Catalyzed Cross-coupling Reaction Research Articles

A six-step synthetic approach to marine natural product (+)-aureol

A concise synthetic approach to the marine natural product (+)-aureol has been achieved from readily available starting materials using obviously fewer steps in comparison to the related report in literature (6 steps versus 12 steps from (+)-sclareolide). Key steps of this protocol include a boron trifluoride-catalyzed domino 1,2-H and 1,2-methyl shifts and a nickel(II)-catalyzed cross-coupling reaction between an alkyl iodide and an aryl Grignard reagent.

Screening system goes with the flow

Optimizing chemical reactions and finding the best ways to scale them up to produce compounds for clinical testing and drug commercialization can be tedious, time-consuming, and expensive. To overcome these limitations, in 2015 Merck & Co. researchers developed a microtiter-plate-based system in which reagents were pipetted at nanoliter volumes and their reactions were analyzed with liquid chromatography/mass spectrometry. The system carried out and evaluated nanomole-scale catalytic cross-coupling reactions at a rate of more than 1,500 per day (Science 2015, DOI: 10.1126/science.1259203). But that system requires the use of nonvolatile solvents that won’t evaporate easily from the open wells of microtiter plates, and its reaction mixtures can’t be heated. Inspired by the Merck system and advances in flow chemistry, researchers at Pfizer aimed to build an even more flexible high-throughput system for chemical reaction screening. Damith Perera, Paul Richardson, Neal W. Sach, and colleagues at Pfizer now re...

Catalytic vinylogous cross-coupling reactions of rhenium vinylcarbenoids.

We report the first example of the rhenium-catalyzed allylation reaction of indolyl compounds by means of cross-coupling with propargyl ethers as non-obvious allylating reagents. Data from isotope-labeling and kinetic isotopic studies are consistent with a mechanism that proceeds by vinylidene formation as the rate determining step, followed by 1,5-hydride shift to generate a key rhenium vinylcarbenoid complex. Bond formation occurs at the vinylogous site and the reaction is conveniently carried out in air.

Synthesis of Functionalized Triphenodioxazines via Palladium Catalyzed Cross-Coupling Reactions

Synthesis of Functionalized Triphenodioxazines via Palladium Catalyzed Cross-Coupling Reactions

Synthesis of 2-Benzazepines from Benzylamines and MBH Adducts Under Rhodium(III) Catalysis via C(sp2)–H Functionalization

The rhodium(III)-catalyzed cross-coupling reaction between commercially available benzylamines and Morita–Baylis–Hillman (MBH) adducts is described. This protocol provides a facile access to various 2-benzazepine derivatives via the C(sp2)–H activation of N-allylated benzylamines and subsequent intramolecular olefin insertion followed by N-allylation reaction. A range of substrates has been used, and a high level of chemoselectivity as well as functional group tolerance was observed. To gain mechanistic insight of this transformation, DFT calculations were also performed.

Ru/Ni Dual Catalytic Desulfinative Photoredox Csp2-Csp3 Cross-Coupling of Alkyl Sulfinate Salts and Aryl Halides.

A mild Ru/Ni dual catalytic desulfinative photoredox Csp2-Csp3 cross-coupling reaction of alkyl sulfinate salts with aryl halides has been developed. The optimized catalyst system, consisting of Ru(bpy)3Cl2, Ni(COD)2, and DBU, smoothly mediates the coupling of a diverse set of secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl groups on pharmaceutical intermediates, and the Csp2-Csp3 cross-coupling reaction allowed the rapid synthesis of caseine kinase 1δ inhibitor analogues via a parallel medicinal chemistry effort.

Catalytic cross-coupling reaction of aryl iodides with triarylbismuths by an N-heterocyclic carbene-PdCl2 based on benzo-9-crown-3 catalyst at room temperature

We have developed the N-heterocyclic carbene ligand/PdCl2 catalyst for CC coupling reaction of aryl iodides and organobismuths at room temperature. The established catalytic system exhibited high cross-coupling reactivity between a variety of orgnobismuths and aryl iodides in the presence of K2CO3 as base in NMP or DMSO at room temperature. The simple and efficient transformation can tolerate either electron-withdrawing or electron-donating functional groups. It was notably found that both aryl bromide and aryl chloride generated moderate to good yields of the corresponding biphenyl products using 5mol% of PPh3/ligand 5 (1:1) as catalyst.

Convenient Synthesis of [closo-B10H9-1-I]2- and [closo-B10H8-1,10-I2]2- Anions.

Two iodo derivatives, [closo-B10H9-1-I]2- (1) and [closo-B10H8-1,10-I2]2- (2), were obtained from the parent [closo-B10H10]2- anion in a two-step process and about 60% and 80% overall yields, respectively. Molecular and crystal structures of 2[Pr4N] were established with XRD methods: I422; a = b = 10.1531(1) Å, c = 18.0149(2) Å; α = β = γ = 90°; Z = 2. Synthetic applications of 1[Bu4N] were demonstrated in a Pd(0)-catalyzed cross-coupling reaction with 4-MeOC6H4MgBr.

How to Control Inversion vs Retention Transmetalation between PdII-Phenyl and CuI-Alkyl Complexes: Theoretical Insight.

Transmetalation between Pd(Br)(PhA)(PCyp3)2 (Ph = phenyl, Cyp = cyclopentyl) and Cu(CaHMePhB)(NHC) (NHC = 1,3-bis(2,6-diisopropylphenyl)-imidazolidin-2-ylidene) is an important elementary step in recently reported catalytic cross-coupling reaction by Pd/Cu cooperative system. DFT study discloses that the transmetalation occurs with inversion of the stereochemistry of the CaHMePhB group. In its transition state, the CaHMePhB group has almost planar structure around the Ca atom. That planar geometry is stabilized by conjugation between the π* orbital of the PhB and the 2p orbital of the Ca. Another important factor is activation entropy (ΔS°‡); retention transmetalation occurs through Br-bridging transition state, which is less flexible than that of the inversion transmetalation because of the Br-bridging structure, leading to a smaller activation entropy in the retention transition state than in the inversion transition state. For CaHMeEt group, transmetalation occurs in a retention manner. In the planar CaHMeEt group of the inversion transition state, the Ca 2p orbital cannot find a conjugation partner because of the absence of π-electron system in the CaHMeEt. Transmetalation of CaHMe(CH═CH2) occurs in a retention manner because the vinyl π* is less effective for the conjugation with the Ca 2p because of its higher orbital energy than the Ph π*. The introduction of electron-withdrawing substituent on the PhB is favorable for inversion transmetalation. These results suggest that the stereochemistry of the Ca atom in transmetalation can be controlled by electronic effect of the CaHMeR (R = phenyl, vinyl, or alkyl) and sizes of the substituent and ligand.

Acceptor and donor substituted alkoxy(phenyleneethynylenes) (Alkoxy-PEs): Synthesis, thermal, linear and nonlinear optical properties

A series of acceptor and donor substituted bis(alkoxy)phenyl ethynyl oligomers 4,4′-((2,5-alkyoxy-1,4-phenylene)bis(ethyne-2,1-diyl))bis(nitrobenzene) (alkyl=C4H93a; C8H173b and C12H253c) and 4,4′-((2,5-alkyoxy-1,4-phenylene)bis(ethyne-2,1-diyl))bis(methylbenzene) (alkyl=C4H94a; C8H174b and C12H254c) has been synthesized by the palladium catalyzed cross coupling reaction of 1,4-dialkoxy-2,5-diiodobenzene with appropriate alkynes. The newly synthesized products were characterized by UV–Vis, IR and multinuclear NMR spectroscopic techniques as well as elemental analyses. All the synthesized bis-(alkoxy)phenyl ethynyl derivatives exhibit good thermal stability (T5=329–347°C) as evident by thermo gravimetric analysis. In nitrophenyl substituted 3a-c, emission is observed in the green region, while in tolyl substituted 4a-c, emission is observed in the blue region of the electromagnetic radiation. Continuous wave (CW) closed aperture Z-scan technique reveals the signature of third-order nonlinearity in the materials that are thermal in nature.

Cyclopalladation in the Periphery of a NHC Ligand as the Crucial Step in the Synthesis of Highly Active Suzuki–Miyaura Cross‐Coupling Catalysts

Starting from 2,4-dichloropyrimidine, 4-(2-dialkylamino)pyrimidinyl functionalized mesitylimidazolium chlorides are accessible in a five-step reaction sequence. Two routes leading to palladium NHC complexes derived from these ligands have been worked out: By transmetalation with the corresponding NHC-AgCl complexes, C,N-coordinated palladium(II) complexes can be obtained. Treatment of palladium dichloride with the imidazolium salts in pyridine and in the presence of K2 CO3 gives cyclometalated and thus C,C-coordinated compounds. The reactivities of all these compounds were investigated in detail as well as their performance in the catalytic Suzuki-Miyaura cross-coupling reaction. It turned out that the C,C-coordinated derivatives exhibit high catalytic activities in the coupling of arylboronic acids with aryl chlorides, which is consistent with the generally accepted mechanistic ideas on substrate activation.

Corrigendum: Aryl(triethyl)silanes for Biaryl and Teraryl Synthesis by Copper(II)-Catalyzed Cross-Coupling Reaction.

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Modeling reduces nickel needed in catalytic reactions

Nickel catalysts are much less expensive than precious metal catalysts, but the large amounts of nickel catalyst used in many catalytic cross-coupling reactions still discourage industrial adoption. Over roughly the past two years, the vast majority of newly reported nickel-catalyzed cross-coupling reactions required 5 to 20 mole % of nickel catalyst. Neil K. Garg of the University of California, Los Angeles, grad student Nicholas A. Weires, and colleague Daniel D. Caspi of AbbVie have now collaborated to develop a technique that reduces loading (mole percent of catalyst required) in nickel-catalyzed amide esterifications (ACS Catal. 2017, DOI: 10.1021/acscatal.7b01444). They used a kinetic-modeling program, DynoChem, to assess the effect of several variables—ligand-to-metal ratio, reactant stoichiometry, product and by-product generation rate, catalyst temperature-equilibration time, catalyst loading, and reaction concentration—on the rate of benzamide-menthol esterification. They then used the data to d...

Synthesis of Dichlorophosphinenickel(II) Compounds and Their Catalytic Activity in Suzuki Cross-Coupling Reactions: A Simple Air-Free Experiment for Inorganic Chemistry Laboratory

In this experiment, students perform an air-free synthesis of three dichlorophosphinenickel(II) compounds, NiCl2(PPh3)2, NiCl2(PCy3)2, and NiCl2(DPPE), using NiCl2·6H2O and the appropriate phosphine as the precursors. These colorful nickel compounds are air-sensitive in solution, but are stable toward air once isolated in the solid form. The synthesized nickel products will be utilized in a catalytic Suzuki cross-coupling reaction between phenylboronic acid and 1-bromo-4-(trifluoromethyl)benzene. The formation of the desired product, 4-(trifluoromethyl)biphenyl, is observed and determined quantitatively by 19F{1H} NMR spectroscopy. The effect of the phosphine ligands on the formation of the nickel products and their catalytic activity will also be determined.

Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I): Uncovering Hidden Species and Implications in Catalytic Cross-Coupling Reactions.

The reduction of Pd(II) intermediates to Pd(0) is a key elementary step in a vast number of Pd-catalyzed processes, ranging from cross-coupling, C-H activation, to Wacker chemistry. For one of the most powerful new generation phosphine ligands, PtBu3, oxidation state Pd(I), and not Pd(0), is generated upon reduction from Pd(II). The mechanism of the reduction of Pd(II) to Pd(I) has been investigated by means of experimental and computational studies for the formation of the highly active precatalyst {Pd(μ-Br)(PtBu3)}2. The formation of dinuclear Pd(I), as opposed to the Pd(0) complex, (tBu3P)2Pd was shown to depend on the stoichiometry of Pd to phosphine ligand, the order of addition of the reagents, and, most importantly, the nature of the palladium precursor and the choice of the phosphine ligand utilized. In addition, through experiments on gram scale in palladium, mechanistically important additional Pd- and phosphine-containing species were detected. An ionic Pd(II)Br3 dimer side product was isolated, characterized, and identified as the crucial driving force in the mechanism of formation of the Pd(I) bromide dimer. The potential impact of the presence of these side species for in situ formed Pd complexes in catalysis was investigated in Buchwald-Hartwig, α-arylation, and Suzuki-Miyaura reactions. The use of preformed and isolated Pd(I) bromide dimer as a precatalyst provided superior results, in terms of catalytic activity, in comparison to catalysts generated in situ.

Cross-Coupling Catalysis by an Anionic Palladium Complex

Recent studies have shown that anionic palladium complexes are viable catalysts for a range of catalytic cross-coupling reactions. We present a one-step synthesis of the anionic “ligandless” palladium complex [NBu4][Pd(DMSO)Cl3] together with its crystal structure. This compound has been shown to be an active precatalyst in the Mizoroki–Heck reaction. Under Jeffery conditions, activated aryl chlorides can be coupled in yields of up to 94% without the need of an additional ligand. The presence of a small amount of water was necessary for product formation. An Amatore–Jutand-type catalytic cycle is consistent with the results presented herein. For comparison with the known mixed complex [(pym-Im-Me)2PdCl][Pd(DMSO)Cl3], the cationic complex [(pym-Im-Me)2PdCl]PF6 (pym = pyrimidyl, Im = imidazolin-2-ylidene) has been synthesized and characterized using standard techniques.

Synthesis of Quinoxaline Derivatives via Copper(I)-Catalyzed Cross-Coupling Reaction of 1,2-Dihalobenzenes with N,N′-Disubstituted Ethane-1,2-diamines under Ligand- and Solvent-Free Conditions

An efficient ligand- and solvent-free method for the synthesis of quinoxaline derivatives via copper(I)-catalyzed cross-coupling process has been developed. 1,2-Halobenzenes or 1,8-diiodonaphthalene coupled with N,N′-disubstituted ethane-1,2-diamines to give the corresponding products in moderate yields under the reaction conditions.

Sub-nanometre metal clusters for catalytic carbon-carbon and carbon-heteroatom cross-coupling reactions.

Catalytic cross-coupling reactions are fundamental transformations in modern organic synthesis. Traditionally based on single-atom transition metal complex catalysts, the use of sub-nanometre metal clusters with enhanced redox and coordinating properties may lead to more efficient catalysts. Recent developments and potential new directions of catalytic sub-nanometre metal clusters for cross-coupling reactions are briefly discussed here.

3,3]-Sigmatropic rearrangement of allenic alcohols: stereoselective synthesis of 1,3-diene-2-ol sulfonates.

An efficient synthetic pathway to 1,3-diene-2-ol sulfonates involving the [3,3]-sigmatropic rearrangement of allenic alcohols with sulfonic acids under mild reaction conditions is described. These products can easily undergo reduction or transition-metal catalyzed cross-coupling reactions to yield a series of stereodefined multisubstituted 1,3-dienes.

Synthesis of C-4 Substituted Amido Nicotine Derivatives via Copper(I)- and (II)-Catalyzed Cross-Coupling Reactions.

The syntheses of seven novel amido nicotine derivatives 12-18 from (S)-nicotine are presented. (S)-Nicotine and (S)-6-chloronicotine derivatives were cross-coupled with the corresponding amides 6-10 at the C-4 position of the pyridine ring via copper(I)-mediated reactions. Derivatives 16-18 were also obtained via copper(II)-mediated reactions from (S)-nicotine containing a C-4 boronic acid pinacol ester group. The optimization of reaction conditions for both routes provided a useful method for preparing C-4 amide-containing nicotine analogs.