Intramolecular aza-Diels-Alder reactions

This methodology has the potential to be generally applicable to the synthesis of various alkaloids that have a bridgehead nitrogen via the intramolecular aza-Diels-Alder reaction (Eq. 12.43).108... 

There are relatively few fully conjugated heterocycles within the scope of this chapter. Compound 7 is one of a number of similar structures which undergo an intramolecular aza-Diels-Alder reaction followed by extrusion of molecular nitrogen to give fused pyridine derivatives such as 8 (Equation 1) <2003T8489>. 

An intramolecular cyclization of iV-anilino- and iV-benzyl-substituted propargyl trimethylsilyl ethers with Lewis acid catalysis provides the quinolines and isoquinolines, respectively <20040L2361>. An intramolecular aza-Diels-Alder reaction has been used as a key step in the synthesis of luotonin (Scheme 69) <20040L4913>. An analogous reaction afforded the dihydroquinoline as a single diastereomer (Equation 132) <2000TL5715>. 

Bi(OTf)3, cyclic epoxides also react with amines, Me3SiN3, and Me3SiCl to afford the corresponding a-functionalized alcohols (Equation (82)).138,138a BiCl3 and Bi(OTf)3 catalyze aza-Diels-Alder reactions of A-arylimines with both Danishefsky s diene and dienophiles (Equation (83))139 and the intramolecular aza-Diels-Alder reaction of A-vinyloxypropyl-2-cyano-l-azadienes (Equation (84)).140... 

An intramolecular aza Diels-Alder reaction of as well electronically neutral N-aryl imines useful for the synthesis of novel tetrahydropyridine derivatives has been introduced by our group [268]. The reactive intermediate 3-43 exhibiting the 2-aza-l,3-butadiene subunit was generated in situ from the aldehyde 3-41 and the amino isoxazole 3-42 and led directly to the diastereomerically pure cycloadduct 3-44 (Fig. 3-14). In contrast to the reactions studied by Barlu-enga, the 2-aza-1,3-butadiene acts as electron-deficient component in this case. 

Theoretical and synthetical studies carried out by van der Plas et al. deal with intramolecular aza Diels-Alder reactions of co-alkynylpyrimidines [311, 312]. The substrate 3-71 initially formed a bridged adduct 3-72 upon heating with subsequent release of the fused pyridine derivative 3-73 by retro-Diels-Alder reaction (Fig. 3-22). 

An investigation concerning intramolecular aza Diels-Alder reactions of 3-(co-alkynyl)-l,2,4-triazines has been published by Taylor et al. [327] and trichloro-1,2,4-triazine has been introduced as novel triazine diene recently [328]. 1,2,4-Triazines are a useful alternative of 1,4-diaza-l,3-butadienes with regard to the aforementioned synthesis of pyrazines since Taylor s group has found them to undergo cycloadditions with nitriles followed by extrusion of nitrogen [329]. This reaction is noteworthy since it is a Diels-Alder reaction of both electron-deficient diene and dienophile. 

The in situ release of a reactive iminium ion by cycloreversion of an azanor-bornene [211, 212] and a subsequent intramolecular aza Diels-Alder reaction... 

Scheme 10. Intramolecular aza-Diels-Alder reaction with benzylamine hydrochloride...

This result shows both the strengths and the weaknesses of such intramolecular aza-Diels-Alder reactions. The stereochemical outcome is controlled by the tether and such considerations as endo/exo selectivity matter very little. The molecule must fold 110 so that the preferred transition state 111 has the newly formed carbocyclic ring (not the ring formed by the cycloaddition itself) in the best chair conformation 112. The reaction is useful only if you want the stereochemistry it naturally gives. 

Aza-Diels-Alder reactions, where the nitrogen is part of the diene component, have also featured prominently this year. Fowler and co-workers, in a continuation of their studies of the formation and trapping of 1-aza-dienes generated by thermal elimination of acetic acid from hydroxamic acid derivatives, have now described an application of the reaction to the total synthesis of the quino-lizidine alkaloid (-)-deoxynupharidine (288) (Scheme 25). Reaction to give (286) and (28 ) probably proceeds via exo, chair transition states where the major product (286) is derived from the transition state which has the methyl group on the connecting chain in an equatorial position. Kametani and co-workers have reported a useful extension to their earlier work on the Intramolecular aza-Diels-Alder reaction. Cycloaddition can now be carried out under much milder conditions than those previously described by using a trialkylsilyl trifluoromethanesulphonate as catalyst. BenzoCa ]-quinolizidine (290), for example, is obtained in excellent yield from the enamide (289). ... 

The Au(I)- or Ag(I)-catalysed intermolecular hetero-Diels—Alder cycloaddition of push-pull l,3-dien-5-ynes (76) with aldimines or silylaldimines (77) produced 5,6-dihydropyridin-2-ones (78) with high diastereo- and regio-selectivities (Scheme 24). A copper-catalysed intramolecular aza-Diels—Alder reaction has been used to produce dihydrochromeno[4,3-Mpyrrolo[3,2-/ quinolmes in good yields. The cinchonidine-derived quaternary ammonium catalyst, A-2, 3, 4 -trifluorobenzyl-0-benzylcinchonidinum bromide (79), catalysed the aza-Diels—Alder reactions between... 

The intramolecular aza-Diels-Alder reaction also occurs in aqueous media. This reaction gave fused ring system (Scheme 11). 

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