Electrocyclic Process Research Articles

Syntheses of 3-(2-Nitrovinyl)-indoles, Benzo[a]carbazoles, Naphtho[2,1-a]carbazoles, and 1-Hydroxy-β-carbolines Lead to Identification of Antiproliferative Compounds Active under Hypoxia.

Herein, we describe a novel reaction between C-2-substituted indoles and 2-nitroacetophenones leading to a variety of indole-containing heterocyclic scaffolds. At 60 °C in AcOH with H2SO4 as catalyst, C-2 aryl indoles give 3-(2-nitrovinyl)-indoles with high Z or E geometric selectivity depending on the type of substrate utilized. These compounds undergo an electrocyclization process in a sealed vial in a microwave apparatus in DMF at 250 °C to give benzo[a]carbazoles and naphtho[2,1-a]carbazoles depending on whether the C-2 aromatic moiety is phenyl or naphthyl. Utilization of 2-methylindoles in the reaction with 2-nitroacetophenones and performing the reaction in a sealed vial in a microwave apparatus in AcOH at 200 °C leads to 1-hydroxy-β-carbolines. Selected compounds from each scaffold were tested for antiproliferative activities against MDA-MB-231 triple-negative breast cancer cells under normoxic and hypoxic conditions, and three compounds belonging to the 3-(2-nitrovinyl)-indole and 1-hydroxy-β-carboline series were identified to have single-digit micromolar IC50 values.

Skeletal Rearrangement of Oxazole to Azepine and Pyrrole through Dynamic 8π Electrocyclizations.

We present a novel approach for the skeletal rearrangement of an oxazole into an azepine and pyrrole through a dynamic electrocyclization process, showing an innovative, unconventional reaction sequence. This method enables precise control of regioselectivity in competitive 6π and 8π electrocyclization reactions, rendering the final products rich in functional groups that can be further developed for the synthesis of nitrogen-containing scaffolds. This is an unprecedented example of the selective synthesis of seven- and five-member heterocycles via dynamic electrocyclization ring opening or closure.

Highly Enantioselective 6π Photoelectrocyclizations Engineered by Hydrogen Bonding.

Photochemical electrocyclization reactions are valued for both their ability to produce structurally complex molecules and their central role in elucidating fundamental mechanistic principles of photochemistry. We present herein a highly enantioselective 6π photoelectrocyclization catalyzed by a chiral Ir(III) photosensitizer. This transformation was successfully realized by engineering a strong hydrogen-bonding interaction between a pyrazole moiety on the catalyst and a basic imidazolyl ketone on the substrate. To shed light on the origin of stereoinduction, we conducted a comprehensive investigation combining experimental and computational mechanistic studies. Results from density functional theory calculations underscore the crucial role played by the prochirality and the torquoselectivity in the electrocyclization process as well as the steric demand in the subsequent [1,4]-H shift step. Our findings not only offer valuable guidance for developing chiral photocatalysts but also serve as a significant reference for achieving high levels of enantioselectivity in the 6π photoelectrocyclization reaction.

Metal free synthesis of substituted 5-aryl/alkyl aminotetrazoles in water

The synthesis of tetrazoles is established under metal free conditions at room temperature in the presence of open air. The reaction of 2-bromoaryl isothiocyantes with amines gives thiourea that undergoes reaction in situ with NaN3 using Iodine in the presence of water medium to afford 1-(2-bromophenyl)-N-5-arylaminotetrazoles via substitution followed by electrocyclization processes at ambient temperature. All electron donating and withdrawing substituents readily underwent the reaction to get the corresponding final products 2a–2ab in moderate to good yield. This methodology has also applied for gram-scale quantity of tetrazoles. In addition, our aqueous micellar medium has shown good recyclability activity and it has exhibited good yield of the product up to four cycles.

Construction of Benzocyclobutenes Enabled by Visible‐Light‐Induced Triplet Biradical Atom Transfer of Olefins

AbstractHerein, we report a method that provides an array of benzocyclobutanol and benzocyclobutylamine derivatives with broad substrate scope and good functional group tolerance under mild reaction conditions. The reaction proceeds by engaging triplet biradical atom transfer of olefinic compounds in the activation of remote C(sp3)−H bonds upon visible‐light irradiation. The reaction mechanism involves the generation of triplet excited state of diarylethylene derivative and subsequent HAT process, and then the further ring‐closing reaction affording the product via an electrocyclization process. The plausible mechanism is supported by control and deuterium labeling experiments, kinetic analysis, and DFT calculations.

Construction of Benzocyclobutenes Enabled by Visible‐Light‐Induced Triplet Biradical Atom Transfer of Olefins

Herein, we report a method that provides an array of benzocyclobutanol and benzocyclobutylamine derivatives with broad substrate scope and good functional group tolerance under mild reaction conditions. The reaction proceeds by engaging triplet biradical atom transfer of olefinic compounds in the activation of remote C(sp3 )-H bonds upon visible-light irradiation. The reaction mechanism involves the generation of triplet excited state of diarylethylene derivative and subsequent HAT process, and then the further ring-closing reaction affording the product via an electrocyclization process. The plausible mechanism is supported by control and deuterium labeling experiments, kinetic analysis, and DFT calculations.

Photostability and Dynamic Helical Behavior in Chiral Poly(phenylacetylene)s with a Preferred Screw-Sense.

Helical polymers such as poly(phenylacetylene)s (PPAs) are interesting materials due to the possibility of tuning their helical scaffold (sense and elongation) once they have been prepared and by the presence of external stimuli. The main limitation in the application of PPAs is their poor photostability. These polymers degrade under visible light exposure through a photochemical electrocyclization process. In this work, it was demonstrated, through a selected example, how the photochemical degradation in PPAs is directly related to their dynamic helical behavior. Thus, while PPAs with dynamic helical structures show poor photostability under UV/Vis light exposure, poly‐(R)‐1, bearing an enantiopure sulfoxide group as pendant group and designed to have a quasi‐static helical behavior, shows a large photostability due to the restricted conformational composition at the polyene backbone, needed to orient the conjugated double bonds prior to the photochemical electrocyclization process and the subsequent degradation of the material.

Photostability and Dynamic Helical Behavior in Chiral Poly(phenylacetylene)s with a Preferred Screw‐Sense

AbstractHelical polymers such as poly(phenylacetylene)s (PPAs) are interesting materials due to the possibility of tuning their helical scaffold (sense and elongation) once they have been prepared and by the presence of external stimuli. The main limitation in the application of PPAs is their poor photostability. These polymers degrade under visible light exposure through a photochemical electrocyclization process. In this work, it was demonstrated, through a selected example, how the photochemical degradation in PPAs is directly related to their dynamic helical behavior. Thus, while PPAs with dynamic helical structures show poor photostability under UV/Vis light exposure, poly‐(R)‐1, bearing an enantiopure sulfoxide group as pendant group and designed to have a quasi‐static helical behavior, shows a large photostability due to the restricted conformational composition at the polyene backbone, needed to orient the conjugated double bonds prior to the photochemical electrocyclization process and the subsequent degradation of the material.

An Easy Access to Furan-Fused Polyheterocyclic Systems.

Nitrostilbenes characterized by two different or differently substituted aryl moieties can be obtained from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines. Such versatile building blocks couple the well-recognized double electrophilic reactivity of the nitrovinyl moiety (addition to the double bond, followed by, e.g., intramolecular replacement of the nitro group) with the possibility to exploit a conjugated system of double bonds within an electrocyclization process. Herein, nitrostilbenes are reacted with different aromatic enols provided by a double (carbon and oxygen) nucleophilicity, leading to novel, interesting naphthodihydrofurans. From these, as a viable application, aromatization and electrocyclization lead in turn to valuable polycondensed, fully aromatic O-heterocycles.

Recent Advances on Piancatelli Reactions and Related Cascade Processes

AbstractThe Piancatelli reaction, which is the rearrangement of 2-furylcarbinol to cyclopentenone, involves a key furanoxonium ion intermediate and a furan ring opening-4π electrocyclization process. In recent years, the original oxa-Piancatelli reaction has been extended to a large family of aza- and carbo-Piancatelli reactions and related cascade processes, providing a powerful platform for the construction of diverse functionalized cyclopentenones and polycyclic cyclopentanones. Meanwhile, chiral Brønsted/Lewis acid based catalytic asymmetric approaches to Piancatelli reactions have also been achieved for the assembly of highly valued chiral cyclopentenone scaffolds. In this short review, we present an overview of the recent developments in these areas and focus primarily on reports published in the last five years.1 Introduction2 Diastereoselective Oxa-, Aza- and Carbo-Piancatelli Reactions3 Diastereoselective Cascade Piancatelli Reactions4 Asymmetric Piancatelli Reactions and Related Cascade Processes5 Miscellaneous Furanoxonium Ion-Based Rearrangements6 Conclusion

Synthesis and photochemistry of novel 1,2,3-triazole di-heterostilbenes. An experimental and computational study

The synthesis, photoreactivity, and spectroscopic characterization of novel 1,2,3-triazole di-heterostilbenes bearing various aliphatic and aromatic substituents on the triazole rings were thoroughly explored. By introducing triazole rings into the o-divinylbenzene moiety, compared with the 2-furyl and 2-thienyl heteroanalogues, these compounds did not show any photochemical reactivity toward intramolecular cycloaddition reactions or electrocyclization processes. The research is further extended to the more in-depth examination of photochemical and photophysical characteristics of the investigated triazolo-stilbenes to explain the lack of reactivity in intramolecular photochemical cyclizations by configuration and substituent effects. Conformations of synthetically obtained novel triazoles are examined by Density Functional Theory (DFT). The time dependent-DFT approach was employed to obtain additional insight into the properties observed with UV/Vis spectroscopy. The frontier orbital energy was computationally investigated to determine the influence of cis–trans isomerism and the nature of substituents on the spectroscopic properties of the triazoles. Along with our previous studies of similar compounds containing furan and thiophene, respectively, this study shows that introducing various heteroaromatic rings induces diverse photochemistry and photophysics due to the conformational changes and change in electronic distribution within the molecular system.

Synthesis of new furan polycycles via photochemical reaction in neutral and acidic medium

New furan derivatives of o-divinylbenzenes were synthesized and their photochemical reactivity has been investigated in neutral and acidic medium. Depending of the structure of the starting materials and pH value, the new cyclization (11, 16, 20), cycloaddiotion (12, 13, endo-17, exo-18), electrocyclization (21, 22) and dimeric (15, 19) products were isolated. While photochemical investigation in neutral medium showed that the main intramolecular process is cycloaddition, in the case of acidic photochemistry, due to the protonation of the starting molecule, electrocyclization process comes to expression and formation of dihydronaphtalene products 21 and 22.

Solvent-Free Synthesis and Key Intermediate Isolation in Ni2Dy2 Catalyst Development in the Domino Ring-Opening Electrocyclization Reaction of Furfural and Amines.

A solvent-free methodology that yields trans-4,5-diaminocyclopent-2-enones, main domains of natural products and a variety of N-heterocycles, is described. The bimetallic catalyst [NiII2DyIII2L4(DMF)6] 2(OTf) 2(DMF) (1) promotes the domino reaction of furfural and amines, with loadings as low as 0.01%, under stirring or microwave-assisted conditions to afford the corresponding frameworks in very good to excellent yields. Crystallographic and theoretical studies shed light on the exclusive formation of the trans-diastereoisomers via a 4π-conrotatory electrocyclization process elucidating the key step in the catalytic process.

Ir-Catalyzed Intramolecular Transannulation/C(sp2)-H Amination of 1,2,3,4-Tetrazoles by Electrocyclization.

An efficient strategy for the intramolecular denitrogenative transannulation/C(sp2)-H amination of 1,2,3,4-tetrazoles bearing C8-substituted arenes, heteroarenes, and alkenes is described. The process involves the generation of the metal-nitrene intermediate from tetrazole by the combination of [Cp*IrCl2]2 and AgSbF6. It has been shown that the reaction proceeds via an unprecedented electrocyclization process. The method has been successfully applied for the synthesis of a diverse array of α-carbolines and 7-azaindoles.

Efficient Synthesis of Chromenes from Vinyl o-Quinone Methides via a Brønsted Acid Catalyzed Electrocyclization Process

An efficient approach for the synthesis of chromene derivatives from vinyl o-quinone methides was established via a Brønsted acid catalyzed electrocyclization. By using this methodology, a series of structurally diversified chromenes was synthesized in a highly atom-economic and environmentally benign manner with generally good to excellent yields (up to 98% yield). This reaction will not only provide an efficient method for the construction of chromene scaffolds, but also enrich the research area of o-quinone methides.

Cethrene: The Chameleon of Woodward-Hoffmann Rules.

We demonstrate that the electrocyclic (EC) ring-closure of cethrene in solution proceeds in a conrotatory mode both thermally and photochemically. The facile photochemical EC process promises that cethrene can serve as an efficient chiroptical switch operated solely by light. As for the thermally activated EC reaction, a low reaction barrier and a solvation effect on the EC rate indicate that the C2-symmetric pathway predicted by DFT calculations might not be the correct mechanism. Instead, we argue that the molecular symmetry decreases along the reaction coordinate as a consequence of the low-energy singlet excited state in this diradicaloid molecule, which might lead to a lower activation energy in accord with that determined through kinetic studies. Cethrene, therefore, represents a thought-provoking molecular chameleon of the Woodward-Hoffmann rules that puts our chemical concepts and intuition to test.

Control of the Chemoselectivity of Metal N-Aryl Nitrene Reactivity: C-H Bond Amination versus Electrocyclization.

A mechanism study to identify the elements that control the chemoselectivity of metal-catalyzed N-atom transfer reactions of styryl azides is presented. Our studies show that the proclivity of the metal N-aryl nitrene to participate in sp3-C-H bond amination or electrocyclization reactions can be controlled by either the substrate or the catalyst. Electrocyclization is favored for mono-β-substituted and sterically noncongested styryl azides, whereas sp3-C-H bond amination through an H-atom abstraction-radical recombination mechanism is preferred when a tertiary allylic reaction center is present. Even when a weakened allylic C-H bond is present, our data suggest that the indole is still formed through an electrocyclization instead of a common allyl radical intermediate. The site selectivity of metal N-aryl nitrenes was found to be controlled by the choice of catalyst: Ir(I)-alkene complexes trigger electrocyclization processes while Fe(III) porphyrin complexes catalyze sp3-C-H bond amination in substrates where Rh2(II) carboxylate catalysts provide both products.

Cellulose sulfonic acid as a green, efficient, and reusable catalyst for Nazarov cyclization of unactivated dienones and pyrazoline synthesis

A high yielding and eco-friendly procedure for the preparation of cyclopentenoid and pyrazoline derivatives via cellulose sulfonic acid-mediated electrocyclization processes.

New synthetic methods for 2,3-diarylacridin-9(10H)-one and (E)-2-aryl-4-styrylfuro[3,2-c]quinoline derivatives

Two new synthetic methodologies for 2,3-diarylacridin-9(10H)-ones were developed. The first one involves the Heck reaction of (E)-3-iodo-2-styrylquinolin-4(1H)-ones with styrenes, leading to (E,E)-2,3-distyrylquinolin-4(1H)-ones, which when heated at high temperatures cyclize in two different ways. Electrocyclization and further in situ oxidation leads to 2,3-diarylacridin-9(10H)-ones, while tautomerization, cyclization by nucleophilic addition and further in situ oxidation produces (E)-2-aryl-4-styrylfuro[3,2-c]quinolines as the main compound. The second method gives only 2,3-diaryl-10-methylacridin-9(10H)-ones and involves the Heck reaction of (E)-3-iodo-1-methyl-2-styrylquinolin-4(1H)-ones and styrenes, leading to (E,E)-1-methyl-2,3-distyrylquinolin-4(1H)-ones, which when heated at high temperatures cyclize through electrocyclization and oxidation processes affording the expected compounds. The structures of all new compounds were established by extensive NMR studies.

Mechanism of gold (I)-catalyzed double migration-benzannulation cascade toward naphthalenes: Deprotonation/protonation mediated by water

The mechanisms of the gold (I)-catalyzed cycloisomerization of propargylic esters leading to unsymmetrically substituted naphthalenes have been investigated using density functional theory calculations done at the B3LYP/6-31G (d, p) (SDD for Au) level of theory. Solvent effects on these reactions have been explored by calculations that included a polarizable continuum model (PCM) for the solvent (CH2Cl2). Three possible pathways which lead to forming 1,3-diene, allene or carbenoid intermediate via an unprecedented tandem sequence of [1,3]- and [1,2]-migration of two different migrating groups were proposed. Calculations suggest that the [1,3]-rearrangement is a two-step process with activation free energies below 11.0kcal/mol for both steps. The following of [1,2]-migration reaction is also easy with an activation free energy of 20.4kcal/mol in CH2Cl2. The next step in the catalytic cycle is a [1,2]-hydride shift, and this step is the rate-limiting step (with a calculated activation free energy of 23.2kcal/mol) without water. In the presence of water, the direct [1,2]-hydride shift has been changed into a deprotonation/protonation process with an activation free energy of 9.7kcal/mol. The higher activation free energies for the intramolecular 6π electrocyclic ring closure process indicate that this step became the rate-determining one. Calculations show that a water-catalyzed [1,2]-hydrogen shift adopts a proton-transport catalysis strategy, in which the acetoxy group in the substrate is critical because it acts as either a proton acceptor when one water molecule or a water cluster is involved in catalysis. Our calculated results are consistent with the experimental observations of Gevorgyan et al. for the gold (I)-catalyzed cycloisomerization of propargylic esters leading to unsymmetrically substituted naphthalenes.