New Methods for the Synthesis of Functionalised Arenes

A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Science and Engineering

Danielle L. Bunting

School of Chemistry Faculty of Science & Engineering

2018 2 Contents

List of abbreviations5 Abstract ...... 10 Declaration ...... 11 Copyright statement ...... 11 Acknowledgements ...... 12

1 Ruthenium catalysed C–H activation 13 1.1 Introduction ...... 13 1.1.1 Background: C–H activation ...... 13 1.1.2 ortho-Functionalisation ...... 14 1.1.3 meta-Functionalisation ...... 34 1.2 Investigations into meta-functionalisation ...... 48 1.2.1 Aims and objectives ...... 48 1.2.2 Results and discussion ...... 48 1.2.3 Conclusions ...... 65 1.3 Ruthenium catalysed ortho-halogenation ...... 67 1.3.1 Aims and objectives ...... 67 1.3.2 Results and discussion ...... 67 1.3.3 Conclusions and future work ...... 96 1.4 Tandem N,C-diarylation of pyrazole ...... 99 1.4.1 Background: Diaryliodonium salts ...... 99 1.4.2 Aims and objectives ...... 112 1.4.3 Results and discussion ...... 113 1.4.4 Conclusions and future work ...... 131

2 Arynes for the synthesis of substituted arenes 133 2.1 Introduction ...... 133 2.2 Hexadehydro-Diels–Alder (HDDA) reaction ...... 137 2.2.1 Background: HDDA ...... 137 2.2.2 Aims and objectives ...... 143 2.2.3 Results and discussion ...... 144 2.2.4 Conclusions ...... 151 2.3 Benzyne Truce–Smiles rearrangement ...... 154 2.3.1 Background ...... 154 2.3.2 Aims and objectives ...... 163 2.3.3 Results and discussion ...... 164 2.3.4 Conclusions and future work ...... 182

3 3 Experimental 184 3.1 General ...... 184 3.2 meta-Functionalisation experimental ...... 186 3.3 ICl experimental ...... 190 3.3.1 General procedures ...... 190 3.3.2 Preparation of starting materials ...... 191 3.3.3 ortho-Halogenation products ...... 198 3.3.4 Kinetic isotope experiments ...... 214 3.4 Tandem N,C-diarylation of pyrazole experimental ...... 221 3.4.1 Preparation of iodonium salts ...... 221 3.4.2 N–H/C–H arylation of pyrazoles ...... 226 3.4.3 Screening of other heterocycles ...... 232 3.5 HHDDA experimental ...... 237 3.6 Benzyne–Smiles experimental ...... 244 3.6.1 Synthesis of starting materials ...... 244 3.6.2 Screening of conditions ...... 258

Bibliography 267

4 List of abbreviations

δ Chemical shift (in ppm) 1,10-phen 1,10-Phenanthroline 1,2-DCE 1,2-Dichloroethane A˚ Angstr¨om˚ µL microlitre(s) J NMR coupling constant k Rate constant k rel Relative rate of reaction mCPBA meta-Chloroperoxybenzoic acid o-DCB 1,2-Dichlorobenzene

AdCO2H 1-Adamantanecarboxylic acid AIBN Azobisisobutyronitrile APCI Atmospheric Pressure Chemical Ionisation app. apparent aq. Aqueous Ar Aryl ATRA Atom transfer radical addition BHT 2,6-Di-tert-butyl-4-methylphenol BNDHP 1,1’-Binaphthyl-2,2’-diylhydrogen phosphate Boc tert-Butyloxycarbonyl bpy 2,2’-Bipyridyl br Broad calcd Calculated cat. Catalyst/catalytic cm centimetre(s) cm−1 wavenumbers CMD Concerted metallation deprotonation COD 1,5-Cyclooctadiene Conc. Concentration

5 Cp* Pentamethyl cyclopentadiene d doublet DABCO 1,4-Diazabicyclo[2.2.2]octane dap 2,9-Bis(4-methoxyphenyl)-1,10-phenanthroline DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane dF-ppy 2-(2,4-Diﬂuorophenyl)pyridine DFT Density functional theory DG Directing group DIPA Diisopropylamine DIPEA N,N -Diisopropylethylamine DMEDA N,N ’-Dimethylethane-1,2-diamine DMF N,N -Dimethylformamide DMSO Dimethylsulfoxide DPPB Butane-1,3-diylbis(diphenylphosphine) DPPE Ethane-1,2-diylbis(diphenylphosphine) dppf 1,1’-Ferrocenediyl-bis(diphenylphosphine) DPPH Di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium DPPP Propane-1,3-diylbis(diphenylphosphine) DTBP Di-tert-butyl peroxide dtbpy 4,4’-Di-tert-butyl-2,2’-dipyridyl e− Electron EAS Electrophilic aromatic substitution EI Electron Ionisation Eosin Y 2-(2,4,5,7-Tetrabromo-6-oxido-3-oxo-3H -xanthen-9-yl)benzoate eq. Equivalents ESI Electrospray Ionisation EWG Electron withdrawing group Fluorescein 3’,6’-Dihydroxyspiro[isobenzofuran-1(3H ),9’-[9H ]xanthen]-3-one g gram(s) Galvinoxyl 2,6-Di-tert-butyl-α-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1- ylidene)-p-tolyloxy, free radical GCMS Gas Chromatography Mass Spectrometry

6 h hour(s) HDDA Hexadehydro-Diels–Alder HHDDA Hetero-Hexadehydro-Diels–Alder HMDS Bis(trimethylsilyl)amine Hz Hertz IR Infra-Red kcal/mol kilocalories per mole KIE Kinetic isotope eﬀect L Ligand LDA Lithium diisopropylamide LED Light emitting diode LG Leaving group LR Low resolution M Molecular mass (in mass spectrometry) M mol dm−3 m medium (IR absorbance) m multiplet (NMR peak) m.p. Melting point mA milliamp Mes Mesityl mg milligram(s) MHz megahertz MIDA N -Methyliminodiacetic acid min minute(s) mL millilitre(s) MLCT Metal to Ligand Charge Transfer mmol millimole(s) mol% molar percentage MPAA Mono-protected amino acid MS Mass Spectrometry MS Molecular sieves MW Microwave NBE Norbornene

7 NBS N -Bromosuccinimide NCS N -Chlorosuccinimide NIS N -Iodosuccinimide nm nanometre(s) NMP N -Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance NR No reaction Nu Nucleophile PE Petroleum ether pin Pinacolato Piv Pivaloyl PMP para-Methoxyphenyl ppm parts per million PPTS pyridinium p-toluenesulfonate ppy 2-Phenylpyridine PRC Photoredox Catalyst psi Pound per square inch PTFE Poly(tetraﬂuoroethylene) q quartet quant. Quantitative yield RDS Rate determining step rt Room temperature s second(s) s singlet (NMR peak) s strong (IR absorbance) sat. saturated sept septet SET Single electron transfer SM Starting material soln. solution t triplet t1/2 Half life TBA-OAc Tetra-n-butylammonium acetate

8 TBAF Tetra-n-butylammonium fluoride TBAT Tetra-n-butylammonium difluorotriphenylsilicate TBATB Tetra-n-butylammonium tribromide TBHP tert-Butyl hydroperoxide temp Temperature TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl Tf Triflyl TFA Trifluoroacetic acid THF Tetrahydrofuran THP 2-Tetrahydropyranyl TLC Thin Layer Chromatography TM Transition metal TMEDA N,N,N ’,N ’-Tetramethylethylenediamine Ts Tosyl UPLC Ultra Performance Liquid Chromatography UV Ultraviolet Val Valine vis Visible w weak w/u Work-up w/w weight/weight Xyl 3,5-(Dimethyl)phenyl

9 Abstract

The University of Manchester Danielle L. Bunting School of Chemistry Doctor of Philosophy 2018

New methods for the synthesis of functionalised arenes

Arenes are a cornerstone of organic chemistry, and new methods for their functionalisation, whether with improved eﬃciency, or for the synthesis of novel, highly functionalised skeletons remain crucial. The methods available for achieving such transformations are diverse.

This thesis is comprised of two chapters, one investigating the use of ruthenium catalysis for directed C–H functionalisation of arenes possessing a strongly coordinating directing group. The second concerns the use of arynes for the construction of highly functionalised pyridines (via a hexadehydro-Diels–Alder (HDDA) reaction) and ortho- hydroxy biaryls (via a tandem benzyne-Truce–Smiles rearrangement).

Ruthenium catalysis has successfully been used to introduce a number of functional groups by C–H activation. Combined with halocarbons, it could be used to introduce novel functionalities such as tetrasubstituted alkenes, or a formyl group in the meta- position of phenylpyridine. Pleasingly, the use of iodine monochloride as a halogenating agent allowed catalyst dependent ortho-halogenation of phenylpyridine substrates. Use of Ru3(CO)12 catalysis resulted in selective iodination, whereas RuCl2(PPh3)3 enabled chlorination. The substrate scope, as well as the reasons behind this intriguing change in selectivity were investigated.

Ruthenium catalysis has also been used to achieve a one-pot tandem N,C-arylation of pyrazoles, using both aryl components of diaryliodonium salts, avoiding the waste of one equivalent of aryl iodide. Eﬀective for both symmetrical and unsymmetrical diaryliodoniums in good yields, this could also be extended to the use of styrylphenyliodoniums for synthesis of trisubstituted alkenes.

The use of arynes also provides a powerful method for the synthesis of functionalised arynes. Attempts to achieve a pyridyne synthesis and subsequent trapping in a HDDA cascade were unsuccessful. However, generation of benzyne from ortho-trimethylsilyl aryl triﬂate, followed by nucleophilic attack, and subsequent Truce–Smiles rearrangement of an aryl sulfonate ester was successful in the synthesis of ortho-functionalised biaryls.

Word count: 56627

10 Declaration

Work towards Sections 1.2 & 1.3 has been submitted in support of an application for a degree of PhD at this university:

Christopher J. Teskey, Strategic use of transition metals for selective C–H bond functionalisation. Ph.D. thesis, University of Manchester, 2016.

Part of this work (Section 1.4) has been published in a peer reviewed journal:

Christopher J. Teskey, Shariar M. A. Sohel, Danielle L. Bunting, Sachin G. Modha and Michael F. Greaney, Domino N-/C-Arylation via In Situ Generation of a Directing Group: Atom-Eﬃcient Arylation Using Diaryliodonium Salts, Angew. Chem. Int. Ed. 2017, 56, 5263–5266.

i The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and she has given The University of Manchester certain rights to use such Copyright, including for administrative purposes.

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11 Acknowledgements

Firstly, apologies if this is not the most well written section of my thesis, but it will be very diﬃcult to acknowledge all of the people who have helped me over the past 4 years without extremely repetitive use of the phrase ‘thank you’.

Obviously, the ﬁrst person I would like to thank is Mike, for his support and guidance throughout my PhD – I really appreciate it.

Thank you to the BBSRC and Novartis for iCASE funding, as well as Cliﬀ Jones and everyone else at RedX Pharma for letting me join them for my industrial placement. I had a great time, and everyone was really supportive.

Of course, big thanks to members of the Greaney group, past and present, for your support, ideas, and ability to make even the tough times fun. Thank you to Chris, Lucas and Sohel, who I have worked on projects with. Thanks so much to the people who helped to proofread this thesis: Helen, Humera, Chris, Pauline, Alastair, Stuart, Robin, Fayez. I really appreciate the time you all took to do this.

Thank you to the staﬀ in mass spectrometry, NMR, and stores. Without them, this thesis would be considerably shorter.

I would also like to thank Jordi Bur´es,for his help with NMR experiments on the ICl project.

Thank you so much to Gaz, for all of the travelling you’ve done over the past three years, and for putting up with me during the writing up period. Without you, I’m not sure I’d have made it through.

12 1. Ruthenium catalysed C–H activation

1.1. Introduction

1.1.1. Background: C–H activation

C–H activation is an area which has blossomed in the past couple of decades. This is unsurprising, given the efficient way in which it allows the functionalisation of ‘inert’ C–H bonds in one step (Scheme 1). Its benefits compared to traditional cross-coupling reactions are numerous, in that it avoids the need for prefunctionalisation of the starting material. Often, multiple steps are required to install said functionalisation, which wastes material, solvent, time, and stoichiometric quantities of M (e.g. tin, which is toxic). C–H functionalisation via C–H activation with a metal catalyst enables a more direct, efficient, and environmentally friendly process, where only a hydrogen atom is lost from the molecule being functionalised. Substrates often contain a directing group, which can coordinate the metal catalyst and enable selective functionalisation of a particular C–H bond.

H C–H activation/functionalisation R2 [TM] (cat.), R2 X R1 R1 – HX

M prefunctionalisation [TM] (cat.), R2 X

R1 – MX M = B(OR)2, SnR3, SiR3, Mg, Zn, Cl, Br, I... traditional cross-coupling routes

Scheme 1: Comparison of traditional cross-coupling routes to substituted arenes vs direct C–H functionalisation

13 The most common mechanisms by which C–H metallation is proposed to take place are oxidative addition, concerted metallation deprotonation (CMD), and electrophilic substitution (Scheme 2).(1,2) Oxidative addition (Scheme 2 a) is typical for electron rich, late transition metals. As the name suggests, it results in a +2 increase in the oxidation state of the metal. CMD (Scheme 2 b) could also be described as σ-bond metathesis of the C–H bond, and is common for early transition metals. The M–C bond formation takes place simultaneously to deprotonation (which is often carried out by a base such as a carboxylate coordinated to the metal). The oxidation state of the metal remains the same. For late, electron poor transition metals, electrophilic substitution (Scheme 2 c) is traditionally proposed, which also results in no change of the overall oxidation state of the metal.

a) Oxidative addition R R R x x x+2 LnM + RH LnM LnM LnM H H H

b) Concerted metallation deprotonation (CMD)

R' x x LnM LnM -R' + RH LnM H + R' H R R c) Electrophilic substitution

Y x x LnM LnM -Y + RH LnM H + YH R R

Scheme 2: Mechanisms for C–H bond metallation

1.1.2. ortho-Functionalisation

Chelation-directed ortho-functionalisation involves the use of a directing group, which can coordinate to the metal catalyst, which then usually enables directed metallation of the ortho-C–H bond, to form a metallacycle 3 (Scheme 3). This allows functionalisation of that site in a variety of ways. Commonly used are second row, low oxidation state transition metals such as palladium and rhodium. Ruthenium presents a number of advantages over these catalysts, the principle being its cost—worldwide average ruthenium metal prices per mmol in June 2018 (by Johnson Matthey) were 4 times

14 less than that for palladium, and 9 times less than the price of rhodium.(3) In addition, ruthenium catalysts display good stability, ease of use, and sometimes exhibit selectivity which is orthogonal to their palladium alternatives.(4) Ruthenium catalysis has been successfully used to install a variety of functionalities in the ortho-position by C–H activation.(4–7)

DG DG DG DG MLn MLn ML XY H H n X co-ordination metallation functionalisation

1 2 3 4

Scheme 3: General scheme for directed metal catalysed ortho-functionalisation

Early work by Lewis reported the ﬁrst example of a C–C bond forming reaction catalysed by an ortho-metallated complex (Scheme 4).(8) Phenol was alkylated selectively in the ortho-position using ruthenium(II) catalyst 7 and ethylene.

OPh P = P(OPh)3 PhO O P

Ru O 7 (6 mol%) OH P P OH OH OH PhO OPhP

95 psi, KOPh (9 mol%), THF 177 °C, 3.5 h

5 6 5 8 9 12% 13% 75%

Scheme 4: Lewis’ catalytic ortho-C–H alkylation of phenol(8)

This approach of using a coordinating group with ruthenium, allowing cleavage of an otherwise unreactive C–H bond and subsequent ortho-alkylation, was further developed by the group of Murai (Scheme 5).(9) Using ketones as directing groups, and RuH2(CO)(PPh3)3 as a precursor to the active Ru(0) catalyst, alkylation could be carried out selectively at the ortho-position using a variety of oleﬁns.

Since these early examples, much work has been done in the development of Ru(II) catalysed ortho-functionalisation, particularly by the groups of Oi/Inoue, Ackermann

15 O O RuH2(CO)(PPh3)3 (2 mol%) 1 1 R Y 2 R R2 toluene, 135 °C, 0.5–33 h R Y 10 11 13 1.0 eq. 1.0–5.0 eq. R1

O R2 Ru(0) Ru H 12

Scheme 5: Ruthenium(0) catalysed ortho-alkylation by Murai and co-workers(9) and Dixneuf.(4) Ruthenium catalysis can be used to eﬀect a wide variety of transformations directed in the ortho-position, such as: alkylation(7,10,11), alkenylation (using alkynes),(5,12,13) alkenylation (using alkenes),(5) arylation (vide infra),(6,14) hydroxy- lation,(5,15,16) amination,(17) amidation,(18–21) carbonylation,(5,22–24) C–H/Het–H an- nulation using alkynes,(25) homocoupling,(26) borylation,(27) and silylation.(28,29)

Amongst the directing groups which have been reported to be eﬀective for ruthenium catalysed ortho-C–H functionalisation are: pyrimidines,(4) triazoles,(2,4,30) hydroxypyridine,(31–33) oxazolines,(4) 2-substituted pyridines, anilides, amides, pyrazoles, carboxylic acids, ketones, tertiary alcohols, 2-substituted phenols, anilines, benzylic amines, aryl imines, N -Ts imines, N -unsubstituted benzophenone imines, oximes, O- methyl oxime ethers, aryl carbamates, 2-aryl-3-hydroxy-2-cyclohexenones and azoxy- benzenes.(4,5)

1.1.2.1. ortho-Halogenation

Aryl halides provide an important handle for further functionalisation of molecules by a variety of methods, including metal-catalysed cross coupling reactions, the synthesis of organometallic reagents, and nucleophilic aromatic substitution. They also represent an important motif in medicinal chemistry in their own right.(34) Therefore, there remains high demand for the development of methods for the formation of C(sp2)–X

16 bonds, where X is a halogen.

One typical method for the halogenation of aromatic rings is electrophilic aromatic substitution (EAS) using halogenating agents such as Cl2 with Lewis acid catalysts. However, this approach works much more eﬀectively on electron rich substrates, and can only result in substitution of certain positions.(35) Directed ortho-lithiation can also be used to introduce halogens, but the necessity of extremely basic and nucleophilic alkyllithiums means that the scope is very narrow, and many functional groups are not tolerated under the harsh conditions.(36) The Sandmeyer reaction is another traditional route to aryl halides, from unstable and potentially dangerous aryldiazonium salts.(37) Direct C–H functionalisation is therefore an attractive prospect for the development of new methods for C–H halogenation, allowing controlled functionalisation of certain C–H bonds by the use of a metal catalyst and directing group. It could avoid the use of harsh bases, expand the available positions for C–H halogenation in a manner that is complementary for substrates which can undergo electrophilic aromatic substitution, and provide a new reactivity mode for those substrates which cannot.

There are only a couple of reports of ortho-halogenation using ruthenium catalysis, however other metals such as palladium and copper have frequently been used eﬀectively for this transformation.(38) This section will focus mainly on the ortho- halogenation of aromatics with heteroaromatic directing groups, although much work has also been done with non-cyclic directing groups such as carboxylic acids, and anilides.(38)

Ru3(CO)12 (3.3 mol%) i i O N( Pr)2 AgO2C(1-Ad) (20 mol%) O N( Pr)2 NXS (2.0 eq.) X R DCE, 120 °C, 22 h R

1 X = Br, I 14

Scheme 6: Ruthenium catalysed ortho-halogenation of benzamides(39)

With respect to ruthenium catalysis, one example of the use of Ru(0) catalyst

17 Ru3(CO)12 for the ortho-bromination or iodination of benzamides has been reported by Ackermann and Wang (Scheme 6).(39) The reaction uses NXS as the halogenating agent, and results in satisfactory to high yields for the halogenation of both electron rich and electron poor benzamides, but the directing group scope has yet to be expanded further.

The Li group has reported the use of aryl sulfonyl chlorides with Ru(II) catalysis for the dual ortho/meta-functionalisation of 2-phenoxypyri(mi)dines (Scheme 7).(33) This is proposed to proceed via initial cycloruthenation and meta-sulfonation (vide infra for more on meta-functionalisation), followed by oxidative addition of ArSO2Cl onto the Ru(II), to aﬀord a Ru(IV) species. Reductive elimination of the substrate and Cl forms the C–Cl bond. The appeal of this methodology in its ability to form two bonds regioselectively in one procedure is, in a way, also its limitation in that it does not enable selective chlorination or sulfonation.

X X

[RuCl2(p-cymene)]2 (5 mol%) O N ArSO2Cl O N (3.0 eq.) xylene, 120 °C, 24 h Cl R O S Ar 1 O 15 X=CH, N X=CH, N

Scheme 7: Ruthenium catalysed ortho/meta dual C–H functionalisation(33)

The use of arylsulfonyl chlorides selectively as chlorinating agents has been reported by Dong (Scheme 8).(40) Using a palladium catalyst and copper co-catalyst, a few examples are shown to proceed in high yields (71–85%). This is contrary to the reactivity of arylsulfonylchlorides with Ru(II) catalysis, which resulted in dual ortho/meta C–H activation (Scheme 7). The examples all involve electron rich phenylpyridines which are sterically encumbered, presumably to avoid a second ortho-chlorination.

If 1,4-dioxane was used as solvent with K2CO3 as base and no copper co-catalyst, the ortho-sulfone products were formed instead in satisfactory to high yields. It is proposed that the arylsulfonyl chlorides can react with the DMF to form amidinium

18 arenesulfonate salts,(41) and the authors believe that this may be involved in allowing chlorination to take place.

R1 Pd(CH3CN)2Cl2 (10 mol%) R1 N CuCl2 (10 mol%) N

TsCl (3.0 eq.) Cl R2 DMF, 120 °C, 10 h R2

1 16 4 examples, 71–85% yield

Scheme 8: Palladium catalysed ortho-chlorination with tosyl chloride(40)

An early example of the use of copper catalysis for C–H halogenation is presented in (42) the work of Jin-Quan Yu (Scheme 9). They were able to use Cl2CHCHCl2 as both the solvent and chlorine source for the chlorination. They believe that this proceeds by partial conversion in situ of Cl2CHCHCl2 to Cl2CCHCl and HCl, providing a chloride anion which can act as a nucleophile. A radical cation pathway is proposed for the mechanism, ﬁrst involving a single electron transfer (SET) from the aryl ring to Cu(II) as the rate limiting step. The ortho-selectivity is then rationalised by intramolecular transfer of a chloride ion, from coordinated Cu “ate” complex 19, followed by a single electron transfer and loss of a proton to aﬀord the product. Many of the reactions

1 1 R1 CuCl2 (20 mol%), R R N Cl2CHCHCl2 N N Cl Cl Cl O2 (1 atm.), 130 °C, 24 h R2 R2 R2

1 16 17

Proposed mechanism

Cl Cl Cl N SET N N N CuII CuI CuI SET Cl Cl Cl Cl H H

18 19 20 16

Scheme 9: Copper catalysed ortho-chlorination of 2-phenylpyridines, by Jin-Quan Yu(42)

19 result in dichlorination of the 2-arylpyridine, but steric hindrance around the ortho- position can result in selective mono-chlorination. The reaction was also successful for bromination, in Br2CHCHBr2 solvent, or with I2 as an anion source for iodination. Conveniently, other anion sources could introduce other functionalities, such as -CN, -SMe, -SPh, -OH, -OPh-p-CN.

The use of N -halosuccinimides as halogenating agents with palladium catalysis has been explored by the Sanford group (Scheme 10).(43,44) ortho-Halogenation of

2-arylpyridine substrates proceeded with Pd(OAc)2 catalysis, affording mono- or di- halogenated products in pleasing yields, depending upon how sterically hindered the second ortho-position was. Notably, all the reactions were tolerant of ambient air and moisture, and several reactions were scaled up considerably with little reduction in the yield. The Pd catalyst loading could be reduced to 1 mol% without much yield reduction. The substrates were divided into separate classifications. “Type 1” substrates do not react in the absence of palladium catalyst. “Type 2” substrates exhibit different reactivity in the absence and presence of palladium catalyst. “Type 3” substrates afford the same products/product mixtures with or without palladium catalyst, and will not be discussed further here. “Type 4” substrates had reactivity patterns dependent on the oxidant in the presence or absence of palladium. With type 1 substrates, which typically contain electron neutral or electron-deficient rings, the reactions proceeded well. Alternative directing groups could be used to good effect, such as tetrazoles, oxime ethers and isoxazolines. Type 2 substrates could undergo EAS in the absence of palladium, resulting in halogenation of different position(s) compared to if Pd(OAc)2 was used, in which case the directed ortho-halogenation out-competed EAS. These substrates were typically electron rich. They could react in good yields with palladium catalysis enabling complementary reactivity to the uncatalysed pathway, and pyrazole could be used as a directing group. Type 4 substrates had pyrrolidinone directing groups. In the absence of palladium, mixtures of ortho- and para-halogenated products were formed, with a greater bias for the para-substituted products with larger halogens. With N -chlorosuccinimide and palladium catalyst, the palladium could cause

20 DG Pd(OAc)2 (5 mol%) DG NXS (1.2 eq.) X X= Cl 16 X = Br 21 100–120 °C, 12 h, X = I 22 AcOH or MeCN 1

Selected examples: Type 1:

N N N N N

X Cl Cl Cl Br Br

MeO2C CHO CHO 16a X = Cl 65% 16b 17a 21b 21c 21a X = Br 56% a 22a X = I 79% 57% 72% 70% 63% OAc N N OMe I N O N N N N O N N Br I I I I I

Br CF3 21d 23a 22b 22c 22d 22e 56% 41% 78% 41% 57% 54%

Type 2: Type 4:

N N N N N O Cl Cl Cl Cl

OMe 16c 16d 16e 16f 76% 58% 53% 77% a 2.5 eq. NCS

Proposed mechanism: L

H L II L L Pd PdII L L L L – H 24

L X X Electrophilic L L PdIV halogenating L + L agent "X " 25

Scheme 10: Sanford’s palladium catalysed ortho-halogenation using N -halosuccinimides(43,44)

21 selective formation of the ortho-substituted products. However, it was ineﬀective for NBS and NIS, resulting in similar product mixtures to the uncatalysed reaction.

More recent work has found that N -halosuccinimides can also be used to carry out copper mediated ortho-chlorinations and brominations (Scheme 11).(45) Moderate to very good selectivity between mono-and di-ortho-halogenation is reported for a variety of unhindered N -arylpyridines in satisfactory to excellent yields. Hindered substrates underwent mono-halogenation selectively. By changing the acid to benzoic acid, and the solvent to DCE, selective di-halogenation could be carried out in excellent yields. Whilst stoichiometric copper is required (generating stoichiometric waste), copper is considerably cheaper and more readily available than palladium or rhodium. The acid is required for the generation of an acyl hypohalite species, which is the active halogenating agent. Unlike in Jin-Quan Yu’s paper (Scheme 9), which suggests a Cu(II)-Cu(I) catalytic cycle, this work suggests a Cu(I)-Cu(III) catalytic cycle involving oxidative addition of the acyl hypohalite to coordinated Cu(I), attack of the aryl ring onto Cu(III), and subsequent deprotonation and reductive elimination to aﬀord the product. This is based on kinetic isotope experiments.

R1 CuX (1.0 eq.), NXS (2.0 eq.), R1 N HOAc (0.5 eq.) N X MeCN, N2, 100 °C, 24 h R2 R2

1 X = Cl 16 X = Br 21

Scheme 11: Copper-mediated ortho-halogenation with NXS, by the Shen group(45)

Cu-MnO has been used as a heterogeneous catalyst, with N -halo-succinimides as halogenating agents in visible light (Scheme 12).(46) The reaction worked well for the mono-chlorination of electron rich 2-arylpyridines, and moderately when an electron withdrawing group was present. It could also be used with benzo[h]quinoline. In addition, bromination could be carried out on electron rich 2-arylpyridines in good yields, and in a modest yield when a para-CF3 group was present. Iodination products

22 were obtained in moderate yields. Pleasingly, it was found that the Cu-MnO catalyst could be recycled, and reused eﬀectively for multiple runs. The reaction mechanism is proposed to be similar to that proposed by Yu and co-workers, via a single electron transfer (SET) pathway.

R1 CuMnO, NXS*, nitrobenzene R1 N N O2, light, 125 °C, 24 h * If X = Cl (3.0 eq.); Br (1.5 eq.); I (1.25 eq.) X R2 R2

1 X = Cl 16 6 examples, 42–83% yield X = Br 21 4 examples, 36–62% yield X = I 22 4 examples, 32–51% yield

Scheme 12: Use of NXS for halogenation, with heterogeneous CuMnO catalysis(46)

N -Iodosuccinimide and N -bromosuccinimide (or N -bromophthalimide) have also successfully been used with cobalt catalysis and rhodium catalysis for ortho-iodination and bromination, by the Glorius group.(47,48)

Kakiuchi et al. exemplified the use of HX as a halogenating agent for ortho-halogenations (Scheme 13) with palladium catalysis.(49) By electrochemical oxidation, they were able to carry out direct C–H halogenation using simple HX as the halogen source, resulting in extremely high atom economy, as the only waste created was two protons. The methodology was effective for phenylpyridines and phenylpyrimidines with electron withdrawing and electron donating substituents on the aryl ring in excellent yields. As has been the case with many reported ortho-chlorination reactions, in the absence of steric hindrance at the second ortho-position, dichlorination took place. The dichlorinated products 17b and 17c were obtained cleanly and in high yields. The X− anion is proposed to be oxidised at the anode to X+ which can react with the palladacycle to afford the product.

PhI(OAc)Cl can be generated in situ from the combination of PhI(OAc)2 and either

PhICl2 or NBu4Cl, and can act as a radical chlorine source for the palladium catalysed ortho-chlorination of phenylpyridines (Scheme 14).(50) The reported scope is extremely

23 anode cathode anode cathode 1 1 1 R PdBr2 (10–15 mol%) 2 M aq. HBr R PdCl2 (2 mol%) 2 M aq. HCl R N DMA or DMF N DMF N

Br divided cell, (Pt)-(Pt) divided cell, (Pt)-(Pt) Cl R2 90 °C, 20 mA, 2.5–6.5 h R2 90 °C, 20 mA, 2.5–6.5 h R2

21 1 16

Selected examples:

N N N N NN N NN

Cl Cl X Cl X Cl Cl Cl Cl

MeO2C F3C 17b X = Cl 16g 16h X = Cl 16i 17c 16j 16k 94% 87% 87% 88% 91% quant. 95% X = Br 21e X = Br 21f 95% 83%

Scheme 13: Use of electrochemical oxidation for palladium catalysed ortho-halogenation with HX(49)

limited, with PhICl2 able to eﬀect either mono or di-chlorination of 2-(p-tolyl)pyridine with satisfactory selectivity, depending on the number of equivalents of PhICl2 used.

The use of NBu4Cl resulted in selective mono-chlorination for 2-phenylpyridine, 2-(p- tolyl)pyridine and benzo[h]quinoline in moderate to good yields, and could also be used with an acetanilide directing group in pleasing yield.

Pd(OAc)2 (4 mol%) and R1 PhI(OAc)2 (1 eq.) R1 N PhICl2 (0.5 eq.), DCE, 110 °C, 8 h N Cl or PhI(OAc)2 (2 eq.) 2 2 R NBu4Cl (2 eq.), benzene, 110 °C, 8–36 h R

1 16 6 examples, 58–91% yield

(50) Scheme 14: Palladium catalysed ortho-chlorination using PhI(OAc)2

Using a similar approach, Hong and Wang reported the use of PhI(OAc)2 with sodium halides for the in situ generation of PhIX2, to eﬀect ortho-chlorination, bromination or iodination with rhodium catalysis (Scheme 15).(51) Whilst sodium halides represent a non-toxic and low cost halogen source, the use of expensive rhodium catal-

24 ysis likely oﬀsets this cost reduction. The scope for this reaction included pyridine, isoquinoline, pyrimidine and pyrazole directing groups. Electron-rich phenylpyridines worked in particularly high yields, with moderate to good yields for the other directing groups. Generally, iodination proceeded in lower yields than chlorination and bromination. The mechanism is tentatively proposed to proceed via an electrophilic halogenation with PhIX2 acting as the halogenating agent, and insertion of the halogen into the Rh–Ar bond.

DG [Cp*RhCl2]2 (4 mol%), PhI(OAc)2 (1.5 eq.) DG CF CO H (1.5 eq.), NaX (3.0 eq.) 3 2 X R acetone, 50 °C, 12 h R

1 X = Cl 16 10 examples, 42–86% yield X = Br 21 10 examples, 24–99% yield X = I 22 10 examples, 20–89% yield

Scheme 15: Rhodium catalysed ortho-halogenation using sodium halides(51)

A different approach involving the use of a hypervalent iodine compound and sodium iodide has been reported for the synthesis of ortho-iodides by the Li group (Scheme 16).(52) Through rhodium catalysed C–H activation, an iodonium salt can be formed in short reaction times at room temperature. This is in effect an oxidised form of the arene, which can therefore undergo nucleophilic substitution with iodide to form the ortho-iodinated product, in a one-pot process. Whilst the majority of the paper focused on sulfinate nucleophiles for sulfonation, the one example of iodination on phenylpyridine proceeded in 91% yield, and a large range of other nucleophiles were shown to work well, showing promise for the use of this umpolung approach to ortho- functionalisation.

Copper is a considerably cheaper alternative to palladium, and can be used with lithium halides as halogenating agents (Scheme 17).(53) This presents a particularly green method for the synthesis of ortho-halogenated phenylpyridines, using cheap, abundant copper, low cost LiX as the halogen source, and oxygen as the oxidant. Un- fortunately, di-chlorination of unhindered phenylpyridines was predominant, however

25 [RhCp*Cl2]2 (4 mol%) N MesCO H (20 mol%) N NaI (3.0 eq.) N 2 OMs I I PhI(OH)(OMs) (1.3 eq.) Ph acetone, 60 °C acetone, rt, 1 h

26 27 26a

Scheme 16: Use of rhodium catalysis for iodonium formation, and subsequent iodination(52) these products could be obtained in good to excellent yields. Mono-chlorinated products could be obtained by introducing a steric block, and were obtained in satisfactory to very good yields. Benzo[h]quinoline could be ortho-chlorinated in 78% yield, and pyrimidines were also eﬀective as directing groups, although selectivity between the mono and di-chloro products was lower for these. Bromination proceeded with marginally less reactivity than chlorination. The authors also report that other chloride salts such as NaCl, CaCl2 and KCl also work eﬀectively, albeit in slightly lower yields.

1 1 1 R Cu(NO3)2•3H2O (20 mol%) R R N LiX (3.0 eq.) N N X Cl Cl HOAc, O2, 150 °C, 5–47 h R2 R2 R2

1 X = Cl 16 17 X = Br 21

Scheme 17: Use of copper catalysis for ortho-halogenation with lithium halides(53)

Work by Yang, Wu and Wu found that benzyl chloride could be used as a chlorinating agent (Scheme 18).(54) Under oxygen atmosphere, tert-butyl hydroperoxide (TBHP) was used to oxidise the benzyl chloride, giving tBuOCl and benzaldehyde. The addition of tBuOCl to the palladacycle and dissociation of palladium from the phenylpyridine was proposed to form the C–Cl bond via a free-radical process. The reaction did not result in the formation of di-ortho-chlorinated products, and worked on substituted pyridines, benzo[h]quinoline, and 2-thienylpyridine. Interestingly, by changing to a cyclopalladated ferrocenylimine catalyst, addition of base, and use of an

26 air atmosphere, the benzyl chloride could instead act as an acylating agent.

1 R PdCl2 (5 mol%), TBHP (5.0 eq.) R1 N BnCl (2.0 eq.) N Cl DMSO, O2, 100 °C, 24 h R2 R2

1 16 18 examples, 43–85% yield

Scheme 18: Use of benzyl chloride as a halogenating agent, with Pd catalysis(54)

Jafarpour and co-workers reported the use of aroyl chlorides as chlorinating agents for the ortho-chlorination of phenylpyridines, with palladium catalysis and Cu(II) oxidant (Scheme 19).(55) The scope of substitution of the phenylpyridine was limited, with methyl substitution in most positions tolerated. However the reaction was also shown to work for benzo[h]quinoline, and N -phenylpyrazole. They propose that the reaction proceeds via oxidative addition of the aroyl chloride to a Pd(II) palladacycle, then reductive elimination to form the C–Cl bond.

O PdCl (10 mol%) DG 2 2.0 eq. DG CuCl2 (10 mol%) Ar Cl Cl R 1,4-dioxane, 4 Å MS, 140 °C, 24 h R

1 16 10 examples, 48–92% yield

Scheme 19: Use of aroyl chlorides as halogenating agents, with Pd catalysis(55)

Whilst many examples exist with pyridine directing groups, the use of pyrimidine directing groups often results in lower yields, and poorer selectivity between the mono- and di-halogenated products. One example of C–H chlorination using palladium catal- (56) ysis by the Xu group sought to redress this (Scheme 20). Using CaCl2 as the chloride source, phenylpyrimidines could be halogenated with excellent selectivity for the mono-chlorinated products. Notably, the reaction worked well with electron-poor arenes, even with para-nitro substitution, which is rarely documented for this kind of

27 reaction. Under the originally optimised conditions, electron-rich arenes with no steric hindrance around the ortho-position were found to undergo dichlorination, however it was found that the use of acetic anhydride as a co-solvent could be used for these substrates to result in good selectivity for the mono-ortho-chlorinated product. The reaction was also shown to work for bromination in good yields.

Pd(OAc)2 (5 mol%) Cu(OTFA)2 (1.0 eq.) NN NN CaCl2 (4.0–8.0 eq.)

HOAc, air, 110 °C, 1–24 h Cl R R

1 16

Selected examples:

NN NN NN NN NN NN

Cl Cl Cl Cl Cl Cl

O2N OHC MeO CO2Et 16l 16m 16n 16o 16pa 16qa 74% 92% (8%) 89% (6%) 91% 92% (8%) 90% (9%)

a Yields in brackets are yields of the di-ortho-chlorinated products. HOAc/Ac2O (1.2:1).

Scheme 20: Palladium catalysed ortho-chlorination of 2-phenylpyrimidines(56)

As has been shown, whilst there are many examples of C–H ortho-chlorination methodologies, the issue of mono-chlorination vs dichlorination remains a problem which is usually only solved by means of steric hindrance. Methods for ortho-iodination remain more scarce, and those reported use expensive metal catalysts such a Pd or Rh,(43,44,52) or result in only moderate yields of the desired products.(46) Many of the halogenating agents currently in use generate large amounts of organic waste. Some progress has been made with the use of low-cost copper catalysts for these transformations, however it is still met with the problem of mono-selectivity, and is not always catalytic. Little progress has been made so far with relatively cheap ruthenium catalysis, and there is much room for the development of a C–H halogenation using this, particularly if it could be used for iodination.

28 1.1.2.2. ortho-Arylation

The synthesis of biaryl compounds represents a fundamental transformation, key to the production of pharmaceuticals. Biaryls are considered priveledged structures by the pharmaceutical industry,(57) a term which means that they are “a single molecular framework able to provide ligands for diverse receptors”.(58) Molecules containing a biaryl frame have been listed as having the following distinct properties: antiame- bic, antifungal, antiinfective, antihypercholesteremic, antihyperlipoproteinemic, fas- ciolicide, antirheumatic, analgesic, antiinﬂammatory, antithrombotic, uricosuric, and antiarrhythmic.(59) 4.3% of all known drugs (as of 2000) contained a biphenyl framework.(60) It is for this reason that the development of new and more eﬃcient methods for their synthesis receives so much attention.

Whilst a variety of methods for the metal-directed C–H arylation of arenes have been reported, mainly using Pd, Rh and Ru catalysis,(14) this section will focus mainly on the use of aryl halides with ruthenium catalysis for ortho-C–H arylation. Despite their lower cost, ruthenium complexes can be utilised for ortho-arylations with similar yields to their more expensive, less sustainable alternatives.(14)

The ﬁrst example of ruthenium catalysed ortho-C–H arylation was reported by Oi, Inoue and co-workers in 2001 (Scheme 21).(61) With a catalytic Ru(II)-phosphine complex, 2-arylpyridines could be arylated using aryl bromides. Those substrates without steric hindrance around the ortho-position resulted in the formation of some di-ortho-arylated product. Using three equivalents of bromobenzene and K2CO3, 2-phenylpyridine could be selectively di-ortho-arylated in 77% yield.

Since the ﬁrst report, much work has been done to expand the scope and generality of this reaction.(6,14) Generally, reaction conditions involve high temperatures, and work well in polar aprotic solvents (such as NMP, DMF, DMA, DMSO, MeCN), however non-polar solvents such as toluene have also been used eﬀectively. Base is generally t found to be required, and inorganic bases such as K2CO3, Cs2CO3, KOAc and BuOK

29 1 1 R Br [RuCl2(C6H6)]2 (2.5 mol%) R N N PPh3 (10 mol%) H 3 R K CO (2.0 eq.), NMP 2 2 3 2 R3 R 120 °C, 20 h R

1 28 29

Selected examples:

N Me N F N N N Me

F3C 29a 29b 29c 29d 29e 60% (18%) 64% (16%) 90% (0%) 90% (0%) 95% (0%)

Scheme 21: The ﬁrst example of ruthenium catalysed ortho-C–H-arylation. (Yields in brackets are those of di-ortho-arylated products)(61)

[RuCl2(p-cymene)]2 via X (2.5 mol%) N MesCO H (30 mol%) N N Y 2 Y Y 2 Ru O H R K CO (2.0 eq.) 2 3 2 R 1 1 R 1 R toluene R R H O 120 °C, 16–20 h 1 X = Br (28) 29 32 (1.0 eq.) Cl (30), OTs (31) (1.5 eq.)

Selected examples:

Bu N OMe N N CO Et O N N R2 N 2 N OMe N Me Me R1 Me OMe

CF3 29f 29h 29i 29j 29k 1 2 R =Me, R =CO2Me 87% 73% X=Br 99% 73% 59% 29g X=Cl 87% R1=OMe, R2=Cl 87% X=OTs 70%

Scheme 22: Use of MesCO2H as an additive for ortho-C–H arylation. Unless otherwsie stated, X = Br.(2,30)

30 are commonly used.(14)

Ackermann and co-workers have shown that the use of a catalytic amount of carboxylic acid can be used to aid the formation of the Ru–C bond, which is proposed to proceed via a concerted metallation-deprotonation (CMD) type mechanism. This additive enabled the use of apolar solvent toluene for the ortho-arylation of N -aryl triazoles with aryl bromides (Scheme 22).(2,30) The directing group could also be a pyrazole, pyridine or oxazoline, and aryl chlorides and tosylates also functioned well as arylating agents. In addition, the methodology could be used for the functionalisation of an alkene to give 29k. The reaction is proposed to go via a transition state 32,

Me iPr 33 (5 mol%) Cl Ru O N MesCO N Y 2 O Mes Y 2 H R K CO (2.0 eq.), toluene 2 3 2 R1 120 °C, 18 h R1 R

1 30 29 1.0 eq. 1.5 eq.

Proposed mechanism:

N N Y Y Ru O H 2 X R1 R O Mes 33 29 1

Ar X O CMes Ru O2CMes Ru 2 X N N Ph Y Y

34 36

Ru O2CMes K2CO3

ArX N Y KX, KHCO3

Scheme 23: Use of Ru(II) carboxylate catalyst for ortho-arylation(62)

31 where the carboxylate is coordinated to the ruthenium, and aids ruthenacycle formation by a CMD mechanism. This is similar to the mechanism proposed by Dixneuf and Maseras, based on computational studies.(63) Their study does not use a carboxylate additive, but suggests that coordination of the carbonate base to ruthenium enables deprotonation via a CMD process.

Since then, Ackermann’s group has also reported the use of a ruthenium (II) carboxylate complex 33 as catalyst (Scheme 23), synthesised in 99% yield in 2 hours from (62) [RuCl2(p-cymene)]2 and MesCO2H with K2CO3 in toluene. The catalyst allowed the ortho-arylation of aryl rings with a number of diﬀerent directing groups including pyridines, pyrazoles, oxazolines, as well as the arylation of alkenes with high yields. Experimental studies with this catalyst supported a mechanism beginning with a reversible CMD step aided by the carboxylate ligand, followed by oxidative addition of the aryl halide to the ruthenacycle, and reductive elimination to aﬀord the product.

N RuII N Y Y RuII H N Y H N 1 37 Y 1

Y N Y N II Y N Ru IV Y Ru N X 38 39

Scheme 24: Larrosa’s recently reported mechanism for ruthenium catalysed ortho-arylation of 1. Note, not all of the ligands are shown on the ruthenium.(64)

32 (PF6) N N X N Y Ru(MeCN)4 37a (10 mol%) Y H 2 R 2 R1 R1 R KOAc (30 mol%), K2CO3 (2–4 eq.) NMP, 35 °C, Ar, 72 h X = Cl (30), Br (28), 1 29 I (40), OTf (41) 1 eq. 1–2 eq.

Selected examples:

N (Et)2N O Xyl Xyl N N Bn O N H N OMe Cl ArN N O tBu N N F Xyl H H NH OH tBu O MeO N H O 29la 29mb,c,d 29nc,d,e From atazanavir (HIV treatment) From flurazepam (hypnotic) From harmol (antineoplastic) 80% 92% 70%

N N H O N H Me2N O O HN N N O H H N ArN S S O N N O N N N O H N H H2N

29oa,c,d 29pf 29qc,f From sulfenazole and strychnine From zolpidem (hypnotic) and From diazoxide (vasodilator) 67% clozapine (neuroleptic) 91% 76%

Me OH OH N H HO OH Ar N N H H HO Ar = O O Me ArN 29re 29sc,e From oestradiol (HRT) From arbutin (from bearberry) 97% 88%

a X = Br. b X = I. c 48 h. d 50 °C. e X = OTf. f X = Cl.

Scheme 25: Selected examples of ortho-arylation catalysed by cyclometallated Ru catalyst 37a(64)

33 Larrosa and co-workers recently investigated the mechanism of ruthenium catalysed ortho-C–H arylation (Scheme 24), and found it to differ from the general mechanism which had been proposed for the past couple of decades.(64) Their investigations revealed that following the formation of cyclometallated complex 37 a second C–H activation takes place, to form bis-cyclometallated complex 38. This then undergoes an oxidative addition step with an aryl (pseudo)halide to afford Ru(IV) species 39. Subsequent reductive elimination forms the biaryl product 29, and crucially, the active catalyst 37. This is contrary to the previously proposed mechanism, which involved 37 undergoing oxidative addition with the aryl (pseudo)halide, followed by reductive elimination to form the product and regenerate an non-cyclometallated Ru(II) species.(63) These findings allowed the development of superior ‘on-cycle’ catalysts of the type 37 which allowed ortho-arylation to take place with high efficiency, equimolar aryl (pseudo)halide, and at remarkably low temperatures. The substrate scope demonstrated the late-stage functionalisation of a wide range of pharmaceuticals containing aryl (pseudo)halides or sp2-nitrogen directing groups (Scheme 25), and is tolerant of a wide range of functionalities such as alcohols and competing heteroatoms.

1.1.3. meta-Functionalisation

1.1.3.1. Approaches to meta-functionalisation

Whilst metal directed ortho-C–H functionalisation is now widely reported for a variety of transition metals, substrates and functional groups, meta-C–H functionalisation remains more of a challenge due to its more distant position from the directing group. In recent years however, some inventive ways of overcoming this obstacle have been reported by a number of groups.

One approach to this is to make use of intrinsic steric and electronic interactions between the substrate and catalyst, causing functionalisation to take place at the least hindered position, meta to other substituents (Scheme 26 a). This approach has been

34 a) Steric control (Iridium, Rhodium)(65–67) b) Oxy-cupration(68–70)

R R via R η5 ( -C9H7)Ir(COD) (cat.) R1 R2 Cu(OTf)2 1 2 R R PR3 ligand Y O Ar2IX Y O Y O

HBPin Y = C, N H BPin R = N(OMe)Me, OTf Ar III CMe3 H Cu 42 43 44 45 46 Ar c) Removable templates(71–75)

template template template R R Pd(II) R R N N N R2 H Pd R2 H R2 47 48 49 50 d) Transient mediator (norbornene)(76,77) e) Traceless directing group(78–82)

DG DG DG R R R

Pd(II) RX CO2H Pd(II) CO2H -CO2

ArX H Ar Ar H Pd R H 51 52 53 54 55 56 f) Non-covalent interactions(83–87) R n = 0,1,2,3 Cy H bonding N n N H X = PR , BPin O O X 2 C(OEt), ion pair N H H C(NR2) O O PinB BPin S Ir R O N N N N 57 Ir PinB BPin BPin PinB

Scheme 26: Approaches towards selective meta-C–H functionalisation

35 pioneered by the groups of Milton R. Smith, Hartwig, Miyaura and Ishigama for meta- borylation.(65–67)

A diﬀerent approach taken by Gaunt is that of meta-C–H bond cupration, directed by an amide group, resulting in meta-arylation (Scheme 26 b).(68,69) The mechanism is proposed by Gaunt to proceed via a dearomatising anti-‘oxy-cupration’ (promoted by the highly electrophilic Cu(III) species) to give 46, which then is rearomatised, followed by reductive elimination at the meta-position to give 45. The authors do however note that this mechanism is tentatively proposed, as within a very narrow temperature band (higher than with copper catalysis), the reaction can proceed with the same meta-selectivity in the absence of copper, albeit in reduced yield. Since these reports, Li, Wu and co-workers have carried out DFT calculations, and suggest that instead the mechanism involves a Cu(III) metallacycle, and that meta-arylation is achieved via a Heck-like 4-membered-ring transition state where the aryl group is transferred to the meta-position.(70) They also report that the reaction proceeds much more slowly in the absence of copper, with high purity reagents.

The use of removable nitrile templates with Pd(II) catalysis was pioneered by Jin- Quan Yu (Scheme 26 c).(71) The nitrile templates undergo weak, end-on binding with the Pd(II) catalyst, to form a cyclophane-like pre-transition state. Metallation at the ortho-position would result in high ring strain due to the linear nitrile, so the meta-position is favoured. The templates feature removable linkers. Since the original report, the substrate scope (R in 47) has been expanded using a variety of template linkers, and examples of acetoxylation and arylation have also been reported.(72–75)

Yu and Dong separately reported the use of norbornene as a transient mediator for meta-alkenylation (Scheme 26 d).(76,77) The norbornene shuttles the palladium to the meta-position following initial ortho-functionalisation. Following meta- functionalisation, the nornbornene can be regenerated by β-carbon elimination and ortho-protonation.

36 Another approach is the use of traceless directing groups, such as carboxylic acids (Scheme 26 e), which can direct functionalisation to their ortho-position, then be removed to result in overall meta-substitution relative to R (54).(78–82) Satoh and Miura reported the overall meta-oleﬁnation of arenes using this approach.(79) Work in this area by Larrosa enables the formal meta-arylation of various arenes with in situ (81) removal of the −CO2H group, and was later extended to one-pot meta-arylation (82) of phenols, with in situ installation and removal of the −CO2H directing group.

The use of interactions between the ligand of the catalyst and the substrate has been demonstrated for meta-borylation.(83–87) Non-covalent interactions have been explored by the groups of Phipps and Kanai (Scheme 26 f). Phipps reported the use of an anionic ligand with iridium catalysis, which can ion pair with a cationic substrate to direct borylation to the meta-position.(85,87) This anionic ligand has also been shown to be capable of H-bonding interactions with amides on the substrate.(86) Kanai reported the use of a urea on the ligand to undergo H-bonding interactions with amide, ester, phosphonate and phosphine oxide groups on the substrate, which directed functionalisation to the meta-position.(83)

Whilst these methods for forming meta-C–H bonds are innovative, there is much work yet to be done. The directing group scope remains limited, often large quantities of ligands or other additives are required, and the synthesis of templates can add several steps and puriﬁcations to a procedure. Most of these approaches rely on expensive palladium or iridium catalysis. It is expected that in time, the development of procedures using cheaper metal catalysts will take place, and that the currently limited scope of these transformations will be greatly expanded.

1.1.3.2. Ruthenium catalysed meta-functionalisation

Ruthenium catalysis has been used to eﬀect meta-C–H functionalisation by σ-activation.

This activation results in a strong directing eﬀect para to the Ru–CAryl σ bond, which

37 can be used to achieve functionalisation which is overall meta to the directing group (Scheme 27).

N N RX RuLn Ru–C σ-bond H R C–H bond para to overall meta ruthenium activated substitution

Scheme 27: Ruthenium-catalysed σ-activation and meta-functionalisation

The ﬁrst example of this approach was reported by the Frost group in 2011.(88) Using Ru(II) catalysis, 2-phenylpyridines could be sulfonated using aryl sulfonyl chlorides (Scheme 28). Interestingly, when the phenylpyridine substrate was blocked in one of the meta-positions with a methyl group, none of the product 58e was obtained. This supports the proposed σ-activation pathway, as if the cyclometallation occurs on the less hindered ortho-C–H bond, then the Ru–C bond would be formed para to the blocking group, preventing further reaction. This reaction has similar conditions to the dual ortho/meta functionalisation paper by Li (Scheme 7, p18), however it allows

R1 ArSO2Cl (3.0 eq.), K2CO3 (2.0 eq.) R1 N N [RuCl2(p-cymene)]2 (5 mol%)

MeCN, 115 °C, 15 h R2 R2

SO2Ar 1 58

Selected examples:

N N N N N

O O O O O S S S S S O O O O O Br CF 58a 58b 58c 58d 3 58e 70% 63% 74% 50% 0%

Scheme 28: Ruthenium-catalysed meta-sulfonation(88)

38 the selective sulfonation.(33)

Since then, meta-selective C–H bond alkylation with secondary alkyl halides has been reported by the Ackermann group (Scheme 29).(89) In situ generation of the ruthenium biscarboxylate catalyst previously reported for ortho-functionalisations such as arylation (Scheme 23, p31) allowed selective meta-alkylation (Scheme 29).(2,25,30,62) The reaction was tolerant of electron donating and withdrawing groups on the substrate. In addition to pyridine directing groups, pyrazole, imidazole and benzimidazole were effective. Use of pyrimidine resulted in a modest yield with significant di-meta- alkylation. The reaction could also be carried out neat, or in water. Interestingly, unlike in Frost’s meta-sulfonation report, where meta-methyl-substitution resulted in 0% yield (Scheme 28, 58e), Ackermann reported that meta-substitution was tolerated, although with reduced yields. Compound 60e was formed in 40% yield, and the reaction also worked in modest to low yields with nPrO- and fluorine substituents in the meta-position. What is particularly intriguing about this report is that Ackermann and co-workers had previously reported the use of ruthenium(II) carboxylate catalysts with primary alkyl halides for ortho-alkylation.(90,91) The switch in regioselectivity is proposed to be a result of the steric bulk and lower electrophilicity of secondary alkyl halides making oxidative addition less favourable. The proposed mechanism involves initial reversible C–H ruthenation to form 35 followed by a SEAr-type alkylation at the position para to the metal. Protodemetallation affords the product 60 and regenerates the catalyst.

Frost and Ackermann have independently reported the use of ruthenium catalysis for meta-alkylation with tertiary alkyl halides, to construct quaternary carbon centres (Scheme 30).(92,93) In Frost’s paper, 2-phenylpyridine substrates can be alkylated in the meta position using tertiary alkyl bromides and KOAc as base, with

[RuCl2(p-cymene)]2 as the catalyst. Tertiary alkyl chlorides could instead be used, by replacing some of the KOAc with K2CO3. Tertiary α-bromo esters could also be coupled. Unlike the meta-sulfonation, a radical-type mechanism is proposed. The

39 R1 [RuCl2(p-cymene)]2 (2.5–5.0 mol%) R1 N N Br R3 MesCO2H (30 mol%)

4 R K2CO3 (2.0 eq.), 1,4-dioxane 2 R2 R 100 °C, 20 h R3

1 59 60 R4 (3.0 eq.)

Selected examples:

N N N N N N N

nBu nBu nBu nPr nPr MeO MeO

OMe Me F Me MeO2C Me Me Me 60a 60b 60c 60d 60e 60f 70% 62% 63% 76% 40% 50%

Proposed mechanism: R3 R4 Me iPr N K2CO3 N Ru O 60 MesCO H 2 O Mes 33 1 KO2CR, KHCO3

Me iPr Me iPr

Ru O2CMes Ru O2CMes MesCO2 R3 N Ph N R4 61 Me iPr 34 KHCO3, KBr K CO Ru O2CMes 2 3 Br R3 SEAr N C–H ruthenation H KO CR, KHCO R4 2 3 K CO 2 3 35

Scheme 29: Ruthenium-catalysed meta-alkylation(89)

steric eﬀects of tertiary alkyl bromides rule out an SN2 type mechanism, and the fact that α-bromo esters can be used suggests an SN1 pathway is disfavoured (as formation of a carbocation alpha to an ester would be strongly disfavoured). Ackermann’s

40 Frost:

[RuCl2(p-cymene)]2 (5 mol%) N X R2 1,4-dioxane 120 °C, 15 h N 3 4 R R If X = Cl : KOAc (50 mol%), K2CO3 (1.5 eq.) 1 R1 R2 R or if X = Br : KOAc (2.0 eq.) R3

1 62 63 R4 (3.0 eq.)

Ackermann: DG DG [RuCl2(p-cymene)]2 (2.5–5 mol%) 2 Br R Piv-Val-OH (30 mol%), K2CO3 (2.0 eq.) 1 2 3 R R 3 1 R R R R4 1,4-dioxane, 100–120 °C, 16–20 h R4 1 62 DG = 2-aminopyrimidine, 2-pyridine, 63 (3.0 eq.) 2-pyrimidine, N-pyrazole

Proposed mechanism: 2 3 R X R2 R N R3 R4 N R4

1 62 63 Ru(II)

Ru(II) cat. single electron transfer (SET) −HX proto-demetallation cyclometallation Base

Ru(III)X R2 R3 H H R3 2 4 N R 4 R N R radical addition RuLn RuLn 37 64

Scheme 30: Ruthenium-catalysed meta-tert-alkylation(92,93)

report uses ruthenium(II) catalysis with a mono protected amino acid (MPAA) ligand (Piv-Val-OH) for the meta-tert-alkylation of N -(pyrimidine-2-yl)-anilines, as well as 2-arylpyridines, 2-arylpyrimidines and N -phenylpyrazoles. The pre-prepared catalyst [RuCl(Piv-Val-O)(p-cymene)] was also tested for the reaction and found to have similar eﬃcacy. Notably, the N -(pyrimidine-2-yl)-anilines represent a class of compounds with removable directing groups. Ackermann also proposes a radical mechanism, with

41 a separate ruthenium(II) complex to the ruthenacycle undergoing single electron transfer to form a tertiary alkyl radical. Experiments suggested that the C–H ruthenation step was reversible, but that meta-C–H cleavage was not.

The scope of directing groups for meta-sec/tert-alkylation has since been increased to include 2-hydroxypyridines, which can then be deprotected resulting in overall meta- alkylation of phenols.(94)

[RuCl2(p-cymene)]2 (5 mol%) RuCl3 (20 mol%) i C3F7I (2.0 eq.) N Ferrocene (10 mol%) Y N Na2CO3 (2.0 eq.) DTBP (4.0 eq.) N Y H Y H 4-ClPhCHO (0.5 eq.) R1 BNDHP (10 mol%.) H 1 2 Ar 2 1 R R CH2Ar/H2O (9:1) R CH2Ar (25 eq.) R 140 °C, 48 h R2 130 °C, 24 h 1 65 1 R2 = H, Me R2 = H 26 examples 29 examples 35–77% 33–79%

Scheme 31: Ruthenium-catalysed meta-benzylation(95,96)

meta-Benzylation has been reported separately by the groups of Bing-Feng Shi and Da-Qing Shi/Yingsheng Zhao, using toluene derivatives as the benzyl source (Scheme 31).(95,96) Shi/Zhao used ferrocene to facilitate the formation of benzyl radicals, and DTBP as oxidant, whereas in Bing-Feng Shi’s paper heptaﬂuoroisopropyl iodide was used as a mild oxidant and radical initiator. The benzyl radicals could then attack the ruthenacycle in a manner analogous to that proposed for meta-alkylation (Scheme 30). Shi/Zhao suggest that the ruthenacycle undergoing radical attack actually has two phenylpyridine rings (similar to 67, see Scheme 32). They also interestingly observe that by switching the catalyst to [RuCl2(PPh3)3], without the BNDHP ligand, selectivity for ortho-benzylation is observed. The bulky ligand 1,10-binaphthyl- 2,20-diylhydrogen phosphate (BNDHP) is proposed to have a large eﬀect on this selectivity due to sterics. Both groups reported that their reactions were successful with 2-pyridine, 2-pyrimidine and N -pyrazole directing groups.

(97) Zhang and co-workers have reported meta-nitration using Ru3(CO)12 (Scheme 32).

42 The directing group scope includes pyridines, pyrimidines, pyrazoles, quinoxaline and benzimidazoles. The complex 67 is proposed as the active catalyst in the transformation, which could be formed from Ru3(CO)12 and 2-phenylpyridine by heating to 95 ◦C in DCE for 36 hours, and was shown to give similar yields of meta- substituted product to Ru3(CO)12 both when used stoichiometrically and catalytically.

The silver triﬂuoroacetate mediates generation of the NO2 radical by a radical process, which then undergoes electrophilic attack of the carbon which is para to the Ru–C

R1 Ru3(CO)12 (10 mol%), oxone (1.5 eq.) R1 N AgTFA (1.5 eq.), TBA-OAc (0.5 eq.) N Cu(NO3)2•3H2O DCE 95 °C, 36 h R2 R2

NO2 1 66

Proposed mechanism: 66

1 CO CO N N Ru3(CO)12 N N Ru Ru CO CO

2CO, H2O O2N 69 NO2 67

CF3CO2H Cu(I) NO2 N2O4 [O]

Cu(II) CO N N Cu(CF CO )NO Ru 3 2 3 CO

O2N H 68 NO2 H oxone CF3CO2Ag AgNO3 AgNO2 [Ag(II)NO2] [O] H Cu(NO3)2 NO2

Scheme 32: Ruthenium-catalysed meta-nitration(97)

43 bond. Cu(CF3CO2)NO3 is proposed to aid deprotonation of 68 to aﬀord complex 69, and subsequent protodemetallation and ligand exchange with another phenylpyridine molecule aﬀords the product 66 and regenerates the active catalyst. The group have more recently reported meta-nitration with oxime directing groups, and AgNO3 as a (98) source of NO2 radical.

A few reports also exist of the use of BrCF2CO2Et (or its corresponding amides) for the meta-difluoromethylation of substrates bearing directing groups such as 2-pyridine, N -pyrazole, oxazoline, 2-pyrimidine and purine using ruthenium catalysis.(99–101) The use of triarylphosphine additives (whether free, or as Pd(PPh3)4) was found to be key to these transformations by the groups of Ackermann and Wang.(99,100) In contrast, a report by Zhao and co-workers achieves these transformations without phosphine, (101) but with catalytic AgNTf2 additive. Analogous monofluoromethylations were also achieved, as well as a few examples of non-fluoromethylation, which, despite the primary alkyl starting materials, were selective for the meta-position.

1.1.3.3. meta-Halogenation

Whilst examples of metal catalysed C–H ortho-halogenation in the literature generally use metals such as Pd, Cu, Rh (vide supra), examples of the use of ruthenium with this regioselectivity in halogenations are scarce. However, there are several examples of the use of ruthenium for C–H meta-halogenation, in fact, they make up the majority of this ﬁeld.

The seminal example of C–H meta-halogenation was a bromination reaction reported by Greaney and co-workers in 2015 (Scheme 33).(102) Tetrabutylammonium tribromide (TBATB) acted as the bromine source, with [RuCl2(p-cymene)]2 as the catalyst. Electron withdrawing and donating substituents were tolerated in the para- position of 2-arylpyridines to aﬀord the products in moderate to excellent yields. The reaction could be combined with one-pot Suzuki Miyaura or Heck couplings to provide

44 meta-arylated or alkenylated products with pleasing eﬃciency.

[RuCl2(p-cymene)]2 (5 mol%) K2CO3 (2.0 eq.) R1 MesCO2H (30 mol%) R1 N TBATB (3.0 eq.) N

1,4-dioxane, 110 °C, 20 h R2 R2 Br 1 70

Scheme 33: Ruthenium-catalysed meta-bromination using TBATB(102)

Shortly afterwards, Huang et al. reported that NBS could also be eﬀective as a brominating agent, with the use of the same [RuCl2(p-cymene)]2 catalyst in DMA (Scheme 34).(103) This paper reported a slightly broader substrate scope for 2-arylpyridines than the previous report, and again, electron withdrawing/donating substituents were tolerated in the para-position. Some examples of ortho-substitution (with F, Cl or Me) were tolerated (albeit in a low yield for Cl), which were not tolerated under the reaction conditions reported by Greaney.(102) Pyrimidine was also shown to work eﬀectively as a directing group in moderate to excellent yields, as well as 4- halopyrazoles in low yields. The authors report that under their conditions, the use of NCS and NIS failed to result in chlorination or iodination. The utility of meta- bromination methodology was also elegantly demonstrated in a 4 step synthesis of anti-cancer drug Vismodegib from commercially available 2-phenylpyridine, in overall 47% yield.

R1 [RuCl2(p-cymene)]2 (5 mol%) R1 N NBS (2.0 eq.) N

DMA, 80 °C, 24 h R2 R2 Br 1 70

Scheme 34: Ruthenium-catalysed meta-bromination using N -bromosuccinimide(103)

Ackermann reported the ﬁrst example of heterogeneous catalysis for meta-C–H halo- (104) genations in 2017. Ru@SiO2 could be used to catalyse the meta-bromination of

45 purine derivatives, as well as 2-arylpyridine and 2-arylpyrimidines. N -Bromosuccinimide was used as the brominating agent. Importantly, the heterogeneous, silica-supported catalyst could be recovered and reused eﬀectively over multiple runs. Other transition metals were screened for this reaction but failed to aﬀord the meta-substituted products, highlighting the unique reactivity of ruthenium.

The ﬁrst example of meta-C–H chlorination was reported by Yu in 2016, on anilines and phenols (Scheme 35).(105) This was achieved using norbornene (NBE) derivative methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate (NBE-CO2Me), as a transient mediator (Scheme 35), in the same approach as described earlier (Scheme 26, p35).

Pd(PhCN)2Cl2 (10 mol%) Me Ligand 72 (10 mol%) Me Ligand 72 = F PhCN (20 mol%) Boc OMe i Boc OMe F R N 2,6-di Pr-C6H3OSO2Cl (2.0 eq.) N O N N Cl Me NBE-CO2Me (1.5 eq.) Me N F R1 R1 H Ag2CO3 (2.0 eq.) F toluene/cyclohexane Cl N OH 100 °C, 14 h R = CF or CN 71 73 3

Scheme 35: Palladium catalysed meta-C–H-chlorination of anilines(105)

In the first example of meta-C–H iodination, and the first example of meta-chlorination on phenylpyridines, Maheswaran and co-workers reported N -halosuccinimides to (106) be effective as halogenating agents in 2018 (Scheme 36). With [Ru(C5H5)(CO)2]2,

PhI(OTf)2 and NXS, 2-phenylpyridines and N -phenylpyrazoles can be chlorinated, brominated or iodinated selectively in the meta-position. The reaction is not air sen- sitive, and the reaction time is only 5 hours. Whilst Huang’s paper reported the use of NCS and NIS to be ineﬀective under their conditions,(103) Maheswaran’s conditions require the use of catalytic PhI(OTf)2 oxidant. They note that their reaction gave product in trace quantities with [RuCl2(p-cymene)]2 catalyst, both with and without oxidant.

The use of ruthenium catalysis for meta-functionalisation is still very much in its

46 [Ru(C5H5)(CO)2]2 (2.5 mol%) 1 1 R PhI(OTf)2 (20 mol%) R N NXS (1.5 eq.) N X = Br 70 X = Cl 74 toluene, 110 °C, 5 h X = I 75 R2 R2 X 1

Selected examples:

N N N N N N

X Br Br O I X F O OH X = Br 70a 85% 70b 70c 75b X = Br 70d 96% X = Cl 74a 72% 68% 82% 83% X = Cl 74b 94% X = I 75a 76% X = I 75c 90%

Scheme 36: Ruthenium catalysed meta-C–H halogenation using NXS(106) early days. There is vast potential for the development of this ﬁeld, by expanding the functional groups which can be incorporated, as well as the directing group scope and generality of conditions in order to provide a greener, more sustainable alternative to other meta-C–H functionalisation methodologies.

47 1.2. Investigations into meta-functionalisation

1.2.1. Aims and objectives

Given the scarcity of methodologies for installation of different functional groups in the meta-position using directed ruthenium catalysis, there was a desire to investigate this area further. Several existing reports of ruthenium catalysed meta-functionalisation suggest a mechanism involving radical attack (see Section 1.1.3.2).(92–101) Therefore it was envisaged that by generating different types of radicals under the reaction conditions, novel functional groups might be introduced to the meta-position (Scheme 37). With this in mind, different radical precursors were investigated, as well as different approaches to radical generation.

via N Ru(II) catalysis N N II Ru Ln R–X (radical source)

R H R

Scheme 37: General scheme for the meta-functionalisation of phenylpyridine via a radical mechanism

1.2.2. Results and discussion

1.2.2.1. Photoredox generation of radicals

One well established and mild method for the generation of radicals species is the use of photoredox chemistry.(107) Photoredox catalysis involves the use of a photoredox catalyst such as an organic dye, which, when irradiated with visible light accesses a photoexcited state (Scheme 38). This excited state then undergoes a quenching cycle, which can involve transfer of an electron either to or from the substrate, activating it towards a range of reactions which might otherwise not be feasible under such mild

48 n-1 PRC Reductive quenchers: Xanthate Reductive Quenching Ascorbate - - e Cycle e Tertiary amines Tertiary amides Visible light Oxalate PRCn PRCn* MLCT Oxidative quenchers: Viologens Oxidative Quenching Persulfate e- Cycle e- Iron(III) Nitroaryls PRCn+1

Scheme 38: General photoredox catalysis cycle. PRC = photoredox catalyst. conditions (Scheme 38).(107,108) Using photoredox catalysts and light, a plethora of radical species can be generated, meaning huge potential for expansion of the meta- functionalisation scope.

For the combination of photoredox radical generation with ruthenium catalysed meta-C–H functionalisation, a general mechanism resembling that in Scheme 39 is proposed. Excitation of the photoredox catalyst would result in generation of radical species R•, which could attack ruthenacycle 37 in the meta-position affording aryl radical 76. This could reductively quench the photoredox catalyst and generate cation 77. Deprotonation and protodemetallation would afford the product. Two radical sources chosen initially for screening were bromoacetonitrile (79, Table 1) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H )-one 80(109) (Table 1, also known as Togni reagent II). The use of alkyl bromides such as bromoacetonitrile with photoredox catalysis is well established,(110–112) and would allow the installation of a nitrile moiety, which can easily be transformed into a number of different functionalities. Use of (109) 80 could enable the installation of a CF3 group, an extremely valuable functional group in medicinal chemistry.(113) The use of 80 with photoredox catalysis for the (114–116) generation of CF3 radicals has been previously reported.

With this in mind, conditions were screened for the potential meta-functionalisation of 2-phenylpyridine with 79 and 80 as radical sources (Table 1). The commonly used

49 N

H N H R B II Ru Ln BH protodemetallation C–H ruthenation N N II II Ru Ln Ru Ln

RX PRCn* R light H 78 MLCT 37 R

n n+1 H PRC PRC

N N II II Ru Ln Ru Ln

H SET H R R 77 76

Scheme 39: Proposed mechanism for the proposed meta-functionalisation of 2-phenylpyridine with photoredox catalysis

[RuCl2(p-cymene)]2 was chosen as the meta-functionalisation catalyst, in degassed 1,4-dioxane, under visible light at 100 ◦C. Several photoredox catalysts were tested, with either K2CO3 or KOAc as base. With bromoacetonitrile as the radical source, and K2CO3 as base, no reaction took place with any of the three catalysts (Entries 1– 3), and clean starting material was recovered. When the Togni II reagent (80) was used with K2CO3 base, none of the desired meta-triﬂuoromethylated product was observed with either Ir(ppy)3, Ru(bpy)3PF6, or Cu(dap)2Cl catalysis (Entries 4–6). However, recovered starting material was observed as well as signiﬁcant quantities of 83 (Table 1), which is the result of reaction of the Togni reagent with the 1,4-dioxane used as solvent. This was isolated from the reaction using Ru(bpy)3PF6 in 34% yield (Entry 5). When KOAc was employed as the base, with 80 as radical source, none

50 1 of the desired meta-CF3 product was observed in the crude H NMR for any of the photoredox catalysts used (Entries 7–10).

radical source photoredox catalyst (1 mol%) O 79: NC Br (4.0 eq.) [RuCl2(p-cymene)]2 (5 mol%) O N base (2.0 eq.) N CF3 O O 1,4-dioxane, 100 °C I visible light, 16 h 80: O (1.0 eq.) I R O 26 81 (R = CH CN) 2 83 82 (R = CF3)

Table 1: Screening of conditions for the photoredox catalysed meta-functionalisation of 2-phenylpyridine

Entry Radical source Base Catalyst Result

1 79 K2CO3 Ir(ppy)3 NR

2 79 K2CO3 Ru(bpy)3PF6 NR

3 79 K2CO3 Cu(dap)2Cl NR

4 80 K2CO3 Ir(ppy)3 SM + 83 a 5 80 K2CO3 Ru(bpy)3PF6 SM + 83 (34%)

6 80 K2CO3 Cu(dap)2Cl SM + 83

7 80 KOAc Ir(ppy)3 None of desired product observed

8 80 KOAc Ru(bpy)3PF6 None of desired product observed 9b 80 KOAc Fluorescein None of desired product observed 10b 80 KOAc Eosin Y None of desired product observed a Isolated yield. b See Figure 1 for structure of catalyst.

Fluorescein Eosin Y O CO O 2 Br Br

HO O OH O O O Br Br

Figure 1: Structures of Fluorescein and Eosin Y

Bromoacetonitrile has been shown to generate alkyl radicals with Ir(ppy)3 with visible light,(110) so it was surprising to ﬁnd that no reaction at all had taken place under the conditions in Table 1 Entry 1. In order to investigate whether this was due

51 to the conditions being unsuitable for initial formation of the necessary ruthenacycle, or alternatively, radical generation/attack at the meta-position being the unfavourable step of the reaction, pre-synthesised ruthenacycle 84 was used as the starting material (Table 2).

The ruthenacycle 84 has been shown to participate in several ruthenium catalysed C–H functionalisation reactions.(88,99,117,118) Interestingly, Stephenson and Flowers have reported the in situ deactivation of Ir(ppy)3 catalyst when used with BrCH2CO2Et as a radical source. The catalyst was functionalised by radicals generated in the reaction, in positions including the meta-position of the phenylpyridine ligands on the iridium.(119) This took place even at a low temperature of 5 ◦C. It was considered that this might similarly allow functionalisation of the ruthenacycle with the alkyl radical species in the meta-position, perhaps without the need for heat.

BrCH2CN Ir(ppy)3 (x mol%) N base (2.0 eq.) N Ru solvent, rt, visible light, 16 h Cl CN

84 81

Table 2: Screening of meta-functionalisation conditions, using ruthenacycle 84

Entry Eq. BrCH2CN x Base Solvent Result

1 4.0 0 K2CO3 1,4-Dioxane NR

2 4.0 1.0 K2CO3 1,4-Dioxane NR

3 4.0 0 K2CO3 MeCN NR

4 4.0 1.0 K2CO3 MeCN NR

5 3.0 1.0 K2CO3 DCM NR 6 3.0 1.0 NaOAc (3.0 eq.) DCM 81 not observed

The reactions were carried out using Ir(ppy)3 as photoredox catalyst, under visible light, at room temperature (Table 2). In 1,4-dioxane, clean starting ruthenacycle was recovered, both with the catalyst and in the control without (Entries 1 & 2).

52 This was likewise for MeCN (Entries 3 & 4), a commonly used solvent in photoredox catalysis.(107) Using DCM (which was found by Stephenson and Flowers to be the optimal solvent for functionalisation of the iridium catalyst) no reaction took place with K2CO3 base (Entry 5). Using the same base as the Stephenson/Flowers paper (NaOAc), some reaction did take place, however, all the protons on the phenylpyridine ring were intact by 1H NMR, so it did not involve meta-functionalisation to form 81 as hoped. There was no peak visible for any CH2 protons, so the alkyl radical had not been incorporated. It is possible that ligand exchange (e.g. Cl to Br) had occurred on the ruthenium.

The radical source used by Stephenson, Flowers and co-workers (ethyl bromoacetate) was used with the ruthenacycle 84 to see if this would be more eﬀective for meta- functionalisation (Table 3). Ir(dF-ppy)3 (an iridium catalyst with ﬂuorine substitution in the ortho and para positions of the phenylpyridine ligands) was used, as this might reduce deactivation of the catalyst by blocking positions from functionalisation. With blue LEDs, the desired product was not observed (Entry 1). Using stoichiometric quantities of the same catalyst, and visible light, 85 was not observed, with starting material recovered (Entry 2). Ru(bpy)3PF6 was also tested as a catalyst, with the use

O Br (3.0 eq.) EtO photoredox catalyst (x mol%) N NaOAc (3.0 eq.) N Ru Cl p-MeO-C6H4NPh2 (y eq.) DCM, rt, light, 16 h CO2Et 84 85

Table 3: Screening of meta-functionalisation conditions, using ruthenacycle 84, and ethylbromoacetate

Entry Photocatalyst x Light y Result

1 Ir(dF-ppy)3 1 Blue LED 0 85 not observed

2 Ir(dF-ppy)3 100 Visible 0 NR

3 Ru(bpy)3PF6 1 Visible 1.0 NR

53 of 4-methoxy-N,N -diphenylaniline as an additive which could act as an external reductive quencher. However, 1H NMR of the crude reaction mixture after 16 hours showed pure starting material 84 (Entry 3).

During the investigations with photoredox catalysis, it was observed that the reactions which were heated turned dark very quickly. It is likely that this reduced the efficiency of irradiation, and may be one reason why the reactions were unsuccessful. However, the room temperature reactions with stoichiometric ruthenacycle were also unsuccessful. Ir(ppy)3 is known to generate radicals with bromoacetonitrile, so the problem is not that of redox potentials.(110) The possibility that the radicals generated may not be reactive enough to react with the ruthenacycle was also considered. A variety of radical species of differing reactivities have been reported to undergo meta-functionalisation in this manner, including electrophilic (e.g. bromine) and nucleophilic (e.g. tertiary alkyl, benzyl) examples.(120) Therefore, perhaps a more likely explanation is that the electron transfer step between the ruthenium and photocatalyst is inefficient, preventing the photoredox catalytic cycle from being completed (Scheme 39, p50). Given this, it was decided to explore other approaches to radical generation.

1.2.2.2. Ruthenium catalysed radical generation

Kharasch and co-workers reported in 1945 the use of halocarbons such as CCl4 and

CHCl3 as radical sources, which could add across oleﬁns by a radical chain process initiated by an organic peroxide (Scheme 40).(121,122) This kind of reaction is known as atom transfer radical addition (ATRA). Since then, the use of Ru(II) catalysts such as RuCl2(PPh3)3 has been reported to improve the yield of this type of reaction by reducing formation of side-products.(123) This proceeds via a Ru(II)/Ru(III) mechanism

R(COO)2 initiator Cl CCl3 R CCl4 R

Scheme 40: Example of Kharasch’s ATRA reaction using carbon tetrachloride

54 (Scheme 41), where Ru(II) initially abstracts a chloro atom to give a Ru(III)–Cl complex, and an R• radical species. Addition of R• to the alkene generates an alkyl radical, and the alkyl radical then abstracts the chloro atom from the Ru(III)–Cl species, aﬀording the product and regenerating the Ru(II) catalyst. The chain can also termi- nate by combination of two R• radicals to give the side product R–R.(123,124)

R X R II III III II 1) [LnRu ] + RX [LnRu –X] + R 3) [LnRu –X] [LnRu ] + R1 R1 R 2) R + 4) R + R RR R1 R1

Scheme 41: Ruthenium catalysed ATRA reaction mechanism

This was very interesting, as ruthenium catalysis is already being utilised for the meta-C–H functionalisation reactions. The ruthenium catalyst has been proposed to generate alkyl radical species in several meta-functionalisation papers.(92–94,101) It was suggested that instead of using a separate catalyst (as was used in the photoredox examples tried previously) for the generation of radical species, the Ru(II) C–H functionalisation catalyst could also be used for the generation of radical species from the kinds of haloalkanes known to work well in ATRA reactions. It is possible that the Ru(II) catalyst could catalyse this reaction (analogous to, for example, Ackermann’s tert-alkylation(93)), or it could be catalysed by the Ru(II) ruthenacycle itself. Given that formation of the ruthenacycle can take place readily at room temperature, the latter is perhaps more likely.

Investigations were begun using CCl4 as a radical source. Under the same conditions as used previously by the group for the meta-bromination of 2-phenylpyridine,(102) the chloroalkene substituted product 86 was isolated in 20% yield (Scheme 42). The acci- dental addition of nonaflyl fluoride (another possible radical source, originally intended for separate investigation) to this reaction mixture proved to be fortunate, as in its absence only trace quantities of 86 were observed in the crude after work-up, and the majority of recovered material was starting material. No products from nonaflyl

55 [RuCl2(p-cymene)]2 (5 mol%) K2CO3 (2.0 eq.) N N MesCO2H (30 mol%) nonaflyl fluoride (2.0 eq.) Cl CCl4 (2.0 eq.) 1,4-dioxane, 110 °C, 18 h Cl Cl 26 86 20%

Scheme 42: Use of CCl4 for meta-functionalisation of 2-phenylpyridine substitution were observed. The product 86 is the result of a chain reaction, either before or after meta-substitution, and the –CCl3 substituted product was not observed.

In the absence of nonaflyl fluoride, CCl3Br gave only trace quantities of 86, and with nonaflyl fluoride, the reaction gave a mixture of products, but the ratio of 86 to side products and starting material did not appear to have increased.

CCl4 has been used for the installation of carboxylic acids resulting from hydrolysis of (125) the –CCl3 moiety. None of the reactions using CCl4 had resulted in the observation of any meta-carboxylated product, however there was concern that this may have been lost in the aqueous work-up. This may also account for the poor recovery of material.

It was thought that if hydrolysis of the –CCl3 was taking place to form carboxylic acid, the addition of dry methanol to the reaction mixture might instead result in the formation of meta-methyl ester 87a, as the use of CCl4 with alcohols has been reported for the carboxylation of benzofurans with iron catalysis.(126) It was considered that hydrolysis of any meta-CCl3 product might be taking place with adventitious water in the reaction mixture, or during the aqueous work-up.

Addition of an excess of methanol to the reaction mixture at the start of the reaction (Table 4, Entry 1) did not result in 87a being observed, nor did addition of methanol prior to work-up (Entry 2). Both reactions resulted in recovery of starting material as the major product, with some dimerised phenylpyridine, and some of the product 86 being observed. It was subsequently found by Helen L. Barlow that by using CBr4, and a much larger excess of MeOH as a co-solvent, 87a could be obtained. Optimisation

56 [RuCl2(p-cymene)]2 (5 mol%) N N K2CO3 (2.0 eq.) MesCO2H (30 mol%)

CCl4 (2.0 eq.), MeOH (20 eq.) OMe 1,4-dioxane, 110 °C, 16 h O 26 87a

Table 4: Use of CCl4 with added MeOH.

Entry Addition of MeOH Result 1 At start of reaction 87a not observed 2 After 16 hours (then heated to 110 ◦C for 20 min) 87a not observed

of the reaction found that use of RuCl3 · xH2O catalyst could aﬀord a 59% isolated yield of 87a (Scheme 43).(127) The scope was extended to the use of purines, isoquinoline, and pyrimidine as directing groups, and the eﬀect of substitution on the aryl ring was also investigated. 15 examples were reported, with moderate to good yields.

RuCl3•xH2O (10 mol%) N CBr (3.0 eq.) N Y 4 Y H MeOH/1,4-dioxane (1:1) R1 85 °C, 16 h R1 OMe

1 87 O 1.0 eq. 15 examples 40–63% yields

Scheme 43: Ruthenium catalysed meta-carboxylation reported by the Greaney group(127)

Cl3CCO2Et was found to result in formation of meta-alkenylated product 88 as the major product (Table 5, Entry 1) in 7% yield, with a mixture of other products which also appeared to be a result of radical chain reactions. Note that in the ratio of 26 : products in Table 5, ‘products’ refers to a mixture of substituted phenylpyridine products, including 88, which was generally the major of these. When carried out in toluene, none of the starting material was recovered, however 88 was observed with at least one other major product (Entry 2). It was desirable to control the radical chain

57 extension, to achieve only one major product. With this in mind, a selection of mono- protected amino acid (MPAA) ligands (shown to work well with ruthenium catalysis by Ackermann)(93) were screened, as well as solvents. Boc-Val-OH in 1,4-dioxane resulted in consumption of the starting material, however the resulting crude contained a mixture of diﬀerent products (Entry 3), more so than for MesCO2H (Entry 2). AdCO2H did not result in consumption of the starting material (Entry 4). Reducing the number of equivalents of Cl3CCO2Et was hoped to reduce the formation of side products, however unfortunately this reduced the conversion of the reaction without increasing selectivity (Entry 5). Use of Piv-Val-OH resulted in similar conversions (Entry 6). Switching the solvent to 2-Me-THF resulted in very low conversions (Entries 7 & 8).

Use of toluene (which had given good conversions with 20 equivalents of Cl3CCO2Et) with three equivalents of Cl3CCO2Et resulted in slightly better conversions than using

[RuCl2(p-cymene)]2 (5 mol%) K2CO3 (2.0 eq.) N carboxylic acid (30 mol%) N

Cl3CCO2Et (x eq.) Cl solvent, T °C, 16 h CO2Et CO2Et 26 88

Table 5: Screening of conditions for the meta-functionalisation of 2-phenylpyridine with Cl3CCO2Et.

Entry Solvent Carboxylic acid x T (◦C) 26 : Productsa b 1 1,4-Dioxane MesCO2H 20 110 1.0 : 2.8

2 Toluene MesCO2H 20 110 0.0 : 1.0 3 1,4-Dioxane Boc-Val-OH 20 110 0.0 : 1.0

4 1,4-Dioxane AdCO2H 20 110 1.0 : 5.2 5 1,4-Dioxane Boc-Val-OH 3 110 1.0 : 0.92 6 1,4-Dioxane Piv-Val-OH 3 110 1.0 : 0.80 7 2-Me-THF Boc-Val-OH 3 110 1.0 : 0.22 8 2-Me-THF Piv-Val-OH 3 110 1.0 : 0.12 9 Toluene Boc-Val-OH 3 110 1.0 : 1.4 10 Toluene Boc-Val-OH 3 80 1.0 : 0.30 a Ratio by 1H NMR. ‘Products’ refers to a mixture of substituted phenylpyridine products, including 88, which was generally the major of these. b 7% isolated yield of 88.

58 1,4-dioxane solvent (Entry 9). Unfortunately, using internal standard, the overall recovery for this was shown to be low, with only 15% of 26 recovered. Reducing the temperature to 80 ◦C resulted in lower conversion (Entry 10). When one equivalent of

Cl3CCO2Et was used only trace amounts of products were observed.

Use of CHCl3 as radical source was found not to aﬀord the meta-CHCl2 product as expected, but instead meta-formylated product 89 was observed (Scheme 44).(128) It appeared that this could be a result of hydrolysis of the meta-CHCl3 product, either by adventitious water in situ, or during aqueous work-up. The use of chloroform for the ortho/para-formylation of phenols, known as the Reimer–Tiemann reaction, has been established for over 140 years.(125) The formyl group presented a novel functionality for installation using ruthenium catalysis, and it is an extremely versatile moiety for further functionalisation.

[RuCl2(p-cymene)]2 (5 mol%) N K2CO3 (2.0 eq.) N Piv-Val-OH (30 mol%) CHCl3 (25 eq.) 1,4-dioxane 110 °C, 16–18 h H

26 89 O 21%

Scheme 44: meta-Formylation of 2-phenylpyridine

Pleased with the regioselective introduction of this functional group, optimisation of the reaction was undertaken. These were carried out with Christopher Teskey, who found Boc-Val-OH, Piv-Val-OH and MesCO2H to have similar eﬃcacies as ligands.

With K2CO3 base and [RuCl2(p-cymene)]2 catalyst in 1,4-dioxane, 89 could be isolated in a very modest 21% yield (Scheme 44).(128)

In an attempt to improve this yield, both organic and inorganic bases were screened

(Table 6). K3PO4 was found to give a similar yield to K2CO3 (Entry 1). Use of

18-crown-6 to increase the basicity of the K3PO4 did not increase the yield (Entry 2).

59 [RuCl2(p-cymene)]2 (5 mol%) N base (x eq.) N Piv-Val-OH (30 mol%) CHCl3 (25 eq.) 1,4-dioxane 110 °C, 16–18 h H

O 26 89

Table 6: Screening of bases for the meta-formylation of 2-phenylpyridine

Entry Base 26 (%)a 89 (%)a

1 K3PO4 (2.0 eq.) 28 17 b 2 K3PO4 (2.0 eq.) 45 16

3 K3PO4 (4.0 eq.) 74 0 c 4 K3PO4 (2.0 eq.) 64 8 d 5 K3PO4 (2.0 eq.) 50 5

6 K2HPO4 (2.0 eq.) 40 7 7 tBuOK (2.0 eq.) 74 trace (<1%) 8 NaSMe (2.0 eq.) 94 0 9 DIPEA (2.0 eq.) 80 0 10 Pentamethylpiperidine (2.0 eq.) 61 4 11 DBU (2.0 eq.) 86 0 12 DABCO (2.0 eq.) 84 0 a Determined by 1H NMR spectroscopy, using 1,3,5- trimethoxybenzene as an internal standard. b 2.0 eq. 18-crown-6 added. c 10 times more dilute. d Benzene solvent.

Increasing the number of equivalents of base to 4.0 stopped the reaction, resulting in a 0% yield of 89 and relatively good recovery of starting material (Entry 3). Increasing the dilution of the reaction by 10 times, and carrying it out in a Schlenk tube, rather than a microwave vial decreased the yield of the reaction to 8% (Entry 4). Use of benzene as solvent also decreased the yield (Entry 5). Toluene, DMA and MeCN were (128) shown to be unsuitable as solvents. K2HPO4 was a less suitable base for the reac- t tion than K3PO4 (Entry 6), and BuOK only resulted in trace quantities of 89 being observed (Entry 7). NaSMe aﬀorded almost quantitative recovery of starting material (Entry 8). Organic bases were generally ineﬀective (Entries 9–12), with the only product observed from these reactions being a 4% yield using pentamethylpiperidine

60 as base (Entry 10).

Screening of ruthenium catalysts, loadings, and reaction temperatures was carried out (Table 7). Increasing the reaction dilution slightly, and carrying the reaction out in a Schlenk tube with K2CO3 base resulted in only 8% isolated yield of the product, ◦ with [RuCl2(p-cymene)]2 catalyst (Entry 1). A lower temperature of 80 C resulted in only trace amounts of product, and poor recovery of starting material (Entry 2). Increasing the catalyst loading to 30 mol% resulted in none of the product 89 being formed, and poor recovery of the starting material, probably due to large amounts of ruthenacycle formation (Entry 3). Reducing the catalyst loading to 1 mol% also had a detrimental eﬀect on the reaction, with only trace formation of product, but good recovery of starting material (Entry 4). Using K3PO4 base, the temperature was increased to 150 ◦C (Entry 5), which resulted in a low yield of 8%, and a low recovered

catalyst (x mol%) N base (2.0 eq.) N Piv-Val-OH (30 mol%) CHCl3 (25 eq.) 1,4-dioxane T °C, 16–18 h H

O 26 89

Table 7: Screening of conditions for the meta-formylation of 2-phenylpyridine

Entry Catalyst x Base T 26 (%)a 89 (%)a b c c 1 [RuCl2(p-cymene)]2 5 K2CO3 110 50 8

2 [RuCl2(p-cymene)]2 5 K2CO3 80 18 trace

3 [RuCl2(p-cymene)]2 30 K2CO3 110 18 0

4 [RuCl2(p-cymene)]2 1 K2CO3 110 70 trace

5 [RuCl2(p-cymene)]2 5 K3PO4 150 22 8

6 Grubbs I 10 K3PO4 110 55 7 d 7 [RuCl2(p-cymene)]2 5 K3PO4 110 26 15 e 8 [RuCl2(p-cymene)]2 5 K3PO4 110 45 12 a Determined by 1H NMR spectroscopy, using 1,3,5-trimethoxybenzene as an internal standard. b Carried out in schlenk tube rather than microwave vial. 1.7 times more dilute. c d e Isolated yield. Extra catalyst (5 mol%) added after 5 h. Total of 12.0 eq. CHCl3 used, added in portions of 3.0 equivalents every 2 hours for 6 hours.

61 yield of 2-phenylpyridine. Grubbs I catalyst did not improve the yield of the reaction (Entry 6). To see whether deactivation of the catalyst was aﬀecting the yield, extra catalyst (5 mol%) was added to the reaction after 5 hours, but this only resulted in a yield of 15% (Entry 7). A similar experiment was carried out, where the entire reaction mixture was syringed into a ﬂask containing fresh catalyst, ligand, CHCl3 and base after 17 hours, before a further 25 hours heating, but this did not improve the yield.

To see whether consumption of the CHCl3 in side-reactions was occuring faster than meta-functionalisation, and limiting the yield, CHCl3 was added in portions over time (Entry 8). This did not improve the yield either.

It was expected that CHBr3 and CHI3 would be more reactive than CHCl3. However, the reverse was found to be true (Table 8), with CHBr3 resulting in a lower yield than

CHCl3 (Entries 1 & 2), and CHI3 returning only unreacted phenylpyridine (Entry 3).

[RuCl2(p-cymene)]2 (5 mol%) N K3PO4 (2.0 eq.) N Piv-Val-OH (30 mol%) CHX3 (5.0 eq.) 1,4-dioxane 110 °C, 18 h H

26 89 O

Table 8: Comparison of CHX3 compounds for meta-formylation

a a Entry CHX3 26 (%) 89 (%) b 1 CHCl3 20

2 CHBr3 38 11

3 CHI3 50 0 a Determined by 1H NMR spectroscopy, using 1,3,5-trimethoxybenzene b as an internal standard. MesCO2H and K2CO3 used in place of Piv- (128) Val-OH and K3PO4. Carried out by Christopher Teskey. Isolated yield.

In an eﬀort to probe the mechanism, the reaction was carried out with the addition of two equivalents of radical scavenger galvinoxyl (Scheme 45). This resulted in a 0% yield of 89, and 82% recovery of starting material. No adducts were observed by 1H

62 NMR spectroscopy. This supports a possible radical mechanism for the reaction.

[RuCl2(p-cymene)]2 (5 mol%) K2CO3 (2.0 eq.) N Boc-Val-OH (30 mol%) N Galvinoxyl (2.0 eq.) CHCl3 26 (25 eq.) 1,4-dioxane 82% 110 °C, 18 h H

26 89 O 0%

Scheme 45: Eﬀect of galvinoxyl on the yield of 89

A number of additives were screened to see if they would improve the yield (Table 9). Reducing agents have been proposed to aid ruthenium catalysed ATRA reactions by regenerating Ru(II) from Ru(III)–Cl by chloro atom abstraction.(124) In addition to this, it was considered that using less equivalents of CHCl3 might reduce catalyst poisoning. Metallic reducing agents such as zinc and magnesium did not improve the yield of the reaction (Entries 1–4). AIBN has been reported to aid the TON of ruthenium catalysts in ATRA reactions, and can be used sub-stoichiometrically.(129) Despite this, the use of 5 mol% did not increase the yield for the meta-formylation

(Entries 5 & 6). Yields with 5.0 equivalents of CHCl3 were similar or lower than those with 25 equivalents (Entries 1–6). Use of peroxide (BzO)2 resulted in a 0% yield of the aldehyde product 89 (Entry 7). Metal salts such as FeCl2 and CuCl had a slightly negative impact on the yield (Entries 8 & 9). Nonaﬂyl ﬂuoride, which had appeared to improve the yield of the meta-alkenylation using CCl4, resulted in a decreased yield of 7% (Entry 10).

To see the eﬀect of electronics on the yield of the reaction, 4-methoxyphenylpyridine (90) and 4-ﬂuorophenylpyridine (91) were subjected to the formylation conditions (Scheme 46). Interestingly, both substrates resulted in a lower yield of aldehyde than the unsubstituted phenylpyridine. Electron rich 90 resulted in a larger yield than electron poor 91, although both yields were very low.

63 [RuCl2(p-cymene)]2 (5 mol%) K3PO4 (2.0 eq.) N Piv-Val-OH (30 mol%) N additive CHCl3 (x eq.) 1,4-dioxane 110 °C, 18 h H

26 89 O Table 9: Eﬀect of additives on the meta-formylation

Entry Additive x 26 (%)a 89 (%)a 1 Zn (1.1 eq.) 5 43 10 2 Zn (1.1 eq.) 25 34 15 3 Mg (3.0 eq.) 5 50 10 4 Mg (3.0 eq.) 25 36 10 5 AIBN (5 mol%) 5 65 7 6 AIBN (5 mol%) 25 35 16

7 (BzO)2 (1.0 eq.) 25 56 0

8 FeCl2 (10 mol%) 25 40 12 9 CuCl (10 mol%) 25 49 9 10b Nonaﬂyl ﬂuoride (2.0 eq.) 25 42 7 a Determined by 1H NMR spectroscopy, using 1,3,5-trimethoxybenzene as an b internal standard. Boc-Val-OH used instead of Piv-Val-OH, and K2CO3 instead of K3PO4.

[RuCl2(p-cymene)]2 (5 mol%) N K3PO4 (2.0 eq.) N Piv-Val-OH (30 mol%) CHCl3 (25 eq.) 1,4-dioxane 110 °C, 22 h H R R O 90 R = OMe 92 R = OMe (8%) 91 R = F 93 R = F (4%)

Scheme 46: meta-Formylation of 2-(4-ﬂuorophenyl)pyridine and 2-(4-methoxyphenyl)pyridine

The mechanism is tentatively proposed in Scheme 47. Initial C–H ruthenation to form Ru(II) ruthenacycle 94 is followed by Cl abstraction from chloroform by ruthe- • nium(II). This gives the Cl2HC radical species, and Ru(III) ruthenacycle 95, although it is also possible that a separate Ru(II) species carries out this step in place of the

64 ruthenacycle. Radical addition para to the ruthenium affords 96, which can undergo a deprotonation, and an intramolecular SET to afford the ruthenium(II) species 97. Proto-demetallation affords 98, and in situ hydrolysis affords the aldehyde 89. It is worth noting that in no cases was the unhydrolysed 98 observed, even when the reaction was carried out using flame dried K3PO4, in flame-dried glassware, with dry, degassed CHCl3.

N N H2O

H hydrolysis H N K3PO4 26 H OHC Cl2HC 89 98 K3PO4 II Ru Ln K2HPO4 KX + K2HPO4 proto- C–H ruthenation iPr demetallation iPr

N N 97 RuII RuII 94 O O Me Me Cl HC O H O 2 R R PivHN PivHN

CHCl KCl + K HPO 3 2 4 SET + deprotonation Cl abstraction CHCl K PO 2 3 4 iPr iPr

Cl radical Cl N attack N RuIII RuIII O O Me Me H O H O CHCl2 CHCl2 R R PivHN PivHN

96 95

Scheme 47: Proposed mechanism for the meta-formylation of 2-phenylpyridine

1.2.3. Conclusions

Whilst ruthenium catalysed meta-C–H functionalisation remains an attractive prospect, attempts at developing novel methodologies came across several obstacles. Use of

65 photoredox for the generation of alkyl and CF3 radicals did not result in meta- functionalisation, possibly due to the inefficiency of electron transfer between the ruthenacycle and photoredox catalyst. Use of ruthenium(II) for the generation of radicals from halocarbons saw more success, with the installation of tetrasubstituted alkenes, and aldehydes shown to be possible. Unfortunately these reactions suffered from low yields, and in the cases of radical sources CCl4 and Cl3CCO2Et gave a mixture of products of radical chain extensions which were difficult to control. As a result, attention was turned to alternative ruthenium catalysed C–H activation chemistry.

66 1.3. Ruthenium catalysed ortho-halogenation

1.3.1. Aims and objectives

At the time of this work being carried out, there were no reported examples of ruthenium catalysed meta-C–H-iodination. Examples of ortho-C–H iodination relied on expensive rhodium(52) or palladium catalysts,(43,44) or proceeded in moderate yields with copper catalysis.(42,46) Aryl iodides are valuable synthetic targets; they provide a handle for further functionalisation of molecules by metal catalysed cross-coupling reactions, as they undergo oxidative addition more readily than aryl bromides or chlorides. This increased reactivity makes methodology for the late stage installation of iodine desirable. Aryl iodides also feature in a number of approved drugs,(34) such as X-ray contrast agents, and those for the imaging of tumours.(130,131)

There was a desire to develop a directed C–H iodination reaction, compatible with strong directing groups (e.g. pyridyl), and using low-cost ruthenium. Previous work in the group had developed a ruthenium catalysed meta-C–H bromination (Section 1.1.3.3, p44).(102) Building upon this, iodinating agents were screened in the expectation that ruthenium would direct any iodination to the meta-position, analogous to its previously displayed reactivity in brominations with pyridyl directing groups.(128)

1.3.2. Results and discussion

1.3.2.1. Initial investigations and optimisation

Initial investigations and optimisation were carried out by Christopher Teskey(128) and Lucas Fr´ed´eric. It was found that iodine monochloride, a reagent which is generally reported to act as a source of electrophilic iodine for iodinations,(132) resulted in the ortho-chlorination of 2-phenylpyridine when used under the same conditions reported in the meta-bromination paper (Table 10, Entry 1).(102) ortho-Chlorinated compound

67 26b was isolated in 30% yield. This was surprising on two levels: ﬁrstly, as ruthenium catalysed C–H halogenations had previously been reported to proceed in the meta- position using pyridyl directing groups;(102–104,106) and secondly, as the chlorine had been incorporated instead of the iodine. When iodine monobromide was used instead, neither iodination or bromination took place, and the major product was dimer 100 (Entry 2).

[RuCl2(p-cymene)]2 (5 mol%) N K2CO3 (2.0 eq.) N N N N MesCO2H (30 mol%) " I " I Cl 1,4-dioxane 110 °C, 20 h N I

26 99 100 26a 26b

Table 10: Initial investigations with iodinating agents(128)

Entry Iodinating agent Producta 1 ICl 26b (30%) 2 IBr 100 a Isolated yields in brackets.

Iodine monochloride is a volatile solid, with a melting point of 27 ◦C, and is therefore diﬃcult to weigh out accurately, particularly on a small scale. This was resolved by use of an easily prepared 2:1 complex with 1,4-dioxane. [1,4-Dioxane(ICl)2](101) has been previously reported in the literature,(133,134) and was found to be easily prepared, taking the form of a bright orange solid which was easily weighed out. This complex is stable in the freezer at −18 ◦C for many months, and was found to work equally as well as pure ICl in the reaction. Optimisation of the reaction found that RuCl2(PPh3)3 gave slightly higher yields that [RuCl2(p-cymene)]2. The use of triphenylphosphine as a ligand increased the yield slightly compared to MesCO2H, as well as increasing selectivity for the mono-ortho-chlorinated product 26b compared to dichlorinated 26c. The addition of base was found not to be necessary for the reaction to proceed. Using an air atmosphere instead of nitrogen signiﬁcantly increased the combined yields of

68 RuCl2(PPh3)3 (2.5 mol%) N PPh3 (30 mol%) N N Cl I OO I Cl 1,4-dioxane, air Cl Cl Cl 110 °C, 20 h

26 101 26b 26c (1.0 eq.) 62% 12%

Scheme 48: Optimised conditions for the ortho-chlorination of 2-phenylpyridine(128)

26b and 26c, and reducing the equivalents of 101 from two to one greatly improved the ratio between 26b and 26c, with little eﬀect on the yield of 26b. Pleasingly, the catalyst loading could be reduced to 2.5 mol%, however reducing the temperature resulted in a lower yield. The optimised conditions that were selected are as shown in Scheme 48.

Whilst screening catalysts in the optimisation of the ortho-chlorination reaction, it was found that Ru3(CO)12 resulted selectively in iodination at the ortho-position (Scheme 49). The change of ruthenium catalyst had reversed the chemoselectivity of the halogenating agent completely. Similar catalyst dependent reactivity has not previously been reported. Excited by this unexpected ﬁnding, temperature and catalyst loading were screened. Lower loadings/temperatures resulted in decreased yields. Un- like the chlorination reaction, carrying out the reaction under air was found to decrease the yield, so the initial conditions were considered optimal.

N N N N N 101 Ru3(CO)12 (3 mol%) (1.0 eq.) Cl Cl Cl I I I N2, 1,4-dioxane 110 °C, 20 h

26 26b 26c 26a 26d 0% 0% 75% 1%

Scheme 49: Optimised conditions for the ortho-iodination of 2-phenylpyridine

These reactions were interesting for several reasons. Firstly, whilst the use of ruthenium catalysis for ortho-halogenation has been reported once using weakly coordinating

69 benzamide directing groups (Scheme 6, p17),(39) examples of ruthenium catalysed halogenation with strong coordinating pyridyl directing groups have so far all resulted in selectivity for the meta-position (Section 1.1.3.3). The use of low-cost ruthenium catalysis for the synthesis of valuable aryl halide targets is also appealing. Secondly, the novel switch in chemoselectivity of halogenation depending simply upon the choice of catalyst was an exciting prospect. This early example of catalyst dependent reagent reactivity could lead to further interesting developments, particularly with better understanding of the mechanism.

1.3.2.2. Substrate scope

Pleasingly, investigations into the substrate scope found that a range of substrates could be successfully and selectively iodinated or chlorinated under the two sets of conditions (Scheme 50). It was found that substrates without any steric hindrance around the ortho-position could aﬀord the di-ortho-chlorinated compound as a minor product (Scheme 50: 102 & 105). Fortunately, introducing a steric block in the ortho- or meta-position helped to overcome this issue and resulted in selective formation of the mono-chlorinated product (103b & 104b), which is consistent with the ﬁndings of many metal catalysed ortho-C–H functionalisation protocols (see Section 1.1.2.1). Di-iodination however did not seem to pose a problem. This is perhaps due to the larger iodine atom creating a steric clash with the adjacent hydrogen on the pyridine ring, disfavouring the planar conformation that would be required for formation of the ruthenacycle and a second iodination.

Methyl substitution was tolerated at various points on both rings, and both iodination and chlorination proceeded in moderate to excellent yields (26, 102–105). 103 required an extended reaction time for the iodination reaction, likely due to the same reason of steric hindrance mentioned previously.

Gratifyingly, 26b could be submitted to the iodination conditions to aﬀord 106a

70 Conditions B: Conditions A: DG RuCl2(PPh3)3 (2.5 mol%) DG Ru3(CO)12 (3 mol%), DG PPh (30 mol%), 101 (1.0 eq.) 101 (1.0 eq.) Cl 3 I

1,4-dioxane, air 1,4-dioxane, N2 110 °C, 20 h 110 °C, 20 h

101 Cl I OO I Cl

N N N N N N

X X X X X Cl X

26a 75%a 102a 65% 103a 50%d (84%) 104a 51% (89%)a 105a 67% 106a 32% (94%) 26b 62%b 102b 45% (78%)c 103b 55% (85%) 104b 54% (77%) 105b 43% (56%)c -

N N N NN N

X X X X X

CO2Et CHO 107a 53% (98%) 108a 44% (78%) 109a 36% (61%) 110a 32% (83%)f 111a 40%b 107b 42% (63%) 108b 29% (43%)e 109b 46% (60%) 110b 34% (53%)f,g 111b 78%b

Isolated yields. Yields in brackets indicate yields by recovered starting material. a Reaction carried out by Lucas Frédéric. b Reaction carried out by Christopher Teskey. c 9% of the dichlorinated product was also obtained. d Reaction time was 72 hours. e A mixture of other f g products involving reaction of the aldehyde were also obtained. Carried out using 2 eq. K2CO3. 10% of the dichlorinated product (110c) was also obtained.

Scheme 50: Substrate scope for the ortho-halogenation reaction

in 32% yield. Whilst this is a relatively modest yield, there was almost quantitative recovery of the unreacted starting material, providing the opportunity to recycle it. The synthesis of a compound bearing two distinct halogen groups with differing levels of reactivity presents a valuable tool for further functionalisation of the molecule to afford complex molecules.(135) Furthermore, this could be carried out with the need for only one halogenating agent, avoiding the need to purchase two different halogen sources. For instance, ICl is significantly cheaper per mole than N -iodosuccinimide, which can be used for ortho-iodinations.(43,44,46–48) It is also cheaper per mole than

71 the combined cost of NCS and NIS.1

Valuable electron-withdrawing groups such as esters and aldehydes (which have the potential for diversiﬁcation into a range of other functional groups) were tolerated in the para-position for both iodination and chlorination (107 & 108), albeit in slightly lower yields than for electron rich substrates. The reduced yield for 108b is owing to side reactions of the aldehyde moiety. meta-Brominated substrate 109 was chlorinated and iodinated in moderate yields. However, the ortho-iodination product was accompanied by another mono-iodinated product, the regiochemistry of which could not be deﬁnitively assigned. There are reports of substrate 109 undergoing ortho- bromination or chlorination in the ortho-position adjacent to bromine, so it is possible that this was also the case here.(45)

Pyrimidine was found to function as a directing group, although the yields were modest. It was thought that the lower basicity of pyrimidine to pyridine might be responsible for this, given the absence of external base in the reaction. The addition of K2CO3 was found to improve the yield of 110a, albeit only to 32% yield. However, addition of K2CO3 had a much smaller effect on the yield of 110b. A significant quantity (10%) of dichlorinated 110c was also obtained from this reaction. Isoquinoline was also found to be an effective directing group, yielding the iodinated product 111a in 40% yield, and chlorinated 111b in a very pleasing 78% yield.(128)

Iodinations with halogens in the para-position resulted in moderate overall yields, with formation of a mixture of ortho-chlorinated and iodinated products (Scheme 51 a). Although interestingly, when 113 was submitted to the chlorination conditions (Scheme 51 b), no iodinated product was observed. Mono-chlorinated product 113b was formed in a modest 33% yield, with relatively poor selectivity over the di-chlorinated product 113c which was formed in 7% yield.

It was found that oxazoline was an ineﬀective directing group for the iodination

1Merck online prices, 22nd September 2018: NIS (95%) 100 g = £218.00 (£0.97 per mole); (136) NCS (137) (138) (98%) 100 g = £17.40 (£0.13 per mole); ICl (>95%) 100 g = £59.50 (£0.37 per mole).

72 a) N N N Ru3(CO)12 (3 mol%) 101 I Cl (1.0 eq.) 1,4-dioxane N2, 110 °C, 20 h X X X X = Cl 112 X = Cl : 112a (15%) 112b (21%) 112 (49%) X = Br 113 X = Br : 113a (28%) 113b (20%)

N RuCl2(PPh3)3 (2.5 mol%) N N N 101 PPh3 (30 mol%) Cl I Cl Cl + 113 (1.0 eq.) 1,4-dioxane 25% air, 110 °C, 20 h Br Br Br Br 113 113b 113a 113c 33% 0% 7%

Scheme 51: Reaction of (a) para-chlorinated 112 and para-brominated 113 under the iodination conditions. (b) Chlorination of 113

(Scheme 52), as the reaction of 2-phenyl-2-oxazoline 114 under the iodination conditions resulted in the the formation of HCl salt 115 as the major product in 36% yield, in addition to a complex mix of other products. None of the desired ortho-iodinated product could be identiﬁed.

Cl O N O N O N Ru3(CO)12 (3 mol%) H Cl I OO I Cl 1,4-dioxane I N2, 110 °C, 20 h

114 101 115 114a (1.0 eq.) 36% not observed

Scheme 52: Reaction of 2-phenyl-2-oxazoline 114 under the iodination conditions.

2-Phenyl-1H -benzo[d]imidazole 116 was submitted to the iodination conditions but only trace quantities of the desired ortho-iodinated product were observed (Scheme 53).

4-Methyl-1-phenylpyrazole 117 did result in the formation of small quantities of ortho-iodinated 117a under the iodination conditions (Scheme 54), however this was

73 Ru (CO) (3 mol%) HN N 3 12 HN N Cl I OO I Cl 1,4-dioxane I N2, 110 °C, 20 h

116 101 116a (1.0 eq.) trace

Scheme 53: Reaction of 2-phenyl-1H -benzo[d]imidazole 116 under the iodination conditions not the major product. The major products were shown by GCMS to be mono- chlorinated or mono-iodinated, but analysis of the NMR spectra suggested that the substitutions were on the pyrazole ring.

N Ru (CO) (3 mol%) N N 3 12 N Cl I OO I Cl 1,4-dioxane I N2, 110 °C, 20 h

117 101 117a (1.0 eq.) <10%

Scheme 54: Reaction of 4-methyl-1-phenyl-1H pyrazole 117 under the iodination conditions

1.3.2.3. Optimisation of co-solvents

During initial 1H NMR studies of the iodination reaction in collaboration with Jordi Bur´es,the reaction was observed to form two phases as it proceeded, which would have made NMR analysis diﬃcult. Analysis of the two phases for iodination found that whilst the top layer contained some of the product 26a, the bottom layer contained 2–3 times more, as well as some unreacted phenylpyridine. The top layer also contained a compound similar to phenylpyridine, but with the protons near the nitrogen more deshielded, which may indicate formation of an adduct on the nitrogen or perhaps protonation of this position. Similarly, the top phase of the chlorination reaction was

74 observed to contain only small quantities of phenylpyridine derivatives (26, 26b and 26c). The lower layer contained the same relative ratios of these products, but in around 5 times higher quantity. Both layers for the chlorination were found to have a pH of 1, presumably due to the formation of large quantities of HX from the C–H activation step.

With the aim of achieving a monophasic reaction mixture, in order to allow 1H NMR analysis and potentially speed up the reaction or increase the yield, co-solvents for the reaction were screened, ﬁrst for the iodination (Table 11). The choice of co-solvents was limited by the need to avoid those which might undergo a background reaction with the ICl (e.g. aromatic solvents). In addition, solvents which might react with the ruthenium catalyst were avoided. When DCM was used as a co-solvent, the reaction mixture was biphasic (Entry 1), however use of 1,2-dichloroethane (1,2-DCE) resulted in a single phase after 21 hours, and the reaction yield was 66% by NMR (Entry 2). This is lower than the 75% isolated yield which had previously been obtained with 1,4-dioxane alone. DMSO resulted only in recovery of unreacted starting material (Entry 3), likely due to its ligation of ruthenium,(139) which may have poisoned the catalyst. DMF did result in a homogeneous reaction mixture, however the yield was signiﬁcantly lower (Entry 4).

The reaction time was investigated, revealing a comparable yield after both 4 and 21 hours (Table 11, Entries 2 & 5), rendering the 21 hour reaction time unnecessary.

Investigating the relative ratio of 1,4-dioxane to 1,2-DCE showed that increasing the proportion of 1,4-dioxane to 1,2-DCE to 5:1 had no eﬀect on the yield (Table 11, Entries 5 & 6), however a further increase to 14:1 resulted in a biphasic reaction mixture (Entry 7). Increasing the relative amount of 1,2-DCE such that it was in a 1:1 ratio with 1,4- dioxane resulted in a slight increase in the reaction yield (Entry 8). Increasing further to a 2:1 ratio gave a yield comparable to that expected for 1,4-dioxane (Entry 9). In fact, it was found that when only 1,2-DCE was used (with no 1,4-dioxane) the yield was in fact higher (85%) than that with 1,4-dioxane alone. Unfortunately, reducing

75 the temperature to 90 ◦C resulted in a reduced yield (Entry 11).

N N N N N 101 Ru3(CO)12 (3 mol%) (1.0 eq.) Cl Cl Cl I I I 1,4-dioxane, co-solvent N2, T °C, t h

26 26b 26c 26a 26d

Table 11: Screening of co-solvents for the ortho-iodination of 2-phenylpyridine, 26

Entry Co-solvent Monophasic T t 26 : 26b : 26c : 26a : 26da 1 DCM (2:1 ) N 110 21 – 2 1,2-DCE (2:1 ) Y 110 21 25 : 6 : 0 : 66 : 3 3 DMSO (2:1 ) Y 110 21 89 : 0 : 0 : 0 : 0 4 DMF (2:1 ) Y 110 21 37 : 6 : 0 : 44 : 4 5 1,2-DCE (2:1 ) Y 110 4 24 : 4 : 0 : 66 : 0 6 1,2-DCE (5:1 ) Y 110 4 28 : 4 : 0 : 66 : 0 7 1,2-DCE (14:1 ) N 110 4 – 8 1,2-DCE (1:1 ) Y 110 4 21 : 3 : 0 : 70 : 0 9 1,2-DCE (1:2 ) Y 110 4 21 : 3 : 0 : 73 : 0 10 1,2-DCE (0:1 ) Y 110 4 11 : 3 : 0 : 85 : 1 11 1,2-DCE (0:1 ) Y 90 8 21 : 2 : 0 : 72 : 2 a Percentage yields calculated from 1H NMR using an internal standard.

The conditions in Table 11 Entry 10 resulted in an 80% isolated yield of 26a, and when scaled up to 0.50 mmol (the same scale as previous scope experiments) an isolated yield of 71%, with 19% of recovered starting material (Scheme 55). This yield is similar to that obtained with 1,4-dioxane, albeit with a much reduced reaction time, showing that both 1,4-dioxane and 1,2-DCE are good solvents for this reaction. Two other examples from the scope were also tested under the reaction conditions. para-Methyl substituted 102 resulted in a similar (though slightly reduced) yield of 60% (c.f. 65% in Scheme 50). Substrate 107 with a para-ester gave an increased yield of 70% (c.f. 53% in Scheme 50).

76 N N Ru3(CO)12 (3 mol%) Cl I OO I Cl 1,2-DCE I N2, 110 °C, 4 h

R R R = H 26 101 R = H 26a (71%)a R = Me 102 (1.0 eq.) R = Me 102a (60%)a 107a b R = CO2Et 107 R = CO2Et (70%)

a 0.50 mmol scale. b 0.25 mmol scale.

Scheme 55: Iodination of substrates under the conditions from Table 11 (Entry 10).

Similar screening was carried out for the ortho-chlorination reaction (Table 12). 1,2- DCE in a 1:1 ratio with 1,4-dioxane was found to result in a homogenous reaction mixture (Entry 1). Unfortunately, the yield of the reaction was reduced compared to the 62% isolated yield previously obtained when carried out in 1,4-dioxane. Using 1,2-DCE alone also resulted in a reduced yield (Entry 3), although recovery of starting material was much higher than for the 1:1 mixture. It was hoped that by using a minimal quantity of 1,2-DCE, the yield obtained in 1,4-dioxane could be reached while maintaining a single phase. The highest ratio of 1,4-dioxane to 1,2-DCE to result in a homogeneous reaction mixture was 5:1, but the yield was still only 47% (Entry 4). 1,4-Dioxane with a DCM co-solvent (2:1) did not result in one phase (Entry 5), but increasing the proportion of DCM to 1:2 was more successful, and resulted in the highest yield of all the co-solvents, of 56% (Entry 6). However, this is still lower than desired. The use of DMF, unlike in the iodination protocol, completely inhibited the reaction and only unreacted starting material was recovered (Entry 7).

It should be noted that whilst it was intended to carry out NMR experiments (in collaboration with Jordi Bur´es)to probe the kinetics of the reactions, these studies were subsequently not carried out. The unfortunate failure to ﬁnd a suitable co-solvent for the chlorination reaction, in addition to other factors such as the overlapping of a number of peaks on the 1H NMR spectrum, some of which were poorly resolved at low conversions meant that these studies were not completed.

77 Ru(PPh3)3Cl2 (2.5 mol%) N N N N N 101 PPh3 (30 mol%) (1.0 eq.) Cl Cl Cl I I I 1,4-dioxane, co-solvent air, 110 °C, t h

26 26b 26c 26a 26d

Table 12: Screening of co-solvents for the ortho-chlorination of 2-phenylpyridine, 26

Entry Co-solvent Monophasic t 26 : 26b : 26c : 26a : 26da 1 1,2-DCE (1:1 ) Y 4 14 : 45 : 6 : 0 : 0 2 1,2-DCE (1:0 ) N 4 – 3 1,2-DCE (0:1 ) Y 4 43 : 39 : 5 : 0 : 0 4 1,2-DCE (5:1 ) Y 4 28 : 47 : 6 : 0 : 0 5 DCM (2:1 ) N 16 – 6 DCM (1:2 ) Y 16 24 : 56 : 6 : 0 : 0 7 DMF (2:1 ) Y 16 91 : 0 : 0 : 0 : 0 a Percentage yields calculated from 1H NMR using an internal standard.

1.3.2.4. Eﬀect of base on the reactions

During the initial NMR studies of the iodination reaction in collaboration with Jordi Bur´es,it was observed that large quantities of H+ were being formed as a by-product of the reaction. This is unsurprising, and is consistent with the ﬁndings of the reaction with 2-phenyl-2-oxazoline, where the major product of the reaction was in fact the HCl salt (Scheme 52). It was suggested that this HCl might be protonating the directing group, and preventing coordination of the nitrogen to the ruthenium catalyst, hence inhibiting the reaction. Thus, it seemed sensible to investigate whether the addition of base to the reaction might improve the yield (Table 13).

It was found that addition of one equivalent of K2CO3 improved the yield of the iodination reaction over 2 hours (Table 13, Entries 1 & 2), however when the reaction time was extended to 4 hours, the yields with and without K2CO3 were very similar

78 (Entries 4 & 5). NaOAc, whilst increasing the overall yield of the reaction, resulted in decreased selectivity between the mono- and di-substituted products 26a and 26d.

The effect of base on the chlorination was also investigated in more detail. Contrary to the findings for the iodination, K2CO3 was found to greatly inhibit the chlorination reaction (Entries 6 & 7). Acetate bases had a less detrimental effect, but still reduced the yield significantly (Entries 8 & 9). Other carbonate bases were tested, and whilst

Na2CO3 had a negligible eﬀect (Entry 10), Cs2CO3 completely prevented the reaction from taking place (Entry 11). Similarly, K3PO4 only resulted in a trace yield of the mono-chlorinated product 26b (Entry 12). The reduced inhibitory eﬀect of Na2CO3

Conditions A: Ru3(CO)12 (3 mol%) base (1.0 eq.), 1,2-DCE N N N N N 101 N2, 110 °C, t h (1.0 eq.) Cl Cl Cl I I I or Conditions B: RuCl2(PPh3)3 (2.5 mol%) PPh3 (30 mol%) 26 base (1.0 eq.) 26b 26c 26a 26d 1,4-dioxane, air 110 °C, t h

Table 13: Eﬀect of bases on the ortho-halogenation of 2-phenylpyridine.

Entry Conditions t (h) Base 26 : 26b : 26c : 26a : 26da 1 A (Iodination) 2 none 29 : 3 : 0 : 59 : 0

2 A (Iodination) 2 K2CO3 5 : 4 : 0 : 82 : 3 3 A (Iodination) 2 NaOAc 13 : 3 : 0 : 54 : 18 4 A (Iodination) 4 none 23 : 4 : 0 : 71 : 0

5 A (Iodination) 4 K2CO3 19 : 5 : 0 : 76 : 3 6 B (Chlorination) 4 none 26 : 47 : 8 : 0 : 0

7 B (Chlorination) 4 K2CO3 82 : 8 : 0 : 0 : 0 8 B (Chlorination) 4 NaOAc 36 : 31 : 4 : 0 : 0 9 B (Chlorination) 4 KOAc 44 : 26 : 3 : 0 : 0

10 B (Chlorination) 4 Na2CO3 27 : 49 : 6 : 0 : 0

11 B (Chlorination) 4 Cs2CO3 88 : 0 : 0 : 0 : 0

12 B (Chlorination) 4 K3PO4 88 : 3 : 0 : 0 : 0 a Percentage yields calculated from 1H NMR using an internal standard.

79 is most likely due its lower solubility in organic solvents compared to K2CO3. The more soluble Cs2CO3 inhibits the reaction completely.

This observation is in part consistent with the ﬁndings for the halogenation of 2- phenylpyrimidine 110 (Scheme 50, p71), which found that the iodination yield was improved from 24% to 32% by addition of two equivalents of K2CO3, but the yield for the chlorination, whilst not reduced, was only aﬀected by a possibly negligible amount (34% with base vs 31% without).

Gratifyingly, the opposing eﬀect of bases on the two reactions could be utilised to expand the scope of the iodination reaction. Previously, several substrates (particularly para-halogenated examples) resulted in formation of a mixture of ortho-chlorinated and iodinated compounds under the iodination conditions (Scheme 51, p73). However, the addition of one equivalent of K2CO3 to the reaction of para-bromo substituted 113 allowed isolation of the ortho-iodinated product 113a in a very pleasing 59% yield

(Scheme 56). It is proposed that the addition of K2CO3 to the iodination reaction could similarly be extended to other substrates which displayed poor selectivity without it, to enable their selective synthesis.

Ru3(CO)12 (3 mol%) N N K2CO3 (1.0 eq.) Cl I OO I Cl 1,2-DCE I N2, 110 °C, 4 h

Br Br 113 101 113a (1.0 eq.) 59%

Scheme 56: Iodination of 113 with the addition of K2CO3

1.3.2.5. Eﬀect of catalyst and ligands

During the optimisation, several ruthenium catalysts had been screened by Lucas Fr´ed´eric,and it was noted that all of those which had resulted in ortho-chlorination (i.e.

80 [RuCl2(C6H6)]2, [RuCl2(p-cymene)]2, RuCl2(PPh3)3) had contained chloride ligands.

It was speculated that this, alongside the eﬀect of the more electron rich PPh3 ligand (compared to CO) for the chlorination might be responsible for the chemoselectivity. Therefore, the eﬀect of these ligands on the selectivity was explored in more detail.

The iodination, when carried out with the addition of PPh3, resulted in a slightly decreased yield (Scheme 57), but with no formation of the chlorinated product.

Ru3(CO)12 (3 mol%) N PPh (30 mol%) N N 3 26 Cl I OO I Cl + 1,2-DCE I Cl 30% N2, 110 °C, 4 h

26 101 26a 26b (1.0 eq.) 61% 0%

1 Scheme 57: Iodination of 26 carried out with added PPh3. Yields calculated by H NMR with an internal standard.

The eﬀect of two catalysts containing either CO or PPh3 ligands on the product distribution was investigated (Table 14). Ru(PPh3)2(CO)2Cl2 contains CO, Cl and

PPh3 ligands, so it was interesting to find that when this was used with added PPh3 ligand, the major product was that of iodination (26a), and small amounts of chlorinated product were also observed (Entry 1). Without the presence of added PPh3, the iodinated product was still the major product, and was formed in higher yield (En- try 3), although the proportion of 26b had increased. Interestingly, this shows that the PPh3 and chloride ligands have little effect on the selectivity between chlorination and iodination, but possibly the CO ligand does have a significant effect. Notably, this also displays the use of a ruthenium(II) catalyst for iodination, suggesting that the oxidation state of the Ru3(CO)12 catalyst is not behind the selectivity, and also suggesting that it is oxidised to Ru(II) in situ. [Ru(CO)3Cl2]2 was also found to result in the formation of iodinated 26a as the major product, with small amounts of

26b formed, both with and without added PPh3 (Entries 2 & 4). The yields of iodinated 26a were higher with [Ru(CO)3Cl2]2 than Ru(PPh3)2(CO)2Cl2. These ﬁndings

81 support the previous results, highlighting the importance of the CO ligand, and indicating that whilst the PPh3 has no eﬀect on selectivity, the presence of Cl ligands may have a small eﬀect.

Ru catalyst N N N N N 101 PPh3 (x mol%) (1.0 eq.) Cl Cl Cl I I I 1,4-dioxane N2, 110 °C, 20 h

26 26b 26c 26a 26d

Table 14: Eﬀect of ligands on the catalyst on formation of 26b and 26a

Entry Ru catalyst x 26 : 26b : 26c : 26a : 26da a 1 Ru(PPh3)2(CO)2Cl2 (10 mol%) 30 30 : 6 : 0 : 40 : 0 a 2 [Ru(CO)3Cl2]2 (5 mol%) 30 14 : 7 : 0 : 61 : 3 b 3 Ru(PPh3)2(CO)2Cl2 (10 mol%) 0 16 : 16 : 0 : 47 : 1 b 4 [Ru(CO)3Cl2]2 (5 mol%) 0 7 : 8 : 0 : 68 : 3 a Percentage yields calculated from 1H NMR following column chromatography. b Percentage yields calculated from 1H NMR with internal standard following work-up.

A more electron-rich phosphine (P(C6H4OMe)3) was used as an additive with the

Ru(PPh3)3(CO)2Cl2 catalyst (Scheme 58), to investigate whether the increased electronic diﬀerence between the triarylphosphine and CO might lead to an increase in the proportion of 26b. However, it did not.

Ru(PPh3)3(CO)2Cl2 (10 mol%) N P(C H OMe) (30 mol%) N N 6 4 3 + 26 Cl I OO I Cl Cl I 33% 1,4-dioxane, N2 110 °C, 20 h

26 101 26b 26a (1.0 eq.) 6% 38%

Scheme 58: Eﬀect of electron-rich phosphine ligand on formation of 26a and 26b. Percentage yields calculated from 1H NMR with internal standard.

82 1.3.2.6. Iodination catalyst testing

In Zhang and co-workers’ paper on meta-nitration using Ru3(CO)12 catalyst, the active catalyst is proposed to be 67, a Ru(II) complex with two phenylpyridines coordinated at both the nitrogens and ortho-carbons (See Scheme 32, Section 1.1.3.2, p43).(97) This complex was synthesised, to test whether it might be the active catalyst in the iodination reaction. It was found that when complex 67 was used catalytically (Scheme 59 a), the iodinated product was obtained in 74% yield, with 7% 26b. The yield of 26a is comparable to when using Ru3(CO)12, although in that case, no 26b is observed. Thus, 67 is capable of either acting as a slightly less selective catalyst, or generating the active catalyst in situ. However, it was found that when complex 67 was used stoichiometrically in the reaction, a mixture of mono and di-halogenated compounds was obtained (Scheme 59 b), with the major mono-halogenated compound being that of chlorination, 26b. The product mixture did not reﬂect that obtained with Ru3(CO)12, suggesting that complex 67 is not part of the catalytic cycle.

CO N 67 (9 mol%) N N N 101 a) Ru (1.0 eq.) X CO 1,4-dioxane, N2 110 °C, 20 h

26 26a (X=I) 74% 67 26b (X=Cl) 7%

1,4-dioxane, N2 N N b) 67 101 + 1 2 (2.0 eq.) 110 °C, 20 h X X X

26a (X=I) 1% 26d (X1=X2=I) 28% 26b (X=Cl) 5% 26e (X1=I; X2=Cl) 12% 26c (X1=X2=Cl) 5%

Scheme 59: Iodination experiments with complex 67 (a) catalytically and (b) stoichiometrically.

83 1.3.2.7. Radical trapping experiments

Radical trapping experiments were carried out using three diﬀerent radical scavengers (Table 15). For both chlorination and iodination, all of the radical traps resulted in a huge reduction of the yield. In some cases (Entries 2–5), GCMS revealed that trace quantities of the product had formed. Products resulting from reaction of radicals with the radical traps were not observed by GCMS in any case. Therefore, whilst the mechanisms may involve radical species, it has not been proven deﬁnitively. It is possible that the radical traps may have interfered with the reactions in other ways such as by interaction with the ruthenium, or by reacting with the ICl, for instance in an electrophilic aromatic substitution.

A) Ru3(CO)12 (3 mol%), 101 (1.0 eq.) N N radical trap (2.0 eq.), 1,4-dioxane, N2, 110 °C, 20 h X or B) RuCl2(PPh3)3 (2.5 mol%), PPh3 (30 mol%) 101 (1.0 eq.), radical trap (2.0 eq.) 1,4-dioxane, air, 110 °C, 20 h 26 X = I 26a X = Cl 26b

Table 15: Radical trapping experiments

Entry Conditions Radical trap Result Radical scavenged products 1a A BHT 26a (not observed) Not observed 2 A TEMPO 26a (trace-GCMS) Not observed 3 A DPPH 26a (trace-GCMS) Not observed 4a B BHT 26b (trace-GCMS) Not observed 5 B TEMPO 26b (trace-GCMS) Not observed 6 B DPPH 26b (not observed) Not observed a Reaction carried out by Christopher Teskey. (128)

1.3.2.8. Kinetic isotope eﬀect studies

Experiments were conducted to determine the kinetic isotope eﬀects of the chlorination and iodination reactions (Scheme 60).(140)

84 (a) KIE determined by intramolecular competition experiment Recovered starting material: Conditions A: N Ru3(CO)12 (3 mol%), 101 (1.0 eq.) N N 1,4-dioxane, N2, 110 °C, 20 h D H D/H X D H/D or Conditions B: RuCl2(PPh3)3 (2.5 mol%), PPh3 (30 mol%) 101 (1.0 eq.), 1,4-dioxane, air, 110 °C, 20 h 118 118a/118b 118

Conditions A (X=I): KIE = 4 ratio H : D = 1 : 0

Conditions B (X=Cl): KIE = 3 ratio H : D = 0.4 : 1.6

(b) Kinetic isotope effects from parallel reactions (carried out in separate flasks):

Conditions A: N N Ru3(CO)12 (3 mol%), 101 (1.0 eq.) N N 1,4-dioxane, N2, 110 °C H H or D D H X or D X or Conditions B: H H D D RuCl2(PPh3)3 (2.5 mol%) H H D D PPh (30 mol%), 101 (1.0 eq.) H D 3 H D 1,4-dioxane, air, 110 °C 26 119 26a/26b 119a/119b

Conditions A (X=I): KIE = kH/kD = 1.2

Conditions B (X=Cl): KIE = kH/kD = 1.2

Conditions A: N N Ru3(CO)12 (3 mol%), 101 (1.0 eq.) N N 1,4-dioxane, N2, 110 °C H H and D D H X and D X or Conditions B: H H D D RuCl2(PPh3)3 (2.5 mol%) H H D D PPh (30 mol%), 101 (1.0 eq.) H D 3 H D 1,4-dioxane, air, 110 °C 26 119 26a/26b 119a/119b (0.5 eq.) (0.5 eq.)

Conditions A (X=I): KIE = PH/PD = 3.1

Conditions B (X=Cl): KIE = PH/PD = 3.0

Scheme 60: Kinetic isotope experiments by (a) intramolecular competition (Carried out by Christopher Teskey); (b) parallel reactions; (c) intermolecular competition.

Intramolecular competition experiments These experiments were carried out by Christopher Teskey (Scheme 60 a).(128) If no KIE is observed from an intramolecular

85 competition experiment, it means that C–H bond cleavage doesn’t occur during the rate determining step (RDS); however, if a KIE is observed, it is not certain that C–H bond cleavage is involved in the RDS.(140) It was found that KIEs were observed for both the iodination and chlorination reactions, meaning that C–H bond cleavage cannot be ruled out as the RDS for either reaction. It is noteworthy that recovered starting material from the iodination reaction had not undergone any H/D exchange, whereas that from the chlorination reaction was enriched with deuterium, suggesting that C–H bond cleavage is reversible for the chlorination but not for the iodination.

Parallel reactions The KIEs were measured by parallel reactions of 26 and 119 in separate flasks (Scheme 60 b). The reaction rate constants for each substrate were obtained, and the KIEs calculated from these. A small KIE value of 1.2 was observed for iodination, suggesting that C–H activation is the rate determining step for this reaction. The KIE value for the chlorination was also 1.2. The data used to calculate this gave two straight lines from which the initial rate constants could be obtained (Figure 8, p216). However, it was observed that the yields at the first time-point (30 seconds) differed considerably, as did the y-intercepts of the two lines, which suggested that the relative initial rate and KIE was actually much higher than 1.2. For 26, the rate appeared to have slowed down considerably after 30 seconds, whereas for deuterated 119, it appeared to speed up after 30 seconds. Unfortunately, it was not feasible to collect accurate data using the current method for time points less than 30 seconds in order to investigate this further. It is possible that the use of methods such as IR analysis of the reaction mixture over time might allow more accurate analysis over short time intervals.

Intermolecular competition experiments Using equimolar mixtures of 26 and 119 (Scheme 60 c), intermolecular competition experiments were carried out. The KIEs were calculated from the relative product ratio. Both iodination and chlorination resulted in signiﬁcant KIE values, of 3.1 and 3.0 respectively. Like the intramolecular

86 competition experiments, the presence of a KIE for this type of experiment indicates that C–H bond cleavage may (or may not) be involved in the RDS.

Conclusions drawn from KIE experiments For the iodination reaction, a KIE value was observed for all three experiments, suggesting that C–H bond cleavage is irreversible and the rate determining step. However, it is also possible (depending upon the error in the KIE value for the parallel reactions) that this KIE may be closer to 1. If this were the case it would suggest that the C–H bond step was irreversible, but that it is preceded by a diﬀerent step not including the phenylpyridine substrate, which would be rate-determining. For the chlorination reaction, KIEs were observed for all of the experiments, again suggesting that C–H bond cleavage is rate determining. This would also suggest an irreversible C–H bond cleavage, however, H/D exchange was observed, indicating that this is in fact reversible. The exact KIE value for the parallel reaction may be higher than calculated, and requires more investigation.(140)

1.3.2.9. Mechanism

A few key differences between the iodination and chlorination reactions were noted. Firstly, the addition of base had opposing effects on the two reactions – it acceler- ated the iodination, whilst being detrimental to the chlorination. Unfortunately, the reasons behind this contrasting effect of base remain unclear. In addition, the use of homogeneous reaction conditions was unfavourable for the chlorination, perhaps due to solvent effects, or perhaps due to the existence of two phases being important for the mechanism. Conversely, the iodination proceeded equally as well, if not better under homogeneous conditions with 1,2-dichloroethane as solvent.

Pyridine has been shown to form complexes with iodine monochloride in solution by coordination on the nitrogen.(141–144) The pyridine nitrogen on 2-phenylpyridine is more basic than the oxygen on 1,4-dioxane, so it is likely that both chlorination

87 and iodination proceed with competitive formation of nitrogen–ICl complexes and nitrogen–Ru complexes.

One possible mechanistic explanation for the selectivity between iodination and chlorination would be a pathway such as that in Scheme 61. Cycloruthenation, followed by oxidative addition of the iodine monochloride would aﬀord Ru(IV) species 120. Reductive elimination could form the C–X bond, with the selectivity between C–Cl formation and C–I formation controlled by the electronics of the ligands L. This type of mechanism is often proposed for Pd(II) catalysed ortho-C–H halogenation reactions, and in some cases of Pd(II) mediated C–X bond formations, Pd(IV) intermediates have been isolated and characterised.(38) In addition, reductive elimination from a Ru(IV) intermediate to form a C–X bond has previously been proposed for the ruthenium catalysed transformation of aryl triﬂates to aryl halides.(145) Iodine monochloride is a strong oxidising agent, thus the involvement of a Ru(IV) intermediate is not un- reasonable. However, there is little precedent for the irreversible selective reductive elimination to form one C–X bond in favour of another.(38)

Ru(II)Ln Ru(II)Ln cycloruthenation 37

reductive elimination oxidative addition

I Cl L N N Cl IV X Ru I L

X = I/Cl 120

Scheme 61: Possible overlapping mechanism for the two halogenations, where reductive elimination is controlled by ligands L

88 Instead, the possibility that the chlorinated product might be formed from the iodinated product was considered (Scheme 62). The more electron rich RuCl2(PPh3)3 catalyst could enable oxidative addition of the C–I bond, and reductive elimination to form a C–Cl bond. The increased strength of the C–Cl bond would thermody- namically favour formation of this product. Similar thermodynamic control has been used by Schoenebeck for the conversion of aryl iodides to aryl bromides mediated by a Pd(I) dimer.(146) This conversion between the two may account for the formation of mixtures of iodinated and chlorinated products in para-halogenated substrates, as oxidative addition is more favourable for electron poor substrates. However, it would not account for the lack of this eﬀect with para-ester or aldehyde substrates (Scheme 51, p73). The lack of any traces of iodinated product from the chlorination reactions in general suggests that conversion from iodo to chloro should be much faster than initial iodination if this mechanism is responsible for chlorination. The ortho-iodinated phenylpyridine 26a, and the analogous para-brominated compound 113a were submitted to the chlorination conditions. It was found that whilst some conversion from the iodinated product to the chlorinated product had taken place, the majority of recovered material still contained an ortho-iodine. Therefore whilst this reaction can take place, it seems unlikely to be the dominant mechanism responsible for chlorination.

reversible oxidative reductive N N N I N addition elimination RuIVL I n Cl Cl

26 26a 120 26b

Scheme 62: Possible conversion of iodinated product to chlorinated product

Ru3(CO)12 has been shown to undergo oxidative addition with halides to aﬀord bridged intermediates of the form [X(CO)3Ru(µ-X)2Ru(CO)3X], where X = Cl, Br, I (Scheme 63).(147–149) However, depending upon the reaction conditions, a mixture of halogenocarbonyl compounds can be obtained, such as Ru(CO)4X2, which decomposes (150) in solution above room temperature to give trimeric Ru3(CO)12X6. It is proposed

89 X CO N X2 OC X CO –CO Ru3(CO)12 Y Ru Ru Ru(CO)2X OC X CO CO X Y N 2 121

Scheme 63: Formation of dinuclear [Ru(CO)3X2]2 compounds, and reaction to form metallacycle 121

that ICl would undergo an analogous oxidative addition with Ru3(CO)12 to aﬀord

[Ru(CO)3ICl]2, where either I or Cl act as the bridging ligands. When Ru3(CO)12 was added to [1,4-dioxane(ICl)2] 101 in 1,4-dioxane at room temperature, bubbling was observed. The reaction mixture was heated to 50 ◦C overnight, and a yellow/green precipitate formed (122, Scheme 64 a), which could be isolated by ﬁltration. Mass + + spectrometry (ESI+) showed ions corresponding to [Ru(CO)3ICl2] , [Ru(CO)3I2Cl] , + + + [Ru(CO)3I3] , [Ru(CO)3Cl3] and [Ru(CO)2I3] , suggesting that the compound obtained may be the trimer, or a mixture of compounds. Heating this solid (122) with two equivalents of phenylpyridine in 1,4-dioxane at 110 ◦C did not result in the observation of 26a (Scheme 64 b). A precipitate which was insoluble in all organic solvents tested was obtained, as well as a product which appeared by ESI mass spectrometry to be phenylpyridine coordinated to –RuCl2CO on the nitrogen. The same reaction

1,4-dioxane a) Ru3(CO)12 + 1,4-dioxane(ICl)2 RuaClbIc(CO)d 101 50 °C, 18 h 122 1.0 eq. 1.5 eq.

N 1,4-dioxane N b) + 122 + 1,4-dioxane(ICl)2 1.0 eq. 101 110 °C, T h I x eq.

26 26a 2.0 eq. x = 0, T = 20 h not observed or x = 2.0, T = 4 h

Scheme 64: (a) Reaction of Ru3(CO)12 with 101 to form 122. (b) Reaction of 122 with phenylpyridine.

90 carried out with two equivalents of ICl yielded similar results. Given that halogens ◦ (150) can react with Ru3(CO)12 in minutes at temperatures as low as −80 C, and ICl is a strong oxidant, it seems unlikely that C–H activation precedes reaction between the catalyst and ICl. Therefore two possibilities seem likely. The isolated solid 122 may not be the active form of the Ru(II) catalyst, perhaps as a result of its isolation, the reaction conditions it was formed in being diﬀerent to that of the usual iodination (lower temperature), or the instability of the active catalyst over time/out of solution. Alternatively, 122 may be ineﬀective at mediating the reaction when present in stoichiometric quantities–an excess of ICl or phenylpyridine might be required for product formation or turnover. It should also be noted that [Ru(CO)3Cl2]2 catalysed the C–H iodination almost as well as Ru3(CO)12, with similar selectivity (Table 14, Entry 3, p82), supporting the possibility of the active catalyst taking this form.

Figure 2: Proposed dinuclear structures for ruthenacycle 121a(151)

N N CO N CO N N N Ru(CO) Cl C Cl CO C Cl C N 2 = Ru Ru Ru Ru = OC Cl C OC Cl CO C CO N CO N 2 121a 121a' 121a''

Cycloruthenation using [Ru(CO)3Cl2]2 to form 121 (Scheme 63) is often challenging, and requires high temperatures as it involves loss of a CO ligand.(152) This may explain the results of the KIE experiments for the iodination, which suggested that C–H activation could be preceded by a rate determining step not involving 2-phenylpyridine – the loss of CO to form a 16-electron complex prior to cycloruthenation may be rate limiting. The exact structure of ruthenacycles of type 121 is generally poorly understood, however Hiraki and co-workers have isolated the cyclometallated N -phenylpyrazole compound 121a, and based on IR data they suggest the dinuclear structures 121a0 and 121a00 as the most likely conﬁgurations (Figure 2).(151)

Based on this, the mechanism for iodination is proposed to proceed initially via

91 oxidative addition of iodine monochloride to Ru3(CO)12 to form an active Ru(II) catalyst of the form [Ru(CO)3ICl]2 (Scheme 65). Loss of CO may be the rate determining step, before irreversible cycloruthenation to form ruthenacycle 121b, which may exist as a dinuclear structure similar to 121a (Figure 2).

Ru3(CO)12 N oxidative addition I Cl I 26 CO, HX deprotonation II [Ru (CO)3ICl]2

N Path A N Path A N II Ru (CO)2XCl RuII(CO) X II I 2 Ru (CO)2X Cl I 2 125 121b electrophilic aromatic substitution Path B I Cl oxidative addition CO CO

CO N X N Path B RuII(CO)XCl RuIV I reductive elimination I Cl

124 123

Scheme 65: Proposed mechanistic explanations for the formation of ortho-iodinated 26a

From 121b, two pathways are proposed. The ﬁrst (Path A) is based on the fact that metal-backbonding with the CO ligands results in a more electron poor ruthenium centre. This may disfavour an oxidative addition pathway (relative to a ruthenium catalyst without CO ligands). Instead, an electrophilic aromatic substitution type mechanism may take place with the ICl. Selectivity for the ortho-position could be controlled by interaction with the ICl before its heterolytic cleavage into I+ and Cl−. This may be

92 by interaction of the weakly basic Cl with the ruthenium, or may be due to interactions of the ICl with the carbonyl ligands, and the heterolytic cleavage/electrophilic aromatic stubstitution may be concerted or stepwise. The reactions of halogens X2 with transition metal carbonyl compounds has been shown to proceed with rapid initial formation of adducts of the form complex · nX2. These reactions are proposed to involve electrophilic attack at the oxygen atoms on their CO ligands.(153–156) This would result in the electrophilic iodine being coordinated in close proximity to the ruthenium, and increases the nucleophilicity of the chlorine, enabling site-selective iodination. This mechanism could also explain the poor selectivity between iodination and chlorination for substrates featuring halogens in the para-position, as the position meta to the halogens would be the least susceptible on the ring to electrophilic aromatic substitution. This may disfavour these pathways for para-halogenated substrates and result in a diﬀerent pathway to form the chlorinated products preferentially. Whilst the para-carbonylated substrates are electron poor, the meta-position to the carbonyl is the most electron rich on the ring so this may still be feasible, which could explain their success as substrates for iodination.

An alternative pathway which may take place is path B, where 121b undergoes oxidative addition with ICl to form a Ru(IV) complex 123. This could then undergo selective reductive elimination to form a C–I bond. Reasons why the iodide and not the chloride might be selective for the reductive elimination include the relief of steric crowding around the ruthenium centre, and the Ru–I bond being weaker than the Ru–Cl bond. In addition, chloride is a better π-donor than iodide, so is better able to stabilise a CO bond which is trans to it by increasing the electron density available at the metal for backbonding. However, there are reasons why this oxidative addition mechanism might seem unlikely, one being that the catalyst Ru(PPh3)2(CO)2Cl2 was able to catalyse the reaction with good selectivity for iodination. With this catalyst, the initially formed ruthenacycle 126 would only contain one CO ligand, meaning a relatively smaller electronic diﬀerence c.f. RuCl2(PPh3)3, so selectivity here would be expected to be poorer. DFT calculations would aid in determining the feasibility of

93 this pathway, and whether one CO ligand would be suﬃcient to control the selectivity. In addition, triphenylphosphine ligands are generally used to increase the rate of oxidative addition due to the increased electron density on the ruthenium, so the yield from reaction with Ru(PPh3)2(CO)2Cl2 would be expected to be higher than with Ru3(CO)12. By this reasoning, Ru3(CO)12 is also less likely to proceed via a

Ru(II)/Ru(IV) pathway than RuCl2(PPh3)3. For these reasons, a mechanism resembling Path A seems more plausible.

Two possible pathways were tentatively proposed for the ortho-chlorination reaction (Scheme 66). The first (Path B) is a Ru(II)/Ru(IV) mechanism analogous to that proposed as a possible route for iodination. Following reversible formation of the ruthenacycle 127, oxidative addition of ICl followed by selective reductive elimination to form a C–Cl bond would afford the ortho-chlorinated product. Phosphine ligands are often used to promote oxidative additions, making this pathway seem more likely for the chlorination than iodination. However, the excellent selectivity of the C–Cl bond formation over C–I by reductive elimination might seem unlikely, given the steric advantages of C–I bond formation, and the strength of the Ru–Cl bond being higher than Ru–I. It is possible that the lone PPh3 ligand is influencing the reductive elimination electronically, and because the ruthenium centre is more electron rich, it retains the less electron donating of the two ligands (I).

Use of iodine monochloride as a chlorinating agent has been proposed to involve formation of charge transfer complexes, to generate the metastable radical anion [ICl]•−.(157,158) This can undergo cleavage to form I• and Cl−. Kochi et al. reported the formation of charge transfer complexes between ICl and electron rich arenes, resulting in iodination or chlorination of the arene. This selectivity, due to competition between ion-pair and radical-pair collapse was aﬀected by factors such as solvent polarity, salt eﬀects, and substrate sterics.(159)

It is proposed that the ruthenacycle 127 could form a charge transfer complex with ICl, with electron transfer from the Ru(II) to form Ru(III) intermediate 130 taking

94 N

Cl 26 PPh3, HCl deprotonation II Ru (PPh3)3Cl2

PPh3 PPh3 I Cl Cl N N PPh3 N PPh3 II Path B Path B Ru (PPh3)2ICl RuIV RuII PPh Cl 3 reductive I oxidative Cl elimination Cl addition 129 128 127

ICl

ICl Path C ICl N PPh3 SET III Ru PPh3

PPh3 PPh Cl N Path C N 3 II II PPh3 130 Ru PPh3 Ru ion-pair Cl Cl Cl Cl I collapse I N PPh3 PPh3 133 132 III Ru Cl Cl abstraction Cl I 131

Scheme 66: Proposed mechanistic explanations for the formation of ortho-chlorinated 26b place (Scheme 66, Path C). Alternatively, abstraction of Cl by ruthenium, analogous to the Cl abstraction in the ruthenium catalysed Kharasch-type chemistry could take place, forming a ruthenium(III) ruthenacycle 131 and an iodine radical. RuCl2(PPh3)3 is well established as a catalyst of ATRA reactions.(160) Single electron transfer from the aromatic ring to the ruthenium may take place to generate Ru(II) species 132 and an aromatic radical cation (as well as dissociation of the radical ion to chloride and I• in the case of the CT complex). The selectivity between chlorination and iodination could then be controlled by a number of factors. Coordination of the chloride

95 ion to the ruthenium (in a manner similar to that proposed by Yu for Cu catalysed ortho-chlorination(42) (Scheme 9, p19)) or its trapping within a solvent cage, may induce the ortho selectivity. The relatively non-polar 1,4-dioxane solvent is proposed to better stabilise the iodine radical than the chloride ion, promoting ion-pair collapse. In addition, if the mechanism proceeded via Cl abstraction (131), the proximity of the chloride ion may affect the selectivity, as the iodine radical may have had more time to diffuse away from the ruthenacycle. Finally, another factor that could disfavour attack of the iodine radical is sterics, particularly if the cyclometallated species was one containing two phenylpyridine rings rather than the one shown in Scheme 66. This could explain the formation of significant quantities of chlorinated product in the reaction of stoichiometric 67 under the chlorination conditions (Scheme 59, p83). The synthesis of an analogous bis-cyclometallated catalyst from RuCl2(PPh3)3 may help to determine this, or kinetic experiments to identify the order of the chlorination reaction with respect to phenylpyridine.

Another factor which may increase the propensity for chlorination is the reaction be- + − (161) tween PPh3 and iodine monochloride, to form [Ph3PI] and Cl . Whilst this alone cannot be responsible for the chlorination (as the addition of PPh3 to the iodination reaction still resulted in iodination, see Scheme 57, p57), the increase of free chloride ions for ion-pair collapse would favour this. This is in line with Kochi’s ﬁndings, and is also perhaps why the addition of PPh3 increases the yield.

1.3.3. Conclusions and future work

In conclusion, iodine monochloride can be used as a versatile halogenating agent for directed ortho-C–H chlorination or iodination. Selectivity between incorporation of iodine or chlorine is governed by the choice of ruthenium catalyst, with Ru3(CO)12 resulting in iodination, and RuCl2(PPh3)3 enabling chlorination.

Both reactions were most eﬀective on 2-arylpyridines, although isoquinoline was also an eﬀective directing group, and pyrimidine also worked to a lesser extent. Weak

96 electron donating methyl substituents were tolerated in various positions on the substrate, and versatile electron withdrawing groups such as esters and aldehydes were also tolerated. Halogens in the ortho and meta-positions were also tolerated, however para-halogens were poorly selective for the iodination. Added base has converse eﬀects on the rate of chlorination/iodination, and by speeding up the rate of iodination could be used to allow selective iodination of a para-brominated substrate.

Kinetic isotope eﬀects found that for the iodination, irreversible C–H bond cleavage may be the rate determining step, or may be preceded by a step not involving the aromatic substrate. For the chlorination, C–H bond cleavage appears to be the rate determining step, however, the exact value of the KIE for the parallel reactions may be higher than calculated.

Radical trapping experiments found that both reactions are halted by the addition of radical scavengers, but no radical scavenged products were observed in any case.

Experiments found that the presence of CO ligands in the catalyst is a crucial factor in determining selectivity between iodination and chlorination, whereas the presence of PPh3 or Cl ligands have little eﬀect.

The iodination reaction is proposed to proceed via an electrophilic aromatic substitution type mechanism, with regioselectivity for the ortho-position controlled by electrostatic interactions between the iodine monochloride and the CO ligands. Chlo- rination, on the other hand, is proposed to proceed via a mechanism involving a SET from ruthenacycle to ICl, to aﬀord a chloride ion and iodine radical, with an aromatic cation radical. Selective ion-pair collapse then results in chlorination. It is also possible that either chlorination or iodination may proceed via a Ru(II)/Ru(IV) cycle, with selective reductive elimination to form the C–Hal bond. This pathway is suggested to be more likely for the more electron-rich RuCl2(PPh3)3 catalyst for the chlorination, however, DFT calculations may help to assess the relative likelihood of the proposed reaction mechanisms.

97 Kinetic measurements were attempted by GCMS, however the biphasic nature of the reactions led to results which were inconsistent. It is possible that the use of other analysis methods such as IR might enable kinetic measurements, which might in turn aid elucidation of the reaction mechanism.

The methodology provides a route towards ortho-halogenated phenylpyridines which are particularly valuable as substrates for further functionalisation. The use of low cost ruthenium catalysis was combined with ICl, which provides a cheaper alternative to iodinating agents such as NIS and generates no organic waste. The reaction demon- strates the diversity of reactivity that can be observed by simple exchange of a few ligands on the catalyst. The ability of base to strongly aﬀect the reaction outcome was also observed. Better understanding of these eﬀects could lead to the development of new reactions in ruthenium catalysed directed C–H functionalisation.

98 1.4. Tandem N,C-diarylation of pyrazole

1.4.1. Background: Diaryliodonium salts

1.4.1.1. General

Diaryliodonium salts (also, less commonly, referred to as diaryl-λ3-iodanes) were ﬁrst discovered in 1894 by Hartmann and Meyer.(162,163) Whilst they are generally referred to as salts, X-ray structures of iodine(III) compounds actually show a T-shaped structure, with one aryl group in the equatorial position (Figure 3). The two other ligands occupy axial positions, and share a hypervalent 3-centre-4-electron bond with the iodine.(163,164) The diaryliodonium salt structure in solution is disputed, it could be of a more ionic nature or remain as a T-shape, it is likely to depend on the solvent and the nature of X.(164–166)

Figure 3: General T-shaped structure of diaryliodonium salts

X = Cl, Br, I, OTs, OTf, BF4

Diaryliodonium salts are highly electrophilic at iodine, so react with nucleophiles by attack at the iodine and replacement of one of the ligands to form a Nu–I bond, generally followed by reductive elimination to form Nu–L.(164,167–170) They are also able to react with metal catalysts, as a more reactive version of an aryl iodide, undergoing oxidative addition with the metal to form Ar–M–L, which can then go on to form various products.

99 1.4.1.2. Arylation of nitrogen nucleophiles with diaryliodonium salts

The arylation of heteroatom nucleophiles using diaryliodonium salts is a long established reaction. Early reports by the group of Beringer describe the phenylation of various organic and inorganic bases, such as sulfonamides, amines, cyanides, alkoxides, sulﬁtes and benzoates, by reﬂuxing in aqueous solution.(171) Since then, much has been achieved in terms of increasing the scope of such reactions, as well providing milder reaction conditions, and higher yields.(163,172)

N -heterocyclic substrates comprise a large part of the literature and copper catalysis has enabled the N-arylation of a broad range of heterocycles.(173–180)

Work by the Kang group has reported the copper catalysed N-arylation of amines, N -heterocycles and amides.(173) Amine substrates could be arylated under particularly mild conditions, at room temperature in DCM. Na2CO3 was found to be the best base for this reaction, and CuI the optimal catalyst, but it was noted that CuBr and

CuCl2 were also eﬀective (Scheme 67). Amides and azoles required higher reaction ◦ temperatures of 50 C (Scheme 68). Cu(acac)2 was found to be a superior catalyst for these reactions, and K2CO3 was the base of choice. Azoles such as benzotriazole, 3,5-dimethylpyrazole, imidazole and benzimidazole were phenylated in pleasing yields.

Ar2IBF4 (1.0 eq.), CuI (10 mol%) Na2CO3 (2.0 eq.) R1R2NH R1R2NAr 1.5 eq. DCM, rt, 6 h

Selected examples Ph I

NH NH NH NH N Ph Ph Ph Ph Ph

134 135 136 137 138 65% 75% 80% 72% 70%

Scheme 67: Kang’s copper catalysed N-arylation of amines in mild conditions(173)

100 Ar2IBF4 (1.2 eq.), Cu(acac)2 (5 mol%) K2CO3 (1.2 eq.) R1R2NH R1R2NAr toluene, 50 °C, 6 h

Selected examples O O N N O N N Ph N Ph Ph N N N N N Ph H Ph Ph p-tol 139 140 141 142 143 144 80% 85% 85% 70% 65%* 42%*

*CuI used in place of Cu(acac)2

Scheme 68: Kang’s copper catalysed N-arylation of azoles and amides(173)

In the case of lactams, the formation of products 142 and 143 was found to be very dependent on the choice of catalyst (CuI or Cu(acac)2), with the alternative to that shown in Scheme 68 giving yields of around half as much. An acyclic amide could be converted to 144 with catalytic CuI, albeit in a modest 42% yield. Zhou and Chen have also reported a CuI catalysed N-arylation of benzimidazoles with similar conditions to Kang’s paper, but a slightly higher temperature of 80 ◦C in DMF. They examined a slightly broader scope of diaryliodoniums, and saw yields of 54–80%.(174)

O2N

Me (p-tol)2IBF4 (1.0 eq.), CuI (20 mol%) N DBU (1.0 eq.) N Me N N NO2 MeCN, MW H 145

146

Scheme 69: Copper catalysed N-arylation of unsymmetrical pyrazole 145(175)

Chertkov and co-workers have also reported a copper catalysed N-arylation of unsymmetrical azoles, in which they study in particular regioselectivity between the two nitrogens for N-arylation (Scheme 69).(175)

Indoles have also successfully been arylated with diaryliodonium salts and CuI

101 catalysis in good yields, however high reaction temperatures of 140–150 ◦C were required (Scheme 70).(176)

Ar2IBF4 (1.0 eq.), CuI (10 mol%) K2CO3 (3.0 eq.) N N DMF, 140–150 °C, 6–7 h H Ar 147 148 7 examples 72–92% yield

Scheme 70: Copper catalysed N-arylation of indoles(176)

Copper catalysis is not always a requirement for N-arylation using diaryliodonium salts, and there are some recent examples of metal-free N-arylations. For instance, Car- roll and Wood published a metal-free arylation of anilines, providing the N -arylaniline products in good to excellent yields by heating to 130 ◦C in DMF for 24 hours.(181) In this work, they also investigate the eﬀect of the counterion used in the iodonium salt.

Work by Nov´akand Gonda reports the extremely mild, metal-free N-arylation of pyrazoles at room temperature in the presence of mild base (Scheme 71).(182) In the paper, they study experimentally the chemoselectivity of aryl transfer in unsymmetrical diaryliodonium salts (vide infra).

Ar Ar

Ar X R2 NH (aq.)/C H Cl (1:1) N N I 3 2 4 2 Ar N Ar N N Ar N rt, 20 min H 1 2 R1 R R

149 150 151a 151b (1.0 eq.) (1.1 eq.) 72 examples 8–100% yield

Scheme 71: General scheme for Nov´ak’sN-arylation of 3,5-diarylpyrazoles(182)

1.4.1.3. Mechanism of the N-arylation of pyrazoles

Nov´ak, Stirling and co-workers have investigated the mechanism of metal-free N- arylation of pyrazole and similar heterocycles with diaryliodonium salts, experimentally

102 as well as theoretically (using DFT).(165) They propose that the mechanism begins with coordination of the neighbouring, Lewis basic N atom (blue, in Scheme 72) to the iodonium cation to form a T-shaped adduct 153. This increases the acidity of the neighbouring N–H proton, and facilitates its deprotonation to form 154. The rate determining step is then the N-arylation, which takes place by a [2,2] rearrangement via transition state 155 to give the product 156. Key to this mechanism is the presence of neighbouring Lewis and Brønsted acidic heteroatoms, which act consecutively, and enable the use of a mild base. This allowed the authors to successfully predict other heterocycles which could (e.g. 7-azaindole) and could not (indole, which lacks a neighbouring heteroatom) be arylated under the mild, metal-free conditions.

Ph Ph Ph Ph Ph

N N N N Ph I Ph N Ph Ph Ph N N Ph N I Ph N I N Ph Ph H H Ph Ph Ph B 152 153 154 155 156

Scheme 72: Nov´akand Stirling’s proposed mechanism of metal-free arylation of 3,5-diphenylpyrazole 152 with diaryliodonium salts(165)

However, it is unlikely that the mechanism is as clear-cut as this explanation suggested, as it fails to address a result from a previous report by Novák,in which the arylation of 3-phenyl-1H -pyrazole 157 gave a 1:1 mixture of 1N - and 2N -aryl products (158a and 158b) (Scheme 73).(182) Whilst the formation of 158a is explained by the mechanism in Scheme 72, that of 158b is not. If Novákand Stirling’s calculations (which suggest that deprotonation of the free pyrazole is unfavourable) are assumed to be true, then it could be postulated that the mechanism goes by one of two routes. One of these is suggested in their original paper, based only on preliminary findings (Scheme 74 a).(182) This is similar to the mechanism in Scheme 72, but the iodonium cation coordinates to the protonated nitrogen, facilitating its deprotonation to form 160, which can the undergo [2,2]-rearrangement to afford 158b. Alternatively, metal-free reactions between nucleophiles and iodoniums have generally been proposed

103 Ph Ph (Ph)(Mes)IOTf (1 eq.) Ph N N 25 w/w% NH (aq. soln.) - DCE (1:1) N N N 3 N Mes H RT Mes 157 158a 158b 1 : 1

Scheme 73: An example of N-arylation by Nov´akwhich does not conform to the mechanism reported in Scheme 72(182) to proceed via reductive elimination.(164,167–170) It is possible that formation of 158b may occur via the same initial route as 158a, but instead of a [2,2] rearrangement step, 163 could undergo reductive elimination to form 158b (Scheme 74 b). Reports (171,183–186) also exist of the existence of SNAr-type mechanisms, and, in some circum- stances (when the reactant is an electron rich arene), a radical mechanism involving single electron transfer (SET) from electron-rich aromatics to iodine.(187–190)

Ph Ph Ph Ph Ph N N N a) N N N N Mes N H N Mes H I Mes I Mes I N Ph Ph Ph 157 159 160 161 158b

Ph Ph Ph reductive Ph elimination b) N N N N I Ph I N N N Ph N Mes H H Mes Mes B 157 162 163 158b

Scheme 74: Possible mechanistic explanations for the formation of 158b

1.4.1.4. Mechanism for copper catalysed N-arylation

The copper catalysed reaction is generally proposed to proceed via a Cu(III) intermediate (Scheme 75).(172,179,191–193) If a Cu(II) catalyst is used, this is ﬁrst reduced to Cu(I) by a nucleophile. Oxidative addition takes place between the Cu(I) and the

104 diaryliodonium salt to furnish a copper(III) species and PhI. Ligand exchange then takes place, such that the nucleophile is a ligand to the copper (this may be preceded by deprotonation of the nucleophile). Reductive elimination furnishes Nu–Ph and the Cu(I) catalyst.(192)

Ph I Y Nu-Ph CuIX Ph

reductive oxidative elimination addition PhI

X X CuIII CuIII Nu Ph Y Ph

B BH Y NuH

Scheme 75: Mechanism for the copper catalysed reaction of diaryliodonium salts with nucleophiles

1.4.1.5. Atom economical use of diaryliodonium salts

Diaryliodonium salts are highly versatile arylating agents, and are compatible with a number of metal catalysts,(163) however unfortunately their use is associated with one major drawback: poor atom economy. Most transformations result in the formation of an equivalent of waste aryl iodide. In order for their use to continue to be sustainable, and to comply with the principles of green chemistry, this issue needs to be addressed.(195) There are very few examples in the literature where both parts of a diaryliodonium salt have been put to use. A very early example is in work by Bu- magin, Beletskaya and colleagues, involving the overall reaction of two equivalents of diaryliodonium salt with sodium tetraphenyl borate to give four equivalents of diaryl product 164 (Scheme 76).(194) This proceeds in extremely high and pleasingly eﬃcient yields of 96–98%. Beletskaya followed this with a palladium and copper catalysed arylation of benzotriazole, using both parts of the diaryliodonium (Scheme 77).(196)

105 PdCl2 (1 mol%) Ph4BNa Ar2IX 4 Ar Ph Na CO , H O, 150 2 3 2 164 80 °C, 1 h Ar = Ph, m-NO2C6H4, 96–98% p-FC6H4 X = HSO4, BF4, CF3COO

Scheme 76: Pd catalysed cross-coupling of diaryliodonium salts with sodium tetraphenylborate(194)

There are some examples of the use of other iodine(III) compounds in atom economical ways, for instance the 2-iodobenzoic acid waste generated by use of alkynylbenzio- doxolones 167 has been trapped to form furans(197) and oxy-alkynes(198) (Scheme 78). Dauban and co-workers have reported the sequential role of oxidant/arylating reagent (199,200) for iodine(III) reagents ArI(OAc)2. In one example, they report a tandem catalytic C(sp3)–H amination/cross-coupling reaction (Scheme 79 A).(199) In the ﬁrst step, the iodine(III) acts as an oxidising agent to enable a rhodium catalysed C(sp3)–H amination. The generated aryl iodide is then able to act as an arylating agent, in a sila-Sonogashira–Hagihara coupling. The yields are good to excellent, with a range of scaﬀolds such as aromatic, heteroaromatic, alkenes and alkanes tolerated, and the products were formed with a high level of diastereocontrol. In work that builds further upon this concept, they reported a catalytic auto C(sp3)–H amination reaction, in which the iodine(III) substrate acts as both the substrate and the oxidant, followed by a variety of palladium catalysed cross coupling reactions utilising the aryl iodide (Scheme 79 B).(200)

Pd(OAc)2 (2 mol%) N CuX2 (2 mol%) N 2 N + Ar2IBF4 2 N N 2TPPTS, NaOH N H 150 H2O, 100 °C, 6 h, N2 Ar 165 Ar = Ph, p-MeC6H4, 166 p-MeOC6H4, p-ClC6H4 93–96%

Ph X = TPPTS = OOC P SO3Na 3

Scheme 77: Pd- and Cu-catalysed arylation of benzotriazole, using both parts of the diaryliodonium salt(196)

106 PMPN N2 1 1 I R1 R I O R O R4 EWG R2 R3 O O Cu cat. Pd cat. R2 O rt rt R3 I R4 EWG 168 167 169

Scheme 78: Trapping of 2-iodobenzoic acid residues from 167(197,198)

A) catalytic C(sp3)–H amination sila-Sonogashira–Hagihara S*HN coupling S*HN

[Rh2(S-nta)4] (3 mol%) Pd(PPh ) (10 mol%) Various S*NH2 (1.2 eq.) Various 3 4 Various scaffolds scaffolds scaffolds PhI(OPiv)2 or ArI(OAc)2 (1.4 eq.) CuCl (1 eq.), DABCO (4 eq.)

n (Cl2CH)2/MeOH (3:1) Bu4NF (2 eq.) –35 °C, 72 h THF, 70 °C, overnight TMS TMS Ar with ArI 170 171 172

B) Suzuki Miyaura coupling 3 catalytic auto C(sp )–H (Pd(dppf)Cl2, K2CO3, 2 amination Ar BMIDA or RCHCHBF3K)

H [Rh2(S-nta)4] (3 mol%) S*HN or Sonogashira coupling S*HN S*NH2 (1.2 eq.) (Pd(PPh3)4, CuCl, NEt3, RCCH)

Ar (Cl2CH)2/MeOH (3:1) Ar or Mizoroki-Heck Ar –35 °C, 72 h (Pd(OAc) , NEt , EWGCHCH ) 2 3 2 1 (AcO)2I I R 173 174 175

N O 1 2 [Rh2(S-nta)4] = O S*NH2 = S R = Ar , R p-Tol NH2 R O O Rh TsN Rh

Scheme 79: A) Dauban’s tandem catalytic C(sp3)–H amination/cross coupling reaction using iodine(III)(199) B) Tandem catalytic auto C(sp3)–H amination/cross coupling reactions(200)

107 Work by the Greaney group has reported the tandem C,N-arylation of indole, using copper catalysis and diaryliodonium salts (Scheme 80).(201) This is believed to be the first example of the use of two distinct aryl groups from a diaryliodonium salt for two separate bond forming events. The same metal catalyst (CuI) is used to achieve two different transformations in one pot, with the mode of reactivity switched simply by addition of a different base and ligand.

R2 1) CuI (20 mol%), dtbpy (1.1 eq.) TfO I dioxane, 60 °C, 24 h 1 2 R R R1 N 3 H R 2) DMEDA (30 mol%) N K3PO4 (2 eq.), 110 °C, 16 h

147 150 176

Selected examples: Cl F OMe Me Cl

MeO N O N N N N O N N N N O O F OMe Me 176a 176b 176c 176da 176ea 58% 41% 65% 48% 51%

a Step 2: DMEDA (40 mol%), K3PO4 (2 eq.), 95 °C, 24 h

Scheme 80: Sequential C,N-arylation of indole using both aryl groups from diaryliodonium salts(201)

More recent work by the Greaney group exempliﬁes the synthesis of triarylamines from anilines and diaryliodonium salts, again using copper catalysis (Scheme 81).(202) Whilst the chemistry itself is relatively simple, it provides a valuable strategy towards improving the atom economy of diaryliodonium use.

Mu˜nizand co-workers have disclosed a tandem borylation/Suzuki–Miyaura cross-

108 coupling of diaryliodonium salts to form biaryls in satisfactory to very good yields (Scheme 82).(203)

1) CuI (2 mol%), dtbpy (1.03 eq.) 2 2 NH2 R R TfO I toluene, rt, 12 h R2 N R1 R2 2) CuI (10 mol%), 1,10-phen (30 mol%), tBuOK (4.5 eq.), 120 °C, 24 h R1

177 150 178 15 examples, yields up to 75%

Scheme 81: Synthesis of triarylamines from anilines and diaryliodonium salts via tandem C–N bond formation(202)

Jiang and co-workers have described the conversion of diaryliodonium salts into diarylsulfides using Cu(II) catalysis, and KSAc as a sulfur source. This allows access to diarylsulfides from a odourless and safe sulfur source, and uses both parts of the diaryliodonium in an efficient manner (Scheme 83).(204) The reaction works for both symmetrical and unsymmetrical diaryliodoniums, as well as for cyclic iodoniums to form 5- to 8-membered rings. There are several other examples in the literature of the reactions of cyclic iodonium salts in sequential bond formations, often to form bridged biaryls. Whilst elegant in their utilisation of the generated aryl iodide moiety for further functionalisation, these examples do not involve the capture of an otherwise waste species.(192,205–209)

The development of methods for the recycling of aryl iodides, for instance using polymer supports, is an important step towards more environmentally friendly use of

R 1) B pin (1.5 eq.), R AcO I 2 2 MeOH, 50 °C, 24 h R

R 2) Pd(PPh3)4 (10 mol%) Cs2CO3 (2 eq.), toluene, 80 °C, 16 h 150 179 4 examples, 42–87% yield

Scheme 82: Tandem borylation/Suzuki–Miyaura coupling(203)

109 R2

Cu(OTf)2 (10 mol%), 1,10-phen (12 mol%) X I S KSAc (2 eq.), K3PO4 (2 eq.) R1 R2 R1 DMSO, 100 °C, 3–12 h

150 180 X = OTs, OTf

Scheme 83: Jiang’s construction of diarylsulﬁdes from diaryliodonium salts(204) hypervalent iodine reagents which has seen some progress.(210,211) In addition, the use of oxidising agents in situ for the generation of aryl-λ3- and aryl-λ5-iodanes has enabled the use of catalytic quantities of aryl iodide.(211–213) However, these methodologies are largely limited to use with iodine(V), or iodine(III) in the form of ArIX2 for oxidation reactions, rather than diaryliodonium species.

1.4.1.6. Unsymmetrical iodonium salts: selectivity

There are a number of factors affecting which aryl group of an unsymmetrical diaryliodonium salt will transfer during a reaction with a nucleophile. The general rule observed is that the more electron-poor aromatic will be transferred onto the nucleophile.(164,182,214) This has been rationalised by a transition state in a ligand coupling mechanism in which the developing charges are better stabilised when the electron (164,215) deficient ring is transferred. It could also be rationalised by an SNAr type mechanism, where attack at the ipso position is preferential for the more electron poor ring.(171,183,185) However, this selectivity can be superseded by the presence of steric bulk in the ortho-position. This results in selective transfer of that aryl group, regardless of its electronic properties. This is known as the ‘ortho-effect’. It is proposed to arise from the more sterically bulky aryl group preferentially occupying the less crowded equatorial position in the T-shaped intermediate, from which it is then able to react with the nucleophile (the apical aryl group is too distant).(216) It has also been suggested that the ortho-effect may be due to a relief of steric strain accelerating

110 one pathway in a reductive elimination mechanism.(164,167) However there are some examples in which ortho-substituted aryl groups have not been transferred,(215,217) and it has been reported by Olofsson that the nucleophile can aﬀect the strength of the ortho-eﬀect.(214) It should also be noted that for metal-catalysed reactions of unsymmetrical iodonium salts, the reverse selectivity is observed, and the more electron-rich aryl is generally transferred to the product.(163)

Ph Ph

Ph X R2 N N I NH3 (aq.)/C2H4Cl2 (1:1) Ph N Ph N N Ph N rt, 20 min H 1 2 R1 R R

152 150 181a 181b (1.0 eq.) (1.1 eq.)

Selected examples: OTf F OTf OTf OTf I I I I

OHC O2N 150a 150b 150c 150d 92% (0 : 1) 100% (0 : 1) 99% (1 : 11.4) 67% (1 : 3.2)

OTf OTs OTs OTf I I I I

O2N OMe OMe Cl F 150e 150f 150g 150h 86% (1 : 0) 64% (20 : 1) 46% (10.5 : 1) 83% (7.3 : 1)

OTf OTf I I

150i 150j 28% (1.1 : 1) 95% (1 : 23)

Scheme 84: Reactions of unsymmetrical diaryliodonium salts with 3,5-diphenylpyrazole, by Nov´akand co-workers(182)

Work by Nov´akinvestigated experimentally the selectivity between aryl groups in unsymmetrical diaryliodonium salts in their metal-free reactions with pyrazoles (Scheme 84).(182) It was shown that without the presence of ortho-substitution, the

111 more electron poor aryl group would be transferred, and the larger the electronic differences between the rings, the greater the selectivity (150e –150g). The ortho-effect was exemplified, with ortho-substituted aromatics undergoing preferential transfer regardless of the electronics of the other aromatic group (150a–150d, 150j). The meta- methyl substitution of 150i was shown to have little effect on the selectivity, as it is in the wrong position to have either strong electronic or steric effects. Halogens were found to effect the selectivity electronically when in the para-position. The better the ability of the halogen to conjugate with the π system, the more of a directing effect it had. The para-fluoro group in 150h had a strong directing effect, unlike the para-chloro, causing para-chlorophenyl transfer to be favoured.

1.4.2. Aims and objectives

Given the vast potential for further development of reactions utilising both of the aryl groups from a diaryliodonium salt, it was hoped that a new approach to this could be developed. This kind of tandem reaction not only complies with the rules of green chemistry due to its consumption of the otherwise waste aryl iodide, but also by its ‘one-pot’ nature, cutting down on solvent waste, and purification costs.(195) Using both aryl groups from the iodonium salt has the potential to afford a complex product efficiently, particularly if the methodology could be extended to the use of unsymmetrical diaryliodonium salts.

It was envisioned that the N-arylation of heterocycles using diaryliodonium salts, which is already well precedented (as previously discussed), might be combined with ruthenium catalysed ortho-arylation chemistry, using the ‘waste’ aryl iodide as the arylating agent (Scheme 85). This would result in a tandem N,C-arylation and importantly, would break the symmetry of the starting iodonium salt, resulting in diverse and complex structures. The resulting products would feature a heterocycle and a biaryl structure, both important functionalities in medicinal chemistry. The heterocycle of choice needed to be capable of acting as a directing group for the C–H activation step.

112 R2 DG TfO I 1) base DG 2) Ru catalysis, heat R1 R2 R1

STEP 1: DG I STEP 2: C–N bond formation C–C bond formation R1 R2 directing group (DG) is 'waste' aryl iodide is generated in situ utilised

Scheme 85: Proposal for the tandem N,C-arylation of heterocycles using diaryliodonium salts, where DG = heterocycle (Directing Group)

To begin investigations, pyrazole was selected as the heterocycle/directing group, as its N-arylation using diaryliodonium salts has been thoroughly investigated without the use of copper catalysis by Nov´ak.(182) The directed ortho-arylation of N -arylpyrazoles has been reported using both aryl chlorides and aryl bromides, so it was expected that this could potentially be extended to the use of the waste aryl iodide.(6,218–223)

1.4.3. Results and discussion

1.4.3.1. Initial investigations

Initial investigations and optimisation were carried out by Shariah M. A. Sohel and Christopher J. Teskey. They found that pyrazole 182 could be N-arylated using copper-free conditions, with K2CO3 base and 1.2 equivalents of diphenyliodonium tri- ﬂate 150k (Scheme 86, Part I). Both toluene and p-xylene as solvents gave yields of over 80% after 12 hours at 70 ◦C. Copper iodide as a catalyst was found to speed up the reaction however in this case was not found to be necessary. The second step of the reaction was investigated using 183 and iodobenzene, with a [RuCl2(p-cymene)]2 catalyst system that the group was already familiar with using (Scheme 86, Part II).(102) The reaction was found to proceed well under these conditions, however competitive diarylation was found to be a problem, and there was little selectivity between

113 mono-arylated product 184a and di-arylated product 184b when 183a was used as the starting material. Switching the substrate to more sterically hindered 183b (R = Me) addressed this problem, with only the mono-arylated product 185a being formed.

TfO I N K2CO3 (1.2 eq.) N I) N N H 70 °C, 12 h

182 150k 183a yields >80% in toluene and p-xylene

R [RuCl2(p-cymene)]2 (10 mol%) R R MesCO2H (30 mol%) N R K2CO3 (2.0 eq.) R N R N II) N + PhI N + N p-xylene, 140 °C, 18 h Ph Ph Ph

183 R = H 184a 3 : 2 184b R = Me 185a 1 : 0 185b

Scheme 86: I) Conditions found to be optimal for the N-arylation of pyrazole. II) Optimised conditions for the C-arylation of 183.

1. K2CO3 (1.2 eq.), p-xylene TfO I 70 °C, 12 h N N N N 2. [RuCl (p-cymene)] (10 mol%) H 2 2 MesCO2H (30 mol%) K2CO3 (2.0 eq.) 186 150k 140 °C, 18 h 185a 1.2 eq. 68%

Scheme 87: Optimised conditions for the tandem N,C-arylation of 3,5-dimethylpyrazole 186

Combining these conditions was found to work best by first carrying out the N- arylation at 70 ◦C, then adding the ruthenium catalyst and reagents for the second step and increasing the temperature to 140 ◦C, (as opposed to adding all reagents at the start). Completion of the first step was confirmed by NMR of a small aliquot of the crude reaction mixture. This enabled the isolation of 185a in a pleasing 68% yield

114 (Scheme 87). With the optimised conditions in hand, attention could then be turned towards the reaction scope.

1.4.3.2. Synthesis of diaryliodonium salts

Synthesis of diaryliodonium salts generally proceeds via initial oxidation of an iodoarene to iodine(III). This is followed by ligand exchange with either an organometallic reagent or an arene.(163) para-Fluorosubstituted diaryliodonium salts 150l and 150m were synthesised in a one-pot oxidation and ligand exchange process developed by Olofs- son and co-workers, with mCPBA as oxidant (Scheme 88 a).(224,225) The iodine(III) species then undergoes electrophilic aromatic substitution with ﬂuorobenzene to afford the diaryliodonium triﬂate. Both unsymmetrical example 150l and symmetrical 150m were obtained in pleasing yields.(182,225)

Symmetrical diaryliodonium salts 150n and 150o were synthesised by a multistep process (Scheme 88 b). Again, initial oxidation of the iodoarene was carried out using mCPBA. Addition of Lewis acidic boron triﬂuoride diethyl etherate, with a boronic

R1 OTf mCPBA (1.1 eq.) I I F TfOH (2.0–3.0 eq.) a) DCM R1 F 40 187 150l R1 = o-Me (83%) 1.0 eq. 1.1 eq. 150m R1 = p-F (73%)

1) mCPBA (1.1 eq.), DCM 2) BF3•OEt2 (2.5 eq.)

2 (1.1 eq.) OTf R B(OH)2 I I b) R2 R2 3) TfOH (1.1 eq.) R2 40 150n R2 = OMe (20%) 1.0 eq. 150o R2 = Cl (53%)

Scheme 88: Synthesis of diaryliodonium salts

115 acid, enabled boron-iodine(III) exchange to form the diaryliodonium tetrafluoroborate salt. Triflic acid was then added to carry out anion exchange and convert the tetrafluoroborate salts to the desired triflate products. The para-chloro substituted product 150o was isolated in a satisfactory 53% yield, however the para-methoxy product 150n was isolated in disappointing 20% yield. The electron rich nature of the starting materials resulted in significant formation of side products, both lowering the yield, and making crystallisation of the desired product difficult.

All other diaryliodonium salts used were synthesised by other lab members, and hence their synthesis will not be discussed further.

1.4.3.3. Substrate scope: symmetrical diaryliodonium salts

Gratifyingly, the reaction worked with symmetrical diaryliodonium triﬂates to give the product 189. Halogens were well tolerated in the para-position, with para-chlorinated

Part II R1 [RuCl2(p-cymene)]2 Part I (10 mol%), N I N TfO I K2CO3 (1.2 eq.) MesCO2H (0.3 eq.) N N N N 2 H p-xylene R K2CO3 (2.0 eq.) 2 1 2 R 70 °C, 12 h R1 140 °C, 18 h R R

186 150 188 40 189 (1.0 eq.) (1.2 eq.)

Cl N Cl N F N N OMe N N N N

Cl Cl F OMe 189a 189b 189c 189d 49%a 50% 49% 0%b

a Part I left for 18 h. b After 14 h (Part I), ratio of dimethylpyrazole 186 : N-aryl-dimethylpyrazole was 1.44 : 1.00 by 1H NMR analysis of the crude.

Scheme 89: Symmetrical examples of diarylation of 3,5-dimethylpyrazole, 186

116 product 189a being isolated in 49% yield, albeit with a slightly extended reaction time for part I (the N-arylation). para-Fluorinated 189b was isolated in 50% yield. These yields are pleasing given the formation of two bonds, one being a C–C bond, in one tandem process. Chlorine was also tolerated in the meta-position, and 189c was obtained in 49% yield, however this reaction worked substantially better with the addition of catalytic copper iodide in the first step (as carried out by Shariah M. A. Sohel) to afford the product 189c in 70% yield.(226) Unfortunately, in the absence of copper catalyst, the N-arylation with di(4-methoxyphenyl)iodonium triflate 150n proceeded slowly, and after 14 hours the ratio of 186 to N-arylated product was 1.44 : 1.00. This was, however, found to proceed well with catalytic copper iodide (5 mol%), allowing the subsequent isolation of 189d in 73% yield.(226)

1.4.3.4. Substrate scope: unsymmetrical diaryliodonium salts

Pleasingly, unsymmetrical iodonium salts could be used (Scheme 90). In an example with phenyl(2,4-methoxyphenyl)iodonium tosylate, the phenyl group selectively transferred first, and the resulting 1-iodo-2,4-methoxybenzene underwent the C–H functionalisation, to afford product 189e in 44% yield overall. This chemoselectivity is contrary to what would be expected from the ortho-effect, as the ortho-substituted group would be expected to transfer first. Methoxy groups, whilst more sterically bulky than protons, are still quite small, and it seems that the strong electron donating effect from the two methoxy groups has had a stronger effect than steric factors in the chemoselectivity of this reaction. There is an example reported by Ochiai and co-workers where a phenyl group selectively transfers over an ((o)-allyloxy)phenyl group, which has a similar degree of bulk close to the ring in the ortho-position to a methoxy group.(215) An X-ray structure showed the pyrazole ring to be orthogonal to the phenyl ring, and the dimethoxyphenyl ring to be twisted out of plane with the phenyl ring. A small quantity of ruthenacycle 190 was also isolated from the reaction to form 189e, which may be the active catalytic species in the C–H arylation reaction.

117 Part II 1 R [RuCl2(p-cymene)]2 Part I (10 mol%), N I N TfO I K2CO3 (1.2 eq.) MesCO H (0.3 eq.) N N 2 N N 2 H p-xylene R K CO (2.0 eq.) R2 1 2 3 1 2 70 °C, 12 h R 140 °C, 18 h R R

186 150 188 40 189 (1.0 eq.) (1.2 eq.)

N OMe N F N N N N Ru I OMe

Cl 189e 189e 189f 190 44%a (X-ray structure) 0%b 3% (from formation of 189e)

a The iodonium tosylate salt was used. b After 28 h, part I had not gone to completion, and the chemoselectivity between p-chloro and p- fluoro was poor.

Scheme 90: Unsymmetrical examples of diarylation of 3,5-dimethylpyrazole, 186

Mixed halogen iodonium salt 150h was shown to have a 7.3 : 1 selectivity for transfer of the para-chlorophenyl group in the N-arylation of 3,5-diphenylpyrazole by Novák (Scheme 84, p111), and proceeded in good yield under his conditions in 20 minutes at room temperature.(182) However, under standard conditions for this methodology (Scheme 90), the N-arylation reaction was slow, and had not gone to completion after 28 hours. The selectivity between the para-chloro and -fluoro groups was poorer than reported by Novák,so the reaction mixture was not carried through to the C–H functionalisation.

1.4.3.5. Synthesis of (E)-styrylphenyliodonium salts

N-Alkenylation has been previously reported using (E)-styrylphenyliodonium salts.(227) There is also precedent for the α-arylation of alkenes with directing groups using ruthenium catalysis (for an example see Scheme 22, p30). Therefore it was hoped that (E)-styrylphenyliodonium salts could be used eﬀectively for the current methodology.

118 (E)-Styrylphenyl iodonium salts could be synthesised by boron-iodine(III) exchange between styryl boronic acids and a pre-made, commercially available iodine(III) substrate, PhI(OAc)2 in the presence of a strong lewis acid (boron trifluoride) (Scheme 91). Anion exchange to form the triflate salt was carried out in one pot. The para-methoxy styryl product was of limited stability, and after some time would decompose to form a viscous black oil. It could be isolated in only 28% yield. The fluorinated product 192b was obtained in a much more satisfactory 56% using this method.

1) BF3•OEt2 (1.2 eq.), DCM, 0 °C, 15 min OTf B(OH) I 2 2) PhI(OAc)2 (1.2 eq.), 0 °C, 60 min

R 3) TfOH (1.2 eq.), 15 min, 0 °C R

191 192a R = OMe (28%) 192b R = F (56%)

Scheme 91: Synthesis of (E)-styrylphenyl iodonium salts

1.4.3.6. Substrate scope: (E)-styrylphenyliodonium salts

Gratifyingly, it was found that the scope of the reaction could also be expanded to (E)- styrylphenyliodoniums, to afford trisubstituted alkene products (Scheme 92). Given the difficulty of forming sterically congested trisubstituted alkenes, the yields were pleasing. With pyrazole as the heterocycle of choice, 194a was formed in a 43% yield. The use of the two methyl groups as steric hindrance on the pyrazole was unnecessary for these examples, as there is no site for a second C–H arylation to take place. All of the successful examples with styrylphenyliodoniums required catalytic copper iodide in the first step, which resulted in selective N-alkenylation. The ruthenium catalysed C–H activation then resulted in arylation of the alkene C–H bond. The reaction was not tolerant of the electron rich para-methoxystyrylphenyl iodonium salt, and none of the desired product was observed. However, para-fluorostyrylphenyl iodonium triflate 192b resulted in 194c being formed in 55% yield. It had been found that benzotriazole was an effective heterocycle for the tandem N,C-diarylation.(226) Unfortunately this

119 was not the case with styrylphenyliodoniums, as the N-alkenylation step was very slow even in the presence of copper catalysis, and after 61 hours this step had still not gone to completion. 1,2,4-Triazole was also ineﬀective in the N-alkenylation step, and after 17 hours, the crude reaction mixture was shown by 1H NMR spectroscopy to be predominantly starting material. Part II 3 R Part I X X I [RuCl2(p-cymene)]2 R3 K CO (1.2 eq.) R1 N (10 mol%), R1 N X TfO I 2 3 N N CuI (5 mol%) MesCO2H (0.3 eq.) 1 N R3 R N H p-xylene K2CO3 (2.0 eq.) 70 °C, 12 h 2 140 °C, 18 h 2 R2 R R

186 192 193 40 194 (1.0 eq.) (1.2 eq.)

N N N N N N N N N N N N

OMe F 194a 194b 194c 194d 194e 43% 0% 55%a 0%b 0%c

a Yield determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard. b After 61 h, part I had still not gone to completion. c After 17 h, part I was predominantly unreacted starting material.

Scheme 92: Preparation of trisubstituted alkenes using (E)-styryl(phenyl)iodoniums

1.4.3.7. Substrate scope: heteroatomic nucleophiles

Work by Christopher Teskey had shown benzotriazole and triazole to work eﬀectively in place of pyrazole,(226) however there was a desire to expand the scope further to other nucleophiles, to increase the generality and utility of this methodology. Several N-heterocycles and other O- and N- nucleophiles were screened with this is mind.

Tetrazoles Given the previous success had with pyrazoles and triazoles, it was hoped that tetrazoles would follow suit. 5-Methyltetrazole 195 underwent N-arylation both

120 with and without copper catalyst, however in both cases the selectivity was poor between the nitrogen in the 1- and 3- positions (Scheme 93). This is unsurprising given the proposed mechanism for N-arylation (Scheme 72, p103). Neither of these stereoiso- mers underwent C–H arylation when the mixtures were subjected to the conditions for part II.

Part I Part II K CO (1.2 eq.) [RuCl (p-cymene)] 2 3 N 2 2 Ph IOTf (1.2 eq.) N (10 mol%) 2 N N CuI (x mol%) MesCO H (0.3 eq.) N N 2 N Me no reaction N N Me N p-xylene, 70 °C, 12 h N K2CO3 (2.0 eq.) H 140 °C, 18 h Me N

195 196 197

x = 0 1.4 : 1.0 x = 5 1.0 : 1.0

Scheme 93: Attempt at the N,C-arylation of 5-methyltetrazole 195

Indazole Indazole underwent N-arylation without copper catalyst with an increased reaction time of 27 hours to aﬀord the N-arylated products 199 and 200 in a 1.00 : 0.50 mixture. This is unsurprising, and the major product 199 supports Nov´akand

Part I K2CO3 (1.2 eq.) N Ph2IOTf (1.2 eq.) N N N N p-xylene, 70 °C N H 27 h 198 199 200 1.00 : 0.50 Part I Part II [RuCl (p-cymene)] K2CO3 (1.2 eq.) 2 2 (10 mol%) Ph2IOTf (1.2 eq.) N MesCO2H (0.3 eq.) N CuI (5 mol%) N N N K CO (2.0 eq.) p-xylene, 70 °C N 2 3 16 h 140 °C, 18 h

199 200 201 0.15 : 1.00 not observed

Scheme 94: Attempt at the tandem N,C-arylation of indazole

121 Stirling’s proposed metal-free arylation mechanism being the predominant mechanism of product formation here (Scheme 72).(165) In the presence of copper iodide catalyst (5 mol%), the N-arylation was more selective, favouring arylation at the 2-nitrogen to give 200. Unfortunately, when carried through to the second step, 200 did not prove to be a suitable substrate for the C–H functionalisation, and none of the desired product 201 was observed, nor its analagous 1N-substituted product.

Hydroxybenzotriazole (HOBt) Su and Mo have reported a one-pot synthesis of N -(2-hydroxyaryl)benzotriazoles (204) from hydroxybenzotriazole (HOBt, 202) and diaryliodonium salts (Scheme 95).(228) The ﬁrst step involves metal-free O-arylation, and whilst found to work best with tBuOK base and MeCN solvent, also worked well with KOH, Cs2CO3 and Et3N, in toluene, 1,4-dioxane, DMSO, DMF, and moderately in THF. The second step works by increasing the temperature to 60 ◦C, to eﬀect a [3,3]-rearrangement and produce an N -(2-hydroxyaryl) product 204. The potential for the application of this methodology to the tandem N,C-arylation, to give more diverse 2-hydroxy-5-arylated products inspired the screening of conditions with this in mind (Table 16).

t N N BuOK (1.5 eq.) 60 °C N N Ar IOTf (1.5 eq.) N 18–24 h 2 R N N N OH N MeCN, 25 °C O 18–24 h OH R 202 203 204 16 examples 43–89% yield

Scheme 95: Su and Mo’s synthesis of N -(2-hydroxyaryl)benzotriazoles using diaryliodonium salts(228)

It was found that K2CO3 was a poor choice of base for the initial O-arylation in both MeCN solvent and in 1,4-dioxane, with the ratio of unreacted diaryliodonium salt to 203 being high after 20 hours at room temperature (Table 16, Entries 1 & 4). As was found in the paper, tBuOK was found to work well for part Ia, in 1,4-dioxane, p-xylene

122 or MeCN (Entries 2, 3, 5). These reaction mixtures were then heated to 60 ◦C for part Ib, the [3,3]-rearrangement. All were successful in the production of 204 although the reactions in p-xylene and MeCN resulted in the formation of an unidentiﬁed impurity (Entries 3 & 5). The reaction in 1,4-dioxane was cleaner (Entry 2), and was subjected to the standard conditions for C–H activation. Unfortunately, after this step, none of the desired product 205 was observed in the crude reaction mixture, by 1H NMR, or GCMS.

Part Ia Part II base (1.2 eq.) [RuCl2(p-cymene)]2 N PhI N Ph2IOTf (1.2 eq.) (10 mol%) N N N solvent, 25 °C, 23 h K2CO3 (2.0 eq.) N N N OH then Part Ib N MesCO2H (30 mol%) HO OH 60 °C, 20 h 140 °C, 18 h

202 204 205

N PhI Part Ia N Part Ib N O Ph 203

Table 16: Screening of conditions for the diarylation of HOBt hydrate 202

Entry Base Solvent Part Ia (203 : Ph2IOTf) Part Ib Part II: 205 (%)

1 K2CO3 MeCN 1.00 : 0.93 - - 2 tBuOK 1,4-dioxane 1.00 : 0.14 worked 0 3 tBuOK p-xylene 1.00 : 0.18 workeda -

4 K2CO3 1,4-dioxane 1.00 : 0.61 - - 5 tBuOK MeCN 1.00 : 0.26 workeda - a Some unknown impurity also present.

To investigate whether the optimised conditions for part I might have been incom- patible with part II, the N-arylated compound 204 was synthesised and isolated, in order to carry out the C–H functionalisation in isolation to part I. This was carried out under the standard conditions (but with 1,4-dioxane, a commonly used solvent in ruthenium catalysed C–H activation), with iodobenzene (Table 17, Entry 1). None of the C-arylated product 205 was observed in the 1H NMR spectrum of the crude. This

123 PhI (1.2 eq.), N N reagents/catalysts N N (see table) N N OH 1,4-dioxane HO 120 °C, 19 h

204 205

Table 17: Screening of catalysts and additives for the ortho-arylation of 204

Entry Conditions 205 (%)

1 [RuCl2(p-cymene)]2 (0.1 eq.), K2CO3 (2 eq.), MesCO2H (0.3 eq.) 0 ∗ 2 (RhCp Cl2)2 (5 mol%), AgSbF6 (25 mol%), AgTFA (2 eq.) 0 ∗ 3 (IrCp Cl2)2 (5 mol%), AgSbF6 (25 mol%), AgTFA (2 eq.) 0

suggested that the failure of this step in a one-pot process was not due to the presence of the tBuOK, but due to the unsuitability of the substrate for C–H activation under the standard conditions. The use of (RhCp*Cl2)2 with silver salts has been reported for directed ortho-arylation.(229) The silver cations are proposed to act as halide scavengers, to abstract the chlorides from the catalyst and result in a Rh cationic species, which is more electrophilic and can more readily co-ordinate to the directing group. However, under these conditions (Entry 2), and also with the analogous iridium catalyst (Entry 3), 205 was not observed. The hydroxyl group presents steric hindrance, which may make the required planar geometry for formation of the ruthenacycle (or metallacycle) unfavourable (Figure 4). It is also possible that the phenol could coordinate to the ruthenium, blocking the catalyst.

Figure 4: Steric clash in the ruthenacycle formed by 204

N N N steric clash H RuLn HO

124 2-Hydroxypyridine Whilst examples of ruthenium catalysed C–H activation are more common when involving 5-membered ruthenacycle intermediates, there are some examples of the successful use of 6-membered ruthenacycles.(6) A couple of examples of the use of ruthenium to carry out ortho-arylation with 2-phenoxypyridines have been reported, the ﬁrst by Ackermann and co-workers actually involved the use of the hydroxypyridine moiety as a removable directing group.(31,32)

We were interested to see whether our own directing group scope could be extended to include 2-hydroxypyridines (Table 18). Subjecting 2-hydroxypyridine with diphenyliodonium triﬂate to the standard conditions for part I resulted in formation of a mixture of both the O-arylated product 207a and N-arylated product 207b (En- try 1). This mixture was unsuccessful in the subsequent C–H functionalisation step.

R1 Part II R1 R2 K2CO3 (2.0 eq.) OH Part I N R2 [RuCl (p-cymene)] N TfO I 2 2 K2CO3 (1.2 eq.) (10 mol%) R2 O O N I R2 R2 p-xylene, T °C MesCO2H (30 mol%) R1 14 h p-xylene 40 2 140 °C, 18 h R 206 150 207a 208 1.2 eq. R1

N R2 O 207b

Table 18: Screening of conditions for the diarylation of 2-hydroxypyridines 206

Part I Part II - 208 (%) Entry R1 R2 T 207a : 207b 1 H H 70 0.43 : 1.00 0 2 H H rt No reaction - 3 H Me 70 0.23 : 1.00 - 4a HH 100 0.88 : 1.00b - 5 Me H 70 1.00 : 0 trace

a ◦ Conditions for Step 1: Ph2IOTf (1.0 eq.), K2CO3 (3.0 eq.), toluene, 110 C (microwave) 5 min. b Ratio of recovered 2-hydroxypyridine was 0.21.

125 It was desirable to try to tip the balance for the first step in favour of the selective O-arylation. Reducing the temperature for the first step (Entry 2) simply halted the reaction. Using a more hindered iodonium salt, with ortho-methyl groups (Entry 3) improved the selectivity between O- and N-arylation, but unfortunately in favour of N- arylation. Kumar and co-workers have reported the use of microwave conditions for the selective O-arylation of 2-quinolones.(230) However, when these conditions were tested for 2-hydroxypyridine and diphenyliodonium triflate (Entry 4), the selectivity between 207a and 207b was worse than under the standard conditions, and the reaction had not gone to completion. Pleasingly, placing a methyl group ortho to the nitrogen on the hydroxypyridine (Entry 5) proved to be enough steric hindrance to result in selective formation of the O-arylated product. Unfortunately, the second step resulted only in formation of trace quantities of what appeared by GCMS to be the desired product 208.

2-Aminopyridine The use of 2-aminopyridine as a directing group for ruthenium catalysed C–H activation remains undeveloped. A few examples have been reported of success with palladium catalysed ortho-arylations, with potassium aryl triﬂuorobo- rates as the arylating agent, by Ming-Jung Wu, Jean-Ho Chu and co-workers.(231,232) N-Arylation of 2-aminopyridine was unsuccessful under the standard conditions both with and without catalytic CuI (Table 19, Entries 1 & 2). Huang, Wen and co-workers, in their paper on the copper catalysed insertion of amines into cyclic diphenyleneiodo- niums, were able to N-arylate 2-aminopyridine with the use of Na2CO3 base and cat- (192) alytic Cu(OAc)2. Use of these conditions did result in formation of 210 (Entry 3), but at 70 ◦C the reaction was slow, and starting material 209 still remained after 97 hours. Increasing the temperature and equivalents of base resulted in N-arylation going to completion in 26 hours (Entry 4). This was then carried forward to part II, the major product of which was unfortunately 212, the result of a second N-arylation. The dominance of this Ullmann-type reaction is perhaps unsurprising, as in Huang and Wen’s paper, after the initial N-arylation, they go on to carry out a second copper

126 catalysed N-arylation, albeit intramolecularly using the aryl iodide formed in situ. These side products were also observed in palladium catalysed reactions by Wu and Chu, for some substrates when Cu(II) oxidants were used.(231) Ribas and colleagues have published the copper catalysed intermolecular reaction of 210 and PhI to form 212.(233) The Greaney group has also since published a copper catalysed tandem N,N- diarylation of anilines using both components of a diaryliodonium salt (Scheme 81, p109).(202) None of the desired C-arylated product 211 was observed in the product mixture. A product that was observed in small amounts was 213. This may have formed from 211 – there are a few examples of intramolecular C–N cyclisation of substrates such as 210 via palladium catalysed C–H activation with an oxidant to form 213.(231,232,234) In fact, Wu and Chu report that the use of 1,4-dioxane as a solvent makes this process particularly favourable (compared to when tert-butyl alcohol is used, which favours products of type 211).(231,232,234)

Part II Part I K2CO3 (2.0 eq.) Ph IOTf (1.2 eq.) [RuCl (p-cymene)] 2 N 2 2 N N N base (1.2 eq.) (10 mol%) Cu cat. (5 mol%) MesCO H (30 mol%) Ph N NH 2 NH N N Ph p-xylene, 70 °C, t h p-xylene, 140 °C, 18 h NH2

209 210 211 212 213

Table 19: Screening of conditions for the diarylation of 2-aminopyridine 209

Part I Part II Entry Base cat. t (h) Result 210 : 211 : 212 : 213

1 K2CO3 none 27 210 not observed -

2 K2CO3 CuI 14 210 not observed -

3 Na2CO3 Cu(OAc)2 97 0.25 : 1.00 209 : 210 211 not observed a 4 Na2CO3 Cu(OAc)2 26 successful trace : 0 : major : minor a Part I used 1.5 eq. of base, and was carried out at 100 ◦C.

It was envisioned that protection of the amine nitrogen would prevent the second N-arylation, therefore favouring the C-arylation step instead. When 2-(methylamino)-

127 pyridine 214 was subjected to the previously optimised conditions for part I, this proceeded well. Unfortunately, after part II, the major product was recovered 215 (Scheme 96). None of the desired C-arylated product was observed, nor was N- arylation prevented entirely, as some of the product 215 deprotected in situ to form 210, some of which was then able to N-arylate to give 212.

Part II Part I [RuCl2(p-cymene)]2 Na2CO3 (1.5 eq.) (10 mol%) Ph IOTf (1.2 eq.) Me Ph Me 2 N N K2CO3 (2.0 eq.) N N N N N NH N Cu(OAc)2 (5 mol%) MesCO2H (30 mol%) NHMe p-xylene p-xylene 100 °C, 22 h 140 °C, 20 h minor major minor 214 215 212215 210

Scheme 96: Attempt at the N,C-diarylation of 2-(methylamino)pyridine 214

The ortho-arylation step (part II) was attempted with silver additive, to see if it increased the reactivity of the ruthenium catalyst by chloride abstraction, which might have assisted the C-arylation step (Scheme 97). In addition, carrying out part II in isolation to part I meant that there would not be copper catalyst present for this step, which is known to catalyse the second N-arylation. However, despite the lack of copper, some of the N-arylated products were observed, showing that whilst copper may aid this step, it is not a requirement. The silver additive didn’t result in the formation of the desired product 211. The major product was recovered starting material.

Part II

[RuCl2(p-cymene)]2 (10 mol%) K2CO3 (2.0 eq.) MesCO2H (30 mol%) N NH AgSbF6 (50 mol%) PhI 210 N N N N (1.2 eq.) p-xylene 120 °C, 18 h

210 212 213 0.85 : 0.15 : 0.20 none of desired C-arylated product observed

Scheme 97: Attempted ortho-arylation of 210 with silver additive

128 2-Aminopyrimidine Although examples of the use of 2-aminopyrimidines as directing groups for ruthenium catalysed C–H activation are lacking, there are some examples of its success as a directing group for C–H activation using second row transition metal catalysts such as rhodium or palladium.(235–237) Given this, it was proposed that 2- aminopyrimidine might be a viable heterocycle starting material for the N,C-arylation. It was initially found that 2-aminopyrimidine did not undergo N-arylation under the standard conditions for part I with or without copper (Table 20, Entries 1 & 2). For- tunately, switching the base to NaOtBu for part I with catalytic copper iodide resulted in complete consumption of the starting material after 19 hours (Entry 3). However, the C–H functionalisation step was unsuccessful, with no reaction taking place.

Part I Part II Ph IOTf (1.2 eq.) K CO (2.0 eq.) 2 N 2 3 N base (1.2 eq.) [RuCl2(p-cymene)]2 (10 mol%) MesCO H (30 mol%) Cu catalyst (5 mol%) N NH 2 N NH NN PhI p-xylene, 70 °C, t h p-xylene, 140 °C, 18 h NH2

216 217 218

Table 20: Screening of conditions for the diarylation of 2-aminopyrimidine 216

Part I Part II Entry Base cat. t (h) Result

1 K2CO3 none 14 217 not observed -

2 K2CO3 CuI 14 217 not observed - 3 NaOtBu CuI 19 successful no reaction

The use of silver additive did not result in the formation of any of the C-arylated product, only recovered starting material was observed (Scheme 98).

The use of rhodium and iridium catalysis with silver additives was investigated for part II for both the N -aminopyridine and N -aminopyrimidine directing groups (Scheme 99). However, neither catalyst resulted in formation of ortho-C-arylated product for either directing group. The only reaction observed in 1H NMR analysis of the crude appeared to be deprotonation of the starting material.

129 Part II

[RuCl2(p-cymene)]2 (10 mol%) K CO (2.0 eq.) N 2 3 N MesCO2H (30 mol%) AgSbF6 (50 mol%) N NH PhI (1.2 eq.) N NH p-xylene 120 °C, 18 h

217 218 0%

Scheme 98: Attempted ortho-arylation of 217 with silver additive

Part II

AgSbF6 (25 mol%) X AgTFA (2.0 eq.) X catalyst (5 mol%) none of C-arylated N NH PhI N NH product observed in (1.2 eq.) p-xylene any case 120 °C, 18 h

catalyst = (RhCp*Cl2)2 or (IrCp*Cl2)2 210 (X= C) 211 (X= C) or 217 (X=N) or 218 (X=N)

Scheme 99: Rh and Ir catalysis for the attempted ortho-arylation of 210 and 217

2-Quinoxalinol and quinolin-2-ol 2-Quinoxalinol 219 did not undergo the desired O-arylation under the conditions for part I, even after an extended reaction time of 27 hours (Scheme 100 a). It was unclear after the ﬁrst step whether O-arylation of quinolin-2-ol 220 (Scheme 100 b) had been successful (based on 1H NMR analysis of an aliquot of the reaction mixture). However, after submission to the reaction conditions

Part I K CO (1.2 eq.) N OH 2 3 Ph2IOTf (1.2 eq.) a) none of desired product visible N p-xylene, 70 °C 219 27 h Part II Part I [RuCl2(p-cymene)]2 K2CO3 (1.2 eq.) (10 mol%) Ph2IOTf (1.2 eq.) MesCO2H (0.3 eq.) N O b) N OH p-xylene, 70 °C K2CO3 (2.0 eq.) 16 h 140 °C, 18 h 220 221

Scheme 100: Attempted tandem O,C-arylation of (a) 2-quinoxalinol 219; and (b) quinolin-2-ol 220

130 for part II, no C-arylated product was observed, and the major product was in fact 221, the product of O-arylation from the ﬁrst step.

7-Azaindole Nov´akand Stirling have reported the copper free N-arylation of 7- ◦ (165) azaindole in 1:1 NH3/toluene at 50 C. Under the conditions for part I, after 16 hours only trace quantities of the N-arylated product 223 were observed in the absence of copper catalyst. Fortunately, with catalytic copper iodide, 7-azaindole 222 did successfully undergo N-arylation to give the N -aryl product 223 in around a 1:1 mixture with an unidentiﬁed impurity. Carrying this mixture through to part II did result in formation of some of the desired product 224, though only in a 6% yield.

Part II

Part I [RuCl2(p-cymene)]2 K2CO3 (1.2 eq.) (10 mol%) Ph IOTf (1.2 eq.) MesCO2H (30 mol%) 2 N N N N N N H CuI (5 mol%) K2CO3 (2.0 eq.) p-xylene, 70 °C 140 °C, 18 h 14 h 222 223 224 ~1:1 mixture with 6% unknown compound

Scheme 101: Tandem N,C-arylation of 7-azaindole 222

1.4.4. Conclusions and future work

In conclusion, a one pot N,C-arylation of pyrazoles has been developed, enabling the atom economical use of diaryliodonium salts. The in situ generation of a directing group for C–H activation allows the otherwise waste aryl iodide to be utilised to generate a C–C bond. This breaks the symmetry of the starting iodonium and results in the formation of functionalised biaryl structures which represent ‘priveledged’ moieties and useful building blocks in medicinal chemistry. This works for both symmetrical and unsymmetrical iodoniums, with predictable selectivity, and can be extended to the use of styrylphenyliodoniums for the synthesis of trisubstituted alkenes. Attempts to expand the scope of the heterocycle beyond pyrazole had some success, with triazole

131 and benzotriazole shown to be eﬀective by Christopher Teskey.(128) Unfortunately, other heterocycles were not tolerated, predominantly due to the failure of the C–H activation step.

It is proposed that the use of other catalytic systems for the C–H activation might allow the expansion of the heterocycle scope. For instance, ‘on-cycle’ ruthenium catalysts such as that proposed by the Larrosa group (Scheme 25, p33)(64) have been shown to have a large directing group scope, and work in relatively mild conditions to aﬀord high yields. These catalysts might be utilised eﬀectively with some of the N -aryl compounds which did not undergo C–H functionalisation using [RuCl2(p-cymene)]2. Alternatively, other metal catalysts might be successful, however the avoidance of expensive metals such as palladium and rhodium is preferable.

132 2. Arynes for the synthesis of substituted arenes

2.1. Introduction

Arynes are some of the oldest and most well studied reactive intermediates, with evidence for their existence ﬁrst being published by Stoermer and Kahlert in 1902.(238,239) Since the original discovery of ortho-benzyne, a multitude of ways to generate it have been developed, generally involving the removal of two adjacent groups from a pre- existing arene (Scheme 102).(240–248) However, many of these methods require harsh alkaline conditions with the use of organometallic bases (e.g. Scheme 102 (f)–(i))

1 X N2

2 X CO2 (a) (i) (b) Mg or RMgX heat F N N (h) (c) N M –20 °C (if M = Li) Pb(OAc)2 NH2 or 0 °C (if M= MgBr)

strong base F (g) (d) nBuLi F OTf (f) (e) X TMS OTf OTf I Ph X TMS

Scheme 102: Methods for the generation of benzyne

133 or high temperatures (Scheme 102 (b)). For these reasons as well as due to the high reactivity of benzyne, its use in synthetic chemistry remained underdeveloped for many decades. More recently, the development of 2-(trimethylsilyl)phenyltriﬂate for generation of benzyne under mild conditions, with good functional group tolerance (Scheme 102 (d))(244) has seen a revival in benzyne chemistry.(240,249)

In the past few years, much development has gone into another new way of generating ortho-arynes: the Hexadehydro-Diels–Alder reaction (HDDA) (Scheme 102 (a)).(241,250) This is analogous to the Diels–Alder reaction, but with the replacement of the diene and dienophile with a diyne and a diynophile. The resulting ortho-aryne (226) can undergo subsequent trapping to aﬀord highly substituted arenes (Scheme 103).

R1 R1 R1 2 2 2 R1 HDDA R R trapping R

R2 R3 4 225 226a 226b R ortho-aryne 227

Scheme 103: General scheme for the Hexadehydro-Diels–Alder reaction

Direct evidence for the existence of ortho-benzyne as a reactive intermediate has been reported by IR,(251) and 13C dipolar NMR spectroscopy.(252) 1H and 13C NMR spectra of ortho-benzyne in a molecular container(253,254) and UV photoelectron spectroscopy have also been used for the direct observation of benzyne.(255) Both experimental and theoretical ﬁndings have concluded that that the structure of benzyne resembles that with a strained triple bond, but possesses some diradical character (Scheme 104).(256) The triple bond is much weaker that that of an alkyne, as shown by IR stretching vibrations.(251)

Scheme 104: Resonance forms of benzyne

134 R

R R

[4+2] R El Polar [2+2] R reactions R Nu R Nu El

1,3-dipolar σ-bond cycloaddition insertion Y Nu El X Z

X El Y Z Nu

Scheme 105: Examples of the reactivity of benzyne

Benzynes are versatile reactive intermediates, and can react in a number of ways (Scheme 105).(240) Pericyclic reactions such as [2+2], [4+2] and 1,3-dipolar cycloadditions can aﬀord a huge variety of fused ring systems.(256) Reactions such as σ bond insertions have been reported,(257–262) as well as metal catalysed reactions to aﬀord diverse products.(256) Benzynes are electrophilic, so can undergo nucleophilic attack followed by either protonation,(256) or quenching with an electrophile in a three component coupling reaction.(263,264)

Steric model Charge controlled model Aryne distortion model

EWG EWG EWG δ−

δ+ Nu Nu Nu Attack favours less Attack favours more Attack favours the more hindered position positively charged position linear aryne carbon (to afford more stabilised anion)

Scheme 106: Models to account for the regioselectivity of benzyne reactivity

135 The substitution on the benzyne ring can aﬀect the regioselectivity of nucleophilic attack. Substituents in the 4-position exert poor control over regioselectivity, often resulting in a 1:1 mixture of products.(265) Substitution in the 3-position allows greater control. With electron donating groups (e.g. methyl), control can be poor, however inductively electron withdrawing groups such as methoxy or halides strongly favour attack at the meta position.(266,267) Several models have been proposed to rationalise this (Scheme 106).(266,267)

136 2.2. Hexadehydro-Diels–Alder (HDDA) reaction

2.2.1. Background: HDDA

The HDDA reaction was ﬁrst reported in 1997, in two separate reports by Johnson and Ueda (Scheme 107).(268,269) By subjecting 1,3,8-nonatriyne 228 to ﬂash vacuum pyrolysis, Johnson and co-workers were able to isolate indane 229 and indene 230 in a combined yield of >95% (6.1:1 ratio respectively) (Scheme 107 a). The indene product was found to be formed as a result of dehydrogenation of indane. DFT calculations have been carried out for the cycloaddition reaction of acetylene with butadiyne. These revealed that the HDDA reaction to form benzyne would be highly exothermic

a) Johnson (HDDA by flash vacuum thermolysis)

Flash vacuum thermolysis

580 °C, 10-2 Torr

228 229 230 86% 14% b) Ueda (HDDA at room temperature)

HO TMS TMS OR benzene

rt, 72 h O H O

231 232 R= H 66% 233 R= CH2CH=CH2 6% TMS OH HO TMS THF, Et2O, anthracene

rt, 72 h

234

235 72%

Scheme 107: a) Johnson’s HDDA reaction of 1,3,8-nonatriyne 228.(268) b) Ueda’s HDDA reactions, yielding 5H -ﬂuorenol derivatives.(269)

137 (−52 kcal/mol), despite the highly reactive nature of the product. Not surprisingly, the reaction would be accompanied by a large free energy of activation (37 kcal/mol).(270)

In contrast to the very harsh conditions used by the Johnson group, Ueda and co- workers reported a HDDA cyclisation of substrates such as 231 (Scheme 107 b) to give 5H -ﬂuorenol derivatives. To conﬁrm the involvement of a benzyne intermediate, trapping experiments were carried out using anthracene. Isolation of product 235 in 72% yield (and its regioisomer in 8% yield), supported the involvement of an ortho- benzyne intermediate in the mechanism.

Much progress has been made since the publication of these two initial reports. Contributions by several groups, particularly that of Hoye, have greatly expanded the substrate scope of the reaction and introduced a large range of intermolecular and intramolecular trapping events (Schemes 108 & 109).(271–277) Trapping can be carried out by nucleophiles/electrophiles to give products such as 238a, or can occur with dienes in a Diels–Alder reaction to give products such as 238b (Scheme 108). Intermolecular trapping can result in the formation of regioisomeric products, and can be diﬃcult to control. A study by Lee and co-workers investigated the steric and electronic eﬀects of the nucleophiles and substituents on the regioselectivity.(278)

O O TMS O TMS TMS CHCl3 R Nu El R

85 °C, 18 h or π-donor R Nu El 236 R= CH2CH2OAc 237 238

O TMS O TMS O TMS O TMS R R R R

Ac N H H Ph H H HO 238a 238b 238c 238d PhNHAc (0.15 M); 82% Benzene (solvent, 14 h); Phenol (0.1 M); 85% Norbornene (0.1 M); 63% 19:1 ratio of isomers 70% Single isomer Single (exo) diastereomer

Scheme 108: Examples of intermolecular trapping of benzyne 237(271)

138 Variation of the R1 group on substrate 225 (Scheme 103, p134) enables a variety of intramolecular trapping events, which considerably increase structural complexity. For instance, a tethered arene with a suitable benzylic hydrogen can undergo an aromatic- ene reaction with the benzyne intermediate, with examples of this reported by both Hoye and Lee.(279,280)

OTBS

R1 R2 OTBS MnO , DCM 2 O

t rt, 5 h SiMe2 Bu O O R1, R2 TBS 239 H, OH 241 240 =O 53%

TMS O TMS O TMS O O HDDA O O

CHCl3 Ph OMe H MeO H OMe 242 competing 243 (88%) 244 (not isolated) ratio (NMR) ≥ 50:1

Scheme 109: Examples of intramolecular trapping events(271,274,281)

Other particularly interesting examples include substrates such as 239, which undergo trapping by the nucleophilic oxygen atom, followed by retro-Brook rearrangement to form product 241 (Scheme 109).(271,281) The trapping of benzyne intermediates by tethered arenes in an intramolecular Diels–Alder reaction to form products such as 243 is another elegant transformation to show the potency of this reaction (Scheme 109). Use of diphenyl substrates resulted in selective trapping by the more electron-rich ring.(274) Ueda and co-workers also undertook further investigation into the scope of the reaction,(282) particularly with respect to the DNA strand cleaving ability of the benzyne intermediate.(283,284)

139 Work by Lee and co-workers showed the use of catalytic silver to be eﬀective in mediating the HDDA reaction of tetraynes such as 245, followed by C–H insertion to trap the benzyne intermediate. The trapping event was successful with 1◦, 2◦ and 3◦ C–H bonds undergoing reaction to form complex polycyclic products (Scheme 110).(285)

The use of silver catalysis has since been extended by Lee with the use of AgF, AgCF3 and AgSCF3, which can all be used to promote HDDA reactions, with subsequent incorporation of their counterions into the products.(286) Such compounds are highly valued in agrochemistry and medicinal chemistry.

n n Bu Bu AgBF4 (10 mol%) pyridinium tetrafluoroborate (1.5 eq.) R AgOTf (10 mol%) n TsN Bu toluene, 90 °C, 4 h R toluene, 90 °C, 5 h TsN 84% 96% TsN n 245 F R = Bu R = 246 247 n AgF (1.5 eq.), TMSCF3 (2 eq.) Bu toluene, 90 °C, 4 h 76% (o : m = 3 : 2) R = nBu All via: nBu R

nBu R TsN TsN Ag CF3 248 249

Scheme 110: Examples of silver mediated HDDA reactions(285,286)

Hoye and co-workers have investigated how the structure of the linker between the diyne and diynophile affects the rate of HDDA cyclisations.(287) They found that substrates which contain an electronegative heteroatom within the 3-atom linker cy- clise faster than those without (Scheme 111). A carbonyl substituent adjacent to the diynophile also increases the rate, particularly compared to a protected alcohol. The nature of the carbonyl effects the population of the reactive conformation, and hence the rate. 4-Atom linkers have been found to be unsuitable, as they accommodate [2+2] (275) cyclisation to form fused cyclobutadienes. Sulfur based tethers (SCR2S) have recently been reported as effective, and can be removed after HDDA cyclisation using

140 Raney-Nickel, enabling access to a new class of products without the presence of a 5-membered tethering ring.(288)

a) O AcO TMS TMS

R R

250 251

krel 9000 1

b) 252a 252b 252c O O TMS (X = CH ) (X = O) (X = NPh) TMS 2 k X X ca. rel 1 3000 30000

O t1/2 @ temp 6 h, 180 °C 5 h, 110 °C 5 h, 90 °C OTBS TBS yield 80% 95% 76% 252 253

c) R1 254a 254b 254c R (X = C(CO Me) ) (X = NTs) (X = O) X X 2 2 ca. k 1 170 210 R O rel TBS t1/2 @ temp 4 h, 115 °C 6 h, 65 °C 5 h, 65 °C 254 255 yield 75% 88% 64% 1 R= CH2CH2OTBS R = R

Scheme 111: a) Relative cyclisation rates. b) & c) Eﬀects on cyclisation rate of including heteroatoms in the linker.(287)

Experiments carried out by Ueda and co-workers showed the reaction of an alkyne and a dialkyne to be preferable over that between a dialkyne and a nitrile (Scheme 112).(289) Subjecting compound 257 to the cyanation conditions with the aim of synthesising nitrile 258, resulted in spontaneous cycloaromatisation to the product 259. This shows that, from the two competing cyclisation modes (a and b), mode b (forming ﬂuorenol 259) is greatly favoured over mode a (which would form the pyridyne intermediate 261).

Evidence suggests that the intermolecular HDDA reaction is involved in the pyrolysis of acetylene to form benzene (Scheme 113), as the high temperature fragmentation of

141 ortho-benzyne is shown to produce acetylene and diacetylene.(290,291)

3 THPO THPO R O O R1 CuCN, LiI, THF R1 cyclisation

R2 reflux, 72 h CN CN 258 256 R1 = , R2 = H 3 NIS, 259 R = THP AgNO , PPTS, MeOH, rt, 12 h 3 256 acetone, MeO 11% (over 3 steps) from 29% recovery of ene-triyne-nitrile rt, 1 h 1 2 257 R = , R = I 260 R3 = H

MeO

Two possible cyclisation modes: Ar Ar

THPO trapping THPO N N

MeO a R5 THPO R4 261 262 b a N THPO b THPO OMe O 258 trapping

263 259

Scheme 112: Formation of 260 from intermediate 258, which could undergo two possible cyclisation modes (a & b), to form either benzyne or pyridyne reactive intermediates(289)

via: heat

benzene ortho-benzyne

Scheme 113: Pyrolysis of acetylene to form benzene, and the possible involvement of a benzyne intermediate(290,291)

142 2.2.2. Aims and objectives

Despite the progress made in the ﬁeld so far, the HDDA reaction remains in its infancy, and there remains huge opportunity for development. It was proposed that the replacement of the alkyne with a nitrile might be used to generate ortho-pyridyne analogue 265, in a Hetero-Hexadehydro-Diels–Alder reaction (HHDDA) (Scheme 114). Whilst heteroarynes in general have received less attention in the literature than arynes, 3,4- pyridynes are amongst the most extensively studied of these and provide a valuable precursor for the synthesis of highly functionalised pyridines.(292)

1 1 1 N HHDDA N R N R trapping N R

R1 R2 3 264 265a 265b R ortho-pyridyne 266

Scheme 114: General scheme for the Hetero-Hexadehydro-Diels–Alder (HHDDA) reaction, to form ortho-pyridyne intermediate 265, and subsequent trapping

This would hugely expand the current scope of the HDDA reaction and allow simple access to a huge range of substituted pyridine compounds via diﬀerent trapping events. These compounds are important motifs in organic chemistry. One of the most impres- sive aspects of the HDDA reaction is the ability to build complex polycyclic systems in one step, and the extension of this methodology to previously unexplored heterocyclic systems would be an important development. Examples of Diels–Alder reactions with unactivated nitriles as dienophiles are uncommon, often requiring harsh conditions. However, Danheiser and co-workers have reported the reaction of unactivated nitriles as dienophile cycloaddition partners under mild conditions.(293–295) Many more examples exist of [4+2] cycloadditions using activated nitriles.(296,297) It is worth noting that the linker used by Ueda (a benzene with a protected alcohol adjacent to it) is very similar to that in compound 251 (Scheme 111, p141), which was shown by Hoye et al. to display a relatively low rate of cyclisation. This may have contributed to the

143 poor reactivity of the nitrile in this example. In addition, Ueda’s work only showed that cyclisation of the nitrile was less favourable than that with an alkyne. This is unsurprising, as alkynes are generally more reactive than nitriles. It was envisaged that by eliminating the competing cyclisation pathway, and using a more reactive linker structure, cyclisation with a nitrile in a HHDDA fashion would be feasible.

2.2.3. Results and discussion

2.2.3.1. Design of substrates

The basic skeleton of the starting material for the proposed HHDDA reaction would 1 take the form of 264 (Scheme 114). For the R group, the CH2CH2OTBS motif was selected, as this is well precedented in the literature and would allow regioselective, intramolecular trapping of the pyridyne intermediate.(271,287) This would avoid the need to add any external reagents to trap the pyridyne. In light of Hoye’s paper on linker structures, two initial linkers were decided upon, based on structures 254a and 254b (Scheme 111, p141).(287) Although Hoye’s work does not provide values of k rel for comparison between general structures 252 (containing a carbonyl α- to the diynophile) and 254 (without the carbonyl), comparison of the t1/2 and temperature used for the cyclisation of substrate 254a with those used for 252b (the carbonyl with medium reactivity) suggest that they are of similar reactivity. The t1/2 and temperature for substrate 254b suggest its cyclisation to be more favourable than 252b, so the linkers chosen should give a high relative reactivity.

MeO2C N N MeO2C TsN

OTBS OTBS 267 268

Figure 5: Starting materials 267 and 268 for the proposed HHDDA reaction

Having decided upon substrates 267 and 268 (Figure 5), routes towards them were planned starting from literature procedures (Scheme 115 and Scheme 116).(271,298–300)

144 TBSCl (1.2 eq.), AgNO3 (10 mol%) NBS (1.1 eq.) OH imidazole (2.4 eq.) OTBS OTBS

THF, rt, 3 h acetone, rt, 1 h Br 269 84% 270 95% 271

PPh3 (1.1 eq.), I2 (1.2 eq.) HO (1.2 eq.) OTBS imidazole (2.0 eq.) OTBS

CuCl (10 mol%) HO DCM, 0 °C, 2 h I piperidine, 0 °C, 1 h 80% 272 273 84%

NaH (1.0 eq.), then O O NaH (1.0 eq.), Br (0.5 eq.) 273 O O N then (1.0 eq.) MeO2C N TBSO MeO OMe MeO OMe THF, rt, 24 h THF, rt, 6 h MeO2C 274 90% N 84% 275 267

Scheme 115: Synthesis of 273, and subsequent synthesis of 267

The syntheses of both 267 and 268 began with TBS protection of alcohol 269, followed by bromination of the alkyne to aﬀord 271 in excellent yield over two steps. Cadiot–Chodkiewicz coupling of bromoalkyne 271 with propargyl alcohol generated 272, which contains the diyne moiety. The Appel reaction was then used to replace the propargylic alcohol with iodine, a good leaving group for the subsequent nucleophilic substitution reactions (Scheme 115). The resulting compound 273 was subsequently used for the syntheses of both 267 and 268. For the synthesis of 267, coupling of dimethyl malonate 274 with bromoacetonitrile produced 275, which could then undergo another nucleophilic substitution with 273 to aﬀord substrate 267 in 84% yield (Scheme 115).

For 268, Boc-protection of p-toluenesulfonamide 276 was followed by nucleophilic substitution with bromoacetonitrile to install the nitrile group, and afford 277 in an excellent overall 82% yield (Scheme 116). Removal of the Boc group afforded 278 in a more modest 47% yield, due to the formation of an undesired side product. Reaction of 278 with 273 in the presence of potassium carbonate afforded substrate 268 in 72% yield.

145 1) Boc2O (3.0 eq.), DMAP (0.5 eq.), Et3N O (1.2 eq.), THF, rt, 3 h O N S NH2 S N 2) Br (2.5 eq.) O O N O K CO (2.0 eq.), rt, 16 h O 276 2 3 277 82%

273 (0.9 eq.), TBSO TFA O N K2CO3 (2.1 eq.) N S NH Ts N DCM, rt, 4 h O DMF, rt, 16 h 47% 72% 278 268

Scheme 116: Synthesis of 268

2.2.3.2. Solvent screening (thermal conditions)

Initial screening conditions involved conventional heating of the substrates in various solvents which have been used successfully for the HDDA reaction.(271) The reactions were monitored by TLC and 1H NMR spectroscopy. The starting material was recovered in its entirety for both substrates, regardless of the reaction conditions used (Table 21).

N N solvent X X O heat OTBS TBS

267 (X= C(CO2Me)2) 279 (X= C(CO2Me)2) 268 (X= NTs) 280 (X= NTs)

Table 21: Solvent screening for the thermal HHDDA reaction of substrates 267 and 268

267 268 Entry Solvent Temp (◦C) Time (h) Result Temp (◦C) Time (h) Result 1 Chloroform 60 92 NR 60 48 NR 2 Toluene 110 92 NR 110 48 NR 3 Benzene 85 93 NR 90 48 NR 4 Heptane 100 93 NR 100 48 NR 5 o-DCB 120 89 NR ---

146 It was suggested that more intense microwave heating could initiate the reaction. Therefore, solvent screening was repeated, but at higher temperatures in the microwave (Table 22). However, even when heated to 250 ◦C in 1,2-dichlorobenzene (o-DCB), clean starting material was recovered for both substrates. This indicates that the activation energy for the reaction is very high, and thoughts were turned to how to overcome this.

N N solvent X X O microwave OTBS TBS

267 (X= C(CO2Me)2) 279 (X= C(CO2Me)2) 268 (X= NTs) 280 (X= NTs)

Table 22: Solvent screening for the thermal HHDDA reaction of substrates 267 and 268 (microwave conditions)

267 268 Entry Solvent Temp (◦C) Time (h) Result Temp (◦C) Time (h) Result 1 Chloroform 100 1 NR 100 1 NR 2 Toluene 150 1 NR 150 1 NR 3 Benzene 130 1 NR 130 1 NR 4 Heptane 150 1 NR 150 1 NR 5 o-DCB 250 2 NR 250 1 NR

2.2.3.3. Screening of metal catalysts

Lee and co-workers have had success with the use of silver catalysis to eﬀect classical HDDA reactions, with formal addition of C–H bonds across the arynes formed.(285,286) It was proposed that π-acid metal catalysts might be eﬀective in catalysing the HHDDA reaction, by lowering its activation energy. Several π-acid catalysts, as well as some Lewis acid catalysts, were screened for both the substrates using toluene as a solvent (as this was used successfully by Lee).

Au(I) salts such as AuCl are known to be alkynophilic, and it was thought that

147 they might coordinate to the alkyne and/or nitrile to catalyse the cyclisation. This complexation might also orient the alkynes and nitrile in the reactive conformation, favouring reaction. Unfortunately, this was not effective (Table 23, Entry 1). Cationic gold complexes, which are stronger π-acids, were suggested to be more effective as coordinating centres. Use of Au(PPh3)Cl with an equivalent of silver salt AgOTf (301) generated the cationic gold complex Au(PPh3)OTf in situ. Unfortunately, when subjecting 267 to these reaction conditions a complex mixture of products was formed, none of which were desired product 279 (Entry 3). Neither platinum nor silver catalysis were any more effective than gold (Entries 2, 5–7) although AgSbF6 resulted in partial deprotection of the TBS alcohol 267 to form 281 (Entry 6). Lewis acids such as

Zn(OTf)2 and CoCl2 resulted in recovery of the pure starting material (Entries 9 & 11).

N N catalyst (10 mol%) N X X + X O toluene, 90 °C, t h OTBS TBS OH

267 (X= C(CO2Me)2) 279 (X= C(CO2Me)2) 281 (X= C(CO2Me)2) 268 (X= NTs) 280 (X= NTs) 282 (X= NTs)

Table 23: Screening of metal catalysts for substrates 267 and 268

267 268 Entry Catalyst t (h) Result t (h) Result 1 AuCl 24 NR 24 NR

2 PtCl2 24 NR 24 NR a b 3 Au(PPh3)OTf 20 279 not observed 48 NR c 4 FeCl3 24 NR 48 268 : 282 = 1 : 0.3 5 AgOTf 24 NR 48 NR d 6 AgSbF6 50 267 (70%) + 281 (32%) 48 NR

7 AgNO3 24 NR 48 NR d c 8 Cu(OTf)2 50 267 + 281 (5%) 48 268 : 282 = 1 : 0.6

9 Zn(OTf)2 24 NR 48 NR

10 Au(PPh3)Cl -- 48 NR

11 CoCl2 -- 48 NR a (301) 5 mol% catalyst formed in situ by mixing Au(PPh3)Cl (5 mol%) and AgOTf (5 mol%). b Carried out at room temperature. c Ratio by 1H NMR of the crude. d Isolated yield.

148 FeCl3 resulted in partial TBS deprotection of 268 to form 282 (Entry 4), and Cu(OTf)2 resulted in partial TBS deprotection of both substrates (Entry 8).

2.2.3.4. Cobalt catalysis

Work by Starýand co-workers has shown the cobalt complex [Co(CO)2(Cp)] to be effective in mediating the [2+2+2] cycloisomerisation of ynedinitriles 283 to pyridazines 284 (Scheme 117).(302) The mechanism was proposed either to be triggered by a single electron transfer from a Co(II) species, or to follow a more conventional organometallic pathway. The cobalt has an activating effect on the two nitrile groups, and it was thought this catalyst might have the same activating effect on substrate 267, enabling the HHDDA reaction to proceed.

N [Co(CO)2(Cp)] (0.1–7.0 eq) N p-xylene, 140 °C N N 283 284

Scheme 117: General scheme for the cobalt mediated [2+2+2] cycloisomerisation of ynedinitrile 283 to pyridazine 284(302)

[Co(CO)2(Cp)] (2 eq.) MeO C N MeO2C N 2 Au(PPh3)Cl (x mol%) MeO C MeO2C 2 O p-xylene, 135 °C, 24 h OTBS TBS 267 279

Table 24: Reaction conditions for the reaction of 267 in the presence of [Co(CO)2(Cp)]

Entry x Result 1 0 None of desired product formed 2 10 None of desired product formed

The HHDDA reaction was attempted using substrate 267, with two equivalents of

149 the [Co(CO)2(Cp)] complex either in the presence or absence of 10 mol% Au(PPh3)Cl (Table 24). Neither experiment resulted in the formation of any of the desired product; however, none of the starting material could be recovered for either reaction. It is suggested that the starting material had decomposed, or polymerised.

2.2.3.5. Iridium catalysis

In a work by Takeuchi and co-workers, iridium catalysis has been shown to mediate the [2+2+2] cycloaddition of α,ω-diynes such as 285 with nitriles (Scheme 118).(303)

via Me [Ir(cod)Cl]2 (1 mol%) Ar MeO2C Me dppf (2 mol%) MeO2C Ar MeO2C MeO C ArCN MeO C MeO2C Ir 2 2 N N Me benzene, reflux 285 286 287 Me 288

Scheme 118: General scheme for the iridium catalysed reaction between α,ω-diyne 285 and aromatic nitrile 286 to yield substituted pyridine 287(303)

In several ways this transformation looks similar to the desired transformation of 267 to 279, due to the use of an identical linker, as well as the use of both aromatic nitriles (such as 286) and unactivated alkyl nitriles. However, the proposed mechanism involves iridacyclopentadiene intermediate 288, to which the nitrile then adds. Formation of such an intermediate would be impossible with substrates 267 or 268, as they do not contain a α,ω-diyne, but it was thought that the α,ω-alkynenitrile might be able to form an analogous structure instead.

The iridium catalyst was screened in the presence of several diﬀerent phosphine ligands on compound 267, to see whether any pyridine product (279) would be formed (Table 25). No reaction took place in the presence of any of the ligands, with recovery of the starting material for all reactions.

150 MeO C N MeO2C N 2 [Ir(cod)Cl]2 (2 mol%) MeO C MeO2C 2 O ligand (x mol%) OTBS toluene, reflux, 24 h TBS 267 279

Table 25: Screening of ligands for the reaction of 267 with iridium catalysis.

Entry Ligand x Result

1 PPh3 8 NR 2 DPPE 4 NR 3 DPPP 4 NR 4 DPPB 4 NR

2.2.3.6. Deprotonation of the HHDDA precursor

It was thought that deprotonation of substrate 267 adjacent to the nitrile, to form intermediate 289, might activate the nitrile towards cyclisation with the diyne (Scheme 119). This was attempted using sodium hydride, reﬂuxing in toluene for 22 hours. Unfortunately, none of the desired product was formed, with recovery of pure starting material.

MeO C N MeO2C N 2 NaH (1.0 eq) MeO C MeO2C 2 O toluene, reflux, 22 h OTBS TBS 267 279 0% via: MeO C 2 N MeO2C • N MeO2C MeO2C

OTBS OTBS 289a 289b

Scheme 119: Attempted deprotonation of 267 to form 279.

2.2.4. Conclusions

In conclusion, attempts to carry out a Hetero-Hexadehydro-Diels–Alder reaction between a diyne, and a nitrile diynophile, to form a pyridyne intermediate were not

151 successful. Thermal conditions were screened in a variety of solvents, using both traditional and microwave heat sources, but neither resulted in any reaction taking place for either substrate 267 or 268. Use of π-acid and Lewis acid catalysis were unsuccessful. Attempts to deprotonate the starting material α- to the nitrile, with the aim of activating the nitrile towards the HHDDA reaction, were also fruitless. It is proposed that the substrates 267 and 268 are very stable, and the activation barrier for the HHDDA reaction involving the nitrile is very high. These results, and the low reactivity of nitriles compared to alkynes might suggest that the reaction with the nitrile might not be feasible. After this work was carried out, the group of Hoye has also reported that nitriles have failed to undergo HDDA reactivity under thermal conditions.(304) However, they were able to use substrates of the form 290 (Scheme 120), similar to 268 for a new type of reaction to aﬀord substituted pyridines 291. The “pentadehydro-Diels–Alder” (PDDA) reaction is proposed to proceed via initial rate- limiting base-promoted isomerisation of 290 to 292, which can undergo cyclisation to form 293, a α,3-dehydrotoluene. This is trapped by NuH to aﬀord the product 291. The gem-dimethyl group was found to be crucial for the PDDA step to out-compete formation of an enamine side-product. The reaction proceeded in generally pleasing yields, and allows access to complex substituted pyridine structures in one step, at

N DMF:NuH (1:1) N R N DBU (1.0 eq.) R N H rt, 3 h Nu 290 291 NuH = ROH, R NH or H O R = Ts, Ms, COPh 2 2 12 examples, 18–84% yield

Proposed mechanism: N N N N NuH R N R N RN R N • H H Nu H 290 292 293 291

Scheme 120: Hoye’s pentadehydro-Diels–Alder (PDDA) reaction to form pyridines(304)

152 room temperature and with a short reaction time.

153 2.3. Benzyne Truce–Smiles rearrangement

2.3.1. Background

2.3.1.1. The Smiles rearrangement

The Smiles rearrangement was first reported for naphtholsulfides by Rob Henriques in 1894,(305) and then 20 years later by Hinsberg(306,307) for naphtholsulfones. How- ever, it was not until the 1930s that its namesake, Samuel Smiles, published a number of papers investigating the nature of the reaction, and its generality.(308–314) The reaction is an intramolecular SNAr (Scheme 121), involving ipso substitution of an aromatic ring by a nucleophile (Y), with breaking of the C–X bond. The mechanism is proposed to proceed via a Meisenheimer complex (Scheme 122), which, following deprotonation, collapses to afford the product. Depending on the nature of Y, deprotonation may precede formation of the Meisenheimer complex.(315) The Meisenheimer complex is an anionic σ complex, and has been characterised by NMR and UV/Vis spectroscopy.(315–317)

X H base X EWG Y Y EWG H

. 294 295 Scheme 121: General scheme for the Smiles rearrangement, where Y is a nucleophile, and X a leaving group

Smiles found that three major factors contributed to the success of this reaction: the electrophilicity of the aromatic ring, the nucleophilicity of Y, and the leaving group ability of X.

The aromatic ring is typically activated by a strong electron withdrawing group in the ortho or para position. Nitro groups work particularly well for this, although

154 . X Y X YH –H X Y Y X H H EWG EWG EWG EWG

294 Meisenheimer Meisenheimer 295 complex complex

Scheme 122: General mechanism for the Smiles rearrangement migration has also been shown to take place with groups such as anthraquinone, p- sulfonyl, 2-pyridyl, naphthyl and o-halogenated aromatics.(318)

Smiles found that the importance of the natures of the leaving group X and the nucleophile YH are strongly linked. Increasing strength of Y− as a nucleophile allows use of poorer leaving groups (X) and visa versa.(311) In addition, the acidity of YH has an eﬀect on the reaction. As YH becomes more acidic its nucleophilicity also increases, however if YH is too acidic, a stable conjugate base can form for which nucleophilic attack may be unfavourable. Hence the acidity of YH is a delicate balance for reactivity.

The linker between the nucleophile and leaving group also aﬀects the reaction. It can be altered to make use of the Thorpe–Ingold eﬀect to promote reactivity.(319–321) The length of the linker is important, and examples are most common proceeding via a 5-membered Meisenheimer intermediate.

2.3.1.2. Variations of the Smiles rearrangement

In 1958, Truce reported a variation of the Smiles rearrangement involving the rearrangement of aryl sulfones, promoted by a strong lithium base (Scheme 123).(322,323) This reaction, and others like it which involve a stabilised carbanion nucleophile, have come to be known as the Truce–Smiles rearrangement.(324,325) However, the ﬁrst report of this type of reaction can actually be attributed to Dohmori and co-workers, who in 1954 published work on the base mediated rearrangement of aryl sulfonamides (Scheme 124).(326,327) They went on to publish a series of papers in this area over

155 the following decade, expanding the scope to the use of diﬀerent electron withdrawing groups on the acceptor ring, or the use of heterocycles such as pyridine N -oxides as the acceptor.(328–332) Investigations into the kinetics and mechanism of the reaction were also carried out.(328,333)

O S O S SO Li 2 nBuLi 2 2 Me Me Me Me Li

Me Me Me 296 297 298

Scheme 123: The Truce-Smiles rearrangement(322,323)

Rearrangement O O NH2 O NH2 O2 S R NaOH or Na2CO3 N R H –SO2 R = COMe, O N 2 O2N CO2R O2N 299 300 301 R = COMe, CN, CO2R, Ph

Scheme 124: Base mediated rearrangement of aryl sulfonamides, reported by Dohmori(326,327)

According to Truce, a deﬁning characteristic of the Truce–Smiles rearrangement is the lack of requirement for an activating electron withdrawing group in the ortho or para-position of the migrating arene.(334) However, whilst the examples reported by Truce lack substituents such as para-nitro groups (e.g. Scheme 123), and some can proceed with electron donating groups present(325) (e.g. with para-methoxy substitution on the migrating ring of 296 in Scheme 123, rearrangement proceeds in 78% yield), the rings are not without activation. The sulfonyl group itself has a strong inductive electron withdrawing eﬀect, which can stabilise the Meisenheimer intermediate.(325) Many other reported Truce–Smiles rearrangements require the use of activating groups such as nitro.(325)

156 The one-electron Smiles rearrangement allows the formation of carbon–heteroatom or carbon–carbon bonds by a radical mechanism. It was ﬁrst reported by Speck- amp(335,336), and developed by Motherwell(337–339) (vide infra). One advantage of this approach is that an activating group is not required on the migrating aryl ring. The loss of SO2 (or sometimes CO2) as a driving force for these reactions is common. This type of reaction has seen renewed interest in recent years for several reasons, such as the variety of methods available for radical generation and the lack of requirement for activation. Many researchers have been drawn by its ability to form C–C bonds simply and eﬃciently, and its capacity to take part in cascade reactions to generate a high level of complexity in one step.(340,341)

A number of other variations of the Smiles rearrangement exist, including the Clay- den rearrangement, the Ugi–Smiles and Passerini–Smiles reactions. The Smiles rearrangement is also a key step of the Julia–Kocienski oleﬁnation reaction. These and other modern advances in Smiles rearrangement chemistry have been recently reviewed by Holden and Greaney.(341)

2.3.1.3. Use of the (Truce–)Smiles rearrangement for biaryl synthesis

As previously discussed (Section 1.1.2.2, p29), biaryl compounds are a vital motif in many areas of chemistry, such as medicinal chemistry. Hence, the drive for new methods for their synthesis continues. Traditional methods to access biaryls involve metal catalysed cross-coupling reactions, which require expensive metal catalysts and stoichiometric quantities of pre-functionalised arenes, generating stoichiometric waste. Newer methods such as directed metal catalysed C–H functionalisation help to reduce waste (Section 1.1.2.2, p29), however some of the metals used to effect this can be toxic. It is often difficult to remove sufficient traces of these metals from the product to enable its use in a medicinal context. Furthermore, synthesis of biaryls with substitution in multiple ortho positions is challenging using these methods, due to the large steric hindrance disfavouring oxidative addition. The prospect of biaryl synthesis without

157 the need for any transition metal catalyst, whilst displaying a broad substrate scope is a very appealing one. Currently, examples of aryl anion rearrangement are rare, so there is much potential for development in this ﬁeld.

A seminal report on the use of the Truce–Smiles rearrangement for biaryl synthesis came from P¨utterand Waldau in 1972 (Scheme 125).(342) Phenolate anions generated from substrates such as 302 underwent rearrangement with loss of SO2 to aﬀord biaryls with hydroxy and amine substituents such as 303. There was a requirement for one of the positions ortho to the sulfonamide on the donor ring to be unsubstituted. In addition, if the position para to the hydroxy group was substituted, ipso attack would take place from the carbon between the OH and sulfonamide moieties. An electron withdrawing group such as nitro, sulfonyl or carbonyl was required to activate the acceptor ring. Reactions were carried out in DMSO or H2O.

HN SO2 NH2 KOH (3.0 eq.) HO HO NO2 H2O, 100 °C, 14 h NO 302 2 303 80%

Proposed mechanism: H HN SO2 N SO2 SO2 NH2 O HO O NO2 303 H N O NO2 302 304O 305

Scheme 125: Truce–Smiles rearrangement of 302 to form 303(342)

Weaver et al. reported an example of a biaryl synthesis using a Truce–Smiles rearrangement which proceeds via an uncommon 4-membered Meisenheimer intermediate 309 (Scheme 126).(343) The rearrangement proceeded for perﬂuorinated pyridyl ether 306 in modest yield. However when the corresponding sulﬁde was used, intramolecular

SNAr at the 3-position of the pyridine took place instead. The equivalent perﬂuori- nated benzene ether was demonstrated to form a ﬂuorinated benzofuran, but it was unclear whether this had proceeded by a Truce–Smiles pathway.

158 Br 1) nBuLi (1.1 eq.) O THF, –78 °C to rt, overnight OH F F F F 2) H2O

F N F F N F 306 307 34%

Proposed mechanism: Li

O O OLi H OH F F F F F F F F

F N F F N F F N F F N F 308 309 310 307

Scheme 126: Smiles rearrangement of 306 via a four-membered Meisenheimer intermediate(343)

The Motherwell biaryl synthesis represents a one-electron variant of the Truce– Smiles rearrangement, for the synthesis of biaryl compounds (Scheme 127).(337–339) Sulfonamide and sulfonate ester linkers can be used in the starting material 311, although sulfonamides are more successful. The arene undergoing ipso substitution can be aromatic or heteroaromatic. Unlike with many transition metal mediated cross coupling reactions, the formation of sterically congested biaryls actually proceeds better than for substrates without ortho-substitution. In addition, electron withdrawing and donating groups in the ortho and para position of the aromatic ring undergoing ipso attack are equally well tolerated. Unfortunately, a drawback of this methodology is the generation of stoichiometric quantities of toxic tin waste, required for radical generation.

O2 S n XH X (Het)Ar Bu SnH (1.3 eq.), AIBN (0.7 eq.) 3 (Het)Ar I benzene, reflux

311 312 X = NMe, O X = NMe, O

Scheme 127: Motherwell biaryl synthesis(337–339)

159 Quayle and co-workers reported a transition-metal free biaryl synthesis by a two- electron Truce–Smiles rearrangement (Scheme 128).(344) The methodology was unex- pectedly discovered during an attempt to generate benzyne from a substrate 313, using the Kobayashi method of ﬂuoride mediated fragmentation of an aryl sulfonate ester with a TMS group in the ortho position. Instead of generation of benzyne and subsequent trapping, the biaryl product 314a was obtained in 74% yield. This is proposed to result from formation of pentavalent silicon intermediate 315, which with an electrophilic acceptor arene undergoes an aryl Truce–Smiles rearrangement to afford the biaryl product. Exploring the scope of the reaction, the authors found the presence of a nitro group on the acceptor ring to be crucial for reactivity, with other

EWG OH TBAF (3.0 eq.) SO O 2 MeCN, 20 °C, 16 h EWG R TMS R

313 314

Selected examples:

Me NO Me NO Me Br Me CHO 2 2 NH

OH OH OH OH OH O

NO2 NO2

NO2 NO2 NO2 NO2 NO2 314a 314b 314c 314d 314e 314f 74% 75% 49% 63% 71% 61%

Proposed mechanism:

EWG EWG EWG O2 EWG S TBAF O –SO2 SO SO O 2 O 2 OH

TMS FMe3Si R R R R

313 315 316 314

Scheme 128: Truce–Smiles generation of biaryls by Quayle(344)

160 electron withdrawing groups proving ineﬀective. Rearrangement often competed with protodesilylation. However, susbstituents tolerated on the donor ring included nitro, methyl, aldehyde and bromine. The use of a heterocycle as the donor ring was also successful (314f) in good yield. Interestingly, the group also found that attempting to generate an aryl anion from the ortho-halo arene sulfonate ester using alkyl lithium or Grignard reagents did not result in the formation of any biaryl products, highlighting how the reaction is subject to subtle electronic eﬀects.

A similar reaction worthy of note here, although not a biaryl synthesis, is the anionic thia-Fries rearrangement reported by Lloyd-Jones (Scheme 129).(345) This involves the deprotonation of triflates with an electron withdrawing group in the ortho position, and results in a rearrangement to form the aryl triflone, rather than benzyne formation (which is observed with electron donating groups present). These triflone products have also been observed by the Quayle and Greaney groups when using ortho-trimethylsilyl aryl triflates with electron withdrawing groups ortho to the triflate moiety for the generation of benzyne.(344,346)

Cl Cl O O LDA (1.0 eq.) OH S CF O 3 THF, –78 °C, 10 min SO2CF3 317 318 80%

Scheme 129: Anionic thia-Fries rearrangement, reported by Lloyd-Jones(345)

The Truce–Smiles rearrangement has previously been combined with benzyne chemistry in a report by the Greaney group (Scheme 130).(347) Aryl sulfonamides 319 can add to benzyne (generated from 320 using ﬂuoride), and the resulting aryl anion can undergo a Truce-Smiles rearrangement with loss of SO2 to form a biaryl amine 321. This reaction represents an elegant, metal-free biaryl synthesis, under mild conditions, and is operationally simple. There is a requirement for activation of the migrating aryl ring, however as well as the traditional nitro group, electron withdrawing groups such as nitriles and ketones work (321b & 321c). Halogens in the ortho and para-positions

161 (321d) worked particularly well. The nitro group also worked well in the ortho position. N -Alkyl sulfonamides could be used, although they resulted in a second arylation with the benzyne species (e.g. 321e, where the Ph in NBnPh comes from 320). Ster- ically congested tri- and tetra-ortho-substituted biaryls, which are difficult to access using methods such as transition metal catalysed cross-coupling, could be formed in pleasing yields. Some of these were shown to be atropisomers (e.g. 321f). Heterocycles could also be used effectively, with pyridine, pyrimidine and benzothiazole products being afforded in modest to good yields (321g–321i).

SO NHR1 2 R2 OTf KF (3.0 eq.), 18-crown-6 (3.0 eq.) NHR1 EWG R2 TMS THF, reflux, 24 h EWG

319 320 321

SO2 2 1 1 R 1 R R SO2NHR N N O2S O2S EWG R2 EWG EWG

319 322 323 324

Selected examples:

NHPh NHPh NBnPh MeO NHPh NHPh NHPh Cl Cl O2N MeO N X NS

X Br NO2

321a X = NO2 321d 321e 321f 321g X = CH 321i a 62% 88% 72% 62% (Sa/Ra 1:1) 43% 73% 321b X = CN 321h X = N 50% 57% 321c X = COMe 69%

a 2.0 eq. of 320 used

Scheme 130: Benzyne Truce–Smiles rearrangement with aryl sulfonamides(347)

162 2.3.2. Aims and objectives

There was a desire to further explore the use of the Truce–Smiles methodology for biaryl synthesis, given its ability to generate otherwise diﬃcult to access hindered biaryls, without the need for metal catalysis. The combination of benzyne chemistry with the Truce–Smiles rearrangement has already proven successful for the synthesis of ortho-amino biaryls from aryl sulfonamides (Scheme 130).(347) It was envisaged that by combining this approach with that of Quayle (Scheme 128),(344) a new benzyne Truce– Smiles reaction could be developed, using aryl sulfonate esters for the generation of ortho-hydroxy biaryls (Scheme 131). Phenolic compounds can possess a diverse array of properties, and are utilised in dyes, antioxidants in food, plastic production and much more.(348,349) Many have been reported to display bioactivity against a variety of diseases. Therefore methodology enabling easy access to compounds containing both phenol and biaryl moieties is highly desirable.

O2 OSO Ar EWG OH 2 S O SO EWG Nu O 2 H EWG

Nu Nu Nu 325 326 327 328

Scheme 131: Proposed benzyne Truce–Smiles rearrangement with aryl sulfonate esters

The reaction would proceed with generation (using the Kobayashi method) of a benzyne intermediate 325, with a sulfonate ester in the ortho position.(244) Attack of a nucleophile would be expected to take place meta to the inductively electron withdrawing sulfonate ester to aﬀord aryl anion 326, which is similar to the intermediate 315 of Quayle’s biaryl synthesis (Scheme 128).(267,344) Therefore, with suitable activation of the acceptor ring, 326 should be able to undergo a Truce–Smiles rearrangement via the Meisenheimer complex 327, to aﬀord 328. This builds upon the work of Quayle by allowing the incorporation of a nucleophile meta to the hydroxy group formed, expanding the scope of biaryls which can be accessed, as a huge range of nucleophiles

163 have been reported to react with benzyne.(256,266) The opportunity for expansion of the scope is also large due to the potential for variation of substituents on both of the aryl rings.

2.3.3. Results and discussion

2.3.3.1. Starting material synthesis

For the starting material 325 (Scheme 131), para-nitrobenzene was selected as the acceptor aryl group, as it is typically one of the most effective migrating rings for Smiles rearrangements.(318,325) Two different arrangements of the ortho-trimethylsilylaryl triflate could result in benzyne formation (Scheme 132). Substrates with the relative geometry of 329 have successfully been used for benzyne nucleophilic addition/Fries rearrangement by Bronner and co-workers (Scheme 133).(350) However, an example by Li et al. found substrates with the relative geometry of 330 to be more effective benzyne precursors for their chemistry (Scheme 134), with the alternative giving a lower yield and reduced stability at higher temperatures.(351)

OSO2Ar OSO2Ar OSO2Ar F F OTf TMS

Ar = p-NO2C6H4 Ar = p-NO2C6H4 TMS OTf 329 325 330

Scheme 132: Benzyne precursors for the tandem benzyne Truce–Smiles rearrangement

R3 O O O TBAT HN OH O (2.0 eq.) R1 O 1 2 R O (1.5 eq.) R1 O R THF R1 OTf NaH (2.0 eq.) 60 °C, 16 h NR3 3 NR 2 TMS R 2 331 332 333 R 334 7 examples, 61–80% yield

Scheme 133: Benzyne nucleophilic addition/Fries rearrangement, by Bronner(350)

164 O O O O OTf OTf Ph S Ph (1.0 eq.) Ph Ph S Ph (1.0 eq.) N N N N TMS OTf H H N O H H S K2CO3 (4.0 eq.) N O K2CO3 (4.0 eq.) OTf TMS 18-crown-6 (4.0 eq.) Ph 18-crown-6 (4.0 eq.) MeCN, rt, 8 h MeCN, 80 °C, 8 h 335 38% 336 85% 337 (1.5 eq.) (1.5 eq.)

Scheme 134: Comparison of benzyne precursors for Li’s domino benzyne diamination(351)

Therefore, it was decided to synthesise both potential benzyne precursors (329 and 330). Three routes were proposed for the synthesis of 329. The first route (Scheme 135) was the shortest, and started from 2,6-dibromophenol 338. Using literature procedures, 338 could be converted to 340, via initial TMS protection, and retro-Brook rearrangement to form 339.(352,353) This proceeded in a satisfactory 47% yield, and was followed by installation of the triflate which afforded 340 in 46% yield. There is much precedent for the copper catalysed conversion of aryl bromides to phenols using copper catalysis.(354–356) Thus, it was considered that this approach might be used to convert 340 to 341, which could then be converted into the sulfonate ester 329 using base and aryl sulfonyl chloride. Whilst other methods have been reported for the conversion of aryl bromides to phenols involving bromine-lithium exchange, these approaches would likely generate benzyne with substrate 340, so were not attempted.(357,358)

i OH 1) TMSCl (3.1 eq.), Et3N OH Pr2NEt (2.0 eq.) OTf (2.4 eq.), THF, rt, 3 h Tf O (1.5 eq.) Br Br TMS Br 2 TMS Br 2) nBuLi (1.0 eq.), THF DCM, 0 °C to rt –78 °C to rt, 16 h 16 h 338 339 340 47% 46%

Cu catalysis

OTf OTf ArSO2Cl TMS OSO2Ar TMS OH base

Ar = p-NO2C6H4 329 341

Scheme 135: Route for the synthesis of 329 from 338

165 Conversion of 340 to 341 was attempted using conditions developed by Punniya- murthy and co-workers (Scheme 136 a).(354) Use of catalytic copper iodide with ligand 342, and tetrabutylammonium hydroxide as base, at 130 ◦C, followed by acidic work- up resulted in a mixture of products, none of which appeared to be 341 by 1H NMR spectroscopy, or GCMS.

a) OTf OTf CuI (10 mol%), Ligand 342 (20 mol%) TMS Br TMS OH N n Bu4NOH (3.0 eq.), DMSO-H2O (2:3) OH 130 °C, 17 h Ligand 342 340 341 not observed

b) OTf CuCl2 (10 mol%) OTf 1,10-phen (10 mol%) TMS Br TMS OH n KOH (2.0 eq.), Bu4NBr (10 mol%) H2O, MW, 120 °C, 40 min 340 341 not observed

c) OH MeO (1.5 eq.) OTf CuI (10 mol%) TMS O OTf OTf 1,10-phen (20 mol%) TFA TMS Br TMS OH

Cs2CO3 (1.5 eq.) toluene, 110 °C, 22 h OMe 340 343 341 Not observed

Scheme 136: Attempted conversion of 340 to 341 using copper catalysis

Using a diﬀerent set of conditions developed by Zhou et al. which involved the use of microwave heating, 341 was not observed following acidic work-up (Scheme 136 b).(355) The resulting crude was very messy by 1H NMR spectroscopy but did not indicate the presence of 341.

It was considered that the strong acidic work-up might be causing decomposition of 341. A procedure has been reported by Tao and co-workers involving in situ formation of aryl ethers, followed by hydrolysis of these using TFA to aﬀord the phenolic product.(356) However, when using this methodology on 340 (Scheme 136 c), the ether

166 343 was not observed by 1H NMR of the crude reaction mixture, instead the major product appeared to be a compound not containing the TMS moiety. This indicates that the work-up was not the issue, and that the problem was instead with the Br/OH exchange. Therefore, attention was turned to an alternative route for the synthesis of 329.

The second proposed route to 329 began with a three step synthesis of 3-bromo-2- methoxyphenol 347 from 3-bromo-2-hydroxybenzaldehyde 344, as reported by Njar- darson (Scheme 137).(359) Methyl protection of 344 was followed by Baeyer–Villiger oxidation of the aldehyde to form intermediate 346, which was used immediately without purification to form phenol 347. Installation of the sulfonate ester using conditions reported by Quayle proceeded very well, affording 348 in 86% yield.(344) Deprotection of the methyl ester using BBr3 gave 349 in an excellent 91% yield. It was envisaged that 349 could be converted to 329 by a sequence involving TMS protection of the phenol, followed by bromine-lithium exchange and a retro-Brook rearrangement to install the aryl–TMS moiety. Conversion of the phenolic OH to a triflate with triflic

O O MeI (2.0 eq.), O mCPBA OH K2CO3 (5.0 eq.) (1.5 eq.) O Et N (10 mol%) H H 3 DMF, 50 °C DCM, rt MeOH, rt OMe OH OMe OMe overnight overnight overnight Br Br Br Br 344 345 346 347 96% 53% over 2 steps

NaH (4.1 eq.) ArSO2Cl (1.1 eq.) THF, rt, 90 min

i) NaH, TMSCl BBr (2.0 eq.) OSO2Ar OSO2Ar 3 OSO2Ar ii) nBuLi, THF, –78 °C DCM

OTf iii) w/u OH 0 °C to rt OMe TMS iv) base then Tf2O Br overnight Br 329 349 348 91% 86% Ar = p-NO2C6H4

Scheme 137: Attempted route to 329, from 344

167 anhydride might then aﬀord 329.

This transformation of 349 to 329 was carried out using a procedure similar to Li and co-workers for the installation of ortho-trimethylsilylaryl triflate functionality (Scheme 138).(351) Crude 350 was carried directly through to the next step, where pyridine was used as the base for installation of the triflate. Unfortunately, this procedure resulted in formation of a mixture of products, the major of which was triflated starting material 351. Only small quantities of the desired product 329 were observed, in a mixture with other unidentified products.

The formation of 351 indicated that the lithium-bromine exchange had failed to take place. Therefore the reaction in Scheme 138 was repeated with tBuLi in place of nBuLi. However, this resulted in a mixture of products, none of which were 329.

1) NaH (1.1 eq.) then TMSCl (1.2 eq.) pyridine (2.0 eq.) OSO2Ar OSO2Ar OSO2Ar OSO2Ar 0 °C, 10 min Tf2O (2.0 eq.)

OH 2) nBuLi (1.2 eq.) OH DCM, 0 °C to rt OTf OTf Br THF, –78 °C, 10 min TMS overnight TMS Br 349 3) aq. NaHCO3 350 329 351 <6% 53%

Scheme 138: Attempted conversion of 349 to 329

A third route was investigated, which whilst involving more steps, was better precedented (Scheme 139). This involved a route to 341 reported by Sarah Bronner and co-workers, starting from 2-(benzyloxy)phenol 352.(350) Installation of a carbamate proceeded in 69% yield; this carbamate could then act as a directing group for ortho- lithiation. The ortho-lithiated compound was quenched with TMSCl to afford 354 in a modest yield, with recovery of some starting material. The carbamate was replaced by a triflate to give 355, which underwent hydrogenolysis to remove the benzyl protecting group. This step suffered from selectivity issues, with significant quantities of the de-triflated product 356 also being obtained, in a 0.31 : 1.00 ratio with the product 341. Attempted formation of the sulfonate ester using NaH, as reported by Quayle,

168 and as used successfully for the analogous conversion of 347 to 348 (Scheme 137) was unsuccessful, resulting in a complex mixture of products.(344) Fortunately, use of one equivalent of pyridine in DCM enabled isolation of 329 in 82% yield. Whilst this route did furnish 329, it was ineﬃcient. If larger quantities of 329 were required, it may be worthwhile to optimise the procedure further, or ﬁnd an alternative route to the product.

i) TMSOTf (1.1 eq.) i OBn PrNCO (2.5 eq.) OBn TMEDA (1.4 eq.), Et2O/THF (3:1) OBn H Et N (0.4 eq.) H OH 3 O N 0 °C to rt, 35 min O N

DCM, 35 °C, 4 h O ii) nBuLi (3.0 eq.) O TMEDA (3.0 eq.), –78 °C, 3.5 h TMS 352 353 iii) TMSCl (7.0 eq.), –78 °C, 1.5 h 354 a b 69% iv) aq. NaHSO4 w/u 32%

i) DBU (5.0 eq.), Et2NH (1.7 eq.) MeCN, 40 °C, 50 min t ii) p- BuC6H4NTf2 (3.0 eq.) 100 °C, MW, 30 min

OTf Pyridine (1.0 eq.) OH OBn ArSO2Cl (1.1 eq.) H2, Pd/C (1.5 mol%) TMS OSO2Ar OTf OTf DCM, 0 °C to rt, 26 h iPrOAc, 18 h TMS TMS 329 341 OH 355 Ar = p-NO2C6H4 (341 : 356 = 1.00 : 0.31) 48% yield over 3 steps

TMS side product 356

a Average yield over 3 reactions, 6.5 mmol scale. b Average yield over 7 reactions, 2.1 mmol scale. Average 24% starting material 353 recovered

Scheme 139: Route to 329 from 2-(benzyloxy)phenol 352

Fortunately, synthesis of 330 was more straightforward. Using a procedure by Hosoya and co-workers, 361 could be accessed (Scheme 140).(360) The starting material 357 was TMS protected on both hydroxy groups using HMDS to aﬀord crude 358. Removal of the solvent and excess HMDS under vacuum before redissolving in fresh THF enabled lithium-bromine exchange using nBuLi. This caused a retro-Brook rearrangement, to install the TMS group on the aryl ring aﬀording 359. This com-

169 pound was surprisingly stable, and could be isolated by column chromatography, in a pleasing 70% yield over the first two steps, on a 3 g scale. With the second TMS group i protecting one hydroxy group on 359, triflic anyhydride with Pr2NEt could be used to convert the unprotected phenolic OH into a triflate moiety. Removal of the solvent, and addition of 1 M HCl allowed deprotection of the TMS ether to afford 361 in good yield, again on a 3 g scale. Use of pyridine base for installation of the sulfonate ester resulted in recovery of 361. DIPA was more successful, and when carried out on a 1 g scale, 330 was isolated in an excellent 97% yield without need for further purification. Li and co-workers have recently reported a one-pot synthesis of 361 from 357, which could allow further streamlining of this route in the future.(361)

OH OTMS OTMS Tf2O (1.5 eq.) n iPr NEt (1.5 eq.) Br HMDS (3.0 eq.) Br BuLi (1.1 eq.) TMS 2 THF, rt THF, –78 °C DCM, –78 °C OH overnight OTMS 90 min OH 20 min 357 358 359 70%

O2 S DIPA (1.5 eq.) OH OTMS O p-NO2(C6H4)SO2Cl (1.1 eq.) TMS 1.0 M HCl TMS TMS O2N DCM, 0–20 °C, 20 h THF, rt OTf 15 min OTf OTf 330 361 360 97% 50%

Scheme 140: Synthesis of 330

2.3.3.2. Screening and optimisation

Initial screening of conditions for the proposed benzyne-Truce–Smiles was carried out with pyrrolidine (a readily available nucleophile that has been shown to react well with benzyne), using benzyne precursor 329 (Table 26).(362) Acetonitrile, a commonly used solvent in both benzyne and Smiles rearrangement chemistry was initially used.(341,363) Under these conditions, it was found that CsF and an excess of pyrrolidine resulted in the formation of one major product, 362a in 56% yield (Table 26, Entry 1). None of the

170 desired product 328a was observed. The formation of 362a presumably results from protonation of the intermediate 326 (Scheme 131, p163) taking place preferentially over the Truce–Smiles rearrangement. Screening of fluoride sources found that KF with 18-crown-6 was also effective for formation of 362a, but did not afford 328a (Entries 2 & 4). Use of TBAF did not result in the formation of either product, with a mixture of other, unidentified products being formed (Entry 5). Decreasing the equivalents of nucleophile (Entries 3 & 4) did not afford 328a, but gave similar yields of 362a with KF. Changing the solvent (Entries 7–10) did not result in observation of any 328a.

NO2 NO2 O Fluoride source (2.0 eq.), O NO S Additive (2.0 eq.) OH 2 S O O O pyrrolidine (x eq.) O OTf H Solvent, rt, 5 h – overnight N TMS N

329 328a 362a Table 26: Screening of conditions for the benzyne Truce–Smiles rearrangement of substrate 329 with pyrrolidine nucleophile

Entry F− source Additive x Solvent 328a (%)a 362a (%)a 1 CsF - 10 MeCN 0 56 2 KF 18-crown-6 10 MeCN 0 40 3 CsF - 4.0 MeCN 0 25 4 KF 18-crown-6 4.0 MeCN 0 45 5 TBAF - 4.0 MeCN 0 0 6 KF 18-crown-6 4.0 THF 0 40 7 KF 18-crown-6 4.0 1,4-Dioxane 0 39 8 KF 18-crown-6 4.0 MeCN/Toluene (1:1) 0 40 9 KF 18-crown-6 4.0 DCM 0 36 a Monitored by 1H NMR using an internal standard.

To investigate whether the use of benzyne precursor 330 aﬀected the yield or product distribution, and also due to the greater ease of synthesising 330 on a gram scale, screening was continued using this substrate (Table 27). Use of TBAF did result in the formation of product 362a when carried out at 50 ◦C, although its yield was lower than

171 with CsF or KF/18-crown-6 (Entries 1–3). None of these resulted in the formation of any 328a at 50 ◦C in MeCN. Neither increasing nor decreasing the temperature resulted in the observation of 328a in anything larger than trace quantities (Entries 4–6). Increasing the dilution of the reaction gave no 328a (Entry 7), and a selection of solvents were tried, which gave (at most) trace quantities of 328a (Entries 8–14). Generally, the yield of 362a formed was quite consistent, ranging from about 50–60%. Another product observed in small yields from some of the reactions was 363a. This may have been formed from the rearranged product 328a, indicating that to a small

NO2 NO2 O O Fluoride source (2.0 eq.), NO2 NO2 OH S ONs S Additive (2.0 eq.) O O O O pyrrolidine (4.0 eq.) H TMS Solvent, T °C, 5 h N N N OTf 330 328a362a 363a

Table 27: Screening of conditions for the benzyne Truce–Smiles rearrangement of substrate 330 with pyrrolidine nucleophile

Entry F− Additive Solvent T 328aa 362aa 363aa 1 CsF - MeCN 50 0 50 3 2 KF 18-crown-6 MeCN 50 <1 58 3 3 TBAF - MeCN 50 <1 38 1 4 KF 18-crown-6 MeCN rt 0 60 3 5 KF 18-crown-6 MeCN 70 <1 57 3 6 KF 18-crown-6 MeCN 90 0 50 3 7 KF 18-crown-6 MeCNb 70 0 53 5 8 KF 18-crown-6 1,4-Dioxane 70 1 50 2 9 KF 18-crown-6 MeCN/Toluene (1:1) 70 1 57 3 10 KF 18-crown-6 THF 70 <1 49 5 11 KF 18-crown-6 Toluene 70 <1 55 3 12 KF 18-crown-6 DCM 70 0 35 1 13 KF 18-crown-6 THF rt 2 50 4 14 KF 18-crown-6 1,4-Dioxane rt 3 55 <1 a Percentage yield, monitored by 1H NMR using an internal standard. b 5 × more dilute.

172 degree, Truce–Smiles rearrangement was taking place. The largest yields of 363a were obtained in MeCN or THF at 70 ◦C (Entries 7 & 10). Another product resulting from Truce–Smiles rearrangement was also observed (364a, Figure 6), in very small yields of 1% or less for most entries.

Several other products were observed in these reactions in small amounts, some of which could be isolated and characterised (Figure 6). Product 365a, a result of nucleophilic substitution of the sulfonate ester with pyrrolidine, was often observed by UPLC-MS in the crude reaction mixture. It could only be isolated as a mixture with 366, which presumably resulted from attack of adventitious water onto the benzyne intermediate. A product which appeared to be 367a, a regioisomer of 362a, was also observed in small quantities, although not enough could be isolated for full charac- terisation. This highlights the excellent regioselectivity of nucleophilic attack on the benzyne intermediate, favouring the meta-position.

Figure 6: Side products observed in the reaction of 330 with pyrrolidine

OTf ONs ONs O N N S NO2 N O NO2 OH

364a 365a 366 367a

A general mechanism for the formation of 328 and the two side products 362 and 363 is shown in Scheme 141. Initial benzyne formation, followed by nucleophilic attack could result in the formation of either 326 or 368. More likely 368 is formed, which can undergo intramolecular proton transfer to afford 362, or intramolecular Truce– Smiles rearrangement (directly, or via 326) to afford 369. Phenolate 369 can pick up a proton to afford 328, or a nosyl group by nucleophilic addition-elimination to afford 363.

Having thus far worked up the reactions using an acidic work-up analogous to that used by Quayle, it was found that by switching to a neutral work-up, a larger yield of

173 362

NO2 NO2 O S O O –SO2 HO Nu NO2 H ONs ONs Nu TMS F 326 328 NuH Truce– Smiles OTf O Nu NO 2 NO2 330 325 O LG-Ns –H S 369 O –SO O 2 NsO Nu H Nu 368 363

NO2 O S O O H

Nu 362

Scheme 141: Formation of the benzyne-Truce–Smiles rearrangement products, and major side product 362

328a could be obtained (Scheme 142). Unfortunately, whilst the yield had increased, the ratio of 328a to 362a was still low.

In a paper on three-component coupling reactions (using arynes, amines as nucleophiles, and CO2 as the electrophile) Yoshida and co-workers reported pyrrolidine as being a poor nucleophile for the reaction.(264) Higher yields were observed using nucleophiles such as dibutylamine, diisopropylamine, and piperidine. These three nucleophiles were tested on a small scale for the benzyne Truce–Smiles rearrangement in THF, with KF/18-crown-6. UPLC-MS analysis conﬁrmed the formation of the desired rearrangement product in each case. Extremely pleased with this, optimisation of the

174 NO2 NO2 O O KF (2.0 eq.) NO2 NO2 OH S ONs S 18-crown-6 (2.0 eq.) O O O O pyrrolidine (4.0 eq.) H TMS THF, 70 °C, 1 h N N N OTf 330 328a 362a 363a 7% (9%) 48% 2%

Scheme 142: Results of benzyne Truce–Smiles rearrangement of 330, with a neutral work-up. Yields calculated by 1H NMR with an internal standard (Isolated yields in brackets). reaction was proceeded using diisopropylamine (DIPA) nucleophile, in the hope that it would perform better than pyrrolidine. DIPA was chosen as it had given a relatively good ratio of desired product to side products by UPLC-MS. It was also considered that its sterically hindered structure might reduce formation of side products such as 365a (Figure 6), and further increase the regioselectivity of attack of the benzyne.

Pleasingly, the first reaction of 330 with DIPA as a nucleophile at room temperature gave a 10% yield of the desired benzyne-Truce–Smiles product 328b (Table 28, Entry 1), albeit with a 45% yield of the undesired side product 362b. Eager to improve the ratio between these two products in favour of the Truce–Smiles-rearranged product, we started by varying the reaction temperature. It was found that increasing the temperature to 70 ◦C considerably improved the yield of 328b to 25% (Entries 2 & 3), whereas decreasing the reaction temperature did not improve the yield of 328b (Entry 4). It should be noted that for Entry 4, after consumption of the starting material was confirmed by UPLC-MS the reaction mixture was left at room temperature overnight before work-up and obtaining an NMR yield. A second UPLC-MS analysis was also carried out in the morning, showing that the relative proportion of 363b to 328b had increased. This demonstrated the importance of avoiding extended reaction times, particularly at higher temperatures, to reduce the formation of the side product 363b from 328b. Decreasing the reaction concentration had a large positive effect on the

175 yield of 328b at room temperature (Entries 1 & 5), and the same effect was noted at 70 ◦C, although to a lesser extent (Entries 2 & 6). Increasing the temperature to 90 ◦C had no effect on the yield of either product. It was considered that dropwise addition of the benzyne precursor might improve the yield. Unfortunately at the lower concentration, neither addition over 40 minutes, nor a much slower addition over 5 hours had a significant effect on the yield or product ratio (Entries 8 & 9).

NO 2 NO2 O KF (2.0 eq.) NO O NO OH 2 ONs 2 S 18-crown-6 (2.0 eq.) S O O O DIPA O TMS H THF, T °C, t h N N OTf N

330 328b 362b 363b

Table 28: Screening of conditions for the benzyne-Truce–Smiles rearrangement of substrate 330 with DIPA nucleophile

Entry Eq. DIPA T (◦C) Conc. (M) t (h) 328b (%)a 362b (%)a 363b (%)a 1 4.0 rt 0.031 1 10 45 5 2 4.0 70 0.031 1 25 35 4 3 4.0 50 0.031 1 16 47 3 4 4.0 0 0.031 4 9 36 6 5 4.0 rt 0.0063 2 23 31 4 6 4.0 70 0.0063 1 31 32 3 7 4.0 90 0.0063 1 31 29 2 8b 4.0 70 0.0063 1 31 28 0 9c 4.0 70 0.0063 6 34d 35 2 10e 4.0 70 0.031 1.5 16 53 3 11 2.0 70 0.0063 1 28 34 0 12 8.0 70 0.0063 1 31 36 0 13f 4.0 70 0.0063 1 29 30 2 a Monitored by 1H NMR using an internal standard. b Dropwise addition of a solution of the benzyne precursor 330 over 40 minutes. c Dropwise addition of a solution of the benzyne precursor 330 over 5 hours. d 31% isolated yield. e Dropwise addition of a solution of the benzyne precursor 330 over 1.5 hours. f Heating was carried out using a microwave reactor.

An attempt to move back to a more economical higher concentration by using

176 dropwise addition of the benzyne precursor was also unsuccessful (Entry 10), and actually resulted in a decreased yield of 328b compared to the analogous fast addition reaction at that concentration (Entry 2).

Pleasingly, reducing the number of equivalents of DIPA had little eﬀect on the yield, and would make the reaction more economical (Table 28, Entry 11). Increasing the number of equivalents of DIPA did not increase the yield of 328b (Entry 12). Carrying out the reaction in a microwave reactor instead of heating in a sand bath also had no eﬀect on the yield (Entry 13).

It was hoped that changing the solvent might improve the relative ratio of 328b to 363b, if a solvent could be found which had a large enough stabilising eﬀect on the anionic intermediate 368 (Scheme 141, p174) to favour intramolecular Truce–Smiles rearrangement over protonation. Ideally, a more polar solvent should be better capable of this, however, solvent choice was limited by the need to avoid protic solvents, or solvents which might in any other way react with the benzyne intermediate under the reaction conditions. Screening of solvents showed THF to give the highest yield (31%) of desired product 328b (Table 29, Entry 1), with none of the other solvents screened providing an improvement to this. 1,4-Dioxane, MeCN, a 1:1 mixture of toluene and MeCN, monoglyme, and 2-methyl THF all gave similar yields (Entries 2, 3, 5, 9), albeit with higher yields of the unwanted side product 362b. Toluene as the sole solvent gave a slightly lower yield of both major products (Entry 4). Chlorobenzene resulted in a slower reaction time and gave only a 19% yield of 328b (Entry 8). MTBE also slowed down the reaction signiﬁcantly, and after 4 hours the major product of the reaction was 362b, with only a 6% yield of 328b.

Screening of ﬂuoride sources (Table 30) revealed that KF (with added 18-crown-6) and CsF gave very similar yields of both 328b and 362b, however, the reaction was much slower for CsF than KF (Entries 1 & 2). TBAF did not result in the formation of any of the desired product 328b, but it did give a 29% yield of 362b (Entry 3).

177 NO 2 NO2 O KF (2.0 eq.) NO O NO OH 2 ONs 2 S 18-crown-6 (2.0 eq.) S O O O DIPA (4.0 eq.) O TMS H Solvent, 70 °C, t h N N OTf N

330 328b 362b 363b

Table 29: Screening of solvents for the benzyne-Truce–Smiles rearrangement of substrate 330 with DIPA nucleophile

Entry Solvent t (h) 328b (%)a 362b (%)a 363b (%)a 1 THF 1 31 32 3 2 1,4-Dioxane 2 28 43 0 3 MeCN 1 29 39 6 4 Toluene 1 22 33 0 5 Toluene:MeCN (1:1) 1 26 40 5 6 MTBE 4 6 46 1 7 Monoglyme 1 29 43 0 8 Chlorobenzene 3 19 45 1 9 2-MeTHF 1 27 36 0 a Monitored by 1H NMR using an internal standard.

There are a few reports of the use of K2CO3 as an alternative to ﬂuoride sources for the generation of benzyne, at high temperatures.(351,361) Whilst this did generate the benzyne intermediate in chlorobenzene solvent at 130 ◦C, the benzyne generation step appeared slow. Monitoring by 1H NMR showed there to be starting material remaining; even after 45 hours the yield of the desired product 328b was only 11% (Table 30, Entry 4). Further optimisation with KF showed that increasing the equivalents of it had no eﬀect on the yield of 328b, but resulted in a slight increase in formation of side product 362b (Entry 5). Decreasing the equivalents of KF and 18-crown-6 resulted in slightly decreased yields of both the major products, and eliminated formation of the side product 363b (Entry 6). Control experiments were carried out without the KF (Entry 7), showing that this is necessary for the reaction to take place. Without the 18-crown-6 (Entry 8), the reaction is able to proceed, but it is slower and after four

178 hours, there was still 31% starting material remaining.

NO 2 NO2 O Fluoride source NO O NO OH 2 ONs 2 S Additive S O O O DIPA (4.0 eq.) O TMS H THF, 70 °C, t h N N OTf N

330 328b 362b 363b

Table 30: Screening of ﬂuoride sources for the benzyne-Truce–Smiles rearrangement of substrate 330 with DIPA nucleophile

Entry Fluoride source Additive t (h) 328b (%)a 362b (%)a 363b (%)a 1 KF (2.0 eq.) 18-crown-6 (2.0 eq.) 1 31 32 3 2 CsF (2.0 eq.) - 5 34 32 <1 3 TBAF (2.0 eq.) - 1 0 29 6 b 4 K2CO3 (2.0 eq.) 18-crown-6 (2.0 eq.) 45 11 45 6 5 KF (3.0 eq.) 18-crown-6 (3.0 eq.) 1 29 38 3 6 KF (1.0 eq.) 18-crown-6 (1.0 eq.) 1 25 25 0 7 - 18-crown-6 (2.0 eq.) 22 0 0 0 8 KF (2.0 eq.) - 4 15 19 0 a Monitored by 1H NMR using an internal standard. b Carried out using chlorobenzene solvent, at 130 ◦C.

It should be noted that 328b, 362b and 363b were not the only products observed from the reaction, but the only ones isolated and characterised. 365b, the DIPA analogue to 365a (Figure 6) was commonly observed by UPLC-MS of crude reaction mixtures, although only in small quantities. Other products appearing to result from the action of phenolic products as nucleophiles were also observed in small quantities by GCMS.

In order to improve the reaction, more thought was given to how the other side products might be formed. It was noted that TBAF is a commonly used reagent for the deprotection of tosyl groups, and can even be used eﬀectively at low temperatures in relatively short reaction times for this.(364) The only reported example of the use of

179 KF for tosyl deprotection requires KF-Al2O3 and uses solvent-free microwave conditions.(365) The authors note that their substrates did not deprotect when unsupported KF was used. This may explain why the desired product 328b was not formed when TBAF was used, but was with KF (Table 30). Although examples are lacking in the literature for the use of ﬂuoride for nosyl deprotection, there was concern that this might be taking place, to give the sulfonyl ﬂuoride 370 (Scheme 143). This species (370) was not observed by 1H NMR or UPLC-MS analysis, however it is likely highly reactive. It has potential to be attacked by the nucleophile present, to form species such as 365a, which was observed when pyrrolidine was used as the nucleophile. Al- ternatively, 365a may have been formed by the direct attack of pyrrolidine on the sulfonate ester. This would help account for the higher yields of the desired product when DIPA was used as the nucleophile instead, as it is much more sterically hindered than pyrrolidine, hence disfavouring the pathway involving nucleophilic attack of the sulfonate ester. It should be noted that in the control experiment without KF (Table 30, Entry 7), no 365b was observed, only clean starting material was recovered. This suggests that DIPA is not capable of direct attack of the sulfonate ester, although it is possible that less hindered pyrrolidine may be.

NO2 O S O NO2 O F TMS O S F O OTf 330 370

Scheme 143: Potential formation of sulfonyl ﬂuoride 370

In order to test whether the KF was capable of deprotecting the nosyl group under the reaction conditions being used, test substrate 371 was synthesised from phenol. Sulfonate ester 371 was heated to 70 ◦C with KF and 18-crown-6 in THF, both with and without DIPA (Scheme 144). The reaction mixtures were worked up and then analysed by 1H NMR spectroscopy and GCMS. Phenol 372 was not observed in either case, nor was sulfonyl ﬂuoride 370. In both cases, pure starting material was recovered,

180 in 89% yield (by 1H NMR with an internal standard). This supports the conclusion that ﬂuoride is not deprotecting the sulfonate ester, however this should be treated with caution, as it is possible that phenol was lost to the aqueous layer during work-up.

NO2 O S KF (2.0 eq.) O OH NO2 O 18-crown-6 (2.0 eq.) A) O S THF, 70 °C, 1 h F O

371 372 370 not observed not observed

NO2 O KF (2.0 eq.) S 18-crown-6 (2.0 eq.) O OH NO2 NO2 O DIPA (4.0 eq.) B) O O S S THF, 70 °C, 1 h F N O O

371 372 370 365b not observed not observed not observed

Scheme 144: Attempts at the deprotection of nosyl ester 371 both without (A) and with (B) the presence of DIPA

It was considered that perhaps the use of LDA instead of DIPA might avoid the formation of 362b, as there would be no labile protons available to quench the intermediate 326 (Scheme 141), and formation of 368 would be avoided entirely. This in turn might favour the formation of the desired product 328b. It was found that the LDA did increase the relative ratio of 328b to 362b, however unfortunately the overall yield of both these products was vastly reduced. It is possible that the increased nucleophilicity of LDA compared to DIPA may have led to more side reactions such as nucleophilic attack of the nosyl group, causing this to be removed, and making the intramolecular benzyne Truce–Smiles rearrangement impossible. The fact that 362b was able to form is possibly due to some DIPA being present in the LDA, or the potential presence of small amounts of water in the reaction, from the THF or hygroscopic KF and 18-crown-6.

181 NO2 NO 2 KF (2.0 eq.) NO O NO OH 2 ONs 2 O 18-crown-6 (2.0 eq.) S S LDA (2.0 eq.) O O O O H TMS THF, 70 °C, 30 min N N N OTf

330 328b 362b 363b 17% 10% 0%

Scheme 145: Use of LDA as a nucleophile for the benzyne-Truce–Smiles reaction of 330

It was also noted that the use of LDA appeared to slow down generation of the benzyne species. The reaction in Scheme 145 was repeated at room temperature, with one equivalent of freshly prepared LDA, and dropwise addition of the benzyne precursor over 15 minutes. Even after 20 hours, UPLC-MS analysis showed there to be unreacted starting material 330 remaining, whereas with pyrrolidine or DIPA starting material was consumed within an hour at room temperature.

2.3.4. Conclusions and future work

Initial results for the use of a benzyne-Truce–Smiles rearrangement for the formation of biaryl phenols 328 are extremely promising (Scheme 146). However, the formation of unrearranged side product 362 is currently a limitation of this methodology which has yet to be overcome. The use of DIPA as a nucleophile was more eﬀective than pyrrolidine, and has resulted in yields of up to 34% of the rearranged product 328b. Both CsF and KF/18-crown-6 were eﬀective for benzyne generation, and the reaction was shown to function best at 70 ◦C in THF, at concentrations of 0.0063 M. Short reaction times were found to limit formation of 363b.

Further investigation of the reaction conditions with substrate 329 may reveal a higher yield of 328. Whilst the use of LDA did not reduce formation of 362b, it is possible that the use of other added bases may be eﬀective for this. Such an approach was successful in achieving this in the work of Bronner (Scheme 133).(350) Whilst NaH is

182 NO2 NO 2 KF (2.0 eq.) NO O NO OH 2 ONs 2 O 18-crown-6 (2.0 eq.) S S DIPA (4.0 eq.) O O O O H TMS THF, 70 °C, 1 h N N N OTf

330 328b 362b 363b 31% 32% 3%

Scheme 146: Currently optimised conditions for the benzyne-Truce–Smiles rearrangement reaction not quite basic enough to deprotonate DIPA, switching to an alternative, more acidic nucleophile such as an aniline, or perhaps an oxygen based nucleophile may enable quenching of any labile protons otherwise capable of protonating the intermediate anionic arene 326/368 (Scheme 141).

183 3. Experimental

3.1. General

1H NMR, 13C NMR and 19F NMR were recorded at 500/400 MHz, 125/100 MHz,

470/376 MHz on Bruker Avance 500 or 400 spectrometers, in CDCl3, CD3CN or 1 DMSO-d6. All spectra are referenced to the residual solvent peak ( H NMR δ = 13 1 13 7.26 ppm, C NMR δ = 77.16 ppm for CDCl3; H NMR δ = 1.94 ppm, C NMR 1 13 δ = 118.26 ppm for CD3CN; H NMR δ = 2.50 ppm, C NMR δ = 39.52 ppm for DMSO-d6). All chemical shifts are quoted in parts per million (ppm), measured from the centre of the signal except in the case of multiplets, which are quoted as a range. Coupling constants (J ) are quoted to the nearest 0.1 Hz, and are reported as observed. Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), sextet (sxt), septet (sept), multiplet (m), broad singlet (br s) and combinations thereof. NMR spectra of novel compounds were assigned with the aid of 2D NMR and DEPT-135 spectra.

Low resolution mass spectrometry was performed on an Agilent 6100 mass spectrometer (ESI ionisation) and Hewlett Packard 5971 MSD (GC/MS with EI). High resolution mass spectrometry was performed on a Waters QTOF with ESI/APCI ionisation and a Thermo Finnigan MAT95XP (EI). UPLC-MS spectra (ESI+ and ESI−) were acquired using a Waters Acquity SQ Detector 2, ﬁtted with UPLC column (C18, 50 × 2.1 mm, < 2 µm). The diode array detector wavelength was 254 nM, and the temperature was 40 ◦C. Flow rate = 0.6 mL/min; mobile phase system composed of A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid in MeCN) gradient 5% B to 95% B.

Infrared spectra were recorded on a spectrometer as as a thin ﬁlm (CDCl3) or neat us-

184 ing a Perkin-Elmer FT-IR Spectrum RX1 or BX spectrometers. Absorbance strengths are denoted as strong (s), medium (m), weak (w), broad (br), and combinations thereof. Melting points were determined using a Koﬂer hot-stage apparatus or Stuart Scientiﬁc SMP10 apparatus and are uncorrected. Microwave experiments were carried out using a Biotage Initiator. Elemental analysis was performed using a Metrohm potentiometric autotitrator.

Thin layer chromatography (TLC) was performed using pre-coated Merck 60F254 silica plates. Visualisation was performed using either UV light or treatment with acidic potassium permanganate. Flash chromatography was performed using Merck Kieselgel (mesh size 220-240) silica, or using Biotage cartridges (Snap Ultra or KP-Sil) on a Biotage Isolera automated columning machine.

All reagents and solvents were used as obtained from commercial source, unless otherwise stated. All reactions were carried out under N2, unless otherwise stated. Where necessary, dry THF was distilled from sodium/benzophenone ketyl immediately before use, otherise it was purchased as anhydrous quality. Dry DCM and toluene were either distilled over calcium hydride, purchased as anhydrous quality, or puriﬁed using a solvent puriﬁcation system (Innovative Technology, Puresolv, PS MD-5).

185 3.2. meta-Functionalisation experimental

General procedure 1: Screening of photoredox conditions for the meta- functionalisation of 2-phenylpyridine 26

A ﬂat bottomed vial equipped with stirrer bar was charged with base, photocatalyst,

[RuCl2(p-cymene)]2 (7.7 mg, 0.013 mmol, 5.0 mol%), and 80. The vial was sealed with a subaseal, and evacuated/backfilled with N2 (× 3). Freshly degassed, dry solvent (1.25 mL) was added, followed by phenylpyridine (36.0 µL, 0.250 mmol, 1.00 eq.). The subaseal was replaced by a cap under a flow of nitrogen, and sealed with parafilm, and the reaction mixture was left stirring on a hotplate at 100 ◦C, 1 cm away from a visible light source, overnight. The reaction mixture was concentrated, and analysed by 1H NMR spectroscopy of the crude reaction mixture. N.B. If bromoacetonitrile 79 was used as the radical source, this was added with the solvent, rather than with the solid reagents.

General procedure 2: Screening of conditions for the meta-functionalisation of 2-phenylpyridine using haloalkanes

An oven-dried microwave vial was charged with a stirrer bar, [RuCl2(p-cymene)]2 (7.7 mg, 0.013 mmol, 5.0 mol%), base (2.00 eq.), and ligand (30 mol%). The vial was sealed, and evacuated/backﬁlled with N2 (× 3). Dry solvent (1.5 mL) was added (in the case of meta-formylation, dry solvent (1.0 mL) was added, with CHCl3 (0.500 mL, 6.24 mmol, 25.0 eq.)), followed by 2-phenylpyridine (36.0 µL, 0.250 mmol, 1.00 eq.) and haloalkane radical source. The reaction mixture was heated to 110 ◦C for 16 – 18 hours. The reaction mixture was then diluted with water (10 mL), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4, and concentrated in vacuo. Reactions carried out using CHCl3 or Cl3CCO2Et were worked up by ﬁltration of the crude reaction mixture through a pad of silica with DCM or 10% MeOH in EtOAc before concentration. A 1H NMR spectrum of the crude reaction mixture was obtained. NMR yields were obtained by

186 addition of 1,3,5-trimethoxybenzene (14.0 mg, 0.0833 mmol) internal standard.

1,4-Dioxan-2-yl 2-iodobenzoate, 83

O O

O O 83

Prepared according to general procedure 1, using K2CO3 (69.1 mg, 0.500 mmol,

2.00 eq.), Ru(bpy)3PF6 (2.2 mg, 0.0025 mmol, 1.0 mol%) and 1-trifluoromethyl-1,2- benziodoxol-3(1H )-one 80 (79.0 mg, 0.250 mmol, 1.00 eq.) with 1,4-dioxane solvent. The crude reaction mixture was purified by column chromatography (eluent: 2% to 30% EtOAc in hexane) to afford the product 83 as an orange oil (28.0 mg, 0.0838 mmol, 34% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.02 (dd, J = 8.0, 1.2 Hz, 1H), 7.94 (dd, J = 7.8, 1.7 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (td, J = 7.7, 1.7 Hz, 1H), 6.11 (t, J = 1.9 Hz, 1H), 4.26 (dt, J = 11.7, 6.6 Hz, 1H), 3.96 – 3.86 (m, 2H), 3.86 – 3.81 13 (m, 2H), 3.70 (dt, J = 11.7, 2.5 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ 165.1, 141.7, 134.4, 133.2, 131.6, 128.1, 94.4, 90.8, 67.8, 66.2, 62.0; LRMS: ESI+ m/z 357.0 [M+Na]+. Data is consistent with literature values.(366)

2-(3-(1,2,2-Trichlorovinyl)phenyl)pyridine, 86

2 3 1

4 N 5 6 7 11 Cl 8 10 13 9 12 Cl Cl 86

Prepared according to general procedure 2, in a Schlenk tube, using K2CO3 (69.1 mg,

0.500 mmol, 2.00 eq.), MesCO2H (12.3 mg, 0.0750 mmol, 30.0 mol%), with added nonaflyl fluoride (89.9 µL, 0.500 mmol, 2.00 eq.), in 1,4-dioxane solvent. Purification

187 by column chromatography (eluent: 15% to 100% DCM in hexane) aﬀorded 86 as a brown oil (14.0 mg, 0.0491 mmol, 20% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.71 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H, H1),

8.13 (dt, J = 1.8, 1.1 Hz, 1H, H11), 8.04 – 7.97 (m, 1H, H7), 7.82 – 7.71 (m, 2H, H3 13 + H4), 7.55 – 7.49 (m, 2H, H8 + H9), 7.27 (ddd, J = 7.1, 4.8, 1.4 Hz, 1H, H2); C

NMR (101 MHz, CDCl3, ppm): δ 156.4 (C5), 150.0 (C1), 139.8 (C6), 137.1 (C3),

136.2 (C10), 129.8 (C12), 129.5 (C8 or C9), 129.0 (C8 or C9), 128.1 (C7), 127.8 (C11),

122.7 (C2), 120.8 (C4), 119.8 (C13); Accurate Mass: ESI+ m/z calcd for C13H9Cl3N [M+H]+ 283.9795, found 283.9789; IR (thin ﬁlm, cm−1): 2925 (w), 2854 (w), 1739 (w), 1585 (m), 1565 (w), 1460 (m), 1432 (m), 898 (m), 770 (s).

Diethyl 2-chloro-3-(3-(pyridin-2-yl)phenyl)but-2-enedioate, 88

2 3 1

4 N 16 15 5 6 OO 7 11 14 8 10 13 9 12 Cl 17 OO 18 88 19

Prepared according to general procedure 2, using K2CO3 (69.1 mg, 0.500 mmol,

2.00 eq.), MesCO2H (12.3 mg, 0.0750 mmol, 30.0 mol%), 1,4-dioxane solvent, with an aqueous work-up. The crude product was puriﬁed by column chromatography in 100% DCM, followed by preparative TLC (100% DCM) to aﬀord 88 as a yellow oil (6.5 mg, 0.0181 mmol, 7% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.70 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H, H1),

8.09 – 8.04 (m, 2H, H7 + H11), 7.80 – 7.71 (m, 2H, H3 + H4), 7.54 (td, J = 7.6,

0.8 Hz, 1H, H8), 7.49 (dt, J = 7.8, 1.5 Hz, 1H, H9), 7.26 (ddd, J = 7.0, 4.8, 1.5 Hz,

1H, H2), 4.36 (q, J = 7.1 Hz, 2H, 2H15 or 2H18), 4.28 (q, J = 7.1 Hz, 2H, 2H15 or

2H18), 1.38 (t, J = 7.1 Hz, 3H, 3H16 or 3H19), 1.29 (t, J = 7.1 Hz, 3H, 3H16 or 3H19);

188 13 C NMR (101 MHz, CDCl3, ppm): δ 166.1 (C14 or C17), 162.8 (C14 or C17),

156.7 (C5), 149.9 (C1), 141.0 (C12), 139.8 (C10), 137.0 (C3), 133.7 (C6), 129.1 (C8),

129.0 (C9), 128.0 (C7 or C11), 127.5 (C13), 127.1 (C7 or C11), 122.6 (C2), 120.8 (C4),

63.1 (C15 or C18), 62.4 (C15 or C18), 14.1 (C16 or C19), 14.0 (C16 or C19); Accurate + Mass: APCI+ m/z calcd for C19H19O4NCl [M+H] 360.0997, found 360.0997; IR (thin ﬁlm, cm−1): 2981 (w), 2929 (w), 1726 (s), 1585 (m), 1565 (w), 1461 (m), 1367 (mw), 1252 (s), 1197 (ms), 1023 (m).

3-(Pyridin-2-yl)benzaldehyde, 89

O 89

An oven-dried Schlenk tube under a positive pressure of N2 was charged with K2CO3

(140 mg, 1.01 mmol, 2.00 eq.), [RuCl2(p-cymene)]2 (15.4 mg, 0.0250 mmol, 5.0 mol%), Piv-Val-OH (30.2 mg, 0.150 mmol, 30.0 mol%). The tube was evacuated/backfilled with N2 (× 3), and degassed 1,4-dioxane (4.0 mL) was added followed by degassed µ CHCl3 (1.00 mL, 12.5 mmol, 25.0 eq.) and phenylpyridine (72.0 L, 0.500 mmol, 1.00 eq.). The tube was sealed. After 18 hours stirring at 110 ◦C, the reaction mixture was concentrated and purified by column chromatography (eluent: 2% to 50% EtOAc in hexane) to afford the product 89 as a yellow oil (7.3 mg, 0.040 mmol, 8% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 10.12 (s, 1H), 8.73 (dt, J = 4.8, 1.4 Hz, 1H), 8.51 (td, J = 1.8, 0.5 Hz, 1H), 8.30 (ddd, J = 7.8, 1.9, 1.2 Hz, 1H), 7.95 (dt, J = 7.6, 1.4 Hz, 1H), 7.83 – 7.80 (m, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.33 – 7.27 (m, 1H); 13 C NMR (101 MHz, CDCl3, ppm): δ 192.5, 156.0, 150.0, 140.4, 137.2, 137.0, 132.9, 129.9, 129.7, 128.6, 123.0, 120.8; LRMS: EI m/z 183.1 [M]; IR (thin ﬁlm, cm−1): 2924 (w), 2853 (w), 1698 (s), 1586 (m), 1567 (w), 1463 (m), 1437 (m), 1183 (m), 1167 (m), 771 (s). Data is consistent with literature values.(367)

189 3.3. ICl experimental

3.3.1. General procedures

(102) General procedure 3 for Suzuki couplings using Pd(OAc)2:

To the boronic acid (4.50 mmol, 1.50 eq.), palladium acetate (10.1 mg, 0.0450 mmol,

1.50 mol%), and K2CO3 (829 mg, 6.00 mmol, 2.00 eq.) was added ethanol (14 mL), water (4.5 mL) and 2-bromopyridine (3.00 mmol, 1.00 eq.). The reaction mixture was heated to 80 ◦C for 20 hours. Once cooled, water was added and the reaction mixture was extracted with EtOAc (× 3). The combined organic extracts were washed once with brine, dried over MgSO4, and concentrated. The crude product was puriﬁed by column chromatography on a Biotage Isolera.

General procedure 4 for ortho-iodination:

To a microwave vial equipped with a stirrer bar was added [(1,4-dioxane)(ICl)2] (206 mg,

0.500 mmol, 1.00 eq.), then Ru3(CO)12 (9.6 mg, 0.015 mmol, 3.0 mol%). The vial was capped, and evacuated and backﬁlled with N2 (× 3). The substrate (0.500 mmol, 1.00 eq.) was then added to the vial in a solution of dry 1,4-dioxane (3 mL). The reaction mixture was heated to 110 ◦C for 20 hours. Once cool, the reaction mixture was quenched with aq. Na2S2O3 solution (20 mL, 10 wt%), and extracted with EtOAc

(× 3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was puriﬁed by column chromatography on a Biotage Isolera (eluent typically 2–15% EtOAc in hexane).

General procedure 5 for ortho-chlorination:

To a microwave vial equipped with a stirrer bar was added [(1,4-dioxane)(ICl)2] (206 mg,

0.500 mmol, 1.00 eq.), then RuCl2(PPh3)3 (12.0 mg, 0.0125 mmol, 2.5 mol%). The substrate (0.500 mmol, 1.00 eq.) was then added to the vial in a solution of dry 1,4- dioxane (3 mL), and the vial was capped. The reaction mixture was heated to 110 ◦C

190 for 20 hours. Once cool, the reaction mixture was quenched with aq. Na2S2O3 solution (20 mL, 10 wt%), and extracted with EtOAc (× 3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was pu- riﬁed by column chromatography on a Biotage Isolera (eluent typically 2–15% EtOAc in hexane).

3.3.2. Preparation of starting materials

[1,4-Dioxane(ICl)2], 101

Cl I OO I Cl

101

Iodine monochloride (1.0 eq.) was weighed into a flask before dichloromethane was added. This was added dropwise to a solution of 1,4-dioxane (1.0 eq.) in the same volume of dichloromethane. After stirring at room temperature, most of the solvent was blown off using nitrogen; yielding a bright orange solid which was further dried under vacuum. Average yield over 8 reactions was 83%. Elemental analysis confirmed that the sample was a 2:1 mixture of ICl to 1,4-dioxane: Elemental calculated C 11.64, H 1.95, Cl 17.17, I 61.48; found C 11.76, H 2.04, Cl approx. 17, I approx. 57 (halides are difficult to separate by elemental analysis hence the approximate values given).

3-Methyl-2-phenylpyridine, 103

103

Prepared on a 2.00 mmol scale according to general procedure 3, using 2-bromo-3- methylpyridine, and phenylboronic acid. The product was obtained as a yellow oil (141 mg, 0.831 mmol, 42% yield).

191 1 H NMR (400 MHz, CDCl3, ppm): δ 8.53 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 7.58 (dtd, J = 7.7, 1.5, 0.7 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.48 – 7.42 (m, 2H), 7.42 – 7.35 (m, 1H), 7.18 (dd, J = 7.7, 4.7 Hz, 1H), 2.36 (d, J = 0.7 Hz, 3H); 13C

NMR (101 MHz, CDCl3, ppm): δ 158.8, 147.1, 140.7, 138.6, 130.9, 129.0, 128.3, 128.0, 122.2, 20.2; LRMS: ESI+ m/z 170.0 [M+H]+. Data is consistent with previous literature reports.(368)

5-Methyl-2-phenylpyridine, 105

105

Prepared according to general procedure 3, using phenylboronic acid, and 2-bromo-5- methylpyridine. The product was obtained as a pale yellow oil (408 mg, 2.41 mmol, 80% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.52 (dt, J = 2.4, 0.9 Hz, 1H), 7.99 – 7.94 (m, 2H), 7.63 (dd, J = 8.0, 0.8 Hz, 1H), 7.55 (app. ddq, J = 8.1, 2.2, 0.7 Hz, 1H), 7.46 13 (m, 2H), 7.42 – 7.36 (m, 1H), 2.37 (t, J = 0.7 Hz, 3H); C NMR (101 MHz, CDCl3, ppm): δ 154.9, 150.2, 139.5, 137.5, 131.7, 128.8, 128.7, 126.8, 120.2, 18.3; LRMS: ESI+ m/z 170.0 [M+H]+. Data is consistent with previous literature reports.(369)

Ethyl 4-(pyridin-2-yl)benzoate, 107

CO2Et 107

Prepared according to a procedure by Frost and co-workers.(92) A solution of 4-meth- oxycarbonylphenylboronic acid (540 mg, 3.00 mmol, 1.50 eq.) in EtOH (2.0 mL) was

192 added dropwise under N2 to a mixture of Pd(PPh3)4 (23.1 mg, 0.0200 mmol, 1.0 mol%) and K2CO3 (553 mg, 4.00 mmol, 2.00 eq.) whilst stirring at room temperature. 2- Bromopyridine (191 µL, 316 mg, 2.00 mmol, 1.00 eq.) was added, and the reaction mixture was heated in a sealed vial to 100 ◦C overnight. Once cool, 1 M aq. NaOH was added to the reaction mixture, and it was extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The resulting crude product was puriﬁed by column chromatography on a Biotage Isolera (eluent: 2% to 30% EtOAc in hexane) to aﬀord the desired product 107 as a colourless oil (257 mg, 1.13 mmol, 56% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.72 (dt, J = 4.8, 1.4 Hz, 1H), 8.14 (dt, J = 8.4, 1.7, 1.7 Hz, 2H), 8.06 (dt, J = 8.4, 1.7 Hz, 2H), 7.79 – 7.75 (m, 2H), 7.31 – 7.23 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR

(101 MHz, CDCl3, ppm): δ 166.5, 156.4, 150.0, 143.5, 137.0, 130.8, 130.1, 126.9, 123.0, 121.1, 61.2, 14.5; LRMS: ESI+ m/z 228.0 [M+H]+. Data is consistent with previous literature reports.(92)

2-(3-Bromophenyl)pyridine, 109

Br 109

(102) Prepared according to the procedure by Greaney and co-workers. K2CO3 (415 mg,

3.00 mmol, 2.00 eq.), [RuCl2(p-cymene)]2 (45.9 mg, 0.075 mmol, 5.0 mol%), MesCO2H (73.9 mg, 0.450 mmol, 30.0 mol%) and TBATB (2.17 g, 4.50 mmol, 3.00 eq.) were added to an oven dried Schlenk tube under a flow of N2. The tube was evacuated/backfilled with N2 3 times, before adding dry 1,4-dioxane (6.0 mL), followed by a solution of 2-phenylpyridine (214 µL, 233 mg, 1.50 mmol, 1.00 eq.) in dry 1,4-dioxane (3.0 mL). The flask was sealed, and heated to 110 ◦C for 20 hours. Once cooled,

193 sodium thiosulfate (aq. 10 wt%, 60 mL) was added to the reaction mixture. The mixture was extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The resulting crude was puriﬁed by column chromatography (eluent: 2% to 20% EtOAc in hexane), to aﬀord the desired product as a yellow oil (average 77% yield over 2 reactions).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.70 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.17 (t, J = 1.8 Hz, 1H), 7.91 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.76 (ddd, J = 8.0, 7.3, 1.8 Hz, 1H), 7.70 (dt, J = 8.0, 1.1 Hz, 1H), 7.54 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.26 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H); 13C NMR (101 MHz,

CDCl3, ppm): δ 155.9, 149.9, 141.5, 137.1, 132.0, 130.4, 130.2, 125.6, 123.2, 122.8, 120.8; LRMS: ESI+ m/z 234.0 (97%), 235.9 (100%) [M+H]+. Data is consistent with previous literature reports.(102)

2-Phenylpyrimidine, 110

110

To a microwave vial equipped with a stirrer bar was added phenylboronic acid (366 mg,

3.00 mmol, 1.50 eq.), 2-chloropyrimidine (229 mg, 2.00 mmol, 1.00 eq.) and Pd(PPh3)4 (23.1 mg, 0.0200 mmol, 1.00 mol%). The vial was capped, then evacuated and back-

filled with nitrogen three times. A 2.0 M aqueous solution of K2CO3 was added (2.00 mL, 4.00 mmol, 2.00 eq.), followed by ethanol (9.0 mL) and water (1.0 mL). The reaction mixture was heated to 100 ◦C for 24 hours. Once cooled, the reaction mixture was diluted with water, and extracted with EtOAc (× 3). The combined organic extracts were washed once with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography, to afford the product 110 as a white crystalline solid (220 mg, 1.41 mmol, 71% yield).

194 1 H NMR (400 MHz, CDCl3, ppm): δ 8.81 (d, J = 4.8 Hz, 2H), 8.48 – 8.41 (m, 13 2H), 7.54 – 7.47 (m, 3H), 7.19 (t, J = 4.8 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ 164.9, 157.4, 137.7, 130.9, 128.7, 128.3, 119.2; LRMS: ESI+ m/z 157.0 [M+H]+. Data is consistent with previous literature reports.(370)

2-(4-Bromophenyl)pyridine, 113

Br 113

To a ﬂask containing (4-bromophenyl)boronic acid (402 mg, 2.00 mmol, 1.00 eq.) and

Pd(PPh3)4 (23.1 mg, 0.0200 mmol, 1.00 mol%) under N2 was added K2CO3 (2.0 M soln. in H2O, 1.59 mL, 3.18 mmol, 1.59 eq.), toluene (3.2 mL), ethanol (1.6 mL) and 2-bromopyridine (289 µL, 477 mg, 3.00 mmol, 1.50 eq.). The reaction mixture was ◦ heated to reflux (110 C) for 24 hours. Once cooled, H2O was added , and the aqueous layer was extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. The product was purified by column chromatography (eluent: 0% to 8% EtOAc in hexane) to afford the product as a white solid (average 70% yield over two reactions).

1 H NMR (500 MHz, CDCl3, ppm): δ 8.69 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 7.88 (dt, J = 8.8, 2.1 Hz, 2H), 7.75 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.70 (dt, J = 8.0, 1.1 Hz, 1H), 7.60 (dt, J = 8.8, 2.1 Hz, 2H), 7.25 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H); 13C

NMR (101 MHz, CDCl3, ppm): δ 156.4, 149.9, 138.4, 137.0, 132.0, 128.6, 123.6, 122.6, 120.4; LRMS: EI m/z 232.9 [M]. Data is consistent with previous literature reports.(371)

195 4-Methyl-1-phenyl-1H -pyrazole, 117

N N

117

Prepared according to a procedure by H.-J. Cristau, M. Taillefer and co-workers.(372) An oven dried schlenk tube equipped with a stirrer bar was evacuated/backﬁlled with

N2 (× 3). Under a stream of N2, Cu2O (14.3 mg, 0.100 mmol, 5.00 mol%), Cs2CO3 (1.30 g, 4.00 mmol, 2.00 eq.), (E)-2-hydroxybenzaldehyde oxime (54.9 mg, 0.400 mmol, 20.0 mol%) and 4-methyl-1H -pyrazole (166 µL, 164 mg, 2.00 mmol, 1.00 eq.) were added. The flask was evacuated and backfilled with N2, and iodobenzene was added (336 µL, 612 mg, 3.00 mmol, 1.50 eq.) was added, followed by dry, degassed MeCN (1.2 mL). The flask was sealed and the reaction mixture heated to 80 ◦C for 24 hours. Once cooled, the reaction mixture was diltued with DCM and filtered through a celite plug with DCM. The filtrate was concentrated and purified by column chromatography (eluent: 0% to 40% DCM in hexane) to afford the product as a yellow oil (214 mg, 1.35 mmol, 68% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.70 (t, J = 0.9 Hz, 1H), 7.67 – 7.63 (m, 2H), 7.53 (s, 1H), 7.46 – 7.40 (m, 2H), 7.25 (tt, J = 7.3, 1.3 Hz, 1H), 2.16 (s, 3H); 13C

NMR (126 MHz, CDCl3, ppm): δ 141.9, 140.4, 129.5, 126.1, 125.4, 118.8, 118.3, 9.1; LRMS: ESI+ m/z 159.0 [M+H]+. Data is consistent with previous literature reports.(373) cis-Dicarbonyl bis[2-phenylpyridinato-C 2,N ]ruthenium(II), 67

CO N N Ru CO

196 Prepared according to a procedure by Zhang and co-workers.(97) To a stirring solution of 2-phenylpyridine (85.7 µL, 0.600 mmol, 1.00 eq.) in 1,2-DCE (4 mL) at room temperature under air was added Ru3(CO)12 (383 mg, 0.600 mmol, 1.00 eq.). The reaction mixture was heated to 95 ◦C in a sealed tube for 42 hours, then cooled and filtered. The filtrate was concentrated, and purified by alumnina column (eluent: 0% to 20% EtOAc in hexane). The title compound was isolated as a dark green solid

(28.6 mg, 0.0614 mmol, 20% yield). (N.B. when carried out under N2 atmosphere, for 45 hours, the yield was 19%)

1 H NMR (400 MHz, CDCl3, ppm): δ 9.05 (d, J = 5.4 Hz, 1H), 8.07 (dd, J = 7.6, 1.3 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.90 (td, J = 7.8, 1.7 Hz, 1H), 7.78 (dd, J = 12.9, 8.0 Hz, 2H), 7.65 (dd, J = 7.9, 1.3 Hz, 1H), 7.55 (m, 1H), 7.31 – 7.26 (m, 2H), 7.22 (d, J = 6.0 Hz, 1H), 7.13 (td, J = 7.5, 1.3 Hz, 1H), 6.92 (td, J = 7.4, 1.5 Hz, 1H), 13 6.83 (td, J = 7.2, 1.3 Hz, 1H), 6.74 (m, 2H); C NMR (101 MHz, CDCl3, ppm): δ 203.1, 194.8, 178.4, 177.4, 165.6, 164.7, 153.4, 146.8, 145.6, 142.8, 139.9, 137.8, 136.8, 129.8, 129.2, 124.2, 123.6, 123.3, 122.8, 121.6, 121.1, 119.8, 119.1; LRMS: ESI+ m/z 467.0 [M+H]+. Data is consistent with previous literature reports.(97)

2-(d 5-Phenyl)pyridine, 119

D D

D D D 119

Prepared according to general procedure 3, from d 5-phenylboronic acid. The reaction time was 2 hours. Product 119 was isolated as a pale yellow oil (average yield 84% over two reactions).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.70 (dt, J = 5.0, 1.3 Hz, 1H), 7.78 – 13 7.71 (m, 2H), 7.23 (ddd, J = 6.8, 4.8, 2.2 Hz, 1H); C NMR (101 MHz, CDCl3,

197 ppm): δ 157.6, 149.8 (2C), 139.4, 136.9, 128.4 (t, 2C, J = 24.4 Hz), 126.6 (t, 2C, J = 24.4 Hz), 122.2, 120.7; LRMS: ESI+ m/z 161.1 [M+H]+. Data is consistent with previous literature reports.(374)

3.3.3. ortho-Halogenation products

2-(2-Iodophenyl)pyridine, 26a

26a

Prepared according to general procedure 4, from 2-phenylpyridine. Product 26a was isolated as a yellow oil (106 mg, 0.377 mmol, 75% yield). When carried out on a 1.00 mmol scale, product was isolated in 65% yield.

1 H NMR (400 MHz, CDCl3, ppm): δ 8.71 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.00 – 7.92 (m, 1H), 7.77 (app. td, J = 7.7, 1.8 Hz, 1H), 7.50 (app. dt, J = 7.8, 1.1 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.30 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.08 (ddd, J = 7.9, 13 6.7, 2.4 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ 160.9, 149.4, 145.2, 139.9, 136.1, 130.4, 129.8, 128.4, 124.5, 122.6, 96.8; LRMS: EI m/z 281.0 [M]. Data is consistent with previous literature reports.(52)

2-(2-Chlorophenyl)pyridine, 26b

26b

Prepared according to general procedure 5, from 2-phenylpyridine on a 1.00 mmol scale. Isolated as a colourless oil (85.4 mg, 0.450 mmol, 47% yield).

198 1 H NMR (400 MHz, CDCl3, ppm): δ 8.73 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.65 (dt, J = 7.9, 1.1 Hz, 1H), 7.62 – 7.57 (m, 1H), 7.51 – 7.45 13 (m, 1H), 7.40 – 7.33 (m, 2H), 7.31 – 7.27 (m, 1H); C NMR (101 MHz, CDCl3, ppm): δ 156.9, 149.6, 139.2, 136.0, 132.2, 131.6, 130.2, 129.7, 127.1, 125.0, 122.5; LRMS: EI m/z 189.1 [M]. Data is consistent with previous literature reports.(54)

2-(2-Iodo-4-methylphenyl)pyridine, 102a

Me 102a

Prepared according to general procedure 4, from 2-(p-tolyl)pyridine, with 1,2-DCE as solvent. Reaction time was 4 hours. The title compound was isolated as a pale yellow oil (92.7 mg, 0.300 mmol, 60% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.70 (d, J = 4.8 Hz, 1H), 7.80 (s, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.50 (dt, J = 7.8, 1.1 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.28 (ddd, J = 7.7, 5.0, 1.1 Hz, 1H), 7.23 (ddd, J = 7.8, 1.8, 0.8 Hz, 1H), 2.36 (s, 3H); 13 C NMR (101 MHz, CDCl3, ppm): δ 160.8, 149.3, 142.4, 140.3, 140.0, 136.0, 130.1, 129.2, 124.6, 122.4, 96.6, 20.7; LRMS: EI m/z 295.0 [M]. Data is consistent with previous literature reports.(375)

2-(2-Chloro-4-methylphenyl)pyridine, 102b

N N

Cl Cl Cl

Me Me 102b 102c

Prepared according to general procedure 5, from 2-(p-tolyl)pyridine. Compound 102b

199 was obtained as a colourless oil in a 1.00 : 0.20 mixture with 2-(2,6-dichloro-4-methylphenyl)pyridine 102c.

1 102b: (46.3 mg, 0.227 mmol, 45% yield). H NMR (400 MHz, CDCl3, ppm): δ 8.71 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.64 (dt, J = 7.9, 1.1 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.30 (dd, J = 1.7, 0.9 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.17 (ddd, J = 7.8, 1.7, 0.8 Hz, 1H), 2.38 (d, J = 0.8 Hz, 3H); 13C NMR

(101 MHz, CDCl3, ppm): δ 156.9, 149.6, 140.0, 136.3, 135.9, 131.8, 131.4, 130.6, 128.0, 125.0, 122.3, 21.1; LRMS: EI m/z 203.0 [M]. Data is consistent with previous literature reports.(54)

1 102c: (10.8 mg, 0.0454 mmol, 9% yield). H NMR (400 MHz, CDCl3, ppm): δ 8.76 – 8.73 (m, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.35 – 7.31 (m, 2H), 7.22 (d, J 13 = 0.9 Hz, 2H), 2.36 (s, 3H); C NMR (101 MHz, CDCl3, ppm): δ 155.7, 149.7, 140.6, 136.5, 135.6, 134.2, 128.8, 125.4, 123.0, 21.0; LRMS: EI m/z 236.9 [M]. Data is consistent with previous literature reports.(42)

2-(2-Iodophenyl)-3-methylpyridine, 103a

103a

Prepared according to general procedure 4, from 3-methyl-2-phenylpyridine 103 (scaled down to 0.430 mmol scale, left at 110 ◦C for 72 hours). The product 103a was obtained as a yellow oil (67.1 mg, 0.227 mmol, 50% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.55 (dd, J = 4.9, 1.8 Hz, 1H), 7.95 (dd, J = 8.1, 1.2 Hz, 1H), 7.62 (ddd, J = 7.6, 1.7, 0.8 Hz, 1H), 7.46 (td, J = 7.5, 1.2 Hz, 1H), 7.32 – 7.25 (m, 2H), 7.11 (td, J = 7.7, 1.7 Hz, 1H), 2.15 (s, 3H); 13C NMR

(101 MHz, CDCl3, ppm): δ 161.1, 146.8, 145.5, 139.1, 138.1, 131.5, 129.6, 129.4,

200 128.4, 123.2, 97.8, 19.3; LRMS: ESI+ m/z 296.0 [M+H]+. Data is consistent with previous literature reports.(43)

2-(2-Chlorophenyl)-3-methylpyridine, 103b

103b

Prepared according to general procedure 5, from 3-methyl-2-phenylpyridine 103. The product 103b was obtained as a pale yellow oil (56.2 mg, 0.276 mmol, 55% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.52 (dd, J = 5.0, 1.7 Hz, 1H), 7.60 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.49 – 7.44 (m, 1H), 7.37 – 7.29 (m, 3H), 7.27 – 7.21 (m, 13 1H), 2.16 (s, 3H); C NMR (101 MHz, CDCl3, ppm): δ 157.2, 146.8, 139.6, 137.9, 132.8, 132.3, 130.5, 129.6, 129.5, 127.0, 123.0, 18.9; LRMS: ESI+ m/z 226.0 [M+Na]+. Data is consistent with previous literature reports.(43)

2-(2-Iodo-5-methylphenyl)pyridine, 104a

104a

Prepared according to general procedure 4 from 2-(m-tolyl)pyridine. The product 104a was isolated as a yellow oil (75.2 mg, 0.255 mmol, 51% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.70 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.51 (dt, J = 7.9, 1.1 Hz, 1H), 7.32 – 7.27 (m, 2H), 6.95 – 6.87 (m, 1H), 2.34 (d, J = 0.7 Hz, 3H); 13C NMR

(101 MHz, CDCl3, ppm): δ 161.0, 149.3, 144.9, 139.6, 138.5, 136.0, 131.3, 130.9,

201 124.6, 122.5, 92.7, 21.0; LRMS: ESI+ m/z 296.0 [M+H]+. Data is consistent with previous literature reports.(376)

2-(2-Chloro-5-methylphenyl)pyridine, 104b

104b

Prepared according to general procedure 5, from 2-(m-tolyl)pyridine. The product 104b was obtained as a yellow oil (55.3 mg, 0.272 mmol, 54%).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.71 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.65 (dt, J = 7.9, 1.1 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.27 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 7.13 (ddt, J = 8.2, 2.3, 13 0.7 Hz, 1H), 2.37 (d, J = 0.8 Hz, 3H); C NMR (101 MHz, CDCl3, ppm): δ 157.1, 149.6, 138.8, 137.0, 135.9, 132.2, 130.5, 129.9, 129.1, 125.0, 122.4, 20.9; LRMS: ESI+ m/z 204.0 [M+H]+. Data is consistent with previous literature reports.(54)

2-(2-Iodophenyl)-5-methylpyridine, 105a

12 2 3 1

4 N 5 6 I 7 11 8 10 9 105a

Prepared according to general procedure 4 from 5-methyl-2-phenylpyridine 105. The title compound 105a was isolated as a yellow solid (99.4 mg, 0.337 mmol, 67% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.56 – 8.51 (m, 1H, H1), 7.95 (dd, J =

8.1, 1.0 Hz, 1H, H10), 7.60 – 7.54 (m, 1H, H3), 7.46 – 7.38 (m, 3H, H4 + H7 + H8),

202 13 7.06 (ddd, J = 7.9, 6.8, 2.3 Hz, 1H, H9), 2.40 (s, 3H, 3H12); C NMR (101 MHz,

CDCl3, ppm): δ 158.1 (C5), 149.7 (C1), 145.1 (C6), 139.8 (C10), 136.7 (C3), 132.2

(C2), 130.4 (C7 or C8), 129.7 (C9), 128.4 (C7 or C8), 124.0 (C4), 97.1 (C11), 18.5 (C12); + Accurate Mass: ESI+ m/z calcd for C12H11NI [M+H] 295.9931, found 295.9922; m.p. : 84 – 85 ◦C.

2-(2-Chlorophenyl)-5-methylpyridine, 105b

N N

Cl Cl Cl

105b 105c

Prepared according to general procedure 5 from 5-methyl-2-phenylpyridine 105. Com- pound 105b was isolated as a pale yellow oil in a 1.00 : 0.21 mixture with 2-(2,6-dichlorophenyl)-5-methylpyridine 105c.

1 105b: 44.1 mg, 0.216 mmol, 43% yield. H NMR (400 MHz, CDCl3, ppm): δ 8.55 (dt, J = 1.9, 0.9 Hz, 1H), 7.59 – 7.54 (m, 3H), 7.50 – 7.44 (m, 1H), 7.38 – 7.28 13 (m, 2H), 2.40 (t, J = 0.6 Hz, 3H); C NMR (101 MHz, CDCl3, ppm): δ 154.2, 150.1, 139.3, 136.5, 132.3, 132.1, 131.6, 130.2, 129.5, 127.1, 124.4, 18.4; LRMS: EI m/z 203.0 [M]. Data is consistent with previous literature reports.(55)

1 105c: 10.8 mg, 0.0454 mmol, 9% yield. H NMR (400 MHz, CDCl3, ppm): δ 8.58 (dt, J = 2.2, 0.8 Hz, 1H), 7.61 (ddq, J = 8.0, 2.3, 0.8 Hz, 1H), 7.41 – 7.38 (m, 13 2H), 7.30 – 7.22 (m, 2H), 2.42 (t, J = 0.7 Hz, 3H); C NMR (101 MHz, CDCl3, ppm): δ 152.8, 150.2, 138.6, 137.1, 134.9, 132.7, 129.8, 128.2, 124.5, 18.6; LRMS: EI m/z 237.0 [M]. Data is consistent with previous literature reports.(377)

203 2-(2-Chloro-6-iodophenyl)pyridine, 106a

2 3 1

4 N 5 6 Cl 7 I 11 8 10 9 106a

Prepared according to general procedure 4, from 2-(2-chlorophenyl)pyridine 26b. The product 106a was obtained as an oﬀ-white solid (50.2 mg, 0.159 mmol, 32% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.76 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H, H1),

7.89 – 7.79 (m, 2H, H3 + H10), 7.47 (dd, J = 8.1, 1.1 Hz, 1H, H8), 7.36 (ddd, J = 7.7,

4.9, 1.2 Hz, 1H, H2), 7.29 (dt, J = 7.8, 1.0 Hz, 1H, H4), 7.03 (t, J = 8.0 Hz, 1H, H9); 13 C NMR (101 MHz, CDCl3, ppm): δ 159.9 (C5), 149.6 (C1), 143.5 (C6), 137.7

(C10), 136.8 (C3), 133.2 (C7), 130.8 (C9), 129.7 (C8), 124.7 (C4), 123.3 (C2), 99.0 + (C11); Accurate Mass: ESI+ m/z calcd for C11H8NICl [M+H] 315.9384, found 315.9382; m.p. : 79 – 81 ◦C.

Ethyl 3-iodo-4-(pyridin-2-yl)benzoate, 107a

CO2Et 107a

Prepared according to general procedure 4 from ethyl 4-(pyridin-2-yl)benzoate 107 (0.371 mmol). Compound 107a was isolated as a yellow oil (70.1 mg, 0.198 mmol, 53% yield). N.B. When carried out on a 0.250 mmol scale, with 1,2-DCE solvent, and 4 hour reaction time, the title compound was aﬀorded as a pale yellow oil (61.7 mg, 0.175 mmol, 70% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.73 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.62

204 (d, J = 1.6 Hz, 1H), 8.09 (dd, J = 8.0, 1.7 Hz, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.53 (dt, J = 7.9, 1.2 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.34 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,

CDCl3, ppm): δ 165.0, 160.0, 149.5, 149.0, 140.9, 136.3, 131.6, 130.2, 129.4, 124.5, + 123.1, 96.3, 61.6, 14.5; Accurate Mass: ESI+ m/z calcd for C14H13O2NI [M+H] 353.9985, found 353.9980; IR (neat, cm−1): 2979 (w), 1714 (s, C=O), 1584 (m), 1567 (w), 1460 (mw), 1428 (mw), 1366 (m), 1274 (s), 1232 (s), 1108 (s).

Ethyl 3-chloro-4-(pyridin-2-yl)benzoate, 107b

CO2Et 107b

Prepared according to general procedure 5 from ethyl 4-(pyridin-2-yl)benzoate 107. Compound 107b was isolated as a pale yellow oil (55.2 mg, 0.211 mmol, 42% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.74 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.02 (dd, J = 8.0, 1.7 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.71 – 7.65 (m, 2H), 7.32 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 13 1.42 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl3, ppm): δ 165.4, 156.1, 149.9, 143.2, 136.1, 132.5, 131.8, 131.8, 131.4, 128.1, 125.0, 123.0, 61.6, 14.4; LRMS: ESI+ m/z 262.1 [M+H]+; IR (neat, cm−1): 2987 (w), 1719 (s, C=O), 1586 (m), 1568 (m), 1494 (w), 1464 (m), 1385 (m), 1364 (m), 1293 (s), 1283 (s), 1242 (s), 1111 (s). Data is consistent with previous literature reports.(54)

205 3-Iodo-4-(pyridin-2-yl)benzaldehyde, 108a

CHO 108a

Prepared according to general procedure 4 from 4-(pyridin-2-yl)benzaldehyde. The title compound 108a was isolated as a pale yellow solid (68.6 mg, 0.222 mmol, 44% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 10.00 (s, 1H), 8.74 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.94 (dd, J = 7.8, 1.6 Hz, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.55 (dt, J = 7.9, 1.1 Hz, 1H), 7.36 (ddd, J 13 = 7.6, 4.9, 1.2 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ 190.5, 159.7, 150.4, 149.6, 141.3, 137.2, 136.4, 131.0, 129.3, 124.4, 123.3, 97.2; Accurate Mass: APCI+ + ◦ m/z calcd for C12H9ONI [M+H] 309.9723, found 309.9722; m.p. : 107 – 109 C; IR (neat, cm−1): 2922 (w), 1690 (s, C=O), 1584 (m), 1565 (mw), 1460 (m), 1430 (m), 1363 (mw), 1197 (m), 1186 (ms). Data is consistent with literature values.(376)

3-Chloro-4-(pyridin-2-yl)benzaldehyde, 108b

CHO 108b

Prepared according to general procedure 5 from 4-(pyridin-2-yl)benzaldehyde. The title compound 108b was isolated as a yellow solid (31.6 mg, 0.145 mmol, 29% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 10.02 (s, 1H), 8.75 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.84 – 7.75

206 (m, 2H), 7.69 (dt, J = 7.9, 1.1 Hz, 1H), 7.34 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H); 13C

NMR (101 MHz, CDCl3, ppm): δ 190.7, 155.7, 149.9, 144.6, 137.3, 136.3, 133. 5,

132.5, 131.3, 128.1, 125.0, 123.3; Accurate Mass: ESI+ m/z calcd for C12H9ONCl [M+H]+ 218.0367, found 218.0365; m.p. : 62 – 64 ◦C; IR (neat, cm−1): 2826 (w), 1695 (s, C=O), 1586 (m), 1570 (m), 1551 (mw), 1491 (w), 1464 (m), 1364 (m), 1199 (m). Data is consistent with literature values.(43)

2-(5-Bromo-2-iodophenyl)pyridine, 109a

2 3 1

4 N 5 6 I 7 11 8 10 Br 9 109a

Prepared according to general procedure 4, from 2-(3-bromophenyl)pyridine 109 (on a 0.250 mmol scale). Product 109a was obtained as a yellow oil (27.2 mg, 0.0907 mmol, 36% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.71 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H, H1),

7.80 (d, J = 8.5 Hz, 1H, H10) 7.78 (td, J = 7.8, 1.7 Hz, 1H, H3), 7.60 (d, J = 2.4 Hz,

1H, H7), 7.50 (dt, J = 7.9, 1.0 Hz, 1H, H4), 7.33 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H, 13 H2), 7.22 (dd, J = 8.4, 2.4 Hz, 1H, H9); C NMR (101 MHz, CDCl3, ppm):

δ 159.5 (C5), 149.5 (C1), 146.7 (C6), 141.1 (C10), 136.4 (C3), 133.3 (C7), 132.9 (C9),

124.5 (C4), 123.1 (C2), 122.8 (C8), 94.8 (C11); Accurate Mass: ESI+ m/z calcd for + C11H8NBrI [M+H] 359.8879, found 359.8880.

2-(5-Bromo-2-chlorophenyl)pyridine, 109b

2 3 1

4 N 5 6 Cl 7 11 8 10 Br 9 109b

207 Prepared according to general procedure 5 from 2-(3-bromophenyl)pyridine 109 (on a 0.250 mmol scale). Product 109b was obtained as a pink solid (30.6 mg, 0.114 mmol, 46% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.73 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H, H1),

7.81 – 7.74 (m, 2H, H3 + H7), 7.65 (dt, J = 7.9, 1.1 Hz, 1H, H4), 7.46 (dd, J = 8.5, 13 2.4 Hz, 1H, H9), 7.36 – 7.29 (m, 2H, H2 + H10); C NMR (101 MHz, CDCl3, ppm): δ 155.6 (C5), 149.8 (C1), 140.8 (C6), 136.2 (C3), 134.5 (C7), 132.7 (C9), 131.7

(C10), 131.3 (C11), 125.0 (C4), 123.0 (C2), 120.9 (C8); Accurate Mass: APCI+ m/z + ◦ calcd for C11H8NBrCl [M+H] 267.9523, found 267.9519; m.p. : 77 – 80 C.

2-(2-Iodophenyl)pyrimidine 110a

110a

Prepared according to general procedure 4 from 2-phenylpyrimidine 110, with the addition of K2CO3 (138 mg, 1.00 mmol, 2.00 eq.). Product 110a was obtained as an oﬀ-white solid (48.6 mg) in a 1.00 : 0.11 mixture with 2-(2-chlorophenyl)pyrimidine 110b.

1 110a: (45.2 mg, 0.161 mmol, 32% yield). H NMR (400 MHz, CDCl3, ppm): δ 8.88 (d, J = 4.9 Hz, 2H), 8.00 (dd, J = 8.0, 1.1 Hz, 1H), 7.68 (dd, J = 7.7, 1.7 Hz, 1H), 7.46 (td, J = 7.6, 1.2 Hz, 1H), 7.30 (t, J = 4.9 Hz, 1H), 7.12 (ddd, J = 7.9, 7.4, 13 1.7 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ 167.8, 157.1, 143.1, 140.5, 130.8, 130.6, 128.3, 119.6, 95.4; LRMS: EI m/z 282.0 [M]. Data is consistent with previous literature reports.(375)

110b: (3.3 mg, 0.017 mmol, 3% yield). See below for data.

208 2-(2-Chlorophenyl)pyrimidine, 110b

110b

Prepared according to general procedure 5 from 2-phenylpyrimidine 110 with the addition of K2CO3 (138 mg, 1.00 mmol, 2.00 eq.). Product 110b was isolated as a yellow oil (32.0 mg, 0.168 mmol, 34% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 8.88 (d, J = 4.9 Hz, 2H), 7.77 – 7.69 (m, 1H), 7.53 – 7.47 (m, 1H), 7.42 – 7.35 (m, 2H), 7.29 (t, J = 4.9 Hz, 1H); 13C NMR

(101 MHz, CDCl3, ppm): δ 165.8, 157.2, 137.8, 132.8, 131.8, 130.7, 130.6, 127.0, 119.5; LRMS: ESI+ m/z 191.0 [M+H]+. Data is consistent with previous literature reports.(375)

2-(2,6-Dichlorophenyl)pyrimidine, 110c

Cl Cl

110c

Isolated as a side product from the reaction of 2-phenylpyrimidine 110 according to general procedure 5 with the addition of K2CO3 (138 mg, 1.00 mmol, 2.00 eq.), to give 2-(2-chlorophenyl)pyridine 110b. Product 110c was obtained as an oﬀ-white solid (11.6 mg, 0.0515 mmol, 10% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 8.92 (d, J = 4.9 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.36 (t, J = 4.9 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H); 13C NMR (101 MHz,

CDCl3, ppm): δ 164.4, 157.6, 137.6, 134.1, 130.4, 128.2, 120.2; LRMS: EI m/z 224.0 [M]. Data is consistent with previous literature reports.(56)

209 2-(4-Chloro-2-iodophenyl)pyridine, 112a

2 3 1

4 N 5 6 I 7 11 8 10 9 Cl 112a

Prepared according to general procedure 4 from 2-(4-chlorophenyl)pyridine. Isolated as a yellow oil (24.0 mg, 0.0761 mmol, 15% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.70 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H, H1),

7.96 (d, J = 1.9 Hz, 1H, H10), 7.77 (td, J = 7.7, 1.8 Hz, 1H, H3), 7.49 (dt, J = 7.8,

1.1 Hz, 1H, H4), 7.44 – 7.37 (m, 2H, H7 + H8), 7.31 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H, 13 H2); C NMR (101 MHz, CDCl3, ppm): δ 159.8 (C5), 149.5 (C1), 143.7 (C6),

139.2 (C10), 136.3 (C3), 134.8 (C9), 131.0 (C7), 128.6 (C8), 124.5 (C4), 122.9 (C2), + 96.7 (C11); LRMS: ESI+ m/z 316.0 [M+H] ; Accurate Mass: APCI+ m/z calcd + for C11H8ONClI [M+H] 315.9384, found 315.9380.

2-(2,4-Dichlorophenyl)pyridine, 112b

Cl 112b

Prepared according to general procedure 4 from 2-(4-chlorophenyl)pyridine. Isolated as a pale yellow solid (23.2 mg, 0.104 mmol, 21% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.72 (dt, J = 4.9, 1.7, 1.0 Hz, 1H), 7.76 (td, J = 7.7, 1.9 Hz, 1H), 7.64 (dt, J = 7.9, 1.1 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 8.3, 2.1 Hz, 1H), 7.30 (ddd, J = 7.5, 4.9, 1.2 Hz,

210 13 1H); C NMR (101 MHz, CDCl3, ppm): δ 155.9, 149.8, 137.8, 136.1, 135.0, 133.0, 132.6, 130.0, 127.5, 124.9, 122.8; LRMS: ESI+ m/z 223.9 [M+H]+. Data is consistent with literature values.(53)

2-(4-Bromo-2-iodophenyl)pyridine, 113a

2 3 1

4 N 5 6 I 7 11 8 10 9 Br 113a

To a microwave vial equipped with a stirrer bar was added [(1,4-dioxane)(ICl)2] 101

(206 mg, 0.50 mmol, 1.00 eq.), then Ru3(CO)12 (9.6 mg, 0.015 mmol, 3.0 mol%) and K2CO3 (69.1 mg, 0.500 mmol, 1.00 eq.). The vial was capped, and evacuated and backﬁlled with N2 (× 3). 2-(4-Bromophenyl)pyridine 113 (117 mg, 0.500 mmol, 1.00 eq.) was then added to the vial in a solution of dry 1,2-DCE (3 mL). The reaction mixture was heated to 110 ◦C for 4 hours. Once cool, the reaction mixture was quenched with aq. Na2S2O3 solution (20 mL, 10 wt%), and extracted with EtOAc

1 H NMR (500 MHz, CDCl3, ppm): δ 8.70 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H, H1),

8.12 (d, J = 1.9 Hz, 1H, H10), 7.77 (td, J = 7.7, 1.8 Hz, 1H, H3), 7.57 (dd, J =

8.2, 2.0 Hz, 1H, H8), 7.49 (dt, J = 7.8, 1.1 Hz, 1H, H4), 7.34 – 7.29 (m, 2H, H2 + 13 H7); C NMR (126 MHz, CDCl3, ppm): δ 159.9 (C5), 149.5 (C1), 144.1 (C6),

141.8 (C10), 136.2 (C3), 131.5 (C8), 131.4 (C7), 124.4 (C4), 122.9 (C2), 122.8 (C9), + 97.2 (C11); LRMS: ESI+ m/z 359.9 [M+H] ; Accurate Mass: ESI+ m/z calcd for + C11H8NBrI [M+H] 359.8879, found 359.8869.

211 2-(4-Bromo-2-chlorophenyl)pyridine, 113b

2 3 1

4 N 5 6 Cl 7 11 8 10 9 Br 113b

Prepared according to general procedure 5 from 2-(4-bromophenyl)pyridine 113. The product was isolated as a pale pink solid (44.9 mg, 0.167 mmol, 33% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.71 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H, H1),

7.77 (td, J = 7.7, 1.8 Hz, 1H, H3), 7.67 – 7.62 (m, 2H, H4 + H7 or H8), 7.53 – 7.47 (m, 13 2H, H10 + H7 or H8), 7.30 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H, H2); C NMR (101 MHz,

CDCl3, ppm): δ 155.9 (C5), 149.8 (C1), 138.2 (C6), 136.1 (C3), 133.2 (C11), 132.8

(C7 or C8 or C10), 132.8 (C7 or C8 or C10), 130.4 (C7 or C8 or C10), 124.9 (C4), 122.8 + (C2 or C9), 122.8 (C2 or C9); LRMS: ESI+ m/z 267.9 [M+H] ; Accurate Mass: + ESI+ m/z calcd for C11H8NBrCl [M+H] 267.9523, found 267.9514; m.p. : 74 – 75 ◦C.

2-(4-Bromo-2,6-dichlorophenyl)pyridine, 113c

Cl Cl

Br 113c

Obtained as a side-product from the reaction of 2-(4-bromophenyl)pyridine 113 according to general procedure 5 to form 113b. The product 113c was obtained as a mixture with the starting material 113 (Ratio 113 : 113c was 1.00: 0.29 by 1H NMR). Yield calculated by NMR was 7%.

1 H NMR (400 MHz, CDCl3, ppm): δ 8.75 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 7.82

212 (td, J = 7.7, 1.8 Hz, 1H), 7.58 (s, 2H), 7.36 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H), 7.31 (dt, 13 J = 7.8, 1.1 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ 154.8, 149.9, 137.7, 136.6, 135.5, 131.0, 125.1, 123.3, 122.3; LRMS: EI m/z 300.9 [M]. Data is consistent with literature values.(45)

2-Phenyl-4,5-dihydrooxazol-3-ium chloride, 115

2 1 O NH Cl 3 4 5 5′

6 6′ 7 115 Prepared according to general procedure 4 from 2-phenyl-2-oxazoline 114. Isolated as an oﬀ-white solid (32.6 mg, 0.178 mmol, 36% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.81 – 7.75 (m, 2H, H5 + H50 ), 7.54 – 7.49

(m, 1H, H7), 7.48 – 7.41 (m, 2H, H6 + H60 ), 6.63 (br s, 1H, NH) 3.81 (tdd, J = 5.9, 13 4.9, 1.0 Hz, 2H, 2H1 or 2H2), 3.74 (ddd, J = 6.1, 5.1, 1.1 Hz, 2H, 2H1 or 2H2); C

NMR (101 MHz, CDCl3, ppm): δ 167.8 (C3), 134.2 (C4), 131.9 (C7), 128.8 (C6

+ C60 ), 127.1 (C5 + C50 ), 44.3 (C1 or C2), 41.8 (C1 or C2); Accurate Mass: ESI+ + ◦ m/z calcd for C9H11ONCl [M+H] 184.0524, found 184.0524; m.p. : 89 – 91 C; IR (solid, cm−1): 3297 (br, m), 2944 (w), 1721 (mw), 1634 (s), 1602 (mw), 1579 (mw), 1539 (s), 1491 (m), 1447 (m), 1253 (s).

1-(2-Iodophenyl)-4-methyl-1H -pyrazole, 117a

2 3 1 N N 5 10 I 6

7 9 8 117a

Prepared according to general procedure 4 from 4-methyl-1-phenyl-1H -pyrazole, 117. Obtained as a brown oil (12.4 mg, <10% yield) in a mixture with an unidentiﬁed

213 impurity (1.00:0.14 ratio).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.95 (dd, J = 7.9, 1.4 Hz, 1H, H9), 7.55 (s,

1H, H1 or H3), 7.49 (s, 1H, H1 or H3), 7.42 (app. td, J = 7.6, 1.4 Hz, 1H, H7), 7.37 (dd,

J = 7.9, 1.9 Hz, 1H, H6), 7.11 (ddd, J = 7.9, 7.2, 1.8 Hz, 1H, H8), 2.18 (s, 3H, 3H4); 13 C NMR (101 MHz, CDCl3, ppm): δ 143.7 (C5), 141.7 (C1 or C3), 140.2 (C9),

130.0 (C8), 129.7 (C1 or C3), 129.1 (C7), 128.2 (C6), 117.2 (C2), 94.1 (C10), 9.1 (C4); + Accurate Mass: ESI+ m/z calcd for C10H10N2I [M+H] 284.9883, found 284.9878.

3.3.4. Kinetic isotope experiments

Kinetic isotope eﬀects from parallel reactions

KIE experiment - Procedure for iodination of phenylpyridine or d 5-phenylpyridine in separate ﬂasks:

Conditions A: N N Ru3(CO)12 (3 mol%) N N [1,4-dioxane(ICl)2] (1.0 eq.) H H or D D H I or D I 1,4-dioxane, N2, 110 °C H H D D H H D D H D H D 26 119 26a 119a

To a microwave vial equipped with a stirrer bar was added Ru3(CO)12 (3.8 mg,

0.0059 mmol, 3.0 mol%). The vial was capped, and evacuated/back-ﬁlled with N2 (× 3). Dry 1,4-dioxane (0.60 mL) was added, and the stirring solution was heated in an oil bath to 110 ◦C for at least 5 minutes. To this was added a freshly prepared solution of phenylpyridine 26 (31.0 mg, 0.200 mmol, 1.00 eq.) or d 5-phenylpyridine 119

(32.0 mg, 0.200 mmol, 1.00 eq.) and [1,4-dioxane(ICl)2] 101 (82.6 mg, 0.200 mmol, 1.00 eq.) in 1,4-dioxane (0.60 mL) in one portion. After the allotted time period, the vial was removed from the heat and rapidly cooled in a dry ice/acetone bath. The reaction mixture was then diluted with EtOAc (15 mL) and washed with 10% aq. Na2S2O4 solution (10 mL). The aqueous layer was extracted with EtOAc (2 ×

214 15 mL). The combined organic extracts were washed with brine (5 mL), dried over

MgSO4 and concentrated. The resulting oil was dissolved in CDCl3, and a solution µ of 1,3,5-trimethoxybenzene (internal standard) in CDCl3 (0.33 M, 200 L) was added, before obtaining a quantitative 1H NMR spectrum.

Table 31: Parallel KIE experiments for the iodination of phenylpyridine (26) or d 5-phenylpyridine (119) in separate ﬂasks

Entry Starting Material Time (s) % yield (of 26a or 119a) 1 26 60 3.7 2 26 90 4.2 3 26 120 5.2 4 26 200 9.6 5 26 240 10.3 6 119 30 1.2 7 119 60 2.4 8 119 90 2.9 9 119 120 4.0 10 119 200 6.2 11 119 240 8.6

y = 0.0406x + 0.8281 8 R² = 0.9738

6 26 y = 0.0331x + 0.1294 R² = 0.9807 119

4 Yield Yield of 26a 119a or (%)

0 0 50 100 150 200 250 300 Time (s)

Figure 7: Relative initial rates of the iodination of 26 and 119

Iodination KIE (from parallel reactions) = k H / k D = 0.0406 / 0.0331 = 1.2

215 KIE experiment - Procedure for chlorination of phenylpyridine or d 5-phenylpyridine in separate ﬂasks: Conditions B: RuCl2(PPh3)3 (2.5 mol%) N N PPh3 (30 mol%) N N [1,4-dioxane(ICl)2] (1.0 eq.) H H or D D H Cl or D Cl 1,4-dioxane, air, 110 °C H H D D H H D D H D H D 26 119 26b 119b To a microwave vial equipped with a stirrer bar was added 1,4-dioxane (0.60 mL). The ◦ solvent was heated to 110 C in an oil bath for 3 minutes. RuCl2(PPh3)3 (4.8 mg,

0.0050 mmol, 2.5 mol%) and PPh3 (15.7 mg, 0.0600 mmol, 30.0 mol%) were added, and the vial was capped. To this was added a freshly prepared solution of phenylpyridine

26 (31.0 mg, 0.200 mmol, 1.00 eq.) or d 5-phenylpyridine 119 (32.0 mg, 0.200 mmol,

1.00 eq.) and [1,4-dioxane(ICl)2] 101 (82.6 mg, 0.200 mmol, 1.00 eq.) in 1,4-dioxane (0.60 mL) in one portion. After the allotted time period, the vial was removed from the heat and rapidly cooled in a dry ice/acetone bath. The reaction mixture was then diluted with EtOAc (15 mL) and washed with 10% aq. Na2S2O4 (10 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4 and concentrated. The resulting oil was dissolved in CDCl3, and a solution of 1,3,5-trimethoxybenzene (internal standard) in µ 1 CDCl3 (0.33 M, 200 L) was added, before obtaining a quantitative H NMR spectrum. 25

20 y = 0.1089x + 5.6147 R² = 0.9747

26 10 119 y = 0.0925x - 1.9972 Yield Yield of26b or 119b(%) R² = 0.993 5

0 0 20 40 60 80 100 120 140 160 Time (s)

Figure 8: Relative initial rates of the chlorination of 26 and 119 216 Table 32: Parallel KIE experiments for the chlorination of phenylpyridine (26) or d 5-phenylpyridine (119) in separate ﬂasks

Entry Starting Material Time (s) % yield (of 26b or 119b) 1 26 30 8.6 2 26 45 9.6 3 26 60 13.4 4 26 90 15.4 5 26 120 19.3 6 26 150 21.3 7 119 30 0.3 8 119 45 2.2 9 119 60 4.1 10 119 90 6.3 11 119 120 9.3 12 119 150 11.6

Chlorination KIE (from parallel reactions) = k H / k D = 0.1089 / 0.0925 = 1.2

Kinetic isotope eﬀects from intermolecular competition experiments

KIE experiment - Procedure for competitive iodination of phenylpyridine and d 5-phenylpyridine in the same ﬂask:

Conditions A: N N Ru3(CO)12 (3 mol%) N N [1,4-dioxane(ICl)2] (1.0 eq.) H H and D D H I D I 1,4-dioxane, N2, 110 °C H H D D H H D D H D H D 26 119 26a 119a (0.5 eq.) (0.5 eq.)

To a microwave vial equipped with a stirrer bar was added Ru3(CO)12 (3.8 mg,

217 neously to the reaction mixture, one being a solution of phenylpyridine 26 (15.5 mg,

0.100 mmol, 0.50 eq.) and d 5-phenylpyridine 119 (16.0 mg, 0.100 mmol, 0.50 eq.) in 1,4-dioxane (0.30 mL); the other a solution of [1,4-dioxane(ICl)2] 101 (82.6 mg, 0.200 mmol, 1.00 eq.) in 1,4-dioxane (0.30 mL). After 10 minutes, the reaction mixture was removed from the heat and rapidly cooled in a dry ice/acetone bath. The reaction mixture was then diluted with EtOAc (15 mL) and washed with 10% aq. Na2S2O4 (10 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4 and concentrated.

The resulting oil was dissolved in CDCl3, and a solution of 1,3,5-trimethoxybenzene µ (internal standard) in CDCl3 (0.33 M, 200 L) was added, before obtaining a quantitative 1H NMR spectrum, from which the percentage yields were obtained.

% yield of 26a = PH = 24.1%

% yield of 119a = PD = 7.6%

Iodination KIE (from intermolecular competition experiment) = PH /PD = 24.1 / 7.6 = 3.1

KIE experiment - Procedure for competitive chlorination of phenylpyridine and d 5-phenylpyridine in the same ﬂask:

Conditions B: RuCl2(PPh3)3 (2.5 mol%) N N PPh3 (30 mol%) N N [1,4-dioxane(ICl)2] (1.0 eq.) H H and D D H Cl D Cl 1,4-dioxane, air, 110 °C H H D D H H D D H D H D 26 119 26b 119b (0.5 eq.) (0.5 eq.)

To a microwave vial equipped with a stirrer bar was added 1,4-dioxane (0.60 mL). The ◦ solvent was heated to 110 C in an oil bath for 3 minutes. RuCl2(PPh3)3 (4.8 mg,

0.0050 mmol, 2.5 mol%) and PPh3 (15.7 mg, 0.0600 mmol, 30.0 mol%) were added, and the vial was capped. Two solutions were then added simultaneously to the reaction

218 mixture, one being a solution of phenylpyridine 26 (15.5 mg, 0.100 mmol, 0.50 eq.) and d 5-phenylpyridine 119 (16.0 mg, 0.100 mmol, 0.50 eq.) in 1,4-dioxane (0.30 mL); the other a solution of [1,4-dioxane(ICl)2] 101 (82.6 mg, 0.200 mmol, 1.00 eq.) in 1,4- dioxane (0.30 mL). After 4 minutes, the reaction mixture was removed from the heat and rapidly cooled in a dry ice/acetone bath. The reaction mixture was then diluted with EtOAc (15 mL) and washed with 10% aq. Na2S2O4 (10 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4 and concentrated. The crude product was passed through a short pipette column (eluent: 5% EtOAc in hexane) to remove the PPh3 and any ruthenium compounds, then concentrated. The resulting oil was dissolved in CDCl3, and a solution of 1,3,5-trimethoxybenzene (internal standard) in CDCl3 (0.33 M, 200 µL) was added, before obtaining a quantitative 1H NMR spectrum, from which the percentage yields were obtained.

% yield of 26b = PH = 16.2%

% yield of 119b = PD = 5.4%

Chlorination KIE (from intermolecular competition experiment) = PH /PD = 16.2 / 5.4 = 3.0

Data for deuterated products:

2-(2-Iodophenyl-3,4,5,6-d 4)pyridine, 119a

D I

D D D 119a

1 Pale yellow oil. H NMR (500 MHz, CDCl3, ppm): δ 8.71 (d, J = 5.0 Hz, 1H), 7.77 (app td, J = 7.7, 1.8 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.30 (dd, J = 7.7,

219 13 5.0 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ 160.9, 149.4, 145.1, 136.1, 124.5, 122.6, 96.6; LRMS: EI m/z 284.9 [M]; Accurate Mass: APCI+ m/z calcd + for C11H5D4NI [M+H] 286.0025, found 286.0022.

2-(2-Chlorophenyl-3,4,5,6-d 4)pyridine, 119b

D Cl

D D D 119b

1 Colourless oil. H NMR (500 MHz, CDCl3, ppm): δ 8.73 (s, 1H), 7.80 – 7.74 13 (m, 1H), 7.69 – 7.63 (m, 1H), 7.32 – 7.27 (m, 1H); C NMR (101 MHz, CDCl3, ppm): δ 157.0, 149.7, 139.2, 136.0, 132.2, 131.3 (t, J = 25.1 Hz), 129.8 (t, J = 25.1 Hz), 129.2, (t, J = 25.0 Hz), 126.6 (t, J = 24.8 Hz), 125.0, 122.5; LRMS: EI m/z + 193.0 [M]; Accurate Mass: APCI+ m/z calcd for C11H5D4NCl [M+H] 194.0669, found 194.0670.

220 3.4. Tandem N,C-diarylation of pyrazole experimental

3.4.1. Preparation of iodonium salts

General procedure 6: Preparation of phenyl(styryl) iodonium triflate salts To a stirring suspension of (E)-styrylboronic acid (6.00 mmol, 1.00 eq.) in DCM (48 mL) at 0 ◦C was added boron trifluoride diethyl etherate (0.889 mL, 7.20 mmol, 1.20 eq.). After 15 minutes, a solution of (diacetoxyiodo)benzene (2.32 g, 7.20 mmol, 1.20 eq.) in DCM (22 mL) was added slowly to the reaction mixture. The reaction mixture was stirred at 0 ◦C for one hour, followed by the dropwise addition of tri- fluoromethanesulfonic acid (0.637 mL, 7.20 mmol, 1.20 eq.). The mixture was stirred for 15 minutes and then water (60 mL) was added. The phases were separated, and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4, then concentrated to afford an oil. The residue was either: repeatedly triturated using Et2O/DCM, to afford the desired product or sonicated in Et2O multiple times, each time decanting away the liquid before being dried under vacuum to afford the product.

Bis(4-ﬂuorophenyl)iodonium triﬂate, 150m

OTf F I

F 150m

To a solution of mCPBA (70% in water, 1.22 g, 4.96 mmol, 1.10 eq) in DCM (15 mL) under N2 was added 1-fluoro-4-iodobenzene (520 µL, 1.00 g, 4.51 mmol, 1.00 eq). The reaction mixture was stirred at room temperature for five minutes, then cooled to 0 ◦C. Fluorobenzene (465 µL, 476 mg, 4.96 mmol, 1.10 eq) was added to the reaction mixture, followed by dropwise addition of a solution of triflic acid (1.20 mL, 2.06 g, 13.5 mmol,

221 3.00 eq) in DCM (5 mL). The reaction was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated, and the title compound was aﬀorded as a white solid (1.53 g, 3.27 mmol, 73% yield) by trituration with Et2O.

1 H NMR (500 MHz, DMSO-d 6, ppm): δ 8.34 – 8.29 (m, 4H), 7.45 – 7.39 (m, 13 4H); C NMR (126 MHz, DMSO-d 6, ppm): δ 164.0 (d, J = 251.0 Hz) 138.0 (d, J = 9.0 Hz), 120.7 (q, J = 322.0 Hz), 119.3 (d, J = 23.0 Hz), 111.3 (d, J = 3.0 Hz); 19 F NMR (470 MHz, DMSO-d 6, ppm): δ −77.7, −106.6; LRMS: ESI+ m/z 316.9 [M−OTf]+. Data is consistent with literature values.(378)

Di(4-methoxyphenyl)iodonium triﬂate, 150n

OTf MeO I

OMe 150n

Prepared according to a procedure by Onamura and co-workers.(379)To a stirring solution of mCPBA (75% purity, 1.55 g, 9.00 mmol, 1.10 eq.) in DCM (31 mL) under N2 at room temperature was added 4-iodoanisole (1.90 g, 8.10 mmol, 1.00 eq.). The flask was equipped with a condenser, and heated to 80 ◦C for 10 minutes. The reaction mixture was then cooled to −78 ◦C. A solution of boron trifluoride diethyl etherate (2.50 mL, 2.87 g, 20.3 mmol, 2.50 eq.) and 4-methoxyphenylboronic acid (1.37 g, 9.00 mmol, 1.10 eq.) in DCM (31.2 mL) was added to the reaction mixture dropwise at −78 ◦C. The reaction mixture was stirred at −78 ◦C for 30 minutes, then warmed to room temperature. Triflic acid (0.796 mL, 1.35 g, 9.00 mmol, 1.10 eq.) was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 15 minutes. The crude reaction mixture was then applied to a silica plug (25 g), and eluted with DCM (300 mL) to elute the mCPBA and 4-iodoanisole, then with DCM/MeOH (20:1, 900 mL). The last fraction (eluted with DCM/MeOH) was concentrated, to give the crude product as a black oil. The crude product was triturated with Et2O to afford

222 the title compound as a black crystalline solid (795 mg, 1.62 mmol, 20% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.90 (d, J = 9.2 Hz, 4H), 6.90 (d, J = 13 9.2 Hz, 4H), 3.79 (s, 6H); C NMR (101 MHz, CDCl3, ppm): δ 162.9, 137.1, 19 120.5 (q, J = 321 Hz), 118.0, 102.5, 55.8; F NMR (376 MHz, CDCl3, ppm): δ −78.2; LRMS: ESI+ m/z 341.1 [M−OTf]+, ESI− m/z 148.9 [OTf]−. Data is consistent with literature values.(379)

Di(3-chlorophenyl)iodonium triﬂate, 150o

Cl 7 5 6 OTf 1 4 I 1 3 2 2 6

3 5 4 Cl 150o

Prepared according to a procedure developed by Oloffson and co-workers.(380) To a stirring solution of mCPBA (75% pure, 1.59 g, 9.20 mmol, 1.10 eq.) in DCM (34 mL) at room temperature under air was added 3-chloroiodobenzene (1.04 mL, 2.00 g, 8.40 mmol, 1.00 eq.), followed by dropwise addition of borontrifluoride diethyl etherate (2.59 mL, 2.98 g, 21.0 mmol, 2.50 eq.). The solution was stirred for 30 minutes at room temperature, then cooled to 0 ◦C. 3-Chlorophenylboronic acid (1.44 g, 9.24 mmol, 1.10 eq.) was added, and the reaction mixture was warmed to room temperature and stirred for 15 minutes before dropwise addition of triflic acid (0.814 mL, 1.38 g, 9.24 mmol, 1.10 eq.). The reaction was left stirring overnight, then applied to a silica plug (25 g), and eluted with DCM (300 mL) to elute the mCPBA and 3-chloroiodobenzene, followed by DCM/MeOH (20:1, 900 mL), to elute the product. Any boric acid derivatives were left on the column. The fraction containing the product was concentrated, to give the crude product as an oil. This was triturated with

Et2O, to aﬀord the product 150o as an oﬀ-white solid (2.22 g, 4.45 mmol, 53% yield).

1 H NMR (400 MHz, DMSO-d 6, ppm): δ 8.50 (t, J = 1.8 Hz, 2H, 2H6), 8.26

(ddd, J = 8.0, 1.7, 0.9 Hz, 2H, 2H2 or 2H4), 7.76 (ddd, J = 8.2, 2.1, 0.9 Hz, 2H, 2H2

223 13 or 2H4), 7.59 (t, J = 8.1 Hz, 2H, 2H3); C NMR (101 MHz, DMSO-d 6, ppm):

δ 134.9 (C5), 134.4 (C6), 133.8 (C2 or C4), 133.3 (C3), 132.4 (C2 or C4), 120.7 (app 19 d, J = 321.9 Hz, C7), 117.0 (C1); F NMR (376 MHz, DMSO-d 6, ppm): δ + −77.7; Accurate Mass: ESI+ m/z calcd for C12H8Cl2I [M−OTf] 348.9042, found 348.9051; m.p. : 133 – 134 ◦C.

4-Fluorophenyl(2-tolyl)iodonium triﬂate, 150l

OTf F I Me

150l

Prepared according to the procedure by Novákand co-workers.(182) A stirring solution of mCPBA (87% pure1, 1.34 g, 7.79 mmol, 1.10 eq.), 2-iodotoluene (0.901 mL, 1.54 g, 7.08 mmol, 1.00 eq.), and fluorobenzene (0.731 mL, 749 mg, 7.79 mmol, 1.10 eq.) in DCM (47 mL) was cooled to 0 ◦C. A solution of triflic acid (1.25 mL, 2.13 g, 14.2 mmol, 2.00 eq.) in DCM (10 mL) was added dropwise via dropping funnel. The reaction mixture was left stirring at room temperature for 24 hours. The reaction mixture was then concentrated in vacuo. The resulting oil was triturated with Et2O to afford the product 150l as a pale yellow solid (2.72 g, 5.90 mmol, 83% yield).

1 H NMR (400 MHz, DMSO-d 6, ppm): δ 8.40 (d, J = 8.0 Hz, 1H), 8.31 – 8.25 (m, 2H), 7.63 – 7.51 (m, 2H), 7.40 (app. t, J = 8.9 Hz, 2H), 7.25 – 7.19 (m, 1H), 2.62 13 (s, 3H); C NMR (101 MHz, DMSO-d 6, ppm): δ 163.9 (d, J = 251.7 Hz), 140.6, 137.9 (d, J = 8.9 Hz), 137.0, 132.9, 131.5, 129.4, 121.8, 120.7 (app. d, J = 321.4 Hz), 119.3 (d, J = 23.0 Hz), 110.1 (d, J = 3.3 Hz), 25.0; 19F NMR (376 MHz, DMSO- + − d 6, ppm): δ −77.8, −106.8; LRMS: ESI+ m/z [M−OTf] 313.0, ESI− m/z [OTf] 148.8. Data is consistent with literature values.(182)

1The mCPBA was dried under high vacuum for a few hours before use, and its purity was determined by iodometric titration (381)

224 (Phenyl)[(E)-(4-methoxystyryl)]iodonium triﬂate, 192a

9′ 8′ 12 11 MeO 10 6 OTf 7 I 9 8 5 1 2 2′

3 3′ 4 192a

Prepared according to general procedure 6. The residue was sonicated in Et2O, and the liquid decanted (× 2), and the resulting solid was dried under high vacuum to aﬀord the desired product 192a as a black solid (817 mg, 1.68 mmol, 28% yield).

1 H NMR (500 MHz, CD3CN, ppm): δ 8.02 (app. d, J = 8.1 Hz, 2H), 7.84 (d, J = 14.2 Hz, 1H), 7.71 (app. t, J = 7.5 Hz, 1H), 7.55 (app. t, J = 7.8 Hz, 2H), 7.46 (app. d, J = 8.6 Hz, 2H), 7.36 (d, J = 14.2 Hz, 1H), 6.97 (app. d, J = 8.6 Hz, 2H), 1 3.80 (s, 3H); H NMR (400 MHz, CDCl3, ppm): δ 7.99 (app. d, J = 8.4 Hz,

2H, H2 + H20 ), 7.68 (app. t, J = 7.5 Hz, 1H, H4), 7.61 (d, J = 14.2 Hz, 1H, H6),

7.52 (app. t, J = 7.9 Hz, 2H, H3 + H30 ), 7.37 (app. d, J = 8.8 Hz, 2H, H8 + H80 ),

7.25 (d, J = 14.2 Hz, 1H, H5), 6.90 (app. d, J = 8.8 Hz, 2H, H9 + H90 ), 3.83 (s, 3H, 13 3H12); C NMR (126 MHz, CDCl3, ppm): δ 162.2 (C10), 150.7 (C6), 135.5 (C2

+ C20 ), 132.7 (C4), 132.4 (C3 + C30 ), 129.9 (C8 + C80 ), 127.0 (C7), 120.4 (app. d, 19 J = 320.8 Hz, C11), 114.6 (C9 + C90 ), 111.6 (C1), 94.1 (C5), 55.6 (C12); F NMR + (376 MHz, CDCl3, ppm): δ −78.2; LRMS: ESI+ m/z 337.1 [M−OTf] ; LRMS: − + ESI− m/z 149.0 [OTf] ; Accurate Mass: ESI+ m/z calcd for C15H14OI [M−OTf] 337.0084, found 337.0098; m.p. : 86 – 89 ◦C

(Phenyl)[(E)-(4-ﬂuorostyryl)]iodonium triﬂate, 192b

9′ 8′ 11 F 10 6 OTf 7 I 9 8 5 1 2 2′

3 3′ 4 192b

225 Prepared according to general procedure 6. The residue was repeatedly triturated using Et2O/DCM, to afford the desired product as an off-white solid. The solid was filtered, and dried under high vacuum, to afford the product 192b as an off-white solid (1.59 g, 3.35 mmol, 56% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 8.04 (app. d, J = 7.8 Hz, 2H, H2 + H20 ),

7.71 – 7.58 (m, 2H, H4 + H5), 7.49 – 7.38 (m, 5H, H3 + H30 + H6 + H8 + H80 ), 13 7.02 (app. t, J = 8.6 Hz, 2H, H9 + H90 ); C NMR (126 MHz, CDCl3, ppm):

δ 164.4 (d, J = 253.0 Hz, C10), 149.0 (C5), 135.8 (C2 + C20 ), 132.8 (C4), 132.4 (C3

+ C30 ), 130.6 (d, J = 3.4 Hz, C7), 130.1 (d, J = 8.8 Hz, C8 + C80 ), 120.3 (q, J =

320.0 Hz, C11), 116.4 (d, J = 22.2 Hz, C9 + C90 ), 111.4 (C1), 97.4 (d, J = 2.6 Hz, C6); 19 F NMR (376 MHz, CDCl3, ppm): δ −78.2, −107.8; LRMS: ESI+ m/z 325.1 [M−OTf]+; LRMS: ESI− m/z 149.0 [OTf]−; Accurate Mass: ESI+ m/z calcd for + ◦ C14H11FI [M−OTf] 324.9884, found 324.9894; m.p. : 75 – 78 C.

3.4.2. N–H/C–H arylation of pyrazoles

General procedure 7: One pot N–H/C–H arylation with diaryliodonium salts

To an oven dried 10 mL glass vial equipped with a magnetic stirrer bar was added the heterocycle (0.520 mmol, 1.00 eq.), diaryliodonium salt (0.624 mmol, 1.20 eq.), K2CO3 (86.2 mg, 0.624 mmol, 1.20 eq.) and, where indicated, CuI (5.0 mg, 0.026 mmol, 5.0 mol%). The glass vial was sealed with a PTFE septa containing crimp cap.

A vacuum/N2 cycle was applied three times to the vial before anhydrous p-xylene (1.5 mL) was added. The reaction mixture was stirred at 70 ◦C for 12 h. After con- ﬁrming the completion of the reaction by crude NMR analysis the crimp cap was removed to add [RuCl2(p-cymene)]2 (31.8 mg, 0.0520 mmol, 10 mol%), K2CO3 (143 mg,

1.04 mmol, 2.00 eq.) and MesCO2H (25.6 mg, 0.156 mmol, 30 mol%) and the vial was

ﬂushed with N2 to ensure the inert atmosphere and sealed again with a new crimp cap. The reaction mixture was allowed to stir at 140 ◦C for 18 hours. After conﬁrm-

226 ing completion of reaction by TLC the reaction mixture was cooled and diluted with

Et2O (75 mL). The reaction mixture was washed with 75 mL water and the separated aqueous phase was extracted with Et2O (2 × 75 mL). The combined organics were washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo to give the crude product. The crude product was subsequently puriﬁed either by manual or automated column chromatography over silica gel, typically using 5–10% EtOAc in hexane as eluent.

1-(40,5-Dichloro-[1,10-biphenyl]-2-yl)-3,5-dimethyl-1H -pyrazole, 189a

5 Me 3 4 1 14′ N 15 Cl Me 2 N 13′ 6 11 7 12 14 13 8 10 9 Cl 189a

Prepared according to general procedure 7, with the N-arylation step left for 18 hours, to aﬀord a dark green oil (80.1 mg, 0.253 mmol, 49% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.47 (d, J = 2.3 Hz, 1H, H10), 7.44 – 7.38

(m, 2H, H7 + H8), 7.24 (d, J = 8.6 Hz, 2H, H14 + H140 ), 7.00 (d, J = 8.6 Hz, 2H, H13 13 + H130 ), 5.77 (m, 1H, H3), 2.27 (s, 3H, 3H1 or 3H5), 1.62 (s, 3H, 3H1 or 3H5); C

NMR (101 MHz, CDCl3, ppm): δ 149.1 (C2 or C4), 140.5 (C2 or C4), 139.5 (C11),

136.0 (C6 or C9), 135.6 (C12), 134.8 (C6 or C9), 134.1 (C15), 130.3 (C7 or C8), 130.0

(C10), 129.6 (C13 + C130 ), 128.7 (C14 + C140 ), 128.5 (C7 or C8), 106.0 (C3), 13.5 (C1 + or C5), 11.0 (C1 or C5); Accurate Mass: ESI+ m/z calcd for C17H15N2Cl2 [M+H] 317.0607, found 317.0593.

227 1-(40,5-Diﬂuoro-[1,10-biphenyl]-2-yl)-3,5-dimethyl-1H -pyrazole, 189b

5 Me 3 4 1 14′ N 15 F Me 2 N 13′ 6 11 7 12 14 13 8 10 9 F 189b

Prepared according to general procedure 7 to aﬀord a dark green solid (74.4 mg, 0.262 mmol, 50% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 7.42 (dd, J = 8.7, 5.5 Hz, 1H, H7), 7.18

(dd, J = 9.2, 2.9 Hz, 1H, H10), 7.13 (app. dt, J = 8.1, 2.9 Hz, 1H, H8), 7.06 – 7.03 (m,

2H, H13 + H130 ), 6.95 (app. t, J = 8.7 Hz, 2H, H14 + H140 ), 5.76 (s, 1H, H3), 2.27 (s, 13 3H, 3H1 or 3H5), 1.62 (s, 3H, 3H1 or 3H5); C NMR (101 MHz, CDCl3, ppm):

δ 162.4 (d, J = 248.5 Hz, 2 × C, C9 + C15), 148.8 (C2 or C4), 140.6 (C2 or C4), 140.3

(d, J = 8.7 Hz, C11), 133.5 (d, J = 3.2 Hz, C6), 133.3 (dd, J = 3.2, 1.4 Hz, C12),

130.8 (d, J = 9.1 Hz, C7), 130.0 (d, J = 8.1 Hz, C13 + C130 ), 116.7 (d, J = 23.2 Hz,

C10), 115.5 (d, J = 21.7 Hz, C14 + C140 ), 115.1 (d, J = 22.6 Hz, C8), 105.7 (C3), 19 13.5 (C1 or C5), 11.0 (C1 or C5); F NMR (470 MHz, CDCl3, ppm): δ −112.08, + −113.90; Accurate Mass: ESI+ m/z calcd for C17H15N2F2 [M+H] 285.1198, found 285.1193; m.p. : 86 – 88 ◦C.

1-(30,4-Dichloro-[1,10-biphenyl]-2-yl)-3,5-dimethyl-1H -pyrazole, 189c

5 Me 3 4 1 N 16 Me 2 N 17 15 6 14 11 7 12 Cl 13 8 10 Cl 9 189c

Synthesised according to general procedure 7 to aﬀord a dark brown oil (81.9 mg,

228 0.258 mmol, 49% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 7.51 – 7.48 (m, 2H, H7 + H9), 7.43 (d,

J = 8.4 Hz, 1H, H10), 7.25 – 7.22 (m, 1H, H15), 7.18 (app. t, J = 7.9 Hz, 1H, H16),

7.06 (app. t, J = 1.8 Hz, 1H, H13), 6.91 (app. dt, J = 7.7, 1.5 Hz, 1H, H17), 5.79 (s, 13 1H, H3), 2.28 (s, 3H, 3H1 or 3H5), 1.65 (s, 3H, 3H1 or 3H5); C NMR (101 MHz,

CDCl3, ppm): δ 149.4 (C2 or C4), 140.6 (C2 or C4), 139.1 (C12), 138.4 (C6 or C8),

136.4 (C11), 134.3 (C6 or C8 or C14), 134.2 (C6 or C8 or C14), 131.1 (C10), 129.6 (C16),

129.4 (C7 or C9), 129.2 (C7 or C9); 128.4 (C13), 127.7 (C15), 126.4 (C17), 106.1 (C3),

13.5 (C1 or C5), 11.1 (C1 or C5); Accurate Mass: ESI+ m/z calcd for C17H15N2Cl2 [M+H]+ 317.0607, found 317.0597.

1-(20,40-Dimethoxy-[1,10-biphenyl]-2-yl)-3,5-dimethyl-1H-pyrazole, 189e

5 Me 3 4 19 1 16 N 15 OMe Me 2 N 17 6 11 14 7 12 13 8 10 OMe 18 9 189e

Synthesised according to general procedure 7 from the iodonium tosylate to aﬀord an oﬀ-white solid (71.0 mg, 0.233 mmol, 45% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.48 – 7.36 (m, 4H, H7 + H8 + H9 +

H10), 6.86 (d, J = 8.4 Hz, 1H, H17), 6.41 (d, J = 2.4 Hz, 1H, H14), 6.36 (dd, J =

8.4, 2.4 Hz, 1H, H16), 5.70 (s, 1H, H3), 3.79 (s, 3H, 3H18 or 3H19), 3.65 (s, 3H, 3H18 13 or 3H19), 2.23 (s, 3H, 3H1 or 3H5), 1.73 (s, 3H, 3H1 or 3H5); C NMR (101 MHz,

CDCl3, ppm): δ 160.3 (C13 or C15), 157.3 (C13 or C15), 148.0 (C2 or C4), 140.4 (C2 or C4), 138.3 (C6), 135.7 (C11), 132.0 (C7 or C8 or C9 or C10), 131.7 (C17), 128.2 (C7 or C8 or C9 or C10), 127.9 (C7 or C8 or C9 or C10), 127.6 (C7 or C8 or C9 or C10),

120.0 (C12), 104.9 (C3), 104.1 (C16), 98.2 (C14), 55.3 (C18 or C19), 55.2 (C18 or C19),

13.5 (C1 or C5), 10.9 (C1 or C5); Accurate Mass: ESI+ m/z calcd for C19H21N2O2

229 [M+H]+ 309.1598, found 309.1589; m.p. : 103 – 104 ◦C.

(N -phenylκC2-3,5-dimethylpyrazole-κN2)iodo(p-xylene)ruthenium, 190

5 12 15 3 4 13 15′ 2 1 N 14 N 13 14′ 12 6 Ru I 7 11 8 10 9 190

Isolated as a side product from the synthesis of 189e, as a rust coloured orange solid (7.4 mg, 0.015 mmol, 3% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.99 (dd, J = 7.5, 1.5 Hz, 1H, H7 or H10),

7.29 (dd, J = 8.0, 1.3 Hz, 1H, H7 or H10), 7.03 (app. td, J = 7.3, 1.3 Hz, 1H, H8 or

H9), 6.93 (ddd, J = 8.0, 7.2, 1.5 Hz, 1H, H8 or H9), 6.03 (s, 1H, H3), 5.48 (app. dd, J

= 5.9, 1.3 Hz, 2H, (H14 + H140 )/(H15 + H150 )), 5.12 – 5.08 (m, 2H, (H14 + H140 )/(H15 13 + H150 )), 2.67 (s, 3H, 3H1 or 3H5), 2.65 (s, 3H, 3H1 or 3H5), 2.08 (s, 6H, 6H12); C

NMR (101 MHz, CDCl3, ppm): δ 160.1 (C6 or C11), 150.9 (C2 or C4), 143.4 (C6 or C11), 142.0 (C7 or C10), 139.5 (C2 or C4), 124.9 (C8 or C9), 122.6 (C8 or C9), 112.0

(C7 or C10), 109.7 (C3), 96.3 (C13), 90.5 ((C14 + C140 )/(C15 + C150 )), 84.4 ((C14 +

C140 )/(C15 + C150 )), 19.6 (C12), 17.2 (C1 or C5), 14.8 (C1 or C5); Accurate Mass: + −1 ESI+ m/z calcd for C19H21N2IRu [M] 505.9787, found 505.9774; IR (solid, cm ): 2920 (m), 2851 (w), 1549 (m), 1467 (s), 1438 (s), 1416 (m), 1388 (ms), 1374 (s), 1272 (m), 1148 (m), 1024 (m).

1-(2,2-Diphenylvinyl)-1H -pyrazole, 194a

2 3

1 N 12′ N 11′ 13 4 10 12 H 5 11 6 7 7′

8 8′ 9 194a

230 Synthesised according to general procedure 7 (0.208 mmol scale) with catalytic copper iodide in the ﬁrst step to aﬀord a light brown oil (21.9 mg, 0.0889 mmol, 43% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.56 (d, J = 1.8 Hz, 1H, H1 or H3), 7.54

(s, 1H, H4), 7.45 – 7.37 (m, 3H, 3HAr), 7.35 – 7.28 (m, 5H, 5HAr), 7.25 – 7.20 (m, 2H, 13 2HAr), 6.83 (d, J = 2.5 Hz, 1H, H1 or H3), 6.09 (dd, J = 2.5, 1.8 Hz, 1H, H2); C

NMR (101 MHz, CDCl3, ppm): δ 140.3 (C5), 140.2 (C1 or C3), 138.1 (C6 or C10),

131.1 (C6 or C10), 130.0 (CAr), 129.3 (2 × C, CAr + C1 or C3), 128.6 (CAr), 128.3

(CAr), 127.9 (CAr), 127.5 (CAr), 125.7 (C4), 106.7 (C2); Accurate Mass: ESI+ m/z + calcd for C17H15N2 [M+H] 247.1230, found 247.1228.

(E)-1-(2-(4-Fluorophenyl)-2-phenylvinyl)-1H -pyrazole, 194c

2 3

1 N 12′ N 11′ 13 4 10 12 H 5 11 6 7 7′

8 8′ 9 F 194c

Synthesised according to general procedure 7 with catalytic copper iodide in the first step (55% yield by NMR analysis with 1,3,5-trimethoxybenzene as an internal standard). A small portion was purified by preparative TLC (eluent: 0.5% acetone in toluene) to afford the title compound as a white solid.

1 H NMR (400 MHz, CDCl3, ppm): δ 7.55 (d, J = 1.7 Hz, 1H, H1 or H3), 7.46

(s, 1H, H4), 7.44 – 7.37 (m, 3H, H13 + ((H11 + H110 ) or (H12 + H120 )), 7.29 – 7.22

(m, 2H, H7 + H70 ), 7.23 – 7.16 (m, 2H, (H11 + H110 ) or (H12 + H120 )), 7.05 – 6.97

(m, 2H, H8 + H80 ), 6.82 (d, J = 2.5 Hz, 1H, H1 or H3), 6.09 (app. t, J = 2.2 Hz, 1H, 13 H2); C NMR (126 MHz, CDCl3, ppm): δ 162.7 (d, J = 247.5 Hz, C9), 140.3

(C1 or C3), 137.9 (C10), 136.4 (d, J = 3.2 Hz, C6), 130.2 (C5), 130.0 ((C11 + C110 ) or (C12 + C120 ), 129.4 ((C11 + C110 ) or (C12 + C120 ), 129.2 (C1 or C3), 129.2 (d, J

231 19 = 7.9 Hz, C7), 128.5 (C13), 125.5 (C4), 115.5 (d, J = 21.4 Hz, C8), 106.8 (C2); F

NMR (471 MHz, CDCl3, ppm): δ −114.30; Accurate Mass: APCI m/z calcd + ◦ for C17H14N2F [M+H] 265.1136, found 265.1136; m.p. : 96 – 99 C.

3.4.3. Screening of other heterocycles

1-Phenoxy-1H -benzo[d][1,2,3]triazole, 203

N N N O

203

(228) Prepared according to the procedure by Su and Mo. To a microwave vial under N2 was added HOBt hydrate (6% H2O, 37.4 mg, 0.260 mmol, 1.00 eq.), K2CO3 (43.1 mg,

0.312 mmol, 1.20 eq.), Ph2IOTf (134 mg, 0.312 mmol, 1.20 eq.) and MeCN (0.75 mL). The reaction vessel was sealed and the reaction mixture stirred for 20 hours at room temperature. The solvent was removed in vacuo and the crude reaction mixture was puriﬁed by column chromatography (eluent: 20% to 30% EtOAc in hexane). The title compound was isolated as a colourless oil (32.4 mg, 0.153 mmol, 59% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.09 (app. dt, J = 8.4, 1.0 Hz, 1H), 7.53 (d, J = 3.9 Hz, 2H), 7.44 (app. dt, J = 8.2, 4.0 Hz, 1H), 7.38 – 7.31 (m, 2H), 7.18 13 (app. tt, J = 7.3, 1.0 Hz, 1H), 6.96 – 6.91 (m, 2H); C NMR (101 MHz, CDCl3, ppm): δ 159.5, 143.6, 130.2, 128.8, 127.9, 125.4, 125.1, 120.6, 114.2, 108.9; LRMS: ESI+ m/z 234.0 [M+Na]+. Data is consistent with literature values.(228)

2-(1H -Benzo[d][1,2,3]triazol-1-yl)phenol, 204

N N N OH

204

232 Prepared according to the procedure by G. -F. Su, D. -L. Mo and co-workers.(228) To a solution of HOBt hydrate (6% H2O, 359 mg, 2.50 mmol, 1.00 eq.) in MeCN (25 mL) was added tBuOK (421 mg, 3.75 mmol, 1.50 eq.). The reaction mixture was stirred at room temperature under air for five minutes, then Ph2IOTf (1.61 g, 3.75 mmol, 1.50 eq.) was added in one portion. The vial was sealed and the reaction mixture heated to 60 ◦C for 20 hours. The solvent was removed in vacuo, and the resulting residue was purified by column chromatography (eluent: 5% to 33% EtOAc in hexane) to afford a fraction of the clean product as an off-white solid (115 mg, 0.545 mmol, 22% yield) and a fraction containing white solid product and oil impurities. This impure fraction was washed with a small amount of EtOAc, and the resulting white solid filtered and dried to afford pure product 204 as an off-white solid (70.0 mg, 0.33 mmol, 13% yield). The total yield of 204 isolated was 35% (185 mg, 0.874 mmol).

1 H NMR (500 MHz, DMSO-d 6, ppm): δ 10.38 (s, 1H), 8.14 (app. dt, J = 8.4, 1.0 Hz, 1H), 7.57 (ddd, J = 8.4, 6.8, 1.1 Hz, 1H), 7.52 – 7.44 (m, 4H), 7.19 (dd, J = 8.2, 1.3 Hz, 1H), 7.06 (app. td, J = 7.6, 1.3 Hz, 1H); 13C NMR (101 MHz,

DMSO-d 6, ppm): δ 151.9, 144.9, 133.6, 131.1, 128.0, 127.8, 124.0, 123.3, 119.6, 119.2, 117.1, 111.6; LRMS: ESI+ m/z 234.0 [M+Na]+. Data is consistent with literature values.(228)

N -Phenylpyridin-2-amine, 210

210

A schlenk tube was charged with a stirrer bar, CuI (3.8 mg, 0.020 mmol, 1.0 mol%), 2-aminopyridine (282 mg, 3.00 mmol, 1.50 eq.) and tBuOK (448 mg, 4.00 mmol,

2.00 eq.), then evacuated/backﬁlled with N2 (× 3). Under a stream of nitrogen, dry 1,4-dioxane was added (3.0 mL), followed by iodobenzene (224 µL, 2.00 mmol, 1.00 eq.).

233 The ﬂask was sealed, and heated to 110 ◦C for 24 hours. Once cool, brine (40 mL) was added to the reaction mixture, and the aqueous layer was extracted with EtOAc (× 3).

The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting crude was purified by column chromatography (eluent: 5% to 25% EtOAc in hexane) to afford the product 210 as a yellow solid (194 mg, 1.14 mmol, 57% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.21 (ddd, J = 5.0, 1.9, 0.8 Hz, 1H), 7.49 (ddd, J = 8.9, 7.2, 1.9 Hz, 1H), 7.33 (app. d, J = 4.5 Hz, 4H), 7.09 – 7.02 (m, 1H), 6.88 (app. dt, J = 8.4, 0.8 Hz, 1H), 6.74 (ddd, J = 7.2, 5.0, 0.9 Hz, 1H), 6.56 (s, 13 1H); C NMR (101 MHz, CDCl3, ppm): δ 156.1, 148.6, 140.6, 137.8, 129.4, 123.0, 120.4, 115.2, 108.4; LRMS: ESI+ m/z 171.1 [M+H]+. Data is consistent with literature values.(382)

N,N -diphenylpyridin-2-amine, 212

212

1 H NMR (400 MHz, CDCl3, ppm): δ 8.23 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 7.45 (ddd, J = 8.4, 7.2, 2.0 Hz, 1H), 7.32 (app. tt, J = 7.5, 1.8 Hz, 4H), 7.20 – 7.16 (m, 4H), 13 7.16 – 7.10 (m, 2H), 6.79 – 6.73 (m, 2H); C NMR (126 MHz, CDCl3, ppm): δ 159.2, 148.5, 146.3, 137.4, 129.5, 126.4, 124.6, 116.3, 114.0; LRMS: EI m/z 245.1 [M−H]+. Data is consistent with literature values.(383)

9-(Pyridin-2-yl)-9H -carbazole, 213

N N

213

234 1 H NMR (400 MHz, CDCl3, ppm): δ 8.74 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 8.13 (app. dt, J = 7.7, 1.1 Hz, 2H), 7.97 – 7.91 (m, 1H), 7.85 (app. dt, J = 8.3, 0.9 Hz, 2H), 7.66 (app. dt, J = 8.2, 1.0 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.35 – 7.27 (m, 3H); 13 C NMR (126 MHz, CDCl3, ppm): δ 151.9, 149.6, 139.6, 138.5, 126.3, 124.5, 121.2, 120.9, 120.1, 119.2, 111.0; LRMS: EI m/z 244.1 [M]. Data is consistent with literature values.(384)

N -Methyl-N -phenylpyridin-2-amine, 215

N Me N

215

1 H NMR (500 MHz, CDCl3, ppm): δ 8.23 (ddd, J = 5.0, 2.0, 0.9 Hz, 1H), 7.40 (app. t, J = 8.1 Hz, 2H), 7.34 – 7.27 (m, 3H), 7.24 – 7.19 (m, 1H), 6.61 (ddd, J = 7.0, 5.0, 0.9 Hz, 1H), 6.53 (app. dt, J = 8.6, 1.0 Hz, 1H), 3.48 (s, 3H); 13C

NMR (126 MHz, CDCl3, ppm): δ 159.0, 147.9, 147.0, 136.7, 129.8, 126.5, 125.6, 113.3, 109.3, 38.6; LRMS: EI m/z 183.1 [M−H]+. Data is consistent with literature values.(383)

1-Phenyl-1H -pyrrolo[2,3-b]pyridine, 223

N N

223

Prepared according to general procedure 7 (0.260 mmol scale) from 7-azaindole, with catalytic copper iodide in the ﬁrst step, to aﬀord 223 as the major product. This was isolated as a yellow oil (19.0 mg, 0.0978 mmol, 38% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.39 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (dd,

235 J = 7.8, 1.6 Hz, 1H), 7.80 – 7.74 (m, 2H), 7.56 – 7.50 (m, 3H), 7.37 – 7.31 (m, 1H), 7.14 (dd, J = 7.8, 4.7 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H); 13C NMR (101 MHz,

CDCl3, ppm): δ 147.6, 143.7, 138.6, 129.5, 129.3, 128.1, 126.5, 124.2, 121.7, 116.8, 101.7; LRMS: EI m/z 194.0 [M]. Data is consistent with literature values.(385)

1-([1,10-Biphenyl]-2-yl)-1H -pyrrolo[2,3-b]pyridine, 224

N N

224

Prepared according to general procedure 7 (0.260 mmol scale) from 7-azaindole, with catalytic copper iodide in the ﬁrst step. Isolated as a light brown oil (4.5 mg, 0.017 mmol, 6% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.31 (dd, J = 4.7, 1.6 Hz, 1H), 7.89 (dd, J = 7.8, 1.6 Hz, 1H), 7.66 – 7.62 (m, 1H), 7.58 – 7.47 (m, 3H), 7.18 – 7.11 (m, 3H), 7.10 – 7.00 (m, 3H), 6.88 (d, J = 3.6 Hz, 1H), 6.36 (d, J = 3.6 Hz, 1H); 13C NMR

(101 MHz, CDCl3, ppm): δ 148.5, 143.7, 139.3, 139.0, 135.7, 131.4, 129.9, 128.9, 128.8, 128.5, 128.5, 128.4, 128.3, 127.3, 120.7, 116.4, 100.7; LRMS: EI m/z 269.1 [M−H]. Data is consistent with literature values.(386)

236 3.5. HHDDA experimental

(But-3-yn-1-yloxy)(tert-butyl)dimethylsilane, 270

OTBS 270

Prepared according to the procedure by Liu et al.(298) To solution of 3-butyn-1-ol (4.32 mL, 4.00 g, 57.1 mmol, 1.00 eq.) and imidazole (9.33 g, 137 mmol, 2.40 eq.) in THF (86 mL), tert-butyldimethylsilyl chloride (10.3 g, 68.6 mmol, 1.20 eq.) was added. The reaction mixture was stirred at room temperature for 3 hours, then ﬁltered through a pad of silica, and concentrated under reduced pressure (at room temperature). The resulting crude product was puriﬁed by column chromatography (gradient elution:

100% hexane to 5% Et2O in hexane). The title compound was obtained as a colourless oil (8.87 g, 48.1 mmol, 84% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 3.74 (t, J = 7.2 Hz, 2H), 2.40 (td, J = 7.2, 2.7 Hz, 2H), 1.96 (t, J = 2.7 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR

(100 MHz, CDCl3, ppm): δ 81.7, 69.4, 61.9, 26.0, 23.0, 18.5, −5.1; LRMS: EI m/z t (298) 169.1 [M−CH3], 127.1 [M− Bu]. Data consistent with previous literature reports.

((4-Bromobut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane, 271

Br OTBS 271

Prepared according to the procedure by Hoye et al.(271) A flask was charged with a solution of (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane 270 (5.00 g, 27.1 mmol, 1.00 eq.) and N -bromosuccinimide (5.31 g, 29.8 mmol, 1.10 eq.) in acetone (270 mL). The flask was wrapped in aluminium foil, followed by addition of AgNO3 (0.461 g, 2.71 mmol, 10.0 mol%). The reaction mixture was stirred for 1 hour, then filtered through celite, and concentrated (at room temperature). The crude mixture was purified by column chromatography (gradient elution: 2% to 4% Et2O in hexane), to afford the title

237 compound as a pale yellow oil (6.78 g, 25.7 mmol, 95% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 3.73 (t, J = 7.0 Hz, 2H), 2.42 (t, J = 13 7.0 Hz, 2H), 0.90 (s, 9H), 0.07 (s, 6H); C NMR (100 MHz, CDCl3, ppm): δ 77.7, 61.6, 39.2, 26.0, 24.2, 18.5, −5.2; LRMS: EI m/z 263.1 [M+H]. Data is consistent with previous literature reports.(387)

7-((tert-Butyldimethylsilyl)oxy)hepta-2,4-diyn-1-ol, 272

OTBS 272

Prepared according to the procedure by Hoye et al.(271) To a ﬂask containing freshly ◦ degassed piperidine (13.4 mL) under N2 at 0 C was added ((4-bromobut-3-yn-1- yl)oxy)(tert-butyl)dimethylsilane 271 (3.35 g, 12.7 mmol, 1.00 eq.) and propargyl alcohol (0.890 mL, 0.857 g, 15.3 mmol, 1.20 eq.), followed by CuCl (0.126 g, 1.27 mmol,

10.0 mol%). After 1 hour, the reaction mixture was diluted with sat. aq. NH4Cl

(25 mL), and extracted with Et2O (2 × 15 mL), then EtOAc (15 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4 and concentrated (at room temperature). The crude product was puriﬁed by column chromatography

(eluent: 30% Et2O in hexane), to aﬀord the title compound as a pale yellow oil (2.56 g, 10.8 mmol, 84% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 4.32 (dt, J = 6.3, 1.0 Hz, 2H), 3.74 (t, J = 6.9 Hz, 2H), 2.50 (tt, J = 6.9, 1.0 Hz, 2H), 1.55 (t, J = 6.3 Hz, 1H), 0.89 (s, 9H), 13 0.07 (s, 6H); C NMR (100 MHz, CDCl3, ppm): δ 78.9, 73.9, 70.9, 65.6, 61.4, 51.7, 26.0, 23.9, 18.5, −5.2; LRMS: ESI+ m/z 261.1 [M+Na]+. Data is consistent with previous literature reports.(271) tert-Butyl((7-iodohepta-3,5-diyn-1-yl)oxy)dimethylsilane, 273

OTBS 273

238 Prepared according to the procedure by Hoye et al.(271) 7-((tert-Butyldimethylsil- yl)oxy)hepta-2,4-diyn-1-ol 272 (1.00 g, 4.19 mmol, 1.00 eq.) was dissolved in DCM (20 mL) at 0 ◦C. To this solution was added triphenylphosphine (1.21 g, 4.61 mmol,

1.10 eq.), followed by I2 (1.28 g, 5.03 mmol, 1.20 eq.), then imidazole (0.571 g, 8.39 mmol, 2.00 eq.). The reaction mixture was stirred for 2 hours, then diluted with DCM (20 mL), and washed with sat. aq. Na2S2O3 (25 mL), then brine (25 mL).

The organic extract was dried over Na2SO4 and concentrated. The crude product was puriﬁed by column chromatography (eluent: 15% Et2O in hexane), to aﬀord the title compound as a yellow oil (1.17 g, 3.34 mmol, 80% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 3.76 – 3.71 (m, 4H), 2.49 (tt, J = 7.0, 13 1.2 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 6H); C NMR (100 MHz, CDCl3, ppm): δ 79.9, 72.5, 70.4, 66.0, 61.4, 26.0, 24.0, 18.5, −5.2, −18.5; LRMS: ESI+ m/z 349.1 [M+H]+. Data is consistent with previous literature reports.(271)

Dimethyl 2-(cyanomethyl)malonate, 275

N MeO2C

MeO2C 275

Prepared according to the procedure by Louie et al.(299) To a stirring solution of NaH

(0.720 g, 30.0 mmol, 2.10 eq.) in THF (60 mL) under N2 was added dimethylmalonate (3.43 mL, 3.96 g, 30.0 mmol, 2.10 eq.). The mixture was stirred at room temperature for 1 hour, followed by addition of bromoacetonitrile (1.00 mL, 1.72 g, 14.4 mmol, 1.00 eq.). The reaction mixture was stirred at room temperature for 24 hours, then quenched with sat. aq. NH4Cl (40 mL). The aqueous layer was extracted with Et2O (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), then dried over MgSO4, and concentrated. The crude product was puriﬁed by column chromatography (gradient elution: 20% to 50% EtOAc in PE), to aﬀord the title compound as a yellow solid (2.21 g, 12.9 mmol, 90% yield).

239 1 H NMR (400 MHz, CDCl3, ppm): δ 3.81 (s, 6H), 3.75 (t, J = 7.4 Hz, 1H), 2.93 13 (d, J = 7.4 Hz, 2H); C NMR (100 MHz, CDCl3, ppm): δ 166.9, 116.8, 53.6, 47.9, 17.1; LRMS: ESI+ m/z 194.0 [M+Na]+; IR (cm−1): 2959 (w), 2254 (w), 1733 (s), 1436 (m), 1351 (m) 1281 (m), 1242 (m), 1196 (m) 1160 (m). Data is consistent with previous literature reports.(299)

Dimethyl 2-(7-((tert-butyldimethylsilyl)oxy)hepta-2,4-diyn-1-yl)-2-(cyanomethyl)malonate, 267

15 14 2 1 N 10 MeO2C 3 O 13 15 14 12 13 MeO C Si 2 4 5 6 7 8 9 11 13 11 267

NaH (80.3 mg, 3.34 mmol, 1.00 eq.) was dissolved in dry THF (40 mL) under N2. To this was added a solution of dimethyl 2-(cyanomethyl)malonate 275 (0.572 g, 3.34 mmol, 1.00 eq.) in dry THF (5 mL). After 1 hour at room temperature (or once ef- fervescence had ceased), tert-butyl((7-iodohepta-3,5-diyn-1-yl)oxy)dimethylsilane 273 (1.17 g, 3.34 mmol, 1.00 eq.) was dissolved in dry THF (5 mL) and added to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours, then quenched with sat. aq. NH4Cl (50 mL). The layers were separated, and the aqueous layer extracted with Et2O (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated. The crude product was pu- riﬁed by column chromatography (gradient elution: 0% to 20% EtOAc in hexane) to aﬀord the title compound as a yellow oil (1.11 g, 2.82 mmol, 84% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 3.82 (s, 6H, 6H15), 3.73 (t, J = 7.0 Hz,

2H, 2H10), 3.13 (s, 2H, 2H2), 3.09 (s, 2H, 2H4), 2.46 (t, J = 7.0 Hz, 2H, 2H9), 0.89 13 (s, 9H, 9H13), 0.07 (s, 6H, 6H11); C NMR (100 MHz, CDCl3, ppm): δ 167.6

(C14), 115.9 (C1), 77.0 (C8), 69.8 (C5 or C6), 69.3 (C5 or C6), 65.7 (C7), 61.4 (C10),

55.2 (C3), 54.0 (C15), 26.0 (C13), 24.5 (C4), 23.7 (C9), 22.1 (C2), 18.5 (C12), −5.2 + (C11); Accurate Mass: ESI+ m/z calcd for C20H29NO5NaSi [M+Na] 414.1713, found 414.1722; IR (cm−1): 2955 (w), 2929 (w), 2856 (w), 2261 (w), 1743 (s), 1472 (w), 1463 (w), 1436 (m), 1333 (w), 1294 (m), 1250 (m), 1214 (s), 1104 (s).

240 tert-Butyl (cyanomethyl)(tosyl)carbamate, 277

1 8 7 O 2 N 10 9 6 S N 3 O 8' 7' O O 4 5 277 5 5 A round bottomed flask was charged with boc anhydride (6.55 g, 30.0 mmol, 3.00 eq.), N,N -dimethylamino pyridine (0.611 g, 5.00 mmol, 0.500 eq.), 4-methylbenzene-sulfonamide (1.71 g, 10.0 mmol, 1.00 eq.), THF (60 mL) and triethylamine (1.67 mL, 12.0 mmol, 1.20 eq.). The reaction mixture was stirred at room temperature for 3 hours, followed by addition of K2CO3 (2.76 g, 20.0 mmol, 2.00 eq.), and bromoacetonitrile (1.74 mL, 3.00 g, 25.0 mmol, 2.50 eq.). The reaction was left to stir overnight at room temperature, then quenched with sat. aq. NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (eluent: 9% EtOAc in PE) to afford the title compound as an off-white solid (2.54 g, 8.19 mmol, 82% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 7.89 (app. d, J = 8.5 Hz, 2H, H7 + H70 ),

7.36 (app. d, J = 8.5 Hz, 2H, H8 + H80 ), 4.73 (s, 2H, 2H2), 2.46 (s, 3H, 3H10), 1.38 13 (s, 9H, 9H5); C NMR (126 MHz, CDCl3, ppm): δ 149.6 (C3), 145.6 (C9),

135.5 (C6), 129.8 (C8 + C80 ), 128.5 (C7 + C70 ), 115.3 (C1), 86.7 (C4), 33.7 (C2), 27.9 + (C5), 21.9 (C10); Accurate Mass: ESI+ m/z calcd for C14H18N2O4NaS [M+Na] 333.0885, found 333.0883; m.p. : 46 – 49 ◦C; IR (cm−1): 2981 (w), 1733 (s), 1597 (w), 1362 (s), 1309 (m), 1284 (m), 1247 (m), 1168 (s), 1142 (s).

N -(Cyanomethyl)-4-methylbenzenesulfonamide, 278

N Ts N H 278 tert-Butyl (cyanomethyl)(tosyl)carbamate 277 (1.00 g, 3.22 mmol) was dissolved in DCM (29 mL), and TFA (29 mL), and left to stir for 3 hours. The reaction mixture was concentrated to remove the solvent and TFA. The resulting crude compound was

241 triturated with CHCl3, to obtain the title compound 278 as a white solid. The filtrate was concentrated and triturated again. The filtrate was then concentrated and purified by column chromatography (gradient elution: 15% to 35% EtOAc in hexane). The title compound was isolated as a white crystalline solid (321 mg, 1.53 mmol, 47% yield).

1 H NMR (400 MHz, DMSO-d6, ppm): δ 8.47 (t, J = 6.0 Hz, 1H), 7.72 (app. d, J = 8.2 Hz, 2H), 7.43 (app. d, J = 8.2 Hz, 2H), 4.07 (d, J = 6.0 Hz, 2H), 2.39 (s, 3H); 13 C NMR (100 MHz, DMSO-d6, ppm): δ 143.2, 136.4, 129.6, 126.5, 116.5, 30.1, 20.8; LRMS: ESI+ m/z 233.1 [M+Na]+ . Data is consistent with previous literature reports.(388)

N -(7-((tert-Butyldimethylsilyl)oxy)hepta-2,4-diyn-1-yl)-N -(cyanomethyl)- 4-methylbenzenesulfonamide, 268

2 1 15 14 O N 17 16 13 S N 9 O 12 Si 11 12 15' 14' O 8 3 4 5 6 7 10 12 10 268

Synthesised according to a procedure by Hoye et al.(271)N -(Cyanomethyl)-4-methylbenzenesulfonamide 278 (210 mg, 1.00 mmol, 1.14 eq.) was dissolved in dry DMF

(3.0 mL) under N2. To this, K2CO3 (252 mg, 1.82 mmol, 2.07 eq.), and a solution of tert-butyl((7-iodohepta-3,5-diyn-1-yl)oxy)dimethylsilane 273 (304 mg, 0.873 mmol, 1.00 eq.) in dry DMF (1.6 mL) were added. The reaction mixture was left to stir at room temperature overnight, then diluted with EtOAc (15 mL), and washed with

H2O (5 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were washed with aq. LiCl (10% w/w) (4 × 20 mL), then dried over

MgSO4 and concentrated. The crude product was puriﬁed by column chromatography (gradient elution: 10% to 20% EtOAc in PE), to furnish the title compound as a brown oil (266 mg, 0.618 mmol, 71% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 7.71 (app. d, J = 8.2 Hz, 2H, H14 + H140 ),

242 7.37 (app. d, J = 8.0 Hz, 2H, H15 + H150 ), 4.29 (s, 2H, 2H2), 4.19 (s, 2H, 2H3), 3.72

(t, J = 7.0 Hz, 2H, 2H9), 2.46 (t, J = 7.0 Hz, 2H, 2H8), 2.45 (s, 3H, 3H17), 0.89 13 (s, 9H, 9H12), 0.07 (s, 6H, 6H10); C NMR (126 MHz, CDCl3, ppm): δ 145.3

(C16), 133.8 (C13), 130.3 (C15 + C150 ), 127.9 (C14 + C140 ), 113.4 (C1), 79.2 (C7), 72.4

(C4), 66.8 (C5 or C6), 65.1 (C5 or C6), 61.3 (C9), 38.4 (C3), 35.1 (C2), 26.0 (C12),

23.8 (C8), 21.8 (C17), 18.4 (C11), −5.2 (C10); Accurate Mass: ESI+ m/z calcd for + −1 C22H30N2O3SNaSi [M+Na] 453.1644, found 453.1652; IR (cm ): 2954 (w), 2928 (w), 2856 (w), 2261 (w), 1597 (w), 1472 (w), 1359 (m), 1252 (w), 1165 (s), 1093 (s).

243 3.6. Benzyne–Smiles experimental

3.6.1. Synthesis of starting materials

General Procedure 8: Preparation of sulfonate esters from phenol derivatives

A solution of phenol derivative (1.0 eq.) in DCM (0.05 M) under N2 was cooled to 0 ◦C. Pyridine (1.0 eq.) was added dropwise to the reaction mixture, and the mixture was stirred for 5 minutes. Aryl sulfonyl chloride (1.1 eq.) was added to the reaction mixture, and the reaction mixture was stirred for 20 minutes at 0 ◦C, then allowed to warm to room temperature. After 24 hours, the reaction mixture was diluted with

DCM, washed with H2O then brine, dried over MgSO4 and concentrated. The resulting crude was puriﬁed by column chromatography to aﬀord the desired product.

2-Bromo-6-(trimethylsilyl)phenol, 339

OH Br TMS

339

Prepared according to a procedure by Ishihara and co-workers.(352) To a stirring solution of 2,6-dibromophenol 338 (1.51 g, 6.00 mmol, 1.00 eq.) and Et3N (0.770 mL, 5.52 mmol, 0.92 eq.) in THF (20 mL) at room temperature was added TMSCl (1.24 mL, 9.77 mmol, 1.63 eq.). After 2 hours, the reaction mixture was ﬁltered 1 through celite with Et2O, and the resulting solution was concentrated in vacuo. H NMR analysis showed there to be remaining starting material present, so the residue was dissolved in THF, and Et3N (1.50 eq. w.r.t. remaining starting material) and TMSCl (1.50 eq. w.r.t. remaining starting material) were added. After 1 hour, the reaction mixture was worked up as previously, to aﬀord the crude (2,6-dibromophenoxy)trimethylsilane 373 in a 1.00:0.14 ratio with 2,6-dibromophenol (1.84 g), which

244 was used in the next step without further puriﬁcation. To a stirring mixture of crude (2,6-dibromophenoxy)trimethylsilane 373 (1.84 g, <5.68 mmol, 1.00 eq.) in THF (18.9 mL) at −78 ◦C, nBuLi (1.62 M in hexanes, 3.55 mL, 5.68 mmol, 1.00 eq.) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight, then quenched with sat. aq. NH4Cl. The aqueous layers were extracted twice with Et2O. The combined organic extracts were washed with brine, dried over

MgSO4 and concentrated to afford the crude product as a grey oil. Purification by column chromatography (eluent: 1% to 5% EtOAc in hexane) afforded the product as a colourless oil (691 mg, 2.82 mmol, 47% yield over 2 steps from 2,6-dibromophenol 338).

1 H NMR (500 MHz, CDCl3, ppm): δ 7.46 (dd, J = 7.9, 1.6 Hz, 1H), 7.29 (dd, J = 7.2, 1.6 Hz, 1H), 6.79 (dd, J = 7.9, 7.2 Hz, 1H), 5.70 (s, 1H), 0.31 (s, 9H); 13C NMR

(126 MHz, CDCl3, ppm): δ 156.2, 134.7, 133.1, 127.2, 121.7, 110.6, −1.0; LRMS: ESI− m/z 243.0, 245.0 [M−H]−. Data is consistent with literature values.(389)

2-Bromo-6-(trimethylsilyl)phenyl triﬂuoromethanesulfonate, 340

OTf Br TMS

340

Prepared according to the procedure by Danishefsky and co-workers.(353) DIPEA (0.98 mL, 5.64 mmol, 2.00 eq.) was added to a solution of 2-bromo-6-(trimethylsilyl)phenol 339 (691 mg, 2.82 mmol, 1.00 eq.) in DCM (2.0 mL) at room temperature. The reaction mixture was cooled to 0 ◦C, and triﬂic anhydride (0.71 mL, 1.19 g, 4.23 mmol, 1.50 eq.) was slowly added. The reaction was allowed to warm to room temperature overnight. The reaction mixture was then poured into Et2O, and the organic phase was washed with sat. aq. NH4Cl, then sat. aq. NaHCO3, then brine. The organic phase was then dried over MgSO4 and concentrated. The resulting crude was puriﬁed by column chromatography (eluent: 100% hexane – 1% EtOAc in hexane) to

245 aﬀord the desired product as a colourless oil (489 mg, 1.30 mmol, 46% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.67 (dd, J = 7.8, 1.7 Hz, 1H), 7.51 (dd, J = 7.4, 1.7 Hz, 1H), 7.23 (dd, J = 7.8, 7.4 Hz, 1H), 0.40 (s, 9H); 13C NMR (101 MHz,

CDCl3, ppm): δ 148.9, 137.9, 136.0, 135.9, 129.2, 118.8 (app. d, J = 321.0 Hz), 19 116.7, 0.2; F NMR (376 MHz, CDCl3, ppm): δ −71.64; LRMS: EI m/z 360.9 (389) [M−CH3]. Data is consistent with literature values.

2-(Benzyloxy)phenyl isopropylcarbamate, 353

OBn H O N

353

Prepared according to a procedure by Sarah Bronner and co-workers.(350) To a solution of 2-benzyloxyphenol 352 (1.14 mL, 1.30 g, 6.50 mmol, 1.00 eq.) in dry DCM under

N2 was added isopropyl isocyanate (1.60 mL, 1.36 g, 16.0 mmol, 2.46 eq.), and Et3N (0.362 mL, 263 mg, 2.60 mmol, 0.400 eq.). The reaction mixture was stirred at 35 ◦C for 3.5 hours, then cooled to room temperature, and the solvent removed in vacuo.

The resulting solid was recrystallised from Et2O, to aﬀord the desired product as a white solid (average 69% yield over 3 reactions).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.47 – 7.40 (m, 2H), 7.39 – 7.28 (m, 3H), 7.17 – 7.08 (m, 2H), 7.00 (dd, J = 8.2, 1.5 Hz, 1H), 6.95 (app. td, J = 7.7, 1.5 Hz, 1H), 5.09 (s, 2H), 4.94 – 4.81 (m, 1H), 3.97 – 3.80 (m, 1H), 1.18 (d, J = 6.6 Hz, 6H); 13 C NMR (101 MHz, CDCl3, ppm): δ 153.6, 151.1, 140.7, 137.0, 128.5, 128.0, 127.4, 126.4, 123.4, 121.3, 114.0, 70.8, 43.6, 23.0; LRMS: ESI+ m/z 308.2 [M+Na]+. Data is consistent with literature values.(350)

246 2-(Benzyloxy)-6-(trimethylsilyl)phenyl isopropylcarbamate, 354

OBn H O N

O TMS 354

Prepared according to a procedure by Sarah Bronner and co-workers.(350) A solution of 2-(benzyloxy)phenyl isopropylcarbamate 353 (0.605 g, 2.12 mmol, 1.00 eq.) and

TMEDA (0.449 mL, 349 mg, 3.00 mmol, 1.41 eq.) in a 3:1 mixture of dry Et2O (25.1 mL) and dry THF (8.4 mL) was cooled to 0 ◦C. To this, a solution of TMSOTf (0.422 mL, 518 mg, 2.33 mmol, 1.10 eq.) in dry pentane (1.9 mL) was added dropwise. The reaction mixture was stirred at 0 ◦C for ﬁve minutes, then allowed to warm to room temperature over 30 minutes. Once at room temperature, TMEDA (0.957 mL, 744 mg, 6.40 mmol, 3.02 eq.) was added to the reaction mixture, as well as dry THF (16.5 mL). The reaction mixture was cooled to −78 ◦C, and nBuLi (1.62 M solution in hexane, 6.40 mmol, 3.95 mL, 3.02 eq.) was added dropwise by syringe pump over 20 minutes. The reaction mixture was stirred for a further 3 hours at −78 ◦C, then TMSCl (1.90 mL, 1.63 g, 15.0 mmol, 7.08 eq.) was added dropwise by syringe pump over 30 minutes, followed by stirring at −78 ◦C for 1 hour. The reaction mixture was slowly quenched with 2 M aq. NaHSO4 solution (20 mL), then allowed to warm to room temperature over 30 minutes with vigorous stirring. The layers were separated, and the aq. layer was extracted with Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated, and puriﬁed by column chromatography (eluent:

10% to 30% Et2O in hexane) to aﬀord the desired product as a white solid (average 33% yield over 7 reactions).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.47 – 7.42 (m, 2H), 7.38 – 7.27 (m, 3H), 7.15 (t, J = 7.7 Hz, 1H), 7.06 – 7.00 (m, 2H), 5.07 (s, 2H), 4.82 (d, J = 8.0 Hz, 1H), 3.94 – 3.82 (m, 1H), 1.16, (d, J = 6.5 Hz, 6H), 0.28 (s, 9H); 13C NMR (101 MHz,

CDCl3, ppm): δ 153.4, 150.7, 145.0, 137.2, 133.9, 128.5, 127.9, 127.5, 126.5, 126.2, 115.0, 70.8, 43.5, 23.1, −0.8; LRMS: ESI+ m/z 380.2 [M+Na]+. Data is consistent

247 with literature values.(350)

2-(Benzyloxy)-6-(trimethylsilyl)phenyl triﬂuoromethanesulfonate, 355

OBn OTf

TMS 355

Prepared according to a procedure by Sarah Bronner and co-workers.(350) A solution of 2-(benzyloxy)-6-(trimethylsilyl)phenyl isopropylcarbamate 354 (1.06 g, 2.96 mmol, 1.00 eq.) in dry MeCN (27.1 mL) was split equally between two large microwave vials under N2. To each was added DBU (1.11 mL, 1.13 g, 7.40 mmol, 5.00 eq.), followed by Et2NH (0.260 mL, 184 mg, 2.52 mmol, 1.70 eq.). The reaction mixture was heated to 40 ◦C in an oil bath for 50 minutes, then cooled to room temperature. To each vial was added N -(4-tert-butylphenyl)bis(trifluoromethanesulfonimide) (1.84 g, 4.44 mmol, 3.00 eq.). The reaction mixtures were stirred briefly to homogenise them, then microwaved for 30 minutes at 100 ◦C. The reaction mixtures were combined, and passed through a silica plug, eluting with iPrOAc, and concentrated. The combined reaction mixtures were then purified by column chromatography (100% hexane – 10%

Et2O in hexane) to aﬀord the desired product as a pale yellow oil (1.16 g) with small impurities. This was used without further puriﬁcation.

1 H NMR (400 MHz, CDCl3, ppm): δ 7.43 – 7.28 (m, 5H), 7.22 (dd, J = 8.1, 7.4 Hz, 1H), 7.06 (dd, J = 7.4, 1.6 Hz, 1H), 6.99 (dd, J = 8.1, 1.6 Hz, 1H), 5.17 (s, 2H), 13 0.39 (s, 9H); C NMR (101 MHz, CDCl3, ppm): δ 149.6, 143.2, 136.0, 135.5, 128.8, 128.6, 128.3, 127.5, 127.2, 118.9 (app. d, J = 321.5 Hz), 115.5, 71.0, −0.3; 19F + NMR (471 MHz, CDCl3, ppm): δ −71.03; LRMS: ESI+ m/z 427.0 [M+Na] .

2-Hydroxy-6-(trimethylsilyl)phenyl triﬂuoromethanesulfonate, 341

OH OTf

TMS 341

248 Prepared according to a procedure by Sarah Bronner and co-workers.(350) A sample of crude 2-(benzyloxy)-6-(trimethylsilyl)phenyl trifluoromethanesulfonate, 355 (753 mg, i <1.86 mmol, 1.00 eq.) was dissolved in PrOAc (16.4 mL). Under N2, Degussa type Pd/C (10% Pd by mass, 29.7 mg, 1.5 mol%) was added, and the reaction was put under an atmosphere of H2. The reaction mixture was stirred at room temperature for 75 minutes, then filtered through celite and eluted using iPrOAc. The filtrate was concentrated, and purified immediately by column chromatography to afford the title product as an orange oil (59.8 mg, 0.190 mmol, 10% yield) and unreacted starting material 355 (627 mg, 1.55 mmol, 83% recovery). The unreacted starting material was then resubmitted to the reaction conditions, with iPrOAc (13.6 mL) and Pd/C (24.7 mg), with a reaction time of 16.5 hours. Following work-up, and column chromatography (eluent: 0% to 20% Et2O in hexane), the product 341 was obtained as a yellow oil (410 mg) in a 1.00 : 0.31 mixture with side product 3-(trimethylsilyl)phenol 356. This was used without further purification.

1 H NMR (400 MHz, CDCl3, ppm): δ 7.24 (dd, J = 8.0, 7.4 Hz, 1H), 7.09 (dd, J = 7.4, 1.6 Hz, 1H), 7.02 (dd, J = 8.0, 1.6 Hz, 1H), 5.38 (br s, 1H), 0.37 (s, 9H); 13C

NMR (101 MHz, CDCl3, ppm): δ 146.8, 141.5, 135.9, 129.1, 128.2, 120.0, 118.8 19 (app. d, J = 320.8 Hz), −0.2; F NMR (376 MHz, CDCl3, ppm): δ −71.70; LRMS: ESI− m/z 312.9 [M−H]−. Data is consistent with literature values.(350)

2-(((Triﬂuoromethyl)sulfonyl)oxy)-3-(trimethylsilyl)phenyl 4-nitrobenzenesulfonate, 329

9 O N 10 2 8 7 O 9′ S 8′ O O 11 1 6 OTf 2

3 5 4 TMS 329

Prepared according to general procedure 8 from impure 2-hydroxy-6-(trimethylsilyl)phenyl triﬂuoromethanesulfonate 341 (contaminated in a 1.00 : 0.31 ratio with 3-(trimethylsil-

249 yl)phenol 356) (232 mg, 0.829 mmol (combined mmol of 341 and 356), 1.00 eq.), to aﬀord the desired product 329 as an oﬀ-white solid (261 mg, 0.523 mmol, 48% yield over 3 steps from 354).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.37 (dt, J = 8.8, 2.4, 1.7 Hz, 2H, H9 +

H90 ), 8.02 (dt, J = 8.8, 2.4, 2.0 Hz, 2H, H8 + H80 ), 7.50 – 7.37 (m, 3H, H2 + H3 + H4), 13 0.30 (s, 9H, Si(CH3)3); C NMR (126 MHz, CDCl3, ppm): δ 151.4 (C10), 144.2

(C1 or C6), 140.4 (C1 or C6), 140.4 (C7), 137.9 (C5), 135.3 (C2 or C3 or C4), 130.3 (C8

+ C80 ), 129.3 (C2 or C3 or C4), 125.2 (C2 or C3 or C4), 124.4 (C9 + C90 ), 118.5 (q, J = 19 320.8 Hz, CF3), −0.2 (Si(CH3)3); F NMR (376 MHz, CDCl3, ppm): δ −72.40; + Accurate Mass: ESI+ m/z calcd for C16H16O8NF3S2SiK [M+K] 537.9670, found 537.9673; m.p. : 71 – 77 ◦C; IR (thin ﬁlm, cm−1): 2982 (w), 1537 (s), 1350 (m), 1241 (m).

3-Bromo-2-methoxybenzaldehyde, 345

OMe Br 345

Prepared according to a literature procedure by Njardarson.(359) To a microwave vial equipped with a stirrer bar, 3-bromo-2-hydroxybenzaldehyde (704 mg, 3.50 mmol,

1.00 eq.) and K2CO3 (484 mg, 3.50 mmol, 1.00 eq.) under N2 atmosphere was added DMF (7.0 mL) and MeI (0.44 mL, 994 mg, 7.00 mmol, 2.00 eq.). The reaction mixture was heated to 50 ◦C overnight. The reaction mixture was then cooled, diluted with EtOAc (60 mL), and washed with water (30 mL), then brine (3 × 30 mL), and 10% aq. LiCl solution (30 mL). The organic layer was dried over Na2SO4, and the solvent removed in vacuo to aﬀord the desired product as a yellow solid (724 mg, 3.37 mmol, 96% yield). This was used without further puriﬁcation.

1 H NMR (400 MHz, CDCl3, ppm): δ 10.36 (d, J = 0.8 Hz, 1H), 7.81 (app. dq,

250 J = 7.8, 1.6 Hz, 2H), 7.14 (app. td, J = 7.8, 0.9 Hz, 1H), 4.00 (s, 3H); 13C NMR

(101 MHz, CDCl3, ppm): δ 189.3, 160.3, 139.7, 131.1, 128.0, 125.9, 118.4, 63.7; LRMS: ESI+ m/z 236.9 [M+Na]+. Data is consistent with literature values.(390)

3-Bromo-2-methoxyphenol, 347

OMe Br 347

Prepared according to a procedure by Njardarson.(359) To a round bottomed ﬂask under N2, containing a stirrer bar and a solution of 3-bromo-2-methoxybenzaldehyde 345 (362 mg, 1.68 mmol, 1.00 eq.) in DCM (6.7 mL) was added mCPBA (436 mg, 2.52 mmol, 1.50 eq., 89% pure2). The mixture was stirred at room temperature overnight, then diluted with DCM, and washed with a 1:1 mixture of sat. aq. NaHCO3 and sat. aq. Na2S2O3 (3 × 5 mL). The organic layer was then washed with H2O

(5 mL) and brine (5 mL), and dried over Na2SO4, before removal of the solvent in vacuo to afford crude 3-bromo-2-methoxyphenyl formate 346 as an off-white solid. This was used immediately for the next step without purification. The crude 3-bromo-

2-methoxyphenyl formate 346 (61.68 mmol, 1.00 eq.) was dissolved in MeOH (6.7 mL) µ under N2. To this was added Et3N (23.4 L, 17.0 mg, 0.168 mmol, 0.100 eq.) dropwise. The reaction mixture was stirred at room temperature overnight, before removal of the solvent in vacuo. The crude product was puriﬁed by column chromatography (2% to 10% EtOAc in hexane) to aﬀord pure 3-bromo-2-methoxyphenol 347 as a pale yellow oil (181 mg, 0.891 mmol, 53% over 2 steps).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.06 (dd, J = 7.1, 2.5 Hz, 1H), 6.94 – 13 6.86 (m, 2H), 5.71 (s, 1H), 3.91 (s, 3H); C NMR (101 MHz, CDCl3, ppm): δ 150.2, 144.6, 126.1, 124.8, 116.0, 115.1, 61.3; LRMS: ESI− m/z 200.9 [M−H]−. Data is consistent with literature values.(359)

2Recrystallised from DCM. Purity determined by iodometric titration (381)

251 3-Bromo-2-methoxyphenyl 4-nitrobenzenesulfonate, 348

9 O N 10 2 8 7 O 9′ S 8′ O O 11 1 6 OMe 2

3 5 4 Br 348

An oven dried ﬂask was equipped with a stirrer bar and NaH (60% purity, 243 mg,

6.09 mmol, 4.12 eq.) under a N2 atmosphere. To this was added a solution of 3-bromo- 2-methoxyphenol 347 (300 mg, 1.48 mmol, 1.00 eq.) in dry THF (24.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. 4-Nitrobenzenesulfonyl chloride (360 mg, 1.63 mmol, 1.10 eq.) was added under a flow of N2, and the reaction mixture was stirred at room temperature for 1 hour, before pouring it into Et2O, and washing with H2O, then brine. The organic layer was dried over MgSO4, and concentrated to afford the crude product as a yellow solid. The crude was purified by column chromatography (eluent 0% to 100% EtOAc in hexane) to afford the desired product as a yellow solid (494 mg, 1.27 mmol, 86% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.39 (d, J = 8.6 Hz, 2H, H9 + H90 ), 8.10

(d, J = 8.6 Hz, 2H, H8 + H80 ), 7.49 (dd, J = 8.3, 1.3 Hz, 1H, H2 or H4), 7.24 (dd,

J = 8.3, 1.3 Hz, 1H, H2 or H4), 7.02 (t, J = 8.3 Hz, 1H, H3), 3.69 (s, 3H, 3H11); 13 C NMR (101 MHz, CDCl3, ppm): δ 151.2 (C10), 150.0 (C6), 143.3 (C1), 141.6

(C7), 132.7 (C2 or C4), 129.9 (C8 + C80 ), 125.5 (C3), 124.4 (C9 + C90 ), 123.6 (C2 or

C4), 118.6 (C5), 61.4 (C11); Accurate Mass: APCI+ m/z calcd for C13H11BrNO6S [M+H]+ 387.9485, found 387.9483; m.p. : 87 – 98 ◦C; IR (thin ﬁlm, cm−1): 3108 (w), 1533 (s), 1473 (m), 1386 (m), 1350 (m), 1260 (m), 1191 (s).

252 3-Bromo-2-hydroxyphenyl 4-nitrobenzenesulfonate, 349

9 O N 10 2 8 7 O 9′ S 8′ O O 1 6 OH 2

3 5 4 Br 349

3-Bromo-2-methoxyphenyl 4-nitrobenzenesulfonate 348 (493 mg, 1.27 mmol, 1.00 eq.) ◦ was dissolved in dry DCM (7.04 mL) under N2, and cooled to 0 C. BBr3 (1 M solution in DCM, 1.65 mL, 1.65 mmol, 1.30 eq.) was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight, and monitored by TLC. As the reaction was incomplete, a further 0.70 eq. (0.889 mmol, 0.889 mL) BBr3 solution was added. The reaction mixture was left stirring overnight, before slow addition of

10% aq. NaHCO3 (4.7 mL). The reaction mixture was stirred for 10 minutes, then extracted with DCM (3 × 15 mL). The organic extracts were washed with brine, dried over Na2SO4, and concentrated. The product was puriﬁed by column chromatography (eluent: 2% to 20% EtOAc in hexane) to aﬀord the desired product as a pale yellow solid (436 mg, 1.16 mmol, 91% yield). Starting material 348 (23.6 mg, 5%) was also recovered.

1 H NMR (400 MHz, CDCl3, ppm): δ 8.39 (app. dt, J = 8.9, 2.2 Hz, 2H, H9 +

H90 ), 8.14 (app. dt, J = 8.8, 2.2 Hz, 2H, H8 + H80 ), 7.42 (dd, J = 8.2, 1.4 Hz, 1H, H2 or H4), 7.13 (dd, J = 8.2, 1.4 Hz, 1H, H2 or H4), 6.82 (app. t, J = 8.2 Hz, 1H, H3), 13 5.54 (s, 1H, OH); C NMR (101 MHz, CDCl3, ppm): δ 151.3 (C10), 145.7 (C6),

141.3 (C7), 136.8 (C1), 131.6 (C2 or C4), 130.2 (C8 + C80 ), 124.4 (C9 + C90 ), 123.7 (C2 or C4), 121.6 (C3), 111.8 (C5); Accurate Mass: ESI− m/z calcd for C12H7O6NBrS [M−H]− 371.9181, found 371.9172; m.p. : 105 – 106 ◦C; IR (thin ﬁlm, cm−1): 3460 (br, OH), 3111 (w), 1532 (s), 1350 (m), 1201 (s), 1180 (s).

253 3-Bromo-2-(((triﬂuoromethyl)sulfonyl)oxy)phenyl 4-nitrobenzenesulfonate, 351

9 O N 10 2 8 7 O 9′ S 8′ O O 11 1 6 OSO CF 2 2 3

3 5 4 Br 351

To an oven dried microwave vial under N2 was added a solution of 3-bromo-2-hydroxyphenyl 4-nitrobenzenesulfonate 349 (200 mg, 0.535 mmol, 1.00 eq.) in dry THF (4.3 mL). The reaction mixture was cooled to 0 ◦C, and NaH (60% purity, 23.5 mg, 0.588 mmol, 1.10 eq.) was added. After 10 minutes stirring at 0 ◦C, TMSCl (81.5 µL, 69.7 mg, 0.642 mmol, 1.20 eq.) was added slowly. The reaction mixture was stirred at 0 ◦C for a further 10 minutes before cooling to −78 ◦C. nBuLi (1.60 M in hexanes, 0.401 mL, 0.642 mmol, 1.20 eq.) was added dropwise, and after stirring at −78 ◦C for

10 minutes, H2O (0.2 mL) and aq. NaHCO3 (5%, 4 mL) were added. The reaction mixture was warmed to room temperature, extracted twice with Et2O, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dry DCM (1.2 mL) under ◦ µ N2, and cooled to 0 C. Pyridine (86.0 L 84.6 mg, 1.07 mmol, 2.00 eq.) was added, followed by slow addition of triflic anhydride (180 µL, 302 mg, 1.07 mmol, 2.0 eq.). The reaction mixture was allowed to warm to room temperature whilst stirring overnight, then poured into Et2O. The organic phase was washed with sat. aq. NH4Cl, then sat. aq. NaHCO3 then brine. The organic phase was dried over Na2SO4 and concentrated. Purification of the residue by column chromatography (eluent: 0% to 20% EtOAc in hexane) afford the title compound as an orange oil (142 mg, 0.281 mmol, 53% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 8.43 (app. d, J = 7.9 Hz, 2H, H9 + H90 ),

8.13 (app. d, J = 7.9 Hz, 2H, H8 + H80 ), 7.64 (d, J = 8.3 Hz, 1H, H2 or H4), 7.50 (d, J 13 = 8.5 Hz, 1H, H2 or H4), 7.32 (app. t, J = 8.3 Hz, 1H, H3); C NMR (126 MHz,

CDCl3, ppm): δ 151.6 (C10), 141.9 (C1 or C6), 140.2 (C7), 139.4 (C1 or C6), 133.2

254 (C2 or C4), 130.4 (C8 + C80 ), 129.8 (C3), 124.6 (C9 + C90 ), 123.5 (C2 or C4), 117.8 13 (C5); C NMR (126 MHz, CDCl3, ppm): δ −72.4; Accurate Mass: ESI− m/z − −1 calcd for C12H7O6NBrS [M−Tf] 371.9183, found 371.9186; IR (neat, cm ): 3114 (w), 1609 (w), 1583 (w), 1534 (s), 1450 (m), 1430 (s), 1384 (s), 1347 (m), 1211 (s), 1190 (s), 1131 (s).

2-(Trimethylsilyl)-3-(trimethylsilyloxy)phenol, 359

OH OTMS OTMS HMDS, THF, rt n Br Br BuLi, THF, -78 °C TMS overnight OH OTMS OH 357 358 359

Prepared according to a procedure by Hosoya and co-workers.(360) A round bottomed flask was charged with 2-bromoresorcinol 357 (3.18 g, 16.8 mmol, 1.00 eq.) and a stirrer bar, and evacuated/backfilled with N2 × 3. To this was added dry THF (6.7 mL), followed by HMDS (10.6 mL, 8.13 g, 50.4 mmol, 3.00 eq.). The reaction mixture was left stirring at room temperature overnight. The reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in dry THF (34 mL) under N2, and cooled to −78 ◦C. To this was added nBuLi (1.60 M in hexanes, 11.6 mL, 18.5 mmol, 1.10 eq.) dropwise. The reaction mixture was stirred for 1.5 hours at −78 ◦C, then sat. aq. NH4Cl (35 mL) was added. The layers were separated, and the aqueous layer was extracted with DCM (25 mL × 2). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated in vacuo. The resulting crude product was purified by column chromatography (100 g column) (eluent: 3% to 4% EtOAc in hexane) to afford pure 2-(trimethylsilyl)-3-(trimethylsilyloxy)phenol 359 as a white solid (2.98 g, 11.7 mmol, 70% yield).

1 H NMR (500 MHz, CDCl3, ppm): δ 7.08 (t, J = 8.1 Hz, 1H), 6.35 (ddd, J = 8.1, 5.2, 0.8 Hz, 2H), 5.02 (s, 1H), 0.35 (s, 9H), 0.32 (s, 9H); 13C NMR (126 MHz,

CDCl3, ppm): δ 161.9, 161.7, 131.3, 114.0, 109.7, 108.5, 1.4, 0.8.; LRMS: ESI− m/z 253.1 [M−H]−. Data is consistent with literature values.(360)

255 3-Hydroxy-2-(trimethylsilyl)phenyl triﬂate, 361

OTMS OTMS OH Tf O, iPr NEt 1.0 M HCl TMS 2 2 TMS TMS DCM, –78 °C THF, rt OH 20 min OTf 15 min OTf 359 360 361

Prepared according to a procedure by Hosoya and co-workers.(360) To a stirring solution of 2-(trimethylsilyl)-3-(trimethylsilyloxy)phenol 359 (2.98 g, 11.7 mmol, 1.00 eq.) i in dry DCM under N2 was added Pr2NEt (3.06 mL, 2.27 g, 17.6 mmol, 1.50 eq.). The reaction mixture was cooled to −78 ◦C, and triflic anyhydride (2.96 mL, 4.96 g, 17.6 mmol, 1.50 eq.) was added dropwise. The reaction mixture was stirred for 20 ◦ minutes at −78 C, then sat. aq. NaHCO3 (35 mL) was added, and the mixture was extracted with DCM (25 mL × 3). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated to give crude 2-(trimethylsilyl)-3- ((trimethylsilyl)oxy)phenyl triflate 360, which was used without further purification.

1.0 M aq. HCl (11.7 mL, 11.7 mmol, 1.00 eq.) was added to a stirring solution of

2-(trimethylsilyl)-3-((trimethylsilyl)oxy)phenyl triflate 360 (611.7 mmol, 1.00 eq.) in THF (11.7 mL). After 15 minutes at room temperature, the reaction was quenched with sat. aq. NaHCO3 (7 mL). The mixture was extracted with EtOAc (25 mL × 3), and the combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography (eluent: 0% to 10% EtOAc in hexane) to afford the 3-hydroxy-2-(trimethylsilyl)phenyl triflate, 361 as a yellow oil (1.86 g, 5.90 mmol, 50% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 7.30 – 7.22 (m, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 8.0, 0.8 Hz, 1H), 5.23 (s, 1H), 0.42 (s, 9H); 13C NMR (101 MHz,

CDCl3, ppm): δ 161.8, 155.3, 131.6, 118.7 (q, J = 321.0 Hz), 118.6, 114.8, 112.7, 19 0.9; F NMR (376 MHz, CDCl3, ppm): δ −73.0; LRMS: ESI− m/z 627.1

256 [2M−H]−. Data is consistent with literature values.(360)

3-(((Triﬂuoromethyl)sulfonyl)oxy)-2-(trimethylsilyl)phenyl 4-nitrobenzenesulfonate, 330

9 O N 10 2 8 7 O 9′ S 8′ O O 1 6 TMS 2

3 11 5 4 OTf 330

A stirring solution of 3-hydroxy-2-(trimethylsilyl)phenyl triflate, 361 (1.04 g, 3.31 mmol, 1.00 eq.) in dry DCM (61 mL) was cooled to 0 ◦C. To this was added DIPA (0.696 mL, 502 mg, 4.96 mmol, 1.50 eq.). After five minutes at 0 ◦C, 4-nitrobenzenesulfonyl chloride (807 mg, 3.64 mmol, 1.10 eq.) was added. The reaction mixture was stirred for a further 20 minutes at 0 ◦C, before being allowed to warm to room temperature overnight. After 20 hours, sat. aq. NH4Cl was added to the reaction mixture. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The desired product 330 was obtained as a pale yellow solid (1.61 g, 3.22 mmol, 97% yield), without need for further purification.

1 H NMR (500 MHz, CDCl3, ppm): δ 8.44 (app. dt, J = 8.7, 1.8 Hz, 2H, H9 +

H90 ), 8.12 (app. dt, J = 8.7, 1.8 Hz, 2H, H8 + H80 ), 7.39 (t, J = 8.3 Hz, 1H, H3),

7.31 (d, J = 8.3 Hz, 1H, H2 or H4), 7.05 (d, J = 8.3 Hz, 1H, H2 or H4), 0.36 (s, 9H, 13 Si(CH3)3); C NMR (126 MHz, CDCl3, ppm): δ 155.1 (C1 or C5), 154.8 (C1 or

C5), 151.3 (C10), 141.6 (C7), 131.8 (C3), 130.0 (C8 + C80 ), 127.0 (C6), 124.7 (C9 + C90 ), 19 120.2 (C2 or C4), 119.0 (C2 or C4), 118.6 (q, J = 320.3 Hz, C11), 0.9 (Si(CH3)3); F + NMR (471 MHz, CDCl3, ppm): δ −73.25; LRMS: ESI+ m/z 522.0 [M+Na] , + − 537.9 [M+K] ; Accurate Mass: APCI− m/z calcd for C13H7F3NO8S2 [M − SiMe3] 425.9576, found 425.9571; m.p. : 113 – 116 ◦C; IR (thin ﬁlm, cm−1): 2981 (w),

257 1596 (w), 1537 (m), 1350 (m), 1212 (s).

Phenyl 4-nitrobenzenesulfonate, 371

NO2 O S O O

371

Prepared according to general procedure 8 from phenol (47.1 mg, 0.500 mmol, 1.00 eq.) and 4-nitrobenzenesulfonyl chloride (122 mg, 0.550 mmol, 1.10 eq.). Instead of using pyridine base (1.0 eq.), DIPA (105 µL, 0.750 mmol, 1.50 eq.) was used. The product was aﬀorded as an oﬀ-white solid (125 mg, 0.447 mmol, 89% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.37 (app. dt, J = 8.9, 2.0 Hz, 2H), 8.04 (app. dt, J = 8.9, 2.0 Hz, 2H), 7.36 – 7.27 (m, 3H), 7.02 – 6.97 (m, 2H); 13C NMR

(101 MHz, CDCl3, ppm): δ 151.1, 149.4, 141.2, 130.2, 130.1, 127.9, 124.5, 122.2; LRMS: EI m/z 279.0 [M]. Data is consistent with literature values.(391)

3.6.2. Screening of conditions

General procedure 9 for the reaction of 330 (or 329) with pyrrolidine nucleophile

A microwave vial was charged with a stirrer bar, KF (7.0 mg, 0.120 mmol, 2.00 eq.) and 18-crown-6 (31.7 mg, 0.120 mmol, 2.00 eq.), then capped, and evacuated/backﬁlled µ with N2 (× 3). To this was added THF (0.96 mL), pyrrolidine (19.7 L, 17.1 mg, 0.240 mmol, 4.00 eq.), then a solution of 330 (30.0 mg, 0.0601 mmol, 1.00 eq.) in THF (0.96 mL). The reaction mixture was left stirring at room temperature for 5 hours. The reaction mixture was diluted with Et2O, washed with 1.0 M HCl (2 mL), then H2O 1 (2 × 2 mL), dried over MgSO4 and concentrated. The yield was determined using H NMR spectroscopy, with methyl 3,5-dinitrobenzoate or 3,4,5-trimethoxybenzaldehyde

258 as internal standard.

Representative procedure for optimisation of benzyne-Truce–Smiles reaction with DIPA as nucleophile

A microwave vial was charged with a stirrer bar, KF (11.6 mg, 0.200 mmol, 2.00 eq.), and 18-crown-6 (52.9 mg, 0.200 mg, 2.00 eq.), then capped and evacuated/backﬁlled µ with N2 (× 3). To this was added DIPA (56.1 L, 40.5 mg, 0.400 mmol, 4.00 eq.) and THF (14.4 mL). The reaction mixture was heated to 70 ◦C for 10 min, before the addition of a solution of [3-(triﬂuoromethylsulfonyloxy-2-trimethylsilyl-phenyl] 4- nitrobenzenesulfonate 330 (50.0 mg, 0.100 mmol, 1.00 eq.) in THF (1.6 mL). The reaction mixture was left stirring in a sealed vial at 70 ◦C for 1 hour, or until the starting material was shown to be consumed by LCMS. The reaction mixture was then cooled to room temperature, diluted with Et2O, and H2O was added. The pH was adjusted to between 6 and 7 using 1 M aq. HCl, and the layers were separated, then the organic layer was washed with brine (2 × 2 mL). The organic layer was dried 1 over Na2SO4, then the solvent removed in vacuo. The yield was calculated using H NMR, with 3,4,5-trimethoxybenzaldehyde as internal standard.

40-Nitro-6-(pyrrolidin-1-yl)-[1,10-biphenyl]-2-ol, 328a

9 10 NO2 OH 8 1 7 6 9′ 2 8′ 3 11′ 5 4 N 12′ 11 12 328a

To a solution of KF (11.6 mg, 0.200 mmol, 2.00 eq.) and 18-crown-6 (52.9 mg, µ 0.200 mmol, 2.00 eq.) in THF (14.4 mL) under N2 was added pyrrolidine (33.4 L, 28.5 mg, 0.400 mmol, 4.00 eq.). The reaction mixture was heated to 70 ◦C for 10 minutes before addition of a solution of 3-(((triﬂuoromethyl)sulfonyl)oxy)-2-(trimethylsilyl)- phenyl 4-nitrobenzenesulfonate, 330 (50.0 mg, 0.100 mmol, 1.00 eq.) in THF (1.6 mL) was added to the reaction mixture. The reaction mixture was heated to 70 ◦C in a

259 sealed vial for 1 hour. The reaction mixture was then diluted with Et2O, and the pH was adjusted to 7 using 1 M aq. HCl. The solution was washed with brine (2

× 2 mL). The organic layer was then dried over Na2SO4 and concentrated. 3,4,5- Trimethoxybenzaldehyde internal standard (0.0111 mmol from a stock solution in 1 CDCl3) was added, to allow determination of yields from H NMR analysis. The crude product was then dissolved in Et2O, and extracted with 1 M aq. HCl (3 × 5 mL). The aqueous extracts were neutralised to pH 7–8 using 4 M aq. NaOH and extracted with Et2O (3 × 15 mL). The organic extracts were dried over Na2SO4, concentrated, and puriﬁed by column chromatography (eluent: 10–15% EtOAc in hexane). The title compound was isolated as a dark red crystalline solid (2.5 mg, 0.0088 mmol, 9% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.29 (app. d, J = 8.9 Hz, 2H, H9 + H90 ),

7.59 (app. d, J = 8.8 Hz, 2H, H8 + H80 ), 7.15 (app. t, J = 8.2 Hz, 1H, H3), 6.51 (dd,

J = 8.2, 1.0 Hz, 1H, H2 or H4), 6.42 (dd, J = 8.2, 1.0 Hz, 1H, H2 or H4), 4.63 (s, 13 1H, OH), 2.84 – 2.78 (m, 4H, 2H11 + 2H110 ), 1.74 – 1.69 (m, 4H, 2H12 + 2H120 ); C

NMR (126 MHz, CDCl3, ppm): δ 153.4 (C1), 149.4 (C5), 146.9 (C10), 144.9 (C7),

132.3 (C8 + C80 ), 130.0 (C3), 123.9 (C9 + C90 ), 114.5 (C6), 107.8 (C2 or C4), 105.8

(C2 or C4), 51.4 (C11 + C110 ), 25.6 (C12 + C120 ); Accurate Mass: ESI− m/z calcd − ◦ for C16H15O3N2 [M−H] 283.1088, found 283.1087; m.p. : > 300 C; IR (thin ﬁlm, cm−1): 3460 (br, w), 2926 (w), 2851 (w), 1598 (m), 1514 (m), 1458 (ms), 1346 (s), 1292 (w), 1145 (w).

3-(Pyrrolidin-1-yl)phenyl 4-nitrobenzenesulfonate, 362a

9 O N 10 2 8 7 O 9′ S 8′ O O 1 6 H 2

3 11′ 5 4 N 12′ 11 362a 12

260 Isolated as an orange solid (7.1 mg, 0.020 mmol, 20% yield) from the reaction of 330 according to general procedure 9, using column chromatography (eluent: 0% to 26% EtOAc in hexane).

1 H NMR (500 MHz, CDCl3, ppm): δ 8.36 (d, J = 8.4 Hz, 2H, H9 + H90 ), 8.07

(d, J = 8.4 Hz, 2H, H8 + H80 ), 7.06 (t, J = 8.2 Hz, 1H, H3), 6.42 (dd, J = 8.4, 2.2 Hz,

1H, H2 or H4), 6.19 (t, J = 2.2 Hz, 1H, H6), 6.11 (dd, J = 8.0, 2.2 Hz, 1H, H2 or H4), 13 3.22 – 3.16 (m, 4H, 2H11 + 2H110 ), 2.01 – 1.97 (m, 4H, 2H12 + 2H120 ); C NMR

(126 MHz, CDCl3, ppm): δ 151.0 (C10), 150.7 (C1 or C5), 149.2 (C1 or C5), 141.6

(C7), 130.1 (C3), 130.1 (C8 + C80 ), 124.3 (C9 + C90 ), 110.9 (C2 or C4), 107.8 (C2 or

C4), 105.0 (C6), 47.8 (C11 + C110 ), 25.6 (C12 + C120 ); Accurate Mass: APCI+ m/z + ◦ calcd for C16H17O5N2S [M+H] 349.0836, found 349.0853; m.p. : 134 – 136 C; IR (thin ﬁlm, cm−1): 3107 (w), 2923 (m), 2852 (m), 1609 (s), 1532 (s), 1504 (m), 1379 (s), 1350 (s), 1194 (s).

40-Nitro-6-(pyrrolidin-1-yl)-[1,10-biphenyl]-2-yl 4-nitrobenzenesulfonate, 363a

15 O N 16 2 14 13 O 15′ 9 S 10 NO2 14′ O 8 O 1 7 6 9′ 2 8′ 3 11′ 5 4 N 12′ 11 12 363a

Obtained as an orange oil (4.4 mg) with some impurities from the reaction of 330 according to general procedure 9, using column chromatography (eluent: 0% to 26% EtOAc in hexane).

1 H NMR (400 MHz, CD3CN, ppm): δ 8.14 – 8.09 (m, 2H), 7.99 – 7.94 (m, 2H), 7.60 – 7.56 (m, 2H), 7.32 (app. t, J = 8.3 Hz, 1H), 7.25 – 7.20 (m, 2H), 6.91 (dd, J = 8.5, 1.0 Hz, 1H), 6.86 (dd, J = 8.2, 1.0 Hz, 1H), 2.75 – 2.69 (m, 4H), 1.68 – 1.61 (m, 1 4H); H NMR (500 MHz, CDCl3, ppm): δ 8.17 (app. d, J = 8.2 Hz, 2H, H15 +

H150 ), 8.06 (app. d, J = 8.0 Hz, 2H, H9 + H90 ), 7.65 (app. d, J = 8.2 Hz, 2H, H14 +

261 H140 ), 7.32 (app. d, J = 8.0 Hz, 2H, H8 + H80 ), 7.29 – 7.24 (m, 1H, H3), 6.83 (d, J =

8.5 Hz, 1H, H2 or H4), 6.77 (d, J = 8.1 Hz, 1H, H2 or H4), 2.78 – 2.73 (m, 4H, 2H11 + 13 2H110 ), 1.73 – 1.68 (m, 4H, 2H12 + 2H120 ); C NMR (126 MHz, CDCl3, ppm):

δ 150.8 (C16), 149.8 (C1 or C5), 147.7 (C1 or C5), 146.7 (C10), 143.4 (C7), 141.7 (C13),

132.2 (C8 + C80 ), 129.9 (C3), 129.4 (C14 + C140 ), 124.2 (C15 + C150 ), 122.9 (C9 +

C90 ), 120.1 (C6), 114.2 (C2 or C4), 111.2 (C2 or C4), 51.4 (C11 or C110 ), 25.6 (C12 or + C120 ); Accurate Mass: ESI+ m/z calcd for C22H20O7N3S [M+H] 470.1016, found 470.1018; IR (thin ﬁlm, cm−1): 3108 (w), 2926 (w), 2852 (w), 1692 (w), 1603 (m), 1533 (s), 1517 (s), 1472 (m), 1461 (m), 1448 (m), 1350 (s).

40-Nitro-6-(pyrrolidin-1-yl)-[1,10-biphenyl]-2-yl triﬂuoromethanesulfonate, 364a

9 10 NO2 OTf 8 1 7 6 9′ 2 8′ 3 11′ 5 4 N 12′ 11 12 364a

Isolated as a yellow/brown oil (1.2 mg, 0.0029 mmol, 5% yield) from the reaction of 330 according to general procedure 9, using column chromatography (eluent: 0% to 26% EtOAc in hexane).

1 H NMR (500 MHz, CDCl3, ppm): δ 8.27 (app. d, J = 8.3 Hz, 2H, H9 + H90 ),

7.54 (app. d, J = 8.4 Hz, 2H, H8 + H80 ), 7.31 (app. t, J = 8.5 Hz, 1H, H3), 6.86 (d,

J = 8.6 Hz, 1H, H2 or H4), 6.79 (d, J = 8.2 Hz, 1H, H2 or H4), 2.87 – 2.81 (m, 4H, 19 2H11 + 2H110 ), 1.75 (m, 4H, 2H12 + 2H120 ); F NMR (471 MHz, CDCl3, ppm): + δ −74.3; Accurate Mass: ESI+ m/z calcd for C17H15O5N2F3SK [M+K] 455.0285, found 455.0281; IR (thin ﬁlm, cm−1): 3729 (w), 3702 (w), 3627 (w), 2930 (w), 2852 (w), 2359 (w), 1608 (m), 1521 (m), 1448 (w), 1418 (m), 1350 (s), 1213 (s), 1140 (s).

262 3-Hydroxyphenyl 4-nitrobenzenesulfonate, 366

9 O N 10 2 8 7 O 9′ S O O 8′ O + O N S N 1 - 6 H O 2 O

3 5 4 OH 366 365a

Obtained as an orange solid (5.0 mg) in a 1.0 : 2.3 mixture with 1-((4-nitrophenyl)- sulfonyl)pyrrolidine, 365a, from the reaction of 330 according to general procedure 9, using TBAF (1.0 M in THF, 0.120 mL, 2.00 eq.) in place of KF/18-crown-6, and MeCN solvent. Puriﬁed by column chromatography (eluent: 0% to 50% EtOAc in hexane).

1 366: H NMR (400 MHz, CDCl3, ppm): δ 8.38 (app. dt, J = 8.9, 1.7 Hz, 2H,

H9 + H90 ), 8.05 (app. dt, J = 8.8, 1.7 Hz, 2H, H8 + H80 ), 7.16 (app. t, J = 8.4 Hz,

1H, H3), 6.76 (ddd, J = 8.3, 2.4, 1.1 Hz, 1H, H2 or H4), 6.57 (app. t, J = 2.3 Hz, 13 1H, H6), 6.52 (ddd, J = 8.2, 2.4, 1.1 Hz, 1H, H2 or H4), 5.34 (br s, 1H, OH); C

NMR (126 MHz, CDCl3, ppm): δ 156.9 (C1 or C5), 151.1 (C10), 150.1 (C1 or C5),

141.1 (C7), 130.7 (C3), 130.0 (C8 + C80 ), 124.5 (C9 + C90 ), 115.1 (C2 or C4), 114.2 − (C2 or C4), 109.8 (C6); Accurate Mass: ESI− m/z calcd for C12H8O6NS [M−H] 294.0067, found 294.0081; IR (thin ﬁlm, cm−1): mixture shows peak at 3429 (br, OH).

1 365a: H NMR (400 MHz, CDCl3, ppm): δ 8.41 – 8.35 (m, 2H), 8.03 – 8.00 13 (m, 2H), 3.33 – 3.27 (m, 4H), 1.84 – 1.79 (m, 4H); C NMR (126 MHz, CDCl3, ppm): δ 150.2, 143.3, 128.6, 124.5, 48.2, 25.5; LRMS: UPLC-MS, ESI+ m/z 257.0 [M+H]+. Data is consistent with literature values.(392)

263 3-(Diisopropylamino)-2-(4-nitrophenyl)phenol, 328b

9 10 NO2 OH 8 1 7 6 9′ 2 8′ 12 3 5 4 N 11 12 11 12 12 328b

A microwave vial was charged with a stirrer bar, KF (11.6 mg, 0.200 mmol, 2.00 eq.) and 18-crown-6 (52.9 mg, 0.200 mmol, 2.00 eq.), then capped and evacuated/backfilled µ with N2 (× 3). To this was added dry THF (12.8 mL) and diisopropylamine (56.1 L, 0.400 mmol, 4.00 eq). After 10 minutes stirring at 70 ◦C, a solution of 330 (50.0 mg, 0.100 mmol, 1.00 eq.) in dry THF (3.2 mL) was added dropwise by syringe pump over a period of 5 hours. After a further 30 minutes at 70 ◦C, the reaction mixture was diluted with Et2O, and the pH was adjusted to 7 using 1 M aq. HCl if necessary. The solution was washed with brine (2 × 2 mL), dired over Na2SO4 and concentrated. Fol- lowing addition of 3,4,5-trimethoxybenzaldehyde (0.0111 mmol from a stock solution 1 in CDCl3, and analysis of the yield by H NMR spectroscopy, the resulting crude was purified by column chromatography (eluent: 7% to 20% EtOAc in hexane) to afford the product 328b as a yellow solid (9.9 mg, 0.032 mmol, 31% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.31 – 8.27 (m, 2H, H9 + H90 ), 7.58 – 7.54

(m, 2H, H8 + H80 ), 7.21 (app. t, J = 8.1 Hz, 1H, H3), 6.94 (dd, J = 8.1, 1.1 Hz, 1H,

H2), 6.78 (dd, J = 8.1, 1.0 Hz, 1H, H4), 3.30 (sept, J = 6.5 Hz, 2H, 2H11), 0.88 (d, J 13 = 6.5 Hz, 12H, 12H12); C NMR (101 MHz, CDCl3, ppm): δ 153.1 (C1 or C5),

149.0 (C1 or C5), 147.0 (C10), 143.8 (C7), 132.8 (C8 + C80 ), 128.9 (C3), 127.1 (C6),

123.4 (C9 + C90 ), 121.1 (C2), 112.3 (C4), 50.6 (C11), 21.8 (C12); Accurate Mass: − ESI− m/z calcd for C18H21O3N2 [M−H] 313.1558, found 313.1555; m.p. : 123 – 124 ◦C; IR (thin ﬁlm, cm−1): 3498 (br, w), 2970 (w), 2933 (w), 1600 (m), 1575 (w), 1514 (m), 1460 (m), 1346 (s), 1250 (w), 1186 (w).

264 3-(Diisopropylamino)phenyl 4-nitrobenzene sulfonate, 362b

9 O N 10 2 8 7 O 9′ S 8′ O O 1 6 H 2 12 3 11 12 5 4 N 11 12 362b 12

A microwave vial was charged with a stirrer bar, KF (11.6 mg, 0.200 mmol, 2.00 eq.) and 18-crown-6 (52.9 mg, 0.200 mmol, 2.00 eq.), then capped and evacuated/backfilled µ with N2 (× 3). To this was added dry THF (1.6 mL) and diisopropylamine (28.1 L, 0.200 mmol, 2.00 eq). A solution of 330 (50.0 mg, 0.100 mmol, 1.00 eq.) in dry THF (1.6 mL) was added to the stirring reaction mixture at room temperature. After 1 hour stirring at room temperature, the reaction mixture was diluted with DCM, and washed with 1 M aq. HCl (2.5 mL), then with H2O (2 × 2 mL). The reaction mixture was dried using a phase separation funnel, then concentrated. The resulting crude was purified by column chromatography (eluent: 10% to 20% EtOAc in petroleum ether), to afford the product 362b as an orange solid (15.1 mg, 0.0399 mmol, 40% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.37 – 8.33 (m, 2H, H9 + H90 ), 8.08 – 8.03

(m, 2H, H8 + H80 ), 7.04 (app. t, J = 8.3 Hz, 1H, H3), 6.69 (dd, J = 8.4, 2.3 Hz, 1H,

H2), 6.41 (app. t, J = 2.3 Hz, 1H, H6), 6.21 (dd, J = 7.8, 2.3 Hz, 1H, H4), 3.71 (sept, 13 J = 6.8 Hz, 2H, 2H11), 1.16 (d, J = 6.8 Hz, 12H, 12H12); C NMR (101 MHz,

CDCl3, ppm): δ 151.0 (C10), 150.1 (C1 or C5), 149.6 (C1 or C5), 141.5 (C7), 130.1

(C8 + C80 ), 129.5 (C3), 124.3 (C9 + C90 ), 115.8 (C2), 110.3 (C6), 109.4 (C4), 47.7 (C11), + 21.1 (C12); Accurate Mass: ESI+ m/z calcd for C18H23O5N2S [M+H] 379.1322, found 379.1322; m.p. : 83 – 84 ◦C; IR (thin ﬁlm, cm−1): 3107 (w), 2969 (w), 2925 (w), 1607 (m), 1565 (w), 1532 (s), 1497 (m), 1404 (w), 1379 (m), 1349 (m), 1192 (s).

265 [3-(Diisopropylamino)-2-(4-nitrophenyl)phenyl] 4-nitrobenzenesulfonate, 363b

15 O N 16 2 14 13 O 15′ 9 S 10 NO2 14′ O 8 O 1 7 6 9′ 2 8′ 12 3 11 5 4 N 12 11 12 12 363b

Isolated from the same reaction as 362b (vide supra for procedure). Isolated as a yellow solid (3.1 mg, 0.0062 mmol, 6% yield).

1 H NMR (400 MHz, CDCl3, ppm): δ 8.16 – 8.12 (m, 2H), 8.08 – 8.03 (m, 2H), 7.62 – 7.58 (m, 2H), 7.38 (app. t, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.1, 1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (dd, J = 8.4, 1.5 Hz, 1H), 3.35 – 3.22 (m, 2H), 0.83 (d, J = 6.5 Hz, 1 12H); H NMR (500 MHz, CD3CN, ppm): δ 8.08 – 8.04 (m, 2H, H15 + H150 ),

7.97 – 7.93 (m, 2H, H9 + H90 ), 7.50 – 7.46 (m, 2H, H14 + H140 ), 7.46 (app. t, J =

8.1 Hz, 1H, H3), 7.40 (dd, J = 8.2, 1.3 Hz, 1H, H2), 7.34 (dd, J = 8.1, 1.3 Hz, 1H,

H4), 7.19 – 7.15 (m, 2H, H8 + H80 ), 3.26 (sept, J = 6.6 Hz, 2H, 2H11), 0.78 (d, J 13 = 6.5 Hz, 12H, 12H12); C NMR (126 MHz, CD3CN, ppm): δ 152.0 (C16),

150.4 (C1 or C5), 147.9 (C1 or C5), 147.5 (C7 or C10), 142.7 (C7 or C10), 141.2 (C13),

134.2 (C6), 133.6 (C8 + C80 ), 130.4 (C14 + C140 ), 129.8 (C3), 129.5 (C2), 125.3 (C15 +

C150 ), 123.1 (C9 + C90 ), 120.6 (C4), 51.2 (C11), 21.5 (C12); LRMS: ESI+ m/z 538.2 + + [M+K] ; Accurate Mass: ESI+ m/z calcd for C24H25O7N3SK [M+K] 538.1045, found 538.1026; m.p. : 135 – 137 ◦C; IR (thin ﬁlm, cm−1): 2968 (w), 2926 (w), 1602 (w), 1534 (m), 1518 (m), 1463 (w), 1384 (mw), 1349 (s), 1189 (m).

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