Aza Diels-Alder Research Articles

Multicomponent synthesis of 7-(diethylamino)coumarin–pyrrolo[3,4-b]pyridin-5-one conjugates and modulation of their twisted intramolecular charge transfer (TICT) processes

By coupling an Ugi-Zhu three-component reaction to a cascade sequence (aza Diels-Alder cycloaddition / N-acylation / decarboxylation / dehydration) into a one-pot process, seven new 7-(diethylamino)coumarin-pyrrolo[3,4-b]pyridin-5-one bis-heterocyclic conjugates were synthesized in moderate overall yields (15–38%). Next, the photophysical properties of all products were determined using UV-Vis and fluorescence spectroscopy. These products exhibited fluorescence quantum yields (FQY) ranging from 17% to 25%. In contrast, one of their precursors, the free 7-(diethylamino)-3-carbaldehyde displayed a low FQY of 2%, and, also exhibited dual emission across all solvents used for the measurements. The increase in quantum yield observed upon incorporation of the coumarin moiety into MCR products was attributed to the inhibition of the twisted intramolecular charge transfer (TICT) process. This one naturally occurs in the free coumarin but was suppressed in the products due to a decrease in the acceptor strength of the substituent at position 3 of the coumarin moiety. Furthermore, the electronic structure of the compounds was computed by DFT/TD-DFT calculations allowing to determine which molecular orbitals (MO) were involved in the electronic transitions.

Multicomponent synthesis and photophysical properties of meso-thienyl BODIPY-pyrrolo[3,4-b]pyridin-5-ones. An experimental and theoretical study

Seven new pyrrolo[3,4-b]pyridin-5-ones linked to a meso-thienyl BODIPY moiety by an ethynylbenzene π-conjugated system were synthesized in one-pot manner via an Ugi-Zhu reaction coupled to a cascade process [aza Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration]. The photophysical properties of the polyheterocyclic compounds were evaluated by UV–Vis and fluorescence spectroscopy in five solvents of different polarities. All synthesized products showed two distinct absorption/emission bands, corresponding to both fluorophores separately. The fluorescence intensity of the pyrrolo[3,4-b]pyridin-5-one was the highest in toluene, and it decreased with increasing solvent polarity. On the other hand, the fluorescence intensity of the meso-thienyl BODIPY fragment was insensitive to solvent polarity. The effect of different substituents bonded to the pyrrole ring was evaluated, finding that strong electron-donating groups influence the fluorescence intensity and decay rate of the compounds, even with the presence of a methylene spacer. Moreover, the electronic structure was assessed by DFT and TD-DFT calculations, which reproduced the experimental results reasonably well, showing that the HOMO is located on the pyrrolo[3,4-b]pyridin-5-one core, while the LUMO is on the BODIPY fragment.

Unveiling the zwitterionic and stepwise mechanism for the domino reactions of amidine with 1,2,4,5‐ and 1,2,3,5‐tetrazines

AbstractThe mechanisms of the domino reactions between 4,6‐diphenyl‐1,2,3,5‐tetrazine (TTZ 1) and 3,6‐diphenyl‐1,2,4,5‐tetrazine (TTZ 2) with amidine 3, have been studied at the M06‐2X/6‐311G(d,p) level of theory. The domino reactions of TTZ1 with amidine comprise three consecutive reactions, an aza Diels‐Alder (ADA) reaction with a stepwise mechanism, a retro Diels‐Alder (rDA) reaction, and an amine elimination process, which leads to the resulting aromatic triazine ring. However, the most favorable pathway for domino reaction of the amidine with TTZ2 consists of nucleophilic addition, N2 elimination, and cyclization steps which is deal with the formation of a neutral intermediate. The N2 loss step in both mechanisms is spontaneously, with extremely exergonic formation of the corresponding intermediates. Finally, NH3 is removed through an irreversible intramolecular elimination. The global electron density transfer (GEDT) calculations unleash the polar natures of the first step of the reactions.

Synthesis And Characterization Of New 1,2,4- Triazine Based On 2,5-Dihydrazino-1,3,4- Thiadiazole

The chemistry of 1,2,4-triazine derivatives received a great deals of attention in recent year due to the use of such ring system as the core structure in many heterocyclic compound covering wide range of applications in many different field especially in industrial and biological fields. An efficient aza Diels-Alder reaction have been used in this presentation to prepare the hetero adducts represented by N2,N5-di(3,5,6-tri aryl-5,6-dihydro-1,2,4-triazine-4(3H)-yl)-1,3,4-thiadiazole-2,5-diamino( 9-20)from hetero dienes and hetero dienophile. However the preparation starting form 1,3,4-thiadiazole-2,5 dithaiole (1) which converted directly to the dihydrazino derivatives(2) which then afford under condensation reaction hetero dienophile represented by 2,5-bis Schiff bases of 1,3,4-thiadiazole(3-6) by its reaction with substituted benzaldehyde . The last compound were reacted through one-pot free solvent aza Diels-Alder reaction with appropriate hetero diene( hydrazine with substituted benzaldehyde in ratio 1:2) (7&8 ) to afford 1,2,5-triazine derivatives (9-20) using grinding and MWI techniques as a types of green chemistry approaches.

Elucidation of the molecular mechanisms of 1,2,3,5- and 1,2,4,5-tetrazines with strained and electron-rich alkynes

The mechanisms of the domino reactions between 4,6-diphenyl-1,2,3,5-tetrazine (TTZ 1) and 3,6-diphenyl-1,2,4,5-tetrazine (TTZ 2) with ynamine 3 and cyclooctyne 4, have been studied by DFT method. The domino reactions of TTZs with alkynes comprise two consecutive reactions, an aza Diels-Alder (ADA), and a retro Diels-Alder (rDA) reaction which leads to the resulting aromatic rings through loss of N2. Accordingly, the ADA step of the reaction of TTZ 1 with ynamine 3 proceeds through a stepwise mechanism, when the formation of the C4–C6 bond leads to zwitterionic intermediate IN1a in a regioselective manner. The second step consists of cyclization and spontaneously N2 loss. A stepwise ADA reaction between TTZ 2 and ynamine 3 results in zwitterionic intermediate IN1e and bicyclic intermediate IN2e. Subsequently, N2 removes with no significant energy barrier. The electron localization function (ELF) analysis shows that the ADA reactions of cyclooctyne 4 with TTZs 1 and 2 occur through a two-stage one-step mechanism, and a symmetric synchronous one-step mechanism, respectively. The global electron density transfer (GEDT) calculations indicated that the ADA reactions of TTZs with ynamine 3 and cyclooctyne 4 have strong and moderate polar natures, respectively.

CuI/Cu(OSO2CF3)2 catalysed convenient approach to dichromenopyridines and triazole-thiazole appended chromone derivatives

A variety of new pentacyclic dichromenopyridines have been synthesized from 2-amino chromone and O-propargyloxy salicilaldehydes through intramolecular Povarov reaction using CuI/Cu(OSO2CF3)2 as a Lewis acid catalyst. The dichromenopyridines synthesis involve two sequential steps, insitu N-heteryl aldimine formation and an intramolecular Aza Diels-Alder[4 + 2] cycloaddition. Furthermore the key intermediate, terminal alkyne tethered Schiff bases subjected to Cu(I) mediated click [3 + 2] cycloaddition with thiazole appended azide to afford imine linked chromone-1,2,3-triazole -thiazole tri heterocyclic molecular hybrids.

Regio- and stereochemistry in the aza-Diels–Alder reaction of an azoalkene with furan and 2,3-dihydrofuran: a molecular electron density theory study

In the present work, a molecular electron density theory (MEDT) study is carried out to shed light on the regio- and stereochemistry in two Diels–Alder (DA) reactions explored experimentally by Lemos and coworkers. These reactions involve the aza-Diels–Alder (ADA) reaction of an azoalkene AA with both furan FU and dihydrofuran DHFU in the presence of dichloromethane at room temperature. The regiochemistry of the obtained cycloadducts is completely opposite in the considered ADA reactions. The results of the local reactivity indices analysis based on the Parr functions confirmed the regiochemistry experimentally observed. Exploration of potential energy surfaces (PESs) indicated that the formation of endo adducts, P-1n and PDH-2n, are more favorable than exo ones. It was found that the electrostatic as well as the stabilizing π···π stacking interactions between two interacting fragments in the transition states associated with the endo attack can be considered as the origin of the endo stereochemistry predominance.

Theoretical Study on the Aza-Diels-Alder Reaction Catalyzed by PHCl2 Lewis Acid via Pnicogen Bonding.

The reaction mechanism of the Aza-Diels-Alder (A-D-A) cycloaddition reaction between X2C═NNH2, where X = H, F, Cl, Br, and 1,3-butadiene catalyzed by a PHCl2 Lewis acid was characterized using density functional theory calculations. The influences of various substituents of X on the studied reaction were analyzed using the activation strain model (ASM), which is also termed as the distortion-interaction model. Calculations showed that the smallest and largest values of the activation energies belong to the substituents of F and Br, respectively. The activation energy of the studied reactions was decreased within 8.6 kcal·mol-1 in the presence of PHCl2 catalyst. Investigations showed that the pnicogen bonding is adequately capable of activating the A-D-A reaction. The quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis were implemented to understand the nature of C4,Cbut···CXIm and C1,Cbut···NXIm bonds at the TS structures. Additionally, the energy decomposition analysis (EDA) based on the ETS-NOCV scheme was used to characterize the nature of C4,Cbut···CXIm and C1,Cbut···NXIm bond. The results of the study mirror the fact that the PHCl2 Lewis acid may be suggested as a simple suitable catalyst for experimental studies on the A-D-A reactions.

Organo-catalytic [4+2] Aza Diels Alder Cycloaddition Reaction in an Environmentally Benign Solvent System

Green chemistry brings an attention on a research work emerging from scientific innovations regarding toxic waste acquaintance and it make the use of principles that reduces the use or generation of hazardous materials in an intermediate as well as final steps of Organic synthesis or Chemical progression. Researchers can significantly diminish the hazard to human health as well as environment by following all the valuable philosophy of green chemistry. The most simple way in application of green chemistry in pharmaceuticals is to use efficient, reproducible, eco-friendly, non-hazardous green solvents and green catalysts in synthesis of Organic Moiety, drug intermediates and in researches concerning synthetic chemistry. Organic catalyst brings an exceptional advantage considering the principles of “green chemistry” in Environment as well as economic point of view. Solvents states major serving of the environmental concert of a process and also impact safety and health issues. Water has been found to be very efficient green Solvent and thus can replace many poisonous and harmful solvents. Cycloaddition reactions are fundamental and substantial part of organic chemistry in research. Research work on the aza Diels alder cycloaddition reactions in aqueous systems would be green pathway for organic processes and will definitely protect health as well as environment from toxic materials.

Efficient One Pot Synthesis of Chromenonaphthyridine Derivatives by CuI/InCl3 Catalyzed Aza Diels-Alder Reaction

Efficient One Pot Synthesis of Chromenonaphthyridine Derivatives by CuI/InCl3 Catalyzed Aza Diels-Alder Reaction

Synthesis of α-CF3- and α-CCl3 substituted nitrogen heterocycles by aza Diels-Alder and cyclocondensation reactions

Convenient synthetic approaches for α-CF3- and α-CCl3 substituted pyridines, hydrogenated pyridines, azanorbornenes, 4H-1,2,4-thiadiazine- and 2H-1,2,6-thiadiazine-1,1-dioxides were developed on the basis of cycloaddition and cyclocondensation reactions of trihaloethaneimines and imidoyl chlorides.

Selective Aza Diels-Alder and Domino [4+2]/[2+2] Cycloaddition Reactions of Arynes with N-Sulfonyl Ketimines.

Transition-metal-free inverse electron-demand aza Diels-Alder and domino [4+2]/[2+2] cycloaddition reaction of arynes and N-sulfonyl ketimines has been demonstrated. This novel, mild, and efficient protocol allows rapid access to isothiazole dioxide-fused dihydroquinoline or dihydrocyclobutaquinoline derivatives selectively by simply varying the equivalents of aryne precursors. The application of this method has been amply illustrated in the synthesis of 2,4-diarylquinolines.

Synthesis of Dihydrophenanthridines and Oxoimidazolidines from Anilines and Ethylglyoxylate via Aza Diels-Alder Reaction of Arynes and KF-Induced Annulation.

The transition-metal-free multicomponent coupling of arynes, anilines, and ethylglyoxylate, proceeding via an inverse electron-demand aza Diels-Alder cycloaddition and N-arylation, has been demonstrated. This protocol allows rapid access to N-aryl dihydrophenanthridine derivatives in moderate to high yields at room temperature from readily available starting materials. In addition, an unprecedented fluoride induced annulation of ethyl(arylimino)acetates led to the formation of highly functionalized oxoimidazolidine derivatives in good yields under mild conditions.

Reactivity of the Chiral Metallic Brønsted Acid [(η6-p-MeC6H4iPr)Ru(κ3P,O,O′-POH)][SbF6]2(POH= (SC1,RC2)-Ph2PC(Ph)HC(OH)HCH2OMe) toward Aldimines

Dichloromethane solutions of complex 1 catalyze both the aza-Diels–Alder (ADA) reaction of aldimines with cyclopentadiene and the aza-Friedel–Crafts (AFC) reaction between aldimines and indoles. Racemic adducts were obtained in both cases. NMR measurements of mixtures of the aldimine N-(4-methylbenzylidene)aniline (I) and 1, in a 20/1 molar ratio, reveal the formation of the deprotonated compound 2 and the corresponding iminium cation HI+ (H–N+). This cation is responsible for the achiral catalysis. Below 273 K, in 1/1 molar ratio mixtures of 1 and I, the chiral species 1·I (O–H···N) and 2·HI+ (O–···H–N+) were formed by intermolecular hydrogen bonding and proton transfer, respectively. The latter solutions catalyze stoichiometrically the ADA reaction between aldimine I and HCp with 16% ee. With 5 mol % of catalyst loading, a 6% ee can be obtained if the aldimine is slowly added to the solution (20 equiv in 60 h). Above 273 K, solutions containing 1 and aldimine I irreversibly evolve to the aniline complex...

Understanding the mechanism of the Povarov reaction. A DFT study

The molecular mechanism of the Povarov reaction in acetonitrile has been studied at the MPWB1K/6-311G** level of theory. This reaction follows a domino process that comprises two sequential reactions: (i) a Lewis acid catalysed aza-Diels–Alder (A-DA) reaction between a N-aryl imine and a nucleophilic ethylene yielding a formal [4 + 2] cycloadduct; (ii) a stepwise 1,3-hydrogen shift at this intermediate affording the final tetrahydroquinoline. At this computational level, the Lewis acid catalysed A-DA reaction presents a two-step mechanism as a consequence of the large stabilisation of the corresponding zwitterionic intermediate. Our study allows establishing that the N-aryl substituent has no remarkable incidence in the activation energy, but the presence of a second C-aryl substituent has a relevant role in the reaction rate. Analysis of the DFT-based reactivity indices of the reagents provides further explanation of the behaviours of the mechanism of the A-DA reaction involved in the Povarov reaction.

Synthesis of canthine analogues using intramolecular aza-Diels–Alder strategy and evaluation of their activity against HeLa cervical cancer cells

Synthesis of six new canthine analogues has been developed using a one pot intramolecular aza-Diels–Alder (ADA) reaction as the key step. The synthesized compounds demonstrated moderate activity against HeLa cervical cancer cell lines.

ChemInform Abstract: Iminium Ions as Dienophiles in Aza‐Diels—Alder Reactions: A Closer Look

AbstractReview: 83 refs.

Brønsted-Acid-Catalyzed Asymmetric Multicomponent Reactions for the Facile Synthesis of Highly Enantioenriched Structurally Diverse Nitrogenous Heterocycles

Optically pure nitrogenous compounds, and especially nitrogen-containing heterocycles, have drawn intense research attention because of their frequent isolation as natural products. These compounds have wide-ranging biological and pharmaceutical activities, offering potential as new drug candidates. Among the various synthetic approaches to nitrogenous heterocycles, the use of asymmetric multicomponent reactions (MCRs) catalyzed by chiral phosphoric acids has recently emerged as a particularly robust tool. This method combines the prominent merits of MCRs with organocatalysis, thus affording enantio-enriched nitrogenous heterocyclic compounds with excellent enantioselectivity, atom economy, bond-forming efficiency, structural diversity, and complexity. In this Account, we discuss a variety of asymmetric MCRs catalyzed by chiral phosphoric acids that lead to the production of structurally diverse nitrogenous heterocycles. In MCRs, three or more reagents are combined simultaneously to produce a single product containing structural contributions from all the components. These one-pot processes are especially useful in the construction of heterocyclic cores: they can provide a high degree of both complexity and diversity for a targeted set of scaffolds while minimizing the number of synthetic operations. Unfortunately, enantioselective MCRs have thus far been relatively underdeveloped. Particularly lacking are reactions that proceed through imine intermediates, which are formed from the condensation of carbonyls and amines. The concomitant generation of water in the condensation reaction can deactivate some Lewis acid catalysts, resulting in premature termination of the reaction. Thus, chiral catalysts typically must be compatible with water for MCRs to generate nitrogenous compounds. Recently, organocatalytic MCRs have proven valuable in this respect. Brønsted acids, an important class of organocatalysts, are highly compatible with water and thereby offer great potential as chiral catalysts for multicomponent protocols that unavoidably release water molecules during the course of the reaction. We present a detailed investigation of several MCRs catalyzed by chiral phosphoric acids, including Biginelli and Biginelli-like reactions; 1,3-dipolar cycloadditions; aza Diels-Alder reactions; and some other cyclization reactions. These approaches have enabled the facile preparation of 3,4-dihydropyrimidinones, pyrrolidines, piperidines, and dihydropyridines with high optical purity. The synthetic applications of these new protocols are also discussed, together with theoretical studies of the reaction transition states that address the regio- and stereochemistry. In addition, we briefly illustrate the application of a recently developed strategy that involves relay catalysis by a binary system consisting of a chiral phosphoric acid and a metal complex. This technique has provided access to new reactions that generate structurally diverse and complex heterocycles. Enantioselective organocatalytic MCRs remain a challenge, but we illustrate success on several fronts with chiral phosphoric acids as the primary catalysts. Further progress will undoubtedly provide even better access to the chiral nitrogen-containing heterocycles that are not only prevalent as natural products but also serve as key chiral building blocks in organic synthesis.

Metal-free aerobic oxidative coupling of amines to imines

Oxidative coupling of primary amines to imines is achieved with high to moderate yields by refluxing suspensions of amines and water under one atmosphere dioxygen without any additives. Tandem acid-free aza Diels-Alder reactions for synthesis of N-alkyl-4-pyridones are also accomplished.

Substrate-Induced Covalent Assembly of a Chemzyme and Crystallographic Characterization of a Chemzyme−Substrate Complex

A substrate induced covalent assembly of a highly organized chemzyme known to be effective in both catalytic asymmetric aziridination and aza Diels-Alder reactions is described and the information gained from which led to an efficient one-pot aziridination protocol. The crystal structures of two chemzyme-iminium complexes were elucidated by X-ray diffraction analysis that provides critical insights into the binding of the substrates with the chemzyme.