Uppsala University Project Thesis Suzuki coupling of functionalized arylboronic acids to a 2-Amino-5-(4-bromophenyl)-1,3,4-thiadiazole scaffold Supervisors: Author: Dr. Wei Berts Fredric Ingner Dr. Jonas Malmström February 21, 2015 Abstract Seven arylboronic acids, all but one containing functional groups, were cho- sen for Suzuki cross coupling to a predetermined scaffold for a contract project. The scaffold was synthesized and catalytic ability was assesed for three palla- dium catalysts: Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), (1,1’- Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(DPPF)Cl2) and PEPPSI-iPr. Library reactions proceeded with Tetrakis since it was found to be the only catalyst capable of producing product during trials. All reactions were worked up by flash chromatography, except one where preperative HPLC had to be used. Reactions and purification steps were analyzed crudely with TLC and more thoroughly through LC-MS with ESI. Structural analysis in form of 1H-NMR was made of the scaffold and two products. It was found that all but one of the seven reactions proceeded to completion with 0.1 eq of catalyst under alkali conditions at 80o C. 1 Acknowledgements I would like to thank Dr. Fredrik Lehmann for allowing me to do my thesis work at OnTarget Chemistry. I am very grateful to have been supervised by Dr. Wei Berts and Dr. Jonas Malmström, without whom this thesis would not have been possible. I also extend my gratitude to all of the employees of OnTarget Chemistry who have made me feel very much at home and as a part of the team. Last but not least, I would like to thank my family, friends and girlfriend for showing me great support through adversity and rough times. 2 Contents 1 Introduction 4 1.1 Suzuki coupling . .5 1.2 General mechanism . .6 1.2.1 Ligand dissociation and oxidative addition . .6 1.2.2 Transmetalation . .7 1.2.3 Reductive elimination . .8 1.3 Aim . .8 2 Experimental 9 2.1 Materials and method . .9 2.1.1 Preparation of the scaffold 3a ...................9 2.1.2 Catalyst screening . .9 2.1.3 Substrate scope - General method . 10 2.1.4 Substrate scope - Purification . 10 3 Results and discussion 12 3.1 Scaffold synthesis . 12 3.2 Catalyst screening . 12 3.3 Library reactions . 13 3.4 General discussion . 21 3.5 Conclusions . 22 Appendices 25 I Purification techniques 25 I.I Flash chromatography . 25 I.II Preparative HPLC . 25 II Preperative HPLC results 26 III HPLC results 27 IV NMR results 37 3 1 Introduction There exists a steady demand for new pharmaceutical and other tailored organic molecules. A key factor in order to meet this demand in a sustainable and economic way is to efficiently develop and produce these molecules. Metal catalysis has proven to be an important tool in this development and can often be favored to stoichiometric "old fashion" C-C bond forming reaction in terms of selec- tivity and efficiency. In metal catalyzed reactions it can however be more difficult to foresee the outcome of a reaction and an empirical approach is often taken, as will be done in this project. The molecules synthesized in this paper are intended for a contract project. No further information regarding the project can be disclosed due to confidentiality agreement. In this paper, seven selected boronic acids will be coupled to a scaffold through C- C bond formation. The reaction of choice is a palladium-catalyzed reaction commonly referred to as the Suzuki cross coupling reaction. A general reaction depicting the scaffold and selected boronic acids are shown below in Figure 1 and Figure 2. A more detailed explanation of Suzuki cross coupling and the reaction mechanism is found in section 1.1. Br R OH OH N + B Pd(PPh3)4/K2CO3(aq) N N N S R DME S 1c-n H2N H2N 3a 2c-n Figure 1: General reaction between scaffold and boronic acid substrate F F OH O OH OH F OH B B B B OH O OH OH OH 1c-1 1c-2 1c-3 1c-4 OH OH OH B Cl B B N OH OH OH 1c-5 1c-6 1c-7 Figure 2: The seven arylboronic acids 1c-n selected for coupling The main tasks of the project will focus on synthesis of the scaffold, finding a suitable catalyst and substrate scope. 4 1.1 Suzuki coupling Suzuki coupling, also known as Suzuki-Miyaura coupling or the Suzuki reaction, is a palladium catalyzed reaction in which a halide is coupled to an organoboronic com- pound, commonly an boronic acid or ester, thus resulting in the formation of a new C-C bond. The Suzuki cross coupling reaction was first presented in 1979 by Akira Suzuki and Norio Miyaura[12]. In 2010, Akira Suzuki was, along with Richard F. Heck and Ei-ichi Negishi, awarded the nobel prize in chemistry "for palladium-catalyzed cross couplings in organic synthesis"[15]. Today, the Suzuki reaction is the most utilized cross coupling reaction in both academic and industrial applications[6]. Suzuki coupling is widely used in drug development since it allows for a broad selection of functionalized groups whereas most other organometallic reactions, for example Grignard reactions[8], will attack reactive functionalized groups. Though there are other d-metal coupling reactions which also have a large tolerance for functional groups, for example the Stille coupling[19], Suzuki coupling is often prefered due to a number of following reasons. Suzuki coupling reactions, in contrast to other d-metal coupling reactions, are usually carried out under mild conditions[8]. Studies have shown satisfying reaction condition with water as solvent[5][20][4] which paves for a greener route than the use of organic solvents, this is of great importance for industrial scale application. Boronic acids and their by-products are considered non-toxic and easy to work- up which makes them preferable to, for example, organotin compounds used in Stille coupling. One of the great benefits of using Suzuki cross coupling is that boronic acids are readily available in an extensive variety of structures[6][22]. 5 1.2 General mechanism The Suzuki cross coupling reaction can be summarized as a three-step catalytic cycle which is shown in Figure 3. The reaction steps and other mechanistic aspects will be disclosed in the following paragraphs. Figure 3: Catalytic cycle of the Suzuki cross coupling reaction 1.2.1 Ligand dissociation and oxidative addition As previously mentioned, the Suzuki reaction uses a palladium based catalyst. There are several catalysts available, all containing different ligands with different structures and properties. In general, a ligand should be a good σ-bond donor since this facilitates oxidative addition, the first step in the catalytic cycle. A ligand should also be bulky since this benefits reductive elimination, the last step in the cycle[7]. This paper will focus on a catalyst called Tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4, which is the most commonly used catalyst[13]. In the first step of the catalytic cycle, oxidative addition, the halide is bonded to the palladium complex thus oxidizing the palladium. However, in order for oxida- tive addition to take place, a non-occupied coordination site is needed[23]. This is achieved through ligand dissociation where the loss of ligands are in equlibrium with the solution[3], see Figure 4. 6 Figure 4: Ligand dissociation and oxidative addition with oxidation states[3] The figure shows how palladium transforms from a four-coordinate saturated 18 electron confirmation to a two-coordinate unsaturated 14 electron confirmation. The unsaturated complex contains two available coordination sites which enables for ox- idative addition of the halide. The result is the stable trans-σ-palladium(II) complex which is also shown between the first and second step in Figure 3[13]. 1.2.2 Transmetalation During the transmetalation step the halide on palladium is substituted with the R2 group of the boronic acid. Although several different routes have been proposed, a full explanation of the mechanism is yet to be found. It is however known, empirically, that a base needs to be added in order for the trans- metalation step to proceed at a notable rate. There are two suggested main routes describing the role of base[1], these are shown in Figure 5 below. Figure 5: Two main pathways describing the role of base in transmetalation[2] 7 In Path A, the base forms an negatively charged "ate" complex with the boronic acid. Boric acid and the halide anion is then excluded in the transmetalation step when the R2 switches from the boronic acid and binds to the palladium. In Path B, the base instead substitutes the halide on the palladium before undergoing transmetalation. The halide anion is thereby excluded already in the first step. Boric acid is then excluded during the transmetalation step. 1.2.3 Reductive elimination Reductive elimination is the last step in the catalytic cyle. This step forms the final desired C-C bond between R1 and R2 thus completing the cross coupling reaction. An illustration of the reductive elimination step is shown below in Figure 6. Figure 6: Reductive elimination step When the R-groups are ejected, palladium regains an electron pair. This lowers the oxidation state for palladium from Pd(II)→ Pd(0). The catalyst is thereby regenerated with two available coordination sites. John P. Wolfe and Jie Jack Li describes in their book Palladium in Heterocyclic Chem- istry under which conditions reductive elimination works best. The following is a direct quote from Chapter 1 of the book[9]: "The reductive elimination step can often be facilitated by the use of catalysts bear- ing bulky, monodentate phopshine ligands, and is believed to be most rapid when the two coupling partners have opposite electronic properties." As described, bulky monodentate phosphine ligands is found in the catalyst "Tetrakis" which will be compared to other catalysts later in this paper.