Hetero Diels-Alder reactions defined

Jorgensen et al. [84] studied how solvent effects could influence the course of Diels-Alder reactions catalyzed by copper(II)-bisoxazoline. They assumed that the use of polar solvents (generally nitroalkanes) improved the activity and selectivity of the cationic copper-Lewis acid used in the hetero Diels-Alder reaction of alkylglyoxylates with dienes (Scheme 31, reaction 1). The explanation, close to that given by Evans regarding the crucial role of the counterion, is a stabilization of the dissociated ion, leading to a more defined complex conformation. They also used this reaction for the synthesis of a precursor for highly valuable sesquiterpene lactones with an enantiomeric excess superior to 99%. 

This three-component reaction as the key step of this synthesis is called a domino-Knoevenagel-hetero-Diels-Alder reaction. Domino reactions are defined as processes of two or more bond forming reactions in which a subsequent transformation takes place by virtue of the functionalities introduced in a former transformation.2,16 The tetrahydrocarbolinaldehyde 11 first reacts in a Knoevenagel type condensation with Meldrum s acid 14 and ethyleneammonium diacetate 41 as the catalyst to oxabutadiene 44 which then undergoes a Diels-Alder reaction with enol ether 13. 

The emphasis in this work is on the scope and preparative synthetic utility of the hetero Diels-Alder reaction. No attempt has been made to carefully define or delineate the important mechanistic questions, many of which are as yet unanswered, of the various [4 -I- 2] cycloaddition reactions other than to try to provide a rationale for the facility with which the cycloadditions proceed and to provide a basis for the stereo- and regio-chemical observations. We have purposely excluded reactions of singlet oxygen as a dienophile, since extensive surveys are available elsewhere. Many miscellaneous heterodienophiles and heterodienes have not been covered if in our opinion they are not of general synthetic value. A comprehensive treatment of all recorded hetero [4 + 2] cycloadditions is beyond the scope of this monograph. However, we do hope to provide a broad survey of this reaction type as it exists today in order to furnish a foundation for continued development. 

Hetero substituted 2-cyclopropylideneacetates are ring-strain activated acrylates, highly reactive dienophiles in Diels-Alder reactions, but also powerful Michael acceptors. The reactivity of these compounds is enhanced by the same strain release in the Diels-Alder cycloadditions as well as in the 1,4-additions, and indeed the borderline between tandem Michael-cyclization and Diels-Alder-type cycloaddition is not well defined in many cases. 

Cocyclotrimerization, if applied to 1,5-hexadiynes 7, leads to benzocyclobutenes 8. After smooth thermal ring opening, these give highly reactive ort/io-quinodimethanes 9, which can be trapped by Diels-Alder reaction with an alkene or hetero-carbon multiple bond. If these dienophiles are in a side chain of the primary diync, the conversion leads in a one-pot version to carbo- and heterocyclic polycyclic systems with defined trans stereochemistry at the newly... 

Hetero-intramolecular Diels-Alder reactions are defined here as those of substrates with a heteroatom (i.c., not carbon or hydrogen) in either the diene or the dienophile, or both. The present discussion has been subdivided according to the location of the heteroatom in either of the reacting 7t-systems. 

The Diels-Alder reaction is defined as a [4-1-2] cycloaddition between a conjugated diene and a substituted dienophile (alkene or alkyne) to form a (hetero-)cyclohexene system. Based on the electronic effects of the substituent on the diene and dienophile, Diels-Alder reactions can be classified as normal electron-demand (electron-rich diene reacts with electron-deficient dienophile) or inverse electron-demand (iEDDA, electron-deficient diene reacts with electron-rich dienophile) reactions (Scheme la). In a normal electron-demand Diels-Alder reaction, the electron-deficient dienophile, typically a Michael acceptor, is likely to be attacked by endogenous nucleophiles such as free amino and thiol groups in vivo. For this reason, the use of this reaction in bioorthogonal chemistry apphcations poses a challenge. 

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