Amdt-Eistert Rearrangement

The reaction of acyl chlorides with diazomethane is fast and selective in the presence of a C=C bond, but not in the presence of other carbene acceptors. Knowledge of the chemoselective reactivity of carbenes is of prime importance for planning the retro-Amdt-Eistert disconnection of the target molecule. 

Example 8.4 Consider the retrosynthesis and then propose the synthesis of TM 8.4. 

At first sight the maximal simplification of TM 8.4 can be achieved by the initial FGI introducing a carbinol OH group instead of the C=C bond in TM 8.4a 

By cutting off one methylene group in TM 8.4a in retro-Amdt-Eistert mode b, an unfavorable effect of the carbethoxy group in TM 8.4a is inverted by moving this group one bond closer to the carbanion to obtain synthon TM 8.4b. One FGI disconnection leads to TM 8.4c and retro-Grignard to an acceptable reagent derived from a-bromoisobutyric acid. 

Selective reactivity of the Grignard reagent with the ketone group and not with the sterically hindered carbethoxy group in the second molecule of the reagent is expected. Before preparation of carboxylic chloride to react with diazomethane, previous elimination of the reactive tert-OYi group is needed to form a C=C bond less reactive with carbene. 

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The Wolff and Amdt-Eistert rearrangements are probably among the earliest known reactions promoted by silver ions.2,3 Discovered at the turn of the nineteenth/ twentieth century, the Wolff rearrangement allows the transformation of a-diazo-ketones to carboxylic acids,4 while the Arndt-Eistert rearrangement is a similar sequence also leading to carboxylic acids, but including the preparation of a-dia-zoketones from a shorter acid chloride (Scheme 3.1).5... 

Scheme 8.10 Presentation of the retro-Amdt-Eistert rearrangement...

A synthesis of papaverine-l- C in 11 % yield was performed starting from veratric acid labeled at the carboxyl group (CXII). The diazoketone prepared from the aeid chloride was eondensed with homoveratrylamine and the resulting amide (CXIII) cyclized to 3,4-dihydropapaverine (CXIV). Dehydrogenation of the latter with palladium-charcoal in tetralin afforded papaverine. The loealization of the labeled carbon atom, indicative of an Amdt-Eistert rearrangement, was confirmed because the base, on oxidation with neutral 5% potassium permanganate, afforded 6,7-dimethoxyisoquinoline-l-i C-l-carboxylic acid (CXV) (183). 

Acyloin condensation, 30 Aldol condensation, 21-22, 30, 1S7 Aldol reaction, 166 Amdt-Eistert rearrangement, 77-79... 

Rearrangement (ring contraction) of a-diazokelones to cartioxylic adds or their derivatives (esters, amides) via ketenes (see also Amdt-Eistert). 

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. 

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 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. 

This chapter follows on from chapter 12 where we introduced some basic ideas on stereocontrol. Since then we have met many stereospecific reactions such as pericyclic reactions including Diels-Alder (chapter 17), 2 + 2 photochemical cycloadditions (chapter 32), thermal (chapter 33) cycloadditions, and electrocyclic reactions (chapter 35). Then we have seen rearrangements where migration occurs with retention at the migrating group such as the Baeyer-Villiger (chapters 27 and 33), the Amdt-Eistert (chapter 31) and the pinacol (chapter 31). 

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. 

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. 

This ester is one carbon atom short of the full side chain of grandisol, so an Arndt-Eistert reaction was used to lengthen the chain by one atom. First, the ester was converted into the diazoketone with diazomethane and, then, the Wolff rearrangement was initiated by formation of the carbene with a Amdt-Eistert chain extension of ester silver compound at the Ag(II) oxidation state. 

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... 

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. 

WofS rearrangement (Amdt-Eistert reaction. The reagent has been used in acetonitrile-methanol to effect homogeneous rearrangement, for example of a-diazoacetophenone. After standing for several hours at room temperature, methyl phenylacetate is obtained in good yield. 

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