Palladium Cross-coupling Reactions Research Articles

Synthesis of D-A-A and D-A-D Pyrimidine π-Systems Using Triorganoindium Reagents: Optical, Vibrational, and Electrochemical Studies.

A series of donor-acceptor-acceptor (D-A-A) and donor-acceptor-donor (D-A-D) systems based on a pyrimidine π-spacer with various substituents at the C-2 position has been successfully prepared. The synthesis involved site-selective palladium cross-coupling reactions of chloropyrimidines with triorganoindium reagents and proceed in good yields and with atom economy. 4-(N,N-Diphenylamino)phenyl was chosen as the donor group and thien-2-yl dicyanovinylene as the acceptor one. The optical, vibrational, electrochemical, and density functional theory (DFT) calculations of these molecular systems were analyzed, and experimental values show the important role of the substituents at the C-2 position of the pyrimidine with stronger electron accepting ability, absorption in a wide range of UV/vis, acceptable fluorescence lifetime, and effective intramolecular charge transfer (ICT) properties. The ICT was observed in both series by the bathochromic shift on increasing the polarity of the solvent. In addition, DFT calculations found lower lowest unoccupied molecular orbitals of D-A-A molecules that suggest good electron ejection and transportation, being good properties for their application in various organic optoelectronic devices.

Synthesis of arylated chalcone derivatives via palladium cross-coupling reactions

A useful protocol for arylation of the olefin double bond of chalcones to afford tri- and tetra-substituted chalcone derivatives is reported. The protocol begins with the Heck reaction between chalcones and aryl iodides providing β-arylchalcones. This reaction tolerates various functional groups on both rings, as well as deactivated aryl iodides. The products are obtained in moderate to excellent yields and the (E)-β-arylchalcones (E:Z > 96:4) can be isolated via precipitation. Competitive Heck reactions pointed to a significant effect of ring one substituents on the reaction rate, while substituents on ring two have a much smaller effect. To access α,β-diarylchalcones, a sequential bromination-Suzuki cross coupling strategy was applied to the β-arylated compounds which afforded double arylated chalcone derivatives in 60–99% yield over two steps.

Three successive and regiocontroled palladium cross-coupling reactions to easily synthesize novel series of 2,4,6-tris(het)aryl pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines.

The first access to tris(het)arylated pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. The series were generated from 4-chloroaminopyridinium, which afforded the key intermediate bearing three leaving groups, i.e. a C-2 methylsulfanyl, a lactame carbonyl group in C-4 and a chlorine atom in C-6. The regioselective reactions led to the tris(het)aryl derivatives with satisfying to high yields. The three successive cross-coupling reactions occurred first in C-6 by the displacement of chlorine, next in C-4 position by a sequential Pd-catalyzed phosphonium coupling and finally in C-2 under a Pd/Cu-catalyzed desulfitative cross-coupling reaction. The optimization and scope of each reaction are discussed and the original compounds characterized.

Palladium-Catalyzed Heck Cross-Coupling Reactions in Water: A Comprehensive Review

Palladium-catalyzed cross-coupling reactions have emerged as one of the most versatile tools in organic chemistry. Extensive efforts were made to adapt these reactions to aqueous media, not only for the purpose of environmental conservation but also to expand the scope, increase the efficiency and implement bio-compatible protocols. Among different palladium cross-coupling reactions, the Heck reaction turned out to be the most challenging in an aqueous environment. This led to various original developments in catalyst design. This review summarizes the different approaches pursued to perform Heck reactions in neat water as well as aqueous mixtures. Both, homogeneous and immobilized catalysts, including nanoparticles are presented herein.

Heck and Sonogashira couplings in aqueous media – application to unprotected nucleosides and nucleotides

Amongst all synthetic nucleosides having high potential biological activities, C5-modified pyrimidines and C7-deaza or C8-modified purines have been particularly studied. These main chemical modifications have been developed using palladium cross-coupling reactions. This review focus on both Heck and Sonogashira cross-coupling of nucleosides using different aspects of the twelve principles of green chemistry: use of aqueous medium and no protection/deprotection steps.

ChemInform Abstract: Palladium‐Catalyzed Suzuki Reaction in Aqueous Solvents Applied to Unprotected Nucleosides and Nucleotides

AbstractReview: [56 refs.

ChemInform Abstract: FeCl3‐Diorganyl Dichalcogenides Promoted Cyclization of 2‐Organochalcogen‐3‐alkynylthiophenes: Synthesis of Chalcogenophene[2,3‐b]thiophenes.

AbstractThe reaction proceeds exclusively via a 5‐endo‐dig cyclization.

FeCl3–diorganyl dichalcogenides promoted cyclization of 2-organochalcogen-3-alkynylthiophenes: synthesis of chalcogenophene[2,3-b]thiophenes

We report here our results on the FeCl3-diorganyl dichalcogenides intramolecular cyclization of 2-organochalcogen-3-alkynylthiophenes. The cyclization reaction proceeded cleanly under mild reaction conditions giving the (S)-Se-, (S)-S- and (S)-Te-heterocycles in good yields. In addition, the obtained chalcogenophenes were readily transformed into more complex products using the palladium cross-coupling reaction with boronic acids. Conversely, using a metal-halogen exchange reaction with n-BuLi, the chalcogenophenes produced the lithium-intermediate which was trapped with aldehyde furnishing the desired secondary alcohol in good yield.

Trisubstitution of pyridine through sequential and regioselective palladium cross-coupling reactions affording analogs of known GPR54 antagonists

Because of their large spectrum of applications, poly-functionalized pyridines remain an attractive challenge in modern organic chemistry. We describe the poly-functionalization of halopyridines through a series of sequential and regioselective palladium-catalyzed cross-coupling reactions (Suzuki–Miyaura, Sonogashira and Buchwald–Hartwig reactions). This strategy was applied to the synthesis of several analogs of single non-peptidic known GPR54 antagonists.

Practical and efficient applications of novel dioxaborolanes and dioxaborinanes in the synthesis of corresponding boronates and their use in the palladium-catalyzed cross coupling reactions

The syntheses of boronates derived from the reaction of dioxaborolanes and dioxaborinanes with either organolithium or organomagnesium reagents are investigated along with their subsequent use in the palladium cross coupling reaction. The intrinsic stability of these cyclic esters contributes to their facile reaction with both lithium and magnesium nucleophiles at mild and safe conditions. We have found that many of the reactions proceed at room temperature which is a significant improvement over the traditional routes which require cryogenic temperatures. The scope of these reactions and their practical application to large scale process synthesis is described.

The potential antioxidant activity of 2,3-dihydroselenophene, a prototype drug of 4-aryl-2,3-dihydroselenophenes

Here we present our results in palladium cross-coupling reaction of aryl boronic acids with 4-iodo-2,3-dihydroselenophene derivatives. The cross-coupled products were obtained in satisfactory yields. A dehydrogenation of4,5-diphenyl-2,3-dihydroselenophene was activated by DDQ and the 2,3-diarylselenophene was obtained in good yield. Regarding the antioxidant activity, the selenophene derivative 3a was effective in counteracting lipid and protein oxidation as well as scavenging ABTS radical. The findings of the present study indicate that 3a is a prototype for future drug development programs to treat disorders mediated by reactive oxygen species.

Efficient synthesis of new 3-heteroaryl-1-functionalized 1 H-indazoles

The efficient synthesis of novel 3-heteroaryl N-1-functionalized indazoles, via palladium cross-coupling reactions of ethyl (3-iodo-1 H-indazol-1-yl)acetate with 2- and 3-pyrrolylboronic acids, 2-, 4- and 5-thiazolylstannanes, and other heteroarylmetallated derivatives are reported.

Synthesis, characterization and preliminary investigation of the electro redox properties of anthracenyl-functionalized terpyridyl ligands

We report the synthesis, characterization and preliminary investigation of the electro redox properties of soluble bromoterpyridine ligand precursors L1, L2 and L3 having one to three anthracenyl modules. The synthetic protocol is based on sequential palladium cross-coupling reactions between 9,10-dibromoanthracene and bromoterpyridine, 9-bromoanthracene-terpyridine or 9-bromo-dianthraceneterpyridine synthons. With increasing numbers of anthracene units on the terpyridine ligand, common absorption wavelengths at the near visible region and enhanced molar absorptivity coefficients were recorded. However, the luminescence intensity decreases with increasing length of π-conjugation relating to aggregation effects in the molecules. The cyclic voltammograms of L1 and L2 display good electro redox activity, being better than that of L3.

Efficient access to disubstituted exo-glycals. Application to the preparation of C-glycosyl compounds

Efficient methods of preparation of disubstituted exo-glycals by palladium cross-coupling reaction on the readily available dibromo exo-glycal and methoxycarbonyl exo-glycal have been developed. Hydrogenation of these new monosubstituted and disubstituted exo-glycals proceeded with a high stereocontrol and led to original C-glycosyl compounds.

Synthesis of α-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-Carbamates and an Internal N→C Alkyloxycarbonyl Migration

A novel and efficient synthesis of precursors of α-amino acids is described. The key step involves a carbolithiation reaction on acyclic ene-carbamates generated from the corresponding vinylphosphates via a palladium cross-coupling reaction followed by a spontaneous internal N→C alkyloxycarbonyl migration.

Synthesis of Tri- and Tetrasubstituted Olefins by Palladium Cross-Coupling Reaction

Tri- and tetrasubstituted olefins were obtained in high yields and regioselectivities using stilbene as starting material. First, stilbene was converted into (E)-bromostilbene by a bromination-dehydrobromination sequence. Then, (E)-bromostilbene was coupled with arylboronic acids at room temperature and low loading of Pd catalyst precursor (0.5-0.05 mol%) to afford selectively (E)-1-aryl-1,2-phenylethylenes in high yields (87-98%). Bromination of triphenylethylene afforded directly the bromotriphenylethylene that also underwent coupling reactions with arylboronic acids under mild conditions to afford tetrarylethylene (88-90% yield). Under the same conditions attempted Suzuki cross-coupling reactions of (E)-bromostilbene or 1,1,2-triphenylethene with alkylboronic acids were unsuccessful. However, the alkyl group could be introduced under mild conditions and high yields by using a Pd-catalyzed Negishi coupling protocol.

Sequential regio and chemoselective cross-coupling reactions by means of O6-tri-isopropylsulfonate of 4-bromo-pyridazine 3,6-dione

Regioselective desymmetrization of 4-substituted pyridazin-3,6-diones using sterically hindered 2,4,6-triisopropylphenyl-sulfonylchloride allowed efficient sequential palladium cross-coupling reactions.

Synthesis and Liquid-crystalline Properties of Bromoalkyloxy-substituted Terphenylenes

Abstract A series of bromoalkyloxy-substituted terphenylenes were synthesized through a Palladium cross-coupling reaction between arylboronic acids and bromoaryl derivatives. By DSC it was observed that these intermediates show a rich thermotropism in a wide range of temperature (110–180 °C) and by X-ray diffraction it was determined that the liquid-crystalline nature corresponds to tilted type smectic mesophases (SmC, SmF/SmI, and a two-dimensional ordered tilted mesophase SmX).

Use of Polyfunctionalized Pyridazines as Reactive Species for Building Chemical Diversity

Efficient chemical pathways leading to differently substituted 3-aminopyridazines have been reviewed with the general objective to help to design the most straightforward chemical pathways to produce libraries of compounds with largest chemical diversity. Thus 3-chloropyridazines bearing at different positions halogens may offer opportunities, when submitted two tandem of selected reactions leading to the expected compounds (amination vs. palladium cross coupling reactions (PCCR)). As a result of its electron-deficient system, the commercially available 3,6-dichloropyridazine offers a large panel of reactivities in particular the access to 4-functionalized systems (vicarious nucleophilic substitution, halogenation, metalation/alkylation, arylation using Lewis acid catalyst). In other cases, the functionalized pyridazin-3- one precursors may be helpful as the free amide could also deal with PCCR by means of its O-Triflate derivative. A particular attention was given to opportunities offered by electron deficient 3,6, 3,4,6, 3,4,5, and 3,4,5,6- polychloropyridazines. However increasing the number of chlorines increased the number of possible combinations toward both amination and PCCR, and in general, led to a loss of regioselectivity. Thus introduction of different functionalities (bromine, iodine, enol, nitro, cyano, methyl and other carbon acids) at the pyridazine ring significantly increased their potentials, (increased reactivity and regioselectivity). Finally tetra-functionalized pyridazines were briefly introduced. They may constitute the most suitable scaffolds for building in an expeditive manner different 3- aminopyridazine sub-series by means of combinatorial chemistry.

Adenosine Kinase Inhibitors. 4. 6,8-Disubstituted Purine Nucleoside Derivatives. Synthesis, Conformation, and Enzyme Inhibition

6,8-Disubstituted purine nucleosides were synthesized and evaluated as adenosine kinase inhibitors (AKIs). A method was developed to selectively substitute arylamines for halogens at C6 and C8 which utilizes alkali salts of arylamino anions. Regioselectivity was found to be counterion dependent. Potassium and sodium salts add selectively to C6 of 6-chloro-8-iodo-9-(2,3,5-tris-O-tert-butyldimethylsilyl-beta-d-ribofuranosyl)purine (7a) while lithium salts add to C6 and C8 positions. Differential 6,8-bisarylamin-N,N'-diylpurine nucleosides such as 8-anilin-N-yl-6-indolin-N-yl-9-(beta-d-ribofuranosyl)purine (10b) can be prepared by employing stepwise reactions of potassium and then lithium salts of different arylamino anions followed by fluoride ion-induced desilylation. Other C8-substituted compounds were prepared by way of either C8 lithiation chemistry or palladium cross-coupling reactions. Several of these compounds were potent AKIs (e.g. 10b, AK IC(50) = 0.019 microM) and are more potent than the previous best purine-based AKI 5'-deoxy-5'-aminoadenosine (AK IC(50) = 0.170 microM). AK inhibitory potency was greatest for those compounds with (1)H NMR evidence of a predominant anti glycosyl bond conformation, whereas most analogues adopt a syn conformation because of steric repulsions between the C8 substituent and the ribose group. The inhibitors are proposed to bind in the anti conformation with the hydrophobic C6 and C8 substituents contributing to AK affinity in a manner similar to the C4 and C5 aryl substituents of the potent diaryltubercidin nucleoside inhibitor series.