Palladium-catalyzed Stille cross-couplings of sulfonyl chlorides and organostannanes

Arene and phenylmethanesulfonyl chlorides can be cross-coupled with aryl, heteroaryl, and alkenylstannanes with desulfitation in the presence of 10 mol % CuBr.Me2S, 1.5 mol % Pd2dba3, and 5 mol % tri-2-furylphosphine in tetrahydrofuran or toluene under reflux. This extension of the Stille cross-coupling reaction realizes a new and economical method for the generation of C-C bonds. The palladium-catalyzed carbonylative Stille cross-coupling reactions of arenesulfonyl chlorides and organostannanes in the presence of CO (60 bar) at 110 degrees C in toluene generate the corresponding ketones. Arenesulfonyl chlorides are more reactive than aryl chlorides and aryl bromides in their Stille cross-coupling with organostannanes but less reactive than aryl iodides. The new methods disclosed for the generation of C-C bonds open new possibilities for medicinal chemistry and material sciences.     

A General Palladium‐Catalyzed Hiyama Cross‐Coupling Reaction of Aryl and Heteroaryl Chlorides

A general palladium‐catalyzed Hiyama cross‐coupling reaction of aryl and heteroaryl chlorides with aryl and heteroaryl trialkoxysilanes by a Pd(OAc)₂/ L2 catalytic system is presented. A newly developed water addition protocol can dramatically improve the product yields. The conjugation of the Pd/ L2 system and the water addition protocol can efficiently catalyze a broad range of electron‐rich, ‐neutral, ‐deficient, and sterically hindered aryl chlorides and heteroaryl chlorides with excellent yields within three hours and the catalyst loading can be down to 0.05 mol % Pd for the first time. Hiyama coupling of heteroaryl chlorides with heteroaryl silanes is also reported for the first time. The reaction can be easily scaled up 200 times (100 mmol) without any degasification and purification of reactants; this facilitates the practical application in routine synthesis.     

CuI/Oxalamide Catalyzed Couplings of (Hetero)aryl Chlorides and Phenols for Diaryl Ether Formation

Couplings between (hetero)aryl chlorides and phenols can be effectively promoted by CuI in combination with an N‐aryl‐N′‐alkyl‐substituted oxalamide ligand to proceed smoothly at 120 °C. For this process, N‐aryl‐N′‐alkyl‐substituted oxalamides are more effective ligands than bis(N‐aryl)‐substituted oxalamides. A wide range of electron‐rich and electron‐poor aryl and heteroaryl chlorides gave the corresponding coupling products in good yields. Satisfactory conversions were achieved with electron‐rich phenols as well as a limited range of electron‐poor phenols. Catalyst and ligand loadings as low as 1.5 mol % are sufficient for the scaled‐up variants of some of these reactions.     

An Alternative Approach to PEPPSI Catalysts: From Palladium Isonitriles to Highly Active Unsymmetrically Substituted PEPPSI Catalysts

A series of new pyridine‐enhanced precatalyst preparation, stabilization, and initiation (PEPPSI)‐type complexes bearing different types of carbene ligands was prepared by the modular and convergent template synthesis strategy. Nitrogen acyclic carbenes, saturated and unsaturated five‐membered NHC, saturated six‐membered NHCs, and five‐membered N‐heterocyclic oxo‐carbene (NHOC) ligands on palladium were prepared this way. These new organometallic compounds then were tested in Suzuki and Negishi cross‐coupling reactions by using substrates with one or two substituents in ortho‐position of the new C?C bond being formed. Both aryl chlorides and bromides were tested as coupling partners. In some cases, the new ligands gave results similar to Organ’s successful IPr‐based and IPent‐based PEPPSI derivatives, with aryl bromides 0.05 mol % catalyst load still gave satisfactory results, with aryl chlorides 0.5 mol % were needed.     

An extremely active and general catalyst for Suzuki coupling reaction of unreactive aryl chlorides

β-Diketiminatophosphane Pd complex 2a acted as a powerful catalyst which allows easy access to the Suzuki coupling reaction of less reactive aryl chlorides under mild conditions. A wide range of sterically hindered and deactivated aryl chlorides could be efficiently coupled at a low catalyst loading of 0.1 mol %. Furthermore, this catalytic system also proved to be highly effective in one-pot multiple couplings.     

Facile synthesis of 2-bromo-3-fluorobenzonitrile: an application and study of the halodeboronation of aryl boronic acids

A scaleable synthesis of 2-bromo-3-fluorobenzonitrile via the NaOMe-catalyzed bromodeboronation of 2-cyano-6-fluorophenylboronic acid was developed. The generality of this transformation was demonstrated through the halodeboronation of a series of aryl boronic acids. Both aryl bromides and aryl chlorides were formed in good to excellent yields when the corresponding aryl boronic acid was treated with 1,3-dihalo-5,5-dimethylhydantoin and 5 mol % NaOMe.     

环钯-[PPh4]Br体系催化氯代芳烃的Heck芳基化反应研究

以氯代芳烃为底物，季鏻盐[PPh4]Br为助催化剂，用于环钯催化的Heek芳基化反应．结果表明，在环钯-[PPh4]Br催化体系中，以Na2CO3作为碱性试剂，使用0．3mol％Pd的环钯催化剂催化氯苯的Heek反应，就可得到比较高的产率（88％）和转化率（90％）．对于大部分卤代芳烃Heck反应而言，环钯-[PPh4]Br是一种有效的催化体系，即使是对含推电子基团的不活泼的氯代芳烃，在此体系中也能获得比较好的结果．此外，文中还探讨了反应温度、[PPh4]Br／Pd比值及催化剂回用对反应活性的影响．     

Carbon-boron bond cross-coupling reaction catalyzed by -PPh(2) containing palladium-indolylphosphine complexes

This study describes the application of indolylphosphine ligands with a diphenylphosphino moiety to the palladium-catalyzed borylation of aryl chlorides. The combination of palladium metal precursor with PPh(2)-Andole-phos, which comprises an inexpensive -PPh(2) group, provides highly effective catalysts for the borylation of aryl chlorides. A range of functional groups such as -CN, -NO(2), -CHO, -COMe, -COOMe, and -CF(3) was compatible, and the catalyst loading down to 0.025 mol % of Pd can be achieved. The Pd/PPh(2)-Andole-phos system is able to catalyze both borylation reaction and Suzuki-Miyaura coupling reaction in a one-pot sequential manner for the direct synthesis of biaryl compounds in excellent yields.     

Highly efficient Suzuki-Miyaura coupling of heterocyclic substrates through rational reaction design

A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl)phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na(2)PdCl(4)] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridine- or indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol % of Pd catalyst at 100 degrees C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol % of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).     

Coupling Reactions of Alkynylsilanes Mediated by a Cu(I) Salt: Novel Syntheses of Conjugate Diynes and Disubstituted Ethynes

Reaction of 1-trimethylsilylalkyne with copper(I) chloride in a polar solvent, DMF, at 60 degrees C under an aerobic conditions smoothly undergoes homo-coupling to give the corresponding symmetrical 1,3-butadiynes in 70-99% yields. In addition, (arylethynyl)trimethylsilanes are found to couple with aryl triflates and chlorides in the presence of Cu(I)/Pd(0) (10 mol %/5 or 10 mol %) cocatalyst system to give the corresponding diarylethynes in 49-99% yields. The cross-coupling reaction is applied to a one-pot synthesis of the corresponding unsymmetrical diarylethynes from (trimethylsilyl)ethyne via sequential Sonogashira-Hagihara and the present cross-coupling reactions using two different aryl triflates. The reactions of (arylethynyl)trimethylsilanes with aryl(chloro)ethynes in the presence of 10 mol % of CuCl also yield the corresponding unsymmetrical 1,3-butadiynes in 43-97% yields.     

Scope and limitations of Pd2(dba)3/P(i-BuNCH2CH2)3N-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides

Proazaphosphatrane ligands in combination with Pd(2)(dba)(3) generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides. In particular, commercially available P(i-BuNCH(2)CH(2))(3)N is a highly general and efficient ligand, allowing the coupling of an electronically diverse set of aryl chlorides, including chloropyridines, with a wide variety of amines using 1 mol % of Pd at 100 degrees C. Either a 1:1 or 2:1 ratio of ligand to Pd was found to be effective. This catalyst system performs exceptionally well for sterically hindered substrates, even with only 0.25 mol % of Pd. It is shown that NaOH can also be used as the base (instead of NaO-t-Bu) allowing functionalized substrates to participate in these reactions.     

Sterically bulky thioureas as air- and moisture-stable ligands for pd-catalyzed Heck reactions of aryl halides

We demonstrate that sterically bulky N,N'-disubstituted cyclic thiourea-Pd(0) complexes are air- and moisture-stable and highly active catalysts for palladium-catalyzed Heck reaction of aryl iodides and bromides with olefins (TONs up to 500000 for the reaction of PhI and methyl acrylate). Even activated aryl chlorides can undergo complete conversion in Bu(4)NBr in the presence of 1 mol % Pd catalyst.     

A general and efficient copper catalyst for the amidation of aryl halides

An experimentally simple and inexpensive catalyst system was developed for the amidation of aryl halides by using 0.2-10 mol % of CuI, 5-20 mol % of a 1,2-diamine ligand, and K(3)PO(4), K(2)CO(3), or Cs(2)CO(3) as base. Catalyst systems based on N,N'-dimethylethylenediamine or trans-N,N'-dimethyl-1,2-cyclohexanediamine were found to be the most active even though several other 1,2-diamine ligands could be used in the easiest cases. Aryl iodides, bromides, and in some cases even aryl chlorides can be efficiently amidated. A variety of functional groups are tolerated in the reaction, including many that are not compatible with Pd-catalyzed amidation or amination methodology.     

Catalytic efficiency of a new tridentate ferrocenyl phosphine auxiliary: Sonogashira cross-coupling reactions of alkynes with aryl bromides and chlorides at low catalyst loadings of 10(-1) to 10(-4) mol %

[structure: see text] The catalytic activity in Sonogashira cross-coupling reactions of alkynes with a variety of aryl halides (including chlorides) using a multidentate ferrocenyl phosphine is presented. The novel mixed ferrocenyl aryl/alkyl triphosphine is thermally stable and insensitive to air or moisture, and its robustness allows aryl alkynylation at 10(-1) to 10(-4) mol % catalyst loadings with TONs up to 250,000. Copper-free coupling using phenylacetylene is also accessible in good yield.     

Cross-Coupling of Diarylborinic Acids and Anhydrides with Arylhalides Catalyzed by a Phosphite/N-Heterocyclic Carbene Co-supported Palladium Catalyst System

A highly efficient cross-coupling of diarylborinic acids and anhydrides with aryl chlorides and bromides has been effected by using a palladium catalyst system co-supported by a strong σ-donor N-heterocyclic carbene (NHC), N,N'-bis(2,6-diisopropylphenyl) imidazol-2-ylidene, and a strong π-acceptor phosphite, triphenylphosphite, in tert-BuOH in the present of K(3)PO(4)·3H(2)O. Unsymmetrical biaryls with a variety of functional groups could be obtained in good to excellent yields using as low as 0.01, 0.2-0.5, and 1 mol % palladium loadings for aryl bromides and activated and deactivated aryl chlorides, respectively, under mild conditions. A ligand synergy between the σ-donor NHC and the π-acceptor phosphite in the Pd/NHC/P(OPh)(3) catalytic system has been proposed to be responsible for the high efficacy to arylchlorides in the cross-coupling. A scalable and economical process has therefore been developed for synthesis of Sartan biphenyl from the Pd/NHC/P(OPh)(3) catalyzed cross-coupling of di(4-methylphenyl)borinic acid with 2-chlorobenzonitrile.     

Palladium-catalyzed amination of aryl and heteroaryl tosylates at room temperature

Mild palladium-catalyzed aminations of aryl tosylates and the first aminations of heteroaryl tosylates are described. In the presence of the combination of L2Pd(0) (L = P(o-tol)3) and the hindered Josiphos ligand CyPF-t-Bu, a variety of primary alkylamines and arylamines react with both aryl and heteroaryl tosylates at room temperature to form the corresponding secondary arylamines in high yields with complete selectivity for the monoarylamine. These reactions at room temperature occur in many cases with catalyst loadings of 0.1 mol % and 0.01 mol % in one case, constituting the most efficient aminations of aryl tosylates by nearly 2 orders of magnitude. This catalyst is made practical by the development of a convenient method to synthesize the L2Pd(0) precursor. This complex is stable to air as a solid. In contrast to conventional relative rates for reactions of aryl sulfonates, the reactions of aryl tosylates are faster than parallel reactions of aryl triflates, and the reactions of aryl tosylates are faster than parallel or competitive reactions of aryl chlorides.     

A new family of tunable indolylphosphine ligands by one-pot assembly and their applications in Suzuki-Miyaura coupling of aryl chlorides

This study describes a new class of indolylphosphine ligands, which can be easily accessed by a simple one-pot assembly from commercially available indoles, acid chlorides, and chlorophosphines. A combination of these three starting materials provides a high diversification of the ligand structure. The application of this ligand array in palladium-catalyzed Suzuki-Miyaura coupling reaction of aryl chlorides with arylboronic acids is described. A catalyst loading down to 0.01 mol % of Pd can be achieved.     

Palladium-catalyzed chemoselective cross-coupling of acyl chlorides and organostannanes

Chemoselective cross-coupling of aliphatic and aromatic acyl chlorides with aryl-, heteroaryl-, and alkynylstannanes proceeds in up to 98% yield using 2.5 mol % of bis(di-tert-butylchlorophosphine)palladium(II) dichloride as the precatalyst. Various functional groups including aryl chlorides and bromides that usually undergo oxidative addition to palladium complexes bearing phosphinous acid or dialkylchlorophosphine ligands are tolerated. This procedure allows convenient ketone formation and eliminates inherent limitations of Friedel-Crafts acylations such as substituent-directing effects and typical reactivity requirements of Lewis acid-catalyzed electrophilic aromatic substitutions.     

Efficient copper-catalyzed S-vinylation of thiols with vinyl halides

The synthesis of vinyl sulfides through the coupling reaction of thiols with vinyl iodides, bromides, and chlorides is described. The thiols can couple with aryl iodides in the presence of only 0.5 mol % Cu(2)O without the need for an ancillary ligand. In the presence of 5 mol % of Cu(2)O and 10 mol % 1,10-phenanthroline as the ligand, the more challenging alkyl vinyl bromides can also be coupled with thiols, giving the vinyl sulfides in good to excellent yields.     

Highly reactive, general and long-lived catalysts for palladium-catalyzed amination of heteroaryl and aryl chlorides, bromides, and iodides: scope and structure-activity relationships

We describe a systematic study of the scope and relationship between ligand structure and activity for a highly efficient and selective class of catalysts containing sterically hindered chelating alkylphosphines for the amination of heteroaryl and aryl chlorides, bromides, and iodides. In the presence of this catalyst, aryl and heteroaryl chlorides, bromides, and iodides react with many primary amines in high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary amines with both heteroaryl and aryl chlorides, bromides, and iodides occur to completion with 0.0005-0.05 mol % catalyst. A comparison of the reactivity of this catalyst for the coupling of primary amines at these loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data illustrate the benefits of chelation. Studies on structural variants of the most active catalyst indicate that a rigid backbone in the bidentate structure, strong electron donation, and severe hindrance all contribute to its high reactivity. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl halides, whose activity complements catalysts based on monophosphines and carbenes.