Favorskii reactions

The rearrangement with ring contraction probably is the most important synthetic application of the Favorskii reaction it is for example used in the synthesis of steroids. Yields can vary from good to moderate. As solvents diethyl ether or alcohols are often used. With acyclic a-halo ketones bearing voluminous substituents in a -position, yields can be low a tcrt-butyl substituent will prevent the rearrangement. 

Bromo-6,6-diinethylcyclohexanone gives 2,2-dimethylcyclopentane-carboxylic acid on treatment with aqueous NaOH followed by acidification, a process called the Favorskii reaction. Propose a mechanism. 

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). ... 

A reaction related to the pure carbanion rearrangement, but one that eventually involves an external displacing agent as well, is the Favorskii reaction. It has been shown with the aid of isotopic tracers that the mechanism is 429... 

Due to both the moderate yield and difficulties encountered in preparing large amounts of TEB by this procedure, a new route was developed based on the Hagihara (17) modification of the Stephens-Castro coupling (18). In this two-step procedure (Scheme 4), 1,3,5-tribromobenzene (VII) was coupled with a monoprotected acetylene using a Pd/Cu catalyst system. The protecting groups of the intermediate (IX) were then removed by a retro-Favorskii reaction (19). 

Ethinyl estradiol Ethinyl estradiol, 17a-ethinyl-l,3,5(10)-estratrien-3-17)3-diol (28.1.26), is made either by condensing estrone with acetylene in the presence of potassium hydroxide (Favorskii reaction), or by reacting sodium acetylenide in liquid ammonia with estrone [34-36]. 

The Favorskii reaction has been used to effect ring contraction in the synthesis of strained ring compounds. Entry 4 in Scheme 10.3 illustrates this application of the reaction. With 7,7 -dihalo ketones, the rearrangement is accompanied by dehydrohalo-genation to yield an a,/ -unsaturated ester, as illustrated by entry 3 in Scheme 10.3. 

Favorskii Reaction The reaction of aldehydes with terminal acetylenes is known as Favorskii reaction. 

The method is simple, and has the additional virtue of great versatility. The requisite ally lie alcohol can be prepared via the Favorskii reaction of a 20-ketopregnane, or via ethoxyacetylene addition to a 17-ketoandrostane. Additional functional groups may be present prior to these reactions or introduced into the A17(20)-compound later. An aromatic A-ring, A-ring unsaturated ketones and the 11 /1-hydroxyl group are all stable to the oxidative attack on the A17(20)-olefln, and the 21-acetate is not hydrolyzed during the reaction. 

The classic labeling studies of Loftfield 49a> have demonstrated that cyclopropanones are intermediates in the Favorskii reaction 49b) — the base-induced rearrangement of a-haloketones (Scheme 8). The related reaction of a,a -dibromoketones has, in fact, become a convenient preparative route for cyclopropenones, e.g., 48 ->- 49 via 50.50>... 

In the Favorskii reaction a haloketone reacts with alkali to give a carboxylic acid with simultaneous skeletal rearrangement thus 2-chlorocyclohexanone (XXX) gives cyclopentanecarboxylic acid (XXXI)... 

But is the same cyclopropanone an intermediate in the Favorskii reaction If the bromoketone is treated with methoxide in methanol, it gives the Favorskii product but, if it is treated with a much more hindered base, such as the potassium phenoxide shown, it gives the same cyclopropanone with the same stereochemistry. 

Other, less stable cyclopropanones, such as the 2,2-dimethyl compound, can be made by carbene addition (Chapter 40) to ketenes. This compound did the Favorskii reaction with methoxide in methanol the only product came from the expected loss of the less unstable carbanion. This will, of course, be general-acid-catalysed by methanol as no free carbanion can be released into an alcoholic solvent. 

The electrophilic component in these co-cyclisation reactions can bear other functionality. For example, reaction of isobutenyl dichloride 10 with the appropriate linear dithiols gives good yields of polythiacycles such as 11, 12 and 13.11 A related reaction allows the direct introduction of a keto group into such poly-thia macrocycles. The electrophilic component in this case is 1,3-dichloropropanone, 14. The reaction conditions (Cs2C03, DMF, 60 °C), are insufficiently basic to induce a Favorskii reaction. Furthermore, under the aprotic, basic conditions, thioketal formation cannot take place, allowing successful co-cyclisation to be undertaken, such as in the formation of 15 (Scheme 3.4). Similar reactions allow the preparation of 16,17 and 18.11... 

In a more polar solvent, Favorskii reactions cease to be stereospecific, and presumably take place by ionisation of the chloride to give the same cation from each diastereoisomer. Whether the reaction takes place by way of the cation or with concerted loss of the chloride ion, this reaction presented a serious puzzle before its pericyclic nature was recognised. The a overlap of the p orbital on C-2 of the enolate with the p orbital at the other end of the allyl cation 6.340 or with the orbital of the C—Cl bond 6.341 looked forbiddingly unlikely—it is 3-endo-trig at C-2. It is made possible by its pericyclic nature, where the tilt of the orbitals can begin to sense the development of overlap. The torquoselectivity in the development of overlap 6.341, however improbable it looks, corresponds to inversion of configuration at the carbon atom from which the chloride departs. 

The formation of hydrazodicarbonamide by the reaction of chlorobiuret sodium salt with ammonia is through the Favorskii reaction illustrated in Eq. 2 ... 

A number of the condensation reactions of 2-ethynyl-l-methylbenzimidazole are summarized in Scheme 114. The oxidative self-condensation of the compound can take two courses depending on the reaction solvent (74CHE1491). Under Favorskii reaction conditions (KOH in ether) the expected product (212) with acetone is not formed. Instead, further... 

Favorskii rearrangements, and other examples are known in the steroid nucleus (see below). Highly polar solvents (methanol or aqueous methanol) were originally used for these reactions the bromoketones may undergo dehydrobromination or substitution reactions in basic media of low polarity, such as pyridine or KOAc/HOAc. Recent work, however, has shown that sodium methoxide in aprotic solvents e.g. 1,2-dimethoxy-ethane) can be used, and tlxat the stereospecificity of various Favorskii reactions using simple alicyclic and aliphatic compounds is markedly dependent upon the nature of the solvent [301],... 

Although experimental evidence makes it unlikely that the latter has any general relevance to Favorskii reactions, it is included for consideration here because it appears as a likely mechanism in the special case of 5a,7a-dibromocholestan-6-one (31) [3iy]. This compound undergoes a ring contraction on treatment with pyridine to give the unsaturated carboxylic... 

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