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
Copyright
6
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
1.8 Aims and Objectives
27
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-tetramethyl1,3,2-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
3
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 sixmembered 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.
4
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.
5
Copyright
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.
Copies of this dissertation, either in full or in extracts, may be made only in accordance with
the regulations of the John Rylands University Library of Manchester. Details of these
regulations may be obtained from the Librarian. This page must form part of any such copies
made.
The ownership of any patents, designs, trademarks and any and all other intellectual property
rights except for the Copyright (the “Intellectual Property Rights”) and any reproductions of
copyright works, for example graphs and tables (“Reproductions”), which may be described
in this dissertation, may not be owned by the author and may be owned by third parties. Such
Intellectual Property Rights and Reproductions cannot and must not be made available for
use without the prior written permission of the owner(s) of the relevant Intellectual Property
Rights and/or Reproductions.
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.
6
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.
7
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
8
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 2position 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.
9
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
10
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
11
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
reactive superoxide anion and H2O2.8
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.
12
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
13
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
14
Extraction
Duration (h)
Recovery
(mg/mL)
Recovery
(%)
2
5
10
0.93
1.56
1.06
36
58
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.
15
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
16
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-1,4naphthoquinone 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
18
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 3hydroxy-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
19
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
potential prodrug chelators.34,35 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 4position 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
20
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
21
Sreeleetha et al. synthesised a range of plumbagin derivatives as they recognised the 1,4naphthoquinone 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.
22
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 Bu 3SnH 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-2,2,2trichloroacetates into benzo-fused aromatics, a process which is catalysed by a large variety
24
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).
25
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.
26
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
27
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-1yl
H
Table 2 - List of synthesised chrysene derivatives.
28
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 electrondonating 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.
31
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 5positions 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).
33
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).
34
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.
35
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,Ndiethylaniline however the reaction appears to form desired product 43 in addition to phenol
41 from the previous step.
36
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).
37
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
38
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] retroaddition 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.
39
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-2,6diisopropylphenylimidizolin-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.
41
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.
42
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
43
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.
44
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.
45
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.
46
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 (iPrOB-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-1,3,2dioxaborolane. Thermal ellipsoids at 50% probability.
49
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)-4,4,5,5tetramethyl-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.
51
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).
52
Fig. 24 - ORTEP representation of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1,4dione. 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.
53
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.
55
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.
56
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
57
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.
58
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.
59
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 AtmosphericPressure 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 FTIR instrument and absorption peaks (νmax) were measured in wave numbers (cm-1).
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.
60
39 - 1-4-Dimethoxy-2-methylbenzene56
39
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. NaHCO 3 (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).
1H
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,
Ar5/6-H), 6.84 (s,1 H, Ar3-H) ppm;
13C
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
(Ar2), 152.5 (Ar1), 153.5 (Ar4) ppm; IR: νmax/cm-1 1220 (C-O), 1658 (Ar-CH3); MS ES+ m/z
153.1 ([M+H]+,100%).
61
40 - 2,5-Dimethoxy-4-methylbenzaldehyde56
40
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
1H
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)
ppm;
13C
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),
189.2 (-CHO) ppm; IR: νmax/cm-1 1267 (C-O), 1372 (-CH3), 2830 (OC-H), 1656 (-CHO),
3009 (Ar-H); MS ES+ m/z 181.1 ([M+H]+), 100%).
62
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
1H
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)
ppm;
13C
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:
νmax/cm-1 1277 (C-O), 1378 (-CH3), 3004 (Ar-H), 3351 (-OH); MS ES- m/z 167.0 ([M-H]-,
100%).
63
42 - 1-(Allyloxy)-2,5-dimethoxy-4-methylbenzene57
42
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).
1H
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),
6.55 (s, 1 H, Ar6-H), 6.73 (s, 1 H, Ar3-H) ppm;
13C
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;
IR: νmax/cm-1 1263 (C-O), 1397 (-CH3), 1611 (C=C), 2850 (-CH2), 3080 (Ar-H); MS ES+ m/z
231.0 ([M+Na]+), 100%).
64
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).
1H
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,
Ar1-OH), 6.00 - 6.13 (m, 1 H, -CH=) 6.58 (s, 1 H, Ar5-H) ppm;
13C
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
(Ar6), 150.8 (Ar1-OH) ppm; IR: νmax/cm-1 1193 (C-O),1656 (C=C), 2842 (-CH2-),3046 (ArH), 3514 (-OH); MS ES- m/z 207.0 ([M-H]-, 100%).
65
44 - 2-Allyl-3,6-dimethoxy-4-methylphenol-2,2,2trichloroacetate
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).
1H
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;
13C
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
(CH=), 136.2 (Ar1-O-), 147.0 (Ar6), 150.3 (Ar3), 159.6 (O-C=O) ppm; IR: νmax/cm-1 1209 (CO), 1634 (C=C), 1764 (C=O), 2842 (-CH2-), 3081 (Ar-H); MS ES+ m/z 363.0
([M{35Cl3}+Na]+), 100%), 365.0 ([M{35Cl2 + 37Cl}+Na]+, 40%).
66
45 - 5-Chloro-1,4-dimethoxy-2-methylnaphthalene
45
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.
1H
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,
8.3 Hz, 1H, Ar6-H), 7.99 (dd, J=1.3, 8.3 Hz, 1H, Ar8-H) ppm;
13C
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),
147.3 (Ar1), 152.3 (Ar4) ppm; IR: νmax/cm-1 1232 (C-O), 1381 (-CH3), 2833 (-CH=); MS ES+
m/z 237.1 ([M{35Cl}+H]+, 100%), 239.1 (M{37Cl}+H]+, 40%); HRMS EI+ C13H13O2Cl1
([M{35Cl}+H]+) requires 237.0599, found 237.0589.
67
46 - 5-Chloro-2-methyl-1,4-naphthoquinone
46
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.
1H
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,
Ar6-H), 8.10 (dd, J=1.5, 8.1 Hz, 1 H, Ar8-H) ppm; 13C 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
(Ar6), 146.3 (Ar2), 153.3 (Ar7), 183.4 (Ar4),  (Ar1) ppm; IR: νmax/cm-1 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%).
68
47 - 2-Allyl-3,6-dimethoxy-4-methylphenol-2,2,2tribromoacetate
47
After initially cooling a round bottomed flask to 0 °C, the previously synthesised 2-allyl-3,6dimethoxy-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.
1H
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
H, -CH=), 6.72 (s, 1 H, Ar5-H) ppm; 13C NMR (125 MHz, CHLOROFORM-d) 16.5 (Ar4CH3), 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
(O-C=O) ppm; IR: νmax/cm-1 1233 (Ar-O-), 1463 (-CH2-) 1635 (C=C), 2938 (Ar-H); MS ES+
m/z 509.2 ([M{79Br2 + 81Br1}+Na]+, 100%), 507.8 ([M{79Br3}+Na]+), 60%), 511.0 ([M{79Br1
+ 81Br2}+Na]+), 50%).
69
48 - 5-Bromo-1,4-dimethoxy-2-methylnaphthalene
48
Mild thermolysis of a solution of tribromoacetate 32 (1 g, 2.10 mmol) in diglyme (bis-(2methoxyethyl) 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.
1H
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,
J=7.3, 8.3 Hz, 1 H, Ar6-H), 8.06 (d, J=8.3 Hz, 1 H, Ar8-H) ppm;
13C
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),
147.2 (Ar1), 151.8 (Ar4) ppm; IR: νmax/cm-1 1267 (Ar-O), 1380 (-CH3), 3071 (Ar-H); MS
APCI+ m/z 281.2 ([M{79Br}+H]+, 95%), 283.1 ([M{81Br}+H]+, 100%).
70
49 - 2-(5,8-Dimethoxy-6-methylnaphthalen-1-yl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane
49
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.
1H
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,
Ar3-H), 8.04 (m, 1 H, Ar4-H) ppm;
13C
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
(Ar5), 151.8 (Ar8) ppm (Ar1-B unresolvable on
13
C NMR spectrum due to quadrupole
broadening); IR: νmax/cm-1 1232 (C-O), 2846 (C=CH), 2975 (CH3); MS ES+ m/z 329.4
([M{11B}+H]+, 100%); HRMS ESI+ C19H26O4B1([M{11B}+H]+) requires 329.19119, found
329.1923.
71
50 - 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)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
Hz, 1 H, Ar6-H), 8.08 (dd, J=1.6, 7.3 Hz, 1 H, Ar8-H) ppm;
13C
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
(Ar4=O) ppm (Ar5-Bunresolvable on 13C NMR spectrum due to quadrupole broadening); IR:
νmax/cm-1 1117 (C-O), 1257 (-CH3), 1697 (C=O), 2871 (C=CH); MS ES+ m/z 323.2
([M{11B}+Na]+, 100%).
72
1 - 5-Hydroxy-2-methyl-1,4-naphthoquinone
1
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).
1H
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.
73
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77
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°.
78
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)
82
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)
91
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)
96
4. Crystal structure for 2-(5,8-dimethoxy-6-methylnaphthalen-1-yl)-4,4,5,5-tetramethyl1,3,2-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-2yl)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
0.404 and -0.201 e.Å-3
Largest diff. peak and hole
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