Organic & Biomolecular Chemistry最新文献

Azoles have widespread applications in medicinal chemistry; for example, thiazoles, imidazoles, benzimidazoles, isoxazoles, tetrazoles and triazoles appear in the top 25 most frequently used N-heterocycles in FDA-approved drugs. Efficient routes for the late-stage C-H functionalisation of azole cores would therefore be highly desirable. The Minisci reaction, a nucleophilic radical addition reaction onto N-heterocyclic bases, is a direct C-H functionalisation reaction that has the potential to be a powerful method for C-H functionalisations of azole scaffolds. However, azoles have not been as widely studied as substrates for modern Minisci-type reactions as they are often more electron-rich and thus more challenging substrates compared to electron-poor 6-membered N-heterocycles such as quinolines, pyrazines and pyridines typically used in Minisci reactions. Nevertheless, with the prevalence of azole scaffolds in drug design, the Minisci reaction has the potential to be a transformative tool for late-stage C-H functionalisations to efficiently access decorated azole motifs. This review thus aims to give an overview of the C-H functionalisation of azoles via Minisci-type reactions, highlighting recent progress, existing limitations and potential areas for growth.

In the area of esterification of heteroatomic acids, after the microwave-assisted ionic liquid-catalyzed esterification of phosphinic acids, the esterification of arylsulfonic acids was also developed applying a 14-fold excess of alcohols at 200 °C in the presence of 10% butyl-methylimidazolium hexafluorophosphate as an additive. The esterifications were optimized, and the effect of the substituents in the aromatic ring was evaluated. At the same time, a similar procedure described by Mandal et al. using only one equivalent of alcohol at 120 °C for 5 min in toluene was refuted. The mechanism and energetics of the reaction of benzenesulfonic acid and butyl alcohol were determined at the B3LYPD3/def2TZVP[PCM(BuOH)] level of theory using the explicit-implicit solvent model, and, as a comparison, the implicit solvent model. Three possible reaction pathways were explored: the direct esterification of benzenesulfonic acid through an S_N2 protocol including the nucleophilic addition of butyl alcohol to the SO function of the sulfonic acid via an intermediate with a hexavalent-pentacoordinated S atom (Route I), via protonation of the alcohol by the arenesulfonic acid followed by the recombination of the sulfonate anion and the alkyl cation formed by dehydration (Route II), and an S_N1 route involving the initial formation of a sulfonium cation by dehydration of the protonated sulfonic acid followed by the nucleophilic attack of the alcohol (Route III). Judging from the energetics of the three potential pathways, the alkylating esterification (Route II) seems to be the predominant route. Microwave irradiation may overcome the enthalpy of activation of 132 kJ mol^-1 required for this protocol. The addition-elimination (S_N2) sequence (Route I) may also be operative as a minor reaction component.

We report an efficient photocatalytic protocol for the defluorocyanoalkylation and defluoroacylation of α-trifluoromethyl styrenes by utilizing oxime esters as radical donors, allowing for the preparation of diverse gem-difluoroalkenes. The treatment of α-trifluoromethyl styrenes with cyclobutanone oxime esters led to the formation of distal cyano group-anchored gem-difluoroalkenes. Notably, adding K₂CO₃ as an inorganic base to the photocatalytic system afforded γ,γ-difluoroallylic ketones by utilizing acyl oxime esters as the acylating agents. Preliminary mechanistic investigations into this reaction pathway revealed the involvement of single-electron reduction, C-C bond cleavage initiated by iminyl radicals, radical addition, and β-fluoride elimination steps.

Herein, we disclose the asymmetric total synthesis of 1'-deshydroxymethyl analogues of naturally occurring aporpinone A, aporpinone B, and 4'-hydroxyaporpinone A, featuring a γ-Z-alkylidene butenolide framework. Bimetallic (Pd-Cu) cascade cyclization on a properly functionalized bis-alkyne with Z-2-bromoacrylic acid was employed to construct the butenolide framework with an alkyne appendage. Late-stage enzymatic kinetic resolution (EKR) was adopted for the synthesis of (R)-1'-deshydroxymethyl aporpinone A and (S)-1'-deshydroxymethyl acetyl aporpinone A. The enantiopure bis-alkyne required for the synthesis of (S)-1'-deshydroxymethyl aporpinone B and (R)-1'-deshydroxymethyl 4'-hydroxyaporpinone A was constructed through the Sonogashira cross-coupling reaction.

An effective approach for the highly selective synthesis of selenium-containing (E)-N-propenolquinazolinones via an FeCl₃·6H₂O mediated cascade reaction of propargyl quinazoline-4-yl ethers and diselenides has been developed. Mechanistic investigations revealed that the reaction of FeCl₃ and (PhSe)₂ generates, in situ, the electrophilic species PhSe[FeCl₄]·6H₂O, which triggers the cascade reaction.

Incorporating a steric barrier between the two stations in a bistable [2]rotaxane based on monopyrrolotetrathiafulvalene and cyclobis(paraquat-p-phenylene) allows the high-energy metastable-state co-conformation to be physically isolated following a single redox cycle, thus making it possible to store energy (4.4 J L^-1) and to follow its interconversion back to the ground-state co-conformation.

A simple and efficient Ru(II)-catalyzed olefination of 3-(arylbenzylidene)indolin-2-ones with alkenes is described. This is an atom and step-economical strategy with a wide substrate scope, good functional group tolerance, and suitability for gram scale synthesis. A plausible mechanism is also proposed for this synthetic transformation involving the formation of a 5-membered ruthenacycle and insertion of the alkene followed by β-hydride elimination to deliver the desired product.

A diverse array of fused [6-6-5] tricyclic heterocycles has been synthesized via the dimerization and dearomative cyclization of benzene derivatives under visible light irradiation. The initiation of the cascade process is likely from aryloxy radicals, engendered through proton-coupled electron transfer by the photoexcited vinylidene ortho-quinone methide (VQM) and a Brønsted base.

NMR spectral and theoretical analyses of homologous prolyl carbamates reveal subtle charge transfer tetrel bonding interactions (TBIs), selectively stabilizing their cisPro rotamers. These TBIs involve C-terminal-amide to N-terminal carbamate carbonyl-carbonyl (n → π* type) followed by intra-carbamate (n → σ* type) charge transfer interactions exclusively in the cisPro motif. The number of TBIs and hence the cisPro stability increase with increasing number of C^β groups at the carbamate alcohol. Increasing solvent polarities also increase the relative cisPro carbamate stabilities.

We described herein a three-component radical alkyl-acylation of [1.1.1]propellane via a visible-light photoredox single electron transfer process, demonstrating an efficient approach for accessing a diverse array of 1,3-disubstituted BCP ketone derivatives. The synthetic utility of the present radical protocol was further demonstrated by the Baeyer-Villiger oxidation of the BCP ketone for BCP ester formation.