1,3-Dimethylorotic acid

When 1,3-dimethylorotic acid (233) was heated at 198 °C in benzyl bromide for 3h, 6-benzyl-1,3-dimethyluracil (236) was formed in 10% yield together with the product of decarboxylation, 1,3-dimethyluracil (235). This finding supports the involvement of a carbon-6-centred nucleophilic intermediate in the decarboxylation reaction a carbanion (234) could be involved or a carbene (237)." ... 

Decarboxylation of 1,3-dimethylorotic acid in the presence of benzyl bromide yields 6-benzyl-1,3-dimethyluracil and presumably involves a C(6) centered nucleophilic intermediate which could nonetheless have either a carbene or ylide structure. Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry has been used to explore the gas-phase reactions of methyl nitrate with anions from active methylene compounds anions of aliphatic ketones and nitriles react by the 5n2 mechanism and Fco reactions yielding N02 ions are also observed nitronate ions are formed on reaction with the carbanions derived from toluenes and methylpyridines. 

The solvent effect of ionic liquids on the decarboxylation of 1,3-dimethylorotic acid and its analogue has been investigated.12 The rate acceleration observed has been attributed to stabilization of the zwitterionic intermediates by the charged groups available in these special solvents. 

Although it is reasonable to assume from the enzymic studies cited162 that orotidine possesses the /3 configuration at the anomeric center, unequivocal determination of this feature is to be desired. Of interest is the fact that 1,3-dimethylorotic acid,119 3-methylorotic acid,119 163 and orotic acid itself are decarboxylated to the corresponding uracil derivatives at elevated temperatures. If orotidine could be decarboxylated in some similar fashion to uridine, the complete structure of XXXII would be established. 

The thermal decarboxylation of 1,3-dimethylorotic acid 56 was studied as a model for uncatalysed decarboxylation of orotidine 5 -monophosphate to form uridine 5 -monophosphate.97 This reaction catalysed by the enzyme oritidine 5 -monophosphate decarboxylase is the essential step in nucleic acid biosynthesis.98 Samples of 1,3-dimethylorotic acid were heated at 190°C to conversion over 90% and unreacted substrate was recovered after conversion into the methyl ester. 

In solution the decarboxylation of 1,3-dimethylorotic acid in sulfolane has been shown through a combination of theoretically predicted and experimentally observed isotope effects to proceed via protonation of the 4-oxygen. 

When 1,3-dimethylorotic acid (233) was heated at 198 °C in benzyl bromide for 3h,... 

The lack of evidence for the involvement of cofactors in ODCase catalyzed decarboxylation prompted Beak and Siegel to propose a novel mechanism, which was supported by experiments on model systems [5]. They showed that the decarboxylation of 1,3-dimethylorotic acid in sulfolane follows two different pH-dependent pathways. In neutral solution, decarboxylation is initiated by zwitterion formation. This led to the proposal of a zwitterion intermediate in the ODCase catalyzed reaction in which the 02 of the pyrimidine ring is protonated, promoting the release of CO2. 

Beak and Siegel [8] presented a thorough study of the decarboxylation of 1,3-dimethylorotate and analogs in non-aqueous solvents. The decarboxylation of 1,3-dimethylorotic acid was found to be first order, and slightly faster with the anion 1,3-dimethylorotate than with the acid, indicating a decarboxylation of the carboxylate without general acid catalysis (Fig. 2). 

Fig. 2 Proposed mechanism for non-enzymatic decarboxylation of 1,3-dimethylorotic acid, in the absence upper route) or presence lower route) of added base. From [8]...

B5 Beak, B. and Siegel, B. Mechanism of decarboxylation of 1,3-dimethylorotic acid. A possible role for orotate decarboxylase. J. Am. Chem. Soc., 95, 7919-7920 (1973)... 

Wong FM, Wu WM. Accelerated decarboxylation of 1,3-dimethylorotic acid in ionic liquid. Bioorg Chem. 2006 34 99-104. 

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