Ketones homologization with diazo

Aldehydes and ketones can be converted to their homologs with diazo-methane. ° Several other reagents are also effective, including MesSil, and then silica gel, or LiCH(B-0CH2CH20-)2- With the diazomethane reaction. 

Homologization of ketones with diazo compounds from oc Diketones... 

We have seen that the traditional Roskamp process and its stereoselective variants allow one to substitute a synthetically valuable unsubstituted or substituted alkoxy ethanoyl functicm in place of the formyl C-H bmid. The analogous homologation of ketone acceptors with stabilized diazo compounds promises to become a highly advantageous tool for the synthetic chemist. Unfortunately, since ketones are far less reactive than aldehydes, comparably fewer reports in this area are known that still meet the modem criteria of catalysis, high efficiency, and stereocontrol. 

Esters of the homologous acids are prepared by adding silver oxide in portions rather than in one lot to a hot solution or suspension of the diazo ketone in an anhydrous alcohol (methyl, ethyl or n-propyl alcohol) methanol is generally used and the silver oxide is reduced to metallic silver, which usually deposits as a mirror on the sides of the flask. The production of the ester may frequently be carried out in a homogeneous medium by treating a solution of the diazo ketone in the alcohol with a solution of silver benzoate in triethylamlne. 

Dauben et al. (15) applied the Aratani catalyst to intramolecular cyclopropanation reactions. Diazoketoesters were poor substrates for this catalyst, conferring little asymmetric induction to the product, Eq. 10. Better results were found using diazo ketones (34). The product cyclopropane was formed in selectivities as high as 77% ee (35a, n = 1). A reversal in the absolute sense of induction was noted upon cyclopropanation of the homologous substrate 34b (n = 2) using this catalyst, Eq. 11. Dauben notes that the reaction does not proceed at low temperature, as expected for a Cu(II) precatalyst, but that thermal activation of the catalyst results in lower selectivities (44% ee, 80°C, PhH, 35a, n = 1). Complex ent-11 may be activated at ambient temperature by reduction with 0.25 equiv (to catalyst) DIBAL-H, affording the optimized selectivities in this reaction. The active species in these reactions is presumably the aluminum alkoxide (33). Dauben cautions that this catalyst slowly decomposes under these conditions. 

Reaction of carbonyl compounds with aliphatic diazo compounds to deliver homologated ketones. 

The suitably protected amino acid is activated as the mixed anhydride and treated with diazomethane to produce the corresponding diazo ketone. Rearrangement in the presence of water furnishes the p-amino acid. Diazomethane contains varying amounts of water, which is able to hydrolyze the activated amino acid. This leads to subsequent methylation by diazomethane to form the methyl ester as a side product. This cannot easily be removed from the diazo ketone, but can be separated during work-up of the homologated amino acids. 

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. 

Wolff rearrangement of /)-diazenyl-a -diazo ketone 83 in the presence of water, methanol (or even with primary and secondary amines) under varied reaction conditions comes with surprise Instead of the expected homologous acid 89, methyl ester 90 (or the respective amide), 2-phenylcinnolin-3(2E0-one (91) is the only product indicative of the anticipated in situ formation of ketene intermediate 88 (Scheme 22). Obviously, the apparent 67r-electrocyclization reaction prevails forming the isolated heterocyclic product 91, a so far unknown compound. 

Diazo compounds react with aldehydes and ketones to give homologated carbonyl compounds and epoxides. Lewis acids accelerate these processes, and in some cases direct the reactions to single products. frara-Epoxides result from aldehydes and ethyldiazoacetates in the presence of MeReOs (although this can occur via a metal carbene pathway rather than a Lewis acid mechanism) [139], whereas... 

A diazo ester or alkane will react with a ketone, under Lewis acid catalysis, to give the homologated product. This reaction is most often used for one-carhon ring expansion, as illustrated hy the conversion of (166) to (167 equation 69). The regioselectivity of the (166) to (167) transformation, 98 2 in the example illustrated, was found to depend on both the diazoalkane and the Lewis acid used. With diazomethane and boron trifluoride, a 1 1 mixture of regioisomeric products was observed. 

The Dakin-West reaction provides a source of V-acyl-a-amino ketones (e.g. 1), which Franzen has exploited for the synthesis of secondary diazo ketones, thereby avoiding the need to use the higher homologs of diazomethane (Scheme 2). The ketoamide (1) is first nitrosated using N2O3 in glacial acetic acid. The oily Af-nitroso derivative is separated and then decomposed with sodium methoxide in methanol to give the diazo ketone (2) yields are about 50-60%. 

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. 

The Wolff rearrangement of a-diazocarbonyl compounds (8.58, R = H, alkyl, aryl, OR) has great synthetic importance because in most cases the ketenes formed react smoothly with water, alcohols, and amines (Scheme 8-34). An early application that still has considerable importance is the homologization of carboxylic acids (Arndt-Eistert reaction Arndt and Eistert, 1935). As shown in Scheme 8-34, the reaction starts from the chloride of the acid RCOOH, which leads to an a-diazo ketone with diazomethane (R = H), followed by the Wolff rearrangement and the hydrolysis of the ketene intermediate to give the homologous carboxylic acid (8.59, R =H). In alcohols and amines esters (8.60) and amides (8.61, R = H), respectively. 

When working on the acylation of diazomethane, Arndt and Eistert (1935) found the method for homologization of carboxylic acids in which acylation of the diazo ketone with the acid chloride is followed by a Wolff rearrangement (see discussion in Sect. 8.6). 

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