Regioselectivity cationic pathways

Silver and tliallium salts have been widely employed with halide substrates, either to increase the rate of a Heck reaction [84], to minimize double-bond isomerization in the product [75], or to modify regioselectivity or enantioselectivity [Ig]. These additives divert the Heck reaction to a pathway involving cationic palladium(II) intermediates. It is also possible to divert the Heck reaction of a triflate precursor from the cationic pathway to the neutral pathway (see Scheme 6-1) by the addition of halide salts. In one, possibly exceptional, case studied in our laboratoiy, the addition of halide salts dramatically improves enantioselectivity [65]. 

This exceptional regioselectivity (opposite to that observed in classical organic solvents) was attributed to the preferential cationic pathway induced by the IL (Scheme 4). 

As seen, the charge distribution in the reactants dictates the head-to-tail pathway of the reaction. For the cation-radical, the positional selectivity at the C(l) atom is 100%, regioselectivity being 0% whereas at the C(4) atom, the positional selectivity is 0% and regioselectivity is 100%. In other words, only the addition of the D -C(l) + D°-C(4) type is observed (symbols D° and refer to a neutral diene and diene in cation-radical form, respectively). 

Mattay et al. examined the regioselective and stereoselective cyclization of unsaturated silyl enol ethers by photoinduced electron transfer using DCA and DCN as sensitizers. Thereby the regiochemistry (6-endo versus 5-exo) of the cyclization could be controlled because in the absence of a nucleophile, like an alcohol, the cyclization of the siloxy radical cation is dominant, whereas the presence of a nucleophile favors the reaction pathway via the corresponding a-keto radical. The resulting stereoselective cis ring juncture is due to a favored reactive chair like conformer with the substituents pseudoaxial arranged (Scheme 27) [36,37]. 

The change in the nature of the tetrazole substrate on going from tetrazolide 7 to contact ion pairs, solvent-separated ion pairs with a metal cation, to complexes of 231 and 232 type, etc., can result in deviations from the canonical mechanisms like those described above (Schemes 22 and 23). Also, the possibility cannot be excluded that the ion pairs formed by anion 7 react with the electrophile concurrently by several alternative pathways. We believe that just this versatility of reaction routes explains the difference between the predicted rate and selectivity of the electrophilic attack under ideal conditions and the experimental result. In the light of these comments, new data on the application of ion pairs formed by anions of type 7 to the synthesis of N-substituted tetrazoles are discussed. As far as possible, attention is given to conclusions with respect to the regioselectivity of electrophile attack. 

Another instructive scenario may be found when considering the metalation of arenes. There are two distinct mechanisms for the metalation of aromatic C-H bonds - electrophilic substitution and concerted oxidative addition (Box2). The classical arene mercuration, known for more than a century, serves to illustrate the electrophilic pathway whereas the metal hydride-catalyzed deuterium labeling of arenes document the concerted oxidative addition mechanism [8, 17]. These two processes differ both in kinetic behavior and regioselectivity and thus we may appreciate the need to differentiate these two types of process. However, the choice of C-H bond activation to designate only one, the oxidative addition pathway, creates a similar linguistic paradox. Indeed, it is hard to argue that the C-H bond in the cationic cr-complex is not activated. 

This example makes the matter look deceptively clear-cut. But with epoxides, regioselectivity is not as simple as this because, even with acid catalysts, Sjyj2 substitution at a primary centre is very fast. For example, Br in acid attacks this epoxide mainly at the less substituted end, and only 24% of the product is produced by the cation-stabilized pathway. It is very difficult to override the preference of epoxides unsubstituted at one end to react at that end. 

The protic reaction on occasion is a useful method of alkene formation, but is far from general because the cation intermediate tends to undergo rearrangements.Further, even for cases in which elimination to an alkene is the predominant pathway, the regioselectivity of the process is often mediocre. A key step in the synthesis of (+)-a-eudesmol and (-)-a-selinene exemplifies this point (Scheme 60). There are, however, isolated examples of excellent selectivity, such as the reaction of a 3-ketotetrahydrofuran tosyl-hydrazone salt to give the corresponding cyclic enol ether as the major product (Scheme 61), the intro-... 

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