Contents Abstract: .................................................................................................................................................. 1

Chapter 1: Introduction: ......................................................................................................................... 2

1.1 3(2H)-Furanones: Structure and Nomenclature .................................................................... 2

1.2 Bioactive 3(2H)-Furanones ..................................................................................................... 3

1.3 Synthesis and Functionalization of 3(2H)-Furanones ........................................................... 6

1.4 Introduction of Fluorine at the C4 Position of 3(2H)-Furanones. ....................................... 10

1.5 Application of Organofluorine Compounds in Medicinal Chemistry ................................. 11

1.6 Project Aims and Objectives ................................................................................................ 12

Chapter 2: Results and Discussion ........................................................................................................ 13

2.1 Overview of the Synthetic Route to the Target Compound ............................................... 13

2.2 Synthesis of 3-hydroxy-3-methyl-2-butan-2-one 15 ........................................................... 14

2.3 Synthesis of 4-hydroxy-4-methyl-1-(4’-bromophenyl)-1-penten-3-one 28 ....................... 16

2.4 Synthesis of 4,5-dibromo-2-hydroxy-2-methyl-5-(4’-bromophenyl)-3-pentanone 29 ...... 18

2.5 Synthesis of 2,2-dimethyl-5-(4’-bromophenyl)-3(2H)-furanone 30 ................................... 21

2.6 Synthesis of 2,2-dimethyl-4-bromo-5-(4’-bromophenyl)-3(2H)-furanone 31 .................... 27

2.7 Conclusions ........................................................................................................................... 29

2.8 Further Work ........................................................................................................................ 29

Chapter 3: Experimental ....................................................................................................................... 31

3.1 Synthesis of 3-hydroxy-3-methyl-2-butan-2-one 15 ........................................................... 31

3.2 Synthesis of 4-hydroxy-4-methyl-1-(4’-bromophenyl)-1-penten-3-one 28 ....................... 31

3.3 Synthesis of 4,5-dibromo-2-hydroxy-2-methyl-5-(4’-bromophenyl)-3-pentanone 29 ...... 32

3.4 Synthesis of 2,2-dimethyl-5-(4’-bromophenyl)-3(2H)-furanone 30 ................................... 32

3.5 Synthesis of 2,2-dimethyl-4-bromo-5-(4’-bromophenyl)-3(2H)-furanone 31 .................... 32

Acknowledgement: .................................................................................. Error! Bookmark not defined.

References ............................................................................................................................................ 33

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Abstract: The 3(2H)-furanone moiety is found in a variety of natural products and molecules with

bioactivity. Consequently, robust methods for the synthesis and functionalization of 3(2H)-

furanones are required in order to efficiently synthesise these molecules. Currently, there

are a number of methods which allow for robust and versatile functionalization of the C2

and C5 positions of the 3(2H)-furanone ring but functionalization of the C4 position is largely

limited to substitution reactions involving halogens as leaving groups. There are a number of

electrophilic substitutions which are known at this position but the range of known suitable

substrates for vinyl nucleophilic substitutions at this position is extremely limited.

Of particular interest is the incorporation of fluorine at the C4 position of the 3(2H)-

furanone. Organofluorine compounds have a number of useful properties which make the

study of their synthesis desirable. It has been shown that electrophilic sources of fluorine

incorporate readily at the C4 position but there has been little success in incorporating

fluorine via vinyl nucleophilic substitution. Theoretically, 2,2-dimethyl-4-bromo-5-(4’-

bromophenyl)-3(2H)-furanone would be an ideal compound upon which to carry out vinyl

nucleophilic substitutions of nucleophilic substitution.

The work detailed in this report sought to examine an established synthesis of 2,2-dimethyl-

4-bromo-5-(4’-bromophenyl)-3(2H)-furanone and identify opportunities for improvement of

that synthetic route to this compound.

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Chapter 1: Introduction:

1.1 3(2H)-Furanones: Structure and Nomenclature

3(2H)-Furanones are ketonic oxygen-containing five membered heterocycles of the general

structure shown in Figure 1.1.1 (a). The term “3” indicates the position of the carbonyl group,

while “2H” refers to the site of hydrogenation from the parent furan (Figure 1.1.1 (b)). The

unsubstituted 3(2H)-furanone (Figure 1.1.1 (c)) is also known to be isolable.

Figure 1.1.1 (A) General structure of a 3(2H)-furanone showing the ring numbering system, (B) Furan and (C)

3(2H)-furanone.

Initially, interest in 3(2H)-furanones arose from the discovery of the sesquiterpene

bullatenone 1 by Brandt, Thomas and Taylor1 which has been the subject of many synthetic

investigations due to its fragrance enhancement and cockroach repellent properties2. Later,

other natural compounds containing the 3(2H)-furanone moiety were isolated including the

monoamine oxidase inhibitor geiparvarin 2 and pseurotin A 3.

Figure 1.1.2 (1) Bullatenone (2) Geiparvarin and (3) Pseurotin A.

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As the above structures in figure 1.1.2 highlight, there are a variety of substitution patterns

which can be found on the central 3(2H) structure including the spiro-fused pattern of

pseurotin A 3, a known antiparasitic compound3.

1.2 Bioactive 3(2H)-Furanones

An array of bioactive 3(2H)-furanones have been discovered. Geiparvarin 2 is known to inhibit

the enzyme monoamine oxidase and as such was originally investigated for its potential to

act as an anti-depressant4, however it has since been found that geiparvarin demonstrates

potent cytotoxic activity and much of the work which has been completed on geiparvarin and

its analogues to date has been in examining its potential as an anti-cancer agent5,6. SAR

experiments have demonstrated that the 3(2H)-furanone moiety is essential for the biological

activity of geiparvarin and its analogues7. As such, most of the bioactive analogues are

functionalised at the coumarin moiety only.

2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) 4 is a compound found in a number of foods

and is known to exhibit antimicrobial effects on human pathogenic microorganisms including

clinically isolated antibiotic-resistant strains8. DMHF represents an ideal drug candidate due

to its simple structure, high potency and wide range of action. Its physicochemical properties

would suggest that DMHF would be readily bioavailable. Partition coefficient (Log POW)

calculations using Chem3D Pro© forecast its Log POW to be ca. 1.13, indicating that it is

lipophilic enough to cross cell membranes. DMHF is likely to be soluble in water also due to

the availability of carbonyl and hydroxyl groups to become involved in hydrogen bonding

interactions 5 represented in figure 1.2.1.

Figure 1.2.1 (4) Structure of DMHF and (5) its likely hydrogen bonding sites.

Other compounds of note include the class of spiro-fused 3(2H)-furanones reported in 1993

by the Du Pont-Merck group9 which contain an appended aromatic group at C5 of the

furanone ring and also a cycloalkyl ring at C2 containing a tertiary amine as represented by 6

in figure 1.2.2. A number of compounds of this type demonstrated selective competitive

antagonist behaviour at sigma receptors suggesting potential use as antipsychotic drugs. Two

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compounds, aryl-substituted spirofuranones 7 and 8 represented in figure 1.2.2, in particular

demonstrated potent affinity but their development as drug compounds was discontinued

due to their toxicity profile9.

Figure 1.2.2 (6) General structure of 3(2H)-furanones with sigma receptor affinity (7,8) Examples of the most

potent of this class of compound.

A final example of bioactive 3(2H)-furanones are the 4,5-diaryl 3(2H)-furanone class. These

compounds were designed based on the initial observation that cis-1,2-diaryl alkenes were

selective inhibitors of the COX-2 enzyme once one of the aromatic rings contained a para-

sulphone group 9 shown in figure 1.2.3. In fact, many of the currently approved COX-2

selective NSAIDs (e.g. Etoricoxib 10 and Celecoxib 11 also figure 1.2.3) contain this sulphone

cis-1,2-diaryl alkene moiety.

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Figure 1.2.3 (9) General structure of bioactive sulphone-containing cis-1,2-diaryl alkenes (10) Etoricoxib (11)

Celecoxib

Achieving COX-2 selectivity is a key priority in the development of new anti-inflammatory

drugs as leading compounds in the Non-Steroidal Anti-Inflammatory (NSAID) class (e.g.

Aspirin, Indomethacin, and Diclofenac) also inhibit the COX-1 isoform. COX-1 is responsible

for many physiological functions necessary for regular function (homeostasis) and as such its

inhibition results in a number of side-effects including difficulty in forming blood clots and

adverse gastric effects.

3(2H)-Furanone analogues of 9 were synthesised as outlined in Shin et al.10. Compounds of

type shown in figure 1.2.4 were found to have a selectivity of ca. 1000-fold for COX-2 over

COX-1.

Figure 1.2.4 Examples of COX-2 selective inhibitors of the 3(2H)-Furanone class.

The relevance of the above examples lies in their demonstration of the variety of compounds

in which the 3(2H)-furanone moiety can be found, highlighting the importance of developing

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methods of synthesising and functionalising 3(2H)-furanones for drug development and total

synthesis purposes.

1.3 Synthesis and Functionalization of 3(2H)-Furanones

A number of methods for synthesis of 3(2H)-furanones are reported in the literature. Early

syntheses, such as that reported by Takeda et al.11 generated the 3(2H)-furanone skeleton by

way of the disconnection shown in Scheme 1.3.1.

Scheme 1.3.1 Primary disconnection used in Takeda’s synthesis of substituted 3(2H)-furanones.

Dibromide 14 can be prepared from the anti-bromination of hydroxyenone 17 a product of

the Claisen-Schmidt condensation of α-hydroxyketone 15 and aldehyde 16 as in Scheme

1.3.2.

Scheme 1.3.2 Synthesis of hydroxyenone 17 used in the preparation of dibromide 14

This synthesis allows for robust functionalization of the product 3(2H)-furanone. For instance,

replacing the methyl groups at the alpha position of the ketone in 15 would enable an array

of C2 substituted 3(2H)-Furanones. One such way in which this could be exploited is in the

synthesis of spiro-fused 3(2H)-furanones of the type represented by 6 as per figure 1.2.2.

Using this methodology, α-hydroxyketone 18 would act as a suitable reagent and could be

generated using an adapted version of the approach used to synthesise spiro-fused furanones

employed by Schow and Tam9 as in Scheme 1.3.3.

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Scheme 1.3.3 – Preparation of the advanced spiro-fused α-hydroxyketone intermediate 18 for the synthesis of

spiro-fused 3(2H)-furanones using an adapted approach.

Similarly, altering the structure of aldehyde 15 would afford a variety of substitution patterns

at C5. As the formation hydroxyenone 17 is achieved through Claisen-Schmidt type chemistry

which is known to be reliably reproducible for an array of substrates.

Functionalisation of the C4 position of the 3(2H)-Furanone ring in this method relies on

exploiting the ability for C4 to undergo vinyl nucleophilic substitution reactions. The most

commonly used strategy is to use an electrophilic halogenating agent such as N-

Chlorosuccinimide (NCS) or N-Bromosuccinimide (NBS) to halogenate the C4 position and

then carry out further substitution, shown in Scheme 1.3.4.

Scheme 1.3.4 Functionalization of the C4 position of 3(2H)-furanones by way of electrophilic halogenating agents

There are two principal disadvantages to using the approach employed by Takeda et al.

1) As this is a multi-step process, there are considerable opportunities for loss of yield

and some of the reactions may require long periods of time to complete.

2) Synthetically useful α-hydroxyketone starting materials may not be readily available

and as such, additional synthetic steps may be necessary to prepare them.

To address these issues, multiple strategies have emerged which seek to shorten the length

of the synthesis, improving yield. A variety of one-step cyclisation reactions have been

developed in the past 10 years. These reactions are usually catalysed by Au(III) or Pt(II)

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complexes although base catalysed variants without metal involvement exist also. The

substrates vary in nature but generally include an alkyne neighbouring a carbon with oxygen

bound to it.

In 2010, Egi et al. 12 reported the gold-catalysed reaction shown in Scheme 1.3.5.

Scheme 1.3.5 – Egi et al. synthesis of substituted 3(2H)-furanones.

This methodology was used to synthesise a variety of C2 and C5 substituted 3(2H)-furanones,

examples of which 19-23 are given below in Figure 1.3.1. These reactions are by and large

high yielding and relatively quick. However, as demonstrated in figure 1.3.1, the yield of these

reactions diminishes considerably when C2 is unsubstituted (R1, R2 = H) as for 23.

Figure 1.3.1 Selected products of Egi et al.’s 3(2H)-furanone synthesis. The yield for each compound is included

in parentheses.

Liu et al.’s13 earlier 2006 gold-catalysed synthesis of substituted 3(2H)-furanones is apparently

the earliest synthesis of this type reported in the literature. As shown in Scheme 1.3.6, alkyne-

substituted α-ketoesters cyclise in the presence of alcohols and AuCl3 to form C2-acetal

derivatives of 3(2H)-furanones with the option C5 functionalization.

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Scheme 1.3.6 – Liu et al.’s synthesis of C2-acetal functionalised 3(2H)-furanones

This method is much lower yielding than Egi et al.’s method but the variety of substrates

which can be used makes this a much more robust synthetic approach.

One-step cyclisations which functionalise C4 directly are also possible. Trofimov et al.’s 2010

synthesis14 of C4-nitrile derivatives demonstrates this as shown in Scheme 1.3.7.

Scheme 1.3.7 Trofimov et al.’s Synthesis of C4-nitrile derivatives of 3(2H)-Furanones

This reaction is not known to work for substituents other than nitriles. This limits the

usefulness of this transformation as nitriles are not particularly efficient leaving groups. This

largely limits the chemistry which can be done at C4 to functional group transformations of

the nitrile, such as the acid catalysed transformation of nitriles to carboxylic acids or reaction

with DiBAL-H to form aldehydes. Aldehyde functionalization at C4 adds an additional

electrophilic centre to the molecule which can allow it to undergo Wittig-type chemistry or

react with nucleophiles. Another important reaction which can be carried out on this centre

is the formation of tetrazoles from 1,3-dipolar additions of azides. This type of chemistry is

widely practiced in the pharmaceutical industry, largely because the tetrazole group acts as a

bioisostere of carboxylic acids.

Although these one-step reactions appear attractive initially, they also present problems.

1) The starting materials for these reactions are difficult to prepare and are not generally

commercially available.

2) Metal catalysts increase the cost of synthesis, limiting their use.

3) Many of these reactions have been difficult to reproduce.

4) Takeda et al.’s facilitates the incorporation of a variety of functional groups into the

synthetic plan.

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A combination of these factors and the historical prevalence of Takeda et al’s synthesis has

contributed greatly to the popularity of their approach despite the existence of these one-

step methods.

1.4 Introduction of Fluorine at the C4 Position of 3(2H)-Furanones.

As discussed previously, the functionalization of C2 and C5 of the 3(2H)-furanone is

substantially easier to achieve than the functionalization of C4. As previously noted in Scheme

1.3.4, C4 functionalization can be achieved by halogenating C4 and then substituting the

halogen for another group. Of particular interest to the host research group is the fluorination

of 3(2H)-furanones at C4.

Work previously described15 demonstrates that Selectfluor®, a source of electrophilic

fluorine, can efficiently fluorinate C4 of 3(2H)-furanones. This is generally achieved through

the synthesis of 4-bromo-3(2H)-furanone 24 which is reacted in the presence of Selectfluor®

to give 4-fluoro-3(2H)-furanone 25 as per Scheme 1.4.1.

Scheme 1.4.1 Fluorination at C4 from 4-bromo-3(2H)-furanone 24 is achieved using Selectfluor®

Further, it has also been demonstrated 15 that it is possible to produce 25 using Selectfluor®

directly without proceeding via the 4-bromo-3(2H)-furanone 24 as shown in Scheme 1.4.2.

Scheme 1.4.2 Direct fluorination to form 25

The systems described in Scheme 1.4.1 and Scheme 1.4.2 respectively employ the use of

electrophilic fluorine. Using 4-bromo-3(2H)-furanone 24, it should be hypothetically possible

to substitute fluorine into the molecule by using a nucleophilic source, as in vinyl nucleophilic

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substitution. Successful vinyl nucleophilic substitutions at C4 of 3(2H)-furanones have been

accomplished using nucleophiles such as – CN 16 and it may be possible to carry out

substitution using the fluoride anion. In principal, demonstrating that fluoride can be

incorporated into the C4 of a 3(2H)-furanone system by nucleophilic means would show that

it is at least plausible for other vinyl systems. The ability to incorporate fluorine into organic

molecules by both electrophilic and nucleophilic means greatly increases the versatility of

planned syntheses of fluorinated compounds.

1.5 Application of Organofluorine Compounds in Medicinal Chemistry

Many licenced drug molecules, examples of which can be seen in figure 1.5.1, contain fluorine

in order to exploit its unique properties17.

Figure 1.5.1 Examples of licenced APIs which contain fluorine in their structure. (a) Emtricitabine – a

Nucleoside Reverse Transcriptase Inhibitor (b) Linezolid – an antibiotic and (c) 5-Fluorouracil – a

potent cytotoxic chemotherapeutic drug.

Drug-Design: The carbon-fluorine bond has a number of unique and important physical

properties which make its inclusion in organic molecules, particularly pharmaceutical

compounds, quite attractive. Firstly, it is a known bioisostere of hydrogen, allowing fluorine

to be introduced into positions previously occupied by hydrogen with no increase in steric

bulk. This is particularly important for compounds whose mechanism of action involves

interacting with the active site of enzymes for which steric bulk is an important consideration

as the molecule must successfully enter the active site.

Additionally, the carbon-fluorine bond is a polar bond, owing to the electronegative nature of

fluorine. This allows for the introduction of polarity into organic compounds without the need

to incorporate bulky hydroxyl groups. This is important for the reasons relating to steric bulk

previously described, but also, it offers the opportunity to remove hydrogen bond acceptors

like hydroxyl groups which are an important factor which influences the bioavailability of drug

molecules.

It is also important to note that despite the polarity of the carbon-fluorine bond, the bond is,

resistant to hydrolytic18, 19 and oxidative metabolic activity20, 21. It can also be demonstrated

that the inclusion of fluorine has an effect on the pKa of neighbouring functional groups. The

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perturbation of pKa can strongly modify the binding affinity and the pharmacokinetic

properties of a pharmaceutical agent. Modulation of pKa may impact on bioavailability by

affecting the absorption process of drugs across cell membranes based on their degree of

ionisation at physiological pH 22, 23, 24.

18F-labelled Radiopharmaceuticals: 18F is a radioactive isotope of fluorine and as such can be

detected by its β-decay pattern25. Compounds such as 18F-Fluorodeoxyglucose are routinely

used for diagnostic purposes in the detection of cancerous masses. Imaging using this

technique is only possible because the C-18F bond is not metabolically cleaved in-vivo as

otherwise the metabolites would contribute to background radiation, reducing the sensitivity

of the measurement26.

The use of 18F compounds for PET scans is also well established 27, 28. 18F is widely used for PET

scans as it can be imaged easily, requiring smaller doses than other radionuclides. It also has

a longer half-life than other radionuclides at 109.7 minutes. This provides a sufficient amount

of time for these labelling molecules to be synthesised off-site and brought to hospitals which

don’t have access to the facilities to produce them on-site29.

A potential application of the incorporation of 18F-labelled compounds is the evaluation and

monitoring of in vitro distribution of labelled drug molecules in whole tissue and organ testing

models. The ability to determine the distribution of a drug molecule would provide invaluable

insight into the prediction of in vivo toxicokinetics, pharmacokinetics and mechanism of

action.

1.6 Project Aims and Objectives

Given the previous analysis of the importance of studying the functionalization of C4 of the

3(2H)-furanone system, the work described in this report sought to investigate the synthesis

of 2,2-dimethyl-4-bromo-5-(4’-bromophenyl)-3(2H)-furanone 31 using the synthetic approach

employed by Takeda et al. The 3(2H)-furanone 31 is an ideal substrate for the examination of

the substitution reactions of nucleophilic fluorine at the C4 position of 3(2H)-furanones and

as such can act as a model for the further study of vinyl nucleophilic substitutions of fluoride.

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Chapter 2: Results and Discussion

2.1 Overview of the Synthetic Route to the Target Compound

The method used to synthesise the target compound 2,2-dimethyl-4-bromo-5-(4’-

bromophenyl)-3(2H)-furanone 31 is depicted in Scheme 2.1.1. The five-step synthesis starts

with the hydration of 2-methyl-3-butyn-2-ol 26 to form 3-hydroxy-3-methyl-2-butan-2-one 15.

3-hydroxy-3-methylbutan-2-one 15 is then condensed with p-bromobenzaldehyde 27 in an

aldol-type condensation form 4-hydroxy-4-methyl-1-(4’-bromophenyl)-1-penten-3-one 28.

The alkene group in 4-hydroxy-4-methyl-1-(4’-bromophenyl)-1-penten-3-one 28 is then

brominated forming the anti-dibromide compound 4,5-dibromo-2-hydroxy-2-methyl-5-(4’-

bromophenyl)-3-pentanone 29 which is cyclised in the presence of base forming the 3(2H)-

furanone 2,2-dimethyl-5-(4’-bromophenyl)-3(2H)-furanone 30. Finally, 2,2-dimethyl-5-(4’-

bromophenyl)-3(2H)-furanone 30 is brominated using to N-bromosuccinimide to 2,2-

dimethyl-4-bromo-5-(4’-bromophenyl)-3(2H)-furanone 31.

Scheme 2.1.1 Formation of 4-bromo-3(2H)-furanone 31

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2.2 Synthesis of 3-hydroxy-3-methyl-2-butan-2-one 15

The hydration of 2-methyl-3-butyn-2-ol 26 was achieved using mercuric oxide in a solution of

sulphuric acid and water as per Scheme 2.2.1.

Scheme 2.2.1 Synthesis of 3-hydroxy-methylbutan-2-one 15

The mechanism of this step is outlined in Scheme 2.2.2. The reaction is initiated when the

mercury associates with the π-electrons of the alkyne as in 32 forming a transient three-

membered ring species which undergoes a Markovnikov addition of water 33 to form the enol

34. The enol 34 undergoes tautomerisation to the protonated ketone 35 which forms the enol

36 upon the loss of Hg(II). The enol 36 undergoes a final tautomerisation to form the ketone

15.

The product of this step of the reaction was obtained as a black oil which was purified upon

distillation at atmospheric temperature to yield 48.2g (48%) of the clear, colourless oil.

This step of the reaction is quite low yielding. There are a number of reasons as to why this

might be the case.

1) Compound 15 is likely to be considerably soluble in water. Therefore, the aqueous

washes which are used in the work-up of this compound would remove product with

them also. This may be avoided by carrying out washes with brine, saturating the

water, minimising the solubility of the ketone.

2) Compound 15 is a low boiling liquid and therefore may evaporate during the

distillation or be lost during the heating stages of the reaction.

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Scheme 2.2.2 Mechanism of the hydration of alkyne 26 to ketone 15.

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The progress of this reaction was followed by monitoring the formation of the carbonyl group,

indicated by the appearance of a triplet at ca. 2.25 ppm integrating for 3H using 1H NMR as

shown in figure 2.2.1. Three distinct hydrogen environments were observed in the spectrum

for this compound which are also noted in figure 2.2.1.

Figure 2.2.1 Assignment of 1H NMR spectrum for ketone 15

This reaction could also be potentially be monitored by in-situ FITR spectroscopy by following

the formation of the carbonyl group based on the appearance of an absorption of at ca. 1650

cm-1.

It is at this stage of the process that functionality at the C2 position of the 3(2H)-furanone is

introduced. Altering the structure of the alkyne used at this stage could lead to a variety of

different compounds.

2.3 Synthesis of 4-hydroxy-4-methyl-1-(4’-bromophenyl)-1-penten-3-one 28

The synthesis of the hydroxyenone 28 was accomplished by condensing ketone 15 with p-

bromobenzaldehyde via an aldol condensation as shown in Scheme 2.3.1. As there is only one

enolisable hydrogen environment in this system, this type of chemistry is more accurately

referred to as a Claisen-Schmidt reaction.

Scheme 2.3.1 Synthesis of hydroxyenone 28

The mechanism of this reaction is outlined in Scheme 2.3.2. Enolate 37 is formed by

deprotonating the alpha position of ketone 15 which then attacks the carbonyl of p-

bromobenzaldehyde 27 forming the anionic tetrahedral intermediate 38 which becomes

protonated in solution to form the alcohol 39. The position alpha to the ketone in 38 is

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deprotonated allowing for the irreversible elimination of water, forming the α,β-unsaturated

enone 28 which is promoted by the formation of the conjugated system.

Scheme 2.3.2 Mechanism for the condensation for ketone 15 and p-bromobenzaldehyde 17 to form enone 28.

This reaction preferentially forms the E-isomer rather than the Z-isomer largely for steric

reasons. The configuration at this point is confirmed by examining the coupling constants of

the protons on either end of the alkene as shown in figure 2.3.1. The coupling constants

observed were ca. J = 15 Hz corresponding to the E-configuration expected. The orientation

of these two protons with respect to each other can be confirmed using the Karplus

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equation should appropriate background work be done, establishing the constants required.

Crystallographic data would also confirm this configuration.

Figure 2.3.1 Assignment of chemical shifts to both of the alkene hydrogens, highlighting their coupling constants

in hertz.

The progress of this reaction was monitored by TLC. It was noted that the reaction was

complete after 15 hours. This was determined by monitoring the disappearance of the p-

bromobenzaldehyde 27, of which a commercially purchased sample was available. After an

acid workup, a yellow waxy solid was obtained which was then recrystallized from

DCM/hexane to yield a yellow crystalline solid (8.3g, 87% yield).

This reaction presents another opportunity to utilise in-situ FITR spectroscopy. Given that the

product enone 28 is highly conjugated, a shift in the carbonyl absorbance (to about 1700-

1720 cm-1) from that which is observed in either of the two parent carbonyl compounds could

be detected.

It is at this stage at which the functionality at C5 of the 3(2H)-furanone product is introduced.

p-bromobenzaldehyde was chosen for this reaction because the resulting enone was

predicted to be a crystalline solid where other analogues of lower molecular weight tend to

be waxy solids or oils. This allows for the easier purification by crystallisation rather than the

use of column chromatography.

2.4 Synthesis of 4,5-dibromo-2-hydroxy-2-methyl-5-(4’-bromophenyl)-3-pentanone

29

The next stage in the synthesis of the 3(2H)-furanone is the formation of the anti-dibromide

compound 29, shown in Scheme 2.3.1. This transformation was accomplished by the addition

of bromine across the alkene double bond, forming the anti-dibromide.

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Scheme 2.3.1 Formation of the anti-dibromide 29

The mechanism for this reaction is given in Scheme 2.3.2. The π-electrons of the alkene 28

attack one of the bromine atoms in dibromine, releasing electron density onto the second

bromine forming the syn-bromonium species 40 and bromide. Bromide then adds to the

opposite face of the ring, forming the anti-bromide 29.

Scheme 2.3.2 Mechanism for the formation of dibromide 29

In reality, the opposite stereochemical configuration of the intermediate 40 is equally likely

to be observed, shown in Scheme 2.3.3 as compound 41. This would then undergo attack by

the bromide in the same manor, again shown in Scheme 2.3.3, yielding 42 which is an

enantiomer of 29.

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Scheme 2.3.3 Formation of diastereomer 42

As these compounds are enantiomers, they are expected to have similar physical properties.

The dibromide was not purified before processing to the next step of the reaction as it is

known that the crude intermediate can be forward processed without difficulty.

Crystallographic data would confirm the presence of enantiomers and demonstrate if there

was any enantioselectivity achieved in the course of the reaction.

The loss of conjugation in this step presents another opportunity to measure the progress of

this reaction by either IR or in-situ FITR. As indicated in the previous section, the presence of

the alkene group in conjugation with the ketone causes a shift in the observed absorption of

the carbonyl group. Upon loss of conjugation, it would be expected that the absorbance of

the carbonyl group would return to ca.1650 cm-1.

As highlighted in figure 2.3.1, 1H NMR data suggests the formation of the anti-compound as

the coupling constants for the two hydrogens at the sp2 carbons is ca. 12 Hz. It also interesting

to note that the hydrogens bound to the carbon in the alpha position with respect to ketone

are no longer magnetically equivalent. This is due to those protons now being enatiotopic.

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Figure 2.3.1 Spectral Assignment of dibromide 29

2.5 Synthesis of 2,2-dimethyl-5-(4’-bromophenyl)-3(2H)-furanone 30

The cyclisation of the dibromide 29 to form the furanone 30, represented in Scheme 2.4.1,

was achieved by stirring an ethanolic solution of the dibromide 29 in the presence of sodium

hydroxide overnight. Despite acknowledging previously that both 29 and 41 are produced in

the previous step, both of these compounds are known to undergo this reaction and as such

only 29 will be discussed.

Scheme 2.4.1 Synthesis of 3(2H)-furanone 30 from dibromide 29

A plausible mechanism for this step is given in Scheme 2.4.2. In this mechanism, the hydroxyl

group in 29 becomes deprotonated and attacks the benzylic carbon in an SN2 type manor,

expelling bromide and forming intermediate 42. Due to the reversal of stereochemistry, the

proton is now located anti-periplanar to the bromine on C4 of the ring and can undergo E2

type elimination yielding the 3(2H)-furanone 30.

22 | P a g e

Scheme 2.4.2 The currently accepted mechanism for the formation of 3(2H)-furanone 30

Another plausible mechanism would involve the reaction progressing via an SN1 type

mechanism as per Scheme 2.4.3. In this scheme, the bromine at the benzylic position of 29 is

ejected from the molecule forming the cationic intermediate 43 which undergoes

intramolecular nucleophilic attack yielding the pair cationic diastereomers 44 and 45 which

become deprotonated by either the hydroxide or bromide anions to yield 46 and 42, the

previously described intermediate of the suggested SN2 reaction mechanism.

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Scheme 2.4.3 A possible SN1 mechanism for the formation of 3(2H)-furanone 30

As the conformation of the hydrogen with respect to bromine in both 46 and 42 is fixed

relative to one another, the type of elimination reaction which proceeds is likely different for

the two substrates. Bromide 46 has the bromine leaving group and the hydrogen orientated

24 | P a g e

syn-periplanar to one another and thus cannot undergo an E2 type elimination. It is therefore

likely that it undergoes an E1 type elimination, via the formation of the cationic intermediate

47, to yield the product 3(2H)-furanone 30. Conversely, bromide 42 has its bromine leaving

group and the hydrogen orientated anti-periplanar to one another and can undergo E2 type

elimination to form the product 3(2H)-furanone directly.

This mechanism is at least plausible as the reaction is carried out in ethanol, a polar protic

solvent, which is known to promote SN1/ E1 reactions due to its ability to stabilise the

development of the positive charge in the rate-determining transition state. It is also worth

noting that the formation of benzylic carbocations is possible due to the resonance stabilising

effect of the aromatic ring.

The SN2 reaction mechanism appears attractive on first glance because the deprotonation of

the alcohol presents a readily available nucleophile. However, it is unlikely that complete

deprotonation occurs at the alcohol. Utilising Chem3D Pro©, the approximate pKa of this

proton is ca. 16.8. The pKa of water, the conjugate acid of hydroxide, is approximately 15.

Therefore it is unlikely that complete deprotonation of the alcohol occurs. This presents an

opportunity for the formation of the carbocation, which is sufficiently electrophilic to be

attacked by the unprotonated alcohol.

The formation of carbocationic intermediates may be an issue in this reaction and could

explain low yields. This reaction is completed in the presence of ethanol and water, both of

which have the capacity to act as nucleophiles, presenting the opportunity to form impurities

containing hydroxyl and ethoxide side-chains.

Understanding the mechanism of this reaction provides the opportunity to rationally consider

new reaction conditions and protocols to optimise this step, discussed in the “Further Work”

section of this report. A number of experiments could be carried out to determine (a) which

mechanism is predominant under these conditions and (b) the relative contributions of these

mechanisms to the overall process.

1) Isolating intermediates 42 and 46.

It might be possible to isolate intermediates 42 and 46 and to characterise them using NMR

spectroscopic and crystallographic methods. It is possible that isolation could be achieved by

using a sub-stoichiometric amount of base or by otherwise insuring that the reaction doesn’t

progress to the elimination stage. NMR spectroscopy would allow you to distinguish the

relative position of the benzylic proton and the proton at the alpha position of the ketone by

examining their 1H-3J coupling constants and comparing them with the values predicted by

the Karplus equation for the appropriate dihedral angles. It is anticipated that both of these

25 | P a g e

compounds would form crystalline solids due to their high molecular mass and thus

crystallography could be used to solve for their absolute stereochemistry.

The presence of 46 would indicate that the reaction proceeds, at least in part, via the SN1

pathway.

2) Using kinetic isotope effects

Should the presence of 46 be confirmed, the relative contribution of both pathways could be

estimated by studying the kinetic isotope effect observed on replacing the benzylic proton

with deuterium. Deuteration could be easily achieved by using the deuterated analogue of

p-bromobenzaldehyde 48 shown in figure 2.4.1 instead of the undeuterated analogue for the

reaction described in Scheme 2.3.1.

Figure 2.4.1 Deuterated analogue of p-bromobenzaldehyde

If the reaction proceeds via the SN1 mechanism as opposed to the SN2 mechanism, a

secondary kinetic isotope effect would be observed where KH/KD would be ca. 1.2-1.6. Were

the reaction to proceed via the SN2 mechanism instead, it is unlikely that a kinetic isotope

effect would be observed.

The feasibility of this approach is dependent on determining a way to arrest the reaction at

the formation of intermediates 42 and 46 as determining the mechanism using isotope effects

alone becomes more complicated once the reaction progresses to the elimination phase. This

is because both E1 and E2 reactions are subject to isotope effects. E2 reactions are subject to

a large primary kinetic isotope effect as the rate determining step involves the removal of

deuterium directly where E1 reactions are subject to a much smaller secondary isotope as

deuterium is not involved in the rate determining step but does stabilise the carbocation

intermediate. The SN1 pathway allows for E1 elimination as well as E2 elimination as

previously stated, therefore this complicates the interpretation of the observed kinetic

isotope effect.

The above considerations are important in determining opportunities to optimise the both

the product yield and time taken to complete the reaction. The yield of 3(2H)-furanone 30

from this reaction was 73% requiring 18 hours stirring time. Improving either of these two

26 | P a g e

parameters is important as 3(2H)-furanone 30 is an important substrate upon which further

investigations are carried out.

The progress of the reaction was monitored, using 1 H NMR, based on the appearance of a

signal corresponding to the vinyl proton at ca. 5.90 ppm, as shown in figure 2.4.2. TLC was

not used to monitor this step as no authentic sample of the dibromide compound 29 was

available for analysis. Also, as can be seen in figure 2.4.2, the protons corresponding to the

methyl groups at C2 of the 3(2H)-furanone ring are magnetically equivalent once more as they

are no longer enantiotopic.

Figure 2.4.2 Assignment of noteworthy peaks for 3(2H)-furanone 30.

The product obtained from this step after the initial workup was observed to be a waxy yellow

solid. This compound is normally purified by column chromatography but this is known to be

a considerable cause of yield loss for this step. As such, an alternative method of purifying

this compound was sought. Trituration was investigated as a potential alternative to column

chromatography. It was found that triturating the solid in a solvent system of 40% ether in

hexane purified the sample to >98%. The pure compound was obtained as a yellow feathery

solid.

Trituration takes advantage of the solubility differences of the product of interest and its

impurities in a solvent mixture. The presence of impurities causes melting point depression

and is responsible for causing reaction products to form oils, gums and waxes when they

would otherwise be crystalline solids. In order for trituration to be successful, it is necessary

to develop an appropriate solvent system in which the crude compound is sparingly soluble

but in which the impurities are highly soluble. The crude product is then suspended in the

solvent mixture and the stirred for a length of time. The suspended solids are then filtered,

27 | P a g e

yielding the purified compound, while impurities remain in the mother liquors. If necessary,

multiple crops of the mother liquor can be carried out to improve yield.

HSQC (Heteronuclear Single Quantum Coherence) and HMBC (Heteronuclear Multiple-Bond

Correlation) spectroscopy were carried out on the purified compound to confirm the

assignment of the compound prior to commencement of the next reaction.

2.6 Synthesis of 2,2-dimethyl-4-bromo-5-(4’-bromophenyl)-3(2H)-furanone 31

The synthesis of the bromofuranone 31 was accomplished by reaction of 3(2H)-furanone 30

with N-Bromosuccinimide (NBS) 49, a source of electrophilic bromine as shown in Scheme

2.5.1.

Scheme 2.5.1 Synthesis of bromofuranone 31 using N-Bromosuccinimide.

The mechanism for this reaction is given in Scheme 2.5.2. The NBS used in this reaction was

not pure NBS, but rather trace hydrogen bromide was present. This is important as it initiates

the release of bromine radicals for the bromination step. Initially, NBS 49 deprotonates HBR

forming the quaternary amide 50. The bromide released in this step attacks the N-bromine

releasing electron density onto the quaternary nitrogen producing the acetimide 51 which

tautomerises to form succinimide 52 as well as dibromine. Dibromine then polarises to form

two bromine radicals. One of these radicals attacks the 3(2H)-furanone 29 at the vinyl position

forming intermediate 53. The second bromine radical produced scavanges the hydrogen from

the vinylic position producing the bromofuranone 31 as well as regenerating HBr.

When this transformation was carried out using recrystallised NBS, the reaction was very

slow. A mixture of compounds were obtained which were identified as the unsubstituted

3(2H)-furanone 30 and some of the 4-bromo compound 31. It was found that these

compounds, despite being similar in structure, can be separated efficiently using a 20% ethyl

acetate in hexane eluent system.

Dry DCM, which was stored over 4A molecular sieves, was used as the solvent for this

reaction. Water which is present in the reaction mixture has been observed to cause the

formation of mono- and bis-hydroxy-3(2H)-furanone analogues.

28 | P a g e

Scheme 2.5.2 Mechanism for the synthesis of bromofuranone 31.

This reaction was carried out on a 1 mmol scale in CDCl3 intitally to predict the rate of reaction

by ReactNMR. It was hoped that the progress of the reaction could be followed by the rate of

loss of the vinyl proton of 3(2H)-furanone 30 however it transpired that the reaction occurred

instaneously upon mixing. The reaction was then repeated, adding the NBS portionwise

during which time a transient wine-red colour was observed. This colour is unlikely to be due

to the formation of hydrogen bromide as it is a colourless gas.

A prominent issue when using NBS as a source of electrophilic bromine is the succinimide 51

which is produced as a by-product. It is difficult to separate the succinimide from the product

without using carbon tetrachloride, a solvent which is no longer used routinely due to its

status as a possible carcinogen. Consequently, an alternative method for the removal of the

succinimide was invesitgated.

The NBS reaction was repeated once more using 2.67 g (10 mmol) of 3(2H)-furanone 30 and

the products of the reaction were worked up as normal. Initially, it was attempted to remove

the succinimide from the product by using trituration with cold ether. 1H NMR confirmed that

29 | P a g e

this managed to remove approximately 80% of the succinimide on the first. In order to

remove the remaining succinimide, an appropriate eluent system was investigated for use in

column chromatography. Varying concentrations of EtOAc/Hexane were examined using TLC

of which a 10% ethyl acetate in hexane mixture provided the most pronounced separation,

leaving the succinimide at the baseline.

The product from the 10 mmol scale reaction was then purified by column chromatography

yielding 0.8g (42%) of white solid. 1H NMR was used to confirm complete removal of the

furanone

2.7 Conclusions

- The titular compound 2,2-dimethyl-4-bromo-5-(4’-bromophenyl)-3(2H)-furanone 31 was

synthesised and characterised by NMR.

- There is scope for examination of the cyclisation mechanism for formation of the

unsubstituted 3(2H)-furanone 30 which could lead to optimisation of yield and reaction rate.

- There is considerable scope for the inclusion of modern spectroscopic equipment such as

ReactIR and ReactNMR for the purpose of monitoring the early stages of the reaction.

- Trituration is a convenient and effective technique for the purification of both the

unsubstituted 30 and 4-bromo substituted 31 3(2H)-furanones and may in time be able to

replace Column Chromatography as the method of choice.

- Trituration is also a convenient method for the removal succinimide after the NBS reaction.

2.8 Further Work

Project 1: Vinyl Nucleophilic Substitutions

Given that the 4-bromo compound 31 has been successfully synthesised and purified, the

next step would be to carry out the vinyl nucleophilic substitutions using sources of fluorine.

Initially it would make sense to use KF or other forms of anionic fluorine. In the case that this

doesn’t work, alternative sources of fluorine could be used.

If necessary, 4-iodo derivatives could be used. Iodine is a better leaving group than bromine

and this might promote attack at the 4-position. These may be prepared using N-

iodosuccinimide or perhaps via Finkelstein reaction chemistry.

Nucleophilic catalysis could also be employed. Carrying out the reaction in the presence of an

amine nucleophile, such as pyridine or DMAP (N,N-dimethylaminopyridine) may result in rate

enchancements.

It would also be useful to examine additional nucleophiles which could be used to

functionalise this position. In particular; alcohol and amine analogues may be worth exploring

for 1) bioactivity and 2) functionalization purposes.

30 | P a g e

Project 2: Furanone Cyclisation Optimisation

As argued in section 2.4, there is a case to be made for the cyclisation mechanism to proceed

via an SN1 type mechanism rather than the SN2 mechanism which has been broadly asserted

previously. As outlined in section 2.4, a number of experiments could be carried out,

exploiting kinetic isotope effects and crystallography, to determine if there is a contribution

by the SN1 pathway.

Understanding if the development of positive charge in the mechanism is significant as yield

and rate enhancements may be obtained by designing reaction conditions which either

promote or discourage this charge formation. This may allow for better control over the

formation of side-products.

Project 3: Reactivity of 3(2H)-Furanone C4 Halides

While the focus of the work identified in the project has been on the potential for substitution

reactions to occur on the halides at C4 of the 3(2H)-furanone, it is possible for them to have

other reactivity. It might be useful to examine transition metal catalysed reactions using the

4-halogenated substrates.

Project 4: Further Investigation into the Removal of Succinimide.

Trituration proved to be an effective method for the removal of succinimide from the 4-

bromo compound. It would be useful for further work on this compound to develop a protocol

for the removal of succinimide which can be routinely used.

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Chapter 3: Experimental Note: All chemical reagents, unless specifically synthesised in the course of this work, were

commercially available. Melting points were measured on a Thomas-Hoover Capillary

melting point apparatus.

NMR spectra were recorded in deuteriochloroform (CDCl3) with tetramethylsilane (TMS) as

internal standard unless indicated otherwise. 1H NMR spectra were recorded at 300 MHz on

a BRUKER AVANCE 300 spectrometer.

Thin layer chromatography (TLC) was carried out on pre-coated silica gel 60 (Merck PF254)

plates. Column chromatography was carried out on Merck PF 254 silica gel 60. Solvents were

distilled prior to use according to standard procedures by persons in the lab.

As all of these compounds are known compounds, IR Spectroscopy, Mass Spectroscopy and

Elemental Analysis were not carried out.

3.1 Synthesis of 3-hydroxy-3-methyl-2-butan-2-one 15

2-methyl-3-butyne-2-ol 26 (97 ml, 1 mol) was added over 40 minutes to a solution of yellow

mercuric oxide (13 g, 0.06 mol) in concentrated H2SO4 (18 ml, 0.34 mol) and water (100 ml),

while maintaining the temperature below 70°C. Once the addition was complete, the reaction

was heated to 70°C and refluxed overnight. The product was filtered through a bed of Celite®

under vacuum, and the Celite® washed with diethyl ether (3 x 20 ml). The filtrate was

extracted with ether (2 x 30 ml) and washed with water (1 x 50 ml) and saturated NaHCO3

solution (1 x 40 ml) and dried using sodium sulphate. The resulting dark oil was distilled at

atmospheric pressure to yield (52.71g, 52% yield) of clear colourless oil.

δH (ppm): 1.41 (6H, s, 2 x CH3), 2.25 (3H, s, C(O)CH3), 3.83 (1H, s, OH)

3.2 Synthesis of 4-hydroxy-4-methyl-1-(4’-bromophenyl)-1-penten-3-one 28

3-hydroxy-3-methyl-2-butanone 15 (5 g, 49 mmol) and p-bromobenzaldehyde 27 (9.02g, 49

mmol) were dissolved in 95% ethanol (30 ml) with KOH (3 pellets) and allowed to stir

overnight as the clear colourless solution became cloudy and yellow. The solution was

acidified with 10% HCl to pH 1 upon which it became clear and yellow. The solvent was

removed by distillation under reduced pressure at 60°C. This yielded an orange residue which

was dissolved in ethyl acetate (40 ml) and washed with water (3 x 30 ml) and brine (1 x 50

ml). The solution was dried over sodium sulphate, filtered by gravity and concentrated under

reduced pressure to yield an orange solid. The solid was then recrystallized from DCM/hexane

yielding the yellow crystalline solid (10.28g, 78%)

δH (ppm): 1.47 (6H, s, C(CH3)2), 7.09 (1H, d, J = 15 Hz, O=C-CH), 7.42-7.43 (3H, m, ArH),

7.59-7.62 (2H, m, ArH), 7.79 (1H, d, J=15 Hz, CH-Ar).

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3.3 Synthesis of 4,5-dibromo-2-hydroxy-2-methyl-5-(4’-bromophenyl)-3-pentanone

29

Neat bromine (2.520 g, 15.8 mmol) was added dropwise to a stirred solution of 4-hydroxy-4-

methyl-1-(4’-bromophenyl)-pentene-3-one 28 (4.25 g, 15.8 mmol) in DCM (40 ml). The

reaction was allowed stir for 1 hour. The solvent was concentrated under reduced pressure

to give an orange oil which solidified on cooling (5.28 g, 78.1%%, m.p. 114-115°C).

δH (ppm): 1.54 (3H, s, C(OH)CH3), 1.63 (3H, s, C(OH)CH3), 2.52-2.59 (1H, bs, OH), 5.42 (1H, d,

J=11.7 Hz, HCBrAr), 5.67 (1H, d, J = 11.7 Hz, O=CHCBr), 7.29-7.44 (5H, m, ArH).

3.4 Synthesis of 2,2-dimethyl-5-(4’-bromophenyl)-3(2H)-furanone 30

Potassium hydroxide (4.719 g, 0.0401 mol, 2 equivalents) was added to a solution of 4,5-

dibromo-2-hydroxy-2-methyl-5-(4’-bromophenyl)-3-pentanone 29 (8.62 g, 0.02 mol) in 95%

ethanol (120 ml) and the solution stirred overnight. The brown solution was acidified with 10

% HCl to pH 1 and then concentrated under reduced pressure. The solution was extracted

into ethyl acetate (2 x 30 ml) and washed with water (2 x 30ml). The solution was dried over

sodium sulphate and filtered by gravity, the sodium sulphate cake washed with ethyl acetate

(1 x 20 ml), and the filtrate was concentrated under reduced pressure to give an orange waxy

solid which upon trituration with 40% ether in hexane, was isolated as a white crystalline solid

(4.2 g, 79.3% yield, m.p. 109°C).

δH (ppm): 1.50 (6H, s, C(CH3)2), 5.98 (1H, s, C=CH) 7.49-7.63 (3H, m, m- & p- ArH), 7.83 (2H, d,

o-ArH).

3.5 Synthesis of 2,2-dimethyl-4-bromo-5-(4’-bromophenyl)-3(2H)-furanone 31

N-bromosuccinimide (1.8g, 10 mmol) was added portion wise (over approx. 15 minutes) to a

solution of 2,2-dimethyl-5-(4’-bromophenyl)-3(2H)-furanone 30 (2.67g, 10 mmol) in DCM (30

ml) on ice. The reaction mixture was allowed to stir for 30 minutes before being washed with

saturated NaHCO3 (1 x 20 ml) and water (3 x 20 ml). The solution was then dried using sodium

sulphate, filtered and the filtrate concentrated under reduced pressure to give a white

crystalline solid. The crude product was purified by column chromatography using 10% ethyl

acetate in hexane as an eluent, the solvent was removed by distillation under reduced

pressure to give the product as a white solid (1.45 g, 41.8%, m.p. 73-75°C).

δH (ppm): 1.57 (6H, s, C(CH3)2), 7.50-7.63 (3H, m, m- & p- ArH), 8.19-8.22 (2H, m, o-ArH).

33 | P a g e

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