Decarboxylation and Hydrogenolysis

Hydrogenolysis of the diallyl alkylmalonate 757 with formic acid in boiling dioxane affords the monocarboxylic acid 758. Allyl ethyl malonates are converted into ethyl carboxylates[471]. The malonic allyl ester TV-allylimide 759 undergoes smooth deallylation in refluxing dioxane to give the simple imide 760(472]. The allyl cyanoacetate 761 undergoes smooth decarboxylation to give 

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In Fig. (12) keto ester (94) was selected as starting material. It was converted to the formyl derivative (95) which yielded a,P-unsaturated aldehyde (96) by treatment with DDQ. Michael addition of the sodium enolate of tert-butyl- isovalerylacetate to aldehyde (96) afforded the adduct (97) as a mixture of C-ll diastereomers. By fractional crystallization one of the adducts could be separated but for the synthetic purpose the mixture was not separated. Treatment of the adduct (97) with p-toluenesulfonic acid in glacial acetic acid caused t-butyl ester cleavage, decarboxylation and cyclodehydration leading the formation of tricyclic enedione (98) in 80% yield. This approach was previously utilized by Meyer in the synthesis of nimbiol [29], Treatment of (98) with pyridinium bromide perbromide, followed by hydrogenolysis with palladium and carbon caused aromatization of (98) leading the formation of the phenolic ester (99). 

In practice,benzyl acetoacetate (20) was used so that the free acid could be released and decarboxylated by hydrogenolysis. The benzaldehyde condensation is unambiguous as dehydration of the alternative product is impossible (Chapter 20). 

Hydrogenation of the two alkenes and hydrogenolysis of the benzyl ether (followed by decarboxylation) gives the intermediate amino-ketone shown below. Subsequent cyclization to the imine/enamine is followed by further reduction on the less-hindered (outer, convex face) to give pumiliotoxin C. See L. E. Overman and P. J. Jessup, J. Am. Chem. Soc., 100 (1978), 5179. 

The best way to make pyrimidine in quantity is from 1,1,3,3-tetraethoxypropane (or other such acetal of malondialdehyde) and formamide, by either a continuous (58CB2832) or a batch process (57CB942). Other practical ways to make small amounts in the laboratory are thermal decarboxylation of pyrimidine-4,6-dicarboxylic acid (744), prepared by oxidation of 4,6-dimethylpyrimidine (59JCS525), or hydrogenolysis of 2,4-dichloropyrimidine over palladium-charcoal in the presence of magnesium oxide (53JCS1646). 

The 3-benzyloxyisoxazole system has functioned as a storable /3-keto amide unit in the construction of tetracyclines (78JA3609). Michael addition of the anion of the 3-benzyloxyisoxazole (442) to the dienolone (441) followed by deesterification-decarboxylation gave rise to (443) in 80% yield. Dehydration of this material and sodium hydride-induced cyclization afforded (445). Hydrogenolysis over palladium on carbon produced the desired ( )-dedimethylamino-12a-deoxyanhydrotetracycline (446 Scheme 99). This isoxazole route has also been extended to the preparation of a tetracycline having the usual amino function in the A ring. 

Dimethoxyfuran is readily available from the enolic dimethyl 3,4-dihydroxyfuran-2,5-dicarboxylate. This intermediate, like a phenol, can be readily O-methylated or O-benzy-lated. Hydrolysis and decarboxylation then furnishes the 3,4-dialkoxy compounds (78HCA430). The dimethoxy compound readily enters into Diels-Alder reactions, the Man-nich reaction, and may be lithiated. On mild acid hydrolysis it supplies, in poor yield, 4-methoxyfuran-3(2/f)-one and not tetrahydrofuran-3,4-dione, which is not produced by attempted hydrogenolysis of 3,4-dibenzyloxyfuran either. The dione, however, is known, and surprisingly exists in the diketo form (60JA3219). 

The alkyne insertion reaction is terminated by anion capture. As examples of the termination by the anion capture, the alkenylpalladium intermediate 189, formed by the intramolecular insertion of 188, is terminated by hydrogenolysis with formic acid to give the terminal alkene 192. Palladium formate 190 is formed, and decarboxylated to give the hydridopalladium 191, reductive elimination of which gives the alkene 192 [81]. Similarly the intramolecular insertion of 193 is terminated by transmetallation of 194 with the tin acetylide 195 (or alkynyl anion capture) to give the dienyne 196 [82], Various heterocyclic compounds are prepared by heteroannulation using aryl iodides 68 and 69, and internal alkynes. Although the mechanism is not clear, alkenylpalladiums, formed by insertion of alkynes, are trapped by nucleophiles... 

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