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Reports: UR154968-UR1: Palladium Catalyzed alpha Heteroarylation of Ketones

Lili Ma, PhD, Northern Kentucky University

From August 31st 2016 to August 31st, 2017, we continued our research on palladium-catalyzed direct alpha-heteroarylation of ketones with the support from ACS PRF. While we expanded the substrate scope study we initiated last year, some unusual reactions between ketones and heteroaryl substrates catalyzed by palladium catalysts were discovered. We performed some preliminary experiments to probe the reaction mechanisms which might be involved in the observed unusual reactions. The detailed progress is summarized below:

1. Reaction condition optimization (continued):

The optimal reaction condition we established last year was: 1% XPhos Palladacycle Generation 1 catalyst (STREM 46-0268), 2.4 eq tBuONa, microwave irradiation, 130 oC, 10 min. This year we explored a few more catalyst/ligand system which included XPhos Palladacycle Generation 2 catalyst (STREM 46-0281), XPhos Palladacycle Generation 3 catalyst (STREM 46-0320) and XPhos Palladacycle Generation 4 catalyst (STREM 46-0327). From Generation 1 to Generation 4 catalysts, the steric hindrance of the ligand is getting larger. It was hypothesized that the sterically hindered ligands make the reductive elimination more facile by pushing the aryl and enolate group at the palladium center closer together in space so that they coordinate in a cis mode. In our experiments, the best results were obtained with XPhos Palladacycle Generation 4 catalyst, which was in agreement with our hypothesis.

2. Substrate scope investigation (continued):

Using XPhos Palladacycle Generation 4 catalyst, we continued our investigation on substrate scope. Currently we have 34 ketones and 40 heteroaryl halides in our lab. We tested 12 ketones and 7 heteroaryl halides in 2016. By July 2017, we finished our screening on the rest 22 ketones and 33 heteroaryl halides.

  1. For ketone substrate, 7-methoxy-1-tetralone and acetophenone were studied in detail. 7-methoxy-1-tetralone is less reactive than acetophenone. 7-methoxy-1-tetralone tended to have diheteroalkylation, while acetophenone tend to have monoheteroarylation as major product. Ingeneral, most ketones went smoothly in the palladium-catalyzed direct heteroarylation reactions, including 3-acetylpyridine, 3-acetyl-2,5-dimethylfuran, 3-acetyl-2,5-dimethylthiophene. The ketones with active methylene groups (1-phenyl-1,3-butanedione, 1,3-cyclohexanedione, ethyl levulinate, etc) didn’t give expected products, probably due to the strong basicity of tBuONa. The use of NaOEt as the base might give better results.

  2. For heteroaryl halide substrates, generally speaking, heteroaryla halides with only one heteroatom gave good to excellent yields under the optimized reaction conditions mentioned above. Five-membered ring heteroaryl halides with two heteroatoms such as 5-bromo-1-methyl-1H-imidazole, 4-bromothiazole and 4-bromoisoxazole tended to decompose and were not able to form the desired products. The substituents on the heteroaryl halides also showed different effect on the reaction. For example, amine (-NH2) or hydroxyl (-OH) groups interfered with the reactions probably due to the coordination between these groups and the palladium catalytic center. Methyl, methoxy or halides didn’t not seem to change the reaction outcomes.

3. Unusual domino reaction through palladium catalysis

One interesting product we observed in our palladium research is the domino reaction product from acetophenone and methyl 2-bromopyridine-3-carboxylate (See TOC). This product is likely to be formed via three steps which might include α-heteroarylation, nucleophile formation and cyclization. This domino product resembles the structure of isocoumarin which exhibits many biological activities. The closest example in literature was reported by Clark, R. D. etc using lateral lithiation reactions promoted by heteroatomic substituents. To the best of our knowledge, this is the first example demonstrating the one-step formation of heteroaryl isocoumarin scaffold. Prompted by this discovery, we examined this reaction in details.

  1. About 12 acetophenones with different substituents were tested in this reaction and 8 of them produced the desired products. The acetophenones which didn’t work in this domino reaction were those with –NH2, -OH or NO2 groups.

  2. In addition to methyl 2-bromopyridine-3-carboxylate, we also tested methyl 5-bromopyridine-3-carboxylate and methyl 3-bromoisonicotinate. It was interesting to find out that they all yield domino products but with different structures. Methyl 2-bromopyridine-3-carboxylate yield hemiacetal structure, methyl 5-bromopyridine-3-carboxylate possibly yielded a 14-membered dimer, and methyl 3-bromoisonicotinate yielded the isocoumarin structure.

  3. In order to understand the formation of these products, we carried out several experiments to probe the reaction mechanisms. First, the three component condensation of acetophenone, 2-bromopyridine and methyl benzoate failed to product domino products. This indicated that the 6-membered ring transition state might be important. Second, 3-bromoisonicotinic acid or 3-bromopyridin-4-yl)methanol was used to replace methyl 2-bromopyridine-3-carboxylate and no domino products formed. Both of these compounds could use oxygen as the nucleophile. However, the fact that no domino product formed suggesting that the ketone enol is more likely to be the nucleophile involved in the mechanistic sequence. We will continue our investigation on the domino reaction mechanisms this year.

A manuscript based on the research discoveries discussed above is currently in preparation and it will be submitted to peer-reviewed journals for publication. An NSF RUI grant was awarded to the PI to investigate the unusual reactions through palladium-catalyzed direct heteroarylation. The study on palladium-catalyzed alpha-heteroarylation of ketones also provides excellent research opportunities for NKU undergraduate students, especially women, minorities and other underrepresented groups. In the second year of our direct heteroarylation research supported by ACS PRF, there were 10 undergraduate students involved in this project, including one international intern student from Romania. Three full-time undergraduate researchers were paid through this ACS PRF grant in summer 2017. One of the student received the competitive NKU internal research award in 2017. The rest of the students volunteered to work during the summer. Among these students, half of them are first-generation college students, five (50%) were female research students, and two (20%) were African American and/or Latino research students. Four of these students have presented their research findings at the Kentucky Academy of Science Annual meeting.