Arndt-Eistert synthesis, diazomethane

The reaction between acyl halides and diazomethane is of wide scope and is the best way to prepare diazo ketones.1714 Diazomethane must be present in excess or the HX produced will react with the diazo ketone (0-71). This reaction is the first step of the Arndt-Eistert synthesis (8-8). Diazo ketones can also be prepared directly from a carboxylic acid and diazomethane or diazoethane in the presence of dicyclohexylcarbodiimide.1715 OS III, 119 VI, 386, 613 69, 180. 

Arndt-Eistert reaction.2 This reagent is recommended for use in place of diazomethane in the Arndt-Eistert synthesis (equation I). 

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 Arndt—Eistert synthesis was investigated by Marquardt who obtained 3-diazoacetyl-l,2,5-thiadiazole (92) in good yield from 3-chlorocarbonyl-l,2,5-thiadiazole (81) and diazomethane. When the WolflF rearrangement of 92 was carried out in the usual manner, i.e., with silver oxide as a catalyst, ring degradation resulted and none of the expected l,2,5-thiadiazole-3-acetic acid (93) was isolated. By... 

A carbon chain may be extended by one unit by using the Arndt-Eistert synthesis. In the first step, an acyl halide is treated with diazomethane to form the a-diazo ketone. This is then treated with water and silver oxide. The resultant product is the free acid. If an alcohol is used instead of water, then the related ester is formed. This is the best way of extending a chain by one unit if the carboxylic acid is available. The process of extension in this manner is called homologation. 

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. 

Any reaction involving diazomethane followed by silver oxide is classifiable as an Arndt-Eistert synthesis. This reaction converts an acid chloride into the next higher homolog in the series. Realizing this, partial structures can be proposed for structures A, B and C. 

This reaction was first reported by Arndt and Eistert in 1935. It is the extension of carboxylic acid by one CH2 unit via the reaction of acyl chloride with diazomethane and is generally known as the Arndt-Eistert synthesis. In addition, this reaction is also occasionally referred to as the Arndt-Eistert acid synthesis, Arndt-Eistert homologation," and Arndt-Eistert reaction. This reaction has been extensively reviewed. Other reagents instead of diazomethane have been similarly applied to extend the length of the carboxylic acids7... 

Wilds and coworkers have discussed the influence of highly hindered acyl chlorides on the Arndt-Eistert synthesis. The diazomethanes derived from such acyl chlorides fail to rearrange normally with any of the three conventional catalysts, silver oxide-methanol, silver benzoate-triethylamine-methanol, or tertiary amines-high-boiling solvents. Under special reaction conditions, abnormal reaction products were isolated. 

Arndt, F. Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200. Fritz Arndt (1885—1969) was bom in Hamburg, Germany. He discovered the Arndt—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. Bernd Eistert (1902-1978), bom in Ohlau, Silesia, was Arndt s Ph.D. student. Eistert later joined I. G. Earbenindustrie, which became BASE after the Allies broke the conglomerate up after WWII. 

Conversely, if the substituted phenylacetic acid or its chloride are not readily accessible, the diazo ketone obtained from the corresponding aromatic acid chloride and diazomethane may be treated directly with the substituted phenethylamine. An Arndt-Eistert type rearrangement occurs which leads directly to the phenethylamide of the respective homo acid. An example for this type of reaction may be found in the synthesis of 1-benzylhydrohydrastinine (61). 

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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