Ketones homologation with diazomethane

Addition of the diazoalkane nucleophile is followed by an reaction with ring-closure or a homologous ketone is formed with a 1,2-alkyl rearrangement (shift). Spirooxiranes are produced from cyclic ketone derivatives with diazomethane (Eq. 86). ... 

Nelson and Scliut investigated the reaction of 5a-cholestanone (lb) with diazomethane in a search for a direct, one-step preparation of A-homo ketones. Using a large excess of diazomethane generated in situ from A-methyl-nitrosourea with potassium hydroxide in ether-methanol at 0°, 5a-cholestanone (lb) is converted into the 7-membered ring homolog (3b) as the predominant product. Both theoretically possible A-homo ketones can be expected with an unsymmetrically-substituted cyclohexanone such as 5a-cholestanone (lb). 

A valuable extension of the diazomethane reaction for the preparation of A-homosteroids was discovered by Johnson, Neeman and Birkeland " who found that a,j5-unsaturated ketones are homologated by reaction with diazomethane in the presence of either fluoroboric acid or boron trifluoride. The main product is formed by the insertion of a methylene group between the carbonyl group and the unsaturated a-carbon to give a / ,y-unsaturated ketone. 

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. 

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. 

The use of Lewis acids for the diazomethane and diazoethane homologations of a series of Ce-Cu ketones has been reported to reduce the amount of epoxide formation, although as the ring size increases the amount of unreacted starting material increases (Scheme 12). The expansion of 2-allylcyclohexa-none with diazomethane in the presence of AlCh proceeds with migration of the less-subsdtut bond, in contrast to the Tiffeneau-Demjanov expansion of 2-methyl- and 2-isopropyl-cyclohexanone wherein the alkyl-substituted bond migrates preferentially (Scheme 13). - ... 

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. 

Homologation of aldehydes. Reaction with diazomethane gives epoxides. It should be noted that MeAl(OAr>2 promotes formation of ketones. 

Obviously, the zwitterion 7.141 is the characteristic intermediate for the Tiffeneau rearrangement. This can also be obtained in the reaction of a ketone with diazomethane (7-48) and leads, therefore, also to the next higher homolog of the starting cycloalkanone (see also Sect. 9.1). 

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. 

The aluminium trichloride-catalysed homologation of ketones with diazomethane has been applied to the synthesis of D-bishomo-steroids." Thus,... 

Reaction of 3a.5-cyclo-5a-cholestan-6-one (359) with diazomethane made it possible to prepare a number of B-homo-keto-derivatives (360)—(364). Further homologation of the eight-membered-ring ketones (362), (363), and (364) led to the formation of the four ketones (365)—(368), in which a carbonyl group is contained in a nine-membered ring. ... 

Homologation of Selenol Esters to a-Seleno Ketones with Diazomethane. . 126... 

The reaction of ketones with diazomethane has been thoroughly studied (55) homologous ketones or epoxides are the usual reaction products. With acylmetalloids two alternative ketones could be formed, depending on whether the silyl (or germyl) group or the (R ) group attached to the carbonyl underwent the 1,2-migration. 

Diazomethane reacts with ketonic compounds according to the reactions to give epoxides and homologated ketones. If the ketone employed is cyclic, only a single... 

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