Towards the Total Synthesis of Plumbagin

Synthetic Applications of the BHQ Reaction: Towards the Total Synthesis of Plumbagin

A thesis submitted to the University of Manchester for the degree of Master of Philosophy in the Faculty of Engineering and Physical Sciences

2014

Michael Wong

Supervisor: Dr. Peter Quayle

School of Chemistry

Table of Contents

Abstract 4

Declaration 5

Acknowledgements 7

Abbreviations 8

Section 1: Introduction

1.1 Plumbagin 9 1.2 Properties of Plumbagin 10 1.2.1 Anticancer Properties 10 1.2.2 Agricultural Applications 12 1.2.3 Anthelmintic Properties 13 1.3 Extraction Methods 14 1.4 Synthetic Routes to Plumbagin 16 1.5 Derivatisations 19 1.6 Atom Transfer Radical Cyclisations (ATRC’s) 23 1.7.1 The BHQ Reaction 24 1.7.2 Targeted Syntheses 27 1.8 Aims and Objectives 29

Section 2: Results and Discussion

2.1 Synthesis of Dimethyl Ether 39 30 2.2 Formylation of the Aromatic Ring 32 2.3 Dakin-West Oxidation 33 2.4 Preparation of the Allyl Phenyl Ether 35 2.5 The ortho-Claisen Rearrangement 36 2.6 Esterification 38 2.7 The BHQ Reaction 39

2.8 Oxidation of Dimethyl Ether 45 to Quinone 46 42 2.9 Displacement Reactions 43 2.10 Synthesis of Aryl Bromide 48 46 2.11 Lithium-Halogen Exchange 47 2.12 Final Steps to Plumbagin 50

Section 3: Conclusions and Further Work 56

Section 4: Experimental General Considerations 60 39 - 1-4-dimethoxy-2-methylbenzene 61 40 - 2,5-dimethoxy-4-methylbenzaldehyde 62 41 - 2,5-dimethoxy-4-methylphenol 63 42 - 1-(Allyloxy)-2,5-dimethoxy-4-methylbenzene 64 43 - 2-allyl-3,6-dimethoxy-4-methylphenol 65 44 - 2-allyl-3,6-dimethoxy-4-methylphenol-2,2,2-trichloroacetate 66 45 - 5-chloro-1,4-dimethoxy-2-methylnaphthalene 67 46 - 5-chloro-2-methyl-1,4-naphthoquinone 68 47 - 2-allyl-3,6-dimethoxy-4-methylphenol-2,2,2-tribromoacetate 69 48 - 5-bromo-1,4-dimethoxy-2-methylnaphthalene 70 49 - 2-(5,8-dimethoxy-6-methylnaphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane 71 50 - 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalene-1,4-dione 72 1 – 5-hydroxy-2-methyl-1,4-dione 73

References 74

Appendix 78

Abstract

Plumbagin is a naturally occurring quinone which is well documented for having a plethora of beneficial medicinal properties. This report explores a synthetic preparation of the natural product through the use of the BHQ reaction, a unique and efficient benzannulation method which regiospecifically installs a halogen on the 4-position on the newly formed six- membered ring, during the course of a ten-step total synthesis.

The synthetic route commences with 2-methyl hydroquinone and after subjugation to several chemical transformations 5-chloro-1,4-dimethoxy-2-methyl naphthalene was afforded supported by evidence from X-ray crystal diffraction analysis. Although the installed aryl chloride proved unsuitable for further chemical manipulation an alternative substrate, an aryl bromide, was produced and successfully displaced with a boronic ester providing a suitable functional precursor leading to the target compound however further attempts to isolate plumbagin from the by-products in the last step did not come to fruition.

Declaration

I declare that no portion of the work referred to in the dissertation has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning.

The author of this dissertation (including any appendices and/or schedules to this dissertation) owns any copyright in it (the “Copyright”) and s/he has given The University of Manchester the right to use such Copyright for any administrative, promotional, educational and/or teaching purposes.

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Further information on the conditions under which disclosure, publication and exploitation of this dissertation, the Copyright and any Intellectual Property Rights and/or Reproductions described in it may take place is available from the Head of School of the School of

Chemistry.

Acknowledgements

I would like to thank everybody involved in providing help throughout the course of this project. Firstly, my family and friends for their unfaltering support and comfort during harder times.

A special thank you to Dr. Peter Quayle for his infinite knowledge into the finer intricacies of Chemistry and persistently cheerful disposition as well as the members of the Quayle group in particular Drs Mark Little and Gregory Price for the countless first-to-three’s, practical advice, blunt encouragement, personality quirks and infinite patience, in both professional and recreational settings, during the course of this MPhil for they have taught me everything I know. A personal inclusion of Brohammad Izharul Albakhri for being a conscientious student, taking on board my unorthodox approach to practical Chemistry and, above all, the nicest guy in town. It has been my utmost pleasure and a privilege to work with all of them.

Additional mentions to the analytical skills of Dr. Jim Raftery in X-ray Crystallography,

Gareth Smith in Mass Spectrometry and the ever varying denizens passing through the door of office 2.32.

Abbreviations

AcOH – Acetic acid

ATP – Adenosine triphosphate

ATRC – Atom transfer radical cyclisation

Bipy – 2,2’-Bypyridine

BHQ – Bull-Hutchings-Quayle

B-pin– 4,4,5,5-tetramethyl-1,3-2-dioxaborolane iPrO-B-pin - 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

CAN – Ceric ammonium nitrate

CH3CN – Acetonitrile

DCM - Dichloromethane

DIBAL-H – Diisobutylaluminium hydride

DMF – N,N-Dimethylformamide

DMSO – Dimethyl sulfoxide

EtOAc – Ethyl acetate iPr - Isopropyl

MeI – Methyl iodide m-CPBA – meta-Chloroperoxybenzoic acid

µW – Microwave reactor

Na2S2O4 – Sodium dithionite

NMR – Nuclear Magnetic Resonance n-BuLi – n-Butyllithium

PIFA – [Bis(trifluoroacetoxy)iodo]benzene

Section 1: Introduction

1.1 Plumbagin

Fig. 1 - 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin).

Plants produce a wide variety of metabolites which are divided into two major categories; primary and secondary metabolites. Primary metabolites comprise of compounds directly affecting the plants life cycle such as chlorophyll.1 Secondary metabolites are indirectly involved in the same development processes such as growth, development and reproduction however also have a more unique and interesting ecological functionhelping particular species survive the stresses endured during their life cycles whether that is deterring predators, inhibiting the growth of pathogens or defending against exposure to environmental factors.2,3

Plumbagin (Fig. 1) falls into the second category and is one of the simplest secondary metabolites found in the Plumbagenaeace, Droseraceae and Ebenenaceae families.2 Its structure consists of a 1,4-naphthoquinone core accompanied by a methyl subsitutent in the 2- position and a hydroxyl group in the 5-position appearing visually as a strongly yellow pigment.2 Examples of other naphthoquinone derivatives used in herbal preparations include menadione and juglone (Fig. 2).

Fig. 2 - Structures of menadione, 2, and juglone, 3.

It is well documented that the species Plumbago zeylanica and Plumbago scandens L. are known for containing high levels of the quinone and is suggested to be the pharmacologically active constituent since its first isolation by Dulong D’Astafort in 1828.2 Since then plumbagin had been neglected for a century until being revisited in 1928 when Roy and Dutt recognised the quinone and hydroxyl characteristics were present. They further deduced an empirical formula which was proven to be incorrect however Madinaveitia and Gallego3 went on to elucidate the correct formula.

1.2 Properties of Plumbagin

As with a majority of naturally occurring compounds isolated from plant extracts, extensive documentation shows plumbagin exhibits a broad range of biological activity including, but not limited to, antifungal, antibacterial, antioxidant, anticancer and anti-inflammatory effects.2,3

1.2.1 Anticancer Properties

A relevant property to today’s medical concerns of plumbagin is its ability to affect and disrupt cancerous entities, in particular non-small cancers found in the lung.4 Gomathinayagam et al. reported in their recent publication that chemotherapy and radiotherapy have limitations on non-small cell lung cancers (NSCLC) due to their ability to develop resistance against conventional forms of treatment. Previous research carried out highlights plumbagin has effects on various cancer cell lines and induce apoptosis to in vitro cell cultures and in vivo tumour cultures in mice.4

Of the two cell lines used in this study, H460 and A549, the H460 line was significantly more sensitised than the A549 line suggesting that plumbagin targets EGFR (epidermal growth factor receptor) mediated Akt signalling causing a G2/M arrest inducing apoptosis. Down-regulating, or inhibiting, cyclin B1 and Cdc25B expression is suggested to be the mechanism responsible for G2/M arrest supported by different agents (ionizing radiation, doxorubicin and sulforaphane) instigating apoptosis to a variety of cell lines in the same way. Moreover this is

not exclusive to NSCLC’s; ovarian and breast cancer cells are also susceptible.5,6,7 Observing Bcl-2, another protein present in cancer cells, was consistently down-regulated in the H460 line was an important discovery as it opens up the possibility of synergy with modern chemotherapeutic methods and, therefore, increased therapeutic successes. A further development would be using metal-based complexes of plumbagin such as the copper-complex which is reported to exhibit elevated activity on tumour cell deaths relative to free plumbagin.8

In addition, quinones display concentration dependant cytotoxicity on HaCaT keratinocytes, a transformed epidermal human cell line, via two mechanisms. The more prominent is illustrated below (Scheme 1) in a sequential diagram beginning with step I and ending in step VII.9

Scheme 1 - A reaction cycle illustrating the cytotoxic action of plumbagin and juglone. Abbreviations: GS-QH2 - monoglutathione conjugated hydroquinone. ((GS)2QH2 is di-glutathione conjugated hydroquinone. GPx is glutathione peroxidase. Diagram adapted from Inbaraja and Chignell.9

The first major proposed mechanism is the quinone undergoing a one-electron reduction by enzymes such as NADPH-CYP450-reductase giving the corresponding semi-quinone radical. In aerobic conditions the semi-quinone radical undergoes redox cycling generating the highly 8 reactive superoxide anion and H2O2.

The proposed mechanism of action is enabled by the electrophilic capacities of quinones capable of reacting with both glutathione and thiol groups present in proteins.10 Inclusion of alkyl substituents at the 2- and 3-position simultaneously decreases the overall toxicity of the naphthoquinones10 whereas a hydroxyl group at the 5-position imparts a noticeable increment in toxicity towards rat hepatocytes11 due to the hydroxyl aiding redox cycling.11 This hypothesis is furthered by a study monitoring the relative effects of juglone and plumbagin on keratinocytes with increasing incubation time demonstrated juglone showed no additional activity whereas plumbagin’s efficacy increased with time.

1.2.2 Agricultural Applications

Plumbagin has also been used to control agricultural pests by acting as an antifeedant; a substance which discourages insects consuming the substrate material.12 Due to its existence as a naturally occurring compound and ability to circumvent the resistance crop destroying pests have developed plumbagin appeals on both a social and practical level. Akhtaret al. delved into the use of plumbagin against the cabbage looper, Trichoplusiani, a caterpillar resistant to many synthetic pesticides13 and a common pest across a large geographical area ranging from Canada to Mexico.

The antifeedant effect is two-fold; first is absorption of the vapours produced by the naphthoquinones after exposure followed by a redox reaction inside the target insect.14

Fig. 3 - Structure of naphthazarin.

A study showed 1,4-naphthoquinone and its isomeric forms displayed higher levels of antifeedant activity than their 1-4,benzoquinone and 1-hydroxyanthraquinone counterparts.12 During the experiment an intriguing observation was noted that menadione, its sole functional group being a methyl in the 2-position, and naphthazarin (Fig. 3), bearing two hydroxyl groups, displayed a marked decrease in antifeedant potency whereas plumbagin, bearing both a methyl and hydroxyl, did not have impaired activity implying that simply including either functional group is detrimental and regiochemistry is crucial.12

1.2.3 Anthelmintic Properties

Maintaining the theme of toxicity against organisms however on targets larger than a cellular level, plumbagin has also been implemented against parasitic infections. Schistosoma mansoni, also known as flukes, is a major parasite responsible for causing schistosomiasis,15 a collective name for the parasitic diseases caused by the genus Schistosoma found abundant in environments where properly sanitised water is scarce and any existing facilities are often contaminated. Affecting over 200 million people worldwide it has been identified as a major global health problem by the World Health Organisation in 200116 with no current vaccine available. The primary treatment for schistosomiasis is praziquantel (Fig. 4) which acts by causing a rapid spike in Ca2+ ions and triggering spastic contractions within the target.15 However, due to a lack of variety available in anthelmintic medicine, drug resistance is beginning to emerge17,18 and so an alternative solution is being urgently sought after.

Fig. 4 - Praziquantel, a market leader in treating schistosomiasis.

In the search for a potential new medicine against S. mansoni plumbagin was compared against praziquantel in an in vitro study quantifying the efficacy of each compound by

comparing relative motility, the distance moved, and survival indices, the percentage of flukes still alive, of each group after a given period of exposure. Plumbagin presented a similar pathological sequence to that of praziquantel although required a lower dose to display substantially lower survival indices and relative motility.15 Furthermore plumbagin affects both genders of the species without distinction whereas praziquantel’s mechanism of action favours the male population of flukes.

Whilst it is understood that praziquantel induces spastic contractions the mechanism by which its anthelmintic property arises has not been thoroughly researched.15 In contrast, the hypothesis for plumbagin’s activity is inhibition of mitochondrial enzymes by competing at the ubiquinol binding site, inhibiting the electron transport chain and preventing the production of ATP causing death.19,20,21 Evidence the commercially procured sample of plumbagin outperforms the current market drug of choice for this particular line of diseases shows promise for the treatment of this major health problem.

1.3 Extraction Methods

The roots, in particular, of P. zeylanica and P. scandens L. are known for being a rich and reliable source of plumbagin. Drosera intermedia is known to produce plumbagin although a quantification study carried out by Greventsuk et al. utilised whole plants with no distinction between content in the bark, roots and aerial parts of the plant making it difficult to ascertain where the richest sources of natural product originates from.22 Greventsuk et al. utilised a Soxhlet extraction as their method of choice in a solution of n-hexane and is favoured among many researchers due to the consistently high yields obtained.23

However a study by Paiva et al. highlighted a limitation with the method. Results (Table 1) compiled by from the study showed the amount of plumbagin recovered from Plumbago scandens L. decreased with time after 5 h suggesting that prolonged exposure to heat leads to degradation.24

Extraction Recovery Recovery Duration (h) (mg/mL) (%) 2 0.93 36 5 1.56 58 10 1.06 50

Table 1 - Results adapted from Paiva et al. comparing extraction times to plumbagin recovery.

A different extraction methodology for Plumbago zeylanica L. uses a solution mixture of chloroform and dichloromethane low temperatures contrasting to the relatively high temperatures a Soxhlet extraction would typically demand. Cold maceration of the plant material is achieved by adding plant parts to a chloroform-dichloromethane mixture, storing the sample in conditions of 2-8 °C in a conical flask followed by successive decanting into an actinic container. The combined fractions were then filtered, concentrated under pressure and then washed successively with water and sodium bicarbonate giving the desired extract and lastly recrystallised from n-hexane.25

Harvesting from natural sources is inherently a problem for large scale research due to a number of factors affecting recovery yields. The major problem is acquiring the optimum time of when to harvest the plan during its life cycle as it may vary on a broad range of highly sensitive environmental factors such as amount of sunlight and air composition rationalising a novel synthetic approach to plumbagin would be a beneficial consideration.

1.4 Synthetic Routes to Plumbagin

Plumbagin is synthesised as a secondary metabolite in the tropical pitcher plant Nepenthes, a carnivorous species which produces the naphthoquinone as a chemotaxonomic marker by using L-alanine as a substrate,26 proceeding via the proposed pathway shown in Scheme 2:

Scheme 2 - Proposed biosynthetic pathway of plumbagin.26

It is suggested that this pathway is mediated by an energy dependant mechanism27 similar to the co-transport of H+ ions and amino acids in another species of plant.28 After the uptake of L-alanine 6 conversion into pyruvate 7 is facilitated by deamination through alanine aminotransferase. Decarboxylation gives acetyl-CoA 8 following on to form polyketide 9. 9 is then subject to a series of straightforward aldol condensations and the biosynthesis is concluded with an oxidation to give the quinone and, thus, plumbagin. An interesting observation recorded during this study was this particular biosynthetic pathway is specific to L-alanine as sodium acetate was introduced and monitored for uptake however it was found to have no effect.26

Scheme 3 - Fieser and Dunn’s total synthesis of plumbagin. * indicates cyclisation of 12 into 13 performed by unique method.30

In their direct approach Buruaga and Verdú questioned the oxidation of 2-methyl-1,4- naphthoquinone would afford plumbagin. In reality, although reaction of 2-methyl-1,4- naphthoquinone with Caro’s acid (peroxymonosulphuric acid) did produce plumbagin this hydroxylation process proved to be wholly unselective affording plumbagin together with the undesired regioisomer. Fieser and Dunn sought to resolve this issue and devised a synthetic strategy (Scheme 3) whereby the C-5 hydroxyl group was introduced at a later stage.29 Fieser 17

and Dunn’s synthesis began with the acylation of acetyl diethyl succinate with m-toyl chloride 10 to afford 11 which upon deacylation, decarboxylation and a Clemmensen reduction generated keto acid 12. Cyclisation of 1230 followed by bromination α-to the carbonyl group and subsequent elimination of HBr afforded phenol 15. Protection of the phenol was achieved by conversion to its acetate and subsequent oxidation by CrO3 generated quinone 17 which only required adjustment of its oxidation level and deprotection led to the isolation of plumbagin.

Scheme 4 - retro-Diels-Alder route to plumbagin.29

Fieser and Dunn’s previously explained synthesis in Scheme 3 requires exceptionally long reaction times in order to produce a yield of 40 mg of plumbagin after beginning with 30 g of starting material 10.

Almost half a century later Ichihara et al. devised an alternative route (Scheme 4) which utilised a retro-Diels-Alder sequence in which to introduce a methyl group at C-2.31 In this approach 3 (juglone) was used as the starting material which underwent a Diels-Alder reaction with cyclopentadiene forming diketone 20. Reduction of 20 using DIBAL-H followed by dimethoxypropane in p-toluenesulfonic acid afforded alcohol 21 which when protected and oxidised with CrO3 reintroduced the carbonyl group at C-1 yielding 23. Alkylation of 23 with methyl iodide in the presence of n-BuLi as base followed by a

subsequent retro-Diels-Alder reaction and readjustment of the oxidation level at C-4 ultimately afforded plumbagin.

A rather lengthy sequence developed by Ichihara is in stark contrast to the highly convergent approach reported by Komiyama (Scheme 5) via a Diels-Alder reaction this time between 3- hydroxy-2-pyrone 25 and 2-methyl-1,4-benzoquinone 26. The only drawback of this approach however is the total lack of regiocontrol in the Diels-Alder reaction itself.

Scheme 5- A second Diels-Alder approach utilising 3-hydroxy-2-pyrone and 2-methyl-1,4-benzoquinone.

A one-pot synthesis would be an ideal method for large scale syntheses, especially adopting the conditions in Scheme 5, as the reaction proceeds under mild conditions, however the synthesis of Komiyama et al. creates 27 as the major product and plumbagin as the minor. Additionally, separating the two via chromatographic techniques could be challenging due to the marginal polarity similarities between the two constitutional isomers. Taking the three previous syntheses into account, an ideal route would involve commercially available reagents selectively producing the target compound in a state which can be readily isolated.

1.5 Derivatisations

After previously focussing on the variety of syntheses employed to afford plumbagin it is also employed as a flexible intermediate. Protecting the labile hydroxyl is an important transformation due to the crucial role it plays in therapeutic mechanisms and is protected through a series of facile reactions using a plethora of reagents. One of these reagents is acetic anhydride installing an acetate group; easily removable, widely available and opens many avenues for plumbagin’s synthetic utility. Banditpuritat et al. make use of a modified domestic microwave in an interesting method for their acetylation procedure32 to great

success. Coupled with the discovery of using iodine as a catalyst to promote the reaction33 the method devised proves to be an effective and efficient means to further derivatise the naphthoquinone core.

Organometallic complexes are commonly investigated as potential anticancer agents and for supportive therapy in cancer patients leading to the debate of natural products being used as 34,35 potential prodrug chelators. By refluxing plumbagin with CuCl2.H2O and MeONa in methanol the copper complex was formed and confirmed by crystal structure analysis by Chen et al. showing copper coordinating to the hydroxyl and adjacent carbonyl in the 4- position as displayed in Fig. 5.

Fig. 5 - ORTEP view of [Cu(PLN)2]·2H2O and [Cu(PLN)(bipy)(H2O)]2(NO3)2·4H2O. Thermal ellipsoids drawn at - 30% probability, hydrogen atoms, two lattice water molecules and two NO3 anions have been omitted for clarity. Obtained by Chen et al.8

Plumbagin also reacted under the previous conditions of MeONa with bipy as a co-ligand forming the dimeric species.

Another example of active plumbagin complexes substitutes the copper for elements found in the Lanthanide series. La (III) complexes display an ability to bind to DNA and trigger cell death and have already been employed in treating cancerous cell lines achieving promising results.36 Chen et al. explore the formation of plumbagin complexes containing Yttrium, Samarium, Gadolinium and Dysprosium as the metal centre.

Reactions were achieved using a solution of plumbagin, extracted from P. zeylanica, and reacting with the corresponding metal chloride hexahydrate salt. The pH was adjusted to 6.0 using dilute ammonia and refluxed for two hours giving yields consistently over 50% of the

corresponding lanthanide. An X-ray diffraction study showing exactly how coordination occurs could not be obtained although a proposed structure is shown in Fig. 6.

Fig. 6 - Potential structure for the Lanthanide-plumbagin complex as proposed by Chen et al.36

Scheme 6 - Plumbagin derivatisation strategies.37,38

Sreeleetha et al. synthesised a range of plumbagin derivatives as they recognised the 1,4- naphthoquinone core is essential for the aforementioned antifeedant activity37 discovering introduction of N-acetyl-L-amino acid moiety 28 (Scheme 6), produced a compound with the highest potency. The analogue was made by an initial hydroxyl protection followed by reacting with ethanolamine and condensing the N-acetyl-L-amino acid with the Michael adduct to achieve attachment of the peptidyl chain whilst retaining the quinone structure.37

Additional enhancement of plumbagin’s anti-cancer properties can be achieved by forming hydrazone analogue 29 (Scheme 6) providing cytotoxicity specific to breast cancer cells.38 Retaining the hydroxyl group is imperative because of the role it performs inhibiting the over-expression of Oestrogen Receptor alpha;39 a common occurrence in many breast cancer cases. Plumbagin reacts readily with a variety of aryl amides in the presence of trifluoroacetic acid selectively substituting at the carbonyl in the 4-position producing the desired hydrazone and a set of promising potential anti-cancer compounds.38

Furthermore it is possible to synthesise an artemisinin hybrid as shown by compound 30 (Scheme 6). Artemisinins are a widely used group of drugs in controlling the widespread parasite, Plasmodium falciparum, the organism responsible for causing malaria. During the course of the previous half century P. falciparum has generated resistance to many classes of drugs40,41 with the artemisinin class being a focus due to this mutation potentially threatening the artemisinin-combination-therapy (where an artemisinin is used in tandem with additional antimalarials) strategies already in place. With the multitude of ways plumbagin can be used as both a precursor and as a stand-alone compound it is important to be able to synthesise large quantities to meet the demand for the appropriate field rationalising the total synthesis of plumbagin.

1.6 Atom Transfer Radical Cyclisation (ATRC) Reactions

An atom transfer reaction is among a broad range of reactions where a carbon-heteroatom or heteroatom-heteroatom is added across a carbon with a double or triple bond. An early example of an atom transfer reaction is the reaction between 1-octene and carbon tetrachloride in the presence of radical initiators reported by Kharasch et al. (Scheme 7).

Scheme 7 - Proposed radical mechanism for the addition of carbon tetrachloride to 1-octene.42

Further implementation of atom transfer reactions opens up the ability to create ring systems. Formation of cyclic compounds using carbon-carbon bond transformations has long been a frequently used tool in organic synthesis often involving the use of organostannane or organosilane reagents. These present two disadvantages; one, they are, overall, a reductive cyclisation process where termination involves abstracting a hydrogen and forming a hydride, and two, an issue of their removal and acute toxicity (in particular organstannane species) both of which are concerns which must be weighed against the efficacy as reagents.43

These reactions can also be carried out by replacing the tin species with a copper catalyst presenting conditions that present a number of advantages when carrying out a synthesis. In terms of efficiency the copper mediated reactions are less reductive than their organostannane counterparts; an important factor when considering the rate of addition from the radical intermediate to the target alkene is slow.43 The benefits in terms of cost and safety using a copper catalyst provides a reagent which requires only a small amount in order to push a reaction to completion, is easily removed and significantly less toxic than the alternative stoichiometric volumes of highly toxic tin compounds. Additionally the use of copper provides the interesting product as shown below in Scheme 8: 23

Scheme 8 - Comparison of the cyclisation products between Bu3SnH and CuCl.

When copper chloride is used as the reagent in the presence of a solubilising ligand, such as bipy, the cyclised product is functionalised with a halogen providing a potentially useful substrate that can be utilised in subsequent transformations (Scheme 8).

1.7.1 The BHQ Reaction

Scheme 9 - Overview of the BHQ reaction.

During an investigation into the use of ATRC reactions in organic synthesis Bull had occasion to investigate the use of substrates with the intention of preparing 8-membered lactones.44 Attempted cyclisation under our standard conditions led not to the desired lactone but to the chloronaphthalene species shown in Scheme 9. Further investigations by Bull indicated this to be a general reaction for the conversion of ortho-aryl-allyl-2,2,2- trichloroacetates into benzo-fused aromatics, a process which is catalysed by a large variety

of redox-active transition metal salts or complexes. This chemical transformation is referred to as the Bull-Hutchings-Quayle (BHQ) Reaction.44

Scheme 10 - The BHQ reaction; a potential mechanistic rational.

We consider there are two mechanistically distinct pathways by which the BHQ may proceed. The first, illustrated in Scheme 10, begins with trichloroacetate 31, which in the presence of catalyst, such as a copper (I) salt, initiates an ATRC reaction leading to the generation of 8-membered lactone 32 ring containing three chlorine atoms. The loss of two molecules of HCl from the initial 8-membered ring lactone could lead to the generation of diene-lactone 33 which upon electrocyclisation and extrusion of CO2 would ultimately afford the observed product chloronaphthalene 34. Currently it is uncertain whether the BHQ does proceed via this mechanism. The lactone has been isolated and is found to be relatively stable although when resubjected to the reaction conditions the observed chloronaphthalene is generated.44

Critically the diene-electrocyclisation pathway does not concisely explain the halogen scrambling effect which is observed when using mixed halogenated ester 35 as substrate (Scheme 11).

Scheme 11 - Illustration of observed halogen scrambling occurring.

A second potential pathway for the BHQ reaction invokes for formation of spirocyclic lactone prior to loss of HCl and CO2 extrusion. This pathway can account for halogen scrambling and currently serves as a working model for the reaction sequence (Scheme 12).

Scheme 12 - Alternative radical pathway for the BHQ reaction.

The alternative route proceeds through an ATRC similar to the first step resulting in the same lactone intermediate 32. However, instead of expulsion of HCl to give the diene another ATRC occurs initiating an intramolecular cyclisation to form spirocyclic lactone 36 with the radical being stabilised by the ring. The radical abstracts chlorine from the catalyst to afford 37 reducing the metal species from Cu (II) to Cu (I) before two equivalents of HCl and an equivalent of CO2 is expelled to rearomatise the ring affording chloronaphthalene 34.

1.7.2 Targeted Syntheses

Scheme 13 - Reactions carried out by Bull on benzo-fused coumarins.

Since its serendipitous discovery research has been directed towards the development of a mechanistic understanding of the BHQ reaction and, more currently, towards defining its potential use in synthesis.44 For example, Bull initially applied the BHQ reaction to the synthesis of coumarin derivatives (Scheme 13) presenting potential biological relevance.

Furthermore in response to the surge in interest in polyacene-based materials Little has developed a two-directional BHQ reaction for the syntheses of non-linear acenes (Scheme 14). This acene synthesis is particularly appealing as it enables the facile, regiospecific synthesis of functionalised acene cores via Pd-catalysed and SNAr coupling reactions from relative simple starting materials.45

Scheme 14 - Application of a two-directional BHQ reaction for the synthesis of functionalised chrysenes.45

R Me Ph

p-MeOC6H4 1-naphthyl 3-thienyl SPh SNp O-Ph 1-octyn-1- yl H

Table 2 - List of synthesised chrysene derivatives.

1.8 Aims and Objectives

The aim of the current research project was to develop a strategy for the synthesis of plumbagin. Our approach would utilise the BHQ reaction in the regioselective synthesis of a suitable functionalised quinone such as 46 which could then be converted into plumbagin via a C-halogen to C-OH interconversion.46

Scheme 14 - Proposed synthesis for Plumbagin using the BHQ reaction adapted from Bader.46

Our planned synthetic route (Scheme 14) was to commence with the commercially available hydroquinone 38 which was to be protected as its dimethyl ether. We predicted the Vilsmeier-Haack formylation of the electron-rich aromatic ring of 39 would proceed regioselectively affording 40 where the formyl group is introduced ortho- to the electron- donating methoxy groups and para- to the methyl group. A Dakin-West oxidation of 40 would afford phenol 41, a key intermediate. Allylation of 41 with allyl bromide followed by 29

ortho-Claisen rearrangement of 42 would afford phenol 43. It was anticipated that trichloroacetylation of 43 and subsequent copper-promoted benzannulation of the derived ester 44 would lead to aryl halide 45. This provides a substrate which could be ultimately transformed into plumbagin by way of an SNAr displacement-oxidation sequence.

Section 2: Results and Discussion

2.1 Synthesis of Dimethyl Ether 39

The starting point to our synthetic approach to plumbagin 1 was the commercially available hydroquinone 38 whose conversion to the dimethyl ether is documented in the literature.56

Scheme 15 - Overview of the alkylation of 38.

Various reaction conditions were in fact screened for this seemingly simple alkylation sequence as attempts to push this reaction to completion proved difficult.

Method Solvent Alkylating Base Yield Agent 1 DMSO MeI KOH -

2 Acetone Me2SO4 K2CO3 80+%

3 Acetone MeI K2CO3 90+%

Table 3 - List of different conditions used during this step.

As SN2 reactions are sensitive to a number of variables different conditions were used whilst attempting the reaction (Table 3). The first set of conditions (Table 3, 1) using DMSO as the solvent and sodium hydroxide as base proved to be unfavourable as during one of the procedures the flask containing all of the reagents began to exotherm rapidly well beyond the 30

boiling point of solvent and, thus, was abandoned. Alternatively, while the use of dimethyl sulphate as alkylating agent in this reaction proved successful the removal of excess of reagent from the crude reaction mixture proved difficult and was discontinued on the basis of a safety hazard. Finally the alkylation of 38 with methyl iodide in acetone using potassium carbonate proved to be most effective although it did produce a mixture of products (Fig. 8).

Upon initial analysis the 1H NMR spectrum showed the reaction had gone to completion consistently with 90+% yield and what appeared to be a single product. Later analysis by TLC revealed a series of products were being synthesised during the course of this reaction as illustrated in Fig. 7 and it was discovered the 1H NMR spectrum does not resolve the additional methyl and methoxy environments present from the monoalkylated isomers (Fig. 8).

Fig. 7 - The mixture of products created from the alkylation.

Fig. 8 - 1H NMR spectrum of the alkylation reaction.

This particular alkylation failed to go to completion even when using four equivalents of the alkylating agent and eight equivalents of potassium carbonate. Fortuitously separation of 39 from its isomers proved to be possible by column chromatography.

2.2 Formylation of the Aromatic Ring

Again the Vilsmeier-Haack formylation of 39 is documented in the literature.47 From this precedent we believed that formylation of 39 would proceed in a regioselective fashion affording the regioisomer 40 where the formyl group would be converted into a hydroxyl and ultimately esterified prior to the BHQ reaction.

In practice we observed that the Vilsmeier reagent was best prepared in situ by the reaction between anhydrous DMF and POCl3 at ambient temperature (Scheme 16). Once this reaction was complete 24 was introduced to the reaction vessel and heated at 70 °C overnight. Quenching of the reaction by pouring onto an excess of ice and hydrolysis with base as reported56 afforded the desired aldehyde 40 in 80% yield. Aldehyde was best purified by recrystallization from DCM-hexane rather than methanol.55

Scheme 16 - Formation of the Vilsmeier reagent.

Scheme 17 - Reaction mechanism of the Vilsmeier reagent with compound 39. 32

The diagnostic peaks on the 1H NMR spectrum are at δ 10.42 ppm indicative of an aldehyde group and the disappearance of one peak at δ 6.80 ppm providing sufficient evidence for a successful substitution (Fig. 9). Given the electronic effects of the electron donating dimethoxy groups the most favoured positions for the aldehyde to form would be 3- and 5- positions however the 3-position is sterically hindered from the presence of the methyl group making the 5-position more favourable.

Fig. 9 - 1H NMR spectrum of 2,5-Dimethoxy-4-methylbenzaldehyde 40.

2.3 Dakin-West Oxidation

To afford the phenol 41 a Dakin-West oxidation was performed using m-CPBA. Hydrogen peroxide is typically used however previous research carried out in the group by Bader46 showed an effective conversion using m-CPBA. The peracid begins by attacking the carbonyl group to form an intermediate and formate ester 40A is made before hydrolysis to afford phenol 41 (Scheme 18).

Scheme 18 - Reaction mechanism for the Dakin-West oxidation.

The disappearance of the downfield aldehyde singlet at δ 10.42 ppm and a singlet appearing at δ 8.20 ppm (Fig. 10) provides evidence for isolation of formate ester 40A as the major product with a minor amount of phenol 41 forming from the repeated use of saturated sodium hydrogen carbonate solution during work up giving two products in the crude 1H NMR.

Fig. 10 - 1H NMR spectrum showing the isolated formate ester 40A (-CHO at δ 8.20 ppm) and phenol 41(-OH at δ 5.50 ppm).

Fig. 10- 1H NMR spectrum showing the consumption of the formate ester 40A after hydrolysis.

The singlet at  8.20 ppm then disappears after complete hydrolysis with 50% NaOH solution and the spectrum (Fig. 10) now shows a broad singlet at δ 5.50 ppm indicative of phenol 41 isolated in a reasonable 79% yield.

2.4 Preparation the Allyl Phenyl Ether

To obtain the allyl phenyl ether 42 the phenol 41 was subjected to standard Williamson ether conditions using allyl bromide and K2CO3 in acetone. Subsequent purification by column chromatography gave the desired allyl phenol ether 42 (Fig. 11) in a reasonable yield of 91%.

Scheme 19 - The Williamson ether synthesis of allyl phenyl ether 42 from phenol 41.

Fig. 11 - 1H NMR spectrum of ether 42.

2.5 The ortho-Claisen Rearrangement

A [3,3] sigmatropic rearrangement of the allyl phenyl ether which then rapidly tautomerises giving the ortho-subsituted allyl-phenol as the major product (Scheme 20).

Scheme 20 - The ortho-Claisen rearrangement of 42 to 43.

Initial conditions investigated for this rearrangement involved heating the allyl ether in N,N- diethylaniline however the reaction appears to form desired product 43 in addition to phenol 41 from the previous step.

This step in particular presented numerous difficulties in obtaining a clean sample. Test reactions were initially carried out neat on a 100-500 mg scale however these amounts failed to meet the minimum volume necessary to be detected by a microwave. As the instrument was unable to reach the desired temperature a solvent was introduced in order for the reaction to be suitable for a microwave reactor. The solvent N,N-diethylaniline had been previously employed in the group for the efficient Claisen rearrangement of a large range of allyl phenyl ethers. In this case, however, the use of this solvent promotes a reductive cleavage of the ether leading to phenol 41 (Fig. 12).

Fig 12 - Evidence for the deallylation during the Claisen rearrangement of 42 leading to 43 and 41.

Repeating the reaction at 200 °C in the absence of diethyl aniline still resulted in removal of the allyl chain implying that the high temperature was the cause although it is possible that the electron rich system also has a role in this side reaction. Despite increasing the time required for the reaction to reach completion lowering the temperature to 160 °C and adopting neat conditions significantly improved the quality of the reaction giving quantitative isolation of 43 (Fig. 13).

Fig. 13 - 1H NMR spectrum of the rearrangement carried out neat at 160 °C in a microwave reactor.

2.6 Esterification

Standard esterification conditions were implemented in affording trichloroacetate 44 (Scheme 21).

Scheme 21 - Overview of esterification step.

Pyridine is often employed as a base due to it’s ability to deprotonate alcohol groups generating the alkoxide which attacks the carbonyl present on trichloroacetyl chloride and forms corresponding ester (Scheme 22). As hydrogen chloride is produced during the course of this reaction pyridine has the added advantage of scavenging it forming pyridinium

hydrogen chloride which is easily removed by using an aqueous work up procedure. This, however, does hydrolyse48 a small amount of compound 44 accounting for the loss in yield.

Scheme 22 - Mechanistic overview of the esterification.

2.7 The BHQ Reaction

Applying heat to a mixture of trichloroacetate 44 in the presence of copper (II) chloride and diglyme effects an ATRC reaction (Scheme 23) and instigating the proposed mechanism of the BHQ reaction as discussed in Section 1.7.1. A lactone is first formed with two chlorine atoms at the α-position and a third chlorine at the γ-position followed by the formation of a radical courtesy of the copper source. The system undergoes a suggested 8-endo radical cyclisation to give the spirolactone and six membered non-aromatic ring. A [2+2] retro- addition opens the lactone ring and expels CO2 followed by the removal of two equivalents of HCl and rearomatisation giving rise to chloronaphthalene 45. This was then purified through silica gel flash column chromatography leading to a successful isolation of pure compound 45.

Scheme 23 - Current working model of the BHQ reaction.

This 8-endo approach is proposed to be the more likely mechanism for the BHQ reaction as discussed in Section 1.7 as the diene alternative mechanism (Scheme 10) does not coincide with the additional experimental observations of halogen scrambling. The rationale behind Scheme 23 is the radical on 44A is stabilised by the lone pair on the methoxy group. The electron then abstracts chlorine from the catalyst and whilst halogens are barely a better leaving group than methoxy groups the difference is enough for chlorine to be eliminated and rearomatise the ring explaining why methanol is not produced as a by-product from the benzannulation of this particular system.

Two different reaction methods were investigated in the crucial BHQ benzannulation reaction (Scheme 24); the first involved the use of a Cu(I)-NHC complex, NHC1 (1,3,-bis-2,6- diisopropylphenylimidizolin-2-yliden copper (I)), as a catalyst using 1,2,-dichloroethane as solvent in a microwave-promoted reaction (internal temperature 160 °C). The second protocol utilised a simple preparation of copper(I) chloride as catalyst in diglyme at reflux 40

(162 °C). As both of these procedures resulted in the isolation of 45 in similar yields (circa. 30%) over the same time course (2 hours on a 5 mmol scale), the thermally driven process was adopted as the standard procedure for the scalable preparation of this key intermediate.

Scheme 24 - The two different methods for the BHQ reaction.

At this juncture we were also able to grow crystals suitable for a single crystal X-ray diffraction study (Fig. 14), the result of which diagnostically confirmed the presumed overall regiochemical outcome in the sequence leading to 30 from hydroquinone 23 as shown in Scheme 14.

Fig. 14 - ORTEP representation of 5-chloro-1,4-dimethoxy-2-methylnapthalene 45. Thermal ellipsoids at 50% probability.

2.8 Oxidation of Dimethyl Ether45 to Quinone 46

In order to afford the quinone a straightforward oxidative demethylation of the dimethoxy groups was required (Scheme 25). The use of ceric ammonium nitrate (CAN) facilitated this efficiently in a 60% yield after purification by column chromatography.

Scheme 25 - Formation of the quinone using ceric ammonium nitrate (CAN).

Diagnostic evidence of quinone formation was the disappearance of the methoxy peaks at δ 3.75 ppm and δ 3.85 ppm on the 1H NMR spectrum illustrated in the data in Fig. 15.

Fig. 15 - 1H NMR spectrum of chloroquinone 31 with the aromatic region between δ 7.5 ppm and δ 8.10 ppm expanded.

2.9 Displacement Reactions

Scheme 26 - The planned final two steps to plumbagin.

In order to obtain the target compound of plumbagin the initial proposed synthesis employed a displacement of aryl chloride and functionalise it with a methoxy phenyl ether followed by reacting with ceric ammonium nitrate to cleave off the methoxy benzene and produce the hydroxyl group (Scheme 26). It is important to mention the primary aim of this step is to displace the chlorine directly without additionalfunctionalisation of the ring.

Conditions to install the hydroxyl were previously determined on 48 due to the high degree of similarity shared with compound 45.46

Scheme 27 - Previous conditions adopted from Bader.46,49

The standard conditions of displacing a chlorine group with a hydroxyl using strong base, water and a high temperature proceeded smoothly on substrate 48 (potassium carbonate and DMSO were used as the base and solvent respectively). It was discovered when repeating the same reaction on compound 46 the 1H NMR presented a large number of missing proton environments with the hydrogen adjacent to the methyl group being clearly removed from the

sample suggesting that particular proton is acidic enough to become deprotonated in the presence of base. Dimer 46A (Scheme 28) was a possibility however the theory was later unfounded by data from mass spectrometry showing no molecular ion of a similar weight to the dimer.

Scheme 28 - Illustration of dimer 46A being potentially formed.

To investigate what degree solvent effects the reaction DMSO was substituted with DMF. After carrying out a blank reaction omitting a nucleophile it was confirmed that the substrate was reacting in basic conditions as no starting material was recovered. The hypothesis of compound 31 being base sensitive is supported by an attempted Finkelstein reaction using CuI in DMF at 140 °C in a microwave reactor only to recover the starting material in quantitative yield showing that chloronaphthoquinone 46 does not decompose at high temperatures or in DMF alone however 46 shows a noticeable sensitivity to the presence of base.

As base had to be excluded for this transformation, the use of the pre-formed sodium salt of a reagent circumvented exposure of 46 to basic conditions (Scheme 29). Sodium-4-methoxy phenolate was first made by reacting paramethoxy phenol with sodium hydride in diethyl ether and then reacted with the substrate. After working up the reaction with NaOH, brine and water to remove the remaining paramethoxy phenol the 1H NMR results of the sample showed that no reaction had taken place and the starting material was recovered in quantitative yield.

Scheme 29 - Use of sodium paramethoxide to carry out the displacement.

Proceeding with testing the reactivity at this step sodium thiophenolate was used as a stronger nucleophile (Scheme 30). The only product observable was diphenylsulfide formed by the oxidative dimerization of the sodium thiophenolate. The C-Cl bond of 46 resists reaction even under forceful conditions.

Scheme 30 - Sodium thiophenolate unable to carry out the displacement.

The most likely explanation would be aryl chloride 30 is unable to react with the nucleophiles due sensitivity to base and undesirable electronics of the ring. The first has been strongly suggested with a test reaction involving base and solvent alone. In the case of dimethoxychloronaphthalene 29 deactivation occurs due to the electron donating nature of the methoxy groups making the carbon-chlorine bond poorly electrophilic. Furthermore a lack of electron withdrawing groups in activating positions on the ring causes any carbocation formed to remain unstable so any direct displacement or substitution reactions appear to be difficult to achieve without introducing an additional step to functionalise the ring.

2.10 Synthesis of Aryl Bromide 48

The lack of desirable reactivity of the aryl chloride compound had led to exploration of the aryl bromide compounds as a precursor to plumbagin. A tribromoacetate group was installed as previously described in the esterification step prior to the BHQ by using tribromoacetyl chloride in lieu of the trichloroacetyl chloride forming a bromine group in the 4-position (Scheme 31). The rationale behind this approach is that whilst the bromo-derivatives would be less electrophilic than the chloro-compounds 45 and 46 the bond strength between the carbon and bromine would be much weaker presenting potentially higher reactivity.

Scheme 31 - Synthesis of an alternative precursor.

Following column chromatography 47 was isolated as a crystalline yellow solid and analysed by X-ray diffraction crystallography:

Fig 16 - ORTEP representation of tribromoacetate 47and bromide 48. Thermal ellipsoids at 50% probability.

The BHQ reaction was then repeated with 47 successfully isolating 48 from the reaction as supported by the crystal structure above (Fig. 16). As shown in the diagram the bromine has appeared as predicted providing strong evidence the BHQ reaction as described earlier in this report.

2.11 Lithium-Halogen Exchange

As described above a synthesis of the phenol via ether hydrolysis of intermediate 46 attempted with aryl bromide 48 (Scheme 32) proved unsuccessful as shown by 1H NMR analysis (Fig. 17). Presence of paramethoxy phenol is characterised diagnostically by the singlet representing the phenolic hydroxyl at δ 5.50 ppm.

Scheme 32 - Attempted displacement on 48.

Fig. 17 - 1H NMR analysis of the reaction shown in Scheme 32. 47

A different approach to displacing the bromine was investigated in the form of using a lithium-halogen exchange reaction; a reaction that would be difficult for aryl chloride 45.

Scheme 33 - Reaction conditions for the lithium-halogen exchange.

Whilst the exact mechanism for how the reaction proceeds is debated several theories have been discussed each with their own evidence. A prominent theory is that the akyllithium forms a reversible “ate-complex”50 as postulated by Farnham and Calbrese who collected a crystal structure of the intermediate as well as evidence of the lithium species behaving as a nucleophile and attacking the halogen bearing species.51 These provide more definitive approaches than the alternatives of radical generation and the exchange proceeding via a single electron transfer mechanism.52 We can hypothesise the mechanism should the reaction proceed via the ate-complex intermediate. Addition of n-BuLi forms the ate-complex making butylbromide anion 48A and then the corresponding lithium reagent 48B (Scheme 34):

Scheme 34 - Formation of the lithium salt.

It was decided treatment with2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (iPrO- B-pin) would be ideal due to its stability in air as well as presenting a facile target for oxidative cleavage. Target compound 49 was purified using column chromatography and isolated in a modest 55% yield with a diagnostic methyl peak in the 1H NMR spectrum presenting itself as a large singlet at δ 1.45 ppm. 48

Fig. 18 - 1H NMR spectrum showing the presence of the pinacol ester peak.

Additionally the crystal structure (Fig. 19) was acquired by vapour diffusion using a mixture of concentrated solution of 49 in DCM and n-hexane.

Fig. 19 - ORTEP representation of 2-(5,8-dimethoxy-6-methylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane. Thermal ellipsoids at 50% probability.

2.12 Final Steps to Plumbagin

Upon isolation of 49 only two steps were required to reach the target (Scheme 35).

Scheme 35 - Reaction conditions required to synthesise plumbagin.

After using the oxidative demethylation procedure as previously outlined in Scheme 27 to generate the quinone a simple oxidation using hydrogen peroxide would be used to cleave the carbon-boron bond and form a hydroxyl group in the desired position.

Fig. 20 - 1H NMR spectrum of the reaction between 2-(5,8-dimethoxy-6-methylnaphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane and CAN after work up.

Whilst adopting the demethylation conditions of CAN in a solvent mixture of acetonitrile and water it was discovered by-products were formed during the reaction along with the major product as shown in Fig. 20. Aberrant multiplets appearing in the aromatic region, a new 50

quartet at δ 2.13 ppm adjacent to the major product, suggests that a by-product similar to the starting material has formed leading to the reasonable assumption dimerisation has occurred during the reaction (Fig. 21). After searching in the literature it was discovered that previous research carried out by Tohma et al. had discovered using CAN whilst attempting an oxidative demethylation of their own resulted in dimerisation.53

Fig. 21 - Potential by-product from oxidative demethylation.

Fig. 22 - Magnified image of Fig. 20 highlighting potential by-product peaks.

To overcome the issues experienced [Bis(trifluoroacetoxy)iodo]benzene (PIFA) was used in lieu of CAN (Scheme 36) to great success producing a single product in a 54% yield characterised by the disappearance of the previous methoxy peaks (Fig. 23).

Scheme 36 - Modified conditions transforming 49 to 50.

Fig. 23 - 1H NMR spectrum of the reaction after PIFA oxidation with δ 7.55 ppm to δ 8.2 ppm expanded.

Furthermore, purification using silica gel column chromatography yielded quinone 50 as yellow crystals which were analysed by X-Ray diffraction crystallography definitively proving the isolation of the target compound (Fig. 24).

Fig. 24 - ORTEP representation of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1,4- dione. Thermal ellipsoids at 50% probability.

The final step was cleaving the carbon-boron bond to yield a hydroxyl using a simple oxidation method used previously to effect a similar C-B hydrolysis (Scheme 37).54

Scheme 37 - Conditions adopted from Sun et al. for oxidation of quinone 50.

The sample of compound 49 produced in Fig. 23 was unsuitable to be carried forward and was used as a test substrate yielding a hydrogen bonded OH group as a sharp singlet at δ 12.0 ppm (Fig. 25) with no additional by-products being present in the 1H NMR.

Fig. 25 - Successful cleavage of the C-B bond.

Fig. 26 - 1H NMR spectrum highlighting the product peaks.

Upon repeating the reaction on a bigger scale using compound 50 multiplets similar to the environments observed in the CAN oxidation had formed (Fig. 26). Attempts at isolating plumbagin were carried out using silica gel column chromatography however the retention factor values between that and plumbagin were indiscernible and could not be separated by 54

conventional means. More advanced methods of separation such as preparative HPLC or perhaps reverse phase column chromatography could be considered as possible means to isolation of plumbagin should this synthesis be repeated.

Section 3: Conclusions and Further Work

Over the course of this synthetic project plumbagin has been successfully prepared using the BHQ reaction. Whilst it is unfortunate the final step could not be completely purified the vast majority of the product present is the desired compound when compared against a commercially sourced sample as a reference (Fig. 27).

Fig. 27 - 1H NMR spectrum analysis comparing a commercial sample to the experimental product.

Fig. 28 - Expanded 1H NMR spectrum showing the aromatic region of Fig. 27 between δ 6.8 ppm and δ 7.70 ppm.

Crystal structures have been successfully obtained for the intermediates synthesised via The BHQ reaction providing further evidence the benzannulation method provides promising synthetic utility and a novel route to plumbagin has been devised as a result (Scheme 38).

Scheme 38 - Revised reaction conditions for the synthesis of plumbagin facilitated by the BHQ reaction.

Furthermore the successful implication of the BHQ reaction in synthesising natural products could be extended by adopting a two-directional approach (Scheme 39) in affording 51 3-3’- biplumbagin; a dimer of plumbagin isolated from the roots of P. indica.47

Scheme 39 - Prospective route to 3-3’-biplumbagin.

If the project were to be revisited optimising the final steps of the synthesis are imperative in order to make this total synthesis viable in particular the two final oxidation steps due to their currently low yields. The problematic last reaction step forming the desired phenol could potentially be solved by considering using an N-oxide compound55 as the oxidising agent:

Scheme 40 - An alternative method of oxidising the boronate ester using an N-Oxide.

As shown in Scheme 39 oxidation of boronate esters using N-oxides present a mild mode of oxidation which should be applicable to the base sensitive quinone structure present on plumbagin.

The final route developed to plumbagin proceeding via a boronate ester intermediate incease the number of synthetic possibilities. Application of a BHQ-Suzuki sequence to the synthesis of quinone-biaryls may have application in the design of new ligands for asymmetric syntheses or in the synthesis of molecules of biological interest.

Section 4: Experimental

General Considerations

All reactions were carried out in dry glassware under an inert atmosphere (unless otherwise specified) and all solvents were dried according to appropriate drying procedures. Solvents and commercial reagents were sourced from Sigma Aldrich, Fisher Scientific and Acros Organics. Anhdyrous THF refers to THF dried over Na-benzophenoneketyl. NMR spectral data were recorded using B300 Bruker AvanceUltraShield 300 MHz, B400 Bruker Avance III 400 MHz and B500 Bruker Avance II+ 500 MHz spectrometers.Chemicals shifts (δ) were recorded in parts per million downfield from tetramethlysilane (δ 0.00 ppm). Signal splitting patterns are described as singlet (s), doublet (d), double doublet (dd), triplet (t), quartet (q) and multiplet (m), or any of the combination listed, with assignments for carbon and hydrogen aided through the use of HSQC and HMBC. Coupling constants (J) are recorded in Hz. Mass measurements were recorded using a Micromass Trio 200 spectrometer using Electrospray (ES+/-), Gas Chromatography-Mass Spectrometry (GC/MS) and Atmospheric- Pressure Chemical Ionisation (APCI). High resolution mass spectral data was recorded using a Kratos Concept IS spectrometer. IR spectral data was recorded using a Bruker Alpha FT- -1 IR instrument and absorption peaks (νmax) were measured in wave numbers (cm ). Microwave reactions were carried out with a Biotage Initiatior® focussed microwave reactor (maximum output power 300 watt,operating frequency of 2450 MHz). TLC analysis was carried out using 0.2 mm precoated polyester Machery-Nagel POLYGRAM SIL G/UV254 silica gel plates with a fluorescent indicator and visualised by UV absorption (254 nm). Column chromatography was carried out using glassware sourced from Scientific Glass Laboratories on silical gel with a partical size between 40-60 µm.

39 - 1-4-Dimethoxy-2-methylbenzene56

2-Methyl-1,4-hydroquinone (1 g, 8.06 mmol) was added to a suspension of anhydrous K2CO3 in dry acetone (10 mL) at ambient temperature. Methyl iodide (1.5 mL, 24.18 mmol) was then added via syringe after 5 minutes and the reaction mixture was left to stir at room temperature for 24 hours. The reaction mixture was then diluted with EtOAc (40 mL) and the organic extracts were washed with water (5 x 20 mL) then saturated aq. NaHCO3 (5 x 20 mL) before being dried over anhydrous MgSO4 and concentrated in vacuo to afford the crude product as brown-coloured viscous oil.

Column chromatography (15% EtOAc in petroleum ether, % v/v) of the residue afforded the title compound as a clear yellow oil. 612 mg (50% yield). This was also repeated on a 10 g scale which afforded the title compound in 5.9 g (48% yield).

1 H NMR (400 MHz, CHLOROFORM-d) 2.68 (s, 3 H, Ar2-CH3), 4.17 (s, 3 H, Ar4-OCH3),

4.19 (s, 3 H, Ar1-OCH3), 6.75 (dd, J=6.1, 8.8 Hz, 1 H, Ar5/6-H), 6.79 (s, J=8.88 MHz, 1H, 13 Ar5/6-H), 6.84 (s,1 H, Ar3-H) ppm; C NMR (101 MHz, CHLOROFORM-d) δ 16.5 (Ar2-

CH3), 55.5 (Ar4-OCH3), 58.5 (Ar1-OCH3), 110.7 (Ar5/6), 110.8 (Ar5/6), 117.0 (Ar3), 127.8 -1 + (Ar2), 152.5 (Ar1), 153.5 (Ar4) ppm; IR: νmax/cm 1220 (C-O), 1658 (Ar-CH3); MS ES m/z 153.1 ([M+H]+,100%).

40 - 2,5-Dimethoxy-4-methylbenzaldehyde56

POCl3 (2.45 mL, 26.32 mmol) was added drop-wise via syringe to anhydrous DMF (4.1 mL, 52.64 mmol) at 0 °C. Upon completion of the addition the reaction mixture was left to stir at 0 °C for 3 h to generate the Vilsmeier reagent. Compound 24 (1 g, 6.58 mmol) was then added drop-wise to the Vilsmeier reagent and then heated to 70 °C overnight.

After 16 h the reaction mixture was allowed cool to ambient temperature before being poured over an excess of ice water with care due to possible exotherm from the reaction. The pH of the solution was adjusted to basic conditions (pH 14) by the careful addition of aq. NaOH (50% w/v) at which point the crude product precipitated from the solution and was collected by vacuum filtration.

The crude product, a tan coloured solid, was dissolved in EtOAc (20 mL) and washed with water (5 x 50 mL), saturated aq. NaHCO3 (5 x 50 mL) and the saturated brine solution (5 x

50 mL) before being dried over MgSO4. Concentration in vacuo afforded the title compound as a crystalline, light-brown solid which was recrystallized using hexane affording 972 mg (82% yield). This was also repeated on an 8 g scale which afforded the title compound in

7.6 g (80% yield), m.p 77-79 °C (Lit. m.p. 77-78 °C).55

1 H NMR (400 MHz, CHLOROFORM-d) 2.28 (s, 3 H, Ar4-CH3), 3.82 (s, 3 H, Ar2-OCH3),

3.88 (s, 3 H, Ar5-OCH3), 6.81 (s, 1 H, Ar6-H), 7.24 (s, 1 H, Ar3-H), 10.39 (s, 1 H, -CHO) 13 ppm; C NMR (76 MHz, CHLOROFORM-d) δ 17.3 (Ar4-CH3), 55.7 (Ar2-OCH3), 56.1

(Ar5-OCH3), 107.7 (Ar6), 114.7 (Ar3), 122.8 (Ar1), 136.6 (Ar4), 152.0 (Ar5), 156.6 (Ar2), -1 189.2 (-CHO) ppm; IR: νmax/cm 1267 (C-O), 1372 (-CH3), 2830 (OC-H), 1656 (-CHO), 3009 (Ar-H); MS ES+ m/z 181.1 ([M+H]+), 100%).

41 - 2,5-Dimethoxy-4-methylphenol57

41 m-CPBA (1.72 g, 10 mmol, <77%) was added to a stirring solution ofcompound 25 (1 g, 5.55 mmol) in DCM (20 mL) while maintaining the internal temperature at 0 °C. Once the addition was complete, the reaction mixture was brought to reflux and then allowed to cool down to ambient temperature. The reaction mixture was then extracted with saturated

NaHCO3 solution (40 mL) and the organic layer was washed with water (5 x 20 mL) and saturated NaHCO3 solution (3 x 20 mL) and concentrated in vacuo to afford the crude formate ester as a viscous oil.

This oil was then dissolved in DCM (20 mL) and stirred with 50% NaOH solution (10 mL, 50% w/v) for 1 h. At this stage conc. HCl (10 M) was then added slowly in order to acidify the aqueous phase to pH 1 and monitored using Universal Indicator Paper. The resultant organic layer was then separated, washed with water (7 x 20 mL), dried over anhydrous

MgSO4 and concentrated in vacuo to afford the title compound as a dark brown-coloured crystalline solid and used without further purification. 747 mg (80% yield).This was also repeated on a 10 g scale which afforded the title compound in 7.4 g (79% yield), m.p 77-79 °C (Lit. m.p. 78.3-78.6 °C).57

1 H NMR (400 MHz, CHLOROFORM-d) 2.16 (s, 3 H, Ar4-CH3), 3.77 (s, 3 H, Ar2-OCH3),

3.84 (s, 3 H, Ar5-OCH3), 5.31 - 5.73 (s, 1 H, -OH), 6.54 (s, 1 H, Ar6-H), 6.69 (s, 1 H, Ar3-H)

13 ppm; C NMR (101 MHz, CHLOROFORM-d) 15.7 (Ar4-CH3), 56.0 (Ar2-OCH3), 56.8

(Ar5-OCH3), 114.0 (Ar3), 117.0 (Ar4), 139.8 (Ar2), 144.01 (Ar1-OH), 152.1 (Ar5) ppm; IR: -1 - - νmax/cm 1277 (C-O), 1378 (-CH3), 3004 (Ar-H), 3351 (-OH); MS ES m/z 167.0 ([M-H] , 100%).

42 - 1-(Allyloxy)-2,5-dimethoxy-4-methylbenzene57

2,5-Dimethoxy-4-methylphenol (1 g, 6 mmol) was added to a suspension of potassium carbonate (1.7 g, 12 mmol) in dry acetone (30 mL) and stirred for five minutes under nitrogen. Allyl bromide (1 mL, 12 mmol) was then added drop-wise to the reaction mixture and then brought to a gentle reflux for a period of 8 h. After allowing to cool to ambient temperature the reaction mixture was filtered through a celite pad to remove any inorganic material and the filtrate was then concentrated in vacuo.

The residue was then redissolved in DCM, washed (water, 5 x 20 mL) and then saturated

NaHCO3 solution (5 x 20 mL), dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the residue by column chromatography (10% EtOAc in petroleum ether, % v/v) afforded the title compound as a yellow oil. 1.16 g (94% yield). This was also repeated on an 8 g scale which afforded the title compound in 9 g (91% yield).

1 H NMR (400 MHz, CHLOROFORM-d) 2.17 – 2.19 (s, 3 H, Ar4-CH3), 3.79 (s, 3 H, Ar2-

OCH3), 3.84 (s, 3 H, Ar5-OCH3), 4.62 (dt, J=5.6, 1.5 Hz, 2 H, O-CH2), 5.28 (dq, J=1.5, 10.6 Hz, 1 H, cis C=H), 5.41 (dq, J=1.8, 17.4 Hz, 1 H, trans C=H), 6.11 (ddt, J=5.6, 10.6, 17.4), 13 6.55 (s, 1 H, Ar6-H), 6.73 (s, 1 H, Ar3-H) ppm; C NMR (101 MHz, CHLOROFORM-d)

15.6 (Ar4-CH3), 56.3 (Ar2-OCH3), 56.8 (Ar5-OCH3), 70.7 (O-CH2), 100.3 (Ar6), 115.5

(Ar3), 117.8 (=CH2), 118.7 (Ar1), 133.8 (-CH=), 143.3 (Ar4), 146.4 (Ar2), 151.6 (Ar5) ppm; -1 + IR: νmax/cm 1263 (C-O), 1397 (-CH3), 1611 (C=C), 2850 (-CH2), 3080 (Ar-H); MS ES m/z 231.0 ([M+Na]+), 100%).

43 - 2-Allyl-3,6-dimethoxy-4-methylphenol

43 1-(Allyloxy)-2,5-dimethoxy-4-methylbenzene (1 g, 3.7 mmol) was heated in a microwave reactor at 160 °C for 14 h to give the title compound in quantitative yield as a dark orange oil (1 g) with no further purification. This was repeated on a 6 g scale affording the title compound in quantitative yield (100% yield).

1 H NMR (400 MHz, CHLOROFORM-d) 2.25 (s, 3 H, Ar4-CH3) 3.47 (dt, 1.8, 6.1 Hz, 2 H,

Ar2-CH2) 3.70 (s, 3 H, Ar3-OCH3) 3.85 (s, 3 H, Ar6-OCH3) 5.04 (m, 2 H, C=H2) 5.60 (s, 1 H, 13 Ar1-OH), 6.00 - 6.13 (m, 1 H, -CH=) 6.58 (s, 1 H, Ar5-H) ppm; C NMR (101 MHz,

CHLOROFORM-d) 15.8 (Ar4-CH3), 28.5 (Ar2-CH2-), 56.3 (Ar6-OCH3), 61.0 (Ar3-OCH3),

110.8 (Ar5), 119.4 (Ar2-O-), 114.7 (=CH2), 121.1 (Ar4), 136.8 (CH=), 142.2 (Ar3), 142.7 -1 (Ar6), 150.8 (Ar1-OH) ppm; IR: νmax/cm 1193 (C-O),1656 (C=C), 2842 (-CH2-),3046 (Ar- H), 3514 (-OH); MS ES- m/z 207.0 ([M-H]-, 100%).

44 - 2-Allyl-3,6-dimethoxy-4-methylphenol-2,2,2- trichloroacetate

44 To a solution of compound 28 (1 g, 4.83 mmol) at 0 °C in anhydrous diethyl ether (20 mL) was added dry pyridine (0.58 mL, 7.24 mmol) followed by drop-wise addition of trichloroacetyl chloride (0.81 mL, 7.24 mmol). After the addition was completed the reaction mixture was left to warm up to room temperature over a period of 3 h.

The reaction mixture was then quenched by the addition of saturated NaHCO3 solution and the mixture was extracted with diethyl ether (30 mL). The combined organic extracts were washed with water (3 x 20 mL), NaHCO3 (2 x 10 mL), dried over anhydrous MgSO4 and concentrated in vacuo to afford the title compound as a brown, viscous oil which was carried through crude. 1.55 g (91% yield).

1 H NMR (400 MHz, CHLOROFORM-d) 2.33 (s, 3 H, Ar4-CH3), 3.41 (dt, J=1.6, 6.0 Hz, 2

H, Ar2-CH2), 3.72 (s, 3 H, Ar6-OCH3), 3.81 (s, 3 H, Ar3-OCH3), 5.02 (t, J=1.9 Hz, 1 H,

C=H), 5.04 (dq, J=1.6, 1.9 Hz, 1H, C=H), 5.91 (m, 1 H, -CH=), 6.72 (s, 1 H, Ar5-H) ppm;

13 C NMR (101 MHz, CHLOROFORM-d) 16.4 (Ar4-CH3), 28.9 (-CH2-), 56.3 (Ar6-OCH3),

61.2 (Ar3-OCH3), 112.7 (Ar5), 115.9 (=CH2), 116.1 (-CCl3), 126.5 (Ar2), 130.2 (Ar4), 135.5 -1 (CH=), 136.2 (Ar1-O-), 147.0 (Ar6), 150.3 (Ar3), 159.6 (O-C=O) ppm; IR: νmax/cm 1209 (C- + O), 1634 (C=C), 1764 (C=O), 2842 (-CH2-), 3081 (Ar-H); MS ES m/z 363.0 35 + 35 37 + ([M{ Cl3}+Na] ), 100%), 365.0 ([M{ Cl2 + Cl}+Na] , 40%).

45 - 5-Chloro-1,4-dimethoxy-2-methylnaphthalene

Method A:

A sealable reaction vial was charged with a solution of trichloroacetate 29 (1 g, 2.83 mmol) and NHC1 (1,3,-bis-2,6-diisopropylphenylimidizolin-2-yliden copper (I)) (70 mg, 10mol%) in degassed 1,2-dichloroethane 5 mL) and was then sparged with nitrogen before it was heated in a microwave reactor for 2 h at 200 °C.

Upon cooling to ambient temperature the contents of the vial was added to a solution of 12% EtOAc in petroleum ether (% v/v) and placed directly onto a silica gel column via a wet load isolating the title compound as a yellow crystalline solid. 200 mg (30% yield), m.p.

49-52 °C.

Method B:

Alternatively, mild thermolysis of a solution of trichloroacetate 29 (1 g, 2.83 mmol) in diglyme (bis-(2-methoxyethyl) ether), 1.5 mL) using an aluminium DrySyn at reflux (162 °C) for 2 h in the presence of cuprous chloride (23 mg, 10 mol%) as catalyst followed by purification using silica gel chromatography (12% EtOAc in petroleum ether, % v/v) afforded the title compound as a yellow solid. 200 mg (30% yield), m.p. 49-52 °C.

1 H NMR (400 MHz, CHLOROFORM-d) 2.44 (s, 3 H, Ar2-CH3), 3.84 (s, 3 H, Ar1-OCH3),

3.94 (s, 3 H, Ar4-OCH3), 6.73 (s, 1 H, Ar3-H), 7.35 (t, J=8.3 Hz, 1H, Ar7-H), 7.46 (dd, J=1.3, 13 8.3 Hz, 1H, Ar6-H), 7.99 (dd, J=1.3, 8.3 Hz, 1H, Ar8-H) ppm; C NMR (101 MHz,

CHLOROFORM-d) 16.1 (Ar2-CH3), 56.5 (Ar4-OCH3), 61.2 (Ar1-OCH3), 110.8 (Ar3),

120.9 (Ar8), 122.3 (Ar4a), 126.1 (Ar2), 126.9, 128.0 (Ar8a), (Ar7), 128.3 (Ar6), 131.4 (Ar5-Cl), -1 + 147.3 (Ar1), 152.3 (Ar4) ppm; IR: νmax/cm 1232 (C-O), 1381 (-CH3), 2833 (-CH=); MS ES 35 + 37 + + m/z 237.1 ([M{ Cl}+H] , 100%), 239.1 (M{ Cl}+H] , 40%); HRMS EI C13H13O2Cl1 ([M{35Cl}+H]+) requires 237.0599, found 237.0589.

46 - 5-Chloro-2-methyl-1,4-naphthoquinone

To a solution of 30 (200 mg, 0.84 mmol) in acetonitrile (5 mL) was added an aqueous solution of ceric ammonium nitrate (921 mg, 1.68 mmol, water 5 mL) at 0 °C. After 2 hours at ambient temperature EtOAc was added to the reaction mixture and the organic extracts were washed (water 5 x 10 mL), dried over anhydrous MgSO4 and concentrated in vacuo. Column chromatography of the residue (20% EtOAc in petroleum ether, % v/v) afforded the title compound as a bright yellow solid. 104 mg (60% yield), m.p. 93-95 °C.

1 H NMR (400 MHz, CHLOROFORM-d) 2.18 (d, J=1.51 Hz, 3 H, Ar2-CH3), 6.84 (q,

J=1.51, 3.03 Hz, 1 H, Ar3-H), 7.62 (t, J=8.1 Hz, 1H, Ar7-H), 7.73 (dd, J=1.5, 8.1 Hz, 1 H, 13 Ar6-H), 8.10 (dd, J=1.5, 8.1 Hz, 1 H, Ar8-H) ppm; C NMR (101 MHz, CHLOROFORM-d)

15.9 (Ar2-CH3), 126.2 (Ar8), 128.1 (Ar4a), 134.2 (Ar8a), 134.64 (Ar5), 137.2 (Ar3), 137.4

-1 (Ar6), 146.3 (Ar2), 153.3 (Ar7), 183.4 (Ar4),  (Ar1) ppm; IR: νmax/cm 1381 (Ar-CH3), 1659 (C=O), 2849 (Ar-H), 3076 (Ar-H); MS APCI- m/z 207.0 ([M{35Cl}-H]-, 100%), 209.0 ([M{37Cl}-H]-, 40%).

47 - 2-Allyl-3,6-dimethoxy-4-methylphenol-2,2,2- tribromoacetate

After initially cooling a round bottomed flask to 0 °C, the previously synthesised 2-allyl-3,6- dimethoxy-4-methylphenol 43 (700 mg, 4.83 mmol) was dissolved in sodium dried diethyl ether (10 mL). Pyridine (0.4 mL, 5.04 mmol) was added followed by tribromoacetyl chloride (1.0 mL, 5.04 mmol) and the reaction mixture was left to reach ambient temperature over the course of 3 h. The reaction was quenched with NaHCO3 and the crude product extracted with diethyl ether. The organic layer was washed (water, 5 x 10 mL), saturated NaHCO3solution

(5 x 10 mL) and dried with MgSO4. Rotary evaporation gave the crude productasa dark brown, pungent, and viscous oil. Purification of the residue by silica gel column chromatography (10% EtOAc in petroleum ether, % v/v) gave the title compound as a crystalline yellow solid. 1.05 g (64% yield), m.p. 52-54 °C.

1 H NMR (500 MHz, CHLOROFORM-d) 2.33 (s, 3 H, Ar4-CH3), 3.72 (s, 3 H, Ar6-OCH3),

3.82 (s, 3 H, Ar3-OCH3), 3.45 (d, J= 4.7 Hz, 2 H, Ar2-CH2), 5.05 (m, 2 H, =CH2), 5.94 (m, 1

13 H, -CH=), 6.72 (s, 1 H, Ar5-H) ppm; C NMR (125 MHz, CHLOROFORM-d) 16.5 (Ar4-

CH3), 27.8 (C-Br3), 28.9 (-CH2), 56.3 (Ar6-OCH3), 61.2 (Ar3-OCH3), 112.7 (Ar5), 115.9

(=CH2), 126.6 (Ar2), 130.1 (Ar4), 135.7 (-CH=), 136.3 (Ar1), 147.1 (Ar3), 150.2 (Ar6), 159.6 -1 + (O-C=O) ppm; IR: νmax/cm 1233 (Ar-O-), 1463 (-CH2-) 1635 (C=C), 2938 (Ar-H); MS ES 79 81 + 79 + 79 m/z 509.2 ([M{ Br2 + Br1}+Na] , 100%), 507.8 ([M{ Br3}+Na] ), 60%), 511.0 ([M{ Br1 81 + + Br2}+Na] ), 50%).

48 - 5-Bromo-1,4-dimethoxy-2-methylnaphthalene

Mild thermolysis of a solution of tribromoacetate 32 (1 g, 2.10 mmol) in diglyme (bis-(2- methoxyethyl) ether), 1.5 mL) using an aluminium DrySyn at reflux (162 °C) for 2 h in the presence of cuprous bromide (30 mg, 10 mol%) as catalyst followed by purification using column chromatography (12% EtOAc in petroleum ether, % v/v) isolated the title compound as a yellow, crystalline solid. 260 mg (45% yield), m.p. 62-64 °C.

1 H NMR (400 MHz, CHLOROFORM-d) 2.45 (s, 3 H, Ar2-CH3), 3.84 (s, 3 H, Ar4-OCH3),

3.93 (s, 3 H, Ar1-OCH3), 6.74 (s, 1 H, Ar3-H), 7.26 (t, J=7.3, 8.3 Hz, 1 H, Ar7-H), 7.75 (dd, 13 J=7.3, 8.3 Hz, 1 H, Ar6-H), 8.06 (d, J=8.3 Hz, 1 H, Ar8-H) ppm; C NMR (101 MHz,

CHLOROFORM-d) 16.1 (Ar2-CH3), 56.2 (Ar4-OCH3), 61.2 (Ar1-OCH3), 110.9 (Ar3-H),

117.0 (Ar5-Br), 121.5 (Ar6), 123.2 (Ar4a), 126.4 (Ar7), 126.9 (Ar8a), 131.4 (Ar2), 132.3 (Ar8), -1 147.2 (Ar1), 151.8 (Ar4) ppm; IR: νmax/cm 1267 (Ar-O), 1380 (-CH3), 3071 (Ar-H); MS APCI+ m/z 281.2 ([M{79Br}+H]+, 95%), 283.1 ([M{81Br}+H]+, 100%).

49 - 2-(5,8-Dimethoxy-6-methylnaphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane

To bromide 33 (305 mg, 1.09 mmol) in a dry Schlenk flask under an atmosphere of nitrogen was added anhydrous THF (20 mL). This solution was degassed (three times) under vacuum and cooled to -78 °C. To this solution was added n-BuLi (1.2 mL, 1.8 eq, 1.6 mol solution) and the reaction mixture maintained at this temperature for an additional period of 2 h. At this stage 2-isopropoxy,4,4,5,5,-tetramethyl-1,3,2-dioxaboralane (iPrO-B-pin, 0.45 mL, 2.17 mmol) was added by syringe at -78 °C and the reaction mixture was left to reach ambient temperature overnight.

The organic solvent was removed in vacuo leaving behind a white solid which was dissolved in water (30 mL) and washed with DCM (5 x 10 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to give a precipitate. Purification of the residue by column chromatography (10% EtOAc in petroleum ether) afforded the title compound as a colourless crystalline solid. 196 mg (55% yield), m.p. 146-148 °C.

1 H NMR (400 MHz, CHLOROFORM-d) 1.45 (s, 12 H, B-pin), 2.43 (s, 3 H, Ar6-CH3),

3.83 (s, 3 H, Ar8-OCH3), 3.98 (s, 3 H, Ar5-OCH3), 6.63 (s, 1 H, Ar7-H), 7.48 (m, 2 H, Ar2-H,

13 Ar3-H), 8.04 (m, 1 H, Ar4-H) ppm; C NMR (101 MHz, CHLOROFORM-d) 16.3 (Ar6-

CH3), 25.1 ((CH3)4), 55.7 (Ar8-CH3), 61.3 (Ar5-OCH3), 83.6 (BO-C2), 107.5 (Ar7), 122.4

(Ar4), 125.3 (Ar6), 125.7/129.4 (Ar2), 125.7/129.4 (Ar3), 127.0 (Ar4a), 128.2 (Ar8a), 147.5 13 (Ar5), 151.8 (Ar8) ppm (Ar1-B unresolvable on C NMR spectrum due to quadrupole -1 + broadening); IR: νmax/cm 1232 (C-O), 2846 (C=CH), 2975 (CH3); MS ES m/z 329.4 11 + + 11 + ([M{ B}+H] , 100%); HRMS ESI C19H26O4B1([M{ B}+H] ) requires 329.19119, found 329.1923.

50 - 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalene-1,4-dione

50 Borolane 34 (100mg, 0.3 mmol) was dissolved in a mixture of methanol and water (2 mL, 0.5 mL, 0.25% v/v). [Bis(trifluoroacetoxy)iodo]benzene (PIFA) (232 mg, 0.54 mmol) was added to the suspension and stirred at room temperature for 6 h. Upon completion the mixture was dissolved in water (20 mL) and the extracted with DCM (3 x 10 mL). The combined organic layers were dried over MgSO4 and then concentrated in vacuo to give the crude product which was purified by column chromatography (20% EtOAc in petroleum ether) and isolated the title compound as a yellow solid. 48 mg (54% yield), m.p 98-100 °C.

1H NMR (500 MHz, CHLOROFORM-d) 1.49 (s, 12 H, B-pin), 2.20 (d, J=1.6 Hz, 3 H,

Ar2-CH3),6.86 (d, J=1.6 Hz, 1 H, Ar3-H), 7.69 (t, J=7.3 Hz, 1 H, Ar7-H),7.72 (dd, J=1.6, 7.3 13 Hz, 1 H, Ar6-H), 8.08 (dd, J=1.6, 7.3 Hz, 1 H, Ar8-H) ppm; C NMR (125 MHz,

CHLOROFORM-d) 16.7 (Ar2-CH3), 24.9 ((CH3)4), 84.3 (BO-C2), 127.0 (Ar8), 132.8 (Ar7),

134.9 (Ar3), 135.7 (Ar2), 135.8 (Ar4a), 136.9 (Ar6), 148.8 (Ar8a), 185.6 (Ar1=O), 186.9 13 (Ar4=O) ppm (Ar5-Bunresolvable on C NMR spectrum due to quadrupole broadening); IR: -1 + νmax/cm 1117 (C-O), 1257 (-CH3), 1697 (C=O), 2871 (C=CH); MS ES m/z 323.2 ([M{11B}+Na]+, 100%).

1 - 5-Hydroxy-2-methyl-1,4-naphthoquinone

To a solution of quinone 50 (38 mg, 1.27 mmol) in DMF (5 mL) was added H2O2 (30%, 1 mL per h) at room ambient temperature and stirred for 3 h adding 1 mL of H2O2 every hour. The reaction mixture was dissolved in EtOAc (20 mL) separated, washed with water (2 x 10 mL), brine (2 x 10 mL) and dried over anhydous MgSO4.

Concentration of the organic layer in vacuo afforded the crude product which contained impure plumbagin (16 mg).

1 H NMR (400 MHz, CHLOROFORM-d) in part:  2.20 (d, J=1.5 Hz, 3 H, Ar2-CH3), 6.82

(q, J=1.5 Hz, 1 H, Ar3-H), 7.26 (masked dd, J=1.5, 5.8 Hz, 1 H, Ar6/8-H), 7.62 (t, J=7.5 Hz, 1

H, Ar7-H), 7.64 (dd, J=1.5, 7.5 Hz, 1 H, Ar6/8-H), 12.0 (s, 1 H, Ar5-OH) ppm.

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Appendix

1. Crystal structure of 5-chloro-1,4-dimethoxy-2-methyl naphthalene, 45

Table 1. Crystal data and structure refinement for compound 45 (University of Manchester reference: s4038na).

Identification code s4038na Empirical formula C13 H13 Cl O2 Formula weight 236.68 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 9.0088(3) Å = 90°. b = 17.6752(5) Å = 103.218(2)°. c = 7.2724(2) Å  = 90°. Volume 1127.32(6) Å3 Z 4 Density (calculated) 1.395 Mg/m3 Absorption coefficient 2.848 mm-1 F(000) 496 Crystal size 0.18 x 0.14 x 0.03 mm3 Theta range for data collection 5.04 to 72.26°.

Index ranges -9<=h<=11, -19<=k<=21, -8<=l<=8 Reflections collected 5132 Independent reflections 2157 [R(int) = 0.0201] Completeness to theta = 67.00° 98.7 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9194 and 0.798131 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2157 / 0 / 148 Goodness-of-fit on F2 1.058 Final R indices [I>2sigma(I)] R1 = 0.0312, wR2 = 0.0830 R indices (all data) R1 = 0.0353, wR2 = 0.0856 Largest diff. peak and hole 0.289 and -0.205 e.Å-3

Table 2. Bond lengths [Å] and angles [°] for compound 45.

C(1)-C(10) 1.368(2) C(1)-C(2) 1.4291(19) C(1)-Cl(1) 1.7491(15) C(2)-C(7) 1.4341(19) C(2)-C(3) 1.4364(19) C(3)-O(1) 1.3608(16) C(3)-C(4) 1.3728(19) C(4)-C(5) 1.4127(18) C(4)-H(4) 0.9500 C(5)-C(6) 1.368(2) C(5)-C(12) 1.5072(19) C(6)-O(2) 1.3892(16) C(6)-C(7) 1.425(2) C(7)-C(8) 1.418(2) C(8)-C(9) 1.368(2) C(8)-H(8) 0.9500 C(9)-C(10) 1.404(2) C(9)-H(9) 0.9500 C(10)-H(10) 0.9500 C(11)-O(1) 1.4310(17) C(11)-H(11A) 0.9800 C(11)-H(11B) 0.9800 79

C(11)-H(11C) 0.9800 C(12)-H(12A) 0.9800 C(12)-H(12B) 0.9800 C(12)-H(12C) 0.9800 C(13)-O(2) 1.4325(17) C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800

C(10)-C(1)-C(2) 122.42(14) C(10)-C(1)-Cl(1) 114.88(11) C(2)-C(1)-Cl(1) 122.69(11) C(1)-C(2)-C(7) 116.04(13) C(1)-C(2)-C(3) 126.80(13) C(7)-C(2)-C(3) 117.16(12) O(1)-C(3)-C(4) 122.83(12) O(1)-C(3)-C(2) 116.96(12) C(4)-C(3)-C(2) 120.21(12) C(3)-C(4)-C(5) 122.73(13) C(3)-C(4)-H(4) 118.6 C(5)-C(4)-H(4) 118.6 C(6)-C(5)-C(4) 118.26(13) C(6)-C(5)-C(12) 122.38(13) C(4)-C(5)-C(12) 119.35(12) C(5)-C(6)-O(2) 120.61(12) C(5)-C(6)-C(7) 121.60(12) O(2)-C(6)-C(7) 117.71(12) C(8)-C(7)-C(6) 119.74(13) C(8)-C(7)-C(2) 120.25(13) C(6)-C(7)-C(2) 120.01(13) C(9)-C(8)-C(7) 121.06(14) C(9)-C(8)-H(8) 119.5 C(7)-C(8)-H(8) 119.5 C(8)-C(9)-C(10) 119.72(14) C(8)-C(9)-H(9) 120.1 C(10)-C(9)-H(9) 120.1 C(1)-C(10)-C(9) 120.48(14) 80

C(1)-C(10)-H(10) 119.8 C(9)-C(10)-H(10) 119.8 O(1)-C(11)-H(11A) 109.5 O(1)-C(11)-H(11B) 109.5 H(11A)-C(11)-H(11B) 109.5 O(1)-C(11)-H(11C) 109.5 H(11A)-C(11)-H(11C) 109.5 H(11B)-C(11)-H(11C) 109.5 C(5)-C(12)-H(12A) 109.5 C(5)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12B) 109.5 C(5)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 O(2)-C(13)-H(13A) 109.5 O(2)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 O(2)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 C(3)-O(1)-C(11) 117.56(11) C(6)-O(2)-C(13) 113.28(10)

Table 3.Torsion angles [°] for compound 45.

C(10)-C(1)-C(2)-C(7) -0.6(2) Cl(1)-C(1)-C(2)-C(7) 178.44(10) C(10)-C(1)-C(2)-C(3) -179.81(13) Cl(1)-C(1)-C(2)-C(3) -0.8(2) C(1)-C(2)-C(3)-O(1) 0.5(2) C(7)-C(2)-C(3)-O(1) -178.73(11) C(1)-C(2)-C(3)-C(4) -179.92(13) C(7)-C(2)-C(3)-C(4) 0.84(19) O(1)-C(3)-C(4)-C(5) 179.93(12) C(2)-C(3)-C(4)-C(5) 0.4(2) C(3)-C(4)-C(5)-C(6) -0.6(2) C(3)-C(4)-C(5)-C(12) 179.73(13) 81

C(4)-C(5)-C(6)-O(2) -177.11(12) C(12)-C(5)-C(6)-O(2) 2.5(2) C(4)-C(5)-C(6)-C(7) -0.4(2) C(12)-C(5)-C(6)-C(7) 179.23(13) C(5)-C(6)-C(7)-C(8) -178.43(13) O(2)-C(6)-C(7)-C(8) -1.64(19) C(5)-C(6)-C(7)-C(2) 1.6(2) O(2)-C(6)-C(7)-C(2) 178.44(11) C(1)-C(2)-C(7)-C(8) -1.06(19) C(3)-C(2)-C(7)-C(8) 178.26(12) C(1)-C(2)-C(7)-C(6) 178.86(12) C(3)-C(2)-C(7)-C(6) -1.81(19) C(6)-C(7)-C(8)-C(9) -178.42(13) C(2)-C(7)-C(8)-C(9) 1.5(2) C(7)-C(8)-C(9)-C(10) -0.3(2) C(2)-C(1)-C(10)-C(9) 1.8(2) Cl(1)-C(1)-C(10)-C(9) -177.29(11) C(8)-C(9)-C(10)-C(1) -1.3(2) C(4)-C(3)-O(1)-C(11) -8.64(19) C(2)-C(3)-O(1)-C(11) 170.92(12) C(5)-C(6)-O(2)-C(13) -90.76(16) C(7)-C(6)-O(2)-C(13) 92.42(15)

2. Crystal structure for 2-allyl-3,6-dimethoxy-4-methylphenol-2,2,2-tribromoacetate, 47.

Table 4. Crystal data and structure refinement for compound 47 (University of Manchester reference: s3942nat5)

Identification code s3942nat5 Empirical formula C14 H15 Br3 O4 Formula weight 486.99 Temperature 150.05(16) K Wavelength 0.7107 Å Crystal system Triclinic Space group P -1 Unit cell dimensions a = 9.1421(6) Å = 98.584(6)°. b = 10.7365(5) Å = 95.161(7)°. c = 18.3718(18) Å  = 106.223(5)°. Volume 1695.5(2) Å3 Z 4 Density (calculated) 1.908 Mg/m3 Absorption coefficient 7.148 mm-1 F(000) 944 Crystal size 0.21 x 0.15 x 0.07 mm3 Theta range for data collection 5.2487 to 27.7932°. Index ranges -12<=h<=12, -13<=k<=13, -23<=l<=24 Reflections collected 8664 83

Independent reflections 8664 [R(int) = 0.0000] Completeness to theta = 25.00° 98.8 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.00000 and 0.78040 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 8664 / 0 / 386 Goodness-of-fit on F2 1.085 Final R indices [I>2sigma(I)] R1 = 0.0543, wR2 = 0.1291 R indices (all data) R1 = 0.0747, wR2 = 0.1354 Largest diff. peak and hole 1.383 and -1.371 e.Å-3

Table 5. Bond lengths [Å] and angles [°] for compound 47.

Br(1)-C(8) 1.912(7) Br(2)-C(8) 1.909(7) Br(3)-C(8) 1.968(8) Br(4)-C(22) 1.946(7) Br(5)-C(22) 1.927(7) Br(6)-C(22) 1.906(7) C(1)-C(2) 1.386(10) C(1)-O(1) 1.401(8) C(1)-C(6) 1.417(10) C(2)-O(3) 1.350(9) C(2)-C(3) 1.384(10) C(3)-C(4) 1.399(10) C(3)-H(3) 0.9500 C(4)-C(5) 1.393(11) C(4)-C(10) 1.512(10) C(5)-O(4) 1.388(9) C(5)-C(6) 1.390(10) C(6)-C(12) 1.507(10) C(7)-O(2) 1.216(8) C(7)-O(1) 1.350(9) C(7)-C(8) 1.515(9) C(9)-O(3) 1.449(9) C(9)-H(9A) 0.9800 C(9)-H(9B) 0.9800 84

C(9)-H(9C) 0.9800 C(10)-H(10A) 0.9800 C(10)-H(10B) 0.9800 C(10)-H(10C) 0.9800 C(11)-O(4) 1.454(10) C(11)-H(11A) 0.9800 C(11)-H(11B) 0.9800 C(11)-H(11C) 0.9800 C(12)-C(13) 1.491(11) C(12)-H(12A) 0.9900 C(12)-H(12B) 0.9900 C(13)-C(14) 1.303(11) C(13)-H(13) 0.9500 C(14)-H(14A) 0.9500 C(14)-H(14B) 0.9500 C(15)-C(20) 1.365(11) C(15)-C(16) 1.392(10) C(15)-O(5) 1.403(8) C(16)-O(7) 1.360(8) C(16)-C(17) 1.383(11) C(17)-C(18) 1.425(11) C(17)-H(17) 0.9500 C(18)-C(19) 1.369(11) C(18)-C(24) 1.497(10) C(19)-O(8) 1.390(9) C(19)-C(20) 1.414(10) C(20)-C(26) 1.536(10) C(21)-O(6) 1.196(9) C(21)-O(5) 1.344(9) C(21)-C(22) 1.531(10) C(23)-O(7) 1.449(9) C(23)-H(23A) 0.9800 C(23)-H(23B) 0.9800 C(23)-H(23C) 0.9800 C(24)-H(24A) 0.9800 C(24)-H(24B) 0.9800 C(24)-H(24C) 0.9800 85

C(25)-O(8) 1.440(9) C(25)-H(25A) 0.9800 C(25)-H(25B) 0.9800 C(25)-H(25C) 0.9800 C(26)-C(27) 1.486(12) C(26)-H(26A) 0.9900 C(26)-H(26B) 0.9900 C(27)-C(28) 1.323(12) C(27)-H(27) 0.9500 C(28)-H(28A) 0.9500 C(28)-H(28B) 0.9500

C(2)-C(1)-O(1) 119.7(7) C(2)-C(1)-C(6) 122.0(7) O(1)-C(1)-C(6) 117.8(6) O(3)-C(2)-C(3) 126.6(7) O(3)-C(2)-C(1) 114.5(6) C(3)-C(2)-C(1) 118.9(7) C(2)-C(3)-C(4) 121.1(7) C(2)-C(3)-H(3) 119.4 C(4)-C(3)-H(3) 119.4 C(5)-C(4)-C(3) 118.6(7) C(5)-C(4)-C(10) 122.0(7) C(3)-C(4)-C(10) 119.4(7) C(4)-C(5)-O(4) 120.2(7) C(4)-C(5)-C(6) 122.3(7) O(4)-C(5)-C(6) 117.4(7) C(5)-C(6)-C(1) 116.9(7) C(5)-C(6)-C(12) 123.4(7) C(1)-C(6)-C(12) 119.2(7) O(2)-C(7)-O(1) 125.2(6) O(2)-C(7)-C(8) 124.1(7) O(1)-C(7)-C(8) 110.7(6) C(7)-C(8)-Br(2) 109.0(5) C(7)-C(8)-Br(1) 115.6(5) Br(2)-C(8)-Br(1) 109.9(3) C(7)-C(8)-Br(3) 103.3(4) 86

Br(2)-C(8)-Br(3) 109.3(3) Br(1)-C(8)-Br(3) 109.6(4) O(3)-C(9)-H(9A) 109.5 O(3)-C(9)-H(9B) 109.5 H(9A)-C(9)-H(9B) 109.5 O(3)-C(9)-H(9C) 109.5 H(9A)-C(9)-H(9C) 109.5 H(9B)-C(9)-H(9C) 109.5 C(4)-C(10)-H(10A) 109.5 C(4)-C(10)-H(10B) 109.5 H(10A)-C(10)-H(10B) 109.5 C(4)-C(10)-H(10C) 109.5 H(10A)-C(10)-H(10C) 109.5 H(10B)-C(10)-H(10C) 109.5 O(4)-C(11)-H(11A) 109.5 O(4)-C(11)-H(11B) 109.5 H(11A)-C(11)-H(11B) 109.5 O(4)-C(11)-H(11C) 109.5 H(11A)-C(11)-H(11C) 109.5 H(11B)-C(11)-H(11C) 109.5 C(13)-C(12)-C(6) 111.7(7) C(13)-C(12)-H(12A) 109.3 C(6)-C(12)-H(12A) 109.3 C(13)-C(12)-H(12B) 109.3 C(6)-C(12)-H(12B) 109.3 H(12A)-C(12)-H(12B) 107.9 C(14)-C(13)-C(12) 125.2(9) C(14)-C(13)-H(13) 117.4 C(12)-C(13)-H(13) 117.4 C(13)-C(14)-H(14A) 120.0 C(13)-C(14)-H(14B) 120.0 H(14A)-C(14)-H(14B) 120.0 C(20)-C(15)-C(16) 123.1(7) C(20)-C(15)-O(5) 119.0(7) C(16)-C(15)-O(5) 117.9(7) O(7)-C(16)-C(17) 125.2(7) O(7)-C(16)-C(15) 116.1(7) 87

C(17)-C(16)-C(15) 118.7(7) C(16)-C(17)-C(18) 120.2(7) C(16)-C(17)-H(17) 119.9 C(18)-C(17)-H(17) 119.9 C(19)-C(18)-C(17) 118.6(7) C(19)-C(18)-C(24) 121.8(7) C(17)-C(18)-C(24) 119.5(7) C(18)-C(19)-O(8) 118.6(7) C(18)-C(19)-C(20) 122.1(7) O(8)-C(19)-C(20) 119.2(7) C(15)-C(20)-C(19) 117.3(7) C(15)-C(20)-C(26) 121.8(7) C(19)-C(20)-C(26) 120.9(7) O(6)-C(21)-O(5) 126.6(7) O(6)-C(21)-C(22) 123.0(7) O(5)-C(21)-C(22) 110.3(6) C(21)-C(22)-Br(6) 113.1(5) C(21)-C(22)-Br(5) 108.6(5) Br(6)-C(22)-Br(5) 109.6(4) C(21)-C(22)-Br(4) 105.2(5) Br(6)-C(22)-Br(4) 110.2(4) Br(5)-C(22)-Br(4) 110.1(4) O(7)-C(23)-H(23A) 109.5 O(7)-C(23)-H(23B) 109.5 H(23A)-C(23)-H(23B) 109.5 O(7)-C(23)-H(23C) 109.5 H(23A)-C(23)-H(23C) 109.5 H(23B)-C(23)-H(23C) 109.5 C(18)-C(24)-H(24A) 109.5 C(18)-C(24)-H(24B) 109.5 H(24A)-C(24)-H(24B) 109.5 C(18)-C(24)-H(24C) 109.5 H(24A)-C(24)-H(24C) 109.5 H(24B)-C(24)-H(24C) 109.5 O(8)-C(25)-H(25A) 109.5 O(8)-C(25)-H(25B) 109.5 H(25A)-C(25)-H(25B) 109.5 88

O(8)-C(25)-H(25C) 109.5 H(25A)-C(25)-H(25C) 109.5 H(25B)-C(25)-H(25C) 109.5 C(27)-C(26)-C(20) 110.9(7) C(27)-C(26)-H(26A) 109.5 C(20)-C(26)-H(26A) 109.5 C(27)-C(26)-H(26B) 109.5 C(20)-C(26)-H(26B) 109.5 H(26A)-C(26)-H(26B) 108.0 C(28)-C(27)-C(26) 125.0(9) C(28)-C(27)-H(27) 117.5 C(26)-C(27)-H(27) 117.5 C(27)-C(28)-H(28A) 120.0 C(27)-C(28)-H(28B) 120.0 H(28A)-C(28)-H(28B) 120.0 C(7)-O(1)-C(1) 115.1(5) C(2)-O(3)-C(9) 116.7(6) C(5)-O(4)-C(11) 113.2(6) C(21)-O(5)-C(15) 115.6(5) C(16)-O(7)-C(23) 117.1(6) C(19)-O(8)-C(25) 114.0(6)

Table 6. Torsion angles [°] for compound 47.

O(1)-C(1)-C(2)-O(3) -8.2(10) C(6)-C(1)-C(2)-O(3) -179.4(7) O(1)-C(1)-C(2)-C(3) 175.0(6) C(6)-C(1)-C(2)-C(3) 3.8(11) O(3)-C(2)-C(3)-C(4) -177.4(7) C(1)-C(2)-C(3)-C(4) -1.0(11) C(2)-C(3)-C(4)-C(5) -1.7(11) C(2)-C(3)-C(4)-C(10) 179.6(7) C(3)-C(4)-C(5)-O(4) 177.8(7) C(10)-C(4)-C(5)-O(4) -3.5(11) C(3)-C(4)-C(5)-C(6) 1.7(11) C(10)-C(4)-C(5)-C(6) -179.6(7) C(4)-C(5)-C(6)-C(1) 0.9(11) 89

O(4)-C(5)-C(6)-C(1) -175.3(6) C(4)-C(5)-C(6)-C(12) 173.6(7) O(4)-C(5)-C(6)-C(12) -2.6(11) C(2)-C(1)-C(6)-C(5) -3.7(11) O(1)-C(1)-C(6)-C(5) -175.1(6) C(2)-C(1)-C(6)-C(12) -176.7(7) O(1)-C(1)-C(6)-C(12) 11.8(10) O(2)-C(7)-C(8)-Br(2) 30.7(9) O(1)-C(7)-C(8)-Br(2) -150.2(5) O(2)-C(7)-C(8)-Br(1) 155.0(6) O(1)-C(7)-C(8)-Br(1) -25.9(7) O(2)-C(7)-C(8)-Br(3) -85.3(7) O(1)-C(7)-C(8)-Br(3) 93.7(6) C(5)-C(6)-C(12)-C(13) -96.9(9) C(1)-C(6)-C(12)-C(13) 75.6(9) C(6)-C(12)-C(13)-C(14) -124.2(9) C(20)-C(15)-C(16)-O(7) 180.0(7) O(5)-C(15)-C(16)-O(7) 0.1(10) C(20)-C(15)-C(16)-C(17) 0.1(11) O(5)-C(15)-C(16)-C(17) -179.7(6) O(7)-C(16)-C(17)-C(18) -179.1(7) C(15)-C(16)-C(17)-C(18) 0.8(11) C(16)-C(17)-C(18)-C(19) -0.8(11) C(16)-C(17)-C(18)-C(24) -177.9(7) C(17)-C(18)-C(19)-O(8) -176.2(7) C(24)-C(18)-C(19)-O(8) 0.8(11) C(17)-C(18)-C(19)-C(20) 0.0(11) C(24)-C(18)-C(19)-C(20) 177.0(7) C(16)-C(15)-C(20)-C(19) -0.9(11) O(5)-C(15)-C(20)-C(19) 178.9(6) C(16)-C(15)-C(20)-C(26) 177.2(7) O(5)-C(15)-C(20)-C(26) -2.9(11) C(18)-C(19)-C(20)-C(15) 0.8(11) O(8)-C(19)-C(20)-C(15) 177.0(7) C(18)-C(19)-C(20)-C(26) -177.3(7) O(8)-C(19)-C(20)-C(26) -1.2(11) O(6)-C(21)-C(22)-Br(6) -152.9(6) 90

O(5)-C(21)-C(22)-Br(6) 30.7(7) O(6)-C(21)-C(22)-Br(5) -31.0(8) O(5)-C(21)-C(22)-Br(5) 152.6(5) O(6)-C(21)-C(22)-Br(4) 86.8(7) O(5)-C(21)-C(22)-Br(4) -89.6(6) C(15)-C(20)-C(26)-C(27) -73.7(10) C(19)-C(20)-C(26)-C(27) 104.4(9) C(20)-C(26)-C(27)-C(28) 127.5(9) O(2)-C(7)-O(1)-C(1) 6.3(10) C(8)-C(7)-O(1)-C(1) -172.7(6) C(2)-C(1)-O(1)-C(7) 78.5(8) C(6)-C(1)-O(1)-C(7) -109.9(7) C(3)-C(2)-O(3)-C(9) -4.5(11) C(1)-C(2)-O(3)-C(9) 179.0(6) C(4)-C(5)-O(4)-C(11) 85.8(9) C(6)-C(5)-O(4)-C(11) -97.9(8) O(6)-C(21)-O(5)-C(15) -3.0(10) C(22)-C(21)-O(5)-C(15) 173.2(6) C(20)-C(15)-O(5)-C(21) 103.4(8) C(16)-C(15)-O(5)-C(21) -76.7(8) C(17)-C(16)-O(7)-C(23) 1.9(10) C(15)-C(16)-O(7)-C(23) -178.0(6) C(18)-C(19)-O(8)-C(25) -88.5(9) C(20)-C(19)-O(8)-C(25) 95.2(8)

3. Crystal structure for5-bromo-1,4-dimethoxy-2-methylnaphthalene, 48.

Table 7. Crystal data and structure refinement for compound 48 (University of Manchester Reference: s3936na).

Identification code s3936na Empirical formula C13 H13 Br O2 Formula weight 281.14 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 9.0734(2) Å = 90°. b = 17.9918(5) Å = 101.8740(10)°. c = 7.1981(2) Å  = 90°. Volume 1149.92(5) Å3 Z 4 Density (calculated) 1.624 Mg/m3 Absorption coefficient 4.726 mm-1 F(000) 568 Crystal size 0.28 x 0.22 x 0.16 mm3 Theta range for data collection 4.92 to 72.25°. Index ranges -11<=h<=10, -18<=k<=22, -8<=l<=8 92

Reflections collected 4097 Independent reflections 2173 [R(int) = 0.0153] Completeness to theta = 66.60° 98.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.5185 and 0.450523 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2173 / 0 / 148 Goodness-of-fit on F2 1.130 Final R indices [I>2sigma(I)] R1 = 0.0283, wR2 = 0.0762 R indices (all data) R1 = 0.0300, wR2 = 0.0774 Largest diff. peak and hole 0.487 and -0.360 e.Å-3

Table 8. Bond lengths [Å] and angles [°] for compound 48.

Br(1)-C(1) 1.905(2) C(1)-C(10) 1.365(3) C(1)-C(2) 1.430(3) C(2)-C(3) 1.434(3) C(2)-C(7) 1.436(3) C(3)-O(1) 1.362(3) C(3)-C(4) 1.371(3) C(4)-C(5) 1.417(3) C(4)-H(4) 0.9500 C(5)-C(6) 1.366(3) C(5)-C(12) 1.506(3) C(6)-O(2) 1.393(2) C(6)-C(7) 1.423(3) C(7)-C(8) 1.417(3) C(8)-C(9) 1.367(3) C(8)-H(8) 0.9500 C(9)-C(10) 1.404(3) C(9)-H(9) 0.9500 C(10)-H(10) 0.9500 C(11)-O(1) 1.430(2) C(11)-H(11A) 0.9800 C(11)-H(11B) 0.9800 C(11)-H(11C) 0.9800 93

C(12)-H(12A) 0.9800 C(12)-H(12B) 0.9800 C(12)-H(12C) 0.9800 C(13)-O(2) 1.434(3) C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800

C(10)-C(1)-C(2) 122.8(2) C(10)-C(1)-Br(1) 113.76(17) C(2)-C(1)-Br(1) 123.38(16) C(1)-C(2)-C(3) 127.25(19) C(1)-C(2)-C(7) 115.58(19) C(3)-C(2)-C(7) 117.16(19) O(1)-C(3)-C(4) 122.71(19) O(1)-C(3)-C(2) 116.75(18) C(4)-C(3)-C(2) 120.53(19) C(3)-C(4)-C(5) 122.43(19) C(3)-C(4)-H(4) 118.8 C(5)-C(4)-H(4) 118.8 C(6)-C(5)-C(4) 118.14(19) C(6)-C(5)-C(12) 122.5(2) C(4)-C(5)-C(12) 119.33(19) C(5)-C(6)-O(2) 120.30(19) C(5)-C(6)-C(7) 121.98(19) O(2)-C(6)-C(7) 117.65(19) C(8)-C(7)-C(6) 119.7(2) C(8)-C(7)-C(2) 120.5(2) C(6)-C(7)-C(2) 119.74(19) C(9)-C(8)-C(7) 120.9(2) C(9)-C(8)-H(8) 119.6 C(7)-C(8)-H(8) 119.6 C(8)-C(9)-C(10) 119.9(2) C(8)-C(9)-H(9) 120.0 C(10)-C(9)-H(9) 120.0 C(1)-C(10)-C(9) 120.2(2) C(1)-C(10)-H(10) 119.9 94

C(9)-C(10)-H(10) 119.9 O(1)-C(11)-H(11A) 109.5 O(1)-C(11)-H(11B) 109.5 H(11A)-C(11)-H(11B) 109.5 O(1)-C(11)-H(11C) 109.5 H(11A)-C(11)-H(11C) 109.5 H(11B)-C(11)-H(11C) 109.5 C(5)-C(12)-H(12A) 109.5 C(5)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12B) 109.5 C(5)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 O(2)-C(13)-H(13A) 109.5 O(2)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 O(2)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 C(3)-O(1)-C(11) 117.75(16) C(6)-O(2)-C(13) 113.18(16)

Table 9. Torsion angles [°] for compound 48.

C(10)-C(1)-C(2)-C(3) 179.9(2) Br(1)-C(1)-C(2)-C(3) 1.9(3) C(10)-C(1)-C(2)-C(7) 1.1(3) Br(1)-C(1)-C(2)-C(7) -177.00(15) C(1)-C(2)-C(3)-O(1) 0.6(3) C(7)-C(2)-C(3)-O(1) 179.48(18) C(1)-C(2)-C(3)-C(4) -179.2(2) C(7)-C(2)-C(3)-C(4) -0.4(3) O(1)-C(3)-C(4)-C(5) 179.74(19) C(2)-C(3)-C(4)-C(5) -0.4(3) C(3)-C(4)-C(5)-C(6) 0.3(3) C(3)-C(4)-C(5)-C(12) 179.8(2) C(4)-C(5)-C(6)-O(2) 177.38(18) 95

C(12)-C(5)-C(6)-O(2) -2.1(3) C(4)-C(5)-C(6)-C(7) 0.5(3) C(12)-C(5)-C(6)-C(7) -178.96(19) C(5)-C(6)-C(7)-C(8) 178.4(2) O(2)-C(6)-C(7)-C(8) 1.4(3) C(5)-C(6)-C(7)-C(2) -1.3(3) O(2)-C(6)-C(7)-C(2) -178.25(18) C(1)-C(2)-C(7)-C(8) 0.5(3) C(3)-C(2)-C(7)-C(8) -178.47(19) C(1)-C(2)-C(7)-C(6) -179.80(18) C(3)-C(2)-C(7)-C(6) 1.2(3) C(6)-C(7)-C(8)-C(9) 179.0(2) C(2)-C(7)-C(8)-C(9) -1.3(3) C(7)-C(8)-C(9)-C(10) 0.5(3) C(2)-C(1)-C(10)-C(9) -1.9(3) Br(1)-C(1)-C(10)-C(9) 176.38(17) C(8)-C(9)-C(10)-C(1) 1.0(3) C(4)-C(3)-O(1)-C(11) 8.2(3) C(2)-C(3)-O(1)-C(11) -171.62(18) C(5)-C(6)-O(2)-C(13) 91.0(2) C(7)-C(6)-O(2)-C(13) -92.0(2)

4. Crystal structure for 2-(5,8-dimethoxy-6-methylnaphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, 49.

Table 10. Crystal data and structure refinement for compound 49 (University of Manchester reference: s4041ma).

Identification code s4041ma Empirical formula C19 H25 B O4 Formula weight 328.20 Temperature 180(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group Pbca Unit cell dimensions a = 10.2934(3) Å = 90°. b = 11.6533(4) Å = 90°. c = 29.9643(8) Å  = 90°. Volume 3594.28(19) Å3 Z 8 Density (calculated) 1.213 Mg/m3 Absorption coefficient 0.664 mm-1 97

F(000) 1408 Crystal size 0.29 x 0.25 x 0.23 mm3 Theta range for data collection 5.91 to 72.10°. Index ranges -12<=h<=12, -13<=k<=12, -36<=l<=36 Reflections collected 16330 Independent reflections 3229 [R(int) = 0.0430] Completeness to theta = 67.00° 93.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.8623 and 0.745931 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3229 / 0 / 224 Goodness-of-fit on F2 1.050 Final R indices [I>2sigma(I)] R1 = 0.0471, wR2 = 0.1223 R indices (all data) R1 = 0.0551, wR2 = 0.1285 Largest diff. peak and hole 0.258 and -0.243 e.Å-3

Table 11. Bond lengths [Å] and angles [°] for compound 49.

B(1)-O(4) 1.364(2) B(1)-O(3) 1.365(2) B(1)-C(1) 1.565(3) C(1)-C(10) 1.379(2) C(1)-C(2) 1.431(2) C(2)-C(7) 1.420(2) C(2)-C(3) 1.429(2) C(3)-O(1) 1.365(2) C(3)-C(4) 1.366(2) C(4)-C(5) 1.416(2) C(4)-H(4) 0.9500 C(5)-C(6) 1.366(2) C(5)-C(12) 1.507(2) C(6)-O(2) 1.391(2) C(6)-C(7) 1.424(2) C(7)-C(8) 1.418(2) C(8)-C(9) 1.366(3) C(8)-H(8) 0.9500 C(9)-C(10) 1.404(3) 98

C(9)-H(9) 0.9500 C(10)-H(10) 0.9500 C(11)-O(1) 1.4236(19) C(11)-H(11A) 0.9800 C(11)-H(11B) 0.9800 C(11)-H(11C) 0.9800 C(12)-H(12A) 0.9800 C(12)-H(12B) 0.9800 C(12)-H(12C) 0.9800 C(13)-O(2) 1.432(2) C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800 C(14)-O(3) 1.458(2) C(14)-C(15) 1.515(3) C(14)-C(16) 1.522(3) C(14)-C(17) 1.544(3) C(15)-H(15A) 0.9800 C(15)-H(15B) 0.9800 C(15)-H(15C) 0.9800 C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 C(17)-O(4) 1.459(2) C(17)-C(19) 1.518(3) C(17)-C(18) 1.519(3) C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800

O(4)-B(1)-O(3) 112.89(16) O(4)-B(1)-C(1) 121.61(15) O(3)-B(1)-C(1) 124.53(16) C(10)-C(1)-C(2) 117.42(16) 99

C(10)-C(1)-B(1) 116.26(15) C(2)-C(1)-B(1) 126.17(14) C(7)-C(2)-C(3) 117.70(14) C(7)-C(2)-C(1) 120.52(14) C(3)-C(2)-C(1) 121.77(15) O(1)-C(3)-C(4) 124.71(14) O(1)-C(3)-C(2) 114.11(14) C(4)-C(3)-C(2) 121.18(15) C(3)-C(4)-C(5) 121.13(15) C(3)-C(4)-H(4) 119.4 C(5)-C(4)-H(4) 119.4 C(6)-C(5)-C(4) 118.88(15) C(6)-C(5)-C(12) 121.92(16) C(4)-C(5)-C(12) 119.16(15) C(5)-C(6)-O(2) 120.04(15) C(5)-C(6)-C(7) 121.69(15) O(2)-C(6)-C(7) 118.23(14) C(8)-C(7)-C(2) 119.13(15) C(8)-C(7)-C(6) 121.53(16) C(2)-C(7)-C(6) 119.33(14) C(9)-C(8)-C(7) 119.86(16) C(9)-C(8)-H(8) 120.1 C(7)-C(8)-H(8) 120.1 C(8)-C(9)-C(10) 120.66(15) C(8)-C(9)-H(9) 119.7 C(10)-C(9)-H(9) 119.7 C(1)-C(10)-C(9) 122.33(16) C(1)-C(10)-H(10) 118.8 C(9)-C(10)-H(10) 118.8 O(1)-C(11)-H(11A) 109.5 O(1)-C(11)-H(11B) 109.5 H(11A)-C(11)-H(11B) 109.5 O(1)-C(11)-H(11C) 109.5 H(11A)-C(11)-H(11C) 109.5 H(11B)-C(11)-H(11C) 109.5 C(5)-C(12)-H(12A) 109.5 C(5)-C(12)-H(12B) 109.5 100

H(12A)-C(12)-H(12B) 109.5 C(5)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 O(2)-C(13)-H(13A) 109.5 O(2)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 O(2)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 O(3)-C(14)-C(15) 108.54(18) O(3)-C(14)-C(16) 104.76(18) C(15)-C(14)-C(16) 111.7(2) O(3)-C(14)-C(17) 102.90(13) C(15)-C(14)-C(17) 114.63(19) C(16)-C(14)-C(17) 113.29(19) C(14)-C(15)-H(15A) 109.5 C(14)-C(15)-H(15B) 109.5 H(15A)-C(15)-H(15B) 109.5 C(14)-C(15)-H(15C) 109.5 H(15A)-C(15)-H(15C) 109.5 H(15B)-C(15)-H(15C) 109.5 C(14)-C(16)-H(16A) 109.5 C(14)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(14)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 O(4)-C(17)-C(19) 106.70(14) O(4)-C(17)-C(18) 109.46(15) C(19)-C(17)-C(18) 109.47(18) O(4)-C(17)-C(14) 102.47(14) C(19)-C(17)-C(14) 113.73(17) C(18)-C(17)-C(14) 114.45(16) C(17)-C(18)-H(18A) 109.5 C(17)-C(18)-H(18B) 109.5 H(18A)-C(18)-H(18B) 109.5 101

C(17)-C(18)-H(18C) 109.5 H(18A)-C(18)-H(18C) 109.5 H(18B)-C(18)-H(18C) 109.5 C(17)-C(19)-H(19A) 109.5 C(17)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(17)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 C(3)-O(1)-C(11) 117.41(13) C(6)-O(2)-C(13) 113.02(13) B(1)-O(3)-C(14) 107.45(14) B(1)-O(4)-C(17) 107.43(13)

Table 12. Torsion angles [°] for compound 49.

O(4)-B(1)-C(1)-C(10) 61.1(2) O(3)-B(1)-C(1)-C(10) -106.80(19) O(4)-B(1)-C(1)-C(2) -123.49(18) O(3)-B(1)-C(1)-C(2) 68.6(2) C(10)-C(1)-C(2)-C(7) 2.7(2) B(1)-C(1)-C(2)-C(7) -172.56(15) C(10)-C(1)-C(2)-C(3) -176.46(15) B(1)-C(1)-C(2)-C(3) 8.2(3) C(7)-C(2)-C(3)-O(1) -175.92(13) C(1)-C(2)-C(3)-O(1) 3.3(2) C(7)-C(2)-C(3)-C(4) 3.3(2) C(1)-C(2)-C(3)-C(4) -177.48(15) O(1)-C(3)-C(4)-C(5) 177.80(14) C(2)-C(3)-C(4)-C(5) -1.3(2) C(3)-C(4)-C(5)-C(6) -0.6(2) C(3)-C(4)-C(5)-C(12) -178.05(15) C(4)-C(5)-C(6)-O(2) -177.38(14) C(12)-C(5)-C(6)-O(2) 0.0(2) C(4)-C(5)-C(6)-C(7) 0.3(2) C(12)-C(5)-C(6)-C(7) 177.75(15) C(3)-C(2)-C(7)-C(8) 176.00(14) 102

C(1)-C(2)-C(7)-C(8) -3.2(2) C(3)-C(2)-C(7)-C(6) -3.4(2) C(1)-C(2)-C(7)-C(6) 177.32(14) C(5)-C(6)-C(7)-C(8) -177.70(15) O(2)-C(6)-C(7)-C(8) 0.0(2) C(5)-C(6)-C(7)-C(2) 1.7(2) O(2)-C(6)-C(7)-C(2) 179.46(13) C(2)-C(7)-C(8)-C(9) 1.4(2) C(6)-C(7)-C(8)-C(9) -179.22(16) C(7)-C(8)-C(9)-C(10) 1.0(3) C(2)-C(1)-C(10)-C(9) -0.4(3) B(1)-C(1)-C(10)-C(9) 175.37(16) C(8)-C(9)-C(10)-C(1) -1.5(3) O(3)-C(14)-C(17)-O(4) -25.65(18) C(15)-C(14)-C(17)-O(4) -143.28(18) C(16)-C(14)-C(17)-O(4) 86.9(2) O(3)-C(14)-C(17)-C(19) 89.11(19) C(15)-C(14)-C(17)-C(19) -28.5(2) C(16)-C(14)-C(17)-C(19) -158.4(2) O(3)-C(14)-C(17)-C(18) -144.03(17) C(15)-C(14)-C(17)-C(18) 98.3(2) C(16)-C(14)-C(17)-C(18) -31.5(3) C(4)-C(3)-O(1)-C(11) 10.1(2) C(2)-C(3)-O(1)-C(11) -170.72(14) C(5)-C(6)-O(2)-C(13) -97.41(18) C(7)-C(6)-O(2)-C(13) 84.80(19) O(4)-B(1)-O(3)-C(14) -7.3(2) C(1)-B(1)-O(3)-C(14) 161.59(16) C(15)-C(14)-O(3)-B(1) 142.41(19) C(16)-C(14)-O(3)-B(1) -98.1(2) C(17)-C(14)-O(3)-B(1) 20.55(19) O(3)-B(1)-O(4)-C(17) -10.45(19) C(1)-B(1)-O(4)-C(17) -179.69(14) C(19)-C(17)-O(4)-B(1) -97.50(18) C(18)-C(17)-O(4)-B(1) 144.13(16) C(14)-C(17)-O(4)-B(1) 22.28(17)

103

5. Crystal structure of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalene-1,4-dione, 50.

Table 13. Crystal data and structure refinement for compound 50 (University of Manchester reference: s4052na).

Identification code s4052na Empirical formula C17 H19 B O4 Formula weight 298.13 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group Pbca Unit cell dimensions a = 12.1772(5) Å = 90°. b = 11.4349(4) Å = 90°. c = 22.4631(8) Å  = 90°. Volume 3127.9(2) Å3 Z 8 Density (calculated) 1.266 Mg/m3 Absorption coefficient 0.716 mm-1 104

F(000) 1264 Crystal size 0.29 x 0.17 x 0.11 mm3 Theta range for data collection 3.94 to 72.59°. Index ranges -13<=h<=15, -14<=k<=14, -27<=l<=27 Reflections collected 29180 Independent reflections 3087 [R(int) = 0.0527] Completeness to theta = 67.00° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9254 and 0.820409 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3087 / 0 / 204 Goodness-of-fit on F2 1.107 Final R indices [I>2sigma(I)] R1 = 0.0412, wR2 = 0.0955 R indices (all data) R1 = 0.0448, wR2 = 0.0975 Largest diff. peak and hole 0.404 and -0.201 e.Å-3

Table 14. Bond lengths [Å] and angles [°] for s4052na.

B(1)-O(2) 1.3629(19) B(1)-O(1) 1.3629(19) B(1)-C(1) 1.575(2) C(1)-C(10) 1.396(2) C(1)-C(2) 1.399(2) C(2)-C(7) 1.4010(19) C(2)-C(3) 1.4867(19) C(3)-O(3) 1.2276(17) C(3)-C(4) 1.469(2) C(4)-C(5) 1.346(2) C(4)-H(4) 0.9500 C(5)-C(17) 1.496(2) C(5)-C(6) 1.498(2) C(6)-O(4) 1.2234(17) C(6)-C(7) 1.485(2) C(7)-C(8) 1.392(2) C(8)-C(9) 1.384(2) C(8)-H(8) 0.9500 C(9)-C(10) 1.391(2) 105

C(9)-H(9) 0.9500 C(10)-H(10) 0.9500 C(11)-O(1) 1.4667(17) C(11)-C(12) 1.513(3) C(11)-C(13) 1.521(2) C(11)-C(14) 1.558(2) C(12)-H(12A) 0.9800 C(12)-H(12B) 0.9800 C(12)-H(12C) 0.9800 C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800 C(14)-O(2) 1.4664(16) C(14)-C(15) 1.515(2) C(14)-C(16) 1.521(2) C(15)-H(15A) 0.9800 C(15)-H(15B) 0.9800 C(15)-H(15C) 0.9800 C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 C(17)-H(17A) 0.9800 C(17)-H(17B) 0.9800 C(17)-H(17C) 0.9800

O(2)-B(1)-O(1) 114.17(13) O(2)-B(1)-C(1) 123.90(13) O(1)-B(1)-C(1) 120.76(13) C(10)-C(1)-C(2) 117.66(13) C(10)-C(1)-B(1) 118.79(13) C(2)-C(1)-B(1) 123.55(12) C(1)-C(2)-C(7) 121.25(13) C(1)-C(2)-C(3) 119.01(12) C(7)-C(2)-C(3) 119.73(13) O(3)-C(3)-C(4) 121.51(13) O(3)-C(3)-C(2) 120.08(13) C(4)-C(3)-C(2) 118.39(12) 106

C(5)-C(4)-C(3) 122.76(14) C(5)-C(4)-H(4) 118.6 C(3)-C(4)-H(4) 118.6 C(4)-C(5)-C(17) 123.21(14) C(4)-C(5)-C(6) 119.85(13) C(17)-C(5)-C(6) 116.93(13) O(4)-C(6)-C(7) 121.38(14) O(4)-C(6)-C(5) 120.35(14) C(7)-C(6)-C(5) 118.23(12) C(8)-C(7)-C(2) 119.47(13) C(8)-C(7)-C(6) 120.40(12) C(2)-C(7)-C(6) 120.07(13) C(9)-C(8)-C(7) 120.03(13) C(9)-C(8)-H(8) 120.0 C(7)-C(8)-H(8) 120.0 C(8)-C(9)-C(10) 119.91(14) C(8)-C(9)-H(9) 120.0 C(10)-C(9)-H(9) 120.0 C(9)-C(10)-C(1) 121.56(14) C(9)-C(10)-H(10) 119.2 C(1)-C(10)-H(10) 119.2 O(1)-C(11)-C(12) 106.65(14) O(1)-C(11)-C(13) 108.19(12) C(12)-C(11)-C(13) 111.12(16) O(1)-C(11)-C(14) 102.30(11) C(12)-C(11)-C(14) 113.44(14) C(13)-C(11)-C(14) 114.33(16) C(11)-C(12)-H(12A) 109.5 C(11)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12B) 109.5 C(11)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 C(11)-C(13)-H(13A) 109.5 C(11)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 C(11)-C(13)-H(13C) 109.5 107

H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 O(2)-C(14)-C(15) 109.05(11) O(2)-C(14)-C(16) 105.56(12) C(15)-C(14)-C(16) 109.81(14) O(2)-C(14)-C(11) 102.25(11) C(15)-C(14)-C(11) 115.30(13) C(16)-C(14)-C(11) 114.04(14) C(14)-C(15)-H(15A) 109.5 C(14)-C(15)-H(15B) 109.5 H(15A)-C(15)-H(15B) 109.5 C(14)-C(15)-H(15C) 109.5 H(15A)-C(15)-H(15C) 109.5 H(15B)-C(15)-H(15C) 109.5 C(14)-C(16)-H(16A) 109.5 C(14)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(14)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(5)-C(17)-H(17A) 109.5 C(5)-C(17)-H(17B) 109.5 H(17A)-C(17)-H(17B) 109.5 C(5)-C(17)-H(17C) 109.5 H(17A)-C(17)-H(17C) 109.5 H(17B)-C(17)-H(17C) 109.5 B(1)-O(1)-C(11) 106.48(11) B(1)-O(2)-C(14) 106.72(11)

Table 6. Torsion angles [°] for compound 50.

O(2)-B(1)-C(1)-C(10) -98.92(17) O(1)-B(1)-C(1)-C(10) 68.00(19) O(2)-B(1)-C(1)-C(2) 80.2(2) O(1)-B(1)-C(1)-C(2) -112.84(16) C(10)-C(1)-C(2)-C(7) 3.1(2) B(1)-C(1)-C(2)-C(7) -176.04(13) 108

C(10)-C(1)-C(2)-C(3) -175.48(13) B(1)-C(1)-C(2)-C(3) 5.4(2) C(1)-C(2)-C(3)-O(3) 1.0(2) C(7)-C(2)-C(3)-O(3) -177.63(13) C(1)-C(2)-C(3)-C(4) 179.57(13) C(7)-C(2)-C(3)-C(4) 0.94(19) O(3)-C(3)-C(4)-C(5) -179.65(14) C(2)-C(3)-C(4)-C(5) 1.8(2) C(3)-C(4)-C(5)-C(17) -177.08(13) C(3)-C(4)-C(5)-C(6) 2.6(2) C(4)-C(5)-C(6)-O(4) 168.28(14) C(17)-C(5)-C(6)-O(4) -12.0(2) C(4)-C(5)-C(6)-C(7) -9.4(2) C(17)-C(5)-C(6)-C(7) 170.29(13) C(1)-C(2)-C(7)-C(8) -3.7(2) C(3)-C(2)-C(7)-C(8) 174.90(13) C(1)-C(2)-C(7)-C(6) 173.49(12) C(3)-C(2)-C(7)-C(6) -7.9(2) O(4)-C(6)-C(7)-C(8) 11.6(2) C(5)-C(6)-C(7)-C(8) -170.72(13) O(4)-C(6)-C(7)-C(2) -165.55(14) C(5)-C(6)-C(7)-C(2) 12.12(19) C(2)-C(7)-C(8)-C(9) 1.1(2) C(6)-C(7)-C(8)-C(9) -176.08(13) C(7)-C(8)-C(9)-C(10) 1.9(2) C(8)-C(9)-C(10)-C(1) -2.5(2) C(2)-C(1)-C(10)-C(9) 0.0(2) B(1)-C(1)-C(10)-C(9) 179.19(14) O(1)-C(11)-C(14)-O(2) -27.84(14) C(12)-C(11)-C(14)-O(2) 86.63(14) C(13)-C(11)-C(14)-O(2) -144.53(13) O(1)-C(11)-C(14)-C(15) -146.01(13) C(12)-C(11)-C(14)-C(15) -31.54(18) C(13)-C(11)-C(14)-C(15) 97.30(17) O(1)-C(11)-C(14)-C(16) 85.57(15) C(12)-C(11)-C(14)-C(16) -159.96(14) C(13)-C(11)-C(14)-C(16) -31.12(19) 109

O(2)-B(1)-O(1)-C(11) -10.61(17) C(1)-B(1)-O(1)-C(11) -178.74(13) C(12)-C(11)-O(1)-B(1) -95.68(15) C(13)-C(11)-O(1)-B(1) 144.70(16) C(14)-C(11)-O(1)-B(1) 23.68(15) O(1)-B(1)-O(2)-C(14) -8.62(17) C(1)-B(1)-O(2)-C(14) 159.08(13) C(15)-C(14)-O(2)-B(1) 145.08(14) C(16)-C(14)-O(2)-B(1) -96.99(14) C(11)-C(14)-O(2)-B(1) 22.55(14)

110