Sukbok Chang on the Development of Two New Catalytic Protocols

Fast Moving Front Commentary, January 2012

Sukbok Chang

Article: Palladium-catalyzed C-H functionalization of pyridine N-oxides: Highly selective alkenylation and direct arylation with unactivated arenes

Authors: Cho, SH;Hwang, SJ;Chang, S
Journal: J AM CHEM SOC, 130 (29): 9254-+, JUL 23, 2008
Addresses: Korea Adv Inst Sci & Technol, Dept Chem, Taejon 305701, South Korea.
Korea Adv Inst Sci & Technol, Dept Chem, Taejon 305701, South Korea.
Korea Adv Inst Sci & Technol, Sch Mol Sci BK21, Taejon 305701, South Korea.

Sukbok Chang talks with and answers a few questions about this month's Fast Moving Fronts paper in the field of Chemistry.

SW: Why do you think your paper is highly cited?

Transition metal-catalyzed C–H bond activation of low reacting molecules such as hydrocarbons for the direct C–C bond formation is an emerging research topic especially in recent years. A variety of significant applications of this approach have been revealed in materials and medicinal chemistry as well as in organic synthesis.

With this aspect, this report from the Journal of the American Chemical Society (2008) contributes a new advance in the direct functionalization of pyridine N-oxides, one of the most important heterocycles having an important utility in various research areas. Our paper has been regarded as one of the earlier examples of the sp2 C–H bond activation of pyridine derivatives, thus paving a new avenue as an attractive alternative to the conventional cross-coupling reactions.

SW: Does it describe a new discovery, methodology, or synthesis of knowledge?

In this paper, the development of two new catalytic protocols was revealed leading to the direct C–C bond formation of pyridine N-oxides using palladium catalyst and silver oxidant. With these methods, catalytic alkenylation with olefins and direct arylation with unactivated arenes were achieved with excellent selectivity and efficiency.

In the alkenylation reaction, it was demonstrated that the ortho C–H site to the nitrogen atom of pyridine N-oxides was readily activated by the action of palladium catalyst. The oxidative alkenylation reaction was highly regioselective occurring exclusively at the C-2 position to produce only (E)-double bonds. The chemoselectivity in this transformation was extremely high and, as a result, no double alkenylation proceeded during the course of the reaction.

In addition, oxidative cross-coupling of pyridine N-oxides with unactivated arenes was also developed for the first time under similar conditions. Therefore, it represents a successful example of the dual C–H bond activation strategy in organic synthesis. The direct arylation of benzene derivatives into pyridine N-oxides was highly regio- and chemoselective, and selectivity of the formation of mono- versus double-arylation could be controlled under suitable conditions.

SW: Would you summarize the significance of your paper in layman's terms?

In conventional syntheses, molecules are usually pre-functionalized in order to introduce certain groups into the molecules at the desired position. For example, two pre-functionalized compounds can be coupled together to give coupled products, and this reaction can be facilitated most efficiently by transition metal catalysts.

"...we are optimistic that the present study can be further improved eventually to replace the present pre-functionalization approach in organic synthesis, medicinal, and materials chemistry."

In fact, the Nobel Prize in Chemistry was awarded in 2010 to three organic chemists for their contributions in this area. This approach has been widely utilized in organic synthesis and in pharmaceutical and materials industry. However, this method inevitably generates undesired side products (two pre-functional groups) which need to be discarded with additional costs.

In recent years, chemists have become interested in the development of an alternative approach in which non-pre-functionalized molecules are directly employed to react with other reactants. For instance, in this approach, two benzene molecules can be coupled together to form biphenyl product. Our work in the J. Am. Chem. Soc. report represents an early example of this strategy with pyridine derivatives which are widely used in various research areas. We successfully developed a method of introducing organic groups into pyridine derivatives without pre-functionalization by virtue of Pd catalysts.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

Over the past years, our group had already been involved in the related research area. We studied the hydroesterification reaction of 2-pyridylmethyl formate with alkenes using a ruthenium catalytic system to provide one-carbon elongated esters. Along the way, our interest had been further developed to challenge more basic and fundamental problems.

As a result, we started our program for the development of highly efficient catalytic procedures for the direct C–H bond activation of hydrocarbons. In particular, the direct C–H bond activation of benzenes, which is one of the most readily available chemical feedstocks, for the selective C–C bond formation. We envisioned that our successful results would be an important contribution for the eventual goal to replace the currently used pre-functionalization approach.

SW: Where do you see your research leading in the future?

The next step in the field of C–H bond activation is to provide opportunities to deliver value-added chemical feedstocks from simple hydrocarbons, representatively methane. However, such compounds display inherently low reactivity towards most present catalytic systems, thereby awaiting new synthetic procedures enabling the C–H bond functionalization under ambient and selective conditions. On the basis of our results presented in the J. Am. Chem. Soc. paper, the eventual goal of the selective functionalization of hydrocarbons would be within the touch in due course by our own or other researchers' efforts.

SW: Do you foresee any social or political implications for your research?

Our work is more basic and fundamental rather than practical and applicable to industry at the present stage. Although the eventual impact of our work would be the facile utilization of readily available hydrocarbons such as methane for the manufacture of value-added chemicals, we need efficient and selective catalytic systems to achieve this goal more effectively. Nevertheless, we are optimistic that the present study can be further improved eventually to replace the present pre-functionalization approach in organic synthesis, medicinal, and materials chemistry.End

Sukbok Chang, Ph.D.
Professor, Department of Chemistry
Korea Advanced Institute Science & Technology (KAIST)
Daejeon, Republic of Korea



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