The Arndt-Eistert method

The Arndt-Eistert reaction is a comparatively simple method for converting an acid into its next higher homologue, or to a derivative of the homologous acid, such as an amide or an ester. The reaction is applicable to aliphatic, aromatic, alicyclic and heterocyclic adds, and the yield is generally good. 

The overall reaction is the insertion of a methylene group between the alkyl and carboxyl groups, and involves a rearrangement in the sequence of mechanistic steps. The reaction takes place in three stages  

Formation of the carboxylic add chloride, e.g. with thionyl chloride or with phosphorus pentachloride. 

Formation of a diazoketone (4) by the gradual addition of the acid chloride to an excess of an ethereal solution of diazomethane. This reaction may be represented mechanistically as follows  

If the reaction is carried out with the acid chloride in excess, e.g. by adding the diazomethane solution slowly to the acid chloride, some halomethyl ketone is produced  

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The Arndt-Eistert method is useful for making aryl-acetic acids from benzoic acids. How would you carryout this conversion ... 

The Kojima-Sakai approach, which makes use of trans-cis diester 626, is summarized in Scheme LVII This intermediate was homologated by the Arndt-Eistert method, converted to olefin 627, and oxidatively cleaved to produce ultimately the diester 628. Dieckmann condensation was used to construct the diquinane core which was subsequently transformed to 623 by standard reactions. 

P-Amino acids are useful precursors for the construction of p-peptides, a-substituted p-amino acids and related compounds. They can be prepared enantiomerically pure by homologation of a-amino adds using the Arndt-Eistert method. 

VI) by the Arndt-Eistert method, and thence through the diazo ketone into homopilosinylacetoxymethyl ketone (VII). When this substance is treated with copper acetate, formaldehyde, and ammonia at 100° for one hour, pilosinidine (VIII) is obtained, and this on methylation yields pilosinine (II). A modified synthesis was also described by the same authors, and more recently N. A. Dryamova, S. I. Zav yalova, and N. 

C. Increase of Chain Length by the Arndt-Eistert Method 336... 

The esterification and selective hydrolysis of the trans-diacid (15) led to a semiester with a free carboxy group in the side chain at 0 4. Extension of the side chain via the diazoketone by the Arndt—Eistert method gave the homologous diester (18). Dieckmann cyclization of the latter yielded the 16-methoxycarbonyl derivative (22) which underwent decarboxylation and demethylation on treatment with acids with the formation of t Z-equilenin (23). The c3 -isomer, identical in all respects with the natural product, was obtained by the resolution of the mixture via the Z-menthoxy-... 

The Arndt-Eistert synthesis allows for the conversion of carboxylic acids 1 into the next higher homolog 4. This reaction sequence is considered to be the best method for the extension of a carbon chain by one carbon atom in cases where a carboxylic acid is available. 

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

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... 

The use of the Arndt-Eistert protocol for the homologation of phthaloyl-protected a-amino acids was first established in the early 1950s.[11] Since then the method has been extended to cover carbamate protected a-amino acids and it has become an exceptionally useful method for the synthesis of (3-amino acid derivatives 3[12] (Scheme 3). 

These are usually prepared by the following methods (a) the Willgerodt reaction on the corresponding methyl ketone,82,98,337,485, 557 (6) hydrolysis of the corresponding cyanomethyl compound,77,337, 485,499,517,521,568 cyclization reactions (Section IV, C) (for 3-acetic acids only),143,209,310,311,313,351 or (d) the Arndt-Eistert reaction on the corresponding carbonyl chloride, which may lead directly to the acetic acid 689 or its amide.337, 568... 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

Method 3. An ethereal solution of diazomethane free from ethanol may be prepared by this method such a solution is required, for example, in the Arndt-Eistert reaction with acid chlorides (compare Expt 5.130). In a 100-ml distilling flask provided with a dropping funnel and an efficient downward condenser, place a solution of 6 g of potassium hydroxide in 10 ml of water, 35 ml of carbitol (diethyleneglycol monoethyl ether) and 10 ml of water connect the condenser to two conical flasks in series containing 10 and 35 ml of ether respectively and cooled in an ice-salt bath (see Method 1). Heat the mixture on a water bath at 70-75 °C in a beaker of water placed upon a hot-plate incorporating a magnetic... 

Hendecanedioic acid has been prepared by hydrolysis of the corresponding dinitrile, obtained from 1,9-dibromononane or 1,9-diiodononane 4-6 by oxidation of 11-hydroxyhendecanoic acid 7,8 by the Arndt-Eistert synthesis from 9-carbethoxynonanoyl9 and nonanedioyl chloride 10 and by the Willgerodt reaction on un-decylenic acid.11 The present method, previously described briefly,12 13 appears to represent the most convenient preparation of dibasic acids having an odd number of carbon atoms greater than ten. It has been applied to several other dibasic acids.14... 

In summary, the method described here provides an efficient and convenient route to a variety of a-diazo ketones including unsaturated derivatives that were not previously available by diazo transfer. a-Diazo ketones serve as key intermediates in a number of important synthetic methods including the Arndt-Eistert homologation, the photo-Woltf ring contraction strategy, and the carbenoid-mediated cyclopropanation reaction. We anticipate that improved access to a-diazo ketones will serve to enhance the utility of these valuable synthetic strategies. 

A method for converting an acid into its next higher homologue or its derivative is known as the Arndt-Eistert synthesis. ... 

The presence of an additional carbon atom between the amino and the carboxy function increases the number of possible constitutional and configurational isomers. Several methods have been developed to prepare N-protected (3-amino acid building blocks for the synthesis of (3-peptide oligomers [95, 96], The Arndt-Eistert homologation and the Evans methodology are two versatile strategies to obtain enantiomerically pure N-protected monomers with the side chains at the C(3) and C(2) carbon atoms, respectively [97, 98],... 

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. 

Table 2-1 shows ten types of synthetic process. Methods 1 and 2 are based on aliphatic amines, 3-5 on derivatives of carbonyl compounds, 6 on hydrocarbons with a relatively acidic CH proton, and 7-9 are reactions of diazoalkanes obtained by one of the types 1-6. Reaction 10 involves a diazo ketone, which can be obtained by reaction 9, the first step of the Arndt-Eistert synthesis. 

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. 

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). 

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