A Diels-Alder reaction / oxa-Michael addition / acyloin rearrangement cascade on tropolonic substrates

We describe a novel pericyclic/anionic cascade reaction on tropolonic substrates that combines a Diels-Alder reaction, an oxa-Michael addition, and an acyloin rearrangement to afford tricyclic α-hydroxy-β-methoxyketones. Spectroscopic, crystallographic, and mechanistic studies indicate that the process requires stabilization of reaction intermediates through intramolecular H-bonding to take place, and suggest that the conjugate addition step involves a catalytic cycle with initial formation of an ammonium enolate and sustained by an alkoxide ion pair. Given the rich functionality and structural complexity generated in a single step, the process could be exploited in the preparation of natural product-like compound libraries.     

Efficient electrocatalytic intramolecular anion radical cyclobutanation reactions

Electrochemically initiated, intramolecular anion radical cyclobutanations of bis(enones) and related substrates are presented. The formation of novel anion radical Diels-Alder adducts in minor amounts is also observed. Total yields of pericyclic products, which include both cis- and trans-cyclobutanes and a single Diels-Alder adduct, are generally high (51-88%), with electrocatalytic factors in the range of 1.5-5. Mechanistically, strong evidence for the intervention of distonic anion radical intermediates as precursors of both types of pericyclic products is presented. The scope and limitations of these reactions are rather extensively explored and defined, and in particular the tendency, in some cases, for electrogenerated base-catalyzed reactions to compete with these anion radical pericyclic reactions.     

Intermolecular and intramolecular Diels-Alder cycloadditions of 3-ylidenepiperazine-2,5-diones and 5-acyloxy-2(1h)-pyrazinones

The 3-ylidenepiperazine-2,5-diones 16 and 39 and 5-acyloxy-2(1H)-pyrazinones 17 can serve as starting materials for the Diels-Alder reactions of alkenes and alkynes to the piperazine ring, under acidic conditions or in the presence of acetyl chloride, to afford tricyclic piperazine-2,5-diones 19, 20, 23-25, 27, 44, and 45. Intramolecular cycloadditions occur if 3-ylidenepiperazine-2,5-diones 30 and 32 are used as the starting materials. This procedure is a convenient path to bridged bicyclo[2.2.2]diazaoctane ring systems such as 31 and 33, the former being found in biologically active secondary mold metabolites, such as VM55599 (1) or brevianamide A (5), which have been isolated from various fungi. The synthesis of the indole compound 31 provided evidence for the proposed biochemical pathway with a Diels-Alder reaction as key step. Quantum chemical calculations have revealed that piperazinones with a cationic azadiene moiety are the most reactive species in Diels-Alder cycloadditions.     

Addition of cyclopropyl alkynes to a Brook silene: definitive evidence for a biradical intermediate

The addition of three newly developed mechanistic probes, (trans-2-phenylcyclopropyl)ethyne, (trans,trans-2-methoxy-3-phenylcyclopropyl)ethyne, and (trans,trans-2-methoxy-1-methyl-3-phenylcyclopropyl)ethyne, 1a-c, to a Brook silene, 2-tert-butyl-2-trimethylsiloxy-1,1-bis(trimethylsilyl)-1-silene, 10, was examined. When alkyne 1a was added to silene 10 products derived from a formal ene reaction were obtained. When alkynes 1b-c were added to silene 10, in addition to the typical silacyclobutenes, a variety of silacycloheptenes were obtained in which the cyclopropyl ring had clearly opened. Formal ene-addition products were also produced from the addition of 1b to 10. Based on the relative positions of the phenyl and methoxy substituents within the seven-membered ring of the silacycloheptenes and the known behavior of the alkyne probes under both radical and ionic conditions, it was concluded that a biradical intermediate was formed during the addition of alkynes 1b-c to silene 10. In the addition of alkynes 1a-b to silene 10, the ene products are most likely formed by a competitive pericyclic reaction. We also present a straightforward method for the unambiguous determination of the regiochemistry of silacyclobutenes derived from the cycloaddition of terminal alkynes to silenes.     

Asymmetric catalysis of Diels-Alder reactions with in situ generated heterocyclic ortho-quinodimethanes

The Diels-Alder reaction is probably the most powerful technology in the synthetic repertoire for single-step constructions of complex chiral molecules. The synthetic power of this fundamental pericyclic transformation has greatly increased with the emergence of asymmetric catalytic variants, and research aimed at further expanding its potential is still exciting and fascinating the chemical community. Here, we document the first asymmetric catalytic Diels-Alder reaction of in situ generated heterocyclic ortho-quinodimethanes (oQDMs), reactive diene species that have never before succumbed to a catalytic approach. Asymmetric aminocatalysis, that uses chiral amines as catalysts, is the enabling strategy to induce the transient generation of indole-, pyrrole- or furan-based oQDMs from simple starting materials, while directing the pericyclic reactions with nitroolefins and methyleneindolinones toward a highly stereoselective pathway. The approach provides straightforward access to polycyclic heteroaromatic compounds, which would be difficult to synthesize by other catalytic methods, and should open new synthetic pathways to complex chiral molecules using nontraditional disconnections.     

Competing Diels-Alder reactions of activated nitroethylene derivatives and [3,3]-sigmatropic rearrangements of the cycloadducts

Diels-Alder reaction of nitroethylene derivatives with cyclohexa-1,3-diene afforded three pericyclic products some of which could be converted to others via a new [3,3]-sigmatropic rearrangement or via a Claisen rearrangement.     

The use of Br/Cl to promote regioselective gold-catalyzed rearrangement of propargylic carboxylates: an efficient synthesis of (1Z, 3E)-1-bromo/chloro-2-carboxy-1,3-dienes

A gold-catalyzed synthesis of 1-bromo/chloro-2-carboxy-1,3-dienes is developed using propargylic carboxylates containing halogenated alkynes as substrates. The reaction is highly diastereoselective, and the halogen atom at the alkyne terminus selectively promotes a 1,2-acyloxy migration. The diene products participate in the Diels-Alder and cross-coupling reactions.     

Sequential aminodiene Diels-Alder approach to the ergoline skeleton

Through a novel sequence of aminodiene Diels-Alder reactions, several substituted amidofurans were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system is the result of a ring opening and dehydration of a transient oxabicyclic adduct formed by an intramolecular Diels-Alder cycloaddition of an amidofuran with a cyclohexenone moiety tethered such that it participates in the cycloaddition as the 2pi component. A convenient way to construct the cyclohexenone is to make use of some aminodiene chemistry developed by Rawal. An angular carbomethoxy group is required in order to activate the olefin toward cycloaddition with Rawal's diene. The presence of this activating group not only prevents the isomerization of the advanced ergoline intermediate to a naphthalene but can also be leveraged for an oxidation to provide Uhle's ketone (13). The easily formed Kornfeld ketone analogue 25 was readily transformed into the corresponding triflate 41 by the action of triflic anhydride and a base. Oxidative addition of vinyl triflate 41 to Pd(0) and the ability of the resulting vinyl palladium species to undergo cross-coupling with terminal alkynes prompted us to devise an expeditious route to lysergic acid. Unfortunately, our inability to carry out a regioselective Heck reaction using vinyl triflate 41 and the methylene amino acrylate ester 48 thwarted the completion of the synthesis of lysergic acid.     

A DFT study of the pericyclic/pseudopericyclic character of cycloaddition reactions of ethylene and formaldehyde to buta-1,3-dien-1-one and derivatives

Cycloaddition reactions of ethylene and formaldehyde to buta-1,3-dien-1-one and derivatives were studied by performing a density functional theory study with the 6-31+G* basis set. Reactants, products, and transition states for each reaction were localized, and the path connecting reactants and products was also obtained. Magnetic properties were evaluated along the reaction path to elucidate the characteristics of the reactions studied. Also, a natural bond orbital analysis was performed to study the orbital interactions in the transition states. Calculations indicate that all reactions are pericyclic except three cases, which are pseudopericyclic reactions. In the latter, transition states are almost planar, and magnetic properties do not reveal aromatization enhancement in their transition states. Also, though the participation of lone pairs diminish the pericyclic character of the reactions, sometimes this participation is not enough to generate a change to a pseudopericyclic path. Overall, magnetic properties reveal as a good criterion to elucidate the characteristics of the reactions studied, though a combined application of several criteria is recommended.     

Synthesis of 4-aryl- and 4-alkyl-2-silyl-1,3-butadienes and their Diels-Alder/cross-coupling reactions

An ene-yne cross methasis of silyl-substituted alkynes and alkenes has been developed as a route to 4-aryl- and 4-alkyl-2-silyl-substituted 1,3-dienes. The dienes prepared were used to affect highly diastereoselective Diels-Alder reactions and then the silicon-substituted Diels-Alder cycloadducts were used in Hiyama cross-coupling reactions. The cross-coupling reactions enable these silicon dienes to be used as synthons for a variety of other dienes one might prepare and need access to. Two of the silicon-substituted Diels-Alder cycloadducts and one of the Hiyama cross-coupling products were also characterized by X-ray crystallography.     

Carbopalladation Cascades Using Carbon–Carbon Triple Bonds: Recent Advances to Access Complex Scaffolds

Alkynes are one of the most versatile functional groups as synthetic handles. They allow for a direct access to partially or fully substituted alkenes through difunctionalization reactions. A prominently utilized transformation for these sequences is the carbopalladation of alkynes, which can be followed by various termination steps such as aromatizations, dearomatizations, cross‐coupling reactions, or pericyclic processes, amongst others. This Minireview provides an overview of the recent literature published in the field of carbopalladation chemistry, both with a focus on methodology as well as its application in the syntheses of complex molecular scaffolds, natural products, and functional molecules.     

A conceptual DFT analysis of the plausible mechanism of some pericyclic reactions

Structural Chemistry - Out of several pericyclic reactions, Diels-Alder (DA) reaction is one of the most widely used synthetic processes. In the present work, several models and methodologies have...     

Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives

As part of our continuing studies of polymer-supported pericyclic reactions for preparing biologically interesting heterocyclic compounds, we have introduced a traceless solid-phase synthesis of hexahydrocinnolines. We developed a method in which mild reaction conditions can be used for the hetero-Diels-Alder reactions on a polymeric support. The dienoic 3-vinyl-2-cyclohexenol attached to a Wang resin through an ether linkage undergoes [4 + 2] cycloaddition reaction with several azadienophiles. The highly stereoselective Diels-Alder reaction showed preferential formation of a single cycloadduct resulting from an anti attack of the dienophile on the polymer-bound diene. Trifluoroacetic acid-mediated cleavage of the polymer-bound cycloadducts yields fused nonaromatic hexahydrocinnolines in moderate yields in three steps.     

Stopped-flow kinetics of tetrazine cycloadditions; experimental and computational studies toward sequential transition states

The Diels-Alder cycloadditions of tetrazines (1) with alkynes (2) are expected to give bicyclic adducts (3). Kinetic measurements of the cycloadditions of 1a and 1b with 2a give DeltaG(++) = 19.2 +/- 1.0 and 11.5 +/- 1.2 kcal/mol, respectively. Stopped-flow UV studies on the reaction of 1b with 2a show an isosbestic point at 428 nm; this places an upper limit of 11.6 +/- 2.6 kcal/mol on DeltaG(++) for loss of N(2) from the putative bicyclic intermediate 3b. Calculations (B3LYP/6-31G(d,p) + ZPVE) of transition structures for the reaction of tetrazinediacid 1d with propynylamine 2c are consistent with the experimental results for the reaction of 1b with 2a. This and several related model systems reveal two interesting features of the calculated energy surfaces. First, there may be no barrier for the loss of nitrogen from structures 3 and thus there may be two sequential transition states. This also extends Berson's correlation of activation energy with reaction energy in pericyclic reactions to significantly lower barriers. Second, for the cycloaddition of 4e and 2c, there is neither an intermediate nor a transition state between TS3e and the final product 6e. It appears that the energy surface "turns a corner" in the vicinity of a structure resembling 5e. This is not a mathematically well-defined point but has chemical consequences in that the overall exothermicity of the reaction from 4e to 6e is not felt in TS3e.     

Fischer Carbene Complexes as Chemical Multitalents: The Incredible Range of Products from Carbenepentacarbonylmetal alpha,beta-Unsaturated Complexes

The metal carbene complexes, discovered by E. O. Fischer at the start of the 1960s and carrying his name, have since proved themselves to be irreplaceable building blocks for organic synthesis. In particular, since the discovery of the D?tz reaction, a formal cycloaddition of Fischer alpha,beta-unsaturated carbene complexes to alkynes with CO insertion, this area of chemistry has become increasingly interesting to organic chemists. In spite of the considerable diversity of reactions performed with these complexes, proper selection of substrates and careful adjustment of the reaction conditions have allowed, in most cases the perfectly selective preparation of individual compounds of this enormous range of products. The spectrum of new successes begins with the conventional Diels-Alder reaction of alkynylcarbene complexes and the formal regioselective [3+2] cycloaddition of alkenylcarbene complexes to alkynes. It extends much further, however, from cascade reactions with the formation of oligofunctional and oligocyclic products of impressive molecular complexity to complex, formal [3+6] cocyclizations in which six bonds are formed in a single operational step. Beyond doubt, the methodological arsenal of preparative organic chemistry cannot be imagined any more without the valuable transformations of the Fischer carbene complexes; it only remains to be seen whether one or other of the numerous new types of cocyclization products of these complexes can establish itself as a lead structure in the search for biologically active compounds.     

Silver-catalyzed formal inverse electron-demand Diels-Alder reaction of 1,2-diazines and siloxy alkynes

A highly effective silver-catalyzed formal inverse electron-demand Diels-Alder reaction of 1,2-diazines and siloxy alkynes has been developed. The reactions provide ready access to a wide range of siloxy naphthalenes and anthracenes, which are formed in good to high yields, under mild reaction conditions, using low catalyst loadings.     

AuCl(3)-catalyzed benzannulation: synthesis of naphthyl ketone derivatives from o-alkynylbenzaldehydes with alkynes

The reaction of o-alkynylbenzaldehydes 1 and alkynes 2 in the presence of a catalytic amount of AuCl3 in (CH2Cl)2 at 80 degrees C gave naphthyl ketone products in high yields. The AuCl3-catalyzed formal [4 + 2] benzannulation proceeds most probably through the coordination of the triple bond of 1 to AuCl3, the formation of benzo[c]pyrylium auric ate complex via the nucleophilic addition of the carbonyl oxygen atom, the Diels-Alder addition of alkynes 2 to the auric ate complex, and subsequent bond rearrangement. Similarly, the AuCl3-catalyzed reactions of o-alkynylacetophenone and o-alkynylbenzophenone with phenylacetylene afforded the corresponding naphthyl ketone products in good yields.     

A concise synthesis of substituted stilbenes and styrenes from propargylic phosphonium salts by a cobalt-catalyzed Diels-Alder/Wittig olefination reaction sequence

The cobalt(I)-catalyzed Diels-Alder reaction of propargylic phosphonium salts and longer chained alkyne-functionalized phosphonium salts with 1,3-dienes led to dihydroaromatic phosphonium salt intermediates which were directly used in a one-pot Wittig-type olefination reaction with aldehydes. Subsequent oxidation led to styrene- and stilbene-type products under formation of three new carbon-carbon bonds in a single synthetical step starting from three variable starting materials. The E/Z stereoselectivities of the products revealed that the dihydroaromatic phosphonium ylides behave as semistabilized ylides giving predominantly the E-configured products. The application of unsymmetrical 1,3-dienes as well as internal phosphonium functionalized alkynes is also described.     

硅杂苯与亲二烯体的Diels-Alder反应

采用密度泛函理论(DFT)在B3LYP/6-311G(d,p)水平上研究了硅杂苯与一些亲二烯体的两类可能的Diels-Alder反应的微观机理、势能剖面、取代基效应和溶剂化效应. 计算结果表明, 所研究反应均以协同的方式进行. 亲二烯体分子碳原子上的苯基取代基对两个新键形成的非同步性和反应的活化能垒的影响取决于苯基在产物中的相对位置, 而硅杂苯分子中硅原子上的CCl3取代基有利于杂Diels-Alder反应的进行. 形成一个C—Si键的杂Diels-Alder反应在热力学和动力学上均远比相应的全碳Diels-Alder反应容易进行, 实验观察到的杂Diels-Alder反应中的区域选择性由动力学因素所控制. 硅杂苯与烯烃的反应比与相应炔烃的反应在动力学上容易进行一些, 但在热力学上后者远比前者容易进行. 苯溶剂对所研究反应的势能剖面影响较小.     

Pericyclic reactions involving catalytic metal-vinylidene complexes

The formation of complex polycyclic systems from terminal alkynes based on the concept of pericyclic reactions of catalytic metal-vinylidenes is presented. Metal-vinylidenes, easily formed from terminal alkynes with catalytic amounts of several metal complexes, can be used in electrocyclizations, cycloadditions or sigmatropic rearrangements to afford valuable compounds.