A Microfluidic Approach to the Rapid Screening of Palladium‐Catalysed Aminocarbonylation Reactions

Abstract

Abstract:The evaluation and selection of the most appropriate catalyst for a chemical transformation is an important process in many areas of synthetic chemistry. Conventional catalyst screening involving batch reactor systems can be both time-consuming and expensive, resulting in a large number of individual chemical reactions. Continuous flow microfluidic reactors are increasingly viewed as a powerful alternative format for reacting and processing larger numbers of small-scale reactions in a rapid, more controlled and safer fashion. In this study we demonstrate the use of a planar glass microfluidic reactor for performing the three-component palladium-catalysed aminocarbonylation reaction of iodobenzene, benzylamine and carbon monoxide to form N-benzylbenzamide, and screen a series of palladium catalysts over a range of temperatures. N-Benzylbenz-A C H T U N G T R E N N U N G amide product yields for this reaction were found to be highly dependent on the nature of the catalyst and reaction temperature. The majority of catalysts gave good to high yields under typical flow conditions at high temperatures (150 8C), however the palladium(II) chloride-Xantphos complex [PdCl 2 A C H T U N G T R E N N U N G (Xantphos)] proved to be far superior as a catalyst at lower temperatures (75-120 8C). The utilised method was found to be an efficent and reliable way for screening a large number of palladium-catalysed carbonylation reactions and may prove useful in screening other gas/liquid phase reactions.

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…Of Pd(0) catalysts, Pd-xantphos was surfaced from a screening array for its superior catalytic activity at relatively lower temperatures giving excellent radiochemical yields in aminocarbonylation. 152 Recently, Pd(II)-aryl precursors have been developed as isolable stoichiometric reagents for aminocarbonylation to directly prepare labeled amides rapidly and with high radiochemical purity from [ 11 C]CO. 153 In this case as well, Pd-xantphos complexes appeared to be among the most reactive precursors, though electron-deficient aryl precursors demanded Pd-P( t -Bu) 3 to prevent arene scrambling with the with phosphine ligand. This approach appears to be very promising, though the need to balance each of [ 11 C]CO trapping efficiency, Pd-aryl complex reactivity, and amine nucleophilicity, all of which are highly dependent on the precursor, suggests that significant optimization may be important for each substrate.…”

N‐heterocyclic carbenes as ligands in palladium‐mediated [11C]radiolabelling of [11C]amides for positron emission tomography

“…A range of well‐known and widely used benchmark Pd‐phosphine complexes (Figure 3) were also investigated for the model carbonylation reaction. Pd‐monophosphine and chelating diphosphine catalysts have been widely investigated for a range of carbonylation reactions33, 34 and as such are useful for comparative purposes with the Pd‐NHC catalysts. The results from the model aminocarbonylation reactions using phosphine ligands are shown in Table 1.…”

Palladium-mediated11C-carbonylations using aryl halides and cyanamide

“…The bidentate ligand 4,5-bis(diphenylphosphino)-9,9dimethylxanthene (Xantphos) has previously been successfully in both 11 CO and CO carbonylations. 9,[29][30][31] In our setup complete consumption of 11 CO (RTE >99%) was achieved with this ligand at 120 °C and 150 °C but with lower RCP (61% and 72%, entry 3-4). Interestingly, no formation of acid was detected using this ligand.…”