Sonogashira Coupling Of Aryl Bromides Research Articles

Nickel‐Catalyzed Sonogashira Couplings: Extending the Reaction Scope to Aryl Bromides and Chlorides

AbstractThe alkyne motif is present in several naturally occurring molecules and specialty chemicals. The Sonogashira reaction is recognized as one of the most exploited methods for the synthesis of substituted alkynes. While palladium catalysts have been traditionally employed, recent efforts have been directed towards developing alternatives based on Earth‐abundant metals such as nickel. However, nickel‐catalyzed Sonogashira couplings still present important substrate limitations. While more reactive aryl iodides have been well documented, the coupling of more challenging yet cost‐effective aryl bromides and chlorides lags significantly behind. Herein, we present a method for the nickel‐catalyzed Sonogashira coupling of aryl bromides and chlorides, whose discovery was accelerated thanks to high‐throughput experimentation. Fine‐tuning of the bipyridine ligand was essential to activate chemoselectively C(sp2)−Br or C(sp2)−Cl bonds. A wide range of functionally diverse alkynes, including examples of active ingredients and their intermediates, were accessed in a single step and with yields up to 98%. The developed methodology is expected to be widely adopted by academia and industry, marking a step forward in the field of base metal catalysis.

Aerobic Cu and amine free Sonogashira and Stille couplings of aryl bromides/chlorides with a magnetically recoverable Fe3O4@SiO2 immobilized Pd(II)-thioether containing NHC

Two value added CC cross coupling reactions; Sonogashira and Stille couplings were achieved at milder conditions in the catalytic presence of a magnetically recoverable heterogeneous catalyst Fe3O4@SiO2@NHC^SPh-Pd(II). The catalyst was earlier reported for Suzuki-Miyaura reaction, and as an extension of its catalytic efficiency, the Stille and Sonogashira cross coupling reactions under aerobic condition has been explored in present report. The Sonogashira coupling of aryl bromides and terminal alkynes produced an excellent yield (~96% at 0.25 mol% Pd) of the desired coupling product under copper and amines free conditions. Moreover, an excellent Stille coupling of readily available and more latent aryl chlorides and trialkylstannane was obtained (yields up to 95% at 0.25 mol% Pd) in absence of toxic fluorides additives. The broad substrate scope of the catalyst for both the coupling reactions and the magnetically recoverable feature of catalyst make this reaction highly desirable for industrial applications of present heterogeneous catalysis.

A Parallel Approach to 7-(Hetero)arylpyrazolo[1,5- a]pyrimidin-5-ones.

A modular, two-pot assembly of 7-arylpyrazolo[1,5- a]pyrimidones from aryl/heteroaryl halides and aminopyrazoles in library format was developed. Sonogashira coupling of aryl bromides with triethyl orthopropiolate, followed by in situ orthoester hydrolysis, provides access to β-aryl ynoates, which undergo regioselective cyclocondensation with aminopyrazoles. The ability to vary the C7 vector of 7-arylpyrazolo[1,5- a]pyrimidones in two steps using readily available (hetero)aryl halides significantly enhances synthetic access to this challenging vector.

Chelate Palladium(II) Complexes with Saturated N-Phosphanyl-N-Heterocyclic Carbene Ligands: Synthesis and Catalysis

N-Phosphanyl-N-heterocyclic carbenes (NHCPs) featuring a saturated imidazolin-2-ylidene or tetrahydropyrimid-2-ylidene ring have been synthesized and characterized. The free carbenes exhibit good stability and can be stored in the solid state for months at ambient temperature without decomposition. Contrary to imidazoline-based NHCPs, which decompose by ring opening, N-phosphanyltetrahydropyrimid-2-ylidenes isomerize to 2-phosphanyl tetrahydropyrimidines upon heating. The free carbenes are capable of acting as chelating ligands toward palladium(II), forming very stable mononuclear complexes that have been structurally characterized. The catalytic potential of the complexes has been preliminarily assessed in cross-coupling reactions, most notably in the Suzuki coupling of aryl chlorides, where these complexes display promising activity, and in the copper- and amine-free Sonogashira coupling of aryl bromides.

Palladium-Catalyzed Carbonylative Sonogashira Coupling of Aryl Bromides Using Near Stoichiometric Carbon Monoxide

A general procedure for the palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides is reported, using near stoichiometric amounts of carbon monoxide. The method allows a broad substrate scope in moderate to excellent yields. The formed alkynone motive serves as a platform for synthesis of various heterocyclic structures, including pyrimidines. Furthermore, the presented strategy allows effective (13)C labeling.

A PdII Complex Bearing a Benzimidazole‐Derived Ligand with Potentially “Mesoionic and Remote” Character and Its Catalytic Activity

AbstractThe oxidative addition of palladium(0) to the C2‐protected 5‐bromo‐2‐methylbenzimidazolium tetrafluoroborate 3 affords the complex trans‐[PdBr(bimy)(PPh3)2]BF4 (4), which is the first complex of an unprecedented benzimidazole‐derived ligand (bimy) with a potentially “mesoionic and remote” character. DFT calculations revealed that the bimy ligand bridges the gap between the mesoionic pyrazolin‐4‐ylidene and the anionic phenyl ligand. A preliminary catalytic study revealed the promising activity of 4 in the Sonogashira coupling of aryl bromides with phenylacetylene.

ChemInform Abstract: A Copper‐ and Amine‐Free Sonogashira Reaction Employing Chlorophosphine as New and Efficient Ligand.

AbstractIt is shown that the sterically congested CPP is an efficient ligand for the Sonogashira coupling of aryl bromides.

A General and Convenient Palladium‐Catalyzed Carbonylative Sonogashira Coupling of Aryl Bromides

A variety of aromatic bromides and aromatic terminal alkynes are reacted to afford the products with good yields.

Sonogashira Coupling with UC Pd under Copper-Free Conditions

A novel form of Pd/C (UC Pd) was prepared by ultrasonication of Pd(NO3)2 with activated charcoal in water (eq. 1). UC Pd catalyzed the Sonogashira coupling of aryl bromides 1 with terminal alkynes 2 in the presence of XPhos and K2CO3 to give the corresponding internal alkynes 3 in 55-96% yield (eq. 2, 17 examples). The catalyst was recovered by simple filtration and reused three times without significant loss of its catalytic activity for the formation of 3a (3rd reuse: 87% yield).

Copper-free and amine-free Sonogashira coupling in air in a mixed aqueous medium by palladium complexes of N/ O-functionalized N-heterocyclic carbenes

Highly convenient copper-free and amine-free Sonogashira coupling of aryl bromides and iodides with terminal acetylenes under amenable conditions in air and in a mixed aqueous medium are reported using several new, user friendly and robust palladium precatalysts ( 1– 5) of N/ O-functionalized N-heterocyclic carbenes (NHCs). In particular, the precatalysts, 1 and 2, were synthesized from the imidazolium chloride salts by the treatment with PdCl 2 in pyridine in presence of K 2CO 3 as a base while the precatalysts, 3– 5, were synthesized from the respective silver complexes by the treatment with (COD)PdCl 2. The DFT studies carried out on the 1– 5 complexes suggest the presence of strong NHC–Pd σ-interactions arising out of deeply buried NHC–Pd σ-bonding molecular orbitals (MOs) that account for the inert nature of the metal–carbene bonds and also provide insights into the exceptional stability of these precatalysts.

Fluoride‐Free Hiyama and Copper‐ and Amine‐Free Sonogashira Coupling in Air in a Mixed Aqueous Medium by a Series of PEPPSI‐Themed Precatalysts

AbstractA new series of robust, user‐friendly, and highly active PEPPSI‐themed (pyridine‐enhanced precatalyst preparation, stabilization and initiation) (NHC)PdX2(pyridine)‐type (X = Cl, Br) precatalysts of C4–C5 saturated imidazole‐ (1–4) and triazole‐based (5 and 6) N‐heterocyclic carbenes for the Hiyama and Sonogashira couplings under amenable conditions are reported. Specifically 1–6 efficiently catalyze the fluoride‐free Hiyama coupling of aryl halides with PhSi(OMe)3 and CH2=CHSi(OMe)3 in air in the presence of NaOH as a base in a mixed aqueous medium (dioxane/H2O, 2:1 v/v). Along the same lines, these 1–6 precatalysts also promote the Cu‐free and amine‐free Sonogashira coupling of aryl bromides and iodides with phenylacetylene in air and in a mixed aqueous medium (DMF/H2O, 3/1 v/v). The complexes 1–6 were synthesized by the direct reaction of the respective imidazolinium and triazolium halide salts with PdCl2 in pyridine in the presence of K2CO3 as a base. DFT studies on the catalytically relevant palladium(0) (NHC)Pd(pyridine) precursors 1a–6a reveal significant donation from the N‐heterocyclic carbene lone pair onto the unfilled σ* orbital of the trans Pd–pyridine bond. This weakens the Pd‐bound “throwaway” pyridine ligand, and its dissociation marks the initiation of the catalytic cycle.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Palladium complexes of abnormal N-heterocyclic carbenes as precatalysts for the much preferred Cu-free and amine-free Sonogashira coupling in air in a mixed-aqueous medium

A series of new PEPPSI (Pyridine Enhanced Precatalyst Preparation Stabilization and Initiation) themed precatalysts of abnormal N-heterocyclic carbenes for the highly desirable Cu-free and amine-free Sonogashira coupling in air in a mixed-aqueous medium is reported. Specifically, the PEPPSI themed (NHC)PdI2(pyridine) type precatalysts, 1b-4b, efficiently carried out the highly convenient Cu-free and amine-free Sonogashira coupling of aryl bromides and iodides with terminal acetylenes in air in a mixed aqueous medium. Complexes, 1b-4b, were synthesized by the direct reaction of the corresponding imidazo[1,2-a]pyridinium iodide salts, 1a-4a, with PdCl2 in pyridine in the presence of K2CO3 as a base while the imidazo[1,2-a]pyridinium iodide salts, 1a-4a, were in turn synthesized by the alkylation reactions of the respective imidazo[1,2-a]pyridine derivatives with alkyl iodides. The density functional theory (DFT) studies revealed that these imidazol-3-ylidene[1,2-a]pyridine derived abnormal carbenes are strongly sigma-donating and consequently significantly weaken the catalytically important labile trans pyridine ligand in 1b-4b.

Sterically Demanding, Zwitterionic Trialkylphosphonium Sulfonates as Air-Stable Ligand Precursors for Efficient Palladium-Catalyzed Cross-Couplings of Aryl Bromides and Chlorides

3-(Di-tert-butylphosphonium)propane sulfonate (DTBPPS) and 3-(diadamantylphosphonium)propane sulfonate (DAPPS) are air-stable pre-ligands for aqueous-phase palladium-catalyzed cross-coupling reactions. Both DTBPPS and DAPPS were found to give active catalysts for the Sonogashira coupling of aryl bromides at room temperature and 4-chloroanisole at 80 °C. These ligands also gave effective catalysts for the aqueous-phase Suzuki coupling of aryl bromides at room temperature.

9‐Fluorenylphosphines for the Pd‐Catalyzed Sonogashira, Suzuki, and Buchwald–Hartwig Coupling Reactions in Organic Solvents and Water

The lithiation/alkylation of fluorene leads to various 9-alkyl-fluorenes (alkyl=Me, Et, iPr, -Pr, -C18H25) in>95% yields, for which lithiation and reaction with R2PCl (R=Cy, iPr, tBu) generates 9-alkyl, 9-PR2-fluorenes which constitute electron-rich and bulky phosphine ligands. The in-situ-formed palladium-phosphine complexes ([Na2PdCl4], phosphonium salt, base, substrates) were tested in the Sonogashira, Suzuki, and Buchwald-Hartwig reactions of aryl chlorides and aryl bromides in organic solvents. The Sonogashira coupling of aryl chlorides at 100-120 degrees C leads to>90% yields with 1 mol% of Pd catalyst. The Suzuki coupling of aryl chlorides typically requires 0.05 mol% of Pd catalyst at 100 degrees C in dioxane for quantitative product formation. To carry out "green" cross-coupling reactions in water, 9-ethylfluorenyldicyclohexylphosphine was reacted in sulphuric acid to generate the respective 2-sulfonated phosphonium salt. The Suzuki coupling of activated aryl chlorides by using this water-soluble catalyst requires only 0.01 mol% of Pd catalyst, while a wide range of aryl chlorides can be quantitatively converted into the respective coupling products by using 0.1-0.5 mol% of catalyst in pure water at 100 degrees C. Difficult substrate combinations, such as naphthylboronic acid or 3-pyridylboronic acid and aryl chlorides are coupled at 100 degrees C by using 0.1-0.5 mol% of catalyst in pure water to obtain the respective N-heterocycles in quantitative yields. The copper-free aqueous Sonogashira coupling of aryl bromides generates the respective tolane derivatives in>95% yield.

A Convenient High Activity Catalyst for the Sonogashira Coupling of Aryl Bromides

AbstractA mixture of Na2PdCl4, CuI and (t‐Bu)3PH+BF4− (molar ratio 4 : 3 : 8) dispersed in H2N(i‐Pr)2+Br− can be used as a “single source” precatalyst for the Sonogashira coupling of aryl bromides with various aryl‐ and alkylacetylenes in HN(i‐Pr)2 solvent. Arylacetylenes require just 0.005 mol % of Pd catalyst at 80 °C, with TOFs ranging between 3,200 and 10,000 h−1.

Efficient and General Protocol for the Copper‐Free Sonogashira Coupling of Aryl Bromides at Room Temperature.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient and general protocol for the copper-free sonogashira coupling of aryl bromides at room temperature.

[reaction: see text]. A mild and general protocol for the copper-free Sonogashira coupling of aryl bromides with acetylenes has been developed. The use of (AllylPdCl)2 and P(t-Bu)3 provides the active Pd(0) catalyst that allows subsequent coupling of various alkynes at room temperature with good to excellent yields.

Recyclable Catalyst with Cationic Phase Tags for the Sonogashira Coupling of Aryl Bromides and Aryl Chlorides

The new phase-tagged phosphines 1-(CH2NEt3+), 4-(CH2P(1-Ad)2)C6H4·Br- and 1-(CH2PPh3+), 4-(CH2PH+(1-Ad)2)C6H4·2Br- were prepared in the reaction of 1-(CH2Br), 4-(CH2PH+(1-Ad)2)C6H4·Br- with Et3N or PPh3, respectively. The Pd(0)-phosphine catalysts formed on reaction of Na2PdCl4, CuI, phosphine, and acetylene are able to Sonogashira couple aryl bromides and aryl chlorides in high yields in DMSO or in DMSO/heptane mixtures. The products of the coupling reactions can be isolated from the DMSO solution by extraction with heptane or by separation of the product containing heptane solvent. The phase-tagged catalysts remain in the DMSO solution and can be reused for at least five consecutive coupling reactions. The catalysts retain their high activity throughout all cycles, as evidenced by the high reaction yields and, more importantly, by the almost constant turn-over frequency. Leaching of the catalyst into the product containing heptane solvent is negligible (>99.95% retention in the DMSO catalyst phase) as evidenced by TXRF and by photometric palladium determination.