Intramolecular inverse electron demand

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>. 

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. 

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... 

Table 4 Intramolecular Inverse electron demand DIels-Alder reaction of vinyl sulfonamides...

Partially hydrogenated pyrrolopyridines have been prepared through a sequence that includes an alkynyl-substituted pyrimidine ring. An initial intramolecular inverse electron demand Diels-Alder reaction is followed by a cycloreversion to form a dihydropyrrolopyridine. The pyrimidine ring is generated in four steps starting with an alkynyl carboxylic acid (Scheme 7) <2004JOC9215>. 

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]

Reactions of 3-hydrazino-l,2,4-triazin-5-one derivatives with carbonyl compounds to give triazolotriazine derivatives have been reported <03KGS1376>. Intramolecular inverse electron demand cycloadditions of 2-substituted imidazoles with various 1,2,4-triazines produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-[Pg.387]

In 2002, Bodwell and Li reported an elegant and efficient total synthesis of strychnine based on an intramolecular inverse-electron-demand Diels-Alder reaction that involves a pyridazine as diene. The required cyclophane 91 was built up via hydroboration of A-[2-(l-allyl-l/7-indol-3-yl)ethyl]-6-iodopyridazin-3-amine (90) followed by an intramolecular sp —sp coupling reaction [55]. 

High yield intramolecular inverse-electron-demand [4 -I- 2] cycloadditions have been noted for... 

Preparation of 5-amino-6-oxo-l,6-dihydro-1,2,4-triazine-3-carboxylic acid derivatives and the synthesis of compound libraries thereof have been reported <04TL2791>. Intramolecular inverse electron demand Diels-Alder reactions of imidazoles with 1,2,4-triazines have been described as a new route to obtain l,2,3,4-tetrahydro-l,5-naphthyridines and related heterocycles... 

Andibenin B (117) is a highly oxidized meroterpenoid produced by the fungus Aspergillus variecolor. On the basis of the biosynthetic study,it was proposed that a plausible intermediate 115 from Claisen rearrangement of 114 affords the adduct 116 via the intramolecular inverse-electron demand [4 - - 2] cycloaddition as shown in Scheme 19(b). In this case, an enzyme catalyzes the cyclization of the terpene part on intermediate 114 derived from farnesyl diphosphate, and benzoates might provide the reactive dienophile 116. 

Intermediate 50 was subsequently heated under reflux in triisopropylbenzene (232 °C) for 1.5 to 20 h to provide the basic canthine skeleton 51. Recently, Lindsley et al. reported a rapid MW-mediated procedure for synthesis of 51 [95]. This reaction, performed in a monomode MW reactor at 180 °C, required a reaction time of only 5 min. Even more interesting, treatment of the acryl hydrazide-tethered indole input, with benzil in the presence of 10 equiv. NH4OAC delivered not only the expected triazine 50 but also, directly, the 1,2-diphenyl canthine derivative 51 (Scheme 17.37, reaction path b). The products were formed in a 9 1 ratio of 50 and 51, respectively. In the one-pot reaction, the indole underwent a three-component condensation to generate 50 followed by an intramolecular inverse-electron-demand Diels-Alder reaction and subsequent chelotropic expulsion of N2 to generate the 1,2-diphenyl canthine 51. 

Intramolecular inverse electron demand Diels-Alder reactions of 1,2,4-triazines 63 and 65 have been used to generate the benzo[c][2,7]naphthyridone system 64 <97H(45)11>. 

The intramolecular inverse electron demand Diels-Alder reaction between imidazoles and 1,2,4-triazines linked by trimethylene or tetramethylene tethers from the imidazole N-1 position to the triazine C-3 proceeds smoothly on heating in triisopropylbenzene to give l,2,3,4-tetrahydro-l,5-naphthyridines 178 or 2,3,4,5-tetrahydro-17/-pyrido[3,2- ]azepines 179 in good yields (Scheme 110). The reaction can also be promoted by microwave irradiation <2004JOC7171>. 

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>. 

To generate naphtho[2,l-c]chromenes 23, the ort/to-hydroxylated 3-arylphthalazines were treated with different propargyl bromides to yield the respective propargyl ethers, which were then exposed to reaction conditions, conducive to an intramolecular inverse-electron-demand Diels-Alder reaction (Scheme 14). The propargyl ethers were stirred in... 

Atroposelective cycloaddition reactions of A-2-(r-butylphenyl)- and A-2,5-(di-r-butylphenyl)-maleimide show good to excellent stereoselectivities and the high rotation barriers prevent cycloadducts from interconverting. The stereospeciflc hetero-Diels-Alder reaction of o-quinone methides (80) with o-quinones (79) in MeOH at room temperature produce the 4a,8-di(hydroxymethyl)chromane derivatives (81) and (82) in high yields (Scheme 29). The intramolecular inverse-electron-demand Diels-Alder reaction of o-quinone methides (84) derived from 2-(l-hydroxy-5-alkenyl)phenol derivatives (83) produces l,2,3,3a,4,9b-hexahydrocyclopenta[c][l]benzopyrans (85) under mild acidic conditions (Scheme 30). The Diels-Alder reactions between dimethyl-cyclohexadiene derivatives and di-(-)-menthyl acetylenedicarboxylate exhibit modest diastereoselectivity. ... 

Recently pyrimidine substituted alkynes 476 were subjected to intramolecular inverse-electron-demand hetero-Diels-Alder reaction with extrusion of HCN affording fused fluorinated pyridines 478. The reaction proceeds at high temperatures in sealed tubes for small amount of the starting materials [256] or as scalable flow process [257] (Scheme 89)... 

Scheme 89 Intramolecular inverse-electron-demand hetero-Diels-Alder reaction...

Martin RE, Morawitz F, Kutarii C, Alanine AI, Alker AM (2012) Synthesis of annulated pyridines by intramolecular inverse-electron-demand hetero-Diels-Alder reaction under superheated continuous flow conditions. Eur J Oig Chem 1 47-52... 

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