Inverse electron-demand Diels-Alder reaction

The Diels-Alder reaction, inverse electronic demand Diels-Alder reaction, as well as the hetero-Diels-Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illustrative. 

DIELS-ALDER REACTION, INVERSE ELECTRON DEMAND, 66, 142, 147, 148... 

A. Diels-Alder Reactions-Inverse Electron Demand... 

Diels-Alder reaction, inverse electronic demand Diels-Alder reaction, hetero-Diels-Alder reaction... 

Fluorine-substituted heterodienes are particularly prone to inverse electron demand Diels-Alder reactions with electron-rich dienophiles, as can be seen from the examples in equations 94-97 [113, 114, 115, 116, 117]... 

Conjugated oximes were converted to pyrazoles in a one-pot reaction by refluxing with hydrazine and iodine in ethanol. The process proceeds via an inverse electron-demand Diels-Alder reaction involving electron-deficient heterodienes and diimide species as dipolarophiles . ... 

The reactivity of the produced complexes was also examined [30a,b]. Since the benzopyranylidene complex 106 has an electron-deficient diene moiety due to the strong electron-withdrawing nature of W(CO)5 group, 106 is expected to undergo inverse electron-demand Diels-Alder reaction with electron-rich alkenes. In fact, naphthalenes 116 variously substituted at the 1-, 2-, and 3-positions were prepared by the reaction of benzopyranylidene complexes 106 and typical electron-rich alkenes such as vinyl ethers, ketene acetals, and enamines through the Diels-Alder adducts 115, which simultaneously eliminated W(CO)6 and an alcohol or an amine at rt (Scheme 5.35). 

This procedure describes the preparation of an electron-deficient heterocyclic azadiene suitable for use in inverse electron demand (LUMOd gpg controlled) Diels-Alder reactions with electron-rich dienophiles. 

This procedure describes the preparation and inverse electron demand (LUM0(jjene controlled/ Diels-Alder reaction of an electron-deficient diene. While extensive studies on the preparative utility of the normal (HOMOjjg controlled) Diels-Alder reaction have been detailed, few complementary studies on the preparative value of the inverse electron demand Diels-Alder reaction have been described. Table I details representative 3-carbomethoxy-2-pyrones which have been prepared by procedures similar to that described herein and Tables II and III detail their inverse electron demand Diels-Alder reactions with electron-rich dienophiles. 

Thiophenes can act as dienophiles in Diels-Alder reactions with electron-poor dienes such as hexachlorocyclopen-tadiene, tetrazines, or o-quinone monoimines. The masked o-benzoquinone 64 can undergo inverse electron demand cycloadditions with thiophene itself or simple derivatives such as 2-methyl-, 2-methoxy-, and 2,4-dimethylthiophene (Scheme 5) <2001TL7851>. Depending on the substitution pattern on the thiophene skeleton, different cycloadducts can be observed. The basic thiophene skeleton gives rise to a bis-adduct 65. By blocking the second double bond with a methyl or methoxy group, a 1 1 adduct 66 or 67, respectively, is obtainable in moderate yield. 

Neunhoeffer and Wiley (78HC226) discovered that 1,2,4-triazine served as a reactive, electron-deficient diene in inverse electron demand Diels-Alder reactions with electron-rich or strained olefins. Cycloaddition occurs exclusively across C-3/C-6 of the triazine nucleus and there is a strong preference for the nucleophilic carbon of the dienophile to be attached to C-3... 

The thermal [4+2] Diels-Alder cycloaddition reaction can be classified into three processes the normal Diels-Alder reaction of electron-rich dienes with electron-deficient dienophiles (HOMOdiene-controlled), the neutral Diels-Alder reaction and the inverse electron-demand Diels-Alder reaction of electron-deficient dienes with electron-rich dienophiles (LUMOdiene-controlled). 

Very electron poor dienes can undergo Diels-Alder reactions with electron-rich dienophiles in the inverse electron-demand Diels-Alder reaction. The dominant interaction in the TS of inverse electron-demand Diels-Alder reactions is between the LUMOdiene and the HOMOdienopWie-... 

Dienes containing heteroatoms such as N and O undergo inverse electron-demand Diels-Alder reactions with electron-rich dienophiles such as enol ethers and enamines. The relatively low energy of the heteroatom p orbitals dramatically lowers the energy of both the HOMOdiene and LUMOdiene-... 

The procedure describes the preparation and use of a reactive, electron-deficient heterocyclic azadiene suitable for Diels-Alder reactions with electron-rich, unactivated, and electron-deficient dienophiles. Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate, because of its electron-deficient character, is ideally suited for use in inverse electron demand (LUMOdiene-controlled) Diels-Alder reactions. Table I and Table II detail representative examples of the reaction of dimethyl 1,2,4,5-tetrazine-3.6-... 

Several examples exist of inverse electron demand Diels-Alder reactions involving electron-deficient sym-tetrazines acting as dienes. However, the neutral, electon-rich imino compounds involved in these cycloadditions do not generally e pear to be useful dienophiles with other types of dienes. 

The in situ photochemical generation of 1,2-dithioketones and -aldehydes including dithioglyoxal, 3,3-dimethyl-2-thioxobutanethial, and camphor dithioquinone was confirmed by the subsequent trap of the 1,2-dithiocarbonyl compounds in [4 + 2] cycloadditions. The 1,2-dithioketones and 1,2-dithioaldehydes exhibited a preference for 4ir participation in inverse electron demand (LUMOdlene controlled) Diels-Alder reactions with electron-rich dienophiles (Scheme 8-X).37... 

An extensively investigated and useful hetero-2-azadiene system capable of 4it participation in Diels-Alder reactions is the vinylnitroso compounds.75-78 The complementary addition of electron-withdrawing substituents to the 3 position of the vinylnitroso system enhances the rate of diene participation in inverse electron demand Diels-Alder reactions with electron-rich or neutral dienophiles (simple olefins).75,76 Table 9-IV summarizes a series of representative examples of the 47r participation of vinylnitroso compounds in Diels-Alder reactions, and an extensive review has summarized much of this work.5,75... 

Extensive reviews have summarized101a b and compiled101 the results of many of the studies to date, and Table 10-XI summarizes representative inter- and intramolecular Diels-Alder reactions of 1,2,4,5-tetrazines with carbon dienophiles. Extensive investigations of the participation of electron-deficient 1,2,4,5-tetrazines in inverse electron demand Diels-Alder reactions with electron-rich heterodienophiles have been described, and much of this work is summarized in Table 10-X1I. 

Simple a,/3-unsaturated aldehydes, ketones, and esters participate preferentially in inverse electron demand (LUMOdlcne controlled) Diels-Alder reactions with electron-rich, strained, or simple olefinic and acetylenic dienophiles.3 5 The thermal reaction conditions for promoting the [4 + 2] cycloadditions of simple 1-oxabutadienes (R = H > alkyl, aryl > OR), cf. Eq. (1), are relatively harsh (150-250°C), and the reactions are characterized by competitive a,/3-unsaturated carbonyl compound dimerization or polymerization. Usual experimental techniques employed to compensate for poor conversions include the addition of radical inhibitors to the reaction mixture and the use of excess 1-oxabutadiene for promoting the [4 + 2] cycloaddition. Recent efforts have demonstrated that Lewis acid catalysis and pressure-promoted reaction conditions28-30 may be used successfully to conduct the [4 + 2] cycloaddition under mild thermal conditions (25-100°C). 

Until recently, the reaction of a,/3-unsaturated esters with electron-rich olefins has been reported to afford cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate,108 and the first documented example of the 4v participation of an a,/3-unsatu-rated ester in a Diels-Alder reaction appears to be the report of Snider and co-workers of the reversible, intramolecular cycloaddition of 1-allylic-2,2-dimethyl ethylenetricarboxylates.142 Subsequent efforts have recognized that substitution of the a,/3-unsaturated ester with a C-3 electron withdrawing substituent permits the 4w participation of such oxabutadiene systems in inverse electron demand Diels-Alder reactions with electron-rich olefins. In the instances studied, the rate of the [4 + 2] cycloaddition showed little dependence on solvent polarity [ aeetomtnie/ cycio-hexane — 3, Eq. (15) j acctomtnic toiuene 10, Eq. (20)], and reactions generally... 

An extensive range of hetero-l-oxabutadiene systems containing nitrogen (Chapter 9) and sulfur (Chapter 8) have been investigated and have been found to participate as 4ir components of Diels-Alder reactions. Several reviews have treated aspects of this work.5-9 10 11 221 In summary, the incorporation of an additional heteroatom into the oxabutadiene system generally increases its electrophilic character and facilitates the 477-participation of the diene system in inverse electron demand Diels-Alder reactions with electron-rich dienophiles. This is especially evident in the studies of azaoxabutadiene systems (Chapter 9). 

Despite the early recognition that heterocyclic azadiene systems are typically electron-deficient,1 little effort has been devoted to the exploration of the potential participation of electron-deficient oxazoles in inverse electron demand (LUMOdiene controlled) Diels-Alder reactions with electron-rich or simple olefinic dienophiles. One study has demonstrated the potential of such investigations (Table 10-1, entry 26).34 Breslow and coworkers have adapted the oxazole olefin Diels-Alder reaction for the preparation of a tetrahydroquinoline-based analog of pyridoxamine with the stereochemically defined placement of a catalytic group [Eq. (2)].37b... 

There are a number of examples of substituted pyrroles participating as 4tt components of all-carbon Diels-Alder reactions.63 However, their reported participation as a 1- or 2-azadiene system in [4 + 2] cycloadditions are limited to selected pyrroles.64,65 Pentachloro-2//-pyrrole has been shown to participate in inverse electron demand Diels-Alder reactions with electron-rich dienophiles exclusively in the form of the 2-azadiene system, pentachloro-S/Z-pyrrole,64 and one example of an intramolecular Diels-Alder reaction of a substituted, in situ generated 3//-pyrrole has been described (Chapter 9, Section 2).65... 

The potential of reversing the diene/dienophile polarity of the normal Diels-Alder reaction was first discussed in the course of the early work on the [4 + 2] cycloaddition reaction Bachmann, W. E., and Deno, N. C. (1949). J. Am. Chem. Soc. 71, 3062. The first experimental demonstration of the inverse electron demand Diels-Alder reaction employed electron-deficient perfluoroalkyl-l,2,4,5-tetrazines Carboni, R. A., and Lindsey, R. V., Jr. (1959). J. Am. Chem. Soc. 81,4342. A subsequent study confirmed the [4 + 2] cycloaddition rate acceleration accompanying the complementary inverse electron demand diene/dienophile substituent effects Sauer, J., and Wiest, H. (1962). Angew. Chem. Int. Ed. Engl. 1, 269. 

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