Divergent Photosensitizer Controlled Reactions of 4-Hydroxycoumarins and Unactivated Olefins: Hydroarylation and Subsequent [2+2] Cycloaddition

Herein, we report a photoinduced approach for hydroarylation of unactivated olefins using 4-hydroxycoumarins as the arylating reagent. Key to the success of this reaction is the conversion of nucleophilic 4-hydroxycoumarins into electrophilic carbon radicals via photocatalytic arene oxidation, which not only circumvents the polarity-mismatch issue encountered under ionic conditions but also accommodates a broad substrate scope and inhibits side reactions that were previously observed. Moreover, divergent reactivity was achieved by changing the photocatalyst, enabling a subsequent [2+2] cycloaddition to deliver cyclobutane-fused pentacyclic products that are otherwise challenging to access in high yields and with high diastereoselectivity. Mechanistic studies have elucidated the mechanism of the reactions and the origin of the divergent reactivity.     

Effect of Reaction Media on Photosensitized [2+2]-Cycloaddition of Cinnamates

The outcome of photosensitized [2+2]-cycloaddition reactions of various cinnamates has been compared in different reaction media, including homogeneous organic solutions under inert conditions, degassed water, and aerated physical gels. The reactions were performed under LED blue light (λ_max=455 nm) irradiation and [Ir{dF(CF₃)ppy}₂(dtb-bpy)]PF₆ (1.0 mol%) as photocatalyst. The processes were optimized taking into consideration solvent, gelator, and substrate. Comparative kinetics analyses, as well as the effect of the reaction media on the diastereoselectivity of the process, were evaluated during this investigation. In a number of cases, carrying out the reaction in a less polar solvent, like toluene or highly polar solvent, like water had a tremendous impact on the diastereoselectivity of the process, pointing towards an effect on the stabilization of the putative diradical intermediate in this medium. Moreover, while for reactions run in homogeneous solution oxygen needs to be excluded, no erosion in yield is observed when the photoadditions were run in aerated gel media.     

Mechanisms and Synthetic Strategies in Visible Light-Driven [2+2]-Heterocycloadditions

The synthesis of four membered heterocycles usually requires multi-step procedures and prefunctionalized reactants. A straightforward alternative is the photochemical [2+2]-heterocycloaddition between an alkene and a carbonyl derivative, conventionally based on the photoexcitation of this latter. However, this approach is limited by the absorption profile of the carbonyl, requiring in most of the cases the use of high-energy UV-light, that often results in undesired side reactions and/or the degradation of the reaction components. The development of new and milder visible light-driven [2+2]-heterocycloadditions is, therefore, highly desirable. In this Review, we highlight the most relevant achievements in the development of [2+2]-heterocycloadditions promoted by visible light, with a particular emphasis on the involved reaction mechanisms. The open challenges will also be discussed, suggesting new possible evolutions, and stimulating new methodological developments in the field.     

Intramolecular [4+2] and [3+2] Cycloadditions in Organic Synthesis

Numerous examples of intramolecular cycloaddition of 1,3-dienes, nitrones, and azomethine imines attest the preparative value of this variant for regioselective and stereoselective synthesis of annelated and bridged ring systems. The common features, differences, and limitations of these types of reaction are systematically reviewed.     

Harnessing sun for catalyst and sensitizer free regio- and stereo-selective [2+2] cycloaddition

Presence of cyclobutane rings in bioactive natural products makes them a popular synthetic target. Most common strategy for synthesizing cyclobutanes is [2+2] cycloaddition, which is usually facilitated by using ultraviolet radiation and catalysts. Herein we report the design and synthesis of densely functionalized cyclobutanes by alleviating these drawbacks and using sunlight. Further, we identified the putative mechanism of the transformation based on kinetic, fluorescence and crystallographic studies and evaluated biological activities of the products against MCF7 cell lines. The rational design of the olefinic substrates was based on their UV–vis spectra. The generic aspect of the reaction was elucidated by the syntheses of diverse analogs of cyclobutanes. Further, crystal structures and UV–vis spectra of the olefinic partners assisted us in rationalizing the stereoselectivity of the heterodimers. We believe this energy-efficient mild approach will provide a substantial contribution to the existing repertoire of strategies to regio- and stereoselectively access cyclobutanes.     

Stereoselective [4+2]-Cycloaddition with Chiral Alkenylboranes

A method for the stereoselective [4+2]-cycloaddition of alkenylboranes and dienes is presented. This transformation was accomplished through the introduction of a new strategy that involves the use of chiral N-protonated alkenyl oxazaborolidines as dieneophiles. The reaction leads to the formation of products that can be readily derivatized to more complex structural motifs through stereospecific transformations of the C−B bond such as oxidation and homologation. Detailed computation evaluation of the reaction has uncovered a surprising role of the counterion on stereoselectivity.     

Synthesis of isoindolinones: Intramolecular [4+2] cycloaddition/retro [4+2] of pyridone propiolamides

A new synthesis of isoindolinones was discovered during a screening campaign aimed at the development of novel methods for the synthesis of pyridone-EZH2 inhibitor analogues. The reaction proceeds via an intramolecular [4+2] cycloaddition of a pyridone with a tethered propiolamide moiety followed by extrusion of isocyanic acid. The discovery, optimization, and scope of the methodology are described.     

Reaction of ene-bis(phosphinylallenes): [2+2] versus [4+2] cycloaddition

Reaction of ene-bis(phosphinylallenes), derived from ene-bis(propargyl alcohols) and chlorodiphenylphosphine, was investigated. Benzene-bridged bis(phosphinylallenes) exclusively gave intramolecular [2+2] cycloadducts in the presence of dimethyl fumarate in sharp contrast to the reaction of benzene-bridged bis(sulfinylallenes), which gave the corresponding [4+2] cycloadducts. On the other hand, substituted ethylene- or five-membered heterocycle-bridged bis(phosphinylallenes) provided [4+2] cycloadducts. Reaction of benzene-bridged diallene bearing both a sulfinyl group and a phosphinyl group on the two allenyl groups was also described.     

[2+4]-Cycloaddition reactions of methyl trifluoropyruvate trifluoroacetylimine

Methyl trifluoropyruvate trifluoroacetylimine (I) reacts regioselectively with olefins to form dihydrooxazines (II)-(VII). In its reactions with 1,3-dienes, too, compound (I) exhibits properties of a 1,3-heterodiene rather than a dienophile. Acid hydrolysis of the synthesized oxazines results in their conversion to substituted -amino--trifluoromethyltetrahydrofuran-2-ones (XII)-(XVI).Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1130–1133, May, 1991.     

[2+4]-Cycloaddition of fluoroolefins and fluoroazomethines with furan

Conclusions Terminal and internal fluoroolefins and polyfluoro-1-alkenylsulfonyl fluorides as well as perfluoro-3-aza-2-pentene react with furan to give [2+4]-cycloadducts. Perfluoroazapropene and 1-cyanotetrafluoro-2-azopropene do not undergo this cycloaddition reaction.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp.897–900, April, 1988.     

Lewis Acid Catalyzed Formal (3+2)-Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes

Design, synthesis and application of benzene bioisosteres have attracted a lot of attention in the past 20 years. Recently, bicyclo[2.1.1]hexanes have emerged as highly attractive bioisosteres for ortho- and meta-substituted benzenes. Herein we report a mild, scalable and transition-metal-free protocol for the construction of highly substituted bicyclo[2.1.1]hexan-2-ones through Lewis acid catalyzed (3+2)-cycloaddition of bicyclo[1.1.0]-butane ketones with disubstituted ketenes. The reaction shows high functional group tolerance as documented by the successful preparation of various 3-alkyl-3-aryl as well as 3,3-bisalkyl bicyclo[2.1.1]hexan-2-ones (26 examples, up to 89 % yield). Postfunctionalization of the exocyclic ketone moiety is also demonstrated.     

Silver-Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3-Azabicyclo[3.1.1]heptanes

Synthesis of bicyclic scaffolds has emerged as an important research topic in modern drug development because they can serve as saturated bioisosters to enhance the physicochemical properties and metabolic profiles of drug candidates. Here we report a remarkably simple silver-enabled strategy to access polysubstituted 3-azabicyclo[3.1.1]heptanes in a single operation from readily accessible bicyclobutanes (BCBs) and isocyanides. The process is proposed to involve a formal (3+3)/(3+2)/retro-(3+2) cycloaddition sequence. This novel protocol allows for rapid generation of molecular complexity from simple starting materials, and the products can be easily derivatized, further enriching the BCB cycloaddition chemistry and the growing set of valuable sp³-rich bicyclic building blocks.     

Synthetic Transformations of Higher Terpenoids: VIII. [4+2]-Cycloaddition Reactions of Lambertianic Acid

The Diels-Alder reaction of lambertianic acid with maleic anhydride occurred in a stereoselective fashion and yielded diastereoisomeric (1R,2S,6R,7R)- and (1S,2R,6S,7S)-exo-adducts. The latter reacted with L-valinol to give the corresponding diterpenoid imides, 4-aza-9-oxabicyclo[2.2.1]dec-8-enes. Reactions of lambertianic acid with N-substituted maleimides in the presence of Lewis acids afforded diastereoisomeric adducts having both exo and endo configuration. Some transformations of the adducts were examined with a view to obtain cantharidin and dihydroisoindole analogs.     

Synthesis of pyridone and pyridine rings by [4+2] hetero-cyclocondensation

Substituted pyridones and pyridines have been synthesised efficiently by employing iminium salt as a key precursor. These compounds were prepared using tandem [4+2] cycloaddition/deamination between azabutadiene and dienophiles.     

A DFT study on N-heterocyclic carbene catalyzed [4+2] annulation reaction with in situ generated heterocyclic ortho-quinodimethane: Mechanism,origin of enantioselectivity and role of catalyst

Activation of inert sp³ CH bonds has attracted widespread attention and been developed with significant progress in recent years, but understanding the mechanism of this kind of reaction continues to be one of the most challenging topics in organic chemistry. In this paper, detailed mechanism of N-heterocyclic carbine (NHC) catalyzed [4+2] annulation reaction with in Situ generated heterocyclic ortho-quinodimethane have been investigated using density functional theory (DFT). The computational results show that the additive DBU plays an important role in NHC-catalyzed CH activation. The title reaction proceeds the processes of the introduction of the NHC catalyst to the carboxylic ester, DBU-assisted sp³ CH deprotonation, Michael addition, [4+2] cycloaddition, the dissociation of the catalyst and the product generation. The calculated results indicate that Michael addition is rate-determining and stereoselectivity-determining. With the use of NHC as the chiral catalyst, optically active products were obtained in good yields with excellent enantioselectivities. Furthermore, the theoretically predicted the main product is S configuration, which is in good agreement with the experimental result. The special role of NHC and origin of stereoselectivity were also identified by natural bond orbital (NBO), global reaction index (GRI) and frontier molecular orbital (FMO) analyses. This work might be helpful for understanding the significant roles of NHC catalyst and thus provide insights on the rational design of potential new catalysts for this kind of reactions and suggest enlightening clues on rational design of efficient organocatalysts for the C (sp³)-H activation.     

Synthesis of aromatic aldehydes by organocatalytic [4+2] and [3+3] cycloaddition of α,β-unsaturated aldehydes

Organocatalytic inter- and intramolecular [4+2] and [3+3] cycloadditions of α,β-unsaturated aldehydes to give polysubstituted aromatic aldehydes are described. High periselectivity for the cycloadditions, with catalyst effects exerted by l-proline and pyrrolidine-HOAc, as well as cocatalyst, additive effects, has been observed.