Methyl pivaloylacetate

Conditions (unless otherwise noted) 11.0 mL (83.8 mmol) chloropinacolone, 30.0 mL (0.126 mol) n-BusN, 110 mL MeOH, O.lmmol Pd, 5.4 atm CO, 105°C, 3 h Abbreviations MPA = methyl pivaloylacetate PA = Pinacolone TON = mol MPA produced/mol Pd used Me2lm = 1,3-dimethyl imidazoline-2-ylidene (dimethyl imidazolium carbene complex) Ms2lm = l,3-di-(2,4,6-trimethylphenyl) imidazoline-2-ylidene (dimesityl imidazolium carbene complex) cy-hex = cyclohexyl Used 0.127 mmol Pd catalyst... 

The screening work demonstrated that with a (cj-hex3P)2PdCl2 catalyst the targeted methyl pivaloylacetate concentrations and desired reactor residence times could be achieved. Unfortunately, the process still would not meet the targeted catalyst performance (TON >5,000 mol MPA/mol Pd) and required further development directed at improving catalyst and reactor productivity. 

As indicated in Table 3, reducing the excess methanol to only a 3 fold molar excess (rendering a nearly solvent free process) far exceeded expectations and allowed significant reductions in the catalyst levels. Under these conditions, catalyst turnover numbers exceeding 10,000 mol MPA/mol Pd were achieved with a turnover frequency of >3400 mol MPA/mol Pd/h. The reaction mixtures obtained from this process formed two liquid phases and the product spontaneously separated from the amine and amine hydrochloride. As a consequence of eliminating large methanol excesses, the methyl pivaloylacetate concentration in the product was raised to 26 wt. % without additional reaction time being required. This represents an additional ca. 2.5 fold improvement in reactor productivity. No attempt was made to reduce the methanol further. 

In summary, compared with earlier processes which utilize hazardous solvents and generate large waste streams, the carbonylation of chloropinacolone offers an environmentally and operationally advantaged process since it requires (r) very little excess amine or methanol, (fr) no extraneous reaction solvents, Hi) little or no extraction solvent, and (fr) the tributylamine coreactant and methanol components are readily recycled. This was accomplished while also demonstrating similar yields, shorter reaction times, and higher product concentrations which result in a significant reduction in the number of batches and time required to produce significant quantities of methyl pivaloylacetate. 

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