Suzuki Cross-Coupling of α-brominated Ketones by Means of a Heterogeneous Pd/C catalyst. Kevin Clark

Transcription

1 Suzuki Cross-Coupling of α-brominated Ketones by Means of a Heterogeneous Pd/C catalyst. Kevin Clark Abstract Since the Suzuki cross coupling reaction was first published in 1979, it has become a staple in both academics and industry. The Suzuki cross coupling reaction as a homogeneous catalyst yields reliable and reproducible results under mild conditions. However, particularly in the pharmaceutical industry, the use of the homogeneous catalyst can cause an unsafe amount of transition metal contamination in the final product, and often requires expensive equipment and extra chromatographic steps to remove the metals. The purpose of this research is to eliminate the risk of contamination and create a more cost effective procedure with the use of a heterogeneous palladium catalyst. The intent of this research is to maximize product yield of the Suzuki cross coupling reaction with a heterogeneous palladium catalyst by examining the effects of changing temperature, pressure, base, and solvent.

2 Introduction The Suzuki cross coupling reaction was first published in 1979 and in 2010 the author of the publication, Akira Suzuki, won a Nobel Prize for his work. Since the reactions was first published the components and procedures regarding this reaction and its potentials have been studied with great interest. The interest of the reaction is because the ability to preform a C-C coupling is a fundamental aspect of organic chemistry and the synthesis of organic compounds. The general scheme for a model Suzuki cross coupling reaction can be broken into three distinct parts; the first is an oxidative addition of an aryl halide to the palladium catalyst and is the rate determining step of the overall reaction. This is then followed by transmetalation and ends with reductive elimination, which regenerates the palladium catalyst that can then be reused. Figure 1 depicts the mechanism described for the Suzuki cross coupling reaction. Figure 1: the mechanistic steps of a Suzuki cross coupling reaction. 2

3 The Suzuki cross coupling reaction is very relevant in modern pharmaceutical industries and is growing in popularity due to its mild reaction conditions and ability to be handled with ease. Other reactions that are able to produce similar products commonly require harsher reaction conditions and more toxic reagents. 3 The Suzuki cross coupling reaction is not only favorable for its safer conditions, but also for its ability to remove any boron-containing byproducts while maintaining purity. 1 Examples of a large scale pharmaceuticals that utilize the Suzuki cross coupling reaction are anti-mrs carbapenem, Rofecoxib, Etorocoxib, Losartan. 4 The homogeneous palladium catalyst of the Suzuki cross-coupling reaction can be replaced with homogeneous nickel 5 and copper 6. By doing so, the overall cost will be reduced. Similarly, the purpose of our research is to perform the Suzuki cross coupling reaction with a heterogeneous palladium catalyst. Following the palladium catalyst, we intend to work towards a more cost efficient alternative heterogeneous catalyst, such as nickel or copper.

4 Discussion The Suzuki Cross-Coupling Reaction A heterogeneous palladium catalyst will be used to couple the synthesized α- halogenated ketone with phenylboronic acid as shown below in figure 3. Figure 3: The coupling of phenylboronic acid with Bromoacetophenone. A variety of different conditions and chemicals must be analyzed in order to observe the efficiency of the heterogeneous palladium catalyzed reaction. Trial and error will be utilized to adjust these variables as a response to the observed products. In each case, GC/MS and NMR will be used for product identification. A generic approach will be taken for each of the following scenarios. This approach includes four subsequent steps, each changing a different variable in the reaction to maximize the overall yield and ensure what variables are causing the changes in the reaction. The palladium catalyst will be filtered out after the completion of each reaction. The remaining product of the reactions will be analyzed through both GC/MS and NMR. We will begin this process by placing an equivalent of phenylboronic acid, and bromoacetophenone in a small vial with an excess amount of potassium carbonate. Solid Pd/C will be added as the heterogeneous catalyst. All of the reactions will be ran in an organic/water solvent, which will be the first variable adjusted in the overall reaction. By adjusting the organic solvent to water ratio, the

5 affects of the addition of water can be observed to optimize the amount of product produced. The conditions in which the reactions are run in are important to take into consideration. The effects of temperature and pressure will be evaluated. The reactions will be conducted under heat in an oil bath to observe how heat effects the overall reaction with carful observation of what solvents are used so not to impose limits of the temperature ranges. The pressure will also be varied by evacuation by cycling vacuum/n2. The affects of the heterogeneous palladium catalyst will be observed under both atmospheric pressure, and controlled vacuum pressure. Aside from the solvent and the conditions, the base also acts as an important variable in the Suzuki cross-coupling reaction. 7 It is mainly used to activate the boronic acid to induce cross-coupling. In order to increase the efficiency of this step, both the structure of the base and the equivalence of the corresponding base will be analyzed. Both weak and strong bases will be observed, however it is suspected that strong bases will act more efficiently. Common bases that are used in the Suzuki cross-coupling reaction are K2CO3, K3PO4, and NaOH. Once the optimal base and solvent/water ration is chosen, the boronic acid will also be altered. The phenylboronic acid is used to couple the alpha-halogenated ketone with a phenyl ring. If the structure of the boronic acid is changed, different groups can be coupled to the alpha-halogenated ketone, yielding a wide variety of different products. Lastly, the heterogeneous catalyst being utilized to complete the Suzuki cross-coupling will be varied. While palladium is suspected to be an efficient

6 catalyst, it can also be expensive in comparison to copper, nickel, and platinum. Once all of the previous variables are corrected accordingly, a cheaper alternative to the heterogeneous palladium catalyst will be investigated.

7 Summary It is clear that a heterogeneous catalyst in the Suzuki cross-coupling reaction will result advantages. The overall steps in the procedure to couple both simple and complex compounds will be reduced without the required chromatographic steps to remove a homogeneous catalyst. The elimination of these purification steps will also result in lowering the cost of the overall reaction with the removal of chromatography equipment. With low toxic byproducts and easily obtainable chemicals, the safety of this reaction will also be greatly increased, benefiting chemists working on both large and small scales in industry.

8 References 1 Palladium Nanoparticles as Efficient Catalysts for Suzuki Cross-Coupling Reactions Moisés Pérez-Lorenzo The Journal of Physical Chemistry Letters (2), DOI: /jz Copper-Catalyzed Suzuki Cross-Coupling Using Mixed Nanocluster Catalysts Mehul B. Thathagar,Jurriaan Beckers, and, and Gadi Rothenberg* Journal of the American Chemical Society (40), DOI: /ja Palladium-Catalyzed Cross-Coupling of Sterically Demanding Boronic Acids with α-bromocarbonyl Compounds Bettina Zimmermann, Wojciech I. Dzik, Thomas Himmler, and Lukas J. Goossen The Journal of Organic Chemistry (19), King A.O., Yasuda N. Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals. In: Organometallics in Process Chemistry. Topics in Organometallic Chemistry, vol 6. Springer, Berlin, Heidelberg 5 Copper-Catalyzed Suzuki Cross-Coupling Using Mixed Nanocluster Catalysts Mehul B. Thathagar,Jurriaan Beckers, and, and Gadi Rothenberg* Journal of the American Chemical Society (40), DOI: /ja Enantioselective, Nickel-Catalyzed Suzuki Cross-Coupling of Quinolinium Ions Jason D. Shields, Derek T. Ahneman, Thomas J. A. Graham, and Abigail G. Doyle Organic Letters (1), DOI: /ol Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds Norio. Miyaura and Akira. Suzuki Chemical Reviews (7), DOI: /cr00039a00