5H)-one with sulfuric acid gives angularly fused pyrazolo[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-4-one, whereas in the reaction with sodium methoxide linearly fused pyrazolo[3,4-d][1,3]-thiazolo[3,2-a]pyrimidin-4-one was formed. Linearly fused pyrazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazole derivatives were also obtained by reaction of 1-aryl-6-(3-phenylprop-2-en-1-ylsulfanyl)pyrazolo[3,4-d]pyrimidin-4(5H)-ones with sulfuric acid.     

One-pot three-component reaction of 3-(polyfluoroacyl)chromones with active methylene compounds and ammonium acetate: regioselective synthesis of novel R-containing nicotinic acid derivatives

Reactions of 3-(polyfluoroacyl)chromones with acetoacetamide and ethyl acetoacetate in the presence of ammonium acetate proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent cyclization to 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotinamides, ethyl 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotinates, and ethyl 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5H-chromeno[4,3-b]pyridine-3-carboxylates. Similar reaction with β-aminocrotononitrile gave 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5H-chromeno[4,3-b]pyridine-3-carbonitriles.     

Microwave promoted diastereoselective synthesis of dihydroindeno[1,2-b]furans via one-pot three-component reaction in solvent-free conditions

An efficient method was developed for the synthesis of fused dihydroindeno[1,2-b]furans. One-pot three-component reaction of 1,3-indanedione, aromatic aldehyde and pyridinium ylide in the presence of triethylamine under microwave-irradiation in solvent-free conditions afforded dihydroindeno[1,2-b]furans in a diastereoselective manner in excellent yields.     

A novel kind of dimmer (excimer)-induced-AIE compound 2-phenylisothiazolo[5,4-b]pyridin-3(2H)-one as high selective bisulfite anion probe

An interesting dimmer (excimer)-induced-AIE characteristic of 2-phenylisothiazolo[5,4-b]pyridin-3(2H)-one was observed. By using a ring-opening reaction, we developed a novel fluorescent probe based on sub-micron particles of 2-phenylisothiazolo[5,4-b]pyridin-3(2H)-one in water.     

Novel indole syntheses by ring transformation of β-lactam-condensed 1,3-benzothiazines into indolo[2,3-b][1,4]benzothiazepines and indolo[3,2-c]isoquinolines

ortho-Nitrophenyl-substituted condensed 1,3-benzothiazines proved to be a useful core unit in indole syntheses under non-reductive conditions. Thus, the treatment of ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzothiazin-1-ones with sodium methoxide in methanol provided indolo-1,4-benzothiazepines via a novel rearrangement. Through the sulfur extrusion reaction of indolo[2,3-b][1,4]benzothiazepines, further alkaloid-type indole derivatives, indolo[3,2-c]isoquinolines, were obtained. The structures of the new ring systems were determined by means of NMR spectroscopy.     

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids has been developed for the preparation of vasicinone and deoxyvasicinone by two approaches. The derivative of polymer-supported p-nitrophenyl carbonate was attached to anthranilic acid and then coupled with various bromo-lactams. This resin-linked bromo intermediate upon acetylation, hydrolysis and resin cleavage gave the cyclized [2,1-b]quinazolinones (vasicinone). Alternatively, resin-linked azido-benzoic acids were coupled with bromo-substituted lactams followed by cyclization in an aza-Wittig reductive cyclization process giving the bromo-substituted quinazolinone intermediates, with subsequent acetylation, hydrolysis and resin cleavage affording the fused [2,1-b]quinazolinones.     

A facile domino protocol for the regioselective synthesis and discovery of novel 2-amino-5-arylthieno-[2,3-b]thiophenes as antimycobacterial agents

A series of novel 2-amino-5-arylthieno[2,3-b]thiophenes has been synthesized regioselectively from the reaction of 5-aryldihydro-3(2H)-thiophenones with ethyl cyanoacetate/malononitrile and sulfur powder in the presence of morpholine under thermal as well as microwave irradiation conditions. This transformation presumably occurs via domino Gewald reaction-dehydrogenation sequence. The 2-amino-5-arylthieno[2,3-b]thiophenes were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 12 compounds screened, ethyl 2-amino-5-(1-naphthyl)thieno[2,3-b]thiophene-3-carboxylate was found to be the most active compound with MIC of 1.1 μM against MTB and MDR-TB.     

Synthesis of 3-halo-2,5-disubstituted furans via CuX mediated cyclization-halogenation reactions

The Cu(I) halide (X = I, Br, Cl) mediated reactions of Cbz-protected cis-2-phenylethenyl-3-hydroxypyrrolidine gave novel 3-halo-2,5-trisubstituted furans in good yields, via a cyclization-halogenation, ring-opening reaction sequence. In contrast, the reactions with CuCN gave mainly the corresponding 3-cyanofuro[3,2-b]pyrrole formed from a cyclization-cyanation reaction.     

Unexpected valence bond isomerization of [1,2,4]triazolo[3,4-c][1,2,4]benzotriazines under flash vacuum pyrolytic (fvp) conditions

Flash vacuum pyrolysis (fvp) of some substituted [1,2,4]triazolo[3,4-c][1,2,4]benzotriazine derivatives (1a-d) has been studied between 450 and 600 °C. The only transformation observed up to 525 °C was the unexpected valence bond isomerization of the angularly fused starting compounds to the isomeric linearly fused [1,2,4]triazolo[4,3-b][1,2,4]benzotriazine derivatives (9a-d), whereas at higher temperatures fragmentation products such as aromatic nitriles were also formed. Kinetic measurements revealed negative entropies of activation in the isomerization process, which suggest a concerted ring closure reaction to an intermediate antiaromatic diazirine. Reversibiblity of the title isomerization reaction was also proved by FVP experiments.     

Isatins 3-C annulation vs ring-opening: Two different pathways for synthesis of spiro compounds via multicomponent reactions

An efficient synthesis of spiro compounds via two different pathways from the reactions of isatins, 3-phenylisoxazol-5(4H)-one (3-ethylisoxazol-5(4H)-one), and pyrazol-5-amine (6-aminopyrimidine-2,4(1H,3H)-dione) were reported. The catalyst Amberlyst-15 could be easy recycled and reused for many time without any appreciable loss in catalytic activity. The new type spiro compounds were gained through the ring-opening of isatins process. The structures of spiro[indoline-3,4′-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo[5,4-b]quino line-4,5′-pyrrolo[2,3-d]pyrimidine]-2′,4′,6′(1′H,3′H,7′H)-trione, and spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(5′H)-dione were successfully confirmed by ¹H NMR, ¹³C NMR, HRMS, and X-ray crystal diffraction analysis.     

Synthesis and antimicrobial activity of novel fused [1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indole derivatives

Synthesis of new fused systems of triazino[5,6-b]indole starting with preparation of 3-amino[1,2,4]-triazino[5,6-b]indole 1 by reaction of isatin with 2-aminoguanidinium carbonate in boiling acetic acid is presented [1]. Intermediate compound 1 reacted with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine and gave new heterotetracyclic nitrogen systems, such as 3-(N ²-guanidinylimino)indole-2(1H)-one 2, 3-(N-ethoxycarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 3, 3-(N-ethoxymethyleneamino)-4H-[1,2,4]-triazino[5,6-b]indole 4, 3-(hydrazinothiocarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 5, respectively. N-(1,3-dioxoindene-2-ylidene)-4H-[1,2,4]triazino[5,6-b]indol-3-amine 6 was synthesized by reaction of compound 1 with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine. New fused indole systems, pyrimido[2′,1′:3,4][1,2,4]triazino[5,6-b]indol-3(4H)-one 8, 9, 11, 12 and 1H-imidazo[2′,1′:3,4][1,2,4]triazino-[5,6-b]indol-2(3H)-one 10, were synthesized in the reaction of the intermediate 1 with bifunctional compounds. Structures of the products were elucidated from their elemental analysis and spectral data (IR, ¹H and ¹³C NMR and mass spectra). Antimicrobial activity of some synthesized compounds was tested.     

Regioselectivity of the reaction of 4H-1,2,4-triazole-3-thiol derivatives with chloroethynylphosphonates and structure of the products

Chloroethynylphosphonates reacted with 4H-1,2,4-triazole-3-thiols in anhydrous acetonitrile to afford fused heterocyclic compounds, 6-(dialkoxyphosphoryl)-3H-thiazolo[3,2-b][1,2,4]triazol-7-ium chlorides, with high regioselectivity. The products were converted into inner salts (zwitterions) of the corresponding phosphonic acids or their monoesters with the positive charge localized on N⁷. A probable reaction mechanism implies initial formation of sulfonium ion via attack by the thionic sulfur atom on the acetylenic carbon atom linked to chlorine, followed by intramolecular cyclization involving attack on the other acetylenic carbon atom by N² of the triazole ring.     

A new synthetic method for the 2H-[1,2,3]thiadiazolo[5,4-b]indoles

The systematic study of oxidative cyclization of 3-hydrazono-1,3-dihydroindole-2-thiones has been carried out and a series of new 2H-[1,2,3]thiadiazolo[5,4-b]indoles has been prepared. The elaborated reaction represents an efficient method for the synthesis of fused 1,2,3-thiadiazoles.     

Palladium-catalyzed annulative allylic alkylation for regioselective construction of indole-fused medium-sized cyclic ethers

A new palladium-catalyzed annulative allylic alkylation (AAA) reaction of 2-(indol-2-yl)phenols with dual allylic electrophiles such as isobutylene dicarbonate and butene dicarbonate is described, leading to the regioselective synthesis of tetracyclic medium-sized cyclic ethers possessing a bridged aryl-indole scaffold, namely, benzo[2,3]oxocino[4,5-b]indoles and benzo[2,3]oxepino[4,5-b]indoles, in good to excellent yields. This protocol demonstrates a broad substrate scope, good compatibility with substituents and high regioselectivity, providing a catalytic and flexible method for creating bridged aryl-indole skeletons.     

Revisited synthesis of fused diazepines from 3-(3-aryl-3-oxopropenyl)chromen-4-ones and binucleophilic amino enones in a three-step domino process

The synthesis of tetracyclic 11,12,13,14b-tetrahydrodi-benzo[b, f]pyrido[1,2-d][1,4]diazepines was revisited via a catalyst-free three-step domino reaction involving a pyrone ring-opening/aza-Michael addition/intramolecular cyclization, the reactants having been o-arylenediamine–dimedone adducts and 3-(3-aryl-3-oxopropenyl)chromen-4-ones. The 3-positioned exocyclic α,β-enone fragment on the chromone moiety is involved in the cyclization into the final products at the last step of the process.     

A rapid method for the preparation of 2-substituted oxazolo[4,5-b]pyridines using microwave-assisted direct condensation reactions

The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating is a fast method for producing libraries based on fused 2-substituted oxazolo[4,5-b]pyridines in moderate to good yields.     

Microwave-assisted synthesis of pyrazolo[3,4-b]pyridine-spirocycloalkanediones by three-component reaction of 5-aminopyrazole derivatives, paraformaldehyde and cyclic β-diketones

New pyrazolo[3,4-b]pyridine-5-spirocycloalkanedione derivatives were prepared via three-component reaction between 5-(4-R-benzylamino)pyrazoles, cyclic β-diketones and paraformaldehyde. The use of indandione as β-diketone resulted in the formation of two products, the pyrazolo[3,4-b]pyridine-5-spiroindanediones and 3-tert-butyl-1-phenylindeno[2,3-e]pyrazolo[3,4-b]pyridine. The structures of the pyrazolo[3,4-b]pyridine-5-spirocycloalkanedione were confirmed by single-crystal X-ray diffraction. This protocol provides a simple one-step synthetic methodology with the advantages of easy work-up, mild reaction conditions and environmentally benign.     

A facile,catalyst-free synthesis of new polycyclic pyrrolo[1,2-b]pyrazolone derivatives

A convenient and efficient procedure has been developed for the synthesis of a new ring system, pyrrolo[1,2-b]pyrazolone, via two-component coupling reaction followed by base mediated intramolecular cyclization. Single-pot synthesis replacing the two step process has also been successfully carried out. A series of polycyclic pyrrolo[1,2-b]pyrazolone derivatives have been obtained by employing the procedure along with some fused pyrrol-1-ylamine system. The products were formed very rapidly in catalyst free condition in a good yield (up to 75%) and also it had tolerance to a wide scope of substrates.     

A novel entry into 1-methyl- and 1-aryl-octahydropyrrolo[3,4-b]pyrroles and their N-1-C-2 fused derivatives: stereoselective synthesis via an intramolecular azomethine ylide cycloaddition reaction

Synthesis of some novel pyrrolo[3,4-b]pyrrole derivatives has been accomplished in good yields by the intramolecular azomethine ylide cycloaddition reaction of a strategically situated unactivated alkenyl aldehyde with various secondary amino acids. A cis fused cycloadduct was formed in all cases.