Minimisation of palladium content in Suzuki cross-coupling reactions

A protocol for conducting Suzuki reactions in a plate format amenable to use in library synthesis of biaryl compounds has been developed. A key objective was to determine reaction conditions which give biaryl products containing <10 ppm of Pd for a wide variety of building blocks. A Design of Experiments (DoE) approach for the identification of an optimised set of reaction conditions was successfully applied. The utility of the protocol developed has been demonstrated by preparation of an array of 96 biaryl compounds in a parallel fashion.     

Palladium-catalyzed cross-coupling reaction of resin-bound chlorotriazines

To introduce the biaryl structure as a triazine functionality, we have developed a new synthetic route via the Suzuki cross-coupling reaction of resin-bound chlorotriazines. The Suzuki cross-coupling reaction was achieved using various arylboronic acids, Pd(PPh₃)₄, Cs₂CO₃, and dioxane. With the integration of this chemistry and our previous orthogonal methodology, the triazine library is greatly expanded to a biaryl scaffold.     

Asymmetric synthesis of an axially chiral antimitotic biaryl via an atropo-enantioselective Suzuki cross-coupling

A catalytic asymmetric synthesis of the axially chiral bridged biaryl (-)-2, a structural analogue of natural (-)-rhazinilam possessing original antimitotic properties, is described. The key step is an intermolecular asymmetric Suzuki coupling, furnishing the nonbridged biaryl (-)-6, precursor of (-)-2, with up to 40% ee using binaphthyl ligand 7a. Various known or new binaphthyl and ferrocenyl phosphines as well as phosphetanes were screened as ligands in this reaction, the conditions of which were optimized. The comparison with another Suzuki coupling system showed that 7a is the most versatile ligand described to date for this type of transformation. This work gives the first application of the asymmetric Suzuki coupling to a biologically relevant target.     

Factorial design evaluation of the Suzuki cross-coupling reaction using a magnetically recoverable palladium catalyst

A magnetically recoverable catalyst [Fe₃O₄@SiO₂-AEAPTMS-Pd(II)] was prepared, fully characterized and had its catalytic activity evaluated on the Suzuki cross-coupling reaction under microwave irradiation. The reaction conditions for the synthesis of biaryl compounds was optimized in two stages - an initial fractional design 2⁴, in which the parameters reaction time, temperature, solvent and catalyst loading were evaluated, followed by a Doehlert design. The factorial design proved to be a viable approach for obtaining the optimal reaction conditions based on a relatively small number of experiments. Additionally, the biaryl derivatives synthesized by this method were obtained with good to excellent yields (71–96%) and the recovery and reuse of the palladium catalyst was also evaluated.     

Solution-phase synthesis of an aminomethyl-substituted biaryl library via sequential amine N-alkylation and Suzuki cross-coupling

Described herein is the semiautomated preparation of a 20-member aminomethyl-substituted biaryl library. The two-step solution-phase synthesis was achieved via sequential N-alkylation of various amines with either 3- or 4-bromobenzyl bromide and Suzuki cross-coupling of the resultant aryl bromides with various boronic acids.     

Easily prepared air- and moisture-stable Pd-NHC (NHC=N-heterocyclic carbene) complexes: a reliable, user-friendly, highly active palladium precatalyst for the Suzuki-Miyaura reaction

The synthesis of NHC-PdCl(2)-3-chloropyridine (NHC=N-heterocyclic carbene) complexes from readily available starting materials in air is described. The 2,6-diisopropylphenyl derivative was found to be highly catalytically active in alkyl-alkyl Suzuki and Negishi cross-coupling reactions. The synthesis, ease-of-use, and activity of this complex are substantial improvements over in situ catalyst generation and all current Pd-NHC complexes. The utilization of complex 4 led to the development of a reliable, easily employed Suzuki-Miyama protocol. Employing various reaction conditions allowed a large array of hindered biaryl and drug-like heteroaromatic compounds to be synthesized without difficulty.     

Bis(imino)pyridine palladium(II) complexes as efficient catalysts for the Suzuki–Miyaura reaction in water

Bis(imino)pyridine palladium(II) complexes 3 and 4 of type [PdCl(L)PF₆] are found to be efficient catalysts for Suzuki–Miyaura reactions of aryl halides and arylboronic acids. The reactions proceed smoothly to generate the corresponding biaryl compounds in moderate to excellent yields. The synthesis of various fluorinated biphenyl derivatives was successfully achieved by the complex 4 catalyzed the Suzuki–Miyaura reaction in the presence of surfactants bearing a long alkyl chain. Copyright © 2009 John Wiley & Sons, Ltd.     

Asymmetric synthesis of antimicrotubule biaryl hybrids of allocolchicine and steganacin

The asymmetric synthesis of novel axially chiral biaryl compounds 5 a-f containing a seven- or eight-membered heterocyclic medium ring is described. These molecules can be considered to be structural hybrids of allocolchicine- and steganacin-type natural products. The synthesis featured an atropo-diastereoselective biaryl Suzuki coupling in which a benzylic stereocenter efficiently transferred its stereochemical information to the biaryl axis. The coupling conditions were optimized, and two biphenylphosphane ligands (DavePhos and S-Phos) were found to give the highest yields and diastereoselectivities. A three-element stereochemical model was proposed to explain the observed diastereoselectivities. In a second key step, the medium ring of the target molecules was formed by a stereoselective S(N)1-type cyclodehydration that probably involved a configurationally stable carbocationic intermediate, as supported by calculations. Alternatively, S(N)2-type cyclizations were employed on the same Suzuki coupling products to give the target molecules in a stereodivergent or stereoconvergent manner. These cyclization methods furnished the target hybrid analogues 5 a-f with ee values above 94 %. All analogues were evaluated as antimicrotubule agents and against a panel of cancer-cell lines using colchicine (1) and N-acetylcolchinol (3) as references. Promising activities were found for R,aR-configured compounds 5 a, b and 5 f; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.     

Practical synthesis of biaryl colchicinoids containing 3,4-catechol ether-based A-rings via Suzuki cross-coupling with ligandless palladium in water

Eight new biaryl colchicinoids containing 3^′,4^′-methylene or benzodioxy ether bridges were synthesized. The key synthetic step employed a ligandless, aqueous Suzuki cross-coupling reaction catalyzed by Pd(OAc)₂ with tetrabutylammonium bromide (TBAB) and potassium carbonate (K₂CO₃). The biaryl Suzuki products were typically formed in 5-30 min and always in less than 1 h.     

A Stereospecific, Intermolecular Biaryl-Coupling Approach to Korupensamine A En Route to the Michellamines

By what means and how well can axial chirality be controlled in an intermolecular Suzuki biaryl cross-coupling reaction? The directionality of reductive elimination [Eq. (1)] is completely controlled by using a strategically positioned internal ligand L to afford a single biaryl atropisomer corresponding to the korupensamine A skeleton. TIPS=iPr(3)Si, Ts=H(3)CC(6)H(4)SO(2).     

Exploration of ionic liquids as soluble supports for organic synthesis. Demonstration with a Suzuki coupling reaction

The efficiency of ionic liquid supported synthesis was demonstrated by the Suzuki reaction of ionic liquid supported iodobenzoate compounds with arylboronic acids in aqueous media to give, after cleavage with ammonia/methanol, biaryl products in good yields and high purities, without the need for chromatographic purification. [reaction: see text]     

A simple,quick and novel protocol for biaryl synthesis using LiCl‐promoted in situ‐generated Pd nanoparticles

This paper describes a simple and a very quick protocol for biaryl synthesis using the Suzuki–Miyaura cross‐coupling reaction. A quintessential role of salting‐out agent LiCl was observed in the Suzuki–Miyaura cross‐coupling reaction that enhanced the reduction rate of Pd (II) to a considerable extent, resulting in the formation of nanosized palladium in a few seconds. The isolated Pd nanoparticles were characterized with X‐ray diffraction, dynamic light scattering, TGA, transmission electron microscopy and scanning electron microscopy‐dispersive X‐ray spectroscopy. The Suzuki–Miyaura cross‐coupling reaction proceeded very well with the in situ‐generated Pd nanocatalysts furnishing the desired biaryl adducts with excellent yields.     

Palladium-catalyzed borylation of aryl (pseudo)halides and its applications in biaryl synthesis

A facile and efficient palladium-catalyzed borylation of aryl (pseudo)halides at room temperature has been developed. Arylboronic esters were expeditiously assembled in good yields and with a broad substrate scope and good functional group compatibility. This approach has been successfully applied to the one-pot two-step borylation/Suzuki–Miyaura cross-coupling reaction, providing a concise access to biaryl compounds from readily available aryl halides. Furthermore, a parallel synthesis of biaryl analogs is accomplished at room temperature using the strategy, which enhances the practical usefulness of this method.     

Synthesis of non-peptidyl alpha,alpha-difluoromethylenephosphonic acids on a soluble polymer support

The polymer-supported syntheses of a series of biaryl derivatives bearing the alpha,alpha-difluoromethylenephosphonic acid group is reported. Non-cross-linked polystyrene (NCPS) was used as the support which enabled the reactions to be carried out under homogeneous conditions and reactions to be followed using conventional (19)F NMR. Synthesis of the biaryl phosphonic acids was initiated by attaching mono-ethyl esters of alpha, alpha-difluorophosphonic acids 11 and 12 to 3% alkylhydroxy-modified NCPS via a phosphate ester linkage. Suzuki reaction conditions were developed which allowed for the formation of a series of polymer-bound biaryl phosphonates at ambient temperature. Removal of phosphonic acids from the support and cleavage of the ethyl protecting group was achieved in a single step using TMSI or TMSBr. Yields of the phosphonic acids ranged from 43 to 89% and, in most cases, were obtained in a purity (96-99%), after cleavage from the support, that was sufficient for biological screening.     

Arylation of halogenated pyrimidines via a Suzuki coupling reaction

The Suzuki coupling reaction has been used extensively for the synthesis of a wide variety of unsymmetrical biaryl compounds. We have extended this reaction to demonstrate the utility of preparing monophenyl-, diphenyl-, or triphenylpyrimidine depending on the reaction conditions. Further, it has been shown that chloropyrimidine substrates are preferable over iodo-, bromo-, or fluoropyrimidines.     

Simple and efficient protocol for catalyst recycling and product recovery in the Pd-catalyzed homogeneous Suzuki reaction

Poly(ethylene oxide) (PEO)/methanol can be used as solvent medium for the Pd-catalyzed Suzuki cross-coupling reaction under mild conditions. After the end of the reaction the product is extracted with heptane and the polar phase can be reused several times without any change in the activity. Pure biaryl products are obtained from the nonpolar phase in excellent isolated yields (>90%). The same catalyst-containing polar phase was used to coupling different aryl halides furnishing the biaryl products in good to high isolated yields.     

Enantiopure beta-hydroxysulfoxide derivatives as novel chiral auxiliaries in asymmetric biaryl Suzuki reactions

[reaction: see text] Highly diastereoselective biaryl Suzuki coupling reactions of (1R)-1-(2-iodo or bromophenyl)-2-(R)-(4-tolylsulfinyl)-1-ethanol derivatives with various aryl- or naphthylboronic acids (or esters) were performed with high yields (up to 99%) and an excellent control of the axial chirality (up to 98% de).     

Chemoselective three-component coupling via a tandem Pd-catalyzed boron-Heck and Suzuki reactions

A new approach is herein reported to prepare biaryl derivatives via a tandem Pd-catalyzed boron-Heck and Suzuki reactions. This one-pot tandem process avoided purification or addition of extra catalyst between steps. The resulting biaryl compounds can be prepared with substrate variability in good to moderate yields.     

A concise and diversity-oriented approach to the synthesis of SAG derivatives

An efficient and rapid solution-phase combinatorial synthesis of the SAG library was developed. The salient features for this library synthesis is the application of carbothioamide-derived palladacycle-catalyzed Suzuki coupling reactions for the parallel synthesis of a series of pyridine-based biaryl aldehydes under aerobic conditions and a direct N-alkylation of carbamates using NaH as base in DMF in the presence of catalytic amount of water. The resultant library has been submitted to biological screening to evaluate their potential role in the regulation of Hedgehog pathway.     

Mechanistic study on the coupling reaction of aryl bromides with arylboronic acids catalyzed by (iminophosphine)palladium(0) complexes. Detection of a palladium(II) intermediate with a coordinated boron anion

The complexes [Pd(eta2-dmfu)(P-N)] [P-N = 2-(PPh2)C6H4-1-CH=NR, R = C(6)H(4)OMe-4; CHMe2; C6H3Me2-2,6; C6H3(CHMe2)-2,6] react with an excess of BrC6H4R1-4 (R1= CF3; Me) yielding the oxidative addition products [PdBr(C6H4R1-4)(P-N)] at different rates depending on R [C6H4OMe-4 > C6H3(CHMe2)-2,6 > CHMe2 approximately C6H3Me2-2,6] and R1 (CF3> Me). In the presence of K2CO3 and activated olefins (ol = dmfu, fn), the latter compounds react with an excess of 4-R2C6H4B(OH)2 (R2= H, Me, OMe, Cl) to give [Pd(eta2-ol)(P-N)] and the corresponding biaryl through transmetallation and fast reductive elimination. The transmetallation proceeds via a palladium(II) intermediate with an O-bonded boron anion, the formation of which is markedly retarded by increasing the bulkiness of R. The intermediate was isolated for R = CHMe2, R1 = CF3 and R2= H. The boron anion is formulated as a diphenylborinate anion associated with phenylboronic acid and/or as a phenylboronate anion associated with diphenylborinic acid. In general, the oxidative addition proceeds at a lower rate than transmetallation and represents the rate-determining-step in the coupling reaction of aryl bromides with arylboronic acids catalyzed by [Pd(eta2-dmfu)(P-N)].