Diels-Alder reactions neutral

Diels-Alder reactions Neutral ionic liquids have been found to be excellent solvents for the Diels-Alder reaction. The first example of a Diels-Alder reaction in an ionic liquid was the reaction of methyl acrylate with cyclopentadiene in [EtNH3][N03] [40], in which significant rate enhancement was observed. Howarth et al. investigated the role of chiral imidazolium chloride and trifluoroacetate salts (dissolved in dichloromethane) in the Diels-Alder reactions between cyclopentadiene and either crotonaldehyde or methacroline [41]. It should be noted that this paper describes one of the first examples of a chiral cationic ionic liquid being used in synthesis (Scheme 5.1-17). The enantioselectivity was found to be < 5 % in this reaction for both the endo (10 %) and the exo (90 %) isomers. 

Diels-Alder reactions can be divided into normal electron demand and inverse electron demand additions. This distinction is based on the way the rate of the reaction responds to the introduction of electron withdrawing and electron donating substituents. Normal electron demand Diels-Alder reactions are promoted by electron donating substituents on the diene and electron withdrawii substituents on the dienophile. In contrast, inverse electron demand reactions are accelerated by electron withdrawing substituents on the diene and electron donating ones on the dienophile. There also exists an intermediate class, the neutral Diels-Alder reaction, that is accelerated by both electron withdrawing and donating substituents. 

Note that for 4.42, in which no intramolecular base catalysis is possible, the elimination side reaction is not observed. This result supports the mechanism suggested in Scheme 4.13. Moreover, at pH 2, where both amine groups of 4.44 are protonated, UV-vis measurements indicate that the elimination reaction is significantly retarded as compared to neutral conditions, where protonation is less extensive. Interestingy, addition of copper(II)nitrate also suppresses the elimination reaction to a significant extent. Unfortunately, elimination is still faster than the Diels-Alder reaction on the internal double bond of 4.44. 

The Diels-Alder reaction of dienophiles 5.1a-e, containing neutral, cationic or anionic substituents, with diene 5.2 in the absence of Lewis acids is retarded by micelles of CTAB, SDS and C12E7. In the situation where the dienophile does not bind to the micelle, the reaction is inhibited because uptake of... 

A similar study performed by Welton and co-workers studied the rate and selec-tivities of the Diels-Alder reaction between cyclopentadiene and methyl acrylate in a number of neutral ionic liquids [44]. It was found that endo. exo ratios decreased slightly as the reaction proceeded, and were dependent on reagent concentration and ionic liquid type. Subsequently, they went on to demonstrate that the ionic liquids controlled the endo. exo ratios through a hydrogen bond (Lewis acid) interaction with the electron-withdrawing group of the dienophile. 

Alkoxy alkynylcarbene complexes undergo Diels-Alder reactions with neutral and electron-rich dienes [36f, 104] and also with 1-aza- and 2-aza-l,3-butadi-ene derivatives [84a, 105] (Scheme 57). 

Equation 1.5) [13], Diels Alder reactions which are insensitive to the substituent effects in the diene and/or dienophile are classified as neutral (Equation 1.6) [14]. 

Earle and coworkers [54] have performed Diels-Alder reactions in neutral ionic liquids. The results of reactions of cyclopentadiene with dimethyl maleate, ethyl acrylate and acrylonitrile are reported in Table 6.10. The cycloadditions proceeded at room temperature in all of the ionic liquids tested, except [BMIMJPF4, and gave almost quantitative yields after 18-24h. The endo/exo selectivity depends on dienophile. No enantioselectivity was observed in the [BMIM] lactate reaction. 

Table 6.10 Diels-Alder reactions of cyclopentadiene with dimethyl maleate, ethylacrylate and acrylonitrile in neutral ionic liquids...

Ab initio calculation of Diels-Alder reactions of a series of 5-heteroatom substituted cyclopentadienes Cp-X (65 X = NH, 50 X = NH, 64 X = NH3, 67 X = O", 54 X = OH, 68 X = OH3% 69 X = PH, 51 X = PH, 70 X = PH3% 71 X = S, 55 X = SH, 72 X = SH/) with ethylene at HF/6-31++G(d)//HF/6-31-i i-G(d) level by BumeU and coworkers [37] provided counterexamples of the Cieplak effect. The calculation showed that ionization of substituents has a profound effect on the n facial selectivity deprotonation enhances syn addition and protonation enhances anti addition. The transition states for syn addition to the deprotonated dienes are stabilized relative to those of the neutral dienes, while those for anti addition are destabilized relative to those of the neutral dienes. On the other hand, activation energies for syn addition to the protonated dienes are similar to those of the neutral dienes, but those for anti addition are very much lowered relative to neutral dienes (Table 6). 

Starting from 27, cyclo-Cig was prepared in the gas phase by laser flash heating and the neutral product, formed by stepwise elimination of three anthracene molecules in retro-Diels-Alder reactions, was detected by resonant two-photon-ionization time-of-flight mass spectrometry [23]. However, all attempts to prepare macroscopic quantities of the cyclocarbon by flash vacuum pyrolysis using solvent-assisted sublimation [50] only afforded anthracene and polymeric material. 

Similar aza-Diels-Alder reactions of Danishefsky s diene with imines or aldehydes and amines in water took place smoothly under neutral conditions in the presence of a catalytic amount of an alkaline salt such as sodium triflate or sodium tetraphenylborate to afford dihydro-4-pyridones in high yields (Eq. 12.49).117 Antibodies have also been found to catalyze hetero-Diels-Alder reactions.118... 

The combination of pericyclic transformations as cycloadditions, sigmatropic rearrangements, electrocydic reactions and ene reactions with each other, and also with non-pericyclic transformations, allows a very rapid increase in the complexity of products. As most of the pericyclic reactions run quite well under neutral or mild Lewis acid acidic conditions, many different set-ups are possible. The majority of the published pericyclic domino reactions deals with two successive cycloadditions, mostly as [4+2]/[4+2] combinations, but there are also [2+2], [2+5], [4+3] (Nazarov), [5+2], and [6+2] cycloadditions. Although there are many examples of the combination of hetero-Diels-Alder reactions with 1,3-dipolar cycloadditions (see Section 4.1), no examples could be found of a domino all-carbon-[4+2]/[3+2] cycloaddition. Co-catalyzed [2+2+2] cycloadditions will be discussed in Chapter 6. 

The long-lived isomeric xylylene cation radical then undergoes either coupling to the adducts in equation (72) or back electron transfer followed by Diels-Alder reaction of the resulting neutral xylylenes and chloranil. 

Ionic liquids are excellent solvents for the Diels-Alder reaction providing significant increases in rate and selectivity. Diels-Alder reactions conducted in chloroa-luminate ionic liquids show considerable promise. For example, the endo.exo ratio for the reaction between cyclopentadiene and methyl acrylate (Scheme 7.5) could be varied by changing the composition of the ionic liquid (see Chapter 4) [11]. Although a high yield was obtained, in order to extract the products it was necessary to quench the ionic liquid in water. This is a considerable disadvantage and for this reason neutral ionic liquids have been the focus of subsequent attention. 

Neutral Diels-Alder reactions encompass cycloadditions of dienes and dienophiles with intermediate electronic characters. 

The main stabilization in reactions with activated reaction partners, viz. when one partner is electron-rich and the other electron-poor, arises through interaction between the donor HOMO and the acceptor LUMO which are much closer in energy than the acceptor HOMO and the donor LUMO. Figure 2 illustrates which interactions between the frontier orbitals cause the main stabilization in normal, neutral and inverse Diels-Alder reactions. For example, the main stabilization in the reaction between an electron-rich diene and an electron-poor dienophile stems from the interaction of the diene HOMO with the dienophile LUMO. 

The Diels-Alder reaction is reversible at elevated temperature, and therefore its products can decompose prior to evaporation by RDA reaction of the neutral in the condensed phase. The mass spectral RDA reaction has already been discussed in detail (Chap. 6.8). 

Besides being of considerable commercial interest, Diels-Alder reactions are clean, well-characterized reactions that generally proceed in a single step through a pseudoaromatic transition state. There have been studies on the pressure effect on ionic reactions in SCFs by Zhang et al. (1996) who measured the rates of aryhnethyl cation ion-neutral reactivity in SCF. 

The Diels-Alder reaction is an important and widely used reaction in organic synthesis (Sauer and Sustmann, 1980), and in the chemical industry (Griffiths and Previdoli, 1993). Rate enhancement of this reaction has been achieved by the use of solvents such as water, surfactants, very high pressure, lithium amides, alkylammonium nitrate salts, and macrocyclic hosts (Sherman et ak, 1998). Diels-Alder reactions can be ran in neutral ionic liquids (such as 1-butyl-3-methylimidazolium trifluoromethanesulfo-nate, l-butyl-3-methylimidazolium hexafluorophophate, l-butyl-3-methylimidazolium tetrafluoroborate, and l-butyl-3-methylimidazolium lactate). Rate enhancements and selectivities are similar to those of reactions performed in lithium perchlorate-diethyl ether mixtures. 

Diets-Alder catalysis.2 This cation radical enhances the reactivity of a neutral or electron-rich eis-1,3-diene in Diels-Alder reactions. Thus 1,3-cyclohexadiene undergoes Diels-Alder dimerization only at temperatures around 200°. The presence of 5-10 mole % of this salt effects dimerization even at —78°, with the usual endo/ exo selectivity (5 1). It also permits facile condensation of 1,3-cyclohexadiene with a hindered dienophile such as 2,5-dimethyl-2,4-hexadiene (equation 1) the dimer of the former diene is a minor product (20% yield). 

Furan is readily hydrogenated, hence it is a source of commercial tetrahydrofuran (THF). Reaction with hydrogen sulfide over alumina produces thiophene. A recent patent describes a catalyst based on cobalt and molybdenum oxides supported on alumina for this reaction (105). Furan undergoes the Diels-Alder reaction with strong dienophiles. Hydrogenation of the product resulting from reaction with maleic anhydride, followed by hydrolysis and neutralization gives a herbicide, Endothall. 

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-plienyl-l-aza-2-cyanobuta-l,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Diliydro-4//-1,2-oxazines have been shown to be usefiil as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-l,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(f-butyldimethylsilyloxy)-l-azabuta-1,3 -diene (107) reacts with halobenzo-quinones, naphthoquinones, and A-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with A-(cinnamylidcnc)tritylaminc produces the 3,4-adduct whereas with A -(cinnamylidcnc)bcnzylidinc the 1,2-adduct is produced.190... 

As will become evident in this section, in the net transformation from reactant —s-product transformations many of the synthetically useful reactions involving >C=C<"+ are analogous to those involving neutral, un-ionized carbon-carbon double bonds (e.g. the Diels-Alder reaction, oxidation/reduction reactions, nucleophilic addition etc.). However, many of the reactions involving a neutral >C=C< often require the presence of an activating substituent in order to make the alkene more electron-deficient. In a sense, one-electron oxidation of an alkene to its radical cation provides a simple and unique mechanism for increasing the electrophilic (and, of course, radical) properties of... 

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