Electron-withdrawing-group Diels-Alder reaction

Extensive studies by Gorman and Gassman have shown that an allyl cation can be a 27r-electron component in a normal electron-demand cationic Diels-Alder reaction and, since a carbocation is a very strong electron-withdrawing group, the allyl cation is a highly reactive dienophile [19a, 21]. 

Activation of 2-aza-l,3-butadienes for inverse electron demand aza Diels-Alder reactions can also be achieved by introducing electron-withdrawing substituents. Thus, Barluenga s group has developed 3,4-bismethoxycarbonyl-2-aza-1,3-butadienes which undergo smooth intramolecular cycloadditions upon heating [278]. 

AAAcylimines, e.g., 4, are the most widely recognized and the most extensively investigated hetero-2-azadiene system capable of participation in Diels-Alder reactions, and comprehensive reviews have been published.7,71 In general, substituents X and Y are strongly electron-withdrawing groups and consequently the AAacylimines participate as electron-deficient partners in cycloaddition reactions with electron-rich dienophiles. Diels-Alder reactions of electron-deficient /V-acylimines with vinyl ethers, enamines, olefins, sulfenes, acetylenes, and the carbon-carbon or carbon-oxygen double bond of ketenes have been detailed.57 71 This 47t participation of electron-deficient AAacylimines does complement the ability of many simple AAacylimines to behave as 2ir dienophile components in Diels-Alder reactions with typical electron-rich dienes.6... 

In 2006, Bode and coworkers reported the first enantioselective inverse-electron-demand hetero-Diels-Alder reaction of enals 130 with a,(i-unsaturated imines 131 under the catalysis of carbene precatalyst 123 in combination with Hiinig s base [59]. A broad range of substrates were well tolerated to afford synthetically important dihydropyridinone products 132 in good yields with remarkable enantioselec-tivities (Scheme 38.38). The need to introduce electron-withdrawing groups for enals only lies within the increased electrophilicity of these substrates, which enhances the rate of their reaction with the nucleophilic catalysts. The observed... 

Hydrogen bonding of water to the activating group of (for normal-electron demand Diels-Alder reactions) the dienophile constitutes the second important effect". Hydrogen bonds strengthen the electron-withdrawing capacity of this functionality and thereby decrease the HOMO-LUMO gap... 

Note that the Diels-Alder reaction works best when there is an electron-withdrawing group (here CC>2Et) on the olefinic component. 

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. 

Dienophile (Section 14.5) A compound containing a double bond that can take part in the Diels-Alder cycloaddition reaction. The most reactive dienophiles are those that have electron-withdrawing groups on the double bond. 

The simplest dienophile, ethene, is poorly reactive. Electron-withdrawing and electron-donating groups, on the carbon atom double bond, activate the double bond in normal and inverse electron-demand Diels-Alder reactions, respectively. 

Diels-Alder reactions of butadienes 13 and 2,3-di-w-propylbutadiene 14 with [60]-fullerene 15 led to several fullerene derivatives [15-17] (Scheme 2.10). Dienes 13 and 14 bore electron-donating groups, but the reactions also occurred with electron-withdrawing substituents due to the sufficiently low-energy LUMO of Ceo-... 

A Diels-Alder reaction of arynes with 1,2,4-triazines 102 allows the preparation of isoquinolines substituted with electron-withdrawing groups in the nitrogen-containing ring. The isoquinoline-1-carboxylic esters bearing additional substituents are of particular interest because they are not readily available by the usual routes [100,101] (Scheme 2.42). 

The cationic moiety attached to the carbon-carbon double bond is a strong electron-withdrawing group that increases the dienophilic character of the double bond in the Diels Alder reaction. 

Simple imines are poor dienophiles and must be activated by protonation or by attaching an electron-withdrawing group to the nitrogen atom. Scheme 6.10 illustrates the Diels-Alder reactions of benzyliminium ion 25, generated in situ from an aqueous solution of benzylamine hydrochloride and commercial aqueous formaldehyde, with methylsubstituted 1,3-butadienes [22]. This aqueous Diels-Alder reaction combines three components (an aldehyde, an amine... 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

Figure 17.1 A general Diels-Alder reaction consists of a 4 + 2 cycloaddition between a diene and an alkene, often called a dienophile. The reaction rate and yield increase if the diene contains an electron-donating group and the alkene contains an electron-withdrawing group.

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

When aldehyde containing an electron-withdrawing group is employed, or when a Lewis acid promoter is present, C=0 double bonds can readily undergo Diels-Alder-type reactions. This process is referred to as the oxo Diels-Alder reaction, and it has been explored by Danishefsky and DeNinno35 for the synthesis of a wide range of saccharide derivatives. 

Electron-withdrawing groups attached to the dienophile accelerate the rate of the reaction, donating groups decrease it. For the diene, the opposite is true. Because of the high regiospecificity and the tolerance of a wide number of functional groups, the Diels-Alder reaction is of considerable synthetic importance. 

Cheng and coworkers142 reported the first Diels-Alder reactions of fullerenes with dienes having an electron-withdrawing group at C(l). The reactions with [60]fullerene proceeded at elevated temperatures to afford the corresponding adducts with moderate yields. The adducts appeared to be more stable than the adducts of electron-rich dienes. 

Niggli and Neuenschwander294 studied the reaction of fulvene (461) with cyclopen-tadiene. The main product fraction consisted of three 1 1 adducts, as illustrated in equation 138. Diels-Alder Adducts 462 and 463 resulted from attack of cyclopentadiene at the endocyclic and exocyclic double bonds of fulvene, respectively. The formation of 464 was rationalized by a [6 + 4] cycloaddition reaction followed by two [1,5] hydrogen shifts. It was stated that due to the absence of electron-donating and electron-withdrawing groups on both triene and diene, fulvene may have reacted via its HOMO as well as its LUMO. 

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