Carbocyclization Reaction Research Articles

Systematic Parameter Determination Aimed at a Catalyst-Controlled Asymmetric Rh(I)-Catalyzed Pauson-Khand Reaction.

Transition metal-catalyzed carbocyclization reactions have revolutionized the synthesis of complex cyclic organic compounds. Yet, subtle substrate changes can significantly alter reaction pathways. The asymmetric Rh(I)-catalyzed Pauson-Khand reaction (PKR) exemplifies such a reaction, hindered by a narrow substrate scope and competing reactivity modes. In this study, we identified parameters predictive of the yield and enantioselectivity in the catalyst-controlled asymmetric PKR, using 1,6-enynes with a 2,2-disubstituted alkene. In this way, ring-fused cyclopentenones can be formed with chiral quaternary carbon centers. Using bisphosphine ligand parameters from palladium complexes, including the energy of the Pd lone pair orbital and the angle formed by the phosphorus aryl groups on the ligand, we established strong correlations with experimental ln(er) (R 2 = 0.99 and 0.91) for two distinct precursors. Solvent dipole moments correlated with ln(er) for high-dipole-moment precursors (R 2 = 0.94), while Abraham's hydrogen bond basicity is more relevant for low-dipole-moment precursors (R 2 = 0.93). Additionally, counterions were found to have a significant impact on the PKR reactivity and selectivity, as does the steric demand of the alkyne substituent of the enyne precursor. In the latter case, ln(er) correlates with Sterimol B1 values for products from different alkyne substituents (R 2 = 0.99). Furthermore, the computed C≡C wavenumber of the enyne precursor can be directly aligned with the yield of asymmetric PKRs.

Stereoselective Three-Component Carbocyclization of 1,7-Enynes with Sulfoxonium Ylides and Water under Photoredox Catalysis.

A visible-light-induced photoredox three-component carbocyclization reaction of 1,7-enynes with sulfoxonium ylides and water is reported. The protocol provides a facile entry to structurally valuable highly functionalized cyclopenta[c]quinoline scaffolds in a highly chemoselective and stereoselective manner. Salient features of this method include facile redox-neutral conditions, no requirement of base or other additive, and good functional-group tolerance.

Triflic acid-promoted Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives: Synthesis and photophysical studies of novel 9,10-dihydrophenanthrenes

An efficient metal-free, triflic acid-promoted intramolecular Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives is discussed. This method provides an elegant route for the construction of 9,10-dihydrophenanthrenes of biological significance in good to excellent yields. The carbocyclization reaction is likely to proceeds via activation of terminal CC bond of alkenylated biphenyl derivatives followed by subsequent aromatic electrophilic substitution to give desired carbocyclic products. Single crystal X-ray diffraction analysis of compound 10d revealed that the crystals are packed in AB-AB layer packing, where the molecules are aligned in anti-parallel fashion. Notably, all of the synthesized 9,10-dihydrophenanthrenes exhibited blue to greenish yellow fluorescence with λmax = 418–481 nm range. The stokes shift, quantum yield and optical band gap of tricyclic products were computed using their absorption and emission spectra. A significant positive solvatochromic effect was observed for 9,10-dihydrophenanthrene derivative 10l, which is a characteristic of ICT interactions.

Stereoselective Transition Metal-Catalyzed [(2+2)+1] and [(2+2)+2] Carbocyclization Reactions using 1,6-Enynes with 1,1-Disubstituted Olefins: Construction of Quaternary Centers

Stereoselective Transition Metal-Catalyzed [(2+2)+1] and [(2+2)+2] Carbocyclization Reactions using 1,6-Enynes with 1,1-Disubstituted Olefins: Construction of Quaternary Centers

Cobalt-Catalyzed Chemo- and Stereoselective Arylative Carbocyclization of 1,6-Allenynes.

Different from the well-investigated enynes, transition-metal-catalyzed carbocyclization reactions of allenynes are more attractive as a result of the unique structure and versatile reactivity of allenes. Herein, we report the first cobalt-catalyzed highly chemo- and stereoselective arylative carbocyclization of 1,6-allenynes with arylboronic acids, affording five-membered carbocycles and heterocycles with moderate to high yields, broad substrate scope, and wide functional group compatibility. Moreover, several mechanistic experiments were conducted to gain insight into the reaction process.

Intramolecular Rhodium-Catalyzed [(3+2+2)] Carbocyclization Reactions with Dienylidenecyclopropanes: A Concise and Stereoselective Total Synthesis of the Sesquiterpene (+)-Zizaene.

The development of an intramolecular rhodium-catalyzed [(3+2+2)] carbocyclization reaction of alkylidenecyclopropanes (ACPs) tethered to 1,4- and 1,5-skipped dienes is described. This transformation offers a new approach for the construction of bridged tricyclic compounds with up to three quaternary centers, which are suitable for the synthesis of challenging bioactive natural products. For instance, the synthetic utility of this transformation is illustrated through a concise asymmetric total synthesis of the sesquiterpene (+)-zizaene in ten steps from a commercially available starting material.

NEW ADVANCES IN THE SYNTHESIS OF CYCLOALKA[b]INDOLS

The review summarizes data on the synthesis of compounds whose backbone is a cycloalka[b]indole heterocycle. Approaches to the synthesis of homologous structures are considered, ranging from a carbocyclic fragment with three carbon atoms to eight-membered analogues. Examples of cyclizations are presented, including those with induction of chiral centers using appropriate catalytic systems, with different enantio- and diastereoselectivity. Attention is paid to carbocyclization reactions occurring in the presence of metal complexes, lithium alkylates, inter- or intramolecular cycloaddition of allenes, activated alkenes with 1,3-dipolarophiles or diene-like systems. In the preparation of cycloprop[b]indoles, [2+1]-cycloaddition reactions of indoles with various carbenes are most often used. In approaches to the synthesis of indoles annelated with cyclobutane, [2+2]-cycloaddition reactions are used. To obtain indoles, to which 2,3-annelated carbocycles of medium size, synthetic methods are effectively used, including the use of indole derivatives, 3-nitroindole derivatives as starting materials, intra- and intermolecular reactions of 3-ethynyl-, 3-allenyl -, 3-alkenyl- or functionalized 2-alkyl-substituted indoles in the presence of complexes of palladium, gold, rhodium, copper, silver, indium, organophosphorus acids and their amides, trifluoroethanol, hexafluoroisopropanol, organic sulfo- or trifluoroacetic acids. Methods of photochemical exposure are known, leading to cyclopenta[b]indoles. In the preparation of these heterocycles, cycloaddition reactions of 1,3-dipoles generated from (2-indolyl)diarylmethanols to dipolarophiles are successfully used. Equally effective are cycloaddition reactions of 2-vinylindole derivatives to activated alkenes or carbonyl compounds in the presence of various catalysts, leading to di- or tetrahydrocarbazoles or their seven-membered homologues. One of the frequently used approaches to obtain cycloalka[b]indoles are reactions based on catalyzed transformations of indole-substituted cyclopropanes or intermolecular interaction of cyclopropanes with indoles under various conditions.

Brønsted Acid Catalyzed Carbocyclizations Involving Electrophilic Activation of Alkynes

AbstractThis review focuses on the carbocyclization reactions of alkyne-containing substrates catalyzed by Brønsted acids. The electrophilic activation occurs either by direct protonation of the alkyne or by formation of an intermediate cation that further reacts with the alkyne to give a key vinyl cation intermediate. Specific focus is placed on the selectivity of the various methodologies described herein and on mechanistic rationales.1 Introduction2 Brønsted Acid Catalyzed Alkyne Carbocyclization Involving C(sp) Reaction Partners2.1 Brønsted Acid Catalyzed Cyclization of Diynes2.2 Brønsted Acid Catalyzed Cyclization of Allenynes3 Brønsted Acid Catalyzed Alkyne Carbocyclization Involving C(sp2) Reaction Partners3.1 Brønsted Acid Catalyzed Cycloisomerization of Enynes3.1.1 Initial Protonation of the Alkene Function3.1.2 Initial Protonation of the Alkyne Function3.1.3 A Conia-Ene Reaction3.2 Electrophile-Induced Carbocyclization Involving Other C(sp2)-Based Reaction Partners3.2.1 Iminium Electrophiles3.2.2 Oxonium Electrophiles3.2.3 Isocyanate and Thioisocyanate Electrophiles3.3 Brønsted Acid Catalyzed Cycloisomerization of Aryl-alkynes3.3.1 Reactions Using Excess or Stoichiometric Amounts of Brønsted Acid3.3.2 Reactions Using Substoichiometric Amounts of Brønsted Acid3.3.3 Heteroatom-Substituted Alkynes3.3.4 Enantioselective Brønsted Acid Catalyzed Cycloisomerization of Aryl-alkynes4 Brønsted Acid Catalyzed Alkyne Carbocyclization Involving C(sp3) Reaction Partners: Alkyne-alkane Cycloisomerization5 Conclusion and Outlook

Enantioselective Reductive N-Cyclization–Alkylation Reaction of Alkene-Tethered Oxime Esters and Alkyl Iodides by Nickel Catalysis

Asymmetric cross-electrophile difunctionalization of tethered alkenes has become a powerful tool for the production of chiral cyclic scaffolds; however, the current studies all focus on carbocyclization reactions. Herein, we report an N-cyclization-alkylation reaction and thus showcase the potential of heterocyclization for accessing new enantioenriched cyclic architectures. This work establishes a new approach for enantioselective aza-Heck cyclization/cross-coupling sequence, which remains a long-standing unsolved challenge for the synthetic community. The reaction proceeds with primary, secondary, and a few tertiary alkyl iodides, and the use of newly defined ligands gave highly enantioenriched pyrrolines with improved molecular diversity under mild conditions. The presence of imine functionality allows for further structural variations.

Copper-Catalyzed Chemoselective Silylative Cyclization of 2,2'-Diethynylbiaryl Derivatives.

In this protocol, copper-catalyzed diverse silylative carbocyclization reactions of 2,2'-diethynylbiaryl derivatives with silaboronate were reported. Three new and novel types of domino reactions for the copper-catalyzed transformation of silaboronate were discovered. The corresponding cyclobuta[l]phenanthrene, bis((silyl)methyl)phenanthrene, and silyl-substituted exocyclic diene products were chemoselectively formed with high efficiency.

Diastereoselective Rhodium‐Catalyzed [(3+2+2)] Carbocyclization Reactions with Tethered Alkynylidenecyclopropanes: Synthesis of the Tremulane Sesquiterpene Natural Products

AbstractThe development of a diastereoselective intramolecular rhodium‐catalyzed [(3+2+2)] carbocyclization reactions of allyl ester‐tethered alkynylidenecyclopropanes (ACPs) for the construction of the 5,7,5‐tricyclic scaffold of the tremulane sesquiterpene natural products is described. This work illustrates that the stereoelectronic nature of the phosphite ligand is critical for attaining high levels of stereocontrol, which is supported by density functional theory (DFT) studies that indicate the migratory insertion step favors the formation of the cis‐diastereoisomer. Consequently, several strategies were devised to access the thermodynamically more stable trans‐diastereoisomer for the synthesis of the tremulanes; however, the attempts to either switch the sense of stereocontrol in the carbocyclization reaction or epimerize the C7 stereocenter of the cycloadduct provided only modest improvements. Hence, we elected to highlight the synthetic utility of this strategy with the development of concise and highly efficient syntheses of (±)‐epi‐tremulenolide A, (±)‐epi‐tremulenediol A and (±)‐epi‐ceriponol D.

Copper-catalyzed radical cascade cyclization for synthesis of CF3-containing tetracyclic benzimidazo[2,1-a]iso-quinolin-6(5H)-ones.

Here, a general copper-catalyzed radical cascade carbocyclization reaction with 2-arylbenzoimidazoles and a Togni reagent was realized. Structurally diverse CF3-containing tetracyclic core benzimidazo[2,1-a]isoquinoline-6(5H)-ones were obtained in moderate to good yields. The wide substrate scope, good functional group tolerance, and ease of scale-up of this method are expected to promote its potential applications in pharmacy and biotechnology.

Magnetothermia-Induced Catalytic Hollow Nanoreactor for Bioorthogonal Organic Synthesis in Living Cells.

Nanoreactors, in which the reactions are remotely controlled by magnetic fields, are potentially valuable in bioorthogonal chemistry for future applications. Here, we develop a silica-confined magnetothermia-induced nanoreactor (MAG-NER) by selectively growing Pd nanocrystals on a preinstalled iron-oxide core inside a hollow silica nanoshell. The growth is achieved by magnetic induction. The interfacial catalytic site is activated by stimulating localized magnetothermia, and nanocompartmentalization is realized by the size-selective porous silica. Therefore, MAG-NER can be conveniently used in complex biomedia and can even be internalized to living cells, realizing an on-demand, high-performance intramolecular carbocyclization reaction by remote operation without compromising the cell viability. This work opens avenues for the design of advanced nanoreactors that complement and augment the existing bioorthogonal chemical tools.

Visible-Light-Mediated [2+2+1] Carbocyclization Reactions of 1,7-Enynes with Bromofluoroacetate to Form Fused Monofluorinated Cyclopenta[c]quinolin-4-ones.

Herein, we describe a new protocol for photoinduced radical [2+2+1] carbocyclization reactions of 1,7-enynes with bromofluoroacetate. These reactions, which proceed via a cascade involving fluoroalkylation, 6-exo-dig and 5-endo-trig cyclizations, H-transfer step, and oxidative dehydrogenation, provide an efficient and general route to a variety of fused monofluorinated cyclopenta[c]quinolin-4-one derivatives.

Oxidative Radical Relay Functionalization for the Synthesis of Benzimidazo[2,1‐a]iso‐quinolin‐6(5H)‐ones

AbstractHere, a mild and general oxidative radical relay carbocyclization reaction with 2‐arylbenzoimidazoles and cyclic ethers is reported. This method provides an efficient access to a wide range of structurally diverse benzimidazo[2,1‐a]isoquinoline‐6(5H)‐ones under metal‐free conditions. The wide substrate scope, good functional group tolerance, and scale‐up operation of this method are expected to promote its potential applications in biotechnology and pharmacy.magnified image

Ferrier Carbocyclization-Mediated Synthesis of Enantiopure Azido Inositol Analogues.

Azide-modified inositol (InoAz) analogues are valuable as inhibitors and have shown promise as metabolic chemical reporters (MCRs) for labeling inositol-containing glycoconjugates in eukaryotic cells and potentially in mycobacteria, but the synthesis of enantiomerically pure InoAz analogues via traditional approaches is challenging. As a complementary route, here we investigated the application of the Ferrier carbocyclization reaction to the synthesis of enantiopure InoAz analogues starting from readily available azido glucosides. Using this approach combined with a para-methoxybenzyl protecting group strategy, 3-azido-3-deoxy- and 4-azido-4-deoxy-d-myo-inositol were efficiently synthesized. 5-Azido-5-deoxy-d-myo-inositol was inaccessible due to an unusual β-elimination reaction, wherein the azide anion acted as the leaving group. The reported strategy is expected to facilitate continued development of synthetic InoAz analogues as inhibitors or MCRs of inositol-containing glycoconjugates in eukaryotic and mycobacterial systems.

Gold-Catalyzed 1,2-Acyloxy Migration/Coupling Cascade of Propargyl Diazoacetates: Synthesis of Isomycin Derivatives.

An efficient gold(I)-catalyzed carbocyclization reaction for the synthesis of isomycin derivatives from propargyl diazoacetates has been developed. The suggested cyclization pathway delineated the first example of a vinyl gold carbenoid species generated in situ from gold(I)-catalyzed 1,2-acyloxy migration and intercepted by a cross-coupling reaction with the remaining tethered diazo functionality. The use of protic additives was essential to regulating the reaction outcome by fine-tuning the catalytic preference of the gold(I) complex.

Assessing the Activity of Lewis Bases Organocatalysts in Halonium-Induced Carbocyclization Reactions

Lewis bases were evaluated as catalysts for halocarbocyclization reactions of alkynylstyrenes and a cinnamylaniline derivative. Phosphines and phosphorus chalcogenides exhibited high activity for the conversion of alkynylstyrenes in the presence of N-halosuccinimides with up to a 30-fold increase of the initial reaction rate with respect to the background reaction. Phosphorus sulfides and selenides showed the best catalytic activity for the iodocarbocyclization of a cinnamylaniline derivative in the presence of diiodohydantoin. An asymmetric variant of the iodocarbocyclization reaction of an alkynylstyrene using a chiral phosphorus selenide resulted in a modest enantioselectivity.

Mechanistic Exploration of the Competition Relationship between a Ketone and C═C, C═N, or C═S Bond in the Rh(III)-Catalyzed Carbocyclization Reactions.

The introduction of a C═O, C═C, C═S, or C═N bond has emerged as an effective strategy for carbocycle synthesis. A computational mechanistic study of Rh(III)-catalyzed coupling of alkynes with enaminones, sulfoxonium ylides, or α-carbonyl-nitrones was carried out. Our results uncover the roles of dual directing groups in the three substrates and confirm that the ketone acts as the role of the directing group while the C═C, C═N, or C═S bond serves as the cyclization site. By comparing the coordination of the ketone versus the C═C, C═N, or C═S bond, as well as the chemoselectivity concerning the six- versus five-membered formation, a competition relationship is revealed within the dual directing groups. Furthermore, after the alkyne insertion, instead of the originally proposed direct reductive elimination mechanism, the ketone enolization is found to be essential prior to the reductive elimination. The following C(sp2)-C(sp2) reductive elimination is more favorable than the C(sp3)-C(sp2) formation, which can be explained by the aromaticity difference in the corresponding transition states. The substituent effect on controlling the selectivity was also discussed.

Electrophilic carbocyclization reactions of 2-(2-alkynylphenyl)amino-1,4-naphthoquinones.

An efficient Ag(i)-catalyzed method for the synthesis of 5H-benzo[b]naphtho[2,3-f]azepine-6,11-diones from 2-(2-ethynylphenyl)amino substituted 1,4-naphthoquinones has been developed. In this transformation new C-C bond formation occurred regioselectively via a 7-endo-dig cyclization. The related 13-iodine substituted benzazepine derivatives could also be produced exclusively by the I2-induced carbocyclization reaction of 2-(2-alkynylphenyl)amino substituted 1,4-naphthoquinones. This process has advantages such as mild reaction conditions and tolerance of a broad range of functional groups.