Background

Cross-coupling reactions are widespread in organic chemistry, such as Suzuki coupling reactions in which a carbon-carbon bond is formed in a Pd catalyst mediated reaction between an aryl halide and an aryl boronic acid, and Heck reactions in which a carbon-carbon bond is formed in a Pd catalyst mediated reaction between an unsaturated compound substituted with a halide and an alkene.

Such reactions require one or both starting materials to have a functionalised group such as a halide or boronic acid group and require precious metals such as palladium.

L. Guillemard, N. Kaplaneris, L. Ackermann and M. J. Johansson, “Late-stage C-H functionalization offers new opportunities in drug discovery” Nat. Rev. Chem., 2021, 5, 522 — 545 discloses late-stage C-H functionalization of drugs and drug-like compounds, and describes how the implementation of this can allow increased efficiency in the drug discovery process.

Simonetti, M., Cannas, D.M., Just-Baringo, X., Citorica-Yrezabal I. J. and Larossa I. “Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals”, Nature Chem 10, 724-731 (2018) discloses a C-H arylation catalyst of formula:

RuBnN 1

The benzylamine ligand is included in view of a proposed reaction mechanism in which a substrate having a C-H bond and a nitrogen directing group forms a cyclometalating ligand with Ru(II):

However, this Ru(II) catalyst is not air-stable.

Aebischer et al, Inorg. Chem. 1998, 37, 5915-5924, “Mechanism of Complex Formation of Ruthenium(II) Aquacomplexes with H2C=CH2, MeCN, Me2SO, and CO: Metal-Water Bond Rupture as Rate-Determining Step” discloses the in situ formation of complexes having 1, 2 or 3 MeCN ligands formed during reaction of [Ru(H2O)e] ²⁺ with excess acetonitrile.

It is therefore an object of the invention to provide a catalyst for conversion of a C-H bond of a substrate to a C-C bond. It is a further object of the invention to provide an air-stable catalyst for such conversions.

Summary of the Invention

In a first aspect, the invention provides a compound of formula (I-A):

(I-A) wherein R ¹ in each occurrence is selected from H, optionally substituted C1-12 alkyl and optionally substituted C6-20 aryl;

R ² in each occurrence is selected from optionally substituted C1-12 alkyl and optionally substituted C6-20 aryl; p' is 1 and q’ is 5 or p’ is 2 and q’ is 4;

P + q = 6; Y is an anion; and n is 1 or 2.

Optionally, p' is 1 and q’ is 5.

Optionally, each R ¹ is H.

Optionally, n is 2.

Optionally, Y is a borate, phosphate or perchlorate anion.

In a second aspect, the invention provides a method of forming a compound according to the first aspect, the method comprising reducing a compound of formula RuZs in the presence of a compound of formula R ² -CN to form an intermediate and reacting the intermediate with a compound of formula R^O, wherein Z is an anionic ligand.

Optionally, Z is a halide.

Optionally, the RuZs is reduced by a reducing agent. Optionally, the reducing agent is zinc.

Optionally, the RuZs is reduced electrochemically.

In a third aspect, the invention provides a method of forming a compound according to any the first aspect, the method comprising reacting a compound of formula RuZp’(NC-R ² )q’ with a compound of formula R^O wherein Z is an anionic group.

Optionally according to the third aspect, the reaction is performed the presence of a compound of formula M ⁺ Y" wherein M ⁺ is a cation

In a fourth aspect, the invention provides a method of forming a compound of formula (C), the method comprising a reaction according to Scheme 1 :

Scheme 1 wherein (A) is a compound or a compound fragment; Ar ¹ is an aromatic or heteroaromatic group which is unsubstituted or substituted with one or more substituents; DG is a directing group; R ³ is an aryl, heteroaryl, alkyl, alkenyl or alkynyl group; and X is a leaving group, and wherein the reaction is catalysed by a compound of formula (I): wherein R ¹ in each occurrence is selected from H, optionally substituted C1-12 alkyl and optionally substituted C6-20 aryl;

R ² in each occurrence is selected from optionally substituted C1-12 alkyl and optionally substituted C6-20 aryl; p is at least 1 ; q is at least 1 ; p + q = 6;

Y is an anion; and n is 1 or 2.

Optionally, the method is according to Scheme 2: Scheme 2

Optionally, the compound or compound fragment of formula (A) has formula (A-2) or (A-3): wherein R ⁴ - R ⁷ , are each independently H or a substituent, R ⁴ and R ⁵ may be linked to form an optionally substituted monocyclic or fused ring; and R ⁶ and R ⁷ may be linked to form an optionally substituted monocyclic or fused ring.

Optionally, R ⁴ , R ⁶ and R ⁷ are each independently H, optionally substituted Ci-6 alkyl, optionally substituted C6-20 aryl or -C(=O)R ⁿ wherein R ¹¹ is C1-6 alkyl or optionally substituted C6-20 aryl.

Optionally, R ⁵ is optionally substituted C1-6 alkyl, optionally substituted C6-20 aryl or - C(=O)R ⁿ wherein R ¹¹ is C 1-6 alkyl or optionally substituted C6-20 aryl.

Optionally, the compound or compound fragment of formula (A) has formula (A-4): wherein Ar ² is an optionally substituted monocyclic or fused heteroaromatic ring.

Optionally, Ar ² has C and N ring atoms and, optionally, O or S ring atoms. Optionally, the compound or compound fragment of formula (A) has formula (A-5) or (A-6): wherein R ⁶ and R ⁷ are each independently H or a substituent, and R ⁶ and R ⁷ may be linked to form an optionally substituted monocyclic or fused ring.

Optionally, the compound or compound fragment of formula (A) has formula (A-7): wherein Z ¹ , Z ² and Z ³ are each independently N or CR ⁸ wherein R ⁸ is H or a substituent.

In some embodiments, X is bound to an aromatic carbon atom of R ³ . In these embodiments, R ³ may be an optionally substituted C6-20 aryl, preferably optionally substituted phenyl, or optionally substituted 5-20 membered heteroaryl group.

In some embodiments, X is bound to a sp ³ hybridised primary or secondary carbon atom.

In these embodiments, R ³ is an optionally substituted C1-12 alkyl.

Drawings

The invention will be described with reference to the drawings in which: Figure 1 is a NMR spectrum of Compound 2 according to an embodiment of the invention after exposure to air;

Figure 2A is a NMR spectrum of Comparative Compound 1 before exposure to air

Figure 2B is a NMR spectrum of Comparative Compound 1 after exposure to air; and

Figure 2C shows stacked spectra of Figures 2A and 2B.

Detailed Description

The present inventors have found that compounds of formula (I) are air-stable and can be used for conversion of one or more C-H bonds of an aromatic carbon atom to one or more corresponding C-C bonds:

The present inventors have further found that compounds of formula (I) may be capable of catalysing such conversions at temperatures of no more than about 120°C, for example in the range of 0-120°C, optionally in the range of 0-80°C or 0-50°C.

R ¹ in each occurrence may be the same or different and is selected from H, optionally substituted C1-12 alkyl and optionally substituted C6-20 aryl. Preferably, each R ¹ is H, i.e. R^O is water.

R ² in each occurrence is selected from optionally substituted C1-12 alkyl and optionally substituted C6-20 aryl.

Each of p and q is at least 1, and p + q = 6.

Preferably, p is 1 and q is 5.

Y is an anion and n is 1 or 2. Preferably, n is 2. Y may be any suitable non-coordinating anion known to the skilled person, for example BF4',PF6‘ or CIOw A preferred compound of formula (I) is [Ru(OH2)(R ² CN)s] 2Y’ wherein R ² is preferably a Ci- 6 linear, branched or cyclic alkyl group.

Without wishing to be bound by any theory, in use the R^O ligand is replaced by the compound or compound fragment of formula (A) to form an intermediate which is bound to Ru through a coordinating atom of the directing group DG.

Formula (A)

The compound or compound fragment of formula (A) consists of or comprises a fused or monocyclic aromatic or heteroaromatic ring Ar ¹ bound to a directing group DG:

Ar ¹ may be a monocyclic or fused aromatic or heteroaromatic ring, optionally a C5-20 aromatic ring or a 5-20 membered heteroaromatic ring. A preferred Ar ¹ is a benzene ring. In the case where the group of formula (A) is a compound fragment, the group of formula (A) forms part of a larger molecule, e.g. a pharmaceutical compound. It will be appreciated that the structure of the larger molecule is not particularly limited. The molecule may contain only one fragment of formula (A). The molecule may contain two or more fragments of formula (A).

The directing group DG is a group capable of coordinating to Ru of the catalyst of formula (I) and steering reaction at a carbon atom of a C-H group of Ar ¹ . The C atom of the C-H group is preferably ortho or meta to the carbon atom to which DG is bound. The present inventors have found that the Ru catalyst of formula (I) tends to be ortho-selective for reactions with an aromatic halide or a primary or secondary alkyl halide and meta-selective for reactions with a tertiary alkyl halide.

It will be understood that both DG and Ar ¹ may be substituted with a wide range of substituents, which may be selected according to the structure of a desired end-product or intermediate. Optionally, the or each substituent has a molecular weight of less than 1000 Da.

A preferred compound or compound fragment of formula (A) has formula (A-l):

DG may comprise a coordinating group comprising a O, S or N coordinating atom, preferably aN atom.

In some embodiments, the compound or fragment of formula (A) has formula (A-2) or (A-3):

R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently H or a substituent.

R ⁴ and R ⁵ may be linked to form an optionally substituted monocyclic or fused ring.

R ⁶ and R ⁷ may be linked to form an optionally substituted monocyclic or fused ring.

— represents a carbon-carbon single bond or carbon-carbon double bond.

Optionally, R ⁴ and R ⁵ are linked to form a non-aromatic, optionally fused ring, for example: wherein R ²⁰ is a Ci-2ohydrocarbyl group, preferably a C1-12 alkyl group; R ²¹ in each occurrence is a substituent, optionally a halogen, more preferably Cl; and v is 0, 1, 2, 3 or 4.

Optionally, R ⁴ and R ⁵ are linked to form an optionally substituted monocyclic or fused heteroaryl of formula (A-4):

(A-4)

Ar ² is a fused or monocyclic heteroaromatic ring.

Ar ² may be a monocyclic or fused heteroaromatic ring, optionally a 5-20 membered heteroaromatic ring. Preferred heteroaromatic rings have C and N ring atoms and, optionally, O or S ring atoms.

The compound of formula (A) is optionally a compound of formula (A-5) or (A-6): Optionally, R ⁶ and R ⁷ of (A-5) are linked to form an optionally substituted monocyclic or fused heteroaryl of formula (A-7)

(A-7) wherein Z ¹ , Z ² and Z ³ are each independently N or CR ⁸ wherein R ⁸ is H or a substituent.

Exemplary DG groups include, without limitation:

wherein Z ³ is O, S or NR ⁹ ; R ⁸ in each occurrence is independently H or a substituent; R ⁹ is H or a substituent; w is at least 1, optionally 1, 2, 3, 4 or 5; and two R ⁸ groups bound to the same C atom or bound to adjacent C atoms or an R ⁸ group and an R ⁹ group bound to adjacent C and N atoms may be linked to form an unsubstituted or substituted ring.

Optionally, R ⁸ in each occurrence is independently selected from H, F, optionally substituted phenyl, optionally substituted C1-12 alkyl, OR ³⁰ , SR ³⁰ , COOR ³⁰ , C(=O)R ³⁰ , CONR ³⁰ or NR ³⁰ wherein R ³⁰ in each occurrence is H; or an optionally substituted monocyclic or fused C6-12 aryl, preferably optionally substituted phenyl, or an optionally substituted monocyclic or fused C5-20 heteroaryl group.

Optionally, R ⁹ is H; branched, linear or cyclic C1-12 alkyl; or optionally substituted C6-12 aryl or optionally substituted C5-20 heteroaryl.

Optional substituents of an optionally substituted alkyl group as described anywhere herein include F, CN, NO2, or an optionally substituted aryl or heteroaryl group.

Optional substituents of an optionally substituted aryl or heteroaryl group as described anywhere herein include F, Cl, CN, NO2, or C1-12 alkyl in which one or more non-adjacent C atoms of the C1-12 alkyl may be replaced with O, S, COO, C(=O), CONR ³¹ or NR ³¹ wherein R ³¹ in each occurrence is H or a C1-20 hydrocarbyl group.

Two R ⁸ groups linked to adjacent carbon atoms or an R ⁸ group and an R ⁹ group bound to adjacent C and N atoms may be linked to form an optionally substituted benzene, or azine ring, such as a pyridine or diazine ring, for example:

For simplicity, the compound or compound fragment of formula (A) as illustrated above shows only one C-H group, however it will be appreciated that two C-H groups may be available for reaction, for example two ortho C-H groups as illustrated below:

Compound B

Compound B has formula R ³ -X.

X is bound to a carbon atom of R ³ , preferably an sp ³ -hybridised, primary or secondary carbon atom or an sp ² -hybridised carbon atom of an aromatic or heteroaromatic ring.

It will be understood that a wide range of R ³ groups may be used, according to the desired product of the reaction between compounds A and B, and as such other constituent atoms or units of R ³ are not particularly limited.

It will be appreciated that a wide range of optional substituents may be selected according to the desired product. R ³ may be selected from, without limitation, optionally substituted C1-40 alkyl; optionally substituted C2-40 alkenyl; optionally substituted C2-40 alkynyl; optionally substituted C6-20 aryl, preferably optionally substituted phenyl; and an optionally substituted 5-20 membered heteroaromatic group, wherein one or more non-adjacent -CH2- groups of the C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl may be replaced with O, S, COO, CO, CONR ³¹ or NR ³¹ . . Where present, the or each substituent preferably has a molecular weight of less than 1000 Da. In the case where R ³ is an optionally substituted C1-12 alkyl group, R ³ -X may be a primary, secondary (including cyclic) or tertiary optionally substituted alkyl group, preferably a primary or secondary optionally substituted alkyl group.

X is a leaving group, preferably Cl, Br or I, preferably Br; a pseudohalid, preferably a sulfonate, for example tosylate or triflate; or a group of formula -N(R ¹⁰ )3 ⁺ An' wherein R ¹⁰ in each occurrence is a substituent and An' is an anion.

Preferably, each R ¹⁰ is independently selected from the group consisting of optionally substituted C1-12 alkyl, optionally substituted aryl e.g. optionally substituted phenyl, more preferably selected from C1-12 alkyl and phenyl which is optionally substituted with one or more substituents selected from F, C1-6 alkyl and C 1-6 fluoroalkyl.

An' may be any suitable anion, for example a halide or a sulfonate such as triflate.

Many known compounds, including but not limited to pharmaceuticals or intermediates thereof, contain an aromatic C-H group adjacent to a group capable of acting as a directing group.

Examples of Compound B include, without limitation:

Examples of pharmaceuticals which may be formed by a method as described herein include the following, in which bonds shown with a dashed line extending through them are formed upon functionalisation of a C-H bond as described herein:

from bupropion from chlormezanone from zolimidine from atazanavir zolpidem +clozapine

Examples of products of a reaction between a compound having a primary alkyl halide group and a known compound include the following:

from sulfaphenazole

Examples of products of a reaction between a compound having a secondary alkyl halide group and a known compound include the following: from diazepam from 1 -pyrenecarboxylic acid from indoprofen An optionally substituted C6-20 aryl group as described herein with reference to a compound of formula (I), a compound of formula (I-A), Compound A or Compound B is preferably a C6-12 aryl, e.g. phenyl. The C6-20 aryl group may be, without limitation, a single monocyclic ring; a fused monocyclic aromatic group; or combinations thereof linked by a single bond.

Catalyst synthesis

One method of forming a catalyst as described herein is reduction of a Ru ³⁺ compound in the presence of R ² -CN to form an intermediate which is then reacted with a compound of formula R^O.

Reduction of a Ru ³⁺ compound may be performed electrochemically or by a reducing agent capable of reducing Ru ³⁺ to Ru ²⁺ . An exemplary reducing agent is an elemental metal capable of reducing Ru ³⁺ to Ru ²⁺ , for example zinc.

The RU ³⁺ compound may be, for example, a Ru (III) halide, e.g. RuBn, RuCh or Ruh.

Another method of forming a catalyst as described herein is replacement of an anionic ligand Z in a compound RuZp’(NC-R ² )q’ with a compound of formula R^O. The reaction may be performed in the presence of a compound of formula M ⁺ Y" for providing a counterion Y" of the catalyst, wherein M ⁺ is a cation, e.g. a metal ion. In the case where p’ is 1 and q’ is 5, it will be appreciated that RuZp’(NC-R ² )q’ is cationic and will comprise a suitable anionic counterion.

Examples

General Information

All the starting materials and solvents were purchased from Acros (Fisher), Aldrich (Merck), Alfa Aesar (Fisher), Fluorochem and Generon and used without further purification unless otherwise stated. Column chromatography was carried out on silica gel (particle size 40-63 pm) using flash techniques. High resolution mass spectra were performed by the School of Chemistry Mass Spectrometry Service (University of Manchester) employing a Thermo Finnigan MAT95XP spectrometer. IR spectra were recorded using a Thermo Scientific Nicolet i S 5 FTIR machine, relevant bands are quoted in cm ( ¹ H NMR, ¹⁹ F NMR and ^13C NMR spectra were recorded at 400 or 500 on Bruker instruments. 'H NMR are referenced to the residual solvent peak at 7.26 ppm (CDCh), 5.35 (CD2CI2) or 2.05 ppm ((CD3)2CO). ppm values are quoted to 2 decimal places, with coupling constants (J) to the nearest 0.1 Hz. ¹³ C NMR spectra were recorded at 151, 126 or 100 MHz and quoted in ppm to 1 decimal place with coupling constants (J) to the nearest 0.1 Hz. The spectra were referenced to the residual solvent peak at 77.16 ppm (CDCh), 5.30 ppm (CD2CI2) or 39.52 ppm ((CDs^CO). ¹⁹ F NMR spectra recorded at 471 or 376 MHz in CDCh or CD2CI2 and quoted in ppm to 2 decimal places with coupling constants (J) to the nearest 0.1 Hz.

Preparation of Ruthenium Aqua Complex 2 General Procedure Al i) Zn dust, tBuCN, 115 °C, 2 h RuCI ₃ -H ₂ O - * [Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ ii) AgBF ₄ , H ₂ O, rt, 1 h

2

General procedure for synthesis of ruthenium aqua catalyst 2

Pivalonitrile was dried over 4 A molecular sieves and degassed with three freeze-pump-thaw cycles prior to use. In a glove box, RuCh »xH2O (Reagent Grade purity > 95%, 1 equiv based on anhydrous molecular weight), glove-boxed stored Zn dust (<10 pm, 3.2 equiv) and pivalonitrile were loaded in an Ace pressure tube which was subsequently wrapped in Teflon tape and parafilm. The sealed tube was then taken out from the glovebox and stirred for 2 h at 115 °C ensuring the solid was being thoroughly stirred. The reaction mixture was cooled to room temperature and the pivalonitrile removed under reduced pressure. The resulting mixture was diluted with HPLC-grade water before being filtered through a small plug of Celite® to remove all solids. AgBF4 (2 equiv) was added and the reaction was vigorously stirred for 1 hour at room temperature. After this time the solution was filtered through a plug of Celite® and evaporated to dryness. The residue was dissolved in acetone, filtered through a plug of Celite® and evaporated to dryness. Then, it was dissolved in CH2CI2, filtered through a plug of Celite® and evaporated to dryness. The residue was dissolved in CH2CI2 and precipitated with Et2O affording a light-yellow solid. The solid was collected, dissolved in CH2CI2 and precipitated with Et2O. The last precipitation step was reiterated until the desired complex 2 was obtained as a fluffy light-yellow powder. i) The General Procedure Al was applied using 1.5 g (7.2 mmol) of RuCh »*H2O, 1.5 g (22.9 mmol) of zinc dust and 35 mL of pivalonitrile. After allowing the reaction mixture to stir and removing the pivalonitrile, HPLC grade water (150 mL) and AgBF4 (2.8 g, 14.5 mmol) were added to and the resulting reaction mixture was allowed to stir at room temperature for 1 hour. The product was precipitated with Et2O from a solution in DCM 5 times giving the desired complex 5 as a fluffy light-yellow solid (2.2 g, 42% yield). ii) The General Procedure Al was applied using 20.0 g (96.0 mmol) of RuCh ^xEhO, 20.0 g (307.2 mmol) of zinc dust and 460 mL of pivalonitrile. After allowing the reaction mixture to stir and removing the pivalonitrile, HPLC grade water (2 L) and AgBF4 (37.4 g, 192.0 mmol) were added to and the resulting reaction mixture was allowed to stir at room temperature for 1 hour. The product was precipitated with Et20 from a solution in DCM 6 times giving the desired complex 5 as a fluffy light-yellow solid (26.3 g, 38% yield).

'H NMR (500 MHz, CD2CI2): 8 1.43 (s, 36H), 1.38 (s, 9H).

¹³ C NMR (126 MHz, CD2CI2): 8 135.8, 133.8, 30.8, 30.4, 28.3, 27.9.

¹⁹ F NMR (376 MHz, CD2CI2) : 8 -150.02, -149.97.

IR (neat, cm ⁴ ): 3394 (OH2), 2279 (CN).

MS (ESI+ ): 622.2844.

HRMS (ESI+ ): Calculated for [Ru(OH ₂ )(tBuCN) ₅ ] ⁺ (BF4): 622.2848, found: 622.2848. mp: decomposes at 180 — 182 °C [recrystallised by slow diffusion of diethyl ether into solution in CH2CI2].

Procedure A2: Preparation of Ruthenium Aqua Complex 2

In a glovebox, an electrosyn® vial was charged with RuChHHO (100 mg, 0.48 mmol, 1 equiv), TBAPFe (100 mg, 0.24 mmol, 0.5 equiv) and /BuCN (4 mL). The reaction vessel was sealed, removed from the glovebox, and stirred at 115 °C on an electrosyn® at constant voltage (1 V) for 1 hour. The reaction mixture was cooled to room temperature, filtered through a small plug of Celite® before washing with HPLC grade water (40 mL). AgBF4 was added (0.96 mmol, 2 equiv,) and the reaction was vigorously stirred for 1 hour at room temperature under air in darkness before filtering through a small plug of Celite® and evaporating to dryness. The residue was dissolved in acetone, filtered through a small plug of Celite® and evaporated to dryness. Then, it was dissolved in dichloromethane, filtered through a small plug of Celite® and evaporated to dryness. The residue was dissolved in dichloromethane and precipitated with diethyl ether affording a light-yellow solid. The solid was collected, dissolved in dichloromethane, and precipitated with diethyl ether. The last precipitation step was reiterated another 3 times to give the desired aqua ruthenium complex 5 as an off white solid (20 mg, 6% yield).

Procedure A3: Preparation of Ruthenium Aqua Complex 2

A reaction vessel fited with a magnetic stirrer bar was charged with ruthenium chloride intermediate 6 (341 mg, 0.68 mmol, 1 equiv) and AgBF4 (529.3 mg, 2.72 mmol, 4 equiv). 1.8 mL of DCM and 7 mL of HPLC-grade water were added and the system was allowed to stir at room temperature for 1 hour under air in darkness before filtering through a small plug of Celite® and evaporating to dryness. The residue was dissolved in acetone, filtered through a small plug of Celite® and evaporated to dryness. Then, it was dissolved in dichloromethane, filtered through a small plug of Celite® and evaporated to dryness. The residue was dissolved in dichloromethane and precipitated with diethyl ether affording a light-yellow solid. The solid was collected, dissolved in dichloromethane, and precipitated with diethyl ether. The last precipitation step was reiterated another 3 times to give the desired aqua ruthenium complex 2 as a fine solid (85 mg, 18% yield).

Replacement of a H atom bound to an aromatic C atom was performed for a wide range compounds as set out in the following examples.

General Procedure B: Ru-catalysed arylation of DG-containing arenes with aryl (pseudo)halides

General procedure for the arylation of DG-containing arenes

All liquid reagents were degassed with at least 3 freeze-pump-thaw cycles prior to use. KOAc and K2CO3 were dried at 80 °C in a vacuum oven for 48 hours prior to use. Unless otherwise indicated, a 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with ruthenium aqua catalyst 2 (28.4 mg, 0.04 mmol, 10 mol%), KOAc (11.8 mg, 0.12 mmol, 30 mol%), K2CO3 (2-4 equiv), the appropriate DG-containing arene (0.40 mmol, 1 equiv) and the appropriate aryl halide (0.4 mmol, 1 equiv). After addition of the solids, 3 x 5 minute evac- refill cycles were performed before adding any liquid/oil reagents via injection along with the NMP (0.8 mL, 0.5 M with respect to the DG-containing arene). The vial was capped and stirred at the stated temperature for the indicated time. Upon completion, the crude mixture was loaded onto a silica gel column and purified by flash chromatography.

Data for all compounds following this procedure matches that previously reported by Larrosa et. al.

M. Simonetti, D. M. Cannas, X. Just-Baringo, I. J. Vitorica-Yrezabal and I. Larrosa, Nature Chem., 2018, 10, 724-731.

Reactions were performed as set out below following General Procedure B:

* NMR yield calculated by ^] H Q NMR using trimethoxy benzene as internal standard.

Synthesis of 2-(3,3',5'-trimethyl-[l,l'-biphenyl]-2-yl)pyridine (3a)

The General Procedure B was applied with 2-(o-tolyl)pyridine (67.8 mg, 0.40 mmol, 1 equiv), br-m-xylene (74 mg, 0.40 mmol, 1 equiv), K2CO3 (110.6 mg, 0.8 mmol, 2 equiv) and | R.U(OH2)(/BUCN)5 |(BF4)2 | 2 for 3 h at 40 °C. Column chromatography eluting with 5-15% EtOAc in hexane afforded the title product 3a as a colourless oil (100.5 mg, 92% yield).

'H NMR (400 MHz, CDC13) δ 8.65 (m, 1H), 7.46 (td, J= 7.7, 1.8 Hz, 1H), 7.35 (m, 1H), 7.30 (m, 2H), 7.12 - 7.06 (ppm, 1H), 6.92 (d, J= 7.7 Hz, 1H), 6.77 (s, 1H), 6.72 (s, 2H), 2.21 (s, 3H), 2.16 (s, 6H).

¹³ C NMR (101 MHz, CDC13) δ 159.9, 148.7, 141.5, 141.5, 139.4, 137.0, 136.6, 135.7, 129.3, 128.0, 127.9, 127.9, 127.6, 125.7, 121.2, 21.2, 20.6.

Synthesis of [zolimidine]-[5-/n-xylene] (3b)

The General Procedure B was applied with Zolimidine (109.0 mg, 0.40 mmol, 1 equiv), 5-br- m-xylene (109.0 μL, 0.4 mmol, 2 equiv) and K2CO3 (165.8 mg, mmol, 3 equiv) for 72 h at 40 °C. Column chromatography eluting with 80% Et20 in hexane afforded the title product 3b as a pale yellow solid (176.8 mg, 95%). 'H NMR (500 MHz, CDC13) δ 7.95 (s, 2H), 7.83 (dt, J = 6.9, 1.2 Hz, 1H), 7.44 (dd, J = 9.2, 1.1 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.98 (s, 1H), 6.88 (s, 4H), 6.79 (s, 2H), 6.67 - 6.62 (m, 1H), 3.12 (s, 3H), 2.14 (s, 12H).

¹³ C NMR (126 MHz, CDCh): 8 145.2, 144.0, 142.7, 140.0, 139.8, 137.5, 137.1, 128.8, 127.3, 127.2, 125.4, 124.0, 117.4, 112.3, 112.0, 44.6, 21.1.

Synthesis of [2-(o-tolyl)pyridine]-[trazadone] (3c)

The General Procedure B was applied with 2-(o-tolyl)pyridine (67.8 mg, 0.40 mmol, 1 equiv), Trazodone • HC1 (163.4 mg, 0.40 mmol, 1 equiv) and K2CO3 (165.8 mg, 1.2 mmol, 3 equiv) at 50 °C. Column chromatography eluting with 1-5% MeOH in CH2CI2 afforded the title product 3c as an off-white solid (166.9 mg, 80%).

'H NMR (500 MHz, CDC13) δ 8.65 - 8.59 (m, 1H), 7.75 (dt, J= 7.0, 1.2 Hz, 1H), 7.44 (td, J = 7.6, 1.8 Hz, 1H), 7.36 - 7.31 (m, 1H), 7.31 - 7.23 (m, 2H), 7.12 - 7.01 (m, 4H), 6.90 - 6.80 (d, J= 8.9 Hz, 1H), 6.65 (m, 2H), 6.57 - 6.51 (m, 1H), 6.50 - 6.43 (m, 1H), 4.07 (t, J= 7.0 Hz, 2H), 2.92 (s, 4H), 2.55 - 2.40 (m, 6H), 2.17 (s, 3H), 2.04 (p, J= 7.1 Hz, 2H).

¹³ C NMR (126 MHz, CDC13) δ 160.0, 150.5, 148.8, 148.7, 142.4, 141.8, 141.6, 139.3, 136.8, 136.0, 129.9, 129.4, 128.5, 128.1, 127.6, 125.7, 123.9, 121.4, 121.0, 118.2, 115.5, 114.1, 110.6, 55.7, 53.2, 49.0, 44.6, 26.2, 20.6

Synthesis of [2-(o-tolyl)pyridine]-[Bupropion] (3d) General procedure B was applied. 2-(o-tolyl)pyridine (67.8 mg, 0.4 mmol, 1 equiv), bupropion HC1 (110.5 mg, 0.4 mmol, 1 equiv), KOAc (11.8 mg, 0.12 mmol, 30 mol %) and K2COs (165.8 mg, 1.2 mmol, 3 equiv) were reacted in NMP (0.8 mL) at 50 °C for 24 hours. After this time, quantitative 'H NMR using 1,3,5-trimethoxy benzene as an internal standard indicated conversion to product 3d of 93%.

Synthesis of [2-(o-tolyl)pyridine]-[chIormezanone] (3e)

3e

General procedure B was applied. 2-(o-tolyl)pyridine (67.8 mg, 0.4 mmol, 1 equiv), chlormezanone (109.0 mg, 0.4 mmol, 1 equiv), KOAc (11.8 mg, 0.12 mmol, 30 mol %) and K2CO3 (110.5 mg, 0.8 mmol, 2 equiv) were reacted in NMP (0.8 mL) at 50 °C for 24 hours. After this time, quantitative 'H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 3e of 90%.

Synthesis of [2-(o-tolyl)pyridine]-[chIorpropham] (3f)

The General Procedure B was applied with 2-(o-tolyl)pyridine 1 (67.8 mg, 0.40 mmol, 1 equiv), Chlorpropham (85.4 mg, 0.40 mmol, 1 equiv) and K2CO3 (110.6 mg, 0.4 mmol, 2 equiv) allowing the reaction mixture to stir for 24 hours at 40 °C. Column chromatography eluting with 50% Et20 in hexane afforded the title product 3f as a white solid (117.7 mg, 85%).

'H NMR (400 MHz, CDC13) δ 8.65 - 8.60 (m, 1H), 7.46 (td, J= 7.7, 1.8 Hz, 1H), 7.37 - 7.23 (m, 4H), 7.09 (ddd, J= 7.7, 4.9, 1.2 Hz, 1H), 7.06 - 6.99 (m, 2H), 6.91 (d, J = 7.8 Hz, 1H), 6.68 (d, J= 7.6 Hz, 1H), 6.36 (bs, 1H), 4.98 (hept, J= 6.2 Hz, 1H), 2.17 (s, 3H), 1.28 (d, J = 6.2 Hz, 6H).

¹³ C NMR (126 MHz, CDC13) δ 159.6, 153.2, 149.0, 142.7, 140.9, 139.4, 137.7, 136.8, 135.9, 129.7, 128.4, 128.2, 127.7, 125.7, 125.0, 121.5, 119.8, 116.6, 68.8, 22.2, 20.6.

Synthesis of [2-(o-tolyl)pyridine]-[8-tocopherol] (3g)

The General Procedure B was applied with 2-(o-tolyl)pyridine (33.9 mg, 0.20 mmol, 1 equiv), 8-Tocopherol-OTf (106.9 mg, 0.20 mmol, 1 equiv), [Ru(OH2)(tBuCN)s](BF4)2 2 (14.2 mg, 0.02 mmol, 10 mol%) and K2CO3 (55.3 mg, 0.4 mmol, 2 equiv) allowing the reaction mixture to stir for 24 hours at 40 °C. Column chromatography eluting with 10% Et20 in hexane afforded the title product 3g as a colourless oil (86.4 mg, 90%).

'H NMR (400 MHz, CDC13) δ 8.64 (d, J= 4.6 Hz, 1H), 7.46 (td, J= 7.7, 2.0 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.23 (d, J= 7.2 Hz, 1H), 7.08 (dd, J= 8.0, 4.3 Hz, 1H), 6.89 (d, J= 7.7 Hz, 1H), 6.66 (s, 1H), 6.55 (s, 1H), 2.58 - 2.47 (m, 2H), 2.17 (s, 3H), 1.96 (s, 3H), 1.60-1.76 (m, 2H), 1.59 - 0.97 (m, 24H), 0.80-0.91 (m, 12H).

¹³ C NMR (101 MHz, CDC13) δ 160.5, 151.0, 148.9, 141.6, 139.6, 136.8, 135.9, 132.4, 130.1, 129.0, 128.6, 128.2, 127.8, 126.0, 125.5, 121.3, 119.9, 76.3, 40.4, 39.7, 37.8, 37.6, 33.1, 33.0, 31.6, 28.3, 25.1, 24.8, 24.4, 23.1, 23.0, 22.5, 21.3, 20.9, 20.1, 20.0, 16.2.

Synthesis of [2-(o-tolyl)pyridine]- [Haloperidol] (3h) General procedure B was applied. 2-(o-tolyl)pyridine (67.8 mg, 0.4 mmol, 1 equiv), haloperidol (149.6 mg, 0.4 mmol, 1 equiv), KO Ac (11.8 mg, 0.12 mmol, 30 mol %) and K2CO3 (110.5 mg, 0.8 mmol, 2 equiv) were reacted in NMP (0.8 mL) at 50 °C for 24 hours. After this time, quantitative ^X H NMR using 1,3,5-trimethoxy benzene as an internal standard indicated conversion to product 3h of 87%.

Synthesis of [2-(o-tolyl)pyridine]-[fenofibrate] (3i)

General procedure B was applied. 2-(o-tolyl)pyridine (67.8 mg, 0.4 mmol, 1 equiv), fenofibrate (144.4 mg, 0.4 mmol, 1 equiv), KO Ac (11.8 mg, 0.12 mmol, 30 mol %) and K2CO3 (110.5 mg, 0.8 mmol, 2 equiv) were reacted in NMP (0.8 mL) at 40 °C for 24 hours. After this time, quantitative 'H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 3i of >99%.

Synthesis of [2-(o-tolyl)pyridine]-[diazoxide] (3j)

The General Procedure B was applied with 2-(o-tolyl)pyridine (97.8 mg, 0.40 mmol, 1 equiv), Diazoxide (92.2 mg, 0.40 mmol, 1 equiv) and K2CO3 (110.6 mg, 0.8 mmol, 2 equiv) allowing the reaction mixture to stir at 40 °C for 48 hours. After this time, quantitative ^J H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 3j of 87%.

Synthesis of [2-(o-tolyl)pyridine]-[meclizine] (3k)

The General Procedure B was applied with 2-(o-tolyl)pyridine (67.8 mg, 0.40 mmol, 1 equiv), Meclizine • 2HC1 (195.6 mg, 0.40 mmol, 1 equiv) and K2CO3 (221.2 mg, 1.6 mmol, 4 equiv) at 50 °C for 24 hours. After this time, quantitative ^J H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 3k of >99%.

Synthesis of [diazepam]-[5-/n-xylene] (31)

The General Procedure B was applied with diazepam (57.0 mg, 0.2 mmol, 1 equiv), I-m-xylene (58 μL mg, 0.40 mmol, 2 equiv) and K2CO3 (82.9 mg, 0.6 mmol, 3 equiv) allowing the reaction mixture to stir at 40 °C for 72 hours. After this time, quantitative ^J H NMR using 1,3,5- trimethoxy benzene as internal standard indicated conversion to product 31 of 95%.

Synthesis of 2-(3,3',5'-trimethyl-[l,l'-biphenyl]-2-yl)pyrimidine (3m)

3m

General procedure B was applied setting the reaction up in a microwave vial inside an argon filled glovebox. 2-(o-tolyl)pyrimidine (67.8 mg, 0.4 mmol, 1 equiv), br-m-xylene (74.0 mg, 0.4 mmol, 1 equiv), [RU(OH2)(ABMCA)5](BF4)22 (14.2 mg, 0.02 mmol, 5 mol %), KO Ac (11.8 mg, 0.12 mmol, 30 mol %) and K2CO3 (110.5 mg, 0.8 mmol, 2 equiv) were reacted in NMP (0.8 mL) at 40 °C for 5 hours. After this time, quantitative 'H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 3m of 97%.

Synthesis of 2-(3,3",5,5"-tetramethyl-[l,l':3',l"-terphenyl]-2'-yl)benzo[ d]thiazole (3n)

General procedure B was applied setting the reaction up in a microwave vial inside an argon filled glovebox. 2-phenylbenzo[d]thiazole (42.2 mg, 0.2 mmol, 1 equiv), br-m-xylene (74.0 mg, 0.4 mmol, 1 equiv), [Ru(OH2)(t5i/CA)5](BF4)2 2 (7.1 mg, 0.01 mmol, 5 mol %), KO Ac (5.9 mg, 0.06 mmol, 30 mol %) and K2CO3 (55.3 mg, 0.4 mmol, 2 equiv) were reacted in NMP (0.4 mL) at 40 °C for 16 hours. After this time, quantitative 'H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 3n of 75%.

Synthesis of l-(3,3’,5’-trimethyl-[l,l’-biphenyl]-2-yl)-lH-pyrazole (3o)

General procedure B was applied setting the reaction up in a microwave vial inside an argon filled glovebox. l-(o-tolyl)-lH-pyrazole (31.6 mg, 0.2 mmol, 1 equiv), br-m-xylene (37.0 mg, 0.2 mmol, 1 equiv), [Ru(OH2)(t5i/CJV)5](BF4)22 (7.1 mg, 0.01 mmol, 5 mol %), KO Ac (5.9 mg, 0.06 mmol, 30 mol %) and K2CO3 (55.3 mg, 0.4 mmol, 2 equiv) were reacted in NMP (0.4 mL) at 40 °C for 16 hours. After this time, quantitative 'H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 3o of >99%.

Synthesis of 2-(3',5'-dimethyl-[l,l'-biphenyl]-2-yl)-3-methylpyridine (3p)

General procedure B was applied setting the reaction up in a microwave vial inside an argon filled glovebox. 3-methyl-2-phenylpyridine (67.8 mg, 0.4 mmol, 1 equiv), br-m-xylene (73.2 mg, 0.4 mmol, 1 equiv), [Ru(OH2)(t5MCJV)s](BF4)2 2 (14.2 mg, 0.02 mmol, 5 mol %), KOAc (11.8 mg, 0.12 mmol, 30 mol %) and K2CO3 (110.5 mg, 0.8 mmol, 2 equiv) were reacted in NMP (0.8 mL) at 40 °C for 5 hours. After this time, quantitative 'H NMR using 1,3,5- trimethoxy benzene as internal standard indicated conversion to product 3p of 40%.

Synthesis of 3',5'-dimethyl-6-(pyridin-2-yl)-[l,l'-biphenyl]-3-ol (3q)

General procedure B was applied setting the reaction up in a microwave vial inside an argon filled glovebox. 4-(pyridin-2-yl)phenol (68.5 mg, 0.4 mmol, 1 equiv), l-bromo-3,5- dimethylbenzene (146.4 mg, 0.4 mmol, 2 equiv), [Ru(OH2)(t5i/CJV)5](BF4)2 (2, 14.2 mg, 0.02 mmol, 5 mol%), KOAc (11.8 mg, 0.12 mmol, 30 mol %) and K2CO3 (110.5 mg, 0.8 mmol, 2 equiv) were reacted in NMP (0.8 mL) at 40 °C for 5 hours. After this time, quantitative 'H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 3q of 63%.

General Procedure C: Ru-catalysed secondary alkylation of DG-containing arenes with secondary alkyl bromides [RU(OH ₂ )(ZBUCN)5](BF ₄ )2

2

4

R ¹² and R ¹³ are substituents which may be linked to form a ring.

General procedure for the secondary alkylation of DG-containing arenes

All liquid reagents were degassed with at least 3 freeze-pump-thaw cycles prior to use. A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with ruthenium aqua catalyst 2 (14.2 mg, 0.02 mmol, 5 mol%), K2CO3 (3.0 equiv), the appropriate DG-containing arene (0.40 mmol, 1 equiv) and the appropriate alkyl halide (1-2 equiv). After addition of the solids, 3 x 5 minute evac-refill cycles were performed before adding any liquid/oil reagents via injection along with the NMP (2 mL, 0.2 M with respect to the DG-containing arene). The vial was then stirred at 50 °C for the indicated time. The reaction was then allowed to cool to room temperature before being quenched with H2O (20 mL) and extracted with Et2O (3 x 20 mL). The organic extracts were combined, washed with brine (15 mL), dried over MgSOi. filtered and concentrated in vacuo. The residue was purified by column chromatography under the conditions noted to yield the desired product.

Reactions were performed as set out below following General Procedure C.

Data for all compounds following this procedure matches that previously reported by Larrosa et. al.

G.-W. Wang, M. Wheatley, M. Simonetti, D. M. Cannas and I. Larrosa, Chem, 2020, 6, 1459-1468.

from oxaprozin derivative from epiandrosterone

* NMR yield calculated by ^] H Q NMR using trimethoxy benzene as internal standard.

Synthesis of 2-(2-cyclohexylphenyl)-3-methylpyridine (4a)

4a

Obtained using General procedure C employing 3-methyl-2-phenylpyridine (67.8 mg, 0.40 mmol) and bromocyclohexane (73.8 μL, 0.60 mmol). The reaction was stirred at 50 °C for 24 hours. After this time, quantitative 'H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 4a of 77%.

Synthesis of l-(2-(tetrahydro-2H-pyran-4-yl)phenyl)isoquinoline (4b)

Obtained using General procedure C employing 1 -phenylisoquinoline (94.4 mg, 0.40 mmol) and 4-bromotetrahydro-2H-pyran (47.4 μL, 0.42 mmol). The reaction was stirred at 50 °C for 24 hours. The crude mixture was purified by column chromatography eluting with 50% EtOAc in hexane to yield the title compound 4b (98.4 mg, 89%) as a colourless oil.

'H NMR (400 MHz, CDC13) δ 8.61 (d, J= 5.7 Hz, 1H), 7.91 (d, J= 8.3 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.63 (d, J= 7.6 Hz, 1H), 7.55 - 7.40 (m, 3H), 7.42 - 7.14 (m, 1H), 7.28 (s, 1H), 3.95 - 3.87 (m, 1H), 3.88 - 3.77 (m, 1H), 3.15 (td, J= 11.4, 3.7 Hz, 1H), 3.03 - 2.93 (m, 1H), 2.50 (m, 1H), 1.90 - 1.71 (m, 3H), 1.41 - 1.33 (m, 1H).

¹³ C NMR (101 MHz, CDC13) δ 161.2, 144.3, 142.1, 138.3, 136.3, 130.2, 129.9, 128.9, 128.0, 127.4, 127.2, 126.9, 126.4, 125.9, 120.0, 68.4, 68.2, 38.0, 34.1, 33.3.

Synthesis of 3-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pyridine (4c)

Obtained using General procedure C employing 3-methyl-2-phenylpyridine (67.8 mg, 0.40 mmol) and 4-bromotetrahydro-2H-pyran (47.4 ph. 0.42 mmol). The reaction was stirred at 50 °C for 24 hours. After this time, quantitative 'H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 4c of 75%.

Synthesis of 2-(2-cyclopentylphenyl)-3-methylpyridine (4d)

Obtained using General procedure C employing 3-methyl-2-phenylpyridine (67.8 mg, 0.40 mmol) and bromocyclopentane (64.0 μL, 0.6 mmol). The reaction was stirred at 50 °C for 24 hours. After this time, quantitative ^J H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 4d of 60%.

Synthesis of (4-(3-methyl-2-(pyridin-2-yl)phenyl)piperidin- l-yl)(thiophen-2- yl)methanone (4e)

Obtained using General procedure C employing 2-(o-tolyl)pyridine (67.8 mg, 0.40 mmol) and (4-bromopiperidin-l-yl)(thiophen-2-yl)methanone (120.0 mg, 0.44 mmol. The reaction was stirred at 50 °C for 24 hours. After this time, quantitative ^J H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 4e of 92%.

Synthesis of tert-butyl 4-(3-methyl-2-(pyridin-2-yl)phenyl)piperidine-l-carboxylate (41)

Obtained using General procedure C employing 2-(o-tolyl)pyridine (67.8 mg, 0.40 mmol) and (tert-butyl 4-bromopiperidine-l -carboxylate (132.0 mg, 0.50 mmol). The reaction was stirred at 50 °C for 24 hours. After this time, quantitative ^J H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 4f of 92%. Synthesis of 2-(2-methyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)pyridine (4g)

Obtained using General procedure C employing 2-(o-tolyl)pyridine (64.0 μL, 0.40 mmol) and 4-bromotetrahydro-2H-pyran (47.4 ph. 0.42 mmol). The reaction was stirred at 50 °C for 24 hours. After this time, quantitative ^J H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 4g of 88%.

Synthesis of 2-(2-fluoro-6-(tetrahydro-2H-pyran-4-yl)phenyl)pyridine (4h)

General Procedure C was applied. 2-(2-fluorophenyl)pyridine (69.2 mg, 0.40 mmol) and 4- bromotetrahydro-2H-pyran (47.4 μL, 0.42 mmol) were employed. The reaction was stirred at 50 °C for 24 hours. The crude mixture was purified by column chromatography eluting with 10% EtOAc in hexane to yield the title compound 4h (98.0 mg, 90%) as a colourless oil.

'H NMR (400 MHz, CDC13) δ 8.66 (d, J = 5.0 Hz, 1H), 7.70 (m, 1H), 7.34 - 7.15 (m, 3H), 7.11 (d, J= 7.9 Hz, 1H), 6.93 (m, 1H), 3.95-3.80 (m, 2H), 3.20-3.10 (t, J= 11.8 Hz, 2H), 2.75- 2.60 (m, 1H), 1.80-1.65 (m, 2H), 1.63-1.50 (m, 2H).

¹³ C NMR (101 MHz, CDC13) δ ¹³ C NMR (101 MHz, CDC13) δ 160.2 (d, J= 245.5 Hz), 154.3, 149.8, 146.8 (d, J= 2.0 Hz), 136.4, 130.1 (d, J= 8.8 Hz), 128.2 (d, J= 15.6 Hz), 125.9 (d, J= 2.0 Hz), 122.7, 122.1 (d, J= 3.4 Hz), 113.5 (d, J= 22.5 Hz), 68.5, 37.7 (d, J= 2.4 Hz), 33.9.

¹⁹ F NMR (376 MHz, CDC13) δ -115.42.

Synthesis of 2-(2-methyl-6-(tetrahydro-2H-pyran-4-yl)phenyl)pyrimidine (4i) General Procedure C was applied. 2-(2-methyl-6-(tetrahydro-2H-pyran-4- yl)phenyl)pyrimidine (68.0 mg, 0.40 mmol and 4-bromotetrahydro-2H-pyran (47.4 μL, 0.42 mmol) were employed. The reaction was stirred at 50 ^C for 18 hours. The crude mixture was purified by column chromatography eluting with 50% EtOAc in hexane to yield the title compound 2i (82.3 mg, 81%) as a colourless solid. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 5.0 Hz, 2H), 7.31 – 7.22 (m, 2H), 7.19 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 4.09 – 3.78 (m, 2H), 3.32 – 3.00 (m, 2H), 2.31 (tt, J = 11.9, 3.8 Hz, 1H), 1.98 (s, 3H), 1.87 – 1.70 (m, 2H), 1.72 – 1.54 (m, 2H). 1 ³ C NMR (101 MHz, CDCl ₃ ) δ 168.7, 157.3, 143.1, 138.8, 135.7, 129.0, 128.3, 123.8, 119.3, 68.6, 38.8, 33.9, 20.2. Synthesis of [diazepam]-[4-bromotetrahydro-2H-pyran] (4j) Genera Procedure C was applied. Diazepam (85.4 μL, 0.30 mmol), 4-bromotetrahydro-2H- pyran (74.2 mg, 0.45 mmol), K2CO3 (124.4 mg, 3 equiv) and [Ru(OH2)(tBuCN)5](BF4)22 (14.2 mg, 0.02 mmol) were employed. The reaction was stirred in NMP (1 mL, 0.5 M with respect to the DG-containing arene) at 50 ^C for 48 hours. The crude mixture was purified by column chromatography eluting with 65% EtOAc in hexane to yield the title compound 4j (35.0 mg, 34%) as a colourless oil. ¹ H NMR (500 MHz, CDCl3) δ 7.44 – 7.34 (m, 2H), 7.31 – 7.15 (m, 4H), 6.97 (d, J = 2.6 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 3.97 – 3.67 (m, 3H), 3.42 (s, 3H), 3.11 (t, J = 11.7 Hz, 1H), 2.90 (t, J = 12.2 Hz, 1H), 2.33 (t, J = 12.1 Hz, 1H), 1.76 – 1.56 (m, 2H), 1.48 (d, J = 13.4 Hz, 1H), 1.06 (d, J = 13.4 Hz, 1H). 1 ³ C NMR (126 MHz, CDCl ₃ ) δ 170.8, 169.8, 143.7, 141.3, 138.1, 132.1, 131.5, 130.1, 129.6, 129.4, 129.2, 126.8, 126.3, 122.3, 68.6, 68.3, 56.8, 38.4, 35.0, 33.9, 33.0. 3-(4,5-diphenyloxazol-2-yl)-1-(4-(3-methyl-2-(pyridin-2-yl)p henyl)piperidin-1- yl)propan-1-one (4k) from oxaprozin derivative General Procedure C was applied. 2-(o-tolyl)pyridine (67.8 mg, 0.40 mmol) and 1-(4- bromopiperidin-1-yl)-3-(4,5-diphenyloxazol-2-yl)propan-1-one (194.0 mg, 0.44 mmol) were employed. The reaction was stirred at 50 ^C for 48 hours. The crude mixture was purified by column chromatography eluting with 65% EtOAc in hexane to yield the title compound 4k (146.067%mg, 67%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 5.0 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.63 – 7.58 (m, 2H), 7.57 – 7.52 (m, 2H), 7.39 – 7.27 (m, 7H), 7.25 (t, J = 7.7 Hz, 2H), 7.12 – 7.04 (m, 2H), 4.68 (d, J = 13.0 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.34 – 3.09 (m, 2H), 3.04 – 2.68 (m, 3H), 2.49 – 2.21 (m, 2H), 2.00 (s, 3H), 1.93 – 1.75 (m, 1H), 1.75 – 1.46 (m, 3H). 1 ³ C NMR (101 MHz, CDCl3) δ 169.3, 162.9, 159.7, 149.8, 145.4, 142.9, 140.0, 136.4, 136.2, 135.2, 132.7, 129.1, 128.7, 128.7, 128.5, 128.5, 128.2, 128.1, 128.1, 126.5, 124.7, 123.5, 122.0, 46.3, 42.7, 39.4, 33.8, 32.8, 30.1, 24.0, 20.6. Synthesis of [2-(2-fluorophenyl)pyridine]-[epiandrosterone] 4l

Obtained by using General procedure C. Id (34.6 mg, 0.20 mmol), 3a-21 (106 mg, 0.30 mmol), K2CO3 (124.4 mg, 3 equiv) and [Ru(OH2)(t5i/CA)5](BF4)2 2 (14.2 mg, 0.02 mmol) were employed. The reaction was stirred at 50 °C for 24 hours. After this time, quantitative ^J H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 41 of 80%.

General Procedure D: Ru-catalysed secondary alkylation of DG-containing arenes with primary alkyl bromides

General procedure for the primary alkylation of DG-containing arenes

All liquid reagents were degassed with at least 3 freeze-pump-thaw cycles prior to use. Tribasic potassium phosphate (K3PO4) and potassium phenylphosphonate (PhP(O)O2K2) were dried at 80 °C in a vacuum oven for at least 48 hours prior to use. Unless otherwise indicated, a 10 mL Schlenk tube was charged with ruthenium aqua catalyst 2 (28.4 mg, 0.04 mmol, 10 mol%), K3PO4 (254.7 mg, 1.2 mmol, 3 equiv), and potassium phenylphosphonate (29.0 mg, 0.12 mmol, 30 mol), the appropriate DG-containing arene (0.40 mmol, 1 equiv) and the appropriate alkyl halide (1-2 equiv). After addition of the solids, 3 x 5 minute evac-refill cycles were performed before adding any liquid/oil reagents via injection along with the NMP (2 mL, 0.2 M with respect to the DG-containing arene). The reaction mixture was then stirred at 50 °C for 24 hours. Upon completion, the reaction mixture was diluted with water and washed with Et20, before being dried over MgSOi. filtered, and concentrated in vacuo. The crude mixture was then loaded onto a silica gel column and purified using flash chromatography.

Reactions were performed as set out below following General Procedure D.

Data for all compounds following this procedure matches that previously reported by Larrosa et. al.

M. Wheatley, M. T. Findlay, R. Lopez-Rodriguez, D. M. Cannas, M. Simonetti and I. Larrosa, Chem Catalysis, 2021, 1, 691-703.

* NMR yield calculated by ^] H Q NMR using trimethoxy benzene as internal standard. Synthesis of 2-(2-methyl-6-octylphenyl)pyridine (5a)

The reaction was carried out following General Procedure D with 2-(o-tolyl)pyridine (67.8 mg, 0.40 mmol) and 1-bromooctane (138.7.0 μL, 0.80 mmol) allowing the reaction mixture to stir for 72 hours. After this time, quantitative ^J H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 5a of 89%.

Synthesis of 3-methyl-2-(2-octylphenyl)pyridine (5b)

The reaction was carried out following General Procedure D with 3-methyl-2- phenylpyridine (67.8 mg, 0.40 mmol) and 1-bromooctane (138.7.0 μL, 0.80 mmol) stirring for 24 hours. After this time, quantitative ^J H NMR using 1,3, 5 -trimethoxy benzene as internal standard indicated conversion to product 5b of 75%.

Synthesis of (3-octyl-4-(pyridine-2-yl)phenyl)methanol (5c)

The reaction was carried out following General Procedure D. (4-(pyridine-2- yl)phenyl)methanol (74.1 mg, 0.40 mmol) and 1-bromooctane (138.7.0 μL, 0.80 mmol) were used allowing the reaction mixture to stir for 24 hours. After this time, quantitative ¹ H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 5c of 51%.

Synthesis of 2-(2-methyl-6-octylphenyl)pyrimidine (5d)

The reaction was carried out following General Procedure D. 2-phenylpyrimidine (68.1 mg, 0.40 mmol) and 1 -bromooctane (138.7.0 μL, 0.80 mmol) were used allowing the reaction mixture to stir for 24 hours. After this time, quantitative ^J H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 5d of 72%.

Synthesis of 3-methyl-2-(2-(3-phenylpropyl)phenyl)pyridine (5e)

The reaction was carried out following General Procedure D, with the use of 3-methyl-2- phenylpyridine (67.8 mg, 0.40 mmol) and (3-bromopropyl)benzene (159.3 mg, 0.40 mmol). The crude reaction mixture was purified by column chromatography eluting with 0-10% EtOAc-DCM mixture (1:1) in hexane to give the named compound 5e (105.8 mg, 92%) as a colourless oil.

'H NMR (500 MHz, CDC13) δ 8.43 (d, J= 4.7 Hz, 1H), 7.47 (d, J= 7.8 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.29 - 7.24 (m, 1H), 7.17 - 7.04 (m, 5H), 6.96 (d, J= 7.0 Hz, 2H), 2.50 - 2.45 (m, 4H), 2.02 (s, 3H), 1.77 - 1.61 (m, 2H).

¹³ C NMR (126 MHz, CDC13) δ 159.5, 146.6, 142.2, 140.1, 140.0, 137.7, 131.5, 129.4, 128.9, 128.3, 128.2, 128.1, 125.9, 125.6, 122.2, 35.6, 32.6, 32.2, 19.3. Synthesis of tert-butyl 4-(2-(3-methylpyridin-2-yl)benzyl)piperidine-1-carboxylate (5f) The reaction was carried out following General Procedure D, with the use of 3-methyl-2- phenylpyridine (67.8 mg, 0.40 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (222.5 mg, 0.80 mmol). The crude reaction mixture was purified by column chromatography eluting with 0-10% EtOAc-DCM mixture (1:1) in hexane to give the named compound 5f (108.5 mg, 74%) as a light yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ 8.42 (dd, J = 4.8, 1.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.27 – 7.14 (m, 3H), 7.14 – 7.06 (m, 2H), 3.87 (s, 2H), 2.57 – 2.16 (m, 4H), 2.01 (s, 3H), 1.49 – 1.30 (s, 12H), 0.84 (qd, J = 12.5, 4.4 Hz, 2H). 1 ³ C NMR (126 MHz, CDCl3) δ 159.5, 146.6, 142.2, 140.0, 137.7, 131.5, 129.4, 128.9, 128.3, 128.2, 128.1, 125.9, 125.6, 122.2, 35.6, 32.6, 32.2, 19.3. Synthesis of 2-(5-methoxy-2-octylphenyl)pyridine (5g) T e react on was carried out following General Procedure D, with the use of 2-(3- methoxyphenyl)pyridine (72.3 mg, 0.40 mmol) and 1-bromooctane (138.6 µL, 0.80 mmol). The crude reaction mixture was purified by column chromatography eluting with 0-10% EtOAc-DCM mixture (1:1) in hexane to give the named compound 5g (50.0 mg, 56%) as a colourless oil. ¹ H NMR (500 MHz, CDCl3) δ 8.71 – 8.66 (m, 1H), 7.70 (app. Td, J = 7.6, 2.3 Hz, 1H), 7.30 – 7.18 (m, 3H), 6.91 – 6.87 (m, 1H), 6.79 (d, J = 8.2 Hz, 1H), 3.67 (s, 3H), 2.38 – 2.30 (m, 2H), 1.44 – 1.36 (m, 2H), 1.28 – 1.04 (m, 10H), 0.83 (t, J = 7.2 Hz, 3H). 1 ³ C NMR (126 MHz, CDCl3) δ 157.1, 157.0, 149.3, 142.8, 135.7, 129.6, 128.9, 125.8, 121.7, 121.6, 108.3, 55.7, 33.0, 31.9, 31.0, 29.5, 29.2, 29.1, 22.7, 14.2. Synthesis of 1-(2-octylphenyl)ethan-1-one (5h) The reaction was carried out following General Procedure D, with the use of (E)-N,N-dimethyl- 4-((1- phenylethylidene)amino)aniline (95.3 mg, 0.4 mmol) and 1-bromooctane (138.2 µL, 0.8 mmol) allowing the reaction mixture to stir for 72 hours. K2CO3 (110.5 mg, 2 equiv) was used as the base and KOAc (11.8 mg, 30 mol%) as the additive. After 72 hours, HCl (aq.3M, 2 mL) was added to the reaction mixture, and stirred for a further 1 hour, before being washed with ether. The crude reaction mixture was purified by column chromatography eluting with 0–5% EtOAc in hexane to give the named product 5h as a colourless oil (84.0 mg, 90%). 1H NMR (500 MHz, CDCl3) δ 7.61 (dd, J = 8.3, 1.3 Hz, 1H), 7.38 (td, J = 7.2, 1.4 Hz, 1H), 7.28 – 7.21 (m, 2H), 2.87 – 2.79 (m, 2H), 2.57 (s, 3H), 1.61 – 1.50 (m, 2H), 1.40 – 1.21 (m, 10H), 0.94 – 0.80 (m, 3H). 1 ³ C NMR (101 MHz, CDCl ₃ ) δ 202.3, 142.9, 138.1, 131.2, 131.1, 128.9, 125.6, 34.0, 31.9, 30.0, 29.8, 29.5, 29.3, 27.2, 22.7, 14.1. Synthesis of 1-(2-octylphenyl)-1H-pyrazole 5i The reaction was carried out following General Procedure D, with the use of 1-phenyl-1H- pyrazole (57.7 mg, 0.4 mmol) and 1-bromooctane (138.2 µL, 0.8 mmol) allowing the reaction to stir for 24 hours. After this time, quantitative ¹ H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 5i of 80%. Synthesis of 1-(2-octylphenyl)isoquinoline (5j) The reaction was carried out following General Procedure D, with the use of 1- phenylisoquinoline (82.1 mg, 0.4 mmol) and 1-bromooctane (138.2 µL, 0.8 mmol) allowing the reaction to stir for 24 hours. After this time, quantitative ¹ H NMR using 1,3,5-trimethoxy benzene as internal standard indicated conversion to product 5j of 88%. Synthesis of [diazepam]-[n-octyl] (5k) The reaction was carried out following General Procedure D, with the use of diazepam (57.0 mg, 0.2 mmol), K3PO4 (127.4 mg, 2 equiv), PhP(O)O2K2 (14.3 mg, 30 mol%), [Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ 2 (14.2 mg, 0.02 mmol, 10 mol%) and 1-bromooctane (35.0 µL, 0.4 mmol). The crude reaction mixture was purified by column chromatography eluting with 0– 30% EtOAc in hexane to give the named product 5k (37.1 mg, 47%) as a colourless oil. 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.42 (m, 1H), 7.37 – 7.30(m, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 2.7 Hz, 1H), 4.83 (d, J = 10.8 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 3.41 (s, 3H), 2.37 – 2.26 (m, 1H), 2.20 – 2.06 (m, 1H), 1.38 – 0.92 (m, 12H), 0.83 (t, J = 7.1 Hz, 3H). ¹³ C NMR (126 MHz, CDCl3) δ 171.1, 169.8, 141.64, 141.3, 138.5, 132.0, 131.5, 130.1, 130.0, 129.9, 129.6, 129.3, 126.1, 122.5, 56.9, 35.0, 33.6, 31.9, 31.1, 29.9, 29.5, 29.3, 22.8, 14.2. (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylhe ptan-2-yl)- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclop enta[a]phenanthren-3-yl 6- (2-(3-methylpyridin-2-yl)phenyl)hexanoate (5l) from cholesterol derivative The reaction was carried out following General Procedure D, with the use of 3-methyl-2- phenylpyridine (33.9 mg, 0.2 mmol), (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)- 6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tet radecahydro- 1Hcyclopenta[a]phenanthren-3-yl 2-bromoacetate (225.5, 0.40 mmol), K ₃ PO ₄ (127.4 mg, 2 equiv), PhP(O)O2K2 (14.3 mg, 30 mol%) and [Ru(OH2)(tBuCN)5](BF4)2 2 (14.2 mg, 0.02 mmol, 10 mol%). The crude reaction mixture was purified by column chromatography eluting with 0-10% EtOAc-DCM mixture (1:1) in hexane to give the named compound 5l (97.8 mg, 75%) as a light brown oil. 1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (dd, J = 4.8, 1.9 Hz, 1H), 7.54 (dd, J = 7.7, 1.8 Hz, 1H), 7.31 – 7.18 (m, 3H), 7.15 (dd, J = 7.7, 4.8 Hz, 1H), 7.13 – 7.08 (m, 1H), 5.33 (d, J = 4.9 Hz, 1H), 4.63 – 4.52 (m, 1H), 2.49 – 2.29 (m, 2H), 2.24 (d, J = 8.3 Hz, 2H), 2.12 (t, J = 7.6 Hz, 2H), 2.07 (s, 3H), 2.02 – 1.88 (m, 2H), 1.86 – 1.73 (m, 3H), 1.59 – 1.02 (m, 24H), 1.02 – 0.90 (m, 6H), 0.88 (d, J = 6.6 Hz, 3H), 0.83 (dd, J = 6.6, 1.8 Hz, 6H), 0.65 (s, 3H). 1 ³ C NMR (101 MHz, CDCl3) δ 173.2, 159.7, 146.7, 140.2, 140.0, 139.8, 137.8, 131.6, 129.4, 128.8, 128.1, 125.8, 122.7, 122.3, 73.7, 56.8, 56.2, 50.1, 42.4, 39.8, 39.6, 38.3, 37.1, 36.7, 36.3, 35.9, 34.6, 32.8, 32.0, 32.0, 30.3, 28.9, 28.4, 28.1, 27.9, 24.8, 24.4, 23.9, 22.9, 22.7, 21.1, 19.4, 19.4, 18.8, 12.0. General Procedure E: Ru-catalysed methylation of DG-containing arenes with ammonium salt All liquid reagents were degassed with at least 3 freeze-pump-thaw cycles prior to use. To an oven-dried 10 mL Schlenk tube containing a magnetic stirring bar was added ruthenium aqua catalyst 2 (5 mol%, 0.015 mmol, 10.6 mg), NaI (89.9 mg, 2 equiv., 0.6 mmol), the methylating ammonium salt (1 equiv., 0.3 mmol, 56.0 mg), Na ₂ CO ₃ (31.8 mg, 1 equiv., 0.3 mmol,) and the DG-containing arene (1 equiv., 0.3 mmol) before performing 3 x 5 minute evac-refill cycles. NMP (1.5 mL, 0.2 M with respect to the DG-containing arene) was then added. The reaction mixture was stirred at 40 ^C for 24 hours. Upon completion, the crude reaction mixture was diluted with water (30 mL) and extracted with Et ₂ O (3 x 30 mL) before being loaded onto a silica gel column and purified by flash column chromatography under the conditions noted to afford pure product. The following reactions were performed following General Procedure E:

[Ru(OH ₂ )(fBuCN)5](BF ₄ )2

2 5 10 l% from 5-tocopherol derivative from diazepam

Yields were calculated using ^] H QNMR with nitromethane as an internal standard. Isolated yields are given in brackets.

Synthesis of 2-(2-methyl-5-(trifluoromethyl)phenyl)pyridine (6a) The title compound was synthesised as outlined in General Procedure E, using 2-(3- (trifluoromethyl)phenyl)pyridine (71.1 mg, 0.3 mmol) and | Ru(OH2)(/BuCN)5|(BF4)2 2 (10.6 mg, 0.015 mmol) for 24 hours. After this time, quantitative ^J H NMR using nitromethane as internal standard indicated conversion to product 6a of 98%.

Synthesis of 2-(o-tolyl)pyridine (6b)

6b

The title compound was synthesised as outlined in General Procedure E, using 2- phenylpyridine (46.5 mg, 0.3 mmol) and [Ru(OH2)(tBuCN)s](BF4)2 2 (10.6 mg, 0.015 mmol) for 24 hours. After this time, quantitative ^J H NMR using nitromethane as internal standard indicated conversion to product 6b of 75%.

Synthesis of 3-methyI-2-(o-tolyl)pyridine (6c)

6c

The title compound was synthesised as outlined in General Procedure E, using 3-methyl-2- phenylpyridine (50.7 mg, 0.3 mmol) and [Ru(OH2)(tBuCN)5](BF4)2 2 (10.6 mg, 0.015 mmol) for 24 hours. After this time, quantitative ^J H NMR using nitromethane as internal standard indicated conversion to product 6c of 80%. Synthesis of 1-(o-tolyl)isoquinoline (6d) The title compound was synthesised as outlined in General Procedure E, using 1- phenylisoquinolie (61.5 mg, 0.3 mmol) and [Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ 2 (10.6 mg, 0.015 mmol) for 24 hours. After this time, quantitative ¹ H NMR using nitromethane as internal standard indicated conversion to product 6d of 82%. Synthesis of 2-(4-(tert-butyl)-2-methylphenyl)pyridine (6e) The title compound was synthesised as outlined in General Procedure E, using 2-(4-(tert- butyl)phenyl)pyridine (63 mg, 0.3 mmol) and [Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ 2 (10.6 mg, 0.015 mmol, 5 mol%). The reaction was allowed to stir for 24 hours. After this time, quantitative ¹ H NMR using nitromethane as internal standard indicated conversion to product 6e of 72%. Purification using flash column chromatography eluting with 0–10% EtOAc in hexane afforded the named compound 6e as a yellow oil (43.2 mg, 64 %). 1H NMR (400 MHz, CDCl3) δ 8.59 – 8.51 (m, 1H), 7.59 (td, J = 7.7, 1.8 Hz, 1H), 7.27 (m, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 2.8 Hz, 2H), 7.08 (m, 1H), 2.25 (s, 3H), 1.22 (s, 9H). 1 ³ C NMR (101 MHz, CDCl ₃ ) δ 160.1, 151.2, 149.2, 137.7, 136.0, 135.2, 129.4, 127.8, 124.0, 122.9, 121.4, 34.5, 31.4, 20.6. Synthesis of 2-(2-fluoro-6-methylphenyl)pyridine (6f) The title compound was synthesised as outlined in General Procedure E, using 2-(2- fluorophenyl)pyridine (52 mg, 0.3 mmol and [Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ 2 (10.6 mg, 0.015 mmol, 5 mol%). The reaction was allowed to stir for 24 hours. After this time, quantitative ¹ H NMR using nitromethane as internal standard indicated conversion to product 6f of 88%. Purification using flash column chromatography eluting with 0-10% EtOAc in hexane afforded the named compound 6f as a yellow oil (33.7 mg, 73 %) 1H NMR (400 MHz, CDCl3) δ 8.73 (m, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.40 – 7.32 (m, 1H), 7.32 – 7.19 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 8.8 Hz, 1H), 2.21 (s, 3H). 1 ³ C NMR (101 MHz, CDCl ₃ ) δ 160.2 (d, J = 245.0 Hz), 154.4, 149.6, 139.0 (d, J = 2.4 Hz), 136.2, 129.4 (d, J = 8.8 Hz), 128.4 (d, J = 15.2 Hz), 125.9 (d, J = 3.4 Hz), 125.5 (d, J = 2.4 Hz), 122.3, 113.0 (d, J = 22.5 Hz), 19.74 (d, J = 2.4 Hz). 1 ⁹ F NMR (376 MHz, CDCl ₃ ) δ -117.15. (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17- decahydro-6H- cyclopenta[a]phenanthren-3-yl 4-methyl-3-(pyridin-2-yl)benzoate (6g) from estrone derivative The title compound was synthesised as outlined in General Procedure E, estrone derivative (135.5 mg, 0.3 mmol) and [Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ 2 (10.6 mg, 0.015 mmol, 5 mol%) were employed. The reaction was allowed to stir for 24 hours. After this time, quantitative ¹ H NMR using nitromethane as internal standard indicated conversion to product 6g of 92%. Purification using flash column chromatography eluting with 15–25% EtOAc in hexane afforded the named compound 6g as a colourless oil (113.0 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.74 – 8.71 (m, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.11 (dd, J = 7.9, 2.0 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (dt, J = 7.8, 1.1 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.35 – 7.27 (m, 2H), 6.98 (dd, J = 8.8, 2.9 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 2.97 – 2.89 (m, 2H), 2.56 – 2.39 (m, 5H), 2.37 – 2.27 (m, 1H), 2.21– 1.94 (m, 4H), 1.70 –1.41 (m, 6H), 0.93 (s, 3H). 1 ³ C NMR (101 MHz, CDCl ₃ ) δ 220.8, 165.3, 159.0, 149.4, 148.9, 142.3, 140.8, 138.1, 137.4, 136.4, 131.4, 131.2, 129.9, 127.4, 126.5, 124.3, 122.1, 121.8, 118.9, 50.5, 48.0, 44.2, 38.0, 35.9, 31.6, 29.5, 26.4, 25.8, 21.6, 20.7, 13.9. 2,8-dimethyl-2-(4,8,12-trimethyltridecyl)chroman-7-yl-4-meth yl-3-(pyridin-2- yl)benzoate (6h) from ^-tocopherol derivative The title compound was synthesised as outlined in General Procedure E, using the ^- tocopherol-DG-containing-derivative-arene (175.2 mg, 0.3 mmol) and [Ru(OH2)(tBuCN)5](BF4)22 (10.6 mg, 0.015 mmol, 5 mol%). The reaction was allowed to stir for 24 hours. After this time, quantitative ¹ H NMR using nitromethane as internal standard indicated conversion to product 6h of 78%. Purification using flash column chromatography eluting with 0-10% EtOAc in hexane afforded the named compound as a colourless oil (90.7 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.75 – 8.71 (m, 1H), 8.22 (d, J = 1.9 Hz, 1H), 8.11 (dd, J = 7.9, 1.9 Hz, 1H), 7.78 (td, J = 7.7, 1.8 Hz, 1H), 7.45 (dt, J = 7.8, 1.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.28 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 6.81 (dd, J = 2.8, 0.9 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 2.82 – 2.69 (m, 2H), 2.46 (s, 3H), 2.18 (s, 3H), 1.89 – 1.69 (m, 2H), 1.67 – 0.99 (m, 24H), 0.87 (m, 12H). 1 ³ C NMR (101 MHz, CDCl3) δ 166.0, 159.3, 150.1, 149.6, 143.0, 142.4, 141.0, 136.7, 131.6, 131.4, 130.1, 128.0, 127.6, 124.4, 122.4, 121.6, 121.3, 119.5, 76.4, 40.4, 39.7, 37.8, 37.7 (2C), 37.6, 33.1, 33.0, 31.3, 28.3, 25.1, 24.8, 24.5, 23.0, 22.9, 22.8, 21.3, 20.9, 20.1, 20.0, 16.5. 7-chloro-1-methyl-5-(o-tolyl)-1,3-dihydro-2H-benzo[e][1,4]di azepin-2-one (6i) from diazepam The title compound was synthesised as outlined in General Procedure E, using diazepam (57.0 mg, 0.2 mmol) and [Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ 2 (21.2 mg, 0.03 mmol, 10 mol%). After this time, quantitative ¹ H NMR using nitromethane as internal standard indicated conversion to product 4i of 77%. Purification using flash column chromatography eluting with 25–35% EtOAc in hexane afforded the title product as a white solid (45.0 mg, 75 %). 1H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 8.7, 2.5 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.30 – 7.23 (m, 2H), 7.18 (d, J = 7.1 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 4.86 (d, J = 11.0 Hz, 1H), 3.81 (d, J = 11.0 Hz, 1H), 3.43 (s, 3H), 1.98 (s, 3H). 1 ³ C NMR (101 MHz, CDCl3) δ 170.9, 170.0, 141.8, 138.8, 136.4, 131.9, 131.6, 131.5, 131.0, 129.9, 129.8, 129.1, 126.1, 122.7, 56.9, 34.9, 20.1. General Procedure F: Ru-catalysed meta-alkylation of DG-containing arenes with tertiary alkyl halides Each R ¹⁴ is independently a substituent, e.g. an optionally substituted C1-12 alkyl group.

7a 7c 7d at 40 °C: 89% with blue light: 69% at 50 °C: 84% at 50 °C: 52% with blue light:

The blue light has a wavelength of 440 nm.

General Procedure G: Ru-catalysed H / D exchange

[Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂

2 (5 mol%)

General Procedure H: Oxidative alkene cleavage

[Ru(OH ₂ )(tBuCN) ₅ ](BF ₄ ) ₂ 2

9a 9b 9c

75% [0.33 h] 68% [0.5 h] 32% [2.5 h] from Stilbene from Norbornene from Triprolidine from Lumefantrine from Anethole

• = C atom of the cleaved C=C bond

Each R ¹⁵ is independently a substituent, e.g. an optionally substituted C1-12 alkyl or optionally substituted aryl (e.g. phenyl) or heteroaryl and two or more R ¹⁵ groups may be linked to form a monocyclic or polycyclic ring.

General Procedure I: Transfer hydrogenation

10d 10e

39% ^b 25% ^b from Fe nofib rate

Each R ¹⁶ is independently a substituent, e.g. an optionally substituted C1-12 alkyl or optionally substituted aryl (e.g. phenyl) or heteroaryl.

Intramolecular cyclisation

Compounds of Formula (I) may catalyse intramolecular cyclisation by reaction between a C- H of an sp ² -hybridised aromatic or non-aromatic carbon atom and a primary, secondary or tertiary alkyl halide. Preferably, the cyclisation forms a 5- or 6-membered carbocyclic or heterocyclic ring.

An exemplary intramolecular cyclisation is:

Alkene isomerisation

Compounds of Formula (I) may catalyse alkene isomerisation, for example:

Alkene isomerisation

Compounds of Formula (I) may catalyse hydroalkynylation of an alkyne, for example:

C(sp ³ )-H oxidation

Compounds of Formula (I) may catalyse oxidation by an oxidising agent of C-H to C-OH for a C-H group having an sp ³ -hybridised carbon atom, for example: C(sp ³ )-H amidation

Compounds of Formula (I) may catalyse intramolecular or intermolecular amidation of a C-H group having an sp ³ -hybridised carbon atom, for example:

Air stability

The ³ H NMR spectrum of Ru complex 2 following several weeks of storage in an ambient environment is shown in Figure 1. No significant change in the spectrum or the visible appearance of this complex was observed upon air exposure. The ability of this complex to catalyse C-H bond to C-C bond conversion as described herein was unaffected by air exposure.

Figures 2A and 2B show the ³ H NMR spectra of Comparative Compound 1, illustrated below, before and after exposure to air. Significant differences in the spectra are apparent following air exposure, as can be seen from the stacked spectra of Figure 2C. The appearance of Comparative Compound 1 changed from an off white solid to a black solid upon exposure to the ambient environment. Attempts to convert a C-H bond to a C-C bond catalysed by Comparative Compound 1 after air exposure were unsuccessful. Comparative Compound 1 is disclosed as “Ru9” in Simoneti, M., Cannas, D.M., Just- Baringo, X., Citorica-Yrezabal I. J. and Larossa I. “Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals”, Nature Chem 10, 724-731 (2018).