Research on Au(I)-catalyzed ene-yne cycloisomerization for construction of quassinoid scaffold

Compounds that undergo Au(I)-catalyzed cycloisomerizations affording tetracyclic products that can be converted into compounds with the skeleton of bruceantin are described. The Au(I)-catalyzed cycloisomerizations reported herein are hindered by a 1,3-diaxial interaction between the substituent and the methyl group in the transition state. The use of small substituents was found to increase the yield of the desired product, while the reaction of substrates with large substituents afford undesired constitutional isomers.     

The first broad application of alkynyl sulfides as dienophiles in cobalt(I)-catalyzed Diels-Alder reactions

The cobalt(I)-catalyzed Diels-Alder reaction of nonactivated aryl alkynyl sulfides with acyclic 1,3-dienes generates dihydroaromatic vinyl sulfides under very mild reaction conditions, and these products can be oxidized with mild oxidants to the corresponding diaryl sulfides in good overall yields. The steric and electronic effects of substituents on the aryl, as well as on the alkynyl, moieties of the aryl alkynyl sulfide are discussed. While the cobalt catalyst system is quite efficient in converting alkynyl sulfides to the Diels-Alder adducts, the transformation of the corresponding aryl alkynyl sulfoxides and sulfones under similar mild reaction conditions gave only moderate yields of the desired adducts.     

FeCl3/PPh3-catalyzed Sonogashira coupling reaction of aryl iodides with terminal alkynes

Conditions for a FeCl₃/PPh₃-catalyzed and palladium-, copper-, amine free-Sonogashira coupling reaction of aryl halides with terminal alkynes are reported. The protocol was applicable to a wide variety of substituted aryl iodides and alkynes with different steric and electronic properties and gave excellent yields of the desired coupling products.     

Palladium(II)-catalyzed cycloisomerization of substituted 1,5-hexadienes: a combined experimental and computational study on an open and an interrupted hydropalladation/carbopalladation/β-hydride elimination (HCHe) catalytic cycle

The Pd(II)-catalyzed cycloisomerization of 3-alkoxycarbonyl-3-hydroxy-substituted 1,5-hexadienes has been studied experimentally and computationally. Experimentally, the reaction is characterized by a rapid room temperature formation of monomeric as well as dimeric cycloisomerization products using the commercially available precatalyst [(CH(3)CN)(4)Pd](BF(4))(2). In situ NMR measurements indicate the initial kinetic advantage of the desired cycloisomerization pathway to methylene cyclopentanes; however, double bond isomerization, elimination, and dimer formation are competitive undesired pathways. Evaluation of the obtained product structures by NMR spectroscopy and X-ray crystallography indicates that the sole determinant for the monomer/dimer ratio is the regioselectivity of the initial hydropalladation in favor of the allylic (monomer formation) or the homoallylic double bond (dimer formation). In order to account for the experimental results, we propose the coexistence of two product-forming catalytic cycles, an open, monomer generating, as well as an interrupted and redirected, dimer generating, hydropalladation/carbopalladation/β-hydride elimination (HCHe) process. Results from computational studies of the proposed competing catalytic cycles are supportive to our mechanistic hypothesis and pinpoint the pivotal importance of Pd(II)-hydroxo-chelate complexes for the reactivity-stability interplay of on- and off-pathway intermediates.     

Copper(II)-catalyzed asymmetric henry reaction of o-alkynylbenzaldehydes followed by gold(I)-mediated cycloisomerization: an enantioselective route to chiral 1H-isochromenes and 1,3-dihydroisobenzofurans

By combining the copper(II)-catalyzed asymmetric Henry reaction of o-alkynylbenzaldehydes with subsequent gold(I)-catalyzed cycloisomerization, optically active 1H-isochromenes and 1,3-dihydroisobenzofurans were successfully synthesized in good overall yields with good to excellent enantioselectivities (up to 98%). Various substrates were investigated, and a correlation between the regioselectivity and electronic nature of the substrates was studied. The substrates with electro-donating groups at the alkynyl moiety preferred a 6-endo-dig manner to generated 1H-isochromenes 3 as main products (up to >30:1) while the ones with electron-withdrawing groups were inclined to undergo 5-exo-dig cyclization to form 1,3-dihydroisobenzofurans 4 (up to 1:5).     

Synthesis of fused carbocycles via a selective 6-endo dig gold(I)-catalyzed carbocyclization

A gold-catalyzed synthesis of fused carbocycles via a regioselective 6-endo dig process is reported. The selectivity can be modulated by the steric and electronic properties of gold(I) complexes. The ligands can influence the pathway selectivity for the first bond formation rather than through a common intermediate generated after an initial bond formation. This gold(I)-catalyzed transformation provides access to synthetically useful carbocyclic motifs that are found in numerous diterpenoid natural products.     

Control of regioselectivity in Pd(0)-catalyzed coupling-cyclization reaction of 2-(2',3'-allenyl)malonates with organic halides

The regioselectivity in the Pd(0)-catalyzed coupling-cyclization of 2-(2',3'-allenyl)malonates with organic halides is determined by the steric and electronic effects of both substrates. By deliberate control of the reaction conditions, the regioselectivity of this reaction can be tuned. With conditions A and B, the reaction afforded vinylic cyclopropane derivatives, while with conditions C and D, the reaction afforded cyclopentene derivatives in a highly selective manner. Under similar conditions, 1-alkenyl halides tend to form more three-membered cyclic products. The increased steric hindrance at the 2'-position of the allene moiety and aryl halides favors the formation of five-membered cyclic products. The regioselectivity of the reaction may be explained by the comparison of the relative stabilities of syn- and anti-type pi-allyl palladium intermediates.     

Copper-catalyzed aerobic oxidation and cleavage/formation of C-S bond: a novel synthesis of aryl methyl sulfones from aryl halides and DMSO

With atmospheric oxygen as the oxidant, a novel copper(I)-catalyzed synthesis of aryl methyl sulfones from aryl halides and widely available DMSO is described. The procedure tolerates aryl halides with various functional groups (such as methoxy, acetyl, chloro, fluoro and nitro groups), which could afford aryl methyl sulfones in moderate to high yields. The copper-catalyzed aerobic oxidation and the cleavage/formation of C-S bond are the key steps for this transformation.     

Synthesis of functionalized oxazolones by a sequence of Cu(II)- and Au(I)-catalyzed transformations

A study concerning a two-step sequence leading to the formation of diversely 1,5-disubstituted oxazolones is described. The mild conditions employed allow the efficient and rapid synthesis of a variety of such compounds via an initial Cu(II)-catalyzed coupling of a bromoalkyne with a secondary tert-butyloxycarbamate followed by a Au(I)-catalyzed cycloisomerization of the N-alkynyl tert-butyloxycarbamates thus obtained.     

Convergent and rapid assembly of substituted 2-pyridones through formation of N-alkenyl alkynylamides followed by gold-catalyzed cycloisomerization

A new method for the convergent and rapid assembly of substituted 2-pyridones was developed through the formation of N-alkenyl alkynylamides (amide-linked 1,5-enynes) by N-acylation of imines with alkynoyl chlorides and the subsequent cationic Au(I)/PPh 3-catalyzed cycloisomerization.     

Gold-catalyzed furan/yne cyclizations for the regiodefined assembly of multisubstituted protected 1-naphthols

The gold(I)-catalyzed intramolecular cycloisomerization of furan/ynes bearing a silyloxy or allyloxy group has been developed, which provides a highly efficient access to protected 1-naphthol derivatives with enal or enone moiety. The method offers several advantages such as high stereoselectivities, mild reaction conditions, and easily accessible starting materials. In addition, the naphthyl products could be further transformed into the important benzocoumarins in a one-pot procedure.     

Rhodium(I)-Catalyzed Tertiary Phosphine Directed C−H Arylation: Rapid Construction of Ligand Libraries

Modification of commercially available monophosphine ligands with either aryl bromides or chlorides by rhodium(I)-catalyzed, tertiary phosphine directed C−H activation is described. A series of ligand libraries containing mono- and diaryl-substituted groups, having different steric and electronic properties, were obtained in high yields. Based on the outstanding properties of their parent scaffolds, the modified ligands have been found to be powerful in organic reactions.     

Intermolecular Alkene Difunctionalization via Gold-Catalyzed Oxyarylation

The gold-catalyzed intermolecular oxyarylation of alkenes is reported. This work employed the oxidative addition of aryl iodides to Me−DalphosAu⁺ for the formation of a Au^III−Ar intermediate. The better binding ability of alkenes over O nucleophiles ensured the success of intermolecular oxyarylation, giving desired products with a broad substrate scope and high efficiency (>50 examples with up to 95 % yield). One-pot converting of methoxy groups into other nucleophiles allowed achieving alkene difunctionalization with the construction of C−N, C−S, and C−C bonds under mild conditions.     

A DFT-based theoretical investigation of the mechanism of the PtCl2-mediated cycloisomerization of allenynes

The mechanism of Pt(II)-catalyzed intramolecular cycloisomerization of allenyne systems has been extensively investigated by DFT calculations. Different mechanistic schemes have been proposed and discussed, including the Alder-ene reaction. The free energy results suggest that the kinetically preferred reaction pathway for precursors that are tri- and tetrasubstituted on the allene moiety should proceed by a five-step mechanism. This would involve formation of a platina(IV)cyclopentene intermediate by selective engagement of the external pi bond of the allene, which would undergo regioselective beta-H elimination from the equatorially disposed methyl group. A metal-induced H migration leads to a second octahedral Pt(IV)-chelate complex, which would yield the expected bicyclic system through an intramolecular migratory insertion step. Therefore, depending on the conformation of the initial eta(4)-reactant complex for trisubstituted patterns, two possible intermediates can be formed that would evolve through different paths. In these cases, the regio- and stereochemical outcomes predicted by the mechanistic scheme proposed agree with experimental data. Substituted precursors on the alkyne moiety follow a distinct, four-step, mechanism also involving an oxidative cyclometalation process to an octahedral Pt(IV) intermediate complex. Theoretical results reveal the kinetic preference for beta-H elimination from the allylic group rather than from the gem-dimethyl group, which should account for the observed regioselectivity.     

Gold-catalyzed cycloisomerization of 1,7-diyne benzoates to indeno[1,2-c]azepines and azabicyclo[4.2.0]octa-1(8),5-dines

A synthetic method that relies on Au(I)-catalyzed cycloisomerization reactions of 1,7-diyne benzoates to prepare indeno[1,2-c]azepines and azabicyclo[4.2.0]octa-1(8),5-dines is described.     

Carbopalladation of nitriles: synthesis of 2,3-diarylindenones and polycyclic aromatic ketones by the Pd-catalyzed annulation of alkynes and bicyclic alkenes by 2-iodoarenenitriles

2-iodobenzonitrile, its derivatives, and various heterocyclic analogues undergo palladium(0)-catalyzed annulation onto diarylacetylenes or bicyclic alkenes to afford 2,3-diarylindenones and polycyclic aromatic ketones in very good to excellent yields. This reaction represents one of the first examples of the addition of an organopalladium moiety to the carbon-nitrogen triple bond of a nitrile. The reaction is compatible with a number of functional groups. A reaction mechanism, as well as a model accounting for the electronic effects of substituents on the aromatic ring of the nitrile, is proposed.     

Gold-catalyzed cycloisomerizations of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols to 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols

A method to prepare 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols by gold(I)-catalyzed cycloisomerization of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols with N-iodosuccinimide (NIS) is reported. The reactions were shown to be operationally simplistic and proceed efficiently for a wide variety of substrates, affording the corresponding products in good to excellent yields (70-99%). The mechanism is suggested to involve activation of the alkyne moiety of the substrate by the gold(I) catalyst. This triggers intramolecular addition of the tethered aniline moiety to give a vinyl gold intermediate, which undergoes iododeauration with NIS to give the (E)-2-(iodomethylene)indolin-3-ol adduct. Subsequent 1,3-allylic alcohol isomerization (1,3-AAI) followed by formylation of this vinyl iodide intermediate then gives the 1H-indole-2-carbaldehyde.     

Mechanism of the transition-metal-catalyzed hydroarylation of bromo-alkynes revisited: hydrogen versus bromine migration

A comprehensive mechanistic study of the InCl(3)-, AuCl-, and PtCl(2)-catalyzed cycloisomerization of the 2-(haloethynyl)biphenyl derivatives of Fürstner et al. was carried out by DFT/M06 calculations to uncover the catalyst-dependent selectivity of the reactions. The results revealed that the 6-endo-dig cyclization is the most favorable pathway in both InCl(3)- and AuCl-catalyzed reactions. When AuCl is used, the 9-bromophenanthrene product could be formed by consecutive 1,2-H/1,2-Br migrations from the Wheland-type intermediate of the 6-endo-dig cyclization. However, in the InCl(3)-catalyzed reactions, the chloride-assisted intermolecular H-migrations between two Wheland-type intermediates are more favorable. These Cl-assisted H-migrations would eventually lead to 10-bromophenanthrene through proto-demetalation of the aryl indium intermediate with HCl. The cause of the poor selectivity of the PtCl(2) catalyst in the experiments by the Fürstner group was predicted. It was found that both the PtCl(2)-catalyzed alkyne-vinylidene rearrangement and the 5-exo-dig cyclization pathways have very close activation energies. Further calculations found the former pathway would lead eventually to both 9- and 10-bromophenanthrene products, as a result of the Cl-assisted H-migrations after the cyclization of the Pt-vinylidene intermediate. Alternatively, the intermediate from the 5-exo-dig cyclization would be transformed into a relatively stable Pt-carbene intermediate irreversibly, which could give rise to the 9-alkylidene fluorene product through a 1,2-H shift with a 28.1 kcal mol(-1) activation barrier. These findings shed new light on the complex product mixtures of the PtCl(2)-catalyzed reaction.     

A DFT study on the mechanism of gold(III)-catalyzed synthesis of highly substituted furans via [3, 3]-sigmatropic rearrangements and/or [1, 2]-acyloxy migration based on propargyl ketones

The mechanisms of gold(III)-catalyzed synthesis of highly substituted furans via [3,3]-sigmatropic rearrangements and/or [1,2]-acyloxy migration based on propargyl ketones have been investigated using density functional theory calculations at BHandHLYP/6-31G(d,p) (SDD for Au) level of theory. Solvent effects on these reactions were explored using calculations that included a polarizable continuum model (PCM) for the solvent (toluene). Two plausible pathways that lead to the formation of Au(III) vinyl carbenoid and an allenyl structure through [3,3]-sigmatropic rearrangements, [1,2]-acyloxy migration via oxirenium and dioxolenylium were performed. Our calculated results suggested: (1) the major pathway of the cycle causes an initial Rautenstrauch-type [1,2]-migration via oxirenium to form an Au(III) vinyl carbenoid. Subsequent cycloisomerization of this intermediate then provides the corresponding furan whether for the methyl-substituted propargylic acetates or the phenyl-substituted propargylic acetates; (2) for the methyl-substituted propargylic acetates, the formation of Au(III) vinyl carbenoid structures was the rate-determining step. However, intramolecular nucleophilic attack and subsequent cycloisomerization to give the final product was rate-determining for the phenyl-substituted propargylic acetates. The computational results are consistent with the experimental observations of Gevorgyan, et al. for gold(III)-catalyzed synthesis of highly substituted furans based on propargyl ketones.     

Mechanistic insights into the gold-catalyzed cycloisomerization of bromoallenyl ketones: ligand-controlled regioselectivity

Through computational and experimental studies, the mechanisms of gold-catalyzed cycloisomerization of bromoallenyl ketones in toluene have been elucidated. The divergent 1,2-migrations for the Au(I)- and Au(III)-catalyzed reactions have been investigated, and the results confirmed that the regiochemistry is ligand-dependent in cases of Au(PR3)L (L = Cl, OTf, BF4, and SbF6) catalysts.