Palladium-catalyzed regiocontrolled internal heteroarylation of electron-rich olefins with heteroaryl halides

A highly efficient palladium-catalyzed Heck coupling reaction of heteroaryl halides with electron-rich vinyl ether and hydroxyalkyl vinyl ethers is described. It was found that the choice of solvent, ligand, and reaction temperature had a fundamental influence on the regioselectivity and reactivity of the reaction, and the combination of Pd(OAc)₂ and DPPF in ethylene glycol led to the most effective catalytic system. Under these conditions, a variety of heteroaryl halides reacted very quickly with electron-rich olefins to afford exclusively the branched products in good to excellent yields without employing triflates, halide scavengers, or ionic liquids.     

Palladium-catalyzed aminosulfonylation of aryl halides

The palladium-catalyzed three-component coupling of aryl iodides, sulfur dioxide, and hydrazines to deliver aryl N-aminosulfonamides is described. The colorless crystalline solid DABCO·(SO(2))(2) was used as a convenient source of sulfur dioxide. The reaction tolerates significant variation of both the aryl iodide and hydrazine coupling partners.     

Synthesis of substituted aryl enol ethers

A facile route toward substituted aryl diarylvinyl ethers 4 is developed from CuI-mediated cross-coupling reaction of substituted phenols 2 with diarylvinyl bromides 3 in the presence of various bidentate-based ligands in DMF. Skeleton 3 is prepared by Yan’s bromomethylenation of diarylketones 1 with CHBr₃–TiCl₄–Mg in the co-solvent of DME and CH₂Cl₂. The synthetic route obtains moderate yields from the one-step operation and the key structure of 4k is confirmed by X-ray crystallographic analysis. The CADD docking experiments of 4k have been included.     

Regioselective mannich reactions via trimethylsilyl enol ethers

Site-specific reactions of trimethylsilyl enolates and trimethylsilyldienolates are described.     

An improved protocol for the Pd-catalyzed alpha-arylation of aldehydes with aryl halides

An improved protocol for the Pd-catalyzed alpha-arylation of aldehydes with aryl halides has been developed. The new catalytic system allows for the coupling of an array of substrates including challenging electron-rich aryl bromides and less reactive aryl chlorides. The utility of this method has been demonstrated in a new total synthesis of (+/-)-sporochnol.     

Palladium-catalyzed C-O bond formation: direct synthesis of phenols and aryl/alkyl ethers from activated aryl halides

A simple and efficient palladium-catalyzed carbon-oxygen bond formation is reported. The palladium-tri-tert-butylphosphine complex was found to be effective in converting haloarenes to corresponding substituted phenols. This methodology offers a direct transformation of aryl halides to phenols, as well as the straightforward application to generate a wide variety of diaryl or alkyl/aryl ethers.     

Palladium-catalyzed direct arylation of nitro-substituted aromatics with aryl halides

Direct arylation reactions of nitrobenzenes and aryl halides occur in good yield and high ortho regioselectivity. These reactions can be performed on gram scale with as few as 3 equiv of the nitro arene relative to the aryl halide. The synthetic utility of this method is demonstrated via rapid synthesis of a Boscalid intermediate.     

Palladium-catalyzed aminations of aryl halides with phosphine-functionalized imidazolium ligands

A series of 1-(2-diphenylphosphinoferrocenyl)ethyl-3-substituted imidazolium iodides [3-substituent = methyl (1a); isopropyl (1b); tert-butyl (1c); 1-adenosyl (1d); cyclohexyl (1e); 2,6-dimethylphenyl (1f); 2,4,6-trimethylphenyl (1g); 2,6-diisopropylphenyl (1h)] have been prepared and evaluated as ligands in the palladium-catalyzed aminations of aryl halides with various amines. The scope of the coupling process was carried out for various aryl bromides and chlorides with the catalysts generated in situ from a mixture of Pd(OAc)2 and in the presence of a base. NaO t Bu was found the choice of base in combination with dioxane, toluene, or DME as solvent, although NaOH or Cs2CO3 promoted the coupling of 4-bromotoluene with morpholine in moderate conversion. The steric hindrance from the 3-substituent of imidazolium in the hybrid-bidentate chelating system was found to be only beneficial to the substrates without ortho-substituents. The more sterically hindered 1d or 1h promoted the coupling of bromobenzene with morpholine in nearly quantitative conversion with 0.2 mol% of palladium loading in the presence of NaO t Bu at 110 degrees C, and 94% of conversion was afforded with the less sterical demanding 1a for a longer time. However, for the substrates with ortho-substituents, higher conversions were achieved with 1a. The Pd(OAc)2/1d catalytic system was also active for deactivated aryl chloride, and 71% isolated yield for the desired product was realized for coupling of 4-chloroanisole with morpholine at 2 mol% of catalyst loading. The developed catalyst system has been applied successfully to the synthesis of a key building block for a type of functional polymers.     

Palladium-catalyzed alpha-arylation of oxindoles

A catalyst generated from Pd(dba)2 and the bulky electron-rich phosphine ligand 2-(dicyclohexylphosphino)-2',4', 6'-tri-i-propyl-1-1'-biphenyl is effective for the alpha-arylation of oxindoles. Generation of the potassium-enolates of a range of oxindoles allows coupling with aryl chlorides, bromides, and triflates. Significant variation of the substitution pattern on both the oxindole and aryl halide is possible.     

Palladium-catalyzed cross-coupling of cyclopropanols with aryl halides under mild conditions

Intra- and intermolecular palladium-catalyzed cross-coupling of cyclopropanols with aryl halides can be achieved in good yields under mild conditions.     

Palladium-catalyzed cross-coupling reaction of tricyclopropylbismuth with aryl halides and triflates

The palladium-catalyzed cross-coupling reaction of tricyclopropylbismuth with aryl and heterocyclic halides and triflates is reported. The reaction tolerates numerous functional groups and does not require anhydrous conditions. The method was successfully extended to the cross-coupling of triethylbismuth.     

Palladium-catalyzed cross-coupling reactions of 2-indolyldimethylsilanols with substituted aryl halides

[reaction: see text] A mild and general cross-coupling reaction of 2-indolylsilanols has been developed. The experimental variables that lead to successful coupling are (1) the use of sodium tert-butoxide as the activator, (2) the use of copper(I) iodide in stoichiometric quantities, and (3) the use of Pd2(dba)3.CHCl3 as the catalyst. Under these conditions N-(Boc)-2-indolyldimethylsilanol reacts with a variety of aromatic iodides to afford the coupling products in good yield (70-84%).     

Palladium-catalyzed benzylic direct arylation of benzyl sulfones with aryl halides

An effective palladium catalyst system for the direct arylation of benzyl sulfones with aryl halides has been developed. The catalytic reaction provides a facile route to diarylmethyl sulfones. The products can be transformed further via desulfonylative functionalization mediated by aluminum compounds.     

Palladium-catalyzed cross-coupling of benzyl thioacetates and aryl halides

A method for preparing benzyl aryl thioethers utilizing an in situ deprotection of benzyl thioacetates as an alternative to free thiols as starting materials has been developed and optimized. Good to excellent yields of diverse benzyl aryl thioethers are obtained with air-stable, odor-free, and easy to prepare thioesters. A one-pot protocol for forming benzyl aryl thioethers from a benzyl halide, potassium thioacetate, and an aryl bromide has also been demonstrated.     

Palladium-catalyzed alpha-arylation of esters

A new and simple one-pot procedure for the palladium-catalyzed intermolecular alpha-arylation of esters is described. A number of esters can be functionalized with a wide range of aryl bromides using Pd(OAc)(2) or Pd(2)(dba)(3) and bulky electron-rich o-biphenyl phosphines 1-3. Under the reaction conditions, using LiHMDS as base, alpha-arylation proceeds at room temperature or at 80 degrees C with very good yields and high selectivities for monoarylation. Important nonsteroidal antiinflammatory drug derivatives such as (+/-)-naproxen tert-butyl ester and (+/-)-flurbiprofen tert-butyl ester can be prepared in 79% and 86% yield, respectively. The catalyst system based on the di-tert-butylphosphine (2) is also active for the alpha-arylation of esters using aryl chlorides. Furthermore, using (3) the alpha-arylation of trisubstituted ester enolates can be accomplished to provide compounds that have quaternary centers.     

Palladium-catalyzed alpha-arylation of esters with chloroarenes

Palladium-catalyzed alpha-arylations of esters with chloroarenes are reported. The reactions of chloroarenes with the sodium enolates of tert-butyl propionate and methyl isobutyrate occur in high yields with 0.2-1 mol % of {[P(t-Bu)3]PdBr}2 or the combination of Pd(dba)2 and P(t-Bu)3 as catalyst. The reactions of chloroarenes with the Reformatsky reagent of tert-butyl acetate were most challenging but occurred in high yields for chlorobenzene and electron-poor chloroarenes catalyzed by 1 mol % of Pd(dba)2 and pentaphenylferrocenyl di-tert-butylphosphine (Q-phos).     

Palladium-catalyzed carbonylative coupling of pyridine halides with aryl boronic acids

The carbonylative Suzuki cross-coupling of a variety of mono-iodopyridines and bromopyridines (1a,b, 3a-c, 5) catalyzed by palladium-phosphane systems has been studied to prepare benzoylpyridine derivatives (2, 4, 6). The selectivity and the rate of the reaction are highly dependent on the reaction conditions, i.e. nature of the palladium catalyst precursor, solvent, temperature and CO pressure. The main side-products arise from direct, non-carbonylative cross-coupling. Under optimized conditions, benzoylpyridines are recovered in high yields (80-95%). The order of reactivity decreases from iodo- to bromopyridines and from 2-, 4- to 3-substituted halopyridines. The reactivity of dihalopyridines has been investigated; 2,6-dibromopyridine (7) and 3,5-dibromopyridine (11) are selectively transformed into either the corresponding benzoyl-phenylpyridine (8, 12) or the corresponding dibenzoylpyridine (9, 13). Dissymmetric 2,5-dihalopyridines (15a,b) are transformed into 2-benzoyl-5-bromopyridine (16) or 2,5-dibenzoylpyridine (17) in high yields.     

Palladium-catalyzed decarboxylative coupling of potassium nitrophenyl acetates with aryl halides

A palladium-catalyzed decarboxylative cross-coupling of potassium 2- and 4-nitrophenyl acetates with aryl chlorides and bromides has been developed. Because the nitro group can be readily converted to many other functional groups, the new reaction provides a useful method for the preparation of diverse 1,1-diaryl methanes and their derivatives.