Favorskii rearrangements

During rearrangement, a more stable carbanion usually becomes the leaving group, affording a substantially modified carbon framework. 

Example 8.5 Target molecule TM 8.5 exhibits spasmolytic activity. Consider its retrosynthesis and then propose the synthesis. 

For this industrial method, the introduction of hydrogen into the mixture of MnO/carboxyUc acid at high temperature to prevent the oxidation of Mn(II) to a higher, catalyticaUy inactive oxidation state is characteristically controlled [24]. Chlorination, a base-promoted rearrangement and hydrolysis of the intermediary carboxylic ester are completed under standard conditions. 

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. 

The halogen (X) can either be chloro, bromo, or iodo while the nucleophile (Nuc-H) can be water, alcohol, or amine resulting in the formation of a carboxylic acid, ester, or amide, respectively. The choice of base and solvent plays a key role in the success of the reaction. This rearrangement finds utility in the synthesis of branched carboxylic acids and their derivatives, in particular, molecules possessing a tertiary carbon next to the carboxyl group are readily accessible. Also, cw-a,(3-unsaturated acids can be prepared using either a,a- or a,a -dihaloketones. Trihaloketones can be converted to mono-halo-a,P-unsaturated acids as well.  

In 1894, Alexie Favorskii published an early account of the rearrangement of simple acyclic a-halo ketones. This was followed in subsequent years with additional reports/ In 1914, he published the cyclic version featuring the ring contraction of 2-chlorocyclohexanone. This modification makes this transformation a reliable way to sjmthesize 1-substituted cycloalkane carboxylic acid derivatives. Later in the century, the rearrangement found application in the modification of steroids. Only in the last half of the 20 century has a clearer picture of the mechanism appeared.  

An elegant example of the use of the Favorskii rearrangement was in the first deliberate synthesis of the cubane carbon skeleton in 1964 by Eaton and Cole. Their sequence begins with 2-cyclopentenone 10, which is first mono-brominated with NBS and then di-brominated using Br2 to give 11. Double dehydrobromination is achieved using diethylamine to form transient species 12, which immediately self-dimerizes via a Diels-Alder reaction to form 13. Subsequent ultraviolet light irradiation in the presence of HCl 

White and coworkers used a Favorskii rearranjgement in their synthesis of the natural product ( )-byssochlamic acid 17. 4-Ethylcyclohexanone 18 synthesized by Jones oxidation of the corresponding alcohol, was carboxylated to 19 and then dibrominated to 20. The Favorskii rearrangement was carried out with NaOMe to form the unsaturated diester 

Transformation of enolizable a-haloketones to esters, earboxylie aeids, or amides via alkoxide-, hydroxide-, or amine-eatalyzed rearrangements, respeetively. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 93, Springer-Verlag Berlin Heidelberg 2009 

Baireta, A. Waegell, B. In Reactive Intermediates, Abramovitch, R. A., ed. Plenum Press New York, 1982, 2, pp 527-585. (Review). 

Filipski, K.J. Pfefferkom, J. A. Favorskii rearrangement. In Name Reactions for Ho-mologations-Part IT, Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 238-252. (Review). 

(a) Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533-563. Aleksei E. Favorskii (1860-1945), bom in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became a professor since 1900. (b) Favorskii, A. E. J. Prakt. Chem. 1913, 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 100, Springer International Publishing Switzerland 2014 

In conclusion, the reaction of enolates with alkyl halides and carbonyl compounds provides one of the most powerful and useful of all carbon-carbon bond-forming processes. Not only are a variety of synthetic products available, but the reaction can be made to proceed with excellent diastereoselectivity. In conjunction with the reactions of carbanions, nucleophilic methods constitute the largest single type of methodology for making new carbon-carbon bonds. 

This reaction is regiospecific and highly stereoselective. Give the product and explain the selectively. OMe 

For the reactions shown, draw the syn and anti products. Explain why there is a difference in selectivity and 

Show the Zimmerman-Traxler model for both approaches. 

Explain the inversion of configuration for the alkyl side chain in this reaction. 

In the initial step the a-halo ketone 1 is deprotonated by the base at the a -carbon to give the carbanion 4, which then undergoes a ring-closure reaction by an intramolecular substitution to give the cyclopropanone derivative 2. The halogen substituent functions as the leaving group  

Nucleophilic addition of the base to the intermediate 2 leads to ring opening. With a symmetrically substituted cyclopropanone, cleavage of either C —CO bond leads to the same product. With unsymmetrical cyclopropanones, that bond is broken preferentially that leads to the more stable carbanion 5  

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

The carbanionic species thus formed is protonated to give the final product 3. The use of an alkoxide as base leads to formation of a carboxylic ester as rearrangement product use of a hydroxide will lead to formation of a carboxylic acid salt  

With cyclic a-halo ketones, e.g. 2-chloro cyclohexanone 6, the Favorskii rearrangement leads to a ring contraction by one carbon atom. This type of reaction has for example found application as a key step in the synthesis of cubane by Eaton and Cole for the construction of the cubic carbon skeleton  

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Within the cubane synthesis the initially produced cyclobutadiene moiety (see p. 329) is only stable as an iron(O) complex (M. Avram, 1964 G.F. Emerson, 1965 M.P. Cava, 1967). When this complex is destroyed by oxidation with cerium(lV) in the presence of a dienophilic quinone derivative, the cycloaddition takes place immediately. Irradiation leads to a further cyclobutane ring closure. The cubane synthesis also exemplifies another general approach to cyclobutane derivatives. This starts with cyclopentanone or cyclohexane-dione derivatives which are brominated and treated with strong base. A Favorskii rearrangement then leads to ring contraction (J.C. Barborak, 1966). 

Another useful route to cyciopentanes is the ring contraction of 2-bromo-cydohexanones by a Favorskii rearrangement to give csrdopcntanecarboxylic acids. If a 0 dibromoketones are used, ring opening of the intermediate cydopropanone leads selectively to, y-unsaturated carboxylic acids (S.A, Achmad, 1963, 1965 J. Wolinsky, 1965). 

Cycloundecanecarboxylic acid has been prepared by the bromination of cyclododecanone followed by the Favorskii rearrangement of 2-bromocyclo-dodecanone... 

The currently accepted mechanism for the Favorskii rearrangement of dihalo ketones involves a cyclopropanone intermediate formed by loss of HX. This is followed by attack of alkoxide synchronous with cyclopropanone fragmentation and departure of halide ion to form the unsaturated ester... 

The methyl ester (100, R = CH3), derived from this A-nor acid by treatment with diazomethane, is different from the ester (102) obtained either by Favorskii rearrangement of 2a-bromo-5a-cholestan-3-one (101) or by the action of cyanogen azide on 3-methoxy-5a-cholest-2-ene (103) followed by hydrolysis on alumina. The ketene intermediate involved in photolysis of (99) is expected to be hydrated from the less hindered a-side of the molecule to give the 2j -carboxylic acid. The reactions which afford (102) would be expected to afford the 2a-epimer. These configurational assignments are confirmed by deuteriochloroform-benzene solvent shifts in the NMR spectra of esters (100) and (102). ... 

Favorskii rearrangement, 159, 176 Formation of hetero-radicals, 238 2-Formyl-A-nor-5a-androstan-l 7 -oI, 415 2-Formyl-A-nor-5 a-androst-1 -en-17 S-ol, 416 6/3-Formyl-B-nor-5 -cholestane-3, 5 -dioI 3-acetate, 432... 

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. 

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

The reaction of oc-halo ketones (chloro, bromo, or iodo) with alkoxide ions rearranged esters is called the Favorskii rearrangement. 

Through the years, the mechanism of the Favorskii rearrangement has been the... 

This is usually called the quasi-Favorskii rearrangement. An example is found in the... 

The quasi-Favorskii rearrangement obviously cannot take place by the cyciopropanone mechanism. The mechanism that is generally accepted (called the semi-... 

An interesting analog of the Favorskii rearrangement treats a ketone such as 4-/ r/-butylcyclohexanone, without an oc-halogen with T1(N03)3 to give 3-tert-butylcyclopentane-1 -carboxylic acid. ... 

The subjects of this section are two reactions that do not actually involve carbo-cation intermediates. They do, however, result in carbon to carbon rearrangements that are structurally similar to the pinacol rearrangement. In both reactions cyclic intermediates are formed, at least under some circumstances. In the Favorskii rearrangement, an a-halo ketone rearranges to a carboxylic acid or ester. In the Ramberg-Backlund reaction, an a-halo sulfone gives an alkene. 

The Favorskii Rearrangement. When treated with base, a-halo ketones undergo a skeletal change that is similar to the pinacol rearrangement. The most commonly used bases are alkoxide ions, which lead to esters as the reaction products. This reaction is known as the Favorskii rearrangement.84... 

Quantum mechanical/molecular mechanical study on the Favorskii rearrangement in aqueous media has been carried out.39 The results obtained by QM/MM methods show that, of the two accepted mechanisms for Favorskii rearrangement, the semibenzilic acid mechanism (a) is favored over the cyclopropanone mechanism (b) for the a-chlorocyclobutanone system (Scheme 6.2). However, the study of the ring-size effects reveals that the cyclopropanone mechanism is the energetically preferred reactive channel for the a-chlorocyclohexanone ring, probably due to the straining effects on bicycle cyclopropanone, an intermediate that does not appear on the semibenzilic acid pathway. These results provide new information on the key factors responsible for the behavior of reactant systems embedded in aqueous media. 

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