Wolff rearrangement, Arndt-Eistert

Wolff and Arndt Eistert Rearrangements and Related Reactions... 

WOLFF AND ARNDT-EISTERT REARRANGEMENTS AND RELATED REACTIONS... 

The Arndt-Eistert reaction (Scheme 2.1) which involves the Wolff rearrangement of diazoketones 13 (prepared from the corresponding commercially available N-protected-a-amino acids 12 by reaction of their mixed anhydrides with diazomethane a cautionary note is warranted here the generation and handling of diazomethane require special precautions) has been used extensively by Seebach and coworkers for the preparation of N-protected /9 -amino acids 14 and /9 -amino acid esters 15 and 16. 

Diazoketones (53) may be obtained by the reaction of diazomethane, CH2N2, on acid chlorides, and a subsequent Wolff rearrangement in the presence of water is of importance because it constitutes part of the Arndt-Eistert procedure, by which an acid may be converted into its homologue ... 

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 Wolff and Amdt-Eistert rearrangements are probably among the earliest known reactions promoted by silver ions.2,3 Discovered at the turn of the nineteenth/ twentieth century, the Wolff rearrangement allows the transformation of a-diazo-ketones to carboxylic acids,4 while the Arndt-Eistert rearrangement is a similar sequence also leading to carboxylic acids, but including the preparation of a-dia-zoketones from a shorter acid chloride (Scheme 3.1).5... 

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. 

Fig. 14.28. Twofold Wolff rearrangement in the bishomologation of dicarb-oxylic acids according to Arndt and Eistert. Both alkyl group migrations occur with retention of configuration.

The Wolff rearrangement is the third step of the Arndt-Eistert homologation of carboxylic acids. Figure 11.25 picks up an example that was discussed in Section 7.2, that is, the homologation of trifluoroacetic acid to trifluoropropionic acid. The first step of the Arndt-Eistert synthesis consists of the activation of the carboxylic acid via the acid chloride. The Q elongation to an a-diazoketone occurs in the second step. 

This ester is one carbon atom short of the full side chain of grandisol, so an Arndt-Eistert reaction was used to lengthen the chain by one atom. First, the ester was converted into the diazoketone with diazomethane and, then, the Wolff rearrangement was initiated by formation of the carbene with a Amdt-Eistert chain extension of ester silver compound at the Ag(II) oxidation state. 

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. ... 

The actual rearrangement part of the Arndt-Eistert synthesis, which involves insertion of the carbene to give the ketene, is called the Wolff rearrangement. The ketene then undergoes addition of water to yield the final desired product after suitable tautomerisation has occurred. 

Wolff rearrangement The rearrangement of a diazo ketone, RCOCHN2, via the keto carbene, RCOCH, to the ketene, RCHCO, which may then be hydrated to a carboxylic acid, RCH2C02H, as in the Arndt-Eistert synthesis. 

It is interesting that when R contains a tertiary asymmetric carbon atom bound to the carbonyl group of the diazomethyl ketone, the Wolff rearrangement takes place without racemization or inversion. This is also a characteristic of the Curtius (p. 63), the Hofmann (p. 76), and the Schmidt (p. 65) rearrangements. Thus when (+) -methyl- -phenylcaproic acid (LVI) was taken through an Arndt-Eistert synthesis, followed by a Barbier-Wicland degradation, no loss in optical activity occurred.31 The steps in the sequence may be outlined as follows ... 

Wolff rearrangement. Rearrangement of diazoketone to ketenes by action of heat, light or some metallic catalysts. The rearrangement is the key step in the Arndt-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. 

Diazoketones such as 307 can be formed from acid chlorides by reaction with diazomethane. Subsequent treatment with aqueous Ag20 leads to the Wolff rearrangement and formation of a carboxylic acid of one carbon more than the starting acid chloride. This sequence is known as the Arndt-Eistert synthesis.252 a synthetic example using this is taken from Weinreb s studies toward the synthesis of cylindrospermopsin,253 iu which 315 was treated with (1) oxalyl chloride, (2) CH2N2 and (3) Ag20, MeOH to give a mixture of products 22% of 316 and 39% of 317. 

Carbenes from a-Diazocarbonyl Compounds The Wolff Rearrangement and the Arndt-Eistert Reaction... 

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. 

Finally we will discuss briefly the Arndt-Eistert reaction, mentioned already in the context of the general scheme (8-34) of preparative methods. This reaction (1935) is actually a sequence of three reactions, first a nucleophilic substitution of an acyl chloride by diazomethane, followed by a metal-catalyzed Wolff rearrangement, and finally hydrolysis of the resulting ketene. 

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). 

An important reaction of diazoketones is the Wolff rearrangement. " The reaction is the key step in the well-known Arndt-Eistert method for converting a carboxylic... 

Synthesis of -Amino Acids. /3-Amino acids can be prepared in an Arndt-Eistert-t) e reaction employing tosyl chloride for the activation of the carboxyl group of V-protected amino acids. Formation of the corresponding diazomethane derivatives proceeds in good yield and without racemization of the a-stereogenic center (eq 53). Wolff rearrangement then affords the corresponding -amino acids. 

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