Reports: UR154968-UR1: Palladium Catalyzed alpha Heteroarylation of Ketones
printer friendly1. Reaction condition optimization:
Using valved pressure NMR tubes and the heteroarylation of acetophenone with 3-bromopyridine as the model reaction, we tested a range of palladium catalysts, ligands, bases and solvents in order to optimize the reaction conditions. (1) The best catalysts for this reaction included XPhos Pd G1 (STREM 46-0268), Pd2(dba)3/tBuPHBF4 and Pd2(dba)3/Xphos with reaction yields in the range of 40% - 80%. Some catalysts such as (SIPr)Pd(allyl)Cl, PdCl2, Pd(OAc)2, and Pd(dba)2 showed moderate catalytic reactivity with yields between 20% to 40%. The rest catalysts such as Pd(PPh3)2Cl2, Pd(PPh3)4 had poor or none catalytic ability for this transformation. (2) The ligands which possess bulky groups such as XPhos, tBuXPhos and JackiePhos showed good activities. Electronic and steric effect of ligands can influence the rate of several steps in the catalytic cycle. Our results are in agreement with literature report on similar reaction systems. (3) Pre-coordinated of catalysts and ligands such as Pd2(dba)3/tBuPHBF4and XPhos Palladacycle Gen. 1 catalyst showed enhanced reactivity and selectivity. The pretreatment will let the palladium coordinate to ligands before they are exposed to heteroaryl halides to avoid potential inhibitory effect of heteroatoms on the in situ formation of the catalytically active Pd(0)/ligand complex. These results provided important insights for the direct α-heteroarylation of carbonyl compounds and this information could be used to guide the development of more general and robust catalyst systems.
2. Microwave irradiation:
Microwave irradiation has been applied in palladium-catalyzed cross-coupling reactions to enhance the reaction efficiency. The alpha-heteoarylation of ketones using palladium catalysis normally took 4 - 24 hours at 60 oC under thermal conditions. In order to improve the efficiency, we utilized our recently acquired microwave reactor (Anton Paar Multiwave Pro) to facilitate the reaction process. After careful examination on a range of temperatures and times, it was found that microwave irradiation of the reaction mixutre at 130 oC for 10 min provided the best yields in the range of 40% to 60%. Compared to the traditional thermal heating conditions, the microwave-assisted reactions are rapid, efficient and more selective. The microwave-assisted palladium-catalyzed heteroarylation reaction enabled the establishment of a rapid and efficient approach to functionalize the ketone α-carbons with heteroaryl moiety.
3. Substrate scope investigation:
With the reaction conditions optimized and the microwave-assisted method established, we started to investigate the ketone and heteroaryl halides substrate scopes. Among the 34 ketones and 40 heteroaryl halides purchased by our lab, we have tested 12 ketones and 7 heteroaryl halides and successfully purified the heteroarylation products. Generally speaking, this reaction worked well with substrates such as 3-bromopyridine, 5-bromopyrimidine and 6-bromoquinoxaline. Electron rich small heterocycles such as 5-bromo-1-methyl-1H-imidazole and 4-bromothiazole seemed not successful in this reaction. For ketone substrates, aryl ketones gave better yields than alkyl ketones. This reaction can also be used to selectively heteroarylate certain ketone group if multiple ketones are present in a molecule (e.g., adrenosterone). The investigation on the rest ketones and heteroaryl halides will be continued for the next two years.
The results from this project will provide useful knowledge on transition metal catalysis which can be used to add functionality to petroleum-derived chemicals. The mechanistic study using NMR techniques will shed light on the fundamental steps involved in this catalysis system. Overall, the information obtained from this study will be used to design better catalyst/ligand system for the challenging heteroaryl substrates. The results from this project will also contribute to my professional growth in organic chemistry and my professional recognition nationally. The research discoveries for the palladium-catalyzed heteroarylation of ketones will be presented at regional or national conferences. Manuscripts will be submitted to peer-reviewed journals for publication, which will increase the applicant’s competitiveness in publishing high-quality papers and obtaining continuous and large external grants.
The study on palladium-catalyzed alpha-heteroarylation of ketones is important because it not only explores a new catalytic system, but also provides excellent research opportunities for NKU undergraduate students, especially for women and minorities. From April 1st to August 31st, 2016, there were 9 undergraduate students involved in this project. Two full-time undergraduate researchers were paid through this ACS PRF grant in summer 2015, and two full-time undergraduate researchers were paid through NKU internal grants in summer 2016. The rest of the students volunteered to work in my lab. Among these students, half of them are first-generation college students, seven (78%) were female research students, and two (22%) were African American and/or Latino research students. Undergraduate students benefit significant from their independent research experience. In addition to laboratory techniques necessary for their future positions in graduate schools or professional schools, they also received guidance from the PI on their research result presentations, manuscript preparation and student grant development. They discussed their career plans among themselves, as well as with the PI for advices. Several of those students received awards from NKU, Kentucky or ACS which included NKU Regents Award, ACS Undergraduate Award in Organic Chemistry and 1st place in the KAS Undergraduate Oral Presentation Competition. Undergraduate students involved in research realize that they make important contributions to the field of organic chemistry, and they share the excitement of discovery in this scientific field.
