Alder Products Research Articles

Endergonic synthesis driven by chemical fuelling

AbstractSpontaneous chemical reactions proceed energetically downhill to either a local or global minimum, limiting possible transformations to those that are exergonic. Endergonic reactions do not proceed spontaneously and require an input of energy. Light has been used to drive a number of deracemizations and thermodynamically unfavourable bond-forming reactions, but is restricted to substrates that can absorb, directly or indirectly, energy provided by photons. In contrast, anabolism involves energetically uphill transformations powered by chemical fuels. Here we report on the transduction of energy from an artificial chemical fuel to drive a thermodynamically unfavourable Diels–Alder reaction. Carboxylic acid catalysed carbodiimide-to-urea formation is chemically orthogonal to the reaction of the diene and dienophile, but transiently brings the functional groups into close proximity, causing the otherwise prohibited cycloaddition to proceed in modest yield (15% after two fuelling cycles) and with high levels of regio- (>99%) and stereoselectivity (92:8 exo:endo). Kinetic asymmetry in the fuelling cycle ratchets the Diels–Alder reaction away from the equilibrium distribution of the Diels–Alder:retro-Diels–Alder products. The driving of the endergonic reaction occurs through a ratchet mechanism (an energy or information ratchet, depending on the synthetic protocol), reminiscent of how molecular machines directionally bias motion. Ratcheting synthesis has the potential to expand the synthetic chemistry toolbox in terms of reactivity, complexity and control.

Overcoming Thermodynamically Driven Retro‐Diels–Alder Reaction through a Cascade One‐Pot Process Exemplified for a Bio‐Based Platform Chemical

AbstractIn this contribution, we describe a new approach to apply thermodynamically unfavored reactions in synthetic chemistry and to integrate them in cascade processes. By means of a new developed procedure for multi‐step one‐pot syntheses, we succeeded in nearly completely converting a thermodynamically labile Diels–Alder adduct, which strongly tends to react back, to the target product with high conversion of >99 % and in excellent yield by coupling with a rapid subsequent hydrogenation reaction. In detail, the process is based on the use of a rotating reaction vessel to form a thin product film of the thermodynamically labile Diels–Alder product from 2‐methylfuran and maleic acid anhydride (as two bio‐based raw materials), which then slowly dissolves into solution and is immediately converted by hydrogenation to the target product. Such a combination of Diels–Alder reaction and hydrogenation in a sequential one‐pot process without by‐product formation enables the efficient production of the product, which represents a valuable bio‐based platform chemical. In addition, this process concept generally opens a perspective for the integration of thermodynamically unfavorable reaction steps in multi‐step one‐pot cascade processes while obtaining the desired target products in high yields.

Acid-induced hydrolysis of 1-(methoxydiphenylmethyl)-2-methyldiazene: interception of methyldiazenium ion with 1,3-dienes affording 1-methyl-1,2,3,6-tetrahydropyridazine Diels–Alder products

The conversion of benzophenone methylhydrazone with bromine and pyridine into 1-[(methyldiazenyl)diphenylmethyl]pyridin-1-ium bromide followed by the solvolysis with methanol provides a facile synthesis of 1-(methoxydiphenylmethyl)-2-methyldiazene. The acid-induced hydrolysis of this N,O-ketal releases the methyldiazenyl moiety as the putative intermediate methyldiazenium ion. Reacting as a heterodienophile, methyldiazenium ion is intercepted with 1,3-dienes in [4 + 2+] cycloaddition reactions affording 1-methyl-1,2,3,6-tetrahydropyridazine Diels–Alder products which are transformed into stable and isolated N-benzoyl derivatives.Graphical abstract

First Diels–Alder reaction of a N-nitrogen-substituted iminium ion as dienophile furnishing N-amino-substituted 1,2,5,6-tetrahydropyridines

The exploratory and preliminary work on the reaction of 1-(methoxydiphenylmethyl)-2-methyldiazene with 1,3-dienes reveals a remarkable dichotomy furnishing different heterocyclic Diels–Alder products depending on the presence or absence of water. In contrast to the acid-induced hydrolysis of the N,O-ketal starting material with 1,3-dienes furnishing 1-methyl-1,2,3,6-tetrahydropyridazines (preceding communication), the same acid-promoted reaction albeit under exclusion of water affords N-(methyleneamino)-1,2,5,6-tetrahydropyridines. The serendipitous discovery of the novel 1,2,5,6-tetrahydropyridines was corroborated by an alternative and independent synthesis providing the in situ generated formaldehyde benzophenone azine and its conjugate acid, 2-(diphenylmethylene)-1-methylenehydrazin-1-ium ion. The protonated azine serving as the putative dienophile resembles the first example of an N-nitrogen-substituted iminium ion employed as a dienophile in a bona fide normal electron-demand Diels–Alder reaction.Graphical abstract

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

Prolinol-Derived Catalysts Mediate Route Towards Functionalized trans-Diels–Alder Products

Prolinol-Derived Catalysts Mediate Route Towards Functionalized trans-Diels–Alder Products

A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels-Alder Products Having the Norcarane Scaffold.

An enantioselective methodology to construct trans-Diels-Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels-Alder reaction allowing for the subsequent formation of trans-Diels-Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels-Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN 2-like reaction at a tertiary center to obtain the trans-Diels-Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

A Direct Organocatalytic Enantioselective Route to Functionalizedtrans‐Diels–Alder Products Having the Norcarane Scaffold

AbstractAn enantioselective methodology to construct trans‐Diels–Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo‐halogen effect to direct an endo‐selective, secondary‐amine catalyzed Diels–Alder reaction allowing for the subsequent formation of trans‐Diels–Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α‐brominated or α‐pseudo‐halogenated enone to form a fleeting cis‐Diels–Alder intermediate. The endo‐transition state‐enhanced by the (pseudo‐)halogen effect‐sets the stereochemistry that allows for a subsequent SN2‐like reaction at a tertiary center to obtain the trans‐Diels–Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

Fluorescence Quenching Effects of Tetrazines and Their Diels–Alder Products: Mechanistic Insight Toward Fluorogenic Efficiency

AbstractInverse electron demand Diels–Alder reactions between s‐tetrazines and strained dienophiles have numerous applications in fluorescent labeling of biomolecules. Herein, we investigate the effect of the dienophile on the fluorescence enhancement obtained upon reaction with a tetrazine‐quenched fluorophore and study the possible mechanisms of fluorescence quenching by both the tetrazine and its reaction products. The dihydropyridazine obtained from reaction with a strained cyclooctene shows a residual fluorescence quenching effect, greater than that exerted by the pyridazine arising from reaction with the analogous alkyne. Linear and ultrabroadband two‐dimensional electronic spectroscopy experiments reveal that resonance energy transfer is the mechanism responsible for the fluorescence quenching effect of tetrazines, whereas a mechanism involving more intimate electronic coupling, likely photoinduced electron transfer, is responsible for the quenching effect of the dihydropyridazine. These studies uncover parameters that can be tuned to maximize fluorogenic efficiency in bioconjugation reactions and reveal that strained alkynes are better reaction partners for achieving maximum contrast ratio.

Nitrosocarbonyl Carbohydrate Derivatives: Hetero Diels–Alder and Ene Reaction Products for Useful Organic Synthesis

AbstractThe generation and trapping of two new nitrosocarbonyl intermediates bearing carbohydrate-based chiral substituents is achieved by the mild oxidation of the corresponding nitrile oxides with tertiary amine N-oxides. Their capture with suitable dienes and alkenes afforded the corresponding hetero Diels–Alder cycloadducts and ene adducts from fair to excellent yields. The entire methodology looks highly promising by the easy conversion of aldoximes into hydroxymoyl halides, widening the access to nitrosocarbonyls, versatile tools in organic synthesis.

Preparation of Thietane, Thiolane, and Thiane Perfluorinated Diels–Alder Products

Preparation of Thietane, Thiolane, and Thiane Perfluorinated Diels–Alder Products

Selective Modification of Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs) through Diels-Alder Cycloadditions on Dehydroalanine Residues.

We report the late‐stage chemical modification of ribosomally synthesized and post‐translationally modified peptides (RIPPs) by Diels–Alder cycloadditions to naturally occurring dehydroalanines. The tail region of the thiopeptide thiostrepton could be modified selectively and efficiently under microwave heating and transition‐metal‐free conditions. The Diels–Alder adducts were isolated and the different site‐ and endo/exo isomers were identified by 1D/2D 1H NMR. Via efficient modification of the thiopeptide nosiheptide and the lanthipeptide nisin Z the generality of the method was established. Minimum inhibitory concentration (MIC) assays of the purified thiostrepton Diels–Alder products against thiostrepton‐susceptible strains displayed high activities comparable to that of native thiostrepton. These Diels–Alder products were also subjected successfully to inverse‐electron‐demand Diels–Alder reactions with a variety of functionalized tetrazines, demonstrating the utility of this method for labeling of RiPPs.

9-(3,5-Dimethylbenzylidene)-8-(3,5-dimethylphenyl)-1,3,5,7-tetraphenyl-2,4,7,8-tetrahydro-4,7-methanoazulene acetonitrile disolvate

The title Diels–Alder product, C52H44·2CH3CN, was obtained in trace quantity as the `endo' isomer during the synthesis of 1,3-diphenyl-6-(3,5-dimethylphenyl)fulvene. One of the two co-crystallized acetonitrile molecules is linked to the main molecule by a weak C—H...N hydrogen bond.

Tandem Diels–Alder Reaction of Dimethylfuran and Ethylene and Dehydration to para‐Xylene Catalyzed by Zeotypic Lewis Acids

AbstractThe zeotypic Lewis acids Sn‐BEA, Zr‐BEA, and Ti‐BEA have recently been reported to catalyze the synthesis of p‐xylene by dehydrative aromatization of the Diels–Alder product between 2,5‐dimethylfuran and ethylene. Although it has been shown that these Lewis acids can catalyze the dehydration of the Diels–Alder cycloadduct, the tandem scheme precludes decoupling of the two steps needed to infer whether these same catalysts can catalyze the Diels–Alder step. We have employed electronic structure calculations and microkinetic modelling to investigate the Diels–Alder aromatization of 2,5‐dimethylfuran and ethylene to p‐xylene over the Lewis‐acidic zeotypes Sn‐, Zr‐, and Ti‐BEA. We show that there is only minor catalysis of the Diels–Alder reaction, solely attributable to confinement phenomena varying with the translational freedom allowed to the species inside the zeolite. Microkinetic modelling and sensitivity analysis of the computed rates show that the heterogeneous Diels–Alder pathway does not contribute to the overall rate, and that the homogeneous cycloaddition is rate‐limiting at high acid site concentrations. Only the partially hydrolyzed (“open”) Lewis acid sites are found to be catalytically active, with moderately Brønsted‐acidic silanol groups formed, which catalyze 2,5‐dimethylfuran hydrolysis. Of the Lewis acids tested in this work, Zr‐BEA and Sn‐BEA have similar activities, in agreement with experiment, whereas Ti‐BEA is found to be inactive, suggesting that the recently reported Ti‐BEA activity was likely a result of Brønsted‐acidic defect sites.

Two concurrent pathways of the reaction of pyrrolobenzoxazinetriones with cyclic alkoxyolefins. Synthesis of alkaloid-like pentacyclic 6/6/5/6/5- and 6/6/5/6/6-angularly fused heterocycles

3-Aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with 2,3-dihydrofuran and 3,4-dihydro-2H-pyran to give mixtures of the corresponding hetero-Diels–Alder and Michael addition products.

Density Functional Study of Oxygen Insertion into Niobium–Phosphorus Bonds: Novel Mechanism for Liberating P3– Synthons

We explore the mechanism of oxygen insertion into niobium–phosphorus bonds to liberate synthetically relevant, phosphorus-containing molecules. Oxygen insertion mechanisms generally proceed through either direct oxygen insertion from an oxo ligand, M═O (oxy-insertion), or an insertion of an oxygen atom from an external oxidant, OY (Baeyer–Villiger, BV). Computational methods were employed to elucidate the preferred mechanism for the liberation of the phosphorus moiety from [(η2-P3)Nb(ODipp)3] (Dipp = 2,6-iPr2C6H3, P3 = P3-SnPh3) when treated with pyridine-N-oxide as an external oxidant. Careful analysis of conformational isomers and energies clearly suggests that the BV mechanism is the preferred pathway toward phosphorus liberation. Once free, the P3 moiety can react with 1,3-cyclohexadiene to form the Diels–Alder product, which is also modeled in the computational study.

Highly Ordered Rectangular Columnar Ionic Liquid Crystals: A More Efficient Medium for Intramolecular Diels Alder Reactions

AbstractHerein, we present the synthesis, the thermal and mesophormic properties of trialkyl(1,3,5‐benzene)trisimidazolium salts. These salts form highly ordered rectangular columnar ionic liquid crystal phases and can be used as reaction media for Diels Alder reactions. The use of the ionic liquid crystal phase favours the formation of the intramolecular Diels Alder products, even in high concentration reaction conditions. We show that the ionic liquid crystal phase can be recycled and reused as solvent for at least 10 times, without any loss of yield or selectivity in the Diels Alder reaction.

ChemInform Abstract: Kinetic Separation and Asymmetric Reactions of Norcaradiene Cycloadducts: Facilitated Access via H2O‐Accelerated Cycloaddition.

We exploit the Buchner reaction to access 1,2-disubstituted cyclohexadiene synthons (norcaradienes), which participate in H2O-accelerated cycloaddition with dieneophiles to provide cyclopropyl-fused [2.2.2]-bicyclooctene derivatives in good yields. Regioisomeric mixtures can be kinetically separated by exploiting different reaction rates in Diels–Alder reactions. Meso-Diels–Alder products may be enantioselectively desymmetrized, providing highly substituted cyclohexanes with up to seven contiguous stereocenters.

Asymmetric Formal Aza-Diels-Alder Reaction of Trifluoromethyl Hemiaminals with Enones Catalyzed by Primary Amines.

A primary amine-catalyzed asymmetric formal aza-Diels-Alder reaction of trifluoromethyl hemiaminals with enones was developed via a chiral gem-diamine intermediate. This novel protocol allowed facile access to structurally diverse trifluoromethyl-substituted piperidine scaffolds with high stereoselectivity. The utility of this method was further demonstrated through a concise approach to biologically active 4-hydroxypiperidine. More importantly, a stepwise mechanism involving an asymmetric induction process was proposed to rationalize the positive correlation between the chirality of the gem-diamine intermediate and the formal aza-Diels-Alder product.

Diels–Alder Cycloaddition of Tetraphenylcyclopentadienone and 1,3,5‐Hexatriynes

AbstractDiels–Alder cycloaddition reactions of 1,3,5‐hexatriynes with tetraphenylcyclopentadienone have been performed, and mainly gave 1,2‐diethynyl‐3,4,5,6‐tetraphenylbenzene derivatives as products. The Diels–Alder reactions were optimized under conventional heating and microwave irradiation conditions, and showed good selectivity towards the central carbon–carbon triple bond of the triyne. Empirical evidence suggests that the selectivity of the reaction is governed predominantly by the steric demands of the end‐groups of the triyne. Several of the Diels–Alder products could be further elaborated by a sequence of desilylation and oxidative homocoupling to provide dimeric products. The homocoupling reaction was optimized by Pd catalysis. The X‐ray crystallographic analysis of two derivatives is reported.