Subject Heck reaction

To illustrate the utility of the Heck reaction in organic synthesis, we will address a few of the many spectacular achievements reported thus far. For a much more thorough treatment of this important subject, we direct the reader s attention to a recent review by de Meijere and Meyer.12a... 

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

The Heck reaction is a synthetically powerful reaction wherein a carbon-carbon bond is formed between two sp hybridized carbon atoms. The syn nature of the addition of vinyl-aryl palladium species to carbon-carbon double bond precludes a syn p-hydride elimination for cyclic olefins. As a result, a new chiral center is formed. Shibasaki and Vogl provided a comprehensive review of this subject in 1999 440 Overman and Donde reviewed the intramolecular version of this reaction in 2000. Pfaltz and co-authors specifically reviewed this reaction using PhosOx ligands. ... 

Heck in one of his first papers already demonstrated the feasibility of applying the palladium-catalyzed crosscoupling of aryl and alkenyl halides with alkenes repetitively on appropriate oligofunctional substrates. For example, twofold coupling of 1,4-diiodobenzene with styrene furnished 1,4-distyrylbenzene in 67% yield (Scheme 1). Since then, a large number of ortho-, meta-, and / r< -dihaloarenes and -heteroarenes have been subjected to twofold Heck reactions with various alkenes (Schemes 2-4). 

Whilst, not unexpectedly, the secondary amide 38 failed to undergo a 6-exo trig addition with palladium(0) complex, the corresponding tertiary amide 39 did so, when subjected to Heck reaction conditions, to furnish styrene 40 in good yield. 

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). 

In an example illustrating an approach to tryptamines, the aniline derivative 98, which is available by a Heck reaction involving the corresponding o-iodoaniline, was subjected to rhodium-catalyzed hydroformylation leading to the target indole 99 via the intermediate 100 (Equation 26) <1997JOC6464>. 

Danishefsky and co-workers exploited a 6-exo intramolecular vinylic Heck substitution reaction en route to a total synthesis of ( )-FR-900482 (76) (Scheme 6-12) [26]. The efficient conversion of aryl iodide 70 to tetracycle 71 is illustrative of the impressive functional-group tolerance displayed by the Heck reaction. During the development of this synthesis, attempts were made to introduce the oxygenation present at C —13 at an earlier stage [27]. Enol ethers 72 and 74 were prepared and subjected to Heck conditions. 

Overman s group [67] enlisted an intramolecular Heck reaction to form a quaternary center in their synthesis of gelsemine. When the cyclization precursor 68 was subjected to ligandless conditions [Pd ldbajj, Et N] in the weakly coordinating solvent toluene, the quaternary center was formed with 9 1 diastereoselectivity (70 69 = 89 11). In contrast, use of the coordinating solvent THF and a stoichiometric amount of an added silver salt completely reversed the sense of asymmetric induction in the cyclization reaction (70 69 = 3 97). 

The resin was dried in vacuo and subjected to the intramolecular Heck reaction. 

Heck and related reactions. In certain couplings high pressure is required. While EtjN is used as base in many Heck reactions, it can be replaced by alkali metal acetate or bicarbonate together with a quaternary ammonium salt. Base-free aryla-tion of alkenes is subject to a remarkable chelate effect zinc is present in the system. 

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