Efficient and ligand free palladium catalyst for Suzuki and Heck cross-coupling reactions

A simple and efficient system for Suzuki cross-coupling reactions was developed using a ligandless catalyst of Pd nanoclusters generated in situ from Pd(acac)₂. The cross-coupling reactions proceeded under mild reaction conditions with a high reaction rate (5 min) to give various biaryls in high yields. The system also exhibited catalytic potential for Heck reaction between aryl bromides and styrene.     

Selective enhancement effects of silver salts on the transition metal-catalyzed synthesis of gem-difluorinated heterocyclics using 2,2-difluorohomopropargyl amides

The addition of silver salts had an effect on the catalyst activity in the Pd(0)-catalyzed cyclization-coupling tandem reaction, as well as in the Rh(I)-catalyzed Pauson-Khand reaction. The cationic palladium complex generated from Pd(PPh₃)₄ (2.5 mol%) with AgSbF₆ (1.5 equiv.) activates the triple bond of 2,2-difluoropropargylic amides to give the 4,5-disubstituted 3,3-difluoro-γ-lactams, through a sequential 5-endo-dig cyclization and cross-coupling reaction. The γ-lactam was transformed into ring-opened monofluorovinylic compounds after silica-gel chromatography. Pauson-Khand reaction of fluorinated 1,7-enyne amides using catalytic amounts of [Rh(COD)₂]₂ (5 mol%) and AgOTf (20 mol%) gave the corresponding gem-difluorinated bicyclic lactam.     

Mechanistic studies on the Pd–Cl cleavage of dichloro-[1-alkyl-2-(naphthylazo)imidazole]palladium(II) complexes by 8-quinolinol

8-Quinolinol (HQ) reacts with [Pd(α-/β-NaiR)Cl₂] [α-/β-NaiR = 1-alkyl-2-(naphthyl-α-/β-azo)imidazole] in acetonitrile (MeCN) solution to give [Pd(α-/β-NaiR)(Q)](ClO₄). The products are characterized by spectroscopic techniques (FT-IR, UV–Vis, NMR). The reaction kinetics show a first order dependence of rate on each of the concentration of the metal complex and HQ. Addition of LiCl to the reaction retarded the rate of reaction and has proved the cleavage of the Pd–Cl bond as the rate-determining step. Thermodynamic parameters (Δ^‡H^° and Δ^‡S^°) are determined from variable temperature kinetic studies. The magnitude of the second order rate constant, k₂, increases as in the order: Pd(NaiEt)Cl₂ < Pd(NaiMe)Cl₂ < Pd(NaiBz)Cl₂ as well as Pd(β-NaiR)Cl₂ < Pd(α-NaiR)Cl₂.     

Pd–Cl cleavage of dichloro-[1-alkyl-2-(naphthylazo)imidazole]palladium(II) complexes by picolinic acid: Kinetic and mechanistic studies

Picolinic acid (picH) reacts with [Pd(α-/β-NaiR)Cl₂] [α-/β-NaiR = 1-alkyl-2-(naphthyl-α-/β-azo)imidazole] in acetonitrile (MeCN) medium to give [Pd(α-/β-NaiR)(pic)](ClO₄). The products are characterized by spectroscopic techniques (FT-IR, UV–Vis, NMR). The reaction kinetics show first order dependence of rate on each of the concentration of Pd(II) complex and picH. Addition of LiCl to the reaction decreases the rate of reaction and has proved the cleavage of Pd–Cl bond at the rate-determining step. Thermodynamic parameters (Δ^‡H° and Δ^‡S°) are determined from variable temperature kinetic studies. The magnitude of the second order rate constant, k₂ increases as in the order: Pd(NaiEt)Cl₂ < Pd(NaiMe)Cl₂ <  Pd(NaiBz)Cl₂ as well as Pd(β-NaiR)Cl₂ <  Pd(α-NaiR)Cl₂.     

Tandem versus single C-C bond forming reaction under palladium-copper catalysis: regioselective synthesis of α-pyrones fused with thiophene

We herein report a highly convenient protocol for rapid construction of α-pyrone fused with thiophene. This includes one-pot and regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]pyran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes in a simple synthetic operation. The coupling-cyclization reaction was initially studied in the presence of Pd(PPh₃)₂Cl₂ and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C-C bond forming reaction in the presence of palladium catalyst rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling-cyclization-coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C-C bond forming reaction however, can be restricted to the formation of single C-C bond by using 10% Pd/C-Et₃N-CuI-PPh₃ as catalyst system in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was performed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.     

Potentiometric study of the kinetics and equilibria of formation of chloroglycinate palladium(II) complexes from bis-glycinato palladium(II) complexes

The equilibria and kinetics of the reaction of Pd(gly)₂ complexes with hydrogen ions and chloride ions has been studied by a potentiometric method. The underlying idea of the method is the measurement of solution pH as a function of reaction time t using a glass electrode. The solutions used had the following initial compositions: xM Pd(gly)₂, xM Hgly, and 1 M NaCl with x = 1 × 10^?4, 5 × 10^?4, and 1 × 10^?3; initial pH₀ was from ～3.5 to ～4.4. The experimentally determined pH versus t dependences and the rate equation for a pseudo-second-order reaction were used to determine the equilibrium constant of formation of Pd(gly)(Hgly)Cl complexes from Pd(gly)₂ complexes and the observed rate constant for this reaction, k _obs. The dependence of k _obs on the pH of the acid solutions studied was assigned to a change in the sequence of the reactions of addition of a hydrogen ion and a chloride ion to the complex Pd(gly)₂.     

Selective synthesis of 3-methyleneindolin-2-ones by one-pot multicatalytic processes

A novel one-pot multicatalytic route for the synthesis of 3-methyleneindolin-2-ones has been developed involving sequential copper-catalyzed amination and palladium-catalyzed C-H functionalization processes. In the presence of CuI and Pd(OAc)₂, a variety of propiolamides underwent the reaction with iodides to afford the corresponding 3-methyleneindolin-2-ones in moderate yields.     

A new methodology of intramolecular hetero Diels-Alder reaction with β-alkoxy-substituted conjugated nitroalkenes as heterodienes: stereoselective one-pot synthesis of trans-fused bicyclic γ-lactones

Tandem reaction of (E)-1-ethoxy-2-nitroethylene with δ,ε-unsaturated alcohols leading to stereoselective trans-fused bicyclic γ-lactones has been developed using a catalytic amount of a Lewis acid such as Yb(OTf)₃ and Ni(ClO₄)₂·6H₂O. This process involves the stereoselective tandem transetherification-intramolecular hetero Diels-Alder reaction leading to bicyclic nitronates, and sequential transformation of the nitronate moiety to a lactone functional group under similar reaction conditions in good yields.     

Kinetics and mechanism of cyclohexene hydrocarbomethoxylation catalyzed by a Pd(II) complex

The kinetics of cyclohexene hydrocarbomethoxylation catalyzed by the Pd(PPh₃)₂Cl₂-PPh₃-p-toluenesulfonic acid (TSA) is reported. The reaction is first-order with respect to cyclohexene and TSA and of order 0.5 with respect to Pd(PPh₃)₂Cl₂. The reaction rate as a function of CO pressure or methanol or PPh₃ concentration passes through an extremum. The chloride anion inhibits the reaction. A mechanism involving cationic hydride complexes as intermediates is suggested. A rate equation is set up by the quasi-steady-state treatment of experimental data.     

Arenediazonium salts immobilized in imidazolium ionic liquids as electrophilic partners in the Pd(OAc)2-catalyzed Matsuda-Heck arylation

The utility of arenediazonium salts immobilized in imidazolium-ILs [BMIMPF₆ and BMIMBF₄] for facile, high yielding, synthesis of olefins via the Pd(OAc)₂-catalyzed Matsuda-Heck arylation reaction has been demonstrated. The reaction can also be performed as a two-step process in the IL starting from ArNH₂, by sequential in-situ diazotization-arylation. Simple product isolation and the recycling/re-use of the IL are additional advantages of this one-pot method.     

Catalytic activity of Pd(II) and Pd(II)/DAB-R systems for the Heck arylation of olefins

Palladium-catalyzed reactions of aryl bromides with various olefins involving Pd(II)/diazabutadiene (DAB-R) systems have been investigated. The scope of a coupling process using Pd(II) sources and an α-diimine as ligand in the presence of Cs₂CO₃ as base was tested using various substrates. The Pd(OAc)₂/DAB-Cy (1, DAB-Cy=1,4-dicyclohexyl-diazabutadiene) system presents the highest activity with respect to electron-neutral and electron-deficient aryl bromides in coupling with electron rich olefins. The synthesis and X-ray characterization of a Pd(II)-diazabutadiene ligand is reported. Extensive optimization experiments showed that another Pd(II) source, Pd(acac)₂ (acac=acetylacetonate), proved to activate aryl bromides at high temperatures, low catalyst loadings when the appropriate concentration of ⁿBu₄NBr additive was employed. The effect of the DAB-Cy ligand is important at very low catalyst loadings and high temperatures. Pd(acac)₂ and Pd(acac)₂/DAB-Cy precatalysts were very effective for the arylation of various olefins with aryl bromides with respect to reaction rate, catalyst loadings, and functional group tolerance.     

Catalytic activity of η-(olefin)palladium(0) complexes with iminophosphine ligands in the Suzuki-Miyaura reaction. Role of the olefin in the catalyst stabilization

The catalytic activity of η²-(olefin)palladium(0)(iminophosphine) complexes in the Suzuki-Miyaura coupling is strongly dependent on the reaction conditions and on the nature of the ligands. The reaction is at the best carried out in aromatic solvents in the presence of K₂CO₃ at 90-110 °C. Higher reaction rates are obtained when the R substituent on the N-imino group is an aromatic group of low steric hindrance and the olefin is a moderate π-accepting ligand such as dimethyl fumarate. At temperatures lower than 90 °C, a self-catalyzed process leading to catalyst deactivation becomes predominant. Preliminary mechanistic investigations indicate that the oxidative addition of the aryl bromide to a Pd(0) species is the rate determining step in the catalytic cycle and that the olefin plays a key role in catalyst stabilization. Systems in situ prepared by mixing Pd(OAc)₂ or Pd(dba)₂ with 1 equiv of iminophosphine appear substantially less active than the preformed catalysts.     

Development of a scalable palladium-catalyzed α-arylation process for the synthesis of a CGRP antagonist

The Pd-catalyzed α-arylation of cycloheptapyridyl ketone is a key complexity-building step in the synthesis of BMS-846372, a CGRP antagonist. A first-generation process utilized Pd(OAc)₂/P^tBu₃·HBF₄ catalyst system with a strong base NaO^tBu. Although this process was demonstrated on multi-kilo scale, the harsh conditions led to non-selective metal catalyzed processes, which generated several operational, quality, and throughput issues. By acquiring detailed knowledge around several important process parameters, we were able to design an efficient and scalable second-generation α-arylation process using a Pd(OAc)₂/RuPhos catalyst system with the weaker base, K₃PO₄ in tert-amyl alcohol. This new weak base process was high yielding, efficient, and superior in several respects compared to the strong base process. The strategy behind the reaction and isolation development and the process considerations important to scaling a catalytic reaction from laboratory to manufacturing scale will be discussed.     

A practical synthesis of highly functionalized aryl nitriles through cyanation of aryl bromides employing heterogeneous Pd/C: in quest of an industrially viable process

Preparation of aryl nitrile 2a through classical Rosenmund-von Braun reaction of aryl bromide 1a resulted in a poor yield (61%) due to a high reaction temperature (165 °C) and a lack of efficient procedure for separating 2a from a large quantity of heavy metal waste (Cu salts). To address these issues, a practical synthesis of multifunctional aryl nitriles through cyanation of aryl bromides has been developed with heterogeneous Pd/C used as the catalyst. Treatment of aryl bromides 1 with Zn(CN)₂ in the presence of Pd/C, Zn, ZnBr₂ and PPh₃ in DMA provided aryl nitriles 2 involving those carrying sterically demanding electron-rich substituent in good yields and in highly reproducible manner. The activity of Pd/C is highly dependent on the properties of the Pd/C. Oxidic thickshell type catalyst Pd/C D5 was found to furnish the highest rate acceleration and yield. The use of heterogeneous Pd/C might anchor and disperse Pd over the solid support of the catalyst, at least in the initial stage of the reaction, to assure the formation of monomeric Pd complex without precipitating to inactive Pd black. The use of a slightly excess of Zn(CN)₂ (0.6 equiv) and air oxidation of phosphine ligand, after end of the reaction, converted Pd species to insoluble phosphine-free Pd cyanides, from which Pd was recovered in high yield through simple filtration followed by usual recovery process involving combustion.     

Suzuki–Miyaura cross-coupling reaction of 1,2-oxaborol-2(5H)-ols with carboxylic anhydrides: a new method to furans

An efficient one-step method has been developed to construct furans via a Suzuki–Miyaura cross-coupling reaction of 1,2-oxaborol-2(5H)-ols with carboxylic anhydrides. In the presence of Pd(OAc)₂/PCy₃, the multi-substituted alkenylboron compounds could couple with anhydrides to obtain furans in moderate-to-good yields. The addition of bases promoted the coupling reaction, and the plausible reaction mechanism was proposed.     

A DFT study of the mechanism of palladium-catalyzed alkoxycarbonylation and aminocarbonylation of alkynes: Hydride versus amine pathways

A DFT study on the palladium-bisphosphine catalyzed alkoxycarbonylation and aminocarbonylation of alkyne (propyne) is reported. The theoretical study explores the feasibility and the regioselectivity control of two independent mechanisms: the first is based on the active intermediate [Pd(II)(P₂)(H)]⁺ (where P₂ = PH₂CH₂CH₂CH₂CH₂PH₂) for the alkoxycarbonylation reaction, and the second is based on the active species [Pd(II)(P₂)(NR₂)]⁺ for the aminocarbonylation reaction. The study explains the role of solvent in increasing the yield and in controlling the selectivity of reaction to produce selectively the trans isomer in the alkoxycarbonylation reaction (hydride cycle) and the gem isomer in the aminocarbonylation reaction (amine cycle). In hydride cycle, the regioselectivity is mainly determined by the stability of the complex [Pd(II)(P₂)(COC₃H₅)(CH₃CN)]⁺; however, for the amine cycle, the regioselectivity is determined by the stability of the complex [Pd(II)(P₂)(C₃H₅CON(CH₃)₂)]⁺. The calculations reveal that ligand simplification is not valid in addressing the regioselectivity behavior of alkoxycarbonylation and aminocarbonylation reactions. The kinetic data for the formation of the two key complexes show no difference between the gem and trans isomers which predict the regioselectivity to be a thermodynamically controlled process.     

Elaboration of the ether cleaving ability and selectivity of the classical Pearlman's catalyst [Pd(OH)2/C]: concise synthesis of a precursor for a myo-inositol pyrophosphate

The cleavage of propargyl, allyl, benzyl, and PMB ethers by Pd(OH)₂/C can be tuned in that order, by varying the reaction conditions. Other moieties such as C-C double bonds, esters, trityl ether, p-bromo and p-nitrobenzyl ethers are stable to these reaction conditions. Cleavage of allyl ethers can be made catalytic by using 1:1 mixture of Pd(OH)₂/C and Pd/C. The synthetic potential of the selective ether cleaving ability of Pd(OH)₂/C, essentially under neutral conditions, has been demonstrated by an efficient synthesis of a precursor for the preparation of an inositol pyrophosphate derivative.     

The synthesis of non‐symmetrical stilbene analogs of trans‐resveratrol using the same Pd catalyst in a sequential double‐Heck arylation of ethylene

We have developed a sequential and selective Pd‐catalyzed double‐Heck arylation of ethylene that results in non‐symmetrical nitro‐stilbene analogs of trans‐resveratrol at excellent yields. A catalytic system consisting of Pd(OAc)₂ and P(o‐tolyl)₃ permitted us to carry out the two consecutive Heck arylations without losing activity from the first to the second Heck reaction. After the first Heck arylation of ethylene, no isolation or additional catalyst loading is required for the second Heck arylation reaction. This protocol was applied to the synthesis of methylated trans‐resveratrol, which was obtained at a 65% overall yield. Copyright © 2011 John Wiley & Sons, Ltd.     

Heck-type cross-coupling between halo-exo-glycals and endo-glycals: a practical way to achieve C-glycosidic disaccharides

An effective Heck-type cross-coupling reaction between halo-exo-glycals and endo-glycals to achieve C-glycosidic disaccharides has been developed. Using Pd(OAc)₂ as the catalyst, dppp as ligand and K₂CO₃ as base, the reactions gave C-glycosidic products in good to excellent yields with exclusive stereochemistry.     

Novel approach to 6-alkenyl-substituted pyridoxine derivatives based on the Heck reaction

A new synthetic approach to 6-alkenyl-substituted pyridoxine derivatives was developed based on the Heck reaction. The reaction, which was catalyzed using a mixture of Pd(OAc)₂, (o-Tol)₃P and Bu₃N as a base, led to seven new 6-alkenyl pyridoxine derivatives. When acrylic acid was used the products of decarboxylation and dimerization were formed.