Grob oxidative fragmentation

The last named is an example of a Grob oxidative fragmentation. 

As a preliminary mechanistic proposal, we hypothesize that the palladimn(ll)-phosphoramidite catalyst acts as a chiral n-acid to activate the amine iV-oxide substrate (Scheme 1S.291. similar to the mechanism proposed for the Overman rearrangement of allylic trichloroacetimidates. While it is not clear whether the reactive species is oxide-bound complex 119a or olefin-bound complex 119b, we propose heterocycle 120 as an intermediate in this cyclization-induced mechanism Grob-type fragmentation eventually reveals O-allylhydroxylamine 117 and the palladium(n)-phosphoramidite catalyst, which can reenter the catalytic cycle. 

The occurrence of carbocationic intermediates in the Hofer-Moest variant of the Kolbe reaction can lead to numerous rearrangement processes. For example, electrolysis of carboxylic acid 68 in methanol results in the oxidative ring opening of the norbomane skeleton[30]. In a similar manner, GroB-type fragmentation of the decaline derivative 70 affords the 10-membered-ring ketone 71 in good yield (Scheme 12) [31]. 

Exposure of cyclopropyl silyl ethers to 4 in acetic acid results in an oxidative Grob fragmentation to give unsaturated acids [Eq. (49)] [86]. 

This modification resulted in a yield improvement for the pentacyclization process from 47 % to 66 %. Treatment of the amino ether 192 with diisobutylaluminum hydride in refluxing toluene accomplished Eschenmoser-Grob fragmentation and reduction of the initially formed immonium ion, to give the unsaturated amino alcohol 193 in 86% yield. It was gratifying to find that 193 was the only product formed in this reaction. In the tetrahydropyran derivative, reduction of 192 to 193 is accompanied by about 15 % simple elimination. Displacement of the tosyl group in 196 gives sulfide 197, which is oxidized to sulfone 198. This material is metallated and coupled with enantiomerically pure aldehyde to secure the codaphniphylline skelton [74]. 

Copper-mediated sulfide elimination can lead to ring opening reactions. The hydroxy thioacetal 83, when treated first with n-BuLi and then with CuOTf afforded 84 in 92 % yield via a Grob fragmentation (Sch. 21) [47]. Two equivalents of the Lewis acid were required for the reaction because one equivalent complexes the alk-oxide and a second is necessary to activate the sulfide for elimination. Ring enlargement occurred upon treatment of 85 with CuOTf in benzene through the intermediacy of the thio-substituted epoxide 86 [48]. a-Phenylthiocyclohexanone 87 was obtained in 83 % yield. 

The oxidation of 3-hydroxypiperidine (15) with iodosylbenzene in water affords 2-pyrrolidinone 16 directiy in good yieid (Scheme 6.9) [28], The mechanism of this reaction probabiy invoives oxidative Grob fragmentation yielding an imino aldehyde, which upon hydrolysis affords 2-pyrrolidinone by a cyclization-oxidation sequence [28], The oxidative cyclization of aldoximes using iodosylbenzene in neutral aqueous media in the presence of surfactants has been employed in the synthesis of functionalized isoxazolines [29]. 

There are also a series of more complex eliminations that you should be aware of (Eqs. 10.63-10.67), although we are not going to look at these in any detail. One is the elimination of 1,2-dihaloalkanes and 1,4-dihaloalkanes (the Grob fragmentation) using Zn to create al-kenes or dienes (Eqs. 10.63 and 10.64, respectively). The first step in both reactions involves the oxidative addition of Zn to a C-X bond, a reaction we will cover in detail in Chapter 12. Other eliminations involve y-amino alkyl halides, which can spontaneously undergo elimination (Eq. 10.65), and the base-induced eliminations of both (3-hydroxyketones (Eq. 10.66, the reverse aldol reaction) and 8-ketoketones (Eq. 10.67, the reverse Michael addition). 

When reduced, Grob fragmentations complicate oxidation of C7 side chain. 

The Baeyer-Villiger oxidation of 7-oxabicyclo[2.2.1]heptan-2-ones is the most used reaction to cleave a C-C bond of the 7-oxabicyclo[2.2.1]heptanes. Other routes have used retro-Claisen, retro-Diekmann, and Grob fragmentations. They have been reviewed elsewhere [11]. Enoxysilanes derived from 7-oxanorboman-2-ones can be ozonolyzed into 2,5-anhydrouronic acid derivatives, precursors for C-nucleosides [225]. 

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