3.4- Pyridynes Diels-Alder reactions

The Boekelheide reaction has found utility in other synthetic methodology. An approach to 2,3-pyridynes made use of this chemistry in the preparation of the key intermediate 30. Treatment of 28 with acetic anhydride produced the desired pyridone 29. Lithiation was followed by trapping with trimethylsilyl chloride and exposure to triflic anhydride gave the pyridyne precursor 30. Fluoride initiated the cascade of reactions that resulted in the formation of 2,3-pyridyne 31 that could be trapped with appropriate dienes in Diels-Alder reactions. 

Diels-Alder reaction of the furoindole 544 with 3,4-pyridyne (1193), generated in situ via two different ways, led to a mixture of the two possible cycloadducts 1194 and 1195 in approximately equal amounts. Without purification, the crude adducts 1194 and 1195 were treated with basic sodium borohydride (NaBH4) to afford a separable mixture of ellipticine (228) and isoellipticine (1196) in 23% and 29% yield, respectively (527) (Scheme 5.197). 

Three years later, the same authors also reported a modified Moody approach for the total synthesis of ellipticine (228). In this route, an indolopyrone is used as a stable equivalent of indolo-2,3-quinodimethane in a Diels-Alder reaction with 2-chloro-3,4-pyridyne (1267) (723). 

The intermediates (66), (67), upon in situ oxidation, afford 2(or 3)-pyridynes or 2(or 3)-quinolynes <71JCS(C)3948> which are highly reactive in Diels-Alder reactions, as shown in Schemes 10 and 11 for syntheses of ellipticine (69), isoellipticine (70) (84JOC4518,92T10645), and furo[3,4-c]pyridine (72) (77TL1741). Nitrosation of the aminotriazolopyridines affords the parent triazolopyridines. 

Hetarynes (dehydroaromatic heterocycles) can also act as dienophiles in Diels-Alder reactions. 2 This capacity and the inherent regiochemical problems are illustrated by two syntheses of the alkaloid ellip-ticine, which both feature a [4 + 2] cycloaddition of 3,4-pyridyne (533) (Scheme 126). 2 The first approach used the triazenylcarboxylic acid (534) as a precursor for hetaryne (533), which then underwent an addition to pyranoindolone (535) spontaneous CCh extrusion of the initial cycloadducts (536 X = N, Y = CH) and (536 X = CH, Y = N) gave directly a 50 50 mixture of ellipticine (537) and its undesired regioisomer (538). 2 ... 

An intermolecular Diels-Alder reaction of 3,4-pyridyne has been used in a short synthesis of the important anticancer alkaloid eUipticine. In this case the diene is an a-pyrone the initial Diels-Alder adduct is not isolated since it spontaneously aromatizes by loss of carbon dioxide. Unfortunately, the Diels-Alder reaction is not regioselective and an equal amount of the product arising from the alternative direction of addition to 3,4-pyridyne is formed (Scheme 7.35). 

A more efficient synthesis of l,3-dimethyl-4//-furo[3,4-fcjindole 45 from 3-ethylindole was described by Gribble and colleagues (Scheme 17, equation 1) [94]. Whereas furoindoles 44 and (especially) 45 are air-stable colorless solids, the desulfonylated furoindoles (NaOH) rapidly decompose. Diels-Alder reactions of 45 with DMAD and A-phenylmaleimide gave the expected adducts in quantitative yield. The reaction of 45 with 3,4-pyridyne gave the Diels-Alder adducts in 38% yield. Subsequent conversion... 

May and Moody (52) have reported a full account of their Diels-Alder cycloaddition route to ellipticine (1) and isoellipticine (27) (Scheme 10). Conversion of indole (50) to 3-indole-2-propionic acid (56) with lactic acid was followed by a Plieninger cyclization to the pyranoindole 57. Reaction of 57 with 3,4-pyridyne (59), as generated from triazene 58, afforded equal amounts of ellipticine (1) and isoellipticine (27). Although the overall yield of 1 from indole is only 3%, the sequence involves only three steps. 

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