Parallel Synthesis of Pyrazolone-Fused Cinnolines by the Palladium-Catalyzed [4 + 2] Annulation of Pyrazol-3-ones with Substituted Allenoates.

The synthesis of pyrazolone-fused cinnolines from pyrazol-3-ones and α,γ-substituted allenoates via a palladium-catalyzed C-H activation/annulation cascade was developed. Mechanistic studies revealed the course of the reaction. Initially, N-acyl-valine ligand-assisted ortho-C-H activation gives ortho-alkenylated intermediate. Subsequent cyclopalladation and migratory insertion of allenoate give a seven-membered palladacycle. Reductive elimination finally furnishes pyrazolone-fused cinnolines.

Substrate-Controlled Divergent Synthesis of Benzimidazole-Fused Quinolines and Spirocyclic Benzimidazole-Fused Isoindoles.

A Rh(III)-catalyzed annulation of 2-arylbenzimidazoles with α-diazo carbonyl compounds via C-H activation/carbene insertion/intramolecular cyclization is explored. The switchable product selectivity is achieved by the use of distinct α-diazo carbonyl compounds. Benzimidazole-fused quinolines are obtained through [4 + 2] annulation exclusively when 2-diazocyclohexane-1,3-diones are used, where they act as a C2 synthon. Alternatively, diazonaphthalen-1(2H)-ones merely function as a one-carbon unit synthon to generate a quaternary center through [4 + 1] cyclization to afford spirocyclic benzimidazole-fused isoindole naphthalen-2-ones. A thorough mechanistic study reveals the course of the reaction.

Combinatorial synthesis of substituted pyrazolo-fused quinazolines by the Rh(III)-catalyzed [5 + 1] annulation of phenyl-1H-pyrazol-5-amine with alkynoates and alkynamides.

A Rh(III)-catalyzed C-H activation/cyclization cascade was developed for the first divergent synthesis of pyrazolo[1,5-a]quinazolines through a [5 + 1] annulation reaction exclusively. The one-pot procedure is recognized for its broad substrate scope, functional group tolerance, and high atom economy. Mechanistic studies reveal the reaction pathway, addressing current limitations. Notably, this catalytic transition metal-assisted tandem annulation smoothly proceeds through the reaction of substituted phenyl-1H-pyrazol-5-amine with an alkyne ester or amide, where a one ring carbon is provided by the alkynoate building block. This transformation highlights the potential of transition metal-catalyzed methods for synthesizing diverse pyrazolo[1,5-a]quinazoline frameworks.

Rapid Synthesis of Benzimidazole-Fused Isoindoles by Rh(III)/Ru(II)-Catalyzed [4 + 1] Cascade C-H/N-H Annulation of 2-Arylbenzimidazoles with Alkynoates and Alkynamide.

A Rh(III)-catalyzed [4 + 1] cyclization of 2-arylbenzimidazoles with alkynoates through C-H activation/ortho-alkenylation/intramolecular annulation cascade to obtain benzimidazole-fused isoindoles is reported. The reaction of the Rh catalyst and internal alkyne ester provides benzo[4,5]imidazo[2,1-a]isoindole acetate exclusively. Conversely, internal alkyne amide participates in the annulation process in the presence of a Ru catalyst to provide benzo[4,5]imidazo[2,1-a]isoindole acetamide. The alkyne acts as a C1 synthon and undergoes [4 + 1] cyclization rather than traditional [4 + 2] annulation.

Rh(III)-Catalyzed Switchable [4 + 1] and [4 + 2] Annulation of N-Aryl Pyrazolones with Maleimides: An Access to Spiro Pyrazolo[1,2-a]indazole-pyrrolidine and Fused Pyrazolopyrrolo Cinnolines.

A rhodium(III)-catalyzed controllable [4 + 1] and [4 + 2] annulation of N-aryl pyrazolones with maleimides as C1 and C2 synthon has been explored for the synthesis of spiro[pyrazolo[1,2-a]indazole-pyrrolidines] and fused pyrazolopyrrolo cinnolines. The product selectivity was achieved through time-dependent annulation. The [4 + 1] annulation reaction involves sequential Rh(III)-catalyzed C-H alkenylation of N-aryl pyrazolone, followed by an intramolecular spirocyclization via aza-Michael-type addition to afford spiro[pyrazolo[1,2-a]indazole-pyrrolidine]. However, prolonged reaction time converts in situ formed spiro[pyrazolo[1,2-a]indazole-pyrrolidine] into fused pyrazolopyrrolocinnoline. This unique product formation switch proceeds via strain-driven ring expansion through a 1,2-shift of the C-C bond.

Rh(III)-Catalyzed (4 + 1) Annulation of Pyrazol-3-ones with Alkynoates via Ortho-Alkenylation/Cyclization Cascade: Synthesis of Indazole-Fused Pyrazoles.

A facile synthesis of novel indazole-fused pyrazoles from pyrazol-3-ones and alkynoate esters/amides via Rh(III)-catalyzed sequential C-H activation/ortho-alkenylation/intramolecular cyclization cascade is reported. The important characteristic of this method is that the resulting scaffold bearing quaternary carbon has been obtained through unusual [4 + 1] rather than expected [4 + 2] addition where alkynoate acts as a one-carbon unit.

Substrate-controlled Rh(III)-catalyzed regiodivergent annulation towards fused and spiro benzimidazoles.

A Rh(III)-catalyzed cascade C-H activation and cyclization of 2-aryl benzimidazoles with maleimides for the synthesis of benzimidazole-fused isoquinolines and benzimidazole-spiro isoindoles is reported. Switchable selectivity towards the formation of these two distinct products can be achieved using unsubstituted and substituted benzimidazoles at the ortho-position of the phenyl ring. Mechanistically, C-H activation followed by migratory insertion of maleimide forms a Heck-type intermediate. Unsubstituted benzimidazole undergoes aza-Michael addition to form a (4 + 2) fused product, whereas ortho-substituted phenyl benzimidazole causes steric clash to deliver a (4 + 1) spiro-adduct favorably via acid-catalyzed intramolecular annulation.

Molecular Iodine-Promoted [3 + 2] Oxidative Cyclization for the Synthesis of Heteroarene-Fused [1,2,4] Thiadiazoles/Selenadiazoles.

Two new classes of heteroarene-fused [1,2,4]thiadiazole and [1,2,4]selenadiazole are synthesized through the iodine-mediated [3 + 2] oxidative cyclization of 2-aminoheteroarenes and isothiocyanates/isoselenocyanates. This oxidative [3 + 2] annulation strategy is highly regiospecific to proceed a selective C-N bond formation at the endo-nitrogen of 2-aminoheteroarenes followed by an intramolecular oxidative N-S/N-Se bond formation. It is the first example of an I2-mediated oxidative nitrogen-selenium (N-Se) bond formation.

One-pot synthesis of 4-arylidene imidazolin-5-ones by reaction of amino acid esters with isocyanates and α-bromoketones.

A simple and new multicomponent reaction for the one-pot synthesis of substituted 4-arylidene imidazolin-5-ones from l-amino acid methyl esters, iso-, isothio- or isoselenocyanates, and α-bromoketones is demonstrated. Isolation of thiohydantoin and 5-benzylidene 2-thioxoimidazolidin-4-one intermediates revealed a possible reaction mechanism. The strategy was further extended to the synthesis of 2-iminothiazolines and 2-thioxoimidazolin-4-ones.

Three Component Divergent Reactions: Base-Controlled Amphiphilic Synthesis of Benzimidazole-Linked Thiazetidines and Fused Thiadiazines.

A divergent reaction of 2-aminobenzimidazole with isothiocyanates and dihalomethanes has been developed for the selective synthesis of benzoimidazothiazetidine and benzoimidazothiadiazine. A single-pot reaction of 2-aminobenzimidazole in the presence of sodium hydride delivers benzoimidazothiazetidine, whereas triethylamine promotes the formation of benzoimidazothiadiazine via a sequential stepwise fashion. The reaction sequence involves the initial formation of thiourea followed by regioselective nucleophilic addition and intramolecular ring-closing with dihalo electrophiles. The observed regioselectivity of this reaction is governed by the nature of bases and the reaction sequence.

Diastereoselective synthesis of bridged polycyclic alkaloids via tandem acylation/intramolecular Diels-Alder reaction.

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-ß-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron ß-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-ß-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

Multistep divergent synthesis of benzimidazole linked benzoxazole/benzothiazole via copper catalyzed domino annulation.

An efficient, facile synthesis of structurally diverse benzimidazole integrated benzoxazole and benzothiazoles has been developed. In a multi-step synthetic sequence, 4-fluoro-3-nitrobenzoic acid was converted into benzimidazole bis-heterocycles, via the intermediacy of benzimidazole linked ortho-chloro amines. The amphiphilic reactivity of this intermediate was designed to achieve the title compounds by the reaction of various acid chlorides and isothiocyanates in a single step through the in situ formation of ortho-chloro anilides and thioureas under microwave irradiation. A versatile one pot domino annulation reaction was developed to involve the reaction of benzimidazole linked ortho-chloro amines with acid chlorides and isothiocyanates. The initial acylation and urea formation followed by copper catalyzed intramolecular C-O and C-S cross coupling reactions furnished the angularly oriented bis-heterocycles which bear a close resemblance to the streptomyces antibiotic UK-1.

One pot three component reaction for the rapid synthesis of pyrrolo[1,2-a]benzimidazoles.

An efficient strategy for the synthesis of pyrrolo[1,2-a]-benzimidazole (PBI) linked to an ionic liquid (ILs) as a soluble support under microwave irradiation was explored. The key intermediate benzimidazoles were synthesized via N-acylation followed by cyclodehydration of IL-supported methyl-3-amino-4-(isobutylamino) benzoate. The synthesis of the IL-bound PBI was performed by one-pot three-component condensation under microwave dielectric heating, which involved a Knoevenagel condensation and a [4+1]-cycloaddition reaction. The reaction was monitored directly by means of (1)H NMR. All final products were obtained in good yield and high purity after precipitation.

Palladium-catalyzed regioselective synthesis of 2(2'-biphenyl)benzimidazoles through C-H activation.

An efficient palladium-catalyzed strategy through C-H bond activation for the synthesis of 2(2[Formula: see text]-biphenyl)-benzimidazoles is reported herein. The regioselective C-C bond formation proceeds in a sealed tube via oxidative C-H activation of ortho-directed 2-aryl-benzimidazole to couple with various iodobenzene analogs in high yields. This arylation exhibited high regioselectivity which is able to increase molecular diversity in difficult functionalized positions of parent molecules. This strategy provides a convenient and simple synthesis of biphenyl heterocyclic compounds with high regioselectivity.

Pd(II)-Catalyzed [5 + 2] Cyclization of N-Triflyl Aryl Indoles and α,γ-Substituted Allenoates: A Route to Indole-Fused Benzodiazepines.

A Pd(II)-catalyzed [5 + 2] annulation between N-triflyl aryl indoles and α,γ-substituted allenoates for the synthesis of indole-fused benzodiazepines is reported. This protocol is highly efficient when N-acetylated valine amino acid and DMSO have been used as ligand and cosolvent, respectively. The substrate scope can be further extended to disubstituted allenoates. A reaction mechanism has been proposed based on the mechanistic studies. Mechanistically, the N-acetylated valine amino acid ligand accelerates C-H activation of the C(sp2)-H bond. Consequent cyclopalladation leads to the formation of a six-membered palladacycle. Subsequent coordination and migratory insertion of an allenoate forms the possible eight-membered intermediate. Reductive elimination followed by a [1,3]-H shift results in the indole-fused benzodiazepines.

Qualitative analysis of the fluorophosphonate-based chemical probes using the serine hydrolases from mouse liver and poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis.

The serine hydrolase family consists of more than 200 members and is one of the largest enzyme families in the human genome. Although up to 50 % of this family remains unannotated, there are increasing evidences that activities of certain serine hydrolases are associated with diseases like cancer neoplasia, invasiveness, etc. By now, several activity-based chemical probes have been developed and are applied to profile the global activity of serine hydrolases in diverse proteomes. In this study, two fluorophosphonate (FP)-based chemical probes were synthesized. Further examination of their abilities to label and pull down serine hydrolases was conducted. In addition, the poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis was demonstrated as an appropriate standard serine hydrolase, which can be applied to measure the labeling ability and pull-down efficiency of FP-based probes. Furthermore, mass spectrometry (MS) was used to identify the serine residue that covalently bonded to the active probes. Finally, these FP-based probes were shown capable of establishing the serine hydrolase profiles in diverse mouse tissues; the serine hydrolases pulled down from mouse liver organ were further identified by MS. In summary, our study provides an adequate method to evaluate the reactivity of FP-based probes targeting serine hydrolases.

Ionic liquid-supported synthesis of dihydroquinazolines and tetrahydroquinazolines under microwave irradiation.

An efficient microwave-assisted and water-soluble ionic liquid (IL)-supported synthesis of medicinally important dihydro- and tetrahydroquinazolines has been developed. The protocol involves the S(N)2 substitution reaction of IL-bound 4-bromomethyl-3-nitrobenzoic acid with various primary amines to provide IL-bound 4-((alkylamino) methyl)-3-nitrobenzoate under microwave irradiation. Further elaboration followed by sequential cyclization with various isothiocyanates and aldehydes furnished IL-bound target compounds. Cleavage of the IL support by methanolysis gave dihydro- and tetrahydroquinazolines with high purity and excellent yields. The new protocol has the advantages of shorter reaction time, easy workup process, excellent yields, reduced environmental impact, wide substrate scope, and convenient procedure.

Novel ionic liquid supported-multicomponent reaction toward chimeric bis-heterocycles.

A novel multicomponent reaction between IL-anchored 2-aminobenzoimidazoles, aldehydes, and electron-deficient dienophiles has been explored. The strategy was utilized to develop a rapid parallel synthesis for novel bis-heterocyclic skeleton of benzimidazole-linked dihydropyrimidine on an ionic liquid support. This multicomponent reaction is compatible with a wide range of substrates and furnishes the new chimeric scaffolds with high purity and excellent yields. Use of the ionic liquid as a soluble support facilitates purification by simple precipitation along with advantages like high loading capacity, homogeneous reaction conditions, and monitoring of the reaction progress by conventional NMR spectroscopy.

Exploring a sulfone linker utilizing trimethyl aluminum as a cleavage reagent: solid-phase synthesis of sulfonamides and ureas.

A novel and efficient cleavage reagent, trimethyl aluminum, for traceless sulfinate-functionalized resin has been developed. The synthesis of sulfonamide and urea derivatives via a traceless solid-phase sulfone linker strategy through six synthetic steps comprising utilization of trimethyl aluminum as a novel cleavage reagent was also established. An insight of the plausible mechanism of the cleavage reaction was discussed.

The Anti-Cancer Activity of Pentamidine and Its Derivatives (WLC-4059) Is through Blocking the Interaction between S100A1 and RAGE V Domain.

The S100A1 protein in humans is a calcium-binding protein. Upon Ca2+ binding to S100A1 EF-hand motifs, the conformation of S100A1 changes and promotes interactions with target proteins. RAGE consists of three domains: the cytoplasmic, transmembrane, and extracellular domains. The extracellular domain consists of C1, C2, and V domains. V domains are the primary receptors for the S100 protein. It was reported several years ago that S100A1 and RAGE V domains interact in a pathway involving S100A1-RAGE signaling, whereby S100A1 binds to the V domain, resulting in RAGE dimerization. The autophosphorylation of the cytoplasmic domain initiates a signaling cascade that regulates cell proliferation, cell growth, and tumor formation. In this study, we used pentamidine and a newly synthesized pentamidine analog (WLC-4059) to inhibit the S100A1-RAGE V interaction. 1H-15N HSQC NMR titration was carried out to characterize the interaction between mS100A1 (mutant S100A1, C86S) and pentamidine analogs. We found that pentamidine analogs interact with S100A1 via 1H-15N HSQC NMR spectroscopy. Based on the results, we utilized the HADDOCK program to generate structures of the mS100A1-WLC-4059 binary complex. Interestingly, the binary complex overlapped with the complex crystal structure of the mS100A1-RAGE-V domain, proving that WLC-4059 blocks interaction sites between S100A1 and RAGE-V. A WST-1 cell proliferation assay also supported these results. We conclude that pentamidine analogs could potentially enhance therapeutic approaches against cancers.