Intramolecular reactions Favorskii rearrangement

In the reaction of 2-chlorocyclohexanone with a secondary amine (632) one encounters an intramolecular enamine alkylation analogous to the internal alkylations which constitute the critical step of some Favorskii rearrangements. 

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

The generally accepted mechanism for the Favorskii rearrangement involves the formation of reactive cyclopropanone intermediate C. Base abstracts the a-hydrogen from A to give the carbanion B, which undergoes intramolecular Sn2 displacement of the halide ion. The resulting cyclopropanone intermediate C is opened under the reaction conditions to give the more stable carbanion D, which takes proton from solvent to furnish the final product, an ester E (Scheme 2.25). 

An intramolecular (4+3)-cycloaddition illustrates the potential of the quasi-Favorskii approach in the preparation of complex ring systerns.Reaction of readily available alcohol 80 with triflic anhydride afforded the cycloadduct 81 stereoselectively in 65% yield (Scheme 7.21 V Treatment of this compound with lithium aluminum hydride (LAH) afforded an essentially quantitative yield of alcohol 82 from a sequence of reduction, quasi-Favorskii rearrangement, and further reduction. 

This chapter s final example of caged hydrocarbon synthesis is one that further eii5)hasizes the importance of cycloaddition reactions in creating substrates for the quasi-Favorskii rearrangement. This synthesis also showed, as many polycyclic hydrocarbon syntheses have, the limits that exist in intramolecular photochemical [2+2]-cycloaddition processes. 

In an extension of previous work, it has been found that Pd(0)-catalysed intramolecular cyclization of allylic acetates (21) can be used to prepare the chrysanthemic acid analogues (22). The potentially useful cw-cyclopropane (23) can be simply obtained by base-induced addition of cyanoacetate to ethyl 2-bromo-3,3-dimethylacrylate followed by decarboxylation oddly, a similar reaction using malonate fails to give a cyclopropane. Optically pure dichloro cw-chrysanthemic acid (26) has been obtained by a Favorskii rearrangement of the chiral cyclobutanone (25) prepared from the keten (24) by sequential [2 + 2]cycloaddition, cine-rearrangement, and resolution (Scheme 3). ... 

Both intermolecular and intramolecular [4+3] cycloaddition reactions are known [6], The first example of this process was published by Fort in 1962 in the course of his studies on the mechanism of the Favorskii rearrangement [7]. He was able to capture the oxyallylic cation generated upon treatment of 1 with base in the presence of furan (Scheme 19.2). While the yield for the process was low, this contribution was seminal. It should be noted that this year (2012) marks the golden anniversary of this reaction. Research in both fundamental and applied aspects of the process continues unabated and the reaction can truly now be called synthetically useful. 

A related intramolecular trapping of cyclopropylideneamine intermediate 51 by alkoxide was proposed to explain the formation of the rearranged amides 53 from the Favorskii-type reaction of a, -epoxyketimines 50 with lithium diisopropylamide. ... 

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