Intramolecular 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). 

De Kimpe, N., Stanoeva, E., Schamp, N. Intramolecular trapping of a c clopropylidenamine during the Favorskii rearrangement of a-chloro ketimines. Tetrahedron Lett. 1988, 29, 589-592. 

Harmata, M., Bohnert, G., Kurti, L., Barnes, C. L. Intramolecular 4+3 cycloadditions. A cyclohexenyl cation, its halogenated congener and a quasi-Favorskii rearrangement. Tetrahedron Lett. 2002,43, 2347-2349. 

Cyclopropylideneamines were trapped in an intramolecular manner during the Favorskii rearrangement of suitably functionalized a-chloro ketimines 44 bearing a protected nucleophile in the molecule. Base-induced 1,3-dehydrochlorination generates the three-membered ring intermediate 45 which undergoes intramolecular nucleophilic addition of the deprotected nucleophile to form adducts 46. 

Scheme 7.21 Intramolecular t4+Si-cycloaddition and subsequent quasi-Favorskii rearrangement.

Certain cycloaddition/cyclization processes produce substrates for the quasi-Favorskii rearrangement with good yield and selectivity. For example, the intramolecular cycloaddition of ketene 45, available by dehydrohalogenation of the corresponding acid halide 44, afforded 46 in moderate yield (Scheme 7.131. This conpound reacted smoothly with lithium hydroxide under mild conditions to form the carboxylic acid 47. ... 

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. 

While the RBR does not encompass a true rearrangement of the carbon skeleton, it has been likened, mechanistically, to the Favorskii rearrangement, which does. Indeed, both involve a rate-limiting intramolecular ring-forming step that follows an acid-base equilibrium. The Favorskii intermediate is a cyclopropanone that is formed by a-deprotonation of an a-haloketone, analogous to the episulfone invoked in the RBR mechanism. 

The canonical formulation of the mechanism of the Favorskii rearrangement involves initial deprotonation of the a-carbon to generate an enolate, intramolecular displacement of the leaving group on the a -carbon by the enolate to generate a cyclopropanone, addition of a nucleophile to the cyclopropanone ketone followed by elimination to generate the more stable of two possible carbanions, and protonation to yield the rearranged carboxylic acid derivative. 

The Favorskii rearrangement is a base-mediated carbon skeletal rearrangement that occurs when a nucleophile adds to an a -halo ketone possessing an a-hydrogen. This transformation converts an a-halo ketone 1 to a carboxylic acid derivative 2. There is also an intramolecular variant of this transformation in which the resulting ring size contracts by one-carbon atom. 

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. ... 

---