Intramolecular Research Articles

TBTH (Bu3SnH) catalyzed C-H and C-Cl functionalization: Radical cascade cyclization for the construction of tetracyclic benzimidazole derivatives

A radical cascade cyclization of cyanamides, catalyzed by Tributyltin hydride (Bu3SnH), has been successfully devised. Herein, we present a pioneering and uncomplicated methodology for the fabrication of tetracyclic 11H-benzo [4,5] imidazo[2,1-a] isoindole derivatives. This synthesis entails a sequence of inert Csp2-X/Csp2-H functionalization processes applied to N-cyano groups, followed by the radical cyclization of iminyl motifs. This study represents a significant advancement in the intramolecular radical cascade cyclization reaction of cyanamides, enabling the efficient synthesis of 1,2-disubstituted benzimidazole molecules, specifically the 11H-benzo [4,5] imidazo[2,1-a] isoindol and its analogues, achieved with yields ranging from 42% to 86%. Notably, this approach has been instrumental in the synthesis of a diverse array of compounds, establishing their efficacy as potent antibreast cancer agents. Furthermore, the proposed mechanism has been meticulously elucidated through a series of control experiments.

Regio- and stereoselective access to highly substituted vinylphosphine oxides via metal-free electrophilic phosphonoiodination of alkynes

In general, the P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening is primarily confined to intramolecular nucleophilic reactions, resulting in the formation of phosphorus-containing cyclization products instead of difunctionalized products generated through intermolecular nucleophilic processes. Here, through the promotion of ring-opening of three-member rings by iodine anions and the quenching of electronegative carbon atoms by iodine cations, we successfully synthesize β-functionalized vinylphosphine oxides by the P-addition of QPrS intermediates generated in situ. Multiple β-iodo-substituted vinylphosphine oxides can be obtained with exceptional regio- and stereo-selectivity by reacting secondary phosphine oxides with unactivated alkynes. In addition, a variety of β-functionalized vinylphosphine oxides converted from C-I bonds, especially the rapid construction of benzo[b]phospholes oxides, demonstrates the significance of this strategy.

Highly porous layered carbon nanocomposites from the self-assembly of a poly(amic acid) for efficient oxygen reduction reaction catalysis

Porous layered carbon nanomaterials play important role in the efficient loading of electroactive substances for high performance energy conversion techniques. Herein, an intramolecular cyclization induced self-assembly (ICISA) strategy is proposed to prepare three-dimensional highly porous layered carbon nanostructures (LCs) for efficient loading of various transition metal nanoparticles for oxygen reduction reaction (ORR) catalysis. The amphiphilic alternating copolymer poly(amic acid) (PAA) is synthesized by the stepwise polymerization of hydrazine hydrate and pyromellitic dianhydride. Upon heating above 160 °C, the intramolecular cyclization reaction occurs, leading to the formation of rigid, crystalline and non-soluble polyimide segments in the backbone, which induces the self-assembly of the polymer to form dumbbell-shaped assemblies with a high solid content of 15%. After pyrolysis in a nitrogen atmosphere, LCs are obtained. Cobalt (Co), iron (Fe) and FeCo nanoparticles can be efficiently loaded, noted as Co@LCs, Fe@LCs and FeCo@LCs, respectively. The ORR catalytic performance of the catalysts is evaluated to give half wave potentials of 0.791, 0.787 and 0.812 V, and limit current densities of 4.92, 4.73 and 4.71 mA cm−2 for Co@LCs, Fe@LCs and FeCo@LCs, respectively. Overall, we propose an ICISA strategy to facilely prepare three-dimensional carbon nanomaterials with highly porous layered structure for efficient ORR catalysis.

Syntheses, Characterization, and Redox Activity of Ferrocene-Containing Titanium Complexes.

The chemistry of bis(π-η5:σ-η1-pentafulvene)titanium complexes is characterized by a broad range of E-H activation and Ti-C functionalization reactions, whereas ferrocene derivatives are easily accessible and redox-active compounds. The reaction of ferrocenealdehyde and -ketones with bis(π-η5:σ-η1-pentafulvene)titanium complexes result in the formation of bimetallic complexes via insertion of the C=O double bond of the aldehyde/ketone into the Ti-Cexo bond of the pentafulvene moiety. The reaction of bis(π-η5:σ-η1-pentafulvene)titanium complexes with ferrocenyl alcohols leads to alcoholate complexes via deprotonation of the OH group by the pentafulvene ligand. Because of the one remaining pentafulvene unit, further functionalization of the complexes is possible. In this work, we proceeded with 1,1'-bifunctionalized ferrocene derivatives for intramolecular follow-up reactions. 1,1'-Ferrocenedimethanol reacts with bis(π-η5:σ-η1-pentafulvene)titanium complexes in a double O-H deprotonation reaction to yield the dialcoholate complex. 1,1'-bis(phenylphosphine)ferrocene reacts differently as the double P-H deprotonation reaction results in the formation of a P-P linked phosphine. Therefore, we studied the reactivity of 1,1'-bis(phenylphosphine)ferrocene toward Rosenthal's reagent. As Rosenthal's reagent is regarded as a masked titanocene(II) species, it undergoes redox reactions toward H-acidic substrates, forming a paramagnetic Ti(III) complex.

Copper-Catalyzed Synthesis of Furan-Tethered Benzocyclobutenes via Carbene-Mediated 1,4-Sulfinate Migration-Annulation.

A copper-catalyzed intramolecular cascade reaction of conjugated enynones has been achieved via a pivotal 1,4-sulfinate migration step. This process leverages a cost-effective and ecofriendly copper salt as catalyst, enabling the efficient construction of five- and four-membered rings in a rapid, sequential manner, producing furan-tethered benzocyclobutenes in good to excellent yields under mild conditions. The reaction is characterized by 100% atom economy, outstanding efficiency, and excellent diastereoselectivity in the cases studied. The robustness of this method is evidenced by its compatibility with air exposure and the use of undistilled, commercially available solvents, further enhancing its practicality.

Asymmetric Total Synthesis of (+)-Lemnardosinane A.

The asymmetric total synthesis of (+)-lemnardosinane A, a rare rearranged sesquiterpenoid, has been accomplished from (S)-carvone. Key features of the synthesis are the formation of a bicyclo[3.3.1]nonane skeleton using the intramolecular aldol reaction, the stereoselective introduction of an alkyne group, and the stereoselective formation of a tricyclic skeleton via intramolecular pinacol coupling.

Cyclic Azahelicene Dimers Showing Bright Circularly Polarized Luminescence and Selective Fluoride Recognition.

Although helicenes are promising molecules, the synthetic difficulty and tediousness have often been problems, and only small amounts of optically pure helicenes have been obtained by using chiral HPLC in most cases. Herein, aza[7]helicenes or closed-aza[7]helicenes with (1R)-menthyl substituents were selectively synthesized via the intramolecular Scholl reaction, and the diastereomeric pairs were separated by silica gel column chromatography. The optically pure helicenes were further transformed into the corresponding cyclic dimers, and the chiroptical properties were investigated. The rigid π-frameworks of the dimers led to the high molar extinction coefficients and fluorescence quantum yields, while the twisted helicene moieties induced clear Cotton effects and CPL in the visible region, and the high CPL brightness (BCPL) was achieved. Furthermore, the cyclic dimers were found to have the macrocyclic cavity with the two NH groups suitable for the selective binding of a fluoride anion, which induced significantly redshifted fluorescence and CPL in the red region.

Cyclic Azahelicene Dimers Showing Bright Circularly Polarized Luminescence and Selective Fluoride Recognition

AbstractAlthough helicenes are promising molecules, the synthetic difficulty and tediousness have often been problems, and only small amounts of optically pure helicenes have been obtained by using chiral HPLC in most cases. Herein, aza[7]helicenes or closed‐aza[7]helicenes with (1R)‐menthyl substituents were selectively synthesized via the intramolecular Scholl reaction, and the diastereomeric pairs were separated by silica gel column chromatography. The optically pure helicenes were further transformed into the corresponding cyclic dimers, and the chiroptical properties were investigated. The rigid π‐frameworks of the dimers led to the high molar extinction coefficients and fluorescence quantum yields, while the twisted helicene moieties induced clear Cotton effects and CPL in the visible region, and the high CPL brightness (BCPL) was achieved. Furthermore, the cyclic dimers were found to have the macrocyclic cavity with the two NH groups suitable for the selective binding of a fluoride anion, which induced significantly redshifted fluorescence and CPL in the red region.

From 5-HMF to Novel Cyclopentenone-Based Aza Spirocycles: An Intramolecular Aza-Piancatelli Reaction in Action.

With a double objective to upgrade biobased 5-HMF and to access to original spirocycles via an intramolecular aza-Piancatelli reaction, a multistep sequence was designed toward appropriate furylcarbinols. The impacts of both the nucleophiles, arylamines compared to alkoxyamines, and the length of the intramolecular tether were studied. After an in-depth evaluation of the different parameters, an extension of the scope provided a library of original azaspiro[4.5]non-8-en-7-ones and azaspiro[4.6]dec-3-en-2-ones whose skeletons have so far never been listed. The application of the aza-Piancatelli reaction associated with the use of biobased HMF in fine chemistry gives credit to the development of novative structures, as raised by the green chemistry community. Combining efforts in synthetic methodology with integration of biosourced platforms could open the way to new molecules exhibiting different properties from the ones raised from petrochemical sources.

Regiospecific synthesis of N,N’-disubstituted-2-imino-hydantoins derived from cyanamides

The present work developed a new simple method and convenient procedure to synthesize a novel series of 1-(4,6-dimethylpyrimidin-2-yl)-2-imino-3-arylimidazolidin-4-ones 3. The sodium salt of N-(4,6-dimethylpyrimidin-2-yl)cyanamide (1) was selected to use as the starting material to undergo intramolecular cyclization reaction with 2-chloro-N-arylacetamides in boiling acetone for about 12–18 hours. According to this new synthetic route, eleven imino-hydantoins were readily separated in moderate to excellent yields as single products after cooling the reaction without any purification technique. Also, on the basis of the experimental results and analysis data (IR, NMR, elemental analyses, and GC-MS spectra), the reaction is regiospecific as well as a plausible mechanism to form the target products 3 instead of di-imino-oxazolidines 4 and/or 2-imino-2,3-dihydro-oxazoles 5 is proposed.

Chiral Sulfones via Single-Electron Oxidation-Initiated Photoenzymatic Catalysis

AbstractWe recently achieved an oxidation-initiated photoenzymatic enantioselective hydrosulfonylation of olefins through the utilization of a new Gluconobacter ene-reductase mutant (GluER-W100F-W342F). Our method simplifies the reaction system by eliminating the need for a cofactor regeneration mixture and, in contrast with previous photoenzymatic systems, does not depend on the formation of an electron donor–acceptor (EDA) complex between the substrates and enzyme cofactor. Moreover, the GluER variant exhibits good substrate compatibility and excellent enantioselectivity. Mechanistic investigations indicate that a tyrosine-mediated HAT process is involved and support the proposed oxidation-initiated mechanism. In this Synpacts article, we discuss the conceptual framework that led to the discovery of this reaction and reflect on the key aspects of its development.1 Introduction2 Conceptual Background2.1 Intramolecular Photoenzymatic Reactions via Single-Electron Reduction2.2 Intermolecular Photoenzymatic Reactions via Single-Electron Reduction3 The Development of the Process4 Conclusion

Synthesis of quinazolinone derivatives with a seven‐membered ring using borrowing hydrogen methodology

In this study, we synthesized 23 quinazolinone derivatives with the seven-membered C-ring through intramolecular borrowing hydrogen reaction of 3-(3-hydroxypropyl)-2-(1H-indol-2-yl)-quinazolin-4(3H)-one, in yields ranging from 31 % to 68 %. The reaction took place in the presence of cesium carbonate and DMF, using triphenylphosphine ruthenium chloride (PPh3)3RuCl2 as a catalyst and Xantphos as a ligand. Water was the only byproduct. Furthermore, pharmacological activity tests were conducted on these compounds, revealing that some of the products exhibited anti-inflammatory and anticancer properties.

Synthesis of Aza[n]helicenes up to n = 19: Hydrogen-Bond-Assisted Solubility and Benzannulation Strategy.

Synthetic challenges toward anomalous structures and electronic states often involve handling problems such as insolubility in common organic solvents and oxidative degradation under aerobic conditions. We designed benzo-annulated aza[n]helicenes, which benefit from both the suppressed elevation of highest occupied molecular orbital (HOMO) energies and high solubility due to hydrogen bonding with solvent molecules to overcome these challenges. This strategy enabled the synthesis of six new aza[n]helicenes ([n]AHs) of different lengths (n = 9-19) from acyclic precursors via one-pot intramolecular oxidative fusion reactions. The structures of all of the synthesized aza[n]helicenes were determined by X-ray diffraction (XRD) analysis, and their electrochemical potentials were measured by cyclic voltammetry. Among the synthesized aza[n]helicenes, [17]AH and [19]AH are the first heterohelicenes with a triple-layered helix. The noncovalent interaction (NCI) plots confirm the existence of an effective π-π interaction between the layers. The absorption and fluorescence spectra red-shifted as the helical lengths increased, without any distinct saturation points. The optical resolutions of N-butylated [9]AH, [11]AH, [13]AH, and [15]AH were accomplished, and their circular dichroism (CD) and circularly polarized luminescence (CPL) were measured. Thus, the structural, (chir)optical, and electrochemical properties of the aza[n]helicenes were comprehensively analyzed.

Synthesis of (2R,4S)-4-Amino-5-hydroxybicyclo[3.1.1]heptane-2-carboxylic Acid via an Asymmetric Intramolecular Mannich Reaction.

Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The proposed inactivation mechanism involves a novel α-iminol rearrangement. The synthesis of the proposed inhibitor features an asymmetric intramolecular Mannich reaction, utilizing a chiral sulfinamide. This study presents a novel approach toward the synthesis of functionalized bicyclo[3.1.1]heptanes and highlights an underutilized method to access enantiopure exocyclic amines.

Palladium/Xu‐Phos Catalyzed Enantioselective Intramolecular Heck Reaction of Unactivated Alkenes

Comprehensive SummaryA highly enantioselective palladium‐catalyzed intramolecular Heck reaction of unactivated alkenes is developed, which provides a powerful route to access a broad range of chiral 3,3‐disubstituted‐2,3‐dihydrobenzofurans bearing all‐carbon quaternary stereocenter of interest in pharmaceutical research. Its salient features include high yield, excellent chemo‐ and enantioselectivity, mild conditions, a broad substrate scope as well as versatile transformations of the product.

Insights into the mechanisms of optical cavity-modified ground-state chemical reactions

In this work, we systematically investigate the mechanisms underlying the rate modification of ground-state chemical reactions in an optical cavity under vibrational strong-coupling conditions. We employ a symmetric double-well description of the molecular potential energy surface and a numerically exact open quantum system approach—the hierarchical equations of motion in twin space with a matrix product state solver. Our results predict the existence of multiple peaks in the photon frequency-dependent rate profile for a strongly anharmonic molecular system with multiple vibrational transition energies. The emergence of a new peak in the rate profile is attributed to the opening of an intramolecular reaction pathway, energetically fueled by the cavity photon bath through a resonant cavity mode. The peak intensity is determined jointly by kinetic factors. Going beyond the single-molecule limit, we examine the effects of the collective coupling of two molecules to the cavity. We find that when two identical molecules are simultaneously coupled to the same resonant cavity mode, the reaction rate is further increased. This additional increase is associated with the activation of a cavity-induced intermolecular reaction channel. Furthermore, the rate modification due to these cavity-promoted reaction pathways remains unaffected, regardless of whether the molecular dipole moments are aligned in the same or opposite direction as the light polarization.

Cyclization by metal-catalyzed hydrogen atom transfer/radical-polar crossover

Catalytic transformation of alkenes via the metal-hydride hydrogen atom transfer (MHAT) mechanism has notably advanced synthetic organic chemistry. This review focuses on MHAT/radical-polar crossover (MHAT/RPC) conditions, offering a novel perspective on generating electrophilic intermediates and facilitating various intramolecular reactions. Upon using cobalt hydrides, the MHAT mechanism displayed exceptional chemoselectivity and functional group tolerance, making it invaluable for the construction of complex biologically relevant molecules under mild conditions. Recent developments have enhanced regioselectivity and expanded the scope of MHAT-type reactions, enabling the formation of cyclic molecules via hydroalkoxylation, hydroacyloxylation, and hydroamination. Notably, the addition of an oxidant to traditional MHAT systems enables the synthesis of rare cationic alkylcobalt(IV) complexes, bridging radical mechanisms to ionic reaction systems. This review culminates with examples of natural product syntheses and exploration of asymmetric intramolecular hydroalkoxylation, highlighting the ongoing challenges and opportunities for future research to achieve higher enantioselectivity. This comprehensive study revisits the historical evolution of the MHAT mechanism and provides the groundwork for further innovations in the synthesis of structurally diverse and complex natural products. 1 Introduction 2 Intramolecular hydroalkoxylation and hydroacyloxylation reactions 3 Intramolecular hydroamination reactions 4 Intramolecular hydroarylation reactions 5 Deprotective cyclization 6 Asymmetric intramolecular hydroalkoxylation

Data-Efficient, Chemistry-Aware Machine Learning Predictions of Diels-Alder Reaction Outcomes.

The application of machine learning models to the prediction of reaction outcomes currently needs large and/or highly featurized data sets. We show that a chemistry-aware model, NERF, which mimics the bonding changes that occur during reactions, allows for highly accurate predictions of the outcomes of Diels-Alder reactions using a relatively small training set, with no pretraining and no additional features. We establish a diverse data set of 9537 intramolecular, hetero-, aromatic, and inverse electron demand Diels-Alder reactions. This data set is used to train a NERF model, and the performance is compared against state-of-the-art classification and generative machine learning models across low- and high-data regimes, with and without pretraining. The predictive accuracy (regio- and site selectivity in the major product) achieved by NERF exceeds 90% when as little as 40% of the data set is used for training. Another high-performing model, Chemformer, requires a larger training data set (>45%) and pretraining to reach 90% Top-1 accuracy. Accurate predictions of less-represented reaction subclasses, such as those involving heteroatomic or aromatic substrates, require higher percentages of training data. We also show how NERF can use small amounts of additional training data to quickly learn new systems and improve its overall understanding of reactivity. Synthetic chemists stand to benefit as this model can be rapidly expanded and tailored to areas of chemistry corresponding to the low-data regime.

Visible Light-promoted Preparation of 2,3-Dihydrobenzofurans and Coumaranones

Abstract: 2,3-Dihydrobenzofuran and coumaranone are readily available in numerous naturally occurring compounds. They mostly exist in plenty of food plants and medicinal plants. Such compounds constitute a series of flavor components and bioactive molecules. Their preparation has been an attractive field of research. In the past few decades, great efforts have been made in the preparation of the 2,3-dihydrobenzofuran structure through both metal-catalyzed and organocatalyzed ways. Visible light-promoted reactions sprang up in the early 21st century and represent a green manner of transformations. Under the irradiation of visible light, radicals could be generated under milder conditions. Thus, visible lightpromoted reactions spread widely in the field of chemical synthesis. In recent years, visible light-promoted preparation of 2,3-dihydrobenzofuran and coumaranone has been developed by different groups, including both intramolecular and intermolecular reactions. The benign reaction conditions allow better functional group-tolerance and lead to diverse structures. Several reviews on the synthesis of 2,3- dihydrobenzofuran have been reported. However, visible light-promoted approaches to such structures have not been well reviewed. Our review will cover the literature that has been reported on the discovery of 2,3- dihydrobenzofuran in food and visible light-promoted preparation of 2,3-dihydrobenzofuran, attempting to summarize the existing methods and provide guidance to the chemists on the present challenges.

Increasing enantioselectivity and reactivity in Ir-Catalysed intramolecular hydroamination reactions

A series of axially chiral NHC ligands bearing dialkylated naphthyl side arms and electron-rich substituted phenyl groups in the backbone have been employed in the synthesis of neutral NHC-Ir(COD)Cl complexes. When the halide ligand was abstracted from these compounds by appropriate silver salts AgX (X = PF6, NTf2), chiral cationic, formally 14-electron iridium complexes [(NHC)Ir(COD)][X] were formed. When these species were applied as catalysts for asymmetric intramolecular hydroamination of unactivated, amino-olefin substrates, chiral 5- and 6- membered N-heterocyclic products were obtained with moderate to excellent enantioselectivities. By tuning the substrate through variation of the N-protecting group on the amino-olefin substrates, remarkable improvements in enantioselectivity were obtained.