Arndt-Eistert procedure

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 ... 

Chain Extension with Diazoalkanes The Arndt-Eistert Procedure... 

Chain extension by diazomethane the Arndt-Eistert procedure... 

This method, known as the Arndt-Eistert procedure, is useful when the relationship between the carbonyl groups in the TM is unhelpful but becomes helpful when the chain length is shorter. We saw an example in Chapter 28 where cyanide ion was used as the chain extension reagent. Diazomethane is a more sophisticated version, needing fewer steps. The disconnection is to remove the car bene. 

In Chapter 27 we analysed the synthesis of bicyclic lactone (6). In his vitamine B12 synthesis Eschenmoser needed to lengthen the acetic acid side chain of (6) into the propionic side chain of (7). This he accomplished by the Arndt-Eistert procedure. 

We have met ketenes (1) already as intermediates in the Arndt-Eistert procedure (Chapter 31) for chain elongation. They are highly electrophilic at the curious sp carbon atom ( in 1). Nucleophiles give acyl derivatives (3) via enolate (2). Ketenes are unstable and eannot be stored. In the absence of nucleophiles they dimerise ketene itself gives ester (4) (which is available commercially) and disubstituted ketenes give cyclobutadiones (5). Mono-substituted ketenes may give either type of product. 

Often, esters are homologated by one carbon using the diazomethane-based Arndt-Eistert procedure. Kowalski homologation, addition of the inexpensive dibromomethane followed by a-elimination, is a more scalable alternative. Timothy Gallagher of the University of Bristol recently reported (J. Org. Chem. 2004, 69,4849) the use of Kowalski homologation to prepare P-amino esters from a-amino esters, including the conversion of 3 to 4. Note that the transformation can be carried out without protection of the OH, and that it proceeds without loss of stereochemical integrity. 

Arndt-Eistert synthesis A procedure for converting a carboxylic acid to its next higher homologue, or to a derivative of a homologous acid, e.g. ester or amide. 

The current procedure starts with the ester, ethyl 1-naphthoate, and converts it into homologated product in 81% yield without isolation of any intermediates. Safe, commercially available materials are employed. Based on a recently published variation43 of our original homologation methods,4 1 It represents a general procedure applicable to esters 1 bearing aryl, alkenyl, alkynyl and primary, secondary or tertiary alkyl attachments R. Yields range from 67-90% (on a 25-mmol scale) and like the Arndt-Eistert sequence this procedure affords retention of stereochemistry for the... 

Esters, amides, and primary alcohols are obtained from benzo[6]-thiophene carboxylic acids by standard procedures.337 481,585 692 093,695 Acid chlorides undergo the Arndt-Eistert reaction,337,568,689 react with diethyl ethoxymagnesium malonate to give the corresponding methyl ketone,144 557 and are reduced to the aldehyde with 1 ithium tri-ferf-butoxy aluminohydride.33 7... 

We met ketenes in chapter 31 where they were intermediates in the Arndt-Eistert chain extension procedure. Now we are going to take a wider view of their value in synthesis. A ketene 1 is very electrophilic at the curious sp carbon atom (marked in 1) and combines with nucleophiles 2 to give enolates that are protonated at carbon 3 to give acylated compounds 4. 

A useful reaction of acyl chlorides is with diazomethane. The initial product, a diazo ketone, undergoes a rearrangement with the expulsion of nitrogen and the insertion of a methylene group. This Arndt-Eistert reaction is a useful chain-extension procedure (Scheme 3.69). 

Arndt-Eistert reaction. A few developments since a review of the literature on this reaction of 1942 may be mentioned. In an improved procedure, the diazo-O O... 

Arndt-Eistert synthesis. Procedure for converting an acid to its next higher homolog. 

Amdt-Eistert reaction [1, 194, after citation of ref. 29]. The procedure here described for the preparation of ethyl l-naphthylacetate29a represents a modified Arndt-Eistert reaction as developed by Newman and Beal.29b The use of triethyl-amine in the formation of the diazoketone makes possible the use of only one equivalent of diazomethane.29b... 

In the 1930 s and later, but before instrumental analytical methods (IR, NMR, X-ray, etc.) were easily available, the Arndt-Eistert reaction was very welcome for the characterization of degradation intermediates of natural products (Bachmann and Stuve, 1942). Bridson and Hooz (1988), and Scott and Sumpter (1993) described processes for the first step, and Lee and Newman (1988) for the overall reaction sequence in Organic Syntheses, The reported yields for both steps are excellent (84-90% each). Larock reviewed various procedures for Arndt-Eistert reactions (including the little investigated metal catalysis) in his book Comprehensive Organic Transformations (1989, p. 933). 

The direct diazo transfer from sulfonyl azides to methyl ketones is usually not a practicable process, with the exception of the a-diazotization of ketones with 2,4,6-triisopropylbenzenesulfonyl azide under phase-transfer conditions. However, diazomethyl ketones amenable to the Arndt-Eistert reaction can be easily prepared in two steps by a formylation-deformylation diazo-transfer sequence (Regitz procedure ). A related practical method advantageously applies the detrifluoroacetylation of a-trifluoroacetyl ketones tScheme 3 a). The preparation of 2-diazo-1,3-dicarbonyl compounds is commonly best performed with p-toluenesulfonyl azide (TsNg) as the diazo-transfer reagent tScheme 3.9h). > An issue... 

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