Subsequent Ring Expansion Research Articles

Accessing five- and seven-membered phosphorus-based heterocycles via cycloaddition reactions of azophosphines.

Heterocycles containing both phosphorus and nitrogen have seen increasing use in recent years in luminescent materials, coordination chemistry and as building blocks for inorganic polymers, yet their chemistry is currently dominated by five- and six-membered derivatives. Seven-membered P/N heterocycles are comparatively scarce and lack general, high yielding syntheses. Here, we explore the synthesis and characterisation of 1,2,5-diazaphosphepines from azophosphines. The mechanism has been probed in detail with both computational and experimental studies supporting a stepwise mechanism to form a five-membered ring, and subsequent ring expansion to the diazaphosphepine. Regioselective synthesis of five- and seven-membered rings is possible using asymmetric alkynes. The Lewis acidic borane B(C6F5)3 could either catalyse the formation of the seven-membered ring (iPr derivative) or trap out a key intermediate via a frustrated Lewis pair (FLP) mechanism (tBu derivative).

Access to [6‐7‐6]‐Icetexanes through Sequential Cascade Cyclization and Biomimetic Ring Expansion

AbstractWe herein report an efficient synthetic method for preparing [6‐7‐6]‐icetexane derivatives. This approach employs our previously designed copper‐catalyzed intramolecular cyclization of enyne‐aryl carbonyl substrates to generate a [6‐6‐6]‐tricyclic abietane framework and a subsequent ring expansion protocol for the [6‐7‐6] scaffold. By synergizing these protocols, we established a highly efficient pathway for synthesizing icetexane compounds from readily available enyne‐aryl starting materials, exhibiting remarkable versatility in accommodating various functional groups while delivering consistently high yields.

Double Ring Expansion Strategy for Fused 3-Benzazepines: Alternative Synthesis of the Dolby-Weinreb Enamine.

A double ring expansion strategy for constructing fused 3-benzazepines is described. The oxidative ring expansion of spiroamine compounds with N-chlorosuccinimide and subsequent ring expansion of the resulting ketiminium ion intermediates with trimethylsilyldiazomethane afforded fused 3-benzazepines in a one-pot operation. Importantly, the Dolby-Weinreb enamine, which is a key synthetic intermediate for harringtonine alkaloids, cephalotaxines, can be accessed from commercial materials in only two steps using our developed method.

Divergent Copper-salt-controlled Reactions of Donor-Acceptor Cyclopropanes and N-Fluorobenzene Sulfonimide: Access to the 1,3-Haloamines and Aminoindanes.

We herein report a method for divergent copper salt controlled reactions of donor-acceptor cyclopropanes and N-fluorobenzene sulfonimide (NFSI). Specifically, in the presence of CuX2 (X=Cl, Br), the cyclopropanes underwent formal umpolung 1,3-aminohalogenation bifunctionalization via a free radical mediated ring-opening process to afford 1,3-aminochlorination and 1,3-aminobromination products in moderate to good yields. In addition, by using CuI as a catalyst, we synthesized various aminoindane derivatives via 1,3-aminoarylation cyclization of D-A cyclopropanes, the reactions involved a free radical mediated ring-opening and subsequent ring expansion via C-H bond activation.

Electrosynthesis of Decorated Basket Molecules: [60]Fullerene-Fused 12-Membered Macrolactones.

The electrosynthesis of decorated basket molecules, that is, [60]fullerene-fused 12-membered macrolactones, has been achieved efficiently for the first time by the electrochemical reduction of [60]fullerene-fused 6-membered lactones and subsequent ring expansion with 1,2-bis(1-bromoalkyl)benzenes. The observed isomeric distributions of the obtained macrolactones are elucidated by theoretical calculations. The product structures have been firmly established by single-crystal X-ray analyses.

Leveraging the Domino Skeletal Expansion of Thia-/Selenazolidinones via Nitrogen-Atom Transfer in Hexafluoroisopropanol: Room Temperature Access to Six-Membered S/Se,N-Heterocycles.

Herein, a highly regioselective domino skeletal-expansion process that transforms 2-aminothiazolidinone into six-membered S,N-heterocycle is developed with the aid of TMS-azide in hexafluoroisopropanol (HFIP) at ambient temperature. Functioning of the C2 tertiary amine as latent reactive group on thiazolidinone moiety was the key to this development, which allowed relay substitution with azide and imparted subsequent ring-expansion under metal/acid free-conditions. The reaction also underscored an intermolecular nitrogen-atom transfer process from TMS-azide leading to final products, where any intermediary azidothiazolidinone was absent. The strategy was extendable to analogous synthesis of Se,N-heterocycles, and furthermore, late-stage drug-modification and follow-up transformations were also performed. Density functional theory calculations and control experiments provided important mechanistic insights and highlighted potential roles of HFIP in the transformation.

Experimental and kinetic modeling study of α-methyl-naphthalene pyrolysis: Part II. PAH formation

α-Methyl-naphthalene plays an important role as a functional material in petrochemical industries and as a precursor of soot particles. The formation chemistry of polycyclic aromatic hydrocarbons (PAHs) from α-methyl-naphthalene, therefore, warrants detailed investigations. In this work, we studied PAH formation from its pyrolysis using experiments and kinetic models. Flow reactor pyrolytic experiments at low and atmospheric pressures (30 and 760 Torr) were performed using synchrotron vacuum ultraviolet photoionization molecular beam mass spectrometry (SVUV-PI-MBMS). A kinetic model was then developed to predict PAH formation from α-methyl-naphthalene. According to the kinetic analysis of the proposed model, naphth-1-yl-methyl, benzo-fulvenallene, and benzo-fulvenallenyl are three critical intermediates in the formation of large PAHs. Other than the traditional H-abstraction acetylene-/vinylacetylene-addition mechanisms, three prototypical PAH formation pathways are identified in α-methyl-naphthalene pyrolysis: 1) addition and cyclization reactions of naphth-1-yl-methyl and naphth-1-yl radicals; 2) recombination of resonance stabilized radicals (indenyl, benzo-fulvenallenyl, phenalenyl, etc.) and the subsequent ring expansion reactions; 3) sequential propargyl addition reactions.

Synthesis of 6H-Benzo[c]chromene Scaffolds from O-Benzylated Phenols through a C–H Sulfenylation/Radical Cyclization Sequence

S-Aryl dibenzothiophenium salts, obtained through a highly regioselective C–H sulfenylation of o-benzyl-protected phenols, are used as precursors of 6H-benzo[c]chromenes. The reaction starts with a photocatalytically triggered single-electron transfer to the sulfonium salt, which promotes the formation of an aryl radical via selective mesolitic cleavage of the S–Arexo bond. Mechanistic studies reveal that this initial radical species cyclizes following a kinetically favored 5-exo-trig pathway. Subsequent ring expansion, favored by rearomatization, delivers the desired tricyclic systems.

A homonuclear π-system with a singlet carbene-type α and a nucleophilic β phosphorus - the first use in P-heterocyclic synthesis.

A μ2-(η1,η2)-dinuclear diphosphene complex having two W(CO)5 groups with dimethyl acetylenedicarboxylate, 4-phenyl-1,2,4-triazoline-3,5-dione and diethyl azodicarboxylate was applied to P-heterocyclic synthesis, i.e., using a singlet carbene-type reactivity of a homonuclear π-system assisted by a haptotropic shift thus rendering a more nucleophilic β phosphorus and, hence, a subsequent ring expansion.

Intermolecular Oxidative Friedel-Crafts Reaction Triggered Ring Expansion Affording 9,10-Diarylphenanthrenes.

A novel intermolecular tandem oxidative aromatic coupling between arylidene fluorenes and unfunctionalized aromatics mediated by a DDQ/TFA oxidation system has been developed for the construction of 9,10-diarylphenanthrenes (DAPs). The formation of a benzylic carbocation species possessing a quaternary sp3-carbon center on the fluorene moiety by an intermolecular oxidative Friedel-Crafts reaction of two different arenes successfully triggered the subsequent ring expansion to afford DAPs.

Synthesis of Aza-Eight-Membered Ring-Fused Indolines Initiated by Zn-Catalyzed C2 Alkylation of Indoles and Subsequent Base-Promoted Ring Expansion.

A novel and efficient synthesis of aza-eight-membered ring-fused indolines has been developed. This process is realized by zinc-catalyzed C2 alkylation of indoles and subsequent base-promoted ring expansion of the newly formed six-membered ring with alkynes. Easily accessible starting materials, good functional group tolerance, and high atom economy make this procedure attractive.

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores.

A pharmacophore-directed retrosynthesis strategy applied to rameswaralide provided simplified precursors bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton present in several cembranoid and norcembranoids from Sinularia soft corals. Key steps include a Diels-Alder lactonization organocascade delivering the common 5,5,6 core and a subsequent ring expansion affording a 5,5,7 core serviceable for the synthesis of rameswaralide. Initial structure-activity relationships of intermediates en route to the natural product have revealed interesting differential and selective cytotoxicity.

A Rh(III)-Catalyzed Formal [4+1] Approach to Pyrrolidines from Unactivated Terminal Alkenes and Nitrene Sources.

We have developed a formal [4+1] approach to pyrrolidines from readily available unactivated terminal alkenes as 4-carbon partners. The reaction provides a rapid construction of various pyrrolidine containing structures, especially for the diastereoselective synthesis of spiro-pyrrolidines. Mechanistic investigation suggests a Rh(III)-catalyzed intermolecular aziridination of the alkene and subsequent acid-promoted ring expansion for the pyrrolidine formation.

Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed Intramolecular Diazo Group Transfer from Azide to Alkene.

Alkenes can be cleaved by means of the (3+2) cycloaddition and subsequent cycloreversion of 1,3-dipoles, classically ozone (O3 ), but the azide (R-N3 ) variant is rare. Chemoselectivity for these azide to alkene diazo group transfers (DGT) is typically disfavored, thus limiting their synthetic utility. Herein, this work discloses a palladium-catalyzed intramolecular azide to alkene DGT, which grants chemoselectivity over competing aziridination. The data support a catalytic cycloreversion mechanism distinct from other known metal-catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2) cycloadditions. Kinetics experiments reveal an unusual mechanistic profile in which the catalyst is not operative during the rate-controlling step, rather, it is active during the product-determining step. Catalytic DGT was used to synthesize N-heterocyclic quinazolinones, a medicinally relevant structural core. We also report on the competing aziridination and subsequent ring expansion to another N-heterocyclic core structure of interest, benzodiazepinones.

BF3·Et2O-Promoted Decomposition of Cyclic α-Diazo-β-Hydroxy Ketones: Novel Insights into Mechanistic Aspects

We report novel insights into the cascade rearrangement of destabilized vinyl cations deriving from the BF3·Et2O-induced decomposition of cyclic α-diazo-β-hydroxy ketones in turn prepared by aldol-type condensation of cycloalkanones with diazoacetone. Complexation of the hydroxy group of the α-diazo-β-hydroxy compound with the Lewis acid is the first event, followed by the generation of the cycloalkanylidenediazonium salt that, after nitrogen loss, produces the highly reactive vinyl cation. The subsequent ring expansion results in the formation of a cycloalkenyl vinyl cation that affords the allylic cation by 1,2-methylene shift and ring contraction. The cation can then trap the solvent, the fluoride or the hydroxide released from the [BF3OH]− to afford different reaction products. The effect of both solvent and substrate ring size on products types and ratios were analyzed and discussed from a mechanistic point of view.

Base-Mediated Cascade Substitution-Cyclization of 2H-Azirines: Access to Highly Substituted Oxazoles.

A novel strategy to synthesize highly functionalized oxazoles has been successfully developed via a base-mediated intermolecular substitution between 2-acyloxy-2H-azirines and N-nucleophile or O-nucleophile with a subsequent ring expansion of a 2H-azirine intermediate. This method provides straightforward access to highly substituted oxazoles with high efficiency and excellent functional group compatibility under metal-free reaction conditions.

Electrophilic Derivatization of Trifluoromethyl‐Substituted Semisquarate Using Unsaturated Organosilanes and Subsequent Ring Transformations

AbstractTo extend the synthetic potential of trifluoromethyl‐substituted semisquarate (CF3‐semisquarate) previously synthesized by us as a pluripotent building block, its electrophilic derivatization was investigated. The electrophilic addition of allylic silanes and silyl enolates to CF3‐semisquarate afforded the corresponding 4‐hydroxycyclobutenones. Subsequent ring expansion of these products via thermolysis or oxidation using lead tetraacetate afforded trifluoromethylated bicyclo[3.2.0]heptenones or (Z)‐γ‐alkylidenetetronates.magnified image

An Overview of Triterpenoid Biosynthesis in Plants and Structural Depiction of Gymnemasides and Gymnemosides from Gymnema Sylvestere

An Overview of Triterpenoid Biosynthesis in Plants and Structural Depiction of Gymnemasides and Gymnemosides from Gymnema Sylvestere Plants are rich source of many groups of natural products and one such largest group is consisting of structurally diverse compounds having a skeleton of the 30-carbon precursor oxidosqualene to which glycosyl residues are attached and hence called saponin glycosides. The start point of biosynthesis of triterpenoids pathway is cyclization of the 2,3-oxidosequalene however, the sequalene required here is actually produced as a result of action of squalene synthase which results in head to head condensation of two units of farnesyl pyrophosphate (FPP) which itself is produced under the action of farnesyl pyrophosphate synthase (FPPS) through the condensation of two units of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP) which are the end products of the mevalonate (MVA) pathway in cytosol and 2-C-Methyl-D-Erythritol 4-Phosphate (MEP) pathway in the plastids. Further modification of 2,3-oxidosqualene through oxidation, hydroxylation, and glycosylation reactions generate complex saponins. The cyclization of the 2,3-oxidosqualene and subsequent ring expansion through carbocation and shifting of carbon of the initially generated tetra cyclic dammarane cation leads to the formation of a variety of structurally diverse penta cyclic triterpenoids. A variety of oxidosequalene cyclases (OSCs) are reported to generate structural diversity in triterpenoids. The site-specific oxidization of the cyclic skeleton synthesized by OSCs is caused by cytochrome P450s (P450s) a large gene family in plants. Once the substrate is processed through P450s, it is further diversified through the action of UDP-dependent glycosyltransferase (UGTs) that lead to glycosylations at hydroxyl and/or carboxyl groups. Intra and extracellular transport, storage, taste, bio-absorbality and the biological activity of a triterpenoid are highly influenced by the differential composition of sugars and their fashion of attachment to the triterpene scaffold. There is an ambiguity in the structure of the oleane type saponins in few articles published and the general classification of saponins as far as the gymnemosides from Gymnema sylvestere is concerned since they are depicted under dammarene group. We resolved the ambiguity in this review and tried to simplify and depict the route of triterpenoid biosynthesis in plants starting from MAP/MEV pathway to the structurally most modified forms like glutinol and friedelin.

ChemInform Abstract: CF3‐Substituted Semisquarate: A Pluripotent Building Block for the Divergent Synthesis of Trifluoromethylated Functional Molecules.

AbstractA series of trifluoromethylated quinones is readily prepared by the addition of Grignard reagents to the novel CF3‐substituted semisquarate (III) and subsequent ring expansion and aerobic oxidation.

Carbohydrate-based furopyran-3-ones: synthesis via a rare carbonyl nucleophilic 1,2-migration induced by TMSOTf and antifungal activity

A versatile method for synthesis of chiral furopyran-β-one analogues starting from 1,4:3,6-dianhydrofructose has been developed. The target compounds were acquired by treatment of 1,4:3,6-dianhydrofructose with benzaldehydes in the presence of KF/Al2O3 and subsequent ring expansion of furanones induced by TMSOTf (trimethylsilyl triflate). The ring expansion involves an unprecedented nucleophilic 1,2-migration of a keto-carbonyl as a key step. In vitro antifungal activity of all compounds obtained were evaluated against five human pathogenic fungi (Candida parapsilosis ATCC22019, Candida albicans ATCC10231, Trichophyton rubrum CMCC(F)T1f, Epidermophyton floccosum CMCC(F)E1d, and Microsporum canis CMCC(F)M3d). We found that the furopyran-β-one analogues bearing chloro or fluoro group showed significant inhibitory activity against dermatophytes, especially M. canis.