Amdt-Eistert synthesis

The reaction between acyl halides and diazomethane is of wide scope and is the best way to prepare diazo ketones. Diazomethane must be present in excess or the HX produced will react with the diazo ketone (10-74). This reaction is the first step of the Amdt-Eistert synthesis (18-8). Diazo ketones can also be prepared directly from a carboxylic acid and diazomethane or diazoethane in the presence of dicyclohexyl-carbodiimide. ... 

ANDROSTAN-nU-OL, 52,122 Anthracene, cyanation, 50, 55 Amdt-Eistert reaction, modified, 50, 77 7-Aryl-0-diketones, general synthesis, 51, 131... 

The Kolbe synthesis of nitriles is an important method for the elongation of an alkyl chain by one carbon center (see also the Amdt-Eistert synthesis). The nitrile 2 can for example easily be converted to the corresponding carboxylic acid by hydrolysis. 

Marti et alJ4"1 have used a similar approach involving Fmoc-protection. However, they have demonstrated that it is possible to use Fmoc-protected diazo ketones derived from a-amino acids together with a peptide on a solid support with a free N-terminus in a silver-promoted Amdt-Eistert procedure. Hence, homologation and peptide coupling are achieved in one step. This approach has led to the synthesis of a-peptides containing one (l3-amino acid (Scheme 19) and also, if the homologation procedure is used repetitively, to p3-peptides. 

Scheme 19 Solid-Phase (S-Peptide Synthesis Using Amdt-Eistert Homologation1401...

In chapter 27 we analysed the synthesis of the bicyclic lactone 7 needed by Eschenmoser for his vitamin B12 synthesis.2 The next step was a chain extension by the Amdt-Eistert procedure to the ester 9. 

So, in this instance, cyclopropane formation is the first rather than the last step in the synthesis. Addition of ethyl diazoacetate 42 R = Et to styrene 41 gave a mixture7 of cis and trans isomers of 40 R = Et. Only the cis isomer will be able to cyclise so separation8 of the free acid gave 34% yield of cis-43. Chain extension by the Amdt-Eistert procedure9 (chapter 31) gave cis-35 and the acid chloride duly cyclised to 36. 

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. 

A wide variety of methods have been described for the synthesis of variously substituted phenethylamines. Some frequently used procedures are presented in Scheme 1. Most of these have been discussed in previous reviews (305, 306). Condensation of an appropriately substituted benzaldehyde with nitromethane followed by reduction of the nitrostyrene (Method A) has proved to be a versatile method which has been employed by numerous workers (cf. 306, 358). Another common method (Method B) affords the amines by reduction of substituted phenylacetonitriles obtained via benzylchlorides (cf.. 306) or benzylamines (307). Reduction of phenylacetamides with lithium aluminum hydride (Method C) has also been applied successfully (308, 309). The substituted phenylacetamides were obtained either via diazoketones by an Amdt-Eistert synthesis (308) or by transformation of the corresponding acetophenones (310). 

The acid chlorides have served as useful synthetic intermediates leading to ketones via the malonic acid synthesis and Friedel-Crafts reaction, thiadiazole acetic acid derivatives and halo ketones via the Amdt-Eistert synthesis and carbinols by hydride reduction (68AHC(9)107). The dialkylcadmium conversion of acid chlorides into ketones fails in the... 

In Amdt-Eistert synthesis, and acyl chloride is converted to a carboxylic acid with one additional carbon atom. 

D. Seebach, M. Overhand, F. N. M. Kllhnle, B, Martinoni, L. Oberer, U. Hommel, H. Widmer, (3-Peptides Synthesis by Amdt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-Ray Crystallography. Helical Secondary Structure of a P-Hexapeptide in Solution and its Stability towards Pepsin , Helv. Chim. Acta 1996,79, 913-941. 

J. L. Matthews, C. Braun, C. Guibourdenche, M. Overhand, D. Seebach, Preparation of Enantiopure P-Amino Acids from a-Amino Acids Using the Amdt-Eistert Homologation , in Enantioselective Synthesis of P-Amino Acids , Chapter 5, (Ed. E. Juaristi), Wiley-VCH, New York, 1997, 105- 126. 

Anhydrides—Continued reduction to alcohols, 155 reduction to lactones, 535 Arenes, see Hydrocarbons, aromatic Amdt-Eistert reaction, 433, 487, 573 Aryl esters. Fries rearrangement, 344 hydrolysis, 169 preparation, 169 Aryl halides, see Halides Atyloxy acids, preparation, by aceto-acetic ester synthesis, 430 by malonic ester synthesis, 429 from atyloxy alcohols, 419 from atyloxy cyanides, 414 preparations listed in table 48, 460 Aryloxy acyl halides, preparation, 547 preparations listed in table 61, 553 Aryloxy esters, preparations listed in table 55, 516... 

The Amdt-Eistert synthesis has been extended to the preparation of disubstituted acetic acids and derivatives through the use of higher diazo hydrocarbons. 

One of the more commonly applied chain extension reactions for carboxylic acids utilizes die unique reactivity of diazoalkanes. This sequence, generally referred to as the Amdt-Eistert synthesis, is a two-step process which, in the first step, involves the formation of an a-diazo ketone by reaction of the corresponding acyl chloride with an excess of diazoalkane (Scheme In the second stage of the... 

The Amdt-Eistert synthesis, usually carried out with diazomethane, is fairly general and tolerates a wide range of substituents on both the carboxylic acid and alcohol. An obvious limitation is the reactivity of other functional groups, such as carboxylic acids or phenols, with diazomethane. The use of the more stable trimethylsilyldiazomethane as a replacement for diazomethane has been reported. While the use of diazoalkanes other than diazomethane is fairly rare, it does offer the opportunity to introduce additional functionality. For example, when sulfonyldiazomethanes (7) are used, the result is an a-sulfo-nyl carboxylic ester (Scheme 3). ... 

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 value of the Amdt-Eistert method in synthesis rests with the versatility of the products obtained, and there have been a number of developments which increase the overall appeal. One of these allows the direct synthesis of homologous aldehydes by the reduction of the A -methylanilide with lithium aluminum hydride, or the thiol ester using Raney nickel (Scheme 9). ... 

In an earlier chapter, we saw how to reduce the carbon chain by one methylene unit using the Hunsdiecker reaction. The opposite of this, namely the extension of the carbon chain by one unit, may be achieved with the Amdt-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. Suggest what is the pathway for this reaction. 

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