Heck reaction regiochemistry

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... 

Presumably, the oxidative cyclization of 3 commences with direct palladation at the a position, forming o-arylpalladium(II) complex 5 in a fashion analogous to a typical electrophilic aromatic substitution (this statement will be useful in predicting the regiochemistry of oxidative additions). Subsequently, in a manner akin to an intramolecular Heck reaction, intermediate 5 undergoes an intramolecular insertion onto the other benzene ring, furnishing 6. (i-Hydride elimination of 6 then results in carbazole 4. 

In one case, the intermolecular Heck reaction of 3-pyridyltriflate with ethyl acrylate was accelerated by LiCl to give 159 [127,128], Here, both electronic and steric effects all favored p-substitution. In another case, however, electronic effects prevailed and complete a-substitution was observed. In the presence of an electron-donating substituent (i.e., a protected amine), 3-bromopyridine 160 was coupled with f-butoxyethylene to give 3-pyridyl methyl ketone 162 [126]. The regiochemistry of the Heck reaction was governed by inductive effects, leading to intermediate 161. 

As p-hydride elimination is reversible, hydropalladation with the opposite regiochemistry provides a mechanism for forming regioisomers of the alkene. This allows the most stable alkene that is accessible by the hydropalladation-dehydropalladation sequence to dominate. The only restriction is that all of these processes are syn. The migration can be prevented by the addition of bases like silver carbonate, which effectively removes the hydrogen halide from the palladium complex as soon as it is formed. This synthesis of a complex trans dihydrofuran involves the Heck reaction followed by alkene isomerization and then a Heck reaction without migration to preserve the stereochemistry. 

Control over regioselectivity and stereoselectivity in the formation of new C-C a-bond is required to utilize the Heck reaction in complex molecule synthesis. For the intramolecular Heck reaction, the size of the ring formed in the insertion step controls the regiochemistry, with 5-exo and 6-exo cyclization favoured. A mixture of regioisomers is formed from Heck insertions of acyclic alkenes, whereas cyclic alkenes such as cycloalkenes as a Heck substrate produce a a-arkylpalladium(II) intermediate A, which has only one syn-P-hydrogen. Syn-elimination of the hydrogen provides only product B (Scheme 5.6). 

The intramolecular version of the Heck reaction leads to the formation of cyclic compounds (Scheme 6.40) [130], In this case the C-C bond is generally formed at the most substituted position of the alkene (exo mode), in contrast with the intermolecular case where the opposite regiochemistry holds. The Baldwing rules for cyclization are usually operative. The Scheme 6.40 (a) depicts the general cyclization reaction of an enyne, where the vinylpalladium intermediate is formed by insertion of the alkyne fragment into a Pd-H bond formed by protonation of Pd(0) species the first M-C bond can also be formed by oxidative addition of a... 

Deeth, R.J., Smith, A. and Brown, J.M. (2004) Electronic control of the regiochemistry in palladium-phosphine catalyzed intermolecular Heck reactions. J. Am. Chem. Soc., 126, 7144-51. 

Asymmetric versions of some of these reactions are known an example is the Mizoroki-Heck reaction of a dihydrofuran shown on p. 266. Note that in this case the alkene insertion takes place with the opposite regiochemistry than normal—that is, the R group becomes attached to C-1, next to the ring ether substituent of the C=C double bond. This is because the ether substituent at C-1 is an electron donor, by virtue of the oxygen -lone-pair electrons, and the polarization of the C=C double bond is inverted from the classic Mizoroki-Heck situation with an EWG substituent. The syn atkiition of the Pd-R bond means... 

The successive coordination and iyw-addition of organopalladium(II) intermediates to olefins and alkynes generating a new C—C cr-bond are referred to as migratory insertion or carbopalladation and control the regioselective outcome in the particular reaction. The regiochemistry can be tuned by steric and electronic effects, which will be discussed in more detail for the Heck reaction in Sect. 1.7. 

A variant of this reaction involves the formation of the enamine precursors for Heck cyclization via the hydroamination of alkynes [76]. Examples of this transformation are shown in Scheme 6.55. Notably, the regiochemistry of these reactions can be controlled in the hydroamination step. As such this provides an interesting alternative to Larock chemistry for generating 2,3-substituted indoles (Section 6.4). 

The use of arylamines in the Pd"-catalysed coupling with olefins has been reported. This modification of the classical Heck procedure further extends the utility of the method. A study of the regiochemistry of the cycloaddition of substituted trimethylenemethanepalladium complexes is necessary if they are to be generally adopted in synthesis. Reaction of cyclopentenone with a methyl-substituted trimethylenemethane species afforded a single stereoisomeric product, which was converted to a precursor of the natural product chrysomelidial (Scheme 24). Since previous work on the unsubstituted system suggested a... 

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