Diels-Alder reaction, synthetic methods

The triple bond in benzyne is strained and is a dienophile in Diels-Alder reactions. Alternative methods exist for the generation of benzyne in cycloadditions and other synthetic applications. In the following example, 6>-bromofluorobenzene is treated with magnesium in tetrahydrofuran (THF). When carried out in the presence of cyclohexadiene, a Diels-Alder reaction occurs. 

The most important pericyclic reaction in synthesis, indeed one of the most important of all synthetic methods, is the Diels-Alder reaction. We have seen this many times before. What are the clues for a Diels-Alder disconnection ... 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Literature articles, which report the formation and evaluation of difunctional cyanoacrylate monomers, have been published. The preparation of the difunctional monomers required an alternative synthetic method than the standard Knoevenagel reaction for the monofunctional monomers, because the crosslinked polymer thermally decomposes before it can revert back to the free monomer. The earliest report for the preparation of a difunctional cyanoacrylate monomer involved a reverse Diels-Alder reaction of a dicyanoacrylate precursor [16,17]. Later reports described a transesterification with a dicyanoacrylic acid [18] or their formation from the oxidation of a diphenylselenide precursor, seen in Eq. 3 for the dicyanoacrylate ester of butanediol, 7 [6]. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

The Diels-Alder reaction is of wide scope. Not all the atoms involved in ring formation have to be carbon atoms the hetero-Diels-Alder reaction involving one or more heteroatom centers can be used for the synthesis of six-membered heterocycles. The reverse of the Diels-Alder reaction—the retro-Diels-Alder reaction —also is of interest as a synthetic method. Moreover and most importantly the usefulness of the Diels-Alder reaction is based on its 5y -stereospecifi-city, with respect to the dienophile as well as the diene, and its predictable regio-and c ifo-selectivities. °... 

Immonium ion based synthetic methodology a novel method for the N-methylation of dipeptides and amino acid derivatives via retro aza-Diels-Alder reactions [93]... 

The first chapter presents the general aspects of the reaction Chapters 2-6 illustrate the various methods and their applications in organic synthesis. At the end of each chapter a list of graphically abstracted Diels-Alder reactions is presented to show selected synthetic applications of the specific methodology. The discussion of the various topics is not exhaustive because our aim has been to emphasize the synthetic potential of each method. Chapter 7 reports a list of books, reviews, monographs and symposia proceedings which have appeared since 1990 and an index of keywords to help the reader find a particular paper of interest. 

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. 

Denmark and coworkers have developed an elegant method for generating cyclic nitronates using nitroalkenes as heterodienes in the Diels-Alder reaction (Eq. 8.78). The synthetic utility of this reaction is discussed in Section 8.3. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

The hetero-Diels-Alder reaction is one of the most important methods of synthesis of heterocycles, yet as a potentially powerful synthetic tool it has found relatively little general use. Microwave irradiation has been used to improve reactions involving heterodienophiles and heterodienes of low reactivity. 

A convenient synthetic method for 1,2,3-triazoles unsubstituted at C-4 and C-5 utilizes a reaction of azides with norbornadiene, for example, Scheme 29 <2004JOC1081>. The process is performed in refluxing dioxane. In the first step, norbornadiene undergoes 1,3-dipolar cycloaddition to glucose-derived azide 225 to give triazoline 226. The following retro Diels-Alder reaction results in the elimination of cyclopentadiene to furnish triazole derivative 227 in 79% yield. 

Since its recognition and systematic exploration by Otto Diels and Kurt Alder in the 1920s, the Diels-Alder reaction motif (5.84b) has provided one of the most powerful tools of organic synthesis. The Diels-Alder reaction led directly to the dramatic pre-World War II development of the chemical industry for production of synthetic rubber and other polymeric materials. Today, the commercial impact of Diels-Alder methods extends to virtually all areas of agricultural, pharmaceutical, and natural-products chemistry. 

The reactions include an unusual Diels-Alder reaction and a very useful synthetic method, the dechlorination of polychlorinated compounds. At the present time this procedure is the best one available for the removal of chlorine from an organic molecule. The end product, 7,7-dimethoxybicyclo[2.2.1]heptene, is an interesting and useful intermediate in bicyclic chemistry it has a reactive double bond and a protected carbonyl group in the 7-position. 

As a part of a broad study dealing with the development of synthetic methods for polycyclic aromatic compounds, Minuti and colleagues77 prepared some [5]phenacenes and fluorenoanthracenes via Diels-Alder reactions between dienes such as 59 and several activated dienophiles. Oxidation of the primary adducts with DDQ afforded the desired polycyclic aromatic compounds. Equation 21 shows the reaction between 3,4-dihydro-1-vinylanthracene (59) and in situ generated 2-inden-l-one (60) which afforded a 3 1 mixture of regioisomers 61 and 62 with 51% overall yield. 

The Diels-Alder reaction is one of the most powerful and versatile carbon-carbon bond-forming methods available to synthetic organic chemists attempts to isolate enzymes that catalyze such a process have been unsuccessful. Therefore, the acceleration of this reaction by an abzyme has been an important landmark in the field of catalytic antibodies and of considerable potential for chemical synthesis. 

One of the efficient method for constructing carbohydrates is the Diels-Alder reaction, which gives a variety of important synthetic intermediates for the synthesis of cyclitol derivatives. We therefore were interested in the development of asymmetric Diels-Alder reaction by the use of chiral titanium reagents. 

The most important synthetic methods involve condensation of hydrazine, hydroxylamine or hydrogen peroxide with a 1,4-oxygenated carbon chain, and these procedures are particularly useful for the preparation of pyridazines and 1,2-oxazines. Other methods include Diels-Alder reactions of a diene with an azo or nitroso compound. 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Diels-Alder reactions of thioketones are well documented in the literature471, however, since Schaumann published his review1, advances have been recorded in the cycloadditions with thioaldehydes due, mainly, to the development of new synthetic methods (Section III) and techniques (FVT), and therefore the reactions with aldehydes will be highlighted473. 

Efficient synthetic methods have been developed for the synthesis of 4-functionalized quinolines mediated by triflic acid.703 Electron-rich, highly reactive ethynyl ketene-S,5-acetals react readily with arylamines and aldehydes in an aza-Diels-Alder reaction to afford the desired products [Eq. (5.256)]. Arylimines and ethynyl ketene-S,5-acetals react similarly (60-70% yields). 

The 1,3-dipolar reaction (13DPR), whether concerted or not, undoubtedly rivals Diels-Alder reactions in ubiquity as well as synthetic utility [69], and its synthetic potential is still far from being exhausted. Both inter- and intramolecular 1,3-dipolar cycloadditions represent an efficient method for the... 

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