Electrocyclic Research Articles

Ti-Catalyzed and -Mediated Oxidative Amination Reactions.

Titanium is an attractive metal for catalytic reaction development: it is earth-abundant, inexpensive, and generally nontoxic. However-like most early transition metals-catalytic redox reactions with Ti are difficult because of the stability of the high-valent TiIV state. Understanding the fundamental mechanisms behind Ti redox processes is key for making progress toward potential catalytic applications. This Account details recent progress in Ti-catalyzed (and -mediated) oxidative amination reactions that proceed through formally TiII/TiIV catalytic cycles.This class of reactions is built on our initial discovery of Ti-catalyzed [2 + 2 + 1] pyrrole synthesis from alkynes and azobenzene, where detailed mechanistic studies have revealed important factors that allow for catalytic turnover despite the inherent difficulty of Ti redox. Two important conclusions from mechanistic studies are that (1) low-valent Ti intermediates in catalysis can be stabilized through coordination of π-acceptor substrates or products, where they can act as "redox-noninnocent" ligands through metal-to-ligand π back-donation, and (2) reductive elimination processes with Ti proceed through π-type electrocyclic (or pericyclic) reaction mechanisms rather than direct σ-bond coupling.The key reactive species in Ti-catalyzed oxidative amination reactions are Ti imidos (Ti≡NR), which can be generated from either aryl diazenes (RN═NR) or organic azides (RN3). These Ti imidos can then undergo [2 + 2] cycloadditions with alkynes, resulting in intermediates that can be coupled to an array of other unsaturated functional groups, including alkynes, alkenes, nitriles, and nitrosos. This basic reactivity pattern has been extended into a broad range of catalytic and stoichiometric oxidative multicomponent coupling reactions of alkynes and other reactive small molecules, leading to multicomponent syntheses of various heterocycles and aminated building blocks.For example, catalytic oxidative coupling of Ti imidos with two different alkynes leads to pyrroles, while stoichiometric oxidative coupling with alkynes and nitriles leads to pyrazoles. These heterocycle syntheses often yield substitution patterns that are complementary to those of classical condensation routes and provide access to new electron-rich, highly substituted heteroaromatic scaffolds. Furthermore, catalytic oxidative alkyne carboamination reactions can be accomplished via reaction of Ti imidos with alkynes and alkenes, yielding α,β-unsaturated imine or cyclopropylimine building blocks. New catalytic and stoichiometric oxidative amination methods such as alkyne α-diimination, isocyanide imination, and ring-opening oxidative amination of strained alkenes are continuously emerging as a result of better mechanistic understanding of Ti redox catalysis.Ultimately, these Ti-catalyzed and -mediated oxidative amination methods demonstrate the importance of examining often-overlooked elements like the early transition metals through the lens of modern catalysis: rather than a lack of utility, these elements frequently have undiscovered potential for new transformations with orthogonal or complementary selectivity to their late transition metal counterparts.

Synthesis of Benzazepines through Rhodium-Catalyzed Electrocyclization

Synthesis of Benzazepines through Rhodium-Catalyzed Electrocyclization

Ultrafast Ring-Opening Reaction of 1,3-Cyclohexadiene: Identification of Nonadiabatic Pathway via Doubly Excited State.

The photoinduced ring-opening reaction of 1,3-cyclohexadiene (CHD) to produce 1,3,5-hexatriene (HT) plays an essential role in the photobiological synthesis of vitamin D3 in the skin. This reaction follows the Woodward-Hoffmann rule, and C5-C6 bond rupture via an electronically excited state occurs with conrotatory motion of the end CH2 groups. However, it is noted that the photoexcited S1(π,π*) state of CHD is not electronically correlated with the ground state of HT, and the reaction must proceed via nonadiabatic transitions. In the present study, we have clearly observed the nonadiabatic reaction pathway via the doubly excited state of CHD using ultrafast extreme UV photoelectron spectroscopy. The results indicate that the reaction occurs in only 68 fs and creates product vibrational coherence. Extensive computational simulations support the interpretation of experimental results and provide further insights into the electronic dynamics in this paradigmatic electrocyclic ring-opening reaction.

Designing Force Probes Based on Reversible 6π-Electrocyclizations in Polyenes Using Quantum Chemical Calculations.

The conjugated π-system in polyenes can be interrupted by electrocyclic ring-closure reactions. In this work, this 6π-electrocylization is shown by means of density functional calculations to be reversible by the application of an external mechanical pulling force at the terminal ends of the interrupted polyene chain. The test systems were constrained in a fused ring system, thus locking the orientation of three π-bonds and generally promoting 6π-electrocyclic ring-closure reactions. For several systems, the forward reaction is exergonic and the corresponding reaction barrier is comparable to those reported in the literature. The reverse reaction is triggered by an external pulling force of 2 nN (nano-Newton) or less and also becomes exergonic in all investigated polyenes under these force conditions. Moreover, it proceeds via a low reaction barrier when a pulling force of 2 nN is active, indicating that the mechanical force is an efficient stimulus for triggering ring-opening reactions. Analysis of the strain energy induced by this mechanical force confirms an optimal activation of the corresponding C-C σ-bond that breaks upon ring opening when the pulling positions are located on the polyene chain.

Enantioselective Silicon-Directed Nazarov Cyclization.

The Nazarov electrocyclization reaction is a convenient, widely used method for construction of cyclopentenones. In the past few decades, catalytic asymmetric versions of the reaction have been extensively studied, but the strategies used to control the position of the double bond limit the substituent pattern of the products and thus the synthetic applications of the reaction. Herein, we report highly enantioselective silicon-directed Nazarov reactions which were cooperatively catalyzed by a Lewis acid and a chiral Brønsted acid. The chiral cyclopentenones we synthesized using this method generally cannot be obtained by means of other catalytic enantioselective reactions, including previously reported methods for enantioselective Nazarov cyclization. The silicon group in the dienone substrate stabilized the β-carbocation of the intermediate, thereby determining the position of the double bond in the product. Mechanistic studies suggested that the combination of Lewis and Brønsted acids synergistically activated the dienone substrate and that the enantioselectivity of the reaction originated from a chiral Brønsted acid promoted proton transfer reaction of the enol intermediate.

New insights about electronic mechanism of electrocyclic reactions: theoretical study about stereoselectivity in cyclobutenes

This work presents the study of a series of electrocyclic reactions with the main aim of obtaining new insights into the reaction process along IRCs. The energy variation of the different reaction paths as well as the different transition states have been calculated. These trends are according to the experimental data. The natural bond orbitals have been obtained and the second order perturbational theory analysis has been carried out to determine the main charge transfers due to delocalization. Bond reactivity indexes have been used to describe the reactivity mechanism in a local way. These reactivity indexes are also based on NBOs and this has made it possible to connect the results of the indexes with the previous analysis. To determine quantitatively the bond structure, we used the quantum theory of atoms in molecules and we have hereby completed the information obtained from the NBO analysis. Finally, we used the Hirshfeld population analysis as an approximation to understand how the load density changes in the different reaction pathways, and we have connected these variations with the information obtained from the bond structure.The results has found that the reaction path with the lowest energy barrier Transition State Inward Conrotatory (TSIC) or Transition State Outward Conrotatory (TSOC) is determined by two magnitudes: the charge donations by delocalisation of the substituents (which we obtained from the Second Order Perturbational Theory Analysis of the NBOs) and in the case that these donations were very similar, the non-covalent interactions dominated (which we studied by means of the interaction energies of the Hirshfeld charges). Additionality, the most important factor influencing the lower energy reaction path was the interaction of lone pairs of the substituents with the σ∗(C–C) bond that is broken at the opening of the cycle. The alignment of these lone pairs with the C–C bond favours charge donation between them and, as can be seen in the discussion, this alignment varies depending on whether the structure is TSIC and TSOC.

Construction of Spiro[3-azabicyclo[3.1.0]hexanes] via 1,3-Dipolar Cycloaddition of 1,2-Diphenylcyclopropenes to Ninhydrin-Derived Azomethine Ylides

AbstractThe multi-component 1,3-dipolar cycloaddition of ninhydrin, α-amino acids (or peptides), and cyclopropenes for the synthesis of spirocyclic heterocycles containing both 3-azabicyclo[3.1.0]hexane and 2H-indene-1,3-dione motifs has been developed. This method provides easy access to 3-azabicyclo[3.1.0]hexane-2,2′-indenes with complete stereoselectivity and a high degree of atom economy under mild reaction conditions. A broad range of cyclopropenes and α-amino acids have been found to be compatible with the present protocol, which offers an opportunity to create a new library of biologically significant scaffold (3-azabicyclo[3.1.0]hexane). In addition, the сomprehensive study of mechanism of azomethine ylide formation from ninhydrin and sarcosine was performed by means of M11 density functional theory (DFT) calculations. It has been revealed that experimentally observed 1-methylspiro[aziridine-2,2′-indene]-1′,3′-dione is a kinetically controlled product of this reaction and appears to act as a 1,3-dipole precursor. This theoretical study also shed light on the main transformations of the azomethine ylide derived from ninhydrin and sarcosine such as a 1,3-dipolar cycloaddition to cyclopropene dipolarophiles, a dimerization reaction and a (1+5) electrocyclization reaction. The antitumor activity of some synthesized compounds against cervical carcinoma (HeLa­) cell line was evaluated in vitro by MTS-assay.

Design and synthesis of 1,8-naphthalimide functionalized benzothiadiazoles

Push-pull derivatives BTD2–BTD5 were designed and synthesized via Pd-catalyzed Sonogashira cross-coupling reaction followed by [2+2] cycloaddition–electrocyclic ring-opening reaction.

Palladium-Catalyzed Cascade Reactions for Annulative π -Extension of Indoles to Carbazoles through C–H Bond Activation

The annulative π-extension (APEX) reactions through C-H bond activation has tremendous potential to access fused aromatic systems from relatively simple aromatic compounds in a single step. This state-of-the-art technique has the ability to streamline the synthesis of functionalized materials useful in material science, biomedical research, agroand pharmaceutical industries. Furthermore, C-H activation strategy does not require prefunctionalization steps, which allows for the late-stage modification of the functional molecule with requisite molecular properties. Owing to their unique photophysical properties, carbazoles are widely used in photovoltaic cells, biomedical imaging, fluorescent polymer, etc. It is also ubiquitously found in many natural products, agrochemicals and privileged medicinal scaffolds. Hence, direct conversion of easily accessible indole to carbazole remains an active research area. In the last decades, significant advancement has been made to access carbazole moiety directly from indole through cascade C-H activation. The underlying mechanism behind this cascade π-extension strategy is the facile electrophilic metalation at the C-3 position of the indole moiety, 1,2- migration and electro cyclization. In this review, we will discuss recent literature reports for the palladium-catalyzed π-extension of indole to carbazole moiety through C-H bond activation.

Multiconfigurational Calculations and Nonadiabatic Molecular Dynamics Explain Tricyclooctadiene Photochemical Chemoselectivity

Sunlight is a renewable energy source that can be stored in chemical bonds using photochemical reactions. The synthesis of exotic and strained molecules is especially attractive with photochemical techniques because of the associated efficient and mild reaction conditions. We have understood the photophysics and subsequent photochemistry of a possible cubane precursor, tricyclo[4,2,0,02,5]octa-3,7-diene with complete active space self-consistent field (CASSCF) calculations with an (8,7) active space and the ANO-S-VDZP basis set to. The CASSCF energies were corrected with a second-order perturbative correction CASPT2(8,7)/ANO-S-VDZP. The S0 → S1 vertical excitation energy of 1 is 6.25 eV, which is a π → π* excitation. The minimum energy path from the S1 Franck-Condon point leads to a 4π-disrotatory electrocyclic ring-opening reaction to afford bicyclo[4,2,0]octa-2,4,7-triene. The 2D potential energy surface scan located a rhomboidal S1/S0 minimum energy crossing point connecting 1 and cubane, suggesting that a cycloaddition is theoretically possible. We used the fewest switches surface hopping to study the photodynamics of this cycloaddition: 85% of 1722 trajectories relaxed to eight products; the major products are bicyclo[4,2,0]octa-2,4,7-triene (30%) and cycloocta-1,3,5,7-tetraene (32%). Only 0.4% of trajectories undergo a [2 + 2] cycloaddition to form cubane.

Synthesis of Aspidodispermine via Pericyclic Framework Reconstruction.

A divergent approach to the pyrroloquinoline scaffold as present in the class of Aspidosperma alkaloids was developed. As a case study, abundant and renewable nicotinic acid was transformed via pericyclic framework reconstruction into aspidodispermine, a unique member of pyrroloquinoline alkaloids. The sequence comprises a [2 + 2]-photocycloaddition, a Ramberg-Bäcklund contraction, and a strain-promoted formal electrocyclic rearrangement of a bicyclo[2.2.0]hexene and is potentially extendable to pyrroloindole scaffolds as present in the ibophyllidine alkaloids.

A Hydrolase-Catalyzed Cyclization Forms the Fused Bicyclic β-Lactone in Vibralactone.

Vibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual β-lactone-fused bicycle is derived from an aryl ring moiety by an oxidative ring-expansion prior to an intramolecular cyclization. Herein, we report the discovery of the cyclase VibC which belongs to the α/β-hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the Ser-His-Asp catalytic triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic β-lactone. This presents a naturally occurring, new enzymatic reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical-diversity expansion of natural products.

A Hydrolase‐Catalyzed Cyclization Forms the Fused Bicyclic β‐Lactone in Vibralactone

AbstractVibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual β‐lactone‐fused bicycle is derived from an aryl ring moiety by an oxidative ring‐expansion prior to an intramolecular cyclization. Herein, we report the discovery of the cyclase VibC which belongs to the α/β‐hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the Ser‐His‐Asp catalytic triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic β‐lactone. This presents a naturally occurring, new enzymatic reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical‐diversity expansion of natural products.

Restriction of the conrotatory motion in photo-induced 6π electrocyclic reaction: formation of the excited state of the closed-ring isomer in the cyclization.

The electrocyclic reaction dynamics of a photochromic dithiazolylarylene derivative, 2,3-dithiazolylbenzothiophene (DTA) was investigated by using time-resolved transient absorption and fluorescence spectroscopies. The closed-ring isomer of DTA undergoes cycloreversion through the conical intersection mediating the potential energy surfaces of the excited and ground states, which is in agreement with the Woodward–Hoffmann rules for the electrocyclic reactions of 6π electron systems. On the other hand, a large portion of the open-ring isomer undergoes cyclization along the distinct reaction scheme, in which the cyclization takes place in the excited state manifold leading to the formation of the excited state of the closed-ring isomer. The suppression of the geometrical motion of DTA due to the intramolecular interaction could open a new efficient reaction pathway resulting in the formation of the electronically excited state of the product.

Synthesis of 1-(methylsulfonyl)-1-propene and N,N-dimethyl-1-propene-1-sulfonamide

Various vinylsulfones and vinylsulfonamides have a wide range of biological activities (mainly, inhibition of different types of enzymes) and are frequently used in synthetic organic chemistry (as active dienophiles, Michael acceptors and, generally, active agents in 1,4‑addition and electrocyclization reactions). However, despite numerous synthesized substances of this type, the synthetic protocols for the obtaining of the low molecular weight representatives of these compounds – 1‑(methylsulfonyl)-1-propene and N,N‑dimethyl-1‑propene-1-sulfonamide – seem to be still little known. In the present work we report a simple, efficient and general protocol for the dehydrative synthesis of 1‑(methylsulfonyl)-1‑propene and N,N‑dimethyl-1‑propene-1‑sulfonamide starting from corresponding 1-(methylsulfonyl)-2-propanol and N,N‑dimethyl-2‑hydroxypropanesulfonamide, respectively, using MeSO2Cl/organic base system basing on the preliminary experiment of 2‑(4‑bromophenyl)-N,N‑dimethylethenesulfonamide synthesis from 2‑(4‑bromophenyl)-2‑hydroxy-N,N-dimethylethanesulfonamide. The latter in its turn has been obtained starting from N,N‑dimethylmethanesulfonamide by lithiation with n-BuLi, subsequent action of 4‑bromobenzaldehyde and further workup. The applied protocol of vinyl derivatives synthesis allows to avoid isolation of intermediate mesyl derivatives, consisting of one-pot formation of leaving group and its elimination. Accordingly to coupling constants in 1H NMR spectra, synthesized N,N‑dimethyl-1-propene-1‑sulfonamide exists as mixture of E- and Z-isomers (in the ratio 88:12), while isolated 1‑(methylsulfonyl)-1‑propene and 2-(4-bromophenyl)-N,N‑dimethylethenesulfonamide are the most stable E‑isomers. The structures of the synthesized compounds are confirmed by the methods of 1H NMR-spectroscopy and mass-spectrometry.

The effect of solvation in torquoselectivity: ring opening of monosubstituted cyclobutenes.

The paradigmatic electrocyclic ring opening of monosubstituted cyclobutenes has been used to diagnose possible solvation effects tuning the torquoselectivity observed in these reactions. This kind of selectivity in electrocyclic reactions is mostly due to strong orbital interactions, particularly when they involve powerful electron donors and acceptors, which also combine with usually milder steric effects. Orbital interactions are established between the cleaving C-C bond and the HOMO/LUMO of the EDG/EWG substituent. This implies that the larger torquoselectivity-featuring substrates may also suffer stronger solvation effects due to the higher polarity imposed by the substituent. This premise is tested and the source of solvation effects as a consequence of substitution analyzed.

Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors. HIGHLIGHTS Series of oxazole benzylamines were designed and synthesised The tested compounds showed binding selectivity for BChE Naphthoxazoles were more potent AChE inhibitors

Synthesis of Dibenzoxazonines by Domino [2+2] Cycloaddition—4π Electrocyclic Ring Opening Reaction of Cyclic Imines with Ynamides

Synthesis of Dibenzoxazonines by Domino [2+2] Cycloaddition—4π Electrocyclic Ring Opening Reaction of Cyclic Imines with Ynamides

Keteniminium Salts: Reactivity and Propensity toward Electrocyclization Reactions.

A predictive computational study was conducted in order to assess the efficiency of electrocyclization reactions of keteniminium salts, in an effort to form a variety of heterocyclic systems, namely, 3-amino(benzo)thiophenes, 3-amino(benzo)furans, 3-aminopyrroles, as well as 3-aminoindoles. A density functional theory (DFT) approach was utilized and the effect of heteroatoms (NMe, O, S) was thoroughly investigated by means of population analysis, QTAIM, NICS, ACID, and local reactivity descriptors (Parr and Fukui functions). The electrocyclization of enamines leading to 3-aminopyrroles was shown to be both kinetically and thermodynamically most favorable. Moreover, the pericyclic nature of the electrocyclizations was confirmed using FMO, QTAIM, NICS, and ACID methods. Additionally, substituent effects were investigated in order to give further insight on the reactivity of heteroatom containing keteniminium systems toward electrocyclization reactions. Finally, computational predictions were experimentally confirmed for a selection of keteniminium systems.

Synthesis of fused heterocyclic systems via the Mallory photoreaction of arylthienylethenes.

Photochemical oxidative cyclization of 2- and 3-thienylstilbenes (heterostilbenes) containing mono-, di- and trimethoxy groups in the benzene ring or heterocyclic fragment results in the formation of isomeric thieno-annelated polycyclic aromatic compounds demonstrating optical properties that differ from those of initial stilbene derivatives. The structures of cyclic products were evaluated via1H and 13C NMR, HRMS, elemental analysis and X-ray crystallography. The research was aimed to study the effect of substituents in stilbene derivatives of thiophene as well as the position of the styryl fragment in the thiophene nucleus on the occurrence of photocyclization reactions.