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.     

Novel route to azobenzenes via Pd-catalyzed coupling reactions of aryl hydrazides with aryl halides,followed by direct oxidations

[reaction: see text] N-Boc aryl hydrazines undergo Pd-catalyzed coupling reactions with aryl halides to provide N-Boc diaryl hydrazines in excellent yields. The resulting N-Boc diaryl hydrazines were directly oxidized with NBS/pyridine in CH(2)Cl(2) at room temperature to the azobenzenes.     

Rapid construction of multisubstituted olefin structures using vinylboronate ester platform leading to highly fluorescent materials

[reaction: see text] A catalytic one-pot triarylation on the C=C core of vinylboronate pinacol ester (1) produces extended pi-systems based on a multisubstituted olefin structure very rapidly. We established an efficient protocol for the Pd-catalyzed double C-H arylation of 1 with aryl halides, which was successfully integrated with C-B arylation with aryl halides (cross-coupling) in one pot. By using this method, several highly fluorescent materials with a wide range of color variations (blue to red) were discovered.     

A concise asymmetric synthesis of cis-2,6-disubstituted N-aryl piperazines via Pd-catalyzed carboamination reactions

A concise, modular, asymmetric synthesis of cis-2,6-disubstituted piperazines from readily available amino acid precursors is described. The key step in the synthesis is a Pd-catalyzed carboamination of a N1-aryl-N2-allyl-1,2-diamine with an aryl bromide. The products are obtained in 14-20:1 dr, with >97% ee, and the key cyclizations are the first examples of six-membered ring formation via Pd-catalyzed carboamination reactions of unsaturated amines with aryl halides.     

Synthesis of chromans via Pd-catalyzed alkene carboetherification reactions

A new method for the construction of 2-substituted and 2,2-disubstituted chromans via Pd-catalyzed carboetherification reactions between aryl/alkenyl halides and 2-(but-3-en-1-yl)phenols is described. These reactions effect formation of a C-O bond and a C-C bond to afford the chroman products in good yield, and also provide stereoselective access to tricyclic chroman derivatives.     

One-pot borylation/amination reactions: syntheses of arylamine boronate esters from halogenated arenes

[reaction: see text] A one-pot protocol for converting 1,3- and 1,4-substituted aryl halides to arylamine boronate esters is described. This is achieved by sequential Ir-catalyzed aromatic borylation at the least hindered C-H bond of the aryl halide and subsequent Pd-catalyzed C-N coupling at the halide position of the crude arylboronic ester.     

Directed ortho metalation-based methodology. Halo-, nitroso-, and boro-induced ipso-desilylation. Link to an in situ Suzuki reaction

[reaction: see text] Treatment of DoM-derived silylated aromatics 2-4 under standard electrophilic halogenation conditions cleanly affords ipso-desilyation products 5-7, while nitration of methoxy-substituted analogues 8, 9 leads to non-ipso isomers 10, 12 and 11, 13, controlled by a silicon steric effect. Sequential ipso-borodesilylation of 2a, 3a, and 20 followed by treatment with aryl halides under Pd-catalyzed conditions constitutes an in situ Suzuki-Miyaura cross-coupling protocol to biaryls and heterobiaryls 23.     

An improved palladium-catalyzed conversion of aryl and vinyl triflates to bromides and chlorides

A facile Pd-catalyzed conversion of aryl and vinyl triflates to aryl and vinyl halides (bromides and chlorides) is described. This method allows convenient access to a variety of aryl, heteroaryl, and vinyl halides in good to excellent yields and with greatly simplified conditions relative to our previous report.     

Synthesis of 8-arylquinolines via one-pot Pd-catalyzed borylation of quinoline-8-yl halides and subsequent Suzuki-Miyaura coupling

A one-pot process has been developed for the synthesis of 8-arylquinolines via Pd-catalyzed borylation of quinoline-8-yl halides and subsequent Suzuki-Miyaura coupling with aryl halides using n-BuPAd(2) as ligand. Yields of up to 98% were obtained.     

Completely N1-selective palladium-catalyzed arylation of unsymmetric imidazoles: application to the synthesis of nilotinib

The completely N(1)-selective Pd-catalyzed arylation of unsymmetric imidazoles with aryl halides and triflates is described. This study showed that imidazoles have a strong inhibitory effect on the in situ formation of the catalytically active Pd(0)-ligand complex. The efficacy of the N-arylation reaction was improved drastically by the use of a preactivated solution of Pd(2)(dba)(3) and L1. From these findings, it is clear that while imidazoles can prevent binding of L1 to Pd, once the ligand is bound to the metal, these heterocycles do not displace it. The utility of the present catalytic system was demonstrated by the regioselective synthesis of the clinically important tyrosine kinase inhibitor nilotinib.     

Pd-catalyzed amidation of aryl(Het) halides with tert-butyl carbamate

Pd-catalyzed cross-coupling reaction of tert-butyl carbamate with various aryl(Het) halides with Cs₂CO₃ as base in 1,4-dioxane as solvent was investigated, which resulted in the formation of the desired compounds in moderate to excellent yields.     

Regioselective copper(I)-catalyzed C–H hydroxylation/C–S coupling: expedient construction of 2-(styrylthio)phenols

Regioselective copper(I)-catalyzed C–H hydroxylation/C–S coupling of aryl thiols with vinyl halides was developed. Starting from substituted aryl thiols and vinyl halides, various 2-(styrylthio)phenol derivatives were efficiently prepared. The application of the synthetic methodology to generate the bioactive organic intermediate was also exemplified.     

Improved synthesis of aryltriethoxysilanes via palladium(0)-catalyzed silylation of aryl iodides and bromides with triethoxysilane.

The scope of the palladium-catalyzed silylation of aryl halides with triethoxysilane has been expanded to include aryl bromides. A more general Pd(0) catalyst/ligand system has been developed that activates bromides and iodides: palladium(0) dibenzylideneacetone (Pd(dba)(2)) is activated with 2-(di-tert-butylphosphino)biphenyl (Buchwald's ligand) (1:2 mol ratio of Pd/phosphine). Electron-rich para- and meta-substituted aryl halides (including unprotected aniline and phenol derivatives) undergo silylation to form the corresponding aryltriethoxysilane in fair to excellent yield; however, ortho-substituted aryl halides failed to be silylated.     

Greater variety in Groebke-Blackburn type 3-arylaminoimidazo[1,2-a]azines accessed via Pd-catalyzed arylation of a primary amine precursor

The scope of the Groebke-Blackburn reaction of 2-aminoazines is limited by the availability of isocyanides. To prepare the Groebke-Blackburn type 2-phenyl-3-(hetero)arylaminoimidazo[1,2-a]azines, for which the respective (hetero)arylisocyanides are scarce or unavailable, a general Pd-catalyzed protocol has been developed that is useful for the arylation of known 2-phenylimidazo[1,2-a]pyridin-3-amine and 2-phenylimidazo[1,2-a]pyrazin-3-amine with various electron-deficient aryl and heteroaryl halides.     

Palladium-catalyzed borylation of sterically demanding aryl halides with a silica-supported compact phosphane ligand

Immobile but active: A silica-supported "compact" phosphane, Silica-SMAP, can be used in the Pd-catalyzed borylation of aryl chlorides or bromides with bis(pinacolato)diboron. The Silica-SMAP/Pd system significantly expands the substrate scope of the borylation toward sterically and electronically challenging aryl halides.     

Cascade alkenyl amination/Heck reaction promoted by a bifunctional palladium catalyst: a novel one-pot synthesis of indoles from o-haloanilines and alkenyl halides

A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with alpha-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd2(dba)3]/DavePhos, NaOtBu, toluene combination at 100 degrees C were the optimized reaction conditions to carry out the cascade process (dba=dibenzylideneacetone, DavePhos=2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to o-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd2(dba)3]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.     

Highly efficient route to fused polycyclic aromatics via palladium-catalyzed aryne annulation by aryl halides

Polycyclic aromatic and heteroaromatic hydrocarbons have been synthesized in high yield by two different processes involving the Pd-catalyzed annulation of arynes. The first process involves a Pd-catalyzed annulation of arynes by 2-halobiaryls and related vinylic halides. The second process utilizes a Pd-catalyzed double annulation of arynes by simple aryl halides. Both processes appear to involve the catalytic, stepwise coupling of two very reactive substrates, an aryne and an organopalladium species, to generate excellent yields of cross-coupled products.     

Expanding Pd-catalyzed C-N bond-forming processes: the first amidation of aryl sulfonates,aqueous amination,and complementarity with Cu-catalyzed reactions

The first general method for the Pd-catalyzed amination of aryl tosylates and benzenesulfonates was developed utilizing ligand 1, which belongs to a new generation of biaryl monophosphine ligands. In addition, the new catalyst system for the first time enables amidation of aryl arenesulfonates and aqueous amination protocols that do not necessitate the use of cosolvents. The substrate scope has been significantly expanded to include aryl halides containing primary amides and free carboxylic acid groups. In the case of multifunctional substrates, the Pd-catalyzed amination can provide selectivity that is complementary to the Cu-catalyzed C-N bond-forming processes.     

A new biarylphosphine ligand for the Pd-catalyzed synthesis of diaryl ethers under mild conditions

A new bulky biarylphosphine ligand (L8) has been developed that allows the Pd-catalyzed C-O cross-coupling of a wide range of aryl halides and phenols under milder conditions than previously possible. A direct correlation between the size of the ligand substituents in the 2', 4', and 6' positions of the nonphosphine containing ring and the reactivity of the derived catalyst system was observed. Specifically, the rate of coupling increased with the size of these substituents.     

Aryl transfer between Pd(II) centers or Pd(IV) intermediates in Pd-catalyzed domino reactions

A computational study has been performed to determine the mechanism of the key steps of Pd-catalyzed domino reactions in which C(sp2)-C(sp2) are formed from aryl and alkenyl halides. DFT calculations were done on model complexes of the proposed intermediates, with PH3 and H2O as ancillary ligands, to explore two possible mechanisms: the oxidative addition of aryl or alkenyl halides to palladacycles to give Pd(IV) intermediates, and the transmetalation-type reaction of aryl or alkenyl ligands between two Pd(II) centers, a palladacycle, and a Pd(II) complex formed by oxidative addition of aryl or alkenyl halides to Pd0. We have shown that oxidative addition of iodoethylene to Pd0 precursors is more favorable than oxidative addition to Pd(II) palladacycles, whereas transmetalation-type reactions between Pd(II) complexes are facile. Similar results were obtained with iodobenzene instead of iodoethylene and formamide as the ancillary ligand. These results suggest that Pd(IV) intermediates are not involved in these reactions.