Department of Chemistry Uppsala University Autumn 2018

Degree Project C in Chemistry

Mechanochemistry

C-H arylation and annulative π-extension reactions attempted in ball mill

Author: Oskar Ljungkvist Supervisor: Lukasz T. Pilarski

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Abstract The chemical industry today has a negative impact on the global environment as thousands of tons of chemicals are manufactured for different purposes. Novel ways of sustainable chemical manufacturing are of great interest, which can be seen in the development of green chemistry. One such method is ball milling, a mechanochemical method, where the reaction is carried out without the use of solvents.

This project is focusing on the development of various reactions, such as C-H arylation of 2,1,3-benzothiadiazole, annulative π-extending reaction of substituted pyrroles and indoles and Ullmann amination in a ball mill.

After testing various conditions for the C-H arylation of 2,1,3-benzothiadiazole, annulative π- extending reaction of indoles and Ullmann amination, none of them yielded product with the exception of annulative π-extending reaction of 1-(2-pyrimidinyl)-indole which yielded a different product from the one sought after. The reactions might be made to work if further attempts were conducted. The C-H arylation of 2,1,3-benzothiadiazole should be further tried using liquid assisted grinding or a grinding auxiliary. The annulative π-extending reaction of indoles requires further attempts using 2,2’-diiodo-1,1’-biphenyl as the substrate. Lastly, Ullmann amination should be attempted using a copper analogue to the pyridine-enhanced precatalyst preparation stabilization and initiation catalyst system for palladium.

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Contents Abstract ...... 2 1. Introduction ...... 5 1.1. Mechanochemistry ...... 5 1.2. 2,1,3-Benzothiadiazole ...... 6 1.3. Previous reactions of interest to this work ...... 6 1.3.1. Suzuki-Miyaura reaction ...... 6 1.3.2. Ullmann Coupling ...... 7 1.3.3. Direct Catalytic C-H arylation ...... 7 1.3.4. Annulative π-extending Reactions ...... 8 1.4. Aim of the project ...... 8 1.4.1. C-H arylation of 2,1,3-benzothiadiazole in the ball mill ...... 8 1.4.2. Annulative π-extending reactions of 1-(2-pyrimidinyl)-indole ...... 9 1.4.3. Ullmann coupling in the ball mill ...... 10 2. Results and discussion ...... 11 2.1. Results ...... 11 2.1.1. Attempted synthesis of starting material and the catalyst ...... 11 2.1.2. Attempted C-H Arylation and annulative π-extending reaction of 2,1,3-benzothiadiazole ...... 11 2.1.3. Attempted annulative π-extension reaction of indoles and pyrrole...... 12 2.1.4. Attempted Ullmann coupling in the ball mill ...... 14 2.2. Discussion ...... 15 3. Conclusions and outlook ...... 17 4. Experimental Section ...... 18 4.1. Synthesis of potassium pivalate ...... 18 4.2. Synthesis of palladium(II) pivalate...... 18 4.3. Attempted synthesis of 2,2’-diiodo-1,1’-biphenyl ...... 19 4.3.1. Attempted homo coupling of 2-iodophenylboronic acid using copper(II) catalyst ...... 19 4.3.2. Attempted C-H activation of iodobenzene using [Bis(trifluoroacetoxy)iodo]benzene and boron trifluoride ...... 19 4.4. Attempted C-H arylation of 2,1,3-benzothiadiazole ...... 20 4.4.1. Genera procedure for attempted C-H arylation of 2,1,3-benzothiadiazole in the ball mill ...... 20 4.4.2. Attempted annulative π-extension reaction of 2,1,3-benzothiadiazole in solution ...... 20 4.5. Attempted annulative π-extension reaction of indoles and pyrrole...... 20 4.5.1. General procedure for attempted annulative π-extension reaction of 1-(2-pyrimidinyl)-indole in solution ...... 20 4.5.2. General Procedure for attempted annulative π-extension reaction of indoles and pyrrole in ball mill ...... 22 4.6. General Procedure for attempted Ullmann coupling in the ball mill ...... 22 5. Acknowledgements ...... 23 6. References ...... 24

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Abbreviations

Ad: Adamantyl APEX: Annulative π-Extension BTD: 2,1,3-Benzothiadiazole DCE: 1,2-dichloroethane DCM: Dichloromethane DFBT: 5,6-difluorobenzo[c][1,2,5]thiadiazole DMA: Dimethylacetamide DMF: Dimethylformamide dppf: 1,1’-Bis(diphenylphosphino)ferrocene EWG: Electron-withdrawing group LAG: Liquid assisted grinding LC-MS: Liquid chromatography – Mass spectroscopy NMR: Nuclear Magnetic Resonance PEPPSI: Pyridine-enhanced precatalyst preparation stabilization and initiation PIFA : [Bis(trifluoroacetoxy)iodo]benzene PivO: Pivaloate TLC: Thin layer chromatography XPhos: 2-Dicyclohexylphosphino-2’, 4’, 6’-triisopropylbiphenyl

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1. Introduction

1.1. Mechanochemistry Most common organic chemistry reactions use solvents as the medium for reactions to take place. In addition, solvents are used for the extraction and purification of products. The majority of solvents used today are toxic and non-renewable and this practice is by no means sustainable. The annual production of organic solvents has been estimated to almost 20 million metric tons[1] and industries making complex molecules, such as the fine chemical and pharmaceutical industries, use large amounts of solvents to produce complex molecules. In the pharmaceutical industry, the raw material to prepare a pharmaceutically active ingredient can be up to 85% solvent by mass. [2],[3] Several solutions to this problem have been proposed, one of which is the use of reactions that require very small amounts of, or no solvents at all.

One approach is to use mechanical energy to aid chemical reactions – a field known as mechanochemistry. Mechanochemistry can be performed in several different ways using grinding, milling, shearing or kneading. Mechanochemistry is an old field that has seen a lot of recent development. It was shown that metal catalysis could be done using ball milling techniques, which opened the way to Figure 1 - Ball milling vessels, from the left; stainless steel vessels, Teflon vessels, carry out various important reactions, such as the tungsten carbide vessels Suzuki-Miyaura, Mizoroki-Heck and Sonogashira cross-couplings, among others.[4]

Ball milling as a technique is based on using a vessel made from various materials such as stainless steel, Teflon or tungsten, and small balls made of the same material as the vessel (see Figure 1). The substrate, catalyst and other reagents are added to the vessel together with a ball, the vessel is closed and then shaken or otherwise agitated, depending on the type of ball mill used at somewhere between 1-36 Hz for the duration of the reaction. There are different models of ball mills that agitate the vessel in different ways. Two common machines are planetary ball mills and mixer ball mills (see Figure 2) where the planetary ball mill often uses several smaller balls and rotates the ball milling vessel at high speed whilst the mixer ball mill usually uses only one or two balls and vigorously shakes the vessel back and forth.[5]

Figure 2 – Schematic overview of mixer mill where the Many reactions can be carried out in the ball vessel is oscillated in a shallow figure-of-eight the grinding ball moves back and forth grinding the mill without any solvent and for some reactants together. From ref. 5. reactions the ball mill reaction gives other products than the original reaction in solvent.[6] Sometimes a small amount of solvent is added to a reaction to facilitate the creation of a certain product or in order to speed up the reaction, the use of solvent in this way is called liquid assisted grinding or LAG.[7] In some cases a grinding auxiliary/agent is used to facilitate more efficient energy transfer, this is often the case when one or more of the reagents is a liquid. The grinding agent is a material that is inert to the reaction at hand, usually silica, alumina or inorganic salts are used.

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Ball milling is based on the idea that as the reagents are crushed between the wall of the reaction vessel and the ball(s) a large amount of energy is transferred to the reagents allowing them to overcome the energy barrier. This can allow for reactions that do not take place in solvent to take place, as well as in many cases give a much-reduced reaction time and most often do not require external heating.[5]

1.2. 2,1,3-Benzothiadiazole 2,1,3-Benzothiadiazole (BTD) is an electron deficient thiadiazole structure (Figure 3). This work has focused on trying to find ways to synthesise derivatives of BTD using C-H arylation and APEX coupling reactions. The aim was to extend the π-system of BTD, which is of great interest as it has been shown that such derivatives can be used in organic electronics in polymer-based organic photovoltaics (OPVs) and organic field effect transistors (OFETs) that can be used in solar cells. The selective extension of the BTD π system is a topic that still requires more attention. Most methods rely on the prior introduction of bromides to the C4 and C7 positions, usually via harsh bromination conditions. The focus in this study instead fell on attempts to replace C-H bonds in BTD directly with aryl units via catalysis under mechanochemical conditions, which has not yet been described in the literature.[8]

Figure 3 - Molecular structure of 2,1,3-benzothiadiazole.

1.3. Previous reactions of interest to this work 1.3.1. Suzuki-Miyaura reaction The ability to create new C-C bonds is of vital importance in organic chemistry when it comes to creating larger molecules. One reaction that can facilitate the creation of new C-C bonds is the Suzuki-Miyaura reaction which couples a halide and boronic acid using a palladium catalyst and a base. The Suzuki-Miyaura reaction follows a mechanism that can be seen in Figure 4. The first step of the catalytic cycle is oxidative addition in which the palladium complex coordinates to the halide, X, and R′. This is an oxidative addition, in which Pd(0) inserts into the C-X bond and is oxidized to Pd(II). The second step is transmetallation, prior to which the boronic acid is activated by a base to form a Figure 4 – The general scheme for Pd-catalyzed cross more nucleophilic complex which helps speed up coupling reactions. For the Suzuki-Miyaura reaction, M the transmetallation. The last step of the cycle is = B(OH)2. In the first step oxidative addition occurs where the R’ and X group both form bonds to Pd. In the reductive elimination during which a bond forms second step, transmetallation, the X group is exchanged between R′ and R and the Pd(II) intermediate is for the R group. In the last step, reductive elimination, reduced to Pd(0) to regenerate the catalyst.[9] Pd is reduced as a bond is formed between the R’ and R group. From ref. 9

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1.3.2. Ullmann Coupling Another way to create new C-C bonds as well as C-N, C-O and C-S bonds is the Ullmann coupling, which is a cross-coupling reaction that utilizes a Cu-based catalyst instead of Pd and aryl halides, amines, alcohols or thiophenes as substrates. This has several benefits, including the lower price of Cu and its greater abundance, meaning it is easier to use in larger quantities. However, one of the drawbacks is that the C-C bonds are limited to C-aryl bonds. There is also great variety within Ullmann couplings where some uses a catalytic amount of copper in the form of a copper (I) or (II) salt or complex or reactions where an equivalent amount is used. N-aryl amines and ethers can be made utilizing the Ullmann coupling, see Figure 5.[11]

Figure 5 - Ullmann amination reaction outline.

1. 3.3. Direct Catalytic C-H arylation

Scheme 1 - C-H arylation reaction of 1-(2-pyrimidinyl)-indole using a ruthenium catalyst.[12] Previously , Ackermann and co-workers have reported a ruthenium-catalysed C-H arylation of 1-(2-pyrimidinyl)- indole in solution using carboxylates as cocatalysts (see Scheme 1). They used pyrimidine as a directing group which coordinates with the ruthenium, thus steering it to catalyse the reaction at C2 on the indole even though the C3 position of indoles is usually the more reactive. In addition to this, the pyrimidine group is easily removed using base, which means it can be removed afterwards if the N-indole product is desired.[12] The proposed mechanism by Ackermann for this reaction is as follows (see Figure 6). The initial step of the reaction is the 1- Figure 6 - Proposed mechanism for the C-H arylation of 1-(2-pyrimidinyl)-indole using a ruthenium catalyst. adamantanecarboxylic acid (AdCO2H) being deprotonated First the catalyst is created when the deprotonated by the base and displacing a chloride ligand from adamantanecarboxylic acid displaces a chloride ruthenium thus creating the catalyst. The first step in the ligand from Ru. Then 1-(2-pyrimidinyl)- indole coordinates to the catalyst. This is followed by a bond catalytic cycle is the ruthenium complex coordinating to forming between C2 on the indole and the removal of the nitrogen of the pyrimidine group, followed by base- another ligand. After that transmetallation occurs and assisted activation of the indole unit’s C2-H bond. This is lastly there is the reductive elimination step recovering [13] followed by the oxidative addition of the aryl halide the Ru catalyst and yielding the product. substrate to the ruthenium. Finally, reductive elimination yields the product and regenerates the active catalyst.[13]

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1.3.4. Annulative π-extending Reactions There are many different reactions for forming new C-C bonds, all with their own advantages and drawbacks. Itami and co-workers have developed a range of so-called APEX (annulative π-extension) reactions which extend aromatic substrates with at least two new aromatic rings. This kind of reaction uses the creation of new C-C bonds to extend aromatic systems in a quick and efficient manner. Of particular interest are nitrogen containing fused aromatics as these have interesting electronic properties and are often biologically active. Itami has therefore developed an APEX reaction using 2,2’-diiodo-1,1’-biphenyl and N-methyl indole, see Scheme 2.[14] The suggested reaction mechanism is similar to that of a Suzuki-Miyaura coupling, starting with oxidative addition of the 2,2’-diiodo-1,1’-biphenyl to the palladium species. The silver salt then removes the iodide from the palladium forming, an electron deficient aryl-Pd species. This will then attack at the C2 on indole, after which a reductive elimination occurs yielding the monoarylated product and the original Scheme 2 - APEX reaction of N-methyl Indole and 2,2'-diiodo-1,1'-biphenyl to form an extended aromatic system. Pd species. The same process is repeated for the second iodide containing phenyl group of the now attached biphenyl to give a new extended aromatic system.[15] A key drawback of the system developed by Itami and co-workers it that the solvent used is either DMF (dimethylformamide) or DCE (1,2-dichloroethane). Both are toxic; DCE is scheduled to be banned in all European countries.[26] Such reactions are therefore both attractive from the point of view of how useful the products could be in organic electronics but also because synthesizing them under mechanochemical conditions would be beneficial to the environment and to human safety.

1.4. Aim of the project

The general aim of this project was to explore whether substrates such as BTD or indole derivatives could be reacted under solvent-free conditions in the ball mill using reactions intended to extend their -system.

1.4.1. C-H arylation of 2,1,3-benzothiadiazole in the ball mill The first part of this project was aimed at trying to derivatise BTD through C-H arylation (see Figure 7) as a starting point, before moving on to APEX reactions. C-H arylation of BTD has been demonstrated previously under conventional conditions, using toluene as a solvent, by Marder and co-workers, who used a Pd-based system.[15] The intention of this project was to remove the requirement for toxic solvents by performing the reaction under ball milling conditions, thereby vastly improving the environmental friendliness of the reaction. A further envisaged advantage was to remove the requirement for untypically high reaction temperatures required by the Marder system.

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Figure 7 - Overview of C-H arylation of BTD in the ball mill.

Another approach we pursued was to try the APEX reaction for BTD under ball milling conditions. Our conditions were analogous to those previously reported by Itami and co- workers[15], with the major difference of replacing the solvent with the mechanochemical grinding. (see Scheme 3).

Scheme 3 - APEX reaction of BTD in DMF/DMSO.

1. 4.2. Annulative π-extending reactions of 1-(2-pyrimidinyl)-indole Another part of the project was to attempt to extend Ackermann’s work[12] using 1-(2- pyrimidinyl)-indole by replacing the aryl halide used to 2,2’-dibromo-1,1’-biphenyl and trying to get the second bromide on 2,2’-dibromo-1,1’-biphenyl to react, replacing the hydrogen at C3 to give a ring closure. This would be the first ever Ru-catalysed APEX reaction (see Scheme 4). Since a similar reaction has been done previously by Itami[15], using palladium instead of the ruthenium catalyst used by Ackermann, the natural next step is to attempt both reactions in the ball mill. Ruthenium is much less well established than palladium as a catalyst for C-H functionalisation reactions generally. However, one of its major advantages is its significantly lower cost.

Scheme 4 - APEX reaction of 1-(2-pyrimidinyl)-indole using 2,2'-dibromo-1,1'- biphenyl and a ruthenium or palladium catalyst.

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A small part of the project was also dedicated to making the starting material that Itami used, namely 2,2’-diiodo-1,1’-biphenyl using a homocoupling of 2-iodophenyl boronic acid. Otherwise, the commercially available 2,2’-dibromo-1,1’-biphenyl was used.

1.4.3. Ullmann coupling in the ball mill Since the Ullmann coupling is a classic and very valuable reaction the last part of this project was to attempt to get it to work in the ball mill using traditional substrates such as amines and alcohols (see Scheme 5). Previously, the related Buchwald-Hartwig amination has been shown to work in the ball mill.[16] However, the Buchwald-Hartwig reaction was not specifically shown to work on the same substrates. It also relies on expensive custom-made ligands, which make it more expensive than the Ullman-based approach.

Scheme 5 - Ullmann amination in the ball mill using several different substrates.

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2. Results and discussion 2.1. Results 2.1.1. Attempted synthesis of starting material and the catalyst Potassium pivalate was successfully synthesised according to the literature procedure[17] with a yield of 75% yield. Palladium(II) pivalate was synthesised successfully using the literature procedure.[18] The synthesis yielded an orange powder corresponding to a yield of 76%. Both attempts to synthesise 2,2’-diiodo-1,1’-biphenyl were unsuccessful. Both reactions yielded several new materials but none of them were identified as the product. This analysis was made using TLC-MS.

2.1.2. Attempted C-H Arylation and annulative π-extending reaction of 2,1,3- benzothiadiazole The first attempt, entry 1 in Table 1, is based on previous work done by Doucet and co- workers[21] which used the same conditions with the difference being them doing it in a solution of DMA at 150 ⁰C for 16 hours. These conditions were aimed at yielding the product 3a, however only starting material was left after the reaction was run. Entry 2 in Table 1 is similar to entry 1 with the main differences being a different substrate, 2b, which was also used by Doucet and co-workers[21] and the fact that the vessel was filled with argon gas before the ball milling was started. For entry 3, substrate 2c was used, a different palladium catalyst was tried, pivalic acid was used as an additive[23], and the reaction was run at 30 Hz instead of 36 Hz, but still yielding no product. For entry 4-5, different ligands were tried, as well as , none of them gave any product. After this for entry 6-15 a different substrate, 2d, was used with different additives, bases and palladium salts without producing any trace of product. Using a different vessel and ball, both made out of tungsten carbide was also tried in entry 14. For entry 16 a different substrate was tried, it was however unsuccessful. For entry 17, using TfOH as the additive together with 2f was tried, unsuccessfully. In entry 18 a reaction similar to the classic Suzuki-Miyaura was attempted but yielded only homocoupled product, not 3g, or 4g. As such, all attempts at C-H arylation of BTD in the ball mill were unsuccessful. In various Pd-catalysed arylation reactions, the rate limiting step can be the oxidative addition of Pd(0) to the C-halogen bond. We tested both C-Br and C-I bonds (of which C-I is weaker) and both electron-withdrawing (e.g. NO2) and donating (e.g. OMe) groups to see if any electronic effect could be detected. The fact that no conversion to our product was observed could indicate that rate-limiting step of the desired reaction is not the oxidative addition, but another step. This is consistent with the high temperatures reported by Doucet and co- workers. It seems that they are required specifically because of the BTD component, rather than the aryl halide. This could mean that the C-H activation step is the rate-limiting step and that the energy delivered under our mechanochemical conditions is not enough to overcome the activation barrier.

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Table 1 - C-H arylation of BTD in the ball mill. Different substrates (2a-g) and the results of the reactions.

Entry SM (a-g) Pd catalyst Ligand Additive Base Yield 1b 2a (1 eq) Pd(OAc)2 (1 mol%) DMA (20 mol%) --- PivOK (2 eq) --- 2b, c 2b (1 eq) Pd(OAc)2 (5 mol%) DMA (10 mol%) --- PivOK (2.5 eq) --- 3a 2c (2.2 eq) Pd(dppf)Cl2 (10 mol%) --- PivOH (1 eq) K2CO3 (3 eq) --- 4a 2c (2.2 eq) Pd(OAc)2 (5 mol%) P(Ph)3 (20 mol%) PivOH (1 eq) K2CO3 (3 eq) --- 5 2c (2.2 eq) Pd(OAc)2 (10 mol%) Xphos (20 mol%) PivOH (1 eq) K2CO3 (3 eq) --- 6 2d (2.2 eq) Pd(OAc)2 (10 mol%) Xphos (20 mol%) PivOH (1 eq) K2CO3 (3 eq) --- 7 2d (2.2 eq) Pd(OAc)2 (10 mol%) Xphos (20 mol%) (1-Ad)CO2H (1 eq) K2CO3 (3 eq) --- 8 2d (4 eq) Bedfords cat. dimer (5 mol%) --- ArB(OH)2 (10 mol%) K2CO3 (3 eq) --- 9 2d (4 eq) Pd(PPh3)4 (10 mol%) --- PivOH (1 eq) K2CO3 (3 eq) --- 10 2d (4 eq) Pd(OAc)2 (10 mol%) P(o-tol)3 (20 mol%) PivOH (1 eq) Ag2CO3 (2 eq) --- 11 2d (2.2 eq) Pd(OAc)2 (10 mol%) Xphos (20 mol%) PivOH (1 eq) KOAc (3 eq) --- 12 2d (4 eq) Pd(OAc)2 (10 mol%) Xphos (20 mol%) PivOH (1 eq) Ag2CO3 (1 eq) --- 13b, c 2d (1 eq) Pd(OAc)2 (5 mol%) DMA (10 mol%) --- KOAc (2 eq) --- 14d 2d (2.2 eq) Pd(OAc)2 (10 mol%) Xphos (20 mol%) PivOH (1 eq) K2CO3 (3 eq) --- 15b 2d (1 eq) Pd(OAc)2 (5 mol%) DMA (10 mol%) --- Ag2CO3 (2 eq) --- 16b, c 2e (1 eq) Pd(OAc)2 (5 mol%) DMA (10 mol%) --- KOAc (2 eq) --- 17 2f (1.5 eq) Pd(OAc)2 (10 mol%) DMF (2 eq) TfOH (1 eq) Ag2CO3 (2 eq) --- 18 2g (1.5 eq) Pd(OAc)2 (10 mol%) --- H2O (1 eq) Ag2CO3 (2.5 eq) --- a Experiments carried out at 30Hz. b Used 1.5 equivalents of BTD. c Vessels filled with argon gas before running experiment. d Tungsten carbide vessel, 14 ml, and tungsten carbide ball, d = 5 mm was used.

The APEX reaction of BTD that was attempted in solution, see Scheme 3, did not yield any product.

2.1.3. Attempted annulative π-extension reaction of indoles and pyrrole Out of all the APEX reactions of 1-(2-pyrimidinyl)-indole done in solution (Table 2) several yielded product. However, none of the reactions was a successful APEX reaction. Entry 1 follows Ackermann’s reaction conditions, [12] except using the 2,2’-dibromo-1,1’-biphenyl, 2b as the aryl halide. This yielded 38% of the monoarylated product, 9a. Entry 2 is similar to entry 1 but using Pd(OAc)2 and an increased amount of (1-Ad)CO2H. It did not yield any product. Entries 3-5 all yielded the same product. This product was not the monoarylated product, 9a, but nor was it the product 8a. TLC-MS shows however that the product is the same in all three entries as they all had the same mass. Unfortunately, a large enough sample

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Table 2 - APEX reactions of 1-(2-pyrimidinyl)-indole using ruthenium and palladium catalysts in xylene solution to yield a mono- (9a) or a diarylated (8a) product.

Entry [RuCl2 (p-cymene)]2 Ligand Base Additive Yield b 1 2.5 mol% (1-Ad)CO2H (30 mol%) K2CO3 (1.5 eq) ------a 2 5 mol% (1-Ad)CO2H (1 eq) K2CO3 (1.5 eq) ------3 5 mol% (1-Ad)CO2H (1 eq) K2CO3 (1.5 eq) ------4 5 mol% (1-Ad)CO2H (30 mol%) K2CO3 (1.5 eq) AgOAc (1 eq) --- 5 5 mol% (1-Ad)CO2H (30 mol%) K2CO3 (1.5 eq) AgSbF6 (1 eq) --- a b Pd(OAc)2 was used instead of [RuCl2 (p-cymene)]2. Monoarylated product 9a was isolated with a yield of 38%.

The APEX reaction of pyrrole, N-methyl indole and 1-(2-pyrimidinyl)-indole in the ball mill can be seen in Scheme 6. The three reactions were done using the same reaction conditions but using the different substrates, pyrrole, N-methyl indole and 1-(2-pyrimidinyl)-indole, yielded no product.

Scheme 6 – Attempted APEX reactions of 1-(2-pyrimidinyl)-indole, N-methyl indole and N-methyl pyrrole in the ball mill.

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2.1.4. Attempted Ullmann coupling in the ball mill Ullmann coupling in the ball mill was tried in a number of different ways. These can be seen in Table 3. For entry 1 substrates 10a and 11a were used. For entry 2, a higher loading of CuI catalyst and picolinic acid ligand was used and substrates 10b and 11a were used. For entry 3- 4 Teflon vessels, 14 ml with a steel ball, d = 10 cm were used as well as different substrates and a higher loading of both catalyst and ligand.

Table 3 - Ullmann amination in the ball mill using a range of different substrates.

Entry Substrates CuI Picolinic acid Product Yield 1 1-Naphthol 5 mol% 10 mol% 12aa --- 2 4-Methylphenol 10 mol% 20 mol% 12ba --- 3a Aniline 20 mol% 40 mol% 12cb --- 4a 4-Methylphenol 20 mol% 40 mol% 12bb --- a Teflon vessel, 14 ml with steel ball d = 10 mm

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2.2. Discussion The synthesis of the starting material 2,2’-diiodo-1,1’-biphenyl (2b) turned out to be very difficult. In fact, none of the attempts made were successful preventing the use of this starting material in further trials in the ball mill to achieve a successful APEX reaction.

The C-H arylation of BTD in the ball mill turned out to be a very difficult feat to accomplish. Most of the reactions that have been attempted were based on the successful C-H activation reactions carried out on BTD or 5,6-difluorobenzo[c][1,2,5]–benzothiadiazole, DFBT, previously. All previous attempts have two things in common; they use harsh conditions such as high temperatures and toxic solvents such as DMA. The one exception is the synthesis, carried out by Farinola,[22] who uses solvent free conditions, but such a large excess (4 equivalents) of the aryl iodide, which is a liquid at room temperature, that the reaction is basically in solution anyways. The reactions carried out using DFBT are done at 120 ⁰C and the reactions done using BTD by Doucet and co-workers[21] are carried out at 150 ⁰C. This suggests that the C-H arylation of BTD is one that requires a very high activation energy to proceed. The question then is whether the ball mill can provide that needed activation energy. As the process of energy transference during ball milling is still not completely understood this becomes more difficult to answer.[4] One attempt, to try to increase the energy provided during the ball milling, was done by using both a vessel and ball consisting of tungsten carbide which, being a harder material than steel, should provide a higher energy on impact when run in the ball mill. Schmidt[24] reported reaching 80 ⁰C after 1 hour at 30 Hz, this was using a larger vessel, 35 ml, and lower frequency, 30 Hz, but still gives an idea of the kind of temperatures that can be reached during ball milling. However, since the transfer of energy is not very well understood during ball milling, this does not necessarily suggest that reactions that can be performed at 80 ⁰C in solution would work in the ball mill.

The APEX reaction in solution that was tried for BTD using the same conditions used by Itami,[15] with the difference of using the dibromo-biphenyl rather than the diiodo-biphenyl was unsuccessful. This is not completely unexpected as BTD is a lot more electron poor than the indoles and pyrroles that Itami used to demonstrate his APEX reaction.

The APEX reactions of the 1-(2-pyrimidinyl)-indole in solution using Ackermann’s conditions[12] can be counted at least a partial success seeing as the monoarylation was successful in giving 9a. It turns out, however, that if these conditions are changed even slightly (Table 2, entry 3), a completely new unidentified product is formed, that is not 8a. The product 8a should stain in the TLC and be visible in the LC-MS.

The APEX reactions of N-methyl pyrrole, N-methyl indole and 1-(2-pyrimidinyl)-indole with 2,2’-dibromo-1,1’-biphenyl in the ball mill were not successful. These reactions have been shown to work in solution at 80 ⁰C using 2,2’-diiodo-1,1’-biphenyl.[14] The fact that these reactions did not work in the ball mill could be because the dibromo-biphenyl was used instead as this has not been shown to work in solution. These experiments would be interesting to try using the diiodo-biphenyl in the ball mill to see if this gives any greater success.

The Ullmann coupling in ball mill was tried with a number of different substrates and at relatively high loadings of ligand and catalyst. It was also tried in two different vessels, Teflon and steel. Since the Buchwald-Hartwig reaction, which is similar but uses palladium instead of copper, has been shown to work,[25] it seems reasonable that the Ullmann coupling could work in the ball mill as well. This suggests that more experiments are required. The

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Buchwald-Hartwig reaction was carried out in the ball mill using the PEPPSI catalyst system, which is not the simplest of palladium catalysts whilst nothing was reported on the use of simpler catalysts such as palladium(II) acetate. It is possible the Ullmann coupling might work in the ball mill using a more active Cu(I) catalyst.

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3. Conclusions and outlook • So far, the synthesis route used by Itami[14], originally published by Zhang,[27] of converting 2,2’-dibromo-1,1’-biphenyl to 2,2’-diiodo-1,1’-biphenyl through a halogen exchange reaction, remains the easiest way to synthesise 2,2’-diiodo-1,1’-biphenyl.

• It seems that the C-H arylation of BTD in the ball mill is currently not workable. This is likely due to the high activation energy required to carry out this reaction which is hard to reach in the ball mill. This is consistent with the work reported by Marder and co-workers under conventional conditions, in which high reaction temperatures are required. It might be possible to achieve using some form of LAG, which was explored only to a small extent in this work. Alternatively, an auxiliary grinding agent could be used, but this was not attempted due to time restrictions. A further option might be to undertake extensive ligand screening to tune the catalyst metal centre towards the activation of the BTD C-H bonds under mechanochemical conditions. However, this was beyond the scope of this study.

• The APEX reactions of indole-based substrates in solution using the same conditions as Ackermann[12] were unsuccessful but might be interesting to try using the 2,2’-diiodo-1,1’- biphenyl used by Itami.[14] Interestingly, the C2-H arylation of 1-(2-pyrimidinyl)-indole did occur using 2,2-dibromo-1,1’-biphenyl (2b) with the consumption of only one C-Br bond. This probably indicates that Ru is not able to activate the C3-H bond of indole, and that only after formation of the C-Ru bond does the oxidative addition to C-Br take place. This suggests that the Ru centre is not especially electrophilic, since indoles are potent nucleophiles at C3.

• The APEX reactions of 1-(2-pyrimidinyl)-indole, N-methyl indole and N-methyl pyrrole in the ball mill that were unsuccessful would be interesting to try out again using the diiodo- biphenyl used by Itami[14], as this would give a better indication of whether APEX reactions are feasible in the ball mill at all using these conditions.

• The Ullmann coupling in the ball mill was not successful. It might be interesting to try the Ullmann coupling using some more activated Cu(I) catalysts analogous to the PEPPSI system for palladium(II) catalysts.

In general ball milling is a relatively recently re-discovered technique that has been applied to synthetic organic chemistry. As such it is not fully understood but it also means that there are a lot of traditional reactions developed and carried out in solution that can potentially be made to work in the ball mill.

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4. Experimental Section

All the ball milling experiments were carried out using IST636 High-Energy Mixer Mill from InsolidoTech and vessels with an inner volume of 14 ml and balls with a diameter of 10 mm made from either stainless steel, Teflon or wolfram carbide. Thin layer chromatography (TLC) was carried out using aluminium-backed plates coated with Kieselgel 60 (0.20 mm, UV 254 and visualized under 254 nm, using iodine or a solution of p-anisaldehyde. Purification by column chromatography was performed using Kiesel gel 60 H silica gel (particle size 0.063-0.100mm). The LC-MS samples were analysed using a Waters 2700 Sample Manager connected to an Agilent 1100 Series with a Genesis Lightning C8, 4 μm column, with a length of 50 mm. The mass spectrometer used was a Waters Micromass ZQ – Single Quadrupole. The TLC-MS samples were analysed using a Plate Express TLC Plate Reader, Shimadzu LC-10AD HPLC pump and Expression L CMS. 1H and 19F NMR spectra were recorded on an Agilent MR400-DD2 spectrometer at ambient temperature.

The xylenes used where distilled over dry CaCl2 and then stored over 4Å molecular sieves and Argon.

4.1. Synthesis of potassium pivalate The synthesis was based on a reported literature procedure.[17] To a 50 ml round bottom flask containing a stirring bar, pivalic acid (1.02 g, 10 mmol) and potassium hydroxide (0.56 g, 10 mmol) were added. To this methanol (20 ml) was added and the solution heated with stirring to reflux for 3 hours. The solvent was then evaporated and the solid was washed with 50 ml 1:99 methanol/diethyl ether and the dried over high vacuum affording 1.054 g of the potassium salt of pivalic acid corresponding to a yield of 75%. A melting point analysis was run, confirming the formation of potassium pivalate.

4.2. Synthesis of palladium(II) pivalate The synthesis was based on a reported literature procedure.[18] To a 50 ml round bottom flask containing a stirring bar, palladium(II) acetate (0.50 g, 2.25 mmol) and pivalic acid (0.91 g, 9 mmol) were added. To this toluene (25 ml) was added and the solution was stirred at 40 ⁰C for 2.5 hours. The solvent was then evaporated until 2.5 ml toluene was left. Hexane (2.5 ml) was added and the solution left at 5 ⁰C for 15 hours. The precipitate was washed using hexane (2x 3ml). The product was dried under high vacuum yielding 0.528 g of an orange powder 1 corresponding to 76% yield. An H NMR (400 MHz, CDCl3) spectrum was run, confirming the formation of the palladium(II)pivalate.

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Figure 8 - 1H NMR spectrum of palladium(II) pivalate.

4.3. Attempted synthesis of 2,2’-diiodo-1,1’-biphenyl 4.3.1. Attempted homo coupling of 2-iodophenylboronic acid using copper(II) catalyst The synthesis was based on a reported literature procedure.[19] To a 5 ml round bottom flask containing a stirring bar, 2-iodophenylboronic acid (49.56 mg, 0.2 mmol) and hydrated copper(II) chloride (1.70 mg, 0.01 mmol) were added (see Scheme 7). To this methanol (0.5 ml) was added and the solution was stirred at 25 ⁰C for 20 h. A TLC was run (eluent: EtOAc/pentane), controlled under ultraviolet light and stained using first iodine then using p- anisaldehyde solution. Thin-layer chromatography showed four ultraviolet-active spots. TLC- MS was run, and it was confirmed that none of these spots were 2,2’-diiodo-1,1’-biphenyl.

Scheme 7 – Attempted homo-coupling of 2-iodophenylboronic acid using a Cu(II) catalyst to form 2,2’-diiodo-1,1’-biphenyl.

4.3.2. Attempted C-H activation of iodobenzene using [Bis(trifluoroacetoxy)iodo]benzene and boron trifluoride The synthesis was based on a reported literature procedure (see Scheme 7).[20] To a 25 ml round bottom flask containing a stirring bar, [Bis(trifluoroacetoxy)iodo] (526.79 mg, 1.225 mmol) was added and the vessel evacuated and filled with argon gas three times. Dry dichloromethane (3.0 ml) and BF3 • Et2O (367.32 mg, 2.45 mmol) was added under stirring using a syringe. To a 25 ml round bottom flask containing a stirring bar, iodobenzene (500 mg, 2.45 mmol) was added and the vessel evacuated and filled with argon gas three times. Dry DCM (3.0 ml) was added and the solution cooled to -78 ⁰C. The [Bis(trifluoroacetoxy)iodo] / BF3 • Et2O solution was added dropwise with stirring and then left to react at -78 ⁰C for 5 hours (see Scheme 8). The solution was quenched using saturated sodium hydrogen carbonate solution (10 ml). The solution was allowed to reach rt, extracted

19 using dichloromethane (3x 10 ml). The organic layer was washed with dist. H2O (2x 20ml), brine (20 ml), then dried (Na2SO4). TLC analysis (EtOAc/pentane 1:50) of the filtrate showed only starting material.

Scheme 8 – Attempted C-H activation of iodobenzen using [Bis(trifluoroacetoxy)iodo] and boron trifluoride to form 2,2'- diido-1,1'-biphenyl. 4.4. Attempted C-H arylation of 2,1,3-benzothiadiazole

4.4.1. Genera procedure for attempted C-H arylation of 2,1,3-benzothiadiazole in the ball mill To a 14 ml steel vessel containing a steel ball, 2,1,3-benzothiadiazole (1) (40.85 mg, 0.3 mmol), palladium(II) acetate (6.73 mg, 0.03 mmol), pivalic acid (30.64 mg, 0.3 mmol), potassium carbonate (124.38 mg, 0.9 mmol), 2-Dicyclohexylphosphino-2’, 4’, 6’- triisopropylbiphenyl (28.60 mg, 0.06 mmol) and 1-fluoro-4-iodobenzene (2d) (146.51 mg, 0.66 mmol) were added. The vessel was then run in a mixer ball mill at 36 Hz for 1 hour. The reaction mixture was filtered through celite 545 using chloroform (25 ml). Thin-layer chromatography was run (eluent: EtOAc/pentane), controlled under ultraviolet light and stained using first iodine then using p-anisaldehyde solution. Then an 1H NMR (400 MHz, 19 CDCl3) spectrum and F NMR (376.5 MHz, CDCl3) spectrum were run. See Figure 7 and Table 1 for the different conditions and their results.[21], [22]

4.4.2. Attempted annulative π-extension reaction of 2,1,3-benzothiadiazole in solution To an oven dried microwave pressure tube sealed with a septum, 2,1,3-benzothiadiazole (1) (27.23 mg, 0.2 mmol), 2,2’-dibromo-1,1’-biphenyl (2) (93.6 mg, 0.3 mmol), palladium(II) pivalate (3.08 mg, 0.01 mmol), silver carbonate (82.72 mg, 0.3 mmol) were added. To this dimethylformamide (0.7 ml), dimethyl sulfoxide (0.3 ml) was added, the vessel sealed and allowed to stir at 150 ⁰C for 23 hours (see scheme 7). The reaction mixture was filtered through celite 545 using chloroform (25 ml). Thin-layer chromatography was run (eluent: EtOAc/pentane), controlled under ultraviolet light and stained using first iodine then using p- anisaldehyde solution. The thin-layer chromatography showed only starting materials. This 1 [14] was confirmed by running an H NMR (400 MHz, CDCl3) spectrum.

4.5. Attempted annulative π-extension reaction of indoles and pyrrole 4.5.1. General procedure for attempted annulative π-extension reaction of 1-(2- pyrimidinyl)-indole in solution To an oven dried microwave pressure tube sealed with a septum, 1-(2-pyrimidinyl)-indole (7a) (58.56 mg, 0.3 mmol), 2,2’-dibromo-1,1’-biphenyl (2) (112.32 mg, 0.36 mmol), [RuCl2 (p- cymene)]2 (4.59 mg, 0.0075 mmol), potassium carbonate (62.19 mg, 0.45 mmol) and 1- adamantanecabroxylic acid (16.22 mg, 0.09 mmol) were added. The tube was then evacuated and filled with argon gas three times, after which dried xylenes (2.0 ml) was added, the vessel sealed and allowed to stir at 120 ⁰C for 25 hours. The reaction mixture was allowed to cool to room temperature and then a thin-layer chromatography was run (eluent: EtOAc/pentane), controlled under ultraviolet light and stained using first iodine then using p-anisaldehyde solution. The thin layer chromatography showed the formation of product and EtOAc (30 ml) was added. The solution was washed with saturated potassium carbonate solution (2x 30 ml)

20 and then extracted with EtOAc (2x 30 ml). The organic phase was dried using sodium sulphate, the solvent was evaporated, yielding 49 mg of an off-white powder. A column 1 chromatography was run (eluent: EtOAc/pentane). Then H NMR (400 MHz, CDCl3) spectrum and a LC-MS was run confirming the formation of the monoarylated product (9a) with a yield of 38.3%.[12] See Scheme 9 below and Table 2 for the different conditions and their results.

Scheme 9 – Attempted annulative π-extension reaction of 1-(2-pyrimidinyl)-indole in xylenes to form a mono- (9a) or a diarylated (8a) product.

Figure 9 - 1H NMR spectrum of purified 9a from the reaction of 1-(2-pyrimidinyl-indole) in solution. See Table 2, Entry 1.

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Figure 10 - 1H NMR spectrum of reaction mixture from the reaction of 1-(2-pyrimidinyl- indole) in solution. See Table 2, Entry 3.

4.5.2. General Procedure for attempted annulative π-extension reaction of indoles and pyrrole in ball mill To a 14 ml steel vessel containing a steel ball, 1-(2-Pyrimidinyl)-1H-indole 7a (58.56 mg, 0.3 mmol), 2,2’-dibromo-1,1’-biphenyl (2) (140.4 mg, 0.45 mmol), palladium(II) pivalate (4.63 mg, 0.015 mmol), silver carbonate (124.08 mg, 0.45 mmol), dimethylformamide (35 μL) and dimethoxy sulfoxide (15 μL) was added. The vessel was then run in a mixer ball mill at 36 Hz for 1 hour. The reaction mixture was filtered through celite 545 using chloroform (25 ml). Then thin-layer chromatography was run (eluent: EtOAc/pentane), controlled under ultraviolet light and stained using first iodine then using p-anisaldehyde solution. The solution 1 was evaporated and H NMR (400 MHz, CDCl3) spectrum was run confirming that no product had formed. See Scheme 10 below and Scheme 6 for the different conditions and their results.[14]

Scheme 10 – Attempted annulative π-extension reaction of 1-(2-pyrimidinyl)-indole, N-methyl indole and N-methyl pyrrole in the ball mill.

4.6. General Procedure for attempted Ullmann coupling in the ball mill To a 14 ml steel vessel containing a steel ball, 1-naphthol (10a) (43.25 mg, 0.3 mmol), 1- chloro-4-iodobenzene (11a) (107.30 mg, 0.45 mmol), copper(I) iodide (2.85 mg, 0.015 mmol), picolinic acid (3.69 mg, 0.03 mmol) and potassium phosphate (127.36 mg, 0.6 mmol) was added. The vessel was then run in a mixer ball mill at 36 Hz for 1 hour. The reaction mixture was filtered through celite 545 using chloroform (25 ml). Then thin-layer

22 chromatography was run (eluent: EtOAc/pentane), controlled under ultraviolet light and stained using first iodine then using p-anisaldehyde solution. The solution was evaporated and 1 H NMR (400 MHz, CDCl3) spectrum was run confirming that no product had formed. See Scheme 4 and Table 4 for the different conditions and their results.

5. Acknowledgements Thanks to Lukasz Pilarski for making his lab available, as well as for his guidance during this project. Further thanks to Jagadeesh Kalepu who gave great instruction and help during the lab work. A great thanks to the whole Pilarski group for their support. Lastly, thanks to Adolf Gogoll for proof reading this report and giving feedback.

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