Generation of stoichiometric ethylene and isotopic derivatives and application in transition-metal-catalyzed vinylation and enyne metathesis.

Ethylene is one of the most important building blocks in industry for the production of polymers and commodity chemicals. (13)C- and D-isotope-labeled ethylenes are also valuable reagents with applications ranging from polymer-structure determination, reaction-mechanism elucidation to the preparation of more complex isotopically labeled compounds. However, these isotopic derivatives are expensive, and are flammable gases, which are difficult to handle. We have developed a method for the controlled generation of ethylene and its isotopic variants including, for the first time, fully isotopically labeled ethylene, from simple alkene precursors by using Ru catalysis. Applying a two-chamber reactor allows both the synthesis of ethylene and its immediate consumption in a chemical transformation permitting reactions to be performed with only stoichiometric amounts of this two carbon olefin. This was demonstrated in the Ni-catalyzed Heck reaction with aryl triflates and benzyl chlorides, as well as Ru-mediated enyne metathesis.

Pd-catalyzed carbonylative α-arylation of aryl bromides: scope and mechanistic studies.

Reaction conditions for the three-component synthesis of aryl 1,3-diketones are reported applying the palladium-catalyzed carbonylative α-arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)2] (dba=dibenzylideneacetone) as the palladium source and 1,3-bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two-chamber reactor, COware, applying only 1.5 equivalents of carbon monoxide generated from the CO-releasing compound, 9-methylfluorene-9-carbonyl chloride (COgen). The methodology proved adaptable to a wide variety of aryl and heteroaryl bromides leading to a diverse range of aryl 1,3-diketones. A mechanistic investigation of this transformation relying on 31P and 13C NMR spectroscopy was undertaken to determine the possible catalytic pathway. Our results revealed that the combination of [Pd(dba)2] and DPPP was only reactive towards 4-bromoanisole in the presence of the sodium enolate of propiophenone suggesting that a [Pd(dppp)(enolate)] anion was initially generated before the oxidative-addition step. Subsequent CO insertion into an [Pd(Ar)(dppp)(enolate)] species provided the 1,3-diketone. These results indicate that a catalytic cycle, different from the classical carbonylation mechanism proposed by Heck, is operating. To investigate the effect of the dba ligand, the Pd0 precursor, [Pd(η3-1-PhC3H4)(η5-C5H5)], was examined. In the presence of DPPP, and in contrast to [Pd(dba)2], its oxidative addition with 4-bromoanisole occurred smoothly providing the [PdBr(Ar)(dppp)] complex. After treatment with CO, the acyl complex [Pd(CO)Br(Ar)(dppp)] was generated, however, its treatment with the sodium enolate led exclusively to the acylated enol in high yield. Nevertheless, the carbonylative α-arylation of 4-bromoanisole with either catalytic or stoichiometric [Pd(η3-1-PhC3H4)(η5-C5H5)] over a short reaction time, led to the 1,3-diketone product. Because none of the acylated enol was detected, this implied that a similar mechanistic pathway is operating as that observed for the same transformation with [Pd(dba)2] as the Pd source.

Palladium catalyzed carbonylative Heck reaction affording monoprotected 1,3-ketoaldehydes.

The direct carbonylative palladium catalyzed synthesis of monoprotected 1,3-ketoaldehydes is reported starting from aryl iodides applying near stoichiometric amounts of carbon monoxide. Besides representing platforms for a variety of heterocyclic structures, these motives serve as viable precursors for the highly relevant aryl methyl ketones. The presented strategy can also be adapted for the facile and efficient incorporation of (13)C-labeled carbon monoxide.

An efficient method for the preparation of tertiary esters by palladium-catalyzed alkoxycarbonylation of aryl bromides.

The palladium-catalyzed alkoxycarbonylation of aryl bromides is described for the efficient preparation of tertiary esters. The protocol proved compatible with a wide variety of functionalized (hetero)aromatic bromides, as well as several different sterically hindered tertiary alcohols, affording the alkoxycarbonylated products in high yields. Finally, the formation of aromatic trityl esters is discussed.

Mild and efficient nickel-catalyzed Heck reactions with electron-rich olefins.

A new efficient protocol for the nickel-catalyzed Heck reaction of aryl triflates with vinyl ethers is presented. Mild reaction conditions that equal those of the corresponding palladium-catalyzed Heck reaction are applied, representing a practical and more sustainable alternative to the conventional regioselective arylation of vinyl ethers. A catalytic system comprised of Ni(COD)(2) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF) in combination with the tertiary amine Cy(2)NMe proved effective in the olefination of a wide range of aryl triflates. Both electron-deficient and electron-rich arenes proved compatible, and the corresponding aryl methyl ketone could be secured after hydrolysis in yields approaching quantitative. Good functional group tolerance was observed matching the characteristics of the analogous Pd-catalyzed Heck reaction. The high levels of catalytic activity were explained by the intermediacy of a cationic nickel(II) complex potentially responsible for the successive ß-hydride elimination and base promoted catalyst regeneration. Although these elementary reactions are normally considered challenging, DFT calculations suggested this pathway to be favorable under the applied reaction conditions.

Palladium-catalyzed approach to primary amides using nongaseous precursors.

A simple protocol is reported for the preparation of primary aryl amides under Pd-catalyzed carbonylation chemistry applying a two-chamber system with crystalline and nontransition metal based sources of carbon monoxide and ammonia. The method is suitable for the synthesis of a number of primary amides with good functional group tolerance. Incorporation of (13)CO into the primary amide group was also found to be effective making this approach useful for accessing carbon isotope labeled derivatives.

Carbonylative Heck reactions using CO generated ex situ in a two-chamber system.

A carbonylative Heck reaction of aryl iodides and styrene derivatives employing a two-chamber system using a stable, crystalline, and nontransition metal based carbon monoxide source is reported. By applying near-stoichiometric amounts of the carbon monoxide precursor, an effective exploitation of the hazardous CO gas is obtained affording chalcone derivatives in good yields. Application to isotope labeling, incorporating (13)CO, was further established.

Heteroaromatic sulfonates and phosphates as electrophiles in iron-catalyzed cross-couplings.

Employment of heteroaromatic tosylates and phosphates as suitable electrophiles in iron-catalyzed cross-coupling reactions with alkyl Grignard reagents is reported. These reactions are performed at low temperature allowing good functional group tolerance and full conversion is achieved within minutes. In addition, an aryl-aryl cross-coupling utilizing a heteroaryl sulfamate electrophile is reported.

Heteroaromatic tosylates as electrophiles in regioselective Mizoroki-Heck-coupling reactions with electron-rich olefins.

Heteroaromatic 2-pyridyl tosylates were successfully applied as electrophiles in palladium(0)-catalyzed Mizoroki-Heck-coupling reactions to electron-rich olefins with complete alpha-regioselectivity. This protocol represents a general strategy for the application of pyridyl tosylates and mesylates in the Mizoroki-Heck coupling. The catalytic system also proved adaptable to changes in the heteroaromatic core as well as large-scale applications. Finally, the synthetic utility of the functionalized alpha-heteroarylvinyl amides was established providing straightforward access to highly functionalized heteroaromatic compounds including chiral benzylic amide derivatives.

A ligand free and room temperature protocol for Pd-catalyzed Kumada-Corriu couplings of unactivated alkenyl phosphates.

Kumada-Corriu cross-couplings of nonactivated cyclic and acyclic vinyl phosphates with aryl magnesium reagents afforded a series of 1,1-disubtituted alkenes in good yields for most cases when the reactions were performed at room temperature with the simple palladium salt, PdCl(2), without the presence of phosphine ligands.

Studies on the 1,2-migrations in Pd-catalyzed Negishi couplings with JosiPhos ligands.

We report an initial investigation with the goal of determining the factors that control the 1,2-migration in the Negishi cross-coupling, which is promoted by palladium catalyst systems generated with JosiPhos ligands. Several of the factors that were demonstrated to be important for the 1,2-migration include (1) the nucleophilicity of the organometallic reagent, which possibly influences the transmetalation step in direct competition with the intermediate beta-hydride elimination of the alkenyl Pd(II) species; (2) the structural features of the vinyl tosylates and phosphates, in which substrates possessing a bulky C1 substituent displayed highest propensity for undergoing the 1,2-migration under the coupling reaction conditions; and (3) the structure of the JosiPhos ligand, where both the sterical bulk and choice of substituents on the ferrocenyl phosphino group greatly influence the catalytic activity of the palladium complex and its capacity to facilitate the 1,2-migration.

Direct vinylation and difluorovinylation of arylboronic acids using vinyl- and 2,2-difluorovinyl tosylates via the Suzuki-Miyaura cross coupling.

General reaction conditions were developed for the Pd(0)-catalyzed Suzuki-Miyaura coupling reaction of aryl boronic acids with a simple electrophilic vinylation reagent, vinyl tosylate, providing access to styrene derivatives in good yields. The easily accessible vinyl tosylate represents a stable and less toxic alternative to the vinyl halides and the triflate/nonaflate derivatives. Furthermore, this methodology was expanded to provide a facile and straightforward approach for the introduction of a gem-difluorovinyl substituent onto an aromatic ring using the similar and also readily available 2,2-difluorovinyl tosylate as the electrophilic complement.

Investigations on the Suzuki-Miyaura and Negishi couplings with alkenyl phosphates: application to the synthesis of 1,1-disubstituted alkenes.

The development of versatile Suzuki-Miyaura and Negishi cross-couplings with nonactivated alkenyl phosphates and aromatic boronic acids or organozinc reagents was achieved in acceptable to good yields. A series of 1,1-disubstituted alkenes were synthesized using a combination of either Ni(COD)2/Cy3P/K3PO4 or Pd2dba3/DPPF in THF. When working with alkenyl electrophiles in metal-catalyzed cross-couplings, this method lends itself as a less costly and more stable alternative to the corresponding triflate or nonaflate derivatives. In addition, initial studies are presented regarding an efficient 1,2-migration under Negishi coupling conditions.

Studies on the Heck reaction with alkenyl phosphates: can the 1,2-migration be controlled? Scope and limitations.

A catalyst system was identified which promotes the Heck coupling of nonactivated vinyl phosphates with electron deficient alkenes providing a new entry to diene products from simple and readily accessible starting materials. In contrast to our earlier work exploiting P(t-Bu)3 as the ligand in the presence of PdCl2(COD), the application of Buchwald's dialkylbiarylphosphines, X-Phos, effectively promoted the vinylic substitution with a wide range of alkenyl phosphates in the presence of 10 equiv of lithium chloride. Importantly, these reaction conditions suppressed 1,2-migration of the alkenyl palladium(II) intermediate. Further studies are also reported with the catalytic system which encourages isomerization in order to determine the range of vinyl phosphates that may participate in these coupling reactions. The extent of the 1,2-migration was dependent on the C1-substituent where best results were noted for substrates possessing a C1-alkyl quaternary carbon. Hence, with certain members of this class of alkenyl phosphates either the migrated or nonmigrated Heck products may be preferentially synthesized by selection of the phosphine ligand. Finally, competition experiments between an unactivated aryl chloride and a vinyl phosphate with a palladium catalyst possessing either X-Phos or P(t-Bu)3 as ligand demonstrated the ability to carry out Heck coupling reactions selectively with the aryl halide. Oxidative addition of the metal catalyst into the aryl chloride bond rather than the C-O bond of the alkenyl phosphate is therefore preferred.

Direct synthesis of 1,1-diarylalkenes from alkenyl phosphates via nickel(0)-catalysed Suzuki-Miyaura coupling.

A combination of Ni(COD)(2) and PCy(3) promotes effectively the Suzuki-Miyaura cross coupling of 1-arylalkenyl phosphates with aryl boronic acids with yields attaining 99%.