Synthesis of the decalin structure of cladoic acid.

The intramolecular Diels-Alder (IMDA) reactions of four substituted deca-1,3,9-trienes and one N-methyleneocta-5,7-dien-1-aminium with different electrophilic/nucleophilic activations have been studied within the Molecular Electron Density Theory (MEDT) and compared to their intermolecular processes. The topological analysis of the electron density and DFT-based reactivity indices reveal that substitution does not modify neither the electronic structure nor the reactivity of the reagents relative to those involved in the intermolecular processes. The analysis of the relative energies establishes that the accelerations found in the polar IMDA reactions follow the same trend as those found in the intermolecular processes. The geometries and the electronic structures of the five transition state structures involved in the IMDA reactions are highly similar to those found in the intermolecular processes. A relative interacting atomic energy (RIAE) analysis of Diels-Alder and IMDA reactions allows for the establishment of the substituent effects on the activation energies. Although the nucleophilic frameworks are destabilized, the electrophilic frameworks are further stabilized, resulting in a reduction in the activation energies. The present MEDT study demonstrates the remarkable electronic and energetic similarity between the intermolecular and intramolecular Diels-Alder reactions. Only the lower, unfavorable activation entropy associated with the latter renders it 104 times faster than the former.

Intramolecular Diels-Alder (IMDA) reaction of the hydroxamate-tethered 1,3,9-decatrienes has been investigated under both thermal and microwave heating, and the stereoselectivity has been revisited. It was found that a temperature-dependent rearrangement of (2E,4E)-hexadien-1-yl N-benzylhydroxamates into the corresponding (2E,4)-1-methylpentadien-1-yl derivatives took place prior to IMDA reaction upon heating, and up to four cycloadducts were identified by analysis of the crude reaction mixtures. The IMDA reaction could be accelerated with microwave irradiation at 180 ˚C in MeCN. Stereoselectivity of the microwave-assisted IMDA reaction has been examined by using the substituents appended at C1, C5, and C10 of the hydroxamate-tethered 1,3,9-decatrienes.

[Reaction: see text]. The potential dual behavior as dienes and dienophiles of the diene moieties of masked o-benzoquinones (MOBs) 10a-e-12a-e, generated upon oxidation of 2-methoxyphenols 1-3 with BTIB in the presence of appropriate dienols, in their intramolecular Diels-Alder (IMDA) reactions has been examined. The IMDA reactions of MOBs 10a-d, 11a,b,d, and 12a,b,d resulted in highly functionalized oxatricyclic compounds 18a-d, 19a,b,d, and 20a,b,d, respectively, with concomitant formation of cis-decalin derivatives 21a-d, 22a,b,d, and 23a,b,d in a highly regio- and stereoselective manner. However, the MOBs 10e-12e provided exclusively oxatricyclic compounds 18e-20e. The formation of cis-decalins in these IMDA reactions illustrates the dienophilic character of MOBs, in addition to their behavior as dienes. The ratio of the two cycloadducts obtained in each reaction as a result of the dual character of MOBs depends on the nature and/or position of the substituents on both the cyclohexadienone moiety and the added 2,4-dienol. The majority of the cycloadducts resulted from the diene property of MOBs in intramolecular Diels-Alder reactions smoothly underwent Cope rearrangement to furnish cis-decalins as sole products in excellent to quantitative yields that provides a short and efficient entry to polyfunctionized cis-decalins from 2-methoxyphenols. Furthermore, the variation of dienophilic and diene characters of MOBs in the IMDA reactions with the electron-donating or electron-withdrawing substituent of both cyclohexadienone moiety and the added conjugated acyclic diene or 2,4-dienol has been studied in detail.

A quantitative model based upon Allinger's MM2 force field has been devised to calculate the diastereoselectivity of intramolecular Diels-Alder (IDA) reactions. The parameters for the modified MM2 force field were derived whenever possible from ab initio calculations on the intermolecular transition structure for the Diels-Alder reactions of butadiene plus ethylene, acrolein, and acrolein coordinated to BH 3 . The force field reproduces the ab initio 3-21G transition structures for the intramolecular Diels-Alder reactions of 1,3,8-nonatriene and 1,3,9-decatriene

In this study, we propose a new approach that their purposes to facilitate the theoretical examinations of the intramolecular Diels-Alder (IMDA) reactions of triene amide and other IMDA reactions. In this end, the nature of reaction mechanism (NRM) will be determined by evaluating the contribution of binding chain on the HOMO and LUMO energies of triene amide. During our study, we have used the density functional theory (DFT) combined with B3LYP hybrid and 6-31G(d,p) basis set level. The results found shows that the binding chain has a negligible contribution on the HOMO and LUMO energies of triene amide molecule. Therefore, the diene and dienophile are treated as they were in isolated fragments. Thus the calculation of the NRM reveals that these reactions are at normal electronic demand (NED) in accordance with the results found by charge transfer between fragments in the transition state.

Aza-Morita-Baylis-Hillman (aza-MBH) products derived from arylimines and methyl acrylate or acrylonitrile were N-alkylated with (E)-5-bromopenta-1,3-diene, and the resulting trienes were subjected to intramolecular Diels-Alder (IMDA) cyloadditions to afford the corresponding trans- and cis-fused tetrahydroisoindolines as the major and minor products, respectively. Catalysis with boron trichloride improved the IMDA diastereoselectivities of the nitrile derivatives, while yields were improved in both the nitrile and ester series. Treatment of the nitrile-substituted trienes with DABCO in DMF resulted in unexpected transposition of the N-(pentadienyl)sulfonamide group to the beta-position of the acrylonitrile moiety. Subsequent IMDA cycloadditions produced cis-fused positional isomers of the previous tetrahydroisoindolines. When the products of vinylogous aza-MBH reactions in the nitrile series were N-propargylated, the resulting dienynes underwent a similar transposition and IMDA reaction, producing trans and cis diastereomers of the corresponding dihydroisoindolines as the major and minor products, respectively. In all but one case, only the former products were observed in the presence of methylaluminum dichloride, while the corresponding aromatized isoindolines were obtained when the IMDA reactions were carried out in the presence of DDQ. Thus, a variety of aryl-substituted isoindoline products with different levels of unsaturation and complementary substitution patterns and stereochemistry are readily available through these processes.

Quantum mechanical calculations have been used to investigate type 2 intramolecular N-acylnitroso Diels-Alder reactions. Experimentally observed regioselectivities and diastereoselectivities of these reactions have been reproduced using B3LYP/6-31+G(d) DFT calculations. The factors that govern selectivity (i.e., tether length, tether substitution and diene substitution) were systematically investigated. Tethers less than 6 carbon atoms lead to 1,3-regioisomers due to conformational restrictions. Substituents on the tether lead to diastereoselective outcomes dictated by transannular interactions in the transition states. The modest diastereoselectivity of diene-substituted substrates is rationalized as arising from reduction of eclipsing interactions in the flattened diene transition states. This method should prove valuable for planning syntheses involving type 2 intramolecular Diels-Alder reactions.

Ring-transformations of pyrimidines by intramolecular diels-alder reactions. Synthesis of annelated fyridines

The Diels–Alder reaction is one of the most useful reactions available to the synthetic organic chemist. It is thus surprising that the intramolecular version, in which both diene and dienophile are part of the same molecule, remained virtually unexplored for many years. Early examples were often the result of unexpected observations, and the many advantages of this reaction were recognized and put to use in the synthesis of complex polycyclic molecules only recently. In the intramolecular Diels–Alder reaction, two rings are formed in one step. In addition to the six-membered ring formed by the [4 + 2]cycloaddition, the product contains a second ring, the size of which depends on the length of the chain connecting diene and dienophile. Of the two possible regiochemical modes of addition, that leading to the fused product usually predominates to the virtual exclusion of the bridged product. The Diels–Alder reaction proceeds through a highly ordered transition state that is reflected in large negative activation entropies. In the intramolecular version, some of the ordering has been accomplished in advance by making the two reacting functionalities part of the same molecule. This results in less negative activation entropies and increased reaction rates under often surprisingly mild conditions. On the other hand, by using forcing conditions one can sometimes carry out intramolecular Diels–Alder additions that would be doomed to failure in the intermolecular version. Lower reaction temperatures, together with the constraints imposed by the connecting chain, often result in pronounced regio- and stereoselectivity. Side reactions such as dimerization or polymerization can be avoided by using high dilution or low pressures in the gas phase. Examples where the bimolecular Diels–Alder reaction interferes with the intramolecular cyclization are rare. All of these features suggest that the intramolecular Diels–Alder reaction should be considered for any synthesis of a molecule containing a six-membered ring fused to a second ring, especially if that ring is five- or six-membered. Such a synthetic scheme may be made convergent by building up the diene and dienophile portions separately and connecting them just prior to the actual cyclization. Another potential use of the intramolecular Diels–Alder reaction that has not received much attention to date is as a supplement to the intermolecular Diels–Alder reaction in cases where the latter is unsuccessful or gives the wrong regio- or stereochemistry. By judicious choice of the connecting chain, the reaction may be made to proceed with the desired selectivity; this is followed by cleavage of the chain and conversion of the two ends to the desired functionalities. Once the feasibility of employing the intramolecular Diels–Alder reaction has been recognized, the main challenge often becomes the preparation of the substrate. A discussion of that aspect is beyond the scope of this chapter; however, by scanning the tables for the particular diene, dienophile, and chain one is interested in, and then referring to the original literature, it will often be possible to obtain some indications on how to proceed. An attempt has been made to cover the literature of the thermal intramolecular Diels–Alder reaction as completely as possible up to and including the year 1981. Many of the papers that appeared in 1982 and some from 1983 have also been included. More recent references are given in an addendum at the end of the tabular survey. Keywords: Diels–Alder reaction; intramolecular; mechanisms; regioselectivity; syn/anti-selectivity; diastereoselectivity; dienes; vinyl aromatics; quinodimethanes; furans; chains; dienophile; intramolecular reaction; reverse intramolecular reaction; natural product synthesis; asymmetric centers; cyclic compounds; pyridines; pyridones; pyridazines; pyrimidones; scope; limitations; experimental procedures; heterocyclics

Three different intramolecular Diels-Alder (IMDA) reactions associated with the formation of fused and bridged tricyclodecane skeletons have been studied at the B3LYP/6-31G(d) computational level. While substitution on the diene and dienophile fragments modulates the polar character of the reaction, the strain effect produced by the methylene tether affects the activation energy, and its torsion controls the different regioisomeric channels of the IMDA process. Analysis of the reactivity indices recently proposed [J. Soto-Delgado et al., Org. Biomol. Chem., 2010, 8, 3678] within the conceptual density functional theory allows for the characterization of the mechanism including the charge transfer within the reagents involved in these IMDA reactions as well as for the direction of the electronic flux in the intramolecular processes.

Six chiral hydroxylated pyrrolidine catalysts were synthesized from commercially available D-arabinose in seven steps. Various aromatic substituents α to the amine can be introduced readily by a Grignard reaction, which enables facile optimization of the catalyst performance. The stereoselectivities of these catalysts have been assessed by comparing with those of MacMillan's imidazolidinone in a known intramolecular Diels-Alder (IMDA) reaction of a triene. Two additional IMDA reactions of symmetrical dienals with concomitant desymmetrisation further established the potential use of these novel amine catalysts. These pyrrolidines are valuable catalysts for other synthetic transformations.

Anti-Bredt alkenes, bicyclic molecules that contain a bridgehead double bond, were for many years regarded as chemical curiosities. The type 2 intramolecular Diels-Alder (IMDA) reaction provides a one-step entry into this fascinating class of molecules. The reaction has made available numerous anti-Bredt alkenes for structural and chemical studies. X-ray crystallography has revealed the magnitude of the deformations associated with the bridgehead double bond, and rate studies of reactions of bridgehead alkenes have allowed quantification of the kinetic consequences of the torsional distortions. More recently, the type 2 intramolecular Diels-Alder reaction and the resulting anti-Bredt alkenes have found application in organic synthesis. The constraints resulting from the connectivity in the Diels-Alder precursor creates a strong regio- and stereochemical bias in the cycloaddition step. The end result of this bias is the stereoselective synthesis of highly substituted six-membered rings. The reaction also achieves a facile synthesis of seven- and eight-membered rings in a single step from acyclic precursors. The utility of this reaction has been verified in recent applications of the type 2 IMDA reaction as a key step in the total synthesis of complex natural products.

Herein, we presented an enantioselective intramolecular Diels-Alder (IMDA) reaction with vinyl branched vinylidene ortho-quinone methide (VQM). The control of site selectivity in the IMDA reaction led to both chiral bridged bicyclo[4.3.1] and [5.3.1] architectures with high isolated yields (up to 85%) and excellent enantioselectivities (up to 97% ee).

Regioselectivity for intramolecular Diels-Alder (IMDA) reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones that were formed by oxidation of 2-alkenylphenols with lead tetraacetate in acetic acid were studied. Bridged regioselectivity was observed in the IMDA reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones having a dienophile part which could conjugate with an aromatic group. Bridged seven- and eight-membered rings and bicyclo[2.2.2]octane skeletons were constructed by the present IMDA reactions. Density functional theory (DFT) calculations suggested that conjugation of the dienophile with neighboring aromatic groups lowered the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and preceded bridged [4 + 2] adducts.

[structures: see text] A gas-phase B3LYP/6-31+G(d) study of substituent effects on the stereochemistry of both intramolecular Diels-Alder (IMDA) reactions of 9-E- and 9-Z-substituted pentadienyl acrylates and intermolecular Diels-Alder (DA) reactions between butadiene and monosubstituted alkenes and 3-substituted acrylates is reported and involves the calculation of 230 transition structures. It was found that, although exo ("anti-Alder") addition of monosubstituted ethenes to butadiene is the norm, Alder endo selectivity is more widely predicted for 3-substituted methyl acrylate dienophiles, and this was explained in terms of secondary orbital interactions (SOIs). Whereas cis/trans selectivity for IMDA reactions involving 9-E-substituted pentadienyl acrylates generally follows the normal pattern found for the corresponding intermolecular DA reactions, the 9-Z-substituted stereoisomers generally displayed trans selectivity that was much stronger than can be attributed to effects of the isolated substituent. This is strikingly so with unsaturated electron-withdrawing substituents whose endo selectivities, displayed in intermolecular DA reactions, are reversed in the IMDA reactions of pentadienyl acrylates. The origin of this anomalous Z-effect is explained in terms of the twist-mode asynchronicity concept of Brown and Houk. These ideas are used to explain the stereochemical outcomes of IMDA reactions of other triene systems.