aza-Cope Rearrangement Research Articles

Chemoreactive 2,5-Diketopiperazines from a Penicillium sp., Structure Revision of Reported Analogues and Proposed Facile Transformation Pathways.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer. Two new prenylated indole 2,5-diketopiperazine alkaloids, brevianamides E1 (1) and E2 (2), were isolated from a Penicillium fungus. Both compounds showed moderate cytotoxic activity against select MCC cell lines (i.e., MCC13, MKL-1, UISO, and WaGa) in the low micromolar range. The relative and absolute configurations of 1 and 2 were determined by combined approaches, including NOESY spectroscopy, DFT ECD and DP4 plus calculations, and Marfey's reaction. Literature research and the comparison of NMR and ECD data led to the structure revision of three previously reported natural analogues, notoamides K and P and asperversiamide L. The structurally unstable 1 and 2 underwent steady interconversion under neutral aqueous conditions. Investigation of the degradation of 2 in acidic methanol solutions led to the identification of a new methoxylated derivative (6) and two new ring-opened products (7 and 8) with the rearranged, elongated, 4-methylpent-3-ene side chain. The facile transformation of 2 to 7 and 8 was promoted by the intrinsic impurity (i.e., formaldehyde) of HPLC-grade methanol through the aza-Cope rearrangement.

Recent Progress in the Development of Organic Chemosensors for Formaldehyde Detection.

Formaldehyde has become a prominent topic of interest because of its simple molecular structure, release from various compounds in the near vicinity of humans, and associated hazards. Thus, several researchers designed sophisticated instrumentations for formaldehyde detection that exhibit real-time sensing properties and are cost-effective and portable with high detection limits. On these grounds, this review is centered on an analysis of optical chemosensors for formaldehyde that specifically fall under the broad spectrum of organic probes. In this case, this review discusses different organic functionalities, including amines, imines, aromatic pillar arenes, β-ketoesters, and β-diketones, taking part in various reaction mechanisms ranging from aza-Cope rearrangement and Schiff base and Hanztch reactions to aldimine condensation. In addition, this review distinguishes reaction mechanisms according to photophysical phenomena, that is, aggregation-induced emission, photoinduced electron transfer, and intramolecular charge transfer. Furthermore, it addresses the instrumentation involved in gas-based and liquid formaldehyde detection. Finally, it discusses the gaps in existing technologies followed by a succinct set of recommendations for future research.

Computational Investigation of the Aza-Cope Rearrangement Leading to Angularly Substituted 1-Azabicyclic Rings

AbstractA computational study of the aza-Cope rearrangement leading to angularly substituted 1-azabicyclic ring systems is presented. The calculations estimate the probability of the proton transfer between reaction intermediates and protic solvents, explain the experimentally observed reaction selectivity, and suggest new potentially more efficient systems for further in vitro and in silico investigations.

Direct C(sp3)-H allylation of 2-alkylpyridines with Morita-Baylis-Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement.

A base- and catalyst-free C(sp3)–H allylic alkylation of 2-alkylpyridines with Morita–Baylis–Hillman (MBH) carbonates is described. A plausible mechanism of the reaction might involve a tandem SN2’ type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated in the reaction to give the allylation products in 26–91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives.

When a “Dimroth Rearrangement” Is Not a Dimroth Rearrangement

In the Dimroth rearrangement of heterocycles, often pyrimidines, an exocyclic and a ring substituent are interchanged. However, the term Dimroth rearrangement is frequently used even when there is no knowledge of the reaction mechanism and alternatives are likely. Here, we have employed density functional theory (DFT) calculations at the M06-2X/6-311+G(d,p) level to determine the most plausible rearrangement pathways of 3-aminothiocarbonylquinazoline 5, tetrahydrofuranylpyrimidine 21, and 5-allyltriazocine 30. For the rearrangement of quinazoline 5 to 9, the [1,3]-sigmatropic shift of the thioamido group with an activation barrier of 26.7 kcal/mol is much preferred over the Dimroth rearrangement (∼46 kcal/mol). An even lower barrier of 21.6 kcal/mol applies to a stepwise [1,3]-shift. The migration of the tetrahydrofuranyl unit in pyrimidines like 21 → 23 can take place by means of a [1,3]-sigmatropic shift with a low barrier (≤17.5 kcal/mol) rather than a Dimroth rearrangement under acidic conditions and most likely also under neutral conditions (∼30 kcal/mol). In the rearrangement of 5-allyl-6-iminotriazocine 30 to 32, the [3,3]-sigmatropic shift (aza-Cope rearrangement) is preferred over the Dimroth mechanism under neutral conditions, but in the presence of acid, the azonia-Cope rearrangement of an allyl group and the true Dimroth rearrangement have comparable activation energies.

Mechanistic Investigation on Chemiluminescent Formaldehyde Probes.

A first-generation pair of chemiluminescent formaldehyde (FA) probes (CFAP540 and CFAP700) was reported recently. CFAP540 and CFAP700, with high selectivity and sensitivity to FA, are, respectively, suitable in cell and in vivo. Experimentalists have confirmed that both probes utilize a general 2-aza-Cope FA-reactive trigger and a chemiluminogenic phenoxydioxetane scaffold. The mechanism and detailed process of CFAP chemiluminescence (CL) remain largely unknown. In the present paper, (time-dependent) density functional theory calculations are performed on the entire reaction process of CFAP540 with FA to produce CL. The calculations elucidated the CL-producing process: FA initiates the decomposition of CFAP540 by dehydration condensation, and a phenoxy 1,2-dioxetane is formed through a series of reactions of aza-Cope rearrangement, hydrolysis of imine, and β-elimination of alkoxyl group. Afterwards, the produced phenoxy 1,2-dioxetane decomposes to produce the m-oxybenzoate derivative in the first singlet state (S1 ) via two crossings between potential energy surfaces of the ground state (S0 ) and S1 state. This m-oxybenzoate derivative was assigned as the light emitter of the CFAP540 CL. The CL-producing process and assignment of the light emitter of CFAP700 CL are similar with the corresponding ones of CFAP540. By analyzing the D-π-A architecture of the light emitters of CFAP540 and CFAP700, a series of CFAPs is theoretically designed and a scheme to modulate their CL from visible to near-infrared region is proposed by adjusting the length and structure of the π-bridge.

Understanding the mechanism of the chiral phosphoric acid-catalyzed aza-Cope rearrangement

The first catalytic enantioselective aza-Cope rearrangement was reported in 2008 by Rueping et al. The reaction is catalyzed by a 1,1'-bi-2-naphthol-derived (BINOL-derived) phosphoric acid and achieved high yields and enantioselectivities (up to 97 : 3 er with 75% yield). This work utilizes Density Functional Theory to understand the mechanism of the reaction and explain the origins of the enantioselectivity. An extensive conformational search was carried out to explore the different activation modes by the catalyst and, the Transition State (TS) leading to the major product was found to be 1.3 kcal mol-1 lower in energy than the TS leading to the minor product. The origin of this stabilization was rationalized with NBO and NCI analysis: it was found that the major TS has a greater number of non-bonding interactions between the substrate and the catalyst, and shows stronger H-bond interactions between H atoms in the substrate and the O atoms in the phosphate group of the catalyst.

Recent advances in catalytic asymmetric aza-Cope rearrangement.

Aza-Cope rearrangement, as one of the fundamental reactions for C-C and C-N bond formation, has been extensively utilized for the rapid construction of synthetically challenging organic molecules. Despite significant achievements having been made in the past 80 years, catalytic enantioselective versions still remain a challenge, mainly due to the inherent nature of the reversibility of aza-Cope rearrangement. Recently, owing to the intensive development of asymmetric catalysis strategies, various chiral organocatalysts and transition-metal catalysts have been successfully applied to control the stereoselectivity of aza-Cope rearrangement, and remarkable advances have been achieved. This review highlights recent progress relating to catalytic asymmetric aza-Cope rearrangement and covers important features of these studies, including catalytic system design, mechanistic insights, stereochemistry analysis, and synthetic applications.

Organic-inorganic photoelectrochemical sensor based on aza-cope rearrangement reaction for formaldehyde

Abstract A photoelectrochemical (PEC) sensor was designed by connecting an organic recognize group 1-(4-(3-aminopropoxy)phenyl)-N-(4-nitrobenzyl)but-3-en-1-amine (FOP-1) to a modified photoelectric nanomaterial Pt-BiVO4 nano flowers (NFs) for ultra-sensitive and highly selective detection of formaldehyde (FA). The steric hindrance of the FOP-1 and the strong electron-withdrawing group nitro blocked the transfer of electrons excited to the electrode under illumination, resulting in a decrease in photocurrent. With the addition of FA, it triggered a specific aza-cope remake reaction (2-aza-cope sigmatropic rearrangement), leading to N-(4-nitrobenzyl)but-3-en-1-amin (NBEA) group removed, the steric hindrance weakened, the electron-withdrawing effect decreased, and the photocurrent signal recovered obviously. The entire sensor shows good stability and repeatability, excellent selectivity for FA, its detection limit is 0.4 μM, and the linear range is 1–1000 μM, Moreover, endogenous FA released from live MCF-7 cells and the real mice serum samples were monitored successfully by the PEC sensor, indicating its practicality potential in biological cytology and pathophysiology.

The selective and sensitive detection of formaldehyde by ZIF-90-LWvia aza-Cope rearrangement.

Formaldehyde (FA), as one of the simplest reactive carbonyl species (RCS), is widely known as an environmental toxin and carcinogen. In this work, a new ZIF-90 type material (ZIF-90-LW) was synthesized and investigated, which combines the two strategies of "2-aza-Cope rearrangement" and "MOF structure", by the combination of a pre-functionalized 2-allylaminoimidazole ligand and Zn2+ salt under solvothermal conditions. From this, the hurdle of selectivity over other carbonyl compounds (RCS) could be overcome despite their similar electrophilic reactivities to FA, and a prominent fluorescence turn-on type signal was realized through the 2-aza-Cope rearrangement mechanism. A good linear relationship (R2 = 0.9979) was obtained by fitting the fluorescence intensity towards FA from 0 to 25 mM, and the detection limit of ZIF-90-LW for FA was 2.3 μM. In addition, it also showed potentially useful sensing ability for the detection of FA in the gas phase, and might therefore be used to rapidly detect FA with a response time of 28 s in the liquid phase. All of the above features clearly demonstrate that ZIF-90-LW has great potential for sensitive and selective recognition of FA in the environment.

Ultrafast and Efficient Detection of Formaldehyde in Aqueous Solutions Using Chitosan-based Fluorescent Polymers.

Detection of a toxic formaldehyde (HCHO) pollutant in aqueous solutions is of significant importance, because HCHO is widely found in aquatic food because of illicit addition or improper storage. Many small-molecule-based fluorescent probes, which rely on HCHO-specific formaldehyde-amine condensation or the aza-Cope rearrangement reaction, have been developed in terms of facile operation and high selectivity. However, some primary challenging issues are the restricted sensitivity and long equilibrium response time caused by the slow chemical reaction between these small-molecule-based sensors and low-concentration HCHO pollutant in testing samples. Herein, a robust hydrophilic hydrazino-naphthalimide-functionalized chitosan (HN-Chitosan)-based polymeric probe is reported, which takes advantage of specific chemical reaction between HCHO and grafted hydrazino-naphthalimide groups to trigger a "turn-on" fluorescence response. Superior to its small-molecule analogs, HN-Chitosan is based on random coil polymer chains of biopolymeric chitosan, which is thus capable of employing the cooperative binding effect of multiple hydrazino-naphthalimide recognition sites and adjacent hydroxyl groups to "enrich" the low-concentration HCHO pollutant around the polymer chains via weak supramolecular interactions. Therefore, the HCHO-specific chemical reaction with grafted hydrazino-naphthalimide groups is significantly accelerated, resulting in the unprecedented ultrafast equilibrium fluorescence response (less than 1 min) and high sensitivity. Encouraged by its satisfying sensitivity, selectivity, fast response, and wide linear detection range, we successfully expand its application to real-world food and water analysis. In view of the modular design principle of our polymeric probe, the proposed strategy could be generally applicable to construct powerful polymeric probes for ultrafast detection of other important pollutants.

Deconvoluting the Role of Charge in a Supramolecular Catalyst.

We have demonstrated that the microenvironment of a highly anionic supramolecular catalyst can mimic the active sites of enzymes and impart rate accelerations of a million-fold or more. However, these microenvironments can be challenging to study, especially in the context of understanding which specific features of the catalyst are responsible for its high performance. We report here the development of an experimental mechanistic probe consisting of two isostructural catalysts. When examined in parallel transformations, the behavior of these catalysts provides insight relevant to the importance of anionic host charge on reactivity. These two catalysts exhibit similar host-substrate interactions, but feature a significant difference in overall anionic charge (12- and 8-). Within these systems, we compare the effect of constrictive binding in a net neutral aza-Cope rearrangement. We then demonstrate how the magnitude of anionic host charge has an exceptional influence on the reaction rates for a Nazarov cyclization, evidenced by an impressive 680-fold change in reaction rate as a consequence of a 33% reduction in catalyst charge.

Linear C-Allylation by Iridium-Catalyzed N-Allylation and Aza-Cope Rearrangement

Linear C-Allylation by Iridium-Catalyzed N-Allylation and Aza-Cope Rearrangement

Double Regioselective Asymmetric C-Allylation of Isoxazolinones: Iridium-Catalyzed N-Allylation Followed by an Aza-Cope Rearrangement.

Isoxazolinones are biologically and synthetically interesting densely functionalized heterocycles, which for a long time were not accessible in enantioenriched form by asymmetric catalysis. Next to the deficit of enantioselective methods, the functionalization of isoxazolinones is often plagued by regioselectivity issues due to the competition of various nucleophilic centers within the heterocycles. We report the first regio- and enantioselective C-allylations of isoxazolinones. These occur with high regioselectivity in favor of the linear allylation products, although Ir phosphoramidite catalysts were used, which commonly results in branched isomers. Our studies suggest that this outcome is the result of a reaction cascade via an initial regio- and enantioselective N-allylation to provide a branched allyl intermediate, followed by a spontaneous [3,3]-rearrangement resulting in chirality transfer.

Nanoreactors Technology in Green Organic Synthesis

Background: Nanoreactors technology represents a promising tool for efficient and selective organic synthesis typically under “green” and sustainable reaction conditions. These structures with generating a confined reaction environment to accommodate that both reactants and catalysts can change the reaction pathways and induce new activities and selectivities. Objective: The paper reviews literature examples in which nanoreactors were employed in various types of organic and metal catalyzed reactions including multicomponent reactions, palladium-catalyzed coupling reactions, olefin metathesis, aza-Cope rearrangement, allylic alcohol isomerization, cyclization reactions, ring opening reactions, halogenation reactions, hydrolysis reactions, hydroformylation reactions, cascade reactions, addition reactions, oxidation reactions and reduction reactions. The reactions' survey is accompanied with the explanation of structure and performance of nanoreactors that are applied there. Conclusion: The availability of comprehensive information about the role of nanoreactors technology in green organic synthesis and investigation of different aspects of them such as their structures, mechanisms and synthetic utility can assist researchers in designing the greener approaches in organic synthesis.

Synthesis of Azepinoindoles via Rhodium-Catalyzed Formal Aza-[4 + 3] Cycloaddition Reaction of 3-Diazoindolin-2-imines with 1,3-Dienes in One-Pot.

Rhodium-catalyzed formal aza-[4 + 3] cycloaddition reaction of 3-diazoindolin-2-imines with 1,3-dienes was demonstrated for the synthesis of azepinoindoles in good to excellent yields in one-pot. First, rhodium-catalyzed [2 + 1] cycloaddition reaction smoothly took place to produce iminyl vinyl cyclopropane intermediate at room temperature in chlorobenzene for 1 h, which was thermally converted to azepinoindoles via aza-Cope rearrangement.

Rhodium-Catalyzed Regioselective Domino Azlactone-Alkyne Coupling/Aza-Cope Rearrangement: Facile Access to 2-Allyl-3-oxazolin-5-ones and Trisubstituted Pyridines.

Rhodium-catalyzed regioselective addition of azlactones to internal alkynes combined with aza-Cope rearrangement provides efficient atom economic access to 2-allyl-3-oxazolin-5-one derivatives. Extension to a triple domino process, in which the above process is combined with in situ azlactone formation starting from amino acids renders this process even more attractive. Subsequent thermolysis of the 2-allyl-3-oxazolines enabled the de novo synthesis of trisubstituted pyridines.

A highly selective two-photon fluorogenic probe for formaldehyde and its bioimaging application in cells and zebrafish

We report a novel turn-on two-photon fluorescent probe (TPNF) for detecting formaldehyde based on aza-Cope rearrangement and intramolecular charge transfer (ICT). The probe, containing a 1,8-naphthalimide dye with a homoallylamino group, has was shown with high selectivity, sensitivity and low cytotoxicity and it was capable of detecting formaldehyde in live cells. Moreover, a time-dependent density functional theory (TD-DFT) calculation was performed to demonstrate the turn on mechanism of the probe via ICT effect. Finally, a zebrafish larvae imaging experiment reveals that TPNF displayed a significant signal change when treated with FA in vivo. These results indicated that TPNF is a promising tool in more biomedical researches.

Organocatalytic Asymmetric 2-Aza-Cope Rearrangement

Key words phosphoric acids - kinetic resolution - asymmetric synthesis - aza-Cope rearrangement - amides - organocatalysis

Facile Installation of 2-Reverse Prenyl Functionality into Indoles by a Tandem N-Alkylation-Aza-Cope Rearrangement Reaction and Its Application in Synthesis.

An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement-hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza-Cope rearrangement reaction proceeds highly regioselectively to give the quaternary-centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2-reverse prenylated indoles, such as indolines, indole-fused sultams and lactams, and the natural product bruceolline D.