Density Functional Theory Study of Mechanisms of [8 + 2] Cycloadditions of Dienylfurans/Dienylisobenzofurans with DMAD.

The mechanisms of [8 + 2] cycloaddition reactions between dienylfurans/dienylisobenzofurans and the activated alkyne, DMAD (dimethyl acetylenedicarboxylate), have been investigated by DFT calculations. The former [8 + 2] reaction is stepwise, starting from attack of the diene substituent on furan, not the furyl moiety in dienylfurans, to DMAD to give a diradical intermediate, which then undergoes ring closure to form the second bond between DMAD and the furan moiety, generating the final [8 + 2] cycloadducts. In contrast, the latter [8 + 2] reaction starts from [4 + 2] cycloaddition of the diene in the furan ring of dienylisobenzofurans toward DMAD, followed by the rate-determining stepwise [1,5]-vinyl shift, forming the [8 + 2] products. The different mechanisms of [8 + 2] reactions are attributed to the facts that for dienylfurans, the reactive diene part is the diene substituent on furan, but in the case of dienylisobenzofurans, it is the diene in the furan ring (its reaction with DMAD to generate an aromatic benzene ring is the driving force for this regiochemistry). Consequently, the [8 + 2] reactions begin with the reaction of the most reactive part of tetraene (either the diene substituent on furan for dienylfurans or the diene in the furan ring for dienylisobenzofurans) with DMAD. FMO analysis and kinetic study have been carried out to gain more information of the reaction mechanisms. Two [8 + 2] reactions of dienylisobenzofurans with different substituents toward DMAD have also been further analyzed by DFT calculations in this paper.

Synthesis of highly substituted benzene ring systems through three-component coupling of enyne imines, Fischer carbene complexes, and electron-deficient alkynes.

Three-component coupling of Fischer carbene complexes, enyne aldehyde hydrazones, and electron-deficient alkynes leads to simple benzoate derivatives in a process involving the formation of an N-aminopyrrole derivative, Diels-Alder reaction, and nitrene extrusion. The products are readily converted into isoquinolones through reaction with primary amines. The reaction proceeds best with highly substituted and electron-rich pyrroles even though these are the sterically least favorable substrates, and this reactivity trend is supported by a computational study.

A novel stereoselective [8+2] double cycloaddition route to hydronaphthalene ring systems.

Substituted hydronaphthalenes where each of the ten carbons of the two-ring system contains functionality were obtained through a tandem [8+2] cycloaddition and base-catalyzed rearrangement process using dienylfurans and electron-deficient alkynes. If the [8+2] process is conducted under solvent-free conditions the process could be conducted in a single reaction flask without isolation of the chromatographically sensitive [8+2] cycloadducts. A mechanism involving base catalysed alkene positional isomerization followed by disrotatory electrocyclic ring closure was proposed for the key reaction step that converts [8+2] cycloadducts to hydronaphthalenes. The products undergo selective ring opening-isomerization processes upon treatment with Lewis acids.

The [5+5] route to the phenanthrene skeleton.

This account describes the historical development of the coupling of γ,δ-unsaturated Fischer carbene complexes and o-alkynylbenzaldehydes, which directly affords hydrophenanthrene ring systems in a process where each reactant contributes five carbons to the newly-formed bicyclo[4.4.0]decane ring system. The process has been termed net [5+5] cycloaddition. Use of the reaction to produce various medicinally important natural products and/or their parent ring systems is discussed.

Direct synthesis of arenecarboxamides through Friedel-Crafts acylation using ureas.

The reaction of urea derivatives that contain the phenothiazine unit with trifluoromethanesulfonic anhydride in the presence of electron-rich aromatic compounds leads to the formation of arenecarboxamides. The reaction has been successfully demonstrated for several inter- and intramolecular systems.

Total synthesis of (+)-antofine and (-)-cryptopleurine.

The tylophorine alkaloid anticancer compounds antofine and cryptopleurine have been synthesized in optically active form. Both syntheses employ optically pure α-amino acids as the starting materials, require only seven steps from known 2-ethynylpyrrolidine or 2-ethynylpiperidine derivatives, and are free of protecting groups. Key steps include an alkyne hydration and a chromium carbene complex based net [5+5]-cycloaddition step. Alkyne hydration was accompanied by racemization of the resulting ß-aminoketone under most of the conditions examined, and successful minimization of this side reaction was achieved through careful pH control and choice of metal additive. Final ring closure involves a Bischler-Napieralski reaction using a carbamate (antofine) or urea (cryptopleurine) precursor.

Preparation of phenalenes and hydronaphthacenes through tandem alkyne Fischer-carbene complex coupling and inter- or intramolecular Diels-Alder reactions.

The rapid construction of phenalenes through the reaction of 8-alkynyltetralones with Fischer carbine complexes followed by either inter- or an intramolecular Diels-Alder reaction is presented. As a showcase of the synthetic utility of this process, the rapid construction of polycyclic ring systems containing the tetracycline core has been demonstrated through an iterative application of this reaction sequence.

Synthesis of benzocycloheptanones through coupling of δ,ε-unsaturated chromium carbene complexes and 2-alkynylbenzoyl derivatives.

The coupling of pentenylcarbene complexes and 2-alkynylbenzoyl derivatives affords naphthocycloheptanones in a single step involving simultaneous construction of both the seven-membered ring and one of the aromatic rings. Aryl tethered systems undergo intramolecular cyclopropanation.

Electronic Control of Product Distribution in the [5+5]-Coupling of ortho-Alkynylbenzaldehyde Derivatives and γ,δ-Unsaturated Carbene Complexes.

The coupling of highly oxygenated ortho-alkynylbenzaldehyde derivatives with γ,δ-carbene complexes was evaluated systematically. In all of the electron-rich systems investigated the exclusive product of the reaction is the dihydrophenanthrene derivative. Only the extremely electron withdrawing methanesulfonate group can prevent this process from occurring. The use of the base additive collidine resulted in a surprising yield enhancement but no other discernable effect on the course of the reaction. Dihydrophenanthrene formation was attributed to rapid dehydration after the opening of a benzo-oxanorbornene intermediate.

Synthesis of hydronaphthalenes through coupling of enyne carbonyl compounds that contain pendant alkene groups with Fischer carbene complexes.

The coupling of enyne carbonyl compounds that contain pendant alkene groups with Fischer carbene complexes to afford furans that contain pendant alkene groups is described. Subsequent intramolecular Diels-Alder reactions are effective in select cases, resulting in hydronaphthalene systems after dehydration. Although the Diels-Alder event is thermodynamically unfavorable, the overall transformation of alkene-furans to dihydronaphthalenes is a favorable process.

Synthesis of naphthalenes through three-component coupling of alkynes, Fischer carbene complexes, and benzaldehyde hydrazones via isoindole intermediates.

The synthesis of naphthalene derivatives through three-component coupling of 2-alkynylbenzaldehyde hydrazones with carbene complexes and electron-deficient alkynes has been examined. The reaction involves formation of an isoindole derivative, followed by intramolecular Diels-Alder reaction, followed by nitrene extrusion. The reaction was highly regioselective using unsymmetrical alkynes.

Coupling of Fischer carbene complexes with conjugated enediynes featuring radical traps; Novel structure and reactivity features of chromium complexed arene diradical species.

The reaction of Fischer carbene complexes with conjugated enediynes that feature a pendant alkene group has been examined. The reaction proceeds through carbene-alkyne coupling to generate an enyne-ketene intermediate. This intermediate then undergoes Moore cyclization to generate a chromium complexed arene diradical, which then undergoes cyclization with the pendant alkene group. The radical cyclization prefers the 6-endo mode unless radical-stabilizing groups are present to favor the 5-exo mode. The intermediate diradical species were evaluated computationally in both the singlet and triplet configurations. Arene triplet diradicals feature minimal spin density at oxygen and delocalization to chromium. The 6-endo cyclization product was kinetically and thermodynamically favored.

Mechanistic twist of the [8+2] cycloadditions of dienylisobenzofurans and dimethyl acetylenedicarboxylate: stepwise [8+2] versus [4+2]/[1,5]-vinyl shift mechanisms revealed through a theoretical and experimental study.

Recently, it was reported that both dienylfurans and dienylisobenzofurans could react with dimethyl acetylenedicarboxylate (DMAD) to give [8+2] cycloadducts. Understanding these [8+2] reactions will aid the design of additional [8+2] reactions, which have the potential for the synthesis of 10-membered and larger carbocycles. The present Article is aimed to understand the detailed mechanisms of the originally reported [8+2] cycloaddition reaction between dienylisobenzofurans and alkynes at the molecular level through the joint forces of computation and experiment. Density functional theory calculations at the (U)B3LYP/6-31+G(d) level suggest that the concerted [8+2] pathway between dienylisobenzofurans and alkynes is not favored. A stepwise reaction pathway involving formation of a zwitterionic intermediate for the [8+2] reactions between dienylisobenzofurans that contain electron-donating methoxy groups present in their diene moieties and DMAD has been predicted computationally. This pathway is in competition with a Diels-Alder [4+2] reaction between the furan moieties of dienylisobenzofurans and DMAD. When there is no electron-donating group present in the diene moieties of dienylisobenzofurans, the [8+2] reaction occurs through an alternative mechanism involving a [4+2] reaction between the furan moiety of the tetraene and DMAD, followed by a [1,5]-vinyl shift. This computationally predicted novel mechanism was supported experimentally.

Synthesis of phenanthrene derivatives through the net [5+5]-cycloaddition of prenylated carbene complexes with 2-alkynylbenzaldehyde derivatives.

The reaction of prenylated carbene complexes and 2-alkynylbenzoyl derivatives has been investigated. Phenanthrene derivatives are produced if iodine is added prior to product isolation. Under these conditions alkyl migration reactions occur to form the observed products. The product yields are considerably higher using bis(prenylated) species owing to an increase in the effective molarity of dienophilic entities.

Synthesis of alkylidenephthalans through fluoride-induced cyclization of electron-deficient 2-siloxymethylphenylacetylene derivatives.

Fluoride-based deprotection of silylated 2-alkynylbenzyl alcohol derivatives featuring carbonyl-substituted alkynes results in the direct synthesis of alkylidenephthalan vinylogous esters. The reaction is selective for the Z alkylidenephthalans in a thermodynamically controlled process. Similar compounds are also produced in the coupling of Fischer carbene complexes with 2-alkynylbenzoyl derivatives in an aqueous solvent system. Subsequent acid-catalyzed inter- or intramolecular Diels-Alder reactions lead to hydronaphthalene or hydrophenanthrene derivatives.

Total synthesis of antofine using the net [5+5]-cycloaddition of gamma,delta-unsaturated carbene complexes and 2-alkynylphenyl ketones as a key step.

A compound containing all of the carbons of the anticancer agent antofine was produced in a single step from the coupling of a gamma,delta-unsaturated carbene complex with a 2-alkynylphenyl ketone derivative. Subsequent conversion to antofine was effected in three steps.

Synthesis of furan-bridged 10-membered rings through [8 + 2]-cycloaddition of dienylfurans and acetylenic esters.

[reaction: see text] The coupling of various dienylfurans with dimethyl acetylenedicarboxylate (DMAD) has been examined. In most cases this reaction proceeds via [8 + 2]-cycloaddition to afford furan-bridged 10-membered ring systems as a single diastereomer. Dienylfuran intermediates were generated using either a chromium carbene-based method or aldol-based methods. Reaction of [8 + 2]-cycloadducts with electrophilic reagents occurred selectively at the enol ether alkene.

Novel synthesis of isoquinolines using isobenzofuran-nitrile Diels-Alder reactions.

[reaction: see text] The synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with beta-cyanocarbene complexes has been examined. The reaction involves formation of an isobenzofuran followed by intramolecular Diels-Alder reaction with the nitrile, a process with limited precedent. The unique success of this process in this system has been attributed to deoxygenation of the initial adduct to form the isoquinoline ring system.

Synthesis of furanophane derivatives through [8+2]-cycloaddition of dienylisobenzofurans and alkynes.

The coupling of various dienylisobenzofurans with dimethyl acetylenedicarboxylate (DMAD) has been examined. In most cases, this reaction proceeds via [8+2]-cycloaddition to afford furan-bridged decatetraene ring systems. The major competing reaction pathway is [4+2]-cycloaddition between DMAD and the isobenzofuran nucleus. Isobenzofuran intermediates were generated using either a chromium carbene-based method or an acid-catalyzed method.

Synthesis of pyrroles through coupling of enyne-hydrazones with Fischer carbene complexes.

[reaction: see text] The coupling of enyne-imines with Fischer carbene complexes leads to the formation of alkenylpyrrole derivatives. Maximum yields of pyrrole adducts were obtained using N,N-dimethylhydrazones. A mechanism involving alkyne insertion followed by nucleophilic attack of the imine nitrogen at the intermediate alkenylcarbene complex was proposed.