Ketones reaction with diazomethane

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. 

Acyl substituents at the 3- and/or 4-positions result in decreased hydrolytic stability compared with the alkyl and aryl derivatives described above. Despite this constraint most of the usual reactions of the carbonyl group are possible. Aldehydes <9ILA1211> and ketones are oxidized to the carboxylic acid, borohydride reduction affords the expected alcohols, and epoxides are formed on reaction with diazomethane. Oximes and arylhydrazones are formed with hydroxylamine and arylhydrazines, and the products may subsequently undergo monocyclic rearrangement involving the oxadiazole to give the corresponding isomeric furazans and 1,2,3-triazoles (Section 4.05.5.1.4). 

Ring expansion of cyclohexanone to cycloeheptanone may be effected by reaction with diazomethane (Expt 7.17). The ring-expanded ketone is obtained in about 60 per cent yield and is accompanied by some epoxide and some cyclo-octanone which results from further ring expansion of the cycloheptanone. Mechanistically the reaction may be represented in the following manner. 

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). ... 

For monocyclic and many fused bicyclic ketones the general order of reactivity of3>4>6>7 5 has been observed in the reaction with diazomethane and derivatives. Cyclopropanones react smoothly with diazomethane and diazoethane in the absence of catalysts to form cyclobutanones (equations 1 and 2). ... 

A number of atypical reactions of enamines have been developed. For example, hydroboration-oxida-tion affords stereochemically defined, vicinal amino alcohols (equation 26). Similarly, enamines have been shown to undergo reaction with diazomethane to form substituted cyclopropanes. These materials can be further transformed to a alkylated ketones by thermolysis followed by hydrolysis (equation 27). ... 

A novel reaction was encountered by Johnson and co-workers in characterizing the noncoitiugated ketone (2) obtained from A -cholcstene-3-one (I) on reaction with diazomethane in the presence of boron fluoride. Treatment of (2) with osmium tetroxide gave the hemikelal (3), which readily forms a methyl ether. 

When a cyclic ketone reacts with diazomethane, the next larger cyclic ketone is formed. This is called a ring expansion reaction. Provide a mechanism for this reaction. 

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

In the context of ring enlargements by the Tiffeneau rearrangement, we have already mentioned in Section 7.7 the ring enlargement of cyclic ketones by reaction with diazomethane (see Scheme 7-48). This process is, of course, also an electrophilic substitution at the C(a)-atom of a diazoalkane. 

Short peptide chains in which one of the amino acid residues is replaced by a moiety related (or sometimes unrelated) to it appear with increased frequency in the literature. In the center of interest are enzyme inhibitors. Synthesis of these compounds is obviously determined by the reactivity of the unusual constituent and therefore it is hardly possible to set rules for such endeavours. We must confine the discussions therefore to generalities. For example chloromethylketones derived from certain amino acids are irreversible inhibitors which not merely interact but indeed react with the active site of an enzyme with the formation of a covalent bond. Chloromethyl ketones are synthesized by activation of the blocked amino acid followed by reaction with diazomethane to yield a diazoketone. This is transformed to the corresponding chloromethyl ketone by HCl in an organic solvent. From p-toluenesulfonyl-L-phenylalanine a chloromethyl ketone is obtained... 

One vital observation made by Nierenstein was that there was a considerable reluctance of acyl bromides to form the corresponding bromomethyl ketones. Acid bromides on reaction with diazomethane were also found to form substituted 1,4-dioxanes or specifically 3,6-dibromo-3,6-diphenyl-1,4-dioxane 8, resulting from the dimerization of adducts. The dimerization according to him could be attributed to the poor mobility of the bromide compared to the chloride group. 

Recent studies > on the reactions with diazomethane of those thio-ketones that cannot exist in the enethiol form yielded conclusive evidence for the occurrence of a 1,3-cycloaddition reaction, because the nitrogen-containing cycloadducts (76) and/or (77) could be isolated under appropriate reaction conditions. Diebert formulated the unstable compound... 

Although aldehydes and ketones can also be converted to epoxides by reaction with diazomethane (CH2N2), it is not uncommon to find that methylene insertion occurs at the same time (often preferentially) as shown in Scheme 9.59. 

Ketoses may also be prepared from the aldonyl chlorides (CXLII) containing one less carbon atom by reaction with diazomethane to give diazomethyl ketones (CXLIII) which, on hydrolysis and careful deacetylation, yield ketoses. 

Reaction of cyclic ketones with diazoraethane leads to ring enlargement. Thus cyctohexanone (I) (1 mol) and diazomethane (1 mol) give /oheptanone (II) in about 60 per cent, yield together with a little epoxide (III) as by product and some cj/cioootanone (IV) resulting from further reaction of cyctoheptanone with diazomethane. ... 

Benzyl chloromethyl ketone has been prepared by the reaction of diazomethane with phenylacetyl chloride. The method of Clibbens and Nierenstein, in which one equivalent of diazomethane is added to the acyl chloride and the chloromethyl ketone obtained directly, could not be duplicated by Bradley and Schwarzenbach or by the submitters. 

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). 

B-Homosteroids have also been prepared by acid-catalyzed reaction of diazomethane with a,/5-unsaturated ketones. 3/ -Hydroxycholest-5-en-7-one acetate (57) reacts with diazomethane in the presence of concentrated fluoroboric acid, boron trifluoride etherate or aluminum chloride to give 3yS-hydroxy-B-homo-cholest-5-en-7a-one acetate (67). The 7a-keto group is reported to be chemically less reactive than an 11-keto group. 

The reactions of diazomethane with heterocycles containing a ketonic grouping in the ring do not differ, in principle, from those of alicyclic ketones (see footnotes 3 and 177) ring expansion and the formation of epoxides compete. In general, ring expansion is the more important reaction for example, tetrahydropyran-4-one (99) is converted to l-oxacycloheptan-4-one (100) (60%) and 4,4 -epoxy-4-methyltetrahydropyran (101) (23%). ... 

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