Heck-Diels-Alder cascades

Diels-Alder reaction of only the ( )-isomer ( )-78 occurred to give the tetracyclic 79, whereas (Z)-78 remained as such, probably due to steric interference of the methoxycarbonyl group. 

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In their pioneering work on the catalytic carbopalladation reaction of 1,2-heptadiene with phenyl iodide in the presence of a suitable base, Shimizu and Tsuji observed the formation of the corresponding substituted 1,3-dienes 62 via a / -hydride elimination from the 7z>allyl intermediate 61 [61]. Based on these observations, a three-component Heck-Diels-Alder cascade process has been developed by Grigg and co-workers [73]. A wide variety of aryl and heteroaryl iodides were used for the intermolecular reaction with dimethylallene to afford the corresponding 1,3-dienes. These subsequently react in situ with N-methylmaleimide to give the bicyclic adducts 63 (Scheme 8.30). 

Double and even triple Heck-Diels-Alder cascade reactions involving bicyclopropyli-dene and 1,4-diiodo- or 1,3,5-triiodobenzene, respectively, have been accomplished. In these sequences, the carbopaUadation across the highly strained alkene is followed by a cyclopropyhnethyl to homoallyl rearrangement with concomitant /3-hydride elimination to yield an allylidenecyclopropane, which subsequently undergoes a smooth [4 + 2] cycloaddition to furnish the spiro[5.2]octene moiety (Scheme 4). ... 

Scheme 8.5 Preferred Heck coupling with the tetrasubstituted alkene bicyclopropylidene (16) (a) single, (b) double, and (c) triple Heck-Diels-Alder cascade reactions [121, 122].

When the carbopalladation of the bicyclopropylidene is performed in the presence of methyl acrylate, the reaction takes a different course (Scheme 8.34) [79]. The 1,3-diene intermediate 75 reacts in situ with the dienophile to give the spiro[2.5]octane derivative 76. An extension of this cascade Heck-Diels-Alder reaction involving l,3-dicyclopropyl-l,2-propadiene as the alkene partner, an alkenyl or aryl halide and a dienophile has been reported [80]. 

These examples demonstrate that a selective Heck-Diels-Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28-30]. At 60 °C the cycloaddition was sufficiently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels-Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CC Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2OH) or allyl acetate 27 (R = CH2OAc) and dimethyl fumarate (28). 

Fuwa H, Sasaki M (2007) A new method for the generation of indole-2,3-quinodunethanes and 2-(A-alkoxycarbonylamino)-l,3-dienes. Intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic a-phosphoryloxy enecarbamates. Chem Commun 2876-2878... 

So-called domino or cascade reactions have become more and more important for the efficient synthesis of complex organic molecules [1211. In this respect methyl 2-chloro-2-cyclopropylideneacetate (1-Me) has been used as a dieno-phile to trap cyclic dienes which were produced by intramolecular Heck reactions in Diels-Alder cycloadditions. Thus, the spirocyclopropanated functionalized bicyclo[4.3.0lnonenes 248,250 (Fig. 11) were obtained from the bromo-diene 247 or enynes 249 in 56-83% yield (Scheme 71) [122,1231. 

The same authors also presented a completely selective three-component cascade reaction but of a slightly different type. By reacting 26 with a vinyl-stannane 27 (R = SnBus) in the presence of methyl acrylate or diethyl maleate, a sequential Stille-type [31] cross-coupling-Diels-Alder reaction took place, which only gave the desired products [30]. Since the Stille coupling proceeds without a base present, the dienophile does not participate in a Heck reaction, but only in a [4 + 2] cycloaddition with the initially formed electron-rich diene. 

Scheme 6 A cascade reaction consisting of a Heck coupling and a transmissive Diels-Alder reaction [37,38]...

Scheme 3-20 A cascade of two intramolecular Heck and a Diels-Alder reaction [172].

The intramolecular Heck reaction followed by a Diels-Alder cycloadditiont leading to bicyclo[4.3.0]nonene derivatives has been developed into a one-pot cascade reaction.f f Various 2-bromo-l,6-heptadienes including systems with heteroatoms in the tether between the double bonds were cyclized under palladium catalysis producing vicinal exodimethylenecycloalkanes, which reacted with dienophiles (either present... 

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