Diels-Alder reactions discovery

Keywords historical background, discovery of Diels-Alder reaction, discovery of orbital symmetry, conservation rule... 

Diels-Alder Reaction Dienophiles Difluoroallene Dioxoindoles Dioxolanyliums Discovery of Diels-Alder reaction Discovery of orbital symmetry conservation rule Diterpenes Domino Drtmane sesquiterpenes Compilation 0031, 9804, 9742, 9741. 9737, 9705, 9410, 9406, 9306, 9218, 9118 9126 9705 9833, 9604 9222 9222 0003 0033, 0024, 9835, 9014 9116... 

An extremely readable historic account describing in more detail the chemistry and the chemists involved in the discovery of Diels-Alder reaction has been published recently by Berson. ... 

Breslow immediately grasped the significance of his observation. He interpreted this discovery in terms of a hydrophobic effect Since in the Diels-Alder reaction. .. the transition state. .. brings together two nonpolar groups, one might expect that in water this reaction could be accelerated by hydrophobic interactions ". ... 

The Diels-Alder reaction is often quoted as an example of a reaction that is little influenced by the solvent. However, this is not fully justified, since particularly water can have a pronounced effect on the rate of this reaction. This was first noticed by E elte et al." in 1973 and rediscovered in 1980 by Breslow In the years that followed this intriguing discovery, it turned out that acceleration of Diels-Alder reactions by water is a general phenomenon that can ultimately result in up to 12,800 fold accelerations". Synthetic applications followed rapidly". ... 

Of all the work described in this thesis, this discovery is probably the most significant. Given the fact that the arene - arene interactions underlying the observed enantioselectivity of ftie Diels-Alder reactions described in Chapter 3 are also encountered in other organic reactions, we infer that, in the near future, the beneficial influence of water on enantioselectivity can also be extended to these transformations. Moreover, the fact that water can now be used as a solvent for enantioselective Lewis-add catalysed reactions facilitates mechanistic studies of these processes, because the number of equilibria that need to be considered is reduced Furthermore, knowledge and techniques from aqueous coordination chemistry can now be used directly in enantioselective catalysis. 

Soon after the discovery of the addition reaction between diene-ophiles and dienes which now bears their names, Diels and Alder extended their investigations to include potential heterocyclic dienes. In 1929 the first compound investigated, furan, was observed to combine with maleic anhydride, like butadiene in a typical Diels-Alder reaction, across the 2,5-positions yielding a 1 1 molar adduct... 

The basis of the Diels-Alder reaction developed in the twenties, and the contribution by Woodward and Hoffmann in the sixties, are two very important milestones in chemistry. Both discoveries were met with widespread interest the applications made are fundamental to modern society the tests which it has survived and the corollary predictions which have been verified are impressive. 

Asymmetric Diels-Alder reactions using a dienophile containing a chiral auxiliary were developed more than 20 years ago. Although the auxiliary-based Diels-Alder reaction is still important, it has two drawbacks - additional steps are necessary, first to introduce the chiral auxiliary into the starting material, and then to remove it after the reaction. At least an equimolar amount of the chiral auxiliary is, moreover, necessary. After the discovery that Lewis acids catalyze the Diels-Alder reaction, the introduction of chirality into such catalysts has been investigated. The Diels-Alder reaction utilizing a chiral Lewis acid is truly a practical synthetic transformation, not only because the products obtained are synthetically useful, but also because a catalytic amount of the chiral component can, in theory, produce a huge amount of the chiral product. 

The discovery that Lewis acids can promote Diels-Alder reactions has become a powerful tool in synthetic organic chemistry. Yates and Eaton [4] first reported the remarkable acceleration of the reactions of anthracene with maleic anhydride, 1,4-benzoquinone and dimethyl fumarate catalyzed by aluminum chloride. The presence of the Lewis-acid catalyst allows the cycloadditions to be carried out under mild conditions, reactions with low reactive dienes and dienophiles are made possible, and the stereoselectivity, regioselectivity and site selectivity of the cycloaddition reaction can be modified [5]. Consequently, increasing attention has been given to these catalysts in order to develop new regio- and stereoselective synthetic routes based on the Diels-Alder reaction. 

After the discovery of the remarkable acceleration of some Diels Alder reactions performed in water, a number of polar non-aqueous solvents and their salty solutions were investigated as reaction medium. This revolutionized the concept that the Diels-Alder reaction is quite insensitive to the effect of the medium and emphasized that a careful choice of the solvent is crucial for the success of the reaction. The polarity of the reaction medium is an important variable which also provides some insights into the mechanism of the reaction. If the reaction rate increases by using a polar medium, this means that the transition state probably has polar character, while the absence of a solvent effect is generally related to an uncharged transition state. 

The Diels-Alder reaction, probably the most widely used methodology in organic synthesis today, has contributed greatly to the development of mechanistic and theoretical chemistry. The recent discovery of a Diels-Alderase enzyme has provided insights into the mechanism of biosynthetic cycloaddition. 

Staudinger observed that the cycloaddition of ketenes with 1,3-dienes afforded cyclobutanones from a formal [2+2] cycloaddition [52] prior to the discovery of the Diels-Alder reaction. The 2+2 cycloadditions were classified into the symmetry-allowed 2+2 cycloaddition reactions [6, 7], It was quite momentous when Machiguchi and Yamabe reported that [4+2] cycloadducts are initial products in the reactions of diphenylketene with cyclic dienes such as cyclopentadiene (Scheme 11) [53, 54], The cyclobutanones arise by a [3, 3]-sigmatropic (Claisen) rearrangement of the initial products. 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

Finally, the discovery of exceptionally efficient catalysts for solvent-free enantioselective hetero-Diels-Alder reactions was made possible by a combinatorial approach.121 The object was to find a chiral titanium catalyst for the reaction of aldehydes (51) with Danishefsky s diene (91), with formation of cycloadduct (92) in >99% enantipurity (Equation (11)). 

The Diels-Alder reaction is a powerful synthetic process for constructing complex molecules. The reaction has been extensively studied and refined since its discovery in 1928.1 The most attractive feature of the Diels-Alder reaction is its simultaneous, regioselective construction of two bonds, resulting in the creation of up to four chiral centers with largely predictable relative stereochemistry at the bond formation sites. Theoretically, there are a total of 24 = 16 stereoisomers when atoms marked with an asterisk are all chiral centers (Scheme 5-1) therefore, the complete control of the reaction process to obtain enantiomeri-cally pure products has been the object of active research in many laboratories. 

In 1990, Choudary [139] reported that titanium-pillared montmorillonites modified with tartrates are very selective solid catalysts for the Sharpless epoxidation, as well as for the oxidation of aromatic sulfides [140], Unfortunately, this research has not been reproduced by other authors. Therefore, a more classical strategy to modify different metal oxides with histidine was used by Moriguchi et al. [141], The catalyst showed a modest e.s. for the solvolysis of activated amino acid esters. Starting from these discoveries, Morihara et al. [142] created in 1993 the so-called molecular footprints on the surface of an Al-doped silica gel using an amino acid derivative as chiral template molecule. After removal of the template, the catalyst showed low but significant e.s. for the hydrolysis of a structurally related anhydride. On the same fines, Cativiela and coworkers [143] treated silica or alumina with diethylaluminum chloride and menthol. The resulting modified material catalyzed Diels-Alder reaction between cyclopentadiene and methacrolein with modest e.s. (30% e.e.). As mentioned in the Introduction, all these catalysts are not yet practically important but rather they demonstrate that amorphous metal oxides can be modified successfully. 

All the chlorinated hydrocarbons belonging to this second group of compounds, once used in large amounts, have been banned for use in the U.S. since 1974. They are made by the Diels-Alder reaction, named after two chemists who won the Nobel Prize in 1950 for the discovery of this important reaction. The synthesis of the important insecticides chlordane, heptachlor, aldrin, dieldrin, and endrin are summarized in Fig. 20.4. 

Another important path of research, especially to organic chemists, resulted from a discovery by Woodward, Rosenblum, and Whiting at Harvard University in 1952 (128). These investigators noted the failure of ferrocene to undergo Diels-Alder reactions and its resistance to catalytic hydrogenation. They reasoned that because of its remarkable stability, ferrocene might behave like an aromatic substance. These suppositions proved to be the case, as ferrocene was readily acylated under Friedel-Crafts conditions to form acyl derivatives. Indeed, the name ferrocene was given to biscyclopentadienyliron because of its chemical similarity to benzene (128). 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

No scientific discovery seems to be totally new, as has been discussed superbly well by Berson (1992) with reference to the discoveries of the Diels-Alder reaction and the Woodward-Hoffmann rule. In the case of C60, the near misses by Iijima (1987) and the unpublished work by Chapman (Diederich 1992), are more pre-eminent examples of the precedence than those described above. 

The application of this principle has also led to the discovery of the first example of an endocyclic Diels-Alder reaction with a benzenoid hydrocarbon including dearomatization of the pyrene system the hydrocarbon 8 reacts with maleic anhydride to form the Diels-Alder adduct 9 [66]. 

In 1983, Jones et al. [104] reported on the photosensitized [4 + 2]-cyclodimeriza-tion of 1,3-cyclohexadiene. They found evidence for a tight complex as an intermediate of the Diels-Alder adducts rather than free radical cations. These findings extended an earlier work of Libman [109] but, however, left a decision open pro or against a triplex intermediate. In a series of papers, Schuster and coworkers elegantly extended these preliminary discoveries to its generalization as the Triplex-Diels-Alder Reaction . 

The discovery that chiral Lewis acids can catalyze the asymmetric Diels-Alder reaction is a major milestone for the scale up and practice of this reaction on an industrial scale. The use of such a catalyst obviates the need for a chiral auxiliary on the diene or dienophile. The vast majority of chiral auxiliaries that have been used in the Diels-Alder reaction are either not commercially available or are expensive. In addition, the chemical steps needed to attach and remove the chiral auxiliary increase the cost and complexity of the synthesis. Chiral catalysts may also be recovered or recycled, further decreasing cost.47 Research in this area is very active, and catalysts based on a number of metals (Table 26.1) have shown encouraging asymmetric induction.21 Our understanding of the role these catalysts play in the asymmetric induction of Diels-Alder reactions is increasing, and more general reagents should appear. 27-48 54... 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

The discovery chemistry approach to benzazepine (8) appears in Scheme 1. Benzyne Diels-Alder reaction of 10 was used in the original Wittig/Grignard protocol with cyclopentadiene and magnesium turnings in THF (45-64% yield).31 Methodological... 

A major breakthrough in the Diels-Alder reaction of oxabutadienes has been accomplished through the introduction of an electron-withdrawing group in the 3-position. In several papers we have demonstrated the usefulness of this concept which found broad acceptance after our discoveries. 

Many examples of the use of catalytic monoclonal antibodies for a variety of organic transformations and especially for Diels-Alder reactions have been described in the last years since its discovery by Lerner and Schultz [563], Recently, a hetero Diels-Alder reaction of an arylnitroso dienophile 9-4 and ( )-piperylene 9-3 to give the two regioisomeric cycloadducts 9-5 and 9-6 in the presence of a catalytic antibody has been published by Pandit and his group [564]. The most successful hapten used was the bridged compound 9-7 (Fig. 9-2). 

However, in the 1980s an extraordinary discovery was made. Water, a most unlikely solvent for most organic reactions, has a large accelerating effect on the Diels-Alder reaction. Even some water added to an organic solvent accelerates the reaction. And that is not all. The endo selectivity of these reactions is often superior to those in no solvent or in a hydrocarbon solvent. Here is a simple example. 

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