Inverse electron demand Diels-Alder cycloaddition

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]. 

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]. 

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... 

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... 

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. 

The dienophilic character of 1//-azepines is demonstrated by the ease with which they enter into inverse electron-demand Diels-Alder cycloadditions with electron-poor dienes. 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

Heterocyclic azadienes like di- and triazines have been used in the synthesis of pyridine rings. In general terms the reaction involves a regiospecific inverse electron demand Diels-Alder cycloaddition between the heterocycle and the enamine 280 followed by elimination of HCN (diazines) or N2 (triazines) and an amine from the primary cycloadduct 281 or 283, respectively, to give pyridines 282 and 284 (equation 61). At least in one case the latter type of intermediate has been isolated and fully characterized148. 

Significantly, the oxygenation pattern found in the two aryl groups, as in 24, would be expected to increase the nucleophilic character of the acetylene and improve what is a typically poor reactivity of alkynes toward 1,2,4,5-tetrazine derivatives <65CB1435> for an inverse electron demand Diels-Alder cycloaddition. 

R Inverse Electron Demand Diels-Alder Cycloaddition of a Ketene... 

Inverse-electron-demand Diels Alder cycloaddition has been used to synthesize trifluoromethyl-substituted pyrido[3,4-r/]pyridazines from 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine164 (see Section C.5.2.5.1.). 

The excellent dienophilic character shown by thiocarbonyl compounds in inverse-electron demand Diels-Alder cycloadditions has been utilized in the synthesis of 1,3,4-thiadiazines (Scheme 41)... 

Inverse Electron Demand Diels-Alder Cycloaddition of a Ketene Dithioacetal. Copper Hydride-Promoted Reduction of a Conjugated Enone. 9-Dithiolanobicyclo[3.2.2]non-en-2-one from Tropone. 

Further, A -alkyl-l,2,4-triazinium salts proved to be appropriate compounds for intramolecular inverse electron demand Diels-Alder cycloaddition reactions. Indeed, l-ethyl-5-phenyl-l,2,4-triazinium tetrafluoroborates bearing acetylenic... 

Examples of reactions in which the 2,3-bond acts as a dienophile in an intramolecular inverse electron demand Diels-Alder cycloaddition have also been recorded. The diester (54b) was more reactive than (54a), as would be expected (Equation (137)) <92JOC5285>. 

A variety of azadienes have been shown to participate in inverse electron demand Diels-Alder cycloadditions [10,11]. A few examples of such reactions with indoles as the dienophiles have been recently reported. 

Racemic pyrone sulfoxide (254), an electrophilic diene, has been reported [13,192,193] to undergo an inverse electron demand Diels-Alder cycloaddition with 1,1-dimethoxyethylene to give the major cycloadduct (255) in high yield under mild conditions, and with good stereoselectivity (Scheme 5.82). The cycloadduct... 

Bode, et al. developed a highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral A-heterocyclic carbenes. Scheme 3.28 [43]. Reactions of alkyl fra -4-oxo-2-butenoate 80 with A-sulfonyl imines 81 and catalyst 82 (10-15 mol%), DIPEA (10 mol%) in toluene-THF (10 1) at room temperature afforded the dihydopyridinones 83 in excellent diastereo- and enantioselectivity (>50 1 cw-diastereoselectivity, 99% ee). The LUMO -controUed inverse electron demand Diels-Alder cycloaddition was facilitated by NHC-carbene catalyst 82. Similar reactions without the catalyst would require high pressure (12 bar) or high temperature. The high cw-diastereoselectivity which would arise from (Z)-enolate reacting with the dienophile is rationalized as depicted in Scheme 3.28. 

Inverse electron-demand Diels-Alder cycloaddition (lEDDA)... 

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