Formal and standard ruthenium-catalyzed [2 + 2 + 2] cycloaddition reaction of 1,6-diynes to alkenes: a mechanistic density functional study

"Formal" and standard Ru(II)-catalyzed [2 + 2 + 2] cycloaddition of 1,6-diynes 1 to alkenes gave bicyclic 1,3-cyclohexadienes in relatively good yields. The neutral Ru(II) catalyst was formed in situ by mixing equimolecular amounts of [Cp*Ru(CH3CN)3]PF6 and Et4NCl. Two isomeric bicyclic 1,3-cyclohexadienes 3 and 8 were obtained depending on the cyclic or acyclic nature of the alkene partner. Mechanistic studies on the Ru catalytic cycle revealed a clue for this difference: (a) when acyclic alkenes were used, linear coupling of 1,6-diynes with alkenes was observed giving 1,3,5-trienes 6 as the only initial reaction products, which after a thermal disrotatory 6e-pi electrocyclization led to the final 1,3-cyclohexadienes 3 as probed by NMR studies. This cascade process behaved as a formal Ru-catalyzed [2 + 2 + 2] cycloaddition. (b) With cyclic alkenes, the standard Ru-catalyzed [2 + 2 + 2] cycloaddition occurred, giving the bicyclic 1,3-cyclohexadienes 8 as reaction products. A complete catalytic cycle for the formal and standard Ru-catalyzed [2 + 2 + 2] cycloaddition of acetylene and cyclic and acyclic alkenes with the Cp*RuCl fragment has been proposed and discussed based on DFT/B3LYP calculations. The most likely mechanism for these processes would involve the formation of ruthenacycloheptadiene intermediates XXIII or XXVII depending on the alkene nature. From these complexes, two alternatives could be envisioned: (a) a reductive elimination in the case of cyclic alkenes 7 and (b) a beta-elimination followed by reductive elimination to give 1,3,5-hexatrienes 6 in the case of acyclic alkenes. Final 6e-pi electrocyclization of 6 gave 1,3-cyclohexadienes 3.     

A new Ru-catalyzed cascade reaction forming polycyclic cyclohexadienes from 1,6-diynes and alkenes

Functionalized bicyclic 1,3-cyclohexadienes can be easily prepared by a new cascade reaction which involves the Ru-catalyzed addition of acyclic alkenes to 1,6-diynes to give (Z)-hexatrienes, followed by a pure thermal 6e-pi electrocyclization.     

"Formal" ruthenium-catalyzed [4+2+2] cycloaddition of 1,6-diynes to 1,3-dienes: formation of cyclooctatrienes vs vinylcyclohexadienes

[reaction: see text] A new "formal" Ru-catalyzed [4+2+2] cycloaddition of 1,6-diynes to 1,3-dienes giving conjugated 1,3,5-cyclooctatrienes and vinylcyclohexadienes is described. This formal cycloaddition is really a tandem process, the Ru(II)-catalyzed formation of (Z)-tetraenes or vinyl-(Z)-trienes followed by a pure thermal conrotatory 8 pi- or disrotatory 6 pi-electrocyclization. The proposed mechanism allows the differences in product ratio to be explained in terms of steric and stereochemical considerations.     

Rhodium-catalyzed [2+2+2] cycloaddition of 1,6-diynes with isothiocyanates and carbon disulfide

[STRUCTURE: SEE TEXT] A neutral rhodium(I)/BINAP complex effectively catalyzed a [2+2+2] cycloaddition of 1,6-diynes with isothiocyanates to give bicyclic thiopyranimines in 59-98% isolated yield. The reaction with carbon disulfide also proceeded to give bicyclic dithiopyrones in 74-85% isolated yield.     

Highly enantioselective construction of a chiral spirocyclic structure by the [2 + 2 + 2] cycloaddition of diynes and exo-methylene cyclic compounds

The enantioselective [2 + 2 + 2] cycloaddition of 1,6-diynes with alpha-methylene lactones and cyclic ketones gave various chiral spirocyclic compounds. The reaction proceeded with high enantioselectivity when the rhodium-xylylBINAP complex was used as a chiral catalyst. Not only exo-methylene cyclic compounds but also exo-methylene acyclic compounds could be used as coupling partners for diynes. The present protocol provides access to a new chiral library possessing a quaternary carbon center, including a spirocyclic system.     

Titanium-mediated [2 + 2 + 2] coupling of diynes with homoallylic alcohols

[reaction: see text] In connection with the known diyne-ene [2 + 2 + 2] cycloaddition reactions mediated by titanium aryloxides, the ability of titanium alkoxides to promote coupling of a titanacyclopentadiene with an alkene has been assessed for the isomerization-free preparation of 1,3-cyclohexadienes. The successful cycloaddition by titanium alkoxides is predicated on the use of homoallylic alcohols as the olefin component. With secondary homoallylic alcohols, high 1,3-diastereoselectivity is observed, which lends itself to enantioselective preparation of functionalized 1,3-cyclohexadienes.     

Enantioselective construction of quaternary carbon centers by catalytic [2 + 2 + 2] cycloaddition of 1,6-enynes and alkynes

[reaction: see text] The enantioselective [2 + 2 + 2] cycloaddition of 1,6-enynes and alkynes using chiral rhodium catalysts gave cycloadducts containing quaternary carbon stereocenters. Both symmetrical and unsymmetrical alkynes and acetylene could be used as coupling partners, and the corresponding bicyclic cyclohexa-1,3-dienes were obtained in good to excellent ee.     

Synthesis of silafluorenes by iridium-catalyzed [2 + 2 + 2] cycloaddition of silicon-bridged diynes with alkynes

[reaction: see text] Silicon-bridged 1,6-diynes underwent [2 + 2 + 2] cycloaddition with alkynes in the presence of an iridium(I)-phosphine catalyst to afford densely substituted silafluorene derivatives. Extended silafluorene skeletons were constructed by the [2 + 2 + 2] cycloaddition of tetraynes.     

NbCl3-catalyzed three-component [2 + 2 + 2] cycloaddition reaction of terminal alkynes, internal alkynes, and alkenes to 1,3,4,5-tetrasubstituted 1,3-cyclohexadienes

Three-component [2 + 2 + 2] cycloaddition of terminal alkynes, internal alkynes, and terminal alkenes is achieved using an NbCl(3)(DME) catalyst, leading to 1,3,4,5-substituted 1,3-cyclohexadienes in excellent yields with high chemo- and regioselectivity.     

Ruthenium(II)-catalyzed selective intramolecular [2 + 2 + 2] alkyne cyclotrimerizations

In the presence of a catalytic amount of Cp*RuCl(cod), 1,6-diynes chemoselectively reacted with monoalkynes at ambient temperature to afford the desired bicyclic benzene derivatives in good yields. A wide variety of diynes and monoynes containing functional groups such as ester, ketone, nitrile, amine, alcohol, sulfide, etc. can be used for the present ruthenium catalysis. The most significant advantage of this protocol is that the cycloaddition of unsymmetrical 1,6-diynes with one internal alkyne moiety regioselectively gave rise to meta-substituted products with excellent regioselectivity. Completely intramolecular alkyne cyclotrimerization was also accomplished using triyne substrates to obtain tricyclic aromatic compounds fused with 5-7-membered rings. A ruthenabicycle complex relevant to these cyclotrimerizations was synthesized from Cp*RuCl(cod) and a 1,6-diyne possessing phenyl terminal groups, and its structure was unambiguously determined by X-ray analysis. The intermediary of such a ruthenacycle intermediate was further confirmed by its reaction with acetylene, giving rise to the expected cycloadduct. The density functional study on the cyclotrimerization mechanism elucidated that the cyclotrimerization proceeds via oxidative cyclization, producing a ruthenacycle intermediate and subsequent alkyne insertion initiated by the formal [2 + 2] cycloaddition of the resultant ruthenacycle with an alkyne.     

Practical enantioselective synthesis of axially chiral biaryl diphosphonates and dicarboxylates by cationic rhodium(I)/Segphos-catalyzed double [2 + 2 + 2] cycloaddition

A cationic rhodium(I)/Segphos complex catalyzes a [2 + 2 + 2] cycloaddition of internal 1,6-diynes with a phosphonate- or ester-substituted 1,3-butadiyne leading to C(2)-symmetric axially chiral biaryl diphosphonates or dicarboxylates, respectively, in high yields with outstanding ee's. The use of a phosphonate- or ester-substituted 1,3-butadiyne as a cycloaddition partner and Segphos as a ligand is crucial for the success of this transformation.     

Silicon-initiated carbonylative carbotricyclization and [2+2+2+1] cycloaddition of enediynes catalyzed by rhodium complexes

The reaction of dodec-11-ene-1,6-diynes or their heteroatom congeners with a hydrosilane catalyzed by Rh(acac)(CO)2 at ambient temperature and pressure of CO gives the corresponding fused 5-7-5 tricyclic products, 5-oxo-1,3a,4,5,7,9-hexahydro-3H-cyclopenta[e]azulenes or their heteroatom congeners, in excellent yields through a unique silicon-initiated cascade carbonylative carbotricyclization (CO-SiCaT) process. It has also been found that the 5-7-5 fused tricyclic products can be obtained from the same type of enediynes and CO through a novel intramolecular [2+2+2+1] cycloaddition process. The characteristics of these two tricyclization processes and the fundamental differences in their reaction mechanisms are discussed. This novel higher-order cycloaddition reaction has also been successfully applied to the tricyclization of undeca-5,10-diyn-1-als, affording the corresponding 5-7-5 fused-ring products bearing a seven-membered lactone moiety. Related [2+2+2] tricyclizations of enediyne and diynal substrates are also discussed. These newly discovered reactions can construct multiple bonds all at once, converting linear starting materials to polycyclic compounds in a single step. Thus, these new processes provide innovative routes to functionalized polycyclic compounds that are useful for the syntheses of natural and unnatural products.     

Eight-membered ring construction by [4 + 2 + 2] annulation involving beta-carbon elimination

Cyclobutanones underwent a formal [4 + 2 + 2] annulation reaction with 1,6- and 1,7-diynes in the presence of nickel(0) catalysts to provide bicyclic eight-membered ring ketones. The annulation reaction proceeds through a ring-expansion of oxanickelacycloheptadiene via beta-carbon elimination to form a nine-membered nickelacycle. This reaction employing cyclobutanones as a C4 unit constructs cyclooctadienone cores in one synthetic step.     

Density functional theory study of ruthenium (II)-catalyzed [2+2+2] cycloaddition of 1,6-diynes with tricarbonyl compounds

Density functional theory has been employed to study the mechanism of the [2+2+2] ruthenium(II)-catalyzed cycloaddition between 1,6-diynes and tricarbonyl compounds, proposing a viable multistep-pathway according with that was previously suggested, but clarifying some aspects. This process is compared with the one-step reaction in absence of catalyst.     

Mechanism, regioselectivity, and the kinetics of phosphine-catalyzed [3+2] cycloaddition reactions of allenoates and electron-deficient alkenes

With the aid of computations and experiments, the detailed mechanism of the phosphine-catalyzed [3+2] cycloaddition reactions of allenoates and electron-deficient alkenes has been investigated. It was found that this reaction includes four consecutive processes: 1) In situ generation of a 1,3-dipole from allenoate and phosphine, 2) stepwise [3+2] cycloaddition, 3) a water-catalyzed [1,2]-hydrogen shift, and 4) elimination of the phosphine catalyst. In situ generation of the 1,3-dipole is key to all nucleophilic phosphine-catalyzed reactions. Through a kinetic study we have shown that the generation of the 1,3-dipole is the rate-determining step of the phosphine-catalyzed [3+2] cycloaddition reaction of allenoates and electron-deficient alkenes. DFT calculations and FMO analysis revealed that an electron-withdrawing group is required in the allene to ensure the generation of the 1,3-dipole kinetically and thermodynamically. Atoms-in-molecules (AIM) theory was used to analyze the stability of the 1,3-dipole. The regioselectivity of the [3+2] cycloaddition can be rationalized very well by FMO and AIM theories. Isotopic labeling experiments combined with DFT calculations showed that the commonly accepted intramolecular [1,2]-proton shift should be corrected to a water-catalyzed [1,2]-proton shift. Additional isotopic labeling experiments of the hetero-[3+2] cycloaddition of allenoates and electron-deficient imines further support this finding. This investigation has also been extended to the study of the phosphine-catalyzed [3+2] cycloaddition reaction of alkynoates as the three-carbon synthon, which showed that the generation of the 1,3-dipole in this reaction also occurs by a water-catalyzed process.     

Iodine atom transfer [3 + 2] cycloaddition reaction with electron-rich alkenes using N-tosyliodoaziridine derivatives as novel azahomoallyl radical precursors

Treatment of N-tosyliodoaziridine derivatives with Et(3)B efficiently produces various azahomoallyl radical (2-akenylamidyl radical) species which give oxygen-functionalized pyrrolidine derivatives through iodine atom transfer [3 + 2] cycloaddition with electron-rich alkenes such as enol ethers and ketene acetal. The present cycloaddition reaction proceeds regioselectively via C-N bond cleavage of an aziridinylalkyl radical intermediate and addition of the resulting azahomoallyl radicals to the terminal carbon of an alkene. The reaction of alkenes with the cyclohexenylamidyl radical generated from an optically active bicyclic iodoaziridine [(1S,2S,6S)-2-iodo-7-(p-toluenesulfonyl)-7-azabicyclo[4.1.0]heptane, 94% ee] also proceeds to give optically active octahydroindole derivatives (84-93% ee).     

Palladium-catalyzed [2 + 2 + 2] cocyclotrimerization of benzynes with bicyclic alkenes: an efficient route to anellated 9,10-dihydrophenanthrene derivatives and polyaromatic compounds

An efficient method for the cocyclotrimerization of bicyclic alkenes and benzynes catalyzed by palladium phosphine complexes to give the corresponding norbornane anellated 9,10-dihydrophenanthrene derivatives is described. Bicyclic alkenes 1a-i undergo [2 + 2 + 2] cocyclotrimerization with benzynes generated from precursors 2a-d [2-(trimethylsilyl)phenyl triflate (2a), 4,5-dimethyl-2-(trimethylsilyl)phenyl triflate (2b), 6-(trimethylsilyl)-2,3-dihydro-1H-5-indenyl triflate (2c), 4-methyl-2-(trimethylsilyl)phenyl triflate (2d)] in the presence of PdCl(2)(PPh(3))(2) in acetonitrile at ambient temperature to yield anellated 9,10-dihydrophenanthrene products 3a-r in moderate to excellent yields. The [2 + 2 + 2] cocyclotrimerization products from oxa- and azabicyclic alkenes can be applied for the synthesis of polyaromatics, substituted benzo[b]triphenylenes (8a-f), via a simple Lewis acid mediated deoxyaromatization in good yields. In addition the [2 + 2 + 2] products undergo retro Diels-Alder reaction readily, providing a new method for the synthesis of substituted phenanthrenes and for generating isobenzofurans. A plausible mechanism is proposed to account for the catalytic [2 + 2 + 2] cycloaddition reaction.     

Study on the reactivity of oxabicyclic alkenes in ruthenium-catalyzed [2+2] cycloadditions

The ruthenium-catalyzed [2+2] cycloadditions of various bicyclic alkenes with an alkyne have been investigated. The presence of the oxygen in the bridgehead of the bicyclic alkene significantly enhanced the rate of the ruthenium-catalyzed [2+2] cycloadditions. The presence of a C1-substituent on the oxanorbornadiene decreased the rate of the cycloaddition and electron-withdrawing C1-substituents were found to be more reactive than electron-donating C1-substituents in the Ru-catalyzed [2+2] cycloaddition. The nature of the substituent on the benzene ring of oxabenzonorbornadienes showed little effect on the rate of the cycloaddition.     

Enantioselective synthesis of axially chiral anilides through rhodium-catalyzed [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides

We have developed a rhodium-catalyzed enantioselective intermolecular [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides for the synthesis of axially chiral anilides. The axial chirality is constructed at the formation of benzene rings with high enantioselectivity (up to 98% ee). It should be noted that the present reaction employs the readily prepared trimethylsilylynamides starting from commercially available bis(trimethysilyl)acetylene and the trimethylsilyl group of the product anilides is expected to be utilized for further functionalization.     

Synergic effect of vicinal stereocenters in [3 + 2] cycloadditions of carbohydrate azadipolarophiles and mesoionic dipoles: origin of diastereofacial selectivity.

The intermolecular [3 + 2] cycloaddition of carbohydrate-derived 1,2-diaza-1,3-butadienes and 1,3-thiazolium-4-olates provides a conceptual basis for the problem of diastereofacial preference in the acyclic series of unsaturated sugars. Experimental results employing a side chain of D-arabino configuration have shown the stereodifferentiation exerted by the first stereogenic center that renders the Re,Re face of the acyclic sugar-chain azadiene eligible for cycloaddition (J. Org. Chem. 2000, 65, 5089). The results of the present work, now utilizing an alternative framework of D-lyxo configuration, evidence the discriminating power of the second stereogenic carbon, which induces the preferential approach to the Re,Si face of the heterocyclic dipole. This scheme of face selectivity is also grounded in theoretical calculations at a semiempirical level. In addition to dihydrothiophenes, which are the expected products of the [3 + 2] cycloaddition, bicyclic systems based on dihydrothieno[2,3-c]piperidine skeleton can also be obtained.