Heck reaction double bond migration

The regiochemistry of the Heck reaction is determined by the competitive removal of the (3-proton in the elimination step. Mixtures are usually obtained if more than one type of (3-hydrogen is present. Often there is also double-bond migration that occurs by reversible Pd-H elimination-addition sequences. For example, the reaction of cyclopentene with bromobenzene leads to all three possible double-bond isomers.146... 

Other Pd cross-coupling reactions such as Heck [52] and Suzuki [53] reactions have also been used for macrocyclizations. The main drawback for Pd catalyzed macrocylization is the yield, that is often somewhat disappointing if compared with other established methods. Also, the introduction of the required coupling components (e.g., trialkyltin group, vinylic iodide) can be difficult in some compounds. In other cases, Pd-catalyzed side reactions such as double bond migration or allylic activation can occur. 

For the Heck reaction as discussed in Section III.2.1 the final position of the olefi-nic double bond of the products must not necessarily be the same as in the starting materials (for example Schemes 8, 9, and 10 of Section III.2.1) [1], The selectivity is often driven by stereochemical requirements, because the /1-hydrogen elimination step which forms the double bond proceeds exclusively in a syn manner (if a trans /3-hydrogen is eliminated, one should suspect major deviations from the general mechanism of the Heck reaction, for example electrophilic substitution instead of carbopalladation). An impressive example of a double bond migration is depicted in Scheme 1 - instead of olefins the coupling reaction of iodobenzene 1 with the olefmic alcohol 2 results in the isomeric aldehydes 3 and 4 as final products [2], Reactions of this type have emerged as valuable tools for the synthesis of carbonyl compounds and also as crucial steps in domino processes. 

Vinylation of heteroaryl triflates also possible. Vinyl halides can be coupled to alkenes to form dienes. " The reaction of dihydrofurans with vinyl triilates and a palladium catalyst leads to a nonconjugated diene, 33. This example illustrates that the product is formed by an elimination step, as with the Heck reaction (13-10), and double bond migration can occur resulting in allylic rearrangement. 

With chiral ligands the Heck reaction can be enantioselective. The amino-acid-derived phosphine ligand in the margin controls the Heck reaction of phenyl triflate with dihydrofuran. The ligand selects one enantiotopic face of the alkene (see Chapter 45 if you have forgotten this term) and the usual double bond migration and (5 elimination complete the reaction. 

The excellent regio- and stereoselectivity of the Heck C-C-coupling has the potential of enantioselective reactions [32]. Hayashi and Ozawa reported the first case of decent optical induction (eq. (8)) (/ )-2-aryl-2,3-dihydro-furanes were thus obtained from the triflate precursors in 96 % ee at 42-66% conversion in benzene when (/f)-BINAP was used as chiral auxiliary [33]. C-C double bond migration occurs under the given reaction conditions. 

Heck reaction and other couplings. The Heck reaction has been promoted by microwave irradiation in DMF or in water at high temperature (225°). In the intramolecular reaction leading to spirocyclic products, the double bond migration can be... 

As mentioned in the discussion of the pathways to indoles (Scheme 27), a detailed indole synthesis with two points of diversity based on the Heck reaction has been reported [164]. The indole core structure was synthesized via a 5-exo-tng transition state, which provided the exocyclic double bond that subsequently underwent exo to endo double-bond migration. The anthranilate building block was prepared in solution and immobilized by a method previously described for the loading of 2-aminobenzophenones [Ij. After Fmoc cleavage, the resulting 4-bromo-3-amino-phenyl ether was treated with acid chlorides and pyridine in CH2CI2. As outlined in Scheme 29, alkylation of the anilide with substituted allyl bromides was achieved in the presence of lithium benzyloxazoHdinone in THF. The reaction mixture was treated with base for 1 h and then an aUylic halide was added and the mixture was vortexed for 6 h at room temperature. The alkylation reactions were... 

Heck-type reaction. Aryl and vinylic mercurials undergo coupling reactions with -alkenyl-/3-lactams in the presence of PdCU, CuCU, and LiCl. Ring opening with double bond migration occurs during the reaction. 

Heck reactions of allylalcohols, with the involvanent of neutral intermediates and more strongly coordinating leaving groups, alternatively provided aldehydes or ketones, as a result of H /3-elimination or double bond migration by hydridopalladium leaddition/elimination to give unstable enols (Sect. B.vii). 

The Heck reaction with the simple representatives of this substracture shown in Scheme 1 generally involves a double bond migration to give aromatized products in moderate to good yields. " The highest yield was achieved for 3-methylindole, because in this case the reaction was driven to completion by the addition of several portions of Pd catalyst. The presence of silver salts inhibits the migration of the double bond as a result, products with an exocyclic methylene group can be isolated (Scheme 1). ... 

Carbopalladation with double bond migration has been utilized to couple fragments. An example from the synthesis of potential anticancer agents is shown in Scheme Aryl iodide 60 couples with exo-alkene 59 to give 61 after Heck coupling and oxidation/arom-atization in modest yield. The reaction is unusual in that the carbopalladation intermediate contains a relatively unstable tertiary alkyl-palladium bond. 

The level of alkene isomerization in the Heck reaction between an aryl bromide and 2,3-dihydrofuran was found to be controlled by the choice of neopentyl phosphine ligands (14JOC10837). Di-fert-butylneopentylphos-phine (DTBNpP) favored the formation of product A through double bond migration via a chain-walking mechanism. This selectivity was dramatically reversed when trineopentylphosphine (TNpP) was used, favoring product B without alkene isomerization. 

The following example stems from an expeditious formal ( )-aphidicolin (66) synthesis by Fukumoto and coworkers [37,38]. The requisite reaction conditions were defined after a screening of the analogous dehydroxylated precursor (not shown), cyclizing in 86% yield. The bridged bicyclo[3.2.1]octane core is efficiently constructed by Mizoroki-Heck reaction of 64 in high yield and without any post-Mizoroki-Heck double-bond migration (64 65, Scheme 5.13). 

En route to the synthesis of mensacarcin (104), a polyfunctionalized hexahy-droanthracene, showing cytostatic and cytotoxic activity, Tietze et al. [49] devised a Mizoroki-Heck cyclization for the formation of the tricyclic core. Several substrates with different protecting groups and substitution patterns were tested, out of which 102 turned out to be the best, affording 103 in 94% yield under optimized reaction conditions (102 103, Scheme 5.20). A similar strategy was pursued by Banerjee and coworkers [50] for the synthesis of tetrahydroanthracenes leading to umbrosone (107). Variation of the substituents in 105 had a minor effect, the reactions proceeded smoothly in 84-86% yield (105 106), and subsequent elimination of H2O provided the tetrahydroanthracene core. When diene 108 was employed the aromatic system in 109 was directly installed by double-bond migration (108 109). 

In situ catalysts formed from Pd(dba)2 precursor and PHOX-type ligands have shown high enantioselectivities in Heck reactions (280). It has to be noted that no C=C double bond migration, a common sidereaction in Pd-phosphine catalyzed reactions, has taken place. 

A positive effect of water was observed in Heck reactions of 2,3-dihydrofuranes (e.g., glycals) with iodo- and bromoderivatives of pyrimidines and other nitrogen-containing heterocycles (Scheme 31). In several cases the reactions that could not be achieved using a standard method (in anhydrous DMF with EtsN and NaOAc as base) took place in aqueous ethanol (1 1, v/v) with NaHCOj-EtsN mixture in the presence of BU4NCI with suppression of double bond migration. ... 

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