Palladium-catalyzed Sonogashira Cross-coupling Reaction Research Articles

Investigation of cationic transformations involving 5-ethynyl-4-arylpyrimidines

An innovative synthetic approach towards 5-ethynyl-4-arylpyrimidines was developed involving acid-catalyzed electrophilic alkylation of phenols with 5-bromopyrimidine, followed by oxidation and palladium-catalyzed Sonogashira cross-coupling reaction. Reactions of these compounds in the presence of trifluoromethanesulfonic acid were investigated. It was discovered these reactions take a different route for precursors with a different position of phenol group in an arene substituent.

Synthesis of desmosine-BSA/KLH conjugates via Sonogashira/Negishi cross-coupling reactions

Desmosine is an elastin crosslinking amino acid that is expected to be a useful biomarker of diseases related to elastin degradation including chronic obstructive pulmonary disease (COPD). In this study, conjugates of desmosine and carrier proteins, such as bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH), with linkers were designed and prepared for the creation of an effective antibody to be used in the development of an enzyme-linked immunosorbent assay (ELISA) system. Synthesis of desmosine along with the linkers having appropriate lengths was achieved via stepwise and chemo/regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions starting from an alkyne with protecting groups over nine steps. Subsequently, Michael addition with a thiolated carrier protein (BSA/KLH) was carried out using Traut’s reagent to afford seven types of desmosine-BSA/KLH conjugates.

Fluorinated Iron(ii) clathrochelate units in metalorganic based copolymers: improved porosity, iodine uptake, and dye adsorption properties.

We report the synthesis of metalorganic copolymers made from the palladium catalyzed Sonogashira cross-coupling reaction between various iron(ii) clathrochelate building blocks with diethynyl–triptycene and fluorene derivatives. The target copolymers CCP1–5 were isolated in excellent yield and characterized by various instrumental analysis techniques. Interestingly, investigation of the copolymers' porosity properties discloses BET surface areas up to 337 m2 g−1 for the target compounds bearing fluorinated iron(ii) clathrochelate units CCP2,5. Moreover, the fluorinated copolymers display an outstanding uptake capacity of iodine with a maximum adsorption of 200 wt%. The target metalorganic copolymers CCP1–5 reveal very good adsorption of organic dyes, namely, methyl blue and methylene blue, from aqueous media.

Electrophilic alkylation of arenes with 5-bromopyrimidine en route to 4-aryl-5-alkynylpyrimidines.

A new synthetic protocol for preparation of medicinally important 4-aryl-5-alkynylpyrimidines is described. The featured approach involves a sequence of chemo- and regioselective Brønsted acid-catalyzed electrophilic alkylation of arenes with 5-bromopyrimidine, followed by oxidative re-aromatization of the formed dihydropyrimidine ring. Finally, palladium-catalyzed Sonogashira cross-coupling reaction provided an end-game strategy.

Synthesis of 4,5-disubstituted-1H-1,2,3-triazoles

Two-step procedure, a palladium catalyzed Sonogashira cross-coupling reaction of aroyl chlorides with aryl acetylenes, and 1,3-dipolar cycloaddition of the 1,3-diarylprop-2-yn-1-ones with sodium azide under catalyst free conditions achieved the synthesis of aryl(4-aryl-1H-1,2,3-triazol-5-yl)methanones in moderate-to-good chemical yields (30–90%). The procedures allowed the synthesis of 4,5-disubstituted-1H-1,2,3-triazol scaffolds containing electron-neutral, -withdrawing, or -donating groups.

Synthesis and acid-responsive spectral properties of near-infrared-absorbing donor-π-donor-type aza boron dipyrromethenes

A series of novel near-infrared-absorbing aza boron dipyrromethenes (aza-BODIPYs) substituted with two electron-donating 4-(dimethylamino)phenylethynyl or 4-(diphenylamino)phenylethynyl groups at the 2- and 6-positions have been synthesized by palladium-catalyzed Sonogashira cross-coupling reactions. It has been found that the introduction of two dodecyloxy chains to the aza-BODIPY skeleton results in improved yield of the coupled products. These compounds have been fully characterized with various spectroscopic methods and elemental analysis. They display a strong Q-band absorption in the near-infrared region (up to 830 nm) and negligible fluorescence emission in toluene. Spectroscopic titration has also been performed for a dimethylamino derivative in chloroform. Upon addition of trifluoroacetic acid, which protonates the amino moieties, the compound shows remarkable ratiometric spectral changes. The Q-band absorption is blue-shifted from 830 to 736 nm and a new fluorescence emission at 756 nm appears, which can be attributed to inhibition of intramolecular charge transfer arising from the amino moieties. The color change from sky-blue to purple can be easily observed by direct visualization.

Synthesis of 8-Substituted 2'-Deoxyisoguanosines via Unprotected 8-Brominated 2-Amino-2'-deoxyadenosine.

A variety of applications of 8-alkynylated nucleosides has prompted the synthesis of new purine analogues. Bromination of unprotected 2-amino-2'-deoxyadenosine with Br2 /AcOH/AcONa gives 2-amino-8-bromo-2'-deoxyadenosine (87%). The brominated derivative is converted to 8-alkynylated 2-amino-2'-deoxyadenosines by palladium-catalyzed Sonogashira cross-coupling reaction via microwave assistance (81 - 95%). The resulting compounds are further transformed to 8-alkynylated 2'-deoxyisoguanosines (52 - 70%). The physical properties of new compounds are investigated.

Luminescent 2,7-disubstituted germafluorenes

A series of six luminescent 2,7-alkynyl(aryl)-3,6-dimethoxy-9,9-diphenylgermafluorenes were synthesized from the corresponding 2,7-dibromo-3,6-dimethoxy-9,9-diphenylgermafluorene utilizing a palladium-catalyzed Sonogashira cross-coupling reaction to incorporate different alkynyl(aryl) groups at the 2,7-positions of the germafluorene ring. The new germafluorenes show an intense absorption band centered between 371 and 388 nm and moderate to strong emission in solution between 401 and 443 nm (ΦF = 0.65–0.83) as well as emission from the solid-state. Germafluorenes 4a–4f were characterized by multinuclear 1H and 13C{1H} NMR, EA, DSC, TGA, UV–Vis, and fluorescence spectroscopy. TGA and DSC studies of germafluorenes 4a–4f showed high thermal stability. The molecular structures of four of the germafluorenes, 4c–4f were determined by X-ray crystallography.

A green protocol for ligand, copper and base free Sonogashira cross-coupling reaction

A convenient methodology has been developed for palladium catalyzed Sonogashira cross-coupling reaction under mild and green reaction conditions. The reaction is catalyzed by an in situ generated catalytic system based on Pd(OAc)2 and WEB (water extract of banana peels ash) in the absence of any organic or inorganic base, ligand and copper salt with excellent yield of cross coupled product. The reaction condition is compatible with electronically diversified aryl iodides and electronically diversified aryl or aliphatic alkyne. The present method developed for the Sonogashira reaction offers many advantages including high conversion, high economy, the involvement of non-toxic green substrates, etc.

Pyrazine- and pyridine-substituted prop-2-yn-1-ols, but-3-yn-2-ols, and but-3-yn-2-ones – purification, stability, and handling revised

A short series of alkynyl-substituted pyrazine and pyridine derivatives was synthesized by the palladium-catalyzed Sonogashira cross-coupling reactions between aryl halides and alkynes. All the products are either white solids or colorless liquids, which is partly in contrast to previous reports. After purification, a color change or intense darkening was observed, in some cases starting almost immediately. Both, the nature of the heteroaromatic ring and the substituents of the alkyne moiety affect their stability. Herein details of synthesis, characterization, and, most importantly, purification and handling are reported.

Optimization of on-resin palladium-catalyzed Sonogashira cross-coupling reaction for peptides and its use in a structure–activity relationship study of a class B GPCR ligand

Class B G protein-coupled receptors are activated by their cognate ligands following a two-step binding model involving a specific network of ligand-receptor intermolecular interactions. In particular, a N-capping structure present in the ligand would contribute significantly to position the N-terminal segment of the ligand once bound to its receptor. The aim of the current study was to implement the use of Pd-catalyzed Sonogashira coupling for the investigation of this structural motif. First, we have developed and evaluated various Sonogashira-based procedures for on-resin post-synthesis modification using a Leu-enkephalin derivative as a model peptide. Next, we have prepared a small library of PACAP-based analogs and evaluated the pharmacological profile of a few of them using a competitive binding assay, as well as functional and survival assays. Notably, our results suggest that the modification of the N-capping region could alter the binding specificity of PACAP without altering its biological activity, thereby opening the way for the design of more selective compounds. Finally, the possibility to achieve sequential multiple point substitutions via the Sonogashira cross-coupling method, during solid phase peptide synthesis, was also evaluated. Altogether, we demonstrated the versatility of such a procedure for the incorporation of various mono- and multiple alkyne-derived modifications during solid phase peptide synthesis and confirmed its usefulness for the structure-activity study of a class B GPCR ligand.

Syntheses of natural and deuterated desmosines via palladium-catalyzed cross-coupling reactions

Desmosine is a crosslinking pyridinium amino acid of elastin and is an attractive biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD). Herein, we describe the total synthesis of natural desmosine and its deuterated derivatives. The synthesized deuterated derivatives could be used as internal standards for the development of an isotope-dilution liquid chromatography–mass spectrometry (LC–MS/MS) analytical method for the accurate determination of desmosine in clinical samples. The key features of our synthesis are stepwise chemo- and regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions for the efficient introduction of the amino acid side chains onto the pyridine core.

Total Synthesis of the COPD Biomarker Desmosine via Stepwise Sonogashira Cross-Coupling Reactions

Abstract Desmosine, a COPD biomarker and elastin crosslinker, is a tetrasubstituted pyridinium amino acid. In this paper, the total synthesis of desmosine is described utilizing stepwise and regioselective palladium-catalyzed Sonogashira cross-coupling reactions of trihalopyridines and terminal alkynes as key steps. The 13-step synthesis starting from 4-hydroxypyridine was achieved in 11% overall yield.

Reactivity of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1$H)$-ones in a palladium catalyzed Sonogashira cross-coupling reaction

Pd/C-PPh$_{3}$--CuI catalyzed Sonogashira cross-coupling of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1$H)$-ones with phenyl acetylene or 3-butyn-1-ol afforded the corresponding 8-alkynylated quinolin-4(1$H)$-one derivatives, exclusively. Double carbo-substitution to afford the 6,8-dialkynyl derivatives was observed when PdCl$_{2}$(PPh$_{3})_{2}$ was used as Pd(0) source. The monoalkynylated derivatives were, in turn, subjected to PdCl$_{2}$ in acetonitrile under reflux to afford either the corresponding 2,4-diaryl-8-bromopyrrolo[3,2,1-\textit{ij}]quinolinones or the 8-(4-hydroxybutanoyl)-substituted quinolinone derivatives, exclusively. Suzuki--Miyaura cross-coupling of the 2-aryl-6-bromo-8-(alkynyl)quinolin-4-ones afforded the 2,4,8-trisubstituted pyrrolo[3,2,1-\textit{ij}]quinolin-6-ones.

ChemInform Abstract: Aryl‐Substituted Unsymmetrical Benzothiadiazoles: Synthesis, Structure, and Properties.

AbstractA family of unsymmetrical ferrocenyl‐substituted benzothiadiazoles bearing a variety of electron‐donating and electron‐withdrawing groups, are synthesized by palladium‐catalyzed Sonogashira cross‐coupling reactions.

The copper-free Sonogashira cross-coupling reaction promoted by palladium complexes of nitrogen-containing chelating ligands in neat water at room temperature

The commercially available 2,2'-dipyridylamine was used as a supporting ligand in the palladium-catalyzed Sonogashira cross-coupling reaction. The reactions between aryl iodides and terminal alkynes with different steric hindrance can be efficiently performed in the absence of copper in neat water at room temperature. The superior catalytic performance of the catalytic system was attributed to water solubility of the palladium 2,2'-dipyridylamine complex. Palladium nanoparticles with small size and narrow size distribution were formed after the cross-coupling reaction.

Donor–acceptor meso-alkynylated ferrocenyl BODIPYs: synthesis, structure, and properties

meso-Alkynylated ferrocenyl BODIPYs (3-6) with varying conjugation length have been designed, and synthesized using the palladium catalyzed Sonogashira cross-coupling reaction of meso-chloro BODIPY with the corresponding ferrocenylethynes. These BODIPYs have been designed to improve the electronic communication between the donor ferrocene, and the acceptor BODIPY. The photonic and electrochemical properties indicate charge transfer (CT) from the ferrocene to the BODIPY. Single crystal X-ray structures of 2', 3, and 6 show interesting supramolecular interactions. Computational studies were used to study the electronic structure of the BODIPYs.

Synthesis of 2,3-Diyne-1,4-naphthoquinone Derivatives and Evaluation of Cytotoxic Activity against Tumor Cell Lines

A series of 2,3-diyne-1,4-naphthoquinone derivatives was synthesized from 2,3-dibromo1,4-naphthoquinone and various functionalized terminal alkynes using palladium-catalyzed Sonogashira cross-coupling reaction. The diynes were evaluated as potential cytotoxic agents against three tumor cell lines: human ovarian adenocarcinoma (OVCAR-8), human metastatic prostate cancer (PC-3M) and human bronchoalveolar lung carcinoma (NCI-H358M), presenting, in general, satisfactory results for inhibition of cell growth.

Total synthesis of the elastin crosslinker (+)-desmopyridine

Desmopyridine, isolated from the acid hydrolysates of bovine ligamentum nuchae, is an elastin crosslinker and an amino acid that has a 3,4,5-trisubstituted pyridine skeleton. Herein we report the first total synthesis of (+)-desmopyridine in 10% yield over six steps starting from 4-aminopyridine via chemo- and regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions.

Synthesis and photophysical properties of poly(aryleneethynylene)s containing dibenzosilole unit

Abstract A series of poly(aryleneethynylene)s containing dibenzosilole unit has been synthesized by palladium-catalyzed Sonogashira cross-coupling reactions with 2,7-diethynyl-9,9-dihexyl-3,6-dimethoxy-9 H -dibenzosilole ( 4 ) as the key monomer. Their photo-physical properties in solution were investigated. All of the polymers showed intense fluorescence with high quantum efficiencies.