Intramolecular aza-Diels-Alder

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...

An ingenious new approach to the synthesis of pseudotabersonine (707) has been developed by Carroll and Grieco (391). Here the intermediate oxindole 708 was constructed by a remarkable process in which the anion from the precursor oxindole 709 was alkylated by Grieco s spiroaziridinium triflate 710. A-Benzylation of the product 711, followed by a reverse Diels-Alder fragmentation, then an intramolecular aza-Diels-Alder cyclization, gave the tetracyclic oxindole 708. Introduction of the three-carbon unit into position 2 in 70iB was achieved by condensation with 2-lithio-l,l-diethoxy-2-... 

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. 

Steinhagen H, Corey EJ (1999) A convenient and versatile route to hydroquinolines by inter-and intramolecular aza-Diels-Alder pathways. Angew Chem Int Ed 38 1928-1931... 

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). 

A unique tandem retro Diels-Alder/intramolecular aza Diels-Alder sequence was successfully applied to the synthesis of tylophorine 116 [38]. The requisite 2-azanorbornene derivative, 115, of phenanthryl amine 113 is prepared under the conventional conditions with cyclopentadiene and formalin. Exposure of a solution of 115 in o-dichlorobenzene containing camphorsulfonic acid (1 equiv) at 155-160°C in a sealed tube for 5 h provides a 35% yield of tylophorine (116) (Scheme 2.18). In addition, the piperidine... 

A total synthesis of pseudotabersonine (119) by Grieco et al. [39] utilizes both the aminoethylation (cf. Scheme 2.17) and tandem retro Diels-Alder/intramolecular aza Diels-Alder (cf. Scheme 2.18) protocols to construct spirofused indolizidine oxindoles, 122 and 123, which serve as precursors to dehydrosecodine 125 (Scheme 2.19). The pentacyclic backbone of the Aspidosperma alkaloid, pseudotabersonine, is postulated to be biogeni-cally [40] derived from a dehydrosecodine. 

The synthesis commences with alkylation of oxindole 120 with spiroaziri-dinium triflate 109, providing the 3,3-disubstituted 121 in 53% yield (cf. Scheme 2.17). Treatment of 121 with boron trifluoride etherate at 100°C in toluene initiates the tandem retro Diels-Alder/intramolecular aza Diels-Alder process, leading to spiro-tetracyclic oxindoles 122 and 123 (1.5/1) in 61% yield. Addition of 2-lithio-l,l-diethoxy-2-propene to oxindole 122 provides carbinolamine 124 (95%). Exposure of 124 to p-toluenesulfonic acid in acetone-water followed by treatment with excess triethylamine in acetonitrile at 80°C effects the biomimetic transformation to adduct 126, which possesses the pentacyclic carbon framework of pseudotabersonine. This unique two-step one-pot transformation generates the inherently unstable dihydropyridine portion of dehydrosecodine 125, which participates in an intramolecular reverse electron-demand Diels-Alder reaction, providing 126 in 50% yield. The total synthesis is completed by transformation of the formyl group into the requisite carbomethoxy unit followed by N-benzyl deprotection (Scheme 2.19). 

The intramolecular aza Diels-Alder cycloaddition is also a valuable tool for the synthesis of alkaloids as demonstrated by the stereocontrolled synthesis of ( )-lepadifor-mine 137 (Scheme 41.29). This tricyclic alkaloid has been isolated from several species of Clavenia and Polycitoridae sea squirts and is moderately cytotoxic toward various tumor cell lines and effective to block potassium ion channels. Initial attempts to perform the aza Diels-Alder reaction with the racemic imino-diene t-butyl ester 134 in toluene at temperatures up to 165°C did not lead to the observation of any cycloadducts but to double bonds isomerization products. The corresponding free carboxylic acid only suffered decarboxylation. The addition of trifluoroacetic acid to generate an imminium species was also unsuccessful. 

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