Inverse-electron-demand Diels-Alder

The reversibility of the conventional Diels-Alder reaction makes it a prime candidate for the synthesis of smart materials that exhibit a temperature-dependent transition between two physical properties (such as viscosity or color). However, many applications (such as biological labeling) require irreversible conjugation chemistry that also is very fast under mild and dilute reaction conditions. Eor such purposes, the inverse electron-demand Diels-Alder (IVED-DA) reaction between electron-deficient tetrazine derivatives and various alkenes is incredibly efficient. 

The reaction of 2 equivalents tetrazine (30 pM) with Trx-ene (15 pM) in aqueous media resulted in complete conversion into the expected Diels-Alder adduct within 5 min under ambient temperature. However, in a model reaction in which tran -cyclooctene and 3,6-di-(2-pyridyl)-s-tetrazine were reacted in a 1 1 ratio and in low micromolar concentrations (5 pM) 40 min was required to attain quantitative conversion, thus further illustrating the extremely efficient and rapid nature of the transformation. Curiously, tetrazines bearing additional functionality were also synthesized, however not utilized in conjugation studies. 

Furthermore, experiments in which model reactions were performed in cell media and in cell lysate produced 80% yield of adduct (analyzed by ESI-MS against an internal standard), indicating that the reaction is tolerant to a broad range of biological functionality. In spite of these encouraging results, 3,6-di-(2-pyridyl)-5-tetrazine was also observed to undergo 

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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... 

The inverse electron demand Diels-Alder [4 + 2] cycloadditions of methyl 1,2,4-triazine-3-carb-oxylates 36 (cf. Section B.2.2.) with cyclopropene followed by loss of nitrogen from the unstable cycloadducts 37 provide useful access to 4//-azepine-2-carboxylates 38.83-85... 

The inverse electron-demand Diels-Alder cycloaddition of ethyl l//-azepine-l-carboxylate (1) with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylatc (36) yields the C4 —C5 adduct 37.266... 

Triazine (38) is ideal for inverse electron-demand Diels-Alder cycloadditions, for example, with azulene to give a l,4-bis(CF3)phthalazine (89CB711). A rare example of the synthesis of a five-membered heterocycle originating from [4 + 1] cycloaddition followed by [4 + 2] cycloreversion was reported using (38). The intermediate tetraazanorbomadienimine (39) is highly strained and eliminates N2 [82AG(E)284]. 

V-Acyliminium ions act as dienophiles in [4 + 2] cycloaddition reactions with conjugated dienes13, while A-acylimimum ions that (can) adopt an x-cis conformation are able to act as heterodienes in an inverse electron demand Diels-Alder process with alkenes or alkynes3 (see Section D. 1.6.1.1.). 

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. 

Whereas electronically activated 2-pyrones can react thermally in both normal and inverse electron-demand Diels-Alder cycloaddition, 2-pyrone by itself requires thermal conditions that are so vigorous that they cause spontaneous extrusion of carbon dioxide from the bicyclic cycloadduct [61]. 

Lee L., Snyder J. K. Indole As a Dienophile in Inverse Electron Demand Diels-Alder and Related Reactions Adv. Cycloaddit. 1999 6 119-171... 

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... 

Posner G. H., Anjeh T. E. N., Carry J. C., French A. N. A New and Efficient Asymmetric Synthesis of an A-Ring Precursor to Physiologically Active 1-a-Hydroxyvitamin D3 Steroids Proc. - NOBCChE 1994 21 383-389 Keywords inverse electron-demand Diels-Alder cycloadditions, (S)-lactate and Lewis acids (-)-Pr(hfc)3 with benzyl vinyl ether... 

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>. 

INVERSE ELECTRON-DEMAND DIELS-ALDER CYCLOADDITION OF A KETENE DITHIOACETAL. COPPER HYDRIDE-PROMOTED REDUCTION OF A CONJUGATED ENONE. 9-DITHIOLANOBICYCLO[3.2.2]NON-6-EN-2-ONE FROM TROPONE... 

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