Amdt-Eistert homologation reaction

The equivalence of sulfur and oxygen in this ring system carries over to NSAIDs as well. Preparation of the sulfur analogue of isoxepac (6-4) starts with the alkylation of thiophenol (27-1) with benzyl chloride (26-1). Cyclization of the intermediate thioether (27-2) then affords the homothioxanthone (27-3). The carboxyl side chain is then extended by means of the Amdt-Eistert homologation reaction. The acid is thus hrst converted to its acid chloride by means of thionyl chloride. Reaction with excess diazomethane leads to the diazoketone (27-4). Treatment of that intermediate with silver benzoate and triethylamine leads the ketone to rearrange to an acetic acid. There is thus obtained tiopinac (27-5) [28]. 

The oligomers of 3-amino acids, as opposed to a-peptides, show a remarkable ability to fold into well-defined secondary structures in solution as well as in the solid state. The 3-amino acid building blocks were synthesized from a-amino acids using the Amdt-Eistert homologation reaction in the laboratory of D. Seebach... 

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. 

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... 

Amdt-Eistert homologation Baylis-Hillman reaction Benzoin condensation Corey-Fuchs reaction Henry reaction (Nitroaldol reaction)... 

Amdt, F. Eistert, B. Ber. 1935, 68, 200-208. Fritz Arndt (1885—1969) was bom in Hamburg, Germany. He discovered the Amdt—Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its reactions with aldehydes, ketones, and acid chlorides. Fritz Arndt s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bemd Eistert (1902—1978), bom in Ohlau, Silesia, was Arndt s Ph.D. student. Eistert later joined 1. G. Farhenindustrie, which became BASF after the Allies broke up the conglomerate after WWII. 

Fuchter, M. J. Amdt-Eistert Homologation. In Name Reactions for Homologations-Part 1 Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 336-349. (Review). 

In general, only slight modifications to the Amdt-Eistert homologation have been reported. As mentioned previously, classically two equivalents of diazomethane are required due to the production of HCl upon reaction of diazomethane with the acid chloride. Newmann and Beal reported a modification whereby triethylamine is added to capture the released HCl and therefore only one equivalent of diazomethane is required. Another major source of diversity in the reported Amdt-Eistert reactions is in the initial activation of the carboxylic acid. While thionyl chloride is classically used, other reagents that mediate the eonversion of a earboxylic acid to an acid chloride are equally suitable. As reported above, alternative activation methods such as the formation of mixed anhydrides and acyl mesylates are also be applicable. 

Aldol Addition Aldol Condensation Amdt-Eistert Homologation Aza-Wittig (Staudinger) Reaction Biginelli Dihydroprimidine Synthesis Bischler-Napieralski Reaction Claisen Condensation Dieckmann Cyclization Diels-Alder Ene... 

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. 

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. 

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