Ag2O nanoparticle-catalyzed substrate-controlled regioselectivities: direct access to 3-ylidenephthalides and isocoumarins

Herein, we disclose the first example of an efficient, silver oxide nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides 11–16 and isocoumarins 17–20via sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively. This one pot coupling involves reaction of substituted 2-halobenzoic acid with meta/para-substituted and ortho-substituted terminal alkynes, which proceeded in a regioselective manner resulting in the formation of 3-ylidenephthalides or isocoumarins, respectively, in excellent yields (up to 95%) with complete Z-selectivity. This protocol features relatively broad substrate scope, mild conditions, operational simplicity, and is favourable with aromatic/alicyclic terminal alkynes. The competition experiments and gram-scale synthesis further highlight the importance and versatility of the methodology. The proposed mechanistic pathways illustrate that the regioselectivity is substantially being controlled by the substituent(s) present on the acetylenic phenyl ring.

We report the first example of an efficient, Ag₂O nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides and isocoumarins via Sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively.     

An efficient route to N-alkylated 3,4-dihydroisoquinolinones with substituents at the 3-position

A facile synthetic procedure for the production of N-alkylated 3,4-dihydroisoquinolinone derivatives is described. The desired products were obtained by N-alkylation of 3,3′-dimethyl-3,4-dihydroisoquinoline derivatives followed by oxidation of the resulting iminium salts. Reaction conditions for both steps were very mild and the desired cyclization products could be obtained in good yield. This strategy allows the generation of N-substituted 3,4-dihydroisoquinolinone derivatives with substituents at the 3-position.

N-Alkylated 3,4-dihydroisoquinolinone derivatives could be synthesized by N-alkylation of 3,3′-dimethyl-3,4-dihydroisoquinoline derivatives followed by oxidation of the resulting iminium salts.     

A regioselective C7 bromination and C7 palladium-catalyzed Suzuki–Miyaura cross-coupling arylation of 4-substituted NH-free indazoles

A direct and efficient regioselective C7-bromination of 4-substituted 1H-indazole has been achieved. Subsequently, a successful palladium-mediated Suzuki–Miyaura reaction of C7-bromo-4-substituted-1H-indazoles with boronic acids has been performed under optimized reaction conditions. A series of new C7 arylated 4-substituted 1H-indazoles was obtained in moderate to good yields.

A regioselective C7-bromination of 4-substituted 1H-indazoles followed by a palladium-catalyzed Suzuki–Miyaura reaction with boronic acids is described.     

Impact of an aryl bulky group on a one-pot reaction of aldehyde with malononitrile and N-substituted 2-cyanoacetamide

In this study, we successfully explored the effect of steric hindrance on the one-pot reaction of different aryl aldehydes with malononitrile and N-substituted 2-cyanoacetamide in the presence of piperidinium acetate as the catalyst. It involved the Knoevenagel condensation of the aldehyde and malononitrile to produce arylidene malononitrile as an intermediate, which was further treated with N-substituted 2-cyanoacetamide to give 6-amino-2-pyridone-3,5-dicarbonitrile derivatives when the less steric bulky group was involved. High steric hindrance changed the earlier reaction route and gave N-substituted 2-cyanoacrylamides via a slower route.

Impact of aryl bulky group on the one-pot reaction of aldehyde with malononitrile and N-substituted 2-cyanoacetamide is examined in the presence of piperidinium acetate as reusable catalyst.     

Preparation of 3-hydroxyquinolines from direct oxidation of dihydroquinolinium salts

A series of functionalized 3,4-dihydroquinolinium salts were prepared from the reaction of aryldiazonium salt with alkene in a nitrile solution. Further oxidation yielding either 3-hydroxyquinoline or quinoline products was investigated. A one-pot process from aryldiazonium salts, alkenes and nitriles leading to 3-hydroxyquinolines was also developed. Furthermore, an intramolecular trapping of an N-arylnitrilium ion with a vinyl group at the ortho position leading to 2-substituted quinolines was revealed.

3-Hydroxyquinoline derivatives can be prepared by a cascade cyclization of aryldiazonium salts with nitriles and alkenes followed by oxygenation.     

Allylation of isatin-derived N-Boc-hydrazones followed by Pd-catalyzed carboamination reaction: an entry to 3-spiro-pyrazolidyl-oxindoles

The indium-mediated allylation of novel 3-(2-Boc-hydrazono)indolin-2-one derivatives, followed by a palladium-catalysed carboamination reaction, is described to afford unprecedented spirocyclic oxindoles in good yields. The method provides an efficient access to both cis and trans diastereoisomers of highly functionalized compounds, bearing an N-Boc, 5-substituted pyrazolidine ring at the C3-oxindole spiro junction. The versatility of the method is fully demonstrated starting from a series of substituted isatins and employing a variety of aryl halides in the key cyclization step.

The indium-mediated allylation of novel 3-(2-Boc-hydrazono)indolin-2-one derivatives, followed by a palladium-catalysed carboamination reaction, is described to afford unprecedented spirocyclic oxindoles in good yields.     

Preparation of 1,2-substituted benzimidazoles via a copper-catalyzed three component coupling reaction

1,2-Substituted benzimidazoles were prepared by simply stirring a mixture of copper catalysts, N-substituted o-phenylenediamines, sulfonyl azides and terminal alkynes. Particularly, the intermediate N-sulfonylketenimine occurred with two nucleophilic addition and the sulfonyl group was eliminated via cyclization. In a way, sulfonyl azides and copper catalysts activated the terminal alkynes to synthesize benzimidazoles.

The intermediate N-sulfonylketenimine occurred with two nucleophilic addition, and the sulfonyl group was easily eliminated through cyclization.     

Efficient and stereoselective one-pot synthesis of benzo[b]oxazolo[3,4-d][1,4]oxazin-1-ones

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization. Various tricyclic fused benzoxazinyl-oxazolidinones (20 examples) were obtained in good to excellent yields and high enantioselectivities with facile operation. Furthermore, four stereoisomers were afforded respectively in high ee values (>97.8%) via using different chiral 2,3-epoxy-4-trityloxybutanol. This methodology has been applied to the synthesis of key intermediates of drug candidates.

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization.     

Transition-metal-free base catalyzed intramolecular cyclization of 2-ynylphenols for efficient and facile synthesis of 2-substituted benzo[b]furans

A transition-metal-free base catalyzed intramolecular cyclization of 2-ynylphenols was developed for the facile synthesis of 2-substituted benzo[b]furans. Various 2-aryl and 2-alkyl substituted benzo[b]furans can be obtained with good to excellent yields using readily available Cs₂CO₃ as the catalyst under mild reaction conditions. The broad substrates scope and the typical maintenance of vigorous efficiency on gram scale make this protocol a potentially practical method to synthesize 2-substituted benzo[b]furans derivatives.

An efficient and practical transition-metal-free synthesis of 2-substituted benzo[b]furans catalyzed by readily accessible base was developed with broad substrates scope.     

Chemodivergent synthesis of N-(pyridin-2-yl)amides and 3-bromoimidazo[1,2-a]pyridines from α-bromoketones and 2-aminopyridines

N-(Pyridin-2-yl)amides and 3-bromoimidazo[1,2-a]pyridines were synthesized respectively from α-bromoketones and 2-aminopyridine under different reaction conditions. N-(Pyridin-2-yl)amides were formed in toluene via C–C bond cleavage promoted by I₂ and TBHP and the reaction conditions were mild and metal-free. Whereas 3-bromoimidazopyridines were obtained in ethyl acetate via one-pot tandem cyclization/bromination when only TBHP was added, the cyclization to form imidazopyridines was promoted by the further bromination, no base was needed, and the versatile 3-bromoimidazopyridines could be further transferred to other skeletons.

N-(Pyridin-2-yl)amides and 3-bromoimidazo[1,2-a]pyridines were synthesized respectively from α-bromoketones and 2-aminopyridine under different reaction conditions.     

Dimroth-type N/S-interchange of N-aminothioglycolurils in the synthesis of 2-hydrazonoimidazo[4,5-d]thiazolones

An original method for the synthesis of 2-hydrazonoimidazo[4,5-d]thiazolone derivatives has been developed based on a one-pot acid-induced sequence of hydrazone formation from 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazinones and aromatic aldehydes, triazine ring contraction to imidazolidine one, and Dimroth-type N/S-interchange of N-aminothioglycolurils formed in situ into 2-hydrazonoimidazo[4,5-d]thiazolones. 3-Phenylacroleine derivatives are also suitable substrates for the reaction with thioxoperhydroimidazotriazinones.

An original method for the synthesis of 2-hydrazonoimidazo[4,5-d]thiazolone derivatives has been developed based on an acid-induced Dimroth-type N/S-interchange of N-aminothioglycolurils formed in situ into 2-hydrazonoimidazo[4,5-d]thiazolones.     

Regioselective,one-pot,multi-component,green synthesis of substituted benzo[c]pyrazolo[2,7]naphthyridines

An efficient and environmentally benign synthetic protocol has been developed for the synthesis of benzo[c]pyrazolo[2,7]naphthyridine derivatives through regioselective multi-component “on-water” reaction of isatin, malononitrile and 3-aminopyrazole. The Knoevenagel condensation of isatin with malononitrile resulted in the formation of arylidene, which subsequently underwent Michael addition with 3-aminopyrazole followed by basic hydrolysis, cyclization, decarboxylation and aromatization to give the target naphthyridines in good to excellent yields. The one-pot multi-component protocol was also employed to obtain the said naphthyridines in a lower yield (10–15%) than obtained by basic hydrolysis of spiro-intermediates. The present study shows attractive features such as the use of water as a green solvent, short reaction time, reduced waste products and transition metal free C–C and C–N bond formation. The structures of the synthesized derivatives were established through FTIR, ¹H-NMR, ¹³C-NMR spectroscopy and ESI-mass spectrometry.

An efficient and environmentally benign synthetic protocol has been developed for the synthesis of benzo[c]pyrazolo[2,7]naphthyridine derivatives through regioselective multi-component “on-water” reaction of isatin, malononitrile and 3-aminopyrazole.     

The synthesis of N,N′-disulfanediyl-bis(N′-((E)-benzylidene)acetohydrazide) from (E)-N′-benzylideneacetohydrazide and S8

Herein we report an oxidative coupling reaction for N–S/S–S bond formation from (E)-N′-benzylideneacetohydrazide and S₈ to furnish substituted N,N′-disulfanediyl-bis(N′-((E)-benzylidene) acetohydrazide). It provides a direct approach for the synthesis of disulfides with good yields.

Herein we report an oxidative coupling reaction for N–S/S–S bond formation substituted N,N′-disulfanediyl bis(N′-((E)-benzylidene)acetohydrazide). It provides a direct approach for the synthesis of disulfides with good yields.     

Facile synthesis of 3-substituted imidazo[1,2-a]pyridines through formimidamide chemistry

A facile entry to 3-aryl/alkenyl/alkynyl substituted imidazo[1,2-a]pyridines (3a–p, 6a–d & 9a–9e) has been developed from readily available benzyl/allyl/propargyl halides and 2-amino pyridines as substrates via formimidamide chemistry that is devoid of caustic or expensive reagents, such as transition metal complexes. Quantum chemical calculations performed to understand the underlying mechanism of the transformation revealed a preference for intramolecular Mannich-type addition over pericyclic 1,5-electrocyclization for the systems reported herein that enable a Baldwin allowed 5-exo-trig cyclization instead of a formally anti-Baldwin 5-endo-trig process.

A facile entry to 3-substituted imidazo[1,2-a]pyridines from halides and 2-amino pyridines via formimidamide chemistry has been developed through a formal anti-Baldwin 5-endo-trig cyclization that becomes a thermally allowed 5-exo-trig cyclization.     

Synthesis of novel series of 3,5-disubstituted imidazo[1,2-d] [1,2,4]thiadiazoles involving SNAr and Suzuki–Miyaura cross-coupling reactions

The first access to 3,5-disubstituted imidazo[1,2-d][1,2,4]thiadiazole derivatives is reported. The series were generated from 2-mercaptoimidazole, which afforded the key intermediate bearing two functional positions. The S_NAr reactivity toward tosyl release at the C-3 position was investigated and a regioselective electrophilic iodination in C-5 position was performed to allow a novel C–C bond using Suzuki–Miyaura reaction. Palladium-catalyzed cross-coupling conditions were optimized. A representative library of various boronic acids was employed to establish the scope and limitations of the method. To complete this methodological study, the influence of the nature of the C-3 imidazo[1,2-d][1,2,4]thiadiazole substitutions on the arylation in C-5 was investigated.

A convenient design of 3,5-disubstituted imidazo[1,2-d][1,2,4]thiadiazoles is reported from 2-mercaptoimidazole, which afforded a versatile platform that was then used to access a variety of original heterocycles.     

Regioselective C–H sulfenylation of N-sulfonyl protected 7-azaindoles promoted by TBAI: a rapid synthesis of 3-thio-7-azaindoles

This paper describes the regioselective C-3 sulfenylation of N-sulfonyl protected 7-azaindoles with sulfonyl chlorides. In this transformation, dual roles of TBAI serving as both promoter and desulfonylation reagent have been demonstrated. The reaction proceeded smoothly under simple conditions to afford 3-thio-7-azaindoles in moderate to good yields with broad substrate scopes. This protocol refrains from using transition-metal catalysts, strong oxidants or bases, and shows its practical synthetic value in organic synthesis.

A novel, practical and highly regioselective TBAI promoted C-3 sulfenylation reaction of N-sulfonyl protected 7-azaindoles with sulfonyl chlorides is presented here.     

PPh3/NaI driven photocatalytic decarboxylative radical cascade alkylarylation reaction of 2-isocyanobiaryls

The first triphenylphosphine/sodium iodide driven photocatalytic decarboxylative cascade cyclization of 2-isocyano-biaryls with alkyl N-hydroxyphthalimide (NHP) esters was developed. This operationally simple protocol results in multiple carbon–carbon bond formation under transition metal free conditions, affording a novel and environmentally benign entry to producing 6-alkyl phenanthridines with moderate to good yields.

PPh₃/NaI driven photocatalytic decarboxylative cyclization of 2-isocyanobiaryls with alkyl NHP esters was developed. This simple protocol afforded a novel and environmentally friendly approach to furnish 6-alkyl phenanthridines in good yields.     

Synthesis of 5-amino-N′-(9H-fluoren-9-ylidene)-8-nitro-7-aryl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbohydrazide derivatives based on heterocyclic ketene aminals

A new class of tetrahydroimidazo[1,2-a]pyridine derivatives has been successfully prepared via a five-component domino reaction using cyanoacetohydrazide, 9-fluorenone, aromatic aldehydes, 1,1-bis(methylthio)-2-nitroethene and ethylenediamine in ethanol at reflux. The new efficient cascade approach involves a sequence of N,N-acetal formation, Knoevenagel condensation, Michael addition, imine–enamine tautomerization and N-cyclization as key steps. The merit of this protocol is highlighted by its available and economical starting compounds, operational simplicity, clean reaction profile and tolerance of a wide diversity of functional groups.

A new class of tetrahydroimidazo[1,2-a]pyridine derivatives has been successfully prepared via a five-component domino reaction using cyanoacetohydrazide, 9-fluorenone, aromatic aldehydes, 1,1-bis(methylthio)-2-nitroethene and ethylenediamine in ethanol at reflux.     

The synthesis of anticancer sulfonated indolo[2,1-a]isoquinoline and benzimidazo[2,1-a]isoquinolin-6(5H)-ones derivatives via a free radical cascade pathway

A facile CuBr₂ induced radical relay addition/cyclization of activated alkenes with substituted-thiosulfonates has been achieved, leading to a broad range of sulfonated indolo[2,1-a]isoquinolines and benzimidazo[2,1-a]isoquinolin-6(5H)-ones in moderate to good yields. In particular, some compounds exhibit bioactivity against cancer cell lines. This protocol shows advantages of low-cost, base-free, simple operation, and broad functional group tolerance.

A facile CuBr₂ induced tandem radical reaction has been achieved, leading to sulfonated indole and benzimidazole derivatives.     

Substrate-controlled selectivity switch in a three-component reaction: sequential synthesis of spiro-oxazolidinedione-cyclopentenones and hydroxy enaminobarbiturates in water

An efficient eco-friendly catalyst-free three-component domino multicyclization for the synthesis of new spirobicyclic oxazolidinedione containing cyclopentenone moieties has been established by mixing amines, β-dicarbonyl compounds and N,N′-dimethylalloxan in water at room temperature. This domino process involves multiple reactions such as enamination/aldol-like reaction/Stork enamine annulation/intramolecular cyclization under mild conditions.

Spiro-oxazolidinedione-cyclopentenones and hydroxy enaminobarbiturates could be selectively formed from amines, β-dicarbonyl compounds and alloxan derivatives under catalyst-free conditions in water.