Elimination Grob Fragmentation

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. 

All decarboxylations occurring with -elimination can be considered as Grob fragmentations.46... 

Thomas investigated the chemistry of 8-azabicyclo[1.2.1]octanes, the core structure of the tropane alkaloids, and unexpectedly observed a Grob fragmentation instead of the predicted elimination reaction. Upon treatment of mesylate 27 with potassium /-butoxide in dimethyl sulfoxide, silyl cleavage affords alkoxide 28 which fragments to yield formaldehyde, a mesylate anion, and bicycle 29. Exposure of 27 to DBU in acetonitrile leads to the desired E2 reaction with complete suppression of the Grob fragmentation. ... 

Scheme 2). In addition to solvent participation (/cj and normal nucleophilic nitrogen participation the observed reactions are elimination (k ) (Scheme 3) and a fragmentation (fey) process sometimes called the Grob fragmentation (Scheme 4).

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). 

Compound 403 is readily reduced with sodium borohydride at -78°C and yields the monoalcohol 405 (115). It also reacts with potassium t -butyl hydroperoxide at -20°C and gives the cis-enone-perester carbonate 406 in high yield (116). This last transformation can be explained by retro-Claisen fragmentation of intermediate 407 followed by the elimination of methoxide ion from 408. It is also possible that 407 undergoes a direct stereoelectronically controlled Grob type fragmentation to compound 406. 

Depending on the point of view, fragmentation reactions may be considered to be eliminations or <7-77 and cr-cr exchanges. They are heterolyses involving five centers or more that yield three or more fragments (Grob and Schiess, 1967). Such reactions are sufficiently close to eliminations in an extended chain, e.g. (169), so that they can be considered with them (Banthorpe, 1963). 

Grob, C. A., Baumann, W. 1,4-Elimination reaction with simultaneous fragmentation. Helv. Chim. Acta 1955, 38, 594-610. 

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