Reactions with electron-deficient dienes

It is also possible to observe [6 + 4] cycloadditions when the very electron-rich 6-dimethylaminofulvenes undergo reaction with electron-deficient dienes, thiophene dioxides86 and coumalic esters87, as well as the relatively electrophilic 1,3-dipole, benzonitrile oxide88. The frontier orbital picture here is somewhat more complex, in that the dimethylamino substituent causes the HOMO and SHOMO to be nearly degenerate78 (Fig. 29). In such a case, [6 + 4] cycloaddition again occurs, since now... 

The HOMO activation of dienophiles (reversed electron demand DA) was reported by Chen and co-workers [32]. They found that the catalytic reaction of crotonaldehyde with prolinol ether 46 resulted in formation of a 1,3-dieneamine 49 that selectively reacted as a dienophile on the terminal double bond in a reversed electron demand Diels-Alder reaction with electron-deficient dienes 48 to give access to highly diastereo- and enantioenriched cyclohexen derivatives 50 (Scheme 6.12). 

Diels-Alder cycloadditions involving norbomene 57 [34], benzonorbomene (83), 7-isopropylidenenorbomadiene and 7-isopropylidenebenzonorbomadiene (84) as dienophiles are characterized as inverse-electron-demand Diels-Alder reactions [161,162], These compounds react with electron-deficient dienes, such as tropone. In the inverse-electron-demand Diels-Alder reaction, orbital interaction between the HOMO of the dienophile and the LUMO of the diene is important. Thus, orbital unsymmetrization of the olefin it orbital of norbomene (57) is assumed to be involved in these top selectivities in the Diels-Alder cycloaddition. 

These phenomena can be illustrated by the cycloaddition reactions of fulvenes with electron-deficient a-pyrones. In general, the Diels-Alder reactions of electron-deficient dienes such as 458 with 6-alkyl substituted fulvenes favor addition across one of the endocyclic... 

Rigby and coworkers305,309 also performed metal mediated [6 + 4] cycloadditions of heterocyclic trienes and tropones with various dienes. In concurrence with the all-carbon trienes, the electronic nature of the diene partners generally had little influence on the cycloaddition efficiency. The only reported exceptions are the reactions of thiepin-1,1-dioxides. Lower yields were observed in the reactions involving electron-deficient dienes in comparison with the reactions with electron-rich dienes. The reaction of complex 514... 

Reaction of l-azirine-3-methylaciylates (155) with imidazoles and pyrazoles under mild conditions results in the formation of 2-aza-1,3-dienes (156), which are useful as dienes in hetero Diels-Alder reactions with electron-deficient dienophiles <99JOC49>. When the related methyl 2-aryl-2ff-azirine-3-carboxylate (157) was used as fee substrate, reaction with an amine induced a ting opening by addition of the amino group onto fee C=N bond followed by cleavage to provide enediamine 158 <99JCS(P1)1305>. 

Tetradehydrodianthracene undergoes 4 + 2-cycloaddition with electron-deficient dienes such as 1,2,4,5-tetrazines.263 The Diels-Alder reactions of [3.3 ortho-anthracenophanes witli A-(p-nitro, chloro, or methoxy-substituted phenyl)malehnides yield approximately equal quantities of inside and outside adducts.264 The photooxidation of bulky water-soluble 1,4-disubstituted naphthalenes with singlet oxygen yields both the expected 1,4- and the unexpected 5,8-endoperoxides.265... 

Synthetic methods for the preparation of dienes and enynes abound, yet the use of alkenyl iodonium salts offers distinct advantages. Their coupling reactions with electron-deficient alkenes and alkenyl- or alkynylstannanes constitute a valuable extension to the previously existing methodology, because of mild conditions, ease of operation, high stereoselectivity and good yields. The simplest reaction of this category is with unsaturated carbonyl compounds and requires palladium catalysis. 

The intramolecular Diels-Alder reaction promises to become widely used in the synthesis of natural products from reports of recent research (142-144). In natural alkaloid synthesis by a Diels-Alder reaction, an enamide was utilized as either a suitable dienophile or diene group. There exist numerous examples of bimolecular and intramolecular Diels-Alder reactions of enamides with various dienophiles as well as bimolecular (4 + 2) cycloadditions of enamines with electron-deficient dienes. On the other hand, there appear to be only few reports of the (4 + 2) cycloaddition reactions of enamides with unactivated dienes. 

The uncoordinated 3-vinylpyrrole complexes (e.g., 1133) resemble an electron-rich diene and, as such, undergo a facile Diels-Alder reaction with electron-deficient alkenes and alkynes under mild conditions, for example T-phenylmaleimide 1134 to generate, after decomplexation and oxidation, a highly functionalized indole 1135 in ca. 60% overall isolated yield (from pyrrole) (Scheme 221) <1996JA7117>. 

In contrast, treatment of the related 277-azirine-3-methylacrylate 785 with imidazoles and pyrazoles gave 2-aza-l,3-dienes 786 derived from a transient addition product (Scheme 189) <1999JOC49>. These dienes are useful in hetero-Diels-Alder reactions with electron-deficient dienophiles. 

Marko and co-workers applied chiral Yb catalysts to enantioselective Diels-Alder reactions of electron-deficient dienes (Table 10) [35]. When the reaction of 3-carbo-methoxy-2-pyrone with phenyl vinyl sulfide was conducted in the presence of THE (5 mol equiv. to Yb), the bicyclic lactone was obtained in 92% yield and in more than 95% ee (entry 5). Vinyl ethers could also be used as dienophiles, affording the corresponding products with excellent selectivities. 

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). 

In electron-demand Diels-Alder reactions, dienes are activated by electron-donating substituents, such as alkyl, -NR2, and -OR. Electron-rich dienes accelerate the reaction with electron-deficient dienophiles, as illustrated by the relative reactivity trend shown below. 

The heterocyclic double bond in simple indoles will take part in cycloaddition reactions with dipolar 4n components,and with electron-deficient dienes (i.e. inverse electron demand), in most reported cases, held close nsing a tetherf° a comparable effect is seen in the intermolecular cycloaddition of 2,3-cycloalkyl-indoles to ortfto-quinone generating a l,4-dioxane. ° The introduction of electron-withdrawing substituents enhances the tendency for cycloaddition to electron-rich dienes 3-acetyl-1-phenylsulfonylin-dole, for example, undergoes aluminium-chloride-catalysed cycloaddition with isoprene, " and 3-nitro-l-phenylsulfonylindole reacts with l-acylamino-buta-l,3-dienes without the need for a catalyst. Both 3- and 2-nitro-l-phenylsulfonyl-indoles undergo dipolar cycloadditions with azomethine ylides. ... 

Cycloadditions of iminium compounds with 1,3-dienes to afford Diels-Alder adducts seems to be a reaction of general applicability.46 On the other hand, simple electron-rich imino species are less reliable dienophiles. Some electron-rich imines will undergo Diels-Alder reactions under acid catalysis and thus are probably actually reacting as iminium salts. However, inverse electron demand [4 + 2] cycloadditions of neutral imines with electron-deficient dienes have been reported, as have additions to exceptionally reactive dienes (vide infra). 

Dimethylamino-2-phenyl-l-thiabuta-l,3-diene gives predominantly the endo-lsomer in reactions with electron deficient dienophiles at low temperature. At room and higher temperatures significant amounts of the more stable exo-adduct are formed and this is also the case when Lewis acids are present in the reaction mixture <97TL1033>. 

A number of cycloaddition reactions involving allene derivatives as dienophiles have been recorded. Allene itself reacts only with electron-deficient dienes but allene carboxylic acid or esters, in which a double bond is activated by conjugation with the carboxylic group, react readily with cyclopentadiene to give 1 1 adducts in excellent yield. For example, the allene 12 gave, with very high yield and selectivity, the cycloadduct 13, used in a synthesis of (-)-P-santalene (3.19). An allene equivalent is vinyl triphenylphosphonium bromide, which is reported to react with a number of dienes to form cyclic phosphonium salts. These can be converted into methylene compounds by the usual Wittig reaction procedure (3.20). 

Irradiation of a solution of thiepine 1,1-dioxide chromium complex (15) in the presence of diene (99), followed by metal decomplexation with oxygen provided [6 -I- 4] cycloadducts (100) <92TL5873, 93JA1382). The relative stereochemistry of the products (100) was shown to be derived from an endo transition state. The electronic character of the diene (99) appears to offer a moderate influence on reaction efficiency. For example, yields were uniformly lower for reactions involving electron-deficient diene partners relative to those employing electron-rich dienes (Equation (17)). 

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