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45433-AC1
Development of Coupling Reactions Catalyzed by Ultra-Low Concentrations of Metal Catalysts Using Microwave Heating
The academic year 2006 / 2007 is the first of the two years of our Type AC project. We have spent the year investigating low catalyst loading C-C and C-N bond forming reactions using microwave heating. As well as being energy efficient, microwave heating can also enhance the rate of reactions and in many cases improve product yields. In the area of C-C bond forming reactions we have focused mainly on Heck couplings as well as carbonylation chemistry. The latter has been particularly fruitful. Since these reactions involved carbon monoxide as a reagent, in order to undertake these experiments we first needed to modify our microwave apparatus so we could safely and predictably load our reaction vessels with CO. This was easily done and we subsequently used the apparatus for hydroxycarbonylation and alkoxycarbonylation reactions involving aryl iodides. We found that we could use palladium loadings in the region of 10 ppm and could use simple palladium salts as opposed to traditional phosphine-ligated palladium catalysts. In addition, the reactions were complete within 10 – 20 min of microwave heating. A review of carbonylation chemistry shows that the conditions for performing reactions can be separated into two general categories. They can be run at atmospheric pressure by bubbling CO through or passing CO over the reaction mixture or they can be run in sealed vessels under elevated pressures of CO. In both cases, carbon monoxide is present in a large stoichiometric excess. There are a number of disadvantages to using a significant excess of CO. From a practical standpoint, it is wasteful, and, since CO is highly toxic, extreme care must be taken when venting reactions. We have recently found that we can perform the reactions using a stoichiometric quantity of carbon monoxide. By reducing the amount of CO used, it is possible to prolong the lifetime of catalysts and increase turnover numbers. Also, if using radiolabeled carbon monoxide, this methodology would represent a significant cost saving since isotopically labeled CO is expensive.
We have fulfilled another of our goals of the project which is to scale-up low-level C-C coupling reactions from the mg to the multigram level. While many reactions have been performed on the small scale using microwave heating, few have been further developed into larger-scale syntheses. This clearly needs to be addressed if the technology is going to impact process chemistry. We have done this successfully for the Suzuki and Heck couplings using between 50 and 500 ppb of ligandless palladium catalysts. We have performed these reactions on the 0.l mole level in a batch reactor. We have also looked at continuous-flow approaches and find that it is necessary to increase the catalyst loading to 1 – 5 ppm in that case but this gives us the ability to process moles of material. We have also scaled up our alkoxycarbonylation chemistry to the multigram level, again working with stoichiometric quantities of carbon monoxide. This scale-up work has been performed in a prototype batch reactor that we had access to in 2007.
Alongside this work we have looked at C-N bond forming reactions using ppm levels of ligandless palladium sources as catalysts in conjunction with microwave heating. Our work was focused around the coupling of bromoarenes with piperidine. While we were able to obtain small quantities of the desired products, problems were encountered with decomposition and poor catalytic activity and are actively looking at alternative strategies at the moment. This will be part of our future efforts as will looking at other low catalyst level reactions involving gaseous reagents, thus building on our success with the low-catalyst loading carbonylation reactions. We also will move to C-O bond forming reactions as outlined in our proposal.
