Synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines from 2,3-dihalopyridines, (hetero)arylalkynes and Na2S. Further functionalizations

A simple and efficient three-step methodology is described for the first time for the synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines. The first step is a Sonogashira coupling from 3-bromo-2-chloropyridine or 2-bromo-3-chloropyridine with several (hetero)arylalkynes to obtain the corresponding 2- or 3-chloro(hetero)arylethynylpyridines. These were cyclized by treatment with Na2S affording the expected 2-(hetero)arylthienopyridines. As an improvement, these reactions were also performed in one-pot, without the isolation of the Sonogashira product, giving the thienopyridines in similar or better yields, reducing significantly the reaction time after the addition of Na2S. Further functionalizations were achieved in the thienopyridine system either by bromination in the thiophene ring or chlorination in the pyridine ring via a N-oxide intermediate, allowing metal-catalyzed coupling reactions and/or nucleophilic substitutions. The functionalization of some substituents is also possible and as an example a 1,3-diarylurea was obtained from the reaction of an aniline derivative with an arylisocyanate.Foundation for the Science and Technology (FCT – Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho). FCT and FEDER -COMPETE/QREN/EU for financial support through the research unity CQ/UM(686) PEst-C/QUI/UI686/2011, the research project PTDC/QUI-QUI/111060/2009 and through the post-doctoral grant attributed to A. Begouin (SFRH/BPD/36753/2007) also financed by POPH and FSE

Palladium-catalyzed amination of electron-rich or poor benzo[b]thienyl bromides

Recently we have applied the palladium-catalyzed amination to the synthesis of ortho-bromodiarylamincs in the benzo[blthiophene series . Here we describe the application of this methodology to the amination of electron-rich or poor 3-bromobenzo[b}thiophcnes, using the same conditions for both cases

Evaluation of the antioxidant properties of diarylamines in the benzo[b]thiophene series by free radical scavenging activity and reducing power

The antioxidant properties of substituted diarylamines in the benzo[b]thiophene series were evaluated by their reducing power and free radical scavenging activity. The results were compared with those of standards: acid ascorbic for the first method and BHA and BHT for the second. For both methods it was possible to establish some structure–activity relationships (SARs) based on the position of the arylamination on the benzo[b]thiophene moiety, the presence of different substituents on the phenyl ring (F, 1 or 2 OMe) and on the thiophene ring (H, CO2Et, CO2H)

Synthesis of the first thieno-δ-carboline. Fluorescence studies in solution and in lipid vesicles

The first thieno-δ-carboline (6,8,9-trimethyl-5H-pyrido[3,2-b]thieno[3,2-f]indole) was prepared in good yield (70%) by intramolecular palladium-assisted cyclization of an ortho-chlorodiarylamine. The latter was in turn selectively synthesized in high yield (90%) by C–N palladiumcatalyzed cross-coupling of 3-bromo-2-chloropyridine with, the also prepared, 6-amino-2,3,7-trimethylbenzo[b]thiophene. Fluorescence studies in solution show that thieno-δ-carboline has a solvatochromic behaviour. Despite the low fluorescence quantum yields in solution, studies of its incorporation in lipid vesicles of DPPC, DOPE and DODAB indicate that thienocarboline is located mainly inside the lipid bilayer, exhibiting different behaviours in gel or liquid-crystalline phases. Our studies are useful for the incorporation of thienocarboline in liposomes and for controlled drug release assays, due to its biological activity

Synthesis of beta-benzo[b]thienyldehydrophenylalanine derivatives by one pot palladium-catalyzed borylation and Suzuki coupling (BSC) and metal-assisted intramolecular cyclization: studies of fluorescence and antimicrobial activity

Palladium-catalyzed borylation and Suzuki coupling (BSC) in a one pot procedure was successfully applied to the synthesis of several beta-substituted dehydrophenylalanines in the benzo[b]thiophene series maintaining the stereochemistry of the starting materials. Bromobenzo[b]thiophenes bearing an ortho EDG (OMe or Me) were used as the components to be borylated with pinacolborane. Pure stereoisomers of beta-bromodehydrophenylalanines were used as the other Suzuki coupling component. Treatment of the methyl ester of N-(tert-butoxycarbonyl)-(Z)-beta-(2,3,5-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine thus obtained, with Pd(OAc)2 and Cu(OAc)2 in DMF at 160 oC gave two indole derivatives (1:3). The major product resulting from isomerization and cyclization and the minor product resulting from direct cyclization (thienoindole). Reaction at 100 oC gave the same products in similar amounts. Using as starting material the methyl ester of N-(tert-butoxycarbonyl)-(Z)-beta-(2,3,7-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine gave only one product, resulting from isomerization and cyclization at 100 oC. Two of the cyclized compounds were submitted to fluorescence studies; the thienoindole could be used as a fluorescent probe. Preliminary studies of antimicrobial activity were performed on the precursors and on the cyclized products.Fundação para a Ciência e Tecnologia - POCTI/99/QUI/32689, SFRH/BD/4709/2001

Palladium-catalysed amination of electron-deficient or relatively-rich benzo[b]thienylbromides: preliminary studies of antimicrobial activity and SARs

Several diarylamines in the benzo[b]thiophene series were prepared by palladium catalyzed amination of ethyl 3-bromobenzo[b]thien-2-yl carboxylate with anilines and 5-aminoindole, in good to high yields using Pd(OAc)2, BINAP, Cs2CO3 in toluene. The presence of the ester group in the position 2 of the benzo[b]thiophene moiety increases the yields and lowers the heating times when compared with reactions using 3-bromobenzo[b]thiophene. When aminopyridines, instead of anilines, were used the ligand and the solvent need to be changed to XANTHPHOS and dioxane in the amination reaction. From 2-aminopyridine a one pot C-N coupling and intramolecular cyclization involving the nitrogen of the pyridine, with lost of ethanol, occurred giving an interesting fluorescent tetracyclic heteroaromatic compound. The antimicrobial activity, the minimal inhibitory concentration (MIC) and structure-activity relationships (SAR) were evaluated. A selectivity with low MICs was observed against Bacillus Cereus and good results were also obtained against Candida albicans. The acids obtained by hydrolysis of the ester group, as non proteinogenic alpha,beta-unsaturated beta-amino acids can be incorporated in a peptide chain to induce conformational constraints.Fundação para a Ciência e Tecnologia. ERASMUS

Virtual screening of thieno[3,2-b]pyridine arylthioether (hetero)aryltriazole derivatives as potential tyrosine kinase VEGFR2 inhibitors.

Recently we presented a series of thieno[3,2-d]pyrimidinc ether I ,3-diaryl ureas with potent VEGFR2 inhibit ion activity. The binding mode was analyzed and the compounds showed a type-11 tyrosine kinase inhibition mode, with the thienopyrimidine moiety forming a Hydrogen Bond (H-bond) with CYS919 residue and the urea moiety forming a H-bonds with key residues G LU885 and ASP I 046 of the kinase domain. In this study, the potential of changing the more widely used urea moiety to a triazole moiety now in thieno[3,2-b)pyridine a rylthioethers, was analyzed. A number of 3D thieno[3.2-b ]pyrid ine arylthioethers (hetero )aryltriazole derivatives (Figure I) were designed and then molecular docking studies, using AutoDock4, were performed against a VEGFR2 crystal

Synthesis of new N-[3-(thieno[3,2-b]pyridine-7-ylthio)phenyl]benzamides as potential inhibitors the tyrosine kinase domain of VEGFR2

Angiogenesis, the growth of new vessels from preexisting vasculature, is a critical step in tumor progression [1]. The tyrosine kinase Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is a crucial mediator in angiogenesis since the VEGF, excreted by the tumor cells, binds to it activating several signaling pathways involved in cell survival and proliferation [2]. Recently thienopyridine derivatives showed to be promising inhibitors of the tyrosine kinase domain of VEGFR2 [3,4]. In this work new N-[3-(thieno[3,2-b]pyridine-7-ylthio)phenyl]benzamides were prepared as potential VEGFR2 inhibitors suggested by rational design, as presented below.FCT -Portugal for financial support through the NMR Portuguese network (Bruker 400 Avance 111-Univ Minho). FCT and FEDER -COMPETE-QREN-EU for financial support through the research unities PEstC/ QUI/UI686/2011, PEst-OE/AGR/UI0690/2011, the research project PTDC/QUI-QUI/111 060/2009 and the post-Doctoral grant A.B.(SFRH/BPD/36753/2007) also financed by POPH and FSE

Mild Pd-Catalyzed Aminocarbonylation of (Hetero)Aryl Bromides with a Palladacycle Precatalyst

A palladacyclic precatalyst is employed to cleanly generate a highly active XantPhos-ligated Pd-catalyst. Its use in low temperature aminocarbonylations of (hetero)aryl bromides provides access to a range of challenging products in good to excellent yields with low catalyst loading and only a slight excess of CO. Some products are unattainable by traditional carbonylative coupling.National Institutes of Health (U.S.) (Award GM46059)Danish National Research Foundation (Grant DNRF59)Villum FoundationDanish Council for Independent Researc

Hexafluoroisopropanol-Promoted Metal-Free Allylation of Silyl Enol Ethers with Allylic Alcohols

A metal-free protocol for the reaction of silyl enol ethers with allylic alcohols based on the use of 1,1,1,3,3,3-hexafluoroisopropanol as a promoter able to activate both reactants, is described. This simple and straightforward transformation proceeds smoothly under mild conditions, rendering the corresponding allylated products in generally good yields.Financial support from the University of Alicante (UAUSTI16-03, UAUSTI16-10, VIGROB-173) and the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P) is acknowledged