Inverse electronic demand 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]... 

The total syntheses of fredericamycin 71 and camptothecin 72 made use of similar strategies. N-Sulfonyl-l-aza-1,3-butadienes in conjunction with electron rich dienophiles participated in the inverse electron demand Diels-Alder reaction to afford pyridines after treatment with base. 

Reaction of 2-(arylmethyleneamino)pyridines 335 and styrenes in the presence of hydroquinone afforded 2,4-diaryl-3,4-dihydro-2/f-pyrido[l,2-n]pyrimidines 336 by means of an inverse electron demand Diels-Alder reaction (95MI10). Reaction of 2-(benzylideneamino)pyridines 337 and chloroacetyl chloride gave 2-aryl-4//-pyrido[l,2-n]pyrimidin-4-ones 338 (97JMC2266). 

The inverse electron-demand Diels-Alder reaction is also accelerated by Lewis acids, but the successful application of chiral Lewis acids to this kind of Diels-Alder reaction is very rare. Marko and coworkers applied Kobayashi s catalyst system (Yb(OTf)3-BINOL-amine) to the Diels-Alder reaction of 3-methoxycarbonyl-2-py-rone with vinyl ether or sulfide [58] (Scheme 1.72, Table 1.29). A bulky ether or... 

Table 1.29 Asymmetric inverse electron demand Diels-Alder reactions catalyzed by 39 [58 ...

Interestingly, in the inverse-electron-demand Diels-Alder reactions of oxepin with various enophiles such as cyclopentadienones and tetrazines the oxepin form, rather than the benzene oxide, undergoes the cycloaddition.234 236 Usually, the central C-C double bond acts as dienophile. Oxepin reacts with 2,5-dimethyl-3,4-diphenylcyclopenta-2,4-dienone to give the cycloadduct 6 across the 4,5-C-C double bond of the heterocycle.234 The adduct resists thermal carbon monoxide elimination but undergoes cycloreversion to oxepin and the cyclopenta-dienone.234... 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

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. 

Sauer and Heldmann [97] recently reported an interesting application of ethynyltributyltin as an electron-rich dienophile in an inverse electron-demand Diels-Alder reaction with the electron-deficient triazine derivative 94. This method is interesting because the reaction is highly regioselective and the trialkylstannyl group is easily replaced by several groups under mild conditions, leading to substituted pyridines 95 (Scheme 2.41). 

Lewis-acid catalyzed inverse electron-demand Diels-Alder reactions between conjugated carbonyl compounds and simple alkenes and enolethers also allow dihydropyranes to be prepared. SnCU-Catalyzed cycloaddition of... 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

The study was extended to the inverse electron-demand Diels-Alder reaction between the (E)-l-carboalkoxybutadienes 21 with ethylvinylether 22 (Figure 5.1). No reaction was observed in any case either the starting materials were recovered or polymeric material was produced. 

Boger D. L. Heterocyclic and Acyclic Azadiene Diels-Alder Reactions Total Synthesis of Nothapodytine B. J. Heterocycl. Chem. 1998 35 1003-1011 Keywords inverse electron-demand Diels-Alder reactions, acyclic azadienes, synthesis of natural products... 

Merour J. Y., Piroelle S., Joseph B. Synthesis and Reactivity of lH-Indol-3(2H)-One and Related Compounds Trends Heterocycl. Chem. 1997 J 115-126 Keywords inverse electron-demand Diels-Alder reaction, indolone... 

Keywords inverse electron-demand Diels-Alder reactions, N-sulfonyl-1-aza-1,3-butadiene... 

Marko I. E., Evans G. R., Seres P., Chelle L, Janousek Z. Catalytic, Enantiose-lective, Inverse Electron-Demand Diels-Alder Reactions of 2-Pyrone Derivatives... 

Keywords asymmetric synthesis, stereochemistry, inverse electron-demand Diels-Alder reaction, rare earth metals... 

The inverse electron demand Diels-Alder reaction has also been used to provide expedient access to unnatural 6-carboline alkaloids from 1,2,4-triazines, prepared by microwave-assisted MCR [92]. One-pot reaction of an acyl hydrazide-tethered indole 73, 1,2-diketone and ammonium acetate in acetic acid provided triazines 74 (see Sect. 3.2, Scheme 22), bearing an electron-rich dienophilic indole moiety (Scheme 31). By carrying out the... 

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. 

The inverse electron demand Diels-Alder reaction of 3-substituted indoles with 1,2,4-triazines and 1,2,4,5-tetrazines proceeds in excellent yields both inter- and intramolecularly. The cycloaddition of tryptophan 124 with a tethered 1,2,4-triazine produced a diastereomerically pure cycloadduct 125 <96TL5061>. 

Intramolecular inverse electron-demand Diels-Alder reaction of iV-propargyl-2-(pyrimidin-2-yl)pyrrolidine provides an alternative route to pyridopyrrolizines. For example, heating of 130 to 170 °C in nitrobenzene affords the cyclized product with the loss of HCN <1992JOC3000> (Equation 9). The above reference includes molecular orbital (MO) calculations on relative reactivities in this series. 

The intramolecular inverse electron demand Diels-Alder reaction between the azadiene and the tethered alkene of compound 176 gives the corresponding benzoxazolo- and benzothiazolopyranopyridines. Terminal alkenes (RZ = H) give the tvr-products 177, whereas 1,2-disubstituted alkenes (R2 = Me or Ph) give the /ram-products 178 (Equation 46) <1995J(P1)1759>. 

The doubly protected indolinethiol 275 undergoes deprotection by treatment with silica gel at low pressure the intermediate heterodiene then reacts with the protected glucal 276 in an inverse electron demand Diels-Alder reaction to give the fused tetracyclic product 277 (Equation 96) <2003JOC7907>. 

An even more complex pathway involving inverse-electron-demand Diels-Alder reactions between imidazoles and 1,2,4-triazines linked by a tri- or tetramethylene... 

In work reminiscent of earlier studies by van der Plas <89T803, 89T5611>, Dehaen and co-workers illustrated how the electron deficient pyrimidine ring can be exploited in the intramolecular inverse electron demand Diels-Alder reactions of pyrimidine-tethered alkynes 102 <00SL625>. Under thermal conditions, pyridines 103 were produced in modest to excellent yields. 

Mark6 and colleagues178 studied the Eu(hfc)3 catalyzed inverse electron demand Diels-Alder reactions between (—)-pantolactone derived chiral a-pyrones 279 and vinyl ethers and thio ethers 280. This auxiliary proved superior to other auxiliaries in these reactions. The reactions generally proceeded with high yields, affording the endo adducts 281 with de values generally above 95%. The de proved independent of the chirality or achirality of the Lewis acid employed, as (+)-Eu(hfc)3, (—)-Eu(hfc)3 and Eu(fod)3 all afforded the same diastereomer with >95% de (equation 78, Table 13). 

A semiempirical AMI study of the inverse-electron-demand Diels-Alder reaction of 4-substituted 6-nitrobenzofurans with enol ethers and enamines favours a stepwise mechanism involving short-lived diradical intermediates. The inverse-electron-demand intermolecular Diels-Alder reactions of 3,6-bis(trifluoromethyl)-l,2,4,5-tetra-zine with acyclic and cyclic dienophiles followed by the elimination of N2 produce 4,5-dihydropyridazines, which cycloadd further to yield cage compounds. The preparation of jS-carbolines (90) via an intramolecular inverse-electron-demand Diels-Alder... 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

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. 

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