Tetrasubstituted compounds ketone preparation

Several preparative methods exist for the synthesis of 3(2//)-dihydrofuranones. 2,5-Disubstituted or 2,2,5,5-tetrasubstituted 3(2i/)-dihydrofuranones are usually prepared by reaction of sodium or lithium acetylide with a ketone to yield an alkynic alcohol which is then treated with a carbonyl compound in the presence of base to afford alkynic diols. Mercury catalyzed hydration of the resultant diols in the presence of acid affords the furanones in good yields (76JMC709). 

The transformation of tetrasubstituted ethylenes into 1,2,4-trioxolanes may also be achieved if the ozonolysis is carried out in the presence of a foreign carbonyl compound as described in Section 4.33.3.4. With formaldehyde as added carbonyl compound, 3,3-disubstituted derivatives are obtained, whereas in the presence of excess ketone (e.g. by using the latter as solvent), the ozonolysis gives rise to tetrasubstituted 1,2,4-trioxolanes which are difficult to prepare by other methods. Reactions (163) -> (164) and (165) -> (166) provide two examples of this versatile 1,2,4-trioxolane synthesis. Unlike the parent system (2), alkyl- and/or aryl-substituted 1,2,4-trioxolanes generally are stable, non-explosive compounds. Mixtures of crossed ozonides (cf. Section 4.33.3.1.1) or of cis and trans isomers can be separated by thin layer, column or gas chromatography. The cis isomers of symmetrical 3,5-disubstituted 1,2,4-trioxolanes are meso forms, whereas the corresponding trans isomers represent racemates which in some cases have been resolved into their optical... 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

Since conocephalenol (56) has a very similar structure to tamariscol, the synthetic strategy used was similar to those used in the tamariscol synthesis. If the trisubstituted double bond of the a,P-unsaturated ester, 61 or 62, could be isomerized into the ester, 63, with the tetrasubstituted double bond, compound 56 might easily be prepared. If this isomerization does not proceed, this could be accomplished through the epoxide 64. The optically active compound might be synthesized from the ketone 65 or its alcohol (Scheme 11). 

PET from EtjN to the all- /nio-7-oxanorbomanone derivative (+)-143 prepared by radical C-C bond formation between enone 141" and acetobromogalactone 142" led, as expected, to the reductive ring opening of the oxabridge and provided the tetrasubstituted cyclohexanone (+)-144 without epimerization a to the ketone. Compound (+)-144 was then converted into 145, a dicarba analog of 2-0-(a-0-galactopyranosyl)-Cl-xylopyrano-dialdehyde (Scheme 55). 

In 1999, Katritzky reported a novel [3+2+1] synthesis of 2,4,6-trisubstituted pyridine derivatives that used the Michael addition of a-benzotriazolyl ketones to a,P-unsaturated carbonyl compounds. This reaction resembles the Krohnke pyridine synthesis and is an extension of Katritzky s earlier studies with benzotriazolyl derivatives that provided access to pyridones, 2-thiopyridones, 5-alkyl-2,4-diphenylpyridines and 2-aminopyridines. This approach is attractive as both components are readily synthesized or commercially available. The availability of these starting materials allows for an efficient access to structurally diverse 2,4,6-triaryl pyridines when combined with ammonium acetate in acetic acid at reflux. In addition, it is possible to access fused 2,3,4,6-tetrasubstituted pyridines from the requisite fused bicyclic ketone starting material. The preparation of the pyridine ring via benzotriazole methodology has resulted in improved yields for many compounds and the opportunity to synthesize molecules with a substitution pattern that would be difficult to prepare by other methods. 

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