Base catalyzed intramolecular transamidation of 2-aminoquinazoline derivatives on solid phase

A novel intramolecular cyclo-elimination via transamidation on the Rink Amide AM resin under mild basic conditions is presented. The methodology led to the synthesis of an important class of cardiotonic agents: imdiazo- and pyrimido-quinazolines from the corresponding 2-aminoquinazoline hydrobromide salt under mild basic conditions. NMR based titration studies revealed the role of hydrobromide as a molecular switch, which on removal triggers the cyclisation of aminoquinazoline to tricyclic structures. The main advantage of transamidation under basic conditions over the TFA cleavage is the recyclability of the resin obtained after cyclo-elimination. This has been demonstrated by successive synthesis of four structurally diverse imidazoquianzolin-2-ones using the same batch of resin without any cross contamination.     

Novel approaches for the solid-phase synthesis of biheterocyclic dihydroimidazole analogues

The solid-phase syntheses of dihydroimidazolyl 2-alkylthiobenzimidazoles, dihydroimidazolyl 2-alkylsulfonylbenzimidazoles, dihydroimidazolyl dihydroquinoxalin-2,3-diones, and dihydroimidazolyl dihydrobenzimidazol-2-imines are described. Following reduction of a resin-bound amino acid amide, the primary amine of the resulting resin-bound diamine was N-acylated with 4-fluoro-3-nitrobenzoic acid. Treatment with POCl3 led to formation of a dihydroimidazole derivative via dehydrative cyclization. The resin-bound dihydroimidazole derivative was then used as the key starting material for the synthesis of the aforementioned biheterocycles. Following cleavage, the resulting compounds, obtained in moderate yield and good purity, were characterized by LC-MS and 1H NMR and 13C NMR spectroscopy.     

A modified strategy for Pictet-Spengler reaction leading to the synthesis of imidazoquinoxalines on solid phase

An alternative strategy for Pictet-Spengler reaction involving an N-1 linked aromatic amine of imidazole and aldehydes is described. This is in contrast to a typical Pictet-Spengler reaction, which involves an aliphatic amine attached to the carbon of an activated aromatic nucleus and an aldehyde. Our strategy commences with the nucleophilic replacement of fluorine in resin-bound o-fluoro-nitrobenzoic acid with mono- or disubstituted imidazole, followed by reduction of the nitro group to give an N1 linked aromatic amine of the resin-bound imidazole. This was subsequently treated with an aldehyde in toluene at 80 degrees C and then oxidized in the presence of DDQ to give resin-bound imidazoquinoxalines. Finally, acidolytic cleavage furnished the desired compounds in high yields and purities.     

Copper-catalyzed aerobic oxidative intramolecular C-H amination leading to imidazobenzimidazole derivatives

A highly efficient copper-catalyzed aerobic oxidative intramolecular C-H amination has been developed using substituted 2-(1H-imidazol-1-yl)-N-alkylbenzenamines as the starting materials, and the corresponding imidazobenzimidazole derivatives were obtained in excellent yields. This is an economical and practical method for the construction of N-heterocycles.     

Novel synthesis of benzoxaphosphacycloalkane derivatives via palladium-catalysed intramolecular formation of carbon-phosphorus bond

A novel synthesis of benzoxaphosphacycloalkane derivatives by palladium-catalysed intramoleclar cyclization of the corresponding alkane-or benzenephosphonous acid mono(ω-o-bromophenylalkyl)ester is presented.     

Unexpected phenyl group rearrangement during an intramolecular Scholl reaction leading to an alkoxy-substituted hexa-peri-hexabenzocoronene

A simple dimethoxy-substituted hexa-peri-hexabenzocoronene (m-dimethoxy HBC) was unexpectedly obtained along with a bis-spirocyclic dienone during an intramolecular Scholl reaction of its para isomer.     

Optimization of spiroimidazolidinone derivatives synthesis on solid phase using SynPhase™ Lanterns

We report the synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives from N-benzyl-4-piperidone and N-protected amino acid amides on solid support. We have translated the chemistry from solution to solid phase using a backbone amide linker (BAL) mimic. Using a parallel combinatorial approach, we performed the optimization of the synthesis on SynPhase™ Lanterns.     

Enantioselective synthesis on the solid phase

Organic transformations on substrates which are immobilized on an insoluble, polymeric carrier have found broad application in compound collection synthesis. In contrast to other synthetic methodologies in solid-phase organic synthesis, reactions that afford non-racemic products are strikingly under-represented. Not only does the introduction of stereoinformation on immobilized, achiral starting materials provide enantioenriched products which can be of value for biological testing, but it also opens up new perspectives for accessible structures. This feature article gives an overview of successful enantioselective transformations on a solid support. Critical differences in the corresponding solution-phase protocols are highlighted, and applications to the generation of compound collections are particularly mentioned.     

Zirconyl chloride promoted highly efficient solid phase synthesis of amide derivatives

An efficient solid phase route for the synthesis of amide derivatives by the reaction of carboxylic acids with urea in the presence of catalytic amount of zirconyl chloride under microwave irradiation conditions was described.In this way,a range of interesting amide derivatives was obtained in good to excellent yields.The catalyst was recycled with fresh reactants and it gave almost similar results without significant loss of activity up to the third run.     

Dimethyl sulfoxide-aided copper(0)-catalyzed intramolecular decarbonylative rearrangement of N-aryl isatins leading to acridones

Described here is the first example of Cu(0)-catalyzed intramolecular decarbonylative rearrangements of readily available N-aryl isatins assisted by solvent dimethyl sulfoxide(DMSO) under air atmosphere and additive-free conditions leading to various biologically important acridones in good to excellent yields.This novel transformation is proposed to go through a sequential DMSO-aided Cu insertion into the amide C-N bond,CO extrusion,Cu migration,reductive elimination and DMSO-aided proton migration processes,involving multiple types of bond cleavage and formation in a single chemical step.     

Microwave assisted DIC-promoted intramolecular cyclization for solid phase synthesis of trisubstituted imidazolidinones and pyrimidinones

A convenient solid phase synthesis of trisubstituted imidazolidinones and pyrimidinones via microwave assisted DIC-promoted intramolecular cyclization is described. Intramolecular cyclization of a resin-bound thiourea prepared by acylation of a dipeptide with an aryl isothiocyanate was rapidly promoted with DIC under microwave to afford imidazolidinones and tetrahydropyrimidinones in good yield and purity.     

A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach

Hydroxyindoline-derived scaffold, 9, was synthesized with the goal of generating a library of indoline-based natural product-like tricyclic derivatives to be utilized as small-molecule chemical probes. The tricyclic ring was obtained by a Mitsunobu reaction of the N-nosyl amino acid conjugate with the primary hydroxyl group. The solid-phase synthesis was achieved by immobilizing scaffold 9 onto the solid support giving a compound, 15. This was then subjected to a series of reactions on solid phase, including the Mitsunobu reaction, leading to the desired indoline-derived tricyclic derivative. The final product has two diversity sites: (i) amino acid as the first diversity and (ii) amidation of the secondary amine for the second diversity. These two diversity sites were utilized in the library generation by IRORI split-and-mix approach.     

The H-phosphonate approach to the synthesis of phosphopeptides on solid phase

[reaction: see text]. Ammonium tert-butyl H-phosphonate was used for the phosphorylation of Tyr- and Ser-containing peptides synthesized by an Fmoc strategy. This reaction, leading to a monoprotected peptide phosphate, was found to be highly efficient and generally applicable. Moreover, the method employed avoids undesired side reactions during chain elongation (pyrophosphate formation and beta-elimination catalyzed by piperidine).     

Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives

As part of our continuing studies of polymer-supported pericyclic reactions for preparing biologically interesting heterocyclic compounds, we have introduced a traceless solid-phase synthesis of hexahydrocinnolines. We developed a method in which mild reaction conditions can be used for the hetero-Diels-Alder reactions on a polymeric support. The dienoic 3-vinyl-2-cyclohexenol attached to a Wang resin through an ether linkage undergoes [4 + 2] cycloaddition reaction with several azadienophiles. The highly stereoselective Diels-Alder reaction showed preferential formation of a single cycloadduct resulting from an anti attack of the dienophile on the polymer-bound diene. Trifluoroacetic acid-mediated cleavage of the polymer-bound cycloadducts yields fused nonaromatic hexahydrocinnolines in moderate yields in three steps.     

Novel synthesis and rearrangement of 3,1,5-benzoxadiazepines

N,N-Diacyl-o-phenylenediamines react with dibromotriphenylphosphorane in the presence of triethylamine as HBr captor to give 3,1,5-benzoxadiazepines in good yields. If the reaction is carried out without acid acceptor the initially formed 3,1,5-benzoxadiazepine finally rearranges into 1-acylbenzimidazole. It has also been found that the isolated 2,4-dimethyl-3,1,5-benzoxadiazepine rearranges under the influence of hydrogen bromide into 1-acetyl-2-methylbenzimidazole.

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Neue Synthese und Umlagerung des 3,1,5-Benzoxadiazepins

Zusammenfassung Die Umsetzung von N,N-Diacyl-o-phenylendiaminen mit Triphenyldibromphosphoran in Gegenwart von Triethylamin als HBr-bindendes Mittel führt mit guten Ausbeuten zu den 3,1,5-Benzoxadiazepinen. Wird die Reaktion ohne säurebindendes Mittel durchgeführt, dann erleidet das anfänglich entstandene 3,1,5-Benzoxadiazepin eine Umlagerung in 1-Acylbenzimidazol. Es wurde auch gefunden, daß das isolierte 2,4-Dimethyl-3,1,5-benzoxadiazepin unter dem Einfluß des Bromwasserstoffs in 1-Acetyl-2-methylbenzimidazol umgelagert wird.

     

Design and synthesis of a dual linker for solid phase synthesis of oleanolic acid derivatives

A hydrophilic amino-terminated poly(ethylene glycol)-type dual linker for solid phase synthesis of oleanolic acid derivatives using trityl chloride resin was designed and synthesized for the first time. Model reactions in both liquid and solid phase were performed to show the feasibility of its selective cleavage at two different sites. The biological assay results indicated that the long and flexible alkyl ether functionality in the linker is less likely to be critical for the binding event. Following the successful solid-phase synthesis of model compounds, the potential of this dual linker in reaction monitoring and target identification is deemed worthy of further study.     

Palladium-catalyzed rearrangement/arylation of 2-allyloxypyridine leading to the synthesis of N-substituted 2-pyridones

[reaction: see text] The Pd-catalyzed one-pot rearrangement/arylation of 2-allyloxypyridine is described. The catalyst/base combination of Pd[P(t-Bu)(3)](2)/Ag(2)CO(3) was found to be optimal for this one-pot rearrangement/arylation. The initial rearrangement of 2-allyloxypyridine was found to be catalyzed by both Pd(0) and Pd(II) complexes with different mechanisms.     

Traceless Fischer indole synthesis on the solid phase

The Fischer indole synthesis using polymer-bound hydrazines is employed as the key step for the development of a traceless indole synthesis on a solid support.