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Carbon-carbon bond formations using organolithium reagents Heijnen, Dorus

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Cover : Tip of a needle of tert-Butyllithium, a highly pyrophoric organolithium reagent. Credits : Dusan Kolarski The work described in this thesis was carried out at the Stratingh Institute for Chemistry (University of Groningen, The Netherlands) and was financially supported by a NWO-TOP grant Printed by : Ipskamp Printing, Enschede, The Netherlands

ISBN (printed) 978-94-028-1146-9

Carbon-Carbon Bond Formations Using Organolithium Reagents

Proefschrift

Ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties

De openbare verdediging zal plaatsvinden op

Vrijdag 7 september 2018 om 16:15

door Dorus Heijnen Geboren op 16 juli 1988 te Nijmegen

Promotor Prof. dr. B.L. Feringa

Copromotor Prof. dr. S. R. Harutyunyan

Beoordelingscommissie Prof. dr. J.H. van Maarseveen Prof. dr. K. Barta Prof. dr. I. Marek

Table of Contents Chapter 1: Introduction Organolithium Reagents : Discovery, Preparation, Properties and Applications ...... 9 1.1 Discovery and preparation ...... 10 1.2 Properties ...... 11 1.3 Transmetallations and catalysis ...... 14 Direct cross coupling with organolithium compounds ...... 16 Faster ...... 18 Cheaper ...... 20 Functional group compatibility ...... 21 Applications ...... 22 1.4 References...... 25 Chapter 2: Palladium-Catalyzed Cross-Coupling of (Trimethylsilyl)methyllithium with (Hetero)-Aryl Halides ...... 28 2.1 Introduction ...... 29 2.2 Catalyst optimization ...... 30 2.3 Substrate scope with aryl chlorides ...... 31 2.4 Substrate scope with aryl bromides ...... 32 2.5 Selectivity ...... 33 2.6 The sequential coupling of TMS-substituted toluene derivatives...... 34 2.7 Conclusions ...... 35 2.8 References ...... 36 2.9 Experimental section ...... 39 Chapter 3: Pd-Catalyzed, tBuLi-Mediated Dimerization of Aryl Halides and its Application in the Atropselective Total Synthesis of Mastigophorene ...... 47 3.1 Introduction ...... 48 3.2 Optimization and Scope ...... 50 3.3 Synthesis of Mastigophorene ...... 53 3.4 Conclusions ...... 57 3.5 References ...... 57 3.6 Experimental section ...... 60 Chapter 4 : One-Pot Strategies for Developing Synthetic Methods with Organolithium Reagents ..... 78 4.1 Introduction ...... 79 4.2 One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed α-Arylation ...... 79 4.2.1 Introduction ...... 79 4.2.2 Optimization ...... 80 4.2.3 Scope of the reaction ...... 83 4.2.4 Competition studies ...... 84 4.2.5 Other use of the tetrahedral intermediate ...... 85 4.2.6 Conclusions ...... 86 4.2.7 References ...... 86 4.2.8 Experimental section ...... 88 4.3 The Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot Reduction/Cross-Coupling Procedure ...... 99 4.4.1 Introduction ...... 100 4.4.2 Optimization ...... 101 4.4.3 Substrate scope ...... 102 4.4.4 In situ reduction of ketones...... 105 4.4.5 Conclusions ...... 105 4.4.6 References ...... 105 4.4.7 Experimental section ...... 107 4.4 Conclusions and outlook ...... 114 Chapter 5 : Synthesis of chiral catalysts for palladium catalyzed organolithium cross coupling reactions...... 115 5..1 Introduction ...... 116 5.2 Initial testing ...... 117 5.3 Design of potential chiral ligands for atroposelective coupling...... 118 5.3.1 Chiral backbone ...... 118 5.3.2 Chiral flanking groups ...... 121 5.4 Conclusions and outlook ...... 123 5.5 References ...... 123 5.6 Experimental section ...... 125 Chapter 6 : Nickel-Catalyzed Cross-Coupling of Organolithium Reagents with (Hetero)Aryl Electrophiles ...... 129 6.1 Introduction ...... 130 6.2 Optimization and scope ...... 131 6.3 Conclusions ...... 138 6.4 References ...... 139 Acknowledgements ...... 141 6.5 Experimental section ...... 141 Chapter 7 : Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-Coupling of Organolithium Reagents and its Application in Nuclear Medicine ...... 155 7.1 Introduction ...... 156 7.2 Oxygen activation ...... 157 7.3 Scope ...... 158 7.4 Active catalyst investigation ...... 160 7.5 Application in the coupling of 11C and the synthesis of Celecoxib ...... 164 7.6 Conclusions and outlook ...... 165 7.7 Experimental section ...... 165 Chapter 8 : The Cross-Coupling of Carbolithiated Acetylenes and the Synthesis of Z-Tamoxifen ..... 188 8.1 Introduction ...... 189 8.2 Atom economy, reaction mass efficiency and E-factor ...... 189 8.3 Goal ...... 190 Current syntheses ...... 190 8.4 Optimization synthesis of Tamoxifen ...... 191 Purification ...... 195 One pot procedure and alternative electrophile coupling...... 196 8.5 Conclusions and outlook ...... 197 8.6 References ...... 197 8.7 Experimental section ...... 200 Chapter 9 : The Cross- Coupling of Organo-lithium Reagents at Cryogenic Temperatures ...... 202 9.1 Introduction ...... 203 9.2 Catalyst design and SAR ...... 204 9.3 Scope ...... 205 9.3.1 Sequential coupling ...... 207 9.3.2 Attempts at improving the scope ...... 209 9.4 Conclusion ...... 211 9.5 References ...... 212 9.6 Experimental section ...... 214 Summary ...... 231 Samenvatting ...... 234 Summary for non chemists ...... 237 List of publications ...... 242 Acknowledgements ...... 244

Chapter 1: Introduction Organolithium Reagents : Discovery, Preparation, Properties and Applications

Wilhelm Schlenk, the discoverer of alkyllithium reagents. 1.1 Discovery and preparation “Methyllithium ignites in air and burns with a luminous red flame and a golden-colored shower of sparks”.1 The special properties of organolithium reagents, with its highly reactive ionic character, were first discovered by Wilhelm Schlenk and Johanna Holz in 1917 by the preparation of methyl-, ethyl- and phenyllithium.1 Starting from the organomercury compounds, metallic lithium provided the pyrophoric compounds that are now common reagents in synthetic laboratories and industry. We are currently 100 years after the discovery of organolithium compounds (and 200 years after the discovery of metallic lithium), and it has changed our world. The global hunger for lithium anno 2018 might be dominated by the demand for lithium-based batteries, but lithium is also used for the preparation of the organometallic reagents, which are vital to the field of organic synthesis, and therefore also for the pharmaceutical and chemical industry.2 Fortunately, the highly toxic organomercury precursor used by Schlenk in his seminal work is no longer used in the synthesis, since the direct reaction with a carbon-halide bond by means of an umpolung reaction proved to be a much safer substitute.3 The improved synthesis, and use of these organolithium reagents was developed by some of the giants in organic chemistry. Ziegler, Wittig and Gillman were responsible for the first major steps in the maturing of organolithium chemistry by properly handling and using the reagents for reactions such as polymerization, lithium halogen exchange and other metalations.4 It is not only the high reactivity that makes organolithium reagents so popular amongst chemists; the price of n-butyllithium in combination with its solubility in simple alkanes or aromatic solvents (pentane/toluene) make it cheap and easy to handle.8 The relatively nontoxic byproduct from any deprotonation usually consists of butane, and lithium salts which are easily washed away and even have their own medical application. The preparation of (non commercial) organolithium reagents from the corresponding halides is usually straightforward by means of reductive lithiation, or lithium halogen exchange (Scheme 1.1).4

Scheme 1.1 Common organolithium forming reactions

The mechanism of the important lithium halogen exchange is substrate dependent (alkyl vs aryl and iodide vs bromide).5b Studies on the reaction pathway and structures involved by means of spectroscopy, competition experiments, isotope labelling and crystallography have been conducted over the years, and have led to the confirmation of both radical, as well as ate-complex intermediates (Scheme 2).5c The preparation of aryllithium reagents from the corresponding arylhalide and an alkyllithium proceeds via nucleophilic attack on the halide, and is hypothesized to yield the aryllithium reagent in a concerted fashion, or via a relatively stable ate-complex intermediate, which collapses to give the most stable product.5c For alkyl bromide substrates, it is a single electron transfer between the alkyl bromide and the organolithium reagent that yields an alkyl-radical species, which after a second electron donation results in the anionic alkyl fragment. For alkyl iodides however, this mechanism has not been proven, since products arising from radical formation and consecutive cyclization were not detected (Scheme 1.2).5d

Scheme 1.2 lithium-halogen exchange, mechanism and intermediates

Beside the standard safety precautions with respect to toxicity or corrosiveness, working with organometallic reagents, and alkyl-lithiums in particular, requires proper training and safe handling to prevent unwanted exposure to air/water that can cause the spontaneous ignition.5e Though serious (lethal) accidents have happened,10 organolithium reagents are used throughout the world and can be safely applied on a small as well as a large scale.

1.2 Properties Already in an early stage, the pioneers in the field found that organolithium reagents existed not as monomers in solution, but provided stable aggregates (Figure 1.1), the size of which varies with alkyl substituent, solvent and additive.5f The alkyllithium reagents react differently with additives and solvents, and the rate thereof is often described as the time required to reduce the initial concentration by half (½ life). In Table 1.1 some of the aggregation states and other properties of the most common organolithium reagents are shown.5a

Table 1.1. Common (commercially available) organolithium reagents and their properties

R-Li PhLi (Bu2O) MeLi (Ether) n-BuLi (Hex) iPr-Li (Cyclohex) t-BuLi (Pentane) pKa 43 48 50 51 53 Aggregation Dimer Tetramer Hexamer Tetramer Tetramer state ½ life in THF >100 h >100 h 2 h 1 min ½ min

Figure 1.1 Aggregation states or organolithium reagents

The aggregation state of the reagent is of great importance for its reactivity, and can quite easily be influenced by solvents or additives.5a (This will also show to be a key aspect in the cross coupling reactions presented in later chapters.) Some of the common solvents and additives are shown below (Figure 1.2). The coordinating effect of the lone pairs in the heteroatom of ethers or (tertiary) amines shifts the aggregate toward the monomer or dimer and by doing so, a more reactive species is formed. In contrast to Schlosser (KOtBu + RLi) type reaction mixtures, the mentioned additives change the reactivity of the organolithium without altering the chemical nature or pKa of the organolithium reagent.5g

Figure 1.2 Common solvents and additives for organolithium reagents

The high basicity of the carbanion makes (alkyl) organolithium reagents a common choice when it comes to strong bases. Illustrative examples of deprotonations are shown below in Figure 1.3. Lithium Diisopropyl Amide (LDA) and its silyl- analogue lithium hexamethyldisilamide (LiHMDS) are made by deprotonation of the corresponding amine, which generates the non-nucleophilic bases that are widely used for a range of (alpha-) deprotonations to form kinetic enolates. Furan is readily deprotonated, and for consecutive cross coupling, is generally used via a transmetallation step with boron, zinc or tin reagents.6b Alkyl substituted fluorene molecules are useful building blocks for the emerging field of organic materials, and the corresponding alkyl chain can easily be installed by a substitution reaction with the lithiated fluorene.6c Ortho lithiation of substituted benzenes has been pioneered by (amongst others) Snieckus and Beak, and has paved the way for an easy, fast and high yielding method for installing ortho-subsitutents on arenes.6d Finally, THF is one of the solvents that can have a strong effect on the aggregation state of the organolithium reagent, but as a solvent is also prone to react as proton donor, and after lithiation undergo a ring opening (retro 3+2 ring closing) to yield the enolate of acetaldehyde as well as ethylene.5

Figure 1.3 Examples of lithiations by alkyllithium reagents

Historically, one of the first reactions where the organolithium reagent showed nucleophilic behavior was found during its very synthesis, where it reacted with the starting material halide in the Wurtz type coupling.6a As commonly seen for (strong) bases, organolithium reagents also generally possess a strong nucleophilic character. At room temperature, they easily react with any carbonyl moiety, epoxide or nitrile.5 Be it desirable or an unwanted side reaction, these additions are generally very fast, and as such often outcompete other reaction pathways. As the solvent has a great effect on the aggregation state and thus the reactivity of the organolithium reagent, it also controls the selectivity between (for example) transmetallation and addition to an electrophile or lithium halogen exchange.

Figure 1.4 Examples of reactivity of n-butyl-lithium

Figure 1.4 shows some examples of interactions of butyllithium with electrophiles. Lithium halogen exchange, deprotonation and ortho-lithiation were already mentioned. Together with the elimination of (for example) alkyl halides, these transformations do not incorporate the alkyl fragment of the organolithium reagent. In contrary to this, the addition of butyllithium to benzaldehyde yields the corresponding 1,1-phenyl-butylmethanol. The rate and selectivity for this reaction is difficult to compete with, and the addition of benzaldehyde can therefore be used to capture excess organolithium reagent and thereby determine yields/conversions.7a The (carbo)lithiation of styrene was one of the first reactions performed by Ziegler, and depending on the order of addition of the reagents yields the intermediate shown above (figure 1.4), or upon reversed (n-Buli added to styrene) addition triggers the polymerization of styrene to oligo/poly-styrene.1 Methyl iodide will rapidly react with many nucleophiles, and organolithium reagents are no exception to this, explaining why it is one of the most used trapping agents. Though ethyl- and other alkyl iodides also undergo substitution, they are also susceptible to elimination and thereby generate the corresponding alkene.8 Finally, the trapping of organolithium reagents with carbon dioxide yields the corresponding lithium carboxylate that upon protonation gives carboxylic acids

1.3 Transmetallations and catalysis Stoichiometric transmetallation of organolithium reagents to zinc, tin or boron has found widespread use in the preparation of (air) stable organometallic reagents which provide suitable coupling partners for transition metal catalysis.6b The lowering of reactivity of the organolithium (or organomagnesium) reagent is balanced by means of a gain in stability, reaction control and functional group tolerance.6b A clear preference in favor of the softer organometallic reagents has led to numerous transmetallation strategies and has left the direct use of organolithium reagents an underexplored area.7b However, additional transmetallations increase the waste production, toxicity and cost of a reaction, and are therefore inherently less (atom) efficient. The transmetallations to these other metals, and their use in transition metal catalysis (cross-coupling, palladium used as example) are shown in Scheme 1.3. It is this catalytic cycle that is believed to take place in in reactions such as Kumada, Stille, Negischi, Suzuki and Hyiama cross coupling methods, and consists of an oxidative addition into the carbon-halide bond of the electrophile, followed by transmetallation with the organometallic reagent of choice. Finally, reductive elimination yields the desired cross coupling product, and regenerates the active palladium catalyst. In the case of palladium(II) precatalysts, this cycle is preceded by activation by means of reduction. This can be achieved by double transmetallatoin with the organometallic coupling partner followed by reductive elimination. As a consequence, this yields a catalytic amount of homo-coupled byproduct.

Scheme 1.3 Transmetallations using organolithium reagents, and their use in transition metal catalysis

Beside the above mentioned transmetallations with zinc, tin and boron, copper has also found its use in transmetallation reactions with organolithium reagents.7c, 7d In contrast to the hard organolithium nucleophile, the formed organocuprate reagent shows properties of a soft nucleophile, and therefore showcases a remarkable preference for 1,4-addition at the expense of 1,2-addition to the carbonyl in a 1,4-unsaturated system (Scheme 1.4).8b Whereas organocuprate formation and its use have been known for decades, the catalytic use of copper with alkyllithium reagents for allylic substitution reactions was discovered only recently (Scheme 1.4).8c Over the years, the method of substituting an allylic halide has been found to proceed with both alkyl- and aryllithium reagents, and for the synthesis of tertiary as well as the very challenging quaternary stereocentres.8c The selectivity for Sn2’ over Sn2 (Branched : Linear ) product is highly dependent on the solvent, and is easily controlled by the addition or exclusion of ethereal solvents.

Scheme 1.4 Transformations using organocuprate and organolithium reagents

Direct cross coupling with organolithium compounds In 1979 Murahashi showed the potential of direct organolithium cross coupling reactions in the transformation of a range or alkenyl (mostly styryl) bromides (Scheme 1.5).11 For the following decades, despite being well established reagents by then, organolithiums were exclusively used for reactions other than (direct) cross coupling reactions. In 2010, Yoshida presented the application of organolithium reagents in cross coupling reactions by means of flow chemistry, with the in situ formation of aryllithium reagents.12 Up to this point, both methods were limited in scope (only styryl or phenyl coupling), but the stage was set for further development.

Scheme 1.5 Examples of early organolithium cross coupling chemistry

In 2013 our group published a more general approach for the coupling of organolithium reagents, employing bulky palladium phosphine complexes.13 It was found that the controlled addition of the nucleophile as well as a non-coordinating solvent such as toluene was crucial to achieve the desired results, which suppresses unwanted side reactions or catalyst deactivation. The work describes the coupling of alkyl, as well as aryl and alkenyl lithium reagents with aryl and alkenyl bromides (Figure 1.5), and although some limits towards functional group tolerance were met, the inherently less waste producing reagents showed the potential for organolithium reagents to provide a cheap and environmental friendly substitute for more commonly used cross coupling reactions such as Suzuki, Negishi or Stille procedures.14 Key findings were the slow addition of the organolithium coupling partner, and the absence of ethereal solvents such as THF or diethylether (avoiding the de- aggregation of the organolithium reagent). Toluene showed to be the solvent of choice, and allowed for rapid (1 h) coupling at room temperature. Expanding the scope, the system was quickly found to be suitable for a range of hindered substrates by using NHC-ligands,14b yielding tri- or tetra ortho substituted biaryl motifs that are a common feature in natural products and biologically active compounds.14c Different strategies for the synthesis of these products are available, but many require long reaction times with considerable heating, leaving space for improvement.15 Whereas phosphine ligated palladium complexes had already proven themselves to be the catalyst of choice for the selective coupling of unhindered alkyl substrates, the sterically congested biaryl products required a different approach. Very hindered/bulky Pd-carbene complexes had already shown to speed up the coupling of other cross coupling reactions by facilitating the otherwise slow reductive elimination to provide the tri- or tetra- ortho substituted biaryl product.16

Figure 1.5 Charactaristic palladium catalyzed organolithium cross coupling reactions : Catalysts and products

The Pd-PEPPSI complex shown in Figure 1.5 was found capable of catalyzing these reactions with remarkable selectivity and conversion for a reaction that is carried out in just one hour at room temperature.14d As electrophile, aryl bromides and the cheaper and more stable aryl chlorides were both found to be active, and the method was showcased in the facile synthesis of sterically demanding BINOL-derived products.17 The amount of solvent had surprisingly little effect, and these hindered biaryls were later also synthesized in the absence of any additional solvent (vide supra), creating a general, low solvent method for the synthesis of these motifs (Scheme 1.6).14e This resulted in an improved synthesis of key intermediates, including 4-chlorophenyl-thiophene, with significant lower E-factors and reduced reaction times.

Scheme 1.6 Solvent free cross coupling of organolithium reagents

Faster A positive effect in terms of reaction speed was observed when the once thought to be crucial solvent toluene was completely omitted, and the reaction was carried out using the substrate as the solvent for the palladium NHC catalyst.14e Solvents are often deemed crucial for reactions and cross coupling chemistry in particular, and little is known about extremely concentrated reaction mixtures.18 We observed that under these high concentrations, products were now obtained in 10 min at room temperature and the strict inert conditions were no longer required (vide supra). The impact of omitting the additional solvent in these reactions greatly enhances the waste to product ratio described by the E-factor and at the same time increases the effective capacity of the (laboratory) setup.19 Having only a catalytic amount (down to 1.5 mol%) of Pd-complex, and benign lithium salts as the only stoichiometric waste, the method yielded very clean reaction mixtures, that after a quick filtration step were obtained analytically pure. Simultaneously, in order to test the limits of the palladium phosphine complex that were previously employed in the general cross coupling procedure, the addition time of the solution of alkyl (methyl) lithium was graduately decreased. With addition times of just 2 min, full conversion with near perfect selectivity was still achieved (Scheme 1.7).20

Scheme 1.7 Oxygen activated fast cross coupling

The initial notice of methyl lithium being a special case was quickly found to be incorrect when other alkyllithium reagents gave identical results. Testing different batches of the commercially available t Pd(P Bu3)2 complex, results began to vary greatly. A systematic approach, ruling out a large variety of factors finally showed molecular oxygen to be essential for the fast coupling. Further studies showed that purging with molecular oxygen yielded an extremely active catalyst, that consisted of palladium nanoparticles.20b After full activation of the catalyst, manual addition of alkyllithium over a period of 5 sec gave full conversion of the starting material, with good selectivity towards the desired product (Figure 1.6).

Figure 1.6 Optimization of catalytic systems All mentioned catalytic setups show great selectivity for cross coupling at the expense of (for example) lithium halogen exchange. But what if lithium halogen exchange at the expense of cross coupling is desired? Ethereal solvents such as THF are well known to change the aggregation state of the organolithium reagent enhancing their reactivity, but also therefore hamper the desired direct cross coupling reaction.21 Whereas n-BuLi and sec-BuLi couple with excellent yields, the most reactive of the butyl series, t-BuLi does not participate in the catalytic cycle. Since transmetallation of the tertiary alkyllithium with the palladium catalyst is not favored, lithium halogen exchange with an aryl halide is next in the line of events, and will create the corresponding aryllithium coupling partner in situ (Scheme 1.8).

Scheme 1.8 tBuli mediated In situ formation and coupling of aryllithium reagents

The palladium catalyzed coupling of this in situ made aryllithium with the remaining excess aryl halide presented little challenge in the case of symmetrical biaryls.22 For a highly selective heterocoupling however, an ortho directing group facilitates significant faster lithium-halogen exchange in one of the substrates (Pathway B), and slows down oxidative addition with the palladium (0) catalyst, thereby creating a selective process of forming a single aryllithium reagent. With the selective in situ preparation of the organometallic reagent, the remaining (less reactive towards lithium-halogen exchange) aryl bromide solely reacts with the palladium(0) catalyst via oxidative addition (Pathway A), generating the palladium(II) intermediate that undergoes transmetallation (TM), followed by reductive elimination (RE) to yield the desired cross coupled product.23

Cheaper Compared to other more established cross coupling methods, the intrinsically cheaper and more environmentally benign organolithium reagents provide a perfect platform for an exceedingly cost efficient cross coupling.23b As has been done for other cross coupling methods, we envisioned we could avoid the use of bromide electrophiles and palladium catalysts, and employ aryl chlorides and nickel complexes instead. Cheaper transition metal catalysts such as nickel were already investigated by Rueping and Chatani (amongst others) in for example the cross coupling of the bifunctional Li-

CH2TMS with aryl ethers and have previously shown to be active in Kumada, Suzuki and Negishi coupling reactions.24 For the lithium chemistry, a clear similarity between nickel and palladium catalysis was observed after careful optimization of the catalytic system.25 An alkylphosphine based nickel catalyst proved to be the most suitable candidate for the coupling of alkyllithium reagents, whereas (hindered) aryllithium reagents proved most compatible with a carbene-nickel complex (Scheme 1.9).

Scheme 1.9 Palladium vs Nickel catalysis

The much less reactive methoxide and fluoride electrophiles, could also be activated, allowing for the late stage functionalization of molecules.26 Additional studies on the coupling of organolithium reagents with not only these often inert ether groups, but also ammonium salts was published the same year by Wang and Ochiyama.27 In the cross coupling with aryllithium reagents, a near identical functional group tolerance was observed, leading to substituted biaryl products.

Functional group compatibility Some substrates and applications deserve special attention due to their applicability or remarkable selectivity. The previously discussed strong basic and nucleophilic character of organolithium reagents provide some challenges in their cross coupling. It is therefore surprising to see that our developed method(s) are capable of selectively incorporating the organolithium reagent, suppressing nucleophilic attack to a large extend (Figure 1.7A ). One of the key examples of this selectivity, is the cross coupling wit aryl bromides in the presence of unhindered epoxides, with minimal side products arising from ring opening reactions. Though further electrophilic sites are absent in indoles and alcohols, the corresponding alkoxide or amide (generated upon deprotonation) is prone to interfere with the palladium catalyst. Yet, we were able to use a variety of alcohols (including phenol), unprotected indole, as well as sulfonamides (vide infra) (Figure 1.7B). Finally, the exclusive coupling with bromides at the expense of triflates or chlorides provides a vital chemoselectivity that leaves room for additional/further functionalization with the less reactive electrophilic center (Figure 1.7C).28

Figure 1.7 Special examples of selectivity obtained with the Pd-Phosphine precatalyst.

Similar chemoselectivity with respect to bromides and chlorides to that of the one shown above was also found in the Pd-PEPPSI catalyzed, temperature controlled, cross coupling with bromochloroarenes (Scheme 1.10). Lowering reaction temperatures, full selectivity was observed in the coupling of alkyllithium reagents. Unlike the phosphine based nanoparticle catalyst, the Pd- PEPPSI catalyst that showed this distinction, is also very active with the less reactive aryl chlorides, but only at (or close to) room temperature. Moreover, previous work showed the Pd-NHC complex to be a very suitable catalyst for other cross coupling methodologies such as aminations and Negishi and Stille coupling reactions.29 This allowed us to develop a method for the temperature controlled, one pot cross coupling of bromo-chloro-arenes to provide highly functionalized small molecules with excellent diversity of the desired substituents.30

Scheme 1.10 Examples of functionalized molecules synthesized via a sequential one pot procedure30

Specialized Pd-PEPPSI catalysts were synthesised and tested in the coupling of alkyllithium reagents, and even proved capable of coupling it to iodonaphthalene at -78°C. This is the first example of reactivity with these reagents at such low temperatures, and could pave the way to new selectivity and reactivity that is impossible using conventional cross coupling methodology.30

Applications The synthesis of natural products has always attracted the attention of organic chemists to prove or validate the power of their developed methodology.24c The first synthesis of a natural product using an organolithium cross coupling was shown by the preparation of Mastigophorene A (Figure 1.8). The previously synthesized dimethyl herbertenediol could easily be brominated and subsequently homocoupled to give the natural product. The axial chirality in the biaryl was installed with a 9.1 d.r. Since a non-chiral (Pd-PEPPSI-Ipent) catalyst was used, the point to axial chirality transfer is hypothesized to be transferred via the large ligand on the palladium catalyst.

Figure 1.8 Applications of organolithium cross coupling.

The above mentioned fast coupling of alkyl lithium reagents also paved the way for the incorporation of short lived radio isotopes that require short reaction times for high yielding reactions. The radiolabeling of biologically active compounds allows us to map their distribution throughout the human body, and elucidate their mode of action via PET imaging.25b The unique rate of the cross coupling is especially suitable for the synthesis of PET-tracers, since it allows for radiolabeled drugs to be constructed in shorter times, and thus with a lower extend of decay, generating an overall more efficient synthesis. Celecoxib is a widely used anti-inflammatory drug, and was chosen as target to showcase the power of the organolithium cross coupling methodology.25c Not only biologically active compounds are within the scope of organolithium cross coupling chemistry, as showcased by the improved synthesis of building blocks for optoelectronic material, and the preparation of highly sterically congested BINOL derrivatives. These biaryls with axial chirality are crucial precursors in the synthesis of ligands for transition metal catalysis, as well as chiral phosphoric acids for asymmetric organocatalysis.25d

To conclude, the cross coupling of organolithium reagents has shown great potential in the environmentally friendly, fast and cheap construction of carbon-carbon bonds. By means of slow addition of the nucleophile, and by employing the proper solvent, notorious side reactions can be suppressed, and the desired products are generally isolated in high yields. Natural products, pharmaceuticals and (precursors to) optoelectronic materials and ligands are within the scope of the methodology.

The method that is applicable to the coupling of the bifunctional LiCH2TMS reagent is described in chapter 2, and has led to the synthesis of TMS-substituted toluene derivatives, suitable for a range of transformations. The first application of the organolithium based coupling in the synthesis of a complex natural product, and other (sterically hindered) biaryl structures is presented in chapter 3. In chapter 4, several one pot procedures are described. Briefly looking back at the previously reported method for the synthesis of aryl-alkyl ketones, these new approaches provide novel strategies for the synthesis of an array of α-substituted ketones, substituted benzaldehydes or anilines. The attempts at utilizing the advantageous properties of the organolithium cross coupling in the atroposelective construction of chiral biaryls by employing bulky Pd-NHC complexes are described in chapter 5. Moving away from palladium to more earth abundant metals, nickel was found to be very active in the cross coupling of both alkyl and aryllithium reagents with a range of aryl bromides and chlorides, but unlike palladium, also with the less reactive methoxy substituted aryl compounds and arylfluorides. These results are described in chapter 6. The suprising effect of molecular oxygen in the activation of palladium phosphine complexes, and their considerable effect in the rate of the reaction is shown in chapter 7. This chapter also explains the application of the oxygenated catalyst in the synthesis of radiolabeled pharmaceuticals. Further applications in the synthesis of pharmaceuticals can be found in chapter 8, where the atom efficient preparation of Z-tamoxifen is achieved by a carbolithiation-cross-coupling strategy. Finally, the combination of organolithium cross coupling reactions, that proceed at cryogenic temperatures, with more traditional cross coupling methods such as Suzuki, Negishi or Buchwald-Hartwig is presented in the final chapter 9.

1.4 References. 1) U. Wietelmann, J. Klett Z. Anorg. Allg. Chem. 2018, 644, 194–204 and references therein

2) https://minerals.usgs.gov/

3) a) D. Seyferth, M. Weiner, J. Org. Chem., 1961, 26 (12), pp 4797-4800, b) METAL-ORGANIC COMPOUNDS, Volume 23 1959 AMERICAN CHEMICAL SOCIETY, ISBN13: 9780841200241

4) a) H. Gilman, F. W. Moore, O. Baine J. Am. Chem. Soc., 1941, 63 (9), 2479–2482. b) K. Ziegler H. Colonius, Justus Liebigs Ann. Chem. 1930, 479, 135–149. c) G. Wittig, Ber. Dtsch. Chem. Ges. 1931, 64, 2395–2405. d) H. Gilman, E. A. Zoellner, W. M. Selby J. Am. Chem. Soc. 1932, 54, 1957–1962. e) G. Wittig U. Pockels H. Dröge, Ber. Dtsch. Chem. Ges. 1938, 71, 1903–1912. f) O. Diels K. Alder Justus Liebigs Ann. Chem. 1928, 463, 1–97. g) K. Ziegler F. Crössmann H. Kleiner O. Schäfer, Justus Liebigs Ann. Chem. 1928, 463, 98–227. h) H. Gilman, Jr. Morton, W.John, Org. React. 1954, 8, 258–293

5) a) Lithium Compounds in Organic Synthesis, R. Luisi, V. Capriati, 2014 Wiley‐VCH Verlag GmbH & Co. KGaA ISBN:9783527333431. b) Newcomb, M; Willams, W. G.; Crumpacker, E. L. Tetrahedron Lett. 1985, 26, 1183-1184. Newcomb, M; Willams, W. G. Tetrahedron Lett. 1985, 26, 1179-1182 c) Bailey, W.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1-46. d) E. C. Ashby, Tung N. Pham J. Org. Chem. 1987,52, 1291-1300 e) Michael R. Gau , Michael J. Zdilla, J. Vis. Exp. (117), e54705, doi:10.3791/54705 (2016). f) The Chemistry of Organolithium Compounds, Z. Rappoport, I. Marek, 2004, John Wiley & Sons (Verlag), ISBN: 978-0-470-02110-1. g) M. Schlosser, Pure&Appl. Chem, Vol. 60, 1627-1634, 1988.

6) a) G. M. Lampman, J. C. Aumiller, Org. Synth. 1971, 51, 55. A. Wurtz, Ann. Ch. Phys. 1855 (3), 364 b) U. V. Mentzel, D. Tanner, J. E. Tønder J. Org. Chem. 2006, 71, 5807-5810, Metal‐Catalyzed Cross‐ Coupling Reactions, F. Diederich, P. J. Stang, Wiley‐VCH Verlag GmbH, Online ISBN: 9783527612222 |DOI:10.1002/9783527612222. c) E. Bundgaard, F. C. Krebs, Solar Energy Materials & Solar Cells 91 ,2007, 954–985. d) M. Kauch, D. Hoppe, Synthesis, 2006, 1575-1577. S. L. MacNeil, O. B. Familoni, V. Snieckus, J. Org. Chem, 2001, 66, 3662-3670.

7) a) This thesis b) Less than 20 papers on the direct cross coupling of organolithium reagents have been published to date. c) N. J. Rijs, N. Yoshikai, E. Nakamura, R.A. J. O’Hair J. Org.Chem. 2014, 79, 1320–1334 d) Organocuprate Aggregation and Reactivity: Decoding the 'Black Box, Aliaksei Putau, Südwestdeutscher Verlag für Hochschulschriften, ISBN-13: 978-3838136981

8) a) K. Ziegler, H. G. Gellert, Justus Liebigs Ann. Chem. 1950, 567, 179–184. b) F. López, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc., 2004, 126, 12784-12785. R. P. Jumde, F. Lanza, M. J. Veenstra, S. R. Harutyunyan. Science, 2016, Vol. 352, Issue 6284, pp. 433-437 c) A. Samuel Vellekoop, R. A. J. Smith J. Am. Chem. Soc., 1994, 116, 2902–2913 and references therein. C. Vila, V. Hornillos, M. Fañanás-Mastral and B. L. Feringa, Org. Biomol. Chem., 2014, 12, 9321. M. Fananas-Mastral, R.Vitale, M. Perez, B. L. Feringa, Chem. Eur. J. 2015, 21, 4209 – 4212

9) a) www.acros.com b) Sigmaaldrich.com 10) http://discovermagazine.com/2015/june/20-death-in-the-lab 11) S. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, and K. Kondo J. Org. Chem., 1979, 44, 2408–2417 12) A. Nagaki A. Kenmoku Y. Moriwaki A. Hayashi J. Yoshida, Angew. Chem. Int. Ed. 2010, 49, 7543 –7547 13) M.Giannerini, M. Fañanás-Mastral B. L. Feringa, Nature Chemistry 2013, 5, 667-672. 14) a) M. Busch, M. D. Wodrich, C. Corminboeuf, ACS Catal., 2017, 7 (9), pp 5643–5653, E. Negishi, Angew. Chem. Int. Ed. 2011, 50, 6738 – 6764 b) V.Hornillos, M. Giannerini, C.Vila, M. Fañanás- Mastral, B. L. Feringa Org. Lett. 2013 15, 19, 5114-5117. L. M. Castelló, V. Hornillos, C. Vila, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa Org. Lett., 2015, 17, 62–65. c) G. Bringmann, R. Walter, and R. Weirich, Angew. Chem. In. Ed. 29, 1990, 977-991. d) J. Buter, D. Heijnen, C. Vila, V. Hornillos, E. Otten, M. Giannerini, A. J. Minnaard, and B. L. Feringa. Angew. Chem. Int. Ed. 2016, 55, 3620 –3624. e) E. B. Pinxterhuis, M. Giannerini, V. Hornillos B. L. Feringa NatureCommunications Volume 7, 2016, 11698 DOI: 10.1038/ncomms11698

15) a) I. Hussain, J. Capricho, M. A. Yawer, Adv.synth. Catal. 2016, 358,3320-3349, b) A. H. Cherney, N. T. Kadunce, and S. E. Reisman, Chem. Rev. 2015, 115, 9587−9652, c) J. Wencel-Delord, A. Panossian, F. R. Lerouxb F. Colobert, Chem. Soc. Rev., 2015, 44, 3418-3430 16) a) C.Valente S. Çalimsiz K. Hoi D. Mallik M. Sayah M. G. Organ Angew. Chem. Int. Ed. 2012, 51, 3314 – 3332, b) G. C. Fortmana S. P. Nolan, Chem. Soc. Rev., 2011, 40, 5151–5169 17) a) L. M. Castelló, V. Hornillos, C. Vila, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa Org. Lett., 2015, 17, 62–65 b) V. Hornillos, M. Giannerini, C. Vila, M. Fañanás-Mastral, and Ben L. Feringa, Org. Lett., 2013, 15 (19), pp 5114–5117 18) a) A. Asachenko, K. Sorochkina, P. B. Dzhevakov, M. A. Topchiy, S.M. Nechaev Adv. Synth. Catal. 2013, 355, 3553 – 3557, b) Y. Liang, Y. Xie, J. Li J. Org. Chem., 2006, 71 (1), pp 379–381, c) Y. Zhang, R.J. Song, Y.X. Xie, C.L. Deng, Y. Liang, Synthetic Communications, 37:14, 2433-2448 19) R. A. Scheldon, Green Chem., 2007, 9, 1273-1283 20) D. Heijnen, F. Tosi, C. Vila, M. C. A. Stuart, P. H. Elsinga, W. Szymanski and B. L. Feringa, Angew. Chem. Int. Ed. 2017, 56, 3354 –3359 21) Organolithiums: Selectivity for Synthesis, J.Clayden, Tetrahedon Organic Chemistry Series Vol 23, 2002, Elsevier Science, Oxford, ISBN 008043262. 22) a) D. Toummini, F. Ouazzani, M. Taillefer, Org. Lett., 2013, 15 (18), pp 4690–4693, b) J. Buter, D. Heijnen, C. Vila, V. Hornillos, E. Otten, M. Giannerini, A. J. Minnaard,B. L. Feringa Angew. Chem. Int. Ed. 2016, 55,3620 –3624 23) a) E. Negishi, Angew. Chem. Int. Ed. 2011, 50, 6738 – 6764, 5520. b) n-BuLi = € 50-60/250mmol. n-BuB(OH)2 = €200/250mmol. 24) a) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.Resmerita, N. K. Garg, and V. Percec, Chem. Rev. 2011, 111, 1346–1416, b) L. Guo, C.Hsiao, H.Yue, X. Liu, M. Rueping, ACS Catal. 2016, 6, 4438−4442, M. Tobisu, T. Takahira, T. Morioka, N. Chatani J. Am. Chem. Soc. 2016, 138, 6711−6714. b) see chapter 9 c) Total Synthesis of Natural Products, At the Frontiers of Organic Chemistry, Li, Jie Jack, Corey, E.J, ISBN 978-3-642-34065-9, Springer 25) D. Heijnen. J. Gualtierotti, V. Hornillos, B. L. Feringa. Chem. Eur. J. 2016, 22, 3991-3995 b) A. Berger, BMJ. 2003, 326(7404): 1449. c) I.Egashira, F. Takahashi-Yanaga, R. Nishida, M. Arioka, K. Igawa, K. Tomooka, Y. Nakatsu, T.Tsuzuki, Y. Nakabeppu, T. Kitazono, T. Sasagur. Cancer Sci, 2017 vol. 108, 108–115 d) S.Shirakawa, K.Maruoka. Chem 2, 326–333, 2017

26) C. Zarate, M. Nakajima, R. Martin, J. Am. Chem. Soc. 2017, 139 (3), 1191-1197 and references therein 27) a) L. Tao, Z. Wang, Asian J. Org. Chem. 2016, 5, 521 – 527, b) Z.Yang, D. Wang, H. Minami, H. Ogawa, T. Ozaki, T. Saito, K. Miyamoto, C. Wang, M. Uchiyama Chem. Eur. J. 2016, 22, 15693 – 15699 28) Unpublished results 29) G. A. Price, A. R. Bogdan, A. L. Aguirre, T. Iwai, S. W. Djuricb M. G. Organ, Catal. Sci. Technol., 2016, 6 , 4733-4742. see also ref 16a 30) see chapter 9

Chapter 2: Palladium-Catalyzed Cross-Coupling of (Trimethylsilyl)methyllithium with (Hetero)- Aryl Halides

Abstract : The palladium-catalyzed direct cross-coupling of a range of organic chlorides and bromides with the bifunctional C(sp3)-(trimethylsilyl)methyllithium reagent is described in this chapter. The use of Pd-PEPPSI-IPent as the catalyst allows for the preparation of structurally diverse and synthetically versatile benzyl- and allylsilanes in high yields under mild conditions (room temperature) with short reaction times (1h). Part of this chapter was published: D. Heijnen, V. Hornillos, B. P. Corbet, M. Giannerini, and B. L. Feringa. Org. Lett., 2015, 17 (9), pp 2262–2265.

2.1 Introduction The development of new catalytic methods for carbon–carbon bond formation continues to present major challenges in organic synthesis.1 In particular, palladium-catalyzed cross-coupling of organometallic reagents with organic halides represents one of the most powerful methods for C–C bond formation.2 Several well established methods for this transformation are available using different organometallic partners including organozinc,3 organotin,4 organoboron,5 organosilicon, 6 and organomagnesium7 reagents. Murahashi and co-workers pioneered the use of highly reactive aryl- and alkyl-lithium reagents in catalytic cross-coupling reactions.8 Our group recently described methods for the palladium-catalyzed direct cross-coupling of organolithium reagents with (hetero)aryl- and alkenyl (pseudo)halides under mild conditions, avoiding side reactions such as lithium–halogen exchange or homocoupling.9,10 Additionally, we also reported the reaction of sp3 carbon nucleophiles with aryl bromides that allows a fast, selective, and high yielding coupling of primary and secondary alkyl groups with the notorious β-hydride elimination being suppressed in nearly all cases.9a,9e,11 Preliminary experiments showed the successful use of the functionalized C(sp3) 9a,9e nucleophile TMSCH2Li in metal-catalyzed cross-coupling reactions. This bifunctional CH2 moiety enables the preparation of stable ArCH2SiMe3 products that can further undergo a wide array of possible transformations including Peterson olefination,12 photocatalyzed13 and gold catalyzed14 reactions, and oxidation to the corresponding acylsilanes15 (Scheme 1). Furthermore, the

CH2 group can act as a nucleophile in fluoride-mediated processes giving rise to the formation of saturated products.16a

Scheme 2.1. Pd-catalyzed cross-coupling of aryl halides employing TMSCH2Li and possible further transformations at the TMSCH2 group.

Following our initial report,9a the use of this functionalized organolithium reagent recently attracted increasing attention in metal-catalyzed cross-coupling reactions, specifically using Ni catalysis.16 Considering the relevance of the (trimethylsilyl)methyllithium nucleophile, we wondered if readily available but less reactive organic chlorides17 could also be a precursors for the synthesis of highly versatile TMSCH2-functionalized compounds. Costs, waste production, and availability benefit from the use of aryl chlorides as starting materials. However, due to their low reactivity, the use of high temperatures and long reaction times is usually required while the application of aryl chlorides in metal-catalyzed C(sp3)–C(sp2) cross-coupling reactions with organolithium reagents remains a challenge.18 Here, we report the development of a Pd-catalyzed cross-coupling reaction employing aryl chlorides and TMSCH2Li that allows selective preparation of a variety of ArCH2TMS compounds in high yields under mild conditions (rt) and short reaction times (1 h) (Scheme 2.1).

2.2 Catalyst optimization The reaction between 4-methoxychlorobenzene 1a, a reluctant aryl chloride in coupling reactions, and TMSCH2Li was chosen as a model system since conditions for the successful coupling of this substrate will enable access to a wide variety of other coupling partners. Under the optimized 9a t 19 conditions for the cross-coupling of alkyllithium reagents with aryl bromides, using Pd(P Bu3)2 as a catalyst (Table 1, entry 1), less than 5% conversion to the coupling product 2a was observed. The in t situ prepared palladium complexes, using Pd2(dba)3 in combination with P( Bu)3 or dialkylbiaryl phosphines,20 previously reported to be effective for the Pd-catalyzed cross-coupling with other aryl and alkyllithium reagents, led to similar results (Table 2.1, entries 2–4).

Table 2.1 Catalyst screening

entrya [Pd] ligand conv (%) 2a:3:4b t 1 Pd(P Bu3)2 <5 t c 2 Pd2(dba)3 L1, P( Bu)3 <5

3 Pd2(dba)3 L2, SPhos <5

4 Pd2(dba)3 L3, XPhos <5 5 Pd-PEPPSI-IPent full 98:<1<1

6 Pd-PEPPSI-IPr ~85 98:<1<1

a Conditions: TMSCH2Li (0.72 mL, 1.0 M in pentane) was added to a solution of 4-bromoanisole (0.6 mmol) in toluene (2 mL). 1 h addition time. b2a:3:4 ratio determined by GCMS analysis. c7.5 mol % was used. dba = dibenzylideneacetone.

We were delighted to find that the air stable Pd-PEPPSI-IPent catalyst, introduced by the group of Organ,21 afforded full conversion and nearly perfect selectivity toward the coupled product 2a at rt in 1 h, avoiding dehalogenation or homocoupling side products 3 and 4, respectively (entry 5, Table 1). It should be mentioned that, for the corresponding Pd-catalyzed cross-couplings of 1a with aryllithium reagents, higher temperatures (40 °C) and longer addition times (3 h) of the organolithium reagent were necessary to reach full conversion and high selectivity.9c The structurally related Pd-PEPPSI-IPr complex also performed well in the reaction, although full conversion was not reached (entry 6).

2.3 Substrate scope with aryl chlorides With Pd-PEPPSI-IPent as a highly efficient catalyst, we set out to investigate the cross-coupling between TMSCH2Li and different aryl chlorides (Scheme 2.2). The reactions employing other electron-rich aryl chlorides such as 1b, 1c, or more sterically hindered 1d also proceed with full conversion and high selectivity without the need to increase the temperature or reaction time. Remarkably, highly deactivated amine-substituted aryl chlorides 1e and 1f, which did not perform well in the cross-coupling with aryllithium reagents,9c were also converted under the optimized reaction conditions to the desired product in good yields and with excellent selectivities (Scheme 2). It should be emphasized that benzyl alcohol 1g, as the Mg alkoxide, and 6-chloro-1H-indole 1h, as the Mg amide, were also tolerated, affording products 2g and 2h with high selectivity. The catalytic system also proved to be efficient in the reaction with 1- and 2-chloronaphthalene 1i and 1j, providing the corresponding trimethyl(naphthalenylmethyl)silanes 2i and 2j with no trace of regioisomers, indicating that benzyne intermediates via 1,2-elimination are not formed. Importantly, 2j was obtained quantitatively when the reaction was scaled up to 4.0 mmol. The electron-deficient 1-chloro-4-(trifluoromethyl)benzene 1k and 4-chloro-1-fluoro-2- methylbenzene 1l underwent clean coupling, giving high isolated yields of the fluorinated structures 2k and 2l. Pyridyl rings, which are susceptible to nucleophilic addition of alkyllithium reagents, also participated in the cross-coupling with high selectivity, albeit with lower yield after purification, as illustrated for substrate 1m. Facile multiple coupling is illustrated in the reaction of 1n with 2.1 equiv of TMSCH2Li providing bis-silylated product 2n in good yield.

a Scheme 2.2 Conditions: Aryl halide (0.6 mmol), TMSCH2Li (0.72 mmol, 1.0 M in pentane). Toluene (2 mL). 1 h addition time. Selectivity >98%. Yield values refer to isolated yields after purification. biPrMgCl (1.0 equiv, 2 c M in Et2O) was added over 5 min prior to the organolithium. TMSCH2Li (1.44 mmol).

2.4 Substrate scope with aryl bromides After having established Pd-PEPPSI-IPent as a highly efficient catalyst for the cross-coupling of

TMSCH2Li with aryl chlorides, we studied the scope of this catalyst in the reaction with challenging organic bromides. Sterically hindered bromides, known for being more reluctant substrates for the 22 coupling of alkyl units, were tested for the first time in combination with TMSCH2Li. As shown in Scheme 2.3, a variety of bulky organic bromides (5a–d) could be coupled with excellent selectivity at room temperature within 1 h, indicating that the transmetalation step takes place rapidly, facilitating a fast coupling process. Notably, di-ortho-substituted tert-butyl aryl bromide 5d was tolerated, affording the TMS-functionalized product 6d at rt in high yield. Remarkably, bromofluorene was successfully employed, despite the acidity of the benzylic protons (pKa = 22). Alkenyl bromide 5f also undergoes this cross-coupling, leading to allyltrimethylsilane 6f with high selectivity with no presence of Fritsh–Butlenberg–Wiechell type rearrangement side products.23Fluorinated bromides 5g and 5h also underwent clean coupling without any traces of side products. Similar to the corresponding aryl chloride 1g, (4-bromophenyl)methanol 5i, bearing an unprotected hydroxyl group, could also be coupled with this organolithium reagent, provided the corresponding Mg alkoxide was first generated. In the presence of an excess of TMSCH2Li, both the −OTf and −Cl groups present in aryl bromides 5j and 5k were also coupled leading to products which contain two or three

TMSCH2 functional groups

a Scheme 2.3 Conditions: Aryl halide (0.6 mmol), TMSCH2Li (0.72 mmol, 1.0 M in pentane). Toluene (2 mL). Selectivity >98%. Yield values refer to isolated yields after purification. bYield determined by 1H NMR using tetrachloroethane as internal standard. cModerate yield obtained after purification by column chromatography. d e iPrMgCl (1.0 equiv, 2 M in Et2O) was added over 5 min prior to the organolithium. TMSCH2Li (1.44 mmol). f TMSCH2Li (2.16 mmol).

2.5 Selectivity As shown above, the Pd-PEPPSI-IPent complex has been shown to be an extremely efficient and versatile catalyst for the cross-coupling of (trimethylsilyl)methyllithium with (hetero)aryl chlorides, bromides, and triflates. However, the use of aryl chlorides presents additional advantages compared to the aforementioned, as they are less prone to undergo halogen–lithium exchange with the organolithium compound, preventing the formation of homocoupling or dehalogenated side products.24 We have recently shown that this different behavior is particularly evident in the Pd- catalyzed cross-coupling of 2-alkoxy-substituted bromo- and chloroarenes where the coordination of the ortho-methoxy group with the organolithium compound facilitates the Li–Br exchange and 9f 3 further stabilizes the resulting aryllithium compound. Here, the C(sp ) character of TMSCH2Li, when compared with C(sp2) in aryl lithium reagents, could further enhance this effect. As shown in Scheme 2.4, this difference in reactivity was confirmed in the cross-coupling with 1-bromo-2- methoxybenzene 7a, where the TMSCH2 functionalized product was obtained along with a homocoupling side product. However, the use of the corresponding aryl chloride 7b led to the desired silylated product 8 with nearly perfect selectivity and high yield, in accordance with the reduced tendency to undergo halogen–lithium exchange, and this enhanced selectivity will be beneficial in synthetic applications.

Scheme 2.4 Comparison between the Pd-catalyzed cross-coupling of TMSCH2Li with 1-chloro- and 1 bromo-2-methoxybenzene.

2.6 The sequential coupling of TMS-substituted toluene derivatives Part of the unpublished work is the further functionalization of the benzylic TMS product by means of deprotonation (lithation) and a second cross-coupling reaction. (scheme 2.5) The facile deprotonation of the TMSCH2 coupled products has been previously described, and is performed in a hexane/TMEDA mixture.26 The solid (insoluble) secondary organolithium reagent is easily separated from the solvent by removal of the supernatant, and washing with dry hexane. In preliminary experiments, we showed that sequential coupling gave the di-arylated TMS-methylene unit in moderate (40 % GC) yield. The synthetic applicability of this method however might be limited, since the products (the double benzylic methylene moiety) could easily be made by deprotonation of the relatively acidic proton and TMS-Cl quench. An enantioselective version might be investigated, but since most further functionalization steps yield achiral products we decided to not investigate this aspect any further.

Scheme 2.5 Further functionalization of TMS substituted products

2.7 Conclusions

In summary, we have shown the direct Pd-catalysed cross-coupling of TMSCH2Li with organic (pseudo)halides, including reluctant but cheap and readily available organic chlorides, in high yields and excellent selectivity. The method is based on the use of commercially available Pd-PEPPSI-IPent catalyst. The reactions take place under mild conditions with broad substrate scope. The products formed are attractive stable α-C-activated systems,25 and precursors for various further transformations.

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(15) (a) Huckins, J. R.; Rychnovsky, S. D. J. Org. Chem. 2003, 68, 10135. For selected reviews regarding acyl silanes, see: (b) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147. (c) Patrocnio, A. F.; Moran, J. S. Braz. J. Chem. Soc. 2001, 12, 7. (d) Zhang, H.-J.; Priebbenow, D. L.; Bolm, C. Chem. Soc. Rev. 2013, 42, 8540.

(16) (a) Leiendecker, M.; Hsiao, C.-C.; Guo, L.; Alandini, N.; Rueping, M. Angew. Chem., Int. Ed. 2014, 53, 12912. (b) Guo, L.; Leiendecker, M.; Hsiao, C.-C.; Baumann, C.; Rueping, M. Chem. Commun. 2015, 51, 1937.

(17) For reviews on catalytic cross-coupling of aryl chlorides, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (b) Noyori, S.; Nisihara, Y. In Applied Cross-Coupling Reactions; Nisihara, Y., Ed.; Springer-Verlag: Berlin Heidelberg, 2013; Chapter 7.

(18) For the corresponding Pd-catalyzed C(sp2 )−C(sp2 ) crosscoupling of aryl chlorides with aryllithium reagents, see ref 9c, f. For reviews about transition-metal-catalyzed cross-coupling reactions of alkylmetal reagents, see: (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417. (b) Doucet, H. Eur. J. Org. Chem. 2008, 2013.

(19) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555.

(20) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.

(21) Organ, M. G.; Çalimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem., Int. Ed. 2009, 48, 2383.

(22) Li, C.; Chen, T.; Li, B.; Xiao, G.; Tang, W. Angew. Chem., Int. Ed. 2015, 54, 3792. (23) Rezaei, H.; Yamanoi, S.; Chemla, F.; Normant, J. F. Org. Lett. 2010, 2, 419.

(24) Seyferth, D. Organometallics 2006, 25, 2. (25) Das, M.; O’Shea, D. F. J. Org. Chem. 2014, 79, 5595 and references cited therein.

(26) P.B. Hitchcock et al. J. Organom. Chem. 694 (2009) 3487–3499

Acknowledgements

Valentin Hornillos contributed to the overall process of the work, Brian Corbet contributed to the optimization of the catalyst, and the isolation of some of the reported products.

2.9 Experimental section General methods: Chromatography: Grace Reveleris X2 flash chromatography system used with Grace® Flash Cartridges, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and cerium/molybdenum or potassium permanganate staining. Progress, conversion and masses of the products in the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). 1H- and 13C-NMR were recorded on a Varian AMX400

(400 and 100.59 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm 1 13 with the solvent resonance as the internal standard (CHCl3: 7.26 for H, 77.0 for C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Melting points were measured using a Büchi Melting Point B-545. All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. THF, Et2O and toluene were dried and distilled over sodium. Pd-PEPPSI-Ipent was purchased from Aldrich and used without further purification. TMSCH2Li (1.0 M in pentane) and all the bromides and chlorides were commercially available and were purchased from Aldrich and TCI Europe.

General procedure for cross coupling of TMSCH2Li with aryl halides.

The corresponding halide (0.6 mmol) and Pd-PEPPSI-IPent complex (5 mol %) were dissolved in toluene (4 ml) in a dried Schlenk flask under inert atmosphere, and the mixture stirred for 5 min.

Subsequently, a solution of TMSCH2Li (0.72 mmol, 1.2 eq.) diluted to 2 ml (to reach a final concentration of 0.36 M) with toluene was added over 1h by the use of a syringe pump. After complete addition, MeOH (1ml) was added to quench the remaining TMSCH2Li. The reaction mixture was transferred to a round-bottom flask, Celite was added, and the solvents evaporated in vacuo. The remaining solid was directly loaded on a silica gel column.

General procedure for the lithiation and cross coupling of benzylic, trimethylsilyl compounds.

The corresponding Aryl-CH2-TMS (0.9 mmol, 1 eq.) was dissolved in dry hexane. Dry TMEDA (0.9 mmol, 1 eq.) was added. n-BuLi was added dropwise, resulting in a darkening of the solution. The mixture was stirred overnight, after which a solid had formed. The supernatant was carefully removed, and the solid washed with dry hexane (2 ml). THF (0.2 ml) and toluene (1.8 ml) were added, and 1 ml of this solution (0.45 mmol) was added to a stirred solution of aryl halide (0.3 mmol) and Pd-PEPPSI-IPent (5 mol %) catalyst as described above. The reaction was quenched, and an aliquot filtered and injected on a GC/MS.

(4-Methoxybenzyl)trimethylsilane (2a):1 Synthesized according to general method. The product was 1 obtained after column chromatography as a yellow oil (SiO2, n-pentane). [99 mg, 85% yield]. H- NMR (400MHz, Chloroform-d) δ 6.93 (d, J = 8.69 Hz, 2H), 6.79 (d, J = 8.66 Hz, 2H), 3.78 (s, 3H), 2.02 (s, 2H), 0.01 (s, 9H) 13C-NMR (100MHz, Chloroform-d) δ 156.5, 132.3, 128.8, 113.6, 55.2, 25.7, 1.9. EI-MS m/z: 194, 179(100%), 121, 73.

(3-Methoxybenzyl)trimethylsilane (2b):2 Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [107 mg, 92% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.15 (t, J = 7.88 Hz, 1H), 6.67-6.58 (m, 3H), 3.80 (s, 3H), 2.09 (s, 2H), 0.02 (s, 9H) 13C-NMR (100MHz, Chloroform-d) δ 160.0, 142.3, 129.1, 120.8, 113.9, 109.2, 55.1, 27.3, -1.7. EI-MS m/z: 194, 179, 73(100%).

(4-Butylbenzyl)trimethylsilane (2c): Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid (SiO2, n-pentane). [115 mg, 87% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.08 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 2.60 (t, 2H), 2.09 (s, 2H), 1.63 (p, J = 7.5 Hz, 2H), 1.40 (dq, J = 14.6, 7.3 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H), 0.04 (s, 9H). 13C-NMR (100 MHz, Chloroform-d) δ 138.2, 137.4, 128.2, 127.9, 35.2, 33.8, 26.5, 22.5, 14.0, - 1.8. EI-MS m/z: 220, 73 (100%).

(2,4-Dimethylbenzyl)trimethylsilane (2d): Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [90 mg, 78% yield]. 1H-NMR (400MHz, Chloroform-d) δ 6.96 (s, 1H), 6.92 – 6.86 (m, 2H), 2.29 (s, 3H), 2.22 (s, 3H), 2.08 (s, 2H), 0.03 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 135.8, 134.5, 133.4, 131.0, 128.8, 126.4, 26.3, 21.0, 20.4, -1.2. EI-MS m/z: 192, 177, 161, 73(100%).

N,N-Dimethyl-3-((trimethylsilyl)methyl)aniline (2e): Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [107 mg, 86% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.11 (t, J = 8.04 Hz, 1H), 6.52 (m, 1H), 6.42 (m, 2H), 2.94 (s, 6H), 2.07 (s, 2H), 0.03 (s, 9H) 13C-NMR (100MHz, Chloroform-d) δ 150.6, 141.2, 128.7, 117.1, 112.8, 108.7, 40.8, 27.4, -1.7. EI-MS m/z: 207(100%), 192, 135, 133, 73

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4-(4-((Trimethylsilyl)methyl)phenyl)morpholine (2f): Synthesized according to general method.

The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [102 mg, 68% yield]. 1H-NMR (400MHz, Chloroform-d) δ 6.92 (d, J = 8.26 Hz, 2H), 6.81 (d, J = 8.26 Hz, 2H), 3.86 (t, J = 4.71 Hz, 4H), 3.10 (t, J = 4.86 Hz, 4H), 2.00 (s, 2H), 0.02 (s, 9H) 13C-NMR

(100MHz, Chloroform-d 3) δ 148.0, 132.2, 128.7, 116.0, 67.0, 50.0, 25.7, -1.9. EI-MS m/z: 249(100%), 176, 73.

(4-((Trimethylsilyl)methyl)phenyl)methanol (2g):3 Synthesized according to general method with the slow addition of 1.0 eq. of isopropylmagnesiumchloride (2.0 M in THF) prior to the addition of the catalyst. The product was obtained after column chromatography as a brown oil (SiO2, n-pentane). [75 mg, 65% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.18 (d, J = 7.9 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.58 (d, J = 4.6 Hz, 2H), 2.06 (s, 2H), 1.91 (s, 1H), -0.03 (s, 9H). 13C-NMR (101 MHz, Chloroform-d) δ 140.0, 136.3, 128.2, 127.20, 65.3, 26.8, -1.9. EI-MS m/z: 194, 179, 104 (100%), 73.

6-((Trimethylsilyl)methyl)-1H-indole (2h): Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [84 mg, 69% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.97 (s, 1H), 7.51 (d, J = 8.1Hz, 1H), 7.09-7.10 (m, 1H), 7.02 (s, 1H), 6.81-6.83 (m, 1H), 6.50-6.51 (m, 1H), 2.20 (s, 2H), 0.03 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 136.6, 134.6, 124.8, 123.0, 121.4, 120.2, 109.8, 102.4, 27.2, -1.6. EI-MS m/z: 203, 130, 73(100%).

Trimethyl(naphtalen-2-ylmethyl)silane (2i):4 Synthesized according to general method. The product was obtained after column chromatography as a white solid (SiO2, n-pentane). [110 mg, 89% yield]. 1H-NMR: (400MHz, Chloroform-d) δ 7.82 - 7.73 (m, 3H), 7.46 - 7.38 (m, 3H), 7.20 (dd, J = 8.32, 1.69 Hz, 1H), 2.29 (s, 2H), 0.06 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 138.2, 133.8, 131.0, 127.9, 124,5, 127.5, 127.0, 125.7, 125.1, 124.4, 27.3, -1.7. EI-MS m/z: 214, 141, 73(100%).

Trimethyl(naphthalen-1-ylmethyl)silane (2j):5 Synthesized according to general method. The product was obtained after column chromatography as a colorless oil. (SiO2, n-pentane). [116 mg, 90% yield]. 1H-NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 6.8, 2.9 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 2.59 (s, 2H), 0.01 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 137.2, 133.9, 131.7, 128.6, 125.5, 125.3, 125.2, 124.9, 124.8, 124.6, 23.4, -1.2. EI-MS m/z: 214, 141, 73(100%).

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Trimethyl(4-(trifluoromethyl)benzyl)silane (2k):6 Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [100 mg, 72% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.48 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 2.17 (s, 2H), 0.02 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 145.1, 145.1, 128.0, 126.4, 126.1, 125.9, 125.0(q, J = 3.8 Hz), 123.2, 27.4, -2.1. 19F-NMR (376-MHz, Chloroform-d) δ -62.05 . EI-MS m/z: 232, 217, 140 (100%), 73.

(4-Fluoro-3-methylbenzyl)trimethylsilane (2l): Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [103 mg, 88% yield]. 1H-NMR (400MHz, Chloroform-d) δ 6.95 – 6.68 (m, 3H), 2.26 (s, 3H), 2.03 (s, 2H), 0.02 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 160.0, 157.6, 135.6, 130.7, 130.7, 129.0, 128.2, 126.4, 124.2,124.0, 114.6, 114.3, 25.9, 14.6, -2.0. 19F-NMR (376MHz, Chloroform-d) δ -124.9. EI-MS m/z: 196, 181, 104 (100%), 73.

((2,5-Dimethyl-1,4-phenylene(bis(methylene))bis(trimethylsilane) (2n):7 Synthesized according to general method with the addition of 2.4 eq. of Li-CH2TMS. The product was obtained after column 1 chromatography as a colorless liquid. (SiO2, n-pentane). [147 mg, 88% yield]. H-NMR (400MHz, Chloroform-d) δ 6.73 (s, 2H), 2.17 (s, 6H), 2.03 (s, 4H), 0.02 (s, 18H). 13C-NMR (100MHz, Chloroform-d) δ 134.1, 131.5, 130.5, 22.8, 19.9, -1.3. EI-MS m/z: 278(100%), 190, 175, 73.

3-((Trimethylsilyl)methyl)pyridine (2m):8 Synthesized according to general method. The product was obtained after column chromatography as a yellow oil (SiO2, n-pentane). [Full conversion, 30 mg, 31% yield]. 1H-NMR (400 MHz, Chloroform-d) δ 8.31 (dd, J = 4.8, 1.5 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.32 – 7.26 (m, 1H), 7.12 (dd, J = 7.8, 4.8 Hz, 1H), 2.03 (s, 2H), -0.01 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 149.2 , 145.4, 136.1, 135.0, 123.0, 23.9, -2.1. EI-MS m/z: 165, 150, 73(100%).

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(Anthracen-9-ylmethyl)trimethylsilane (6a)9: Synthesized according to general method. The product was obtained after column chromatography as a yellow solid (SiO2, n-pentane). [143 mg, 90% yield]. 1H-NMR (400MHz, Chloroform-d) δ 8.28 (s, 1H), 8.23 (d, J = 9.4 Hz, 2H), 8.03 (d, J = 9.7 Hz, 2H), 7.55 – 7.46 (m, 4H), 3.23 (s, 2H), 0.06 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 134.3, 131.7, 129.2, 129.0, 125.5, 124.8, 124.5, 123.7, 19.0, -0.3. EI-MS m/z: 264(100%), 249, 191, 73.

(2-Isopropylbenzyl)trimethylsilane (6b): Synthesized according to general method. The product was 1 obtained after column chromatography as a yellow oil. (SiO2, n-pentane). [105 mg, 85% yield] H- NMR (400MHz, Chloroform-d) δ 7.27 (dd, J = 7.4, 1.7 Hz, 1H), 7.11 (dtd, J = 14.5, 7.2, 1.7 Hz, 2H), 7.01 (dd, J = 7.4, 1.7 Hz, 1H), 3.10 (hept, J = 6.9 Hz, 1H), 2.21 (s, 2H), 1.27 (dd, J = 6.8, 0.4 Hz, 6H), 0.07 (d, J = 0.5 Hz, 9H). 13C-NMR (100MHz, Chloroform-d) δ 145.1, 137.2, 129.2, 125.2, 124.9, 124.5, 29.1, 23.5, 23.2 , -1.4. EI-MS m/z: 206, 191, 117, 73(100%).

([1,1'-Biphenyl]-2-ylmethyl)trimethylsilane (6c):10 Synthesized according to general method. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [133 mg, 92% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.46 – 7.13 (m, 9H), 2.26 (s, 2H), -0.13 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 142.5, 140.7, 138.2, 130.3, 129.7, 129.2, 128.0, 127.0, 126.6, 124.1, 23.5, -1.3. EI-MS m/z: 240, 225, 165, 73(100%).

Trimethyl(2,4,6-tri-tert-butylbenzyl)silane (6d): Synthesized according to general method. The product was obtained after column chromatography as a yellow oil. (SiO2, n-pentane). GC/MS analysis showed 8% 2,4,6-tri-tert-butylbenzene. [182 mg, 85% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.25 (d, J = 10.5 Hz, 2H), 7.16 (t, J = 1.8 Hz, 2H), 1.62 – 1.54 (m, 2H), 1.33 (d, J = 1.9 Hz, 20H), 1.28 (d, J = 1.9 Hz, 7H), 0.30 – 0.22 (m, 2H), -0.07 (d, J = 1.9 Hz, 9H). 13C-NMR (100MHz, Chloroform-d) δ 149.7, 149.3, 120.2, 119.0, 38.9, 38.4, 34.9, 31.6, 28.6, 10.9, -1.9. EI-MS m/z: 332, 274, 231(100%), 215, 73.

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((9H-Fluoren-2-yl)methyl)trimethylsilane (6e): Synthesized according to general method. The product was obtained after column chromatography as a pale yellow solid (SiO2, n-pentane). [145 mg, 96% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.32 – 7.26 (m, 1H), 7.23 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H), 3.89 (s, 2H), 2.21 (s, 2H), 0.07 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 143.5, 142.9, 142.0, 139.4, 137.8, 126.6 (2x), 125.9, 124.9, 124.6, 119.5, 119.3, 36.8, 27.3, -1.8. EI-MS m/z: 252, 237, 179, 73(100%).

Trimethyl(2-(trifluoromethoxy)benzyl)silane (6h): Synthesized according to general method. The product was obtained after column chromatography as a yellow oil. (SiO2, n-pentane). [80 mg, 54% yield] 1H-NMR (400 MHz, Chloroform-d) δ 7.22 – 7.05 (m, 4H), 2.16 (s, 2H), 0.02 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 146.7, 133.2, 130.4, 126.2, 125.2, 121.9, 119.9, 119.4, 20.8, -1.7. 19F- NMR (376MHz, Chloroform-d) δ -56.9. EI-MS m/z: 248, 156, 90, 73(100%).

2,6-Bis((trimethylsilyl)methyl)naphthalene (6k): Synthesized according to general method. The product was obtained after column chromatography as a white solid (SiO2, n-pentane). [120 mg, 66% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.60 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 7.12 (dd, J = 8.3, 1.5 Hz, 1H), 2.23 (s, 2H), 0.04 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 136.5, 131.4, 127.8, 126.6, 124.9, 27.1, -1.8. EI-MS m/z: 300, 299, 212, 197, 73 (100%).

1,3,5-Tris((trimethylsilyl)methyl)benzene (6j):11 Synthesized according to general method with the addition of 3.6 equiv. of TMS-CH2-Li. The product was obtained after column chromatography as a 1 colorless liquid. (SiO2, n-pentane). [165 mg, 82% yield]. H-NMR (400MHz, Chloroform-d) δ 6.39 (s, 1H), 1.99 (s, 2H), 0.01 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 139.8, 123.7, 26.8, -1.6. EI-MS m/z: 336, 335, 320, 248(100%), 73, 141, 73(100%).

(2-Methoxybenzyl)trimethylsilane (8):2 Synthesized according to general method using 1-chloro-2- methoxybenzene. The product was obtained after column chromatography as a colorless liquid. (SiO2, n-pentane). [109 mg, 94% yield]. 1H-NMR (400MHz, Chloroform-d) δ 7.08 (td, J = 7.9, 1.7 Hz, 1H), 6.99 (dd, J = 7.4, 1.5 Hz, 1H), 6.89 – 6.77 (m, 2H), 3.79 (s, 3H), 2.11 (s, 2H), -0.01 (s, 9H). 13C-NMR (100MHz, Chloroform-d) δ 156.4, 129.4, 129.2, 124.9, 120.2, 109.8, 54.8, 20.5, -1.5. EI-MS m/z: 194, 179, 164, 149, 73(100%).

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1 Giannerini, M.; Fañanás, M. F.; Feringa, B.L. Nature Chem., 2013, 5, 667–672 2 Das, M.; O'Shea, D. Tetrahedron, 2013, 96, 6448-6460 3 Trahanovsky, W.S.; Lorimor, S. P. J. Org. Chem. 2006, 71, 1784-1794 4 Huckins, J.R.; Rychnovsky S.D. J. Org. Chem. 2003, 68, 10135-10145 5 Molander, G.A.; Yun, C.; Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534-5539 6 Tobisu, M.; Kita,Y.; Ano, Y.; Chatani, N. J. Am. Chem. Soc., 2008, 130, 15982-15989 7 Bock, H.; Kaim, W.; Chem. Ber. 1978, 111, 3552-3572 8 Wu, Y.; Li, L.; Li, H.; Gao, L.; Xie, H.; Zhang, Z.; Su, Z.; Hu, C.; Song, Z. Org. Lett., 2014, 16, 1880-1883 9 Kendall, K.J.; Engler, T.A.; Shechter, H. J. Org. Chem., 1999, 64, 4255-4266 10 Sengupta, S.; Leite, M.; Raslan, D.S.; Quesnelle, C.; Snieckus, V. J. Org. Chem., 1992, 57, 4066-4068 11 Mohapatra, S.K.; Romanov, A.; Timofeeva, T.V.; Marder, S.R.; Barlow, S. J. Organomet. Chem.. 2014, 751, Chapter 3: Pd-Catalyzed, tBuLi-Mediated Dimerization of Aryl Halides and its Application in the Atropselective Total Synthesis of Mastigophorene

Parts of this chapter were published in : J. Buter, D. Heijnen, C. Vila, V.

Hornillos, E. Otten, M. Giannerini, A. J. Minnaard, and B. L. Feringa. Angew. Chem. Int. Ed. 2016, 55, 3620 –3624 Abstract : A Pd-catalyzed direct synthesis of symmetric biaryls from aryl halides in the presence of tBuLi is described in this chapter. In-situ lithium-halogen exchange generates the corresponding aryl lithium reagent that undergoes a homo-coupling reaction with a second molecule of aryl halide using 1 mol% of Pd catalyst. The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl in good to excellent yields. Application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9 : 1 due to catalyst-induced remote point-to-axial chirality transfer.

3.1 Introduction

The synthesis of biaryl compounds has been studied for more than a century[1] and is an important process in organic chemistry, since the biaryl structure is present in numerous natural products, bioactive compounds, agrochemicals, dyes and ligands. Symmetric biaryls play a crucial role in catalysis as a range of ligands possess this structural motif (Figure 1). Furthermore, natural products with a symmetric biaryl moiety, not necessarily enantiopure, show interesting biological activities.[2] Synthesis of symmetrical biaryl compounds can be carried out in various ways. A classic approach is the Ullmann coupling[3,4] but also Ni, Pd, or Fe-catalyzed couplings between different organic halides and organometallics such as Grignard, zinc, boron or tin reagents are known in the literature.[5] These methods, however, are generally not employed in the synthesis of symmetric tetra-ortho-substituted biaryls, with the exception of the Suzuki-Miyaura coupling. The formation of hindered biaryls generally requires long reaction times and high reaction temperatures. Despite its efficiency, the Suzuki-Miyaura coupling requires two independently synthesized reagents to be coupled, namely an aryl halide and an aryl boron reagent. This feature makes the synthesis of symmetrical biaryl compounds inherently less efficient, especially when considering natural product synthesis where step-count is an important issue.5b This disadvantage, however, can be circumvented by homo- coupling of aryl halides via in-situ generation of aryl lithium reagents by lithium-halogen exchange,[6,7] therefore providing a valuable alternative. Despite important recent advances, the homo-coupling of organolithium reagents using Pd-catalysis has received little attention.[8-12] The reported methodologies are rather limited in their scope and do not involve the construction of sterically congested tetra-ortho-substituted biaryls, except for three examples of a Cu-mediated coupling reported by Spring and co-workers.[8] Additionally, the application of this type of coupling methodology in the synthesis of biaryl containing natural products has not yet been reported.

As part of our research program using organolithium compounds in Pd-catalyzed cross-coupling reactions,[13,14] we are interested in the synthesis of symmetric biaryls using these highly reactive reagents. We present here a highly efficient and selective homo-coupling of aryl halides. In addition, we applied this methodology in the construction of the naturally occurring symmetric, tetra-ortho- substituted, biaryl compound mastigophorene A (Figure 3.1).

Figure 3.1. Representative ligands and natural products with a symmetric biaryl structure.

3.2 Optimization and Scope As a starting point for developing the homo-coupling reaction we initially chose 2-bromoanisole 1a as a model substrate (table 3.1). Starting with the addition of isopropyllithium (iPrLi) to trigger the selective lithium halogen exchange at the expense of direct alkyl coupling, different catalysts were screened. A small selection of phosphine ligands was employed, but the bulky alkyl or aryl ligands (entries 1-4) yielded large ammounts of dehalogenated starting material The ferrocene based Pd- QPhos complex (entry 5), and Pd-PEPPSi-IPent (entry 6) complex were found to give satisfactory yields towards the desired biaryl product 2a, with no detectable ammounts of dehalogenation 3, or alkyl-anisole 4.

Table 3.1 Homo-coupling of 2-bromoanisole in the presence of organolithium reagent

Entry Pd (x mol%) Ligand (x mol%) RLi (1.1 Conv. 2a 3 (%)a 4 (%)a eq) (%)a (%)a

1 Pd(PtBu3)2 (5 mol%) - iPrLi Full 0 100 0

2 Pd2dba3 (2.5 mol%) XPhos (10 mol%) iPrLi Full 32 68 0

3 Pd2dba3 (2.5 mol%) JohnPhos(10 mol% iPrLi Full 9 91 0

4 Pd2dba3 (2.5 mol%) DavePhos (10 mol%) iPrLi Full 30 70 0

5 Pd2dba3 (2.5 mol%) QPhos (10 mol%) iPrLi Full 100 0 0

6 Pd-PEPPSI-iPent (5 mol%) - iPrLi Full 100 0 0

a. Determined by GC-analysis

In further opzimization of the reaction conditions (table 3.2) lithiating reagents n, sec and tert butyllithium were combined with different catalysts and catalyst loadings, and we eventually arrived at Pd-PEPPSI-IPent[15] C1 (1 mol%) as the catalyst and tBuLi (0.7 eq) as the lithiating reagent. Though isoproyllithium had proven usefull in the optimization shown above, the butyl organometallic reagents are significantly cheaper. Full conversion was obtained and an isolated yield of 91% of 2a was achieved. Pd-PEPPSI-IPr[16] C2 proved to be an equally efficient catalyst giving comparable results as for C1. The use 0.7 eq of tBuLi in the reaction is intriguing. Generally in Li-X exchange reactions with tBuLi, 2 eq of the reagent is used to compensate for the elimination of in-situ formed tBuBr.[17]

Table 3.2. Homo-coupling of 2-bromoanisole in the presence of organolithium reagent: [a]

Entry Pd-cat RLi 2a (%)[b] 3 (%)[b] 4 (%)[b]

1 (xC1 mol%) (5 mol %) (nnBuLi eq) (1[b] eq) Yield62 (%)[c] trace 38

2 C1 (5 mol%) sBuLi (1 eq) 83 10 7[d]

3 C1 (5 mol%) tBuLi (1 eq) 96 trace 4

4 C2 (5 mol%) nBuLi (1 eq) 64 3 33

5 C2 (5 mol%) sBuLi (1 eq) 94 4 2

6 C2 (5 mol%) tBuLi (1 eq) full[e] trace trace

7 C1 (2.5 mol%) tBuLi (0.7 eq) 89 trace 11[d]

8 C2 (2.5 mol%) tBuLi (0.7 eq) full[e] (84) trace trace

9 C2 (1 mol%) tBuLi (0.7 eq) 98 (86) trace 2[d]

10 C3 (1 mol%) tBuLi (0.7 eq) full[e] (91) trace trace

11 - tBuLi (1 eq) - full -

[a] Reaction conditions: 1a (0.3 mmol) and the palladium catalyst in 2 mL of toluene at 20 °C; RLi (n eq) diluted to 1 mL with toluene was added dropwise over 1 h. [b] Conversions were determined by GC- analysis. [c] Isolated yield, after column chromatography, in brackets. [d] R = iBu. [e] >99% conversion.

We postulate that the solvent (toluene), slow addition of tBuLi, and the high reaction rate for transmetallation allows us to suppress the elimination of tBuBr. In toluene, tBuLi is known to form a tetrameric aggregate,[18] exhibiting a lower reactivity compared to the monomeric tBuLi in THF, a solvent generally used in Li-X exchange reactions.

Scheme 3.1. Scope of the Pd-catalyzed homo-coupling of aryl bromides in the presence of tBuLi a1 mol% C1 was used. b1 mol% C2 was used. c6 mmol scale reaction using 0.5 mol% of C2 in 2 h. dThe reaction was performed at 50 °C. eThe reaction was performed at 35 °C.

With the optimized conditions in hand, we studied the scope and limitations of our new homo- coupling methodology (Scheme 3.1). With 2-chloroanisole, full conversion was not achieved and 2a was obtained in 69% isolated yield using C1, while with 2-iodoanisole 2a was obtained in 95% yield. Next, various aromatic bromides with a methoxy group at the ortho position were studied. Biaryls 2b, 2c and 2d, with different electron-donating substituents at the aromatic ring, were obtained with excellent yields. Even 2e, a tetra-ortho-substituted biaryl, was successfully synthesized in 75% yield in 1 h at room temperature. In order to construct 2f the reaction had to be performed at 50 °C, providing in 2f in 85% yield, without affecting the selectivity. Biaryls 2g and 2h were obtained in 90% and 92% yields, respectively. Heterocycles are also efficient coupling partners, as is shown by the smooth dimerization of 3- bromo-2-methoxypyridine, to afford the corresponding bipyridine 2i in 85% yield. Other aryl bromides with electron-donating groups at the ortho position such as thiomethyl- or N,N- dimethylamino- were also tested, providing the corresponding biaryls 2k and 2l. Subsequently, we performed the reaction with aryl bromides bearing electron-withdrawing groups such as ortho- and meta-bromotrifluoromethylbenzene that afforded the corresponding fluorinated biaryls 2m and 2n with good yields. Lower selectivities were obtained for the products 2o-q, consequently providing moderate yields. However, 4-bromodibenzofuran reacted efficiently and afforded biaryl 2r in 88% yield. To demonstrate the synthetic utility of the present methodology, 2a was prepared on a gram scale (1.12 g, 6 mmol) using 0.5 mol% of Pd-PEPPSI-IPr in 98% yield in 2 h. Although the recently developed Pd-catalyzed cross-coupling reactions using lithium reagents display a broad scope,[14] no application has been reported so far within the realms of natural product synthesis. The efficiency of the homo-coupling procedure described here prompted us to explore the method in a total synthesis leading to the dimeric sesquiterpene mastigophorene A (Figure 3.2).

3.3 Synthesis of Mastigophorene Isolated from the liverwort Mastigophora diclados,[19a] mastigophorene A and B (Figure 3.2) showed neurotrophic (nerve growth stimulating) activity,[19b] and have therefore been regarded as potential therapeutic agents for neurodegenerative diseases.[20] Additionally, it was found that mastigophorene A and B exhibit neuroprotective properties at concentrations as low as 0.1-1 µM.[19c] But foremost it is their molecular architecture; a highly sterically congested benzylic quaternary stereocenter together with a chiral biaryl axis, which sparked our interest.

Figure 3.2 Mastigophorene A

To date, two atropselective total syntheses of mastigophorene A and B have been reported which consisted of more than 20 steps.[21,22] Recently, the Minnaard group reported an asymmetric Pd- catalyzed conjugate addition of ortho-substituted aryl boronic acids to cyclic enones, with application in the asymmetric total synthesis of (–)-herbertenediol (the mastigophorene A and B monomer), in just six steps.[23] This synthetic sequence in combination with the herein described Pd-catalyzed homo-coupling was envisioned to give straightforward access to enantiopure mastigophorenes A and B. The hindered biaryl axis in the mastigophorenes presented us with the formidable challenge to construct this stereochemical element in a diastereoselective manner. Our synthetic approach thus relied on the construction of enantiopure 11 (Scheme 3.2), following the previously reported route to herbertenediol.[23] This compound was synthesized starting with the Pd- catalyzed asymmetric conjugate addition of aryl boronic acid 6 to pentenone 5 (46%, 92% ee).[23] Dehydrogenation of 7 provided enone 8 in 72% yield.[22] Geminal dimethylation and subsequent removal of the enone functionality (thioenone formation and RaNi reduction)[21] gave rise to dimethylherbertenediol 10 in 56% over the three steps. Subsequently, 10 was brominated with furnishing 11, setting the stage for the pivotal homo-coupling.

Scheme 3.2. Asymmetric Synthesis of bromo-dimethylherbertenediol 11 Initial attempts, employing the optimized conditions of the reported method for homo-coupling (vide supra), barely afforded the desired homo-coupling product (<5% yield) since the reaction suffered from significant dehalogenation of 11, and incomplete conversion. We reasoned that the crowded cyclopentyl scaffold in 11, although apparently remote from the coupling site, impeded successful homo-coupling. This led us to investigate the influence of steric bulk of the para-substituent in the homo-coupling reaction. As model substrates, analogues of 11 with a methyl or a tBu substituent were prepared. Homo-coupling of methyl substrate 12a under slightly modified conditions, using 5 mol% C1 and 1.2 eq tBuLi, gave 68% isolated yield of the corresponding biaryl product (table 3.3, entry 1). However, upon application of these conditions on tBu substituted 12b, a poor selectivity for homo-coupling over debromination was observed, and consequently the isolated yield dropped significantly. This result indicates there is indeed an influence of the para-substituent on the homo- coupling, suggesting either an interaction between the catalyst/ligand system and the para- substituent, or simply an electronic effect. When considering steric interactions, these are potentially detrimental for the formation of the homo-coupled product, however stereochemical information in the para-substituent might be transferred in this way.

Table 3.3. Optimization of the homo-coupling for sterically congested substrates

Entrya Substrate Dehalogenationb (%) Productb/c (%) yield (%) note

1 12a 25 75 (68%) rt 2 12c 80 20 (15%) rt 3 12a 15 85 (79%) 0 °C 4 12a 15 85 rt,slow additiond

5 12b 20 80% (75%) 0°C,slow additiond

a In all cases 5 mol% of catalyst was used, at rt unless noted otherwise b Conversion and selectivity determined by GC/MS analysis c Isolated yield in brackets d tBuLi added at 2 drops per 5 min interval.

In further optimization efforts, for methyl substrate 12a, it was found that a lower reaction temperature (0 °C) and aliquoted addition (two drops per 5 min) of the tBuLi (entry 3 and 4 respectively) did lead to significant improvement of the selectivity for product 13a. When applying a combination of these conditions to the homo-coupling of the sterically demanding tBu substrate 12b, we were pleased to see that this reaction smoothly provided the homo-coupled product in an excellent 75% isolated yield (entry 5). Following the optimization, the anticipated homo-coupling of enantiopure mastigophorene building block 11 was performed (Scheme 3). Gratifyingly, applying the optimized conditions we obtained 14, although inseparable at this stage (vide infra) from the debrominated product, dimethylherbertenediol 10 (Scheme 3.3). Investigation of the homo-coupling product mixture by 1H- NMR and GC/MS analysis indicated that the homo-coupling reaction afforded a surprising dr of 9 : 1 in favor of (P)-helicity for the biaryl axis. This result is close to the 98 : 2 and comparable to the 88 : 12 diastereoselectivity obtained in Bringmann’s and Meyers’ atropselective total synthesis,[21,22] respectively. The exact mechanism for stereoinduction is unknown but it most likely is a consequence of the steric clash between the, apparently remote, benzylic quaternary stereocenter in 11 and the aromatic residues of the C1 catalyst.

Scheme 3.3. End-game of the Mastigophorene A Synthesis The observed diastereoselectivity strongly suggests a catalyst induced point-to-axial chirality transfer, involving a steric interaction between the catalyst and the para-benzylic quaternary stereocenter. This hypothesis is substantiated by the fact that an oxidative coupling of the herbertenediol monomethyl ether (no imposed steric hindrance of the added reagent) using di-tert- butyl peroxide, provided the mastigophorenes A and B analogues with very low asymmetric induction (dr = 40 : 60) in favor of mastigophorene B.[25] The same ratio was obtained from the natural component, clearly indicating a chiral bias towards (M)-helicity exerted by the crowded cyclopentyl moiety alone.[17a,b] It is therefore even more noticeable that the catalyst induced point- to-axial chirality transfer[26] in the homo-coupling to (P)-14 had overcome this intrinsic stereochemical bias towards (M)-helicity. The high diastereoselectivity also indicates the reaction proceeds via an ionic (polar) mechanism rather than a radical (oxidative coupling) mechanism. This hypothesis is further supported by the fact that we did not observe at all side-products arising from H• abstraction from the solvent toluene. Product 14 was thus obtained together with the dehalogenated compound 10 which we were not able to separate by flash column chromatography. We therefore decided to subject the mixture to

BBr3 (90% yield), cleaving the methoxy groups. The side-products from the previous step were removed by flash column chromatography providing us with pure mastigophorene A (observed [19b] rotation [α] = –67.9 (c = 0.4, CHCl3); literature = –65.3 (c = 0.4, CHCl3)) in 27% yield over two steps. Conclusive evidence of the axial configuration was obtained by X-ray crystallography, clearly showing (P)-helicity (Figure 3.4).

Figure 3.4. X-ray Structure of Mastigophorene A

3.4 Conclusions

In summary, we have developed a new catalytic system for the synthesis of symmetric biaryls from aryl halides in the presence of tBuLi (0.7 eq) using only 1 mol% of C2. The reaction takes place at ambient temperatures. Moreover, this methodology allows for the synthesis of tetra-ortho- substituted symmetric biaryls in high yields. Additionally, we successfully implemented the newly developed methodology in the shortest atropselective total synthesis of mastigophorene A in just eight steps. Compared to the previous stereoselective syntheses (>20 steps) this is a major improvement and a consequence of the straightforward enantioselective installation of the benzylic quaternary stereocenter and the highly diastereoselective homo-coupling.

3.5 References [1] a) Synthesis of Biaryls; (Ed. I. Cepanec) Elsevier. Amsterdam, 2004. b) G. Bringmann, R. Walter, R. Weirch, Angew. Chem. Int. Ed. 1990, 29, 977. c) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J. Garner, M. Breuning, Angew. Chem. Int. Ed. 2005, 44, 5384. d) J. Wencel-Delord, A. Panossian, F. R. Leroux, F. Colobert, F. Chem. Soc. Rev. 2015, 44, 3481. [2] a) O. Baudoin, F. Gueritte, Stud. Nat. Prod. Chem. 2003, 29, 355. b) M. C. Kozlowski, B. J. Morgan, E. C. Linton, Chem. Soc. Rev. 2009, 38, 3193. c) G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem. Rev. 2011, 111, 563. [3] F. Ullmann J. Bielecki, Chem. Ber. 1901, 34, 2174. [4] J. Hassan, M. Sévignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359. [5] a) Metal-Catalyzed Cross-Coupling Reactions, Vol. 1, (Eds. A. de Meijere, S. Brase, M. Oestreich) Wiley-VCH, Weinheim, 2013. b) Metal-Catalyzed Cross-Coupling Reactions and more, 3 volume set, (Eds. A de Meijere, F. Diederich) Wiley-VCH, Weinheim, 2004. (c) Transition Metals for Organic Synthesis (Eds. M. Beller, C. Bolm) Wiley-VCH, Weinheim, 2004. (d) New Trends in Cross-Coupling: theory and applications, (Ed. T. Colacot) Royal Society of Chemistry, Cambridge, 2014. 5b : Paul A. Wender, Vishal A. Verma, Thomas J. Paxton, and Thomas H. Pillow. Acc. Chem. Res., 2008, 41 (1), pp 40–49 [6] a) The Chemistry of Organolithium Compounds, Z. Rappoport, I. Marek, 2004, John Wiley & Sons (Verlag), ISBN: 978-0-470-02110-1 (b) Lithium Compounds in Organic Synthesis (Eds. R. Luisi, V. Capriati) WILEY-VCH: Weinheim, 2014. (c) V. Snieckus, Chem. Rev. 1990, 90, 879. [7] a) J. Board, J. L. Cosman, T. Rantanen, S. P. Singh, V. Snieckus, Platinum Metals Rev. 2013, 57, 234. b) E. J. Anctil, V. Snieckus in Metal Catalyzed Cross-Coupling Reactions, Vol. 1 (Eds. A. de Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004, 761. [8] D. S. Surry, D. J. Fox, S. J. F. Macdonald, D. R. Spring, Chem. Commun, 2005, 2589. [9] a) A. Nagaki, Y. Uesugi, Y. Tomida, J-I. Yoshida, Beilstein J. Org. Chem. 2011, 7, 1064. b) A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi, J-I. Yoshida,. Angew. Chem. Int. Ed. 2010, 49, 7543. c) A. Nagaki, Y. Moriwaki, S. Haraki, A. Kenmoku, N. Takabayashi, A. Hayashi, J-I. Yoshida, Chem. Asian J. 2012, 7, 1061. [10] D. Toummini, F. Ouazzani, M. Taillefer, Org. Lett. 2013, 15, 4690. [11] F. Lu, Tetrahedron Lett. 2012, 53, 2444. [12] S. B. Jhaveri, K. R. Carter, Chem. Eur. J. 2008, 14, 6845. [13] For seminal work: a) S-I. Murahashi, M. Yamamura, K-I. Yanagisawa, N. Mita, K. Kondo, J. Org. Chem. 1979, 44, 2408. [14] a) See PhD thesis M. Giannerini 2015 b) C. Vila, V. Hornillos, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa, Chem. Eur. J. 2014, 20, 13078. c) V. Hornillos, M. Giannerini, C. Vila, M. Fañanás- Mastral, B. L. Feringa, Chem. Sci. 2015, 6, 1394. d) L. M. Castelló, V. Hornillos, C. Vila, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa, Org. Lett. 2015, 17, 62. e) D. Heijnen, V. Hornillos, B. P Corbet, M. Giannerini, B. L. Feringa, Org. Lett. 2015, 17, 2662. f) C. Vila, S. Cembellín, V. Hornillos, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa, Chem. Eur. J. 2015, 21, 15520. [15] a) M. G. Organ, S. Çalimsiz, M. Sayah, K. H. Hoi, A. J. Lough, Angew. Chem. Int. Ed. 2009, 48, 2383. [16] a) C. J. O’Brien, E. A. B. Kantchev, N. Hadei, C. Valente, G. A. Chass, J. C. Nasielski, A. Lough, A. C. Hopkinson, M. G. Organ, Chem. Eur. J. 2006, 12, 4743. [17]a) W. F. Bailey, E. R. Punzalan, J. Org. Chem. 1990, 55, 5406. b) D. Seebach, H. Neumann, Chem. Ber 1974, 107, 847. [18]W. Bauer, W. R. Winchester, P. von Ragué Schleyer, Organometallics 1987, 6, 2371. [19] a) Y. Fukuyama, M. Toyota, Y. Asakawa, J. Chem. Soc., Chem. Commun. 1 1988, 1341. b) Y. Fukuyama, Y. Asakawa, J. Chem. Soc., Perkin Trans. 1 1991, 2737. c) Y. Fukuyama, K. Matsumoto Y. Tonoi, R. Yokoyama H. Takahashi H. Minami H. Okazaki Y. Mitsumoto Tetrahedron, 2001, 57, 7127. [20] S. D. Skaper, F. S. Walsh, Mol. Cell. Neurosci. 1998, 12, 179. [21] A. P. Degnan, A.I. Meyers, J. Am. Chem. Soc. 1999, 121, 2762. [22] G. Bringmann, T. Pabst, P. Henschel, J. Kraus, K. Peters, E-M. Peters, D. S. Rycroft, J. D. Connolly, J. Am. Chem. Soc. 2000, 122, 9127. [23] J. Buter, R. Moezelaar, A. J. Minnaard, Org. Biomol. Chem. 2014, 12, 5883. [24] T. Diao, T. J. Wadzinski, S. S. Stahl, Chem. Sci. 2012, 3, 887. [25] a) G. Bringmann, T. Pabst, D. S. Rycroft, J. D. Connolly, Tetrahedron Lett. 1999, 40, 483. b) G. Bringmann, T. Pabst, S. Busemann, K. Peters, E-M. Peters, Tetrahedron, 1998, 54, 1425. [26] T. Qin, S. L. Skraba-Joiner, Z. G. Khalil, R. P. Johnson, R. J. Capon, J. A. Porco Jr. Nat. Chem. 2015, 7, 234.

Acknowledgements

This work was performed together with Jeffrey Buter from the Minnaard group (Herbertenediol synthesis), and Carlos Villa (general optimization and isolation for the homo-coupling). X-Ray analysis was performed by Prof. Edwin Otten.

3.6 Experimental section General methods: All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. Reaction temperature refers to the temperature of the oil bath. THF and toluene were dried and distilled over sodium or taken from The dry solvents were taken from an MBraun solvent purification system (SPS-800). Pd2(dba)3, SPhos, XPhos, t DavePhos, CPhos, Qphos, P( Bu)3, PCy3 and Pd-PEPPSI-Ipent were purchased from Aldrich and used without further purification. nBuLi (1.6 M solution in hexane) was purchased from Acros. tBuLi (1.7 M in pentane), secBuLi (1.4 M in cyclohexane), iPrLi (0.7 M in pentane) were purchased from Aldrich. All the aromatic halides were commercially available and were purchased from Aldrich, with the exception of 3-bromo-2-methoxypyridine, 2-bromo-3- methoxynaphthalene and 1-bromo-2-methoxynaphthalene (TCI Europe). TLC analysis was performed on Merck silica gel 60/Kieselguhr F254, 0.25 mm. Compounds were visualized using either Seebach’s reagent (a mixture of phosphomolybdic acid (25 g),cerium (IV) sulfate (7.5 g), H2O (500 mL) and H2SO4 (25 mL)), a KMnO4 stain (K2CO3 (40 g), KMnO4 (6 g), water (600 mL) and 10% NaOH (5 mL)), or elemental iodine. Flash chromatography was performed using SiliCycle silica gel type SiliaFlash P60 (230 – 400 mesh) as obtained from Screening Devices or with automated column chromatography using a Reveleris flash purification system purchased from Grace Davison Discovery Sciences. Reveleris pre-fabricated silica cartridges were purchased and used, for automated column chromatography, containing 40 µm silica. GC-MS measurements were performed with an HP 6890 series gas chromatography system with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA), equipped with an HP 5973 mass sensitive detector. High resolution mass spectra (HRMS) were recorded on a Thermo Scientific LTQ Orbitrap XL. (ESI+, ESI- and APCI). 1H-, 13C- and 19F-NMR spectra were recorded on a Varian

AMX400 (400, 100.59 and 376 MHz, respectively) using CDCl3 as solvent unless stated otherwise. Chemical shift values are reported in ppm with the solvent resonance as the 1 13 internal standard (CDCl3: δ 7.26 for H, δ 77.16 for C). Data are reported as follows: chemical shifts (δ), multiplicity (s = singlet, d = doublet, dd = double doublet, ddd = double double doublet, td = triple doublet, t = triplet, q = quartet, b = broad, m = multiplet), coupling constants J (Hz), and integration. Enantiomeric excesses were determined by chiral HPLC analysis using a Shimadzu LC- 10ADVP HPLC instrument equipped with a Shimadzu SPD-M10AVP diode-array detector. Integration at three different wavelengths (254, 225, 190 nm) was performed and the reported enantiomeric excess is an average of the three integrations. Optical rotations were measured on a Schmidt+Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/mL) at ambient temperature (±20 °C). General procedure for the palladium catalyzed homo-coupling of aryl halides reagents in the presence of tBuLi: In a dry Schlenk flask, Pd-PEPPSI-iPr or Pd-PEPPSI-iPent (1 mol%) and aromatic halide (0.3 mmol) were dissolved in 2 mL of dry toluene and the solution was stirred at room temperature. tBuLi (0.7 eq., 0.21 mmol, 0.12 mL of 1.7 M commercial solution) was diluted with toluene to reach the concentration of 0.21 M; this solution was slowly added (flow rate=1 mL/h) by the use of a syringe pump. After the addition was completed, the reaction was quenched with methanol, and the solvent was evaporated under reduced pressure to afford the crude product, which was then purified by column chromatography.

Gram scale reaction:

In a dry Schlenk flask Pd-PEPPSI-iPr (0.5 mol%, 0.003 mmol, 22.5 mg) and 2-bromoanisole (6 mmol, 1.12 g, 0.75 mL) were dissolved in 30 mL of dry toluene. A solution of tBuLi (0.7 eq., 4.2 mmol, 2.5 mL of 1.7 M commercial solution) was slowly added over 2h by the use of a syringe pump. After the addition was completed, the reaction was quenched with methanol, and the solvent was evaporated under reduced pressure to afford the crude mixture. The product 2a was then purified by column chromatography (SiO2, n-pentane/Et2O 95:5) [2.973 mmol, 636.9 mg, 98% yield].

Spectral data of compounds 2a-2q:

2,2'-dimethoxy-1,1'-biphenyl (2a):1

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 29.4 mg, 1 91% yield. H NMR (400 MHz, CDCl3) δ 7.38-7.33 (m, 2H), 7.28 (dd, J = 7.4, 1.5 Hz, 2H), 13 7.07-6.98 (m, 4H), 3.80 (s, 6H) ppm. C NMR (101 MHz, CDCl3) δ 157.0, 131.5, 128.6, 127.8, 120.3, 111.1, 55.7 ppm.

2,2',4,4'-tetramethoxy-1,1'-biphenyl (2b):

1 Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005, 7, 1943. Yellow solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 38.1 mg, 1 93% yield, m.p. = 92-94 °C . H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.6 Hz, 2H), 6.58- 13 6.53 (m, 4H), 3.85 (s, 3H), 3.77 (s, 3H) ppm. C NMR (101 MHz, CDCl3) δ 160.0, 158.1, + 131.9, 120.1, 104.1, 98.9, 55.7, 55.3 ppm. HRMS (ESI+, m/z): calcd for C16H19O4 [M+H] : 275.12779; found: 275.12807.

2,2',5,5'-tetramethoxy-1,1'-biphenyl (2c): 2

Yellow solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 40.4 mg, 1 98% yield. H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 8.6 Hz, 2H), 6.89-6.84 (m, 4H), 3.79 (s, 13 6H), 3.74 (s, 6H) ppm. C NMR (101 MHz, CDCl3) δ 153.3, 151.3, 128.6, 117.1, 113.4, 112.4, 56.5, 55.7 ppm.

2,2'-dimethoxy-5,5’-dimethyl-1,1'-biphenyl (2d): 3

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 29.7 mg, 1 82% yield, m.p.= 58-60 °C. H NMR (400 MHz, CDCl3) 7.13 (dd, J = 8.3, 1.8 Hz, 2H), 7.05 (d, J = 2.2 Hz, 2H), 6.88 (d, J = 8.3 Hz, 0H), 3.76 (s, 6H), 2.33 (s, 6H) ppm. 13C NMR (101

MHz, CDCl3) δ 155.0, 132.0, 129.5, 128.9, 127.8, 111.1, 55.9, 20.5 ppm. HRMS (ESI+, m/z): + calcd for C16H18O2 [M+H] : 243.13796; found: 243.13824.

2,2',4,4'-tetramethoxy-6,6'-dimethyl-1,1'-biphenyl (2e): 4

2 P. J. Montoya-Pelaez, Y.-S. Uh, C. Lata, M. P. Thompson, R. P. Lemieux, C. M. Crudden, J. Org. Chem. 2006, 71, 5921. 3 Haberhauer, G.; Tepper, C.; Woelper, C.; Blaeser, D., Eur. J. Org. Chem., 2013, 2325. 4 Graff, J.; Debande, T.; Praz, J.; Guenee, L.; Alexakis, A., Org. Lett., 2013, 15, 4270. White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 33.8 mg, 1 75% yield. H NMR (400 MHz, CDCl3) 6.45 (d, J = 2.1 Hz, 2H), 6.41 (d, J = 2.3 Hz, 2H), 13 3.84 (s, 6H), 3.69 (s, 6H), 1.94 (s, 6H) ppm. C NMR (101 MHz, CDCl3) δ 159.4, 158.2, 139.2, 118.4, 106.1, 96.2, 55.8, 55.1, 20.0 ppm.

2,2',6,6'-tetramethoxy-1,1'-biphenyl (2f): 5

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 34.9 mg, 1 85% yield. H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 8.3 Hz, 2H), 6.67 (d, J = 8.3 Hz, 4H), 13 3.74 (s, 12H) ppm. C NMR (101 MHz, CDCl3) δ 158.4, 128.7, 104.5, 56.2 ppm.

3,3'-dimethoxy-2,2'-binaphthalene (2g):6

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 42.4 mg, 1 90% yield. H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.7 Hz, 4H), 7.80 (s, 2H), 7.49 (d, J = 13 7.6 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.26 (s, 2H), 3.90 (s, 6H). C NMR (101 MHz, CDCl3) δ 156.3, 134.4, 130.3, 129.9, 128.7, 127.7, 126.5, 126.3, 123.7, 105.4, 55.7 ppm.

2,2'-dimethoxy-1,1'-binaphthalene (2h):7

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 43.2 mg, 1 92% yield. H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.34-7.30 (m, 2H), 7.22 (t, J = 7.3 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 13 3.77 (s, 6H) ppm. C NMR (101 MHz, CDCl3) δ 155.0, 134.0, 129.4, 129.2, 127.9, 126.3, 125.2, 123.5, 119.6, 114.2, 56.9 ppm.

5 Bastug, G.; Nolan, S. P. Organometallics, 2014 , 33, 1253. 6 Motomura, T.; Nakamura, H.; Suginome, M.; Murakami, M.; Ito, Y., Bull. Chem. Soc. Jap., 2005, 78, 142. 7 Tu, T.; Sun, Z.; Fang, W.; Xu, M.; Zhou, Y., Org. Lett. 2012, 14, 4250.

2,2'-dimethoxy-3,3'-bipyridine (2i):8

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 29.4 mg, 1 91% yield. H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 5.0, 1.9 Hz, 2H), 7.59 (dd, J = 7.3, 1.9 13 Hz, 2H), 6.95 (dd, J = 7.3, 5.0 Hz, 2H), 3.92 (s, 6H) ppm. C NMR (101 MHz, CDCl3) δ 161.2, 146.2, 139.6, 119.9, 116.5, 53.5 ppm.

2,2'-bis(methoxymethyl)-1,1'-biphenyl (2j):

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 34.7 mg, 1 95% yield, m.p. = 71-73 °C. H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz, 2H), 7.39 (td, J = 7.5, 1.4 Hz, 2H), 7.32 (td, J = 7.5, 1.3 Hz, 2H), 7.16 (dd, J = 7.5, 1.1 Hz, 2H), 4.15 (s, 4H), 13 3.24 (s, 6H) ppm. C NMR (101 MHz, CDCl3) δ 139.5, 136.2, 129.6, 128.0, 127.6, 127.1, + 72.2, 58.3 ppm. HRMS (ESI+, m/z): calcd for C16H18O2Na [M+Na] : 265.11990; found: 265.12013.

2,2'-bis(methylthio)-1,1'-biphenyl (2k):9

White solid obtained after column chromatography (SiO2, n-pentane:ether 99:1), 28.6 mg, 1 77% yield. H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 7.5 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.4 Hz, 2H), 7.19 (t, J = 7.7 Hz, 2H), 2.39 (s, 6H) ppm. 13C NMR (101 MHz,

CDCl3) δ 138.8, 138.1, 130.0, 128.5, 125.0, 124.5, 15.7 ppm.

8 Dayaker, G.; Chevallier, F.; Gros, P. C.; Mongin, F. Tetrahedron, 2010, 66, 8904. 9 Barbero, M.; Bazzi, S.; Cadamuro, S.; Dughera, S.; Magistris, C.; Venturello, P., Synlett, 2010, 1803.

N2,N2,N2',N2'-tetramethyl-[1,1'-biphenyl]-2,2'-diamine (2l):

White solid obtained after column chromatography (SiO2, n-pentane:ether 95:5), 30.4 mg, 1 84% yield, m.p. = 69-71 °C. H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 7.6, 1.5 Hz, 2H), 7.27 (t, J = 7.6 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.99 (t, J = 7.4 Hz, 2H), 2.61 (s, 6H) ppm. 13 C NMR (101 MHz, CDCl3) δ 150.3, 133.3, 131.5, 127.6, 120.9, 118.0, 42.9 ppm. HRMS + (ESI+, m/z): calcd for C16H21N2 [M+H] : 241.16993; found: 241.17014.

2,2'-bis(trifluoromethyl)-1,1'-biphenyl (2m):10 1 Oil obtained after column chromatography (SiO2, n-pentane), 39.0 mg, 90% yield. H NMR (400 MHz, CDCl3) 7.75 (dd, J = 7.6, 1.2 Hz, 2H), 7.59-7.47 (m, 4H), 7.30 (d, J = 7.4 Hz, 1H) 13 ppm. C NMR (101 MHz, CDCl3) δ 137.4, 131.5, 130.6, 128.1, 125.9, 123.9 (q, J C-F = 274.0 19 Hz) ppm. F NMR (376 MHz, CDCl3) δ -58.2 ppm.

3,3'-bis(trifluoromethyl)-1,1'-biphenyl (2n):10

Colorless oil obtained after column chromatography (SiO2, n-pentane), 31.1 mg, 71% yield. 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 2H), 7.78 (d, J = 7.7 Hz, 2H), 7.67 (d, J = 7.8 Hz, 2H), 13 7.60 (t, J = 7.7 Hz, 2H) ppm. C NMR (101 MHz, CDCl3) δ 140.5, 130.5, 129.5, 124.7 (q, J 19 = 7.5 Hz), 124.0(q, J C-F = 272.3 Hz), 124.0 (q, J C-F = 3.8 Hz) ppm. F NMR (376 MHz, CDCl3) δ -62.5 ppm.

10 Toummini, D.; Ouazzani, F.; Taillefer, M., Org. Lett., 2013, 15, 4690. 1,1'-binaphthalene (2o):10 1 White solid obtained after column chromatography (SiO2, n-pentane), 19.2 mg, 50% yield. H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.61 (t, J = 7.5 Hz, 2H), 7.53-7.46 (m, 4H), 7.41 (d, J = 8.4 Hz, 2H), 7.30 (ddd, J = 8.3, 6.8, 1.1, 2H) ppm. 13 C NMR (101 MHz, CDCl3) δ 138.4, 133.5, 132.8, 128.1, 127.9, 127.8, 126.6, 126.0, 125.8, 125.4 ppm.

2,2'-binaphthalene (2p):10 1 White solid obtained after column chromatography (SiO2, n-pentane), 23.7 mg, 62% yield. H NMR (400 MHz, CDCl3) δ 8.19 (s, 2H), 7.96 (t, J = 9.1 Hz, 4H), 7.90 (dd, J = 8.4, 1.7 Hz, 13 2H), 7.57-7.48 (m, 4H) ppm. C NMR (101 MHz, CDCl3) δ 138.4, 133.7, 132.7, 128.5, 128.2, 127.7, 126.4, 126.1, 126.0, 125.7 ppm.

4,4'-dichloro-1,1'-biphenyl (2q): 11 1 White solid obtained after column chromatography (SiO2, n-pentane), 15.1 mg, 45% yield. H 13 NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.7 Hz, 4H), 7.41 (d, J = 8.7 Hz, 4H). ppm. C NMR (101 MHz, CDCl3) 138.4, 133.7, 129.0, 128.2 ppm.

4,4'-bidibenzo[b,d]furan (2r): 12

White solid obtained after column chromatography (SiO2, n-pentane:ether 98:2), 44 mg, 50% 1 yield. H NMR (400 MHz, CDCl3) δ 8.08-8.03 (m, 4H), 8.02 (dd, J = 7.6, 1.2 Hz, 2H), 7.62- 7.53 (m, 4H), 7.51-7.46 (m, 2H), 7.40 (td, J = 7.5, 1.0 Hz, 2H) ppm. 13C NMR (101 MHz,

CDCl3) δ 156.2, 153.7, 128.6, 127.2, 124.9, 124.3, 122.9, 122.8, 121.0, 120.7, 120.3, 111.9 ppm.

11 Ortgies, D. H.; Chen, F.; Forgione, P. Eur. J. Org. Chem., 2014, 3917. 12 Eberson, L.; Hartshorn, M.P.; Persson, O.; Radner, F.; Rhodes, C. J., J. Chem. Soc., Perkin Trans. 2: Phys. Org. Chem. 1996, 7, 1289. General scheme for model substrate syntheses:

Scheme 1: Synthesis of the test substrates.

Experimental section and data for the Mastigophorene total synthesis:

1,2-dimethoxy-3,5-dimethylbenzene (B):

To a solution of 1,2-dimethoxy-4-methylbenzene (5 ml, 34.8 mmol) in dry THF (75 mL), cooled to -78 °C, was added dropwise tBuLi (22.5 mL, 1.7 M in hexanes, 1.1 eq) by syringe pump (22.5 mL/h). A bright yellow solution formed upon addition. After addition the reaction mixture was allowed to warm-up to 0 °C, whereupon a suspension formed. The reaction mixture was then cooled to -78 °C and iodomethane (2.60 ml, 41.8 mmol, 1.2 eq) was added dropwise. The reaction mixture was allowed to warm-up to rt and was stirred an additional hour at this temperature.

The reaction mixture was quenched using an aqueous saturated NH4Cl solution (100 mL). After phase separation, the aqueous layer was washed three times with ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. Flash column chromatography was performed employing pentane : ether = 9 : 1. The individual fractions were analyzed with GC/MS and the fractions of >85% purity (the desired compound elutes first!) were combined affording 1,2-dimethoxy-3,5-dimethylbenzene B (3.1 g, 18.7 mmol, 54% yield) with 1 ~85% purity based on H-NMR analysis. H NMR (400 MHz, CDCl3) δ 6.58 (s, 2H), 3.84 (s, 3H), 3.77 (s, 13 3H), 2.28 (s, 3H), 2.24 (s, 3H). C NMR (101 MHz, CDCl3) δ 152.42, 145.18, 133.39, 131.54, 123.30, + + 110.92, 60.20, 55.72, 21.29, 15.78.HRMS: (ESI ) Calculated mass [M+H] C10H15O2 = 167.1067, found: 167.1066.

2-bromo-3,4-dimethoxy-1,5-dimethylbenzene (12a):

To a solution of 1,2-dimethoxy-3,5-dimethylbenzene B (3.0 g, 18 mmol) in dry CH2Cl2 (150 mL) was added pyridinium tribromide (11.5, 36.1 mmol, 2 eq) portionwise over 1 h. The wall of the Schlenk flask was rinsed with dry CH2Cl2 after each addition. The progress of reaction was followed by TLC analysis (2% ether in pentane) and complete conversion was reached after 5 h. To the reaction mixture was added an aqueous saturated NaHCO3 solution (10 mL). The phases were separated and the organic layer was washed twice with water (2 x 10 mL). The combined aqueous layers were back- extracted once with CH2Cl2 (10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Flash column chromatography using 2% ether in pentane as the eluent afforded 2-bromo-3,4-dimethoxy-1,5-dimethylbenzene 5 (4.0 g, 16.3 mmol, 90% yield) as a slight yellow oil with ~90% purity based on H-NMR analysis.1H NMR (400 13 MHz, CDCl3) δ 6.69 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H). C NMR (101 MHz,

CDCl3) δ 151.55, 145.86, 133.63, 132.39, 118.50, 111.97, 60.66, 55.97, 24.05, 16.79. HRMS (ESI+ and APCI) analysis could not be performed due to ion-suppression. GC-MS analysis gave the following + 79 + + mass fragmentation: Calculated mass [M] C10H13O2 Br = 244.01, found: 246 (M isotope), 244 (M ), + + + + 231 (M-CH3 isotope) , 229 (M-CH3) , 216 (M-(CH3)2 isotope) , 214 (M-(CH3)2) .

1-(tert-butyl)-2,3-dimethoxy-5-methylbenzene (E): 13

14 To a cooled (0 °C) solution of 3-(tert-butyl)-5-methylbenzene-1,2-diol C (1.1 g, 6.10 mmol) in CH2Cl2 (8 mL) and water (4 mL) were added sodium hydroxide (976 mg, 24.4 mmol, 4 eq) and dimethyl sulfate (1.73 ml, 18.3 mmol, 3 eq). The reaction mixture was allowed to stir for 90 min after which GC/MS analysis showed complete conversion to the monomethylated compound. No significant change was observed upon subsequent stirring overnight.

The reaction mixture was carefully quenched using conc. aqueous NH3 and the organic phase was removed by evaporation. The aqueous layer was extracted twice with pentane. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. NMR analysis and GC/MS analysis indicated ~95% monomethylated compound D with ~5% of the desired dimethylated product E. The crude product was used in the next step.

To a suspension of NaH (732 mg, 60% dispersion in oil, 3 eq) in dry THF (8 mL), cooled to 0 °C, was slowly added a solution of the monomethylated product in dry THF (7 mL). After addition, iodomethane (1.52 ml, 24.4 mmol, 4 eq) was added dropwise after which the reaction mixture was allowed to warm to rt. GC/MS analysis after 1h indicated complete conversion.

The reaction mixture was cooled to 0 °C, diluted with ether, and carefully quenched by the dropwise addition of water. After quenching the phases were separated and the aqueous phase was extracted twice with ether. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure affording 1-(tert-butyl)-2,3-dimethoxy-5-methylbenzene E (992 mg, 4.76 mmol, 78% yield over 2 steps).

1 Spectral data of the monomethylated compound D: H NMR (400 MHz, CDCl3) δ 6.69 (s, 1H), 6.60 (s, 13 1H), 5.82 (s, 1H), 3.87 (s, 3H), 2.29 (s, 3H), 1.40 (s, 9H). C NMR (101 MHz, CDCl3) δ 146.56, 142.02, 135.25, 127.92, 119.45, 109.44, 56.17, 34.68, 29.57, 21.53.

1 Spectral data of the bismethylated compound E: H NMR (400 MHz, CDCl3) δ 6.74 (s, 1H), 6.67 (s, 1H), 13 3.88 (s, 3H), 3.87 (s, 3H), 2.33 (s, 3H), 1.41 (s, 9H). C NMR (101 MHz, CDCl3) δ 153.08, 146.36, 142.95, 132.39, 119.36, 111.57, 60.47, 55.77, 35.07, 30.72, 21.71.

13 Bringmann, G.; Pabst, T.; Busemann, S. Tetrahedron, 1998, 54, 1425. 14 Pospíšil, J.; Taimr, L. Collect. Czech. Chem. Commun. 1965, 30, 1092.

2-bromo-5-(tert-butyl)-3,4-dimethoxy-1-methylbenzene (12b):13

To a cooled (0 °C) solution of 1-(tert-butyl)-2,3-dimethoxy-5-methylbenzene E (625 mg, 3.00 mmol) in dry CH2Cl2 (10 mL) was added a solution of bromine (201 µl, 3.90 mmol, 1.05 eq) in dry CH2Cl2 (1.5 mL). After addition the reaction mixture was allowed to warm to rt and stir for 1h. GC/MS and TLC analysis indicated complete conversion of the starting material. The reaction mixture was then quenched with an aqueous saturated Na2S2O3 solution. The phases were separated and the organic phase was washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual oil was subjected to flash column chromatography employing pentane : ether (99 : 1) as the eluent, affording 2-bromo-5-(tert-butyl)-3,4-dimethoxy-1- 1 methylbenzene 12b (756 mg, 2.63 mmol, 88% yield) as a slightly yellow oil. H NMR (400 MHz, CDCl3) 13 δ 6.95 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.37 (s, 3H), 1.37 (s, 9H). C NMR (101 MHz, CDCl3) δ 151.44, 150.76, 142.47, 132.72, 123.50, 118.04, 60.40, 59.97, 35.05, 30.53, 23.07.

General procedure for the optimized Pd-catalyzed homo-coupling of the sterically hindered substrates 12a and 12b:

In a dry Schlenk flask, Pd-PEPPSI-iPent (5 mol%, 1 µmol) and the substrate (0.2 mmol) were dissolved in dry toluene (0.7 ml) and the solution was cooled to 0 °C with an ice bath. tBuLi (141 μL,1.7 M in hexanes, 0.24 mmol, 1.2 eq) was slowly added (per 2 drops with 5 min intervals, total addition time = 40 min) by the aid of a syringe pump. After the addition was completed the reaction mixture was stirred for one additional hour after which the reaction was quenched with methanol. Celite was added, and the solvent evaporated under reduced pressure. The residue was directly loaded onto a prepared flash column, and eluted using pentane : ether as the eluent affording the homo-coupling product as an oil.

2,2',3,3'-tetramethoxy-4,4',6,6'-tetramethyl-1,1'-biphenyl (13a):

Prepared according to the general procedure of the Pd-catalyzed homo-coupling in 79% isolated yield.

1 13 H NMR (400 MHz, CDCl3) δ 6.58 (s, 2H), 3.84 (s, 6H), 3.77 (s, 6H), 2.28 (s, 6H), 2.23 (s, 6H). C NMR

(101 MHz, CDCl3) δ 151.16, 145.51, 132.90, 131.55, 130.16, 111.25, 60.41, 55.63, 19.99, 12.86. + + HRMS: (ESI ) Calculated mass [M+H] C20H27O4 = 331.1904, found: 331.1902.

4,4'-di-tert-butyl-2,2',3,3'-tetramethoxy-6,6'-dimethyl-1,1'-biphenyl (13b):13

Prepared according to the general procedure of the Pd-catalyzed homo-coupling in 75% isolated 1 yield as a waxy solid. H NMR (400 MHz, CDCl3) δ 6.93 (s, 2H), 3.86 (s, 6H), 3.64 (s, 6H), 1.95 (s, 6H), 13 1.42 (s, 18H) C NMR (101 MHz, CDCl3) δ 151.10, 150.55, 142.05, 130.82, 130.03, 122.83, 59.93, + + 59.68, 35.04, 30.81, 19.88. HRMS: (ESI ) Calculated mass [M+H] C24H39O4 = 415.2843, found: 415.2839.

For the synthesis of dimethoxyherbertenediol 10 (92% ee) see: Buter, J.; Moezelaar, R.; Minnaard, A. J. Org. Biomol. Chem. 2014, 12, 5883 - Supporting Information.

(S)-2-bromo-3,4-dimethoxy-1-methyl-5-(1,2,2-trimethylcyclopentyl)benzene (11) (Method A):15,16

15 Degnan, A. P.; Meyers, A. I. J. Am. Chem. Soc. 1999, 121, 2762. 16 Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000, 122, 9127. To a solution of (S)-1,2-dimethoxy-5-methyl-3-(1,2,2-trimethylcyclopentyl)benzene 10 (230 mg, 0.877 mmol) in dry CH2Cl2 (10 mL) was added pyridinium tribromide (841 mg, 2.63 mmol, 3 eq) in four portions over 1 h (not all solids dissolved!). The reaction was monitored by TLC analysis (2% ether in pentane) and GC/MS analysis which both showed complete conversion after 2.5 h.

To the reaction mixture was added aqueous saturated NaHCO3 (10 mL). The phases were separated and the organic layer was washed twice with water (2 x 10 mL). The combined aqueous layers were back-extracted once with CH2Cl2 (10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Flash column chromatography using 2% ether in pentane as the eluent afforded pure (S)-2-bromo-3,4-dimethoxy-1-methyl-5-(1,2,2- trimethylcyclopentyl)benzene 11 (287 mg, 0.842 mmol, 96% yield) as a slight yellow oil. 1H NMR (400

MHz, CDCl3) δ 6.98 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.63 – 2.46 (m, 1H), 2.35 (s, 3H), 1.84 – 1.55 (m, 13 5H), 1.35 (s, 3H), 1.13 (s, 3H), 0.69 (s, 3H). C NMR (101 MHz, CDCl3) δ 151.90, 150.86, 139.83, 132.11, 125.74, 117.68, 60.40, 59.88, 51.62, 44.92, 41.07, 39.19, 26.98, 25.37, 24.08, 23.14, 20.52.

(S)-2-bromo-3,4-dimethoxy-1-methyl-5-(1,2,2-trimethylcyclopentyl)benzene (11) (Method B):15

To a cooled (0 °C) solution of (S)-1,2-dimethoxy-5-methyl-3-(1,2,2-trimethylcyclopentyl)benzene 10

(110 mg, 0.42 mmol) in dry CH2Cl2 (4 mL) was added dibromine (23 µl, 3.90 mmol, 1.1 eq). After addition the reaction mixture was stirred for 15 min. after which GC/MS and TLC analysis indicated complete conversion of the starting material. The reaction mixture was then quenched with an aqueous saturated NaHCO3 solution. The phases were separated and the aqueous phase was extracted twice with CH2Cl2. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual oil was subjected to flash column chromatography employing pentane as the eluent afforded pure (S)-2-bromo-3,4-dimethoxy-1-methyl-5-(1,2,2- trimethylcyclopentyl)benzene 11 (140 mg, 0.410 mmol, 98% yield) as a slight yellow oil. 1H NMR (400

MHz, CDCl3) δ 6.98 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.63 – 2.46 (m, 1H), 2.35 (s, 3H), 1.84 – 1.55 (m, 13 5H), 1.35 (s, 3H), 1.13 (s, 3H), 0.69 (s, 3H). C NMR (101 MHz, CDCl3) δ 151.90, 150.86, 139.83, 132.11, 125.74, 117.68, 60.40, 59.88, 51.62, 44.92, 41.07, 39.19, 26.98, 25.37, 24.08, 23.14, 20.52.

2,2',3,3'-tetramethoxy-6,6'-dimethyl-4,4'-bis((S)-1,2,2-trimethylcyclopentyl)-1,1'-biphenyl (tetramethoxy mastigophorene A) (18):15

In a dry Schlenk flask, Pd-PEPPSI-iPent (12 mg, 19 µmol, 5 mol%) and (S)-2-bromo-3,4-dimethoxy-1- methyl-5-(1,2,2-trimethylcyclopentyl)benzene 11 (125 mg, 0.37 mmol) were dissolved in dry toluene (1.5 ml) and the solution was cooled to 0 °C with an ice bath. tBuLi (265 μL,1.7 M in hexanes, 0.44 mmol, 1.2 eq) was slowly added (per 2 drops with 5 min intervals, total addition time = 40 min) by the aid of a syringe pump. After the addition was completed the reaction mixture was stirred for one additional hour after which the reaction was quenched with methanol. Celite was added, and the solvent evaporated under reduced pressure. The residue was directly loaded onto a prepared flash column, and eluted using pentane as the eluent, affording a mixture of the two diastereoisomers in a diastereomeric ratio of 9:1 (detected by GC/MS), mixed with dimethoxyherbertenediol 10. 1H NMR analysis showed a major resonance at δ 1.95 which corresponds to (P)-helicity as found in mastigophorene A.

(S)-6,6'-dimethyl-4,4'-bis((S)-1,2,2-trimethylcyclopentyl)-[1,1'-biphenyl]-2,2',3,3'-tetraol (Mastigophorene A):15

To a solution of 2,2',3,3'-tetramethoxy-6,6'-dimethyl-4,4'-bis((S)-1,2,2-trimethylcyclopentyl)-1,1'- biphenyl 18 (contaminated with dimethoxyherbertenediol 10) (62 mg, 0.119 mmol) in dry CH2Cl2 cooled to 0 °C was added dropwise BBr3 (1.2 mL, 1 M in CH2Cl2, 1.2 mmol, 10 eq). The ice-bath was removed and the reaction mixture was allowed to warm to rt and stirred for 1 h. TLC indicated complete conversion of the starting material after which the reaction mixture was poured onto 5% aqueous NaHCO3 (4 mL). The phases were separated and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and loaded on Celite. This concentrated sample was loaded on a silica cartridge where after automated flash column chromatography was performed employing a pentane : ether (9 : 1 to 8 : 2) gradient as the eluent, to give pure Mastigophorene A (23 mg, 27% over 2 steps, 0.05 mmol) which crystallized upon standing 1 at rt. H NMR (400 MHz, CDCl3) δ 6.87 (s, 2H), 5.58 (s, 2H), 4.73 (s, 2H), 2.73 – 2.65 (m, 2H), 1.94 (s, 13 6H), 1.83 – 1.53 (m, 10H), 1.46 (s, 6H), 1.21 (s, 6H), 0.80 (s, 6H). C NMR (101 MHz, CDCl3) δ 141.72, 140.65, 134.02, 126.81, 122.88, 117.09, 51.49, 45.13, 41.31, 39.05, 27.35, 25.69, 22.98, 20.59, 19.37. 20 19 17 [α]D = -67.9 (CHCl3, c = 0.4) for a 92% ee sample; literature value: [α]D = -65.3 (CHCl3, c = 0.4)

X-ray structure determination of mastigophorene A:

A suitable crystal of mastigophorene A was mounted on a cryo-loop and transferred into the cold nitrogen stream of a Bruker D8 Venture diffractometer. The final unit cell was obtained from the xyz centroids of 9205 reflections after integration. Intensity data were corrected for Lorentz and polarisation effects, scale variation, for decay and absorption: a multiscan absorption correction was applied, based on the intensities of symmetry-related reflections measured at different angular settings (SADABS).18 The structures were solved by direct methods using the program SHELXS.19 The hydrogen atoms were generated by geometrical considerations and constrained to idealised geometries and allowed to ride on their carrier atoms with an isotropic displacement parameter related to the equivalent displacement parameter of their carrier atoms. Structure refinement was performed with the program package SHELXL.2 Crystal data and details on data collection and refinement are presented in the table below.

Crystallographic data for mastigophorene A:

chem formula C30 H42 O4

Mr 466.63

cryst syst monoclinic

color, habit colourless, block

size (mm) 0.24 x 0.12 x 0.10

space group C2

a (Å) 22.8846(13)

b (Å) 7.0294(4)

c (Å) 16.2378(9)

17 Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1 1991, 2737. 18 Bruker. APEX2 (v2012.4-3), SAINT (Version 8.18C) and SADABS (Version 2012/1). Bruker AXS Inc., Madison, Wisconsin, USA. 2012. 19 Sheldrick, G. Acta Crystallographica Section A 2008, 64, 112. V (Å3) 2577.4(3)

Z 4

-3 calc, g.cm 1.203 µ(Cu K ), mm-1 0.612 α F(000) 1016 temp (K) 100(2)

 range (°) 5.145 –74.859 data collected (h,k,l) -28:26, -8:8, -20:20 min, max transm 0.7067, 0.7538 rflns collected 28645 indpndt reflns 5279 observed reflns Fo  2.0 σ (Fo) 5079

R(F) (%) 4.16 wR(F2) (%) 11.29

GooF 1.033 weighting a,b 0.0713, 1.4028

Flack x 0.10(5) params refined 319 min, max resid dens -0.223, 0.442

Optimization tables for homo-coupling of various aryl bromides:

Entry Catalysta 12a Bb 13ab/c

1 PEPPSI Ipent 2% 0 20 80

2 PEPPSI Ipent 2.5 % 0 25 75 (68%)

3 PEPPSI Ipent 6% 0 25 75

4 PEPPSI Ipent 0 °C 0 15 85 (79%)

5 PEPPSI Ipent portion addition d 0 15 85

6 PEPPSI-Ipr e 10 90 0

7 Pd2DBA3 + XPhos 40 60 0

t 8 Pd(P Bu3)2 0 100 0

9 dilute tBuli 20 55 25

10 concentrated d 0 80 20

11 40 °C 0 75 25

12 0 °C 0 15 85

13 continuous add. 0 100 0

14 2 x 5% catalyst 0 50 50

15 sep. lithiatione 45 55 0 a) Unless noted otherwise, 5 mol% of Pd-PEPPSI-Ipent catalyst was used at room temperature b) Conversion and selectivity determined by GC/MS analysis c) Isolated yield in brackets d) tert- butyllithium added per 2 drops with 5 min intervals e) average of 2 experiments.

Entry Conditionsa 12b F 13bb/c

1 Normal 0°C 0 50 50

2 Portion 0°C d 0 20 80 (75%)

3 Portion 0°C e 0 20 80 a) Unless noted otherwise, 5 mol% of Pd-PEPPSI-Ipent catalyst was used b) Conversion and selectivity determined by GC/MS analysis c) Isolated yield in brackets d) tert-butyllithium added per 2 drops with 5 min interval e) tert-butyllithium added per 4 drops with 10 min intervals.

Chapter 4 : One-Pot Strategies for Developing Synthetic Methods with Organolithium Reagents

Parts of this chapter have been published in A. T. Wolters, V. Hornillos, D. Heijnen, M. Giannerini, and B. L. Feringa ACS Catal, 2016, 6 (4), pp 2622-2625 4.1 Introduction In this chapter several methods of utilizing organolithium reagents in a multi-step, one-pot procedure for the synthesis of small functionalized molecules are described. The obvious advantages of one-pot procedures in terms of time, ease of reaction and purification often outweigh a slightly lower yield per step. The use of organolithium reagents for one pot procedures has additional challenges due to the high reactivity of the organometallic reagent. Excess nucleophile meant for the primary transformation is likely to react with other added reagents or solvents that are necessary for the consecutive functionalization. Utilizing organolithium reagents as a nucleophile in the 1,2- addition to (Weinreb) amides, a tetrahedral intermediate is formed, that can acts as a temporary protecting group for carbonyl compounds. Upon heating, this tetrahedral intermediate collapses into the carbonyl compound, thereby liberating a lithium amide base. This base is capable of taking part in further reactions. It is because of this in situ formation of a stoichiometric amount of lithium amide that the use of additional base is no longer required in the consecutive, one-pot alpha arylation of ketones, or the Buchwald-Hartwig amine coupling with aryl bromides. The use of these metal aminal intermediates as protecting groups, or lithium amide releasing compounds is described in this chapter, and can lead to functionalized ketones, aldehydes or anilines.

4.2 One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed α-Arylation

An efficient, in situ sequential 1,2-addition of alkyllithium reagents to benzamides followed by α- t arylation of the resulting alkyl ketones is described in this part of the chapter. The use of Pd[P( Bu)3]2, as catalyst for the α-arylation reaction, allows access to a wide variety of functionalized benzyl ketones in a modular way. The decomposition of the tetrahedral intermediate originated from the 1,2-addition liberates in situ a lithium amide, therefore avoiding the need of an external base for the α-arylation. The method affords good overall yields with a variety of alkyl lithium reagents, benzamides, and aryl bromides, bearing a range of functional groups with complete selectivity toward the monoarylated products.

4.2.1 Introduction Palladium-catalyzed α-arylation of carbonyl and related compounds has emerged as an effective Csp2–Csp3 bond-forming methodology that does not generally require preformation of an organometallic reaction partner.1 This is an important transformation in organic chemistry as the α- aryl carbonyl moiety is found in a wide variety of biologically active molecules of interest in medicinal chemistry.2 Moreover, α-arylated carbonyl compounds are precursors to functionalized molecules carrying amine, olefin, nitrile, alcohol, and other groups located α or β to the aryl ring.3 The groups of Buchwald, Hartwig, and Miura independently reported methods based on palladium catalysts for the intermolecular α-arylation of ketones.4 Improved procedures5 and methods involving α-arylation of simple acetone,6 esters,7 α-amino acid esters,8 nitroalkanes,9amides,10 imides bearing the Evans auxiliary,11 aldehydes,12 and nitriles13 have since been described. A requirement frequently found in α-arylation reactions is that an excess of a strong base is employed to reach full conversion to the final product, and to avoid quenching of the starting enolate by the more acidic benzylic protons of the tertiary α-aryl carbonyl product, which can lead to the formation of diarylated compounds. The use of an excess of base can also limit the functional group tolerance, and promote racemization of carbonyl compounds with an α-proton at a stereogenic center under the reaction conditions.

Our group has recently described a highly efficient one-pot synthesis of functionalized ketones via sequential 1,2-addition, Pd-catalyzed cross-coupling of Weinreb amides using two distinct organolithium reagents.14 After 1,2-addition of the first organolithium reagent to the Weinreb amide, the tetrahedral intermediate formed acts as a masked ketone moiety allowing for an in situ cross- coupling reaction with the second organolithium compound. The corresponding ketones are then obtained without the necessity to separately prepare, purify, and protect/deprotect the ketone intermediate. Inspired by this process, we envisioned the possibility to combine, in a one-pot procedure, the 1,2-addition of an alkyllithium reagent to a benzamide 1 with a Pd-catalyzed α- arylation of the resulting alkylketone 2, where the lithium amide expelled after the collapse of the tetrahedral intermediate th could act as a base in the arylation process, therefore avoiding the use of an external base (Scheme 4.1).

Scheme 4.1 General scheme for the one pot 1,2-addition/alpha arylation approach The realization of this process would not only eliminate an extra synthetic step and the eventual purification of ketone intermediate, but it also allows the arylation reaction to occur in the presence of rather low amount of base, as this is slowly released from th and then consumed in the catalytic reaction. The modular combination of organolithium reagents, benzamides, and aryl bromides would allow easy access to a variety of structurally diverse α-aryl ketones from simple starting materials. Here we describe the implementation of this three-component strategy which to the best of our knowledge is unprecedented in the literature.

4.2.2 Optimization We selected the reaction between n-BuLi and the Weinreb amide 1a, at 0 °C, as a model for the first step, then screened a variety of palladium catalysts for the subsequent α-arylation reaction using 2 equiv. of 4-bromotoluene (Table 4.1).

Table 4.1. Optimization for the one-pot, nucleophilic addition, Pd-catalyzed α-arylation

Entrya Solvent/T (°C) Pd cat. (5 mol%) R 2a/3a/4a (%)b

1 Toluene/80 Pd-PEPPSI-IPr (C1) OCH3 66:34:0

2 Toluene/80 Pd-PEPPSI-IPent (C2) OCH3 61:39:0

3 Toluene/80 Pd2(dba)3, XPhos (L1) OCH3 51:17:32

4 Toluene/80 Pd[P(t-Bu)3]2 (C3) OCH3 27:56:17

5 THF/60 Pd-PEPPSI-IPr (C1) OCH3 71:29:0

6 THF/60 Pd-PEPPSI-IPent (C2) OCH3 59:17:24

7 THF/60 Pd2(dba)3, XPhos (L1) OCH3 54:4:42

8 THF/60 Pd2(dba)3, SPhos (L2) OCH3 52:10:38

9 THF/60 PdCl2(dppf) (C4) OCH3 100:0:0

10 THF/60 Pd2(dba)3, (L4) OCH3 100:0:0

11 THF/60 Pd[P(t-Bu)3]2 (C3) OCH3 3:88:9

12 THF/60 Pd[P(t-Bu)3]2 (C3) CH3 2:98:0

c 13 THF/60 Pd[P(t-Bu)3]2 (C3) CH3 1:99:0 86% yieldd

d,e 14 THF/60 Pd[P(t-Bu)3]2 (C3) CH3 86% yield

c 15 THF/50 Pd[P(t-Bu)3]2 (C3) CH3 8:92:0 aReaction conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd complex and 4-bromotoluene (2 eq.). bDetermined by GC and 1H NMR. cUsing 1.2 eq. of 4-bromotoluene. dIsolated yield. e6.0 mmol (0.9 g) scale reaction using 2.5 mol% of catalyst.

For this step, the reaction mixture was warmed to 80 °C in toluene to promote the collapse of the tetrahedral intermediate as it is stable at rt. The use of Pd-PEPPSI-IPr or Pd-PEPPSI-IPent 15 provided a mixture of the desired α-arylated product 3a and nonarylated ketone 2a in a 34:66 and 39:61 ratio, respectively (Table 4.1, entries 1 and 2). Low conversion toward 3a was also obtained using 16 17 Pd2(dba)3/XPhos as catalyst, and the presence of the Buchwald–Hartwig coupling product between lithium methoxy(methyl)amide generated and 4-bromotoluene was detected in the reaction mixture (entry 3). The formation of 4a involves the consumption of LiNMe(OMe) that consequently cannot further act as a base for the α-arylation reaction, resulting in drastically reduced 18 yields of 3a. Employing Pd[P(t-Bu)3]2 as catalyst, the conversion toward 3a was increased, although large amounts of 2a and 4a were still observed in the mixture (Table 4.1, Entry 4). With the aim to reduce the stability of the tetrahedral intermediate th and then increase the conversion toward 3a, we moved to the more polar solvent THF with heating at 60 °C. A further survey of different palladium catalysts (entries 5–11) revealed Pd[P(t-Bu)3]2 (C3) to be optimal, although the presence of product 4a was still observed (Entry 11). To our delight, when the less expensive and simple N,N- dimethyl benzamide (1b) was used as substrate, the α-arylated product 3a was obtained with excellent selectivity (98%), inhibiting the formation of the Buchwald–Hartwig amination product 4a (entry 12). Moreover, the amount of aryl bromide could be reduced from 2.0 to 1.2 eq, still affording product 3a as the exclusive product in 86% isolated yield (entry 13).19 Importantly, when this reaction was performed on a larger scale (6 mmol), using a lower catalyst loading (2.5 mol %), product 3a was still obtained with similar yield (entry 14). Decreasing the reaction temperature to 50 °C still gave 3a with high selectivity although the conversion decreased slightly (entry 15).

4.2.3 Scope of the reaction With the optimized reaction conditions in hand, we next evaluated the efficacy of this catalyst system in the arylation of a variety of aryl bromides (Table 4.2). Table 4.2. Scope of (hetero)aryl bromidesa,b,c

a Reaction conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd[P(t-Bu)3]2 (C3) (5 mol %) and (hetero)aryl bromide (1.2 eq.). bSelectivity >98% as determined by GCMS and 1H NMR. cIsolated yield. Both electron-rich (3a–3d, 3g–3i, 3l, and 3n) and electron-poor aryl bromides (3e, 3f, 3j, 3k, and 3m) participate in this reaction affording high selectivity and good overall yields. A sterically more congested aryl bromide could also be converted to the corresponding arylated ketone without loss of selectivity (3d). The reaction proceeds successfully in the presence of a variety of functional groups including CF3 (3e), OMe (3g), SMe (3h), NMe2 (3i), an ester (3j), a ketone (3k), and an acetal-protected aldehyde (3l). Using p-chloro-bromobenzene, the coupling occurs exclusively at the bromine- substituted carbon, leaving the chloride untouched, thereby providing an opportunity for subsequent Pd-catalyzed cross-coupling reactions (3f).20 Heterocyclic bromides could also be coupled with high selectivity as demonstrated in the preparation of 3m and 3n. Importantly, no traces of isomerized products derived from β-hydride elimination-reinsertion reactions in the alkyl chain were observed in any of these examples.21 We next explored the scope of the reaction with respect to the alkyl lithium and benzamide components. As shown in Table 4.3, alkyllithium reagents bearing different linear or branched aliphatic substituents provided the desired products in high selectivity and good overall yields.22 Table 4.3. Scope of organolithium reagents and benzamides.a,b,c

a 2 Reaction conditions: R Li (1 eq.) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd[P(t-Bu)3]2 (C3) (5 mol %) and (hetero)aryl bromide (1.2 eq.). bSelectivity >98% as determined by GC and 1H NMR unless otherwise noted. cIsolated yield. dReaction performed in refluxing toluene. eGC selectivity (monoarylated/diarylated/triarylated 60:34:6). fThe corresponding Weinreb amide was used instead. The use of the more challenging s-BuLi allows for the synthesis of a more congested α-quaternary carbon (3q) without isomerization of the alkyl chain, presumably due to a fast reductive elimination step.20c The use of MeLi as nucleophile also allowed the formation of product 3r in the subsequent arylation reaction with 4-bromoanisole, although the presence of some diarylated and triarylated products was also observed (3r). Nonetheless, a more sterically hindered aryl bromide afforded exclusively the monoarylated product in good overall yield (3s). In addition, this protocol was also found efficient with different benzamides bearing electron-withdrawing (3t, 3u) and electron donating substituents (3v). As mentioned before, the C-sp2–Cl bond remained untouched during the reaction (3u).

4.2.4 Competition studies To further determine if the ketone enolate is formed directly from the tetrahedral intermediate or in a subsequent stage by reaction with the lithium amide released in the reaction media, we performed a competition experiment. One equivalent of butyrophenone and hexanophenone, respectively, were added after the 1,2-addition reaction of n-BuLi and benzamide 1b together with 4- bromoanisole and the palladium catalyst. As shown in Scheme 4.4, the formation of a mixture of the three possible α-aryl ketones and the corresponding starting materials was observed, supporting therefore the pathway involving lithium amide release prior to arylation.

Scheme 4.4. Study of the one-pot, nucleophilic addition of 1, Pd-catalyzed α-arylation in the presence of butyrophenone and hexanophenone. Conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd complex, butyrophenone (1.0 eq.), hexanophenone (1.0 eq.) and 4-bromoanisole (1.2 eq.). Relative product distribution determined by GC.

4.2.5 Other use of the tetrahedral intermediate The tetrahedral intermediate (th) described at the beginning of this chapter was found to split of lithium dimethylamide, deprotonating the formed carbonyl moiety and triggering selective mono arylation with aryl bromides (scheme 4.5, top reaction). The Buchwald-Hartwig coupling that led to side product 4a was suppressed by optimizing the reaction conditions. We were interested, however, to see if this undesired amination reaction pathway could be promoted, and lead to an alternative one-pot procedure, to give substituted anilines (scheme 4.5, bottom reaction)

Scheme 4.5 Alternative use of liberated lithium-amide base.

When tertiary alkyl or aryl nucleophiles (= tBuLi, ArLi shown in red) were chosen for the first step, the tetrahedral intermediate, and (after collapse) the corresponding ketone does not have any acidic alpha protons. The liberated lithium amide (scheme 4,3 shown in pink) therefore cannot act as a base (pathway 1), and thus participates in the cross coupling cycle instead. Reacting with an aryl bromide moiety, Buchwald-Hartig amination leads to substituted anilines (pathway 2). This alternative route, and the synthesis of substituted anilines is currently being investigated

4.2.6 Conclusions In conclusion, we have developed a mild, modular, and highly efficient one-pot 1,2-addition of organolithium reagents to benzamides, followed by a palladium-catalyzed α-arylation of the resulting ketones. The method is based on the use of commercially available Pd[P(t-Bu)3]2 as catalyst for the α- arylation reaction and does not need the addition of an external base to proceed. Moreover, the formation of di- and triarylated side products is prevented while arylation is observed solely at the α- position without isomerized products. The substrate scope encompasses primary and secondary alkyllithium reagents, benzamides and aryl bromides. It comprises a range of functional groups or ortho-substitution, allowing rapid access to functionalized ketones in a three component modular approach. The alternative use of the tetrahedral intermediate towards the synthesis of substituted anilines could prove to be a promising method for the one pot preparation of these building blocks.

4.2.7 References (1) a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082-1146; b) Johansson, C. C. C.; Colacot, T. J. Angew. Chem. Int. Ed. 2010, 49, 676-707; c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234- 245; d) Novak, P.; Martin, R. Curr. Org. Chem. 2011, 15, 3233-3262; e) Potukuchi, H. K.; Spork, A. P.; Donohoe, T. J. Org. Biomol. Chem. 2015, 13, 4367-4373; f) Sivanandan, S. T.; Shaji, A.; Ibnusaud, I.; Seechurn, C. C. C. J.; Colacot, T. J. Eur. J. Org. Chem. 2015, 38-49. (2) a) Dörwald, F. Z. in Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds, Chapter 30, ed. Dörwald, F. Z. Wiley-VCH, Weinheim, 2012; b) For a recent example see: Donohoe, T. J.; Pilgrim, B. S.; Jones, G. R.; Bassuto, J. A. Proc. Natl. Acad. Sci. USA 2012, 109, 11605-11608. (3) a) Lawrence, N. J. Chem. Soc., Perkin Trans. 1 1998, 1739-1750; b) Otera, J. Modern Carbonyl Chemistry, Wiley-VCH, Weinheim, 2000. (4) a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108-11109; b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382-12383; c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem. Int. Ed. 1997, 36, 1740-1742. (5) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (6) a) Hesp, K. D.; Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194-5197; b) Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed. 2013, 52, 7242-7246; c) Gäbler, C.; Korb, M.; Schaarschmidt, D.; Hildebrandt, A.; Lang, H. Adv. Synth. Catal. 2014, 356, 2979-2983. e) Ackermann, L.: Mehta, V. P. Chem. Eur. J. 2012, 18, 10230-10233; f) Rotta-Loria, N. L.; Borzenko, A.; Alsabeh, P. G., Lavery; C. B.; Stradiotto, M. Adv. Synth. Catal. 2015, 357, 100-106; g) Fu, W. C.; So, C. M.; Chow, W. K.; Yuen, O. Y.; Kwong, F. Y. Org. Lett. 2015, 17, 4612-4615; h) MacQueen, P. M.; Chisholm, A. J.; Hargreaves, Br. K. V.; Stradiotto, M. Chem. Eur. J. 2015, 21, 11006-11009. For a recent review see: Schranck, J.; Rotzler, J. Org. Process Res. Dev. 2015, 19, 1936-1943. (7) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996-80002. (8) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465-475. (9) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370. (10) a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546-6553; b) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976-4985. (11) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182-5191. (12) Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2002, 43, 101-104. (13) a) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824-15832; b) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051-5053. (14) Giannerini, M.; Vila, C.; Hornillos, V.; Feringa, B. L. Chem. Commun. 2016, 52, 1206-1209. (15) a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2006, 12, 4743-4748; b) Valente, C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 3314-3332. (16) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461-1473. (17) a) Surry, D. S.; Buchwald, S. L. Chem. Sci., 2011, 2, 27-50; b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534-1544. (18) a) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555; b) He, L.-Y. Synlett 2015, 26, 851-852. (19) Following the conversion of 1a into 3a in time showed that 97% conversion was achieved in 6 h (See experimental section, Graph 1). However, for practicality, the reactions were conducted overnight. (20) Negishi, E. Angew. Chem. Int. Ed. 2011, 50, 6738-6764; b) Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6723-6737; c) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, Vol. 1, Wiley-VCH, Weinheim, 2004. (21) Vila, C.; Giannerini, M.; Hornillos, V.; Fañanás-Mastral, M.; Feringa, B. L. Chem. Sci. 2014, 5, 1361-1367. (22) The reaction using the corresponding Grignard reagents for the 1,2-addition step led to a complex mixture of products under the optimized conditions.

Acknowledgements

The work described in this chapter was performed in collaboration with Alexander Wolters and Valentin Hornillos.

4.2.8 Experimental section All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. THF and toluene were dried and distilled over sodium. Chromatography: Grace Reveleris X2 flash chromatography system used with Grace® Flash Cartridges, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and phosphomolybdic Acid (PMA) or potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59

MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent 1 13 resonance as the internal standard (CHCl3:  7.26 for H,  77.0 for C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Melting points were measured using a Büchi Melting Point

B-545. XPhos, SPhos, Pd2(dba)3, Josiphos (L4), C4, Pd-PEPPSI-IPr and Pd-PEPPSI-IPent were purchased from Aldrich and used without further purification. Pd[P(t-Bu)3]2, was purchased from Strem. Methyllithium (MeLi, 1.6 M in diethylether), ethyllithium, (EtLi, 0.5 M in benzene:cyclohexane), hexyllithium (HexLi, 2.3 M in hexane) and sec-butyllithium (s-BuLi, 1.4 M in cyclohexane) were purchased from Sigma Aldrich. n-Butyllithium (n-BuLi, 1.6 M solution in hexane) was purchased from Acros. The benzamides, aryl bromides, acid chlorides, carboxylic acid, and the reagents used for the preparation of the Weinreb amides as well as N,O-dimethylhydroxylamine hydrochloride were purchased from Aldrich. The concentration of alkyllithium solutions was determined by titration in THF over diphenyl acetic acid.1

Synthesis of the amides 1:

4-fluoro-N,N-dimethylbenzamide (1t) was synthesized according to a reported procedure1 starting from 0.24 ml of 4-fluorobenzoyl chloride. Yellow oil, 268 mg, 80% yield. 1 H-NMR (400 MHz, CDCl3): δ 7.42 (dd, J = 8.6, 5.4 Hz, 2H), 7.08 (t, J = 8.7 Hz, 2H), 3.09 13 (s, 3H), 2.99 (s, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 170.6, 163.2 (d, J = 249.4 Hz), 129.3 (d, J = 8.5 Hz), 115.3 (d, J = 21.8 Hz), 39.6, 35.4 ppm.

4-chloro-N-methoxy-N-methylbenzamide (1u)2 was synthesized according to a i 1 reported procedure. H-NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.6 13 Hz, 2H), 3.53 (s, 3H), 3.35 (s, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 168.7, 136.7, 132.3, 129.8, 128.3, 61.1, 33.5 ppm.

4-methoxy-N,N-dimethylbenzamide (1v) was synthetized according to a reported 3 1 procedure. H-NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 13 3.83 (s, 3H), 3.05 (s, 6H). C-NMR (100.59 MHz, CDCl3): δ 171.4, 160.5, 129.0, 128.3, 113.5, 55.3, 39.8, 35.5.

1 Y. Sunada, H. Kawakami, T. Imaoka, Y. Motoyama, and H. Nagashima, Angew. Chem. Int. Ed. 2009, 48, 9511. 2 T. Niu, W. Zhang, D. Huang, C. Xu, H. Wang and Y. Hu, Org. Lett. 2009, 11, 4474. 3 E. F. Kleinman, WO 00/09504.

General Procedure for the one-pot, 1,2-addition, Pd-catalyzed α-arylation:

In a dry Schlenk flask the corresponding amide 1 (0.5 mmol) was dissolved in 2 mL of dry THF, the mixture was cooled down to 0 °C and the corresponding alkyllithium reagent

(1.0 eq.) was added dropwise. After one hour, Pd[P(tBu)3]2 (5 mol%) and the corresponding aryl bromide (0.6 mmol, 1.2 eq) were added to the reaction mixsture and the vessel was heated with a preheated oil bath to 60 ̊C overnight (unless otherwise noted). After allowing the reaction mixture to cool to rt, a saturated aqueous solution of NH4Cl (2 mL) was added whereupon the mixture was extracted with ether (3 x 5mL). The organic phases were combined, dried over MgSO4 and filtered, after which evaporation of the solvent under reduced pressure afforded the crude product 3 that was then purified by column chromatography using different mixtures of n-pentane/EtOAc as the eluent.

Experimental details and spectral data of compounds

1-Phenyl-2-(p-tolyl)pentan-1-one (3a): Synthesized using N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4-bromotoluene (0.6 mmol,

103 mg). Colorless oil obtained after column chromatography (SiO2, n-pentane/ EtOAc 98:2), 108 mg, 86% yield. Reaction performed using 6 mmol (895 mg) of substrate 1a: 1.38 g, 86% 1 yield. H-NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 4.52 (t, J = 7.3 Hz, 1H), 2.28 (s, 3H), 2.19-2.08 (m, 1H), 1.85-1.74 (m, 1H), 1.38-1.19 (m, 2H), 0.92 (t, J = 7.3 Hz, 13 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 200.2, 137.0, 136.8, 136.5, 132.7, 129.5, 128.6, 128.5, 128.1, 53.0, 36.1, 21.0, 20.9, 14.1 ppm. HRMS (ESI+, m/z): calcd for C18H21O [M+H]+: 253.1587; found: 253.1588.

2-([1,1'-Biphenyl]-4-yl)-1-phenylpentan-1-one (3b): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4- bromo-1,1'-biphenyl (0.6 mmol, 140 mg). White crystals obtained after column chromatography and further recrystallization from n-pentane (SiO2, n-pentane/ EtOAc 98:2), 1 123 mg, 78% yield. M.p.: 117 °C-118 °C. H-NMR (400 MHz, CDCl3): δ 8.00 (d, J = 7.3 Hz, 2H), 7.56-7.47 (m, 5H), 7.44-7.36 (m, 6H), 7.32 (t, J = 7.3 Hz, 1H), 4.61 (t, J = 7.3 Hz, 1H), 2.24-2.14 (m, 1H), 1.91-1.80 (m, 1H), 1.40-1.24 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) ppm. 13C-

NMR (100.59 MHz, CDCl3): δ 200.1, 140.6, 139.8, 138.8, 137.0, 132.8, 128.7, 128.64, 128.61, 128.5, 127.5, 127.2, 127.0, 53.0, 36.2, 20.9, 14.1 ppm. HRMS (ESI+, m/z): calcd for + C23H23O [M+H] : 315.1743; found: 315.1745.

2-(Naphthalen-2-yl)-1-phenylpentan-1-one (3c): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 2- bromonaphthalene (0.6 mmol, 124 mg). Brown waxy solid obtained after column 1 chromatography (SiO2, n-pentane/ EtOAc 98:2), 98 mg, 68% yield. H-NMR (400 MHz, CDCl3): δ 8.00 (d, J = 7.4 Hz, 2H), 7.80-7.55 (m, 3H), 7.74 (s, 1H), 7.48-7.40 (m, 4H), 7.37 (t, J = 7.6 Hz, 2H), 4.72 (t, J = 7.3 Hz, 1H), 2.28-2.18 (m, 1H), 1.96-1.86 (m, 1H), 1.43-1.22 13 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 199.8, 137.4, 137.0, 133.6, 132.8, 132.4, 128.6, 128.51, 128.47, 127.6, 127.5, 127.0, 126.3, 126.1, 125.7, + 53.4, 36.1, 20.9, 14.0 ppm. HRMS (ESI+, m/z): calcd for C21H21O [M+H] : 289.1586; found: 289.1587.

1-Phenyl-2-(o-tolyl)pentan-1-one (3d): Synthesized using N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 2-bromotoluene (0.6 mmol,

103 mg, 73 µL). Colorless oil obtained after column chromatography (SiO2, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under vacuum at 60°C, 81 mg, 65% 1 yield. H-NMR (400 MHz, CDCl3): δ 7.84 (d, J = 7.1 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.16-7.20 (m, 1H), 7.14-7.07 (m, 3H), 4.71 (dd, J = 8.2, 5.8 Hz, 1H), 2.50 (s, 3H), 2.26-2.16 (m, 2H), 1.47-1.37 (m, 1H), 1.34-1.24 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H) 13 ppm. C-NMR (100.59 MHz, CDCl3): δ 200.6, 138.6, 137.4, 135.0, 132.6, 130.9, 128.5, 128.3, 127.2, 126.8, 126.6, 49.5, 35.9, 21.2, 19.9, 14.3 ppm. HRMS (ESI+, m/z): calcd for + C18H21O [M+H] : 253.1586; found: 253.1587.

1-Phenyl-2-(4-(trifluoromethyl)phenyl)pentan-1-one (3e): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 1- bromo-4-(trifluoromethyl)benzene (0.6 mmol, 135 mg). Pale yellow oil obtained after column chromatography (SiO2, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under 1 vacuum at 60°C, 103 mg, 67% yield. H-NMR (400 MHz, CDCl3): δ 7.95 (d, J = 7.3 Hz, 2H), 7.57-7.49 (m, 3H), 7.46-7.39 (m, 4H), 4.64 (t, J = 7.3 Hz, 1H), 2.23-2.12 (m, 1H), 1.88-1.77 13 (m, 1H), 1.38-1.20 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 199.4, 143.78, 143.77, 136.7, 133.1, 129.23 (q, J = 32.4 Hz), 128.7, 128.60, 128.55, 125.73 19 (q, J = 3.8 Hz), 53.0, 36.2, 20.8, 14.0 ppm. F-NMR (376 MHz, CDCl3): δ -62.5 ppm. HRMS + (ESI+, m/z): calcd for C18H18F3O [M+H] : 307.1304; found: 307.1304.

2-(4-Chlorophenyl)-1-phenylpentan-1-one (3f): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 1- bromo-4-chlorobenzene (0.6 mmol, 115 mg). Colorless oil obtained after column chromatography (SiO2, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under 1 vacuum at 60°C, 92 mg, 67% yield. H-NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.25 (m, 4H), 4.55 (t, J = 7.3 Hz, 1H), 2.19- 2.08 (m, 1H), 1.85-1.73 (m, 1H), 1.38-1.20 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) ppm. 13C-NMR

(100.59 MHz, CDCl3): δ 199.8, 138.3, 136.8, 133.0, 132.8, 129.6, 129.0, 128.58, 128.56, + 52.6, 36.1, 20.8, 14.0 ppm. HRMS (ESI+, m/z): calcd for C17H18ClO [M+H] : 273.1040; found: 273.1041.

2-(4-Methoxyphenyl)-1-phenylpentan-1-one (3g): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4- bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography 1 (SiO2, n-pentane/ EtOAc 95:5), 114 mg, 85% yield. H-NMR (400 MHz, CDCl3): δ 7.95 (d, J = 7.1 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.50 (t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 2.16-2.06 (m, 1H), 1.84-1.73 (m, 13 1H), 1.36-1.20 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 200.3, 158.2, 137.0, 132.7, 131.8, 129.2, 128.6, 128.5, 114.2, 55.1, 52.5, 36.1, 20.8, 14.1 ppm. + HRMS (ESI+, m/z): calcd for C18H21O2 [M+H] : 269.1536; found: 269.1536.

2-(4-(Methylthio)phenyl)-1-phenylpentan-1-one (3h): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4- bromothioanisole (0.6 mmol, 122 mg). White solid obtained after column chromatography

(SiO2, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under vacuum at 60°C, 1 116 mg, 82% yield. M.p.: 56 -57 °C. H-NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 4.53 (t, J = 7.4 Hz, 1H), 2.45 (s, 3H), 2.19-2.09 (m, 1H), 1.86-1.76 (m, 1H), 1.38-1.22 13 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 200.0, 136.93, 136.90, 136.6, 132.8, 128.7, 128.6, 128.5, 127.0, 52.8, 36.0, 20.8, 15.8, 14.0 ppm. HRMS + (ESI+, m/z): calcd for C18H21OS [M+H] : 285.1307; found: 285.1308.

2-(4-(Dimethylamino)phenyl)-1-phenylpentan-1-one (3i): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4- bromo-N,N-dimethylaniline (0.6 mmol, 120 mg). Yellow solid obtained after column 1 chromatography (SiO2, n-pentane/ EtOAc 90:10), 114 mg, 81% yield. M.p.: 75 °C-76 °C. H- NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.1 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.7 Hz, 2H), 4.45 (t, J = 7.3 Hz, 1H), 2.89 (s, 6H), 2.17-2.04 (m, 1H), 1.84-1.73 (m, 1H), 1.36-1.20 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm. 13 C-NMR (100.59 MHz, CDCl3): δ 200.4, 149.4, 137.2, 132.4, 128.8, 128.5, 128.3, 127.3, + 112.8, 55.3, 40.4, 36.0, 20.8, 14.1 ppm. HRMS (ESI+, m/z): calcd for C19H24NO [M+H] : 282.1852; found: 282.1853.

Ethyl 4-(1-oxo-1-phenylpentan-2-yl)benzoate (3j): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and ethyl 4-bromobenzoate (0.6 mmol, 137 mg, 98 µL). Yellow oil obtained after column 1 chromatography (SiO2, n-pentane/ EtOAc 95:5), 59 mg, 38% yield. H-NMR (400 MHz, CDCl3): δ 7.99-7.91 (m, 4H), 7.49 (t, J = 7.4 Hz, 1H), 7.39 (m, 4H), 4.62 (t, J = 7.3 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.22-2.12 (m, 1H), 1.88-1.77 (m, 1H), 1.38-1.18 (m, 5H), 0.92 (t, J = 13 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 199.5, 166.3, 144.9, 136.7, 133.0, 130.1, 129.2, 128.6 (2C), 128.2, 60.9, 53.4, 36.0, 20.8, 14.3, 14.0 ppm. HRMS (ESI+, m/z): + calcd for C20H23O3 [M+H] : 311.1641; found: 311.1642.

2-(4-Benzoylphenyl)-1-phenylpentan-1-one (3k): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4- bromobenzophenone (0.6 mmol, 157 mg). Yellow oil obtained after column chromatography

(SiO2, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under vacuum at 60°C, 1 147 mg, 86% yield. H-NMR (400 MHz, CDCl3): δ 7.99-7.96 (m, 2H), 7.77-7.73 (m, 4H), 7.57 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.48-7.40 (m, 6H), 4.67 (t, J = 7.3 Hz, 1H), 2.25-2.16 (m, 1H), 1.91-1.81 (m, 1H), 1.40-1.27 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) ppm. 13C-

NMR (100.59 MHz, CDCl3): δ 199.5, 196.2, 144.6, 137.5, 136.7, 136.2, 133.1, 132.4, 130.7, 129.9, 128.64, 128.62, 128.2, 128.2, 53.3, 36.1, 20.9, 14.1 ppm. HRMS (ESI+, m/z): calcd for + C24H23O2 [M+H] : 343.1692; found: 343.1693.

2-(4-(1,3-Dioxolan-2-yl)phenyl)-1-phenylpentan-1-one (3l): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 2-(4- bromophenyl)-1,3-dioxolane (0.6 mmol, 137 mg). Colorless oil obtained after column 1 chromatography (SiO2, n-pentane/ EtOAc 95:5), 121 mg, 78% yield. H-NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.2 Hz, 2H), 7.53-7.45 (m, 1H), 7.42-7.31 (m, 6H), 5.74 (s, 1H), 4.57 (t, J = 7.2 Hz, 1H), 4.15-3.98 (m, 4H), 2.19-2.09 (m, 1H), 1.85-1.75 (m, 1H), 1.36-1.18 (m, 13 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 199.9, 140.9, 136.9, 136.5, 132.8, 128.6, 128.5, 128.3, 127.0, 103.5, 65.3, 65.2, 53.2, 36.1, 20.8, 14.0 ppm. HRMS + (ESI+, m/z): calcd for C20H23O3 [M+H] : 311.1641; found: 311.1642.

1-Phenyl-2-(pyridin-3-yl)pentan-1-one (3m): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 3- bromopyridine (0.6 mmol, 95 mg, 58 µL). Colorless oil obtained after column 1 chromatography (SiO2, n-pentane/ EtOAc 95:5), 83 mg, 69% yield. H-NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.47 (d, J = 3.3 Hz, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.23 (dd, J = 7.9, 4.8 Hz, 1H), 4.62 (t, J = 7.3 Hz, 1H), 2.12-2.23 (m, 1H), 1.87-1.77 (m, 1H), 1.40-1.22 (m, 2H), 0.93 (t, J = 7.3 Hz, 13 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 199.4, 150.0, 148.4, 136.5, 135.3, 133.2, 128.7, 128.5 (2C), 123.7, 50.3, 36.1, 20.8, 13.9 ppm. HRMS (ESI+, m/z): calcd for C16H18NO [M+H]+: 240.1382; found: 240.1383.

5-bromo-1-methyl-1H-indole3 Synthesized using 5-bromo-1H-indole (4.0 mmol, 790 mg). Yellow oil, 555 mg, 66% 1 yield. H-NMR (300 MHz, CDCl3): δ 7.74 (d, J = 1.6 Hz, 1H), 7.29 (dd, J = 8.7, 1.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 3.1 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 3.77 (s, 3H) ppm. 13 C-NMR (100.59 MHz, CDCl3): δ 135.5, 130.3, 130.2, 124.3, 123.3, 112.7, 110.9, 100.6, 33.0 ppm. 1H- and 13C-NMR Spectra in accordance with literature data.3

2-(1-methyl-1H-indol-5-yl)-1-phenylpentan-1-one (3n): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 5- bromo-1-methyl-1H-indole (0.6 mmol, 126 mg). Yellow oil obtained after column chromatography (SiO2, n-pentane/ EtOAc 95:5), 110 mg, 75% yield. 1H-NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.3 Hz, 2H), 7.54 (s, 1H), 7.42 (t, J = 6.7 Hz, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.24 (d, J = 10.9 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 3.1 Hz, 1H), 6.41 (d, J = 3.1 Hz, 1H), 4.62 (t, J = 7.3 Hz, 1H), 3.73 (s, 3H), 2.23-2.13 (m, 1H), 1.91-1.81 (m, 1H), 13 1.38-1.22 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 200.6, 137.3, 135.8, 132.5, 130.7, 129.2, 128.9, 128.7, 128.4, 121.9, 120.5, 109.6, 100.8, 53.6, 36.5,

32.8, 20.9, 14.2 ppm. HRMS (ESI+, m/z): calcd for C20H21NO [M+H]+: 292.1695; found: 292.1696.

2-(4-Methoxyphenyl)-1-phenylpropan-1-one (3o): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), EtLi (1.6 ml, 0.31 M, 0.5 mmol, 1.0 eq) and 4- bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography 1 (SiO2, n-pentane/ EtOAc 95:5), 63 mg, 53% yield. H-NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.0 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.64 (q, J = 6.9 Hz, 1H), 3.75 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H) ppm. 13C-

NMR (100.59 MHz, CDCl3): δ 200.5, 158.5, 136.5, 133.5, 132.7, 128.78, 128.74, 128.5, + 114.4, 55.2, 47.0, 19.5 ppm. HRMS (ESI+, m/z): calcd for C16H17O2 [M+H] : 241.1223; found: 241.1223.

2-(4-Methoxyphenyl)-1-phenylheptan-1-one (3p): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), n-HexLi (0.22 ml, 2.3 M, 0.5 mmol, 1.0 eq) and 4- bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography 1 (SiO2, n-pentane/ EtOAc 95:5), 119 mg, 80% yield. H-NMR (400 MHz, CDCl3): δ 7.95 (d, J = 7.7 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.48 (t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 2.18-2.07 (m, 1H), 1.84-1.70 (m, 13 1H), 1.36-1.19 (m, 6H), 0.85 (t, J = 5.5 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 200.3, 158.5, 137.1, 132.7, 131.9, 129.2, 128.6, 128.5, 114.3, 55.1, 52.8, 34.0, 31.8, 27.4, + 25.5, 14.1 ppm. HRMS (ESI+, m/z): calcd for C20H25O2 [M+H] : 297.1849; found: 297.1849.

2-(4-Methoxyphenyl)-2-methyl-1-phenylbutan-1-one (3q): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), s-BuLi (0.5 ml, 1.0 M, 0.5 mmol, 1.0 eq) and 4- bromoanisole (0.6 mmol, 112 mg, 75 µL) using toluene as solvent, heated to reflux for the α- arylation step. Colorless oil obtained after column chromatography (SiO2, n-pentane/ EtOAc 1 95:5), 67 mg, 50% yield. H-NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.24-7.18 (m, 4H), 6.89 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 2.18-1.98 (m, 2H), 13 1.52 (s, 3H), 0.74 (t, J = 7.4 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 204.1, 158.3, 137.2, 136.2, 131.4, 129.4, 127.9, 127.3, 114.2, 55.2, 54.2, 32.1, 23.7, 8.6 ppm. HRMS (ESI+, + m/z): calcd for C18H21O2 [M+H] : 269.1536; found: 269.1536.

2-(2,6-Dimethoxyphenyl)-1-phenylethan-1-one (3s): Synthesized using N,N- dimethylbenzamide (0.5 mmol, 75 mg), MeLi (0.39 ml, 1.28 M, 0.5 mmol, 1.0 eq) and 2- bromo-1,3-dimethoxybenzene (0.6 mmol, 130 mg). Yellow oil obtained after column 1 chromatography (SiO2, n-pentane/ EtOAc 90:10), 67 mg, 52% yield. H-NMR (400 MHz, CDCl3): δ 8.04 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 8.3 Hz, 1H), 6.57 (d, J = 8.3 Hz, 2H), 4.33 (s, 2H), 3.76 (s, 6H) ppm. 13C-NMR (100.59

MHz, CDCl3): δ 198.0, 158.3, 137.4, 132.6, 128.4, 128.2 (2C), 112.2, 103.7, 55.7, 33.9 ppm. + HRMS (ESI+, m/z): calcd for C16H16O3 [M+H] : 257.1172; found: 257.1172.

1-(4-Fluorophenyl)-2-(4-methoxyphenyl)pentan-1-one (3t): Synthesized using 4- fluoro-N,N-dimethylbenzamide (0.5 mmol, 84 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4-bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column 1 chromatography (SiO2, n-pentane/ EtOAc 95:5), 80 mg, 56% yield. H-NMR (400 MHz, CDCl3): δ 7.97 (dd, J = 8.7, 5.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.43 (t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 2.15-2.05 (m, 1H), 1.83-1.69 13 (m, 1H), 1.34-1.19 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 198.7, 165.4 (d, J = 254.4 Hz), 158.6, 133.4 (d, J = 3.0 Hz), 131.6, 131.2 (d, J = 9.2 Hz), 129.1, 115.5 (d, J = 21.8 Hz), 114.3, 55.1, 52.5, 36.1, 20.8, 14.0 ppm. 19F-NMR (376 MHz, + CDCl3): δ -105.8 ppm. HRMS (ESI+, m/z): calcd for C18H20FO2 [M+H] : 287.1441; found: 287.1442.

1-(4-Chlorophenyl)-2-(4-methoxyphenyl)propan-1-one (3u): Synthesized using 4- chloro-N-methoxy-N-methylbenzamide (0.5 mmol, 100 mg), EtLi (1.6 ml, 0.31 M, 0.5 mmol, 1.0 eq) and 1-bromo-4-methoxybenzene (0.6 mmol, 112 mg). Colorless oil obtained after 1 column chromatography (SiO2, n-pentane/ EtOAc 95:5), 88 mg, 64% yield. H-NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.57 (q, J = 6.8 Hz, 1H), 3.75 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H) ppm. 13 C-NMR (100.59 MHz, CDCl3): δ 199.2, 158.6, 139.0, 134.8, 133.2, 130.2 (2C), 128.7, 128.7, 114.5, 55.2, 47.2, 19.4 ppm.

1,2-Bis(4-methoxyphenyl)pentan-1-one (3v): Synthesized using 4-methoxy-N,N- dimethylbenzamide (0.5 mmol, 90 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4- bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography 1 (SiO2, n-pentane/ EtOAc 90:10), 90 mg, 60% yield. H-NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 4.47 (t, J = 7.3 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 2.17-2.07 (m, 1H), 1.84-1.73 (m, 1H), 13 1.37-1.21 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H) ppm. C-NMR (100.59 MHz, CDCl3): δ 198.8, 163.2, 158.4, 132.3, 130.9, 130.0, 129.1, 114.2, 113.6, 55.4, 55.2, 52.0, 36.2, 20.9, 14.1 ppm. + HRMS (ESI+, m/z): calcd for C19H23O3 [M+H] : 299.1641; found: 299.1642.

3 Greulich, T. W.; Daniliuc, C. G.; Studer, A. Org. Lett. 2015, 17, 254-257.

Additional experimental data:

100 90 80 70 Conversion (%) 60 50 40 30 20 10 0 t (h) 0 2 4 6 8

Figure S1. Conversion of 1a into 3a followed in time by GC analysis. aConditions: n-BuLi (1.0 eq, 1.6 M) is added to a solution of amide 1a (0.5 mmol) in THF (2 mL) followed by addition of Pd[P(t-Bu)3]2 (5 mol %) and 4- bromotoluene (1.2 eq.) heated to 60 °C.

4.3 The Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot Reduction/Cross-Coupling Procedure

The synthesis of functionalized (benz)aldehydes via a two-step, one-pot procedure, is presented in this chapter. The method employs a stable aluminium hemiaminal as tetrahedral intermediate, suitable for subsequent cross-coupling with (strong nucleophilic) organometallic reagents, leading to a variety of alkyl and aryl substituted benzaldehydes. This methodology was also applied to effectively synthesize a 11C radiolabeled aldehyde. An aluminium-ate complex plays a crucial role in the transmetallation of alkyl fragments onto palladium and allows the synthesis of an industrially relevant isobutyl substituted benzylic alcohol by two fold use of DIBAL-H.

D. Heijnen, H. Helbert, B. L. Feringa : Manuscript in preparation 4.4.1 Introduction The synthesis of small, highly functionalized molecules lies at the basis of many areas of chemistry, ranging from drug design, to (hetero-) cyclic materials for photovoltaics and substituted metallocene ligands for transition metal catalysis.1 Transition metal catalyzed cross-coupling methods for derivatization of these compounds mostly rely on rather expensive coupling partners with reduced reactivity and therefore require higher temperatures and long reaction times, as well as traditional protecting group strategies.2 Facing environmental awareness, catalytic methods with lighter reagents that produce less waste and of lower toxicity should be favored according to the principles of green chemistry.3 The application of cheaper and more reactive organometallic reagents as coupling partners in combination with carbonyl functional groups has some precedence, but still remains a synthetic challenge.4 The reactive aldehyde functionality in particular is prone to side reactions with organometallic reagents. It is this high reactivity with a range of reagents that make aldehydes such useful building blocks in organic synthesis, and therefore a general and facile synthesis of substituted (benz)aldehydes would be highly desirable. In order to prevent the fast 1,2- addition of a nucleophile to the aldehyde (Scheme 4.1a), or over addition to a synthetic precursor, Weinreb amides (1) have proven themselves to be valuable precursors to aldehydes moiety (2). By addition of an organometallic compound to 1, a stable reaction intermediate 4 (Scheme 4.1b) is created in situ, which is unsusceptible to further nucleophilic attack.5 We discovered that these metal chelated intermediates are stable towards organolithium cross-coupling conditions. As a consequence, a method for the synthesis of cross-coupled ketones, with organolithium reagents and bromo-substituted Weinreb amides as the coupling partners via reaction intermediate 4 was developed (scheme 4.1b).6 Adding to the already known transformations of Weinreb amides, this method provides an easy approach to cross-coupled carbonyl compounds, and we envisioned that reduction with a (aluminium-) hydride source would yield a hemiaminal with similar stability, facilitating a procedure for the cross-coupling of masked aldehydes.

Scheme 4.1 Reduction of Weinreb amides and stabile cross coupling intermediates

The Weinreb amides are easily prepared on a multigram scale from cheap, commercially available benzoic acids, thus providing a viable synthetic pathway for laboratory scale and the semi preparative synthesis of aldehyde building blocks. 4.4.2 Optimization Reduction of the Weinreb amide was performed with the reductants diisobutylaluminium hydride (DIBAL-H) and sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) due to their ease of handling and their availability. The screening of Pd-based carbene and phosphine catalysts showed the latter to be more reactive and selective for the cross-coupling of aryl bromides with organolithium reagents. In agreement with our previously observed increase in reactivity pre-oxidation of the t phosphine based catalyst Pd(P Bu3)2 leads to a higher yield, and allowed for a drastic reduction of the reaction time, while maintaining excellent conversion and selectivity towards the desired aldehyde.7 By switching the reductant to Red-Al, the conversion towards the aldehyde remained quantitative, but selectivity in the subsequent coupling reaction dropped due to dehalogenation of the aryl bromide. The formation of benzaldehyde is attributed to the lithium halogen exchange, promoted by the chelating effect of the ether moieties in the Red-Al.5b

Entry Cat “H”/Solvent Yield1 t 1 Pd(P Bu3)2 DIBAL-H(1 eq.)/Toluene 85 t 2 2 Pd(P Bu3)2 DIBAL-H(1 eq.) /Toluene 87 t 3 Pd(P Bu3)2 DIBAL-H(1 eq.)/THF 40 t 2 4 Pd(P Bu3)2, O2 DIBAL-H(1 eq.) /Toluene 92 t 2 3 5 Pd(P Bu3)2, O2 DIBAL-H(1 eq.) /Toluene 90 t 4 6 Pd(P Bu3)2, O2 Red-Al (1eq.)/Toluene 30 Table 4.1. Reaction optimization 1Yield determined by GC/MS analysis. 2DIBAL-H added over 1 min. 3 The organolithium reagent was added over 5 min. 4 Sodium bis(2-methoxyethoxy)aluminium hydride

4.4.3 Substrate scope Having established the optimal conditions for the reduction/aryl cross-coupling (fast DIBAL-H addition at 0°C in toluene over 1 min, and Ar-Li addition at rt over 5 min, table 4.1, entry 5), a range of organolithium reagents were employed, including phenyllithium, (functionalized) aryllithium reagents (6,7), enol ether derivatives (8) and lithiated heterocycles that are commercially available, or easily prepared via direct deprotonation (9, 10). Finally, the direct deprotonation and coupling of ferrocene provided aldehyde, paving the way for the cheap and easy synthesis of functionalizable ferrocenes (11). Expanding the scope of the organolithium coupling partner to alkyl fragments, allowed the formation of methyl (12), ethyl (13), trimethylsilylmethylene (14) and cyclopropyl (15) substituted benzaldehydes with little or no modification of the previously optimized procedure. The relatively light and volatile aldehydes showed significant loss in yield during isolation due to evaporation.

Figure 4.1 Scope of the one pot reduction/Cross-coupling strategy for substituted benzaldehydesa a) Yields refer to isolated yields after column chromatography. b) Lower yield due to volatile product c) Yield corrected for minor isobutylbenzaldehyde impurities. d) performed on 1 mmol scale

The less volatile naphthyl-analogue 16 proved less prone to evaporation, and was isolated in 63% 11 yield. We have previously successfully incorporated the short lived C isotope (t½ = 20.3 min) by means of a palladium catalyzed cross-coupling of methyllithium with aryl bromides. Expanding the scope of the organolithium cross-coupling, radiolabeled aldehydes remain a synthetically challenging goal.7b,7c Due to the limited amount of methods available for the preparation7d,7e or functionalization7f- i of radiolabeled aldehydes, we set out to design a method for the 11C incorporation in (substituted) benzaldehydes. Employing the general reduction/cross-coupling strategy introduced here we aimed to synthesize compound [methyl-11C]16 as a model substrate. Taking advantage of our previously reported method for making [11C]methyllithium from [11C]methyliodide by means of an in situ lithium halogen exchange with n-BuLi, the one pot procedure described above yields the isolated target molecule in a 23% decay corrected yield with a radiochemical purity of >99% (Scheme 4.2).

Scheme 4.2 Synthesis of radiolabelled 6-methyl-2-naphthaldehyde

This is one of the few examples of the radiolabeling of (substituted) benzaldehydes, and we envision an important role in the synthesis of new PET-tracers, vital for mapping of processes and biological targets in the human body.7b,7c Though near perfect selectivity for the desired product was observed when using MeLi, (Figure 4.1, 12) we sometimes found the competing coupling of an isobutyl group, originating from the DIBAL- hemiaminal intermediate, while employing other alkyllithium coupling partners. It is known that in cross-coupling reactions, mixed aryl/alkyl aluminum species selectively transmetallate the sp2 hybridized carbon fragment, and only trialkyl-aluminum species transfer the sp3 moiety.8,9 We expected the isobutyl to originate from the aluminium-ate complex, which is formed after addition of the alkyllithium reagent.

entry R-Li T (°C) Selectivitya 17a/17b 1 nBuLi 23 95-60b/5-40 2 nBuLi 0 65/35 3 nBuLi 45 85/15 4 iPr-Li 23 68/32 5 iPr-Li 0 61/39 6 tBu-Li 23 <1/99c,d 7 tBu-Li 0 <1/99c,d Table 4.2 Scrambling of alkyl fragments upon alkyllithium addition and cross coupling. a As determined by GC/MS analysis. b Selectivity varied under identical reaction conditions. c Varying amounts of homocoupling (bis-benzaldehyde) were also observed.d Reversed selectivity : only the isobutyl coupled benzaldehyde observed Table 4.2 shows the selectivity of isobutyl versus the added alkyl fragment. Tetrahedral intermediate 1-th is formed upon DIBAL-H addition, which is the precursor to the anionic aluminium-ate complex 1-ate upon alkyllithium addition. For both n-butyl- (entry 1-3), and isopropyl- lithium (entry 4 and 5), poor or varying selectivity for the alkyl substituted benzaldehyde was found, regardless of addition speed or reaction temperature. We were unable to find reaction conditions that gave satisfactory selectivity towards the desired product 17a. In order to force the selectivity towards isobutyl (originating from the DIBAL-H fragment) coupling, we decided to add the reluctant coupling partner t-BuLi, which showed full selectivity in alkyl transfer towards the isobutyl coupled benzaldehyde. Similar to our previous findings on homocoupling reactions of arylbromides the lithium halogen exchange is a prominent reaction pathway, and thus a substantial amount of of 4,4’-bisbenzaldehyde was observed.

7

6

5

4

3

2

1

2 .4 2 .2 2 .0 1 .8 1 .6 1 .4 1 .2 1 .0 0 .8 0 .6 0 .4 0 .2 0 .0 - 0 .2 - 0 .4 - 0 .6 - 0 .8 - 1 .0 - 1 .2 - 1 .4 - 1 .6 - 1 .8 - 2 .0 f1 (p p m ) Figure 4.2 1H-NMR studies of DIBAL-H reduction of Weinreb amide 1. Conditions : concentration of all reagents : 0.1 mmol in 0.5 ml tol-d8, Reduction and n-BuLi addition performed at 0°C.

In order to check for the formation of free isobutyllithium (displacement of the alkyl fragment by n-butyllithium), a selection of starting materials and reaction mixtures was subjected to 1H-NMR analysis (Figure 4.2). The CH2 fragment of the isobutyl in DIBAL-H (spectrum 1) is clearly visible at 0.44 ppm, and is completely consumed upon addition to the Weinreb amide (spectrum 2). The large number of signals between 0 and 0.4 ppm can be explained by the generation of unequal alkyl fragments at the aluminium center, in combination with diastereotopic protons. Upon addition of n-butyllithium, the CH2 fragment of the linear alkyl chains becomes apparent at -0.17 ppm (spectrum 3). A similar trend is visible when the trialkyl-aluminium complex (doublet at 0.38, spectrum 4) is also mixed with n-butyllithium (spectrum 5) where an upfield shift is observed that leads to a signal at - 0.32 ppm. When this mixture is added to a stirred solution of Pd-catalyst and 1-bromonaphthalene, a similar product distribution (table 2 entry 1) between n- and iso- butyl coupled naphthalene is observed. Finally, the pure sample of both n-butyllithium (spectrum 6) and isobutyllithium (spectrum 7) provided the reference for the hypothesis that no free alkyllithium is present in sample/spectrum 3 and 5. These observations, together with literature precedence supports the hypothesis of the unselective alkyl transmetallation from aluminium to palladium.11 4.4.4 In situ reduction of ketones. The reduction/cross-coupling strategy could be further expanded from Weinreb amides to ketones. Ketones such as acetophenones are easily prepared via Friedel-Craft acetylation, and make up an important class of chemical intermediates. Reduction of the acetophenone moiety yields a substituted benzylic alcohol that can be further functionalized. Unlike carbonyl moieties, benzylic alcohols do not act as a electrophiles with organolithium reagents and as such do not have to be protected, but the acidic proton would nevertheless consume a stoichiometric amount of organolithium reagent. It is therefore that this group is suitably protected as a metal alkoxide (for example an aluminium alkoxide). The isobutyl transfer observed in previous examples, led us to the attempt of the two fold use of DIBAL-H in the reaction with 4-bromoacetophenone. The transfer of the hydride leads to an aluminium alkoxide, and addition of tert-butyllithium is hypothesized to generate the intermediate shown in scheme 4.3. Selective isobutyl transmetallation from aluminium to palladium and consecutive cross-coupling was found to provide industrially relevant alcohol 18, a precursor to anti-inflammatory agent Ibuprofen, in 43 % yield (scheme 4.3).10

Scheme 4.3 Two fold use of DIBAL-H in the reduction and cross coupling of 4-bromoacetophenone

4.4.5 Conclusions In conclusion, we have shown that the DIBAL-H reduction of Weinreb amides, yields a masked aldehyde in the form of a stable aluminum hemiaminal intermediate, providing a platform for subsequent functionalization with nucleophilic cross-coupling partners. The scrambling of alkyl fragments in the cross-coupling of alkyllithium reagents is caused by a mixed aluminium-ate complex, as observed by 1H-NMR analysis. The method was also applied to an industrially relevant ketone, yielding an Ibuprofen precursor, and showcased the two fold use (reducing agent and alkyl transfer agent) of DIBAL-H in the synthesis of secondary alcohols. Further research on the use of these aluminium hemiaminal intermediates is currently ongoing.

4.4.6 References 1) a) The Organic Chemistry of Drug Design and Drug Action 3rd Edition, R. B. Silverman, M. W. Holladay. Elsevier 2014 San Diego. Hardcover ISBN: 9780123820303 b) Photovoltaics Practical Handbook of Photovoltaics (Second Edition)Fundamentals and Application. A. McEvoy, T. Markvart and L. Castaner, Elsevier 2012 ISBN: 978-0-12-385934-1 c) V. Mamame, Mini-Reviews in Organic Chemistry, 2008, 5, 303-312 d) Bozak, R. E. Advances in Photochemistry (Chapter : Photochemistry in the Metallocenes,) , Volume 8 (eds J. N. Pitts, G. S. Hammond and W. A. Noyes), John Wiley & Sons, Inc., Hoboken, NJ, USA. 2007 ISSN: 1934-4570 2) a) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012, 51, 5062–5085; b) G. C. Fortman, S. P. Nolan, Chem. Soc. Rev. 2011, 40, 5151–5169; c) E. I. Negishi, Angew. Chem. Int. Ed. 2011, 50, 6738–6764; d) V. L. Andersen, H. D. Hansen, M. M. Herth, G. M. Knudsen, J. L. Kristensen, Bioorganic Med. Chem. Lett. 2014, 24, 2408–2411; e) H. G. Lee, P. J. Milner, M. S. Placzek, S. L. Buchwald, J. M. Hooker, J. Am. Chem. Soc. 2015, 137, 648–651; f) A. M. Echavarren, D. J. Cárdenas, in Metal Catalyzed Cross-Coupling Reactions, Wiley-VCH Verlag GmbH, Weinheim, Germany, 2004, pp. 1–40

3) The 12 principles of green chemistry https://www.acs.org/content/acs/en/greenchemistry/what- is-green-hemistry/principles/12 -principles-of-green-chemistry.html Retrieved : 2-Feb-2018

4) J. Adrio, J. C. Carretero, ChemCatChem, 2010, 2, 1384 – 1386. Knochel P, Dohle W, Gommermann N, Kneisel FF, Kopp F, Korn T, Sapountzis I, Vu VA. Angew. Chem. Int. Ed. 2003, 42, 4302 – 4320. R. Martin, S. L. Buchwald, J. Am. Chem. Soc. 2007, 129, 3844-3845. Vechorkin O, Hu X, Angew. Chem. Int. Ed. 2009, 48, 2937 –2940.

5) S. Nahm and S. M. Weinreb. Tetrahedron Letters, Vo1.22, No.39, pp 3815 - 3818, 1981 b) Lithium Compounds in Organic Synthesis, Eds. R. Luisi, V. Capriati, Wiley-VCH, Weinheim, 2014.

6) M. Giannerini, C. Vila, V. Hornillos and B. L. Feringa, Chem. Commun., 2016, 52, 1206

7) Heijnen D, Tosi F, Vila C, Stuart MC, Elsinga PH, Szymanski W, Feringa B. L. Angew Chem. Int. Ed. 2017, 56, 33 54 –3359 b) K. Dahl,M. Schou,N. Amini, C. Halldin Eur. J. Org. Chem. 2013, 1228–1231. c) B. H. Rotstein, S. H. Liang, M. S. Placzek, J. M. Hooker, A. D. Gee, F. Dollé, A. A. Wilson, N. Vasdev Chem. Soc. Rev., 2016,45, 4708-4726 d) N. Khanum, S. K. Luthra, Y. Zhao, E. Aboagye, P. M. Price, P. Burke and F. Brady, J. Labelled Cpd. Radiopharm., 2001, 44, Suppl. I, S319-S321 e) C. Halldin and B. Långström, Acta Chem. Scand., 1984, 38B, 1-4. f) K. J. Makaravage, X. Shao, A. F. Brooks, L. Yang, M. S. Sanford, and P. J. H. Scott, Org. Lett., 2018, 20 (6), pp 1530–1533 g) P. Nordeman, S. Y. Chow, A. F. Odell, G. Antonia and L. R. Odell, Org. Biomol. Chem., 2017, 15, 4875 h) H. Geun Lee, P. J. Milner, M. S. Placzek, S. L. Buchwald, and J. M. Hooker, J. Am. Chem. Soc., 2015, 137, 648−651 i) P. J. Riss, S. Lu, S. Telu, F. I. Aigbirhio, V. W. Pike, Angew. Chem. Int. Ed., 2012, 51, 2698–2702

8) R. Polt, M. A. Peterson, and L. DeYoung. J. Org. Chem., 1992, vol. 57, 5469-5480, H. Naka, M. Uchiyama, Y. Matsumoto, A. E. H. Wheatley, M. McPartlin, J. V. Morey, and Y. Kondo. J. Am. Chem. Soc. 2007, 129, 1921-1930. N.A. Bumagin, A.B. Ponomaryov, I.P. Beletskaya. J. Organomet. Chemistry, 291 (1985) 129-132. B. Lipshuts, G. Bulow, R. F. Lowe, K.L. Stevens. Tetrahedron Vol 52, 7265, 7267, 1996.

9) M. Shenglof, D.i Gelman, G. A Molander, J. Blum, Tetrahedron Lett. 44 (2003) 8593–8595 10) S. Jayasree, A. Seayad, and R. V. Chaudhari. Org. Lett., Vol. 2, No. 2, 2000,

11) E. Schaschel, M. C. Day J. Am. Chem. Soc. 17, I968, 902. b) T. Blumke, Y. Chen, Z. Peng and P. Knochel Nat. Chem 2010 Vol 2, 313-318 DOI: 10.1038/NCHEM.590 c) E. Merino, R. P. A. Melo, M. Ortega-Guerra, M.Ribagorda, and M. C. Carreno, J. Org. Chem. Vol. 74, No. 7, 2009 Acknowledgements

This work was done in collaboration with Hugo Helbert, who synthesized and isolated the alkyl substituted benzaldehydes, as well as the radiolabeled compound.

4.4.7 Experimental section All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. THF and toluene were dried and distilled over sodium. Chromatography: Grace Reveleris X2 flash chromatography system used with Grace® Flash Cartridges, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and phosphomolybdic Acid (PMA) or potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59

MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent 1 13 resonance as the internal standard (CHCl3:  7.26 for H,  77.0 for C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Melting points were measured using a Büchi Melting Point

B-545. XPhos, SPhos, Pd2(dba)3, Josiphos (L4), C4, Pd-PEPPSI-IPr and Pd-PEPPSI-IPent were purchased from Aldrich and used without further purification. Pd[P(t-Bu)3]2, was purchased from Strem or Sigma Aldrich. DIBAL-H (1.0 M in cyclohexane), methyllithium (MeLi, 1.6 M in diethylether), ethyllithium, (EtLi, 0.5 M in benzene:cyclohexane), hexyllithium (HexLi, 2.3 M in hexane) and sec-butyllithium (s- BuLi, 1.4 M in cyclohexane) were purchased from Sigma Aldrich. n-butyllithium (n-BuLi, 1.6 M solution in hexanes) was purchased from Acros. The benzamides, aryl bromides, acid chlorides, carboxylic acid, and the reagents used for the preparation of the Weinreb amides as well as N,O- dimethylhydroxylamine hydrochloride were purchased from Aldrich. The concentration of alkyllithium solutions was determined by titration in THF over diphenyl acetic acid.5

General procedure for the reduction and cross coupling of bromo-substituted Weinreb amides

In a dry Schlenk flask the corresponding Weinreb amide 1 (0.5 mmol) was dissolved in 2 mL of dry toluene, the mixture was cooled down to 0 °C and DIBAL-H in cyclohexane (1.0 eq. 0.5 mmol) was added dropwise over 1 min. After the addition the reaction mixture was allowed to warm to room temperature, and a solution of pre-oxidized PdP(tBu)3)2 (1.2 ml of 10 mg/ml, stirred vigorously under

O2 atmosphere for 1 h) was added. The corresponding organolithium reagent (1.5 eq. 0.75 mmol) was diluted with toluene to reach a final concentration of 0.45 M, and was added over 10 min by means of a syringe pump. After the addition of the organolithium reagent was completed, the reaction was quenched with 1 ml of 1 M aqueous HCl, and transferred to a separatory funnel. The organic layer was diluted with EtOAc, and washed 3 times with 1 M aqueous HCl. The organic layers were combined, dried with MgSO4, and concentrated in vacuo to yield the crude product which was further purified by column chromatography (SiO2). (pentane/EtOAc)

[1,1'-biphenyl]-4-carbaldehyde. Synthesized according to the general procedure, using Weinreb amide 1 and phenyllithium. The product was obtained as a white solid after column chromatrography 1 (SiO2) using Pentane/EtOAc (0-5 %) The product was isolated as a white solid (68 mg, 75 %). H NMR (400 MHz, Chloroform-d) δ 10.06 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 192.02, 147.32, 139.85, 135.33, 130.39, 129.14, 128.60, 127.81, 127.49. The data is consistent with that of the commercially available product.

2'-(methoxymethoxy)-[1,1'-biphenyl]-4-carbaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and 2-MOM-phenyllithium prepared via literature procedure.1

The product was obtained as a white solid after column chromatography (SiO2) using Pentane/EtOAc (0-5 %) (61 mg, 50 %). 1H NMR (400 MHz, Chloroform-d) δ 10.06 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.38 – 7.31 (m, 2H), 7.29 – 7.21 (m, 2H), 7.12 (td, J = 7.5, 1.2 Hz, 1H), 5.15 (s, 2H), 3.40 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 192.22, 154.33, 145.21, 135.03, 130.92, 130.34, 129.85, 129.58, 122.50, 115.71, 115.42, 95.15, 56.36. HRMS Measured : 243.10163, Calculated [M+H]: 243.10157

2',6'-dimethoxy-[1,1'-biphenyl]-4-carbaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and 2,6-dimethoxy-phenyllithium prepared via literature procedure.1 The product was obtained as a white solid after column chromatography (SiO2) using Pentane/EtOAc (0-5 %) (57 mg, 47%) 1H NMR (400 MHz, Chloroform-d) δ 10.04 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.33 (t, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 3.75 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 192.34, 157.55, 141.38, 134.91, 131.92, 129.70, 129.18, 118.27, 104.31, 56.00. HRMS Measured : 243.10170, Calculated [M+H]: 243.10157

4-(3,4-dihydro-2H-pyran-6-yl)benzaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and (3,4-dihydro-2H-pyran-6-yl)lithium prepared via literature procedure.1b The product was obtained as a colorless liquid after column chromatography (SiO2) using Pentane/EtOAc (0-5 %) (35 mg, 37%) 1H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 5.54 (t, J = 4.1 Hz, 1H), 4.19 (d, J = 4.9 Hz, 2H), 2.25 (q, J = 6.3 Hz, 2H), 1.92 (dt, J = 11.6, 6.2 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 191.96, 150.81, 142.00, 135.58, 129.78, 124.71, 100.97, 66.68, 22.30, 21.14. HRMS Measured : 189.09105, Calculated [M+H]: 189.09101

4-(thiophen-2-yl)benzaldehyde

Synthesized according to the general procedure, using Weinreb amide 1 and 2-thienyllithium. The product was obtained as a colorless liquid after column chromatography (SiO2) using Pentane/EtOAc (0-5 %) (56 mg, 60%) 1H NMR (400 MHz, Chloroform-d) δ 10.00 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 6.8 Hz, 2H), 7.46 (d, J = 3.5 Hz, 1H), 7.40 (d, J = 4.9 Hz, 1H), 7.13 (dd, J = 5.0, 3.7 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 191.55, 142.84, 140.20, 135.21, 130.58, 128.60, 127.04, 126.15, 125.16. The data matches literature.2

4-(furan-2-yl)benzaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and 2-furyllithium prepared via literature procedure.1 The product was obtained as a colorless liquid 1 after column chromatography (SiO2) using Pentane/EtOAc (0-5 %) (66 mg, 77%) H NMR (400 MHz, Chloroform-d) δ 9.98 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 0.9 Hz, 1H), 6.83 (d, J = 3.4 Hz, 1H), 6.57 – 6.49 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ 191.62, 152.72, 143.72, 136.19, 135.01, 130.43, 124.02, 112.34, 108.24. The data matches literature.3

4-(ferrocenyl)benzaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and ferrocenyllithium prepared via literature procedure. The product was obtained as a bright red 1 solid after column chromatography (SiO2) using Pentane/EtOAc (0-5 %) (15 mg, 10%) H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 4.74 (s, 2H), 4.43 (s, 2H), 4.05 (s, 5H). 13C NMR (101 MHz, Chloroform-d) δ 191.82, 147.46, 134.14, 130.10, 126.25, 82.95, 70.31, 70.06, 67.21. HRMS Measured : 291.04640, Calculated [M+H]: 291.04723

4-methylbenzaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and methyllithium on a 1 mmol scale. The product was obtained after column chromatography (SiO2) using Pentane/EtOAc (0-5 %) (58 mg, 49%) 1H NMR (400 MHz, Chloroform-d) δ 9.96 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 194.62, 148.18, 136.86, 132.49, 132.35, 24.53. The data is consistent with the commercially available product.

4-ethylbenzaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and ethyllithium. The product was obtained after column chromatography (SiO2) using Pentane/EtOAc (0- 5 %) (41 mg, 61%) 1H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 194.66, 154.33, 137.06, 132.61, 131.18, 31.81, 17.78. The data is consistent with the commercially available product.

4-((trimethylsilyl)methyl)benzaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and trimethylsilyl-methyllithium. The product was obtained as a white solid after 1 column chromatography (SiO2) using Pentane/EtOAc (0-5%)( 56 mg, 58%) H NMR (400 MHz, Chloroform-d) δ 9.93 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 2.21 (s, 2H), 0.01 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 194.50, 151.74, 135.63, 132.55, 131.06, 31.08. The data matches literature 4

4-((trimethylsilyl)methyl)benzaldehyde Synthesized according to the general procedure, using Weinreb amide 1 and cyclopropyllithium, which was prepared according to literature procedure.1 The product was obtained as a mixture with isobutyl-benzaldehyde after column chromatography

(SiO2) using Pentane/EtOAc (0-5 %) (NMR yield: 52%) HRMS Measured : 147.04037, Calculated [M+H]: 147.08044

6-methyl-2-naphthaldehyde Synthesized according to the general procedure, using Weinreb amide 1b and methyllithium. The product was obtained as a white solid after column chromatography 1 (SiO2) using Pentane/EtOAc (0-5 %) (54 mg, 63%) H NMR (400 MHz, Chloroform-d) δ 10.13 (s, 1H), 8.30 (s, 1H), 7.91 (t, J = 7.9 Hz, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.43 (d, J = 7.5 Hz, 1H), 2.56 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 194.88, 142.14, 139.40, 137.00, 136.14, 133.50, 132.01, 131.97, 131.04, 129.81, 125.58, 24.64. The data matches literature 7

1-(4-isobutylphenyl)ethan-1-ol Synthesized according to the general procedure, using 4- bromoacetophenone and tert-butyllithium. The product was obtained as a colorless liquid after 1 column chromatography (SiO2) using Pentane/EtOAc (5-15 %)(38 mg, 43%). H NMR (400 MHz, Chloroform-d) δ 7.28 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 4.87 (q, J = 6.5 Hz, 1H), 2.47 (d, J = 7.2 Hz, 2H), 1.92 – 1.78 (m, 2H), 1.49 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 143.05, 140.98, 129.21, 125.19, 70.28, 45.08, 30.24, 25.02, 22.38. The data matches literature 5

6-bromo-N-methoxy-N-methyl-2-naphthamide 1b Synthesized according to literature procedure, using the corresponding naphthylbenzoic acid.6 The product was obtained as a white solid after 1 column chromatography (SiO2) using Pentane/EtOAc (5-10 %). H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 8.03 (s, 1H), 7.83 – 7.71 (m, 3H), 7.60 (dd, J = 8.7, 1.8 Hz, 1H), 3.55 (s, 3H), 3.41 (s, 3H).

[11C]6-(methyl-11C)-2-naphthaldehyde To an oven dried, argon purged 4 mL vial containing 6-bromo-N-methoxy-N-methyl-2-naphthamide (58.8 mg, 0.2 mmol) in 0.5 mL of dry toluene was added dropwise at 0oC a solution of DIBAL-H (0.2 mL, 0.2 mmol, 1 M in cyclohexane) and the mixture was stirred at the same temperature for 1 h. The t mixture was allowed to warm to room temperature and a solution of fully pre-oxidized Pd(P Bu3)2 in toluene (0.5mL, 0.01 mmol) was added. In another oven dried, argon purged 4 mL vial containing a solution of n-BuLi (0.12 mL, 0.20 mmol, 1.6 M in hexanes) in 0.87 mL of dry toluene was bubbled [11C]MeI for 4 min. This solution was then taken up into a syringe and added at room temperature over 2 min using a syringe pump into the reaction mixture containing the catalyst. After an additional 2 min of stirring, the reaction was quenched by addition of 1 mL of an aq. 1 M HCl solution. A sample was taken from the organic phase and the solvent evaporated at 60oC under argon flow. The residue was dissolved in 1 mL of eluent (MeCN/H2O : 65/35 with 0.1% formic acid) and purified by HPLC

(column: Phenomenex Luna 5µ C18(2) 100 Å 250x10mm ; eluent : MeCN/H2O : 65/35 with 0.1% formic acid ; flow : 5 mL/min). The title product was collected (retention time : 7.5 ± 0.5 min, matching the unlabeled reference compound) in 23 ± 4 % Radiochemical yield decay-corrected from [11C]MeI (n= 3).

References

1) D. Heijnen J. Gualtierotti, V. Hornillos, and B. L. Feringa Chem. Eur. J. 2016, 22, 3991-3995 b) V.Hornillos, M. Giannerini, C. Vila, M, Fañanás-Mastral and B, L. Feringa Chem. Sci., 2015, 6, 1394-1398

2) M. Baghbanzadeh, C. Pilger, and C. O. Kappe J. Org. Chem. 2011, 76, 8138–8142

3) N. A. Bumagin, I. S. Veselov , and D. S. Belov, Chem. Heterocycl. Compd., Vol. 50, No. 1, 2014

4) A. Nagaki, Y. Tsuchihashi, S.Haraki and J. Yoshida. Org. Biomol. Chem., 2015, 13, 7140–7145

5) H. Song, W. Ding, Q. Zhou, J. Liu, L. Lu, and W. Xiao J. Org. Chem., 2016, 81 (16), pp 7250–7255

6) Chinese Academy Of Sciences Shanghai Organic Chemistry Institute; Z.; G. Shoulai; S. Xiaojia; X. Jingjing; S. Jian - CN107286150, 2017

7) L. K. Sydnes, I. C. Burkow and S. H. Hansen Tetrahedron Vol 41, 1985 No. 23, pp. 5703 5706.

4.4 Conclusions and outlook In the search for synthetic procedures that produce less waste by combining 2 or more steps in a one-pot fashion, we have successfully combined the use of organolithium reagents as (cross coupling) nucleophile to afford (alpha substituted) ketones, anilines or aldehydes. Starting from easily accessible and robust (Weinreb-) amides, the tetrahedral intermediate that is formed after the addition of a nucleophile can either release a lithium amide (to be used as base, or coupling partner (4.2)) in the synthesis of substituted ketones or anilines, or provide a stable, masked carbonyl compound that successfully undergoes a series of cross coupling reactions (4.3). The addition of extra base for the alpha-arylation or C-N coupling is redundant, and the method thus provides an atom efficient alternative to existing (2 step-) procedures. With the currently published one pot strategies, and those that are being developed at the moment, the key tetrahedral intermediate has been used for a range of transformations and protections. Research into the expansion of functional group tolerance and the application in natural product synthesis or the construction of biologically active compounds can be used to further establish these methods as viable alternatives to current strategies.

Chapter 5 : Synthesis of chiral catalysts for palladium catalyzed organolithium cross coupling reactions.

Attempts towards enantioselective synthesis using NHC-Pd complexes and organolithium reagents are described in this chapter. The synthesis of chiral Pd-PEPPSI derivatives that fit the requirements for organolithium cross coupling reactions has proven challenging. Stereogenic centres were installed at the diamine backbone as well as at the flanking alkyl fragments but the complete synthesis of the Pd-complex was unsuccessful. The use of chiral catalysts for enantioselective synthesis of a biaryl moiety using organolithium reagents remains a potentially promising method due to the low reaction temperatures, generally high yields (in the achiral cross-coupling) and ease of the preparation of starting materials. 5..1 Introduction The chiral biaryl motif consists of two arenes, that are hindered in their rotation around the bond that connects them, due to 2 or more ortho-substituents (shown in figure 5.1).1a The construction of these compounds is relatively straightforward, and the products find use in a wide variety of applications, such as ligands, pharmaceuticals and chiral recognition or asymmetric transformation. It is therefore that the enantioselective synthesis of these atropoisomeric molecules has received a vast amount of attention in the past decades.1b-h It is the size and number of the substituents that determine the barrier and speed of rotation, which is by itself temperature dependent. Though structures such as the one shown in figure 5.1 are always chiral, they are only called atropoisomers if their half-life for rotary isomerization is above 1000 seconds at a given temperature.1i Strategies that generate atropoisomers include the asymmetric reduction of a lactone, followed by ring opening, yielding the corresponding chiral phenol, as well as methods that construct the second half of the biaryl by means of an annulation.1 The formation of the biaryl by the generation of the chiral axis can be performed by means of a chiral auxiliary attached to one of the coupling partners, generating a stoichiometric amount of waste, but can preferably also be achieved by means of chiral catalysts.2

Figure 5.1 Different approaches to atroposelective biaryl formation.

The bulky but achiral Pd-PEPPSI complex (scheme 5.1) has shown to be particularly active in the cross-coupling of hindered aryl halides and organolithium reagents.3 The large but flexible alkyl groups are hypothesised to facilitate a faster reductive elimination,4a and even larger substituents at the aryl ring have shown to improve similar cross-coupling reactions.4b With the commercially available Pd-PEPPSI-Ipent, conversion with alkyllithium reagents was observed at temperatures as low as -60 °C, unlike other ligands (such as phosphines and other NHC ligands) that were only active at or close to room temperature.5 This activity at low temperatures greatly enhances the possibility to design a catalytic system that is able to yield an enantio-(atropo-)selective reaction. The PEPPSI core (scheme 5.1) allows for functionalization in either the backbone (blue) or the flanking alkyl groups (red). The transformation shown below the PEPPSI structures, are organolithium based cross coupling reactions that have previously yielded the corresponding (racemic) products in high yields when these achiral catalyst were employed.

Scheme 5.1 Pd-PEPPSI catalyst complexes and examples of potential enantio(-atropo)-selective coupling.

5.2 Initial testing Based on several preliminary experiments, the application of the above mentioned N-heterocyclic carbene complexes (scheme 5.1) appears crucial for catalytic turnover in the cross coupling with organolithium reagents. Some of the key features that make the complex suitable for this transformations are:

1) A direct nitrogen-aryl coupled motif on the imidazolium/imidazolinium ring (figure 5.2)

2) Bulky alkyl groups on the flanking aryl substituents for hindered substrates and conversion at low temperature

3) Ex situ generation of the metal-carbene complexes. Figure 5.2 Structures of Pd-PEPPSI-complex

Attempts to deviate from any of the structural features of this ligand led to inactive systems, or very low turnover numbers in our model reactions with 1-bromonaphthalene and phenyllithium (Scheme 5.2 top). The in situ formation of NHC-metal complexes by means of deprotonation of the corresponding imidazolium salts with organolithium reagents has shown feasible in allylic substitution reactions,6 but screening with commercial PEPPSI-SIpr (Scheme 5.1) and its imidazolinium salt precursor only showed catalytic turnover for the preformed complex. Attempts with saturated imidazolinium based complexes 4-6 showed modest to good (50-80%, Scheme 2) conversion for unhindered substrates (3a, 3b), but were unable to yield more hindered cross-coupled products such as 3c and 3d. Pd-PEPPSI complex 7 derived from an IPr-BOX ligand was synthesized,7 but it showed a reactivity similar to that of the complexes 4-6.

Scheme 5.2 attempted Pd-PEPPSI-complexes

5.3 Design of potential chiral ligands for atroposelective coupling.

5.3.1 Chiral backbone With the initial testing of the Pd-NHC structures performed, a strategy for the synthesis of a suitable chiral Pd-NHC complex could be made. Since the ortho-substituted phenyl rings appear to be crucial for (chiral) product formation, a combination of bulky isopentyl (or isoheptyl) groups, and a chiral imidazolinium ring could provide a suitable structural motif. The coupling of these chiral diamine complexes with phenyl, mono substituted or mesityl halides is well described,8 but at the time of this research, no method for the Buchwald-Hartwig coupling of very hindered (di-ortho-isopropyl or larger) substrates had been reported. Our attempts at the formation of this crucial C-N bond are presented in Table 5.1. The commonly used combination of Pd2dba3 and racemic BINAP did not yield any of the desired product, with either the sterically hindered aryl bromide or iodide (entry 1, 3, 5). Only under more forcing conditions, a small amount of the desired product could be observed (entry 6). Alternatively, Pd-PEPPSI-IpentCl was also employed in the attempted coupling of aryl iodides and bromides (entry 2 and 4) without any success. In order to test the quality of the reagents and reaction setup, mesitylbromide was coupled in presence of Pd2dba3 and racemic BINAP, which gave 81% isolated yield of the desired compound.

Table 5.1 Buchwald Hartwig coupling with chiral diamines

Entry Catalyst Arylhalide Result

1 2 1 Pd2dba3/BINAP R =R = Ipr X =Br s.m. 2 Pd-PEPPSI-IPentCl R1=R2= Ipr X =Br s.m.2

1 2 3 Pd2dba3/BINAP R =R = IPent X =I s.m. 4 Pd-PEPPSI-IPentCl R1=R2= IPent X =I s.m.

1 2 5 Pd2dba3/BINAP R =R = IPent X =Br s.m.

1 3 2 2 6 Pd2dba3/BINAP R =R =Me, R =IPent X = I s.m.

1 2 3 7 Pd2dba3/BINAP R =R =R =Me X=Br 81% isolated yield 1Reaction conditions : Diamine (1 eq.), aryl bromide (2,5 eq.), catalyst (5%) and base (KOtBu) (3 eq.) suspended in toluene in a closed vial at 110°C. 2 Under more forcing conditions (140°C, 72 h) ~10% of product isolated.

The viability of the desired coupling of the above mentioned chiral diamine with sterically hindered aryl halides was proven by the group of Montgomery in 2017,9 using a tailor made imidazolium salt, harsh reaction conditions and prolonged reaction times. The reproduced synthesis of the imidazolinium salt, and consecutive Pd-complexation to afford Pd-PEPPSI-IPr* is shown in Scheme

5.3. The key Buchwald-Hartwig coupling was performed in trifluorotoluene, with Pd2dba3 and imidazolium salt IPrMe-Cl, yielding the corresponding dicoupled amine 9 in 52% isolated yield. Ring closure was achieved by means of triethylorthoformate in the presence of NH4BF4 and catalytic amount of formic acid, to yield the tetrafluoborate imidazolinium salt 10. Complexation with palladiumchloride could be performed from the BF4 salt, as well from the corresponding chloride, which was obtained after ion exchange.

Scheme 5.3 Synthesis of Pd-PEPPSI-IPr*9 With the successful synthesis of chiral imidazolium salts 10 and 10b, and the corresponding Pd complex Pd-PEPPSI-IPr*, the catalyst was applied in the coupling of the standard coupling partners, to yield the trisubstituted biaryl 3c in 47%10 (scheme 5.4). The coupling of phenyllithium was used to compare the activity of the catalyst in the coupling of unhindered substrates 3a, which gave a satisfactory 98% yield.10

Scheme 5.4 Synthesis of tri and tetra substituted biaryl motifs

Based on the sharp decline in yield when switching between constructing a mono (3a) or a trisubstituted (3c) biaryl, it was much to our surprise that the homocoupling of naphthalene 1c gave the binol derivative 3e in high yields. Chiral HPLC analysis, however, showed the product to be racemic. Since no chiral induction was observed, further investigations into the catalysts were not conducted.

5.3.2 Chiral flanking groups Since the large alkyl fragments have such a major influence on the conversion of hindered coupling substrates, their effect on the reductive elimination and the enantiodetermining step could not be ruled out. The synthesis of chiral alkyl fragments was therefore pursued simultaneously with the chiral diamine strategy shown above. Initially, the coupling of alkene fragments to the 2,6- dibromoaniline seemed like a viable synthetic route towards to precursor 12 that (upon asymmetric reduction) would give chiral aniline 13 (Scheme 5.5). This route was substituted by the previously reported direct diastereoselective coupling of menthyl derivatives by means of a Negishi coupling due to expected difficulties in the enantioselective reduction of the alkene fragment (methyl vs ethyl differentiation).11 Unfortunately, the double coupling of the menthyl-zinc-bromide complex yielded a mixture of starting material, mono and di-coupled product 14 which were inseparable via chromatography or crystallization. The mono coupling with xylene derivative 15, however, gave the desired product 16 in 60% yield.11

Scheme 5.5 Synthesis of chiral aniline derivatives

Having the chiral aniline 16 in hand, our goal was to synthesize an unsymmetric imidazolium salt (Scheme 5.6) as well as a symmetric variant (Scheme 5.7). Using a literature procedure,12 ring formation with oxazolinone 17 was expected to yield acetate intermediate 18, which upon elimination by means of thionylchloride would generate the corresponding perchlorate imidazolium salt 19. NMR analysis of the crude reaction mixture indeed showed the expected signal of the proton between the two nitrogen atoms around 10 ppm, as well as all the aliphatic and aromatic signals, but the product repeatedly degraded upon attempted purification using column chromatography.

Scheme 5.6 Attempted synthesis of mono-menthyl chiral imidazolium salts

Alternatively, the synthesis of a bis-menthyl imidazolium core was attempted by condensation of monomenthyl aniline 16 with glyoxal to yield bis-imine 20 which was subjected to ring closure using the reaction conditions shown in scheme 5.7. Though the triflate and chloride imidazolium salts 21 and 22 were detected in crude 1H-NMR analysis by means of their characteristic signals around 10 ppm, the products were found to be unstable during the purification step, much like perchlorate imidazolium salt 19.

Scheme 5.7 Attempted synthesis of bis-menthyl chiral imidazolium salts

5.4 Conclusions and outlook The synthesis of chiral derivatives of the bulky Pd-PEPPSI-family that match with the requirements for organolithium cross couplings has proven very challenging. Related Pd-carbene catalysts that lacked crucial steric hindrance were successfully prepared, and gave significant turnover in the coupling of less challenging substrate, but lacked reactivity in the desired synthesis of tri and tetra- ortho substituted biaryl compounds. Despite several synthetic approaches, the envisioned catalyst containing both large flexible side groups as well as a chiral imidazolinium backbone was only obtained for the IPr variant by the use of a recently reported procedure.9 Initial testing of the catalyst showed similar activity to the other Pd-carbene catalysts that were capable of coupling unhindered substrates, but failed to sufficiently provide turnover for sterically demanding starting materials. Switching the coupling procedure to the in situ preparation of the aryllithium reagent, the product was obtained in good yield, but without e.e. It is therefore that the enantioselective coupling using organolithium reagents was not further pursued. Since the chiral backbone seems to have little effect on the enantiodetermining step, future attempts might focus on the initially abandoned synthesis of chiral alkyl fragments such as in compound 13 via asymmetric reduction, in which the synthesis of the complex could be more successful than the menthyl derived catalysts.

5.5 References

1) a) Introduction to Stereochemistry, K.Mislow, 1965, W. A. Benjamin, Inc, 193, Stereochemistry and Stereoselective Synthesis: An Introduction, M. Nógrádi, L. Poppe, J. Nagy, G. Hornyánszky, Z. Boro, 2016, Wiley VCH, ISBN: 978-3-527-33901-3. b) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J. Garner, M. Breuning; Angew. Chem. Int. Ed. 2005, 44, 5384. c) K. Kamikawa, M. Uemura, Synlett 2000, 938. d) O. Baudoin; Eur. J. Org. Chem. 2005, 4223-4229. e) G. Bringmann, T. Gulder, T.A.M. Gulder; Asymmetric Synthesis 2007, 246. f) A. H. Cherney, N. T. Kadunce, and S. E. Reisman. Chem. Rev., 2015, 115 (17), pp 9587–9652. g) C. Zhao, D. Guo, K.Munkerup, K. Huang, F. Li & J. Wang. Nature Communications, 2018, 9, 611 doi:10.1038/s41467-018-02952-3. h) G. Bringmann, D. Menche, J. Kraus, J.Mühlbacher, K. Peters, E.Peters, R.Brun, M. Bezabih, B. M. Abegaz. J. Org. Chem., 2002, 67 (16), pp 5595–5610. i) Ōki, Michinori, Recent Advances in Atropisomerism, in Topics in Stereochemistry, Vol. 14 Hoboken, NJ:John Wiley & Sons, 2007, DOI: 10.1002/9780470147238.ch1 2) a) J. Malineni, R. L. Jezorek, N. Zhang, V. Percec, Synthesis, 2016, 48, 2795-2807.b) S. K. Gurung, S. Thapa, A. Kafle, D. A. Dickie, R. Giri, Org. Lett., 2014, 16, 1264-1267. c) T. Hatakeyama, M. Nakamura, J. Am. Chem. Soc., 2007, 129, 9844-9845 3) V. Hornillos, M. Giannerini, C. Vila, M. Fañanás-Mastral, B. L. Feringa, Org. Lett., 2013, 15, 5114- 5117. This thesis 4) a) M. G. Organ, s. Calimsiz, M.Sayah, K. Hou Hoi, A. J. Lough, Angew. Chem. Int. Ed. 2009, 48, 2383 –2387 b) B. Atwater, N. Chandrasoma, D. Mitchell, M.J. Rodriguez, M. G. Organ Chem. Eur. J. 2016, 22, 4531, 4534 and references therein

5) Unpublished results 6) S. Guduguntla, V. Hornillos, R. Tessier, M. Fananas-Mastral, and B. L. Feringa. Org. Lett. 2016, 18, 252−255

7) D.l Janssen-Muller, C. Schlepphorst, F.Glorius. Chem. Soc. Rev., 2017, 46, 4845—4854, b) F. Glorius, G. Altenhoff, R. Goddarda C. Lehmanna Chem. Commun., 2002,0, 2704-2705 8) For example : Charles, M. D., Schultz, P. & Buchwald, S. L. Org. Lett. 7, 2005, 3965–3968. 9) H.Wang, G. Lu, G. J. Sormunen, H. A. Malik, P. Liu, J.Montgomery. J. Am. Chem. Soc, 139, 2017 10) As determined by GCMS analysis 11) Zhai, Feng; Jordan, Richard F. - Organometallics, 2017, vol. 36, # 15, p. 2784 - 2799 12) G. A. Price, A. Hassan, N. Chandrasoma, A. R. Bogdan, S. W. Djuric, M. G. Organ, Angew. Chem. Int. Ed. 2017, 56, 13347 –13350

5.6 Experimental section All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. THF and toluene were dried and distilled over sodium. Chromatography: Grace Reveleris X2 flash chromatography system used with Grace® Flash Cartridges, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and phosphomolybdic Acid (PMA) or potassium permanganate staining. Progress and conversion were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent 1 13 resonance as the internal standard (CHCl3:  7.26 for H,  77.0 for C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration.

Pd-PEPPSi-IPr* was synthesised using the corresponding imidazolinium salt (made via a literature 9 procedure) by mixing with Cs2CO3 (5.0 eq.) and PdCl2 (1.1 eq.) in 3-Cl-pyridine overnight. All liquids were removed under reduced pressure, the product crashed out by the addition of pentane, and isolated by filtration as a yellow solid. (74%) 1H NMR (400 MHz, Chloroform-d) δ 8.72 (d, J = 2.3 Hz, 1H), 8.63 (dd, J = 5.6, 1.4 Hz, 1H), 7.54 (ddd, J = 8.2, 2.4, 1.3 Hz, 1H), 7.27 (d, J = 1.5 Hz, 11H), 7.10 – 7.07 (m, 1H), 7.05 (d, J = 2.2 Hz, 2H), 6.89 (d, J = 2.2 Hz, 2H), 3.62 (dhept, J = 19.8, 6.6 Hz, 4H), 2.85 (p, J = 6.9 Hz, 2H), 1.63 (dd, J = 10.8, 6.4 Hz, 12H), 1.49 (d, J = 6.7 Hz, 6H), 1.22 (dd, J = 6.9, 1.1 Hz, 13H), 0.37 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 153.01, 151.90, 151.29, 150.73, 148.69, 140.65, 139.96, 134.73, 134.63, 131.57, 131.42, 130.95, 127.07, 125.59, 125.29, 77.59, 36.37, 32.21, 31.13, 30.85, 29.10, 28.11, 27.15, 26.51, 26.40.

Pd-PEPPSI-IBox 7. was synthesised using the corresponding imidazolinium salt (170 mg, 1 eq) (made 7b via a literature procedure) by mixing with Cs2CO3 (5.0 eq.) and PdCl2 (1.1 eq.) in 3-Cl-pyridine overnight (4 ml). All liquids were removed under reduced pressure, the product crashed out by the addition of pentane, and isolated by filtration as a yellow solid. (65 mg, 17%) 1H NMR (400 MHz, Chloroform-d) δ 8.98 (d, J = 2.4 Hz, 1H), 8.89 (d, J = 5.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.36 – 7.27 (m, 1H), 4.94 – 4.82 (m, 4H), 4.72 (dd, J = 8.1, 3.5 Hz, 2H), 3.25 (pd, J = 7.2, 3.9 Hz, 2H), 1.12 (dd, J = 10.3, 6.9 Hz, 12H). 13C NMR (101 MHz, Chloroform-d) δ 150.34, 149.30, 143.99, 138.01, 127.08, 124.82, 109.99, 61.79, 31.20, 18.63, 15.71.

1-phenylnaphthalene 3a was synthesised using the general procedure described in chapter 2 : 1- Bromonaphthalene (0.3 mmol) and Pd-PEPPSI-IPr* complex (5 mol %) were dissolved in toluene (2 ml) in a dried Schlenk flask under inert atmosphere, and the mixture stirred for 5 min. Subsequently, a solution of Ph-Li in dibutylether (0.45 mmol, 1.5 eq.) diluted to 1 ml (to reach a final concentration of 0.45 M) with toluene was added over 1h by the use of a syringe pump. After complete addition, MeOH (1ml) was added to quench the remaining Ph-Li. A sample was taken, and analyzed by GC-MS, showing the desired product in 98% yield.

1-(2,6-dimethoxyphenyl)naphthalene 3c was synthesized using the general procedure described in chapter 2 : 1-Bromonaphthalene (0.3 mmol) and Pd-PEPPSI-IPr* complex (5 mol %) were dissolved in toluene (2 ml) in a dried Schlenk flask under inert atmosphere, and the mixture stirred for 5 min. Subsequently, a solution of aryllithium (see chapter 6) in THF (0.45 mmol, 1.5 eq.) diluted to 1 ml (to reach a final concentration of 0.45 M) with toluene was added over 1h by the use of a syringe pump. After complete addition, MeOH (1ml) was added to quench the remaining aryl-Li. A sample was analyzed by GC-MS.

2,2'-dimethoxy-1,1'-binaphthalene 3e was synthesized using the general procedure described in chapter 3 : In a dry Schlenk flask, Pd-PEPPSI-iPr* (5 mol%) and 1-bromo-2-methoxynaphthalene (0.3 mmol) were dissolved in 2 mL of dry toluene and the solution was stirred at room temperature. tBuLi (0.7 eq., 0.21 mmol, 0.12 mL of 1.7 M commercial solution) was diluted with toluene to reach the concentration of 0.21 M; this solution was slowly added (flow rate=1 mL/h) by the use of a syringe pump. After complete addition, MeOH (1ml) was added to quench the remaining tBuLi. A sample was taken, and analyzed by GC-MS as wel as chiral HPLC (OJ-H, 95:5 heptane/isopropanol, 0.5 ml/min). No e.e. was observed.

Typical procedures for C-N coupling with sterically hindered arylbromides

t A mixture of Pd2dba3 (5%) , Binap (10%) (or instead, Pd-PEPPSI-IPENT (5%)) and NaO Bu 3.4 eq. was prepared in a glovebox (argon). Toluene was added, and the reaction mixture was stirred for 30 min at rt. A solution of chiral diamine in toluene and arylhalide in toluene were added slowly, and the reaction stirred at 105°C for 18h. The reaction was checked for conversion by TLC and 1H NMR. Generally, only starting material was isolated (see table 5.1).

Preparation of menthyl-bisimine 20

Menthyl dimethyl aniline 16 (480 mg, 1.8 mmol, 2 eq. made according to literature procedure)1 was dissolved in EtOH (2ml) . Glyoxal (110 mg, 1.26 mmol, 1.4 eq.) and formic acid (4 drops) were added, and the reaction mixture was stirred overnight. Filtration and trituration with cold MeOH gave the crude product as a yellow solid (277 mg), which was used without further puricifation.

General methods for attempted syntheses of imidazolium salts.

Bisimine 20 was dissolved in THF at 70°C, the solution subsequently cooled down rt, and 1 eq. of ZnCl (1.1 eq) was added at rt. The reaction mixture was heated to 70°C for 5 min, and cooled down to rt, before adding paraformaldehyde (1.1 eq.). The mixture was reheated to 70°C, and cooled down to rt before adding a solution of HCL in dioxane (1,5 eq.). The mixture was then heated to 60°C for 18h. The expected signal at 10 ppm in the crude 1H-NMR suggested the formation of product, but the imidazolium salt degraded upon column chromatography.

Alternatively, Silver triflate (1.5 eq.) was weighed out in a microwave vial in a glovebox (Ar), capped and taken out. DCM was added to the capped vial, followed by the addition of a solution of bisimine 20 in DCM, and chloromethylpivalate (1.5 eq.). The reaction mixture was stirred overnight at 45 °C. Filtration and evaporation of the solvent gave the crude reaction mixture that showed the expected signal at 10 ppm in the crude 1H-NMR suggesting the formation of product. Similar to the imidazolium salt made via the procedure given above, the product degraded upon column chromatography with silica.

1 Zhai, Feng; Jordan, Richard F. - Organometallics, 2017, vol. 36, # 15, p. 2784 - 2799 Chapter 6 : Nickel-Catalyzed Cross-Coupling of Organolithium Reagents with (Hetero)Aryl Electrophiles

Nickel-catalyzed selective cross-coupling of aromatic electrophiles (bromides, chlorides, fluorides and methyl ethers) with organolithium reagents is described in this chapter. The use of a commercially available nickel N-heterocyclic carbene (NHC) complex allows the reaction with a variety of (hetero)aryllithium compounds, including those prepared via metal- halogen exchange or direct metallation, whereas a commercially available electron-rich nickel-bisphosphine complex also readily converts alkyllithium species into the corresponding coupled product. These reactions proceed rapidly (1h) under mild conditions (room temperature) while avoiding the undesired formation of reduced or homocoupled products.

Part of this chapter was published in : D. Heijnen J. Gualtierotti, V. Hornillos, and B. L. Feringa Chem. Eur. J. 2016, 22, 3991-3995 6.1 Introduction In the ongoing search for more efficient, environmentally benign and economically sustainable processes, current research in cross-coupling methodologies has shown a growing interest in the use of earth-abundant metal-based catalysts.[1] Although palladium is applied in the majority of these processes, catalytic systems based on iron, nickel, or cobalt have proven suitable alternatives in several cases. In particular, the use of nickel has witnessed a rapid growth owing to its low cost and unique properties.[2] Nickel undergoes oxidative addition more readily than palladium although reductive elimination is correspondingly more difficult.[2b,c] Ni0/NiII catalytic cycles are well known,[2c] but NiI and NiIII oxidation states[2d] can be also accessed, allowing for different modes of reactivity and for radical mechanisms to operate.

Scheme 6.1 Previous and current nickel and organolithium catalysis Nickel has been extensively used in cross-coupling of organoboron and organozinc reagents with organic halides (Scheme 6.1a).[3] For example, a highly efficient nickel-catalyzed method for the synthesis of heterobiaryls at low temperature described by the group of Hartwig highlights the potential of nickel in Suzuki-Miyaura reactions.[4] Since the early reports by Kumada and co-workers in 1972, Grignard reagents in combination with nickel are known to be effective in the cross-coupling with aryl halides,[5] and these organometallic reagents were also the first to be efficiently employed in reactions with the less reactive aromatic ethers.[6a-c] Various groups have further developed the use of Grignard reagents and other nucleophiles, including organozinc and organoboron compounds, in nickel-catalyzed cross-coupling with aryl[6d-f] and benzyl ethers[6g] (Scheme 6.1a). Additionally, nickel has also been found to activate very strong C-F bonds.[7] Thus, the coupling of aromatic fluorides with organometallic compounds has been reported, although activated fluoroarenes or polyfluorinated aromatic substrates are usually employed.[7c] Some of these reactions suffer from competing isomerization of the alkyl coupling partners.[7d] In sharp contrast, the direct use of organolithium reagents, among the most versatile and widely used reagents in organic synthesis,[8] in nickel-catalyzed cross-couplings reactions has been limited to the polymerization of lithiated (hetero)arenes,[9a,b] the coupling of (trimethylsilyl)methyllithium with aromatic ethers (Scheme 6.1b),[9c,d] and the homo-coupling of arylbromides.[9e] Despite these important advances, a general method for the nickel- catalyzed cross-coupling of alkyl and (hetero)aryllithium reagents with aryl(pseudo)halides remains elusive. Organolithium compounds[8] are commercially available or readily accessible by lithium- halogen exchange and they are often employed as precursors for other organometallic compounds (Mg, B, Zn, Sn) used in cross-coupling reactions. Their direct use drastically reduces the amount of byproducts with the light lithium halide being the only stoichiometric reaction waste. Our group recently described the direct use of these reagents in palladium- catalyzed cross-coupling under mild conditions of a wide variety of organic bromides,[10] chlorides,[11] and triflates,[12] providing high yields and selectivities (Scheme 6.1c).[13] Considering the advantages associated with the use of nickel-based catalytic systems, the development of a general nickel-catalyzed cross-coupling with easily accessible organolithium reagents will provide a highly desirable alternative to existing methodologies. Moreover, since the palladium-catalyzed methods with these reagents are based on the use of aryl bromides, chlorides, and triflates, we were interested in exploring the coupling of less reactive fluorides and aromatic ethers, the latter being obtained from a pool of starting materials entirely distinct from aryl halides. Herein, we report that the use of a commercially available nickel N-heterocyclic carbene (NHC) or bisphosphine complex allows for the selective cross-coupling of organolithium compounds with aryl bromides, chlorides, fluorides, and methyl ethers in high selectivity under mild conditions (RT) and within short reaction times (1h; Scheme 6.1d).

6.2 Optimization and scope In preliminary studies, we focused on reactions between either nBuLi or PhLi and 1- chloronaphthalene (1a) in toluene at rt (Table 6.1) Surprisingly, the use of [Ni(cod)2] (cod=1,5-cyclooctadiene) which has previously been shown to be effective for the cross- coupling of (trimethylsilyl)methyllithium with aryl ethers,[9c,d] gave no conversion into the desired products 2a or 3a. ( entries 1a,b). Adding a phosphine ligand such as 1,2- bis(diphenylphosphino)ethane (dppe) to the nickel catalyst gave the same disappointing result for nBuLi (entry 2a) and 51% conversion, along with dehalogenated side product 4a, for PhLi (entry 2b).

Table 6.1 Reaction Optimization with nickel catalysts

2a/3a: Entrya R Catalyst Conv. (%)b 4a:5ab

1a n-Bu 2 - Ni(COD)2 1b Ph 0 -

2a n-Bu 3 - Ni(COD)2/dppe 2b Ph 51 53:47:0

3a n-Bu 5 - NiCl2(DME) 3b Ph 39 85:15:0

4a n-Bu 40 42:40:18 NiCl2(PPh3)2 4b Ph 30 90:10:0

5a n-Bu 68 25:60:15 NiCl2(PCy3)2 5b Ph >99 68:30:2

6a n-Bu 69 15:46:23 NiCl2(DME)/Xphos 6b Ph 33 67:33:0 7a n-Bu >99 93::7:0 NiCl2(dppe) 7b Ph 86 73:25:2

8a n-Bu 85 52:35:8 NiCl2(dppf) 8b Ph 92 79:15:6

9a n-Bu >99 94:6:0 C1 9b Ph >99 95:1:4

10a n-Bu 36 11:89:0 C2 10b Ph 98 58:42:0

11a n-Bu 72 57:43:0

11b >99 >99:0:0

11cc C3 >99 >99:0:0 Ph 11dd >99 >99:0:0 (98% yield)

11ee 30 >99:0:0

12 n-Bu Pd-Peppsi-Ipent >99 86:14:0

[a] Conditions: n-Butyllithium (0.45 mmol, 1,6 M in hexanes diluted with toluene to a final concentration of 0.45 M) or phenyllithium (0.45 mmol, 1.8 M solution in dibutyl ether diluted with toluene to a final concentration of 0.5 M) was added to a solution of 2-chloronaphthalene (0.3 mmol) in toluene (1,5 mL) over 1 h. [b] Conversion and 2a/3a:4:5: ratios determined by GC analysis. [c] Using 0.5 mol% of catalyst. [d] 10 mmol (1.63 g) scale reaction using 1.5 mol% of catalyst. [e] using 0.25 mol% of catalyst.

Considering these results and the fact that [Ni(cod)2] requires rigorous air-free conditions, hampering both large-scale applications and optimization efforts, we turned our attention to nickel(II) catalysts. Low to moderate conversions and selectivities were observed when

[NiCl2(dme)] (dme=dimethoxyethane) or [NiCl2(PPh3)2] were used (entries 3a-4b). Using [14] [15] more electron rich and bulky phosphines (PCy3 or XPhos ) resulted in higher conversion, but the selectivity for 2a or 3a remained unsatisfactory (entries 5a-6b). Subsequently, we investigated the effect of common bidentate phosphines, which have been reported to impart high activity in related nickel-catalyzed cross-coupling reactions with other organometallics. [16] 4] The use of [NiCl2(dppe)] and [NiCl2(dppf)] (dppf=1,1'-bis(diphenylphosphino)ferrocene) resulted in even higher conversions but dehalogenation remained substantial (entries 7a-8b). Encouraged by these results, we studied variations in the ligand structure and we found that the use of commercial nickel complex [NiCl2(depe)] (C1; depe=bis(diethylphosphino)ethane17] bearing a bidentate alkylphosphine, led to full conversion in the reaction with both nBuLi and PhLi with excellent selectivity toward the cross-coupled products 2a or 3a (entries 9a,b). The nitrogen-based tridentate ligand C2 (entries 10a,b)[18] was not efficient for this transformation. Remarkably, the use of Pd- PEPPSI-IPent (entry 12), as well as other palladium-based catalysts (not shown) in the reaction of nBuLi gave rise to lower selectivity than that observed with the nickel catalyst C1. We then explored the effectiveness of catalyst C1 with respect to a less reactive non-π- extended aryl chloride, such as 1-butyl-4-chlorobenzene 1b (Scheme 6.2), but incomplete conversion was observed in the case of PhLi, alongside a large amount of n-butylbenzene 4b. As neither elevated nor lower temperatures improved this result, further screening of nickel catalysts was carried out. We found that the use of commercially available nickel(II) complex [9a] [NiCl2(PPh3)IPrC3, bearing a N-heterocyclic carbene, was key to restoring the conversion (87 % yield of isolated product) and selectivity (98:2) toward 2b. Catalyst C3 also gave full conversion with high selectivity in the reaction of 1a with PhLi (Table 1, entry 11b), allowing a decrease in the catalyst loading to 0.5 mol % (entry 11c). Moreover, when this reaction was performed on a larger scale (10 mmol, 1.63g) in the presence of 1.5 mol % of catalyst C3, 2a was still obtained as the exclusive product in excellent yield (98% isolated product). The use of C3 in the reaction of 1a with nBuLi afforded the desired compound 3a, albeit with decreased conversion and selectivity compared to C1 (Table 6.1, entry 11a). With two optimized catalyst systems (C3 for (hetero)aryllithium and C1 for alkyllithium, respectively) we examined the generality of this reaction. A broad range of aryl bromides, chlorides, fluorides, and methoxyarenes could be coupled with PhLi, using C3 as catalyst (Scheme 6.2). Polyaromatic compounds showed high reactivity and could be transformed into the coupled products in good to high yields with excellent selectivity (2a, 2c-e). Substrates containing two aromatic groups could also be transformed selectively (2f, X=Br, and 2g, X=Br, F).

Scheme 6.2. Nickel-catalyzed cross-coupling of phenyllithium with (hetero)aryl (pseudo)halides. [a] Conditions: Phenyllithium (0.75 mmol, 1.8 M solution in dibutyl ether diluted with toluene to a final concentration of 0.6 M) was added to a solution of organic (pseudo)halide (0.5 mmol) in toluene (1.5 mL) over 1 h. Isolated yields after column chromatography. [b] Reaction performed at 0 °C.

It is important to note that high reactivity was also found for simple phenyl halides or methyl ethers, regardless of the electronic nature or the leaving group employed (2i-o). As shown for 2g, 2j, and 2k, the presence of an ortho substituent did not significantly hamper the cross- coupling. A substrate containing an olefin (1h) was also readily converted into the corresponding product 2h with high selectivity (Scheme 2). Trifluoromethylated compounds, which are very important in the agrochemical and pharmaceutical industries,[19] were also suitable substrates, furnishing the corresponding products 2l and 2m in moderate to good yield. As expected, C-Br and C-Cl bonds are more reactive than a C-O bond, allowing the selective coupling of 4-bromo- or 4-chloroanisole at 0°C, leaving the methoxy group untouched (2n). Only dehalogenation was observed in the reaction of 3-bromo-N,N- dimethylaniline 1o with PhLi. However, the corresponding chloride provided biaryl 2o in 45 % yield. A sulfur-containing heterocycle was also coupled, affording compound 2p with high selectivity. We next examined the compatibility of our catalytic system with the most efficient procedures to access (hetero)aryllithium species, which include direct metalation[20] and halogen--lithium exchange[8] (Scheme 6.3). Hindered bis-ortho-substituted (2,6-dimethoxyphenyl)lithium, prepared by directed lithiation, undergoes cross-coupling with 1-chloronaphthalene and electron-rich 4-bromoanisole providing biaryls 2q and 2r, without the need to increase the temperature or reaction time. Moreover a methoxymethyl (MOM) protecting group could be tolerated at the ortho position of the organolithium reagent, allowing for an easy ortho- lithiation/cross-coupling sequence to afford the corresponding MOM-protected phenol (2s, 2t). Furyllithium, obtained by direct lithiation of furan, smoothly couples to provide compounds 2u-w with good yields and high selectivities. Organolithium compounds, obtained through halogen-lithium exchange, could also be used as exemplified in the preparation of 2x and 2z.

Scheme 6.3. Nickel-catalyzed cross-coupling of (hetero)aryllithium reagents with aryl halides. Conditions: Aryl- Li (0.75 mmol, diluted with toluene to reach 0.45 M concentration) was added to a solution of organic halide (0.5 mmol) in toluene (1.5 mL) over 1 h. Selectivity 2 vs dehalogenated + homocoupled >90%. Isolated yields after column chromatography. Importantly, commercially available 2-thienyllithium, which, according to our previous study,[10a] requires the addition of stoichiometric amounts of tetramethylethylenediamine (TMEDA) as activating agent and elevated temperatures, reacted with 1-chloro- and 1- bromonaphthalene at room temperature without the use of any additive (2y). With an efficient procedure for aryl-aryl cross-coupling in hand, we turned our attention to the use of alkyllithium compounds , applying catalyst C1 (Table 6.2).[21] A range of polyaromatic chlorides and fluorides were regioselectively alkylated at position 1 or 2, indicating that benzyne intermediates, formed through 1,2-elimination, are not involved.

Table 6.2. Nickel-catalyzed cross-coupling of alkyllithium compounds

Entrya Aryl halide Alkyllithium Yield (%)b

1 (3a) EtLi 65

2 (3b) n-BuLi 78 1-chloronaphthalene 3 (3c) n-HexLi 87

4 (3d) iPrLic 63

5 (3e) EtLi 67 2-chloroanthracene 6 (3f) n-HexLi 39

7 (3g) EtLi 94

8 (3h) n-BuLi 84

9 (3i) 1-chloroanthracene n-HexLi 85

10 (3j) iPrLic 44

11 (3k) CycloPrLi 66

12 (3b) n-BuLi 76

13 (3a) 1-fluoronaphthalene EtLi 66

14 (3d) iPrLi 63

[a] Conditions: AlkylLi (0.45 mmol, diluted with Toluene to reach 0.45 M concentration) was added to a solution of organic halide (0.3 mmol) in toluene (2 mL) over 1 h. GC selectivity >95%. [b] Isolated yields after column chromatography. [c] GC selectivity > 80%.

No isomerization of the alkyl moiety and less than 5% of reduced product were observed when primary alkyllithium reagents were employed, demonstrating that competing β-hydride elimination/dissociation was almost completely inhibited. Importantly, the use of EtLi, which was unreactive in our previous palladium-based systems, afforded the corresponding products (3a, 3e, 3g) in good yields and nearly perfect selectivity. These results highlight how alternative metals such as nickel, besides being inexpensive, can also display complementary reactivity to palladium. The reaction using iPrLi, which contains an increased number of β- hydrogen atoms, proceeds without isomerization, although a minor amount of the reduced product was formed (entries 4 and 14).[22] Cyclopropyllithium,[23] prepared from cyclopropyl bromide and lithium metal, also provided the coupled product with high selectivity without any ring-opened side products (entry 11).[24]

6.3 Conclusions In summary, we have described for the first time how a range of (hetero)aryl and alkyllithium compounds can be employed in cross-coupling reactions with aryl bromides, chlorides, fluorides, and aromatic ethers, by using nickel as catalyst. The reaction takes place under mild conditions (RT) with a broad scope of organolithium compounds and substrates, enabling transformations that were proven difficult with palladium catalysts, such as the cross-coupling of alkyllithium reagents bearing β-hydrogen with aryl chlorides and the use of EtLi as a coupling partner. The low cost and availability of both organolithium reagents and nickel catalysts, together with the selectivity of the novel method presented herein, make it a valuable alternative with lower environmental impact for atom-economic formation of C-C bonds

6.4 References [1] a) B. Su, Z.-C. Cao, Z.-J. Shi, Acc. Chem. Res. 2015, 48, 886; b) A. A. Toutov, W.-B. Liu, K. N. Betz, A. Fedorov, B. M. Stoltz, R. H. Grubbs,. Nature 2015, 518, 80; c) L. L. Schafer, P. Mountford,; W. E. Piers, Dalton Trans. 2015, 44, 12027; d) Metal-Catalysed Cross-Coupling Reactions, 2nd ed., (Eds.: A. de Meijere and F. Diederich), Wiley-VCH: Weinheim, 2004. Transition Metals for Organic Synthesis, 2nd ed., (Eds.: M. Beller and C. Bolm), Wiley-VCH: Weinheim, 2004. [2] a) S. Z. Tasker, E. A. Standley T. F. Jamison, Nature 2014, 509, 299; b) Modern Organonickel Chemistry Ed. Y. Tamaru, (Wiley-VCH, Weinheim, 2005.; c) T. T. Tsou, J. K. Kochi,. J. Am. Chem. Soc. 1979 101, 6319; d) J. Cornella, E. Gómez-Bengoa, R. Martin, J. Am. Chem. Soc. 2013, 135, 1997. [3] For seminal reports using organoboron compounds see: a) S. Saito, M. Sakai, N. Miyaura, Tetrahedron Lett. 1996, 37, 2993; b) S. Saito, S. Oh-tani, N. Miyaura, J. Org. Chem. 1997, 62, 8024; For reviews see c) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270; d) J. Yamaguchi, K. Muto, K. Itami, Eur. J. Org. Chem. 2013, 19; e) V. B. Phapale, D. J. Cárdenas Chem. Soc. Rev., 2009, 38, 1598; For recent reports see f) X. Chen, H. Ke, G. Zou, ACS Catal. 2014, 4, 379.; g) S. Handa,; E. D. Slack,; B. H. Lipshutz, Angew. Chem. Int. Ed. 2015, 54, 11994. [4] S. Ge and J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 12837. [5] See for example: Y.-C. Xu, J. Zhang, H.-M. Sun, Q. Shen Y. Zhang, Dalton Trans. 2013, 42, 8437. [6] For seminal reports see: a) E. Wenkert, E. L. Michelotti, C. S. Swindell, J. Am. Chem. Soc. 1979, 101, 2246.; b) E. Wenkert, E. L. Michelotti, C. S. Swindell, M. Tingoli, J. Org. Chem. 1984, 49, 4894.; c) J. W. Dankwardt, Angew. Chem. Int. Ed. 2004, 43, 2428. For selected reviews see: d) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Resmerita, N. K. Garg, V. Percec, Chem. Rev. 2011, 111, 1346.; e) J. Cornella, C. Zarate, R. Martin, Chem. Soc. Rev., 2014, 43, 8081; f) M. Tobisu, N. Chatani, Acc. Chem. Res. 2015, 48, 1717; For nickel-catalyzed cross-coupling reactions of benzylic ethers and esters see: g) E. J. Tollefson, L. E. Hanna, E. R. Jarvo, Acc. Chem. Res. 2015, 48, 2344.

[7] a) For a recent example using B2nep2 as nucleophile see: X.-W. Liu, J. Echavarren, C. Zarate, Ruben Martin J. Am. Chem. Soc. 2015, 137, 12470.; b) F. Zhu, Z.-X. Wang J. Org. Chem. 2014, 79, 4285. and references cited therein.; c) A. D. Sun, K. Leung, A. D. Restivo, N. A. LaBerge, H. Takasaki, J. A. Love, Chem. Eur. J. 2014, 20, 3162.; d) H. Guo, F. Kong, K.-I. Kanno, J. He, K. Nakajima, T. Takahashi, Organometallics 2006, 25, 2045. [8] a) The Chemistry of Organolithium Compounds, Eds. Z. Rappoport, I. Marek, Wiley-VCH, Weinheim, 2004; b) Lithium Compounds in Organic Synthesis, Eds. R. Luisi, V. Capriati, Wiley-VCH, Weinheim, 2014. [9] a) K. Fuji, S. Tamba, K. Shono, A. Sugie, A. Mori, J. Am. Chem. Soc. 2013, 135, 12208.; b) S. B. Jhaveri, J. J. Peterson K. R. Carter, Macromolecules, 2008, 41, 8977; c) M. Leiendecker, C.-C. Hsiao, L. Guo, N. Alandini, M. Rueping, Angew. Chem. Int. Ed. 2014, 53, 12912.; d) L. Guo, M. Leiendecker, C.- C. Hsiao, C. Baumann, M. Rueping, Chem. Commun. 2015, 51, 1937.; e) S. B. Jhaveri, K. R. Carter, Chem. Eur. J. 2008, 14, 6845. [10] a) M. Giannerini, M. Fañanás-Mastral, B. L. Feringa, Nature Chem. 2013, 5, 667; b) M. Giannerini, V. Hornillos, C. Vila, M. Fañanás-Mastral, B. L. Feringa, Angew. Chem. Int. Ed. 2013, 52, 13329; c) C. Vila, M. Giannerini, V. Hornillos, M. Fañanás-Mastral, B. L. Feringa, Chem. Sci. 2014, 5, 1361; d) V. Hornillos, M. Giannerini, C. Vila, M. Fañanás-Mastral, B. L. Feringa, Chem. Sci. 2015, 6, 1394. [11] a) V. Hornillos, M. Giannerini, C. Vila, M. Fañanás-Mastral, B. L. Feringa, Org. Lett. 2013, 15, 5114; b) L. M. Castelló, V. Hornillos, M. Giannerini, C. Vila, M. Fañanás-Mastral, B. L. Feringa, Org. Lett. 2015, 17, 62. [12] C. Vila, V. Hornillos, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa, Chem. Eur. J., 2014, 20, 13078. [13] For highlights, see: a) V. Pace and R. Luisi, ChemCatChem, 2014, 6, 1516. b) V. Capriati, F. M. Perna A. Salomone, Dalton Trans. 2014, 43, 14204. [14] G. C. Fu, Acc. Chem. Res. 2008, 41, 1555. [15] R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008. 41, 1461. [16] a) B. M. Rosen, C. Huang,; V. Percec, Org. Lett. 2008, 10, 2597; b) N. V. Lukashev, G. V. Latyshev, P. A. Donez, G. A. Skryabin, I. P. Beletskaya, Synthesis 2006, 533. [17] E. L. Lanni, J. R. Locke, C. M. Gleave, A. J. McNeil, Macromolecules, 2011, 44, 5136. [18] J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2013, 114, 2432. [19] V. Snieckus, Chem. Rev. 1990, 90, 879. [20] R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417; (b) R. J. Lundgren, M. Stradiotto, Chem. Eur. J. 2012, 18, 9758. [21] B. Atwater, N. Chandrasoma, D. Mitchell, M. J. Rodriguez, M. Pompeo, R. D. J. Froese, M. G. Organ, Angew. Chem. Int. Ed. 2012, 51, 12837. [22] For a review on the relevance of arylcyclopropanes and their synthesis via cross-coupling see: A. Gagnon, M. Duplessis, L. Fader, Org. Prep. Proced. Int. 2010, 42, 1. [23] Full conversion was also obtained using aryl bromides although the presence of reduced starting material was also observed in the reaction mixture.

Acknowledgements This work described in this chapter was carried out together with Dr. Valentin Hornillos and Dr. Jean Baptiste Gualtierotti

6.5 Experimental section

A. General procedures:

Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and potassium permanganate staining. Conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 101 MHz, respectively) or a Varian VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. All reactions were carried out under nitrogen or argon atmosphere using oven dried glassware and using standard Schlenk techniques. Diethyl ether, tetrahydrofuran and toluene were used from the solvent purification system (MBRAUN SPS systems, MB-SPS-800). n-Hexane was dried and distilled over sodium. All starting aryl bromides, chlorides and fluorides as well as organolithium precursors were commercially available from Aldrich, Alfa-Aesar, Acros or TCI Europe, unless otherwise indicated. PhLi (1.8 M in n-Bu2O), n-BuLi (1.6 M in n-hexane), t-BuLi (1.7 M in pentane), EtLi (0.5 M in benzene:cyclohexane), n-HexLi (0.7 M in pentane), 2-Thienyllithium (1.0 M in THF/hexanes) and i-PrLi (2.3 M in hexane) were commercially available from Aldrich and were diluted to 0.45 M with dry toluene before use. Pd-Peppsi-i-Pent, all nickel catalysts, except C3, and ligands were commercially available from Aldrich. C3 was available from TCI Europe. All catalysts, ligands and reagents were used as received without further purification.

B. Preparation of organolithium reagents:

4-Methoxy-phenyllithium

In a dry Schlenk flask 4-bromoanisole (623 μl, 5.0 mmol, 1.0 equiv) was dissolved in dry THF (5.55 mL, 0.90 M) and the solution was cooled down to -78 °C. t-BuLi (5.88 ml, 10 mmol, 2.0 equiv) was added slowly and the solution was stirred for 1 h. Then the temperature of the solution was allowed to reach room temperature and the solution of organolithium regents was used without further dilution (final concentration 0.44 M).

Furyllithium

Furan (363 μl, 5.0 mmol, 1.0 equiv) was dissolved in THF (7.93 mL, 0.63 M) and the solution was cooled down to -40 °C. n-BuLi (3.13 ml. 5 mmol, 1 equiv) was added slowly. Then the solution was allowed to reach room temperature and stirred for 1 h and used without further dilution (final concentration 0.45 M).

Cyclopropyllithium

In a dry Schlenk flask, lithium shot (63 mg, 9 mmol, 1.8 equiv) was suspended in dry ether (1.38 mL, 6.5 M) at room temperature. Then bromocyclopropane (401 μL, 5 mmol, 1 equiv) was dissolved in ether (1.39 mL, 3.6 M) and added slowly over 30 min using a syringe pump. After the addition the mixture was stirred for 15 min. The solution was then diluted before use with toluene (8.31 ml) to reach a final concentration of 0.45 M.

2-Methoxymethoxy-phenyllithium.

In a dry Schlenk flask (methoxymethoxy)benzene1 (690 mg, 5.0 mmol, 1 equiv) was dissolved in dry THF (15.15 mL, 0.33 M) and the solution was cooled down to -78 °C. t-BuLi (2.94 ml, 5 mmol, 1 equiv) was added slowly and the solution was stirred for 1 h. Then the solution was allowed to reach room temperature and used without further dilution (final concentration 0.28M).

2.6-Dimethoxyphenyllithium

In a dry Schlenk flask 1,3-dimethoxybenzene (657 μl, 5.0 mmol, 1.0 equiv) was dissolved in dry THF (2.5 mL, 2 M) and the solution was cooled down to -10 °C. n-BuLi (3.13 ml. 5 mmol, 1 equiv) was added slowly and the solution was stirred for 30 min. Then the solution was allowed to reach room temperature. The solution was then diluted before use with toluene (5.48 ml) to reach a final concentration 0.45 M.

C. General Procedures for the Cross-Coupling of Aryllithium Reagents with Arylhalides or Arylmethoxides.

In a dry Schlenk flask, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]triphenylphosphine nickel(II) dichloride C3 (19.51 mg, 0.025 mmol, 5 mol%) and the substrate (0.5 mmol, 1 equiv) were dissolved in dry toluene (1.5 ml, 0.33 M) and the mixture was stirred at room temperature. The corresponding lithium reagent (0.75 mmol, 1.5 equiv) was slowly added over 1 h by syringe pump. When the addition was completed a saturated aqueous solution of NH4Cl was added to the reaction and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate and evaporated to dryness under vacuum to afford the crude product which was then purified by column chromatography.

D. General Procedures for the Cross-Coupling of Alkyllithium Reagents with Arylhalides.

In a dry Schlenk flask, dichloro[1,2-bis(diethylphosphino)ethane]nickel(II) C1 (7.0 mg, 0.021 mmol, 5 mol%) and the substrate (0.3 mmol, 1 equiv) were dissolved in dry toluene (2 ml, 0.15 M) and the mixture was stirred at room temperature. The corresponding lithium reagent (0.45 mmol, 1.5 equiv) was slowly added over 1 h by syringe pump. When the addition was completed a saturated aqueous solution of NH4Cl was added to the reaction flask and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate and evaporated to dryness under vacuum to afford the crude product which was then purified by column chromatography.

1 C. T. Vo, T. A. Mitchell, J. W. Bode, J. Am. Chem. Soc. 2011, 133, 14082-14089. 6

E. Experimental Details and Spectral Data of Compounds

2a) 1-phenylnaphthalene Purified by FCC using pentane. Yield: 88% (from 1-bromonaphthalene), 75% (from 1-fluoronaphthalene), 93% (from 1- chloronaphthalene [>85% GCMS, 9 to 1 mixture with 2-chloronaphthalene], isolated as a 90/10 mixture with 2-phenylnaphthalene) Molecular Formula: 1 13 C16H12 H NMR (300 MHz, CDCl3) δ 7.97-7.91 (m, 2H), 7.91-7.86 (m, 1H), 7.58-7.41 (m, 9H). C NMR

(75MHz, CDCl3) δ 140.7, 140.2, 133.8, 131.6, 130.1, 128.2, 128.2, 127.6, 127.2, 126.9, 126.0, 126.0, 125.7, 125.4. Spectral data match those reported in the literature. 2

2b) 4-butyl-1,1'-biphenyl Purified by FCC using pentane. Isolated with trace biphenyl originating from 1 the commercial Ph-Li used. Yield: 87% Molecular Formula: C16H18 H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 8.1, 3.9 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.51 (q, J = 7.2 Hz, 2H), 7.45-7.37 (m, 1H), 7.34 (d, J = 7.8 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 1.73 (p, J = 7.6 Hz, 2H), 1.49 (h, J = 7.6 Hz, 2H), 1.05 (t, J = 7.6 Hz, 13 3H). C NMR (101MHz, CDCl3) δ 142.0, 141.2, 138.5, 128.8, 128.7, 126.9, 126.9, 126.9, 35.3, 33.6, 22.4, 14.0. Spectral data match those reported in the literature.2

1 2c) 9-phenylphenanthrene Purified by FCC using pentane Yield: 82% Molecular Formula: C20H14 H

NMR (300 MHz, CDCl3) δ 8.82 (dd, J = 8.3, 1.3 Hz, 1H), 8.77 (dd, J = 8.0, 1.5 Hz, 1H), 7.99 (dd, J = 8.3, 13 1.3 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.79-7.43 (m, 10H). C NMR (75MHz, CDCl3) δ 140.8, 138.7, 131.5, 131.1, 130.6, 130.0, 129.9, 128.6, 128.3, 127.5, 127.3, 126.9, 126.8, 126.5, 126.5, 126.4, 122.9, 122.5. Spectral data match those reported in the literature.3

2 B. L. Feringa, Org. Lett., 2013, 15, 5114-5117. 7 3 F. Glorius, Chem. Sci., 2015, 6, 1816-1824. 4 A. K. Mohanakrishnan, Eur. J. Org. Chem., 2015, 5099-5114.

1 2d) 2-phenylanthracene Purified by FCC using pentane. Yield: 43% Molecular Formula: C20H14 H

NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.06-7.98 (m, 13 2H), 7.82-7.74 (m, 3H), 7.56-7.44 (m, 4H), 7.41 (t, J = 7.3 Hz, 1H). C NMR (75MHz, CDCl3) δ 141.0, 137.8, 132.1, 131.9, 131.8, 130.9, 128.9, 128.7, 128.2, 128.1, 127.4, 127.3, 126.6, 126.0, 125.7, 125.5, 125.5, 125.4. Spectral data matcher known literature reference.4

1 2e) 2-phenylnaphthalene Purified by FCC using pentane. Yield: 76% Molecular Formula: C16H12 H

NMR (400 MHz, CDCl3) δ 8.10 (d, J = 1.9 Hz, 1H), 8.00-7.88 (m, 3H), 7.84-7.74 (m, 3H), 7.54 (tt, J = 6.5, 13 2.5 Hz, 4H), 7.46-7.39 (m, 1H). C NMR (101MHz, CDCl3) δ 141.2, 138.4, 133.7, 132.7, 128.9, 128.5, 128.2, 127.7, 127.5, 127.4, 126.3, 126.0, 125.8, 125.6. Spectral data match those reported in the literature. 2

2f) 1,1':4',1''-terphenyl Purified by preparatory layer chromatography (PLC Silica gel 60 F254, 2mm) 1 using pentane. Yield: 61% Molecular Formula: C18H14 H NMR (300 MHz, CDCl3) δ 7.68 (s, 4H), 7.67- 13 7.62 (m, 4H), 7.51-7.42 (m, 4H), 7.36 (t, J = 7.4 Hz, 2H). C NMR (75MHz, CDCl3) δ 140.9, 140.3, 129.0, 127.6, 127.5, 127.2. Spectral data match those reported in the literature . 5

2g) o-Terphenyl Purified by preparatory layer chromatography (PLC Silica gel 60 F254, 2mm) using pentane. Yield: 61% (from 4-bromobiphenyl), 56% (from 4-fluorobiphenyl) Molecular Formula: C18H14 1 13 H NMR (300 MHz, CDCl3) δ 7.43 (s, 4H), 7.26-7.17 (m, 6H), 7.17-7.11 (m, 4H). C NMR (75 MHz,

CDCl3) δ 141.4, 140.5, 130.5, 129.8, 127.8, 127.4, 126.4. Spectral data match those reported in the literature.6 5 J.-X. Wang, Adv. Synth. Catal., 2008, 350, 315-320. 9 6 SDBS database No. 1198 (http://sdbs.db.aist.go.jp, National Institute of Advanced Industrial Science and Technology, 30.07.2015).

2h) (E/Z)-4-methoxy-4'-(prop-1-en-1-yl)-1,1'-biphenyl The reaction was run with 7.5 mol% of catalyst and at 40°C. Purified by FCC using pentane/dichloromethane (95:5-90:10). 1-bromo-4-(prop- 1-en-1-yl)benzene was used as a 1:1 mixture of E/Z isomers and the product was obtained as a 1:1 7 1 mixture of E/Z isomers. Yield: 56% Molecular Formula: C16H16O H NMR (300 MHz, CDCl3) δ 7.64- 7.48 (m, 4H), 7.40 (d, J = 8.5 Hz, 1H) , 7.39 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H) , 6.99 (d, J = 8.8 Hz, 1H), 6.55-6.40 (m, 1H), 6.29 (dq, J = 15.7, 6.5 Hz, 0.45H), 5.84 (dq, J = 11.5, 7.2 Hz, 0.55H), 3.87 (s, 13 1.5H), 3.87 (s, 1.5H), 1.98 (dd, J = 7.2, 1.8 Hz, 1.6H), 1.93 (d, J = 6.5 Hz, 1.4H). C NMR (75MHz, CDCl3) δ 159.1, 159.0, 139.0, 138.7, 136.3, 136.0, 133.4, 133.3, 130.6, 129.4, 129.2, 127.9, 127.8, 126.7,

126.6, 126.3, 126.1, 125.5, 114.1, 114.1, 55.3, 18.5, 14.7. HRMS: Calculated for C16H17O [M+H]+ 225.1270; found 225.1274.

2i) 4-methyl-1,1'-biphenyl Purified by FCC using pentane. Isolated as a 70:30 mixture (GCMS) with biphenyl originating from commercial phenyl lithium. Yield: 43% (from 4-fluorotoluene), 39% (from 1 4-methoxytoluene). Molecular Formula: C13H12 H NMR (400 MHz, CDCl3) δ 7.67-7.59 (m, 5H), 7.56- 7.50 (m, 3H), 7.51-7.42 (m, 5H), 7.41-7.31 (m, 2H), 7.31-7.24 (m, 2H), 2.42 (s, 3H). 13C NMR (101MHz,

CDCl3) δ 141.1, 138.3, 137.0, 129.5, 128.7, 127.0, 127.0, 127.0, 21.1. Spectral data match those reported in the literature.8

2j) 2-methyl-1,1'-biphenyl Purified by FCC using pentane. Isolated as a 78:22 mixture (GCMS) with 1 biphenyl originating from the commercial phenyl lithium. Yield: 94% Molecular Formula: C13H12 H

NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 1H), 7.56-7.46 (m, 3H), 7.46-7.38 (m, 3H), 7.38-7.29 (m, 13 4H), 2.36 (s, 3H). C NMR (101MHz, CDCl3) δ 155.1, 141.9, 135.3, 130.3, 129.8, 129.2, 128.0, 128.0, 126.7, 125.7, 20.5. Spectral data match those reported in the literature. 8

k) 2,4-dimethyl-1,1'-biphenyl Purified by FCC using pentane. Isolated as a 75:25 mixture (GCMS) with 1 biphenyl originating from the commercial phenyl lithium. Yield: 94% Molecular Formula: C14H14 H

NMR (400 MHz, CDCl3) δ 7.68-7.62 (m, 1H), 7.53-7.33 (m, 2H), 7.27-7.13 (m, 1H), 2.40 (s, 3H), 2.22 (s, 13 1H). C NMR (101MHz, CDCl3) δ 142.6, 142.3, 141.3, 137.2, 134.0, 129.4, 128.9, 128.8, 128.0, 127.7, 127.3, 127.2, 126.6, 125.3, 20.8, 17.0. Spectral data match those reported in the literature. 9

2l) 3-(trifluoromethyl)-1,1'-biphenyl Purified by preparatory layer chromatography (PLC Silica gel 60 1 F254, 2mm) using pentane. Yield: 51% Molecular Formula: C13H9F3 H NMR (300 MHz, CDCl3) δ 7.89

(s, 1H), 7.85-7.79 (m, 1H), 7.71-7.57 (m, 4H), 7.57-7.41 (m, 3H). 13C NMR (75MHz, CDCl3) δ. 142.1, 139.8, 131 (q, J = 31.8 Hz), 130.4, 129.3, 129.0, 128.1, 127.2, 124.2 (q, J = 272.1 Hz), 124.0 (m) Spectral data match those reported in the literature10 .

2m) 4-(trifluoromethyl)-1,1'-biphenyl Purified by FCC using pentane. Yield: 88% (from 1-bromo-4- (trifluoromethyl)benzene), 81% (from 1-chloro-4- (trifluoromethyl)benzene), 25% (1-fluoro-4- 1 (trifluoromethyl)benzene). Molecular Formula: C13H9F3 H NMR (300 MHz, CDCl3) δ 7.70 (s, 4H), 7.64- 13 7.59 (m, 2H), 7.52-7.45 (m, 2H), 7.45-7.38 (m, 1H). C NMR (75MHz, CDCl3) δ 144.7, 139.8, 129.0, 128.2, 127.4, 127.3, 125.7, 125.6. Spectral data match those reported in the literature. 2

2n) 4-methoxy-1,1'-biphenyl Purified by FCC using pentane. Yield: 86% (From 4-bromoanisole), 66% 1 (from 4-chloroanisole). Molecular Formula: C13H12O H NMR (300 MHz, CDCl3) δ 7.65-7.50 (m, 4H), 7.52-7.40 (m, 2H), 7.39-7.29 (m, 1H), 7.07-6.93 (m, 2H), 3.87 (d, J = 1.7 Hz, 3H). 13C NMR (75MHz,

CDCl3) δ 159.2, 140.8, 133.8, 128.7, 128.2, 126.7, 126.7, 114.2, 55.3. Spectral data match those reported in the literature. 2

7 K. U. Ingold, J. Am. Chem. Soc., 2002, 124, 6362-6366. 10 8 Z. Zhang, Angew. Chem. Int. Ed., 2015, 54, 4079-4082. 9 J. Dupont, Org. Lett., 2000, 2, 2881–2884. 10 W. Su, Angew. Chem. Int. Ed., 2015, 54, 2199 –2203. 12

2o) N,N-dimethyl-[1,1'-biphenyl]-3-amine Purified by FCC using Pentane/Toluene (75:25). Yield: 45% 1 Molecular Formula: C14H15N H NMR (300 MHz, CDCl3) δ 7.69-7.61 (m, 2H), 7.53-7.44 (m, 2H), 7.43- 13 7.33 (m, 2H), 7.00-6.92 (m, 2H), 6.82-6.72 (m, 1H), 3.07 (s, 6H). C NMR (75 MHz, CDCl3) δ 150.7, 142.2, 142.1, 129.3, 128.5, 127.3, 127.0, 116.0, 111.7, 111.6, 40.7. Spectral data match those reported in the literature. 2

2p) 3-phenylbenzo[b]thiophene Purified by FCC using pentane. Yield: 65% Molecular Formula: 1 C14H10S H NMR (400 MHz, CDCl3) δ 7.96-7.89 (m, 2H), 7.63-7.57 (m, 2H), 7.53-7.46 (m, 2H), 7.46-7.36 13 (m, 4H). C NMR (101MHz, CDCl3) δ 140.7, 138.1, 137.9, 136.0, 128.7, 127.5, 124.4, 124.3, 123.4, 122.9, 122.9. Spectral data match those reported in the literature. 12

2q) 1-(2,6-dimethoxyphenyl)naphthalene Purified by FCC using pentane. Yield: 45% Molecular 1 Formula: C18H16O2 H NMR (400 MHz, CDCl3) δ 7.90 (m, 2H), 7.58 (dd, J = 8.2, 7.0 Hz, 1H), 7.55-7.34 13 (m, 5H), 6.75 (d, J = 8.2 Hz, 2H), 3.66 (s, 6H). C NMR (101MHz, CDCl3) δ 158.4, 133.5, 132.7, 132.6, 129.1, 128.2, 128.0, 127.4, 126.0, 125.5, 125.4, 125.34, 117.6, 104.1, 55.9. Spectral data match those reported in the literature. 13

2r) 2,4',6-trimethoxy-1,1'-biphenyl Purified by FCC using pentane. Yield: 30% Molecular Formula: 1 C15H16O3 H NMR (300 MHz, CDCl3) δ 7.42-7.15 (m, 3H), 7.12-6.87 (m, 2H), 6.68 (d, J = 8.3 Hz, 2H), 13 3.87 (s, 3H), 3.77 (s, 6H). C NMR (75MHz, CDCl3) δ 158.3, 157.8, 131.9, 128.3, 126.1, 119.1, 113.2, 104.2, 55.9, 55.1. Spectral data match those reported in the literature. 14 11 M. Nakamura, J. Am. Chem. Soc., 2007, 129, 9844-9845. 12 S. Oi, Org. Lett., 2012, 14, 6186-6189. 14 13 B. L. Feringa, Angew. Chem. Int. Ed., 2013, 52, 13329-13333. 14 A. Wagner, Org. Lett., 2007, 9, 1781-1783. 15

2s) 1-(2-(methoxymethoxy)phenyl)naphthalene Purified by FCC using pentane. Yield: 72% Molecular 1 Formula: C18H16O2 H NMR (400 MHz, CDCl3) δ 7.90-7.75 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.41-7.32 (m, 3H), 7.28 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 6.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.97 (d, J = 6.8 Hz, 1H), 4.93 (d, J = 6.8 Hz, 1H), 3.18 (s, 3H). 13C NMR (101MHz,

CDCl3) δ 154.8, 137.0, 133.3, 132.1, 131.9, 130.6, 129.0, 128.0, 127.6, 127.2, 126.4, 125.6, 125.5, 125.3, 121.9, 115.1, 94.6, 55.9. Spectral data match those reported in the literature. 2

2t) 2,4',6-trimethoxy-1,1'-biphenyl Purified by FCC using pentane. Yield: 30% Molecular Formula: 1 C15H16O3 H NMR (400 MHz, CDCl3) δ 7.56-7.44 (m, 2H), 7.34 (dd, J = 7.6, 1.8 Hz, 1H), 7.32-7.25 (m, 1H), 7.24- 7.20 (m, 1H), 7.15-7.04 (m, 1H), 7.01-6.92 (m, 2H), 5.14 (s, 2H), 3.87 (s, 3H), 3.42 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 158.7, 154.2, 131.5, 131.0, 130.8, 130.6, 128.2, 122.3, 115.7, 113.5, 95.1, 56.1, 55.3. Spectral data match those reported in the literature. 15

2u) 2-(4-methoxyphenyl)furan Purified by FCC using pentane. Yield: 73% Molecular Formula: 1 C11H10O2 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.43 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.56- 13 6.48 (m, 1H), 6.45 (m, 1H), 3.84 (s, 3H). C NMR (101MHz, CDCl3) δ 159.0, 154.0, 141.4, 125.2, 124.0, 114.1, 111.5, 103.4, 55.3. Spectral data match those reported in the literature. 16

1 2v) 2-(anthracen-2-yl)furan Purified by FCC using pentane. Yield: 65% Molecular Formula: C18H12O H

NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.00 (m, 3H), 7.75 (d, J = 8.8 Hz, 1H), 13 7.56 (s, 1H), 7.52-7.38 (m, 2H), 6.81 (d, J = 3.2 Hz, 1H), 6.60-6.50 (m, 1H). C NMR (101MHz, CDCl3) δ 154.1, 142.5, 132.2, 131.8, 131.6, 130.8, 128.7, 128.2, 128.1, 127.4, 126.5, 126.2, 125.6, 125.4, 122.3, 121.8, 111.9, 106.0. Spectral data match those reported in the literature. 17

15 B. L. Feringa, Org. Lett., 2015, 17, 62-65. 16 16 B. L. Feringa, Chem. Eur. J., 2014, 20, 13078-13083. 17 C.-M. Che, Org. Lett., 2006, 8, 325-328. 17

2w) 2-(naphthalen-2-yl)furan Purified by FCC using pentane. Yield: 43% Molecular Formula: C14H10O 1 H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 8.00-7.69 (m, 4H), 7.58-7.37 (m, 3H), 6.79 (d, J = 3.4 Hz, 1H), 13 6.54 (dd, J = 3.4, 1.8 Hz, 1H). C NMR (75MHz, CDCl3) δ 154.1, 142.3, 133.6, 132.7, 128.4, 128.2, 128.2, 127.8, 126.5, 125.9, 122.3, 122.1, 111.8, 105.6. Spectral data match those reported in the literature. 16

2x) 1-(4-methoxyphenyl)naphthalene Purified by FCC using pentane. Yield: 70% Molecular Formula: 1 C17H14O H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.58-7.54 (m, 1H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H), 7.50-7.43 (m, 4H), 7.07 (d, J = 8.6 Hz, 2H), 3.92 (s, 13 3H). C NMR (101MHz, CDCl3) δ 159.0, 139.9, 133.9, 133.2, 131.9, 131.1, 128.3, 127.4, 126.9, 126.1, 125.9, 125.7, 125.4, 113.8, 55.4. Spectral data match those reported in the literature. 18

2y) 2-(naphthalen-1-yl)thiophene Purified by FCC using pentane. Yield: 79% (From 1- 1 chloronaphtalene), 89% (From 1-bromonapththalene) Molecular Formula: C14H10S H NMR (400 MHz,

CDCl3) δ 8.35-8.25 (m, 1H), 7.98-7.93 (m, 1H), 7.91 (dt, J = 8.2, 1.2 Hz, 1H), 7.64 (dd, J = 7.1, 1.2 Hz, 1H), 7.60-7.51 (m, 3H), 7.48 (dd, J = 5.1, 1.2 Hz, 1H), 7.31 (dd, J = 3.5, 1.2 Hz, 1H), 7.24 (dd, J = 5.1, 3.5 13 Hz, 1H). C NMR (101MHz, CDCl3) δ 141.8, 133.8, 132.4, 131.9, 128.4, 128.3, 128.2, 127.4, 127.2, 126.4, 126.0, 125.7, 125.6, 125.2. Spectral data match those reported in the literature. 16

2z) 2-(4-methoxyphenyl)naphthalene Purified by FCC using pentane/dichloromethane (90:10-85:15). 1 Yield: 80% Molecular Formula: C17H14O H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 2.0 Hz, 1H), 7.99-7.83 (m, 3H), 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.73-7.66 (m, 2H), 7.61-7.38 (m, 2H), 7.15-6.88 (m, 2H), 3.90 (s, 13 3H). C NMR (75MHz, CDCl3) δ 159.4, 138.3, 133.9, 133.7, 132.4, 128.5, 128.5, 128.2, 127.7, 126.3, 125.8, 125.5, 125.1, 114.4, 55.5. Spectral data match those reported in the literature. 19

18 L. X. Shao, J. Organomet. Chem., 2011, 696, 3741-3744. 18 19 B. Jiang, Org. Lett., 2015, 17, 1942-1945. 19

3a) 1-ethylnaphthalene Purified by FCC using pentane. Yield: 66% (from 1-fluoronaphthalene), 65% (isolated as a 88 to 12 mixture with 2-isopropylnaphthalene when starting from 1- chloronaphthalene, >85% GCMS, 9 to 1 mixture with 2- chloronaphthalene) Molecular Formula: 1 C12H12 H NMR (300 MHz, CDCl3) δ 8.12 (q, J = 8.3 Hz, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.62-7.44 (m, 3H), 7.41 (d, J = 7.1 Hz, 1H), 3.18 (d, J = 7.9 Hz, 2H), 1.45 (t, J = 7.8 Hz, 3H). 13C NMR

(75MHz, CDCl3) δ 140.2, 133.8, 131.8, 128.7, 126.4, 125.8, 125.6, 125.4, 124.8, 123.7, 25.9, 15.0. Spectral data match those reported in the literature. 20

3b) 1-butylnaphthalene Purified by FCC using pentane. Yield: 76% (from 1-fluoronaphthtalene), 78% (from 1- chloronaphthalene [>85% GCMS, 9 to 1 mixture with 2-chloronaphthalene], 87 to 13 1 mixture with 2-isopropylnaphthalene) Molecular Formula: C14H16 H NMR (300 MHz, CDCl3) δ 8.12- 8.06 (m, 1H), 7.88 (dd,J = 8.1, 1.6 Hz, 1H,), 7.74 (d, J = 8.1 Hz, 1H), 7.57-7.47 (m, 2H), 7.43 (dd, J = 8.1, 7.0 Hz, 1H), 7.36 (dd, J = 7.0, 1.3 Hz, 1H), 3.25-2.87 (m, 2H), 1.86- 1.67 (m, 2H), 1.50 (h, J = 7.4 Hz, 2H), 13 1.01 (t, J = 7.4 Hz, 3H). C NMR (75MHz, CDCl3) δ 139.0, 133.9, 131.9, 128.7, 126.4, 125.9, 125.6, 125.5, 125.4, 123.9, 33.0, 32.85, 22.9, 14.1. Spectral data match those reported in the literature. 21

3c) 1-hexylnaphthalene Purified by FCC using pentane. Starting from commercially available 1- chloronaphthalene (>85% GCMS, 9 to 1 mixture with 2-chloronaphthalene) Yield: 87% (9 to 1 mixture 1 with 2-hexylnaphthalene) Molecular Formula: C16H20 H NMR (300 MHz, CDCl3) δ 8.11 (dd, J = 8.3, 1.5 Hz, 0.82H), 7.91 (dd, J = 7.8, 1.8 Hz, 0.9H), 7.88-7.80 (m, 0.34H), 7.76 (d, J = 8.1 Hz, 0.77H), 7.67 (s, 0.10H), 7.60-7.49 (m, 1.78H), 7.49-7.42 (m, 1H), 7.38 (dd, J = 6.9, 1.2 Hz, 0.9H), 3.20-3.04 (m, 2H), 2.90-2.71 (m, 0.27H), 1.88-1.70 (m, 2H), 1.57-1.46 (m, 2H), 1.44-1.30 (m, 4H), 1.07-0.89 (m, 3H). 13C NMR (75MHz, CDCl3) δ 139.0, 133.9, 131.9, 128.7, 127.9, 127.7, 127.6, 127.4, 127.4, 126.4, 126.3, 125.8, 125.8, 125.6, 125.5, 125.3, 124.9, 123.9, 36.1, 33.1, 31.8, 31.4, 30.8, 29.5, 29.0, 22.7, 14.1. Spectral data match those reported in the literature. 22

20 Z.-J. Shi, J. Am. Chem. Soc., 2008, 130, 3268-3269. 20 21 B. L. Feringa, Nature Chemistry, 2013, 5, 667-672. 22 1-hexylnaphthalene: Z.-J. Shi, Chem. Commun., 2013, 49, 7794-7796

3d) 1-isopropylnaphthalene Purified by FCC using pentane. Starting from commercially available 1- chloronaphthalene (>85% GCMS, 9 to 1 mixture with 2-chloronaphtalene) Yield: 63% (85 to 15 1 mixture with 2-isopropylnaphthalene) Molecular Formula: C13H14 H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 0.85H), 7.92-7.86 (m, 1H), 7.86-7.79 (m, 0.3H), 7.77- 7.71 (m, 0.85H), 7.59-7.41 (m, 4H), 3.80 (hept, J = 6.7 Hz, 0.85H), 3.21-3.00 (m, 0.15H), 1.45 (d, J = 6.9 Hz, 5.1H), 1.39 (d, J = 6.9 Hz, 0.9H). 13 C NMR (75MHz, CDCl3) δ 144.6, 133.9, 131.3, 128.9, 127.9, 127.8, 127.6, 126.3, 125.8, 125.8, 125.7, 125.6, 125.6, 125.2, 125.0, 124.1, 123.3, 121.7, 28.5, 23.9, 23.5. Spectral data match those reported in the literature. 23

3e) 2-Ethylanthracene Purified by FCC using pentane. Isolated as a 90:10 mixture with anthracene. 1 Yield: 67% (74% as a 90:10 mixture with anthracene) Molecular Formula: C16H14 H NMR (300 MHz,

CDCl3) δ 8.41 (s, 1H), 8.37 (s, 1H), 8.07-7.99 (m, 2H), 7.97 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 7.52-7.44 (m, 2H), 7.38 (dd, J = 8.7, 1.6 Hz, 1H), 2.89 (q, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H). 13C NMR (75MHz,

CDCl3) δ 141.1, 132.0, 131.8, 131.2, 130.5, 128.2, 128.1, 128.0, 127.3, 125.9, 125.4, 125.2, 124.9, 124.9, 29.2, 15.1. Spectral data match those reported in the literature. 24

3f) 2-hexylanthracene Purified by FCC using pentane. Isolated as an 90:10 mixture with anthracene. 1 Yield: 39% (43% as an 90:10 mixture with anthracene) Molecular Formula: C20H22 H NMR (300 MHz,

CDCl3) δ 8.40 (s, 1H), 8.36 (s, 1H), 8.08-7.98 (m, 2H), 7.96 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 7.53-7.42 (m, 2H), 7.36 (dd, J = 8.7, 1.7 Hz, 1H), 2.83 (t, J = 7.7 Hz, 2H), 1.86-1.67 (m, 2H), 1.51-1.25 (m, 6H), 1.00- 13 0.82 (m, 3H). C NMR (75MHz, CDCl3) δ 139.8, 132.0, 131.8, 131.2, 130.5, 128.1, 128.0, 128.0, 127.5,

125.9, 125.7, 125.3, 125.2, 124.9, 36.3, 31.8, 31.0, 29.1, 22.6, 14.1. HRMS: Calculated for C20H23O [M+H]+ 263.1794; found 236.1792.

23 For both 1 & 2-isopropylnaphthalene see: B. L. Feringa, Chem. Sci., 2014, 5, 1361-1367. 24 Y. Pan, Tetrahedron, 2007, 63, 5071-5075 22

3g) 1-ethylanthracene Purified by FCC using pentane. Contains trace amounts anthracene. Yield: 94% 1 Molecular Formula: C16H14 H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.44 (s, 1H), 8.13-7.95 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.52- 7.31 (m, 4H), 3.27 (q, J = 7.5 Hz, 2H), 1.49 (t, J = 7.5 Hz, 3H). 13C NMR

(75MHz, CDCl3) δ 140.1, 132.2, 131.5, 131.3, 130.5, 128.5, 127.9, 126.9, 126.7, 125.3, 125.2, 125.2,

123.7, 122.4, 26.0, 14.7. HRMS: Calculated for C16H15 [M+H]+ 207.1168; found 207.0801.

3h) 1-butylanthracene Purified by FCC using pentane. Isolated as a 95:5 mixture with anthracene 23 1 Yield: 80% (84% as an 95:15 mixture with anthracene) Molecular Formula: C18H18 H NMR (300 MHz,

CDCl3) δ 8.62 (s, 1H), 8.44 (s, 1H), 8.13-7.95 (m, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.53, 7.45 (m, 2H), 7.44- 7.30 (m, 2H), 3.23 (t, 2H), 2.04-1.78 (m, 2H), 1.64-1.41 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H). 13C NMR

(75MHz, CDCl3) δ 138.9, 132.3, 131.5, 131.3, 130.7, 128.6, 127.9, 127.0, 126.8, 125.4, 125.3, 125.2,

124.8, 122.6, 33.1, 32.7, 23.0, 14.1. HRMS: Calculated for C18H19 [M+H]+ 235.1481; found 235.1478.

1 3i) 1-hexylanthracene Purified by FCC using pentane. Yield: 85% Molecular Formula: C20H22 H NMR

(300 MHz, CDCl3) δ 8.62 (s, 1H), 8.44 (s, 1H), 8.12-7.94 (m, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.54- 7.44 (m, 2H), 7.44-7.36 (m, 1H), 7.36-7.29 (m, 1H), 3.22 (t, J = 9 Hz, 2H), 1.99-1.78 (m, 2H), 1.63-1.23 (m, 6H), 13 0.94 (t, J = 6.9 Hz, 3H). C NMR (75MHz, CDCl3) δ 138.8, 132.2, 131.5, 131.2, 130.6, 128.5, 127.9, 126.9, 126.7, 125.3, 125.2, 125.1, 124.7, 122.5, 33.3, 31.8, 30.4, 29.6, 22.7, 14.1. HRMS: Calculated for C20H23 [M+H]+ 236.1794; found 236.1791.

3j) 1-isopropylanthracene Purified by FCC using pentane. Isolated as an 69:41 mixture with 1 anthracene Yield: 55% (79% as an 69:41 mixture with anthracene) Molecular Formula: C17H16 H NMR

(300 MHz, CDCl3) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.14-7.95 (m, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.59- 7.34 (m, 13 4H), 3.94 (hept, J = 6.9 Hz, 1H), 1.50 (d, J = 6.8 Hz, 6H). 24 C NMR (75MHz, CDCl3) δ 144.54, 132.33, 131.49, 131.11, 130.03, 128.62, 127.79, 127.03, 126.58, 125.32, 125.20, 125.16, 122.05, 120.84,

28.77, 23.53. HRMS: Calculated for C16H17O [M+H]+ 221.1325; found 221.0956.

1 3k) 1-cyclopropylanthracene Purified by FCC using pentane. Yield: 66% Molecular Formula: C17H14 H

NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.45 (s, 1H), 8.14- 8.08 (m, 1H), 8.06-7.99 (m, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.55-7.46 (m, 2H), 7.39 (dd, J = 8.5, 6.8 Hz, 1H), 7.32-7.21 (m, 1H), 2.62-2.36 (m, 1H), 13 1.20-1.13 (m, 2H), 0.89-0.81 (m, 2H). C NMR (75MHz, CDCl3) δ 139.3, 132.1, 132.1, 131.7, 131.5, 128.8, 128.1, 127.0, 126.9, 125.5, 125.4, 125.2, 123.2, 123.0, 13.7, 6.5. Chapter 7 : Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-Coupling of Organolithium Reagents and its Application in Nuclear Medicine

Part of this chapter was published in : D. Heijnen, F. Tosi, C. Vila, M. C. A. Stuart, P. H. Elsinga, W. Szymanski and B. L. Feringa. Angew.Chem. Int. Ed. 2017, 56, 3354-3359

Abstract : The discovery of an ultrafast cross-coupling of alkyl- and aryllithium reagents with a range of aryl bromides is described in this chapter. The essential role of molecular oxygen to form the active palladium catalyst was established; palladium nanoparticles that are highly active in cross- coupling reactions with reaction times ranging from 5 s to 5 min are thus generated in situ. High selectivities were observed for a range of heterocycles and functional groups as well as for an expanded scope of organolithium reagents. The applicability of this method was showcased by the synthesis of the [11C]-labeled PET tracer Celecoxib.

7.1 Introduction Transition-metal-catalyzed cross-couplings of organometallic reagents have found widespread application in the synthesis of pharmaceutical products and organic materials, including the formation of important functionalized heterocycles.[1] Despite their prominent role in the modern synthetic repertoire, it remains of considerable interest to shorten reaction times, apply milder conditions, use less expensive starting materials, reduce catalyst loadings and trace residual metals in the desired product, and to minimize the amount of toxic waste. We have recently reported the direct cross-coupling of alkyl-, alkenyl-, and aryllithium reagents with a wide range of (pseudo)halogenated aryl and alkenyl electrophiles catalyzed by either palladium or nickel complexes.[2] These organolithium-based methods typically show cross-coupling with enhanced speed (<1h), operate at mild temperatures (in most cases room temperature), and produce lighter and less toxic stoichiometric waste (LiX). Reactions with excellent chemoselectivity were initially achieved by slow addition of the highly reactive lithium reagent.[2] Typically, commercially available unaltered complexes were employed, including Pd/PEPPSI, Pd(PtBu3)2 (C1), or Pd/dba/XPhos, which are also prominent catalysts in closely related transformations, such as Negishi or Suzuki cross- coupling reactions.[3] We envisioned that the exceptional reactivity and versatility of organolithium reagents could be taken advantage of in developing a fast cross-coupling that proceeds under ambient conditions, especially in light of the major current interest and important advances in fast cross-coupling reactions under mild conditions.[4] To the best of our knowledge, the very recently published procedure by the group of Schoenebeck, based on the use of Grignard and organozinc reagents (Figure 7.1) stands out in terms of short reaction times.[5]

Figure 7.110 Recent fast cross-coupling reactions Herein, we present the discovery of an ultrafast cross-coupling with organolithium reagents. In stark contrast to the common practice of rigorously excluding oxygen when working with such extremely reactive organometallic reagents, we have found that molecular oxygen is essential to form the active catalyst. Under our conditions, rapid C-C bond formation occurs within seconds to minutes at room temperature while catalyst speciation studies point to the involvement of 2-3 nm large Pd nanoparticles. Using this new procedure, chemoselective cross-coupling reactions with organolithium reagents now include an expanded range of heterocycles, functional groups, and organolithium compounds. Furthermore, it provides a 11 versatile method for isotope labeling, that is, for introducing -CD3 labels and short-lived C 11 radioisotopes (t½( C)=20.3min) for PET imaging.

7.2 Oxygen activation In preliminary experiments, we used the cross-coupling of methyllithium and 1- bromonaphthalene in the presence of Pd(PtBu3)2 (C1, 5 mol %) at room temperature to test whether very short reaction times with full conversion would be possible (Scheme 7.1) Under presumably identical conditions, we were puzzled to observe greatly varying results.

Scheme 7.1 Optimization of fast cross-coupling

After eliminating many potential causes (variations in the concentration of the reagents, light, temperature, the presence of salts, water, or trace metal impurities), we established that minute traces of air were essential for catalyst activation. Samples briefly purged with dry oxygen prior to MeLi addition always gave complete and chemoselective conversion into 1-methylnaphthalene. The lack of reactivity observed after adding degassed water or when employing strictly oxygen-free conditions supported the notion that the presence of oxygen greatly enhanced the catalytic activity of the system, leading to optimized reaction conditions with catalyst C1 after short oxygen purging, and allowing for catalyst oxidation for 10 min.

7.3 Scope Under the optimized conditions, an extended range of organolithium and aryl bromide reagents, compared to our previously reported method,[2] underwent highly selective coupling, providing excellent yields in 2-5 min at room temperature (Table 7.1). Substrates from the naphthalene (2a-3f) and anthracene families (4a) gave good yields with near- perfect selectivity when coupled with a variety of commercially available organolithium reagents. Gratifyingly, identical results were achieved with both electron-poor and electron-rich substrates (5a-8a). Unwanted side reactions were suppressed with near-perfect selectivity for C-Br over C-Cl in aromatic and aliphatic substrates with competitive coupling possibilities

(9a-11a), while aryl bromides 12a-15a, including CF3-substituted analogue 16a, gave selectivities similar to those of the naphthalene substrates.[6] Remarkably, the fast coupling of RLi can even be used when an epoxide functional group is present at a temperature as low as -10°C, where the expected epoxide ring opening by the organolithium reagent is effectively suppressed, to provide the desired coupling product 17a. Importantly, alcohols 18a-20a, including an unprotected phenol, provided the corresponding products in good yields, albeit with a larger excess of organolithium reagent. Novel substrates were also found amongst heterocycles 21a-26a. The direct lithiation of inexpensive, commercially available ferrocene is well described in the literature,[7] and the corresponding nucleophile provides an alternative to the less available and costly boron or halide derivatives to yield 27a and 28a. Finally, aryllithium reagents synthesized via lithium--halogen exchange (e.g., 3-anisyllithium) also proved to be suitable coupling partners, providing biaryl 29a.

Table 7.1 Fast cross-coupling of (hetero)aryl bromides with organolithium reagents.

Reaction conditions: Substrate : 0.6 mmol in 4 ml toluene, 5 mol% catalyst, 4 ml oxygen, 1.5 eq (0.9 mmol) organolithium reagent. All reactions were carried out at rt. Yields refer to isolated yields after column chromatography unless noted otherwise. a) Reaction performed at 0 °C; b) Performed with 2.5 eq of organolithium at 40 °C; c) Conversion determined by GCMS analysis; d) Reaction performed with 1 eq of n-BuLi at -10 °C; e) Reaction performed with 2.5 eq of organolithium reagent. The reaction time of the coupling between nBuLi and 1-bromonaphthalene could be reduced to just 5s at room temperature with 5 mol% of the precatalyst, giving full conversion and a turnover frequency of 14×103h-1 (Table 7.2 entry 1), provided that an excess of oxygen was present with respect to Pd complex C1. With a catalyst loading of 0.05 %, we were able to fully convert 1 on gram scale in just 10 min. On the other hand, by reducing the rate of addition of nBuLi, we were able to use a catalyst loading as low as 0.025 mol % (entry 2-5). A slightly higher catalyst loading was necessary for the coupling of 4-bromoanisole (entry 6).

Table 7.2 Screening of catalyst loading

Entry C1 (mol%) Addition time Conv. 1 5 5 sec Full 2 0.5 2 min Full 3 0.05 10 min Full 4 0.025 10 min 40 5 0.025 30 min Full 6 0.05a 30 min Full All experiments were conducted at rt in toluene (0.15 M initial concentration of the substrate), entries 1 and 2 were conducted on 0.3 mmol scale, entries 3-6 on a 12 mmol (2.5 g) scale. Conversions were determined by GCMS analysis. a) 4-Br-anisole was used as substrate.

7.4 Active catalyst investigation Focusing on the crucial role of molecular oxygen, we observed that the catalyst solution turned red upon purging with O2, suggesting that Pd(PtBu3)2 (C1) was converted into the 10 active catalyst. Many d metal complexes are known to rapidly interact with O2 to form stable η2-peroxo complexes; however, C1 has not been reported as one of them.[8] The reason for its stability towards O2 was attributed to the extreme bulkiness of the ligands, which shield the Pd and hence hamper its oxidation. Therefore, the sterically hindered C1 complex needs prolonged oxygen exposure at room temperature to ensure complete oxidation. To investigate whether known peroxo complexes could be excluded as possible 2 [5] catalysts, we tested the η -peroxo derivatives of Pd(PCy3)2 and Pd(PPh3)2, which did not show any catalytic activity (see the experimental section). Extensive 1H and 31PNMR studies with catalytically inactive C1 prior to and after exposure to oxygen revealed the formation of free PtBu3 (see Experimental Section), phosphine oxides, and (yet unidentified) oxidized Pd ox [9,10] species (C1 ) upon reaction with O2. The hypothesis that the monoligated [Pd(PtBu3)] complex, arising from dissociation of one phosphine from the starting complex, acted as the active catalyst was excluded on the basis of the lack of reactivity with aryl chlorides and inhibition experiments by adding an excess of

PtBu3 (up to 10 equiv, see Experimental Section), which had no effect on the outcome of the cross-coupling, suggesting a different active species.[5,11,12] We were able to isolate the oxidized form (C1ox) of C1 by washing the residue of the oxidation step with acetonitrile (see Experimental Section). Addition of 4-bromoanisole to C1ox at room temperature showed no change at all by NMR analysis, which led to the conclusion that up until the addition of the organolithium reagent, no reaction is taking place.[13] Given the fast cross-coupling and the lack of any reaction between C1 or C1ox and the electrophile, we next tested whether the organolithium reagent initiates the catalytic cycle by generation of the active Pd species. Upon stoichiometric addition of nBuLi to a ox [D8]toluene solution of C1 , some of the Pd species were reduced to form again catalytically inactive C1, and stoichiometry indicates the formation of another Pd0 species, presumably the active catalyst (see below). Important information came from independent experiments with the bridged dinuclear PdI complex C2 (Scheme 7.1), which is also a catalyst precursor in our cross-coupling. Oxidation of C2 occurs within seconds at room temperature, although we found that the product C2ox arising from this reaction was not consistent with the one described in the literature (see the Supporting Information).[14] Both C2 and C2ox gave full conversion in cross-couplings with RLi reagents. The oxidation of C2 and subsequent reduction of C2ox by nBuLi was studied in detail by 31P NMR spectroscopy (Figure 7.2), showing, much to our surprise, partial formation of mononuclear complex C1, which we knew to be catalytically inactive.

31 Figure 7.2 P-NMR Spectra of C2 in tol-d8 (a), after O2 exposure (b,c), and n-BuLi addition (d)

The lithium reagent promotes reduction from PdI to Pd0 and the formation of both 0 Pd(PtBu3)2 (C1) and Pd , which becomes evident from the observed stoichiometry (NMR analysis, see the Supporting Information) of the complexes and ligands (Scheme 7.2).

Scheme 7.2 Reduction of C2 with R-Li

Following the cross-coupling reaction of 4-bromoanisole by NMR spectroscopy, we also observed the in situ formation of the bridged complex C2 from C1ox after RLi addition (in accordance with previous observations by Schoenebeck using Grignard reagents),[5] for which we suggest the stoichiometry shown in Scheme 7.3.

Scheme 7.3 Schematic in situ formation of C2 from C1ox

The combined results of the RLi addition experiments with C1ox, C2, and C2ox, which clearly showed reduction in all cases, led to the hypothesis that a common active species, that is, Pd nanoparticles (PdNPs), are formed in situ. TEM measurements were carried out to investigate the presence of nanoparticles in samples of C1 and C1ox prior to RLi addition, but in neither case, any PdNPs were observed. Studying the effect of the addition of the lithium reagent to C1ox, we clearly observed PdNPs with dimensions of 2—3 nm (Figure 7.3).

Figure 7.3 TEM image and corresponding EDX spectrum of PdNPs

In a highly informative set of experiments, under optimized cross-coupling conditions and with all previously mentioned precatalysts (C1ox, C2, and C2ox), samples were taken both during and at the end of the reaction, and analyzed by TEM for the in situ formation of nanoparticles (Figure 7.3). We were pleased to see the formation of nanoparticles in all cases where product was formed. Energy-dispersive X-ray analysis (EDX)[15] revealed the elemental compositions of the samples, and clearly showed an increase in the Pd/P ratio with respect to catalytically inactive complexes, supporting the formation of PdNPs. Isolation of these nanoparticles was successful by centrifugation and repeated washing with toluene, and the absence of homogeneous Pd complexes was confirmed by 1H and 31P NMR spectroscopy. Fast cross-coupling reactions of organolithium reagents with the isolated nanoparticles were successful, strongly supporting the involvement of PdNPs as the active catalyst.

Scheme 7.4 Proposed catalyst activation pathway

Based on the experimental data, the catalyst activation pathway shown in Scheme 7.4 is proposed. PdNPs are known to be formed from PdII sources under reductive conditions.[16] In 0 ox our system, O2 reacts first with the Pd complex, thereby oxidizing it to C1 (Scheme 7.4a) which is then in situ reduced to highly active Pd0 nanoparticles by means of the organolithium reagent, either directly (b) or via C2/C2ox. The striking difference of the novel catalytic system presented here, compared to other PdNP-catalyzed cross-coupling reactions,[17] is the ultrafast cross-coupling of organolithium reagents, which can be explained by the in situ formation of numerous small (2-3 nm) Pd nanoparticles.

7.5 Application in the coupling of 11C and the synthesis of Celecoxib The benefits of the ultrafast coupling presented here can best be exploited in reactions where time restrictions are crucial. Therefore, we focused on the cross-coupling of 11 11 [1,18,19] [ C]methyllithium (t½( C)=20 min) for PET labeling. Such a method would be complementary to the more often used electrophilic quenching of a nucleophilic drug precursor with [11C]iodomethane. The presence of several nucleophilic sites in specific precursors often results in undesired (overalkylated) side products. We selected the synthesis of [11C]celecoxib to illustrate the usefulness of our method (Scheme 7.5).[20,21]

Scheme 7.5 Synthesis of radiolabelled Celecoxib Initially, we explored the reaction of commercially available MeLi and celecoxib precursor 30. Having isolated the target 31 in excellent yield (91 %), we used in situ generated MeLi, prepared from MeI in both a stoichiometric and a substoichiometric (0.1 equiv) ratio with respect to nBuLi.[18] Gratifyingly, we were able to isolate the corresponding product by preparative HPLC in good yield (85 %) with respect to the MeI starting material. With a representative result for the radiolabeling based on the use of substoichiometric MeI in hand, the synthesis of [11C]celecoxib (31*; coupling time 2 min, total preparation time including HPLC purification <15 min) was pursued. The final decay-corrected radiochemical yield for 31* was found to be 65 % (average of three runs). For further application in isotope labelling, we considered the direct incorporation of the -

CD3 moiety in organic compounds. The use of deuterated MeI is desirable from a cost perspective, and its use with a range of electrophiles has recently been shown by Hu et al.[22]

Since the reported procedure requires a large excess of the costly CD3I (3.5 eq) we anticipated that our method using in situ generated CD3Li could provide a viable alternative (Scheme 7.6). As we had already converted unlabeled MeI into MeLi, as well as the [11C]- analogue using n-BuLi and successfully applied it in cross-coupling, an identical experimental setup for CD3I was used. Much to our surprise, no CD3-incorporation could be observed in either a cross-coupling reaction, or electrophilic quench with benzaldehyde.[23,24] Switching to tBuLi gave the desired CD3Li, which coupled readily with 2-Br-naphthalene to provide 2a- d3 in 65 % yield, establishing a new method for the incorporation of the -CD3 moiety.

Scheme 7.6 Cross-coupling of MeLi-d3

7.6 Conclusions and outlook In conclusion, a novel procedure for the rapid palladium-catalyzed coupling of alkyl- and aryllithium reagents has been developed, with a crucial role for O2 in generating the active catalyst. Systematic studies towards the active catalyst species revealed the formation of palladium nanoparticles for all three active precatalysts upon addition of the organolithium reagent, which facilitates rapid cross-couplings with a range of aryl bromides at room temperature. The application of this novel method was showcased in the coupling of [11C]methyllithium in less than two minutes with a decay-corrected yield of 65 % as a key step in the synthesis of the PET tracer celecoxib. Acknowledgements

This work described in this chapter was carried out together with Filippo Tosi. Initial studies were peformed by Dr. Carlos Vila.

7.7 Experimental section General methods: All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques unless noted otherwise. THF and toluene were dried using an SPS- t system. White colored Pd[P( Bu)3]2, was purchased from Strem chemicals and stored under nitrogen t at -25 ºC. Pure [PdBrP( Bu)3]2 was purchased from Strem chemicals, used in a glovebox and stored at -35 ºC. All alkyllithium reagents and aryl bromides were purchased from Aldrich or TCI and used without further purification, unless noted otherwise. Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm, or Grace-Reveleris purification system with Grace cartridges. Components were visualized by UV and cerium/molybdenum or potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). PREP-HPLC was perfomed on a Grace-reveleris PREP with a 5 u Denali C- 18 (15 cm, 10 mm id). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) or a 600 MHz (600 and 125 MHz, respectively) using CDCl3 as solvent, unless noted otherwise. Chemical shift values are reported in ppm with the solvent resonance as the internal 1 13 standard (CHCl3:  7.26 for H,  77.0 for C) unless noted otherwise. Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Samples for TEM and cryo-TEM were analized on graphene grids (Graphene Supermarket). For cryo- TEM analysis, the grids were vitrified in liquid nitrogen (Vitrobot, FEI, Eindhoven, The Netherlands) and transferred to a Tecnai T20 cryo-electron microscope operating at 200 kV. EDX analysis was performed with a EDX Oxford xmax instrument, and the elemental ratio was calculated via INCA software.

General Procedures for the oxygen activated cross-coupling of organolithium reagents with aryl bromides

Method A: General procedure for the cross-coupling with organolithium reagents.

In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of pure oxygen and stirred for 1 min, upon which the color changed from slightly yellow to dark orange. The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 2.0 mL; this solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump After the addition was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was purified by column chromatography.

Method B: General procedure for the cross-coupling with organolithium reagents at lower temperature

In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of pure oxygen and stirred for 1 min at rt, upon which the color changed from slightly yellow to dark orange. Then, the reaction vessel was cooled to the corresponding temperature by means of an ice batch. The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 2.0 mL; this solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump. After the addition was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was purified by column chromatography.

Method C: General procedure for the cross-coupling with alkyllithium reagents in the presence of acidic groups

In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of pure oxygen and stirred for 1 min, upon which the color changed from slightly yellow to dark orange. The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 4.0 mL; this solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump After the addition was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was purified by column chromatography.

Method D: General procedure for the cross-coupling with alkyllithium reagents for large scale and low catalyst loading

In a dry Schlenk flask Pd(PtBu3)2 (0,025 - 5 mol%) and the aryl bromide (0.6 -12 mmol) were dissolved in dry toluene (4 – 80 ml) at room temperature. The mixture was slowly purged with 20 ml of pure oxygen and stirred overnight to ensure complete oxidation of the precatalyst, upon which the color changed from slightly yellow to (dark) orange. In view of safety, excess oxygen was removed from the headspace by 2-3 careful vacuum/nitrogen cycles for the large scale reactions. The corresponding commercial alkyllithium (1.5 eq.) reagent was diluted with toluene (2 - 25 ml); this solution was added by the use of a syringe pump (2 – 30 min). After the addition was completed, the reaction was quenched with MeOH, and conversion checked by GCMS analysis

Experimental data of compounds 2a-29a:

2-methylnaphthalene (2a): Synthesized according to Method A. [68 mg, 80% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.8 Hz, 1H), 7.80 (dd, J = 8.1, 4.1 Hz, 2H), 7.66 (s, 1H), 7.53-7.43 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 2.57 (s, 13 3H) ppm. C NMR (100 MHz, CDCl3) δ 135.5, 133.7, 131.7, 128.1, 127.7, 127.6, 127.3, 126.9, 125.9, 124.5, 21.7 ppm. The physical data were identical in all respects to those previously reported. 1

2-phenylnaphthalene (2b): Synthesized according to Method A. [95 mg, 78% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3)) δ 8.10 (s, 1H), 7.99 – 7.89 (m, 3H), 7.80 (td, J = 8.6, 8.1, 1.3 Hz, 3H), 7.59 – 7.50 (m, 4H), 7.47 – 7.40 (m, 1H). 13C

NMR (101 MHz, CDCl3) δ 141.25, 138.69, 133.82, 132.75, 128.98, 128.54, 128.33, 127.77, 127.56, 127.47, 126.41, 126.05, 125.93, 125.72. The physical data were identical in all respects to those previously reported. 2

2-butylnaphthalene (2c): Synthesized according to Method A. [101 mg, 91% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3)) δ 7.97 – 7.83 (m, 3H), 7.71 (s, 1H), 7.61 – 7.47 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 2.88 (t, J = 7.7 Hz, 2H), 1.80 (p, J = 13 7.6 Hz, 2H), 1.61 – 1.37 (m, 2H), 1.07 (t, J = 8.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 143.15, 136.42, 134.70, 130.47, 130.34, 130.20, 130.15, 129.04, 128.54, 127.72, 38.57, 36.30, 25.17, 16.76. The physical data were identical in all respects to those previously reported. 1

2-(sec-butyl)naphthalene (2d): Synthesized according to Method A. [97 mg, 88% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3)) δ 7.96 – 7.82 (m, 3H), 7.71 – 7.68 (m, 1H), 7.58 – 7.46 (m, 2H), 7.43 (dd, J = 8.5, 1.8 Hz, 1H), 2.85 (h, J = 7.0 Hz, 1H), 13 1.85 – 1.71 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 147.82, 134.92, 130.61, 130.56, 130.30, 130.27, 128.61, 128.49, 127.93, 127.74, 44.56, 33.79, 24.62, 15.04.The physical data were identical in all respects to those previously reported. 3 trimethyl(naphthalen-2-ylmethyl)silane (2e): Synthesized according to Method A. [120 mg, 93% 1 yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz,

CDCl3)) δ 7.82 (dt, J = 7.7, 1.1 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.49 – 7.38 (m, 3H), 7.21 (dd, J = 8.3, 1.8 13 Hz, 1H), 2.30 (s, 2H), 0.07 (s, 9H). C NMR (101 MHz, CDCl3) δ 140.95, 136.53, 133.69, 130.58, 130.26, 130.18, 129.67, 128.42, 127.82, 127.00, 30.06, 0.89. The physical data were identical in all respects to those previously reported. 4

2-(methyl-d3)naphthalene (2e-d3) Synthesized according to Method A. [57 mg, 65% yield].

Preparation of methyllithium-d3: MeI-d3 (1,5 eq. 0,9 mmol, 56 ul) was added dropwise to a stirred solution of tBuLi (2.2 eq. 2 mmol in Hexane) in THF (1 ml) at -78 °C. The reaction mixture was allowed to reach room temperature, diluted with toluene (up to 5 mL) and used as such. 1H NMR (400 MHz,

CDCl3) δ 7.77 (d, J = 7.5 Hz, 1H), 7.73 (ddd, J = 54.1, 8.5, 4.4 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J = 264.2 Hz, 13 2H), 7.29 (dd, J = 8.4, 1.7 Hz, 1H). C NMR (101 MHz, CDCl3) δ 135.45, 133.80, 131.85, 128.23, 128.02, 127.81, 127.73, 127.36, 126.98, 125.98, 125.07, 21.02 (d, J = 19.9 Hz). The physical data were identical in all respects to those previously reported.5

(1) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 1678. (2) Heijnen, D.; Gualtierotti, J.; Hornillos, V.; Feringa, B. L. Chem. - A Eur. J. 2016, 22, 3991–3995. (3) Cabiddu, S.; Cancellu, D.; Floris, C.; Gelli, G.; Melis, S. Synthesis. 1988, 1988, 888–890. (4) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L. Org. Lett., 2015, 17 (9), pp 2262–2265. (5) Ka Young Lee, Jeong Eun Na, Mi Jung Lee Jae, Nyoung Kim, Tetrahedron Lett, 2004, 45, 5977– 5981

1-methylnaphthalene (3a): Synthesized according to Method A. [72 mg, 84% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.60-7.52 (m, 2H), 7.45 – 7.40 (m, 1H), 7.37 (d, 13 J = 6.9 Hz, 1H), 2.75 (s, 3H). C NMR (100 MHz, CDCl3) δ 134.3, 133.6, 132.6, 128.6, 126.6, 126.4, 125.7, 125.6, 125.6, 124.1, 19.4 ppm. The physical data were identical in all respects to those previously reported.1

1-phenylnaphthalene (3b): Synthesized according to Method A. [92 mg, 75% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane) H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 9.5 13 Hz, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.58 – 7.49 (m, 6H), 7.49 – 7.42 (m, 3H). C NMR (101 MHz, CDCl3) δ 140.74, 140.24, 133.77, 131.60, 130.05, 128.23, 128.22, 127.60, 127.20, 126.89, 126.00, 125.98, 125.73, 125.34. The physical data were identical in all respects to those previously reported.2

1-butylnaphthalene (3c): Synthesized according to Method A. [98 mg, 89% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane) H NMR (400 MHz, CDCl3) δ 8.17 (d, 1H), 8.00 – 7.92 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.66 – 7.53 (m, 2H), 7.50 (dd, J = 8.1, 7.0 Hz, 1H), 7.42 (d, J = 7.0, 1.2 Hz, 1H), 3.18 (t, 2H), 1.85 (tt, J = 7.8, 6.5 Hz, 2H), 1.57 (h, J = 7.4 Hz, 2H), 1.09 (t, J = 7.4 Hz, 13 3H). C NMR (101 MHz, CDCl3) δ 139.07, 133.99, 132.02, 128.84, 127.98 (naphthalene), 126.49, 125.95, 125.91 (naphthalene), 125.70, 125.62, 125.44, 124.01, 33.13, 32.94, 23.01, 14.15. The product was obtained with traces of naphthalene.1

1-(sec-butyl)naphthalene (3d): Synthesized according to Method A. [67 mg, 61% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane) H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.5, 5.5 Hz, 2H (+ naphthalene)), 7.75 (d, J = 8.1 Hz, 1H), 7.59 – 7.40 (m, 4H (+ naphthalene)), 3.57 (h, J = 6.9 Hz, 1H), 1.91 (dq, J = 14.0, 7.4 Hz, 1H), 1.78 (dq, J = 13.6, 7.3 Hz, 1H), 13 1.43 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 143.75, 133.97, 131.83, 128.97, 126.22, 125.64, 125.62, 125.22, 123.30, 122.49, 35.34, 30.62, 21.27, 12.34.The physical data were identical in all respects to those previously reported.1

trimethyl(naphthalen-1-ylmethyl)silane (3e): Synthesized according to Method A. [125 mg, 98% 1 yield] Colorless oil obtained after column chromatography (SiO2, n-pentane) H NMR (400 MHz,

CDCl3) δ 8.05 – 7.98 (m, 1H), 7.93 – 7.85 (m, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.47 – 13 7.38 (m, 1H), 7.23 (d, J = 7.1 Hz, 1H), 2.65 (s, 2H), 0.10 – 0.05 (s, 9H). C NMR (101 MHz, CDCl3) δ 139.95, 136.69, 134.43, 131.32, 128.22, 128.08, 127.98, 127.70, 127.50, 127.38, 26.19, 1.56. The physical data were identical in all respects to those previously reported. 4

2-(naphthalen-1-yl)thiophene (3f) Synthesized according to Method A. [77 mg, 61% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane ) H NMR (400 MHz, CDCl3) δ 8.26 – 8.19 (m, 1H), 7.91 – 7.87 (m, 1H), 7.85 (dt, J = 8.2, 1.1 Hz, 1H), 7.57 (dd, J = 7.1, 1.3 Hz, 1H), 7.53 – 7.45 (m, 3H), 7.42 (dd, J = 5.1, 1.2 Hz, 1H), 7.24 (dd, J = 3.5, 1.2 Hz, 1H), 7.18 (dd, J = 5.1, 3.5 Hz, 1H). 13C NMR

(101 MHz, CDCl3) δ 141.77, 133.85, 132.44, 131.87, 128.41, 128.34, 128.22, 127.40, 127.29, 126.46, 126.02, 125.77, 125.64, 125.26.2

9-methylanthracene (4a): Synthesized according to Method A. [112 mg, 97% yield] White solid 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.30 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.54-7.46 (m, 4H), 3.11 (s, 3H) ppm. 13C NMR (100

MHz, CDCl3) δ 131.5, 130.1, 130.0, 129.1, 125.3, 125.2, 124.8, 124.7, 13.9 ppm. Data was consistent with commercially available product.

1-methoxy-4-methylbenzene (5a): Synthesized according to Method A. [50 mg, 67% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz,

CDCl3) δ 157.4, 129.9, 129.8, 113.7, 55.3, 20.5 ppm. Data was consistent with commercially available product.

4-methoxy-1,1'-biphenyl (5b): Synthesized according to Method A. [105 mg, 95% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400 MHz, CDCl3) δ 7.59 (td, J = 8.7, 1.8 Hz, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 13 3.88 (s, 3H). C NMR (101 MHz, CDCl3) δ 159.16, 140.84, 133.78, 128.76, 128.18, 126.76, 126.69, 114.22, 55.35. The physical data were identical in all respects to those previously reported.1

1-butyl-4-methoxybenzene (5c): Synthesized according to Method A. [79 mg, 80% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H), 1.66 – 1.53 (m, 13 2H), 1.38 (dq, J = 14.6, 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3) δ 157.54, 134.95, 129.21, 113.58, 55.18, 34.70, 33.91, 22.29, 13.95. The physical data were identical in all respects to those previously reported.1

1-secbutyl-4-methoxybenzene (5d): Synthesized according to Method A. [75 mg, 76% yield] 1 Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400

MHz, CDCl3) δ 7.13 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 2.58 (q, J = 7.0 Hz, 1H), 1.60 13 (p, J = 7.3 Hz, 2H), 1.25 (d, J = 7.0 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 157.61, 139.74, 127.82, 113.56, 55.16, 40.80, 31.32, 22.03, 12.23. The physical data were identical in all respects to those previously reported.1

(4-methoxybenzyl)trimethylsilane (5e): Synthesized according to Method A. [114 mg, 98% yield] 1 Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400 13 MHz, CDCl3) δ 6.94 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 2.03 (s, 2H), 0.01 (s, 9H). C

NMR (101 MHz, CDCl3) δ 156.49, 132.31, 128.80, 113.64, 55.20, 25.70, -1.91. The physical data were identical in all respects to those previously reported 4

1-methoxy-3-methylbenzene (6a): Synthesized according to Method A. [51 mg, 69% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.75-6.70 (m, 2H), 3.80 (s, 3H), 2.35 (s, 3H) ppm. 13C

NMR (100 MHz, CDCl3) δ 159.5, 139.5, 129.2, 121.5, 114.7, 110.7, 55.1, 21.6 ppm. Data was consistent with commercially available product.

1-methoxy-3-methylbenzene (6b): Synthesized according to Method A. [79 mg, 72% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane/ether 100:1) H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.1 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.40 (td, J = 7.6, 3.2 Hz, 2H), 7.24 (d, J = 9.1 Hz, 1H), 13 7.19 (d, J = 1.8 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 3.90 (s, 3H). C NMR (101 MHz, CDCl3) δ 160.07, 142.88, 141.22, 129.86, 128.84, 127.52, 127.31, 119.79, 113.03, 112.79, 55.38.6

N,N,4-trimethylaniline (7a): Synthesized according to Method A. [71 mg, 88% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 2.94 (s, 6H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz,

CDCl3) δ 148.8, 129.6, 126.2, 113.3, 41.1, 20.3 ppm. The physical data were identical in all respects to those previously reported.7

N,N-dimethyl-[1,1'-biphenyl]-4-amine (7b): Synthesized according to Method A. [102 mg, 86% yield] 1 Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400

MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 6.8 Hz, 13 1H), 6.88 (d, J = 8.8 Hz, 2H), 3.05 (s, 6H). C NMR (101 MHz, CDCl3) δ 150.01, 141.28, 129.27, 128.72, 127.76, 126.35, 126.05, 112.83, 40.64. The physical data were identical in all respects to those previously reported.2

4-butyl-N,N-dimethylaniline (7c): Synthesized according to Method A. [90 mg, 85% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 2.97 (s, 6H), 2.59 (t, J = 7.5 Hz, 2H), 1.67 – 1.57 (m, 13 2H), 1.42 (dq, J = 14.6, 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3) δ 148.95, 131.26, 129.00, 113.04, 41.02, 34.66, 34.07, 22.44, 14.08.The physical data were identical in all respects to those previously reported.1

(6) Jin Yang, Lei, Wang, Dalton Trans., 2012, 41, 12031-12037 (7) Chen, W.-X.; Shao, L.-X. J. Org. Chem., 2012, 77, 9236.

4-(sec-butyl)-N,N-dimethylaniline (7d): Synthesized according to Method A. [85 mg, 80% yield] 1 Colorless oil obtained after column chromatography (SiO2, n-pentane/Ether 100:1). H NMR (400

MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 2.95 (s, 6H), 2.55 (h, J = 7.0 Hz, 1H), 1.75 13 – 1.46 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 148.99, 135.98, 127.57, 112.90, 40.94, 40.64, 31.38, 22.04, 12.37. HRMS [M+H|: 178.1596 Found : 178.1589.

N,N-dimethyl-4-((trimethylsilyl)methyl)aniline (7e): Synthesized according to Method A. [119 mg, 1 96% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane/Ether 100:1). H

NMR (400 MHz, CDCl3) δ 6.95 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 2.94 (s, 6H), 2.03 (s, 2H), 0.04 13 (s, 9H). C NMR (101 MHz, CDCl3) δ 147.92, 128.75 (2x), 113.43, 41.24, 25.49, -1.72. HRMS [M+H|:

Exact Mass: 208,1522 Found 208,1516.

2-(p-tolyl)-1,3-dioxolane (8a): Synthesized according to Method A. [84 mg, 86% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane/Ether 100:1). H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 5.80 (s, 1H), 4.27-3.94 (m, 4H), 2.37 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 139.0, 135.0, 129.0, 126.4, 103.8, 65.2, 21.3 ppm. The physical data were identical in all respects to those previously reported.4

1,3-dichloro-5-methylbenzene (9a): Synthesized according to Method A. [62 mg, 64% yield] 1 Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 13 7.17 (s, 1H), 7.06 (s, 2H), 2.31 (s, 3H) ppm. C NMR (100 MHz, CDCl3) δ 141.1, 134.6, 127.5, 125.7, 20 21.0 ppm. The physical data were identical in all respects to those previously reported.

1-butyl-4-(chloromethyl)benzene (10a) Synthesized according to Method B at 0ºC. [88mg, 80% 1 yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz,

CDCl3) δ 7.31 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 4.59 (s, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.66 – 13 1.55 (m, 2H), 1.37 (dq, J = 14.6, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3) δ 145.99, 137.38, 131.45, 131.21, 48.98, 38.03, 36.20, 25.01, 16.60. The physical data were identical in all respects to those previously reported.8

4-(chloromethyl)-1,1'-biphenyl (10b) Synthesized according to to Method B at 0ºC [121 mg, 100% 1 yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, 13 CDCl3) δ 7.64 – 7.56 (m, 4H), 7.50 – 7.43 (m, 4H), 7.37 (d, J = 7.3 Hz, 1H), 4.65 (s, 2H). C NMR (101

MHz, CDCl3) δ 141.37, 140.47, 136.42, 129.04, 128.80, 127.52, 127.48, 127.11, 46.05. Data was consistent with commercially available product.

( 8) Youichi;, Y.; TakeshiI, Y.; Susumo, M.; Akiko, I. N-Phenyloxamide derivatives. US Patent US20070870741 20071011

1-chloro-4-(prop-1-en-2-yl)benzene (11a): Synthesized according to Method A. [66 mg, 72% yield] 1 Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 5.36 (s, 1H), 5.20-5.04 (m, 1H), 2.14 (d, J = 0.6 Hz, 3H) 13 ppm. C NMR (100 MHz, CDCl3) δ 142.1, 139.6, 133.1, 128.3, 126.8, 113.0, 21.7 ppm. The physical data were identical in all respects to those previously reported.9

2-methyl-1,1'-biphenyl (12a): Synthesized according to Method A. [95 mg, 94% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.50-7.44 (m, 13 2H), 7.43-7.37 (m, 3H), 7.35-7.29 (m, 4H), 2.35 (s, 3H) ppm. C NMR (100 MHz, CDCl3) δ 142.0, 141.9, 135.4, 130.3, 129.8, 129.2, 128.1, 127.3, 126.8, 125.8, 20.5 ppm. The physical data were identical in all respects to those previously reported.10

4,4'-dimethyl-1,1'-biphenyl (13a): Synthesized according to Method A with 2.5 eq organolithium at 1 40 °C. [90 mg, 83% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). H 13 NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H) ppm. C NMR

(100 MHz, CDCl3) δ 138.3, 136.7, 129.5, 126.8, 21.1 ppm. The physical data were identical in all respects to those previously reported.11

(E)-prop-1-en-1-ylbenzene (14a): Synthesized according to Method A. [39 mg, 55% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.1 Hz, 1H), 6.42 (dq, J = 15.8, 1.4 Hz, 1H), 6.25 (dq, J = 13 15.7, 6.5 Hz, 1H), 1.90 (dd, J = 6.5, 1.6 Hz, 3H) ppm. C NMR (100 MHz, CDCl3) δ 137.9, 131.0, 128.5, 126.7, 125.8, 125.7, 18.5 ppm. The physical data were identical in all respects to those previously reported.12

(E)-1,2-diphenylethene (14b) Synthesized according to Method A. [77 mg, 71% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.0 13 Hz, 4H), 7.40 (t, J = 8.4 Hz, 4H), 7.31 (t, J = 7.1 Hz, 2H), 7.16 (s, 2H). C NMR (101 MHz, CDCl3) δ 137.34, 128.73, 128.71, 127.67, 126.55. Data was consistent with commercially available product.

(E)-2-styrylthiophene (14c) Synthesized according to Method A. [92 mg, 82% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 7.0 Hz, 2H), 7.33 – 7.26 (m, 2H), 7.24 (d, J = 5.1 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 13 7.06 (dd, J = 5.1, 3.6 Hz, 1H), 7.00 (d, J = 16.1 Hz, 1H). C NMR (101 MHz, CDCl3) δ 142.92, 136.99, 128.76, 128.36, 127.66, 126.36, 126.20, 124.40, 121.83. The physical data were identical in all respects to those previously reported 6

9) Tripathi, C. B.; Mukherjee, S. Angew. Chem. Int. Ed., 2013, 52, 8450. 10) Rajabi, F.; Thiel, W. R. Adv. Synth. Catal. 2014, 356, 1873 – 1877. 11) Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. Angew. Chem. Int. Ed., 2014, 53, 3475. 12) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J. Am. Chem. Soc., 2010, 132, 7998.

2-methyl-9H-fluorene (15a): Synthesized according to Method A. [102 mg, 95% yield] White solid 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.45-7.40 (m, 2H), 7.34 (td, J = 7.4 , 1.1 Hz, 13 1H), 7.25 (dd, J = 7.7, 0.6 Hz, 1H), 3.91 (s, 2H), 2.50 (s, 3H) ppm. C NMR (100 MHz, CDCl3) δ 143.5, 143.1, 141.9, 139.1, 136.6, 127.6, 126.7, 126.3, 125.8, 125.0, 119.6, 119.6, 36.8, 21.7 ppm. The physical data were identical in all respects to those previously reported.1

2-(4-butylphenyl)oxirane (17a) Synthesized according to to Method B at -10ºC. [61 mg, 58% yield] 1 Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.22 – 7.13 (m, 4H), 3.84 (dd, J = 4.1, 2.6 Hz, 1H), 3.13 (dd, J = 5.5, 4.1 Hz, 1H), 2.82 (dd, J = 5.5, 2.6 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.66 – 1.51 (m, 2H), 1.35 (h, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C

NMR (101 MHz, CDCl3) δ 145.72, 137.36, 131.22, 128.12, 55.02, 53.73, 38.02, 36.26, 24.97, 16.59.The physical data were identical in all respects to those previously reported.13

p-tolylmethanol (18a): Synthesized according to Method C. [65 mg, 88% yield] Colorless oil obtained 1 after column chromatography (SiO2, n-pentane/Ether 90:10). H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 4.63 (s, 2H), 2.36 (s, 3H), 1.90 (s, 1H) ppm. 13C NMR (100 MHz,

CDCl3) δ 137.9, 137.3, 129.2, 127.1, 65.2, 21.1 ppm. The physical data were identical in all respects to those previously reported.14

(4-butylphenyl)methanol (18b): Synthesized according to Method C. [70 mg, 71% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane/Ether 90:10). H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.62 (s, 2H), 2.69 – 2.57 (m, 2H), 2.12 (s, 1H), 1.71 – 13 1.53 (m, 2H), 1.38 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3) δ 142.47 , 138.24, 128.67, 127.19, 65.25, 35.44, 33.77, 22.44, 14.04. Data was consistent with commercially available product.

2-(4-butylphenyl)ethan-1-ol (19a) Synthesized according to Method C. [56 mg, 52% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.62 (s, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.12 (s, 1H), 1.70 – 1.54 (m, 13 2H), 1.38 (dq, J = 14.6, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3) δ 145.05, 140.82, 131.25, 129.77, 67.82, 38.02, 41.44, 36.35, 25.01, 16.62. Exact Mass [M+H|: 179,1436 Found : 179,1430.

[1,1'-biphenyl]-4-ol (20a) Synthesized according to Method C. [85 mg, 83% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane H NMR (400 MHz, CDCl3 + DMSO-d6) δ 8.99 (s, 1H), 7.49 – 7.42 (m, 2H), 7.40 – 7.28 (m, 4H), 7.23 – 7.15 (m, 1H), 6.89 – 6.78 (m, 2H). 13C NMR (101

MHz, CDCl3 + DMSO-d6) δ 157.03, 140.83, 131.85, 128.61, 127.84, 126.26, 117.40, 115.80. Data was consistent with commercially available product.

(13) Maryanoff, B. E.; Mccomsey, D. F.; Gardocki, J. F.; Shank, R. P.; Costanzo, M. J.; Nortey, S.; Schneider, C. R.; Setler, P. E. J. Med. Chem. 1987, 30, 1433–1454. (14) Sutter, M.; Pehlivan, L.; Lafon, R.; Dayoub, W.; Raoul, Y.; Metay, E.; Lemaire, M. Green Chem., 2013, 15, 3020

3-butylbenzo[b]thiophene (21b) Synthesized according to Method A. [96 mg, 84% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.48 – 7.35 (m, 2H), 7.11 (s, 1H), 2.90 (d, J = 6.7 Hz, 2H), 1.79 (ddd, J = 13 15.3, 8.2, 6.9 Hz, 2H), 1.49 (dt, J = 14.7, 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 140.63, 139.28, 137.32, 124.17, 123.84, 122.97, 121.85, 120.92, 31.45, 28.41, 22.79, 14.10. The physical data were identical in all respects to those previously reported. 15

4-butyldibenzo[b,d]furan (22a) Synthesized according to Method A. [116 mg, 86% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 8.00 (ddd, J = 7.7, 1.4, 0.7 Hz, 1H), 7.85 (dd, J = 5.4, 3.6 Hz, 1H), 7.66 (dt, J = 8.2, 0.8 Hz, 1H), 7.51 (ddd, J = 8.3, 7.3, 1.4 Hz, 1H), 7.39 (td, J = 7.5, 1.0 Hz, 1H), 7.35 – 7.30 (m, 2H), (3.06 (t, J = 7.5 Hz, 2H)), 1.99 – 1.75 (m, 13 2H), 1.52 (h, J = 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 156.07, 154.85, 127.27, 127.16, 126.91, 124.72, 123.82, 122.72, 122.54, 120.70, 118.09, 111.71, 32.15, 29.70, 22.66, 14.07.

3-butylthiophene (23a) Synthesized according to Method A. [69 mg, 82% yield] Colorless oil 1 obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.26 (dd, J = 4.9, 2.9 Hz, 1H), 6.96 (dd, J = 8.1, 3.4 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H), 1.71 – 1.59 (m, 2H), 1.40 (h, J = 13 7.3 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 143.21, 128.30, 125.04, 119.78, 32.75, 30.00, 22.43, 13.96. The physical data were identical in all respects to those previously reported. 16

3-butyl-1-(triisopropylsilyl)-1H-pyrrole (24a) Synthesized according to Method A. [117 mg, 70% 1 yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz,

CDCl3) δ 6.69 (t, J = 2.2 Hz, 1H), 6.52 (s, 1H), 6.15 (s, 1H), 2.49 (t, J = 7.7 Hz, 2H), 1.63 – 1.50 (m, 2H), 13 1.49 – 1.29 (m, 5H), 1.09 (d, J = 7.5 Hz, 18H), 0.92 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) δ 126.37, 123.86, 120.98, 110.57, 33.24, 26.71, 22.53, 17.88, 14.02, 11.69. HRMS [M+H|: 280.2461 Found : 280.2455.

3-phenyl-1-(triisopropylsilyl)-1H-pyrrole (24b) Synthesized according to Method A. [151 mg, 84% 1 yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 8.2, 1.3 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.17 (t, J = 6.7 Hz, 1H), 7.08 (t, J = 1.8 Hz, 1H), 6.82 (t, J = 2.4 Hz, 1H), 6.63 (dd, J = 2.8, 1.5 Hz, 1H), 1.59 – 1.41 (m, 3H), 1.15 (d, J = 7.5 Hz, 18H). 13C NMR (101 MHz, Chloroform-d) δ 138.68, 131.19, 129.43, 127.93, 127.88, 127.82, 123.22, 111.27, 20.50, 14.35. HRMS [M+H|: 300.2148 Found : 300.2142.

(15) Cabiddu, S.; Cancellu, D.; Floris, C.; Gelli, G.; Melis, S. Synthesis. 1988, 1988, 888–890 (16) Tan, L.; Curtis, M. D.; Francis, A. H. Macromolecules 2002, 35, 4628–4635.

3-phenylfuran (25a) Synthesized according to Method A. [47 mg, 54% yield] Colorless oil obtained 1 after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.57 – 7.48 13 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 6.73 (s, 1H). C NMR (101 MHz, CDCl3) δ 143.67, 138.48, 132.41, 128.82, 127.01, 126.46, 125.88, 108.86.The physical data were identical in all respects to those previously reported.17

1-methyl-5-phenyl-1H-indole (26a) Synthesized according to Method A. [50 mg, 40% yield] Colorless 1 oil obtained after column chromatography (SiO2, n-pentane). H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.77 – 7.63 (m, 2H), 7.56 – 7.45 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 3.1 13 Hz, 1H), 6.58 (t, J = 2.5 Hz, 1H), 3.84 (s, 3H). C NMR (101 MHz, CDCl3) δ 145.30, 132.17, 131.62, 131.32, 130.07, 128.92, 124.08, 122.09, 112.12, 103.99, 35.63. The physical data were identical in all respects to those previously reported.18

1-(3-methoxyphenyl)naphthalene (27a) Synthesized according to Method A. [75 mg, 40 % yield] Ferrocenyl lithium prepared according to literature procedure.7 Dark red oil 1 obtained after column chromatography (SiO2, n-pentane:DCM). H NMR (400 MHz, CDCl3) δ 8.59 – 8.53 (m, 1H), 7.89 (ddd, J = 8.2, 6.2, 2.5 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.54 – 7.45 (m, 3H), 4.68 (t, J 13 = 1.8 Hz, 2H), 4.42 (t, J = 1.8 Hz, 2H), 4.21 (s, 5H). C NMR (101 MHz, CDCl3) δ 136.07, 133.78, 131.91, 128.44, 127.99, 126.94, 126.02, 125.51, 125.46, 125.22, 87.09, 70.52, 69.64, 68.15. HRMS [M+H|: 313.0680 found 313.0625.

1-(3-methoxyphenyl)naphthalene (28a) Synthesized according to Method A [35 mg, 20 % yield] Ferrocenyl lithium prepared according to literature procedure.7 Dark red oil 1 obtained after column chromatography (SiO2, n-pentane:DCM). H NMR (400 MHz, CDCl3 ) δ 7.41 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.57 (t, J = 1.9 Hz, 2H), 4.27 (t, J = 1.9 Hz, 2H), 4.04 (s, 5H), 3.83 13 (s, 3H). C NMR (101 MHz, CDCl3) δ 160.66, 133.92, 129.83, 116.48, 88.53, 72.10, 71.12, 68.77, 57.93. 8 HRMS Mass : 293.0551 Found : 293.0545.

1-(3-methoxyphenyl)naphthalene (29a) Synthesized according to Method B. 1 [122 mg, 87 % yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). H NMR

(400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 17.5, 8.1 Hz, 2H), 7.67 – 7.41 (m, 5H), 7.18 (d, 13 J = 7.6 Hz, 1H), 7.14 (s, 1H), 7.06 (dd, J = 8.3, 2.1 Hz, 1H), 3.91 (s, 3H). C NMR (101 MHz, CDCl3) δ 162.22, 144.91, 142.85, 136.51, 134.33, 131.97, 130.99, 130.43, 129.51, 128.79, 128.78, 128.51, 128.07, 125.32, 118.38, 115.61. The physical data were identical in all respects to those previously reported.19

(17) Yu, J.; Liu, J.; Shi, G.; Shao, C.; Zhang, Y. Angew. Chem. Int. Ed. Engl. 2015, 54, 4079–4082 (18) Mesganaw, T.; Fine Nathel, N. F.; Garg, N. K. Org. Lett. 2012, 14, 2918–2921. (19) Molander, G. A.; Beaumard, F. Org. Lett. 2010, 12, 4022–4025. Synthesis of Celecoxib

Figure 1 Two-step synthesis of celecoxib precursor20

1-(4-bromophenyl)-4,4,4-trifluorobutane-1,3-dione : Synthesized according to reported procedure.20

1-(4-bromophenyl)ethan-1-one (1.6 g, 8 mmol) was dissolved in 8 mL of DMF under N2 atmosphere and 60% NaH dispersion in oil (500 mg, 10 mmol) was added in three portions at 0°C. After stirring at this temperature for 30 min, ethyl trifluoroacetate (1.2 mL, 10 mmol) was added and the reaction mixture was stirred for 4 h. The reaction mixture was poured on to ice water, acidified with 2N aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water, dried and the solvent evaporated under vacuum. The crude mixture was purified by column 1 chromatography (SiO2, n-pentane:ether 98:2). [2.17 g, 92% yield]. H NMR (400 MHz, CDCl3) δ 7.80 13 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 6.54 (s, 1H) ppm. C NMR (100 MHz, CDCl3) δ 184.9, 177.4 19 (q, JC-F = 36.4 Hz), 132.4, 131.7, 129.3, 128.9, 117.0 (q, JC-F = 283.4 Hz), 92.3 (q, JC-F = 2.0 Hz) ppm. F

NMR (376 MHz, CDCl3) δ -76.51 (s, 3F). The physical data were identical in all respects to those previously reported.21

4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (30): Synthesized according to reported procedure.22 1-(4-bromophenyl)-4,4,4-trifluorobutane-1,3-dione (1.2 g, 4 mmol) and 4-hydrazinylbenzenesulfonamide hydrochloride (1.07 g, 4.8 mmol) were dissolved in 15 mL of EtOH and the mixture heated at reflux for 24 h. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (SiO2, n-pentane:EtOAc 1 65:35). [1.60 gram 90% yield]. H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.77 (s, 1H), 5.33 (s, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 144.2 (q, JC-F = 38.7 Hz), 144.0, 142.1, 141.8, 132.4, 130.3, 127.6, 127.4, 125.6, 124.1, 120.9 19 (q, JC-F = 269.3 Hz), 106.7 (q, JC-F = 1.6 Hz) ppm. F NMR (376 MHz, CDCl3) δ -62.43 (s, 3F).

(20) S. K. Singh, P. G. Reddy, K. S. Rao, B. B. Lohray, P. Misra, S. A. Rajjak, Y. K. Rao, A. Venkateswarlu, Bioor. Med. Chem. Lett., 2004, 14, 499-504. (21) S. Büttner, A. Riahi, I. Hussain, M. A. Yawer, M. Lubbe, A. Villiger, H. Reinke, C. Fischer, P. Langer, Tetrahedron, 2009, 65, 2124-2135. (22) J. Prabhakaran, V. J. Majo, N. R. Simpson, R. L. Van Heertum, J. J. Mann, J. S. D. Kumar, J. Label Compd. Radiopharm., 2005, 48, 887-895.

4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (31): In a dry Schlenk flask

Pd(PtBu3)2 (5 mol%, 0.05 mmol, 5.1 mg), and the aryl bromide (0.1 mmol, 44.5 mg) were dissolved in

1 mL of dry toluene , and 5 ml of O2 was bubbled through the reaction mixture with a syringe, followed by stirring for 10 min. Methyllithium (0.19 mL, 3 eq, 1.6 M in diethyl ether) was diluted with toluene to reach 1 mL; this solution was added over 2 min by the use of a syringe pump. After the addition was completed, the reaction was quenched with 0.5 mL of MeOH. The solvent was evaporated under reduced pressure to afford the crude product that was purified by column 1 chromatography. [35 mg, 91% yield]. H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 6.73 (s, 1H), 5.25 (s, 2H), 2.37 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 145.3, 144.0 (q, JC-F = 38.8 Hz), 142.5, 141.4, 139.8, 129.7, 128.7, 127.5, 19 125.6, 125.5, 121.0 (q, JC-F = 269.1 Hz), 106.3 (q, JC-F = 1.7 Hz), 21.3 ppm. F NMR (376 MHz, CDCl3) δ - 62.42 (s, 3F). The physical data were identical in all respects to those previously reported.23

(23) Ji, G.Wang, X.; Zhang, S.; Xu, Y.; Ye, Y.n; Li, M.; Zhang, Y.; Wang, J. Chem. Commun., 2014, 50, 4361-4363.

General scheme [11C]-labelling experiments with 2-Br-Naphthalene and Precursor 30 [11C]-methyl iodide was trapped in a solution of n-BuLi in THF at -78 °C, and subsequently diluted with toluene and allowed to reach rt. The solution was drawn back up in the syringe, and added to a previously oxygenated mixture of Pd complex and substrate. In the case of the Celecoxib synthesis (31*), the oxygenated mixture was first treated with 1.1 eq. of n-butyllithium to ensure complete deprotonation of the sulfonamide, which would otherwise consume the prepared [11C]-MeLi. After slow addition (2 min) of the organolithium reagents, the reaction was quenched with methanol, and an aliquot of the crude mixture concentrated, dissolved in acetonitrile, and directly loaded onto a RP- HPLC (eluent water:acetonitrile:trifluoroacetic acid 50:49:1). The total reaction time from the start of [11C]-MeI trapping, lithium halogen exchange, cross coupling and injection on HPLC was less than 15 min.

Figure 2 [11C]-labelling experiments

Figure 3 [11C]-labelling experiments setup

Figure 4 Schematic representation of [11C]-labelling experiments

Method for [11C]-labelling experiments

The substrate was transferred to a dry nitrogen purged 20 ml vial equipped with a septum and a stirring bar (vial A), and was further flushed with nitrogen through a septum for 5 min. In a separate, dry conical 4 ml vial (vial B), 0.25 ml dry THF was cooled down to -78 ºC under a nitrogen atmosphere. n-BuLi (0.9 eq. 0.18 ml) was added. The [11C]-MeI inlet needle was inserted in the THF-n- BuLi mixture, and a carbosphere vent added. During the trapping procedure of the [11C]-MeI in vial B, 3 ml of dry toluene was added to the substrate in vial A, and the mixture purged with oxygen (10 ml). n-BuLi (1.1 eq, 0.22 ml) was added to vial A prior to the coupling reaction to deprotonate the sulfonamide. The activity of the trapped and converted MeI of vial B was measured, the solution was diluted with 1 ml of toluene by means of a 2.5 ml syringe, and subsequently drawn up in the syringe. The addition of the MeLi solution to vial A was executed by means of a syringe pump, and was performed in 2 min. After the addition was complete, the reaction was quenched with 0.5 ml MeOH, and the total activity measured. A sample was taken, and dried at 50 ºC under a stream of nitrogen. The sample was taken up in 1.5 ml of eluent, its activity measured, and loaded onto a RP C-18 Denali HPLC column. Finally, residual activity in the used syringe was measured. Peaks from the HPLC-run were collected in vials, and their activity measured. The product was obtained by comparison with retention time of the previously prepared (isolated/injected) product.

Chapter 8 : The Cross-Coupling of Carbolithiated Acetylenes and the Synthesis of Z-Tamoxifen

The direct carbolithiation-cross coupling procedure of diphenylacetylenes is presented in this chapter. Employing a new palladium nanoparticle based catalyst described in chapter 7, we were able to couple an alkenyllithium reagent with near perfect E/Z selectivity and good yield to afford breast cancer drug Z-Tamoxifen in just 2 steps from commercially available starting materials and with excellent atom economy and reaction mass efficiency. A comparison to previous synthetic methods is also presented.

Dorus Heijnen, Milan van Zuylen, Filippo Tosi and Ben L Feringa - Manuscript in preparation 8.1 Introduction The continuous improvement of synthetic routes towards societally relevant materials and/or biologically active compounds has drawn the attention of synthetic chemists for decades.1 In order to reduce waste and increase yields and cost efficiency or to simplify the procedure to prepare the relevant structure, transition metal catalysis has made a large contribution to the field.2 Since the emergence of the Suzuki (B), Stille (Sn) and Negishi (Zn) reactions, the trend in cross coupling methodology,3 has been to transmetallate highly polar (but straightforward to synthesize) organometallic reagents (RMgX, , RLi) to softer nucleophiles, in order to gain stability, functional group tolerance and reduce the overall sensitivity of the reaction. Major drawbacks of these additional synthetic steps, are longer reaction times, the production of stoichiometric (toxic) waste, and a decrease in cost efficiency.4 Nonetheless, the direct coupling of organometallic reagents arising from a deprotonation or umpolung reaction, has shown great advances in recent years.5 Since these reagents have an intrinsic higher reactivity, the corresponding cross coupling reactions generally take less time, and can be performed at significantly lower temperatures albeit with some compromises regarding functional group tolerance.4 In an attempt to expand the synthetic application of our recently4,5 reported organolithium cross coupling reactions, we envisioned the direct carbolithation- cross coupling to be an important alternative. The carbolithiation of (diphenyl)acetylenes is well- studied, and has led to several useful applications in the field of synthetic organic chemistry.6-10 The quenching of the formed sp2 anion with an electrophile is a direct approach to substituted diarylalkenes (stilbenes). Transmetallation to magnesium, boron, zinc or even aluminum yields an active cross coupling partner, but drastically lowers atom economy and the E-factor.11,12 The direct cross coupling of the formed vinyl organolithium reagent is therefore a highly desired synthetic shortcut, but remains unreported to the best of our knowledge

8.2 Atom economy, reaction mass efficiency and E-factor For industrial relevant processes, the amount of generated waste is one of the crucial parameters in determining the best synthetic route. There are several ways of expressing the relationship between desired product and waste products,11,12a,b each having their own advantages and flaws. A Williamson ether synthesis reaction is chosen to show the differences between the 3 methods.13 As can be seen in Scheme 8.1, the atom economy12 merely gives the amount of mass of the reactants that theoretically ends up in the product, disregarding yield, stoichiometry and additives or solvents. With the product having a mass of 128, and the combined starting materials 256, an atom economy of 50 % is achieved. Since even on a laboratory scale, the yields in a multi-step synthesis are crucial, the reaction mass efficieny (RME) is a much more usefull way of describing a (multi step) synthesis. Taking also the stoichiometry of the reagents into account, the same reaction only reaches 29 % for the RME. Where the atom economy and RME disregard solvents, catalysts and substances that are used for the purification, the E factor incorporates all of these in the equation and is an attempt at truly describing the relationship between all reagents used and the final (clean) product.11 For clarity, purification has been omitted in this example, yielding an E factor for the ether synthesis of 12 (1/0.084)

Scheme 8.1 Calculation of atom economy, RME and E-factor

For industrial purposes, the E-factor is the method that gives the most detailed picture of a reaction, and it can be further elaborated with weighing factors for each reagent based on their toxicity, yielding a EQ-Factor.11b Finally, the selectivity of a reaction also indicates the amount of side products that is generated, and thus complicates the purification of the desired product. The EQ factor and the quantification of the purification are outside the scope of this work.

8.3 Goal Trisubstituted alkenes, and triphenylethylenes in particular make up a class of highly potent and valuable drugs with (potential) application in the treatment of a variety of conditions, including (breast) cancer, dyspareunia and osteoporosis.14 Structural variations are found in the substituents on the alkyl-ether substituent (mostly consisting of an amine), para phenylene functionalization, as well as in the alkyl fragment on the remaining alkene position (Figure 8.1).

Figure 8.1 Examples of members of the triphenylethylene family

Current syntheses Because of its societal value, a plethora of syntheses have been described for Z-Tamoxifen (Scheme 8.2).15-37 McMurry coupling of two ketones is a well-established method for the synthesis of (hindered) alkenes, and as such has proven capable of constructing the alkene fragment in Tamoxifen with reagents 4 and 6. Alternatively, 1,2-addition to ketone 4 with Grignard reagent 5, followed by elimination yields the alkene, however, it is common that both isomers (E/Z) are isolated via this approach. The transmetallation of lithium intermediate 1 that is the product of carbolithation of the corresponding acetylene, yields the alkenyl-boronic acid/ester (3, M=B), or organozinc reagents (3, M=Zn). The coupling of these reagents with bromide 2 provides a viable route towards the final drug. The transmetallation, however, generates extra synthetic steps and/or stoichiometric waste. It is therefore that a direct coupling of the alkenyllithium reagent 1 that is obtained upon carbolithiation would be preferred.

Scheme 8.2 Synthetic approaches to Z-Tamoxifen

8.4 Optimization synthesis of Tamoxifen In order to optimize the sequential synthetic steps, the carbolithation of acetylene 7 was performed separately, and after quenching with MeI, subjected to GCMS analysis (Table 8.1). With near perfect selectivity for the Z alkene for all solvents and solvent mixtures, we were hoping to avoid the use of THF (Table 8.1, entry 2) due to expected difficulties for the cross coupling step. However, toluene/TMEDA mixtures (entry 1) or other ethers (entry 3 to 5) did not prove equally efficient as reaction medium compared to THF due to a lower extend of lithiation (70%), and an increased amount of the E-alkene. Attempts to minimize waste production by neat carbolithiation (using only the solvent of the commercially available n-BuLi) resulted in only starting material (entry 6). Reducing the amount of THF by mixing with toluene resulted in incomplete conversion (entry 7). Despite attempts to omit THF as the solvent, we found significantly better results for the carbolithiation in its presence, and therefore decided to use it as the solvent for further optimization. The aim for a synthesis with a high atom-economy/E-factor made the 30% lower conversion of 2-MeTHF a significant drawback. Table 8.1 Carbolithiation optimization

Entry Solvent 60 min Conv.a 120 min Conv.a Selectivitya/b

1 Toluene/TMEDA(1eq) 32% 32% 75% 2 THF 91% 91% 96% 3 2-Methyl-THF 52% 70% 99% 4 MTBE 0% 6% - 5 Ether 0% 4% - 6 Neat 0% 0% - 7 Toluene/THF 3:1 48% 65% 96%

a) As determined by GC-MS analysis after MeI quench b) E/Z selectivity

Having established the optimized conditions for the carbolithiations (Table 8.1, entry 2), the cross coupling with 1-bromonaphthalene provided the test reaction in the pursuit for the best catalyst. The oxygen activated palladium nanoparticle catalyst described in chapter 7 proved to be very active in the coupling of the two reagents (Table 8.2, entry 1), being only slightly outperformed by the commercial Pd-PEPPSI-Ipent complex (entry 4).

Table 8.2 Catalyst optimization

entry Cat. (5%) Conversion to 8a

t 1 Pd(P Bu3)2 + O2 82% 2 Pd-dppf - 3 Ni-dppp - 4 PEPPSI-IPent 88% 5 Ni-NHC 51%

a) As determined by GC-MS analysis

Nickel and palladium bisphosphines (Pd-dppf and Ni-dppp) gave no conversion to the desired product (entry 2 and 3), but the nickel complex Ni-NHC as described in chapter 6 did provide the triphenylethylene target 8 (entry 5) albeit with lower conversion.

Having tested a small variety of catalysts for the one pot cross coupling with 1-bromonaphthalene, we set out to synthesize the desired pharmaceutical Tamoxifen by means of a direct carbolithiation- cross coupling strategy. Changing the nucleophile for the acetylene carbolithiation from n- butyllithium to ethyllithium gave identical results after a slightly longer reaction time. We were t pleased to see that the oxygenated Pd(P Bu3)2 catalyst gave Tamoxifen in a slightly lower yield than with the naphthalene test substrate, but with good E/Z selectivity (table 8.3, entry 1). Pursuing a cheaper catalyst with a more earth abundant metal center the attempted nickel catalyst gave only small amounts of the desired product (entry 2).

Table 8.3 Catalyst screening : Synthesis of Tamoxifen

Entry Cat. (5%) NMR Yielda t 1 Pd(P Bu3)2 + O2 50-65% 2 Ni-NHC 17% 3 PEPPSI-IPent 0%

4 Pd2dba3/Xphos 36%

b 5 C1 60% C1: X = Br C2: X = I 6 C2b 59%

Reaction conditions : 2 eq. of alkenyllithium reagent was added over 20 min to a stirred solution of arylbromide and (preoxidized) catalyst in toluene at 35°C.Yield determined by 1H-NMR with 1,1,2,2-tetrachloroethane as internal standard. b) 2.5 mol% of the dimer was used Much to our surprise, our “working horse” catalyst Pd-PEPPSI Ipent5 was completely inactive with bromophenyl-aminoether electrophile 2 (entry 3), whereas it was the most active catalyst with the bromonaphthalene electrophile. The chelating effect of the amino-ether moiety might play a role in this, functioning as a ligand and overcrowding the palladium center thus hampering its reactivity. Other palladium phosphine complexes that have recently shown to be active in related cross coupling reactions were also tested,5 and were found to have very similar reactivity compared to the phosphine pre-catalyst used in entry 1. Being the cheapest of the three related structures (entry 1, 5 and 6), we decided to continue with the initial catalyst of choice. The results of further optimization studies are shown in table 8.4. Varying the temperature did not lead to increased yield (entry 1 and 2) providing the temperature was kept above 30 °C below which no conversion was observed. In an attempt to break up potential vinyllithium aggregates, and activate the organolithium reagent, TMEDA was added, but this resulted in a scharp decline in yield (entry 3). The excess of organolithium reagent could be lowered to 1.3 equivalents without significant loss in yield (entry 4). Further lowering of the catalyst loading (2.5 mol%) led to an inactive system, with no product formed (entry 6 and 7). This complete deactiviation of the catalyst at 2.5 mol% has not been observed before, and is attributed to the strong chelating effect of the aminoether moiety that is present in the substrate. An attempt to prevent the chelating effect of the aminoether side chain to the palladium center by means of the addition of BF3 or MgCl2 did not prove beneficial for the reaction (entry 8 and 9) . To increase the E factor, and minimize waste caused by solvent, the reaction was performed in a minimal amount of solvent, at a 1 M concentration which led to a slight decrease in yield (entry 10).

Table 8.4 Optimization of carbolithiation-cross-coupling sequence.

Entry Deviation from standard Yielda 1 Temp 50°C 60 2 Temp 35°C 68 3 TMEDA (1 eq.) 25 4 1.3 eq alkenyllithium 65 5 5 % cat., 1.3 eq alkenyl 65 6 2.5 % cat. - 7 2.5 % cat.b -

8 BF3 -

9 MgCl2 58 10 Concentrated (1 M)c 54 Reaction conditions : 2 eq. of alkenyllithium reagent was added over 20 min to a stirred solution of arylbromide and (preoxidized) catalyst in toluene at room temperature. a) Yield determined by 1H-NMR with 1,1,2,2- tetrachloroethane as internal standard. b) Different batch of catalyst c) Initial concentration of aryl-bromide.

Having a setup that produces this pharmaceutical compound in good yield and with minimal waste production (LiBr being the only stoichiometric waste in the last step), we compared our setup with other (recent) reported syntheses of Z-Tamoxifen in the light of atom economy and E-factor. A full overview of the calculated atom economy of various synthetic routes is given in the experimental section. Figure 8.2 shows a large range in atom economy (shown in blue) between different reported syntheses of Tamoxifen. The method described by Hayashi in 2015 is closest to the route described in this chapter in terms of atom economy, but with an overall yield of the Z-Tamoxifen of 41% scores much lower on RME (shown in red).

100% 90% Reaction mass efficiency 80% Atom economy 70% 60% 50% 40% 30% 20% 10% 0%

Figure 8.2 Atom economy and RME per Tamoxifen synthesis

With our current setup, employing commercially available starting materials, a total atom economy of 0.54 is achieved, and the RME is almost twice than that of the runner-up. The QE factor (taking toxicity and other impacting sources into account) scores even higher, since LiBr, NaCl and HCl are the only stoichiometrically produced waste sources, and the reaction can be performed at slightly elevated temperature in a minimal amount of solvent.

Purification To establish the optimal isolation method, the synthesized Tamoxifen was purified by means of crystallization, extraction, column chromatography and distillation. The excess (protonated after quenching) organolithium reagent and formed lithiumbromide pose no difficulty in the separation from the product (Figure 8.3). Acid-base extraction or column chromatography are both suitable means to achieve purification.

Figure 8.3 Z-Tamoxifen and side products The remaining impurity mainly consists of dehalogenated starting material 2-H, as well as 10% of the E-Tamoxifen which exhibit near identical behavior compared to the product in most standard purification techniques. Flash chromatography with an array of different solvents was not able to significantly improve the purity of the Z-Tamoxifen, and would also drastically lower the E factor. Distillation under reduced pressure proved promising, but due to the reaction scale and reaction setup also failed to provide the clean product. Finally, RP-Preperative HPLC in water/acetonitrile yielded the clean product. Though detrimental for the scale up process and E-factor, we believe that the isolation of Z-Tamoxifen on a larger scale is easily perfomed by means of distillation under reduced pressure.

One pot procedure and alternative electrophile coupling. In chapter 7 the cross coupling with free phenol electrophiles, that led to the corresponding cross coupled phenol derivatives was shown. In order to reduce the step count of this synthetic route, we envisioned the one pot procedure with the free 4-bromophenol, followed by electrophilic quenching with an amino-alkyl-chloride (scheme 8.3) of reaction intermediate 9. Unfortunately, the deprotonation/cross coupling of 4-bromophenol strategy did not lead to significant product formation, and upon MeI quench showed methylated alkenyllithium reagent 1-Me, as well as products arising from lithium halogen exchange.

Scheme 8.3 Attempted one pot synthesis of Tamoxifen

In order to increase the atom economy even further, and omit the need for a heavy halogen coupling partner, the electrophile 2 was also substituted by the lighter, less waste producing corresponding chloride (2-Cl) or methyl ether (2-OMe)(Scheme 8.3).

Scheme 8.4 Attempted one pot synthesis of Tamoxifen with alternative electrophiles

Pd-PEPPSI complexes have previously shown to be very reactive in the coupling or aryl chlorides with organolithium reagents. Similarly, the Ni-NHC catalysts described in chapter 6 showed cross coupling with aryl ethers and aryillithium reagents. Unfortunately, the combination of the Pd/Cl and Ni/OMedid not give any observable product formation.

8.5 Conclusions and outlook The carbolithiation of diphenylacetylene, and the consecutive cross coupling with the appropriate 4- bromo-dimethylamine-ethyl-ether(2) yields Z-Tamoxifen with good E/Z selectivity, and with (NMR) yields ranging from 50-65 %. A fraction of the reaction mixture was purified by RP-Prep-HPLC to obtain the pure product, but large scale isolation is yet to be optimized. The method distinguishes itself from previously reported syntheses by its high atom economy, non-toxic waste production, step count and ease of reaction setup. We envision that the final product can be isolated without the need for any column chromatography, by a simple acid-base extraction followed by vacuum distillation. This method showed promising on small scale, but due to scale limitations was replaced by Prep-HPLC. Further optimization could lead to a lowering of the catalyst loading and suppressing the lithium halogen exchange, that leads to the undesired dehalogenated electrophile 2-H, and increasing the E/Z selectivity even further. The organolithium cross coupling platform has proven to be a particularly powerfull strategy for the coupling of less reactive electrophiles (chlorides, fluorides and ethers). Though no results have been achieved with these reagents yet, they would greatly enhance the method, and it would therefore validate further efforts towards this goal.

8.6 References 1) a) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.Resmerita, N. K. Garg, and V. Percec, Chem. Rev. 2011, 111, 1346–1416, b) L. Guo, C.Hsiao, H.Yue, X. Liu, M. Rueping, ACS Catal. 2016, 6, 4438−4442, M. Tobisu, T. Takahira, T. Morioka, N. Chatani J. Am. Chem. Soc. 2016, 138, 6711−6714. b) see chapter 9 c) Total Synthesis of Natural Products, At the Frontiers of Organic Chemistry, L. J. Jack, E.J. Corey, ISBN 978-3-642-34065-9, Springer, Berlin Heidelberg

2) U. V. Mentzel, D. Tanner, J. E. Tønder J. Org. Chem. 2006, 71, 5807-5810, Metal‐Catalyzed Cross‐ Coupling Reactions, F. Diederich, P. J. Stang, Wiley‐VCH Verlag GmbH, Weinheim, Online ISBN: 9783527612222 |DOI:10.1002/9783527612222.

3) E. Negishi, Angew. Chem. Int. Ed. 2011, 50, 6738 – 6764

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5) M. Busch, M. D. Wodrich, C. Corminboeuf, ACS Catal., 2017, 7 (9), pp 5643–5653 b) V.Hornillos, M. Giannerini, C.Vila, M. Fañanás-Mastral, B. L. Feringa Org. Lett. 2013 15, 19, 5114- 5117. L. M. Castelló, V. Hornillos, C. Vila, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa Org. Lett., 2015, 17 (1), pp 62–65. c) J. Buter, D. Heijnen, C. Vila, V. Hornillos, E. Otten, M. Giannerini, A. J. Minnaard, and B. L. Feringa. Angew. Chem. Int. Ed. 2016, 55, 3620 –3624. d) Hornillos, V.; Pinxterhuis, E. B.; Giannerini, M.; Feringa B.L. Nat. Commun. 2016, DOI: 10.1038/ncomms11698

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Acknowledgements

This work described in this chapter was carried out together with Milan van Zuylen and Filippo Tosi

8.7 Experimental section All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques unless noted otherwise. THF and toluene were dried using an SPS- system. White colored Pd(t-Bu3P)2, was purchased from Strem chemicals and stored under nitrogen at -25 ºC. All alkyllithium reagents and aryl bromides were purchased from Aldrich or TCI and used without further purification, unless noted otherwise. Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm, or Grace-Reveleris purification system with Grace cartridges. Components were visualized by UV. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). PREP-HPLC was perfomed on a Grace-reveleris PREP with a 5u Denali silica (15 cm, 10 mm id). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3 as solvent, unless noted otherwise. Chemical shift values are reported in ppm with the 1 13 solvent resonance as the internal standard (CHCl3: δ 7.26 for H, δ 77.0 for C) unless noted otherwise. Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. For quantitative analysis using 1H-NMR, 1,1,2,2-tetrachloroethane was used as an internal standard.

2-(4-Bromophenoxy)-N,N-dimethylethylamine (3)

To a dry Schlenk flask equipped with a stirring bar was added NaH (1.36 g (60%), 34 mmol) and washed twice with 5 mL of dry hexane, 5 mL of dry THF was added and the solution was cooled in an ice bath.

In a separate Schlenk flask 4-bromophenol (3.0 g, 17 mmol) was dissolved in 8 mL of dry THF. The resulting solution was added slowly to the flask containing the washed NaH as described above. After the addition was complete, the ice bath was removed, 2-chloro-N,N-dimethylethylamine hydrochloride (2.4 g, 17 mmol) was added in portions and the reaction mixture was heated to 40 °C. After 72 h the reaction mixture was allowed to cool to room temperature and the precipitate was filtered off. The filtrate was concentrated in vacuo and redissolved in 50 mL of ethyl acetate. The organic layer was extracted three times with 50 mL aq. 1M HCl and concentrated in vacuo. The aqueous layer was neutralized using aq. Na2CO3, and subsequently extracted three times with 100 mL EtOAc. The organic layer was then dried using Na2SO4 and concentrated in vacuo. Without further 1 purification a light brown liquid (4.2 g, 56%) was obtained. H-NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 4.03 (t, J = 5.7 Hz, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.33 (s, 6H). This spectrum is in accordance with literature.1

Tamoxifen ((Z)-1-(p-Dimethylaminoethoxyphenyl)-1,2-diphenyl-1-butene, trans-2-[4-(1,2-Diphenyl- 1-butenyl)phenoxy]-N,N-dimethylethylamine) (4)

Preparation of lithio-stilbene: In a dry Schlenk flask (A) equipped with a stirring bar, 160 mg of diphenylacetylene (0.9 mmol) was dissolved in 1 mL of dry THF. The solution was cooled to 0 °C using an ice bath after which 1.85 mL of 0.5 M ethyllithium in cyclohexane/benzene (0.93 mmol) was added dropwise to the solution. Upon addition, the solution turned orange. The solution was allowed to warm to room temperature and stirred for 3 h, during which it turned yellow, and finally, light green. To this solution was added 2 mL of dry toluene (Solution A)

To a dry Schlenk flask (B) equipped with a stirring bar was added Pd(t-Bu3P)2 (15.4 mg, 30 µmol, 5%) and 2 mL of dry toluene. Using a syringe, 12 mL of dry oxygen was bubbled through the solution after which the solution was allowed to stir vigorously overnight, resulting in a deep red solution. A solution of compound 3 (146.4 mg, 0.6 mmol) in 1 mL of dry toluene was added to the flask. Solution A (freshly prepared) was added over the course of 20 min using a syringe pump. After the addition, the reaction mixture was quenched with 0.5 mL of MeOH, filtered over celite and concentrated in vacuo. The resulting liquid was dissolved in 20 mL of EtOAc and extracted four times with 30 mL of

1M aq. HCl. The aqueous layer was neutralized using Na2CO3 and subsequently extracted four times with 50 mL of ethyl acetate. The organic layer was dried using Na2SO4 and concentrated in vacuo. The crude yield was determined by 1H-NMR analysis, using 1,1,2,2-tetrachloroethane as an internal standard.

A fraction of the crude product was dissolved in a mixture of water/acetonitrile, and purified by RP (C18 Denali) Prep-HPLC chromatography (Water : Acetonitrile : TFA 50:49:1) 1H-NMR (400 MHz,

CDCl3) δ 7.35 (d, J = 7.5 Hz, 2H), 7.25 (m, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 1H), 3.92 (t, J = 5.8 Hz, 2H), 2.64 (t, J = 5.8 Hz, 2H), 2.46 (q, J = 7.4 Hz, 2H), 2.28 (s, 6H), 0.92 (t, J = 7.4 Hz, 3H). This spectrum is in accordance with literature.2

(Z)-1-(1,2-diphenylhex-1-en-1-yl)naphthalene (8)

In a dry Schlenk flask (A) equipped with a stirring bar, diphenylacetylene (89 mg, 0.5 mmol) was dissolved in 1 mL of dry THF. The solution was cooled to 0 °C using an ice bath after which 0.37 mL of 1.5M n-butyllithium (0.55 mmol) was added dropwise to the solution. The solution was allowed to warm to room temperature and stirred for 2 h, resulting in a blue solution. To this solution was added 2 mL of dry toluene (Solution A).

To a dry Schlenk flask (B) equipped with a magnetic stirring bar and nitrogen line was added 11.9 mg of PEPPSI-IPent (15 µmol, 5%), 42 µL of 1-bromonaphthalene (62 mg, 0.3 mmol) and 3 mL of dry toluene. To this flask, solution A was added over the course of 20 min using a syringe pump. The resulting solution was quenched with a small amount of MeOH, filtered over celite and concentrated in vacuo. The conversion of the product was determined using GCMS (88%), Mass = 362.

1Sun, P. -P.; Cheng, Y. -C.; Chang, M. -Y. Synthesis 2017, 49 (11), pp. 2411-2422 2 Al-Hassan, M. I.; Miller, R. B. J. Org. Chem. 1985, 50, pp. 2121-2123

Chapter 9 : The Cross- Coupling of Organo- lithium Reagents at Cryogenic Temperatures

Narayan Sinha, Dorus Heijnen, Ben L. Feringa, and Michael G. Organ. –Manuscript in preparation ABSTRACT: The coupling of organolithium reagents at cryogenic temperatures (as low as -78 C) has been achieved with a highly reactive Pd-NHC catalyst and is described in this chapter. A temperature dependent chemoselectivity has been developed for the selective coupling of bromides in the presence of chlorides. Building on this, a one-pot, sequential cross-coupling strategy has been developed for the rapid construction of advanced building blocks for synthesis (e.g., medicinal chemistry) and process-scale applications.

9.1 Introduction Recent advancements in the cross-coupling of hard organometallic nucleophiles have been accelerated by the development of reactive catalysts with very high turnover frequencies. Published work on the coupling of Grignard and organolithium reagents offers new insights in the active palladium catalyst.1-6 High-reactivity catalysts allow for an increase in functional group tolerance by, for example, outcompeting 1,2-additions, ring-opening reactions or the deprotonation of acidic moieties. The use of hard (Li, Mg) organometallic reagents offer advantages in their ready commercial availability and ease of synthesis, but also in the reduction of (stoichiometric) waste generated when compared to organoboranes, for example, which often are derived from the corresponding Grignard or organolithium reagents.7-12 The methodology was steadily expanded to provide suitable reaction conditions for the synthesis of alkyl, heteroaryl, sterically demanding and radiolabelled products2, 6-11 (see also previous chapters). The cross-coupling of Grignard or organolithium reagents proceeds in seconds to minutes at room temperature with a variety of (alkyl)phosphine-palladium catalysts, but only a few are competent at or below 0 C.2-4 Aryl-phosphine-palladium complexes have been shown to couple Knochel-type aryl Grignard reagents at temperatures below 0°C (Scheme 9.1a), but require several hours to reach complete conversion.13a Additionally, the reactions were allowed to warm to rt before the quenching agent was added.

Scheme 11 Previous examples of cross coupling at low temperatures.

For electrophiles with a strong electron-withdrawing group, iron catalyzed reactions with Grignard reagents have also been reported (Scheme 9.1b), but the scope was limited to just two examples.13b We have recently studied and subsequently optimized similar palladium-phosphine catalytic systems for the coupling of organolithium reagents and found that despite high turnover frequencies, coupling below -10 C was not feasible.2 The Pd-NHC (N-Heterocyclic-Carbene) catalyst family has also shown great stability and reactivity in the cross coupling of aryl- and alkyllithium nucleophiles (Scheme 9.2i) and has simultaneously proven to be a particularly active catalyst system for the cross-coupling of a variety of functionalized and 14-21 challenging nucleophiles (R-ZnBr, R-B(OR)2, R-SnR3) in batch or flow (Scheme 9.2ii). Compared to simple NHC complexes, the design of the Pd-PEPPSI catalyst with increased bulk on the flanking aryl groups facilitates faster reductive elimination and has higher turnover numbers,20 while suppressing competing side reactions in the coupling of secondary alkyl substrates (branched vs linear ratio).16

Scheme 9.2 Overview of cross coupling reactions using Pd-PEPPSI catalysts These same catalysts also facilitate the coupling of profoundly hindered starting materials to make structurally complex products (e.g., tetra ortho-substituted biaryls).22 The fact that these challenging coupling procedures can be conducted routinely at room temperature16,18,21,22 paves the way for applications in the synthesis of natural products, biologically active compounds and complex ligands for metal catalysis.

9.2 Catalyst design and SAR The findings described in this chapter (Scheme 9.2iii, Table 9.1) that naphthalene electrophiles could be coupled to alkyl lithium reagents at temperatures far below conventional cross-coupling temperatures (i.e., < -20C) offers unique opportunities for organic synthesis. To explore the potential of this observation, we embarked on a structure-activity relationship (SAR) study on the NHC ligand to determine its impact on reactivity at low temperatures. The flexible aliphatic groups on the N-aryl substituent were systematically varied, while at the same time assessing the electronic and steric effect of substituents on the NHC backbone (see Table 1). Using sec-BuLi and 1-Br- naphthalene as a model reaction, we evaluated Pd-PEPPSI complexes at -62 C and -78 C temperatures at which a general successful cross-coupling method has yet to be reported.

Table 9.1. Structure-activity relationship (SAR) assessment of Pd-PEPPSI complexes with sec-BuLi.

Z Z R R N N R R R R N N Cl Pd Cl N R R Cl Pd Cl Cl N R = iPr, Z = H; C1 (Pd-PEPPSI-IPr) R = 3-pentyl, Z = H; C2 (Pd-PEPPSI-IPent) Cl R = 3-pentyl, Z = Cl; C3 (Pd-PEPPSI-IPentCl) R = 3-pentyl; C5 R = 4-heptyl, Z = H; C4 (Pd-PEPPSI-IHept) (Pd-PEPPSI-IPent-Acenapht)

X Sec-BuLi (1.5 equiv.) (Addition over 1h)

PEPPSI-Cat (0.05 equiv.) Temp, Toluene

Entry X Catalyst T (ºC)a Conversionb 1 Br C1 -78 (%)0 b 2 Br C2 -78 0 3 Br C4 -78 10 4 Br C3 -78 22 5 Br C5 -78 37 6 Br C1 -62 0 7 Br C2 -62 88 8 Br C4 -62 80 9 Br C3 -62 91 10 Br C5 -62 99 11 I C5 -78 75c 12 Br C3 -62 98d 13 Br None -62 0 aReaction temperature was never allowed to rise and transformations were quenched at this temperature. bPercent conversion of 1-bromonaphthalene to 1-sec-butylnaphthalene as determined by 1H NMR of the crude reaction mixture. cn-BuLi was used. d0.1 mol % catalyst was used.

Changing the size of the N-aryl, alkyl substituents (entries 1-3) had a noticeable impact on the coupling at -78 C, with a similar trend observed at -62 C (entry 6 - 8). Placing chlorides on the NHC core similarly improved reactivity at -78 C (entry 2 vs 4). Changing the substituents on the NHC core from chlorides to a fused acenaphtaquinone system yielded an active catalyst, both at -78 C (entry 5) and -62 C (entry 10). Changing the oxidative addition partner to the corresponding iodide (entry 11) saw conversion at -78 C jump to 75%, which is the first palladium catalyzed cross-coupling to proceed with high conversion below -65 C. As lower temperatures suppress catalyst deactivation, we were able to perform this reaction at a low catalyst loading (0.1 mol %, entry 12). The optimized conditions from entry 10 were used for further reactions.

9.3 Scope The substrate scope was evaluated and substituted naphthalenes proved to be excellent substrates, as were (hetero)aromatic bromides (Scheme 9.3). When the nucleophile was changed from n/sec- butyllithium to other organolithium reagents, we observed a trend between the strength of the base 26 and the temperature cut-off (BuLi > TMS-CH2Li > PhLi). The strongest nucleophile provided cross coupled product at the lowest temperature, suggesting a possible role for the nucleophile in the rate- determining step. In an important observation, near perfect bromide/chloride chemoselectivity at - 22 °C (17 to 21) was obtained with dihalogenated (Br and Cl) oxidative addition partners. Even when the bromide was sterically hindered (18, 20) it was coupled preferentially over the chloride. Of special note, products arising from benzyne formation were not observed with ortho-chloro substrates (21).

R-Li, C5, Br R Toluene, Temp, 1h

Chemoselective S

Cl TMS 1 (-62°C, 90%)b 2 (-62°C, 92%) 3 (-42°C, 81%) 17 (-22°C, 75%) >95% selectivityc S

Cl 4 (-62°C, 89%) 5 (-62°C, 87%) 6 (-22°C, 79%) TMS

TMS 18 (-22°C, 80%)

Cl 7 (-42°C, 93%) 8 (-62°C, 94%) 9 (-42°C, 91%)

19 (-22°C, 67%) TMS O

TMS Cl 10 (-22°C, 77%) 11 (-42°C, 90%) 12 (-22°C, 61%)

20 (-34°C, 78%) O TMS

Cl 13 (-62°C, 87%) 14 (-22°C, 63%)

O 21 (-22°C, 70%) O

d 15 (-22°C, 63%) 16 (-42°C, 73%) Scheme 9.3 Substrate scope for organolithium cross-coupling using a Pd-PEPPSI complex.a aReaction conditions: (hetero)aryl bromide, toluene, 5 mol% catalyst, organolithium reagent (1.5 equiv), 1 h addition of organolithium reagent. The temperature of the reaction was never allowed to rise and the transformation was quenched at this temperature. Yields of isolated products after column chromatography. bIn addition : 89% isolated yield at -42 C in just 10 min/reaction. cSee supporting information for details. d4- Iodoanisole was used.

9.3.1 Sequential coupling

While chemoselectivity (i.e., I>Br~OTf>Cl) in cross-coupling reactions is known,1,4,23 it has been achieved primarily with catalysts that are simply unreactive with the less active electrophiles. In order to take advantage of this ‘selectivity’, a different reaction setup with new solvents/reagents/catalysts is necessary to achieve subsequent coupling with a second nucleophile. The catalytic turnover from C3 at a temperature of -62 C shows that it is one of the most reactive catalysts yet reported for this transformation. With this in mind we envisioned a one-pot methodology where a single catalyst would be capable of sequentially coupling multiple nucleophiles in a chemoselective fashion where a jump in temperature is used as the selectivity trigger. This methodology would allow divergent synthesis to be achieved in an efficient manner, providing a powerful tool for quick SAR studies. Methodology for the sequential coupling of two sp2 hybridized organometallic reagents with a dihalide electrophile is known, but a general cross-coupling procedure in which one of the coupling partners is a sp3 hybridized nucleophile is less prevalent.23 Small alkyl fragments, and in particular secondary (branched) alkyl moieties, are crucial for the development of potent bio-medically active compounds that bind with high selectivity to their protein targets.24 The importance of such motifs in the structure of electronic materials is also well demonstrated.25 Therefore, the development of an operationally simple, one-pot procedure to readily install such alkyl substituents on (hetero)aromatic core structures is highly desirable. Organolithium reagents coupled smoothly at -22 °C with bromo-chloro aromatics to provide intermediates that were subsequently submitted to Suzuki-Miyaura (22), Negishi (23, 25), or Murahashi (24, 26, 27) cross-coupling procedures (Scheme 9.4).27 Not limited to carbon nucleophiles, amine arylation (28 - 35) and sulfination (36 - 38)28 reactions also proceeded well to give highly functionalized, advanced building blocks. The additional functionalization steps make catalyst C3 preferred over catalyst C5, as the C3 IPent-Cl PEPPSI complex has previously shown to be the catalyst of choice for aminations and sulfinations. Functional groups that were tolerated in the second cross coupling step include esters, amines, ethers, nitriles, protected alcohols, and a heterocycle. For all the reactions, additional catalyst or indermediate purification was unnecessary, and products were obtained in a one-pot procedure by simply adding the required reagents for the second coupling and warming as required.

Scheme 9.4 One-pot sequential approach to divergent synthesis of functionalized molecules. Overall yield of isolated products following two-step process after column chromatography are reported in a brackets. Conditions for second coupling: ArB(OH)2, (1.5 equiv.), NaOMe (3 equiv.), THF (3 mL), 75 C 18h.; b c d ArZnBr (1.5 equiv.), 23 C, 18 h; ArLi, dropwise addition, 1h. 40 C, Ar-NH2 or Ar-NHMe (1.2 equiv), e f KOtBu (1.5 equiv), 23 C, 18 h; Ar-NH2 (1.2 equiv), Cs2CO3 (3 equiv), 80 C, 18 h; Ar-SH (1.2 equiv), KOtBu g (2 equiv), 80 C, 18 h; Ar-SH (1.2 equiv), KOtBu (2 equiv), 23 C, 18 h.

The new method for the chemoselective coupling with chloro-arylbromides distinguishes itself from other procedures, where sequential coupling is often achieved by means of two aryl (sp2) coupling partners. The quick, cheap and selective installation of alkyl fragments provides potential application in pharmaceuticals bearing these moieties such as displayed in figure 9.1.

Figure 9.1 Pharmaceuticals bearing small alkyl fragments

The direct alkyl coupling on to heterocycles remains a major challenge in sequential cross coupling procedures. Though palladium catalysed organolithium cross coupling in the presence of indoles, pyrroles (chapter 7), and even pyridines (chapter 3) has previously been shown, functionalization with small alkyl fragments has not yet been achieved at low temperatures with the above mentioned catalytic setup. For widespread application in the synthesis of pharmaceutical compounds, the lowering of the catalyst loading, and the incorporation of these heterocycles in the scope have yet to be achieved.

9.3.2 Attempts at improving the scope Having a procedure that couples several alkyllithium reagents at temperatures below -60C, we were intrigued to see if we would be able to expand the existing scope of our organometallic coupling partner to include unstable alkyllithium reagents. Figure 9.2 shows a selection of alkyl and aryllithium reagents that are known to be stable at cryogenic temperatures, but degrade at or near room temperature. TMS-substituted alkyllithium 39 could successfully be synthesized via carbolithiation of the vinylsilane (as confirmed by MeI quench), but due to the necessity of THF as the solvent (see chapter 1) for its preparation, only yielded dehalogenation upon attempted cross coupling with 1- bromonaphthalene 44.29a Direct lithiation of Boc-protected piperidines (40) or pyrolidines at -65 C yields the alpha-lithio nitrogen compound, and has previously been transmetallated to provide stable cross coupling partners.26 The presence of THF or activating agents such as TMEDA or sparteine, however, are required and the formed organolithium reagent therefore behaves much like compound 39, giving dehalogenated product exclusively. Phthalide 4129b and benzamide 4226 were also prepared according to literature procedures, but following the trend shown above (a more stable organolithium reagent requires higher reaction temperatures) did not afford any product at - 60 C, and degraded upon attempted coupling at higher temperatures (-25 C).

Figure 9.2 Attempted unstable organolithium reagents and electrophiles.

Finally, substituted epoxide 43 could have provided a valuable coupling partner if successfully converted to the desired product, but only starting material could be observed after the reaction. The degradation products arising from this organolithium reagent were too volatile to detect/isolate.29c In an attempt to avoid lithium halogen exchange, aryl triflate 45 was used to substitute 44, but it was inactive at low temperatures (also with n-butyllithium in a control experiment)

Having attempted cross-coupling conditions with several unstable organolithium reagents, we changed our focus to the scope of the electrophile, employing several functional groups that are susceptible to organolithium addition. In a competition experiment, we decided to add a stoichiometric amount of a single additional electrophile that has not been successfully cross coupled with organolithium reagents to date (Scheme 9.5).

Scheme 9.5 competition studies with electrophiles Since arylbromide 44 gave perfect conversion at -68 C with n-butyllithium, we envisioned that at this low temperature, we would have the best chance of outcompeting unwanted side reactions. We ran a series of experiments in which one of the electrophiles (46-49) was added in a equimolar amount with respect to the arylbromide (scheme 8.4), and evaluated the product distribution between the desired cross coupling, and nucleophilic attact on the additional electrophile. Benzonitrile (46) yielded the ketone exclusively (after acidic aqueous workup), whereas acetophenone 47 yielded both the corresponding tertiary alcohol, and unreacted starting material, due to competition between 1,2-addition and the deprotonation of alpha-protons. Benzophenone 48 also proved to outcompete the palladium catalyst in the consumption of organolithium reagent, and yielded the n-butyl-diphenyl tertiary alcohol exclusively. Finally, N,N dimethylbenzamide 49 gave a mixture of starting materials, ketone and tertiary alcohol, originating from a second alkyllithium addition after collapse of the tetrahedral intermediate (see also chapter 4). With these results, the expansion of the functional group tolerance seemed challenging and was not further investigated.

9.4 Conclusion In conclusion, the unprecedented coupling of organolithium reagents at cryogenic temperatures has been attained using highly reactive Pd-NHC catalysts. A ‘thermal trigger’ was used for the two-step, one-pot sequential coupling of alkyl and more functionalized nucleophiles. This methodology allows for rapid, sequential, and divergent preparation of highly functionalized molecules and building blocks with potential applications in the medicinal chemistry/drug discovery and materials science, as well as offering opportunities for telescoped synthesis in process chemistry and fine-chemical manufacturing. Further optimization of the process could lead to the lowering of the catalyst loading, and the addition of heterocycles to the reaction scope, thereby greatly improving its applicability in the large scale synthesis of pharmaceutical compounds. 9.5 References (1) Kalvet, I.; Sperger, T.; Scattolin, T.; Magnin, G.; Schoenebeck, F. Angew. Chem. Int. Ed. 2017, 56, 7078-7082. (2) Heijnen, D.; Tosi, F.; Vila, C.; Stuart, M. C. A.; Elsinga, P. H.; Szy- manski, W.; Feringa, B. L. Angew. Chem. Int. Ed. 2017, 56, 3354-3359. (3) Aufiero, M.; Scattolin, T.; Proutière, F.; Schoenebeck, F. Organometallics 2015, 34, 5191–5195. (4) Kalvet, I.; Magnin, G.; Schoenebeck, F. Angew. Chem. Int. Ed. 2017, 56,1581-1585. (5) Snelders, D. J. M.; Kreiter, R.; Firet, J. J.; Van Koten. G.; Klein Gebbink, R. J. M. Adv. Synth. Catal. 2008, 350, 262 – 266. (6) Hornillos, V.; Pinxterhuis, E. B.; Giannerini, M.; Feringa B.L. Nat. Commun. 2016, DOI: 10.1038/ncomms11698. (7) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 5, 667–672. (8) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L. Org. Lett. 2015, 17, 2262– 2265. (9) Buter, J.; Heijnen, D.; Vila, C; Hornillos, V.; Otten, E.; Giannerini, M.; Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int. Ed. 2016, 55, 3620 –3624. (10) Heijnen, D.; Gualtierotti, J.; Hornillos, V.; Feringa, B. L. Chem. Eur. J. 2016, 22, 3991–3995. (11) Hornillos, V.; Giannerini, M.; Vila, C.; Fañanás-Mastral, M.; Feringa, B. L. Org. Lett. 2013, 15, 5114-5117. (12) Çalimsiz, S.; Sayah, M.; Mallik, D.; Organ, M. G. Angew. Chem. Int. Ed. 2010, 49, 2014–2017. (13) a) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844-3845; b) Kleimark, J.; Larsson, P. F.; Emamy, P.; Hedström, A.; Norrby, P. O. Adv. Synth. Catal. 2012, 354, 448 – 456. (14) Dowlut, M.; Mallik, D.; Organ M. G. Chem. Eur. J. 2010, 16, 4279 – 4283. (15) Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org. Chem. 2010, 4343–4354. (16) a) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Chem. Eur. J. 2016, 22, 14531-14534; b) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2015, 54, 9502 –9506; c) Pompeo, M.; Froese, R. D. J.; Hadei, N. Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 11354 –11357; d) McCann, L. A.; Organ, M. G. Angew. Chem. Int. Ed. 2014, 53, 4386-4389; e) Farmer, J.; Hunter, H. N.; Organ, M. G. J. Am. Chem. Soc. 2012, 134, 17470−17473; f) McCann, L. C,; Hunter, H. N.; Clyburne, J. A. C.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 7024-7027. (17) a) Khadra, A.; Mayer, S.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Organometallics 2017, 36, 3573−3577; b) Khadra, A.; Mayer, S.; Organ, M. G. Chem. Eur. J. 2017, 23, 3206-3212. (18) a) Sharif, S.; Day, J.; Hunter, H. N.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. J. Am. Chem. Soc. 2017,139, 18436–18439; b) Lombardi, C.; Day, J.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Farmer, J. L.; Organ, M. G. Organometallics 2017, 36, 251-254; c) Lombardi, C.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Eur. J. Org. Chem 2017, 2017,1510-1513; d) Sharif, S.; Mitchell, D.; Rodriguez, M. J.; Farmer, J. L.; Organ, M. G. Chem. - Eur. J. 2016, 22, 14860−14863; e) Sharif, S.; Rucker; R. P.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2015, 54, 9507-9511; f) Farmer, J. L.; Pompeo, M.; Lough, A. J.; Organ, M. G. Chem. Eur. J. 2014, 20, 15790-15798; g) Pompeo, M.; Farmer, J. L.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2014, 53, 3223-3226; h) Hoi, K. H.; Coggan, J. A.; Organ, M. G. Chem. Eur. J. 2013, 19, 843–845; i) Hoi, K. H.; Organ, M. G. Chem. Eur. J. 2012, 18, 804-807; j) Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2012, 18, 145-151; k) Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2011, 17, 3086-3090. (19) a) Price, G. A.; Hassan, A.; Chandrasoma, N.; Bogdan, A. R.; Djuric, S. W.; Organ, M. G. Angew. Chem. Int. Ed. 2017, 56. 13347-13350; b) Price, G. A.; Bogdan, A. R.; Aquirre, A. L.; Iway, T.; Djuric, S. W.; Organ, M. G. Catal. Sci. Technol., 2016, 6, 4733-4742. (20) a) Valente, C.; Calimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 3314 – 3332; b) Froese, R. D. J.; Lombardi, C.; Pompeo, M.; Rucker, R. P.; Organ, M. G. Acc. Chem. Res. 2017, 50, 2244−2253; c) Valente, C.; Pompeo, M.; Sayah, M.; Organ, M. G. Org. Proc. Dev. Res. 2014, 18, 180-190; d) Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org. Chem. 2010, 23, 4343-4354. (21) a) Sayah, M.; Organ, M. G. Chem. Eur. J. 2013, 19, 16196-16199; b) Sayah, M.; Lough, A.; Organ, M. G. Chem. Eur. J. 2013, 19, 2749-2756; c) Sayah, M.; Organ, M. G. Chem. Eur. J. 2011, 17, 11719- 11722. (22) a) Çalimsiz, S.; Sayah, M.; Mallik, D.; Organ, M. G. Angew. Chem. Int. Ed. 2010, 49, 2014–2017; b) Organ, M. G.; Çalimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem. Int. Ed. 2009, 48, 2383– 2387. (23) a) Dobrounig, P.; Trobel, M.; Breinbauer, R. Monatsh Chem, 2017, 148:3–35; b) Hadei, N.; Achonduh, G. T.; Valente, C.; O’Brien, C. J.; Organ, M. G. Angew. Chem. Int. Ed. 2011, 50, 3896 –3899. (24) a) Lovering, F. Med. Chem. Commun. 2013, 4, 515−519; b) Damdapani, S.; Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010, 14, 362−370; c) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752−6756. (25) See the following review and references cited therein: Xu, S.; Kim, E. H.; Wei, A.; Negishi, E.-i. Sci. Technol. Adv. Mater. 2014,15, 044201. (26) Lithium Compounds in Organic Synthesis, Renzo Luisi, Vito Capriati, 2014 Wiley VCH Verlag GmbH & Co. KGaA ISBN : 9783527333431 b) The Chemistry of Organolithium Compounds, Z. Rappoport, I. Marek, 2004, John Wiley & Sons (Verlag), ISBN: 978-0-470-02110-1 (27) New Trends in Cross-Coupling: Theory and Applications, Thomas Colacot, 2014 RSC Publishing ISBN : 978-1-84973-896-5 (28) P. Ruiz-Castillo and Buchwald S. L. Chem. Rev., 2016, 11(19), 12564-12649. (29) a) D. Hodgson, B. Stefane, T. Miles, J. Witherington, J. Org.Chem. 2006 vol. 71, 8510 – 8515. b) R. Marsden, D.B. MacLean, Tetrahedron Letters, 1983 vol. 24, 2063 - 2066c) Berger, Markus; Rehwinkel, Hartmut; Zollner, Thomas; May, Ekkehard; Hassfeld, Jorna; Schacke, Heike - US2009/137564, 2009, A1

Acknowledgements

This work described in this chapter was performed in collaboration with York university in Toronto. Catalyst design and synthesis, initial chemoselectivity tests and part of the scope were performed by Narayan Sinha.

9.6 Experimental section

All experiments were carried out under an argon atmosphere in oven-dried or flame-dried glassware using standard Schlenk techniques unless noted otherwise. Glovebox manipulations were performed in an MBraun Unilab glove-box under an argon atmosphere. All reagents were purchased from Sigma-Aldrich or Alfa Aesar and were used without further purification unless noted otherwise. Except Pd-PEPPSI-IPent-Acenapht, all other Pd-PEPPSI precatalysts and 2,6-di(pentan-3-yl)aniline were provided by Total Synthesis Ltd (Toronto, Ontario, Canada). THF was distilled under argon over sodium/benzophenone prior to use. Toluene was distilled under argon over calcium hydride prior to use. Analytical thin layer chromatography (TLC) was performed on EMD 60 F254 pre-coated glass plates and spots were visualized with UV light (254 nm) or a staining solution (KMnO4 or CAM). Column chromatography purifications were carried out using either the flash technique on EMD silica gel 60 (230 – 400 mesh) or the Biotage Isolera Four with 10 g SNAP cartridges. NMR spectra were recorded on Bruker 400 AVANCE or Bruker 300 AVANCE spectrometer. The chemical shifts for 1H NMR spectra are given in parts per million (ppm) referenced to the residual proton signal of the deuterated solvent ( = 7.28 ppm for CDCl3); coupling constants are expressed in Hertz (Hz). 13C{1H} NMR spectra were referenced to the carbon signals of the deuterated solvent ( = 76.9 ppm for CDCl3). The following abbreviations are used to describe peak multiplicities: s = singlet, br s = broad singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, and m = multiplet. High Resolution Mass Spectrometry (HRMS) analysis was performed by the Mass Spectrometry and Proteomics Unit at Queen’s University in Kingston, Ontario.

Synthesis of Pd-PEPPSI-IPent-Acenapht1

Synthesis of compound S2

To a 100 mL round bottom flask containing a stir bar was added acenaphthenequinone (1.0 g, 5.489 mmol) and 40 mL acetonitrile. The resulting suspension was heated to reflux for 1 h, 10 mL glacial acetic acid was added, and the reaction mixture was heated to reflux until acenaphthenequinone dissolved completely. To this hot mixture was then added 2,6- di(pentan-3-yl)aniline, S1 (3.2 g, 13.723 mmol) dropwise, and then the resultant solution heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature and the resulting orange-yellow solid was filtered, and the filtrate was kept in a -4 C freezer for several hours to induce further crystallization. Then the combined orange-yellow solid was washed with 5 mL of cold ethanol, and dried in vacuo to give 2.18 g of S2 (65% yield). 1H

NMR (400 MHz, CDCl3)  7.87 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.25-7.18 (m, 6H), 6.71 (d, J = 7.2 Hz, 2H), 2.68-2.61 (m, 4H), 1.72-1.66 (m, 4H), 1.63-1.57 (m, 4H), 1.54- 1.48 (m, 4H), 1.46-1.37 (m, 4H), 0.85 (t, J = 7.2 Hz, 12H), 0.54 (t, J = 7.4 Hz, 12H); 13C{1H}

(100 MHz, CDCl3)  160.3, 149.6, 140.4, 132.6, 130.8, 129.6, 128.5, 127.3, 124.5, 123.7, 123.1, 42.4, 27.5, 26.0, 11.73, 11.68; HRMS (EI, positive ions): m/z = 612.4449 (calculated for [S2]+ = 612.4443).

Synthesis of Compound S3

To a screw-cap Schlenk flask containing a stir bar was added S2 (1.0 g, 1.631 mmol) and the flask was evacuated and back filled with argon (3 times). Then methoxymethylether (2.63 g, 32.620 mmol) was added. The resulting reaction mixture was heated to 100 C for 18 h. After cooling the reaction mixture at ambient temperature, 100 mL diethyl ether was added, resulting in the formation of a yellow precipitate. The precipitate was filtered and washed with diethyl ether (3  10 mL) and dried in vacuo to obtain 0.99 g of S3 (92% yield) as a 1 yellow powder. H NMR (400 MHz, CDCl3)  10.06 (br, s, 1H), 8.08 (d, J = 8 Hz, 2H), 7.77 (t, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 2H), 7.45 (d, J = 8 Hz, 4H), 7.24 (d, J = 6.8 Hz, 2H), 2.30-2.24 (m, 4H), 1.84-1.76 (m, 8H), 1.64-1.56 (m, 8H), 0.90 (t, J = 6.4 Hz, 12H), 0.59 (t, J 13 1 = 7.2 Hz, 12H); C{ H} NMR (100 MHz, CDCl3)  142.5, 139.5, 138.1, 132.2, 131.3, 131.2, 130.5, 129.9, 128.0, 126.0, 124.2, 122.2, 43.3, 28.5, 27.8, 12.2, 11.9; HRMS (ESI, positive ions): m/z = 625.4537 (calculated for [S3-Cl]+ = 625.4522).

Synthesis of Compound C5

To a Schlenk flask was added S3 (0.40 g, 0.605 mml), PdCl2 (0.11 g, 0.611 mmol), Cs2CO3 (0.99 g, 3.025 mmol), and a stir bar. The flask was then evacuated and backfilled with argon (3 times), and 4 mL of 3-chloropyridine was added. Then the resulting mixture was heated to 80 C for 36 h. After cooling the reaction mixture to ambient temperature dichloromethane was added and the resulting mixture/suspension filtered through a pad of silica and celite, and washed with dichloromethane until the filtrate became colorless. The filtrate was evaporated in vacuo and the excess 3-chloropyridine was distilled off. The residue thus obtained was dissolved in dichloromethane and filtered through a pad of silica and Celite, and washed with dichloromethane until the filtrate became colorless. The filtrate was then evaporated to dryness and then triturated with pentane. The residue was dried in vacuo to obtain 0.49 g of 1 C5 (88% yield) as a bright yellow solid. H NMR (400 MHz, CDCl3)  8.68 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 8 Hz, 2H), 7.59 (t, J = 8 Hz, 3H), 7.39 (d, J = 8 Hz, 4 H), 7.32 (t, J = 7.6 Hz, 2H), 7.11 (dd, J = 8, 5.6 Hz, 1H), 6.70 (d, J = 7.2 Hz, 2H), 3.30-3.24 (m, 4H), 2.05-1.83 (m, 8H), 1.43-1.36 (m, 4H), 1.28-1.19 (m, 4H), 1.12 (t, J = 7.2 Hz, 12H), 13 1 0.52 (t, J = 7.6 Hz, 12H); C{ H} NMR (100 MHz, CDCl3)  157.9, 150.6, 149.5, 144.5, 140.6, 137.3, 135.4, 131.9, 129.4, 129.0, 128.8, 127.9, 126.9, 126.7, 126.5, 124.3, 121.7, 40.7, 26.4, 26.2, 12.4, 9.7; HRMS (ESI, positive ions): m/z = 914.2996 (calculated for [C5+H]+ = 914.2966).

General procedure for cross-coupling

General procedure A: The low temperature cross-coupling of aryl bromides and organolithium reagents

A dry Schlenk flask, equipped with a stir bar was charged (Pd-PEPPSI-IPent-Acenapht (13.7 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to the indicated temperature (-22 C to -78 C). The corresponding alkyl- or aryllithium reagent (1.5 equiv) was diluted with toluene to reach 1 mL, and was added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, the reaction mixture was quenched with methanol (1 mL) at the indicated temperature (-22 C to -78 C). The mixture was warmed to room temperature, Celite was added and all liquids evaporated under reduced pressuer. Dichloromethane (5 mL  2) was added and filtered through a small pad of Celite and the filtrate was evaporated and the residue was purified by column chromatography.

General procedure B: The low temperature chemo-selective cross-coupling of aryl bromides over chlorides and organolithium reagents

A dry Schlenk flask, equipped with a stir bar was charged Pd-PEPPSI-IPent-Acenapht (13.7 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to the indicated temperature (-22 C to -34 C). The corresponding alkyl- or aryllithium reagent(1.2-1.5 equiv) was diluted with toluene to reach 1 mL, and was added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, the reaction mixture was quenched with methanol (1 mL) at the indicated temperature (-22 C to -34 C). Then the flask was warmed to room temperature, Celite was added and all volatiles/liquids evaporated. Dichloromethane (5 mL  2) was added and filtered through a small pad of Celite and the filtrate was evaporated and the residue was purified by column chromatography.

General procedure C: Sequential cross-coupling of aryl halides, organolithium reagents, and organometallic reagents (ArB(OH)2 or ArZnX or ArLi)

In a dry Schlenk flask, Pd-PEPPSI-IPentCl (5 mol%, 0.025 mmol, 21 mg) and the aryl bromide (0.5 mmol) were dissolved in 4 mL of dry toluene at room temperature, and the mixture was subsequently cooled down to -20 °C by means of a cooling bath. The corresponding commercial alkyllithium reagent (1.05 equiv) was diluted with toluene to reach 1.0 mL; this solution was added over 1 h by the use of a syringe pump. After the addition was completed, the second organometallic reagent (1.5 equiv) was added, and the mixture was heated to the indicated temperature for the appropriate time. After the reaction was completed, it was quenched with 1.0 mL of methanol, and Celite was added to the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was directly purified by column chromatography.

General procedure D: Sequential cross-coupling of aryl halides, organolithium reagents, and anilines

A dry Schlenk flask, equipped with a stir bar was charged with Pd-PEPPSI-IPentCl (12.9 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to -22 C. The corresponding alkyl lithium reagent (1.2 equiv) was diluted with toluene to reach 1 mL, and added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, aniline (1.2 equiv), and base (KOtBu

(1.5 equiv) or Cs2CO3 (3 equiv.)) was added to the reaction mixture under Argon at the indicated temperature. The resulting mixture was warmed up to ambient temperature and stirred for 16 h or heated to 80 C for 16 h. Subsequently, dichloromethane (10 mL) was added and the mixture filtered through a pad of Celite followed by washing with dichloromethane. The filtrate was evaporated and the residue was purified by column chromatography.

General procedure E: Sequential cross-coupling of aryl halides, organolithium reagents, and thiophenols

A dry schlenk flask, equipped with a stir bar was charged with Pd-PEPPSI-IPentCl (12.9 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to -22 C. The corresponding alkyllithium reagent (1.2 equiv) diluted with toluene to reach 1 mL, and this was added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, KOtBu (2.0 equiv) and thiophenol (1.2 equiv) were added to the reaction mixture under Argon at the indicated temperature. The resulting mixture was warmed up to ambient temperature and stirred for 16 h or heated to 80 C for 16 h. After that aqueous NaOH (2 mL, 1M) was added and the resulting sollution extracted with dichloromethane (3  5 mL). The combined organic extracts were washed with brine, dried over anhydrous Mg2SO4, filtered, and concentrated in vacuo. The residue thus obtained was purified by column chromatography.

Table S1. Chemoselective cross-coupling of aryl bromide over chloride with organolithium reagents (selectivity study):

dicoupled dicoupled monocoupled product product product monocoupled product dichloromethane

toluene

1 Figure S1. H NMR spectrum (400 MHz, CDCl3) obtained from reaction mixture (Entry 1, Table S1).

1 Figure S2. H NMR spectrum (400 MHz, CDCl3) obtained from reaction mixture (Entry 2, Table S1).

1 Figure S3. H NMR spectrum (400 MHz, CDCl3) obtained from reaction mixture (Entry 3, Table S1).

Experimental data

Following general procedure A (at -62 C), 50 mg of 1 (90% yield) was isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H

NMR (400 MHz, CDCl3)  8.12 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.58-7.50 (m, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H), 3.13 (t, J = 7.6 Hz, 2H), 1.83-1.76 (m, 2H), 1.56-1.46 (m, 2H), 13 1.03 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3)  138.9, 133.8, 131.8, 128.6, 126.3, 125.8, 125.5, 125.4, 125.3, 123.8, 32.9, 32.7, 22.8, 13.9. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -62 C, 0.5 mmol scale reaction), 77 mg of 2 (92% yield) were isolated after flash column chromatography (n-Pentane) 1 as a colorless oil. H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.61 (m, 2H), 7.46 (dd, J =

8.2, 7.1 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 2.56-2.29 (m, 1H), 1.21-1.09 (m, 13 2H), 0.92-0.81 (m, 2H); C NMR (101 MHz, CDCl3) δ 139.3, 133.67, 133.65, 128.6, 126.7, 125.8, 125.7, 125.6, 124.6, 123.9, 13.4, 6.6. The spectral data are consistent with those reported in the literature.3

Following general procedure A (at -42 C), 46 mg of 3 (81% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H

NMR (400 MHz, CDCl3)  7.91 (d, J = 8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.12 (s, 1H), 2.90 (t, J = 7.2 Hz, 2H), 1.83-1.76 (m, 2H), 13 1.55-1.46 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3)  140.4, 139.1, 137.1, 123.9, 123.6, 122.8, 121.7, 120.7, 31.2, 28.2, 22.6, 13.9. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -62 C), 49 mg of 4 (89% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1 H NMR (400 MHz, CDCl3)  8.20 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 7.77 (d, J = 8Hz, 1H), 7.59-7.50 (m, 3H), 7.45 (d, J = 7.2 Hz, 1H), 3.64-3.55 (m, 1H), 1.98-1.88 (m, 1H), 1.84-1.74 (m, 1H), 1.45 (d, J = 6.8 13 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl3)  143.6, 133.8, 131.7, 128.8, 126.1, 125.5, 125.4, 125.1, 123.2, 122.4, 35.2, 30.5, 21.1, 12.2. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -62 C), 48 mg of 5 (87% yield) were isolated after flash chromatography (n-Pentane). 1H NMR (400

MHz, CDCl3)  7.86 (t, J = 7.2 Hz, 3H), 7.67 (s, 1H), 7.53-7.46 (m,

2H), 7.43-741 (d, J = 8.4 Hz, 1H), 2.88-2.79 (m, 1H), 1.80-1.72 (m, 2H), 1.40 (d, J = 6.8 Hz, 13 3H), 0.92 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3)  145.0, 133.6, 132.1, 127.7, 127.5, 127.4, 125.8, 125.7, 125.1, 124.9, 41.7, 30.9, 21.8, 12.2. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -22 C), 38 mg of 6 (79% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H

NMR (400 MHz, CDCl3)  7.64 (d, J = 7.6 Hz, 2H), 7.51-7.39 (m, 5 H), 7.37- 13 7.32 (m, 1H); C NMR (100 MHz, CDCl3)  142.3, 135.8, 128.7, 127.0, 126.4, 126.3, 126.1, 120.2. The spectral data are consistent with those reported in the literature.4

Following general procedure A (at -42 C), 60 mg of 7 (93% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1 H NMR (400 MHz, CDCl3)  8.02-7.99 (m, 1H), 7.89-7.87 (m, 1H), 7.67 (d, J = 8 Hz, 1H), 7.54-7.48 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 13 7.2 Hz, 1H), 2.6 (s, 2H), 0.06 (s, 9H); C NMR (100 MHz, CDCl3)  137.2, 133.9, 131.6, 128.5, 125.4, 125.3, 125.2, 124.9, 124.7, 124.6, 23.4, - 1.26. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -62 C), 52 mg of 8 (94% yield) were isolated after flash chromatography (n-Pentane) as a colorless 1 oil. H NMR (400 MHz, CDCl3)  7.87-7.82 (m, 3H), 7.67 (s, 1H), 7.53-7.45 (m, 2H), 7.40 (dd, J = 1,6, 8.4 Hz, 1H), 2.84 (t, J = 8 Hz, 2H), 1.80-1.72 (m, 2H), 13 1.51-1.42 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3)  140.3, 133.6, 131.9, 127.6, 127.5, 127.4, 127.3, 126.2, 125.7, 124.9, 35.7, 33.5, 22.3, 13.9. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -42 C), 64 mg of 9 (91% yield, branch product / linear product = 48:1) were isolated after flash chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz,

CDCl3)  8.83-8.80 (m, 1H), 8.76-8.71 (m, 1H), 8.27-8.24 (m, 1H), 7.94- 7.90 (m, 1H), 7.71-7.68 (m, 3H), 7.66-7.63 (m, 2H), 3.63-3.54 (m, 1H), 2.08-1.97 (m, 1H), 1.87-1.77 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.06 (t, J 13 = 7.4 Hz, 3H); C NMR (100 MHz, CDCl3)  141.6, 131.9, 131.2, 130.7, 129.3, 128.2, 126.4, 126.3, 125.84, 125.79, 123.8, 123.2, 122.9, 122.3, 35.3, 30.1, 20.8, 12.2. The spectral data are consistent with those reported in the literature.5

Following general procedure A (at -22 C), 46 mg of 10 (77% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H

NMR (400 MHz, CDCl3)  8.00-7.97 (m, 2H), 7.94 (d, J = 8 Hz, 1H), 7.62- 13 7.55 (m, 6H), 7.49-7.28 (m, 3H); C NMR (100 MHz, CDCl3)  140.7, 140.2, 133.7, 131.6, 130.0, 128.2 (2C), 127.6, 127.2, 126.9, 125.9 (2C), 125.7, 125.3.

The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -42 C), 58 mg of 11 (90% yield) were isolated after flash chromatography (n-Pentane) as a colorless 1 solid. H NMR (400 MHz, CDCl3)  7.84 (d, J = 8 Hz, 1H), 7.78 (t, J = 8 Hz, 2H), 7.47 (br m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8 13 Hz, 1H), 2.3 (s, 2H), 0.09 (s, 9H); C NMR (100 MHz, CDCl3)  138.2, 133.8, 130.9, 127.8, 127.5, 127.4, 126.9, 125.7, 125.1, 124.2, 27.3, -1.9. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -22 C), 36 mg of 12 (61% yield) were isolated after flash column chromatography (n-Pentane/ether: 05%) as a 1 colorless oil. H NMR (400 MHz, CDCl3)  7.16 (t, J = 7.6 Hz, 1H), 6.67- 6.62 (m, 2H), 6.58 (s, 1H), 3.81 (s, 3H), 2.09 (s, 2H), 0.03 (s, 9H); 13C

NMR (100 MHz, CDCl3)  159.4, 142.1, 128.9, 120.6, 113.7, 109.0, 54.9, 27.1, -1.9. The spectral data are consistent with those reported in the literature.6

Following general procedure A (at -62 C, 0.5 mmol scale reaction), 74 mg of 13 (87% yield) were isolated after flash column chromatography (n-Pentane) 1 as a colorless oil. H NMR (400 MHz, CDCl3)  8.17 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 – 7.39 (m, 4H), 3.79 13 (hept, J = 6.8 Hz, 1H), 1.44 (d, J = 6.9 Hz, 6H); C NMR (101 MHz, CDCl3) δ 147.3, 136.6, 134.0, 131.6, 128.9, 128.32, 128.31, 127.9, 125.9, 124.4, 31.2, 26.2. The spectral data are consistent with those reported in the literature.7

Following general procedure A (at -42 C, from 4-iodoanisole), 36 mg of 15 (73% yield) were isolated after flash column chromatography (n-Pentane/ether: 1 05%) as a colorless oil. H NMR (400 MHz, CDCl3)  7.13 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H), 2.58 (t, J = 7.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.42-1.33 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,

CDCl3)  157.5, 134.9, 129.1, 113.5, 55.1, 34.6, 33.8, 22.2, 13.9. The spectral data are consistent with those reported in the literature.2

Following general procedure A (at -22 C), 31 mg of 16 (63% yield) were isolated after flash column chromatography (n-Pentane/ether: 05%) as a 1 colorless oil. H NMR (400 MHz, CDCl3)  7.23 (d, J = 8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.76-6.74 (m, 2H), 3.83 (s, 3H), 2.64-2.55 (m, 1H), 1.65-1.58 (m, 2H), 1.25 (d, J = 7.2 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (100

MHz, CDCl3)  159.4, 149.4, 129.0, 119.4, 112.9, 110.6, 54.9, 41.6, 30.9, 21.7, 12.1. The spectral data are consistent with those reported in the literature.8

Following general procedure A (at -22 C), 31 mg of 17 (63% yield) were isolated after flash column chromatography (n-Pentane/ether: 05%) as a 1 colorless oil. H NMR (400 MHz, CDCl3)  7.22 (m, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.76-6.74 (m, 2H), 3.83 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H), 1.67-1.61 (m, 2H), 1.43-1.32 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,

CDCl3)  159.5, 144.5, 129.0, 120.8, 114.0, 110.7, 55.0, 35.6, 33.4, 22.3, 13.8. The spectral data are consistent with those reported in the literature.9

Following general procedure A (at 23 C, 2.5 equiv. TMSCH2Li was used), 56 mg of S5 (75% yield) were isolated after flash column chromatography (n- 1 Pentane) as a colorless oil. H NMR (400 MHz, CDCl3)  6.88 (s, 4H), 2.04 13 (s, 4H), 0.01 ppm (s, 18H); C NMR (100 MHz, CDCl3)  135.4, 127.7, 26.1, -2.00. The spectral data are consistent with those reported in the literature.10

Following general procedure B (at -22 C), 46 mg of 18 (75% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H

NMR (400 MHz, CDCl3)  7.20 (d, J = 8 Hz, 2H), 6.94 (d, J = 8 Hz, 2H), 2.07 13 (s, 2H), 0.01 (s, 9H); C NMR (100 MHz, CDCl3)  138.9, 129.4, 129.1, 128.1, 26.4, -2.1. The spectral data are consistent with those reported in the literature.11

Following general procedure B (at -22 C), 51 mg of 19 (80%) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1 H NMR (400 MHz, CDCl3)  7.12 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 2.22 (s, 3H), 2.08 (s, 2H), 0.03 (9H); 13C NMR (100

MHz, CDCl3)  137.4, 136.2, 129.7, 129.6, 129.1, 125.5, 23.1, 20.1, -1.6; HRMS (EI, positive ions): m/z = 212.0779 (calculated for [19]+ = 212.0788).

Following general procedure B (at -22 C), 34 mg of 20 (67% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H

NMR (400 MHz, CDCl3)  7.26 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.63-1.56 (m, 2H), 1.41-1.32 (m, 2H), 0.96 (t, J = 7.4 13 Hz, 3H); C NMR (100 MHz, CDCl3)  141.2, 131.1, 129.6, 128.2, 34.9, 33.4, 12 22.1, 13.8. The spectral data are consistent with those reported in the literature.

Following general procedure B (at -34 C), 43 mg of 21 (78% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1 H NMR (400 MHz, CDCl3)  7.15 (s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 2.58 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.62-1.52 (m, 2H), 1.46-1.37 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl )  139.4, 137.6, 130.9, 129.9, 129.7, 125.7, 32.3, 32.2, 22.5, 19.1, 3 13.9; HRMS (EI, positive ions): m/z = 182.0869 (calculated for [21]+ = 182.0862).

Following general procedure B (at -22 C), 42 mg of 22 (70% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H

NMR (400 MHz, CDCl3)  7.33-7.28 (m, 1H), 7.17-7.12 (m, 1H), 7.09-7.02 13 (m, 2H), 2.31 (s, 2H), 0.07 (s, 9H); C NMR (100 MHz, CDCl3)  138.7, 132.5, 129.7, 129.3, 126.3, 125.2, 24.2, -1.6. The spectral data are consistent with those reported in the literature.11

Following general procedure C, 85 mg of 23 (55% yield, two step) were isolated after flash column chromatography (n- Pentane/Dichloromethane = 96:4) as a colorless oil. The corresponding boronic acid (1.5 equiv) and sodium methoxide (3 equiv) were added as solids. Degassed THF (3 ml) was subsequently added, and the reaction carried out at 75 C overnight. 1 H NMR (400 MHz, CDCl3)  8.11 (d, J = 8.0 Hz, 2H), 7.70-7.60 (m, 2H), 7.36-7.28 (m, 3H), 7.04 (dt, J = 6.9, 1.7 Hz, 1H), 3.94 (s, 3H), 2.17 (s, 2H), 0.04 (s, 13 9H); C NMR (101 MHz, CDCl3) δ 167.1, 146.1, 141.3, 139.9, 130.1, 128.8, 127.9, 127.1(2C), 126.9, 123.1, 52.1, 27.3, -1.8; HRMS (ESI, positive ions): m/z = 299.1461 (calculated for [23+H]+ = 299.1467).

Following general procedure C (second step at room temperature, stirring for 18 h), 92 mg of 24 (75% yield, two step) were isolated after flash column chromatography (n-Pentane/Ethyl acetate = 99:1) as a colorless oil. The corresponding organozinc reagent was synthesized 13 1 via literature procedure. H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 3.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H); 13C NMR

(101 MHz, CDCl3) δ 161.5, 160.4, 147.6, 146.4, 132.2, 131.4, 131.2, 126.9, 124.9, 122.4, 109.3, 63.5, 31.5, 18.3, 17.1; HRMS (ESI, positive ions): m/z = 245.1172 (calculated for [24+H]+ = 245.1178).

Following general procedure C, with addition of the second organolithium reagent (4-lithio anisole) over 1 h at 40 °C, compound 25 was obtained in 43% yield (two step). The 4-lithio anisole was prepared via a literature procedure.12 Due to difficulties in separating the title compound from 4-methoxy- biphenyl, the yield was determined via NMR with internal standard (tetrachloroethane), and an aliquot was purified via Preperative HPLC (n-Pentane). 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.6 Hz, 2H), 7.40 (s, 1H), 7.38-7.31 (m, 2H), 7.18 (d, J = 6.9 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 2.96 (hept, J = 6.9 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H); GC-MS: 226/211/179/105.

Following general procedure C (second step at room temperature, stirring for 18 h), 106 mg of 26 (82% yield, two step) were isolated after flash column chromatography (n-Pentane/Ethyl acetate = 99:1) as 1 a colorless oil. H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.60 (dd, J = 7.8, 1.4 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 3.4 Hz, 1H), 7.21 (s, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.96 (hept, J = 6.9 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.29 (d, J = 6.9 Hz, 13 6H); C NMR (101 MHz, CDCl3) δ 161.6, 160.5, 152.2, 146.4, 132.2, 131.5, 129.7, 125.6, 125.1, 122.5, 109.3, 63.5, 36.8, 26.6, 17.1; HRMS (ESI, positive ions): m/z = 259.1330 (calculated for [26+H]+ = 259.1334).

Following general procedure C, with addition of the second organolithium reagent (2-(methoxymethoxy)phenyl)lithium) over 1 h at 40 °C, 61 mg of 27 (48% yield, two step) were isolated after column chromatography (n-Pentane/Ethyl acetate = 97:3) as a colorless oil.

Cyclopropyllithium,7 and 2-(methoxymethoxy)phenyllithium12 were prepared via literature 1 procedure. H NMR (400 MHz, CDCl3) δ 7.36-7.27 (m, 4H), 7.21 (dd, J = 8.2, 1.2 Hz, 2H), 7.15-6.98 (m, 2H), 5.12 (s, 2H), 3.41 (s, 3H), 1.95 (tt, J = 8.4, 5.1 Hz, 1H), 1.05-0.90 (m, 2H), 13 0.80-0.67 (m, 2H); C NMR (101 MHz, CDCl3) δ 154.3, 143.7, 138.7, 132.2, 131.1, 128.7, 127.9, 126.9, 126.8, 124.5, 122.4, 115.8, 95.2, 56.2, 15.6, 9.4; GC-MS: 254/221/207/181.

Following general procedure C, with addition of the second organolithium reagent (4-lithio anisole) over 1 h at 40 °C, 78 mg of 28 (58% yield, two step) were isolated after column chromatography (n-Pentane) as a colorless 1 oil. H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 9.3 Hz, 2H), 7.26 (d, J = 5.5 Hz, 2H), 7.19 (s, 1H), 7.03-6.91 (m, 3H), 3.86 (s, 3H), 2.15 (s, 2H), 0.03 (s, 13 9H); C NMR (101 MHz, CDCl3) δ 159.1, 141.0, 140.8, 134.3, 128.6, 128.3, 126.6, 126.6, 122.6, 114.3, 55.5, 27.3, -1.7; GC-MS: 270/255/73.

Following general procedure D (-22 C, 23 C), 60 mg of 29 (78% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a 1 colorless oil. H NMR (400 MHz, CDCl3)  7.20- 7.12 (m, 3H), 6.07 (d, J = 8Hz, 2H), 6.64 (d, J = 7.6 Hz, 2H), 6.49-6.47 (m, 1H), 5.66 (s, 1H), 3.81 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.45-1.36 (m, 2H), 0.99 (t, J = 7.6 13 Hz, 3H); C NMR (100 MHz, CDCl3)  160.6, 145.3, 140.1, 136.2, 129.9, 129.1, 119.1, 109.4, 105.4, 102.4, 55.1, 34.9, 33.7, 22.3, 13.9; HRMS (EI, positive ions): m/z = 255.1629 (calculated for [29]+ = 255.1623).

Following general procedure D (-22 C, 80 C), 40 mg of 30 (47% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 010%) as a colorless oil. 1H NMR (400 MHz,

CDCl3)  7.92 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8 Hz, 2H), 7.11 (d, J = 8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.01 (s, 1H), 3.89 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.44-1.35 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (100

MHz, CDCl3)  166.9, 148.6, 138.14, 138.10, 131.4, 129.3, 121.1, 120.4, 113.9, 51.6, 34.9, 33.6, 22.2, 13.9; HRMS (EI, positive ions): m/z = 283.1566 (calculated for [30]+ = 283.1572).

Following general procedure D (-22 C, 80 C), 45 mg of 31 (60% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 010%) as a light yellow 1 oil. H NMR (300 MHz, CDCl3)  7.30-7.26 (m, 2H), 7.24-7.22

(m, 2H), 7.17-7.08 (m, 2H), 7.06-7.03 (m, 2H), 5.57 (s, 1H), 2.59 (t, J = 7.5 Hz, 2H), 1.63- 13 1.53 (m, 2H), 1.44-1.32 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); C NMR (75 MHz, CDCl3)  146.2, 138.5, 136.4, 130.4, 130.0, 127.0, 124.8, 123.2, 122.6, 119.6, 119.2, 117.7, 113.0, 32.2, 31.1, 22.5, 13.9;

Following general procedure D (-22 C, 80 C), 36 mg of 32 (40% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 010%) as a colorless 1 oil. H NMR (300 MHz, CDCl3)  7.59-7-53 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.27-7.23 (m, 2H), 7.21-7.15 (m, 1H), 7.12-

7.02 (m, 2H), 5.52 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.66-1.56 (m, 2H), 1.44-1.36 (m, 5H), 0.94 (t, J 13 1 = 7.2 Hz, 3H); C{ H} NMR (75 MHz, CDCl3)  166.7, 144.9, 139.9, 134.3, 131.6, 130.1, 129.2, 126.8, 123.2, 120.9 (2C), 120.4, 117.5, 60.9, 31.9, 31.1, 22.6, 14.3, 13.9;

Following general procedure D (-22 C, 23 C), 36 mg of 33 (50% yield, two step) were isolated after flash column chromatography 1 (n-pentane) as a light yellow oil. H NMR (400 MHz, CDCl3)  7.33-7.26 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8 Hz, 2H), 6.92 (t, J = 7.2 Hz, 1H), 3.34 (s, 3H), 2.62 (m, 1H), 1.66-1.59 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H), 0.89 (t, J 13 1 = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl3)  149.2, 146.6, 141.5, 129.1, 128.9, 127.7, 121.8, 120.3, 119.8, 118.5, 40.9, 40.2, 31.2, 21.7, 12.2; HRMS (EI, positive ions): m/z = 239.1679 (calculated for [33]+ = 239.1674).

Following general procedure D (-22 C, 23 C), 61 mg of 34 (80% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a colorless 1 oil. H NMR (400 MHz, CDCl3)  7.29-7.27 (m, 1H), 7.18- 7.13 (m, 4H), 6.94-6.85 (m, 3H), 6.15 (s, 1H), 3.94 (s, 3H), 2.63 (t, J = 7.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.48-1.39 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H); 13 1 C{ H} NMR (100 MHz, CDCl3)  147.8, 140.0, 136.0, 133.7, 129.0, 120.7, 119.3, 119.1, 113.7, 110.3, 55.5, 34.9, 33.7, 22.3, 13.9; HRMS (EI, positive ions): m/z = 255.1619 (calculated for [34]+ = 255.1623).

Following general procedure D (-22 C, 23 C), 64 mg of 35 (79% yield; two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a light yellow oil. 1H NMR (400

MHz, CDCl3)  7.08 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.78-6.76 (m, 2H), 5.41 (s, 1H), 3.84 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 2.29 (s, 3H), 1.61-1.54 (m, 2H), 1.47-

13 1 1.41 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl3)  154.7, 142.5, 136.8, 136.5, 132.7, 129.5, 121.2, 118.1, 114.5, 113.7, 55.5, 32.7, 32.2, 22.6, 19.4, 14.0;

Following general procedure D (-22 C, 23 C), 51 mg of 36 (56% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a light yellow oil. 1H NMR (400

MHz, CDCl3)  7.14 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.79 (br s, 2H), 5.4 (s, 1H), 3.90 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 2.29 (s, 3H), 1.59-1.53 (m, 2H), 1.46- 1.39 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,

CDCl3)  149.7, 141.2, 137.6, 136.9, 133.8, 129.6, 122.9, 120.8, 119.2, 117.9, 114.8, 113.2, 56.6, 32.6, 32.2, 22.6, 19.4, 14.0;

Following general procedure E (-22 C, 80 C), 41 mg of 37 (53% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) 1 as a colorless oil. H NMR (400 MHz, CDCl3)  7.30- 7.27 (m, 4H), 7.14 (br d, J = 7.1 Hz, 4H), 2.62 (t, J = 7.4 Hz, 2H), 2.37 (s, 3H), 1.66-1.58 (m, 13 1 2H), 1.44-1.34 (m, 2H), 0.96 (t, J = 7.1 Hz, 3H); C{ H} NMR (100 MHz, CDCl3)  141.8, 136.9, 132.8, 132.2, 131.1, 130.7, 129.8, 129.2, 35.1, 33.4, 22.2, 21.0, 13.9. The spectral data are consistent with those reported in the literature.14

Following general procedure E (-22 C, 23 C), 52 mg of 38 (64% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) 1 as a colorless oil. H NMR (400 MHz, CDCl3)  7.42 (d, J = 7.5 Hz, 2H), 7.18 (d, J = 7.3 Hz, 2H), 7.12 (d, J = 7.4 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 3.85 (s, 3H), 2.60 (t, J = 7.5 Hz, 2H), 1.64-1.57 (m, 2H), 1.42-1.34 (m, 2H), 0.96 (t, J = 13 1 7.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl3)  159.4, 141.0, 135.3, 134.4, 129.0 (2C), 125.3, 114.8, 55.3, 35.1, 33.5, 22.2, 13.9. The spectral data are consistent with those reported in the literature.15

Following general procedure E (-22 C, 80 C), 40 mg of 39 (52% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a colorless 1 oil. H NMR (400 MHz, CDCl3)  7.27-7.22 (m, 4H), 7.19- 7.14 (m, 4H), 2.63 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.67-1.59 (m, 2H), 1.45-1.35 (m, 2H), 13 1 0.97 (t, J = 6.9 Hz, 3H); C{ H} NMR (100 MHz, CDCl3)  141.8, 138.7, 135.0, 131.7, 131.4, 130.8, 130.3, 129.3, 127.0, 126.5, 35.1, 33.4, 22.3, 20.4, 13.9;

References

(1) The synthesis of Pd-PEPPSI-IPent-Acenapht is slightly differing from the very recently published procedure; see Lu, D.-D.; He, X.-X.; Liu, F.-S. J. Org. Chem. 2017, 82, 1089810911. (2) Heijnen, D.; Tosi, F.; Vila, C.; Stuart, M. C. A.; Elsinga, P. H.; Szymanski, W.; Feringa, B. L. Angew. Chem. Int. Ed. 2017, 56, 33543359. (3) Molander, G. A.; Beaumard, F.; Niethamer, T. K. J. Org. Chem. 2011, 76, 81268130. (4) Ogawa, H.; Yang, J.-K.; Minami, H.; Kojima, K.; Saito, T.; Wang, C.; Uchiyama, M. ACS Catal. 2017, 7, 39883994. (5) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389391. (6) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L. Org. Lett. 2015, 17, 22622265. (7) Vila, C.; Giannerini, M.; Hornillos, V.; Fañanás-Mastral, M.; Feringa, B. L. Chem. Sci. 2014, 5, 13611367. (8) Li, L.; Zhao, S.; Joshi-Pangu, A.; Diane, M.; Biscoe, M. R. J. Am. Chem. Soc. 2014, 136, 1402714030. (9) Jia, Z.; Liu, Q.; Peng, X.-S.; Wong, H. N. C. Nat. Commun. 2016, 7, 10614, doi: 10.1038/ncomms10614. (10) Gómez, C.; Huerta, F. F.; Yus, M. Tetrahedron 1997, 53, 1389713904. (11) Protti, S.; Ravelli, D.; Mannucci, B.; Albini, A.; Fagnoni, M. Angew. Chem. Int. Ed. 2012, 51, 85778580. (12) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 5, 667–672. (13) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 60406044. (14) Liu, X.; Cao, Q.; Xu, W.; Zeng, M.-T.; Dong, Z.-B. Eur. J. Org. Chem. 2017, 57955799.

(15) Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 73977403. Summary From the pioneering work of Murhashi and Negishi in the 1970’s, the cross coupling of organolithium reagents has transformed to a viable alternative for more traditional and costly C-C bond forming reactions.

In chapter 2, we describe the coupling of the bifunctional (Trimethylsilyl)methyllithium, to afford TMS-substituted toluene derivatives. The commercially available alkyllithium reagent is coupled in high yields with both chlorides and bromides, by means of a Pd-PEPPSI carbene complex. The products after the cross coupling can be used for an array of further functionalization. Initial attempts in deprotonating the product at the benzylic position, and perform a second coupling were met with success, but were not further studied.

Scheme 1 Palladium catalysed coupling of bifunctional organolithium reagent The first application of the palladium catalyzed cross coupling of organolithium reagents in the synthesis of a natural product is shown in chapter 3, shortening the total synthesis of Mastigophorene A by 12 steps with regard to the previous reported syntheses (Scheme 2A). In the search of combining reactions without having to switch reaction vessel, solvent or having any means of intermediate purification, the one pot reactions described in chapter 4 use organolithium reagents to yield (alpha substituted) ketones, aldehydes or anilines (scheme 2B).

Scheme 2 A) Mastigophorene A. B) Reagents, intermediates and products of one pot coupling strategies For these transformations, the use of (Weinreb) amides is crucial, and the corresponding tetrahedral intermediate that is formed upon nucleophilic addition is either stabile under cross coupling conditions (for the synthesis of aldehydes) or liberates a lithium amide (for the synthesis of substituted ketones or anilines). In the presence of acidic alpha protons next to the generated carbonyl, the liberated lithium amide acts as in situ formed base and addition of an aryl bromide sets the stage for selective alpha arylation (chapter 4). The high reactivity of organolithium reagents in combination with the catalyst described in chapters 2-5 that lead to cross coupling reactions at relatively low temperatures, and thus provide a promising reaction setup for an enantioselective version of which the attempts are described in chapter 5. Initial attempts with chiral versions of the commercially available Pd-PEPPSI complex showed only to be active with unhindered aryl-aryl coupling reactions, that would not yield stable atropoisomers. A short structure activity relationship study lead to a hypothesized bulky chiral Pd-PEPPSI complex. Its syntheses was attempted, but the initially proposed structures were not successfully synthesized. Alternative catalyst (Pd-PEPPSI-Mes*, Pd-PEPPSI-Box* and Pd-PEPPSI-IPr*) were made (Scheme 3A), but were found to be incapable of coupling hindered aryl substrates with satisfactory yields, much like the initially attempted complexes.

Scheme 3 Palladium and Nickel catalysts Moving away from palladium, a screening of cheaper and more abundant metals in chapter 6 showed that nickel complexes Ni-NHC and Ni-DEPE (scheme 3B) were particularly active in the coupling of organolithium reagents with aryl bromides and chlorides, but also with less reactive aryl methyl ethers and aryl fluorides. Mechanistic studies were not performed, but reactivity in the substrate scope points towards a non-traditional catalytic cycle, facilitated by extended aromatic systems such as naphthalenes. Though the yields with the selected nickel complexes were generally a bit lower than with identical reactions catalyzed by palladium, the coupling of the mentioned less reactive electrophiles increased the scope significantly.

In order to avoid slow addition and speed up the cross coupling reaction, the oxygen activation of a Pd-phosphine complex was studied in chapter 7. After carefully studying the activation process, reaction times down to five seconds were possible. This new improved turnover speed made the cross reaction outcompete other reactions such as the opening of epoxides. Furthermore, a broader range of electrophiles and nucleophiles were coupled in the presence of the new nanoparticle catalyst. The coupling of unstable isotopes with short half-lives (11C, 20 min) was used to showcase the potential of this methodology, and Celecoxib was successfully labelled in good radiochemical yield (Figure 1).

Figure 1 Biologically active compounds Celecoxib and Tamoxifen

Other applications of the oxygen activated, nanoparticle catalyst were found in the synthesis of tetra substituted olefins, the synthesis of Z-Tamoxifen in particular, and are described in chapter 8. The breast cancer drug was made via a direct carbolithiation-cross coupling strategy, giving the product in good yield. The synthesis distinguished itself from previously reported methods by its high atom economy and low step count. If the catalyst loading can be further lowered, the chromatography free synthesis could be an alternative to existing means of obtaining the pharmaceutical compound.

Finally, the one pot procedure for the coupling of C, N and S nucleophiles with a chemoselectivity that is triggered by the reaction temperature is presented in chapter 9. Unprecedented palladium catalyzed cross coupling at -78 °C with aryl iodides is facilitated by specially designed metal-NHC complexes. Arene starting materials containing a bromide and chloride yielded the mono coupled product upon subjecting it to cross croupling conditions at -22 °C. The remaining aryl chloride could be coupled with an array of nucleophiles in a one pot fashion, by simply raising the reaction temperature, and the addition of a second coupling partner. Samenvatting Sinds de ontdekking van Murahashi in de zeventiger jaren, groeide de (palladium) gekatalyseerde koppeling van organolithium verbindingen langzaam richting een volwaardig alternatief voor traditionele cross koppelingen.

In hoofdstuk 2 is de koppeling van een bifunctioneel organolithium reagens beschreven. Het lithium- trimethylsilylmetyllithium reagens koppelt door middel van een Pd-PEPPSi catalysator, en produceert hierbij TMS gesubstitueerde toluene derivaten (Schema 1). De producten die hierbij verkregen worden zijn eenvoudig verder te functionaliseren, en zijn daarom waardevolle bouwstenen voor de organische synthese. De lithiering (deprotonering) van het verkregen product genereert een anion dat gebruikt kan worden een opvolgende koppeling uit te voeren, maar is niet verder in detail bestudeerd.

Schema 1 palladium gekatalyseerde koppeling van bifunctioneel organolithium reagens De formatie van het biaryl motief is een onderwerp dat veel bestudeerd is, aangezien de producten die hierbij verkergen worden veel interessante eigenschappen hebben door bijvoorbeeld hun gebruik als katalysator, ligand, of door hun biologische activiteit. Een nieuwe synthese van deze veelvoorkomende biaryl functionaliteit is beschreven in hoofdstuk 3, en is toegepast in de synthese van mastigophorene A (schema 2A). Door middel van een in situ lithiering wordt het aryl bromide startmateriaal omgezet in een aryllithium verbinding, die vervolgens door middel van een palladium PEPPSI-Ipent katalysator wordt gekoppeld.

Schema 2 A) Mastigophorene A. B) Reagentia, intermediar en producten van de one-pot koppeling strategie

In hoofstruk 4 worden methodes voor het combineren van meerdere reacties in een stap beschreven (schema 2B). Door het optimaliseren van de reactie omstandigheden zijn (Weinreb) amides geschikte startmaterialen om een 1,2-additie te ondergaan, gevolgd door een functionaliseringsstap naar keuze. Alle reacties beschreven in dit hoofstuk maken gebruik van een stabiel metaal-hemiaminal intermediair dat geen verdere elektrofiele eigenschappen heeft. Door gebruik te maken van dit intermediair kunnen gesubstitueerde ketonen worden verkregen door middel van een palladium gekatalyseerde organolithium cross coupling, danwel een alpha arylatie met een arylbomide. De applicatie van deze methode is verder uigebreid naar de synthese van aldehydes door middel van een aluminium hydride nucleofiel in de primaire 1,2-additie stap.

De eigenschappen en reactie omstandigheden van de palladium gekatalyseerde organolithium koppeling zijn in theorie erg geschikt voor een enantioselectieve koppelings strategie. De lage reactie temperaturen en reactive katalysatoren verhogen de kans op de overdracht van chiraliteit van katalysator naar product. Pogingen om een dit proces selectief te laten verlopen zijn beschreven in hoofdstuk 5. In initiële experienten gaven Pd-PEPPSI katalysatoren die gebaseerd zijn op een sterisch gehinderd metaal centrum de beste resultaten. Omdat gerapporteerde en commerciële chirale varianten hiervan niet voldoende reactief bleken te zijn, is de synthese van een nieuw chiraal palladium complex getracht te voltooien. Meerdere strategieën bleken niet succesvol, maar een synthese naar het gewenste ligand werd tijdens dit onderzoek gerapporteerd. Dit ligand werd gemaakt, en vervolgens met palladium gecomplexeerd.

Scheme 3 Palladium and Nikkel katalysatoren

Om het proces van organolithium koppelingen kosten efficiënter te maken, wordt in hoofdstuk 6 beschreven hoe het palladium metaal vervangen kan worden door nikkel. De gebruikte nikkel katalysatoren vertonen grote structurele overeenkomsten met de palladium variant. Hoewel de opbrengsten voor aryl-aryl koppelingen iets lager waren dan voor de duurdere palladium katalysator, bleek het nieuwe complex erg geschikt voor de koppeling van alkyllithium reagentia. Waar palladium niet geschikt is voor de koppeling met aryl-methyl-ether en arylfluorides, koppelen de overeenkomstige nikkel katalysatoren ook deze elektrofielen met alkyl en aryllithium nucleofielen. Door het gebruik van deze elektrofielen is de toepasbaarheid van de reactie significant vergroot.

Het effect van kleine hoeveelheiden onzuiverheden (in de vorm van zuurstof) maken het verschil tussen volledige conversie en (bijna) geen reactie in de snelle koppelingen beschreven in hoofdstuk 7. Door de eerder gerapporteerde Pd-phosphine katalysator te activeren met zuurstof, worden na toevoeging van organolithium reagens nanoparticles van 2-3 nanometer gevormd, welke zeer actief zijn in koppeling van deze zelfde organolithium nucleofielen. Nu deze koppeling in slechts enkele seconden kan worden uitgevoerd, is deze toegepast in de synthese van 11C gelabelde moleculen door middel van de koppeling van 11C methyllithium. Met deze methode is Celecoxib met een uitstekende opbrengst van 65% gemaakt. Door de zeer snelle en reactive katalysator is ook het aantal getolereerde functionele groepen uitgebreid, zodat ook substraten met een epoxide tot de mogelijkheden behoren.

Figuur 1. Biologisch actieve compontenten Celecoxib en Tamoxifen

Verdere toepassing van de palladium nanoparticle gekatalyseerde organolithium koppeling is gevonden in de synthese van borstkanker medicijn Tamoxifen. De begrippen atoom economie, reactie massa efficientie (RME) en E-factor worden uitgelegd in hoofdstuk 8, en worden vervolgens toegepast op verschillende syntheseroutes van Tamoxifen. Door verdere transmetallatie van het carbolitiëringsproduct te vermijden, wordt de hoeveelheid afval drastisch verlaagd, en wordt een efficiënter proces gecreëerd. Indien de hoeveelheid katalysator kan worden verminderd, is deze efficiënte, chromatografie vrije aanpak wellicht een alternatief voor bestaande syntheseroutes

Het laatste hoofdstuk beschrijft de toepassing van de organolithium cross koppeling in combinatie met een tweede koppeling, in één reactiestap. Omdat de Pd-PEPPSI gekatalyseerde koppeling tussen alkyllithium verbindingen en arylbromides al plaatsvindt bij zeer lage temperaturen, en diezelfde reactie met chlorides pas bij hogere temperaturen, is de selectieve 2 staps koppeling mogelijk. Door bij -20 graden Celcius, alkyl fragmenten te installeren, en vervolgens het product verder te functionaliseren door middel van Negishi, Suzuki of Buchwald-Hartig aminatie worden op een snelle manier producten gemaakt die van waarde kunnen zijn voor onderzoek naar nieuwe medicijnen en structuur-activiteit relatie onderzoek.

Summary for non chemists During the 4 years in which this thesis was written, the available methodology for the cross coupling of organolithium reagents was expanded. So what does that mean? Before explaining the theory behind it, it might help to address the practical aspects. Putting it really bluntly, we (organic chemists) mix chemicals, and hope we get the product we (or our boss) want. Sometimes it is really easy, like mixing flour, eggs and some milk in roughly the right ratio, and your product just appears, ready for the next step. More often however it is a bit more complicated, and we have no clue what is going on in our reaction flask. With the help of (expensive) equipment, we can slowly combine pieces of a puzzle. Some machines can give you the weight of your molecule, others tell you the ratio of hydrogen/carbon/oxygen atoms, and the most used one, is like a MRI for molecules. A really big magnet in which you insert your reaction mixture, to look at the interactions of your material with a magnetic field. The interpretation of these types of data, looking at peaks and drawing molecular structures (see also Figure 1) is like a language we all speak, in order to discuss our theories, findings and ideas.

Figure 1 Peaks, molecules and schemes that make perfect sense to an organic chemist.

In order to give an (extremely simplified) overview of how our research is built up and divided, I would like to use the analogy with the car industry to try and visualize what the words in the very first sentence mean. It might be easier to imagine the process (synthesis) of building a car. You would need wheels, a chassis, an engine, and many more parts. But you cannot just pile up all the components and shake it till a car appears, it requires precise handling, and a specific order of steps. Comparable to the vehicle, some people specialize in the general assembly method, while others work in the optimization of the specific parts (the engine, or tires for example), and therefore master the details of one process.

In the comparison to building a car, the field of synthetic organic synthesis can also roughly be divided in two fields. Those who study and master all the details of a single component (the development of methodology), and those who combine the expertise of others to assemble a complex structure such as a (molecular) car (Figure 2).

Figure 3 Schematic overview of assembly of a car (top) and part of the "assembly" of the molecular car (bottom)

In my research I have focused on the formation of carbon-carbon bonds. Its importance is equivalent to making a metal-metal connection (welding, bolting, locking etc.) in a car. In 2013, my predecessor found a new way of making these carbon-carbon bonds in a way that produces just a fraction of the waste, and costs less than half of the existing methods available. So why isn’t the whole (chemical) world using this method already? Going back to the car, the method works great for structures that are only made of steel, but it requires such extreme conditions that it would immediately destroy all sensitive plastic and glass parts (= functional molecular groups) of the car. Though the chemicals I worked with are cheap, easy to make and produce a relatively innocuous waste, they are so reactive that they catch fire spontaneously upon exposure to air. One of my main challenges was to try and control this extreme reactivity, so we can apply the above mentioned method in the presence of more sensitive parts of the car or molecule. Finally, another goal was to further increase the difficulty of the bond (hard to reach, sterically hindered) we could make, and reduce the cost even further by optimizing the nature of the catalyst.

Taking it one step up in terms of chemistry, I will try to explain the terms catalyst and atom economy. The first word might ring a bell for some people, thinking of a car exhaust, and its definition is : “A component that takes part in a reaction, without being consumed”. In other words, it helps the reaction go, but is still intact after it has done its job. As a consequence, a catalyst can undergo several consecutive reactions, and can therefore often be used in relatively small amounts. For work in this thesis, the amount of catalyst is usually 1-5 % of the product, meaning each catalyst molecule undergoes 100-20 catalytic cycles until the reaction is complete. Palladium is a metal that can do just these things, and the fact that it is expensive is compensated by the small amounts that are necessary for the reactions. (Though I have used several thousands of euros of palladium catalysts throughout my research, sorry Ben). The above mentioned catalysts help us improve reactions, and have made an impact on us all. Almost every single piece of plastic that you have ever touched, (bio)fuels you have put in your car, pastries you have eaten, and even some of the drugs you have taken are made via catalytic chemical transformations. Without them our cars would emit a lot more toxic fumes, your future car will not have fuel, our plastics would be unaffordable or unavailable, and even some of our food and medicine would not be the same. It would be an understatement to say that research into catalysis and catalysts is extremely important for our current way of living (be it good or bad). One way these catalysts improve chemical transformations, is by lowering the amount of waste that is produced, or the amount of heat or time required to achieve conversion to the product. Only very few people will wonder about the quantity of side products that were created during the synthesis of their painkiller or antitumor medicine. In reality, the ratio between useful drug and generated waste can be as bad as 1: 100 or more (100 grams of waste per gram of active ingredient), and it makes up an appreciable percentage of the price of the drug to (responsibly) treat this waste. It is not only the weight of the unwanted side product that plays an important role, but also its chemical nature. Some side products are toxic, and therefore even more costly to recycle or dispose of.

Figure 3 Chemical "handles" for increased selectivity and reactivity

Figure 3 shows how this waste is produced, and why it can’t always be avoided. The top reaction represents an unselective or unreactive pair of chemicals, which upon mixing gives the undesired (linked on the corner), or no product. Traditional methods for efficiently coupling these two building blocks often require large, expensive or toxic handles, that generate large amounts of (toxic) waste (the red/orange balls in scheme 2). The methodology that we further developed has the advantage of producing a relatively small amount of non-toxic waste (the green balls). The major side product is lithium chloride, a relatively harmless salt which is sometimes even used as a drug itself. The theoretical relation between product and generated waste is described as Atom Economy, and is shown below.

Chemists (should) always try to achieve the highest possible atom economy without compromising other parameters such as product purity, safety, reaction time, space, efficiency or yield. This everlasting search for the increase in atom economy and decrease of waste and energy are essential for making existing production processes less harmful for the environment, and thus generate greener ways of producing chemical products.

So what is the point and/or relevance of all of this? Beside the curiosity to invent and develop new (chemical) methods, molecules or devices, or in order to explain natural phenomena, fundamental research should not be judged on its immediate output for society. Spending years of research on a topic that was just a curiosity at first, could prove invaluable for the whole world years later. Beside the proof of principle that organolithium reagents can be used for coupling reactions, We have also shown its application in the synthesis of several pharmaceuticals (Figure 4). The methods described and developed in this thesis have no (industrial) application at the moment and despite its great advantages in terms of pollution and cost might also never reach that stage, but already provide an easy lab-scale alternative to existing methods.

Figure 4 Pharmaceuticals made via organolithium cross coupling methodology

Beside the construction of existing pharmaceuticals, we have also shown the tandem coupling with organolithium reagents to synthesize small complex molecules. This method is no cure to a disease itself, but a potentially useful method for the development of new drugs in which the effect of small changes in the structure need to be screened in order to find and create the drugs of the future.

List of publications 1) Gottumukkala, A. L.; Teichert, J.F.; Ferrer, C.; Eisink, N.; Heijnen, D.; van Dijk, S.; van den Hoogenband, A.; Minnaard, A. J. Pd-Diimine: A Highly Selective Catalyst System for the Base-Free Oxidative Heck Reaction J. Org. Chem. 2011,76, 3498. 2) Martín Fañanás-Mastral, Johannes F. Teichert, José Fernández, Dorus Heijnen, Ben L. Feringa. Enantioselective synthesis of almorexant via iridium-catalysed intramolecular allylic amidation Org. Biomol. Chem., 2013,11, 4521-4525 3) Alexander J. Cresswell , Stephen G. Davies, Aude L. A. Figuccia, Ai M. Fletcher, Dorus Heijnen, James A. Lee, Melloney J. Morris, Alice M. R. Kennett, Paul M. Roberts, James E. Thomson. Pinacolatoboron fluoride (pinBF) is an efficient fluoride transfer agent for diastereoselective synthesis of benzylic fluorides Tetrahedron Letters. 2015, 56, 3373–3377 4) Dorus Heijnen, Valentín Hornillos, Brian P. Corbet, Massimo Giannerini, Ben L. Feringa. Palladium-Catalyzed C(sp3)–C(sp2) Cross-Coupling of (Trimethylsilyl)methyllithium with (Hetero)Aryl Halides Org. Lett., 2015, 17 (9), 2262–2265 5) Jeffrey Buter, Dorus Heijnen, Carlos Vila,Valentin Hornillos,Edwin Otten, Massimo Giannerini, Adriaan J. Minnaard, Ben L. Feringa. Palladium-Catalyzed, tert-Butyllithium-Mediated Dimerization of Aryl Halides and Its Application in the Atropselective Total Synthesis of Mastigophorene A Angew.Chem .Int. Ed. 2016, 55,3620 –3624

6) Dorus Heijnen, Jean-Baptiste Gualtierotti, Valentin Hornillos, Ben L. Feringa. Nickel- Catalyzed Cross-Coupling of Organolithium Reagents with (Hetero)Aryl Electrophiles Chem. Eur. J. 2016, 22, 3991–3995 7) Wolters, Alexander T.; Hornillos, Valentin; Heijnen, Dorus; Giannerini, Massimo; Feringa, Ben L. One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed α-Arylation. ACS Catal., 2016, 6, 2622-2625

8) Jeffrey Buter, Dorus Heijnen, Ieng Chim Wan, F. Matthias Bickelhaupt, David C. Young, Edwin Otten, D. Branch Moody, Adriaan J. Minnaard. Stereoselective Synthesis of 1-Tuberculosinyl Adenosine; a Virulence Factor of Mycobacterium tuberculosis J. Org. Chem. 2016, 81, 6686−6696 9) Dorus Heijnen,Filippo Tosi,Carlos Vila, Marc C. A. Stuart, Philip H. Elsinga,Wiktor Szymanski, and Ben L. Feringa Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-Coupling of Organolithium Reagents Angew.Chem. Int. Ed. 2017, 56,3354 –3359 10) Narayan Sinha, Dorus Heijnen,Ben L. Feringa, Micheal G. Organ. The cross-coupling of organolithium reagents at cryogenic temperatures; a one-pot procedure for the sequential coupling of C-, S-, and N-nucleophiles -submitted- 11) Dorus Heijnen, Milan van Zuylen, Filippo Tosi, Ben L Feringa, The cross coupling of carbolithiated acetylenes, and the synthesis of Z-Tamoxifen -Manuscript in preparation- 12) Dorus Heijnen, Hugo Helbert, Ben L. Feringa, The synthesis of substituted benzaldehydes via a one pot reduction/cross coupling procedure -Manuscript in preparation- 13) Hugo Helbert, Jorn, Dorus Heijnen, Ben L. Feringa. One pot strategies for the synthesis of substituted keto-anilines -Manuscript in preparation-

Acknowledgements

Of all the people I want to thank, I off course want to start with Ben. Ben : 4 years ago I walked into your office and asked if you maybe had a PhD position in catalysis for me. Less than 24 hours later I got an email saying I could start working in your group the next month. Even though after the Nobel prize I wished I would have worked in motors (for about 2 days, tops), I am really happy I took the opportunity and we got some nice work out in the literature. Your enthusiasm and passion for chemistry, while at the same time remaining down to earth and fair is something I have never seen before. I also want to thank you for letting me go to Prof Organ in Toronto to work on PEPPSI derivatives. There are many more things I am thankful for, but would like to finish by thanking you for the extremely fast corrections of my thesis. While thanking Ben, Tineke (and now also Inge) can never be far behind. Though I almost forgot about you, I hope you know that I too am thankful for all your efforts. From keeping things running, settling disputes, or doing whatever we as lab-people don’t even know about, thank you.

Dear Professor Organ : Thank you for accepting me in your group, for the guidance and all your help/suggestions in my attempts at making a chiral PEPPSI catalyst.

Valentin : The way I saw it, you were the big guy in the catalysis subgroup, and we worked together on several projects. You shared ideas, gave suggestions, and guided our combined work to a finished product (chapter). Especially the start of my PhD would have been very different (less productive) if it wasn’t for you and your guidance. I would also like to thank the other postdocs and PhD students : Martin, Carlos, Massimo, Shermin and Suresh. You all generated a very friendly, helpful and productive subgroup with everlasting ideas and suggestions for more projects and work.

I am convinced that (at least for me), a social workplace is vital to celebrate the good times, and cope with the bad. Therefore the C-Wing has been of great importance to my life in the last 4 years. Starting with the older generation, Jos and Petra: equally crazy, but showing it in such different ways. Jos, thank you for showing me around in the most awesome lab that Nijenborgh 4 has ever had, how to disassemble the Grace, but also how to work with/around difficult people. Petra… you have contributed close to zero in terms of chemistry, yet you too were part of the initial greeting committee that freaked me out so much in my first weeks. Part of me likes to think it helped me grow as a person. Tom, your dry humor and passion for chemistry I can only hope to once possess. Last but not least: Anouk. We spent a considerable amount of time in the lab, on lab trips and group activities. From screaming at your (broken) glassware, to sitting under the table or just being Anouk, you left some big shoes to fill and the group was never quite the same after you left.

Filippo “it looks like spaghetti” Tosi. We published together, hated and loved our research together, shared an office and shared quite some other (lab) struggles. I admire your extremely systematic and structural way of thinking and doing research, and you have done your part of our mutual project in a way that would have taken me ages (if ever). I don’t always share you enthusiasm for food (with accompanying sounds of approval), but at least you didn’t spit out my amazing Lasagnachos. I am grateful that you want to be my paranymph.

Diederik “relax” Roke. I have yet to meet the person who is calmer (or cares less) in any situation than you. Never during the almost 4 years we have worked in the same lab, have I seen you stress over something. I think I speak for a lot of people around us that we envy this inner calm-ness a bit. I really enjoyed our overlapping sense of humor, and I wonder who is going to take our spot when we no longer join for lunch. The shoes to fill in terms of jokes and comments that we leave are big, I just wonder if the people left behind want them filled. Thank you for joining me on D-Day.

Jana, you could have been the mythical counterpart of Diederik, stressing over every little thing. Though it was always great fun to have a laugh with, I think it also shows how much you care, and want to do things the right way. Always wanting to have things arranged perfectly, organizing things for the group, bringing stuff from Serbia. You are truly a kind and caring person. I have wondered (very briefly) if maybe we were sometimes a bit harsh on you, but it was mostly Diederik anyway. I am sure that with your dedication and brain you will make those switchable peptides or antibodies, and that you really don’t have to stress about your work so much. I hope you and Jeffrey will have a great time together in Groningen. Jeffrey : Thanx a lot G! Glad to hear you are coming back to Groningen, I am sure you will inspire a lot of people, and do great chemistry.

Garcon, ma petite baguette. Of course you keep an emergency baguette in your freezer, that makes total sense. Continuing with the radiolabeling, filling the lab with the sweet smell of aldehydes together and even making some anilines, we could have worked on much more projects if we had the time. I am sure you will manage just fine without me though. Thank you for being part of the lonely lab in building 18, and cheering us up with your smile. Coffee?

Sander, we might have had our differences in the lunchroom, but you are doing a great job in running the C-wing when Ben is not around, thank you. Wiktor, our chemistry did not cross each other’s path much, but your enthusiasm, fairness and kindness are hard to miss. Prof. Minnaard, It was in your group, working on Tbad, when I really started to enjoy doing research, even when sometimes struggling with the chemistry. Thank you for always being such a calm and inspiring person.

The master students that I supervised: Alexander and Milan. Both of you sometimes needed a kick against the behind, but I enjoyed supervising and working with you and your work ended up in my thesis.

Wojtes, I hope that you will not turn into a cigarette yourself one day, though it might just happen. It’s good to see that you are much happier these days, keep up the good spirit! Hennie, the past year, you have shown a different side of you, that is slowly but surely showing resemblance to Anouk. I knew you had it in you! Good luck with your final year. Yuchen, the title of best cook of Chinese food in the institute is quite something already, soon you can add Dr. to this as well. It was always pleasant working next to you. Chi-Chi. Stefano, Que Pizza Que Pasta. I just can’t unsee the ski pants, winter hat and gloves…even with 15 °C outside. I hope I will never forget that you were trying to convince me to ‘ eat on the streets’ in India, because normal restaurants were just trying to rip you off, right before you stomach told you that wasn’t a great idea. Adelio : the adult life has finally gotten a grip on you, yet it’s really nice to see you still like to party every once in a while.

Jose, Jaime and Ruth. It’s something with those Spanish (speaking) postdocs, being the hardest working of them all. Jose, thank you for giving me a reason to make a molecular motor, and good luck with the synthesis of the 3+2=5th generation, you know it has to be done! Ruth, you could have been part of the awesome catalysis lab in 18, but the C-wing wouldn’t let you go. Good luck with the photochemistry, redox chemistry, and motors. Jaime I hope your chemistry will soon do what you want it to, and with your brain and hard work I’m sure it will. Carla, I’m happy you are back in Groningen, and enjoying it here. Thank you for the help with my cover, my awefull ESpanish, cheering me up and everything else.

Jiawen, Michelle, Fan, Anirban, Marco, Brian, Cosima, Lucas, Franco, Piere, Mikkel, Lerch, Tobias, Mark, Friederike, and whomever I might forget. Thank you all for being part of the social hotpot that we have in the Feringa group, and for making my stay at the RuG so pleasant.

Pieter, Monique and Theodora. Everybody knows that you are of great importance to the group. One day or week without NMR, HPLC, GC, LCMS or exact mass, and chaos would appear. Thank you all for helping us with these vital facilties.

To my non chemistry friends : Johan, bedankt voor alle bbq en kampvuur avonden in je achtertuin, en de avonturen in Zoutkamp, het Dwingelerveld, Schiermonnikoog en de ritjes in de magistrale deuxcentcinque. Je begreep redelijk goed wat me bezighield op het lab, en dus kon ik bij jou soms lekker klagen. Ik vind het heel erg jammer dat je Nederland uit bent, en aan al die dingen toch wel een beetje een einde is gekomen, maar het is mooi om te zien en horen hoe je in Vietnam de boel voor elkaar bokst! Loes, nog nooit in de geschiedenis van de wereld is er iemand geweest met zo’n enorme desinteresse en afkeer van alles dat met wetenschap te maken heeft. Ondanks dat waardeer ik je makkelijke omgang, vrolijkheid, doorzettingsvermogen en yolo instelling, en ben ik heel erg blij met jou als vriend. Dat jij de samenvatting voor niet-chemici begreep was een mooi compliment. Carolien : zelfdoen, pas op is zwaar, niet zo aanstellen, ging toch goed, en ach daar voel je niks van. Allemaal uitspraken die jou maken tot wat je bent, een supersterke vrouw met bijbehorende persoonlijkheid, bedankt voor alle leuke momenten samen. Ik hoop dat we nog een keer met zijn allen op vakantie gaan! Berber : Zonder jou zat ik wellicht nog ongelukkig te zijn in Noorwegen. Het heeft tussen ons niet zo mogen zijn, maar door jou ben ik wel in Groningen opnieuw begonnen, en dat heeft me erg veel geluk gebracht. Koning Bert, ook jij was zeker onderdeel van het belangrijke leven buiten het lab, met vakanties, fietsen of kamperen. Succes in Engeland.

Tot slot wil ik graag mijn ouders, broer (en Marielle) en zus (en Tim) bedanken. Niet voor een paar specifieke dingen, maar voor alles.

Dorus