Homologation Wolff rearrangement

The main synthetic application of the Wolff rearrangement is for the one-carbon homologation of carboxylic acids.242 In this procedure, a diazomethyl ketone is synthesized from an acyl chloride. The rearrangement is then carried out in a nucleophilic solvent that traps the ketene to form a carboxylic acid (in water) or an ester (in alcohols). Silver oxide is often used as a catalyst, since it seems to promote the rearrangement over carbene formation.243... 

The use of copper as a catalyst in carbenoid transfer has its roots in the Amdt-Eistert reaction, Eq. 1 (3). Although the original 1935 paper describes the Wolff rearrangement of a-diazo ketones to homologous carboxylic acids using silver, the authors mention that copper may be substituted in this reaction. In 1952, Yates (4) demonstrated that copper bronze induces insertion of diazo compounds into the X-H bond of alcohols, amines, and phenols without rearrangement, Eq. 2. Yates proposal of a distinct metal carbenoid intermediate formed the basis of the currently accepted mechanistic construct for the cyclopropanation reaction using diazo compounds. 

The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or their derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water, alcohols, or amines. 

The key step of the Amdt-Eistert Homologation is the Wolff-Rearrangement of the diazoketones to ketenes, which can be accomplished thermally (over the range between r.t. and 750°C, photochemically or by silver(I) catalysis. The reaction is conducted in the presence of nucleophiles such as water (to yield carboxylic acids), alcohols (to give alcohols) or amines (to give amides), to capture the ketene intermediate and avoid the competing formation of diketenes. 

The formation of a-diazoketones from carboxylic acids (via the acyl chloride or an anhydride) and the subsequent Wolff Rearrangement in the presence of nucleophiles results in a one-carbon homologation of carboxylic acids. This reaction sequence. 

The Wolff rearrangement and the Arndt-Eistert homologation sequence are very useful in organic synthesis. One of the most popular applications involves amino acids. An interesting example has been described as a key reaction in the synthesis of a 14C-labeled amino acid used for deciphering the biosynthesis of penicillin N from glutamic acid (Scheme 3.2).9 This rearrangement proceeds without racemization and can thus be applied in peptide synthesis. 

Since ketene is probably the intermediate of the Wolff rearrangement, the choice of solvents dictates the nature of the product. Indeed, water gave carboxylic acids, whereas alcohols or amines led to esters and amides, respectively. These combinations have been applied to the synthesis of more complex molecules. For example, the total synthesis of carbonolide B, a 16-membered macrolide antibiotic, relied on Amdt-Eistert homologation. In this sequence, a protected furanuronic acid was transformed to the corresponding a-diazoketone, which was then converted to its homologous carboxylic ester. The reaction was achieved using catalytic amounts of silver benzoate and excess of triethylamine in methanol (Scheme 3.4).11... 

The Wolff rearrangement is the third step of the Amdt-Eistert homologation of carboxylic acids. Figure 14.27 picks up an example that was discussed in connection with Figure 8.13, that is, the homologation of trifluoroacetic acid to trifluoropropionic acid. The first step of the Amdt-Eistert synthesis consists of the activation of the carboxylic acid via the acid chloride. The Cj elongation to an a-diazoketone occurs in the second step. 

Silver benzoate in methanol is also the catalyst of choice for the classical homologation of cr-amino acids (and peptides) to the corresponding f3-amino esters by Wolff rearrangement.353 An interesting application in natural... 

One important application of this reaction is the chain extension of acyl chlorides to their homologous esters, known as the Amdt-Eistert reaction. Notice that the starting material for the Wolff rearrangement is easily made from RCO2H by reaction of the acyl chloride with diazomethane the product is RCH2CO2H—the carboxylic acid with one more carbon atom in the chain. A CH2 group, marked in black, comes from diazomethane and is inserted into the C-C bond between R and the carbonyl group. 

Wolff rearrangement of /)-diazenyl-a -diazo ketone 83 in the presence of water, methanol (or even with primary and secondary amines) under varied reaction conditions comes with surprise Instead of the expected homologous acid 89, methyl ester 90 (or the respective amide), 2-phenylcinnolin-3(2E0-one (91) is the only product indicative of the anticipated in situ formation of ketene intermediate 88 (Scheme 22). Obviously, the apparent 67r-electrocyclization reaction prevails forming the isolated heterocyclic product 91, a so far unknown compound. 

Both V and VII are highly unstable species, as is copper carbenoid IV. It is conceivable that both evolutionary alternatives follow downhill energy profiles. Whatever the particular mechanism, the transformation of I into II has been termed the vinylogous Wolff rearrangement, since it was taken as a homolog of the classical Wolff transposition. 

In the first step of the reaction sequence a methyl ester is formed via a Wolff rearrangement. The Wolff rearrangem ent provides acids, esters or amides from a-diazo ketones and is often used in a ring contractive way to form strained ring systems, which are not accessible by other sequences.It also occurs as the key step in the Arndt-Eistert homologation of carboxylic acids. ... 

A straight chain diazomethyl ketone will also undergo Wolff rearrangement on irradiation. Such diazomethyl ketones are readily prepared from the corresponding acid chloride (150) by exposure to diazomethane or, more conveniently, trimethylsilyldiazomethane (Petrarch). Tlie net one-carbon homologation so effected is known as the Amdt-Eistert synthesis. 

The well-known Arndt-Eistert homologation" of an acyl halide to a carboxylic acid also involves the migration of an R group (with its electron pair) to an electron-deficient acyl carbene (presumably through a hypercarbon species) [Eq. (6.132)]. This rearrangement is also known as the Wolff rearrangement. 

Amino acids have been prepared by the homologation of a-amino acids, but the method tends to be low yielding as well as being a relatively long sequence (Scheme 9.39)," or diazo compounds and a Wolff rearrangement have to be employed," "" and these are not amenable to large-scale application. ... 

The Wolff rearrangement of a-diazocarbonyl compounds (8.58, R = H, alkyl, aryl, OR) has great synthetic importance because in most cases the ketenes formed react smoothly with water, alcohols, and amines (Scheme 8-34). An early application that still has considerable importance is the homologization of carboxylic acids (Arndt-Eistert reaction Arndt and Eistert, 1935). As shown in Scheme 8-34, the reaction starts from the chloride of the acid RCOOH, which leads to an a-diazo ketone with diazomethane (R = H), followed by the Wolff rearrangement and the hydrolysis of the ketene intermediate to give the homologous carboxylic acid (8.59, R =H). In alcohols and amines esters (8.60) and amides (8.61, R = H), respectively. 

When working on the acylation of diazomethane, Arndt and Eistert (1935) found the method for homologization of carboxylic acids in which acylation of the diazo ketone with the acid chloride is followed by a Wolff rearrangement (see discussion in Sect. 8.6). 

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