Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles,aldehydes and alkynecarboxylic acids

We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted pyrimido [1,2-a]benzimidazoles, 2,4,10-trisubstituted 2,10-dihydropyrimido [1,2-a]benzimidazoles and 2,3-disubstituted imidazo [2,1-b]benzothiazoles via multicomponent reactions (MCRs) of heterocyclic azoles, aldehydes with easily storable and handling alkynecarboxylic acids. In the presence of a catalytic amount of CuI and K₂CO₃, the pyrimido [1,2-a]benzimidazole or imidazo [2,1-b]benzothiazole scaffold could be rapidly constructed through a 6-endo-dig or 5-exo-dig cyclization, respectively. The preliminary mechanistic study suggested that the formation of 2,3- disubstituted pyrimido [1,2-a]benzimidazoles, which completes the assembly of the scaffold and its C-3 position functionalization in one pot, undergoes a novel cascade process involving a decarboxylation, A [3] coupling, 6-endo-dig cyclization, nucleophilic addition and dehydration.     

A one-pot synthesis of substituted pyrido[2,3-b]indolizines

An efficient and novel approach to the synthesis of substituted pyrido[2,3-b]indolizine-10-carbonitriles was developed. These structures are practically unavailable through previously described methods. The cascade transformation involves the reaction of α,β-unsaturated carbonyl compounds with a stable dimer prepared from 1-(cyanomethyl)pyridinium chloride. The reaction was performed under reflux conditions in ethanol/water and in the presence of sodium acetate. This procedure represents a eco-friendly regioselective approach to the pyrido[2,3-b]indolizine core structure.     

Synthesis of poly-substituted pyrazolo[1,5-a]quinolines through one-pot two component cascade reaction

A diversity-oriented method for the synthesis of novel poly-substituted pyrazolo[1,5-a]quinolines has been developed on the basis of an S_NAr/Knoevenagel cyclization cascade reaction or an S_NAr/Dieckmann–Thorpe cyclization cascade reaction. The methods provide a variety of poly-substituted pyrazolo[1,5-a]quinolines bearing an amino, alkyl or aryl substituent at the 5-position. In addition, a diversity-oriented method for the synthesis of 2-substituted pyrazolo[1,5-a]quinolines from a readily available 2-[[(trifluoromethyl)sulfonyl]oxy]pyrazolo[1,5-a]quinoline has also been disclosed.     

Chemical and electrocatalytic cascade cyclization of salicylaldehyde with three molecules of malononitrile: ‘one-pot’ simple and efficient way to the chromeno[2,3-b]pyridine scaffold

А new type of catalytic cascade cyclization was found: the direct ‘one-pot’ simple and efficient transformation of salicylaldehyde and three molecules of malononitrile into the chromeno[2,3-b]pyridine systems. Chemical and electrochemical methods result in direct ‘one-pot’ formation of chromeno[2,3-b]pyridines in 60–90% yields. The implication of electrocatalysis in complex cascade cyclization reaction is an efficient approach to medicinally relevant chromeno[2,3-b]pyridines—the promising small-molecule ligands with pronounced antihistamic, antirheumatic and antiasthmatic activities. The electrocatalytic method is beneficial from the viewpoint of diversity-oriented large-scale processes and represents fast efficient and environmentally benign synthetic concept for cascade reactions strategy.     

Facile access to a benzoazepinoquinazolinone via a free radical cyclization

An efficient synthetic protocol based on a free-radical cascade reaction via 6-exo-trig and 7-endo-trig cyclization processes is described for a new substituted benzoazepinoquinazolinone system which could in principle be used to form the cyclopropanequinone system found in duocarmycins.     

One-pot synthesis of novel 3,10-dihydro-2H-1,3-oxazepino[7,6-b]indoles via 1,4-dipolar cycloaddition reaction

3,10-Dihydro-2H-1,3-oxazepino[7,6-b]indoles are synthesized via a convenient one-pot three-component 1,4-dipolar cycloaddition reaction, involving 3-alkyl(aryl)imidazo[1,5-a]pyridines, dimethyl acetylenedicarboxylate (DMAD) and N-alkylisatins. Structures of the newly synthesized heterocycles are evidenced from spectral data and further confirmed by single crystal X-ray diffraction. A plausible reaction mechanism is advanced, whereby the intermediate 1,4-dipole, generated in situ from imidazo[1,5-a]pyridine and DMAD, initially adds to the keto group of N-alkylisatins to form the corresponding 1,3-oxazin-spiro-oxindole cycloadduct. The latter undergoes subsequent unprecedented skeletal rearrangement through a cascade of bond breaking and bond making processes, eventually leading to ring enlargement, furnishing the tricyclic oxazepino[7,6-b]indole ring system as the end product.     

Radical cascade cyclizations and platinum(II)-catalyzed cycloisomerizations of ynamides

Ynamides are tested as new partners in radical and organometallic transformations. A radical cascade involving a 5-exo-dig cyclization followed by a 6-endo-trig radical trapping transforms ynamides into hetero-polycyclic compounds such as isoindoles, isoindolinones and pyrido-isoindolones. Various ene-tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated heterocycles. This unprecedented and easily operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a one-pot transformation, which provides cyclobutanones.     

AlCl3-promoted three-component cascade reaction for rapid access to [1,2,3]triazolo[5,1-a]isoquinolines

Novel AlCl₃-promoted, three component cascade Henry reaction-triazole formation-intramolecular 6-endo-dig cyclization reactions between 2-alkynylaryl aldehydes, nitroalkanes, and sodium azide for the assembly of [1,2,3]triazolo[5,1-a]isoquinolines have been developed. Further transformations of representative [1,2,3]triazolo[5,1-a]isoquinolines are also described.     

Multiple chirality transfers in the enantioselective synthesis of 11-O-debenzoyltashironin. Chiroptical analysis of the key cascade

The mechanism of the cascade oxidative dearomatization-transannular Diels-Alder was investigated in the context of an asymmetric route to (−)-11-O-debenzoyltashironin. Although the oxidative dearomatization provides two acetal intermediates, the transannular Diels-Alder proceeds spontaneously from only one of the acetal isomers. Access to enantioenriched tetracyclic adduct was gained through the use of optically active allene.     

4-exo-dig and 5-exo-dig Cyclocarbopalladations: an expeditious solution toward molecular complexity?

The 4-exo-dig and 5-exo-dig cyclocarbopalladations have been efficiently used to produce molecular complexity in a straightforward manner. Strained 1,2-cyclobutanediols are rapidly obtained under microwave irradiation in high yields. In many cases, the cyclocarbopalladation cascade reaction is associated with a 6 or 8π electrocyclic reaction. During the process of the 5-exo-dig cyclocarbopalladation on benzosuberone derivatives, an aromatic C-H activation leads to vinylic substituted aromatics. Polycyclic skeletons of natural products of the family of Ophiobolin and Aleurodiscal can be prepared in few steps from simple starting material.     

Reaction modes of oxidative dimerization of epoxycyclohexenols

Of the 16 possible modes of the oxidation-6π-electrocylization-Diels-Alder reaction cascade for an epoxyquinone, and eight for a 2-alkenyl-3-hydroxymethyl-2-cyclohexen-1-one, only the endo-anti(epoxide)-anti(Me)-hetero and endo-anti(Me)-hetero are respectively observed, while both the endo-anti(epoxide)-anti(Me)-hetero and exo-anti(epoxide)-anti(Me)-homo reaction modes occur with epoxy-4-hydroxycyclohexenones owing to a hydrogen-bonding interaction.     

Aryl pyrrolidinones via radical 1,4-aryl migration and 5-endo-trig cyclisation of N-(2-bromoallyl)arylcarboxamides

Radical reaction of a series of N-(2-bromoallyl)arylcarboxamides led to the production of 4-arylpyrrolidin-2-ones and directly reduced materials in comparable yields. A cascade process, involving sequential 5-exo-trig spirocyclisation, β-scission, and 5-endo-trig cyclisation of the resulting acyl radical, is proposed to explain the pyrrolidinone products.     

Palladium-catalyzed synthesis of indane and cyclobuta[a]indenes from homoallylic alcohols derived from Baylis-Hillman adducts: base-dependent stereoselectivity for the benzylidene group in cyclobuta[a]indene

Various indane and cyclobuta[a]indene derivatives were synthesized by palladium-catalyzed cyclization of homoallylic alcohol derivatives prepared from Baylis-Hillman adducts. Especially, cyclobuta[a]indene derivative was synthesized stereoselectively by palladium-catalyzed 5-exo-trig/4-exo-trig cascade cyclization, albeit in moderate yield. The Z isomer was formed exclusively in the presence of Et₃N by usual Heck-type carbopalladation process while E isomer with Cs₂CO₃ most likely by a concerted metalation/deprotonation (CMD) process.     

Total syntheses of hyperaspidinols A and B enabled by a bioinspired diastereoselective cascade sequence

A bioinspired acid-triggered hemiacetalization/dehydration/[3 + 3]-type cycloaddition cascade process was disclosed, diastereoselectively furnishing furo[2,3-b]chromene skeleton under mild conditions. The viability of this approach was demonstrated by syntheses of a series of furo[2,3-b]chromene and pyrano[2,3-b]chromene derivatives. The successful total syntheses of two lignan-phloroglucinol hybrids,hyperaspidinols A and B, exemplified the synthetic utility of our biomimetic methodology.     

Synthesis of 13a-methylphenanthroindolizidines using radical cascade cyclization: synthetic studies toward (±)-hypoestestatin 1

A radical cascade involving 6-endo cyclization of aryl radicals generated from N-acryloyl-N-(1-methylethenyl)-9-bromophenanthren-10-ylmethylamines, followed by 5-endo-trig cyclization of the resulting α-amidoyl radicals afforded phenanthroindolizidines bearing a methyl substituent at the angular C13a position. 2,3,6-Trimethoxy derivative was synthesized by using this method, but its spectral data were not in accord with those of literature values reported for hypoestestatin 1. Further synthetic study toward hypoestestatin 1 is demonstrated.     

A cascade radical-mediated macrocyclisation–transannulation approach to oestrogen steroids

A new approach to ring A aromatic steroids, based on cascade 13-endo-trig/dig macrocyclisations followed by sequential 5-exo-trig and 6-exo-trig transannulations, exemplified in the syntheses of the cis,anti,trans tetracycle 9 and the trans,syn tetracycle 13 from the ortho-substituted aryl polyen(yne) precursors, 8 and 12 respectively, is described.     

Lewis acid-promoted cascade reaction of primary amine, 2-butynedioate,and propargylic alcohol: a convenient approach to 1,2-dihydropyridines and 1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-diones

1,2-Dihydropyridine-5,6-dicarboxylates were efficiently constructed through a cascade reaction of primary amine, 2-butynedioate and propargylic alcohol in the presence of Lewis acid under mild conditions. As exceptional, 1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-diones were approached when the primary amine was methylamine. Possible mechanism for the formation of 1,2-dihydropyridine skeleton is proposed. The process involves 1,3,4-pentatrien-1-amine as a key intermediate that formed in situ by trapping allenic carbocations with enamines.     

Controlling 6-endo-selectivity in oxidation/bromocyclization cascades for synthesis of aplysiapyranoids and other 2,2,6,6-substituted tetrahydropyrans

A cascade, composed of (i) oxovanadium(V)-catalyzed oxidation of bromide by tert-butyl hydroperoxide and (ii) stereoselective 6-endo-bromocyclization, affords 3-bromo-2-aryl-2,6,6-trimethyltetrahydropyrans from styrene-type tertiary alkenols in synthetically useful yields. (E)-Alkenols add the bromo- and the alkoxy substituent anti-selectively across the double bond, indicating a bromonium ion-mechanism for the ring closure. 6-endo-control of the alkenol cyclization thereby arises from the polar effect of the aryl substituent. Two methyl substituents bound to the alkene terminus are not similarly able to favor 6-endo-cyclization, because strain arising from methyl group repulsion, as the bromonium-activated π-bond and the hydroxyl oxygen approach, directs bromocyclization of tertiary prenyl-type substrates toward tetrahydrofuran formation. A hexasubstituted bromotetrahydropyran prepared from the oxidation/bromocyclization cascade served as starting material for synthesis of racemic aplysiapyranoid A, in a sequence of free radical and polar functional group interconversion.     

An efficient synthesis of substituted chrysenes

Substituted chrysenes have been swiftly synthesised by the 6-endo-dig cyclisation of ethynylnaphthalenes using platinum(II) chloride. Cyclisation precursors were directly prepared from commercially available 2-bromoaldehydes in a telescoped synthetic procedure involving a Cannizzaro triggered cascade and subsequent dehydration and desilylation. This short synthetic procedure allows rapid access to derivatives of biologically active molecules with useful electronic properties.     

Synthesis of novel isoindolone derivatives via cascade reactions. Contrasting diastereoselectivity under solution-phase vis-a-vis solvent-free ball-milling reaction conditions

The highly diastereoselective synthesis, crystallographic analysis, and full characterization of several novel heterocycle-fused isoindolones is described. The synthetic strategy involves a cascade Michael/aldol-like cyclization reaction between N-substituted phthalimides rac-1 or 2 and several α,β-unsaturated electrophiles to afford the tricyclic systems pyrrolo[2,1- a]isoindolone and tetrahydropyrido[2,1-a]isoindolone. This synthetic strategy offers a convenient alternative to existing procedures for the preparation of isoindolone derivatives fused to five- and six-membered rings. X-ray crystallographic analysis allowed the determination of relative configurations and revealed that the synthesized compounds exhibit significant structural distortion, especially in the five membered rings. Relevantly, the diastereomeric distribution of products depends substantially on whether the cascade reaction is carried out under solution vis-a-vis solvent-free conditions.