Intramolecular alkyne hydroalkoxylation and hydroamination catalyzed by iridium hydrides

[reaction: see text] Iridium(III) hydrides prove to be air-stable active catalysts for intramolecular hydroalkoxylation and hydroamination of internal alkynes with proximate nucleophiles. The cyclization follows highly selective 6-endo-dig regiochemistry when regioselectivity is an issue.     

Convenient synthesis of tryptophols and tryptophol homologues by hydroamination of alkynes

A novel method is presented for the one-pot synthesis of substituted 3-(2-hydroxyethyl)- and 3-(3-hydroxypropyl)indoles (tryptophols and homotryptophols) from aryl hydrazines and silyl-protected ω-(hydroxyoalkyl)alkynes. Various tryptophol derivatives were prepared directly in good yield with excellent regioselectivity via a domino reaction sequence consisting of a titanium-catalyzed hydroamination of the alkyne, [3+3]-rearrangement of the resulting aryl hydrazone, and subsequent deprotection of the hydroxy group.     

Direct synthesis of fused indoles by gold-catalyzed cascade cyclization of diynes

A direct, concise, and atom-economical synthetic method for the generation of fused indoles, using a gold-catalyzed cascade cyclization of diynes, has been developed. The reaction gave various fused indoles, such as aryl-annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino- or oxepinoindole derivatives in good to excellent yields, through an intramolecular cascade 5-endo-dig hydroamination followed by a 6- or 7-endo-dig cycloisomerization, without producing theoretical byproduct. Three of the resulting indoles exhibited potent antifungal activities against T. mentagrophytes and T. rubrum, demonstrating the practical application of the described cascade reaction for drug discovery.     

Intramolecular hydroarylation of alkynes catalyzed by platinum or gold: mechanism and endo selectivity

The cyclization of differently substituted aryl alkynes with PtII or AuI catalysts proceeds by endo-dig pathways. When AgI was used to generate reactive cationic AuI catalysts, 2H-chromenes dimerize to form cyclobutane derivatives by a AgI-catalyzed process. A DFT study on the cyclization mechanism shows a kinetic and thermodynamic preference for 6-endo-dig versus 5-exo-dig cyclizations in PtII-catalyzed processes. Calculations indicate that although Friedel-Crafts and the cyclopropanation processes via metal cyclopropyl carbenes show very similar activation energies, platinum cyclopropyl carbenes are the stationary points with the lowest energy.     

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).     

Palladium-catalyzed intramolecular carbopalladation/cyclization cascade: access to polycyclic N-fused heterocycles

An efficient palladium-catalyzed intramolecular carbopalladation/cyclization cascade toward tetra- and pentacyclic N-fused heterocycles has been developed. This transformation proceeds via the palladium-catalyzed coupling of aryl halides with internal propargylic esters or ethers followed by the 5-endo-dig cyclization leading to polycyclic pyrroloheterocycles in moderate to excellent yields.     

Cyclization of 2-dicyanomethylene-1,2-dihydropyridine-3-carbonitriles with amines: a mechanistic rationalization

A mechanistic rationalization for the cyclization of the 1,5-dinitrile system present in pyridines 4{1-3} with amines to lead to 1,6-naphthyridines is proposed. Three factors play an important role on the direction of cyclization: (1) the cyclization involves nucleophilic attack of an amidine onto a nitrile or amidine; (2) the attack has to fulfill strict geometrical constraints to allow the cyclization to proceed; (3) the cyclization step should involve the nucleophilic attack combined with a tautomerism to achieve the high levels of regioselectivity observed.     

Synthesis of 1,2-disubstituted cyclopentenes by palladium-catalyzed reaction of homopropargyl-substituted dicarbonyl compounds with organic halides via 5-endo-dig cyclization

Palladium catalysts with bulky biaryl phosphine ligands allow homopropargyl-substituted dicarbonyl compounds to undergo intramolecular addition via a rare 5-endo-dig pathway. C-C bond forming reductive elimination follows the addition to introduce alkenyl and alkynyl as well as aryl groups by using the corresponding organic halides. The cyclization is versatile enough to be applicable to the synthesis of highly substituted dihydropyrrole and a fused tricyclic compound.     

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.     

Diastereoselective formation of 5-vinylcyclopentenes from 1, 6-enynes: cobalt-mediated C-H allylic activation and formal 5-endo-Dig cyclization

A novel intramolecular cyclization reaction mediated by dicobalt octacarbonyl (Co(2)(CO)(8)) is reported. Thermolysis in an argon atmosphere transforms the cobalt complex of 1-trimethylsilyl-6-hepten-1-ynes into 1-trimethylsilyl-5-vinylcyclopentenes in good yield and in a highly diastereoselective manner. This formal 5-endo-dig cyclization is proposed to proceed via an allylic C-H oxidative addition.     

Electrophile-driven regioselective synthesis of functionalized quinolines

Highly substituted 3-iodoquinolines bearing different alkyl and aryl moieties can be synthesized in moderate to excellent yields (up to 99%) by 6-endo-dig iodocyclization of 2-tosylaminophenylprop-1-yn-3-ols with molecular iodine (I(2)) under mild conditions. The cyclization is highly regioselective and the resulting 3-iodoquinolines can be further functionalized by various coupling reactions.     

Gold(I)-catalyzed intramolecular [4+2] cycloadditions of arylalkynes or 1,3-enynes with alkenes: scope and mechanism

The cyclizations of enynes substituted at the alkyne gives products of formal [4+2] cyclization with Au(I) catalysts. 1,8-Dien-3-ynes cyclize by a 5-exo-dig pathway to form hydrindanes. 1,6-Enynes with an aryl ring at the alkyne give 2,3,9,9a-tetrahydro-1H-cyclopenta[b]naphthalenes by a 5-exo-dig cyclization followed by a Friedel-Crafts-type ring expansion. A 6-endo-dig cyclization is also observed in some cases as a minor process, although in a few cases, this is the major cyclization pathway. In addition to cationic gold complexes bearing bulky biphenyl phosphines, a gold complex with tris(2,6-di-tert-butylphenyl)phosphite is exceptionally reactive as a catalyst for this reaction. This cyclization can also be carried out very efficiently with heating under microwave irradiation. DFT calculations support a stepwise mechanism for the cycloaddition by the initial formation of an anti-cyclopropyl gold(I)-carbene, followed by its opening to form a carbocation stabilized by a pi interaction with the aryl ring, which undergoes a Friedel-Crafts-type reaction.     

Iron(III)-catalyzed Conia-ene cyclization of 2-alkynic 1,3-dicarbonyl compounds

A cheap, simple, and effective FeCl(3)-catalyzed Conia-ene cyclization of 2-alkynic 1,3-dicarbonyl compounds was stereospecific to afford alkylidenecyclopentanes in (E)-isomers via the 5-exo-dig pathway. The 5-endo-dig and 6-exo-dig cyclizations were also possible, depending on the structure of the substrates.     

Free‐Amine‐Directed Alkenylation of C(sp2)?H and Cycloamination by Palladium Catalysis

A new protocol for the palladium‐catalyzed free‐amine‐directed alkenylation of C(sp²)? H bonds and cycloamination is described. Substituted biaryl‐2‐amines react with various alkenes, including electron‐deficient alkenes, aryl alkenes and alkyl alkenes, to give the corresponding phenanthridines with exclusive regioselectivity. The use of α‐branched styrenes leads to the formation of tricyclic compounds with a seven‐membered amine ring. The method operates through a free‐amine‐directed alkenylation and a subsequent hydroamination cyclization reaction.     

Palladium-catalyzed intramolecular asymmetric hydroamination, hydroalkoxylation, and hydrocarbonation of alkynes

A conceptually novel approach for asymmetric intramolecular hydroamination, hydroalkoxylation and hydrocarbonation of alkynes using chiral palladium catalysts are described. The reactions of the aminoalkynes 5, alkynols 7, and alkynylmethines 9 in the presence of Pd2(dba)3 x CHCl3/PhCOOH/renorphos 4 in benzene (or benzene-hexane) at 100 degrees C gave the corresponding cyclization products (nitrogen heterocycles 6, oxygen heterocycles 8, and carbocycles 10) in good yields with good enantioselectivities. The origins of enantioselectivities in the hydroamination reaction are discussed based on DFT computations.     

Ruthenium-catalyzed cyclization of epoxide with a tethered alkyne: formation of ketene intermediates via oxygen transfer from epoxides to terminal alkynes

Treatment of (o-ethynyl)phenyl epoxides with TpRuPPh(3)(CH(3)CN)(2)PF(6) (10 mol %) in hot toluene (100 degrees C, 3-6 h) gave 2-naphthols or 1-alkylidene-2-indanones very selectively with isolated yields exceeding 72%, depending on the nature of the epoxide substituents. Surprisingly, the reaction intermediate proved to be a ruthenium-pi-ketene species that can be trapped efficiently by alcohol to give an ester compound. This phenomenon indicates a novel oxygen transfer from epoxide to its terminal alkyne catalyzed by a ruthenium complex. A plausible mechanism is proposed on the basis of reaction products and the deuterium-labeling experiment. The 2-naphthol products are thought to derive from 6-endo-dig cyclization of (o-alkenyl)phenyl ketene intermediates, whereas 1-alkylidene-2-indanones are given from the 5-endo-dig cyclization pathway.     

A new five-membered ring forming process based on palladium(0)-catalyzed arylative cyclization of allenyl enones

A palladium(0)/monophosphine catalyst promotes a novel arylative cyclization reaction of C1-, C2-, and C3-tethered allenyl enones with arylboronic acids to produce five-membered ring containing products. The regioselectivity of the process, associated with aryl group introduction into the allene moiety, depends on the length of the tether. This finding suggests that the cyclization reaction does not proceed through a carbopalladation pathway but rather via a route involving palladacycle-forming or "anti-Wacker"-type oxidative addition to the Pd(0) catalyst.     

Synthesis of 2H-1,2-oxaphosphorin 2-oxides via Ag2CO3-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters

[reaction: see text]. Six new 2-ethoxy-2H-1,2-oxaphosphorin 2-oxides were synthesized with high regioselectivity in good yields via Ag(2)CO(3)-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters in CH(2)Cl(2) at room temperature. This cyclization of P-OH to substituted alkynes is reported for the first time. The products are a class of phosphorus heterocycles with potential use and are heretofore prepared with difficulty.     

Ruthenium-catalyzed aromatization of aromatic enynes via the 1,2-migration of halo and aryl groups: a new process involving electrocyclization and skeletal rearrangement

The halo and aryl substituents of the 1,2-disubstituted styryl group of aromatic enynes undergo a 1,2-shift in the aromatization reaction catalyzed by TpRuPPh3(CH3CN)2PF6 (10 mol %) in toluene (110 degrees C, 6-8 h). The aryl group shifts to the neighboring olefin carbon, and the iodo (or bromo) substituent migrates to the terminal alkyne carbon. The mechanisms of these two migrations have been elucidated by isotope labeling experiments. It indicates that the 1,2-aryl shift arises from 5-endo-dig electrocyclization of a ruthenium-vinylidene species, whereas the 1,2-iodo shift follows a 6-endo-dig pathway.     

A general study of [(eta5-Cp')2Ti(eta2-Me3SiC2SiMe3)]-catalyzed hydroamination of terminal alkynes: regioselective formation of Markovnikov and anti-Markovnikov products and mechanistic explanation (Cp'=C5H5, C5H4Et, C5Me5)

A general study of the regioselective hydroamination of terminal alkynes in the presence of [(eta5-Cp)2Ti(eta2-Me3SiC2SiMe3)] (1), [(eta5-CpEt)2Ti(eta2-Me3SiC2SiMe3)] (CpEt=ethylcyclopentadienyl) (2), and [(eta5-Cp*)2Ti(eta2-Me3SiC2SiMe3)] (Cp*=pentamethylcyclopentadienyl) (3) is presented. While aliphatic amines give mainly the anti-Markovnikov products, anilines and aryl hydrazines yield the Markovnikov isomer as main products. Interestingly, using aliphatic amines such as n-butylamine and benzylamine the different catalysts lead to a significant change in the observed regioselectivity. Here, for the first time a highly selective switch from the Markovnikov to the anti-Markovnikov product is observed simply by changing the catalyst. Detailed theoretical calculations for the reaction of propyne with different substituted anilines and tert-butylamine in the presence of [(eta5-C5H5)Ti(=NR)(NHR)] (R=4-C6H4X; X=H, F, Cl, CH3, 2,6-dimethylphenyl) reveal that the experimentally observed regioselectivity is determined by the relative stability of the corresponding pi-complexes 10. While electrostatic stabilization favors the Markovnikov performance for aniline, the steric repulsive destabilization disfavors the Markovnikov performance for tert-butylamine.