Chemoselectivity kinetic control

Specific dehydrogenation at the terminal positions of alkanes is a reaction that would be of high utility. The 1-alkenes obtained by such a reaction are the basis of a variety of additional products. Felkin and co-workers discovered that metal complexes are able to mediate the transfer of hydrogen from alkanes 13 to olefins 14 (Scheme 4) [17]. The specific advantages of a transition metal catalyst can be applied to the benefit of the chemoselectivity of this reaction. In a kinetically controlled process, it is predominantly primary C-H bonds that add to the metal complex. A subsequent /Miydride elimination affords the terminal alkenes... 

The relative reactivity of the alcohol and amine in the example just given could be overturned by conducting a reaction under thermodynamic control. In kinetically controlled reactions, the idea that you can conduct chemoselective reactions on the more reactive of a pair of functional groups— carbonyl-based ones, for example—is straightforward. But what if you want to react the less reactive of the pair There are two commonly used solutions. The first is illustrated by a compound needed by chemists at Cambridge to study an epoxidation reaction. They were able to make the following diol, but wanted to acetylate only the more hindered secondary hydroxyl group. 

Among the methods for their preparations, two reactions described by House have been employed widely 7 a thermodynamically controlled sil-ylation with chlorotrimethylsilane/triethylamine in hot dimethylformam-ide or a kinetically controlled reaction which involves lithiation with a lithium dialkylamide followed by quenching with the chlorosilane. Each method has its own merits and drawbacks with respect to three important factors regio-, stereo-, and chemoselectivities. 

The intramolecular conjugate addition of in situ, chemoselectively generated amines 2 bearing an electrophilic double bond in the cu-position leads to functionalized pyrrolidines and piperidines 3 under very mild conditions34. The cyclization step occurs smoothly and the piperidine and pyrrolidine derivatives are obtained as a mixture of diastereomers with good diastereose-lection in most cases. The reactions are under kinetic control and the geometry of the starting alkene does not seem to have an influence on the stereochemical outcome of the cyclization step. 

Cycloalkenes tethered with a y,5- or 5,8-unsaturated acid side chains react with Brj or I2 to furnish the corresponding halolactones. lodolactonization is more commonly used than bromolactonization since iodine is easier to handle (solid) and is more chemoselective (less reactive) than bromine. Halolactonization with aqueous base is kinetically controlled and proceeds via addition of a Br or B atom to the double bond to form a transient halonium ion. In the absence of strong directing steric effects, formation of the halonium ion may occur at either diastereoface of the double bond. However, only the halonium ion intermediate which allows trans-diaxial Sj. 2 opening by the neighboring carboxylate nucleophile leads, if the intramolecular reaction is sterically favorable, to the lactone. 

There are two problems of chemoselectivity in this synthesis. How do we cleave one double bond in (22) without cleaving the other, and how do we control the cyclisation of (20) Epoxidation of (22) selectively attacks the more substituted double bond to give (23) which can be opened to (20) in two steps.The cyclisation of (20) can be controlled by conditions strong base gives (19) by thermodynamic control and weak base enolises only the aldehyde (kinetic control) to give (21). 

As the final product 124Z indicates, this transformation is interestingly not only chemoselective as expected but also regioselective leading to intermediate 122, followed by hydrofuran annulation. The kinetically controlled, substituted (Z)-acrylate 124Z can easily be isomerized with acid to the corresponding ( )-compound 124E. 

In 2011, Connon, Zeitler, and coworkers reported detailed studies on intermolecular cross-benzoin reactions using triazoUum and thiazoUum salts [26]. These systematic studies clearly showed the intricate interplay of various factors influencing the outcome of cross-benzoin reactions. In line with the results of Miller and coworkers, the use of o-substituted benzaldehydes resulted in selective formation of benzylic alcohol products using either triazolium or thiazolium salts. When using o-unsubstituted benzaldehydes, the same chemoselectivity could be achieved with an a-branched aliphatic aldehyde and an N-QFs triazolium catalyst. Crossover experiments showed the reaction to be under kinetic control in many cases. When using chiral catalyst 31, good chemo- and enantioselectivity was achieved in the reaction between o-trifluoromethylbenzaldehyde (30) and propanal (29) (Scheme 18.3). 

The product cystine is presumably formed in the recombination of two thiyl radicals. This free-radical model is suitable for formal treatment of the kinetic data however, it does not account for all possible reactions of the RS radical (68). The rate constants for the reactions of this species with RS-, 02 and Cu L, (n = 2, 3) are comparable, and on the order of 109-10loM-1s-1 (70-72). Because all of these reaction partners are present in relatively high and competitive concentrations, the recombination of the thiyl radical must be a relatively minor reaction compared to the other reaction paths even though it has a diffusion controlled rate constant. It follows that the RS radical is most likely involved in a series of side reactions producing various intermediates. In order to comply with the noted chemoselectivity, at some point these transient species should produce a common intermediate leading to the formation of cystine. 

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