Diethyl 3-oxoglutarate, reaction with

The addition sequence may determine the primary reaction course or influence impurity formation. For example, condensation of diethyl 3-oxoglutarate 33 with chloroacetone and methylamine is expected to give the 5-methylpyrrole 34, the Hantzch pyrrole product (Figure 5.14). The isomeric 4-methylpyrrole 35 (a precursor to zomepirac sodium) was prepared in good yield by first treating 33 with methylamine, then adding chloroacetone [22]. The addition sequence was also important for the chlorination of the sulfinate anion 36 The dimer 37 was produced when N-chlorosuccinimide was added to the reaction, but when 36 was added slowly to excess Cl2, the desired sulfonyl chloride 38 was produced (Figure 5.14) [23], The course of these reactions may be predicted if one takes a mental snapshot of them. 

The reaction, under the same conditions, has been extended to other /3-keto esters. Ethyl 3-oxovalerate, ethyl 3-oxohexanoate, and diethyl 3-oxoglutarate react with 2-amino-2-deoxy-D-glucose to give compounds (11), (12), and (13), respectively, whose oxidations with lead tetraacetate or periodic acid furnish the corresponding aldehydes (14), (IS), and (16). 

The scope of the condensation reaction has been extended considerably by varying the dicarbonyl compound employed. Diethyl 3-oxoglutarate, acetylacetone (2,4-pentanedione), and other compounds with structures analogous to that of ethyl acetoacetate, form compounds of constitution similar to that of II. 

The reactions of D-glucose with 2,4-pentanedione (acetylacetone), diethyl 3-oxoglutarate, ethyl benzoylacetate, ethyl propionylacetate, ethyl butyrylacetate, ethyl isovalerylacetate, and methyl acetoacetate have been effected, with formation of crystalline products. 

Isopropylidene amino(ethoxycarbonylmethyl)methylenemalonate (1611) and boron trifluoride etherate were heated under reflux in ethanol for 48 hr. When the reaction mixture was treated with aqueous potassium carbonate, the triester (1612) was obtained in 40% yield, while after evaporation of the solvent and treatment of the residue with water, diethyl 3-oxoglutarate was isolated in 22% yield (8IS 130). 

Although a tetrahydrodioxodn structure has been suggested for the product of the reaction of bis(2-bromoethyl) ether with diethyl /3-oxoglutarate under basic conditions (43JGU352), the reported data are insufficient to establish this structure. 

The yields of the reaction depend on both steric demand of the substituent of the 1,3-dicarbonyl compounds and the electronic nature of this substituent. Very good yields were obtained by employing dimethyl 3-oxoglutarate 68 or methyl 4-methoxy-3-oxobutanoate 69. The lowest yields were observed while using with methyl 4,4-dimethoxy-3-oxobutanoate 70 or diethyl 2-oxaloacetate 71. 

---