the application of gold(i)-catalysed intramolecular ... application of gold(i)-catalysed...
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The Application of Gold(I)-Catalysed
Intramolecular Hydroarylation Reactions
to the Synthesis of Coumarins
A thesis submitted for the degree of
Doctor of Philosophy
by
Aymeric Thibaut Florian Cervi
Research School of Chemistry,
Canberra, Australia
December, 2016
Declaration
I declare that, to the best of my knowledge, the material presented in this thesis
represents the result of original work carried out by the author during the period 2010−2016
and has not been presented for examination for any other degree. This thesis is less than 100,000
words in length. Established methodologies have been acknowledged, wherever possible, by
citation of the original publications from which they derive.
Aymeric Thibaut Florian Cervi
iii
Acknowledgements
First, I would like to thank Prof. Martin Banwell for first welcoming me so nicely when
I applied to come for my master placement and then his supervision over the years. His support
never stopped despite all the hurdles I went through and his encouragements lifted me during
the hardships. Then, I would like to thank the RSC technical staff for their help and support
throughout the difficulties and bearing with my constant requests. Tony Willis for his invaluable
help with X-ray analysis, Anitha Jeyasingham for bearing with my numerous questions and
always welcoming me with a smile even though she knew I was always coming with problems
and Chris Blake for his help with NMR when my own skills had reached their limits.
I would also like to thank the members of the Banwell group, both past and present, for
making this an enjoyable experience through the bad parts as well as the goods. Firstly, I would
like to commend Dr Xinghua Ma for welcoming me in his lab as a master student and bearing
with my annoying questions and requests in this new environment. He showed me how much
simpler things can be when one organise their work space in their own personal fashion,
something I went on to reproduce while setting up my numerous labs afterwards. Then, Jens
Lange, Brett Schwarz for showing me some more exciting, chemistry and trying to make me a
better chemist. Then, the French contingent with Laurent Petit and Benoit Bolte, who showed
me that even in that small country, there are some really impressive and inspirational chemists!
Then, I would like to thank Yen Vo, Nora Heinrich, Prue Guest, BoRa Lee, Hye-Sun
Kim for giving me such a nice excuse for baking my now regular chocolate croissant. I am most
greatful for Mukesh Kant Sharma and Mohammed Rehmani for their friendship and help
throughout the years. I do severely miss our discussions about chemistry in general and also
about amazing syntheses.
Of note also are Dr Mark Ellison and Prof. Geoff Salem for giving me the opportunity
to do some demonstration with the 1st and 2nd year students, which was a truly transformational
experience.
I would also like to give a special mention to my family who supported me, from afar,
throughout my life despite my being so far from them and having little time to dedicate to them.
iv
Finally, my wife whose support and innumerable questions helped me greatly improve
as a chemist and a teacher, while her cooking kept me writing and happy during the most feared
time of the write-up.
v
Publications and presentation
The following list details the publications and presentations resulting from the work undertaken
during the course of the author’s PhD studies.
Publications
i. Cervi, A.; Aillard, P.; Hazeri, N.; Petit, L.; Chai, C.L.L.; Banwell, M.G.; Willis,
A.C., Total Syntheses of the Coumarin-Containing Natural Products Pimpinellin
and Fraxetin Using Au(I)-Catalysed Intramolecular Hydroarylation (IMHA)
Chemistry, J. Org. Chem., 2013, 78, 9876.
ii. Cervi, A.; Chai, C.L.L.; Willis, A.C.; Banwell, M.G., The Synthesis of Coumarins
Using Au(I)-Catalysed Intramolecular Hydroarylation Chemistry, A
Methodological Study. Manuscript in preparation.
Presentation
i. Cervi, A.; Chai, C.L.L; Willis, A.C.; Banwell, M.G., New Route to Coumarins: the
Golden Pathway, Poster presentation: 7th Singapore Catalysis Forum, Singapore,
23 May, 2014.
ii. Cervi, A.; Chai, C.L.L.; Willis, A.C.; Banwell, M.G., New Route to Coumarins:
the Golden Pathway, Poster presentation: Belgian Organic Synthesis Symposium
XIV, Louvain-La-Neuve, Belgium, 13-18 July, 2014.
vii
Abstract
The studies disclosed in the body of this thesis were focused on the preparation of
coumarin derivatives from aryl propiolates using gold(I)-catalysed intramolecular
hydroarylation reactions (IMHA).
Chapter One focuses on the currently available synthetic methods for the preparation of
coumarins.
Chapter Two begins with a discussion of the mechanism of the IMHA process by which
the author has prepared coumarins from aryl propiolates. Then, it focuses on the implementation
of the IMHA reaction in the synthesis of coumarins (C, X=O) from aryl propiolates (B) that are
themselves derived from the corresponding phenol (A). The extension of such procedures to
related system, chromene (X=Me2), is also described.
Chapter Three focuses on the application of the new methodology to natural product
synthesis, particularly, fraxetin and some of its derivatives as well as pimpinellin.
ix
Glossary
The following abbreviations have been used in this thesis:
Units
Å
°C
eV
g
h
Hz
νmax
M
min
mL
mol
m/z
ppm
W
Ångstrom
degrees celsius
electron volt
gram
hour
Hertz
wavelength (cm−1)
molarity
minutes
millilitre
mole
mass-to-charge ratio
part per million
Watt
x
Chemical abbreviations
Ac
Ar
Bn
Boc
(Boc)2O
Bz
CHCl3
CuTC
DCC
DCM
DCU
DIMCARB
DMA
DMAP
DMF
DMT-MM
EDC
Et
EWG
HATU
HFIP
LiHMDS
L
m-CPBA
Me
NBS
NIS
Nu
OMe
Ph
acetyl
aryl
benzyl
tert-butoxycarbonyl
tert-butoxycarbonyl anhydride
benzoyl
chloroform
copper thiophencarboxylate
N,N-dicyclohexylcarbodiimide
dichloromethane
N,N-dicyclohexylurea
N-methylmethanamine dimethylcarbamate
N,N-dimethylacetamide
4-(N,N-dimethylamino)pyridine
N,N-dimethylformamide
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride
N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide
ethyl
electron-withdrawing group
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]-pyridin-1-
ylmethylene]-N-methylmethanaminium hexafluorophosphate N-
oxide
hexafluoroisopropanol
lithium bis(trimethylsilyl) amide
ligand (generic)
meta-chloroperbenzoic acid
methyl
N-bromosuccinimide
N-iodosuccinimide
nucleophile
methoxy
phenyl
xi
Piv
Py
T3P®
TBS
TES
TfO
THF
TMS
pivaloyl
pyridine
propylphosphonic anhydride solution
tert-butyldimethylsilyl
triethylsilyl
trifluoromethanesulfonyl
tetrahydrofuran
trimethylsilyl
xii
Miscellaneous
aq.
br s
cat.
cf.
d
decomp.
E
EI
equiv.
ESI
hydrol.
HRMS
IMHA
IR
J
m
NMR
ORTEP
q
quant.
Rf
s
SEAr
sept
t
TLC
δ
v/v
vide infra
vide supra
aqueous
broad singlet
catalytic (amount)
confere (compare)
doublet
decomposition
electrophile
electron impact
equivalent
electrospray ionisation
hydrolysis
high resolution mass spectrometry
intramolecular hydroarylation
infra red
coupling constant
multiplet
nuclear magnetic resonance
Oak Ridge Thermal Ellipsoid Program
quartet
quantitative
retardation factor
singlet
electrophilic aromatic substitution
septuplet
triplet
thin layer chromatography
chemical shift (part per million, ppm)
unit volume per unit volume (ratio)
see below
see above
xiii
1. CHAPTER ONE
Coumarin-Containing Natural Products: Occurrence, Structure
and Synthesis ....................................................................................... 1
1.1.1 Introduction ........................................................................................................ 1
1.1.2 Coumarin Derivatives ........................................................................................ 3
1.2.1 Synthesis of Coumarin Derivatives Through C8a-O1 Bond Formation ...... 7
1.2.2 Synthesis of Coumarin Derivatives Through O1-C2 (Lactone) Bond
Formation ....................................................................................................................... 13
1.2.3 Synthesis of Coumarin Derivatives Through O1-C2 then C2-C3 Bond
Formation ....................................................................................................................... 14
1.2.4 Synthesis of Coumarin Derivatives Through O1-C2 then C3-C4 Bond
Formation ....................................................................................................................... 17
1.2.5 Synthesis of Coumarin Derivatives Through O1-C2 then C4-C4a Bond
Formation ....................................................................................................................... 18
1.2.6 Synthesis of Coumarin Derivatives Through C2-O2 Bond Formation ...... 24
1.2.7 Synthesis of Coumarin Derivatives Through C3-C4 Bond Formation ....... 25
1.2.8 Synthesis of Coumarin Derivatives Through C3-C4 then O1-C2 Bond
Formation ....................................................................................................................... 28
1.2.9 Synthesis of Coumarin Derivatives Through C4-C4a Bond Formation ..... 33
1.2.10 Synthesis of Coumarin Derivatives Through C4-C4a then O1-C2 Bond
Formation ....................................................................................................................... 35
1.2.10.2 Suzuki-Miyaura Cross-Coupling.................................................................... 37
xiv
2. CHAPTER TWO
Investigation of a Sequential Esterification/Gold(I)-Catalysed
Route to Coumarins .......................................................................... 39
2.2.1 Optimising the Coupling Process ................................................................... 43
2.2.2 Preparation of Propiolate Derivatives ........................................................... 46
2.3.1 Catalyst Screening ........................................................................................... 52
2.3.2 Scopes of the Reaction ..................................................................................... 53
2.4.1 The Synthesis of gem-Dimethylchromenes .................................................... 62
2.4.2 The Synthesis of Quinolidinones .................................................................... 63
3. CHAPTER THREE
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin ...... 65
3.2.1 Isolation and Characterisation of Fraxetin and its Derivatives .................. 67
3.2.2 Previous Total and Semi-Syntheses ............................................................... 67
3.2.3 Synthesis of Fraxetin and its Derivatives via an IMHA Reaction ............... 68
3.3.1 Isolation and Characterisation of Pimpinellin .............................................. 78
3.3.2 Previous Total Synthesis ................................................................................. 78
3.3.3 Synthesis of Pimpinellin .................................................................................. 80
xv
4. CHAPTER FOUR
Summary and Possible Future Work ............................................. 89
4.1.1 Methodological Studies .................................................................................... 89
4.1.2 Total Syntheses ................................................................................................. 93
5. CHAPTER FIVE
Experimental Procedures ................................................................ 97
5.1.1 Synthesis of Phenol Precursors ....................................................................... 99
5.1.2 Synthesis of Aryl Propiolates ........................................................................ 108
5.1.3 Synthesis of Coumarins ................................................................................. 147
5.1.4 Synthesis of Propargyl Ethers ...................................................................... 189
5.1.5 Synthesis of Chromenes ................................................................................. 193
5.1.6 Synthesis of Propiolamides ........................................................................... 197
5.1.7 Characterisation of By-Products .................................................................. 200
5.2.1 Synthesis of Fraxetin, its Derivatives and Precursors ................................ 204
5.2.2 Synthesis of Pimpinellin ................................................................................ 212
6. REFERENCES ......................................................................... 223
7. APPENDICES ........................................................................... 237
Chapter One
1
1.1 COUMARIN AND ITS DERIVATIVES
Coumarins, or 2H-1-benzopyran-2-ones, according to IUPAC nomenclature, are a
ubiquitous family of secondary metabolites that have been obtained from a diverse range of
plants, animals and microorganisms.1 Vogel first isolated the parent coumarin (1.1) in 1820
from Tonka beans and the clover blossoms of new-mown hay, Melilotus oficinalis.2 It was,
however, Perkin’s seminal article in 1868 that really sparked interest in these natural products
and resulted in the naming of them.3 Although coumarin itself is a naturally occurring toxin that
can damage the liver in high doses, over 45,000 articles, reviews and communications have
been published on coumarin derivatives since their discovery. Nowadays coumarin derivatives
are classified according to the position of the substituents on the coumarin scaffold (Figure
1.1).
Figure 1.1 Numbering of the Coumarin Basic Skeleton.
Natural products of the coumarin family have been isolated from more than 150
different species distributed over nearly 30 different families of plants, for example, Apiaceae,
Caprifoliaceae, Clusiaceae, Guttiferae, Nyctaginaceae, Oleaceae, Rutaceae and Umbelliferae
(Figure 1.2).4
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
2
Figure 1.2 Natural Sources of Coumarins: Tonka Bean (a), Vanilla Grass (b) and Wild Baby's Breath (c).
Although these natural products have been isolated from all parts of the plant, the
highest concentrations are observed, in descending order, in the fruits, seeds, roots, leaves and,
where relevant, the sap. Similarly, high levels can be found in some essential oils derived from
cinnamon,5 and lavender.6 Coumarin derivatives were first investigated in any substantial way
because of their odoriferous properties and, therefore, their potential utility as agents in
perfumery. Nowadays it is the wide array of biological activities of these compounds that
motivates the studies of them, including the development of synthetic methods. These
biological activities include antioxidant,7 inhibition of platelet aggregation,8 antibacterial9,10
and anticancer properties11 as well as steroid 5α-reductase12 and HIV-1 protease13 inhibition.
a)
)
b)
)
c)
)
Chapter One
3
The broad diversity of the natural products embodying the coumarin scaffold has led
to their classification into six sub-types as shown in Table 1.1. The first sub-type comprises
simple coumarins such as esculetin (1.2) featuring hydroxyl groups located at C6 and C7,
fraxetin (1.3) bearing hydroxyl groups on C7 and C8 as well as a methoxy group on C6 and
umbelliferone (1.4) bearing a single hydroxyl group on C7. Members of the second sub-type
are known as furanocoumarins, the core structure of which incorporates both a pyrone and a
furan moiety, such as seen in bergapten (1.5), with a methoxy group located on C5, imperatorin
(1.6) bearing an alkoxy group on C8, and psoralen (1.7), the simplest (parent) member of the
subfamily. The dihydrofuranocoumarins are listed as the third sub-type and they feature both a
coumarin and a dihydrofuran moiety as seen in felamidin (1.8), a naturally occurring ester, and
its biosynthetic precursor marmesin (1.9). The pyranocoumarins, the core of which incorporates
both coumarin and pyran moieties, constitute the fourth sub-type and are subdivided into a
linear variant as seen in xanthyletin (1.10) and an angular form that includes calanolide A (1.11)
and (+)-pseudocordatolide C (1.12). The phenylcoumarins (or neoflavones) such as disparinol
B (1.13) and inophyllum A (1.14), featuring the presence of phenyl group at C4, constitute the
fifth subfamily of coumarin while the bicoumarins such as dicoumarol (1.15) are the final sub-
type featuring two coumarin motifs linked by a methylene bridge.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
4
Table 1.1 The Six Fundamental Classes of Coumarin-Containing Natural Products.
Sub-type Examples
simple coumarins
furanocoumarins
dihydrofuranocoumarins
pyranocoumarins
phenylcoumarins
bicoumarins
Chapter One
5
1.2 SYNTHESIS OF COUMARIN DERIVATIVES
Although coumarin derivatives have fascinated chemists for many decades, studies of
them were originally limited to the manipulation of their naturally occurring congeners.
Syntheses of coumarin derivatives have evolved in parallel with the advances in organic
chemistry more generally. In more recent times various methods have been developed to
prepare coumarins possessing unnatural oxygenation patterns or substituents that would be
difficult to incorporate when starting from other (naturally occurring) coumarins. Thus, the
development of new synthetic methods, the discovery of new reactivities as well as renewed
interest in catalysis as a way to create greener, milder and more efficient synthetic methods
have led to the identification of new means for the preparation of coumarins.
An analysis of the literature reveals that the most common (classical) methods for
assembling coumarin derivatives centers on the creation of bonds between C3 and C4 or
between O1 and C2 (Figure 1.3). The former pathway has been exploited extensively and can
be achieved by various means, especially via Perkin, Pechmann, Knoevenagel, Diels-Alder or
metathesis reactions as well as by oxidation. Processes involving O1-C2 bond formation have
also been accomplished through Perkin, Pechmann or Knoevenagel reactions or by
lactonisation or carbonylation and through sequential reductive cyclisation. Alternate
approaches involving other bond-forming processes such as those leading to the construction
of the C2-C3, C4-C4a or C8a-C1 bonds are also known. The C2-C3 bond-forming processes
generally exploit a carbonylative event. The C4-C4a bond-forming processes, in contrast,
feature coupling/lactonisation followed by coupling or a Pechman reaction. Electrocyclisation
processes may also be invoked. Finally, C8a-C1 bond-forming processes generally involve C-
H activation, radical cyclisation or Ullmann coupling reactions.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
6
Figure 1.3 Overview of the Array of Traditional Methods Used to Assemble the Coumarin Scaffold.
More recent methods for the formation of coumarins are presented in the following
sections according to the nature of the bond(s) being formed.
Chapter One
7
In recent studies the synthesis of the coumarin scaffold through C8a-O1 bond
formation has been established as a viable approach. At least four different methods are
available for this purpose; namely those involving Ullmann coupling, oxidative cyclisation,
radical-mediated cyclisation and flash vacuum thermolytic processes (Scheme 1.1). Each of
these is exemplified in the following paragraphs.
Scheme 1.1 General Scheme for the Synthesis of Coumarin Derivatives Through C8a-O1 Bond Formation.
An effective method used for preparing various coumarin derivatives through C8a-O1
bond formation was reported by Lee14 and featured an Ullmann coupling reaction. So, for
example, upon reaction with copper thiophene carboxylate (CuTC), substrate 1.17 (Scheme 1.2)
undergoes an oxidative addition reaction and the metallated species 1.18 so-formed then
cyclises as indicated to deliver the target coumarin 1.19 in 95% yield. It is noteworthy that
despite the use of elevated temperatures and the long reaction times, the reaction proceeded in
very good yield in the presence of a pyrrole subunit. However, a suitably halogenated (at C8a)
precursor is required. Furthermore, the nature of the method used for the preparation of the
substrate prevents the presence of other halogens, especially Br and I. This is because a
palladium-cross coupling reaction is involved.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
8
Scheme 1.2 Synthesis of Coumarin Through Ullmann Coupling Reaction [Reagents and Conditions: i)
CuTC, DMF, 160 °C, 12 h].
A similar approach was described by Opatz15 in his synthesis of lamellarin D (1.21).
(Scheme 1.3).
Scheme 1.3 Synthesis of Lamellarin D Using an Ullmann Coupling Reaction [Reagents and Conditions: i)
(a) NaOH (6 equiv.) MeOH:THF (1:1 v/v), 64 °C, 16 h; (b) CuTC (1.2 equiv.), DMF, 140 °C, µW, 0.67 h; ii) BBr3,
−78 °C to 25 °C, 20 h].
In 2014, Wei16 described the synthesis of certain types of coumarins through an
oxidative cyclisation that exploited an o-arylated benzoic acid of the general form 1.22 (Scheme
1.4) as substrate. Several coumarin derivatives were prepared efficiently (64−89%) by such
means through heating the relevant substrate at 75 °C in the presence of N-iodosuccinimide
(NIS). The regioselective oxidation removes one hydrogen atom from the distal aryl moiety to
afford coumarin derivatives of the general form 1.24. The regiochemical outcome is controlled
by the electronic nature of the substituent R1. However, the range of substituents studied was
limited as only simple alkyl, alkoxy and halogen-containing ones were investigated. The need
Chapter One
9
to use strong oxidants at elevated temperatures will almost certainly preclude the involvement
of more complex substrates. In a related vein, it should be noted that this process can only be
applied to the synthesis of benzocoumarins.
Scheme 1.4 Synthesis of Benzocoumarins Through Oxidative Cyclisation [Reagents and Conditions: i) NIS,
DCE, 75 °C, 4 h, visible light].
A transformation similar to the one presented above was described by Martin who
achieved the syntheses of certain coumarin derivatives via a radical pathway by employing
metals such as copper17 or silver.18 In these cases, the formation of the pyrone ring of the
coumarins proceeded through either C-O or C-C bond formation (Scheme 1.5). In particular,
reaction of o-arylated benzoic acids of the general form 1.22 with a copper catalyst gave rise to
the corresponding coumarin through the formation of the C8a-O1 bond. The mechanism
proposed starts with the reaction of a copper(II) salt with benzoyl peroxide to give a copper(III)
benzoate 1.25 and a benzoyloxy radical. This radical then abstracts a proximal proton at the
ortho-position within compound 1.25 to give intermediate 1.26 that engages in the C-Cu bond
forming process to afford cuprate 1.27. Reductive elimination within this last species then gives
the observed coumarin derivative 1.24.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
10
Scheme 1.5 Synthesis of Benzocoumarins Through Radical Mediated Cyclisation [Reagents and Conditions:
i) Cu(OAc)2 (5 mol%), (PhCO2)2 (1.25 equiv.), HFIP, 75 °C, 12 h].
This method requires the use of relatively high reaction temperatures and a fluorinated
solvent such as hexafluoroisopropanol (HFIP). In addition, efficient processes are confined to
substrates bearing electron-donating R1 or R2 groups. Thus, the yield was found to correlate
with the electron density of the aryl groups [R1 = CF3 (22%), OBn (98%) and H (95%) with R2
= H or R1 = H with R2 = OAc (54%), OTs (53%) and OMe (84%)].
An example of such a process is seen in Jia’s 2011 synthesis of ningalin B (Scheme
1.6).19 Thus, by treating the highly substituted pyrrole 1.28 with lead acetate at 77 °C for 1 h,
the ningalin B precursor 1.29 was prepared in 68% yield. The drawbacks associated with this
protocol include the need to use toxic lead tetraacetate at elevated temperatures.
Scheme 1.6 Synthesis of Ningalin B Through C-H Activation [Reagents and Conditions: i) Pb(OAc)4 (1.5
equiv.), EtOAc, 77 °C, 1 h].
Chapter One
11
The procedure described by MacFarlane20 for generating mutually fused biscoumarin
derivatives is another example of such a process (Scheme 1.7). Thus, successive inter- then
intramolecular esterification reactions between two molecules of hydroxybenzoate ester 1.30
in dimethylammonium dimethylcarbamate (DIMCARB), an ionic liquid, generated the pivotal
intermediate 1.31. This bis-lactone then underwent an intramolecular and oxidative phenolic
coupling to afford the final product ellagic acid (1.32) in 70% yield.
Scheme 1.7 Synthesis of Ellagic Acid (1.32) Through C-H Functionalisation [Reagents and Conditions: i)
DIMCARB, 18 °C, 5 h].
In 2014, Wentrup21 described the conversion shown in Scheme 1.8 and wherein the
(E)-methylidenefuranone 1.33 was subjected to flash vacuum thermolytic (FVT) conditions and
thus effecting its isomerisation to intermediate 1.34 and the in situ conversion of this into
products of the general form 1.35 (which were obtained in 40 to 52% yield).
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
12
Scheme 1.8 Synthesis of Coumarin Derivatives Through FVT [Reagents and Conditions: i) FVT, ∆].
However, this method is unlikely to be applicable to the synthesis of a wide range of
coumarins because of the need to prepare a relatively inaccessible substrate and the subjection
of this to high reaction temperatures (ca 750 °C). Furthermore, only C4-unsubstituted
coumarins are available by this means.
Chapter One
13
In recent years, the formation of the O1-C2 coumarin bond through lactonisation
processes has been reported. A range of reagents has been used for this purpose including silver
oxide/potassium carbonate, 22 CuI/potassium carbonate, 23 trifluoroacetic acid, 24 potassium
carbonate,25 sodium carbonate,26 hydrochloric acid,27 p-toluenesulfonic acid,28 triethylamine,29
triethylamine/oxalyl chloride, 30 acetic acid, 31 palladium acetate/cesium carbonate, 32 boron
tribromide, 33 tetrachlorosilane 34 and LDA. 35 Neutral conditions involving
dicyclohexylcarbodiimide36 or palladium on charcoal/hydrogen have also been reported.37 Of
particular interest are the recent procedures reported by Snieckus,35 and involving a one pot
metallation-intramolecular carbonylation-lactonisation process, and Wei,38 who describes an
N-iodosuccinimide-induced lactonisation of cinnamate derivatives. The synthesis of coumarin
1.37 through such a lactonisation reaction starts with the deprotection of an o-
hydroxycinnamate 1.36 (Scheme 1.9) and this is followed by spontaneous lactonisation of the
resulting phenol onto the linked ester and so affording various coumarin derivatives in 10 to
73% yield.
Scheme 1.9 Synthesis of Coumarin Derivatives Through Lactonisation [Reagents and Conditions: i) acid or
base, ∆].
The frequent requirement for high reaction temperatures and, often, either a strong
acid or base limit the broad application of this sort of process. Of course, this process requires
access to substituted and (Z)-configured cinnamic acids, substrates that are not always easily
obtained.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
14
Another strategy employed for the synthesis of coumarin derivatives involves
sequential O1-C2 then C2-C3 bond formation. The initial carbonylation can be performed either
in presence or absence of a metal catalyst (Scheme 1.10).
Scheme 1.10 General Scheme for the Synthesis of Coumarin Derivatives Through O1-C2 then C2-C3 Bond
Formation.
In 2014, Mascarenas 39 described the first example of metal-catalysed [5+2]
cycloaddition reaction involving a C-H activation process. Although this work was originally
directed at the synthesis of benzoxepines by functionalisation of o-hydroxystyrenes, it was
discovered that coumarins could be prepared under a carbon monoxide atmosphere. Thus,
reacting o-hydroxystyrene derivatives of the general form 1.39 with a rhodium catalyst led to
the formation, via intermediates 1.40 and 1.41, of the rhodacyclic species 1.42 (Scheme 1.11)
that itself underwent carbon monoxide insertion (to give 1.43) then reductive eliminination to
afford the observed coumarin derivatives 1.44 in 69% (R1 = R2 = H), 85% (R1 = OMe, R2 = H)
and 78% (R1 = CO2Me, R2 = H) yield.
Chapter One
15
Scheme 1.11 Synthesis of Coumarin Derivatives Through Carbonylation [Reagents and Conditions: i)
[Cp*RhCl2]2, Cu(OAc)2, (CO)g, H2O, MeCN, 85 °C, 12 h].
The drawbacks associated with this process include the need to use a chemically sensitive
o-vinylphenol-based substrate, expensive catalysts, elevated temperatures and long reaction
times.
The same transformation as detailed immediately above can also be carried under
metal-free conditions as described recently by Bryce,40 Yang41 and Li.42 This reaction is related
to the Perkin and Knoevenagel processes (vide infra). Furthermore, the studies reported by
Kim,43 in which the synthesis of glycyrol was achieved, and those by Griffin44 and Carotti,45 in
which an eutectic mixture of diphenyl and diphenyl oxide was used as solvent, are of particular
interest. A notable variant of this process features reaction of a salicylaldehyde derivative of
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
16
the general form 1.45 with a carbonyl source so as to assemble the coumarin scaffold through
a carbonylative process (Scheme 1.12). Thus, the anion formed by deprotonation of the methyl
ketone moiety within compound 1.45 reacts with diethyl carbonate, in a nucleophilic
addition/elimination reaction, to afford ester 1.46 and the phenol residue within this product is
itself deprotonated and provides, after lactonization, the desired coumarin derivative of the
general form 1.47 in 66% (R1 = 4-fluoro-Bn, R2 = H) or 92% (R1 = H, R2 = Me) yield. This
method represents an attractive alternative to the above-mentioned transformations when a
suitably functionalised o-hydroxy acetophenone is available. That said, this protocol requires
the use of elevated temperatures and a strong base.
Scheme 1.12 Synthesis of Coumarin Derivatives Through Carbonylation with Diethyl Carbonate [Reagents
and Conditions: i) NaH, ∆].
Chapter One
17
Another method for the formation of coumarins involves sequential O1-C2 then C3-
C4 bond formation, a process that normally proceeds under basic conditions. So, for example,
in 2014, Zhuo 46 described the synthesis of 3-arylcoumarin derivatives by reacting a
salicylaldehyde derivative of the general form 1.48 (Scheme 1.13) with a suitable 1,1-
dibromostyrene derivative in the presence of a combination of bases such as sodium bicarbonate
and diethylamine. It is presumed that the salicylaldehyde engages in a Schiff base condensation
reaction with diethylamine and such that zwiterrion 1.49 is formed. This last species then
undergoes reaction with the halogenated styrene in the manner indicated to give cycloadduct
1.50. Ionisation (leading to the oxonium 1.51), hydrolysis and elimination events then take
place and thus affording the observed 3-aryl coumarin derivatives 1.52 in 23 to 90% yield.
Scheme 1.13 Synthesis of Coumarin Derivatives Through Base-Promoted Tandem Reaction [Reagents and
Conditions: i) 1,1-dibromoalkene, Na2CO3, Et2NH, DMF, ∆].
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
18
Another important synthesis of coumarins proceeds through O1-C2 then C4-C4a bond
formation. Such a sequence is encountered in the Pechmann and hydroarylation reactions as
well as certain radical-mediated couplings (Scheme 1.14).
Scheme 1.14 General Scheme for the Synthesis of Coumarin Derivatives Through O1-C2 then C4-C4a Bond
Formation.
Electrophilic activation pathways for the synthesis of coumarins have been reported
recently. Copper, gold, iron and palladium have each been used to induce the electrophilic
aromatic substitution at the ortho-position of phenols by a suitably activated electrophile. The
reaction normally starts with the catalyst coordinating to the alkyne moiety and thus inducing
the nucleophilic addition of the aryl 1.55 (Scheme 1.15) to the electron-deficient alkyne and so
affording the corresponding cationic intermediate 1.56. This is followed by aromatisation and
protodemetallation steps to afford, after lactonisation, the desired coumarin derivatives of the
general form 1.57.
Chapter One
19
Scheme 1.15 Plausible Mechanism for Hydroarylation Reactions Leading to Coumarins via O1-C2 then
C4-C4a Bond Formation.
The synthesis of coumarin derivatives using this method was described recently by
Maiti 47 and Lu. 48 In 2008, Kim 49 also reported the synthesis of atypical antipsychotics
incorporating coumarin units by related means. Thus, the reaction of aryl propiolates of the
general form 1.58 with a copper catalyst such as copper acetate or copper oxide, was observed
to give rise to coumarins of the general form 1.59 in 26 to 79% yield (Scheme 1.16). However,
such cyclisation reactions require relatively high reaction temperatures and are confined to
relatively electron-rich substrates.
Scheme 1.16 Synthesis of Coumarin Derivatives Through C-H Functionalisation [Reagents and Conditions:
i) copper catalyst, (PhCO2)2, HFIP, 75 °C, 12 h].
In 2011, Kitamura 50 reported that reaction of a phenol of the general form 1.60
(Scheme 1.17) with various propiolic acids in the presence of FeCl3/AgOTf in a mixture of
trifluoroacetic acid and 1,2-dichloroethane lead to the formation of coumarins of the general
form 1.61 in 33 to 93% yield. This method only allows for the synthesis of C3-unsubstituted
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
20
coumarin derivatives. Unfortunately, high catalyst loadings as well as strong acids are required.
Furthermore, only electron-rich phenols participate in this process.
Scheme 1.17 Synthesis of Coumarin Derivatives Through C-H Functionalisation [Reagents and Conditions:
i) FeCl3, TFA, DCE, 60 °C].
Some mechanistic studies of closely related processes have been reported by
Satyanarayana.51
In work related to that detailed above, Yamaguchi 52 described the syntheses of
lamellarins C and I that featured the C-H arylation of a pyrrole (rather than an alkyne ester as
mentioned above) to assemble the coumarin moiety of these target natural products. The
synthesis proceeds through electrophilic activation by palladium and relies on the use of a
phenol of the general form 1.62 (Scheme 1.18) and its annulation to methyl pyrrole carboxylate.
The reaction sequence probably involves the ester moiety being activated toward nucleophilic
attack (by the phenol) through metal co-ordination to the carbonyl oxygen. The trans-
esterification product then undergoes oxidative cyclisation to give the desired coumarin
derivatives 1.63 in 39 to 46% yield. This reaction, nevertheless, suffers from the need to use
high temperatures and extended reaction times (20 h). That said, it does provide a concise
method for the formation of chromeno[3,4-b]pyrrol-4(3H)-one derivatives that are otherwise
difficult to synthesise.
Chapter One
21
Scheme 1.18 Synthesis of Coumarins from Phenol Through Electrophilic Activation and Oxidative
Cyclisation [Reagents and Conditions: i) Pd(OAc)2, Cu(OAc)2, K2CO3, DMA, 80 °C, 27 h].
Shi53 has reported a related process and showcased it in the efficient synthesis of several
natural products.
In medicinal chemistry, the most common method for preparing coumarins involves
the Pechman reaction (Scheme 1.19) in which a phenol derivative 1.64 is condensed with a β-
ketoester. The reaction can be effected using either a Brønsted acid such as acetic acid,54
sulfuric acid,55 sodium bisulfate,56 perchloric acid,57 methanesulfonic acid,58 trifluoroacetic
acid,59 polyphosphoric acid 60 or p-toluene sulfonic acid61 or a Lewis acid such as one based on
aluminium, 62 bismuth, 63 cerium (CeIII), 64 copper (CuII), 65 indium, 66 iron (FeIII), 67 niobium
(NbV),68 phosphoryl chloride,69 titanium (TiIV),70 zinc71 or zirconium.72 In 2012, Xiao and
coworkers73 described effecting a Pechmann reaction at 110 °C in the presence of sulfated
graphene as a catalyst. As shown in Scheme 1.19, the initial transformation is a trans-
esterification that generates a new β-ketoester, 1.65, that itself engages in a cyclodehydration
reaction to give coumarins of the general form 1.66.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
22
Scheme 1.19 Synthesis of Coumarin Derivatives Through Pechmann Reaction [Reagents and Conditions: i)
acid].
An interesting variant was described by Gouda,74 Abdelhamid75 and Proenca76 who
each used a β-cyanoester instead of the β-ketoester. The intermediate imidates so involved
could be hydrolysed to the desired coumarin. Such a route has been showcased by Kikuchi,77
in the preparation of coumarin-containing signalling probes and by Mukhopadhyay,78 in the
synthesis of galectin antagonists.
So-called “green” variants of the original Pechmann reaction have been reported by
Chudasama.72a
In 2014, Heinrich79 reported the synthesis of a novel class of biphenylamine derivative
as part of an investigation of structure-activity relationships associated with US28-related
allosteric modulators used for treating cytomegalovirus in humans. The required coumarin
scaffold was assembled by coupling phenol derivatives of the general form 1.67 (Scheme 1.20)
with aryl diazonium chloride derivatives using a titanium(III) catalyst. The plausible
intermediate 1.68 is formed via an aryl radical coupling process and undergoes spontaneous
lactonization to afford the desired coumarin derivatives 1.69 in 18 to 34% yield.
Chapter One
23
Scheme 1.20 Synthesis of Benzocoumarin Derivatives Through Radical Coupling [Reagents and Conditions:
i) TiCl3, H2O/MeCN, 18 °C, 0.25 h].
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
24
The formation of the bond C2-O2, as exemplified by oxidation of the corresponding
chromene also leads to coumarins. Examples of this approach have been described recently by
Morrow,80 Schmidt81 and Chang.82 Thus, upon reacting pterocarpenes of the general form 1.70
(2,2-dihydrocoumarin derivatives) with various oxidising agents (including pyridinium
chlorochromate, tert-butyl hydroperoxide, cumene hydroperoxide or bis-cumyl peroxide),
coumarins were formed in 30 to 63% yield (Scheme 1.21).
Scheme 1.21 Synthesis of Coumarin Derivatives Through Oxidation [Reagents and Conditions: i) PDC or
peroxides, solvent].
Despite the operational simplicity of this method, its scope is limited by the need to
use a strong oxidant as well as to have the relevant 2H-chromene at hand.
Chapter One
25
An attractive means for assembling the coumarin scaffold involves the creation of the
C3-C4 bond as this can be carried out by one of either a Diels-Alder cycloaddition, oxidation
or ring closing metathesis (RCM) reaction (Scheme 1.22).
Scheme 1.22 General Scheme for the Synthesis of Coumarin Derivatives Through C3-C4 Bond Formation.
In 2014, Yamamoto83 described a new method for preparing coumarin derivatives
involving a tandem transfer-hydrogenative cyclisation/intramolecular Diels-Alder reaction
sequence. Thus, treatment of the 1,6-diyne-phenylacrylate 1.74 (Scheme 1.23) with a cationic
ruthenium catalyst, CpRu(MeCN)3PF6, and Hantzsch ester 1.75 (serving as a hydrogen
surrogate) provided the coumarin-fused polycyclic products in good yield (70−85%). A
plausible mechanism for this conversion would involve a [4+2] cycloaddition of the alkynes
onto the ruthenium catalyst to afford a 5-membered ruthenacycle83 that undergoes hydrogen
transfer to form intermediate 1.76. This last species then engages in an intramolecular Diels-
Alder reaction to afford, after aerobic oxidation of the initially formed cyclohexadiene, the
observed coumarin 1.77.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
26
Scheme 1.23 Synthesis of Coumarin Through Oxidative Cross-Coupling [Reagents and Conditions: i)
CpRu(MeCN)3PF6, 120 °C, 5 h].
Treatment of 3,4-dihydrocoumarins of the general form 1.78 (Scheme 1.24) with
different oxidizing agents such as 2,4-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),
phosphoryl chloride/boron trifluoride (POCl3/BF3), oxygen, copper(I) chloride/triphenyl
phosphine (CuCl/PPh3) or palladium on carbon (Pd/C) also gives rise to the corresponding
coumarin. Procedures reported by Fan,84 Olofsson,85 Shi86 and Zou87 as well as those described
by Yadav, 88 and by Chang, 89 are noteworthy although they all require chroman-2-one
derivatives as substrates and a strong oxidant (PCC, PhIO, Ph2IOTf, t-BuOOH, H2O2) is
involved.
Scheme 1.24 Synthesis of Coumarin from 3,4-Dihydrocoumarin Through Oxidation [Reagents and
Conditions: i) DDQ, PCC, PhIO, Ph2IOTf or peroxides, solvent, 18-65 °C].
The procedure developed by Schmidt 90 affords the coumarin scaffold through
participation of an o-acrylate aryl alkene 1.80 (Scheme 1.25) in a ring-closing metathesis (RCM)
Chapter One
27
reaction. Interestingly, this method was shown to be more efficient than the analoguous Perkin
reaction (vide infra) involving the same precursor 1.79 (albeit requiring two additional steps for
a marginal increase in the overall yield). In mechanistic terms, the styrene 1.80 engages in a
[2+2] cycloaddition reaction with the relevant ruthenium carbene to form a ruthenacyclobutane,
1.81, that itself undergoes a [2+2] cycloreversion to give coumarin 1.1. while simultaneously
regenerating the ruthenium-carbenoid catalyst.
Scheme 1.25 Synthesis of Coumarin 1.1 Through Metathesis Reaction [Reagents and Conditions: i) Grubb’s
I catalyst, 40 °C, 2 h; ii) Ac2O, KOAc, 150 °C, 5 h].
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
28
Coumarins can be prepared through a sequential C3-C4 then O1-C2 bond-forming
event from the relevant o-hydroxybenzaldehyde. Such a sequence lies at the heart of coumarin
syntheses involving the Baylis-Hillman, Knoevenagel, Perkin, reductive cyclisation or Wittig
reactions (Scheme 1.26).
Scheme 1.26 General Scheme for the Synthesis of Coumarin Derivatives Through C3-C4 then O1-C2 Bonds
Formation.
Recently, Kaye91 ,92 and co-workers reported efficient syntheses of a series of N-
benzylated coumarin-AZT conjugates being sought as potential dual-action inhibitors of
HIV-1 protease and reverse transcriptase. The reaction of salicylaldehydes of the general form
1.84 (Scheme 1.27) and an acrylate derivative in the presence of 1,4-diazabicyclo[2.2.2]octane
(DABCO) provided the anticipated Baylis-Hillman-derived adducts which were themselves
treated with either hydrochloric acid or acetic acid to give the relevant 3-(halomethyl)coumarin
1.87. The reaction starts with the activation of the α,β-unsaturated ester by DABCO to form the
expected anion that adds to the carbonyl moiety of benzaldehyde 1.84. to afford δ-hydroxy acid
1.85. Treatment of this compound under acidic conditions promotes the lactonisation to afford,
after protonation, intermediate 1.86. This last species then engages in a SN’ reaction with added
halide ion to give the observed product 1.87. The drawbacks associated with this process are
the limited substrate scope (a halomethyl group is introduced at C3 of the coumarin), the
Chapter One
29
inability to use it to introduce a substituent at C4 due to the requirement for a benzaldehyde
moiety in the precursor as well as the need for a mineral acid (such as HCl or HBr).
Scheme 1.27 Synthesis of Coumarin Derivatives Through Baylis-Hillman Reaction [Reagents and Conditions:
i) acrylic acid ester, DABCO; ii) HX, ∆].
Coumarins can also be prepared by reacting salicylaldehydes such as 1.88 (Scheme
1.28) with a β-ketoester in the presence of either a Lewis or a Brønsted acid/base. This process,
which is known as the Knoevenagel-type reaction, has been exploited extensively since its
discovery and remains extremely widely used. In recent years, it has been effected by added
EPZ-10 (a commercially available catalyst),93 mesoporous borated zirconia,94 pyrophosphoric
acid,95 zinc chloride/phosphoryl chloride,96 iron(III) chloride,97 N-methyl morpholine,98 N,N-
dicyclohexylcarbodiimide/dimethyl sulfoxide, 99 1-butyl-3-methylimidazolium hydroxide, 100
water,101 ethanol,102 hexamethylenetetramine/trifluoroacetic acid103 or also of bases such as
sodium hydride, 104 pyridine, 105 piperidine, 106 piperidinium acetate, 107 piperazine, 108
pyrrolidine109 and sodium metal.110
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
30
It is presumed that a Knoevenagel reaction takes place first and that this is followed by
lactonization. Finally, an E1cb reaction occurs to generate the Δ3,4-double bond of the coumarin
of the general form 1.89.
Scheme 1.28 Synthesis of Coumarin Derivatives Through Knoevenagel Reaction [Reagents and Conditions:
i) Lewis and Brønsted acid/base, ∆].
The Perkin reaction was among the first to be used to prepare coumarins, a process
that has recently been conducted using N,N-dicyclohexylcarbodiimide, 111 4-(N,N)-
dimethylaminopyridine, 112 triethylamine, 113 potassium acetate, 114 potassium carbonate, 115
sodium acetate, 116 sodium ascorbate, 117 sodium metal 118 or cyanuric chloride 119 as the
catalyst/promoter. The key feature of the reaction (Scheme 1.29) is the base-promoted addition
of an enolisable acid anhydride to a salicylaldehyde derivative such as 1.90. This is followed
by lactonization and elimination reactions that lead to the observed coumarin 1.91. Despite
shortcomings such as the need to use an enolisable acid anhydride as well as high temperatures
and a base, this method remains one of the most widely used at the present time.
Chapter One
31
Scheme 1.29 Synthesis of Coumarin Derivatives Using the Perkin Reaction [Reagents and Conditions: i) base,
∆].
In 2012, Enders 120 described a reductive cyclisation process to prepare certain
coumarin derivatives. Thus, reaction of the o-hydroxyarylated propiolate 1.92 with hydrogen
in the presence of a poisoned palladium catalyst gave rise to the desired products (Scheme 1.30).
Presumably, the alkyne is first reduced to the corresponding Z-cinnamate and so allowing for a
spontaneous lactonisation involving the pendant phenolic residue and so delivering the
coumarin 1.93.
Scheme 1.30 Synthesis of a precursor of Smyrindiol (1.93) Through Reductive Cyclisation [Reagents and
Conditions: i) H2, 5% Pd-CaCO3, Pb(OAc)2, EtOAc, 30 °C, 1 d].
This otherwise very simple and elegant method for assembling the coumarin core at a late
stage is constrained by an inability to introduce substituents at C3 or C4.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
32
Recent examples of the preparation of coumarin derivatives using the Wittig reaction
have been reported by Shiao,121 Upadhyay122 and Romeu.123 Thus, reaction of substrate 1.94
with phosphorus ylide can lead, under appropriate conditions, and via the erythro-betaine, to
the formation of the corresponding Z-alkene which spontaneously lactonises to afford the
desired coumarin derivatives 1.95. (Scheme 1.31). This method is limited by the need for rather
high reaction temperatures and a strong base such as n-butyllithium. Nevertheless, the
methodology is powerful as shown in the studies of De Kimpe,124 in which the synthesis of
artanin 1.96 was achieved, and of Tilve,125 in which the synthesis of gravelliferone 1.97 was
realised, being of particular interest.
Scheme 1.31 Synthesis of Artanin (1.96) and Related Compounds Through Wittig Reaction [Reagents and
Conditions: i) solvent, ∆].
Chapter One
33
The synthesis of coumarins can be achieved through C4-C4a bond formation involving
Heck coupling or intramolecular hydroarylation/radical-mediated cyclisation reactions
(Scheme 1.32).
Scheme 1.32 General Scheme for the Synthesis of Coumarin Derivatives Through C4-C4a Bond Formation.
A recent example of a coumarin derivatives being prepared through a Heck coupling
reaction was reported by Shioe.126 The studies by Donner,127 Cordero-Vargas,128 Gulcan,129
Minehan,130 and by López-Cortés,131 are also of particular interests. In these, the synthesis of
benzannulated coumarins such as 1.100 was carried out through Heck coupling (biaryl coupling)
of o-halogenated arylbenzoates such as 1.99 is shown in Scheme 1.33.
Scheme 1.33 Synthesis of Coumarins from Phenol Through Heck Coupling [Reagents and Conditions: i)
Pd(OAc)2, PPh3, sodium acetate, mesitylene, 120 °C, 20 h].
In this transformation, presumably the palladium catalyst oxidatively adds to the C-X
bond proximal to the carboxylic acid group. A nucleophilic addition of the palladium species
so-formed to distal aryl moiety then follows and, after reductive elimination, the desired
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
34
coumarin derivative 1.100 is obtained. This method often requires high reaction temperatures
as well as long reaction times.
In 2014 Wu132,133 described the synthesis of various 3-phosphonated and biologically
active coumarins via a radical phosphonation-cyclisation process that proceeded with high
regioselectivity in generally good yields. Thus, reaction of an o-halobenzoate derivative 1.101
(Scheme 1.34) with dialkyl-H-phosphonate, that serves as a phosphorus-radical precursor, in
the presence of a catalytic amount of silver salt and magnesium nitrate provided the coumarin
1.104 after heating at 100 °C for 12 hours. Presumably, the silver catalyst first reacts with the
dialkyl-H-phosphonate to generate a phosphorus-centered radical that then reacts with the
added alkyne. The ensuing alkenyl radical, 1.102, then undergoes cyclisation to deliver, after
single-electron transfer and aromatisation, the observed coumarin derivative 1.104.
Chapter One
35
Scheme 1.34 Synthesis of 3-Phosphonated Coumarin Derivatives through Radical Cyclisation [Reagents and
Conditions: i) Ag2CO3 (10 mol%), Mg(NO3)2 (0.3 equiv.), 4 Å MS, MeCN, 100 °C, 12 h].
The synthesis of coumarins can also be achieved through sequential formation of the
C4-C4a then the O1-C2 bond. Michael addition and Suzuki coupling reactions (Scheme 1.35)
have been deployed to achieve such conversions.
Scheme 1.35 General Scheme for the Synthesis of Coumarin Derivatives Through C4-C4a then O1-C2
Bonds Formation.
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
36
In 2013, Nair134 described a two-fold Michael addition, Grob-type fragmentation and
cyclisation sequence to form coumarins. Thus, by reacting cinnamaldehyde derivatives of the
general form 1.106 (Scheme 1.36) with a suitable α,β-unsaturated ester in either an inter- or
intra-molecular Michael addition reaction the desired coumarin derivatives were formed in 21
to 93% yield after 2 h at 110 °C.
The suggested mechanism involves first the preparation of intermediate 1.107 followed
by its reaction with N-heterocyclic carbene intermediates to form desired coumarin 1.112. Once
again, this method requires high temperatures, either a strong acid or a strong base and a
structurally restricted substrate.
Scheme 1.36 Synthesis of Coumarin Derivatives Through Michael Addition [Reagents and Conditions: i) 1,3-
dimesityl imidazolinium chloride (15 mol%), DBU (20 mol%), 110 °C, 2 h].
Chapter One
37
The work of Müller,135 Janecki,136 Peddinti137 and Lee138 are of particular note among the
recent examples of coumarins prepared by this method.
Syntheses of several coumarin derivatives were carried out using Suzuki-Miyaura
coupling reactions by Vishnumurthy, 139 Liu 140 and Wang. 141 Furthermore, the studies by
Banwell,142 Podlech143 and Yu,144 in which the synthesis of natural products were achieved, are
of special relevance. Thus, upon reaction of o-hydroxyaryl boronic acid derivatives 1.113
(Scheme 1.37) with benzoic acid derivatives 1.114, the coumarin scaffold was synthesised
through Suzuki-Miyaura coupling reaction. In these reaction sequences, in which the cross-
coupling reaction presumably preceeds the lactonization step, coumarins of the general form
1.115 are obtained.
Scheme 1.37 Synthesis of Coumarin Derivatives Through Suzuki-Miyaura Coupling [Reagents and
Conditions: i) Pd(PPh3)4, benzoquinone, i-Pr2NH/CsCO3, dioxane, 80-125 °C, 0.25-15 h].
Coumarin-Containing Natural Products: Occurrence, Structure and Synthesis
38
1.3 OVERVIEW OF REMAINING CHAPTERS
The work described in this thesis was directed towards investigating the application of
a newly developed gold(I)-catalysed IMHA process to the synthesis of coumarins. Specifically,
then, Chapter Two details the study of this process through the screening of a range of gold
catalysts under a variety of reaction conditions. Chapter Three, on the other hand, focuses on
the application of the most refined form of this methodology to the synthesis of a series of
biologically active natural products embodying the coumarin scaffold. Chapter Four, the
penultimate one, attempts to provide some insights into the possible uses and extensions of this
methodology to related systems. Chapter Five details the experimental protocols and
spectroscopic data that form the basis of the results presented in Chapter Two and Chapter
Three.
Chapter Two
39
2.1 INTRODUCTION
The hydroarylation of alkynes, which can also be described as the alkenylation of
arenes, is an addition reaction in which an aromatic compound adds to an alkyne and thus
forming the corresponding arylated alkene. These addition reactions are normally carried out
in the presence of electrophilic metal salts and complexes. Inter- and intramolecular variants
are known (Scheme 2.1). For example, in 2006, Hashmi145 described the reaction of furan 2.1
with simple alkynes such as phenyl acetylene (2.2) to give a mixture of phenol 2.3, formed
through intermolecular [4+2] cycloaddition followed by cleavage of the resulting oxabicyclic
adduct, and the intermolecular hydroarylation product 2.4. The outcome of the intramolecular
hydroarylation (IMHA) of indole 2.5 varies dramatically with the catalyst used. Thus, the 8-
endo-dig product 2.6a or the 7-exo-dig cyclisation product 2.6b can be formed depending on
the particular catalyst used.146
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
40
Scheme 2.1 Examples of Intramolecular Hydroarylation of Heterocyclic Compounds.
The IMHA reaction is believed to proceed via the pathway shown in Scheme 2.2 and
starts with the coordination of the gold(I) catalyst to the terminal alkyne 2.7. An SEAr reaction
involving the aryl moiety follows in which a (favoured) 6-endo-dig cyclisationa reaction takes
place to give product 2.10.
Scheme 2.2 Proposed Mechanism of the Intramolecular Hydroarylation.
a For more information regarding Baldwin’s rules see Appendix One.
Chapter Two
41
It is worth noting, at this point, that the IMHA of electron-rich arenes can be catalysed
by palladium(II) species,147 while electron-poor arenes can be engaged in the same processes
using gallium(III) or indium(III)-based systems.148
Tandem cyclisation reactions involving an IMHA process and leading to polycyclic
products are known. The conversion of alkynyl ether 2.11 into isomer 2.12 (Scheme 2.3) was
reported by Hashmi149 and is indicative of the possibilities in this regard.
Scheme 2.3 Gold(I)-Catalysed Cascade Cyclisation [Reagents and Conditions: i) Mes3PAuNTf2, CHCl3,
25 °C, 24 h].
The foregoing commentary, as well as earlier work by Kitamura,50 suggests that the
gold(I)-catalysed IMHA reaction of propiolate esters derived from the corresponding phenol
(Scheme 2.4) would provide an effective new means of preparing coumarins. The anticipated
and attractive benefits of such an approach would include complete atom economy, at least in
the second step, and the likely need for very mild reaction conditions. Certainly, no strong acids
or bases should be required and the 6-endo-dig cyclisation reaction involved was also expected
to proceed at or close to ambient temperatures. Finally, the air-insensitive nature of most other
gold(I)-catalysed cyclisation reactions suggested that the illustrated process should proceed
under aerobic conditions.
Scheme 2.4 The Two-Step Reaction Sequence Proposed for the Synthesis of Coumarins and the Basis of the
Studies Reported in the Remainder of this Chapter.
As detailed in the following section, the preparation of the pivotal propiolates 2.14
required extensive optimisation. Then, catalyst screening was performed to determine the most
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
42
effective system for carrying out the intramolecular hydroarylation reaction. Finally, the scope
of the methodology was investigated so as to probe the possible applications and limitations of
this synthetic pathway.
Chapter Two
43
2.2 SYNTHESIS OF ARYL PROPIOLATE DERIVATIVES
The parent phenyl propiolate (2.17) (Scheme 2.5) was prepared in 64% yield through
the esterification of phenol (2.16) with propiolic acid using N,N-dicyclohexylcarbodiimide
(DCC) in chloroform [method A].
Scheme 2.5 Unoptimised Condition for the Synthesis of Phenyl Propiolates [Reagents and Conditions: i)
propiolic acid (1.2 equiv.), DCC (1.2 equiv.), CHCl3, 18 °C, 16 h].
However, the author initial efforts in this area were met with unexpected results when p-
methoxyphenol was used as substrate (Scheme 2.6). The utilisation of DCC alone gave the
desired product in just 20% yield while when used in combination with a catalytic amount of
4-(N,N)-dimethylaminopyridine (DMAP) (Steglich’s conditions 150 ), the by-product BP1,
arising from hetero-Michael addition of the phenol phenolate on the propiolate ester was
observed as the major product of the reaction. It was obtained in ca 30% yield (Figure 2.1).
Figure 2.1 Structure of Michael Adduct BP1.
Further investigation of the esterification conditions using a range of coupling reagents
including DMT-MM,151 T3P®, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) along
with a range of bases such as pyridine, triethylamine and 2,6-lutidine failed to provide useful
quantities of the desired aryl propiolate. Furthermore, the use of HATU as the coupling reagent
gave only BP1 (80% yield). The possibility of using a propiolic acid surrogate was also
investigated. However, the preparation of both the acyl chloride and anhydride of propiolic acid
proved problematic as each decomposed immediately. This result, in conjunction with the
explosive nature of propiolic acid anhydride, led to the abandonment of this pathway.152
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
44
Likewise, the preparation of the mixed anhydride derived from propiolic acid and
trifluoromethanesulfonic acid failed to provide any identifiable product. As a result of such
observations, attention was again focused on the use of propiolic acid as the reaction partner.
Since using DCC produced fewer by-products originally optimisation studies were pursued
with this coupling reagent. The following parameters were varied during such studies: reaction
temperature (heating/cooling), rate/order of addition, presence/absence of base, nature of the
base (Hünig’s base, pyridine, triethylamine, 4-(N,N)-dimethylaminopyridine, 2,6-lutidine,
sodium hydride), solvent (tetrahydrofuran, acetonitrile, dichloromethane, chloroform, ethyl
acetate, diethyl ether) and reaction time. Eventually, it was found that the most suitable reaction
conditions for the synthesis of aryl propiolate derivatives involved using a combination of DCC
and sodium hydride in tetrahydrofuran. In particular, the phenol was subjected to reaction with
the base at the start of the reaction and the ensuing phenolate then added to a magnetically
stirred mixture of the propiolic acid and DCC in tetrahydrofuran maintained at 0 °C [method
Bb]. The corresponding propiolate was then purified by flash chromatography and subjected to
the usual range of spectroscopic analyses. Two new by-products, BP2 and BP3, were isolated
in low yield under such conditions and the structures of which were confirmed by single-crystal
X-ray analyses (Figure 2.2). The formation of the latter probably involves a 5-exo-dig
cyclisation of the N,N-dicyclohexylurea (DCU)-activated acid intermediate BP2 (Scheme 2.6).
Scheme 2.6 Optimised Conditions for the Synthesis of Phenyl Propiolates [Reagents and Conditions: i)
propiolic acid (3.3 equiv.), NaH (1.1 equiv.), DCC (3.3 equiv.), THF 18 °C, 16 h].
b See experimental section
Chapter Two
45
BP2 BP3
Figure 2.2 Plots Arising from the Single-Crystal X-ray Analyses of Compounds BP2 and BP3.
The most conspicuous feature in the 1H NMR spectra of the propiolates thus formed
was a one proton singlet in the range δH = 3.0 to 3.1 ppm. This is attributed to the proton of the
terminal alkyne. In the corresponding 13C NMR spectra, two signals due to the
sp-hybridised carbons of the propiolate residue were evident in the range from δC = 74 to 77
ppm. The carbonyl carbons of the ester residues were observed in the range from δC = 154 to
150 ppm, while a carbonyl stretching band was observed at ca. 1720 cm−1 in the corresponding
IR spectrum. The EI mass spectrum of each of these esters almost invariably showed the loss
of propiolate moiety as the main fragmentation pathway. Furthermore, the structures of several
esters were confirmed by single-crystal X-ray analyses.
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
46
The phenols (2.13) required for the preparation of the title propiolates were sometimes
commercially available but normally prepared using established procedures or straightforward
modifications thereof.c
Esterifications of phenol derivatives with uncapped (terminal) propiolates were
performed using method B (Entries 1–36 in Table 2.1). Such subtrates were required to
investigate the influence of mono- and poly-substitution on the phenol ring during the IMHA
process.
The possibility of applying this methodology to other aromatic systems was also
studied through the preparation of some naphthol propiolates such as
7-methoxynaphthalen-2-yl ester 2.54, naphthalene-1-yl ester 2.55 and naphthalen-2-yl ester
2.56 (Figure 2.3). These were obtained in 89 to 96% yields (see Entries 37–39 in Table 2.1).
Figure 2.3 Naphthyl Derived Propiolates.
The esterification of p-methoxyphenol with capped (non-terminal) propiolates (see
Entries 40–41 in Table 2.1) was carried out using a modification of the method B (B*) as
detailed in the experimental section. Such substrates were required to investigate the influence
of substitution of the alkyne during the IMHA process.
The two-fold esterification reaction of hydroquinone with propiolic acid could also be
effected to give the bis-ester 2.59 although this was only obtained in 23% yield. More complex
phenols such as the tyrosine derivative 2.60, carbazole 2.61 and fluorene 2.62 could also be
esterified with propiolic acid (see Entries 42–45 in Table 2.1). Efforts to prepare the fluorene-
c See Appendix 2 for an exhaustive presentation of the synthetic methods used for the preparation of the non-
commercially available phenols.
Chapter Two
47
containing propiolate 2.62 were prompted by a desire to construct coumarins displaying very
strong fluorescence and the consequent capacities to use them as fluorescent probes in various
bio-assays.153
Figure 2.4 A Fluorene-derived Propiolate.
Table 2.1 The Synthesis of Aryl Propiolates.
Entry Ester Esterification
method
Yield
(%)
1
A 64
2
B 69
3
B 72
4
B 25
5
B 70
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
48
6
B 97
7
B 87
8
B 99
9
B 80
10
B 45
11
B 70
12
B 42
13
B 40
14
B 78
15
B 79
Chapter Two
49
16
B 79
17
B 95
18
B 96
19
B 85
20
B 98
21
B 52
22
B 58
23
B 70
24
B 68
25
B 69
26
B 82
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
50
27
B 88
28
B 88
29
B 40
30
B 67
31
B 95
32
B 86
33
B 79
34
B 78
35
B 76
36
B 93
Chapter Two
51
37
B 89
38
B 90
39
B 96
40
B* 98
41
B* 9
42
B 23
43
B 82
44
B 46
45
B 90
* denotes a modification of method B where the desired derivative is substituted to propiolic acid.
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
52
2.3 INTRAMOLECULAR HYDROARYLATION (IMHA) REACTIONS
With the desired aryl propiolate esters in hand, screening of catalysts for effecting their
IMHA reaction so as to form the corresponding coumarins could be investigated. The
naphthalene derivative 2.54 was chosen as the substrate with which to explore the proposed
gold-catalysed IMHA reaction. This choice arose from the accessibility of the starting material
combined with the ease of monitoring the reaction (Scheme 2.7) due to the very strong UV
activity of both the starting propiolate and product coumarin on TLC. In all cases, cyclisation
occurred exclusively on the alpha position of naphthol and so forming coumarin 2.95 alone
(albeit in variable yields see below).
Scheme 2.7 Model Reaction for the Cyclisation Using Different Catalytic Systems [Reagents and Conditions:
catalyst – see Table 2.2 for list of catalysts investigated, DCM, 18 °C].
As shown in Table 2.2 and as a result of screening a range of gold(I) and gold(III)
catalysts, it was established, as anticipated from earlier results obtained within the Banwell
Group,154 that Echavarren’s gold catalyst (JohnPhos gold MeCN hexafluoroantimonate) could
effect the desired conversion quantitatively using 3% loadings and in just 10 min at ambient
temperatures (see Entry 7).
Chapter Two
53
Table 2.2 Catalyst Screening for the Gold-Catalysed Cyclisation.
Accordingly, these optimal conditions were applied to the series of propiolate esters
prepared as described in Table 2.1. The outcomes of such studies are delineated in Table 2.3
and in the following section.
In broad terms, most of the IMHA reactions worked well, with the targeted coumarins
being formed both rapidly and in high yield. Isolation of the products normally just involved
filtering the crude reaction mixture through a pad of TLC-grade silica gel, a manipulation that
allowed for the ready removal of the gold catalyst. The product coumarins were characterised
by the usual means with the 1H NMR spectrum of each generally being diagnostic by virtue of
the presence, in the case of the C3, C4-unsubstituted systems, of a mutually-coupled pair of
doublet (Jvic = 9–10 Hz) due to the associated protons. Single-crystal X-ray analyses were
carried out on coumarins 1.1, 2.92, 2.93 and 2.95.
The highest yields of product were observed in those systems carrying electron-
donating groups (EDGs) or an aryl ring consistent with the expected mechanism of the reaction
occurring through SEAr. Those substrates bearing electron-withdrawing groups (EWGs) failed
Entry Catalyst Conditions Yield
1 Gold (I) 1,3-bis(2,6-di-isopropylphenyl)imidazol-
2-ylidene
3-15 mol%, 2 d NR
2 Gold (I) chloro tri-tert-butylphosphine 3-15 mol%, 2 d NR
3 Gold (I) chloro tricyclohexylphosphine 3-15 mol%, 2 d 3%
4 Gold (I) chloro triphenylphosphine 3-15 mol%, 2 d 3%
5 Gold (I) chloride 3-15 mol%, 2 d 18%
6 Gold (I) dicyclohexylphosphino-2’,4’,6’-tri-
isopropylbiphenyl bis triflimide
3 mol%, 8 h 95%
7 Echavarren’s gold catalyst 3 mol%, 10 min Quant.
8 Gold (III) acetate 15 mol%, 16 h 8%
9 Gold(III)chloride/Silver triflate 3 mol%, 8 h 89%
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
54
to produce the corresponding coumarins in high yield (see Entries 10, 13, 25 and 31 in Table
2.3) or did not proceed at all (see Entries 4, 5, 11, 12, 15, 24, 30 and 32 in Table 2.3). In some
of these cases it is presumed that ester hydrolysis competes with the desired cyclisation process.
In those cases involving meta-substituted systems, two regio-isomeric coumarin-based
cyclisation products are possible and in many instances both were observed. The conversion of
propiolate 2.26 into coumarins 2.67 and 2.68 (see Entry 8 in Table 2.3) is illustrative. These
chromatographically separable products were readily distinguished using 1H NMR
spectroscopic techniques and it was thereby established that isomer 2.67 was the predominant
one, and presumably formed preferentially because of the absence of destabilising peri-type
interactions at the transition states that are encountered during the formation of the minor
product 2.68. Of course, in certain instances, electronic factors are also likely to be influencing
the observed selectivities.
Substrates embodying certain polysubstituted aryl units were also shown to engage in
the anticipated cyclisation reactions and thus providing concise routes to some simple
coumarin-containing natural products and/or related systems. For example, the dialkylated
propiolates 2.50 and 2.51 each cyclises very efficiently to give the corresponding coumarins
2.91 and 2.92, respectively. Analogous cyclisation of the deoxygenated systems 2.52 and 2.53
gave the natural products ayapin (2.93) and scoparone (2.94), respectively. A single-crystal X-
ray analysis of compound 2.93 was undertaken and served to confirm both the structure of the
synthetically-derived material and that of the natural product. In comparison to the syntheses
by Paknikar155 and De Kimpe,156 which afforded ayapin from sesamol in one step (45% yield)
and two steps (55% yield) respectively, the present synthesis provides a milder and more
efficient means of preparing this system. Similarly, scoparone was obtained in just two steps
and 86% overall yield compared to the three-step synthesis described by Li which afforded the
title compound in 77%.157
Other noteworthy features of the outcomes of the present study include the capacity to
produce benzannulated coumarins (see Entries 37–39 in Table 2.3) and C4-substituted ones
through the cyclisation of so-called capped propiolates such as 2.98 and 2.99 (see Entries 40–
41 in Table 2.3). More complex systems such as the tyrosine-based coumarin 2.100 were also
readily obtained. Product 2.100 is a particularly interesting one because of the capacity it offers
for the incorporation of a fluorescent (coumarin) probe into peptide chains.
Chapter Two
55
Table 2.3 Summary of the Study of the Scope for the Gold(I)-Catalysed Cyclisation Through IMHA.
Entry Ester Cyclisation product Yield (%)
1
93
2
Quant.
3
Quant.
4
NR
5
NR
6
70
7
50
8
70/15
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
56
9
92/4
10
44/14
11
NR
12
NR
13
36/18
14
82/17
15
NR
16
55/5 (8 h)
17
83/16
(8 h)
Chapter Two
57
18
60/14
(8 h)
19
Quant.
20
Quant.
21
91
22
74
23
NR
24
NR
25
52
26
Decomp.
27
66 (8 h)
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
58
28
Hydrol.
29
77
30
NR
31
18
32
NR
33
Quant.
34
91
35
Quant.
36
92
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
60
45
Hydrol.
The various examples of IMHA reactions leading to coumarins delineated above
provides the means for introducing a range of substituents at every position on the framework
of this heterocycle except C3. If one considers the mechanism of the basic IMHA reaction
involved in all these cases (Scheme 2.8) there is the potential, at least, to intercept the C3-
aurylated coumarin 2.103 with a halogen-based electrophile such as N-iodosuccinimide and
thereby form the C3-iodinated system 2.104 rather than, simply, its protio counterpart 2.84.
Accordingly, this possibility was pursued using the usual cyclisation conditions except that NIS
was added prior to the introduction of the gold catalyst. As a result, a chromatographically
separable mixture of the iodinated system 2.104 (36%) and its protio-counterpart 2.84 (38%)
was obtained. The 1H NMR spectrum of this material is shown in Figure 2.4 and the
corresponding 13C NMR spectrum in Figure 2.5. Of particular note is the appearance of a one-
proton singlet at δH = 8.32 ppm that is attributed to C4-H. In addition, the mass spectrum of this
material showed the anticipated molecular ion at m/z 302.
In principle, the acquisition of compound 2.104 would allow, thru the application of
metal-catalysed cross-coupling processes, access to a range of C3-substituted coumarins. Based
on the foregoing, the gold(I)-catalysed IMHA of arylpropiolates provides a useful means for
preparing a wide range of variously, mono- and poly-substituted coumarins, particularly those
carrying electron-donating groups on the benzenoid ring. These reactions proceed under
generally mild conditions and in high yield.
Scheme 2.8 Trapping Experiment of α-Carbonyl Gold Intermediate Using N-Iodosuccinimide [Reagents and
Conditions: i) Echavarren’s gold catalyst (3 mol%), NIS (1.1 equiv.), DCM, 18 C].
Chapter Two
61
Figure 2.5 1H NMR Spectrum of 3-Iodo-6-methoxycoumarin (2.104) Recorded in CDCl3.
Figure 2.6 13C NMR Spectrum of 3-Iodo-6-methoxycoumarin (2.104) Recorded in CDCl3.
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
62
2.4 THE SYNTHESIS OF gem-DIMETHYLCHROMENES AND ATTEMPTS TO
PREPARE QUINOLIDINONES BY THE SAME MEANS
An obvious and potentially very useful extension of the protocols discussed above
would be to the synthesis of gem-dimethylchromenes. Specifically, if phenols 2.105–2.107
could be O-propargylated to give ethers 2.108–2.110 (Scheme 2.9) then the latter compounds
might be expected to engage in gold(I)-catalysed IMHA reactions to give the isomeric and gem-
dimethylated chromenes. The three substrates 2.108–2.110 (Table 2.4) sought in order to study
the proposed cyclisation reaction were readily prepared by reacting the corresponding phenols
with 3-chloro-3-methylbut-1-yne in the presence of potassium iodide and potassium carbonate.
The product ethers were then treated with Echavarren’s catalyst in dichloromethane at ambient
temperature for 1 to 6 hours and so affording, in good yield, the expected chromenes or (in one
case) a regioisomeric mixture thereof (see Entry 2 in Table 2.4). This contrasts with the
stringent conditions required in many other approaches to such systems (anhydrous reagents,
flame drying of glassware and use of argon).158
Scheme 2.9 Synthesis of gem-Dimethyl Ethers [Reagents and Conditions: i) 3-chloro-3-methylbut-1-yne (2.0
equiv.), K2CO3 (5.5 equiv.), KI (7.5 equiv.), acetone, 60 °C, 16 h ii) Echavarren’s gold catalyst (3 mol%), DCM,
18 °C, 1−6 h].
Chapter Two
63
Table 2.4 The Synthesis of gem-Dimethylchromenes via IMHA Reactions.
Entry Phenol Propiolate
[Yield (%)]
Coumarin
[Yield (%)]
1
2.105 2.108 (61) 2.111 (84)
2
2.106 2.109 (71) 2.112 (66) 2.113 (25)
3
2.107 2.110 (54) 2.114 (99)
Attempts were made to extend the protocols described immediately above to the
synthesis of quinolidinones by first converting the relevant anilines 2.115, 2.116 and 2.117 (see
Table 2.5) into the corresponding propiolamides 2.118, 2.119 and 2.120, respectively, under
standard conditions. While these amides were readily obtained by such means and fully
characterised, none of these was able to be converted into the corresponding quinolidinone
2.121, 2.122, 2.123 and 2.124 despite the application of a range of different reaction conditions.
Various reasons can be advanced to account for such outcomes. The first might be the co-
ordinating abilities of the amide residue that allow it to bind with the gold(I)-centre of the
catalyst and thus deactivating it for the IMHA reaction. Another factor that could be
contributing to the lack of any observed IMHA reaction is the preference for the amide-
containing substrate to reside in a s-trans-conformer rather than the s-cis-one required for the
cyclisation.
Investigation of a Sequential Esterification/Gold(I)-Catalysed Cyclisation Route to Coumarins
64
Scheme 2.10 Synthesis of Quinolidinones [Reagents and Conditions: i) propiolic acid (3.3 equiv.), DCC (3.3
equiv.), THF, 18 °C, 16 h; ii) Echavarren’s gold catalyst (3 mol%), DCM].
Table 2.5 Summary of the Synthesis of the Quinolidinones.
Entry Phenol Propiolamide
[Yield (%)]
Coumarin
[Yield (%)]
1
2.115 2.118 (99) 2.121 (0)
2
2.116 2.119 (99) 2.122 (0) 2.123 (0)
3
2.117 2.120 (97) 2.124 (0)
Chapter Three
65
3.1 OVERVIEW
Demonstrating the broader utility of the reaction sequence leading to coumarins as
described in the preceeding Chapter was the objective of the work detailed in this one. The
synthesis of the “challenging” natural product fraxetin (3.1), its derivatives capensin (3.2) and
purpurasol (3.3) as well as pimpinellin (3.4) (Figure 3.1) were particular targets of these studies.
Fraxetin (3.1) was chosen due to its highly oxygenated nature and attendant biological
activity. Despite its therapeutic potential, this natural product had only been the subject of two
previous studies, one resulting in a total synthesis and the other in a semi-synthesis. As detailed
below, the methods presented in Chapter Two do indeed allow for the ready synthesis of
fraxetin and two derivatives [capensin (3.2) and purpurasol (3.3)] that display increased
biological activity (Figure 3.1).159
Figure 3.1 The Structures of Fraxetin (3.1), its Derivatives Capensin (3.2) and Purpurasol (3.3) and that
of Pimpinellin (3.4).
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
66
Pimpinellin (3.4) was also chosen as a synthetic target due to the presence of a fully
substituted aryl core that is annulated to both a furan and a pyrone ring and also bears two
methoxy groups (Figure 3.1). Given its therapeutic potential (vide infra) it is perhaps surprising
that pimpinellin has only been synthesised once through a 13-step sequence starting from
diethyl squarate and featuring an elegant ring-opening/ring-closing electrocyclic process. A
new synthesis of pimpinellin featuring the application of a late-stage IMHA to a sterically
hindered phenol is detailed in the following sections.
Chapter Three
67
3.2 FRAXETIN AND ITS DERIVATIVES
In 1938, Wesseley and Demmer 160 reported the isolation of fraxetin, a 6,7-
dihydroxycoumarin from Fraxinus excelsior, a European ash. Several derivatives of fraxetin
(3.1) were later isolated from natural sources among which were fraxin (an 8-O-glycoside of
fraxetin), esculetin (a 6-demethoxy-8-dehydroxy derivative of fraxetin) and scopoletin (8-
dehydroxyfraxetin).
Fraxetin displays activity against a range of bacteria including Vibrio cholerae. It also
exhibits hypouremic and renal protective effects as well as inhibiting inflammatory cytokine-
mediated apoptosis in osteoblast cells. As such it could be used in the prevention of
osteoporosis. Finally, it can act also as an antioxidant in certain instances.161
In 1992, De Kimpe et al.162 reported the isolation of purpurasol (3.3), a fraxetin
derivative, along with its biosynthetic precursor, capensin (3.2) from Pterocaulon
purpurascens. Although, this plant is used in folk medicines as an insectide and a treatment for
snakebites, only limited evaluations of the biological effects of compound 3.3 have been
undertertaken due to the small amounts of material available from the natural source.
In 1938, Späth and Dobrovolny163 described the first total synthesis of fraxetin through
a Pechmann reaction of 2,3-dihydroxy-4-methoxyphenol (3.5) with sodium (Z)-4-ethoxy-4-
oxobut-2-en-2-olate in sulfuric acid. After refluxing the reaction mixture for 1 day, 4% of the
title compound 3.1 was obtained (Scheme 3.1).
Scheme 3.1 One Step Synthesis of Fraxetin 3.1 [Reagents and Conditions: i) sodium (Z)-4-ethoxy-4-oxobut-
2-en-2-olate (excess), H2SO4 (excess), EtOH, 18 °C, 1 d].
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
68
Aghoramurthy and Seshadri 164 later published a semi-synthesis. Thus, naturally-
occurring 8-acetoherniarin (3.6) was oxidised using potassium hydroxide and potassium
peroxodisulfate to produce the 6-hydroxycoumarin 3.7 in 34% yield. A sulfuric acid-induced
migration of the methyl group from the C7 oxygen to its C6 counterpart then afforded product
3.8 in 67% yield. Finally, Dakin oxidation of the acyl moiety gave the title compound 3.1 in
56% yield. This semi-synthesis was thus completed in 3 steps and ca. 13% overall yield.
Scheme 3.2 Semi-Synthesis of Fraxetin 3.1 [Reagents and Conditions: i) a) KOH (excess), H2O, 100 °C, 1 h;
b) K2S2O8 (excess), 0 to 18 °C, 30 h; ii) H2SO4 (excess), 30 °C, 24 h; iii) H2O2 (excess), NaOH, H2O, 18 °C, 1 h].
The synthesis of fraxetin reported here started with 2,3-dihydro-4-
methoxybenzaldehyde (3.9). Following a literature procedure,165 compound 3.9 (Scheme 3.3)
was bis-O-alkylated using isopropyl bromide in the presence of Hünig’s base to afford aldehyde
3.10 in 73% yield. Dakin oxidation of the last compound led to the isolation of the desired
phenol 3.22 in 93% yield and the structure of this was confirmed by single-crystal X-ray
analysis (Figure 3.2).
Chapter Three
69
Scheme 3.3 Synthesis of Esterification Precursor 3.11 [Reagents and Conditions: i) i-Pr2NEt (3.0 equiv.), i-
PrBr (3.0 equiv.), DCM, 18 °C; ii) a) m-CPBA (3.9 equiv.), KHCO3 (2.9 equiv.), DCM, 18 °C, b) NH4OAc, MeOH,
18 °C].
Figure 3.2 Plot Arising from the Single-Crystal X-ray Analysis of Phenol 3.11.
Subjection of phenol 3.11 (Scheme 3.4) to esterification with propiolic acid under the
optimised conditions defined in the preceeding Chapter provided the anticipated aryl propiolate,
3.12, in 98% yield. Upon treatment of the later with Enchavaren’s catalyst, the expected IMHA
reaction readily took place to give coumarin 3.13 in 96% yield. Finally, reaction of compound
3.13 with boron trichloride (BCl3) effected the expected selective 166 cleavage of the bis-
isopropyl aryl ether and thereby affording fraxetin (3.1) itself in 76% yield.
The 1H NMR spectrum of synthetically-derived fraxetin (3.1) is shown in Figure 3.3 and
reveals resonances due to C3-H and C4-H at δ = 7.82 and 6.20 ppm, respectively. These appear
as one-proton and mutually coupled doublets (J = 8.8 Hz). The remaining aromatic proton (C5-
H) resonates as a one-proton singlet at δ = 6.70 ppm. The methoxy group protons appear as a
three-proton singlet at δ = 3.89 ppm while the phenolic protons were not observed due to their
exchange with CD3OD. The 13C NMR spectrum of fraxetin (3.1) (Figure 3.4) shows diagnostic
α-pyrone ring resonances at δ = 146.7 and 112.7 ppm while the sole remaining aromatic CH
carbon resonates at δ = 101.0 ppm. These data match those reported by De Kimpe (Table
3.1).164
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
70
Scheme 3.4 Synthesis of Fraxetin 3.1 [Reagents and Conditions: i) propiolic acid (3.3 equiv.), DCC (3.3
equiv.), NaH (1.1 equiv.), THF, 18 °C, 16 h; ii) Echavarren's gold catalyst (3 mol%), DCM, 18 °C, 1 h; iii) BCl3
(3.0 equiv.), DCM, 18 °C, 16 h].
Figure 3.3 1H NMR Spectrum of Fraxetin (3.1) Recorded in CD3OD.
Chapter Three
71
Figure 3.4 13C NMR Spectrum of Fraxetin (3.1) Recorded in CD3OD.
Table 3.1 Comparison of the 1H and 13C NMR Data Recorded for Synthetically-Derived Fraxetin (3.1)
with those Reported for the Natural Product.
13C NMR resonances (δC)* 1H NMR resonances (δH)*
Synthetically-
Derived Material
Natural Product Synthetically-
Derived Material
Natural Product
163.7 164.0 7.87, d, J = 8.8 Hz,
1H
7.84, d, J = 9.6 Hz,
1H
147.1 147.0 6.82, s, 1H 6.72, s, 1H
146.7 146.7 6.21, d, J = 8.8 Hz,
1H
6.23, d, J = 9.6 Hz,
1H
140.7 140.8 3.92, s, 3H 3.87, s, 3H
140.6 140.7
134.0 134.0
112.7 112.6
112.2 112.2
101.0 101.3
56.6 56.8
* All spectra recorded in CD3OD.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
72
Following the procedure of De Kimpe,167 the prenylation of fraxetin (3.1) was performed
by treatment of it with prenyl bromide and triethylamine (Et3N). As a result, the
chromatographically separable regioisomeric prenyl ethers 3.2 (41%) and 3.14 (12%) were
obtained. Although the regioselectivity observed is lower than that reported by De Kimpe (3:1
compared to 5:1), capensin (3.2) is still the major product (Scheme 3.5).
Scheme 3.5 Synthesis of Capensin (3.2) and Regioisomer 3.14 from Fraxetin (3.1) [Reagents and Conditions:
i) prenyl bromide (2.0 equiv.), Et3N (2.0 equiv.), acetone, 18 °C, 24 h].
The 1H NMR and 13C NMR spectra of capensin (3.2) are shown in Figure 3.5 and 3.6,
respectively, and these data match those reported by De Kimpe for the natural product (Table
3.2).167
Chapter Three
73
Figure 3.5 1H NMR Spectrum of Capensin (3.2) Recorded in CDCl3.
Figure 3.6 13C NMR Spectrum of Capensin (3.2) Recorded in CDCl3 (* denotes grease).
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
74
Table 3.2 Comparison of the 1H and 13C NMR Data Recorded for Synthetically-Derived Capensin (3.2)
with those Reported for the Natural Product.
13C NMR Resonances (δC)* 1H NMR Resonances(δH)*
Synthetically-
Derived Material
Natural Product Synthetically-
Derived Material
Natural Product
160.4 160.4 7.57, d, J = 9.5 Hz,
1H
7.62, d, J = 9.6 Hz,
1H
149.8 149.8 6.46, s, 1H 6.50, s, 1H
143.7 143.7 6.29, d, J = 9.5 Hz,
1H
6.34, d, J = 9.6 Hz,
1H
140.4 140.5 6.16, s, 1H 6.16, s, 1H
138.0 138.0 5.47, t, J = 8.9 Hz,
1H
5.52, t, J = 7.4 Hz,
1H
138.0 138.0 4.65, d, J = 7.4 Hz,
1H
4.69, d, J = 7.4 Hz,
1H
137.7 137.8 3.85, s, 3H 3.90, s, 3H
119.5 119.5 1.70, s, 3H 1.75, s, 3H
115.2 115.2 1.63, s, 3H 1.68, s, 3H
114.3 114.4
100.0 100.0
69.9 70.0
56.2 56.2
25.8 25.9
25.8 25.9
17.9 18.0
* All spectra recorded in CDCl3.
Chapter Three
75
With capensin (3.2) in hand, a one-pot epoxidation/epoxide ring-opening sequence was
carried out to afford purpurasol (3.3) in 69% yield. This involved treating the former compound
with m-chloroperbenzoic acid (m-CPBA) and the initially formed epoxide undergoing in situ
nucleophilic ring opening in a 6-exo-tet process to give the observed product 3.3 (Scheme 3.6).d
Scheme 3.6 Synthesis of Purpurasol (3.4) from Capensin (3.3) [Reagents and Conditions: i) m-CPBA (1.0
equiv.), EtOAc, 18 °C, 24 h].
The 1H NMR and 13C NMR spectra of purpurasol (3.3), as shown in Figure 3.7 and 3.8
respectively, match those reported by De Kimpe (Table 3.3).167
d For more information regarding Baldwin’s rules, see Appendix One.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
76
Figure 3.7 1H NMR Spectrum of Purpurasol (3.3) Recorded in CDCl3.
Figure 3.8 13C NMR Spectrum of Purpurasol (3.3) Recorded in CDCl3 (* denotes grease).
Chapter Three
77
Table 3.3 Comparison of the 1H and 13C NMR Data Recorded for Synthetically-Derived Purpurasol (3.3)
with those Reported for the Natural Product.
13C NMR Resonance(δC)* 1H NMR Resonance (δH)*
Synthetically-
Derived Material
Natural Product Synthetically-
Derived Material
Natural Product
161.0 160.9 7.57, d, J = 9.6 Hz,
1H
7.61, d, J = 9.6 Hz,
1H
145.9 145.7 6.48, s, 1H 6.51, s, 1H
143.9 143.8 6.32, d, J = 9.6 Hz,
1H
6.31, d, J = 9.6 Hz,
1H
139.2 139.0 4.68, dd, J = 11.3
and 1.9 Hz, 1H
4.65, dd, J = 11.3
and 1.9 Hz, 1H
136.9 136.7 4.16, dd, J = 11.3
and 1.9 Hz, 1H
4.13, dd, J = 11.3
and 1.9 Hz, 1H
132.6 132.40 4.01, dd, J = 9.1
and 1.9 Hz, 1H
3.99, dd, J = 9.1
and 1.9 Hz, 1H
114.3 114.1 3.93, s, 3H 3.92, s, 3H
111.8 111.6 2.59, s, 1H 2.75, s, 1H
100.4 100.1 1.47, s, 3H 1.46, s, 3H
79.1 79.0 1.39, s, 3H 1.37, s, 3H
70.8 70.6
65.7 65.5
56.6 56.4
26.1 26.0
26.1 26.0
25.5 25.1
* All spectra recorded in CDCl3.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
78
3.3 PIMPINELLIN
The structure of pimpinellin (3.4)168,169 has been the subject of debate with the first
(erroneous) structure being proposed at the time of its isolation from Pimpinella saxifraga L. in
1909 by Herzog and Hancu.170 Another one was proposed by Wessely et al. in 1932.171
However, it was Spath172 who advanced the true structure of pimpinellin in 1936 and this was
recently confirmed by single-crystal X-ray analysis.173
Pimpinellin acts as a phytoalexin in parsley and celery as well as exerting inhibitory
effects on trichothecene biosynthesis and nitric oxide synthase.174
In 1988, Reed and Moore175 described the single previous synthesis of pimpinellin (3.4).
Dimethyl squarate (3.15) (Scheme 3.7) was used as the starting material and this underwent
addition of lithium (trimethylsilyl)-acetylide to afford adduct 3.16. On treatment with acid, this
last species rearranged to give diketone 3.17 in 97% yield over the 2 steps involved.
Scheme 3.7 Synthesis of Squarate Precursor 3.17 [Reagents and conditions: i) TMS-acetylene (1.24 equiv.),
n-BuLi (1.05 equiv.), THF, −78 °C, 0.75 h; ii) a) TFAA (1.2 equiv.), 0.25 h; b) H2O].
The addition of 2-lithiofuran to compound 3.17 (Scheme 3.8) led to the formation of
product 3.18 in 72% yield. Upon heating cyclobutenone 3.18 it underwent a thermally-induced
electrocyclic ring-opening reaction to form ketene 3.19 that participated in an intramolecular
Diels-Alder reaction with the pendant furan ring to afford the hydroquinone 3.20. For ease of
purification, this was methylated and the desired product, 3.21, thus isolated in high yield (75%
yield over 2 steps).
Chapter Four
79
Scheme 3.8 Synthesis of Reductive Cyclisation Precursor 3.21 [Reagents and Conditions: i) a) furan (excess),
n-BuLi (1.05 equiv.), THF, −78 °C, 2.5 h; b) TFAA (1.2 equiv.), 0.5 h then H20; ii) ∆; iii) K2CO3 (2.2 equiv.),
CH3I (excess), 18-crown-6 (2.2 equiv.), toluene, 60 °C, 12 h].
Desilylation of alkyne 3.21 (Scheme 3.9) by sequential treatment of it with silver nitrate
then aqueous potassium cyanide afforded the terminal alkyne 3.22 (95% yield) and
deprotonating the latter with n-butyllithium resulted in an acetylide anion that was quenched
with methyl chloroformate to afford the ester 3.23 in 83% yield. Oxidation of hydroquinone
dimethyl ether 3.23 with ceric ammonium nitrate then gave quinone 3.24 that was submitted
directly to reductive cyclisation using a Lindlar-type catalyst (palladium on calcium carbonate)
and so generating 6-demethylpimpinellin (3.25) in fair yield (45% over 2 steps). Finally, O-
methylation of phenol 3.25 using methyl iodide and potassium carbonate afforded compound
3.4 in 79% yield. The total synthesis of pimpinellin was thus completed over 10 steps in an
overall yield of 14.7%.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
80
Scheme 3.9 Synthesis of Pimpinellin(3.4) [Reagents and Conditions: i) a) AgNO3 (aq), EtOH, 18 °C, 0.75 h;
b) KCN (aq) (excess), 18 °C, 1.5 h; ii) a) n-BuLi (1.05 equiv.), THF, −78 °C; b) CH3OCOCl (4.3 equiv.); iii) CAN
(2.2 equiv.), MeCN, 18 °C, 0.25 h; iv) H2, Pd on CaCO3 (5 mol%); v) K2CO3 (4.0 equiv.), CH3I (excess), 18-
crown-6, toluene, 18 °C, 3 h].
The synthesis of pimpinellin (3.4) carried out by the author and reported here started
with vanillin (3.26) (Scheme 3.10). Bromination of this compound, using molecular bromine
in acetic acid, afforded the previously reported 5-bromovanillin (3.27) in 69% yield221.
Replacement of the newly installed bromine by a hydroxyl group was attempted using the
procedure of Ellis and Lenger.176 However, only traces amount of the desired product could be
isolated on attempting to repeat this protocol. Various control experiments eventually
established the source of the hydroxyl group oxygen in this reaction. Notably, bubbling a stream
of oxygen through the reaction mixture stopped the process entirely. Eventually, sodium
hydroxide was identified as the source of this atom and so the reaction solvent had to be
deoxygenated by bubbling nitrogen through it for an extended period of time. By such means
the desired product, 3.28, was obtained in 93% yield. Selective methylation of catechol 3.28
then afforded the dimethoxylated compound 3.29 (87% yield) and bromination of this using
freshly recrystallised NBS afforded the desired halide 3.30 in 84% yield. The structure of this
last compound was confirmed by single-crystal X-ray analysis (Figure 3.9).
Chapter Four
81
Scheme 3.10 Synthesis of Sonogashira Coupling Precursor 3.30 [Reagents and Conditions: i) Br2 (1.1 equiv.),
AcOH, 18 °C, 1 h; ii) Cu(0) (5 mol%), NaOH (10.0 equiv.), H2O, 100 °C, 24 h; iii) Na2CO3 (1.0 equiv.),
(MeO)2SO2 (1.1 equiv.), acetone, 60 °C, 5 h; iv) NBS (1.02 equiv.), THF, 0 to 18 °C, 16 h].
Figure 3.9 Plot Arising from the Single-Crystal X-ray Analysis of Compound 3.30.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
82
As a prelude to establishing the furan ring of target 3.4, the pentasubstituted arene 3.30
was subjected to a Sonogashira cross-coupling reaction with triisopropylsilylacetylene. This
produced a 1:8 mixture of acetylene 3.31 (5%) and the isomeric benzofuran 3.32 (39%). These
were chromatographically separable (Scheme 3.11) and thereby allowing each to be subjected
to comprehensive characterization. The benzofuran 3.31 arises from 5-endo-dig cyclisation of
the phenolate anion onto the proximal alkyne moiety of 3.32, which is a favoured process
according to Baldwin’s rules. The rather modest yields associated with the conversion
3.30 → 3.31 + 3.32 may be attributed to competitive oxidative coupling of the
triisopropylsilylacetylene, although the (likely volatile) product of such a process was not
detected in the crude reaction mixture.
Scheme 3.11 Sonogashira Coupling of Precursor 3.30 [Reagents and Conditions: i) tri-iso-propylsilylacetylene
(2.95 equiv.), Et3N, Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), MeCN, μW, 120 °C, 1.5 h].
Gratifyingly, the structure of the uncyclised product could be confirmed by single-crystal
X-ray analysis (Figure 3.10).
Figure 3.10 Plot Arising from the Single-Crystal X-ray Analysis of Compound 3.31.
Chapter Four
83
The 1H NMR spectrum of compound 3.31 (Figure 3.11) shows a one-proton aromatic
resonance at δ = 7.07 ppm while its aldehyde counterpart resonates at δ = 10.41 ppm. The two
sets of methoxy group protons appear at δ = 3.95 and 3.90 ppm as two three protons singlets
while the signal due to the hydroxyl group appeared at δ = 6.17 ppm. The 13C NMR spectrum
of compound 3.31 (Figure 3.12) shows a diagnostic resonance for an aldehyde carbon at δ =
190.6 ppm while the aromatic carbon appeared at δ = 102.4 ppm. The remaining non-protonated
sp2-hybridised carbons appear as low intensity signals in the range δ = 153.3 to δ = 96.9 ppm.
The two methoxy group carbons appear at δ = 61.2 and 56.4 ppm while the carbons of the three
equivalent isopropyl groups give rise to signals at δ = 18.7 and 11.2 ppm.
The 1H NMR and 13C NMR spectra of compound 3.32 (Figure 3.13 and 3.14, respectively)
reveal analogous characteristics all of which are in keeping with the assigned structure. The
most important peaks that are diagnostic of the furan formation appear as two aromatic signals
at 7.72 and 7.43 ppm and corresponding to the phenyl and furan ring respectively.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
84
Figure 3.11 1H NMR Spectrum of Compound 3.31 Recorded in CDCl3.
Figure 3.12 13C NMR Spectrum of Compound 3.31 Recorded in CDCl3.
Chapter Four
85
Figure 3.13 1H NMR Spectrum of Compound 3.32 Recorded in CDCl3.
Figure 3.14 13C NMR Spectrum of Compound 3.32 Recorded in CDCl3.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
86
For synthetic purposes, it was more convenient to treat the mixture of compounds 3.31
and 3.32 (Scheme 3.12) with tetra-n-butylammonium fluoride (TBAF) and thereby generating
the desilylated benzofuran 3.33. This was obtained as a colorless, crystalline solid in 80% yield.
The completion of the synthesis of pimpinellin from compound 3.33 required installation of the
unsaturated lactone ring, and this proved to be a straightforward matter. Thus, aldehyde 3.33
was subjected to a Dakin oxidation using m-chloroperoxybenzoic acid (m-CPBA), and the
ensuing formate ester was cleaved with ammonia saturated methanol to give phenol 3.34 in 68%
yield.
Scheme 3.12 Synthesis of Phenol Precursor 3.34 [Reagents and Conditions: i) TBAF (6.0 equiv.), THF, 0 to
18 °C, 1 h; ii) a) m-CPBA (1.2 equiv.), KHCO3 (3.4 equiv.), 18 °C, 1 h; b) ammonia saturated methanol (excess),
18 °C, 1 h].
Treatment of the phenol 3.34 (Scheme 3.13) with 3-(trimethylsilyl)propiolic acid in the
presence N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl)
afforded ester 3.35 (79% yield at 48% conversion) with accompanying loss of the TMS group
associated with the alkyne (an event that probably took place during chromatographic
purification). Upon treatment with a 5 mol% Echavarren’s gold(I) catalyst in dichloromethane
at 25 °C, compound 3.35 cyclised to give pimpinellin (3.4) which was obtained as a colorless,
crystalline solid in 72% yield.
Scheme 3.13 Synthesis of Pimpinellin (3.4) [Reagents and Conditions: i) 3-(trimethylsilyl)-propynoic acid (1.2
equiv.), EDC (1.2 equiv.), DCM, 18 °C, 24 h; ii) Echavarren's gold catalyst (5 mol%), DCM, 18 °C, 0.5 h].
Chapter Four
87
All of the spectral data recorded on pimpinellin (3.4), including the 1H and 13C NMR
spectra (Figure 3.15 and 3.16) compared favourably with those reported by Moore (Table
3.4).175
Figure 3.15 1H NMR Spectrum of Pimpinellin (3.4) Recorded in CDCl3.
Figure 3.16 13C NMR Spectrum of Pimpinellin (3.4) Recorded in CDCl3.
Total Syntheses of Fraxetin, its Derivatives and Pimpinellin
88
Table 3.4 Comparison of the 1H and 13C NMR Data Recorded for Synthetically-Derived Pimpinellin
(3.4) with those Reported for the Natural Product.
13C NMR Resonances (δC)* 1H NMR Resonances (δH)*
Synthetically-
Derived Material
Natural Product Synthetically-
Derived Material
Natural Product
161.1 160.4 8.06, d, J = 9.7 Hz,
1H
8.08, d, J = 9.7 Hz,
1H
150.0 149.7 7.64, d, J = 2.2 Hz,
1H
7.65, d, J = 2.2 Hz,
1H
145.6 145.4 7.07, d, J = 2.2 Hz,
1H
7.08, d, J = 2.2 Hz,
1H
144.7 144.4 6.35, d, J = 9.7 Hz,
1H
6.37, d, J = 9.7 Hz,
1H
143.4 143.1 4.13, s, 3H 4.15, s, 3H
140.1 139.8 4.02, s, 3H 4.06, s, 3H
135.4 134.9
114.4 115.5
114.0 113.8
109.7 109.3
104.6 104.1
62.6 62.2
61.5 61.1
* All spectra recorded in CDCl3.
The synthesis of pimpinellin had thus been completed using a late-stage IMHA reaction
with 6% overall yield over 10 steps. It is noteworthy that this synthesis highlights the possibility
to effect the desired transformation on an already pentasubstituted aryl ring.
Chapter Four
89
4.1 SUMMARY
A gold(I)-catalysed, 6-endo-dig cyclisation of arylpropiolates has been developed that
allows for the synthesis of a wide range of coumarins. In principle, heterocycles of this type
that incorporate substituents at all possible positions on the framework are accessible by this
means. That said, the nature of the cyclisation process is such that only aryl propiolates bearing
electron-donating substituents on the aromatic ring participate especially well in such reactions.
Furthermore, the reactive substrates cyclise rapidly under very mild conditions to give the
desired coumarins in generally excellent yield. The various coumarins prepared using this
approach are shown in Figure 4.1. It is noteworthy that meta-substituted propiolates are
expected to afford the regio-isomer favouring para- SEAr reaction.
Summary and Possible Future Work
90
Figure 4.1 The Coumarin Derivatives Synthesised Through the Gold(I)-Catalysed Cyclisation of o, m and
p-Substituted Propiolate Esters.
Chapter Four
91
The extensions of the methodology just described to the synthesis of di-substituted
coumarins as well as annulated variants are summarised in Figures 4.2 and 4.3.
Figure 4.2 Cyclisation of Disubstituted Coumarin Derivatives Synthesised Through the Gold(I)-Catalysed
Cyclisation.
Figure 4.3 The Polycyclic Coumarin Derivatives Synthesised Through the Gold(I)-Catalysed Cyclisation.
The same basic cyclisation process can be exploited in the preparation of certain gem-
dimethylated chromene derivatives as shown in Figure 4.4.
Summary and Possible Future Work
92
Figure 4.4 Summary of the Chromene Derivatives Synthesised Through the Gold(I)-Catalysed Cyclisation.
Chapter Four
93
Two total syntheses of coumarin-containing natural products were completed so as to
emphasise the utility of the methodology summarised in the preceeding section. The scalability
of this method was also shown through the preparation of fraxetin (3.1) on a gram scale and
thus allowing for the preparation of two biologically active derivatives, namely capensin (3.2)
[as well as its regioisomer (3.14)] and purpurasol (3.3). The total synthesis of fraxetin (3.1)
from 2,3-dihydroxy-4-methoxybenzaldehyde (3.20) was achieved in just 7 steps and an overall
yield of 37% (Scheme 4.1).
Scheme 4.1 Synthesis of Fraxetin Derivatives Capensin 3.2, its Regioisomer 3.14 and Purpurasol 3.3
Summary and Possible Future Work
94
The total synthesis of pimpinellin (3.4) from vanillin (3.26) was also achieved, in this
instance in 10 steps and an overall yield of 6% (Scheme 4.2). Once again, the key step was a
late stage gold(I)-catalysed IMHA reaction.
Scheme 4.2 Total Synthesis of Pimpinellin (3.4).
Chapter Four
95
4.2 FUTURE WORK
The methodology detailed in the preceeding sections also provides the potential to
circumvent the lack of participation of most electron-poor substrates in the gold(I)-catalysed
IMHA reaction. Such potential follows from the possibility of performing functional group
interconversion after a successful cyclisation reaction. So, for example, the preparation of 6-
acetamidocoumarin hints at the possibility of performing Sandmeyer reactions on the derived
amine and so preparing various electron-deficient coumarin derivatives (Scheme 4.3).
Scheme 4.3 Preparation of the Substrate for Sandmeyer Reaction from the Corresponding Acetamide
Derivatives.
Given the recent development of a one-pot procedure for transforming anilines into
the corresponding boronic acid, this process could provide yet another means of derivatisation
of the coumarin core and thus extending the current methodology (Scheme 4.4).177
Scheme 4.4 Preparation of Aryl Boronic Acid Derivatives 4.2 from the Corresponding Aniline [Reagents and
conditions: i) a) NaNO2, HCl (aq), 0 °C, 15 min; b) B2(OH)4, NaHCO3, 18 °C, 20 min].
The possibility of introducing a temporary protecting group at the o-position of the
starting phenol could also be tested (Scheme 4.5) as a means for establishing a single cyclisation
product in those cases where mixtures of regioisomeric coumarins are currently produced. A
related strategy was described recently by Smith and Maleczka during the course of the
synthesis of a fluorinated aryl boronate.178 The same type of strategy could be used to convert
aryl propiolate 4.2 via 4.20 into the less-hindered 4.21.
Summary and Possible Future Work
96
Scheme 4.5 Possible Means for the Selective Synthesis of Either the More- or the Less-Hindered Cyclisation
Product.
Chapter Five
97
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were recorded
at 18 °C in base-filtered CDCl3 on a Varian spectrometer operating at 400 MHz for proton and
100 MHz for carbon nuclei. For 1H NMR spectra, signals arising from the residual protio-forms
of the solvent were used as the internal standards. 1H NMR data are recorded as follows:
chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity
is defined as: s = singlet, d = doublet, t = triplet, q = quartet, sept = septuplet,
m = multiplet or combinations of the above. The signal due to residual CHCl3 appearing at δH
7.26 and the central resonance of the CDCl3 “triplet” appearing at δC 77.0 were used to reference
1H and 13C NMR spectra, respectively. Certain infrared spectra (νmax) were recorded on Perkin–
Elmer 1800 Series FTIR Spectrometer as thin films on KBr plates. Those samples subjected to
attenuated total reflectance (ATR) IR spectroscopy were prepared by allowing a CDCl3 solution
of the material to be analyzed to evaporate on the sampling plate before the spectrum was
acquired. Low-resolution ESI mass spectra were recorded on a single-quadrupole liquid
chromatograph−mass spectrometer, while high-resolution measurements were conducted on a
time-of-flight instrument. Low- and high-resolution electron impact (EI) mass spectra were
recorded on a magnetic-sector machine. Melting points were recorded on an Optimelt
automated melting point system and are uncorrected. Analytical thin layer chromatography
(TLC) was performed on aluminum-backed 0.2 mm thick silica gel 60 F254 plates as supplied
by Merck. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip followed by heating. Flash chromatographic separations were carried out following
protocols defined by Still et al.179 with silica gel 60 (40–63 μm) as the stationary phase and
using the AR- or HPLC-grade solvents indicated. Starting materials and reagents were generally
available from the Sigma–Aldrich, Merck, TCI, Strem or Lancaster Chemical Companies and
were used as supplied. Drying agents and other inorganic salts were purchased from the AJAX,
BDH or Unilab Chemical Companies. Tetrahydrofuran, methanol and dichloromethane were
dried using a Glass Contour solvent purification system that is based upon a technology
Experimental Procedures
98
originally described by Grubbs et al.180 Where necessary, reactions were performed under
nitrogen atmosphere.
Chapter Five
99
5.1 INVESTIGATION OF A SEQUENTIAL ESTERIFICATION/GOLD(I)-
CATALYSED CYCLISATION
General Procedure A – Formation of C-silylated p-bromophenol derivatives
A magnetically stirred solution of p-bromophenol (2.133) (1.00 g, 5.78 mmol, 1 equiv.) in dry
tetrahydrofuran (50 mL) was treated with n-butyllithium (13 mL of a 1.33 M solution in
tetrahydrofuran, 17.3 mmol, 3 equiv.) at −78 °C. The resulting solution was stirred for 1 h at
−78 °C then the relevant chlorosilane (17.3 mmol, 3 equiv.) was added and the reaction mixture
allowed to warm to 18 °C. The resulting mixture was stirred at 18 °C for 4 h then ammonium
chloride (1 x 60 mL of a saturated aqueous solution) was added. The separated aqueous phase
was extracted with ethyl acetate (3 x 50 mL) and the combined organic phases washed with
brine (1 x 50 mL) before being dried (MgSO4), filtered and concentrated under reduced pressure.
The residue thus obtained was subjected to flash chromatography (silica gel, 1:8 v/v mixture of
ethyl acetate/hexane elution) and concentration of the relevant fractions then gave the desired
phenol.
Experimental procedures
100
m-Hydroxyphenyl acetate (2.135)
A magnetically stirred solution of resorcinol (2.134) (1.00 g, 9.08 mmol, 1 equiv.) in
dichloromethane (40 mL) maintained at 18 °C was treated with acetyl chloride (650 µL, 9.08
mmol, 1 equiv.). The ensuing mixture was stirred at this temperature for 4 h before being
concentrated under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica gel, 1:4 v/v ethyl acetate/hexane elution) and concentration of the
relevant fractions (Rf = 0.2) afforded compound 2.135 (712 mg, 52%) as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 8.2 Hz, 1H), 6.65–6.61 (complex m, 2H), 6.54 (d, J
= 2.3 Hz, 1H), 6.10 (s, 1H), 2.29 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.5, 156.9, 151.5, 130.2, 113.5, 113.5, 109.3, 21.3;
IR νmax (KBr) 3676, 3404, 2988, 2901, 1765, 1735, 1602, 1486, 1460, 1372, 1226, 1134, 1075
cm−1;
MS (EI, 70 eV) m/z 152 (M+•, 27%), 110 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 175.0358, C8H823NaO3 requires 175.0366. (M+H)+
153.0542, C8H9O3 requires 153.0546.
Chapter Five
101
m-Hydroxyphenyl benzoate (2.136)
A magnetically stirred solution of resorcinol (2.134) (1.00 g, 9.08 mmol, 1 equiv.) in
dichloromethane (40 mL) maintained at 18 °C was treated with benzoyl chloride (1.05 mL, 9.08
mmol, 1 equiv.). The ensuing mixture was stirred at this temperature for 4 h before being
concentrated under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica gel, 1:4 v/v ethyl acetate/hexane elution) and concentration of the
relevant fractions (Rf = 0.3) then gave compound 2.136181 (997 mg, 51%) as a colourless,
crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 8.0 and 1.4 Hz, 2H), 7.70 (tt, J = 8.0 and 1.4 Hz,
1H), 7.57 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 8.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.81–6.77
(complex m, 2H), 5.24 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 165.5, 156.8, 152.0, 133.8, 130.4, 130.3, 129.6, 128.8, 114.0,
113.4, 109.6;
IR νmax (KBr) 3676, 3406, 2988, 2972, 2901, 1734, 1715, 1601, 1484, 1453, 1406, 1394, 1382,
1264, 1139, 1066 cm−1;
MS (EI, 70 eV) m/z 214 (M+•, 21%), 105 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 237.0526, C13H1023NaO3 requires 237.0522. (M+H)+
215.0702, C13H11O3 requires 215.0703;
Mp = 133–134 °C (lit.181 mp = 133–136 °C).
The 1H NMR, 13C NMR and melting point data cited above match those reported in the
literature.181
Experimental procedures
102
m-Hydroxyphenyl pivalate (2.137)
A magnetically stirred solution of resorcinol (2.134) (1.00 g, 9.08 mmol, 1 equiv.) in
dichloromethane (40 mL) maintained at 18 °C was treated with pivaloyl chloride (1.12 mL,
9.08, 1 equiv.). The ensuing mixture was stirred at this temperature for 4 h before being
concentrated under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica gel, 1:4 v/v ethyl acetate/hexane elution) and concentration of the
relevant fractions (Rf = 0.5) then gave compound 2.137182 (860 mg, 49%) as a clear, colorless
oil.
1H NMR (400 MHz, CDCl3) δ 7.16 (t, J = 8.1 Hz, 1H), 6.63–6.60 (complex m, 2H), 6.50 (t, J
= 2.3 Hz, 1H), 6.30 (br s, 1H), 2.07 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 178.1, 157.0, 151.9, 130.1, 113.4, 113.3, 109.3, 39.3, 27.2;
IR νmax (KBr) 3676, 3418, 2973, 2901, 1730, 1604, 1479, 1461, 1395, 1271, 1229, 1139, 1114,
1075, 1066, 1057 cm−1;
MS (EI, 70 eV) m/z 194 (M+•, 26%), 110 (100);
HRMS (ESI, +ve) Found: (M+H)+ 195.1013, C11H15O3 requires 195.1016.
The spectral data cited above match those reported in the literature.182
Chapter Five
103
m-[(tert-Butyldimethylsilyl)oxy]phenol (2.138)
A magnetically stirred solution of resorcinol (2.134) (1.00 g, 9.08 mmol, 1 equiv.) in N,N-
dimethylformamide (40 mL) maintained at 18 °C was treated with tert-butyldimethylsilyl
chloride (1.37 g, 9.08 mmol, 1 equiv.) and imidazole (618 mg, 9.08 mmol, 1 equiv.). The
ensuing mixture was stirred at this temperature for 6 h before being concentrated under reduced
pressure. The residue thus obtained was subjected to flash chromatography (silica gel, 1:4 v/v
ethyl acetate/hexane elution) and concentration of the relevant fractions (Rf = 0.6) then gave
compound 2.138183 (701 mg, 34%) as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.07 (t, J = 8.1 Hz, 1H), 6.47–6.44 (complex m, 2H), 6.39–6.38
(complex m, 1H), 5.65 (br s, 1H), 1.00 (s, 9H), 0.21 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 157.0, 156.6, 130.1, 112.8, 108.8, 107.8, 25.8, 18.3, −4.3;
IR νmax (KBr) 3676, 3390, 2988, 2971, 2930, 2901, 1592, 1491, 1473, 1407, 1394, 1294, 1170,
1146, 1075, 1066, 1057 cm−1;
MS (EI, 70 eV) m/z 224 (M+•, 47%), 167 (100);
HRMS (ESI, +ve) Found: (M+H)+ 225.1301, C12H21O2Si requires 225.1305.
The spectral data cited above match those reported in the literature.183
Experimental procedures
104
m-(Benzyloxy)phenol (2.139)
A magnetically stirred solution of resorcinol (2.134) (1.00 g, 9.08 mmol, 1 equiv.) in acetone
(40 mL) maintained at 18 °C was treated with benzyl bromide (1.08 mL, 9.08 mmol, 1 equiv.)
then potassium carbonate (1.88 g, 13.62 mmol, 1.5 equiv.). The ensuing mixture was stirred at
this temperature for 6 h before being concentrated under reduced pressure and the residue thus
obtained was subjected to flash chromatography (silica gel, 1:4 v/v ethyl acetate/hexane elution).
Concentration of the relevant fractions (Rf = 0.4) then gave compound 2.139184 (764 mg, 42%)
as a clear, pink oil.
1H NMR (400 MHz, CDCl3) δ 7.45–7.32 (complex m, 5H), 7.14 (t, J = 8.1 Hz, 1H), 6.58 (ddd,
J = 8.1, 2.4 and 0.9 Hz, 1H), 6.49 (t, J = 2.4 Hz, 1H), 6.44 (ddd, J = 8.1, 2.4 and 0.9 Hz, 1H),
5.04 (s, 2H), 5.00 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 160.3, 156.9, 137.1, 130.3, 128.7, 128.1, 127.6, 108.3, 107.5,
102.7, 70.2;
IR νmax (KBr) 3676, 3390, 2988, 2973, 2901, 1595, 1491, 1454, 1406, 1394, 1284, 1172, 1147,
1076, 1066, 1050 cm−1;
MS (EI, 70 eV) m/z 200 (M+•, 72%), 91 (100);
HRMS (ESI, +ve) Found: (M+H)+ 201.0912, C13H13O3 requires 201.0910.
The spectral data cited above match those reported in the literature.184
Chapter Five
105
p-(Triethylsilyl)phenol (2.140)
Compound 2.140225 (1.11 g, 92%) (Rf = 0.3 in 1:8 v/v ethyl acetate/hexane) was prepared using
General Procedure A and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.84 (s, 1H),
0.96 (t, J = 7.8 Hz, 9H), 0.77 (q, J = 7.8 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 156.3, 135.9, 128.6, 115.0, 7.5, 3.7;
IR νmax (KBr) 3341, 2954, 2875, 1599, 1583, 1503, 1458, 1416, 1361, 1256, 1237, 1179, 1107,
1054, 1033, 1007 cm−1;
MS (EI, 70 eV) m/z 208 (M+•, 16%), 179 (90), 151 (92), 123 (100);
Mp = 29 °C (lit.225 mp = 31–32 °C).
The spectral data cited above match those reported in the literature.225
p-(tert-Butyldimethylsilyl)phenol (2.141)
Compound 2.141 (609 mg, 51%) (Rf = 0.3 in 1:8 v/v ethyl acetate/hexane) was prepared using
General Procedure A and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.69 (s, 1H),
0.86 (s, 9H), 0.24 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 156.4, 136.2, 129.1, 114.8, 26.6, 17.1, −5.9;
IR νmax (KBr) 3286, 2953, 2927, 2856, 1600, 1585, 1502, 1470, 1427, 1361, 1248, 1182, 1107,
1055, 1033, 1008 cm−1;
MS (EI, 70 eV) m/z 208 (M+•, 4%), 151 (100);
Mp = 96–97 °C.
A HRMS spectrum of this compound could not be obtained due to its instability under the
analysis conditions.
Experimental procedures
106
p-Hydroxyphenyl trifluoromethanesulfonate (2.142)
A magnetically stirred solution of hydroquinone (2.58) (2.00 g, 14.69 mmol, 1 equiv.) in
dichloromethane (150 mL) maintained at 0 °C was treated with trifluoromethane sulfonyl
chloride (1.56 mL, 14.69 mmol, 1 equiv.) then triethylamine (2.05 g, 14.69 mmol, 1 equiv.).
The resulting mixture was stirred for 4 h at 0 °C then quenched by the addition of hydrochloric
acid (20 mL of a 2.0 M aqueous solution). The aqueous phase was extracted with
dichloromethane (2 x 30 mL) and the combined organic phases were then dried (MgSO4),
filtered and the filtrate concentrated under reduced pressure. The residue thus obtained was
subjected to flash chromatography (silica gel, 1:4 v/v ethyl acetate/hexane elution) and
concentration of the relevant fractions (Rf = 0.3 in 1:4 v/v ethyl acetate/hexane) gave compound
2.142185 (580 mg, 19%) as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H), 5.17 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 155.2, 143.2, 122.6, 120.4 (q, JC-F = 322 Hz), 116.6;
IR νmax (KBr) 3277, 1600, 1505, 1420, 1249, 1212, 1167, 1138 cm−1;
MS (EI, 70 eV) m/z 242 (M+•, 25%), 109 (100).
The spectral data cited above match those reported in the literature.185
Chapter Five
107
Methyl (tert-butoxycarbonyl)-L-tyrosinate (2.144)
A magnetically stirred solution of L-tyrosine methyl ester hydrochloride (2.143) (1.00 g, 4.32
mmol, 1 equiv.) in dichloromethane (50 mL) maintained at 0 °C was treated with triethylamine
(1.20 mL, 8.63 mmol, 2 equiv.). The ensuing mixture was stirred for 0.5 h at 0 °C before being
treated with tert-butyloxycarbonyl anhydride (1.04 g, 4.75 mmol, 1.1 equiv.). The resulting
mixture was stirred at 0 °C for 16 h, warmed to room temperature and washed with citric acid
(2 x 20 mL of a 1.0 M aqueous solution) then brine (2 x 20 mL). The combined organic phases
were dried (Na2SO4), filtered and then concentrated under reduced pressure. The residue thus
obtained was subjected to flash chromatography (silica gel, 1:4 v/v ethyl acetate/hexane elution)
and concentration of the relevant fractions (Rf = 0.1) gave compound 2.144186 (1.20 g, 94%) as
a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 2H), 5.68 (s, 1H),
5.00 (d, J = 6.0 Hz, 1H), 4.53 (d, J = 6.0 Hz, 1H), 3.71 (s, 3H), 3.08–2.86 (complex m, 2H),
1.42 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 172.6, 155.2, 155.0, 130.4, 127.7, 115.5, 80.1, 54.6, 52.2, 37.6,
28.3;
IR νmax (KBr) 3265, 2981, 1735, 1688, 1616, 1517, 1445, 1393, 1368, 1249, 1224, 1165, 1105,
1019 cm−1;
MS (ESI, +ve) m/z 296 [(M+H+, 35%]; 282 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 318.1325, C15H21N23NaO5 requires 318.1312;
Mp = 102–103 °C (lit.186 mp = 100–102 °C).
The spectral data cited above match those reported in the literature.186
Experimental procedures
108
General Procedure B – Formation of aryl propiolates using DCC
A magnetically stirred solution of the relevant phenol (1 mmol, 1 equiv.) and propiolic acid
(1.2 mmol, 1.2 equiv.) in chloroform (20 mL) maintained at 0 °C was treated with DCC (1.2
mmol, 1 equiv.). The solution thus obtained was allowed to warm to 18 °C then stirred at this
temperature for 16 h before being concentrated under reduced pressure. The ensuing residue
was taken up in acetonitrile (20 mL) and the mixture thus formed filtered. The filtrate was
concentrated under reduced pressure and the residue subjected to flash chromatography (silica
gel, 1:4 v/v mixture of diethyl ether/hexane elution). Concentration of the relevant fractions
then gave the corresponding aryl propiolate.
General Procedure C – Formation of aryl propiolates using DCC/NaH
A magnetically stirred solution of relevant phenol (1.0 mmol, 1.0 equiv.) in tetrahydrofuran (10
mL) maintained at 0 °C was treated with sodium hydride (60% suspension in mineral oil, 1.1
mmol, 1.1 equiv.). In a second flask, a magnetically stirred solution of propiolic acid (3.3 mmol,
3.3 equiv.) in tetrahydrofuran (10 mL) was cooled to 0 °C then treated with DCC (3.3 mmol,
3.3 equiv.) followed by the mixture obtained by treating the phenol with NaH. The resulting
mixture was allowed to warm to 18 °C then stirred at this temperature for 16 h before being
concentrated under reduced pressure. The residue so obtained was taken up in acetonitrile (10
mL) and filtered. The filtrate was concentrated under reduced pressure and the residue thus
obtained subjected to flash chromatography (silica gel, 1:4 v/v mixture of diethyl ether/hexane
elution). Concentration of the relevant fractions gave the corresponding aryl propiolate.
Chapter Five
109
General Procedure D – Formation of aryl propiolates through in situ acyl chloride
formation
A magnetically stirred solution of the relevant carboxylic acid (1 mmol, 1 equiv.) and oxalyl
chloride (1.1 mmol, 1.1 equiv.) in dichloromethane (10 mL) maintained at 0 °C was treated
with a few drops of N,N-dimethylformamide. After gas evolution had ceased (ca 0.08 h), the
reaction mixture was allowed to warm to 18 °C then stirred at this temperature for 0.33 h before
being treated with the requisite phenol (1.0 mmol, 1.0 equiv.). The ensuing mixture was
concentrated under reduced pressure and the residue thus obtained was taken up in acetonitrile
(10 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue so
formed was subjected to flash chromatography (silica gel, 1:4 v/v mixture of diethyl
ether/hexane elution). Concentration of the relevant fractions then gave the corresponding aryl
propiolate.
Experimental procedures
110
Phenyl propiolate (2.17)
Compound 2.17187 (278 mg, 64%) (Rf = 0.9 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure B and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.07 (d, J =
7.7 Hz, 2H), 2.99 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 151.1, 150.0, 129.8, 126.8, 121.4, 77.0, 74.5;
IR νmax (KBr) 3444, 3278, 3065, 2934, 2857, 2386, 2126, 1947, 1854, 1733, 1649, 1591, 1492,
1456, 1416, 1289, 1202, 1106, 1072, 1024, 1006, 929 cm−1;
MS (ESI, +ve, 70 eV) m/z 169 [(M+Na)+, 100%], 47 [(M+H)+, 40];
HRMS (ESI, +ve) Found: (M+Na)+ 169.0262, C9H623NaO2 requires 169.0265. (M+H)+
147.0443, C9H7O2 requires 147.0446.
The spectral data cited above match those reported in the literature.187
Chapter Five
111
o-Ethylphenyl propiolate (2.20)
Compound 2.20 (198 mg, 69%) (Rf = 0.5 in 1:1 v/v chloroform/hexane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 3.6 Hz, 1H), 7.30–7.22 (complex m, 2H), 7.15–7.07
(complex m, 1H), 3.10 (d, J = 1.5 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 151.2, 148.0, 135.7, 129.8, 127.1, 127.0, 121.9, 76.9, 74.3, 23.2,
14.1;
IR νmax (KBr) 3271, 2973, 2937, 2126, 1730, 1489, 1454, 1193, 1168, 1114 cm−1;
MS (EI, 70 eV) m/z 174 (M+•, 71%), 145 (100);
HRMS (EI, 70 eV) Found: M+• 174.0754, C11H11O2 requires 174. 0574.
Experimental procedures
112
o-Methoxyphenyl propiolate (2.21)
Compound 2.21 (510 mg, 72%) (Rf = 0.8 in chloroform) was prepared using General Procedure
C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 7.9 and 1.7 Hz, 1H), 7.09 (dd, J = 7.9 and 1.7 Hz,
1H), 6.98 (t, J = 7.9 Hz, 1H), 6.96 (td, J = 7.9 and 1.7 Hz, 1H), 3.85 (s, 3H), 3.05 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 151.0, 150.6, 138.9, 127.8, 122.6, 120.9, 112.8, 76.7, 74.3, 56.0;
IR νmax (KBr) 3270, 2125, 1733, 1499, 1309, 1281, 1260, 1193, 1171, 1159, 1110, 1042, 1024
cm−1;
MS (EI, 70 eV) m/z 176 (M+•, 77%), 145 (85), 124 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 199.0372, C10H823NaO3 requires 199.0366. (M+H)+
177.0539, C10H9O3 requires 177.0546.
Chapter Five
113
o-Acetylphenyl propiolate (2.22)
Compound 2.22 (75 mg, 25%) (Rf = 0.3 in 1:4 v/v ethyl acetate/hexane) was prepared using
General Procedure C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.8 and 1.7 Hz, 1H), 7.54 (ddd, J = 8.1, 7.8 and
1.7 Hz, 1H), 7.36 (td, J = 7.8 and 1.2 Hz, 1H), 7.16 (dd, J = 8.1 and 1.2 Hz, 1H), 3.13 (s, 1H),
2.56 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 197.0, 150.8, 147.9, 133.7, 130.6, 130.6, 127.0, 123.6, 77.4,
74.2, 29.5;
IR νmax (KBr) 3258, 2926, 2856, 2126, 1733, 1687, 1605, 1483, 1448, 1359, 1284, 1255, 1186,
1072 cm−1;
MS (EI, 70 eV) m/z 188 (M+•, 16%), 173 (14), 145 (54), 121 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 211.0369, C11H823NaO3 requires 211.0366. (M+H)+
189.0551, C11H9O3 requires 189.0546.
Experimental procedures
114
o-(Trifluoromethyl)phenyl propiolate (2.23)
Compound 2.23 (202 mg, 70%) (Rf = 0.6 in 1:2:3 v/v/v ethyl acetate/dichloromethane/hexane)
was prepared using General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 8.0 and 1.7 Hz, 1H), 7.60 (td, J = 8.0 and 1.7 Hz,
3H), 7.42–7.37 (complex m, 2H), 7.27 (d, J = 8.0 Hz, 2H), 3.12 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 150.4, 147.1 (q, JC-F = 8.0 Hz), 133.4, 127.3 (q, JC-F = 5 Hz),
127.0, 124.2 (d, JC-F = 2 Hz), 123.1 (q, JC-F = 32 Hz), 122.9 (q, JC-F = 272 Hz), 118.8, 77.9,
73.7;
IR νmax (KBr) 3297, 2934, 2856, 2130, 1741, 1613, 1494, 1456, 1321, 1275, 1206, 1168, 1135,
1113, 1056 cm−1;
MS (ESI, +ve) m/z 277 [(M+MeCN+Na)+, 100%], 214 (M+, 18), 186 (22).
The HRMS of this compound could not be recorded due to its instability.
o-Bromophenyl propiolate 2.24
Compound (2.24) (253 mg, 97%) (Rf = 0.7 in chloroform) was prepared using General
Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 8.2 and 1.5 Hz, 1H), 7.36 (ddd, J = 8.2, 7.4 and
1.5 Hz, 1H), 7.20–7.15 (complex m, 2H), 3.11 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.0, 147.4, 133.8, 128.8, 128.2, 123.6, 116.0, 77.6, 74.0;
IR νmax (KBr) 3284, 2973, 2866, 2127, 1734, 1470, 1445, 1179, 1046, 1033 cm−1;
MS (EI, 70 eV) m/z 226 and 224 (M+•, both 13%), 198 and 196 (both 5), 174 and 172 (both 17),
145 (100);
HRMS (ESI, +ve) Found: (M+H)+ 224.9553, C9H679BrO2 requires 224.9546.
Chapter Five
115
o-Chlorophenyl propiolate (2.25)
Compound 2.25 (530 mg, 87%) (Rf = 0.3 in 1:9 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.36 (dd, J =
7.6 and 1.5 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 3.24 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.0, 146.0, 130.7, 128.1, 128.0, 126.8, 123.5, 77.6, 73.8;
IR νmax (KBr) 3286, 2128, 1738, 1583, 1474, 1448, 1262, 1181, 1062 cm−1;
MS (EI, 70 eV) m/z 182 and 180 (M+•, 8 and 25%), 145 (100);
HRMS (EI, 70 eV) Found: M+• 181.9942, C9H537ClO2 requires 181.9949. M+• 179.9972,
C9H535ClO2 requires 179.9978.
m-Methoxyphenyl propiolate (2.26)
Compound 2.26188 (280 mg, 99%) (Rf = 0.6 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 8.2 Hz, 1H), 6.83 (dd, J = 8.2 and 2.4 Hz, 1H), 6.76
(dd, J = 8.2 and 2.4 Hz, 1H), 6.71 (s, 1H), 3.79 (s, 3H), 3.11 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 160.7, 151.0, 150.8, 130.1, 113.5, 112.5, 107.4, 77.2, 74.3, 55.5;
IR νmax (KBr) 3267, 2120, 1727, 1609, 1588, 1488, 1468, 1453, 1439, 1315, 1286, 1263, 1183,
1128, 1077, 1037, 997, 945, 906 cm−1;
MS (EI, 70 eV) m/z 176 (M+•, 80%), 124 (100), 123 (58);
HRMS (EI, 70 eV) Found: M+• 176.0475, C10H8O3 requires 176.0473.
The spectral data cited above match those reported in the literature.188
Experimental procedures
116
m-[(tert-Butyldimethylsilyl)oxy]phenyl propiolate (2.27)
Compound 2.27 (196 mg, 80%) (Rf = 0.3 in 1:2 v/v chloroform/hexane) was prepared using
General Procedure C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 8.2 Hz, 1H), 7.78–7.74 (complex m, 2H), 6.65 (t, J
= 2.3 Hz, 1H), 3.05 (s, 1H), 0.99 (s, 9H), 0.21 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 156.8, 150.9, 150.7, 130.0, 118.5, 114.2, 113.6, 76.8, 74.5, 25.8,
18.3, −4.3;
IR νmax (KBr) 3272, 2957, 2931, 2860, 2126, 1767, 1735, 1604, 1587, 1485, 1282, 1258, 1182,
1130 cm−1;
MS (EI, 70 eV) m/z 276 (M+•, 39%), 219 (54), 163 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 299.1063, C15H2023NaO3Si requires 299.1074. (M+H)+
277.1250, C15H21O3Si requires 277.1254.
m-Acetoxyphenyl propiolate (2.28)
Compound 2.28 (120 mg, 45%) (Rf = 0.6 in 1:2:3 v/v/v ethyl acetate/dichloromethane/hexane)
was prepared using General Procedure C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 8.2 Hz, 1H), 7.05–7.01 (complex m, 2H), 6.99 (t, J
= 2.1 Hz, 1H), 3.11 (s, 1H), 2.26 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.9, 151.3, 150.5, 150.2, 129.9, 119.9, 118.7, 115.2, 77.4,
74.0, 21.0;
IR νmax (KBr) 3262, 2990, 2901, 2123, 1767, 1734, 1601, 1485, 1371, 1182, 1121 cm−1;
MS (EI, 70 eV) m/z 204 (M+•, 25%), 162 (89), 134 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 227.0305, C11H823NaO4 requires 227.0315. (M+H)+
205.0488, C11H9O4 requires 205.0495.
Chapter Five
117
m-Cyanophenyl propiolate (2.29)
Compound 2.29 (202 mg, 70%) (Rf = 0.6 in 1:2:3 v/v/v ethyl acetate/dichloromethane/hexane)
was prepared using General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.58 (dt, J = 7.9 and 1.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.50–
7.47 (complex m, 1H), 7.42 (ddd, J = 7.9, 2.4 and 1.4 Hz, 1H), 3.15 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.2, 150.0, 130.8, 130.4, 126.3, 125.2, 117.6, 114.0, 78.1,
73.8;
IR νmax (KBr) 3269, 2990, 2901, 2236, 2122, 1735, 1584, 1481, 1433, 1394, 1234, 1186, 1066,
1058 cm−1;
MS (CI) m/z 170 [(M−H)−, 27%], 143 (24), 115 (24), 53 (100);
HRMS (ESI, +ve) Found: (M+H)+ 172.0397, C10H6NO2 requires 172.0393.
Mp = 112–113 °C.
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.1.
Experimental procedures
118
m-(Propioloyloxy)phenyl benzoate (2.30)
Compound 2.30 (105 mg, 42%) (Rf = 0.4 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 8.2 and 1.0 Hz, 2H), 7.68–7.61 (complex m, 1H),
7.52 (t, J = 8.2 Hz, 2H), 7.45 (t, J = 8.2 Hz, 1H), 7.18 (ddd, J = 8.2, 2.2 and 1.0 Hz, 1H), 7.14
(t, J = 2.2 Hz, 1H), 7.10 (ddd, J = 8.2, 2.2 and 1.0 Hz, 1H), 3.11 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 164.7, 151.6, 150.6, 150.3, 133.9, 130.3, 130.1, 129.3, 128.7,
120.1, 118.8, 115.5, 77.3, 74.2;
IR νmax (KBr) 3262, 2990, 2901, 2122, 1734, 1699, 1483, 1452, 1262, 1235, 1189, 1124, 1079,
1061, 1025 cm−1;
MS (EI, 70 eV) m/z 266 (M+•, 16%), 105 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 289.0460, C16H1123NaO4 requires 289.0471. (M+H)+
267.0640, C16H11O4 requires 267.0652.
Mp = 64–65 °C.
Chapter Five
119
m-(Pivaloyloxy)phenyl propiolate (2.31)
Compound 2.31 (102 mg, 40%) (Rf = 0.5 in 1:4 v/v ethyl acetate/hexane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 8.2 Hz, 1H), 7.03 (ddd, J = 8.2, 2.2 and 1.0 Hz, 1H),
7.00 (ddd, J = 8.2, 2.2 and 1.0 Hz, 1H), 6.96 (t, J = 2.2 Hz, 1H), 3.10 (s, 1H), 1.35 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 176.6, 151.8, 150.5, 150.3, 129.9, 119.8, 118.5, 115.2, 77.3,
74.1, 39.2, 27.1;
IR νmax (KBr) 3260, 2975, 2875, 2123, 1737, 1599, 1481, 1398, 1368, 1272, 1241, 1188, 1124,
1107, 1032, 1005 cm−1;
MS (EI, 70 eV) m/z 246 (M+•, 16%), 162 (33), 134 (67), 57 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 269.0789, C14H1523NaO4 requires 269.0784. (M+H)+
247.0969, C14H15O4 requires 247.0965.
m-(Benzyloxy)phenyl propiolate (2.32)
Compound 2.32 (196 mg, 78%) (Rf = 0.6 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.45–7.33 (complex m, 5H), 7.30 (t, J = 8.4 Hz, 1H), 6.90 (dd,
J = 8.4 and 2.3 Hz, 1H), 6.80 (t, J = 2.3 Hz, 1H), 6.78 (dd, J = 8.4 and 2.3 Hz, 1H), 5.06 (s, 2H),
3.06 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 159.9, 150.9, 150.8, 136.6, 130.2, 128.8, 128.3, 127.6, 113.8,
113.4, 108.4, 76.9, 74.4, 70.5;
IR νmax (KBr) 3271, 2990, 2901, 2123, 1732, 1607, 1588, 1486, 1454, 1394, 1383, 1287, 1257,
1192, 1129, 1077, 1066, 1044, 1027 cm−1;
MS (EI, 70 eV) m/z 252 (M+•, 10%), 91(100);
HRMS (ESI, +ve) Found: (M+H)+ 253.0854, C16H13O3 requires 253.0859.
Experimental procedures
120
m-Acetylphenyl propiolate (2.33)
Compound 2.33 (219 mg, 79%) (Rf = 0.2 in 1:4 v/v ethyl acetate/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.86 (ddd, J = 7.9, 2.0 and 1.0 Hz, 1H), 7.74–7.72 (complex m,
1H), 7.51 (t, J = 7.9 Hz, 1H), 7.36 (ddd, J = 7.9, 2.0 and 1.0 Hz, 1H), 3.11 (s, 1H), 2.60 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 196.7, 150.8, 150.2, 138.9, 130.0, 126.6, 126.1, 121.3, 77.4,
74.1, 26.8;
IR νmax (KBr) 3258, 2924, 2123, 1733, 1686, 1586, 1483, 1360, 1263, 1190 cm−1;
MS (EI, 70 eV) m/z 188 (M+•, 25%), 187 (73), 173 (49), 160 (38), 145 (66), 121 (56), 53 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 211.0369, C11H823NaO3 requires 211.0366. (M+H)+
189.0551, C11H9O3 requires 189.0546;
Mp = 61–62 °C.
Chapter Five
121
m-Fluorophenyl propiolate (2.34)
Compound 2.34 (575 mg, 79%) (Rf = 0.8 in chloroform) was prepared using General Procedure
C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.37 (td, J = 8.2 and 6.3 Hz, 1H), 7.01 (dd, J = 8.2 and 2.5 Hz,
1H), 6.99–6.95 (complex m, 1H), 6.93 (dt, J = 9.2 and 2.5 Hz, 1H), 3.09 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 163.0 (d, JC-F = 248 Hz), 150.7 (d, JC-F = 11 Hz), 150.5, 130. 6
(d, JC-F = 9 Hz), 117.2 (d, JC-F = 4 Hz), 113.8 (d, JC-F = 21 Hz), 109.6 (d, JC-F = 25 Hz), 77.3,
74.1;
IR νmax (KBr) 3291, 2981, 2126, 1735, 1603, 1486, 1450, 1254, 1187, 1117, 1073 cm−1;
MS (EI, 70 eV) m/z 164 (M+•, 28%), 136 (52).
A molecular-associated ion could not be obtained for this compound under standard HRMS
conditions.
Experimental procedures
122
m-Chlorophenyl propiolate (2.35)
Compound 2.35 (670 mg, 95%) (Rf = 0.7 in chloroform) was prepared using General Procedure
C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 8.1 Hz, 1H), 7.32–7.26 (complex m, 1H), 7.22 (t, J
= 2.1 Hz, 1H), 7.09 (ddd, J = 8.1, 2.3 and 1.1 Hz, 1H), 3.12 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.5, 150.3, 135.1, 130.5, 127.1, 122.1, 119.8, 77.4, 74.1;
IR νmax (KBr) 3288, 2128, 1734, 1590, 1471, 1432, 1266, 1198, 1091, 1070, 1002 cm−1;
MS (EI, 70 eV) m/z 182 and 180 (M+•, 21 and 63%), 53 (100);
HRMS (ESI, +ve) Found: (M+H)+ 183.0023, C9H637ClO2 requires 183.0021. (M+H)+ 181.0053,
C9H635ClO2 requires 181.0051.
m-Bromophenyl propiolate (2.36)
Compound 2.36 (251 mg, 96%) (Rf = 0.8 in chloroform) was prepared using General Procedure
C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.42 (ddd, J = 8.0, 2.0 and 1.0 Hz, 1H), 7.36 (t, J = 2.0 Hz, 1H),
7.27 (t, J = 8.0 Hz, 1H), 7.11 (ddd, J = 8.0, 2.0 and 1.0 Hz, 1H), 3.09 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.5, 150.4, 130.8, 130.0, 124.9, 122.7, 120.3, 77.4, 74.1;
IR νmax (KBr) 3285, 2973, 2127, 1733, 1586, 1470, 1427, 1193, 1063, 1033, 1000 cm−1;
MS (EI, 70 eV) m/z 226 and 224 (M+•, both 35%), 196 and 198 (both 23), 172 and 174 (both
23), 145 (73), 53 (100).
A molecular-associated ion could not be obtained for this compound under standard HRMS
conditions.
Chapter Five
123
p-Tolyl propiolate (2.37)
Compound 2.37189 (253 mg, 85%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 3.10 (s, 1H),
2.38 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 151.3, 147.7, 136.4, 130.2, 121.0, 77.0, 74.3, 20.9;
IR νmax (KBr) 3273, 2125, 1729, 1505, 1217, 1191, 1019, 910 cm−1;
MS (EI, 70 eV) m/z 160 (M+•, 70%), 145 (18), 132 (32), 108 (75), 107 (100), 104 (80), 91 (12),
77 (48);
HRMS (EI, 70 eV) Found: M+• 160.0522, C10H8O2 requires 160.0524.
The 1H NMR and IR spectral data cited above match those reported in the literature.189
Experimental procedures
124
p-Methoxyphenyl propiolate (2.19)
Compound 2.19190 (278 mg, 98%) (Rf = 0.7 in 1:4 v/v diethyl ether/pentane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H),
3.06 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 158.0, 151.6, 143.5, 122.3, 114.8, 76.9, 74.5, 55.8;
IR νmax (KBr) 3260, 2123, 1727, 1597, 1504, 1465, 1442, 1251, 1199, 1177, 1103, 1031, 1009,
905 cm−1;
MS (EI, 70 eV) m/z 176 (M+•, 80%), 124 (100), 123 (70), 120 (52), 109 (50), 95 (48), 91 (20);
HRMS (EI, 70 eV) Found: M+• 176.0474, C10H8O3 requires 176.0473.
The spectral data cited above match those reported in the literature.190
Chapter Five
125
p-Triethylsilylphenyl propiolate (2.38)
Compound 2.38 (130 mg, 52%) (Rf = 0.9 in chloroform) was prepared using General Procedure
C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 3.08 (s, 1H),
0.99 (t, J = 7.8 Hz, 9H), 0.82 (q, J = 7.8 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 151.0, 150.6, 136.3, 135.7, 120.6, 76.7, 74.5, 7.5, 3.5;
IR νmax (KBr) 3275, 2956, 2911, 2876, 2127, 1734, 1616, 1589, 1496, 1457, 1416, 1389, 1288,
1262, 1191, 1124, 1102, 1009 cm−1;
MS (EI, 70 eV) m/z 260 (M+•, 7%), 231 (100), 203 (93), 175 (73);
HRMS (ESI, +ve) Found: (M+H)+ 261.1299, C15H21O2Si requires 261.1305.
p-tert-Butyldimethylsilylphenyl propiolate (2.39)
Compound 2.39 (145 mg, 58%) (Rf = 0.9 in chloroform) was prepared using General Procedure
C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 3.06 (s, 1H),
0.88 (s, 9H), 0.27 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 150.8, 150.5, 136.5, 135.8, 120.2, 76.6, 74.4, 26.4, 16.8, −6.1;
IR νmax (KBr) 3236, 2953, 2928, 2855, 2127, 2109, 1721, 1589, 1497, 1470, 1463, 1389, 1361,
1260, 1209, 1165, 1102, 1019, 1010 cm−1;
MS (EI, 70 eV) m/z 260 (M+•, 5%), 203 (100), 175 (20);
HRMS (ESI, +ve) Found: (M+Na) + 283.1129, C15H2023NaO2Si requires 283.1125.
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.1.
Experimental procedures
126
p-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl propiolate (2.40)
Compound 2.40 (150 mg, 70%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 3.13 (s, 1H),
1.33 (s, 12H);
13C NMR (100 MHz, CDCl3) δ 152.1, 150.5, 136.2, 127.4, 120.5, 83.9, 77.0, 74.0, 24.7;
IR νmax (KBr) 3272, 3046, 2980, 2934, 2859, 2126, 1733, 1635, 1603, 1583, 1517, 1470, 1400,
1361, 1321, 1271, 1200, 1143, 1088, 1019, 962, 915 cm−1;
MS (EI, 70 eV) m/z 272 (M+•, 80%), 257 [(M-CH3•)+, 60], 173 (100), 158 (20);
HRMS (EI, 70 eV) Found: M+• 272.1218, C15H1711BO4 requires 272.1220. (M−CH3•)
+
257.0983, C14H1411BO4 requires 257.0985;
Mp = 72–75 °C.
Chapter Five
127
p-Nitrophenyl propiolate (2.41)
Compound 2.41191 (140 mg, 68%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H), 3.17 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 154.2, 149.6, 145.8, 125.4, 122.2, 78.0, 73.5;
IR νmax (KBr) 3266, 2124, 1730, 1616, 1592, 1518, 1491, 1351, 1290, 1194, 1111, 918 cm−1;
MS (EI, 70 eV) m/z 191 (M+•, 100%), 190 (48), 174 (65), 163 (72), 144 (30), 133 (50), 123
(25), 117 (40), 89 (30);
HRMS (EI, 70 eV) Found: M+• 191.0220, C9H5NO4 requires 191.0219;
Mp = 126–128 °C (lit.191 mp = 132–133 °C).
The spectral data cited above match those reported in the literature.191
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.1.
Experimental procedures
128
p-Acetamidophenyl propiolate (2.42)
Compound 2.42 (462 mg, 69%) (Rf = 0.3 in 1:1 v/v ethyl acetate/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.9 Hz, 2H), 7.29 (s, 1H), 7.10 (d, J = 8.9 Hz, 2H),
3.07 (s, 1H), 2.17 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.4, 151.2, 146.1, 136.4, 121.9, 121.0, 77.0, 74.4, 24.7;
IR νmax (KBr) 3273, 2981, 2125, 1729, 1671, 1612, 1544, 1506, 1407, 1371, 1315, 1187, 1017
cm−1;
MS (EI, 70 eV) m/z 203 (M+•, 52%), 161 (44), 151 (26), 108 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 226.0484, C11H9N23NaO3 requires 226.0475. (M+H)+
204.0658, C11H10NO3 requires 204.0655;
Mp = 118–121 °C.
Chapter Five
129
p-{[(Trifluoromethyl)sulfonyl]oxy}phenyl propiolate (2.43)
Compound 2.43 (500 mg, 82%) (Rf = 0.8 in chloroform) was prepared using General Procedure
C and isolated as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.2 Hz, 2H), 7.27 (d, J = 9.2 Hz, 2H), 3.12 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.4, 149.3, 147.3, 123.3, 122.8, 118.9 (q, J = 321 Hz), 77.7,
73.9;
IR νmax (KBr) 3289, 2129, 1737, 1497, 1427, 1251, 1207, 1188, 1136, 1017 cm−1;
MS (EI, 70 eV) m/z 294 (M+•, 12%).
A molecular-associated ion could not be obtained for this compound under standard HRMS
conditions.
p-Chlorophenyl propiolate (2.44)
Compound 2.44192 (618 mg, 88%) (Rf = 0.8 in chloroform) was prepared using General
Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.9 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 3.01 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.7, 148.4, 132.2, 129.8, 122.8, 77.3, 74.2;
IR νmax (KBr) 3278, 2981, 2889, 2124, 1722, 1487, 1402, 1382, 1197, 1164, 1088, 1016 cm−1;
MS (EI, 70 eV) m/z 182 and 180 (M+•, 9 and 27%), 145 (100);
HRMS (EI, 70 eV) Found: M+• 181.9944, C9H537ClO2 requires 181.9949. M+• 179.9974,
C9H535ClO2 requires 179.9978.
Mp = 41–42 °C (lit.192 mp = 41–43 °C).
Experimental procedures
130
p-Bromophenyl propiolate (2.45)
Compound 2.45 (230 mg, 88%) (Rf = 0.8 in chloroform) was prepared using General Procedure
C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 3.11 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.6, 149.0, 132.9, 123.2, 119.9, 77.3, 74.2;
IR νmax (KBr) 3277, 2967, 2939, 2124, 1723, 1482, 1201, 1066, 1033, 1014 cm−1;
MS (EI, 70 eV) m/z 226 and 224 (M+•, both 37%), 198 and 196 (both 26), 174 and172 (both
52), 145 (44), 53 (100);
Mp = 56–57 °C.
A molecular-associated ion could not be obtained for this compound under standard HRMS
conditions.
p-Iodophenyl propiolate (2.46)
Compound 2.46 (250 mg, 40%) (Rf = 0.7 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 7.8 Hz, 2H), 3.09 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 150.7, 149.8, 138.9, 123.6, 91.0, 77.4, 74.2;
IR νmax (KBr) 3280, 2125, 1728, 1478, 1396, 1273, 1186, 1055, 1009, 910 cm−1;
MS (EI, 70 eV) m/z 272 (M+•, 90%), 244 (30), 220 (100);
HRMS (EI, 70 eV) Found: M+• 271.9334, C9H5IO2 requires 271.9334;
Mp = 72–73 °C.
Chapter Five
131
p-Cyanophenyl propiolate (2.47)
Compound 2.47188 (192 mg, 67%) (Rf = 0.5 in 1:2:3 v/v/v ethyl acetate
/dichloromethane/hexane) was prepared using General Procedure C and isolated as a clear,
yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.9 Hz, 2H), 3.14 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 153.0, 149.9, 134.0, 122.6, 118.0, 110.9, 78.0, 73.8;
IR νmax (KBr) 3237, 2990, 2901, 2239, 2123, 1730, 1604, 1498, 1411, 1394, 1219, 1194, 1166,
1066, 1058 cm−1;
MS (EI, 70 eV) m/z 171 (M+•, 23%), 53 (100);
HRMS (ESI, +ve) Found: (M+H)+ 172.0396, C10H6NO2 requires 172.0393;
Mp = 148–149 °C (lit.188 mp = 154–155 °C).
The spectral data cited above match those reported in the literature.188
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.1.
Experimental procedures
132
Methyl p-(propioloyloxy)benzoate (2.48)
Compound 2.48 (220 mg, 95%) (Rf = 0.4 in 1:4 v/v ethyl acetate/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H),
3.11 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 166.3, 153.5, 150.4, 131.6, 128.7, 121.5, 77.5, 74.2, 52.5;
IR νmax (KBr) 3261, 2958, 2131, 2116, 1716, 1681, 1600, 1503, 1438, 1273, 1219, 1158, 1111,
1098, 1098, 1014 cm−1;
MS (EI, 70 eV) m/z 204 (M+•, 40%), 173 (60), 145 (100);
HRMS (EI, 70 eV) Found: M+• 204.0425, C11H8O4 requires 204.0423;
Mp = 88–89 °C.
This compound was subjected to a single-crystal X-ray analysis. Details are presented in
Appendix 1.1.
Chapter Five
133
4-Formyl-2-methoxyphenyl propiolate (2.49)
Compound 2.49 (230 mg, 86%) (Rf = 0.6 in chloroform) was prepared using General Procedure
C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.48 (dd, J = 8.0 and 1.8
Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.12 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 190.9, 151.8, 149.7, 143.6, 136.0, 124.6, 123.2, 111.3, 77.5,
73.8, 56.3;
IR νmax (KBr) 3258, 2942, 2856, 2126, 1733, 1700, 1602, 1502, 1465, 1423, 1393, 1323, 1287,
1273, 1183, 1146, 1119, 1030 cm−1;
MS (EI, 70 eV) m/z 204 (M+•, 61%), 173 (96), 151 (100);
HRMS (ESI, +ve) Found: (M+H)+ 205.0487, C11H9O4 requires 205.0495;
Mp = 73–74 °C.
Experimental procedures
134
2,4-Dimethylphenyl propiolate (2.50)
Compound 2.50188 (225 mg, 79%) (Rf = 0.7 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H),
3.04 (s, 1H), 2.31 (s, 3H), 2.18 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 151.2, 146.4, 136.6, 132.1, 129.6, 127.8, 121.4, 76.6, 74.4, 21.0,
16.2;
IR νmax (KBr) 3271, 2127, 1736, 1500, 1250, 1206, 1193, 1114 cm−1;
MS (EI, 70 eV) m/z 174 (M+•, 100%), 122 (96);
HRMS (ESI, +ve) Found: (M+Na)+ 197.0581, C11H1023NaO2 requires 197.0573. (M+H)+
175.0758, C11H11O2 requires 175.0754;
Mp = 53–55 °C (lit.188 mp = 51–53 °C).
The spectral data cited above match those reported in the literature.188
This compound was subjected to a single-crystal X-ray analysis. Details are presented in
Appendix 1.1.
Chapter Five
135
2-isoPropyl-5-methylphenyl propiolate (2.51)
Compound 2.51 (210 mg, 78%) (Rf = 0.5 in 3:7 v/v dichloromethane/hexane) was prepared
using General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H),
3.06 (s, 1H), 3.02 (sept, J = 6.0 Hz, 1H), 2.33 (s, 3H), 1.22 (d, J = 6.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 151.5, 147.2, 137.1, 137.0, 128.0, 126.9, 122.5, 76.7, 74.5, 27.3,
23.2, 20.9;
IR νmax (KBr) 3265, 2967, 2871, 2123, 1732, 1507, 1455, 1193, 1084, 1058, 1033, 1011, 909
cm−1;
MS (EI, 70 eV) m/z 202 (M+•, 21%), 187 (16), 159 (71), 149 (100), 135 (61);
HRMS (ESI, +ve) Found: (M+Na)+ 225.0889, C13H1423NaO2 requires 225.0886. (M+H)+
203.1067, C13H15O2 requires 203.1067.
Experimental procedures
136
Benzo[d][1,3]dioxol-5-yl propiolate (2.52)
Compound 2.52188 (210 mg, 76%) (Rf = 0.6 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.59 (dd, J =
8.4 and 2.4 Hz, 1H), 6.00 (s, 2H), 3.06 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 151.5, 148.3, 146.2, 144.2, 114.0, 108.3, 103.6, 102.1, 77.1,
74.4;
IR νmax (KBr) 3228, 2906, 2118, 1723, 1504, 1486, 1444, 1364, 1245, 1203, 1173, 1120, 1095,
1037, 947, 934, 924, 905 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 65%), 138 (100), 137 (95), 134 (48), 107 (40), 79 (30);
HRMS (EI, 70 eV) Found: M+• 190.0268, C10H6O4 requires 190.0266;
Mp = 82–84 °C (lit.188 mp = 80–82 °C).
The spectral data cited above match those reported in the literature.188
This compound was subjected to a single-crystal X-ray analysis. Details are presented in
Appendix 1.1.
Chapter Five
137
3,4-Dimethoxyphenyl propiolate (2.53)
Compound 2.53 (498 mg, 93%) (Rf = 0.3 in 3:7 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 6.81 (s, 1H), 6.73–6.54 (complex m, 2H), 3.84 (s, 3H), 3.83 (s,
3H), 3.09 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 151.4, 149.5, 147.4, 143.4, 112.7, 111.2, 105.3, 77.0, 74.3, 56.2,
56.1;
IR νmax (KBr) 3219, 2120, 1722, 1609, 1514, 1472, 1451, 1416, 1269, 1211, 1125, 1026 cm−1;
MS (EI, 70 eV) m/z 206 (M+•, 100%), 191 (15), 175 (14), 163 (31), 153 (78);
HRMS (EI, 70 eV) Found: M+• 206.0579, C11H10O4 requires 206.0579;
Mp = 79–80 °C.
Experimental procedures
138
7-Methoxynaphthalen-2-yl propiolate (2.54)
Compound 2.54 (230 mg, 89%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H),
7.17-7.08 (complex m, 3H), 3.92 (s, 3H), 3.10 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 158.6, 151.3, 148.3, 135.3, 129.6, 129.5, 127.4, 119.3, 118.1,
117.7, 105.9, 77.0, 74.6, 55.6;
IR νmax (KBr) 3245, 2126, 1733, 1720, 1633, 1514, 1482, 1468, 1390, 1251, 1218, 1200, 1176,
1143, 1027, 918 cm−1;
MS (EI, 70 eV) m/z 226 (M+•, 100%), 198 (30), 174 (85), 170 (70), 155 (30), 145 (50), 140
(25), 131 (35), 102 (50);
HRMS (ESI, +ve) Found: M+ 226.0630, C14H10O3 requires 226.0630;
Mp = 142–143 °C.
This compound was subjected to a single-crystal X-ray analysis. Details are presented in
Appendix 1.1.
Chapter Five
139
Naphthalen-1-yl propiolate (2.55)
Compound 2.55188 (245 mg, 90%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.97–7.86 (complex m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.60–7.51
(complex m, 2H), 7.48 (t, J = 8.3 Hz, 1H), 7.33 (dd, J = 7.6 and 0.9 Hz, 1H), 3.14 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 151.1, 145.9, 134.8, 128.2, 127.0, 126.9, 126.9, 126.4, 125.4,
121.1, 118.1, 77.2, 74.4;
IR νmax (KBr) 3676, 3276, 2988, 2125, 1732, 1390, 1190, 1155, 1066 cm−1;
MS (EI, 70 eV) m/z 196 (M+•, 59%), 168 (49), 144 (81), 115 (100);
HRMS (ESI, +ve) Found: (M+H)+ 197.0594, C13H9O2 requires 197.0597.
Mp = 43–44 °C (lit.188 mp = 41–42 °C).
The spectral data cited above match those reported in the literature.188
Experimental procedures
140
Naphthalen-2-yl propiolate (2.56)
Compound 2.56187 (260 mg, 96%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure C and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 6.9 and 2.3 Hz, 1H),
7.83–7.80 (complex m, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.57–7.45 (complex m, 2H), 7.28 (dd, J
= 8.9 and 2.3 Hz, 1H), 3.10 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 151.2, 147.6, 133.8, 131.9, 129.8, 128.0, 127.9, 127.0, 126.3,
120.5, 118.7, 77.0, 74.5;
IR νmax (KBr) 3676, 3247, 2988, 2121, 1713, 1228, 1066 cm−1;
MS (EI, 70 eV) m/z 196 (M+•, 66%), 168 (29), 144 (100);
HRMS (ESI, +ve) Found: (M+H)+ 197.0594, C13H9O2 requires 197.0597;
Mp = 52–53 °C (lit.187 mp = 51–53 °C).
The spectral data cited above match those reported in the literature.187
Chapter Five
141
p-Methoxyphenyl but-2-ynoate (2.57)
Compound 2.57189 (300 mg, 98%) (Rf = 0.4 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure D and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 3.80 (s, 3H),
2.06 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 157.8, 152.6, 143.8, 122.4, 114.7, 88.2, 72.3, 55.8, 4.2;
IR νmax (KBr) 2959, 2838, 2277, 2231, 1721, 1503, 1229, 1179, 1035 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 60%), 148 (60), 124 (100), 109 (60);
HRMS (EI, 70 eV) Found: M+• 190.0634, C11H10O3 requires 190.0630;
Mp = 59–60 °C (lit.189 mp = 58–60 °C).
The 1H NMR and IR spectral data cited above match those reported in the literature.189
This compound was subjected to a single-crystal X-ray analysis. Details are presented in
Appendix 1.1.
Experimental procedures
142
p-Methoxyphenyl 3-phenylpropiolate (2.58)
Compound 2.58193 (35 mg, 9%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using
General Procedure D and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.41 (t, J =
7.5 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 6.92 (d, J = 9.1 Hz, 2H), 3.81 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 157.6, 152.8, 143.6, 133.2, 131.0, 128.6, 122.2, 119.3, 114.6,
88.6, 80.3, 55.6;
IR νmax (KBr) 2952, 2837, 2233, 1723, 1504, 1282, 1250, 1188, 1165, 1143 cm−1;
MS (EI, 70 eV) m/z 252 (M+•, 30%), 129 (100), 105 (58);
HRMS (EI, 70 eV) Found: M+• 252.0787, C16H12O3 requires 252.0786;
Mp = 64–66 °C. (lit.193 mp = 67–69 °C).
The spectral data cited above match those reported in the literature.193
Chapter Five
143
1,4-Phenylene dipropiolate (2.59)
Compound 2.59194 (90 mg, 23%) (Rf = 0.6 in chloroform) was prepared using General
Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.20 (s, 4H), 3.09 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 150.7, 147.8, 122.6, 77.3, 74.2;
IR νmax (KBr) 3279, 2929, 2126, 1720 1500, 1295, 1220, 1177, 1100, 1019, 920 cm−1;
MS (EI, 70 eV) m/z 214 (M+•, 18%), 162 (36), 134 (14), 110 (23); 53 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 237.0156, C12H623NaO4 requires 237.0158 (M+H)+
215.0345, C12H7O4 requires 215.0339;
Mp = 158–159 °C. (lit.194 mp = 159 °C).
The spectral data cited above match those reported in the literature.194
Experimental procedures
144
(S)-4-{2-[(tert-Butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}phenyl propiolate (2.60)
Compound 2.60 (500 mg, 82%) (Rf = 0.2 in 1:4 v/v ethyl acetate/hexane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 5.04 (d, J =
6.7 Hz, 1H), 4.54 (d, J = 6.7 Hz, 1H), 3.67 (s, 3H), 3.11 (s, 1H), 3.08 (d, J = 5.8 Hz, 1H), 3.04–
2.94 (complex m, 1H), 1.38 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 172.2, 155.1, 150.9, 148.9, 134.7, 130.5, 121.3, 80.1, 77.1, 74.3,
54.4, 52.3, 37.8, 28.3;
IR νmax (KBr) 3265, 2981, 2124, 1733, 1506, 1438, 1393, 1367, 1213, 1189, 1059, 1019 cm−1;
MS (ESI, +ve) m/z 370 [(M+Na)+, 40%], 348 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 370.1269, C18H21N23NaO6 requires 370.1261. (M+H)+
348.1443, C18H22NO6 requires 348.1442.
Chapter Five
145
9H-Carbazol-1-yl propiolate (2.61)
Compound 2.61 (118 mg, 46%) (Rf = 0.3 in 1:1 v/v ethyl acetate/hexane) was prepared using
General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 8.12 (br s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.45–7.41 (complex
m, 2H),7.24 (dt, J = 8.2 and 2.1 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 8.5 and 2.1 Hz,
1H), 3.10 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 151.4, 148.1, 140.1, 139.5, 126.0, 122.7, 121.9, 121.0, 119.9,
112.8, 110.7, 103.6, 76.8, 74.4;
IR νmax (KBr) 3404, 3284, 2932, 2856, 2133, 1714, 1631, 1610, 1461, 1442, 1337, 1327, 1227,
1118 cm−1;
MS (EI, 70 eV) m/z 235 (M+•, 100%), 195 (48), 183 (65), 179 (71);
HRMS (EI, 70 eV) Found: M+• 235.0639, C15H9NO2 requires 235.0633;
Mp = 166–167 °C
Experimental procedures
146
9-Oxo-9H-fluoren-1-yl propiolate (2.62)
Compound 2.62 (245 mg, 90%) (Rf = 0.2 in 2:3 v/v chloroform/hexane) was prepared using
General Procedure C and isolated as a clear, yellow solid.
1H NMR (400 MHz, CDCl3) δ 7.62 (dt, J = 7.4 and 1.0 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.48
(dd, J = 7.4 and 1.0 Hz, 1H), 7.44 (dd, J = 7.4 and 1.0 Hz, 1H), 7.30 (td, J = 7.4 and 1.0 Hz,
1H), 6.97 (d, J = 7.4 Hz, 1H), 3.14 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 190.4, 150.0, 146.6, 146.2, 143.5, 136.5, 134.9, 134.1, 129.8,
124.6, 124.4, 123.0, 120.8, 118.9, 77.3, 74.1;
IR νmax (KBr) 3232, 2917, 2122, 1725, 1713, 1615, 1591, 1471, 1453, 1220, 1191, 1148, 1109
cm−1;
MS (EI, 70 eV) m/z 248 (M+•, 27%), 220 (100), 196 (37);
HRMS (ESI, +ve) Found: (M+Na)+ 271.0363, C16H823NaO3 requires 271.0366;
Mp = 154–155 °C.
Chapter Five
147
General Procedure E – Gold(I)-catalysed cyclisation of aryl propiolates
A magnetically stirred solution of the requisite aryl propiolate (1 mmol, 1 equiv.) in
dichloromethane (50 mL) was treated with Echavarren’s gold(I) catalyst (23 mg, 0.03 mmol,
0.03 equiv.). The resulting solution was stirred at 18 °C for 1 h then filtered through a pad of
TLC-grade silica gel and the filtrate concentrated under reduced pressure. The light-yellow oil
thus obtained was subjected to flash chromatography (silica gel, 3:7 v/v ethyl acetate/hexane
elution) and concentration of the relevant fractions then gave the anticipated coumarin.
Coumarin (1.1)
Compound 1.1195 (28 mg, 93%) (Rf = 0.9 in 1:4 v/v diethyl ether/hexane) was prepared from
aryl propiolate 2.17 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 9.6 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.42 (d, J =
7.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 161.0, 154.2, 143.6, 132.0, 124.6, 119.0, 117.0, 116.8;
IR νmax (KBr) 1708, 1619, 1604, 1563, 1453, 1398, 1278, 1259, 1229, 1177, 1121, 1108 cm−1;
MS (EI, 70 eV) m/z 146 (M+•, 90%); 118 (100);
HRMS (ESI, +ve) Found: (M+H)+ 147.0443, C9H6O2 requires 147.0446;
Mp = 70–72 °C (lit.195 mp = 68–73°C).
The spectral data cited above match those reported by a commercial supplier.195
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.2.
Experimental procedures
148
8-Ethyl-2H-chromen-2-one (2.63)
Compound 2.63196 (100 mg, quant) (Rf = 0.7 in chloroform) was prepared from aryl propiolate
2.20 using General Procedure E and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 9.5 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.27 (d, J =
7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.34 (d, J = 9.5 Hz, 1H), 2.82 (q, J = 7.5 Hz, 2H), 1.23 (t,
J = 7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 160.9, 151.9, 143.9, 132.1, 131.6, 125.6, 124.2, 118.6, 116.2,
22.4, 14.1;
IR νmax (KBr) 3422, 2969, 2934, 2876, 1717, 1601, 1452, 1401, 1235, 1179, 1163, 1118, 1090,
1059, 1013 cm−1;
MS (EI, 70 eV) m/z 174 (M+•, 76%), 159 (100), 131(68);
HRMS (ESI, +ve) Found: (M+Na)+ 197.0565, C11H1023NaO2 requires 197.0573. (M+H)+
175.0749, C11H11O2 requires 175.0754.
The spectral data cited above match those reported in the literature.196
Chapter Five
149
8-Methoxy-2H-chromen-2-one (2.64)
Compound 2.64197 (100 mg, quantitative) (Rf = 0.3 in 1:3:6 v/v/v of ethyl acetate
/dichloromethane/hexane) was prepared from aryl propiolate 2.21 using General Procedure E
and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 9.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.10 (dd, J =
8.0 and 1.3 Hz, 1H), 7.08 (dd, J = 8.0 and 1.3 Hz, 1H), 6.45 (d, J = 9.6 Hz, 1H), 3.99 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.3, 147.5, 144.0, 143.7, 124.4, 119.7, 119.4, 117.2, 114.0,
56.5;
IR νmax (KBr) 1727, 1609, 1572, 1478, 1469, 1439, 1401, 1276, 1258, 1237, 1200, 1168, 1134,
1078 cm−1;
MS (EI, 70 eV) m/z 176 (M+•, 100%), 161 (9), 148 (24), 133 (33);
HRMS (ESI, +ve) Found: (M+Na)+ 199.0366, C10H823NaO3 requires 199.0366. (M+H)+
177.0543, C10H9O3 requires 177.0546;
Mp = 90–91 °C (lit.197 mp = 90–91 °C).
The spectral data cited above match those reported in the literature.197
Experimental procedures
150
8-Bromo-2H-chromen-2-one (2.65)
Compound 2.65198 (70 mg, 70%) (Rf = 0.4 in chloroform) was prepared from aryl propiolate
2.24 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 7.9 and 1.5 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 7.43
(dd, J = 7.9 and 1.5 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 159.6, 150.9, 143.2, 135.4, 127.3, 125.2, 120.2, 117.4, 110.5;
IR νmax (KBr) 1732, 1617, 1594, 1552, 1438, 1399, 1236, 1168, 1146, 1109, 1069 cm−1;
MS (EI, 70 eV) m/z 226 and 224 (M+•, both 100), 198 and 196 (both 85);
HRMS (ESI, +ve) Found: (M+Na)+ 246.9368, C9H579Br23NaO4 requires 246.9365. (M+H)+
224.9546, C9H679BrO4 requires 224.9546;
Mp = 136 °C (lit.198 mp = 135–138 °C).
The spectral data cited above match those reported in the literature.198
Chapter Five
151
8-Chloro-2H-chromen-2-one (2.66)
Compound 2.66199 (40 mg, 50%) (Rf = 0.3 in 0.5:3:6.5 v/v/v of ethyl acetate
/dichloromethane/hexane) was prepared from aryl propiolate 2.25 using General Procedure E
and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 9.6 Hz, 1H), 7.59 (dd, J = 7.9 and 1.5 Hz, 1H), 7.40
(dd, J = 7.9 and 1.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.46 (d, J = 9.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 159.6, 149.9, 143.2, 132.4, 126.5, 124.8, 121.9, 120.3, 117.5;
IR νmax (KBr) 1734, 1599, 1558, 1444, 1400, 1171, 1111 cm−1;
MS (EI, 70 eV) m/z 182 and 180 (M+•, 36 and 100%), 154 and 152 (33 and 98);
HRMS (ESI, +ve) Found: M+• 181.9947, C9H637ClO2 requires 181.9949. M+• 179.9975,
C9H635ClO2 requires 179.9978;
Mp = 145–146 °C (lit.199 mp = 146–147 °C).
The spectral data cited above match those reported in the literature.199
Experimental procedures
152
7-Methoxy-2H-chromen-2-one (2.67) (Herniarin)
Compound 2.67200 (14 mg, 70%) (Rf = 0.4 in chloroform) was prepared from aryl propiolate
2.26 using General Procedure E and isolated as a colourless, crystalline solid after preparative
TLC on silica gel using chloroform as the eluting solvent.
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 9.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.84 (dd, J =
8.5 and 2.5 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 6.24 (d, J = 9.5 Hz, 1H), 3.87 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 163.0, 161.4, 156.1, 143.6, 129.0, 113.3, 112.8, 112.7, 101.1,
56.0;
IR νmax (KBr) 1704, 1611, 1505, 1399, 1351, 1282, 1232, 1205, 1123 cm−1;
MS (EI, 70 eV) m/z 176 (M+•, 100%), 148 (70), 133 (65);
HRMS (EI, 70 eV) Found: M+• 176.0475, C10H8O3 requires 176.0473;
Mp = 115–117 °C (lit.200 mp = 117–118 °C).
The spectral data cited above match those reported in the literature.200
This compound was co-produced with 2.68 and separated from it by flash chromatography.
Chapter Five
153
5-Methoxy-2H-chromen-2-one (2.68)
Compound 2.68201 (3 mg, 15%) (Rf = 0.4 in chloroform) was prepared from aryl propiolate 2.26
using General Procedure E and isolated as a colourless, crystalline solid after preparative TLC
on silica gel using chloroform as the eluting solvent.
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.8 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 6.93 (d, J =
8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 9.8 Hz, 1H), 3.94 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.2, 156.4, 155.4, 138.7, 132.5, 114.8, 109.9, 109.5, 105.3,
56.2;
IR νmax (KBr) 1731, 1605, 1470, 1399, 1187, 1114, 1090 cm−1;
MS (EI, 70 eV) m/z 176 (M+•, 100%), 148 (70), 133 (69);
HRMS (EI, 70 eV) Found: M+• 176.0475, C10H8O3 requires 176.0473;
Mp = 118–119 °C.
The spectral data cited above match those reported in the literature.201
Experimental procedures
154
7-[(tert-Butyldimethylsilyl)oxy]-2H-chromen-2-one (2.69)
Compound 2.69202 (92 mg, 92%) (Rf = 0.6 in 1:8 v/v of ethyl acetate/toluene) was prepared
from aryl propiolate 2.27 using General Procedure E and isolated as a colourless, crystalline
solid.
1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 9.5 and 1.4 Hz, 1H), 7.09 (dd, J = 7.4 and 1.4 Hz,
1H), 6.54–6.50 (complex m, 2H), 6.00 (d, J = 9.5 Hz, 1H), 0.75 (s, 9H), 0.01 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 161.2, 159.5, 155.7, 143.4, 128.8, 117.5, 113.5, 113.3, 107.8,
25.7, 18.4, −4.3;
IR νmax (KBr) 3444, 2961, 2930, 2858, 1729, 1618, 1507, 1473, 1464, 1405, 1332, 1296, 1252,
1242, 1191, 1143 cm−1;
MS (EI, 70 eV) m/z 276 (M+•, 61%), 219 (99), 163 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 299.1068, C15H2123NaO3Si requires 299.1074. (M+H)+
277.1250, C15H21O3Si requires 277.1254;
Mp = 53 °C (lit.202 mp = 53–55 °C).
The spectral data cited above match those reported in the literature.202
This compound was co-produced with 2.70 and separated from it by flash chromatography.
Chapter Five
155
5-((tert-Butyldimethylsilyl)oxy)-2H-chromen-2-one (2.70)
Compound 2.70 (4 mg, 4%) (Rf = 0.7 in 1:8 v/v of ethyl acetate/toluene) was prepared from
aryl propiolate 2.27 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 9.7 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 6.93 (d, J =
8.3 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 9.7 Hz, 1H), 1.04 (s, 9H), 0.29 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 161.1, 155.5, 153.0, 139.0, 132.1, 115.0, 113.6, 112.4, 109.8,
25.9, 18.5, −4.2;
IR νmax (KBr) 2956, 2931, 2859, 1736, 1616, 1606, 1472, 1463, 1392, 1318, 1298, 1250, 1229,
1183, 1104, 1074, 1062 cm−1;
MS (EI, 70 eV) m/z 276 (M+•, 41%), 219 (100), 191 (93);
HRMS (ESI, +ve) Found: (M+Na)+ 299.1072, C15H2023NaO3Si requires 299.1074. (M+H)+
277.1252, C15H21O3Si requires 277.1254;
Mp = 91–93 °C.
Experimental procedures
156
2-Oxo-2H-chromen-7-yl acetate (2.71)
Compound 2.71203 (22 mg, 44%) (Rf = 0.4 in 1:2:3 v/v/v of ethyl
acetate/dichloromethane/pentane) was prepared from aryl propiolate 2.28 using General
Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.12 (d, J =
2.2 Hz, 1H), 7.06 (dd, J = 8.4 and 2.2 Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 2.34 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.8, 160.4, 154.9, 153.4, 142.9, 128.7, 118.5, 116.8, 116.3,
110.6, 21.3;
IR νmax (KBr) 3077, 2988, 1735, 1617, 1403, 1372, 1272, 1223, 1236, 1148, 1123, 1105, 1046,
1017 cm−1;
MS (EI, 70 eV) m/z 204 (M+•, 16%), 162 (100), 134 (90);
HRMS (ESI, +ve) Found: (M+Na)+ 227.0309, C11H823NaO4 requires 227.0315. (M+H)+
205.0495, C11H9O4 requires 205.0495;
Mp = 137 °C.
The spectral data cited above match those reported in the literature.203
This compound was co-produced with 2.72 and separated from it by flash chromatography.
Chapter Five
157
2-Oxo-2H-chromen-5-yl acetate (2.72)
Compound 2.72204 (7 mg, 14%) (Rf = 0.4 in 1:2:3 v/v/v of ethyl acetate/dichloromethane/hexane)
was prepared from aryl propiolate 2.28 using General Procedure E and isolated as a colourless,
crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 9.7 Hz, 1H), 7.52 (t, J = 8.3 Hz, 1H), 7.25–7.21
(complex m, 1H), 7.08 (dd, J = 8.3 and 1.0 Hz, 1H), 6.44 (d, J = 9.7 Hz, 1H), 2.41 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.7, 160.1, 154.9, 147.2, 137.3, 131.9, 117.8, 117.1, 114.7,
112.9, 21.0;
IR νmax (KBr) 1773, 1735, 1622, 1615, 1461, 1371, 1197, 1164, 1110, 1044 cm−1;
MS (EI, 70 eV) m/z 204 (M+•, 25%), 162 (100);
HRMS (ESI, +ve) Found: (M+H)+ 205.0499, C11H9O4 requires 205.0495;
Mp = 86 °C (lit.204 mp = 88–89 °C).
The spectral data cited above match those reported in the literature.204
Experimental procedures
158
2-Oxo-2H-chromen-7-yl pivalate (2.73)
Compound 2.73205 (36 mg, 36%) (Rf = 0.4 in 1:8 v/v ethyl acetate/toluene) was prepared from
aryl propiolate 2.31 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.08 (d, J =
2.2 Hz, 1H), 7.01 (dd, J = 8.6 and 2.2 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 1.37 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 176.6, 160.5, 154.9, 153.9, 143.0, 128.6, 118.5, 116.7, 116.1,
110.5, 39.4, 27.2;
IR νmax (KBr) 2976, 1717, 1616, 1484, 1427, 1264, 1232, 1129, 1115, 1104, 1038 cm−1;
MS (ESI, +ve) m/z 310 [(M+MeCN+Na)+, 100%], 247 [(M+H)+, 95];
HRMS (ESI, +ve) Found: (M+H)+ 247.0971, C14H15O4 requires 247.0970;
Mp = 136–138 °C (lit.205 mp = 139 °C).
The spectral data cited above match those reported in the literature.205
This compound was co-produced with 2.74 and separated from it by flash chromatography.
Chapter Five
159
2-Oxo-2H-chromen-5-yl pivalate (2.79)
Compound 2.79 (18 mg, 18%) (Rf = 0.4 in 1:8 v/v ethyl acetate/toluene) was prepared from aryl
propiolate 2.31 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 9.8 Hz, 1H), 7.52 (t, J = 8.3 Hz, 1H), 7.22 (d, J =
8.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 9.8 Hz, 1H), 1.44 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 176.5, 160.2, 154.8, 147.6, 137.2, 131.9, 117.7, 117.1, 114.5,
113.0, 39.7, 27.3;
IR νmax (KBr) 2973, 1747, 1734, 1622, 1613, 1460, 1240, 1186, 1097, 1040 cm−1;
MS (ESI, +ve) m/z 247 [(M+H)+, 100%];
HRMS (ESI, +ve) Found: (M+H)+ 247.0972, C14H15O4 requires 247.0970;
Mp = 86–87 °C.
Experimental procedures
160
7-(Benzyloxy)-2H-chromen-2-one (2.75)
Compound 2.75201 (82 mg, 82%) (Rf = 0.6 in 1:8 v/v of ethyl acetate/toluene) was prepared
from aryl propiolate 2.32 using General Procedure E and isolated as a colourless, crystalline
solid.
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 9.4 Hz, 1H), 7.47–7.27 (complex m, 6H), 6.90 (dd,
J = 8.6 and 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H), 5.10 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 161.9, 161.1, 155.8, 143.4, 135.8, 128.9, 128.8, 128.4, 127.5,
113.2, 113.2, 112.8, 102.0, 70.5;
IR νmax (KBr) 2918, 1726, 1609, 1464, 1457, 1387, 1349, 1278, 1256, 1229, 1198, 1155, 1125,
1107, 1075, 1013 cm−1;
MS (EI, 70 eV) m/z 252 (M+•, 72%), 91 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 275.0667, C16H1223NaO3 requires 275.0679; (M+H)+
253.0847, C16H13O3 requires 253.0859;
Mp = 153–154 °C (lit.201 mp = 155 °C).
The spectral data cited above match those reported in the literature.201
This compound was co-produced with 2.76 and separated from it by flash chromatography.
Chapter Five
161
5-(Benzyloxy)-2H-chromen-2-one (2.76)
Compound 2.76201 (17 mg, 17%) (Rf = 0.7 in 1:8 v/v of ethyl acetate/toluene) was prepared
from aryl propiolate 2.32 using General Procedure E and isolated as a colourless, crystalline
solid.
1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 9.8 and 0.8 Hz, 1H), 7.49–7.31 (complex m, 6H),
6.93 (dd, J = 8.4 and 0.8 Hz, 1H), 6.79 (dd, J = 8.4 and 0.8 Hz, 1H), 6.33 (d, J = 9.8 Hz, 1H),
5.17 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 161.0, 155.4, 155.4, 138.7, 136.1, 132.4, 128.9, 128.5, 127.6,
114.9, 110.1, 109.6, 106.6, 71.0;
IR νmax (KBr) 2917, 2849, 1733, 1619, 1607, 1498, 1482, 1463, 1381, 1328, 1287, 1255, 1228,
1185, 1107, 1074, 1029 cm−1;
MS (EI, 70 eV) m/z 252 (M+•, 48%), 91 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 275.0677, C16H1223NaO3 requires 275.0679. (M+H)+
253.0849, C16H13O3 requires 253.0859;
Mp = 101–102 °C.
The spectral data cited above match those reported in the literature.201
Experimental procedures
162
7-Fluoro-2H-chromen-2-one (2.77)
Compound 2.77206 (55 mg, 55%) (Rf = 0.2 in 1:6 v/v ethyl acetate/toluene) was prepared from
aryl propiolate 2.34 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 9.7 Hz, 1H), 7.46 (dd, J = 8.4 and 6.1 Hz, 1H), 7.01
(d, J = 8.4 Hz, 1H), 6.99–6.93 (complex m, 1H), 6.34 (d, J = 9.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 164.5 (d, JC-F = 254 Hz), 160.1, 155.3 (d, JC-F = 13 Hz), 142.8,
129.3 (d, JC-F = 10 Hz), 115.6 (d, JC-F = 3 Hz), 115.5 (d, JC-F = 3 Hz), 112.5 (d, JC-F = 23 Hz),
104.5 (d, JC-F = 26 Hz);
IR νmax (KBr) 1726, 1700, 1626, 1498, 1427, 1401, 1280, 1228, 1147, 1120, 1102 cm−1;
MS (EI, 70 eV) m/z 164 (M+•, 92%), 136 (100);
HRMS (ESI, +ve) Found: (M+H)+ 165.0353, C9H6FO2 requires 165.0346;
Mp = 133 °C. (lit.206 mp = 132–133 °C).
The spectral data cited above match those reported in the literature.206
This compound was co-produced with 2.78 and separated from it by flash chromatography.
Chapter Five
163
5-Fluoro-2H-chromen-2-one (2.78)
Compound 2.78 (5 mg, 5%) (Rf = 0.3 in 1:6 v/v of ethyl acetate/toluene) was prepared from
aryl propiolate 2.34 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.7 Hz, 1H), 7.48 (td, J = 8.5 and 6.2 Hz, 1H), 7.07
(d, J = 8.5 Hz, 1H), 6.92 (t, J = 8.5 Hz, 1H), 6.38 (d, J = 9.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 159.9 (s), 156 (d, JC-F = 261 Hz), 136.2 (d, JC-F = 4 Hz), 132.2
(d, JC-F = 10 Hz), 128.7 (d, JC-F = 82 Hz), 116.8 (d, JC-F = 2 Hz), 112.8 (d, JC-F = 4 Hz), 110.4 (d,
JC-F = 20 Hz), 109.6 (d, JC-F = 19 Hz);
IR νmax (KBr) 1733, 1628, 1617, 1461, 1239, 1187, 1107, 1039 cm−1;
MS (EI, 70 eV) m/z 164 (M+•, 90%), 136 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 187.0172, C9H5F23NaO2 requires 187.0171; (M+H)+
165.0352, C9H6FO2 requires 165.0352;
Mp = 111 °C.
Experimental procedures
164
7-Chloro-2H-chromen-2-one (2.79)
Compound 2.79207 (83 mg, 83%) (Rf = 0.4 in 1:3:6 v/v/v of ethyl
acetate/dichloromethane/hexane) was prepared from aryl propiolate 2.35 using General
Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 9.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.35 (d, J =
2.0 Hz, 1H), 7.26 (dd, J = 8.3 and 2.0 Hz, 1H), 6.41 (d, J = 9.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 160.0, 154.6, 142.7, 138.0, 128.8, 125.2, 117.6, 117.4, 116.8;
IR νmax (KBr) 3081, 1721, 1683, 1619, 1604, 1488, 1394, 1267, 1247, 1221, 1180, 1139, 1106,
1076 cm−1;
MS (EI, 70 eV) m/z 182 and 180 (M+•, 23 and 78), 154 and 152 (32 and 100);
HRMS (ESI, +ve) Found: (M+Na)+ 202.9871, C9H535Cl23NaO2 requires 202.9870. (M+H)+
183.0020, C9H637ClO2 requires 183.0021. (M+H)+ 181.0051, C9H6
35ClO2 requires 181.0051;
Mp = 128–129 °C (lit.207 mp = 129 °C).
The spectral data cited above match those reported in the literature.207
This compound was co-produced with 2.80 and separated from it by flash chromatography.
Chapter Five
165
5-Chloro-2H-chromen-2-one (2.80)
Compound 2.80207 (16 mg, 16%) (Rf = 0.7 in 1:8 v/v ethyl acetate/toluene) was prepared from
aryl propiolate 2.35 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.32 (d, J =
8.2 Hz, 1H), 7.25 (d, J = 9.8 Hz, 1H), 6.50 (d, J = 9.8 Hz, 1H)
13C NMR (100 MHz, CDCl3) δ 159.8, 154.9, 139.6, 132.5, 131.8, 125.0, 117.5, 117.4, 115.8;
IR νmax (KBr) 1738, 1615, 1599, 1447, 1265, 1235, 1185, 1113 cm−1;
MS (EI, 70 eV) m/z 182 and 180 (M+•, 23 and 70%), 154 and 152 (33 and 100);
HRMS (ESI, +ve) Found: (M+Na)+ 202.9872, C9H635Cl 23NaO2 requires 202.9870. (M+H)+
181.0060, C9H635ClO2 requires 181.0051;
Mp = 89–90 °C (lit.207 mp = 91–94 °C).
The spectral data cited above match those reported in the literature.207
Experimental procedures
166
7-Bromo-2H-chromen-2-one (2.81)
Compound 2.81198 (30 mg, 60%) (Rf = 0.5 in chloroform) was prepared from aryl propiolate
2.36 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.40 (dd, J =
8.3 and 1.8 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 159.9, 154.4, 142.8, 128.9, 128.0, 125.9, 120.3, 117.9, 117.0;
IR νmax (KBr) 1719, 1618, 1598, 1390, 1266, 1247, 1178, 1138, 1105, 1067 cm−1;
MS (EI, 70 eV) m/z 226 and 224 (M+•, both 80%), 198 and 196 (98 and 100);
Mp = 122–123 °C (lit.198 mp = 120–124 °C).
The spectral data cited above match those reported in the literature.198
This compound was co-produced with 2.82 and separated from it by flash chromatography.
Chapter Five
167
5-Bromo-2H-chromen-2-one (2.82)
Compound 2.82198 (7 mg, 14%) (Rf = 0.3 in 3:2 v/v chloroform/hexane) was prepared from aryl
propiolate 2.36 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 9.8 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.37 (t, J =
8.3 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 9.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 160.0, 155.0, 142.3, 132.3, 128.6, 122.5, 119.0, 117.9, 116.6;
IR νmax (KBr) 1734, 1617, 1594, 1558, 1443, 1389, 1314, 1264, 1233, 1203, 1184, 1139, 1112
cm−1;
MS (EI, 70 eV) m/z 226 and 224 (M+•, 94 and 94%), 198 and 196 (98 and 100);
HRMS (ESI, +ve) Found: (M+Na)+ 248.9352, C9H681Br23NaO2 requires 248.9350. (M+Na)+
246.9372, C9H679Br23NaO2 requires 246.9371; (M+H)+ 226.9533, C9H6
81BrO2 requires
226.9531; (M+H)+ 224.9552, C9H679BrO2 requires 224.9551;
Mp = 94–95 °C.
The spectral data cited above match those reported in the literature.198
Experimental procedures
168
6-Methyl-2H-chromen-2-one (2.83)
Compound 2.83207 (20 mg, quantitative) (Rf = 0.6 in chloroform) was prepared from aryl
propiolate 2.37 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 9.5 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H),
7.14 (d, J = 8.4 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 2.40 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.2, 152.4, 143.6, 134.3, 133.0, 127.9, 118.8, 116.9, 116.7,
20.9;
IR νmax (KBr) 3081, 1760, 1714, 1684, 1623, 1612, 1575, 1487, 1430, 1380, 1278, 1262, 1246,
1189, 1168, 1131, 1106, 913 cm−1;
MS (EI, 70 eV) m/z 160 (M+•, 100%), 132 (70);
HRMS (EI, 70 eV) Found: M+• 160.0523, C10H8O2 requires 160.0524;
Mp = 75–76 °C (lit.207 mp = 76.5 °C).
The spectral data cited above match those reported in the literature.207
Chapter Five
169
6-Methoxy-2H-chromen-2-one (2.84)
Compound 2.84207 (20 mg, quantitative) (Rf = 0.2 in 1:3:6 v/v/v ethyl
acetate/dichloromethane/hexane) was prepared from aryl propiolate 2.19 using General
Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 7.11 (dd, J =
9.0 and 2.9 Hz, 1H), 6.91 (d, J = 2.9 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 3.85 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.1, 156.3, 148.7, 143.3, 119.6, 119.4, 118.1, 117.3, 110.3,
56.0;
IR νmax (KBr) 1702, 1570, 1492, 1453, 1284, 1121, 1048 cm−1;
MS (EI, 70 eV) m/z 176 (M+•, 100%), 161 (39), 148 (33), 133 (49);
HRMS (ESI, +ve) Found: (M+Na)+ 199.0373, C10H823NaO3 requires 199.0366. (M+H)+
177.0548, C10H9O3 requires 177.0546;
Mp = 99–100 °C (lit.207 mp = 101 °C).
The spectral data cited above match those reported in the literature.207
Experimental procedures
170
6-(Triethylsilyl)-2H-chromen-2-one (2.85)
Compound 2.85 (64 mg, 91%) (Rf = 0.5 in chloroform) was prepared from aryl propiolate 2.38
using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 9.5 Hz, 1H), 7.56 (dd, J = 8.2 and 1.5 Hz, 1H), 7.49
(d, J = 1.5 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 9.5 Hz, 1H), 0.90 (t, J = 7.7 Hz, 9H),
0.75 (q, J = 7.7 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 160.9, 154.8, 143.8, 137.7, 134.0, 134.0, 118.7, 116.7, 116.4,
7.4, 3.5;
IR νmax (KBr) 2955, 2910, 2875, 1733, 1618, 1594, 1562, 1457, 1418, 1363, 1283, 1259, 1225,
1183, 1131, 1111, 1085, 1008 cm−1;
MS (EI, 70 eV) m/z 260 (M+•, 33%), 231 (100), 203 (100), 175 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 283.1118, C15H2023NaO2Si requires 283.1125; (M+H)+
261.1296, C15H21O2Si requires 261.1305;
Mp = 48–50 °C.
Chapter Five
171
6-(tert-Butyldimethylsilyl)-2H-chromen-2-one (2.86)
Compound 2.86 (37 mg, 74%) (Rf = 0.5 in chloroform) was prepared from aryl propiolate 2.39
using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 9.5 Hz, 1H), 7.63 (dd, J = 8.2 and 1.6 Hz, 1H), 7.57
(d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 9.5 Hz, 1H), 0.87 (s, 9H), 0.29 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 160.8, 154.8, 143.8, 137.8, 134.3, 134.2, 118.4, 116.6, 116.0,
26.5, 16.9, −6.0;
IR νmax (KBr) 1752, 1728, 1622, 1607, 1564, 1454, 1400, 1276, 1260, 1228, 1178, 1120, 1102
cm−1;
MS (EI, 70 eV) m/z 260 (M+•, 11%), 203 (100);
HRMS (ESI, +ve) Found: (M+H)+ 261.1293, C15H21O2Si requires 261.1305;
Mp = 84–87 °C.
Experimental procedures
172
N-(2-Oxo-2H-chromen-6-yl)acetamide (2.87)
Compound 2.87208 (52 mg, 52%) (Rf = 0.5 in ethyl acetate) was prepared from aryl propiolate
2.42 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR [400 MHz, (CD3)2CO] δ 9.31 (s, 1H), 8.07 (s, 1H), 7.94 (dd, J = 9.6 and 0.8 Hz, 1H),
7.69 (dd, J = 8.9 and 0.8 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 2.10 (s,
3H);
13C NMR [100 MHz, (CD3)2CO] δ 169.0, 160.7, 150.9, 144.6, 137.0, 123.9, 119.9, 118.6, 117.7,
117.4, 24.2;
IR νmax (KBr) 3305, 3105, 2981, 2889, 1721, 1664, 1624, 1577, 1497, 1489, 1442, 1376, 1348,
1270, 1259, 1251, 1192, 1168, 1135, 1099 cm−1;
MS (EI, 70 eV) m/z 203 (M+•, 57%), 161 (100), 133 (63);
HRMS (ESI, +ve) Found: (M+Na)+ 226.0480, C11H9N23NaO3 requires 226.0475; (M+H)+
204.0662, C11H10NO3 requires 204.0655;
Mp = 217 °C. (lit.208 mp = 223–224 °C).
The spectral data cited above match those reported in the literature.208
Chapter Five
173
6-Chloro-2H-chromen-2-one (2.88)
Compound 2.88196 (33 mg, 66%) (Rf = 0.6 in chloroform) was prepared from aryl propiolate
2.44 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 9.6 Hz, 1H), 7.50–7.43 (complex m, 2H), 7.25 (d,
J = 9.5 Hz, 1H), 6.45 (d, J = 9.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 159.9, 152.5, 142.2, 131.7, 129.7, 127.1, 119.8, 118.3, 117.9;
IR νmax (KBr) 1757, 1724, 1678, 1605, 1561, 1479, 1428, 1373, 1259, 1223, 1187, 1118, 1076
cm−1;
MS (EI, 70 eV) m/z 182 and 180 (M+•, 30 and 89%), 154 and 152 (36 and 100);
HRMS (ESI, +ve) Found: (M+H)+ 183.0021, C9H637ClO2 requires 183.0021. (M+H)+ 181.0051,
C9H635ClO2 requires 181.0051;
Mp = 146–147 °C (lit.196 mp = 148–150 °C).
The spectral data cited above match those reported in the literature.196
Experimental procedures
174
6-Iodo-2H-chromen-2-one (2.89)
Compound 2.89209 (77 mg, 77%) (Rf = 0.4 in chloroform) was prepared from aryl propiolate
2.46 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (800 MHz, CDCl3) δ 7.82 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.8 and 2.4 Hz, 1H), 7.61
(d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H);
13C NMR (200 MHz, CDCl3) δ 159.9, 153.7, 141.9, 140.4, 136.3, 120.9, 118.9, 117.7, 87.2;
IR νmax (KBr) 2923, 1726, 1594, 1555, 1472, 1419, 1364, 1259, 1216, 1180, 1107 cm−1;
MS (ESI, +ve) m/z 273 [ (M+H)+, 100%];e
HRMS (ESI, +ve) Found: [M+H]+ 272.9415, C9H6127IO2 requires 272.9413;
Mp = 164–165 °C. (lit.209 mp = 165 °C).
The spectral data cited above match those reported in the literature.209
e Impurity at m/z 393
Chapter Five
175
Methyl 2-oxo-2H-chromene-6-carboxylate (2.90)
Compound 2.90210 (9 mg, 18%) (Rf = 0.5 in 1:99 v/v chloroform/acetone) was prepared from
aryl propiolate 2.48 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.22–8.17 (complex m, 2H), 7.75 (d, J = 9.6 Hz, 1H), 7.37 (d,
J = 8.4 Hz, 1H), 6.48 (d, J = 9.6 Hz, 1H), 3.95 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 165.8, 160.0, 157.1, 143.2, 132.9, 130.1, 126.8, 118.7, 117.7,
117.3, 52.6;
IR νmax (KBr) 1747, 1717, 1628, 1605, 1445, 1428, 1379, 1284, 1265, 1217, 1179, 1129, 1094
cm−1;
MS (EI, 70 eV) m/z 204 (M+•, 100%), 173 (99), 145 (60);
HRMS (ESI, +ve) Found: (M+H)+ 205.0495, C11H9O4 requires 205.0495;
Mp = 174–175 °C (lit.210 mp = 175–176 °C).
The spectral data cited above match those reported in the literature.210
Experimental procedures
176
6,8-Dimethyl-2H-chromen-2-one (2.91)
Compound 2.91188 (20 mg, quantitative) (Rf = 0.5 in 1:4 v/v ethyl acetate/hexane) was prepared
from aryl propiolate 2.50 using General Procedure E and isolated as a colourless, crystalline
solid.
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 9.5 Hz, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.38 (d, J =
9.5 Hz, 1H), 2.42 (s, 3H), 2.36 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.4, 150.7, 143.9, 134.4, 133.7, 126.1, 125.5, 118.5, 116.4,
20.8, 15.4;
IR νmax (KBr) 1720, 1608, 1586, 1429, 1381, 1254, 1161, 1116, 1057 cm−1;
MS (EI, 70 eV) m/z 174 (M+•, 100%), 146 (56), 131 (56);
HRMS (ESI, +ve) Found: (M+Na)+ 197.0573, C11H1023NaO2 requires 197.0573. (M+H)+
175.0754, C11H11O2 requires 175.0754;
Mp = 67–68 °C (lit.188 mp = 71–73 °C).
The spectral data cited above match those reported in the literature.188
Chapter Five
177
8-iso-Propyl-5-methyl-2H-chromen-2-one (2.92)
Compound 2.92 (73 mg, 91%) (Rf = 0.6 in chloroform) was prepared from aryl propiolate 2.51
using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 9.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.06 (d, J =
7.8 Hz, 1H), 6.42 (d, J = 9.8 Hz, 1H), 3.60 (sept, J = 6.9 Hz, 1H), 2.49 (s, 3H), 1.29 (d, J = 6.9
Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 161.1, 152.0, 141.0, 134.7, 133.4, 128.8, 125.7, 117.6, 115.7,
26.4, 22.9, 18.2;
IR νmax (KBr) 2965, 2930, 2872, 1731, 1594, 1485, 1458, 1384, 1239, 1185, 1159, 1124, 1052
cm−1;
MS (EI, 70 eV) m/z 202 (M+•, 90%), 187 (100);
HRMS (ESI, +ve) Found: (M+H)+ 203.1061, C13H15O2 requires 203.1067;
Mp = 56–57 °C.
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.2.
Experimental procedures
178
6H-[1,3]Dioxolo[4,5-g]chromen-6-one (2.93) (Ayapin)
Compound 2.93201 (20 mg, quantitative) (Rf = 0.3 in chloroform) was prepared from aryl
propiolate 2.52 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 9.5 Hz, 1H), 6.83 (s, 2H), 6.28 (d, J = 9.5 Hz, 1H),
6.07 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 161.4, 151.5, 145.1, 143.7, 113.6, 112.9, 105.2, 102.6, 98.6;
IR νmax (KBr) 1705, 1684, 1633, 1581, 1494, 1455, 1419, 1385, 1273, 1258, 1225, 1045, 941
cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 100%);
HRMS (EI, 70 eV) Found: M+• 190.0264, C10H6O4 requires 190.0266;
Mp = 229–230 °C (lit.201 mp = 231–232 °C).
The spectral data cited above match those reported in the literature.201
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.2.
Chapter Five
179
6,7-Dimethoxy-2H-chromen-2-one (2.94) (Scoparone)
Compound 2.94211 (45 mg, 92%) (Rf = 0.3 in 1:1 v/v of ethyl acetate/hexane) was prepared
from aryl propiolate 2.53 using General Procedure E and isolated as a colourless, crystalline
solid.
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 9.5 Hz, 1H), 6.83 (s, 1H), 6.78 (s, 1H), 6.23 (d, J =
9.5 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.4, 152.9, 150.0, 146.4, 143.4, 113.5, 111.5, 108.0, 100.0,
56.4, 56.4;
IR νmax (KBr) 1713, 1614, 1558, 1514, 1463, 1450, 1423, 1383, 1277, 1248, 1205, 1170, 1139,
1095, 1004 cm−1;
MS (EI, 70 eV) m/z 206 (M+•, 100%);
HRMS (EI, 70 eV) Found: M+• 206.0579, C11H10O4 requires 206.0579;
Mp = 144–145 °C (lit.211 mp = 145–146 °C).
The spectral data cited above match those reported in the literature.211
Experimental procedures
180
9-Methoxy-3H-benzo[f]chromen-3-one (2.95)
Compound 2.95211 (20 mg, quantitative) (Rf = 0.2 in chloroform) was prepared from aryl
propiolate 2.54 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 9.8 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.81 (d, J =
8.9 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 8.9 and 2.4 Hz,
1H), 6.55 (d, J = 9.8 Hz, 1H), 4.00 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.3, 160.0, 154.8, 139.4, 133.1, 131.0, 130.8, 125.7, 117.9,
115.2, 114.7, 112.5, 101.5, 55.7;
IR νmax (KBr) 2995, 1729, 1708, 1632, 1614, 1593, 1571, 1514, 1471, 1461, 1434, 1396, 1377,
1327, 1286, 1248, 1228, 1209, 1173, 1137, 1115, 1031, 1017, 911 cm−1;
MS (EI, 70 eV) m/z 226 (M+•, 100%), 195 (20);
HRMS (EI, 70 eV) Found: M+• 226.0630, C14H10O3 requires 226.0630;
Mp = 141–143 °C (lit.211 mp = 143–144 °C).
The spectral data cited above match those reported in the literature.211
This compound was subjected to a single-crystal X-ray analysis. Details are presented in
Appendix 1.2.
Chapter Five
181
2H-Benzo[h]chromen-2-one (2.96)
Compound 2.96207 (20 mg, quantitative) (Rf = 0.2 in 1:4 v/v ethyl acetate/hexane) was prepared
from aryl propiolate 2.55 using General Procedure E and isolated as a colourless, crystalline
solid.
1H NMR (400 MHz, CDCl3) δ 8.55–8.49 (complex m, 1H), 7.87–7.83 (complex m, 1H), 7.80
(dd, J = 9.5 and 0.9 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.63 (ddd, J = 6.8, 3.5 and 0.9 Hz, 1H),
7.62 (d, J = 3.5 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 9.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 161.0, 151.5, 144.3, 135.0, 128.8, 127.9, 127.3, 124.5, 123.7,
123.2, 122.4, 116.1, 114.4;
IR νmax (KBr) 2361, 2342, 1716, 1637, 1605, 1564, 1504, 1472, 1381, 1345, 1279, 1119, 1033,
1009 cm−1;
MS (EI, 70 eV) m/z 196 (M+•, 87%), 168 (100), 139 (67);
HRMS (ESI, +ve) Found: (M+Na)+ 219.0421, C13H823NaO2 requires 219.0417. (M+H)+
197.0601, C13H9O2 requires 197.0597;
Mp = 140–141 °C (lit.207 mp = 141–142 °C).
The spectral data cited above match those reported in the literature.207
Experimental procedures
182
3H-Benzo[f]chromen-3-one (2.97)
Compound 2.97196 (20 mg, quantitative) (Rf = 0.2 in 1:4 v/v ethyl acetate/hexane) was prepared
from aryl propiolate 2.56 using General Procedure E and isolated as a colourless, crystalline
solid.
1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 9.8 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.99 (d, J =
9.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.70 (ddd, J = 8.5, 7.0 and 1.3 Hz, 1H), 7.58 (ddd, J =
8.5, 7.0 and 1.3 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 6.58 (d, J = 9.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 161.0, 154.1, 139.2, 133.3, 130.5, 129.2(3), 129.1(8), 128.4,
126.2, 121.5, 117.3, 115.9, 113.2;
IR νmax (KBr) 3710, 3681, 2973, 2923, 2866, 2844, 2827, 1719, 1566, 1516, 1337, 1176, 1112,
1055, 1033, 1013 cm−1;
MS (ESI, +ve) m/z 196 (M+, 84%), 168 (100), 139 (63);
HRMS (ESI, +ve) Found: (M+Na)+ 219.0419, C13H823NaO2 requires 219.0417. (M+H)+
197.0603, C13H9O2 requires 197.0597;
Mp = 116–117 °C (lit.196 mp = 110–111 °C).
The spectral data cited above match those reported in the literature.196
Chapter Five
183
6-Methoxy-4-methyl-2H-chromen-2-one (2.98)
Compound 2.98212 (16 mg, 80%) (Rf = 0.3 in 1:3:6 v/v/v ethyl acetate /dichloromethane/hexane)
was prepared from aryl propiolate 2.57 using General Procedure E and isolated as a colourless,
crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 9.0 Hz, 1H), 7.10 (dd, J = 9.0 and 2.9 Hz, 1H), 7.01
(d, J = 2.9 Hz, 1H), 6.29 (d, J = 1.4 Hz, 1H), 3.86 (s, 3H), 2.41 (d, J = 1.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 161.0, 156.1, 152.0, 148.1, 120.6, 118.8, 118.1, 115.7, 107.9,
56.0, 18.8;
IR νmax (KBr) 2923, 2866, 1709, 1576, 1494, 1467, 1425, 1384, 1366, 1280, 1262, 1247, 1169,
1055, 1033, 1010 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 100%);
HRMS (ESI, +ve) Found: (M+H)+ 191.0704, C11H11O3 requires 191.0703;
Mp = 164–165 °C (lit.212 mp = 164–166 °C).
The spectral data cited above match those reported in the literature.212
Experimental procedures
184
6-Methoxy-4-phenyl-2H-chromen-2-one (2.99)
Compound 2.99213 (15 mg, 75%) (Rf = 0.5 in 1:4 v/v ethyl acetate/hexane) was prepared from
aryl propiolate 2.58 using General Procedure E and isolated as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.56–7.50 (complex m, 3H), 7.49–7.43 (complex m, 2H), 7.34
(d, J = 9.0 Hz, 1H), 7.13 (dd, J = 9.0 and 3.0 Hz, 1H), 6.93 (d, J = 3.0 Hz, 1H), 6.38 (s, 1H),
3.74 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.1, 156.1, 155.5, 148.8, 135.5, 129.8, 129.1, 128.5, 119.6,
119.1, 118.4, 115.8, 110.2, 55.9;
IR νmax (KBr) 2921, 2845, 1713, 1562, 1483, 1447, 1425, 1361, 1270, 1240, 1179, 1054, 1033,
951 cm−1;
MS (EI, 70 eV) m/z 252 (M+•, 100%), 224 (49), 181 (18);
HRMS (ESI, +ve) Found: (M+Na)+ 275.0682, C16H1223NaO3 requires 275.0679; (M+H)+
253.0857, C16H13O3 requires 253.0859;
Mp = 149–150 °C (lit.213 mp = 148–149 °C).
The spectral data cited above match those reported in the literature.213
Chapter Five
185
Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-oxo-2H-chromen-6-yl)propanoate (2.100)
Compound 2.100 (34 mg, 68%) (Rf = 0.4 in 1:1 v/v ethyl acetate/hexane) was prepared from
aryl propiolate 2.60 using General Procedure E and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 9.6 Hz, 1H), 7.25–7.16 (complex m, 3H), 6.34 (d,
J = 9.6 Hz, 1H), 4.98 (d, J = 6.0 Hz, 1H), 4.52 (d, J = 6.7 Hz, 1H), 3.66 (s, 3H), 3.13 (dd, J =
14.0 and 6.0 Hz, 1H), 2.99 (dd, J = 14.0 and 6.7 Hz, 1H), 1.33 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 172.2, 171.3, 160.8, 155.2, 153.3, 143.3, 133.0, 132.9, 128.5,
119.0, 117.2, 80.4, 54.6, 52.6, 38.0, 28.5;
IR νmax (KBr) 2980, 1725, 1626, 1574, 1508, 1438, 1391, 1367, 1280, 1249, 1217, 1166, 1101,
1058, 1021 cm−1;
MS (ESI, +ve) m/z 348 [(M+H)+, 97%], 333 (65), 292 (100), 282 (76)f;
HRMS (ESI, +ve) Found: (M+Na)+ 370.1278, C18H21N23NaO6 requires 370.1261. (M+H)+
348.1453, C18H22NO6 requires 348.1442.
f Impurity at m/z 151
Experimental procedures
186
Pyrano[2,3-b]carbazol-2(10H)-one (2.101)
Compound 2.101 (120 mg, 60%) (Rf = 0.3 in 1:2 v/v ethyl acetate/hexane) was prepared from
aryl propiolate 2.61 using General Procedure E and isolated as a yellow, crystalline powder.
1H NMR [400 MHz, (CD3)2CO] δ 10.72 (s, 1H), 8.38 (s, 1H), 8.16 (dd, J = 8.0 and 1.0 Hz,
1H), 8.10 (d, J = 9.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (ddd, J = 8.0, 7.1 and 1.0 Hz, 1H),
7.39 (s, 1H), 7.26 (ddd, J = 8.0, 7.1 and 1.0 Hz, 1H), 6.26 (d, J = 9.5 Hz, 1H);
13C NMR [100 MHz, (CD3)2CO] δ 161.4, 154.3, 145.8, 143.4, 142.14, 127.3, 123.5, 121.9,
121.2, 120.9, 120.8, 113.2, 112.9, 112.1, 98.3;
IR νmax (KBr) 3310, 2917, 1716, 1637, 1615, 1458, 1441, 1347, 1227, 1173, 1116 cm−1;
MS (EI, 70 eV) m/z 235 (M+•, 20%), 207 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 258.0536, C15H9N23NaO2 requires 258.0525. (M+H)+
236.0709, C15H10NO2 requires 236.0706;
Mp = 235–236 °C.
Chapter Five
187
Pyrano[3,2-a]carbazol-3(11H)-one (2.102)
Compound 2.102 (10 mg, 5%) (Rf = 0.3 in 1:2 v/v ethyl acetate/hexane) was prepared from aryl
propiolate 2.61 using General Procedure E and isolated as a yellow, crystalline powder.
1H NMR [400 MHz, (CD3)2CO] δ 11.12 (s, 1H), 8.50 (d, J = 9.6 Hz, 1H), 8.30 (d, J = 8.4 Hz,
1H), 8.14 (d, J = 7.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.43 (ddd, J = 8.4, 7.4 and 1.1 Hz, 1H),
7.26 (ddd, J = 8.4, 7.4 and 1.1 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 9.6 Hz, 1H);
13C NMR [100 MHz, (CD3)2CO] δ 161.1, 154.6, 141.3, 139.8, 137.3, 126.6, 124.9, 123.9, 121.1,
120.9, 120.3, 115.6, 112.3, 109.1, 105.3;
IR νmax (KBr) 3361, 2923, 1706, 1637, 1610, 1460, 1326, 1239, 1142 cm−1;
MS (EI, 70 eV) m/z 235 (M+•, 35%), 207 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 258.0533, C15H9N23NaO2 requires 258.0525; (M+H)+
236.0708, C15H10NO2 requires 236.0706;
Mp = 261–262 °C
Experimental procedures
188
3-Iodo-6-methoxy-2H-chromen-2-one (2.104)
Compound 2.104 (123 mg, 36%) (Rf = 0.4 in 1:4 v/v diethyl ether/dichloromethane) was
prepared from aryl propiolate 2.19 using General Procedure E except that NIS (1.1 eq) was
added to the reaction mixture before the gold catalyst. This product was isolated as a colourless,
crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.26 (d, J = 9.1 Hz, 1H), 7.14 (dd, J = 9.1 and 2.9
Hz, 1H), 6.85 (d, J = 2.9 Hz, 1H), 3.84 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 157.9, 156.4, 152.1, 148.6, 120.6, 120.2, 118.0, 108.9, 87.2,
56.0;
IR νmax (KBr) 1719, 1557, 1491, 1466, 1420, 1337, 1257, 1180, 1140, 1121, 1097, 1024 cm−1;
MS (EI, 70 eV) m/z 302 (M+•, 100%), 175 (30), 119 (35);
HRMS (EI, 70 eV) Found: M+• 301.9443, C10H7127IO3 requires 301.9440;
Mp = 186–188 °C.
Chapter Five
189
General Procedure F – Formation of propargyl ether derivatives
A magnetically stirred solution of the relevant methoxyphenol (500 mg, 4.0 mmol, 1 equiv.) in
acetone (20 mL) was treated with 3-chloro-3-methylbut-1-yne (1.14 g, 8.1 mmol, 2 equiv.),
potassium carbonate (3.06 g, 22.2 mmol, 5.5 equiv.) and potassium iodide (5.01 g, 30.2 mmol,
7.5 equiv.). The resulting mixture was stirred at 60 °C for 16 h then cooled and filtered.
Hydrochloric acid (20 mL of 2.0 M aqueous solution) was then added to the filtrate to quench
the reaction. The aqueous phase was extracted with diethyl ether (3 x 40 mL) and then the
combined organic phases were washed with brine (1 x 50 mL) before being dried (MgSO4),
filtered and concentrated under reduced pressure to give a yellow oil. This residue was
subjected to flash chromatography (silica gel, 1:4 v/v diethyl ether/hexane elution) and
concentration of the relevant fractions then gave the title propargyl ether.
Experimental procedures
190
1-Methoxy-2-((2-methylbut-3-yn-2-yl)oxy)benzene (2.108)
Compound 2.108214 (542 mg, 71%) (Rf = 0.6 in 1:4 v/v diethyl ether/hexane) was prepared from
o-methoxyphenol (2.105) using General Procedure F and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.0 and 1.7 Hz, 1H), 7.05 (ddd, J = 8.0, 7.3 and
1.7 Hz, 1H), 6.90 (complex m, 2H), 3.82 (s, 3H), 2.51 (s, 1H), 1.67 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 153.2, 144.9, 124.2, 123.5, 120.5, 112.4, 86.6, 74.1, 73.6, 55.9,
29.5;
IR νmax (KBr) 1593, 1499, 1463, 1456, 1439, 1381, 1363, 1298, 1255, 1215, 1179, 1139, 1114,
1046, 1029 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 40%), 175 (100), 160 (45);
HRMS (ESI, +ve) Found: (M+Na)+ 213.0885, C12H1423NaO2 requires 213.0886; (M+H)+
191.1067, C12H15O2 requires 191.1067.
The 1H NMR, IR spectroscopic and the mass spectrometric data cited above match those
reported in the literature.214
Chapter Five
191
1-Methoxy-3-((2-methylbut-3-yn-2-yl)oxy)benzene (2.109)
Compound 2.109215 (470 mg, 61%) (Rf = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared from
m-methoxyphenol (2.106) using General Procedure F and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 8.2 Hz, 1H), 6.86–6.76 (complex m, 2H), 6.61 (ddd,
J = 8.2, 2.4 and 0.9 Hz, 1H), 3.79 (s, 3H), 2.57 (s, 1H), 1.65 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 160.3, 156.8, 129.2, 113.5, 108.5, 107.3, 86.2, 73.8, 72.3, 55.2,
29.6;
IR νmax (KBr) 1601, 1591, 1487, 1466, 1452, 1382, 1364, 1313, 1282, 1264, 1225, 1196, 1134,
1077, 1043 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 24%), 175 (100);
HRMS (ESI, +ve) Found: (M+H)+ 191.1069, C12H15O2 requires 191.1067.
The 1H NMR spectral data cited above match those reported in the literature.215
Experimental procedures
192
1-Methoxy-4-((2-methylbut-3-yn-2-yl)oxy)benzene (2.110)
Compound 2.110215 (410 mg, 54%) (Rf = 0.8 in 1:4 v/v diethyl ether/hexane) was prepared from
p-methoxyphenol (2.107) using General Procedure F and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H),
2.52 (s, 1H), 1.60 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 156.0, 149.1, 123.8, 114.0, 86.6, 73.7, 73.1, 55.7, 29.7;
IR νmax (KBr) 1505, 1465, 1442, 1381, 1363, 1294, 1232, 1214, 1182, 1138, 1101, 1036 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 24%), 175 (100);
HRMS (ESI, +ve) Found: (M+H)+ 191.1069, C12H15O2 requires 191.1067.
The 1H NMR spectral data cited above match those reported in the literature.215
Chapter Five
193
8-Methoxy-2,2-dimethyl-2H-chromene (2.111)
Compound 2.111216 (84 mg, 84%) (Rf = 0.6 in 1:3 v/v ethyl acetate/hexane) was prepared from
propargyl ether 2.108 using General Procedure E and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 6.80–6.75 (complex m, 2H), 6.66–6.61 (complex m, 1H), 6.31
(d, J = 9.8 Hz, 1H), 5.61 (d, J = 9.8 Hz, 1H), 3.86 (s, 3H), 1.48 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 148.5, 142.2, 131.0, 122.5, 122.2, 120.4, 119.0, 112.7, 76.5,
56.5, 28.0;
IR νmax (KBr) 1575, 1480, 1459, 1393, 1377, 1361, 1269, 1208, 1165, 1131, 1082 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 41%), 175 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 213.0889, C12H1523NaO2 requires 213.0886; (M+H)+
191.1069, C12H15O2 requires 191.1067;
The spectral data cited above match those reported in the literature.216
Experimental procedures
194
7-Methoxy-2,2-dimethyl-2H-chromene (2.112)
Compound 2.112217 (99 mg, 66%) (Rf = 0.6 in 1:1 v/v toluene/hexane) was prepared from
propargyl ether 2.109 using General Procedure E and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 6.88 (d, J = 8.2 Hz, 1H), 6.40 (dd, J = 8.2 and 2.5 Hz, 1H), 6.38
(d, J = 2.5 Hz, 1H), 6.27 (d, J = 9.7 Hz, 1H), 5.47 (d, J = 9.7 Hz, 1H), 3.77 (s, 3H), 1.43 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 160.8, 154.3, 128.0, 127.1, 122.1, 114.8, 106.8, 102.2, 76.5,
55.4, 28.2;
IR νmax (KBr) 1616, 1569, 1504, 1464, 1444, 1390, 1375, 1361, 1316, 1279, 1266, 1240, 1196,
1159, 1130, 1120, 1034 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 36%), 175 (100);
HRMS (ESI, +ve) Found: (M+H)+ 191.1069, C12H15O2 requires 191.1067.
This compound was co-produced with 2.113 and separated from it by flash chromatography
The spectral data cited above match those reported in the literature.217
Chapter Five
195
5-Methoxy-2,2-dimethyl-2H-chromene (2.113)
Compound 2.113218 (38 mg, 25%) (Rf = 0.7 in 1:1 v/v toluene/hexane) was prepared from
propargyl ether (2.109) using General Procedure E and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.05 (t, J = 8.2 Hz, 1H), 6.68 (dd, J = 10.0 and 0.8 Hz, 1H), 6.45
(d, J = 8.2 Hz, 1H), 6.41 (dd, J = 8.2 and 0.8 Hz, 1H), 5.56 (d, J = 10.0 Hz, 1H), 3.82 (s, 3H),
1.43 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 155.4, 153.9, 129.0, 117.0, 110.8, 109.7, 103.1, 75.8, 55.8, 27.9;
IR νmax (KBr) 1635, 1602, 1579, 1483, 1466, 1439, 1391, 1376, 1361, 1314, 1283, 1254, 1245,
1214, 1198, 1163, 1117, 1093 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 41%), 175 (100);
HRMS (ESI, +ve) Found: (M+H)+ 191.1069, C12H15O2 requires 191.1067.
The spectral data cited above match those reported in the literature.218
Experimental procedures
196
6-Methoxy-2,2-dimethyl-2H-chromene (2.114)
Compound 2.114219 (99 mg, 99%) (Rf = 0.6 in 1:1 v/v chloroform/hexane) was prepared from
propargyl ether (2.110) using General Procedure E and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 6.71 (d, J = 8.7 Hz, 1H), 6.66 (dd, J = 8.7 and 2.8 Hz, 1H), 6.55
(d, J = 2.8 Hz, 1H), 6.28 (d, J = 9.8 Hz, 1H), 5.63 (d, J = 9.8 Hz, 1H), 3.75 (s, 3H), 1.41 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 153.9, 146.9, 131.9, 122.5, 122.1, 116.9, 114.4, 111.7, 75.9,
55.9, 27.8;
IR νmax (KBr) 2980, 1611, 1577, 1492, 1465, 1432, 1383, 1370, 1361, 1310, 1266, 1258, 1208,
1167, 1120, 1108, 1040 cm−1;
MS (EI, 70 eV) m/z 190 (M+•, 52%), 175 (100);
HRMS (ESI, +ve) Found: (M+H)+ 191.1071, C12H15O2 requires 191.1067.
The spectral data cited above match those reported in the literature.219
Chapter Five
197
N-(2-Methoxyphenyl)propiolamide (2.129)
Compound 2.129 (705 mg, 99%) (Rf = 0.3 in 1:2 v/v ethyl acetate/hexane) was prepared from
o-methoxyaniline (2.126) using General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 8.1 and 1.6 Hz, 1H), 8.13 (s, 1H), 7.10 (td, J = 7.8
and 1.6 Hz, 1H), 6.98 (td, J = 7.8 and 1.3 Hz, 1H), 6.91 (dd, J = 8.1 and 1.3 Hz, 1H), 3.92 (s,
3H), 2.94 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 149.4, 147.8, 127.0, 124.9, 121.2, 120.5, 110.2, 78.0, 73.7, 55.9;
IR νmax (KBr) 3401, 3278, 2981, 2840, 2106, 1663, 1599, 1523, 1483, 1461, 1435 1331 1291,
1254, 1221, 1205, 1177, 1163, 1117, 1048, 1026 cm−1;
MS (EI, 70 eV) m/z 175 (M+•, 100%);
HRMS (ESI, +ve) Found: (M+H)+ 176.0714, C10H10NO2 requires 176.0706;
Mp = 66 °C.
Experimental procedures
198
N-(3-Methoxyphenyl)propiolamide (2.130)
Compound 2.130 (702 mg, 99%) (Rf = 0.4 in 1:2 v/v ethyl acetate/hexane) was prepared from
m-methoxyaniline (2.127) using General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H),
7.00 (d, J = 8.3 Hz, 1H), 6.70 (dd, J = 8.3 and 2.0 Hz, 1H), 3.79 (s, 3H), 2.91 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 160.3, 149.8, 138.3, 130.0, 112.3, 111.2, 106.1, 77.8, 74.2, 55.5;
IR νmax (KBr) 3276, 2981, 2838, 2110, 1655, 1610, 1596, 1548, 1494, 1456, 1430, 1316, 1294,
1283, 1248, 1155, 1050 cm−1;
MS (EI, 70 eV) m/z 175 (M+•, 83%), 132 (100);
HRMS (ESI, +ve) Found: (M+H)+ 176.0715, C10H10NO2 requires 176.0706;
Mp = 82 °C.
Chapter Five
199
N-(4-Methoxyphenyl)propiolamide (2.131)
Compound 2.131 (687 mg, 97%) (Rf = 0.5 in 1:2 v/v ethyl acetate/hexane) was prepared from
p-methoxyaniline (2.128) using General Procedure C and isolated as a clear, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.42 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H),
3.79 (s, 3H), 2.89 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 157.2, 149.8, 130.2, 122.0, 114.4, 77.9, 74.1, 55.6;
IR νmax (KBr) 3276, 2981, 2935, 2107, 1651, 1604, 1542, 1510, 1465, 1443, 1414, 1316, 1303,
1242, 1176, 1033 cm−1;
MS (EI, 70 eV) m/z 175 (M+•, 46%), 149 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 198.0527, C10H10N23NaO2 requires 198.0525. (M+H)+
176.0711, C10H10NO2 requires 176.0706;
Mp = 96–97 °C.
Experimental procedures
200
4-Methoxyphenyl (E)-3-(4-methoxyphenoxy)acrylate (BP1)
Compound BP1 was observed during the course of the optimisation studies being undertaken
during the synthesis of 4-methoxyphenyl propiolate (Rf = 0.6 in 1:4 v/v diethyl ether/pentane).
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 12.2 Hz, 1H), 7.01(complex m, 4H), 6.88 (complex
m, 4H), 5.60 (d, J = 12.2 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 166.4, 162.0, 157.3, 149.6, 144.4, 122.7, 119.8, 115.2, 114.6,
100.6, 55.9, 55.8;
IR νmax (KBr) 1725, 1646, 1502, 1223, 1178, 1095 cm−1;
MS (EI, 70 eV) m/z 300 (M+•, 10%), 177 (100);
Chapter Five
201
(Z)-(Z)-N,N'-Dicyclohexylcarbamimidic propiolic anhydride (BP2)
Compound BP2 was observed during the course of the optimisation studies being undertaken
during the synthesis of 4-methoxyphenyl propiolate (Rf = 0.5 in 1:4 v/v diethyl ether/pentane).
1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 4.38 (tt, J = 12.0 and 3.9 Hz, 1H), 3.68 (m, 1H),
3.34 (s, 1H), 2.30 (q, J = 12.0 Hz, 2H), 1.99–1.89 (complex m, 2H), 1.89-1.74 (complex m,
4H), 1.74–1.56 (complex m, 4H), 1.47–1.05 (complex m, 8H);
13C NMR (100 MHz, CDCl3) δ 155.3, 152.4, 81.8, 76.1, 60.4, 49.5, 32.7, 30.6, 26.6, 25.6, 25.1,
24.6;
IR νmax (KBr) 3304, 2990, 2934, 2105, 1694, 1632, 1529, 1453, 1394, 1347, 1304, 1258, 1235,
1077, 1066, 1058 cm−1;
MS (EI, 70 eV) m/z 276 (M+•, 90%), 195 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 299.1743, C16H24N223NaO2 requires 299.1730. (M+H)+
277.1914, C16H25N2O2 requires 277.1911;
Mp = 186–188 °C.
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 1.3.
Experimental procedures
202
(Z)-3-Cyclohexyl-2-(cyclohexylimino)-4-methyleneoxazolidin-5-one (BP3)
Compound BP3 was observed during the course of the optimisation studies being undertaken
during the synthesis of 4-methoxyphenyl propiolate (Rf = 0.6 in 1:4 v/v diethyl ether/pentane).
1H NMR (400 MHz, CDCl3) δ 5.22 (d, J = 2.9 Hz, 1H), 4.95 (d, J = 2.9 Hz, 1H), 4.00 (tt, J =
12.2 and 3.9 Hz, 1H), 3.65 (dq, J = 9.5 and 4.8 Hz, 1H), 2.24 (qd, J = 12.2 and 3.9 Hz, 2H),
1.88–1.57 (complex m, 10H), 1.44–1.12 (complex m, 8H);
13C NMR (100 MHz, CDCl3) δ 161.1, 147.0, 141.7, 91.4, 54.1, 53.0, 34.2, 28.5, 25.8, 25.7,
25.08, 24.5;
IR νmax (KBr) 2930, 2856, 1713, 1669, 1451, 1404, 1388, 1347, 1286, 1075, 1053, 997 cm−1;
MS (ESI, +ve) m/z 277 [(M+H)+, 100%], 195 (70);
HRMS (ESI, +ve) Found: (M+H)+ 277.1918, C16H25N2O2 requires 277.1911;
Mp = 81–82 °C.
This compound was subjected to a single-crystal X-ray analysis. Details are presented in
Appendix 1.3.
Experimental procedures
204
5.2 NATURAL PRODUCT SYNTHESES
2,3-Di-iso-propoxy-4-methoxybenzaldehyde (3.10)
A magnetically stirred solution of benzaldehyde 3.9 (2.61 g, 15.5 mmol, 1.0 equiv.) in N,N-
dimethylformamide (30 mL) maintained under nitrogen was treated with anhydrous potassium
carbonate (6.44 g, 45.6 mmol, 2.9 equiv.) and 2-bromopropane (5.73 mL, 46.6 mmol, 3.0
equiv.). The ensuing mixture was heated at 90 °C for 16 h then cooled and diluted with water
(50 mL) before being extracted with dichloromethane (3 x 100 mL). The combined organic
phases were washed with water (1 x 100 mL) and brine (1 x 100 mL) then dried (MgSO4),
filtered and concentrated under reduced pressure. The resulting light-yellow oil was subjected
to flash chromatography (silica gel, 3:7 v/v ethyl acetate/hexane elution) and concentration of
the appropriate fractions (Rf = 0.4) afforded compound 3.10 (3.05 g, 73%) as a clear, light-
yellow oil.
1H NMR (CDCl3, 400 MHz) δ 10.21 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H),
4.75 (sept, J = 6.2 Hz, 1H), 4.38 (sept, J = 6.2 Hz, 1H), 3.84 (s, 3H), 1.22 (complex m, 12H);
13C NMR (400 MHz, CDCl3) δ 189.4, 159.6, 155.2, 139.6, 124.7, 123.4, 107.0, 75.7, 75.2, 55.9,
22.2;
IR νmax (KBr) 2975, 2930, 2852, 1680, 1586, 1491, 1444, 1381, 1332, 1287, 1259, 1224, 1194,
1168, 1139, 1092, 1001 cm−1;
MS (ESI, +ve) m/z 275 [(M+Na)+, 40%], 253 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 275.1259, C14H2023NaO4 requires 275.1259.
Chapter Five
205
2,3-Di-isopropoxy-4-methoxyphenol (3.11)
A magnetically stirred solution of aldehyde 3.10 (1.06 g, 4.41 mmol, 1.0 equiv.) in
dichloromethane (100 mL) was cooled to 0 °C then treated, sequentially, with potassium
hydrogen carbonate (1.26 g, 12.6 mmol, 2.9 equiv.) and m-chloroperbenzoic acid (4.12 g of ca.
77% peracid, 16.84 mmol, 3.8 equiv.). The ensuing mixture was allowed to warm to 18 °C then
stirred at this temperature for 16 h before being concentrated under reduced pressure. The
residue thus obtained was dissolved in methanol (100 mL) and the resulting solution treated
with ammonium acetate (3.44 g, 44.7 mmol, 10.0 equiv.) then stirred at 18 °C for 16 h. The
material thus obtained was diluted with water (100 mL) then extracted with diethyl ether (2 x
100 mL). The combined organic phases were washed with water (1 x 100 mL) and brine (1 x
100 mL) before being dried (MgSO4), filtered and concentrated under reduced pressure to
afford, after concentration of the relevant fractions (Rf = 0.5), phenol 3.11 (980 mg, 93%) as a
clear, colorless oil.
1H NMR (CDCl3, 400 MHz) δ 6.57 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 5.39 (s, 1H),
4.71 (sept, J = 6.2 Hz, 1H), 4.39 (sept, J = 6.2 Hz, 1H), 3.73 (s, 3H), 1.24 (complex m, 12H);
13C NMR (400 MHz, CDCl3) δ 147.4, 144.3, 140.1, 138.6, 107.9, 107.1, 79.9, 56.1, 22.3;
IR νmax (KBr) 3529, 3457, 2975, 2933, 2835, 1490, 1467, 1382, 1372, 1332, 1268, 1182, 1159,
1108, 1089, 1035 cm−1;
MS (ESI, +ve) m/z 263 [(M+Na)+, 50%], 225 (100), 199 (95);
HRMS (ESI, +ve) Found: (M+Na)+ 263.1256, C13H2023NaO4 requires 263.1259.
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 2.1.
Experimental procedures
206
2,3-Di-isopropoxy-4-methoxyphenyl propiolate (3.12)
A magnetically stirred solution of phenol 3.11 (1.00 g, 4.16 mmol, 1.0 equiv.) in
tetrahydrofuran (20 mL) was treated with sodium hydride (183 mg of ca 60% sodium hydride
suspension, 4.58 mmol, 1.1 equiv.). In a separate flask, a magnetically stirred solution of
propiolic acid (0.96 g, 14.33 mmol, 3.3 equiv.) in tetrahydrofuran (20 mL) was cooled to 0 °C
then treated with DCC (2.83 g, 14.33 mmol, 3.3 equiv.). The phenolate solution prepared from
phenol 3.11 was then added to the DCC/propiolic mixture at 0 °C. The reaction mixture thus
obtained was allowed to warm to 18 °C then stirred at this temperature for 16 h before being
concentrated under reduced pressure. Subjection of the resulting light-yellow oil to flash
chromatography (silica gel, 3:7 v/v mixture of ethyl acetate/hexane elution) afforded, after
concentration of the relevant fractions (Rf = 0.3), the desired product 3.12 (1.11 g, 70%) as a
clear, colorless oil.
1H NMR (CDCl3, 400 MHz) δ 6.75 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.53 (sept, J
= 6.2 Hz, 1H), 7.43 (sept, J = 6.2 Hz, 2H), 3.78 (s, 3H), 3.04 (s, 1H), 1.23 (complex m, 12H);
13C NMR (400 MHz, CDCl3) δ 153.0, 151.1, 144.2, 141.6, 138.0, 116.3, 106.1, 76.7, 76.2, 75.9,
74.5, 56.1, 22.6;
IR νmax (KBr) 3249, 2976, 2933, 2122, 1736, 1644, 1589, 1484, 1458, 1442, 1382, 1373, 1340,
1310, 1269, 1241, 1187, 1141, 1092, 1023 cm−1;
MS (ESI, +ve) m/z 293 [(M+H)+, 100%];
HRMS (ESI, +ve) Found: (M+H)+ 293.1389, C16H20O5 requires 293.1389.
Chapter Five
207
7,8-Di-isopropoxy-6-methoxy-2H-chromen-2-one (3.13)
A magnetically stirred solution of propiolate 3.12 (850 mg, 29.08 mmol, 1 equiv.) in
dichloromethane (50 mL) was treated with Echavarren’s gold(I) catalyst (224 mg, 2.91 mmol,
0.03 equiv.). The ensuing mixture was stirred at 18 °C for 5 h then filtered through a pad of
TLC-grade silica gel and the filtrate was concentrated under reduced pressure. The resulting
light-yellow oil was subjected to flash chromatography (silica gel, 3:7 v/v ethyl acetate/hexane
elution) and concentration of the relevant fractions (Rf = 0.1) gave coumarin 3.13 (816 mg, 96%)
as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.8 Hz, 1H), 6.64 (s, 1H), 6.31 (d, J = 8.8 Hz, 1H),
4.62 (complex m, 2H), 3.86 (s, 3H), 1.33 (complex m, 12H);
13C NMR (400 MHz, CDCl3) δ 160.6, 150.9, 144.8, 143.8, 143.4, 140.0, 115.0, 114.2, 103.2,
76.6, 76.5, 56.4, 22.8;
IR νmax (KBr) 2968, 2928, 1701, 1604, 1562, 1484, 1453, 1434, 1409, 1381, 1371, 1347, 1290,
1237, 1197, 1161, 1125, 1105, 1082, 1040 cm−1;
MS (ESI, +ve) m/z 293 [(M+H)+, 58%], 251 (100), 209 (98);
HRMS (ESI, +ve) Found: (M+H)+ 293.1391, C16H20O5 requires 293.1389;
Mp = 97–98 °C.
Experimental procedures
208
7,8-Dihydroxy-6-methoxy-2H-chromen-2-one (3.1) (Fraxetin)
A magnetically stirred solution of coumarin 3.13 (98 mg, 0.33 mmol, 1.0 equiv.) in dry
dichloromethane (20 mL) maintained under nitrogen at 18 °C was treated, dropwise, with boron
trichloride (0.33 mL, 0.33 mmol, 1.0 equiv.). The resulting mixture was stirred at 18 °C for 2 h
then treated with additional boron trichloride (660 µL, 0.66 mmol, 2.0 equiv.) and after stirring
the resulting mixture at 18 °C for 16 h it was poured into NaHCO3 (20 mL of a saturated aqueous
solution) and the separated aqueous phase was acidified with HCl (30 mL of a 2.0 M aqueous
solution) before being extracted with diethyl ether (3 x 50 mL). The combined organic phases
were washed with water (1 x 20 mL) and brine (1 x 20 mL) then dried (MgSO4), filtered and
concentrated under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica gel, 3:7 v/v ethyl acetate/hexane elution) to afford, after concentration
of the relevant fractions (Rf = 0.3 in 4:1 v/v ethyl acetate/hexane), fraxetin 3.1220 (53 mg, 76%)
as a light-yellow solid.
1H NMR [400 MHz, (CD3)2CO] δ 7.82 (d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 6.19 (d, J = 8.8 Hz,
1H), 4.85 (s, 2H), 3.89 (s, 3H);
13C NMR [100 MHz, (CD3)2CO] δ 163.7, 147.1, 146.7, 140.7, 140.6, 134.0, 112.3, 112.2, 101.0,
56.8;
IR νmax (KBr) 3353, 1680, 1605, 1580, 1511, 1468, 1416, 1313, 1158, 1120, 1030 cm−1;
MS (ESI, +ve) m/z 209 [(M+H)+, 100%];
HRMS (ESI, +ve) Found: (M+H)+ 209.0451, C10H8O5 requires 209.0450;
Mp = 224–226 °C (lit.220 mp = 228 °C).
The spectral data cited above match those reported in the literature.220
Chapter Five
209
7-Hydroxy-6-methoxy-8-((3-methylbut-2-en-1-yl)oxy)-2H-chromen-2-one (3.14) and 8-
hydroxy-6-methoxy-7-((3-methylbut-2-en-1-yl)oxy)-2H-chromen-2-one (3.2) (Capensin)
A magnetically stirred solution of fraxetin (3.1) (104 mg, 0.50 mmol, 1.0 equiv.) in acetone (5
mL) maintained under nitrogen at 18 °C was treated with triethylamine (139 µL, 1.00 mmol,
2.0 equiv.) and 4-bromo-2-methyl-2-butene (115 µL, 1.00 mmol, 2.0 equiv.). The resulting
mixture was stirred at 18 °C for 24 h then concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography (silica gel, 1:5:4 v/v/v
tetrahydrofuran/diethyl ether/hexane elution) to afford two fractions, A and B.
Concentration of fraction A [Rf = 0.3(1)] gave compound 3.14162 (39 mg, 12%) as a light-yellow
solid.
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 9.5 Hz, 1H), 6.65 (s, 1H), 6.26 (d, J = 9.5 Hz, 1H),
6.20 (s, 1H), 5.54 (t, J = 7.4 Hz, 1H), 4.79 (d, J = 7.4 Hz, 2H), 3.92 (s, 3H), 1.74 (s, 3H), 1.69
(s, 3H);
13C NMR (400 MHz, CDCl3) δ 160.8, 144.8, 144.1, 143.2, 140.8, 133.3, 119.6, 113.5, 111.3,
103.7, 70.5, 56.7, 26.0, 18.3;
IR νmax (KBr) 3369, 2961, 1606, 1574, 1496, 1453, 1416, 1380, 1305, 1250, 1215, 1196, 1155,
1121, 1078 cm−1;
MS (ESI, +ve) m/z 299 [(M+Na)+, 23%], 276 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 299.0890, C15H1623NaO5 requires 299.0895;
Mp = 123–124 °C (lit.167 mp = 126.5 °C).
The spectral data cited above match those reported in the literature.167
Experimental procedures
210
Concentration of fraction B (Rf = 0.3[3]) gave capensin 3.2162 (57 mg, 41%) as a light-yellow
solid.
1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 9.5 Hz, 1H), 6.50 (s, 1H), 6.32 (d, J = 9.5 Hz, 1H),
6.20 (s, 1H), 5.51 (t, J = 7.5 Hz, 1H), 4.69 (d, J = 7.5 Hz, 2H), 3.89 (s, 3H), 1.74 (s, 3H), 1.68
(s, 3H);
13C NMR (400 MHz, CDCl3) δ 160.4, 149.8, 143.6, 140.4, 138.0, 137.9, 137.7, 119.5, 115.2,
114.3, 100.0, 69.9, 56.1, 25.8, 17.9;
IR νmax (KBr) 3306, 1688, 1609, 1567, 1494, 1455, 1412, 1384, 1359, 1321, 1248, 1189, 1157,
1115, 1086 cm−1;
MS (ESI, +ve) m/z 299 [(M+Na)+, 18%], 277 (100);
HRMS (ESI, +ve) Found: (M+H)+ 277.1077, C15H17O5 requires 277.1071;
Mp = 132–133 °C (lit.162 mp = 135 °C).
The spectral data cited above match those reported in the literature.162
Chapter Five
211
2-(2-Hydroxypropan-2-yl)-5-methoxy-2,3-dihydro-9H-[1,4]dioxino[2,3-h]chromen-9-one
(3.3) (Purpurasol)
A solution of compound 3.2 (28 mg, 0.1 mmol, 1.0 equiv.) in ethyl acetate (1 mL) was cooled
to 0 °C then treated with m-chloroperbenzoic acid (20 mg of ca. 90% material, 0.1 mmol, 1.0
equiv.). The ensuing mixture was stirred at 18 °C for 48 h then concentrated under reduced
pressure. The residue thus obtained was dissolved in dichloromethane (10 mL) and the resulting
solution washed with sodium bicarbonate (1 x 10 mL of a saturated aqueous solution) and water
(1 x 10 mL) before being dried (MgSO4), filtered and concentrated under reduced pressure to
give purpurasol 3.3167 (Rf = 0.3 in 1:4 v/v ethyl acetate/hexane) (20 mg, 69%) as a colourless,
crystalline solid.
1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 9.6 Hz, 1H), 6.51 (s, 1H), 6.31 (d, J = 9.6 Hz, 1H),
4.65 (dd, J = 11.3 and 1.9 Hz, 1H), 4.13 (dd, J = 11.3 and 9.1 Hz, 1H), 3.99 (dd, J = 9.1 and 1.9
Hz, 1H), 3.92 (s, 3H), 2.75 (br s, 1H), 1.46 (s, 3H), 1.37 (s, 3H);
13C NMR (400 MHz, CDCl3) δ 160.9, 145.7, 143.8, 139.0, 136.7, 132.4, 114.1, 111.6, 100.1,
79.0, 70.6, 65.5, 56.4, 26.0, 25.1;
IR νmax (KBr) 3442, 2971, 1703, 1573, 1414 cm−1;
MS (EI, 70 eV) m/z 292 (M+•, 35%), 235 (26), 234 (100), 219 (57);
HRMS (EI, 70 eV) Found: M+• 292.0896, C15H16O6 requires 292.0895;
Mp = 148 °C (lit.167 mp = 148 °C).
The spectral data cited above match those reported in the literature.167
Experimental procedures
212
5-Bromovanillin (3.27)
A solution of molecular bromine (7.4 mL, 144.6 mmol, 1.1 equiv.) in acetic acid (40 mL) was
added, dropwise, to a magnetically stirred suspension of vanillin (3.26) (20.0 g, 131.5 mmol,
1.0 equiv.) in acetic acid (120 mL). The ensuing mixture was stirred at 18 °C for 1 h before
being treated with sodium hydrogen sulfate (20 mL of a saturated aqueous solution) then filtered
to afford the desired product 3.27221 (21.8 g, 69%) as a colourless, crystalline solid.
1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H),
6.47 (s, 1H), 3.97 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 189.9, 149.1, 147.9, 130.3, 130.3, 108.4, 108.2, 56.8;
Mp = 176–178 °C (lit.221 mp = 179 °C).
The spectral data cited above match those reported in the literature.221
Chapter Five
213
3-Methoxy-4,5-dihydroxybenzaldehyde (3.28)
A magnetically stirred solution of 5-bromovanillin (3.27) (4.6 g, 19.2 mmol, 1.0 equiv.) and
sodium hydroxide (7.70 g, 192.4 mmol, 10.0 equiv.) in deoxygenated water (200 mL) was
treated with copper powder (61 mg, 1.0 mmol, 0.05 equiv.) and the ensuing mixture heated at
100 °C for 24 h. The cooled reaction mixture was treated with disodium hydrogen phosphate
(273 mg, 1.9 mmol, 0.1 equiv.) and the resulting mixture heated at 100 °C for 1 h then cooled
and filtered. The filtrate was treated with HCl (30 mL of a 1.0 M aqueous solution) then
extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with
EDTA (1 x 100 mL of a saturated aqueous solution) and brine (1 x 100 mL) before being dried
(MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the light-yellow
oil thus obtained was subjected to flash chromatography (silica gel, 2:1 v/v 1:1 v/v ethyl
acetate/hexane gradient elution). Concentration of the relevant fractions (Rf = 0.25 in 1:1 v/v
ethyl acetate/hexane) then gave the desired catechol 3.28222 (3.00 g, 93%) as a light-brown solid.
1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.12 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H),
5.93 (s, 1H), 5.47 (s, 1H), 3.94 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 191.2, 147.5, 144.2, 138.5, 129.3, 113.28, 103.0, 56.7;
IR νmax (KBr) 3345, 1673, 1595, 1514, 1463, 1335, 1205, 1142, 1093, 1003 cm−1;
MS (ESI, +ve) m/z 191 [(M+Na)+, 100%];
HRMS (ESI, +ve) Found: (M+Na)+ 191.0318, C8H823NaO4requires 191.0320;
Mp = 132 °C (lit.222 mp = 132–133 °C).
The spectral data cited above match those reported in the literature.222
Experimental procedures
214
3-Hydroxy-4,5-dimethoxybenzaldehyde (3.29)
A magnetically stirred suspension of catechol 3.28 (2.15 g, 12.8 mmol, 1.0 equiv.), dimethyl
sulfate (1.20 mL, 12.8 mmol, 1.0 equiv.) and sodium carbonate (1.61 g, 14.1 mmol, 1.1 equiv.)
in acetone (50 mL) was heated at 60 °C for 5 h. The cooled reaction mixture was concentrated
under reduced pressure and the residue thus obtained dissolved in ethyl acetate (60 mL) and the
resulting solution extracted with NaOH (1 x 30 mL of a 1.0 M aqueous solution). The separated
aqueous phase acidified with HCl (70 mL of 2.0 M aqueous solution) and extracted with ethyl
acetate (3 x 150 mL). The combined organic layers were then dried (MgSO4), filtered and
concentrated under reduced pressure to give a light-yellow oil. This oil was subjected to flash
chromatography (silica gel, 1:1 v/v mixture of ethyl acetate/hexane elution) to afford, after
concentration of the relevant fractions (Rf = 0.5), the title compound 3.29223 (2.02 g, 87%) as a
clear, light-yellow oil.
1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.09 (d, J = 1.8 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H),
6.02 (s, 1H), 3.97 (s, 3H), 3.90 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 191.4, 152.9, 149.8, 141.0, 132.3, 111.7, 1.4.0, 61.3, 56.3;
IR νmax (KBr) 3400, 2943, 2843, 1688, 1587, 1505, 1464, 1431, 1392, 1339, 1241, 1203, 1133,
1106 cm−1;
MS (ESI, +ve) m/z 205 [(M+Na)+, 100%], 183 (53);
HRMS (ESI, +ve) Found: (M+Na)+ 205.0478, C9H1023NaO4 requires 205.0477.
The spectral data cited above match those reported in the literature.223
Chapter Five
215
2-Bromo-3-hydroxy-4,5-dimethoxybenzaldehyde (3.30)
A magnetically stirred solution of phenol 3.29 (1.83 g, 10.0 mmol, 1.0 equiv.) in dry
tetrahydrofuran (50 mL) maintained under nitrogen was cooled to 0 °C then treated, in portions,
with N-bromosuccinimide (1.82 g, 10.2 mmol 1.02 equiv.). The ensuing mixture was allowed
to warm to 18 °C over 16 h then concentrated under reduced pressure. The light-yellow solid
thus obtained was subjected to flash chromatography (silica gel, 1:1 v/v ethyl acetate/hexane
elution) and concentration of the relevant fractions (Rf = 0.6) gave compound 3.29 (2.21 g, 84%)
as a light-yellow solid.
1H NMR (400 MHz, CDCl3) δ 10.26 (d, J = 3.0 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.31 (s, 1H),
4.00 (d, J = 3.0 Hz, 3H), 3.89 (d, J = 2.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 191.2, 151.7, 147.1, 141.1, 128.8, 106.9, 104.7, 61.5, 56.4;
IR νmax (KBr) 3748, 3369, 1681, 1587, 1486, 1426, 1346, 1330, 1262, 1199, 1146, 1110, 1018
cm−1;
MS (ESI, +ve) m/z 262 and 260 [(M+H)+, 90 and 100%];
HRMS (ESI, +ve) Found: (M+Na)+ 282.9582, C9H979Br23NaO4 requires 282.9582;
Mp = 55–56 °C.
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 2.2.
Experimental procedures
216
3-Hydroxy-4,5-dimethoxy-2-((triisopropylsilyl)ethynyl)benzaldehyde (3.31) and 6,7-
Dimethoxy-2-(triisopropylsilyl)benzofuran-4-carbaldehyde (3.32)
A tube suitable for placement in a microwave reactor was charged with bromide 3.30 (51 mg,
0.20 mmol, 1.0 equiv.), PdCl2(dppf)•CH2Cl2 (8 mg, 0.01 mmol, 0.05 equiv.) and copper iodide
(2 mg, 0.01 mmol, 0.05 equiv.). The tube and its contents were flushed with nitrogen for 0.17
h then dry acetonitrile (0.75 mL) was added and nitrogen bubbled through the resulting solution
for 0.08 h. Triethylamine (0.50 mL) was then added to the reaction mixture which was again
flushed with nitrogen for 0.08 h. Finally, tri-iso-propylsilylacetylene (107 µL, 0.59 mmol, 3.0
equiv.) was added dropwise and nitrogen was bubbled through the resulting solution for 0.02 h.
The dark-red solution thus obtained was immediately subjected to microwave irradiation at
120 °C (100 W, internal pressure of 200 psi) for 1.5 h before being cooled then subjected
directly to flash chromatography (silica gel, 1:4 1:2 v/v ethyl acetate/hexane gradient elution)
to afford two fractions, A and B.
Concentration of fraction A [Rf = 0.5(1) in 1:2 v/v ethyl acetate/hexane] gave the desired alkyne
3.31 (4 mg, 5%) as colourless needles.
1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 7.07 (s, 1H), 6.17 (s, 1H), 3.95 (s, 3H), 3.90 (s,
3H), 1.13 (s, 21H);
13C NMR (100 MHz, CDCl3) δ 190.6, 153.4, 151.5, 140.6, 132.0, 108.7, 103.8, 102.4, 96.9,
61.2, 56.4, 18.9, 11.5;
IR νmax (KBr) 3327, 2943, 2865, 2145, 1682, 1587, 1492, 1464, 1426, 1389, 1358, 1325, 1268,
1242, 1212, 1197, 1131, 1074, 1014 cm−1;
MS (ESI, +ve) m/z 363 [(M+Na)+, 100%];
HRMS (ESI, +ve) Found: (M+Na)+ 363.1988, C20H3023NaO4Si requires 363.1992;
Mp = 98–99 °C.
This compound was subjected to a single-crystal X-ray analysis. Details of this are presented
in Appendix 2.2.
Chapter Five
217
Concentration of fraction B [Rf = 0.5(3) in 1:2 v/v ethyl acetate/hexane] gave benzofuran 3.32
(30 mg, 39%) as a clear, yellow oil.
1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 7.72 (s, 1H), 7.43 (s, 1H), 4.46 (s, 3H), 4.03 (s,
3H), 1.54–1.39 (complex m, 3H), 1.21 (s, 12H), 1.19 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 190.1, 164.3, 148.6, 147.4, 140.1, 125.5, 120.9, 117.1, 113.7,
60.9, 57.7, 18.7, 11.2;
IR νmax (KBr) 2944, 2891, 2866, 2724, 1684, 1603, 1582, 1528, 1495, 1463, 1370, 1306, 1292,
1234, 1195, 1159, 1133, 1103, 1026 cm−1;
MS (ESI, +ve) m/z 363 [(M+Na)+, 100%];
HRMS (ESI, +ve) Found: (M+Na)+ 363.1986, C20H3123NaO4Si requires 363.1992.
Experimental procedures
218
6,7-Dimethoxybenzofuran-4-carbaldehyde (3.33)
A magnetically stirred solution of the crude mixture of compounds 3.31 and 3.32 (460 mg, 1.27
mmol, 1.0 equiv.) obtained from the above-mentioned Sonogashira cross-coupling reaction in
tetrahydrofuran (2 mL) and maintained at 0 °C was treated with TBAF (7.6 mL of a 1.0 M
solution in tetrahydrofuran, 7.6 mmol, 6.0 equiv.). The ensuing mixture was stirred at 0 °C for
1 h and then at 18 °C for a further 3 h before being concentrated under reduced pressure. The
light-yellow oil thus obtained was subjected to flash chromatography (silica gel, 1:4 1:2 v/v
ethyl acetate/hexane gradient elution) and gave, after concentration of the relevant fractions (Rf
= 0.2 in 1:2 v/v ethyl acetate/hexane), aldehyde 3.33 (210 mg, 80%) as a light-yellow powder.
1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H),
7.38 (s, 1H), 4.35 (s, 3H), 3.97 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 189.9, 147.7, 147.4, 145.9, 140.2, 124.5, 121.4, 113.8, 106.1,
61.0, 57.4;
IR νmax (KBr) 3143, 3109, 2958, 2849, 1680, 1588, 1536, 1509, 1461, 1394, 1376, 1347, 1298,
1247, 1212, 1187, 1131, 1078, 1047, 1015 cm−1;
MS (ESI, +ve) m/z 207 [(M+H)+, 20%], 186 (100);
HRMS (ESI, +ve) Found: (M+H)+ 207.0652, C11H10O4 requires 207.0657;
Mp = 77–78 °C.
Chapter Five
219
6,7-Dimethoxybenzofuran-4-ol (3.34)
A magnetically stirred solution of benzaldehyde 3.33 (210 mg, 1.02 mmol, 1.0 equiv.) in
dichloromethane (4 mL) maintained at 0 °C was treated with NaHCO3 (291 mg, 3.46 mmol,
3.46 equiv.) then m-chloroperbenzoic acid (211 mg of ca. 77% peracid, 1.22 mmol, 1.22 equiv.).
The ensuing mixture was stirred at 0 °C for 1 h then concentrated under reduced pressure. The
residue so-formed was dissolved in ammonia-saturated methanol (12 mL) and the resulting
mixture maintained, with magnetic stirring, in a sealed vessel 1 h at 18 °C before being opened
to the atmosphere. After a further 0.18 h the reaction mixture was concentrated under reduced
pressure and the light-yellow residue so produced subjected to flash chromatography (silica gel,
1:2 v/v ethyl acetate/hexane elution) to give, after concentration of the relevant fractions (Rf =
0.2), the title compound 3.34 (135 mg, 68%) as a cream solid.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 2.2 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.39 (s, 1H),
4.88 (br s, 1H), 4.03 (s, 3H), 3.88 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 143.9, 143.7, 129.5, 112.0, 103.5, 96.6, 61.5, 57.5;
IR νmax (KBr) 3290, 2976, 2850, 1640, 1618, 1545, 1520, 1471, 1448, 1429, 1383, 1364, 1290,
1227, 1210, 1192, 1149, 1135, 1080, 1046, 1012 cm−1;
MS (ESI, +ve) m/z 217 [(M+Na)+, 15%], 186 (100);
HRMS (ESI, +ve) Found: (M+Na)+ 217.0477, C10H1023NaO4 requires 217.0477;
Mp = 142–143 °C.
Experimental procedures
220
6,7-Dimethoxybenzofuran-4-yl propiolate (3.35)
A magnetically stirred solution of phenol 3.34 (50 mg, 0.26 mmol, 1.0 equiv.) and 3-
(trimethylsilyl)propiolic acid (38 mg, 0.31 mmol, 1.2 equiv.) in dichloromethane (2 mL) was
treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (59 mg, 0.31
mmol, 1.2 equiv.). The resulting mixture was stirred at 18 °C for 24 h then concentrated under
reduced pressure and the residue so-obtained subjected to flash chromatography (silica gel, 1:3
v/v ethyl acetate/hexane elution) to give two fractions, A and B.
Concentration of fraction A (Rf = 0.2) gave the starting phenol 3.34 (26 mg, 52% recovery) as
a pale-cream solid that was identical, in all respects, with an authentic sample.
Concentration of fraction B (Rf = 0.5) afforded the propiolate ester 3.35 (24 mg, 79% at 48%
conversion) as a light-brown solid.
1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.3 Hz, 1H), 6.75 (s, 1H), 6.62–6.59 (complex m,
1H), 4.11 (s, 3H), 3.88 (s, 3H), 3.11 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 150.8, 148.8, 147.8, 145.0, 136.4, 133.6, 116.5, 104.0, 103.1,
77.4, 74.2, 61.3, 57.5;
IR νmax (ATR) 3249, 2938, 2847, 2123, 1734, 1636, 1544, 1506, 1448, 1399, 1336, 1189, 1146,
1124, 1077, 1043, 1012 cm−1;
MS (ESI, +ve) m/z 269 [(M+Na)+, 100%];
HRMS (ESI, +ve) Found: (M+Na)+ 269.0424, C13H1023NaO5 requires 269.0426;
Mp = 72–73 °C.
Chapter Five
221
5,6-Dimethoxy-2H-furo[2,3-h]chromen-2-one (3.4) (Pimpinellin)
A magnetically stirred solution of ester 3.35 (20 mg, 0.081 mmol, 1 equiv.) in dichloromethane
maintained at 18 °C was treated with Echevarren’s catalyst (3 mg, 0.004 mmol, 0.05 equiv.).
The resulting mixture was stirred at 18 °C for 0.5 h then filtered through a pad of TLC-grade
silica gel. The filtrate was concentrated under reduced pressure and the residue thus obtained
subjected to flash chromatography (silica gel, 1:3 v/v ethyl acetate/hexane elution) to afford
after concentration of the relevant fractions (Rf = 0.5), pimpinellin (3.4)168 (16 mg, 72%) as a
colourless powder.
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 9.7 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.07 (d, J =
2.2 Hz, 1H), 6.35 (d, J = 9.7 Hz, 1H), 4.13 (s, 3H), 4.02 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.1, 150.0, 145.6, 144.7, 143.4, 140.1, 135.4, 114.4, 114.0,
109.7, 104.6, 62.6, 61.5;
IR νmax (ATR) 2986, 2948, 1737, 1626, 1579, 1482, 1451, 1419, 1388, 1340, 1323, 1156, 1125,
1114, 1092, 1063, 1035, 1013 cm−1;
MS (EI, 70 eV) m/z 246 (M+•, 100%), 231 (81);
HRMS (EI, 70 eV) Found: M+•, 246.0528, C13H10O5 requires 246.0528;
Mp = 117–119 °C (lit.168 mp = 117–119 °C).
The spectral data cited above match those reported in the literature.168
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223
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Appendices
237
7.1 APPENDIX ONE: BALDWIN’S RULES
Due to the emphasis of this thesis on certain cyclisation reactions, Baldwin’s rules,
which govern the formation of cyclic products, are presented. Although the cyclisations detailed
in the body of this thesis are limited to 5-exo-dig and 6-endo-dig processes, the entirety of these
rules are presented below for the sake of completeness.
Baldwin’s rules are empiricisms aimed at predicting the favourability (or otherwise)
of closure for three- to seven-membered rings (Figure 7.1).224 The nomenclature used to
describe these ring closure reactions is dictated by these distinct factors:
i. the size of the ring being formed;
ii. the position of the bond(s) being broken relative to the ring formed, viz there are
endo and exo modes: the former describes a ring closure in which the bond being
broken is incorporated within the ring being formed while the latter describes a
process where it is outside that ring.
iii. the geometry of the electrophilic centre being “attacked” by the internal
nucleophile: tet, trig, dig for sp3, sp2 and sp hybridized centres, respectively.
Appendices
238
Figure 7.1 Nomenclature of Baldwin's Rules.
It is important to note that these rules only describe the relative rate of ring closure and
not the absolute possibility or impossibility of a given reaction taking place. (Table 7.1). The
favoured nature of a ring closure describes the fact that the length and type of linkage between
the two reacting centres allow for the required reaction trajectory to be achieved without severe
distortion of bond angles and distances from normal values. The cases defined below as possible
refer to examples first deemed disfavoured by Baldwin but which have since been reported in
the literature. The origin of these “rules” is stereoelectronic in nature.
Appendices
239
Table 7.1 Amended Baldwin's Rules (F = favourable, D = Disfavoured, P = possible).
Ring Size 3 4 5 6 7
Type of Cyclisation exo endo exo endo exo endo exo endo exo endo
tet
Anionic P F P F P F P
Radical F N/A F N/A F D F D F D
Cationic F N/A F N/A F D F D F D
trig
Anionic F D F P F F F F F F
Radical F D F D F P F F F F
Cationic F D F D F P F F F F
dig
Anionic P F P F F F F F F F
Radical P F P F F F F F F F
Cationic P F P F F F F F F F
Appendices
240
7.2 APPENDIX TWO: SYNTHESIS OF PHENOLS PRECURSORS
A range of phenols was prepared so as to study specific aspects of the gold(I)-catalysed
cyclisation of the derived propiolates. Details of these preparations are presented immediately
below.
Resorcinol (2.134) was mono-protected as an acetate 2.135, benzoate 2.136, pivaloate
2.137, tert-butyldimethylsilyl ether 2.138 or benzyl ether 2.139. The relatively low yields
observed stem from the possibility of di-protection rather than any inefficient process per se.
Products 2.135, 2.136 and 2.137 were prepared by treatment of resorcinol (2.134) with the
corresponding acyl chlorides while compound 2.138 was prepared using TBSCl and imidazole,
and congener 2.139 by treatment of resorcinol (2.134) with benzyl bromide in presence of
potassium carbonate (Scheme 7.1).
Scheme 7.1 Preparation of Resorcinol Derivative Precursors [Reagents and Conditions: i) RCOCl (1.0
equiv.), DCM, 18 °C, 4 h; ii) TBSCl (1.0 equiv.), imidazole (1.0 equiv.), DMF, 18 °C, 6 h; iii) BnBr (1.0 equiv.),
K2CO3 (1.0 equiv.), acetone, 18 °C, 6 h].
4-(Triethylsilyl)phenol (2.140) and 4-(tert-butyldimethylsilyl)phenol (2.141)
(Scheme 7.2) were prepared according to a literature procedure225 by treating commercially
available p-bromophenol (2.133) with n-BuLi then quenching the derived carbanion with the
relevant silyl chloride.
Scheme 7.2 Preparation of C-Silylated Phenol Precursors [Reagents and Conditions: i) a) n-BuLi (3.0 equiv.),
THF, −78 °C, 1 h; b) RCl (3.0 equiv.), THF, −78 °C to 18 °C, 4 h].
4-Hydroxyphenyl trifluoromethanesulfonate (2.142) (Scheme 7.3) was prepared by
treating hydroquinone (2.58) with one molar equivalent of trifluoromethanesulfonyl chloride in
presence of triethylamine at 0 °C.
Appendices
241
Scheme 7.3 Preparation of Monotriflated Hydroquinone [Reagents and Conditions: i) CF3SO2Cl (1.0 equiv.),
Et3N (1.0 equiv.), 0 °C, 4 h].
Methyl (tert-butoxycarbonyl)-L-tyrosinate (2.144) (Scheme 7.4) was prepared by
treating L-tyrosine hydrochloride (2.143) with tert-butyloxycarbonyl anhydride in presence of
triethylamine at 0 °C.
Scheme 7.4 Preparation of Boc-Protected L-Tyrosine [Reagents and Conditions: i) (Boc)2O (1.1 equiv.), Et3N
(2.0 equiv.), DCM, 0 °C, 16 h].
Appendices
242
7.3 APPENDIX THREE: SINGLE-CRYSTAL X-RAY ANALYSIS OF
PROPIOLATES
Plot Arising from the single-crystal X-ray analysis of compound 2.29
Figure 7.2 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.29.
A full X-ray crystallographic report for compound 2.29 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
243
Plot Arising from the single-crystal X-ray analysis of compound 2.39
Figure 7.3 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.39.
A full X-ray crystallographic report for compound 2.39 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
244
ORTEP derived from the single-crystal X-ray analysis of compound 2.41
Figure 7.4 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.41.
A full X-ray crystallographic report for compound 2.41 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
245
ORTEP derived from the single-crystal X-ray analysis of compound 2.47
Figure 7.5 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.47.
A full X-ray crystallographic report for compound 2.47 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
246
ORTEP derived from the single-crystal X-ray analysis of compound 2.48
Figure 7.6 Plot Derived from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.48.
A full X-ray crystallographic report for compound 2.48 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
247
ORTEP derived from the single-crystal X-ray analysis of compound 2.50
Figure 7.7 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.50.
A full X-ray crystallographic report for compound 2.50 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
248
ORTEP derived from the single-crystal X-ray analysis of compound 2.52
Figure 7.8 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.52.
A full X-ray crystallographic report for compound 2.52 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
249
ORTEP derived from the single-crystal X-ray analysis of compound 2.54
Figure 7.9 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.54.
A full X-ray crystallographic report for compound 2.54 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
250
ORTEP derived from the single-crystal X-ray analysis of compound 2.57
Figure 7.10 Plot Arising from the Single-Crystal X-ray Analysis of Aryl Propiolate 2.57.
A full X-ray crystallographic report for compound 2.57 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
251
7.4 APPENDIX FOUR: SINGLE-CRYSTAL X-RAY ANALYSIS OF
COUMARINS
ORTEP derived from the single-crystal X-ray analysis of compound 1.1
Figure 7.11 Plot Arising from the Single-Crystal X-ray Analysis of Coumarin 1.1.
A full X-ray crystallographic report for compound 1.1 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
252
ORTEP derived from the single-crystal X-ray analysis of compound 2.92
Figure 7.12 Plot Arising from the Single-Crystal X-ray Analysis of Coumarin 2.92.
A full X-ray crystallographic report for compound 2.92 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
253
ORTEP derived from the single-crystal X-ray analysis of compound 2.93
Figure 7.13 Plot Arising from the Single-Crystal X-ray Analysis of Ayapin 2.93.
A full X-ray crystallographic report for compound 2.93 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
254
ORTEP derived from the single-crystal X-ray analysis of compound 2.95
Figure 7.14 Plot Arising from the Single-Crystal X-ray Analysis of Coumarin 2.95.
A full X-ray crystallographic report for compound 2.95 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
255
7.5 APPENDIX FIVE: SINGLE-CRYSTAL X-RAY ANALYSIS OF BY-
PRODUCTS
ORTEP derived from the single-crystal X-ray analysis of compound BP2
Figure 7.15 Plot Arising from the Single-Crystal X-ray Analysis of the DCU-Propiolic Acid Adduct BP2.
A full X-ray crystallographic report for compound BP2 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
256
ORTEP derived from the single-crystal X-ray analysis of compound BP3
Figure 7.16 Plot Arising from the Single-Crystal X-ray Analysis of the Cyclised DCC-Propiolic Acid
Adduct BP3.
A full X-ray crystallographic report for compound BP3 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
257
7.6 APPENDIX SIX: SINGLE-CRYSTAL X-RAY ANALYSIS OF FRAXETIN, ITS
DERIVATIVES AND PIMPINELLIN
ORTEP derived from the single-crystal X-ray analysis of compound 3.11
Figure 7.17 Plot Arising from the Single-Crystal X-ray Analysis of Intermediate 3.11.
Atomic coordinates, bond lengths and angles, and displacement parameters have been deposited
at the Cambridge Crystallographic Data Center (CCDC no. 941290).
A full X-ray crystallographic report for compound 3.11 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
258
ORTEP derived from the single-crystal X-ray analysis of compound 3.30
Figure 7.18 Plot Arising from the Single-Crystal X-ray Analysis of Brominated Benzaldehyde 3.30.
Atomic coordinates, bond lengths and angles, and displacement parameters have been deposited
at the Cambridge Crystallographic Data Center (CCDC no. 934659).
A full X-ray crystallographic report for compound 3.30 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
Appendices
259
ORTEP derived from the single-crystal X-ray analysis of compound 3.31
Figure 7.19 Plot Arising from the Single-Crystal X-ray Analysis of Sonogashira Coupling Product 3.31.
Atomic coordinates, bond lengths and angles, and displacement parameters have been deposited
at the Cambridge Crystallographic Data Center (CCDC no. 933272).
A full X-ray crystallographic report for compound 3.31 (as compiled by Anthony C. Willis of
the Australian National University) is provided in PDF-format on the USB stick found on the
inside back cover of this thesis.
261
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