Catalytic generation of arynes and trapping by nucleophilic addition and iodination

A fair exchange: In the title reaction, alkynyllithium serves as an initiator for benzyne generation through an iodine-lithium exchange (see scheme; Tf=trifluoromethanesulfonyl). When performed in the presence of stoichiometric amounts of a nucleophile, the generated benzyne undergoes attack by lithio nucleophiles to generate aryllithium, which is then iodinated by iodoalkyne to give the iodoarenes 1.     

Synthesis of toxyloxanthone B

A synthesis of the naturally occurring xanthone toxyloxanthone B is described, in which the key step is the regioselective addition of a methyl salicylate to a substituted benzyne, followed by cyclization of the intermediate aryl anion to form the xanthone, the regiochemistry of the aryne addition being confirmed by X-ray crystallography. Subsequent introduction of the pyran ring by [3,3]-rearrangement and deprotection completed the synthesis.     

Insertion of benzyne into the Pd-C bond. Synthesis of unnatural amino acid derivatives by sequential insertion of benzyne and CO: 2,2'-functionalized biaryls containing alkylamino and carboxymethyl substituents. Isolation of stable carbopalladated-benzyne intermediates

Reaction of ortho-palladated derivatives of phentermine and homoveratrylamine with benzyne allows the synthesis of enlarged eight-membered palladacycles resulting from the insertion of the aryne into the Pd-C bond, which subsequently react with CO, to render unnatural amino acid derivatives.     

The intermolecular benzyne cycloaddition approach to dehydronoraporprines and oxoaporphines. Total synthesis of PO-3

The synthesis of dehydronoraporphines and oxoaporphines has been achieved by means of the convergent and highly regioselective intermolecular benzyne cycloaddition approach. The first total synthesis of the quaternary oxoaporphine PO-3 is described.     

Iterative benzyne-furan cycloaddition reactions: studies toward the total synthesis of ent-Sch 47554 and ent-Sch 47555

[reaction: see text] 7-Fluoro-5,8-dimethoxy-1-naphthol, prepared from the lithiation and benzyne formation from 1,4-difluoro-2,5-dimethoxybenzene and Diels-Alder cycloaddition with furan, was sequentially C-glycosidated under Suzuki conditions and O-glycosidated using di-O-acetyl-L-rhamnal to provide the corresponding beta-naphthyl C,O-disaccharide. Further lithiation, benzyne formation, and cycloaddition with furan gave an oxa-bridged 1,4-dihydroanthracenyl C,O-disaccharide, a model compound relevant to the total synthesis of Sch 47555.     

Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce–Smiles Rearrangement

A new benzyne transformation is described that affords versatile biaryl structures without recourse to transition‐metal catalysis or stoichiometric amounts of organometallic building blocks. Aryl sulfonamides add to benzyne upon fluoride activation, and then undergo an aryl Truce–Smiles rearrangement to afford biaryls with sulfur dioxide extrusion. The reaction proceeds under simple reaction conditions and has excellent scope for the synthesis of sterically hindered atropisomeric biaryl amines.     

The relative rates of electron-rich and electron-deficient alkene cycloadditions to benzyne. Enhanced electrophilicity as a consequence of alkyne bending distortions.

Benzyne reacts more rapidly with electron-rich alkenes than electron-deficient alkenes, a result of the abnormally low energy LUMO of benzyne, which results from the acetylene bending enforced by the benzyne geometry.     

Oxaza adamantyl cannabinoids. A new class of cannabinoid receptor probes

The preparation of C3 oxaza adamantyl cannabinoids has been described starting from phloroglucinol. Straightforward manipulations of the aromatic ring lead to a bromononaflate that is a benzyne precursor and that serves as a common intermediate for the synthesis of diverse C3-substituted tricyclic cannabinoids. Generation of the benzyne in the presence of an oxaza adamantyl amide anion results in efficient and regiospecific addition to C3 of the aromatic ring. This represents an attractive strategy for the synthesis of classical tricyclic cannabinoids that bear a modified aromatic appendage. The oxaza adamantyl cannabinoids that have been prepared represent a new class of ligands for the CB1 and CB2 receptors.     

Facile preparation of benzo[4,5]thieno[2,3-b]pyridines and naphtho[b-4,5]thieno[2,3-b]pyridines via the reaction of Barton esters and benzynes

Titled compounds were prepared in a one-pot synthesis by generating symmetrically substituted benzyne intermediates by the diazotization of anthranilic acids in the presence of Barton esters. Unsymmetrically substituted aryne either gave mixtures of regioisomers or failed. However, nitro and methyl derivatives of titled compounds could be obtained as single products using appropriately substituted Barton esters.     

New routes to condensed polynuclear compounds—VII : Synthesis of phenanthridines through a novel cyclisation reaction of haloanils

A convenient phenanthridine synthesis based on reaction of haloanils with potassium amide in liquid ammonia has been developed. Experimental evidence supports the postulated mechanism implicating a benzyne intermediate in the cyclisation step and a prior addition of amide ions across the azomethine linkage.     

REGIOSELECTIVE SYNTHESIS OF 1,2-DIARYLBENZAZETIDENES VIA [2 + 2] CYCLOADDITION REACTIONS OF BENZYNE WITH AZOMETHINES

[2 + 2] Cycloaddition reactions of benzyne generated in situ with various substituted azomethines have been carried out leading to the synthesis of 1,2-diarylbenzazetidenes in good yields with a high degree of regioselectivity.     

Intramolecular Benzyne–Phenolate [4+2] Cycloadditions

An intramolecular benzyne–phenolate [4+2] cycloaddition is reported. Benzyne precursors, having vicinal halogen-sulfonate functionalities, linked with a phenol(ate) by various tether groups undergo efficient intramolecular [4+2] cycloaddition by treatment with either Ph₃MgLi or nBuLi for halogen–metal exchange to form various benzobarrelenes.     

Intramolecular Benzyne–Phenolate [4+2] Cycloadditions

An intramolecular benzyne–phenolate [4+2] cycloaddition is reported. Benzyne precursors, having vicinal halogen‐sulfonate functionalities, linked with a phenol(ate) by various tether groups undergo efficient intramolecular [4+2] cycloaddition by treatment with either Ph₃MgLi or nBuLi for halogen–metal exchange to form various benzobarrelenes.     

Reaction of o-benzyne with tropothione involving biradical processes

A benzyne-tropothione reaction was studied experimentally and computationally. Three isomeric products were detected by a careful experiment using two benzyne sources. The three equimolar products were identified. The expected symmetry-allowed [4+2] or [8+2] cycloadduct was not detected. In order to explain the unexpected products, density functional calculations and complete active space self-consistent field (CASSCF) calculations were carried out. The benzyne is, first, added to the tropothione via one-center C-S bond formation. Then a singlet biradical intermediate is formed. In the biradical, an alpha hydrogen atom of the tropothione moiety is moved to the benzyne moiety. A closed-shell intermediate is generated. This allene-type intermediate is isomerized to the second intermediate. The intramolecular proton shift in the latter leads to the three products. The biradical character of the benzyne has a key role in the present reaction and was discussed in reference to other benzyne reactions.     

Biomimetic Total Synthesis of Cyanosporaside Aglycons from a Single Enediyne Precursor through Site‐Selective p‐Benzyne Hydrochlorination

The cyanosporasides A–F are a collection of monochlorinated benzenoid derivatives isolated from the marine actinomycetes Salinispora and Streptomyces sp. All derivatives feature one of two types of cyanocyclopenta[a]indene frameworks, which are regioisomeric in the position of a single chlorine atom. It is proposed that these chloro‐substituted benzenoids are formed biosynthetically through the cycloaromatization of a bicyclic nine‐membered enediyne precursor. Herein, we report the synthesis of such a bicyclic precursor, its spontaneous transannulation into a p‐benzyne, and its differential 1,4 hydrochlorination reactivity under either organochlorine or chloride‐salt conditions. Our bioinspired approach culminated in the first regiodivergent total synthesis of the aglycons A/F and B/C, as well as cyanosporasides D and E. In addition, empirical insights into the site selectivity of a natural‐like p‐benzyne, calculated to be a ground‐state triplet diradical, to hydrogen, chlorine, and chloride sources are revealed.     

Total Synthesis of Actinorhodin

The enantioselective total synthesis of actinorhodin ( 1 ) is described. The synthesis features 1) dual benzyne reactions en route to the monomer, 2) the trans‐selective installation of the side chain, and 3) a regioselective oxidative dimerization.     

A C-N insertion of β-lactam to benzyne: unusual formation of acridone

Intermolecular insertion of benzyne into the C-N bond of a β-lactam is described. This σ-insertion is followed by ring expansion that produces dihydroquinolinone, which rapidly reacts with an additional benzyne unit to afford an acridone through intramolecular C-C bond formation to the carbonyl group and rapid elimination of ethylene.     

Anharmonic Effect of the Unimolecular Isomerization/Decomposition of Benzyne

The anharmonic and harmonic rate constants were calculated for the unimolecular decomposition of o‐benzyne, the isomerization of o‐benzyne to m‐benzyne, the isomerization of m‐benzyne to p‐benzyne and unimolecular decomposition of p‐benzyne by using the Rice–Ramsperger–Kassel–Marcus (RRKM) theory respectively, in the canonical and microcanonical systems. The geometry and the vibrational frequencies were calculated by MP2 and B3LYP methods with 6‐311G(d,p) basis set and the barrier energies were corrected using CBS‐QB3 theory. The anharmonic effect on the reactions was also examined. Comparison of results for the decompositions of benzyne indicate that both in microcanonical and canonical cases, the anharmonic effect on the decomposition of the o‐C₆H₄ and p‐C₆H₄ are significant, while the anharmonic effect on the two isomerizations are not pronounced.     

A Photochemical Route to Dibenzobarrelenes

Dibenzobarrelenes have been prepared by the cycloaddition of benzyne to anthracenes. The first method gives complex mixtures from which only poor yields of 1, 4-adducts may be obtained,¹ exceot wgeb tetragakivebztbes are enokited,^2,3 Muller and Vergne have reported⁴ that dibenzobarrelene is formed by the reaction of acetylene with anthracene, but it may be significant that later workers have chosen to use either the above-mentioned benzyne route or a modification of the cycloaddition to anthracenne involving dichlorethylene followed by dechlorination to prepare the parent compound.⁵ Our approach to the synthesis of this ring system employs our previously described 1,2–photoaramatisation reactions.⁶ A significant feature of the present work is that it demonstrates that a photochemical reaction can be employed to generate compounds, in this case dibenzobarrelenes, known to be photolabile.⁷     

Novel entry into the benzo(C)phenanthridine skeleton through the intermolecular benzyne cycloaddition (IBC) approach

A highly convergent synthesis of the skeleton of benzo(c)phenanthridine alkaloids based on the intermolecular benzyne cycloaddition (IBC) approach is described.