Munashe PhD thesis 2023.pdf

i
Radical Decarboxylation Strategies for Synthesis of Nitrogen-
Containing Heterocycles
A Thesis Submitted to the Faculty of Science, Department of Chemistry at
University of Cape Town
In Fulfilment of the Requirements for the Degree of
Doctor of Philosophy
By
Crispen Munashe Mazodze
Supervisor: Wade F. Petersen
Department of Chemistry
University of Cape Town
Rondebosch, Cape Town
South Africa, 7700 February 2023

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The author retains the copyrights of this thesis. Any quotations or information
derived from it must be fully acknowledged with the appropriate citation. This
thesis is intended for private study or non-commercial research purposes only.
It has been published by the University of Cape Town (UCT) under a non-
exclusive license granted to UCT by the author.

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Declaration
I know the meaning of the word Plagiarism and I am fully aware that plagiarism is a
consequential academic offence, and I shall not allow others to plagiarize my work. I declare
that all the work in this document ‘’Decarboxylation Strategies for Synthesis of Nitrogen-
Containing Heterocycles’’ is my own original work and neither the work as whole nor any part
of it has been, is being, or is to be submitted for another degree at the University of Cape
Town or any other university. I authorise the University of Cape Town to reproduce for the
purposes of research either the whole or any portion of the contents in any manner
whatsoever. All sources of information have been properly cited and where I have used the
words of others, I have indicated this using quotation marks otherwise, I have appropriately
referenced all quotes and suitably acknowledged ideas snavelled from others.
……………………………………………………….. Date…………………………………….
Crispen Munashe Mazodze
12/02/2023

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Acknowledgements
First and foremost, my gratitude goes to Dr WF Petersen for being more of a ‘big brother’ than a
supervisor, also to mention his inspiration, kindness, support, and love, otherwise, this work wouldn’t
have been possible without him – muchas gracias.
Special mention to the WFP and Hunter research group for our time together at UCT, it was a
memorable time while learning a lot at the same instance. A special shout out to Phathu and
Farhaan for all the Nandos, and late-night lab sessions.
A special mention to Prof. Hunter Roger for his big involvement in my professional development and
his inspiring love for chemistry.
To my day one Decision (Dombo Homeboy) Munemo – God knows.
To Johanne Masowe eChishanu Cape Town congregation(s) -basa ramakabata kuti tsananguro
dzizare rinotendwa nehwai.
To Hong Su, and the Stellenbosch University Mass Spectrometry Unit, for their analytical services
during this research.
To the Royal Society of Chemistry (UK), African Academy of Sciences, NRF and UCT PGFO, I express
my gratitude for their financial support which made this research possible.
To God, I am forever grateful and if I forget, kindly align me with your will.

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To my mother Tambudzai Mazodze, this one is for you Mama – I love you!

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Abstract
Nitrogen-containing heteroaromatics are ubiquitous in nature. In addition, 75% of FDA-approved
drugs currently on the market are based on these compounds, establishing them and their analogues
as a primary source of therapeutic agents in the pharmaceutical industry. The structural complexity
exhibited by these nitrogen-based moieties necessitates the development of innovative strategies
that demand mastery beyond routine and traditional organic chemistry that most synthetic chemists
typically cultivate.
The second chapter of this thesis describes the use of novel delayed radical precursors in
Mn(OAc)3·2H2O mediated oxidative radical cyclization-fragmentation-dimerization processes from β-
anilides. The first part presents a sequential oxidative radical cyclization-decarboxylative-dimerization
process from β-oxoacids, forming three bonds in a one-pot manner. This approach was successful
with a diverse range of 3,3′-bisoxindoles substrates obtained in up to 96% yield. The second part of
chapter two details a complementary and closely related sequential one-pot oxidative radical
cyclization-deformation-dimerization process from β-oxoanilides, this motion was also applicable to a
wide array of 3,3′-bisoxindoles with up to 98% yield. There are no clear-cut distinctions between the
decarboxylative and deformylation approaches as they appear to be highly complementary to each
other. The chapter concludes with a further demonstration of the utility of this methodology, in the
formal synthesis of the calycanthaceae alkaloid, (±)-folicanthine via to the best of our knowledge the
shortest linear route.
The third chapter of this thesis describes a general extension of the second chapter, which involves an
atom-efficient silver-catalysed double decarboxylative strategy for the one-step synthesis of quinolin-
2-ones. This is achieved via an oxidative radical addition–cyclisation–elimination cascade sequence of
oxamic acids to acrylic acids, mediated either thermally or photochemically. The reaction proved to
be successful with a wide range of 32 quinolin-2-ones synthesized in of up to 84% yield. The method
features an elegant double-disconnection approach, which constructed the quinolin-2-one
core through the formal and direct addition of a C(sp2)–H/C(sp2)–H olefin moiety to a phenyl
formamide precursor.

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The theme of the thesis is centred around the synthesis of nitrogen-containing heteroaromatics using
facile and efficient protocols that offer catalyst, atom and energy efficiency, while also providing
substantial economic advantages. Additionally, the thesis presents systematic and in-depth
mechanistic studies on both developed protocols to support and offer compelling evidence for the
proposed mechanistic cycles. These studies provide insights into the reaction pathways and help
establish a more comprehensive understanding of the radical synthetic pathways.

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List of Abbreviations and Symbols
𝛼 alpha
𝛽 beta
𝛾 gamma
𝜋 pi
% percentage
𝜇M micromolar
℃ degrees Celsius
4-CzIPN 2,4,5,6-Tetra(9H-carbazol-9-yl)isophthalonitrile
13
C NMR carbon nuclear magnetic spectroscopy
1
H NMR proton nuclear magnetic resonance spectroscopy
AcOH acetic acid
Ar aromatic
ACN acetonitrile
Bs broad singlet
BOC tert-Butoxycarbonyl
BET back electron transfer
Bu butyl
Bn benzyl
C3 carbon number three
CDC cross dehydrogenative coupling
C–C carbon to carbon
CTX-Cl 2-chlorothioxanthone
cm centimetres
CL-4CzIPN 2,4,5,6-tetrakis(3,6-dichloro-9H-carbazol-9-yl)isophthalonitrile
d doublet
dd double doublet
dq double quartet
dr diastereomeric ratio
DCM dichloromethane
DCC N-N-dicyclohexylcarbodiimide
DIPEA N, N-Diisopropylethylamine
DFT density functional theory
DMA dimethylacetamide
DMSO dimethyl sulphoxide
DeXT dexter electron transfer and or dexter electron exchange
DME dimethyl ether
DMF dimethyl formamide
ee enantiomeric excess
Et ethyl
Equiv. equivalent
Et3N triethyl amine
EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EtOH ethanol
ESKOM electricity supply commission/ elektrisiteitsvoorsieningskommissie

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g grams
HOMO highest occupied molecular orbital
Hz hertz
Hex hexyl
hr(s) hour(s)
HPI hexahydropyrrolo[2,3-b]indole
HCl hydrochloric acid
HSQC heteronuclear single quantum coherence or heteronuclear single quantum
correlation experiment
IR infrared
ISC intersystem crossing
J coupling constant
Kisc rate constant for intersystem crossing
KIC rate constant for internal conversion
KHMDS potassium hexamethyldisilazide
LiHMDS lithium hexamethyldisilazide
LiAlH4 lithium aluminium hydride
LUMO lowest occupied molecular orbital
M molar
m multiplet
Me methyl
MOC methoxycarbonyl
mM millimolar
Mes-Acr mesitylene acridinium
MS mass spectroscopy
MeOH methanol
MV megavolts
mL millilitre
min(s) minutes(s)
nm nanometre
NMR nuclear magnetic resonance
NaOH sodium hydroxide
NaHMDS sodium hexamethyldisilazide
NPhth N-phthalimido
O ortho
[OX] oxidation
p para
PhMe toluene
ppm parts per million
PC photocatalyst

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PET photo induced electron transfer
Photoredox photo reduction and oxidation
P.T. proton transfer
q quartet
rt room temperature
redox oxidation and reduction
RM redox mediator
SM starting material
SET single electron transfer
s singlet
SOMO singularly occupied molecular orbital
t triplet
tBuOK potassium tert-butoxide
tBuOOH tert-butyl hydroperoxide
THF tetrahydrofuran
TLC thin layer chromatography
TFA trifluoracetic acid
TBAI tetrabutylammonium iodide
TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl/(2,2,6,6-tetramethylpiperidin-1-
yl)oxidanyl
v/v volume to volume
X Ray Röntgen radiation

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Table of Contents
Declaration......................................................................................................................iii
Acknowledgements .........................................................................................................iv
Abstract ..........................................................................................................................vi
List of Abbreviations and Symbols..................................................................................viii
Chapter 1..........................................................................................................................1
1.1 Nitrogen-Containing Heteroaromatics.................................................................................1
1.2 Biological Importance.........................................................................................................2
1.3 Sustainability: An Ongoing Challenge in Organic Synthesis...................................................2
1.4 The ‘Forgotten’ Challenge for the Synthetic Chemist — Energy Security...............................3
1.5 Key Strategies for Sustainable Synthesis..............................................................................3
1.5.1 Cascade Reaction Sequences............................................................................................3
1.5.2 A Brief Introduction to Photoredox Catalysis ....................................................................5
1.5.2.1 Photophysical Process of Photocatalysis........................................................................6
1.5.3 Mechanism of Photocatalysis...........................................................................................7
1.5.3.1 A) Photoinduced Electron Transfer (PET) .......................................................................7
1.5.3.2 Kinetics and Thermodynamics of PET ............................................................................9
1.5.4 B: Photoinduced Energy Transfer ...................................................................................10
1.5.5 C: Photoinduced Atom Transfer .....................................................................................11
1.5.6 Miscellaneous Modes of Activation................................................................................11
Part 1: Synthetic Approach for the Construction of the Bisoxindole Scaffold and
Applications Towards the Synthesis of Hexahydropyrrolo[2,3-b]indole Alkaloids. ............12
Chapter 2........................................................................................................................13
2.0 Introduction Hexahydropyrrolo[2,3-b]indole Alkaloids......................................................13
2.1 Bisoxindoles – A Gateway to Dimeric Hexahydropyrrolo[2,3-b]indole Scaffold...................14
2.1.1 Radical Dimerization......................................................................................................15
2.1.2 Synthesis via Modification of Bisoxindoles .....................................................................20
2.1.3 Addition to Isatin Derivatives.........................................................................................22
2.1.4 Modification of Acyclic Anilides .....................................................................................23
2.2 Design Strategy and Approach ..........................................................................................25
2.2.1 The Leaving Group: Oxidative Fragmentation .................................................................26
2.3 Proposed Mechanism.......................................................................................................27
2.4 Reaction Route Development ...........................................................................................28
2.4.2 Substrate Scope.............................................................................................................32
2.4.3 Failed Substrates ...........................................................................................................36

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2.5 Complementary Approach – Deformylation Strategy.........................................................36
2.5.1 Substrate Scope – Starting from β-oxoanilide.................................................................37
2.5.2 Unsuitable Substrates – Starting from β-oxoanilide ........................................................39
2.6 Plausible Mechanistic Pathway and Mechanistic Evidence.................................................41
2.7 Application Towards Synthesis of the Dimeric Hexahydropyrrolo[2,3-B]Indole Core...........43
2.8 Conclusion and Outlook....................................................................................................45
Part 2: Synthetic Approaches for the Construction of the Quinolin-2-one Scaffold ............46
Chapter 3........................................................................................................................47
3.1 Introduction.....................................................................................................................47
3.2 The 2-Quinolone Scaffold..................................................................................................53
3.2.1 Current Synthetic Strategies for 2-Quinolone Synthesis ..................................................54
3.3 Thermal Optimization Studies and Synthesis of Quinolin-2-ones........................................57
3.4 Substrate Scope................................................................................................................62
3.4.1 Unsuitable Substrates for the Thermal Cascade Sequence ..............................................63
3.5 Chemistry Without Electricity — An (South) African Story..................................................64
3.6 Visible Light Optimization Studies and Synthesis of Quinolin-2-ones..................................67
3.7 A Comparison of Photoredox Catalysis vs Thermal Catalysis. .............................................76
3.8 Mechanistic Evidence .......................................................................................................77
3.9 Conclusion and Outlook....................................................................................................80
References......................................................................................................................81
Chapter 4-Experimental..................................................................................................95
4.1.0 General information for Cross-Dehydrogenative Cyclization-Dimerization Cascade
Sequence for the Synthesis of Symmetrical 3,3’-Bisoxindoles (Chapter 2) ................................95
4.2.0 General Schemes...........................................................................................................96
4.2.1 General procedure A: Synthesis of Anilides (70) from Acid Chlorides...............................96
4.2.2 General Procedure B: Synthesis of Anilides (66/70) from Carboxylic acids. ......................96
4.2.3. Characterisation Data for Anilides and β–oxoesters 66 ..................................................97
4.3.4 Characterization Data for Anilides................................................................................ 102
4.3.5 Characterisation Data for Carboxylic Acids and Aldehydes............................................ 106
4.3.6 General Procedure D: Mn(OAc)3.2H2O Mediated One-step Synthesis of Bisoxindoles..... 116
4.3.7 General Procedure E: Azidation of (62q)....................................................................... 127
4.3.8 Characterisation Data for (Azidoethyl) Oxindoles ......................................................... 127
4.4. General Information Silver-Catalysed Double Decarboxylative Addition-Cyclisation-
Elimination Cascade Sequence for the Synthesis of Quinolin-2-Ones (Chapter 3) ................... 129
4.4.1 General Schemes......................................................................................................... 129
4.4.2 General Synthetic Procedure F: Synthesis of Oxamic Esters........................................... 130

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4.4.3 General Synthetic Procedure G: Synthesis of Oxamic Acids ........................................... 130
4.4.4 General Synthetic Procedure H: Thermal Mediated Synthesis of Quinoline-2-ones........ 130
4.4.5 General Synthetic Procedure I: Visible-Light Mediated Synthesis of Quinoline-2-ones ... 131
4.6.0 Characterization Data for Oxamic Esters....................................................................... 131
4.7 Characterization Data for Oxamic Acids........................................................................... 137
4.8 Characterization Data for Quinoline-2-ones (105)............................................................ 143
Appendix Graphical NMR Spectra .................................................................................155

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Chapter 1
1.1 Nitrogen-Containing Heteroaromatics
A heteroaromatic compound is a cyclic, aromatic compound which contains at least one heteroatom.
The most common heteroatoms are nitrogen, oxygen and sulphur.1
Amongst the classes of
heteroaromatic molecules, a special class is represented by those containing a nitrogen atom.2–4
Hexahydropyrroloindoles (HPIs), which are tricyclic molecules composed of pyrrole fused to an indole
(Figure 1, 1st
row), and quinolin-2-one, derived (Figure 1, 2nd
row), natural products are typical
examples of naturally occurring nitrogen-containing heterocycles and will be the main focus of the
work presented within this thesis.
Figure 1: Examples of naturally occurring natural products containing quinolin-2-one motifs and
bisoxindole-derived HPI alkaloids.
The molecules displayed above (Figure 1) contain intricate structural features that pose a significant
synthetic challenge for chemists. For example, folicanthine and chimonanthine exhibit vicinal
stereogenic centres with a labile C3a–C3a’ bond 5–7
— demanding not only the ability to form these
chemical bonds but also to do so with perfect selectivity at each stereocentre. It is for this reason that
for decades, natural products have been a key driving force and inspiration for the development of
new and innovative methods for chemical synthesis in organic chemistry and related disciplines.

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1.2 Biological Importance
Within the pharmaceutical industry, natural product-derived therapeutics, particularly those bearing
a nitrogen heterocyclic core, have been widely preferred relative to purely synthetic and non-natural
counterparts due to their wide array of biological activities, fewer side effects, cost-effectiveness and
a minimal level of resistance-making them prerogative scaffolds.8
Importantly, being of biological
origin, they are inherently predisposed to interact with biological targets (i.e. enzymes and receptors)
with high affinity and can provide an informed starting point in drug development.9
In context, HPI cyclotryptamines and quinolin-2-ones, exhibit fascinating biological activities.
calycanthaceae plants have long been used in traditional medicines as antitussive, anti-inflammatory,
and antitumor medicines.10,11
Today in medicinal chemistry (+)-calycanthine and (–)-folicanthine
(Figure 1) have shown strong antifungal,12
antiviral,13
and analgesic activity on μ- and κ-opioid binding
assays.14
More importantly, in light of cancer being one of the leading causes of noncommunicable
diseases and death, (–)-chimonanthine and (–)-folicanthine show cytotoxic effects against gastric
carcinoma NUGC3 and hepatocarcinoma SNU739 cancer cells with IC50 values ranging from 10.3 to
19.7 μM.11
Some of the naturally existing quinolone-bearing motifs have shown profound medicinal
properties while others have served as lead structures and provided an incentive for the design of
novel pharmaceuticals.15
Yaequinolones J1 and J2 (Figure 1) show insecticide and antibiotic effects,16
while flindersine was shown to possess antibacterial and antifungal activities.17
1.3 Sustainability: An Ongoing Challenge in Organic Synthesis
To date, tremendous amounts of effort have been devoted toward synthesising the fascinating
scenery of nitrogen-containing heterocycles that collectively enable synthetic chemists to assemble
even the most complex molecular structures — inclusive of some structures that may have even been
viewed as impossible just a few years ago. With these very impressive transformations at hand, it is
easy for us synthetic chemists to be caught up in their beauty and ‘coolness’ that we forget to
scrutinize their sustainability and true impact on the environment. For example, many of these
methods utilize rare and expensive metals and/or require high reaction temperatures. This places
them within two major areas of environmental concern: 1) the utilization of non-renewable
feedstocks; 2) energy security.
To emphasize, these significant chemical advances should not be undermined. However, in
conjunction with the call for sustainable processes, it is our duty as the younger scientific generation,
to advance these works so that they remain important in future.

3
The landscape is thus set for synthetic chemists to redefine the state of the art by embracing ‘‘green
modifications’’ in assembling molecular frameworks. Hendrickson defined such an ‘’ideal synthesis’’
as the preparation of molecules from simple starting materials and linking them sequentially in
successive synthetic transformations excluding intermediary refunctionalisations. Importantly
Hendrickson’s proposed ideal synthesis had a vision for a sustainable future, incorporating and
exemplifying the fundamental aspects of economic synthesis.18
1.4 The ‘Forgotten’ Challenge for the Synthetic Chemist — Energy Security
The 12 Principles of Green Chemistry, developed by Paul Anastas in 1998, has become a critical
framework within which chemists have worked to update existing protocols.19 And we have certainly
come a long way — specifically in the context of designing more atom-efficient reactions, utilizing
more benign reagents and solvents, and using renewable (bioavailable)/waste feedstocks. Within
these principles, however, one area is typically taken for granted: Design for Energy Efficiency —
requiring deliberate consideration of where or how the energy input utilized for the chemistry is
derived from.20
This brings to the fore arguably the biggest challenge affecting the field of chemistry
today: energy security. It is thus crucial to consider energy consumption/production in the
development of sustainable reactions as energy is still typically generated from non-renewable
resources.
1.5 Key Strategies for Sustainable Synthesis
Maximizing product formation while minimizing waste, i.e., pursuing a perfect atom economy, is
arguably the most important metric for the success and efficiency of a synthetic method within the
twelve Principles of Green Chemistry framework.21,22
Thus, in thinking about this project, we identified two key strategies that would facilitate achieving
our overall project aims of low-cost and energy-efficient syntheses: 1) Cascade Reactions — the ability
to carry out two or more chemical transformations sequentially in a single reaction;23
2) Photocatalysis
— the ability to use visible-light, at ambient temperature, for the synthesis of complex molecules with
sub-stoichiometric reagents under milder conditions to promote a reaction.24
The use of photoredox
catalysis is relevant to Chapter 3 of the work in this thesis.
1.5.1 Cascade Reaction Sequences
Commonly referred to as a tandem or domino reaction, a cascade reaction sequence is a type of
chemical reaction involving at least two sequential transformations, such that each subsequent ‘’step’’
generates an intermediary synthon which goes on to react further and ultimately forms more
advanced products.

4
Cascade reactions, therefore, enable the construction of complex molecules, in a single step, without
the need to isolate intermediates, change the reaction conditions, or add additional reagents (Figure
2).25,26
The efficiency of a given cascade reaction is typically assessed in terms of the number of new
bonds formed in the overall sequence, the level of increase in structural complexity and the broadness
of the substrate scope.23,27
Figure 2: Graphical representation of a tandem reaction in organic synthesis.
A representative example of such a cascade sequence is exemplified in the work by Li et al. in their
redox-neutral hydride transfer cascade cyclisation for the construction of spirocyclic bisoxindoles.28
Scheme 1: Li’s cascade sequence for the construction of spirocyclic bisoxindoles.

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The route enabled the rapid synthesis of spirocyclic bisoxindole alkaloids with three consecutive chiral
centres in good yields and selectivity and featured the in-situ generation of an iminium ion via a [1,5]-
hydride shift (i.e., intermediate II) which was subsequently intercepted to produce the spirocyclic
product (Scheme 1).
1.5.2 A Brief Introduction to Photoredox Catalysis
Nature's ability to harness abundant sunlight using chromophores and converting light into chemical
energy at ambient temperature has inspired generations of developments in mimicking the concept
of photosynthesis in chemical synthesis.29,30
Fast forward to the early 2000s and the field of
photochemical synthesis has expanded significantly with the advent (and predictability) of modern
photocatalysis and the reliability of light sources. The terms photoredox catalysis in general can be
defined as the engagement of a metal complex or organic molecule (termed a photocatalyst or
photosensitizer) in single electron transfer processes (SET) upon excitation with visible light, resulting
in new chemical transformations.31
The structures of the most common photocatalysts are shown in
(Figure 3).
Figure 3: Common metal and organic photocatalysts complexes.

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1.5.2.1 Photophysical Process of Photocatalysis
Generation of a triplet state is a key step towards accessing reactive intermediates and this pathway
to the triplet state can be depicted explicitly using a Jablonski diagram (Figure 4).
Figure 4: Jablonski diagram depicting allowed and forbidden pathways to the triplet excited state generation
from ground singlet states whereas KX refers to rate constants for: (F) fluorescence, (isc) intersystem crossing,
(ic) internal conversion, (P) phosphorescence.
Direct photoexcitation from the ground singlet state to the excited triplet is a forbidden transition (PC
S0 – PC* Tn), given that electron spin in both the excited state and ground state are parallel.32
Thus generation of the triplet state goes via excitation to the excited singlet state followed by
relaxation to the lowest energy excited singlet state (PC Sn – PC* S1), termed internal conversion. Rapid
intersystem crossing of the lowest energy excited singlet state (PC* S1) generates a high-lying triplet
state (PC* T2), which relaxes to the lowest-energy, and long-lived triplet state (PC* T1).33
This triplet
state (PC* T1) is the photoexcited species that engages in SET and it’s long lifetime arises (> 1 μs) from
the fact that decay back to the singlet ground state is spin forbidden.34

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1.5.3 Mechanism of Photocatalysis
Once in its long-lived excited state, there are three main activation modes possible: a) Electron
transfer; b) Energy transfer; c) Atom transfer (Figure 5), with photoinduced electron transfer (PET)
being the focal point of this thesis.
Figure 5: Plausible modes of activation of an excited photocatalyst PC*/ PC*n ; where n is an integer value. a)
photoinduced energy transfer following either reductive or oxidative quenching cycle. b) Photo-induced
energy transfer; instead of energy is transferred to the substrate. c) Photoinduced atom transfer, where an
atom abstraction occurs.
1.5.3.1 A) Photoinduced Electron Transfer (PET)
Many literature reports in photoredox catalysis utilise the ability of photo-excited substrates to
engage in SET events.35–37
Upon irradiation, an excited photocatalyst may proceed either by oxidative
or reductive quenching cycles (Figure 6).
In an oxidative quenching cycle, a SET event occurs from the excited PC* to the substrate,
consequently generating the radical anion S•–
and the oxidised form of the photocatalyst PCn+1
. The
resultant oxidised species of the photocatalyst PCn+1
may accept an electron from a suitable
terminal/sacrificial oxidant for it to return to its ground state PC while turning over the photocatalytic
cycle.
S
S*
b: Photoinduced Energy Tranfer
PC* +
c: Photoinduced Atom Tranfer
a: Photoinduced Electron Tranfer
PCn*
S—H S*
+ +
PC—H
S
+
PCn+1
PC*
PCn*
S
+
S
+
S
+
PCn-1
(oxidative quenching cycle)
(reductive quenching cycle)
PC +

8
Figure 6: Diagram depicting substrate activation via PET: (a) reductive quenching cycle and (b) oxidative
quenching cycle.
Alternatively, in a reductive quenching cycle, a SET event occurs from the substrate to the excited
PC*, resulting in the generation of the radical cation S•+
and the reduced form of the photocatalyst
PCn-1
. The resultant reduced species of the photocatalyst, PCn-1
, may donate an electron to an
appropriate terminal/sacrificial reductant for it to return to its ground state PC, while turning over the
photocatalytic cycle. 31,36,37
For a given PET cycle, following either an oxidative or reductive quenching cycle is dependent on the
relative HOMO/LUMO of the substrate and photocatalyst. Figure 7 provides an orbital energy diagram
that illustrates which quenching cycle is followed based on the energy differences.
Figure 7: Molecular orbital energy level depiction of plausible pathways PET may follow a: reductive quenching
cycle and b: oxidative quenching cycles.

9
In the event of process, a, if the HOMO of the substrate has higher energy than the SOMO of the PC*,
then the substrate is oxidised (reductive quenching cycle). On the contrary in the event of process B;
when the SOMO of the PC* is higher in energy than the LUMO of the substrate, the substrate is
reduced (oxidative quenching cycle).38–40
The exceptional function of the excited states of photocatalysts to act as either a reductant or oxidant
via SET events provides key, novel and elusive photochemistry in organic synthesis, particularly in
comparison to traditional electrochemistry which can either be oxidative or reductive but never
both.24
Furthermore, their unique ability to convert visible light into heightened levels of chemical
energy above ground state makes them unique and indispensable.41
1.5.3.2 Kinetics and Thermodynamics of PET
The feasibility of a given photocatalytic reaction is dependent on the half-cell potentials of the
photocatalyst and the substrate in question. It is not surprising that the most relevant photoredox
reactions in organic chemistry involve the exergonic SET process.31
Nonetheless, the kinetics of SET
should not be overlooked. The rate of electron transfer is described by the Marcus equation, and two
main outer sphere electron transfer processes are mainly applicable in this regard.40
Direct electron transfer can occur between the excited state of the photocatalyst and the substrate,
or between the excited state of the photocatalyst and a redox mediator. The prevailing condition of
the outer sphere mechanism is that the photocatalyst and the substrate form a complex, in which
parameters like solvation, activation energy barrier and nuclear rearrangement become prevalent.
Given this, despite thermodynamics being favourable there is still a requirement for the lifetime of an
excited triplet state to be long enough to accommodate the outer-sphere mechanism.40,42–44
Some PET
processes are thermodynamically feasible but kinetically too slow to be efficacious. A common
strategy used to overcome slow kinetics is the use of a redox mediator.
Generally, redox mediators undergo the redox process independently with both the photocatalyst and
the substrate, such that the electron transfer chain goes through an intermediate instead of direct
electron transfer with the substrate (Figure 8).45–47

10
Figure 8: Redox mediation in an oxidative quenching cycle.
1.5.4 B: Photoinduced Energy Transfer
Excited state PC* can undergo a direct energy transfer to a suitable substrate, particularly those
substrates which are not able to absorb light at a given wavelength thereby inducing chemical
reactivity which is superior relative to its ground state.48,49
Several mechanistic pathways may be
applicable in this context; however, the most common one is the Dexter energy transfer (DEXT). DEXT
is hypothesized to occur without a change in the redox state of the substrate or the photocatalyst as
there is a concerted electron transfer to and from both the excited state of the photocatalyst PC*
resulting in the nonradiative relaxation of the photocatalyst and consequent generation of the excited
triplet state of the substrate (Figure 9, b).50,51
Figure 9: (a) Photo-induced atom transfer (b) Photo-induced energy transfer.
hv
PCn
[PCn]*
PCn-1
A
A
RM
RM
Sub
Sub

11
These intermediates (excited state substrate) have found applications in the construction of strained
and or molecules with unusual molecular scaffolds which are challenging to form by non-
photochemical means.52,53
However such energy transfer pathways account for a relatively minor
subset of organic transformations, although their importance cannot be overlooked.48,54
1.5.5 C: Photoinduced Atom Transfer
Another common mechanistic pathway for photoinduced atom transfer reactions is the resultant of
open-shell intermediates. This involves the concerted transfer of an atom and homolytic breaking of
S–X (S=C/N) bonds by the excited photocatalyst PC* forming a photocatalyst adduct PC–X and yielding
the substrate S•
with unique reactivity as compared to its ground state. While not overlooking the
importance of electron transfer as governed by redox potentials of the substrate and photocatalyst,
the general concern with designing experiments following the atom transfer mode of activation is the
thermodynamic consideration of the S–X bond strength (Figure 10, a). (Such a mode of activation has
been used with S = H (Hydrogen Atom Transfer) being the most popular.31,55
1.5.6 Miscellaneous Modes of Activation
An interesting synergy is observed when photocatalysis is employed together with other non-
photochemical catalytic strategies. In such dual-catalytic systems, catalysts independently manipulate
each other’s reactivity to accomplish a given transformation. For example, an excited photocatalyst
may activate a substrate, and a second co-catalyst then takes advantage of the resultant
photogenerated intermediates.36
This approach considerably bridges the gap of impractical substrate-
photocatalyst pairs under kinetically or thermodynamically unfeasible conditions. Popular dual
catalysis strategies include transition metals-photoredox catalysis and organocatalysis-photoredox
catalysis, which have been shown to enhance the catalytic efficiency of photocatalysis. These methods
are often used to overcome limitations such as low quantum yield, sluggish kinetics, and poor
selectivity. Studies have reported the successful application of these approaches in the synthesis of
various organic compounds, including natural products and pharmaceuticals. 35–37,56

12
Part 1: Synthetic Approach for the Construction of the Bisoxindole
Scaffold and Applications Towards the Synthesis of
Hexahydropyrrolo[2,3-b]indole Alkaloids.
This work was published in Organic Letters (Dobah, F; Mazodze, CM; Petersen, W. Cross-
Dehydrogenative Cyclization-Dimerization Cascade Sequence for the Synthesis of Symmetrical 3,3’-
Bisoxindoles, Org. Lett. 2021, 23, 5466–5470).57
Crispen Munashe Mazodze played a critical role in this study by undertaking several key tasks. These
included optimization studies of the radical decarboxylative pathway and synthesizing all the
substrates discussed herein, conducting all mechanistic studies on both the acid and the aldehyde,
and the formal synthesis of (±)-folicanthine.

13
Chapter 2
2.0 Introduction Hexahydropyrrolo[2,3-b]indole Alkaloids
Hexahydropyrrolo[2,3-b]indole Alkaloids are a prime example of naturally occurring N-heterocycles
that are primarily found in the South-Eastern Asian pacific region. These alkaloids are characterised
by a distinct hexahydropyrrolo[2,3-b]indole (HPI) core and are significant and expectational family of
the indole alkaloids with a wide range of remarkable biological activities.58
The HPI core is commonly
found in various oligomeric structures such as dimers, trimers and other higher oligomeric forms, with
the hallmark of these units is their union with labile carbon-carbon bonds forming all vicinal
quaternary stereogenic centres.59 These cyclotryptamine alkaloids have been studied since the
1800’s, with the pseudo-indole alkaloid calycanthine being the first to be isolated from Calycanthus
Glaucus Willd by Ecless in 1882.60
Despite their intricate structural features, full structure
characterisation and determination was a daunting task that was accomplished over an extended
period of time. It wasn’t until 1960 when Woodward independently elucidated the core structure of
the bridged bicycle. Absolute configuration and 3-dimentional structure of this cryptic molecule were
assigned with X-ray diffraction studies and dichroism.61–63
Figure 10: Naturally occurring hexahydropyrrolo[2,3-b]indole alkaloids.

14
Hexahydropyrrolo[2,3-b]indole alkaloids are known for their varying unique oligomeric architectures,
often featuring multiple HPI cores. Dimeric HPI units linked head-to-head, by a labile C3a– C3a’ bond
are more relevant to this study. The resulting highly strained vicinal and continuous stereogenic
centres create an intricate dimeric 3a–3a’ hexahydropyrrolo[2,3-b]indole scaffold that is found
exclusively in the cis configuration in natural products, presumably because of the higher level of ring
strain in the trans stereoisomer. These complex structures not only challenge standard chemical
transformations but also require innovative strategies from synthetic chemist.64,65
The fascinating biological activities of such natural products have prompted research studies in
pharmacology and drug discovery and development, but their poor recovery from natural sources and
structural complexity often result in lengthy synthetic protocols with poor yields.66,67
2.1 Bisoxindoles – A Gateway to Dimeric Hexahydropyrrolo[2,3-b]indole Scaffold
Bisoxindoles are dimeric molecules consisting of two oxindole units linked together, these units are
normally derived from indole or tryptophan. Generally speaking, they are three types of bisoxindoles
and are characterized according to the type of linkage at the 3-position, however, those with two
monomeric subunits typically connected at the 3,3’ position of the oxindole 1c are the most popular.68–
71
Figure 11: Three most common types of bisoxindoles.
It is easy to see why the 3,3’ bisoxindoles 1a make such versatile synthons, in this arrangement, they
are perfectly poised to construct the C3a-C3’ labile bond bearing the vicinal continuous stereogenic
centres of the dimeric HPI framework. It is worth noting that bisoxindoles themselves have been
identified to exhibit a wide array of biological activities.72,73
A plethora of synthetic protocols have
been described for forging HPI alkaloids utilizing 3,3’ bisoxindole as a key intermediate. In this regard,
3,3’ bisoxindoles can be seen as a get to access the dimeric HPI core.
N
R
O
N
R
O
3
3’
N
N
O
O
R
R
N
N
O
O
R
R
n
n
3 3
3’
1a 1b 1c

15
There are four commonly employed approaches to access 3,3’-disubstituted bisoxindoles (Scheme 2):
a) radical dimerization of methine/methylene radicals; b) modification of unfunctionalized
bisoxindoles; c) addition to isatins/isatin derivatives; d) synthesis from acyclic precursors via cascade
sequences. Once synthesised, various functional group interconversions enable the access to the
target HPI molecules.
Scheme 2: Bisoxindoles as a gateway to a gateway to dimeric hexahydropyrrolo[2,3-b]indole scaffold.
2.1.1 Radical Dimerization
The first notable report in this category was reported by Rodrigo and co-workers. They described an
oxidative dimerization of an oxindole unit 2 using carbon tetraiodide as an oxidant in tandem with
sodium hydride in THF at low temperatures (Scheme 3).74
Mechanistically the authors rationalized that the carbon tetraiodide served as both an iodinating
agent, as well as the requisite oxidant with a radical mechanism being involved. The reaction was
initiated by the reaction of 3-(triiodomethyl)oxindole (R-CI3) with an oxindole enolate (R-
), generating
the radical anion R•
and R-Cl3. The radical anion of R-Cl3 then fragmented to give another equivalent
of R•
– the key radical species that subsequently reacted to form the bisoxindole anion product (R-R)•–
. Finally, the product reacted with R-Cl3 to yield the desired bisoxindole product 3 (Scheme 3).
N
R1
O
N
R1
O
N
R1
O
N
R1
N
R3
N
R1
N
R3
N
R1
O
R2
R2
steps
dimeric
HPI
scaffold
N
R1
O
R2
N
R1
O
R2 3
3’
d). From acyclic precursors
b). modification of
unfunctionalised bisoxindoles
N
O
X
b). radical dimerisation
c). addition to isatin/
isatin derivatives
R1

16
Scheme 3: Rodrigo and co-workers' oxidative radical dimerization approach.
About 2 decades after Rodrigo’s report, Lee and co-workers utilized this approach and disclosed an
efficient direct synthesis of bisoxindoles 6 from 3-substituted oxindoles 4. They followed an oxidative
radical dimerization using either manganese(III) acetate or copper(II) acetate/silver acetate system as
oxidants while refluxing under an inert atmosphere (Scheme 4).
Scheme 4: Lee et al. transition metal-mediated oxidative dimerization.
N
O
CO2Et
Me
N
O
N
O
EtO2C
CO2Et
Me
Me
mechanism
R-Cl3 + R- R + R-Cl3 R = oxindole
R + R-Cl3
propagation
Cl3
- + R
R-
+ R R-R
R-R + R-Cl3 R-R + R-Cl3
initiation
(±), 53%, meso 8%
2 3
CI4 (0.5 equiv.)
NaH (1.05 equiv.)
THF, -65 °C

17
Similarly, the authors proposed a radical dimerization mechanistic pathway involving the formation of
metal enolate 4’ which could then result in the generation of methine radical 5 through single-electron
oxidation from the metal. Subsequent homocoupling would afford the desired bisoxindole 6 in up to
98% yield. While the scope of their study did not include variants on the aromatic ring, they
demonstrated a broad substrate scope that tolerated esters, aliphatic, and aromatics at the C3-C3’
position. (Scheme 4).75
Soon after, Bisai et al. reported an oxidative dimerization strategy towards the total synthesis of (±)-
folicanthine, in which the formation of a 3,3’-disubstituted bisoxindole 10 was employed as a key
step.76
Scheme 5: Bisai’s bisoxindole synthesis and application towards HPI alkaloids.
Their synthesis commenced with the preparation of a phthalimido-protected N-methyl oxindole unit
7, which was deprotonated in situ by tBuOK to give enolate 8 followed by iodine-mediated oxidation
to give radical 9 in resonance with the carbon-centred radical 9’, which subsequently dimerized to give
the diphthalamido 3,3’-disubstituted bisoxindole 10 in a 56% yield and 1.2:1 diastereomeric ratio
(Scheme 5).76
The phthalimido group was cleaved by hydrazine, followed by in situ carbamate
protection to afford a MOC protected bisoxindole 11, which successfully underwent reductive
cyclisation with Red-Al afford (±)-folicanthine 12 in 68% yield.

18
Bisai extended this strategy to an electrochemical approach, where it was envisaged that the methine
radical 15 could be generated under oxidising electrochemical conditions.
In the event, they developed an efficient electrochemical strategy for the synthesis of the dimeric HPI
alkaloids, involving an electrochemical oxidative dimerization of 3-(2-furyl)-2-oxindoles 13. A plausible
mechanistic approach proposed was via electrochemical oxidation, proceeding via proton-coupled
electron transfer pathway involving a step-wise electron transfer followed by proton transfer at the
pseudobenzylic C—H bond being the key step of the oxidative dimerization process, subsequent
methine radical 15 homocoupling generated the desired dimeric bisoxindoles 16 and 17 in 60 and 62%
yields, respectively with excellent dr (6:1 in favour of (±)-isomer) (Scheme 6).77
Scheme 6: Bisai’s electrochemical strategy in radical dimerization.
Ruthenium-mediated oxidative cleavage of furan rings of 3-(2-furyl)-2-bisoxindoles 16 and 17,
followed by treatment with dimethylsulfate and K2CO3 gave bisoxindoles (±)-18 and 19 in 64 and 70%
yields over two steps respectively. These could easily be converted to bis-carboxamides (±)-20 and 21.
The resultant bis-carboxamides easily underwent reductive cyclisation with Red-Al completing the
total synthesis of (±)-folicanthine 12, and the benzyl-protected dimeric hexahydropyrrolo[2,3-b]indole
scaffold (±)-22. Authors also claimed formal synthesis of (±)-chimonanthine 23 and (±)-calycanthine
24 as they are known to be synthesised from (±)-22 in one step and two steps respectively.77
Later in 2018, Huang and co-workers oxidatively dimerized methyl oxindole unit 25 in the presence of
a catalytic amount of copper (II) acetate (10 mol%) and di-tert-butyl peroxide as a terminal oxidant
which furnished the dimeric product 28 in 81% yield.

19
The authors proposed a homolytic fragmentation of DTBP by Cu(ll) metal catalyst, initiating the
reaction and concurrently producing a tert-butoxy radical, which abstracts a hydrogen from the
oxindole unit 25 yielding methine radical 26. Copper-mediated enolization of oxindole unit 25 gives
enol 25’ which then reacts with the methine radical 26 forming a copper complex 27, which then
undergoes an O to C migration to form complex 27’ with subsequent reductive elimination to give the
desired bisoxindole 28 (Scheme 7).
Scheme 7: Base-free conditions oxidative dimerization approach reported by Huang et al.
Notably, they managed this without a base and more importantly, their method tolerated changes to
the aromatic ring, N, and C3 positions.78
However, yields following most attempts to dimerize the C3 position of the oxindole unit have
uniformly been poor, depicting a daunting synthetic challenge in forming a labile bond connecting all-
carbon quaternary stereogenic centres. Furthermore, due to weak solvation interactions, transient
radical species are not ideal candidates for C-C bond formation between two tertiary centres because
they are hampered by steric clashes, consequently, dimerization processes in common have suffered
poor selectivity and yields.65,74,79

20
2.1.2 Synthesis via Modification of Bisoxindoles
An obvious strategy for 3,3’disubstituted bisoxindole synthesis is to add groups to the unsubstituted
scaffold 29, typically through standard nucleophilicity-driven chemistry. This is exemplified in the work
by Kanai who utilized this approach for the total synthesis of (-)-chimonanthine 32 (Scheme 8).70
Following a double Michael addition using nitro ethylene 31 as a Michael acceptor, bearing nitrogen
source of the pyrroloindoline to prolong the chain thus avoiding extensive functional group inter-
conversions. Sequential Michael reaction of nitro ethylene 31 and N-Boc-protected bisoxindole 29,
and manganese Schiff base gave the product 30 in 69% yield, which was efficiently converted into the
desired (-)-chimonanthine 32 in seven steps with an overall 25% yield.
Scheme 8: Bisoxindole dialkylations by Kanai and subsequent total synthesis of (-)-chimonanthine.
Two years later after Kanai’s work, Trost and colleagues reported a twofold palladium-catalysed
decarboxylative allylic alkylation from unmodified N-Boc-protected bisoxindole 29, furnishing two
vicinal all-carbon quaternary stereocenters with defined absolute stereochemistry.80
This process
involved a successful deallylation of dienol dicarbamate 33, to produce enolates that could easily be
transformed into a 3,3’-diallyl substituted bisoxindole 34 asymmetrically. This two-fold Pd-catalysed
sequence proceeds through an initially matched allylation followed by a second mismatched allylation
to deliver the target products. In two steps the resultant diallyl-3,3’ bisoxindole 34, with an N-Boc
group could be shifted to a benzyl group and the diallyl groups subjected to ozonolysis to give aldehyde
moiety that can be further reduced to an alcohol functionality.
N
Boc
O
N
Boc
O
69%, 95% ee, >20:1 dr
over 2 steps
29
N
H
N
Me
H
N
N
Me
steps
32, (-)-chimonanthine
N
Boc
O
NO2
N
Boc
O
30’
N
Boc
O
NO2
N
Boc
O
O2N
30
without isolation
Mg(OAc)2·4H2O (5 mol%),
benzoic acid (10 mol%),
THF, 5 Å mol. sieves., 50 °C, 9 h
Mn(4-F-BzO)2, cat. (2.2 mol%),
PhMe, 5 Å mol. sieves., 50 °C, 9 h
NO2
31
(1.2 equiv.)

21
All these being key advanced intermediates for the formal synthesis of (-)-chimonanthine 32, (-)-
folicanthine 37, (-)-calycanthine 38, and ent-WIN 64821 39, and (-)-ditryptophenaline 40. The authors
claimed a formal synthesis of these compounds. (Scheme 9).
Scheme 9: Bisoxindole dialkylations by Trost and subsequent formal synthesis of HPI alkaloids.
More recently, Chen and co-workers reported an elegant and novel approach for the asymmetric
homo- and hetero-alkylation of unmodified N-Boc-protected bisoxindole 29. They used chiral
spirocyclic amide-derived triazolium organocatalysts 43 to achieve high stereocontrol for the forging
of all-carbon quaternary stereocentres — the optically active core of the dimeric
hexahydropyrrolo[2,3-b]indole 41 and 42 (Scheme 10).81
N
Boc
O
N
Boc
O
1. Alloc-Cl, Et3N
Pd2(dba)3.CHCH3, ligand
(n-hex)4NBr
96% yield, dr = 3.2:1, 92% ee
29
N
Boc
O
N
Boc
O
34
N
Boc
O
N
Boc
O
33
O
O
O
O
93% yield
N
Boc
O
N
Boc
O
35
a. TFA
b. NaH, BnBr
N
Bn
O
N
Bn
O
formal synthesis
95% yield
a. OsO4, NaIO4
2. NaBH4
52% yield
(-)-ditryptophenaline 40,
ent-WIN 64821 39
(-)-calycanthine 38
(-)-folicanthine 37
(-)-chimonanthine 32
36
OH
HO
OH
HO

22
Scheme 10: Triazonium-catalysed asymmetric homo-/hetero-dialkylation of unfunctionalized bisoxindoles.
This protocol addressed the long-standing challenge of hetero-dialkylation of bisoxindoles and authors
accomplished this in a one-pot manner with competent enantio- and diastereoselectivity (Scheme
10).
The importance of this transformation was further highlighted by its application in a hetero-
dialkylation sequence, which delivered a key heterobisoxindole intermediate 42, for the first
asymmetric synthesis of (-)-chimonanthidine. The stabilisation of the enolate intermediate derived
from the deprotonated bisoxindoles was facilitated by the hydrogen bonding interaction with the free
NH of the spirocyclic amide and the charge interaction with the triazolium unit. The sterically hindered
adamantly group of the triazole catalyst prevented the face attack of the enolate intermediate leading
to the formation of the (S,S)-dialkylated products.
The two-step hetero-alkylation of different electrophiles was successfully carried out in one pot,
introducing the two stereocenters of the compound with satisfactory enantio- and
diastereoselectivity.
2.1.3 Addition to Isatin Derivatives
Approaches falling into this category are not very common in the literature and typically involve
standard enolate and or enolate-type chemistry. Tang and co-workers presented an example of this
approach with an asymmetric organocatalytic addition of 3-methyl-2-oxindole 45 to isatin-derived N-
Boc ketimine 44, catalysed by a chiral Lewis acid. The reaction yielded bisoxindole 46 in 96% yield and
9:1 diastereoselectivity for the model reaction (Scheme 11a).82
N
Boc
O
CO2Bn
N
Boc
O
BnO2C
N
Boc
O
CO2Bn
N
Boc
O
BrCH2CO2Bn, (4 equiv.)
K2CO3
70% yield, 90% ee
1. BrCH2CO2Bn, (2 equiv.)
K2CO3
2. Isoprenyl bromide
(3 equiv.)
69% yield, 85 ee
N
Boc
O
N
Boc
O
HN
O
N
H2N
HN
triazolium catalyst
a b
29
43
41 42

23
Scheme 11: Bisoxindole formation via addition to isatins derivatives (a), Addition to isatins (b).
4 years later Wolf et al. (Scheme 11b), reported the synthesis of 3-fluoro-3’-hydroxy-3,3’-bisoxindoles
49 by adding N-phenyl-3-fluoro-oxindoles 48 to isatins 47 under basic conditions at room
temperature. The bisoxindole formation was noteworthy as it could be successfully upscaled to a gram
scale without any loss of yield or diastereoselectivity, thus demonstrating is potential for large-scale
applications.83
2.1.4 Modification of Acyclic Anilides
Most methods for the synthesis of bisoxindoles require an cyclic precursor or the bisoxindole
framework to already be in place. There is however a growing interest in developing approaches
commencing from acyclic precursors due to the simplicity and modularity of the approach.
Zhang and co-workers reported a copper(I) mediated oxidative arylation-dimerization from acyclic
precursor 50, which afforded bisoxindole 51 in 76% yield with modest stereocontrol (DL/meso = 10:
1) and 99% ee using a chiral sulfinamide auxiliary. The copper oxidant not only promoted cyclization
via arylation but also oxidative dimerization in one pot manner, with tert-butyl peroxide serving as a
terminal oxidant to regenerate copper (l) to copper (ll) (Scheme 12).
It is noteworthy that during the time of writing the thesis, this was the only reported example of an
acyclic precursor approach to bisoxindoles.

24
Scheme 12: Zhang’s diastereoselective synthesis of 3,3’ disubstituted bisoxindoles from acyclic precursors.

25
2.2 Design Strategy and Approach
One-pot strategies for the synthesis of 3,3’-disubstituted bisoxindole from acyclic precursors are rare
and highly desirable due to their modular approach. In conceptualizing such one-pot strategy for the
synthesis of 3,3’-disubstituted bisoxindole 55 from acyclic precursor 52, three main retrosynthetic
disconnections were identified (Scheme 13): 1) homocoupling of methine radical 54; 2) in situ
generation of radical 54 from an intermediary oxindole 53; 3) production of oxindole 53 from a cross-
dehydrogenative cyclisation of acyclic precursor 52. Each step had been independently documented
in the literature; all proceeding through oxidative conditions. Thus, we were confident that a one-pot
procedure could be developed and that it would go all way around the cycle.
Scheme 13: Retrosynthetic analysis and conceptualization of bisoxindole synthesis.
The radical dimerization/homocoupling step (i.e., 54 to 55) has already been mentioned in sections
2.1.1 and 2.1.4. The CDC step (i.e., 52 to 53) has similarly been well documented, with pioneering
studies featured in the independent works by Taylor and Kündig (Scheme 14).84,85

26
Scheme 14: Independent pioneering CDC reports by Taylor (a) and Kündig (a) for oxindole formation.
The key step in the mechanism involves the generation and homolytic aromatic substitution (HAS)
cyclisation of acyclic methine radical 56 and 56’, generated in the presence of copper salts via oxidative
single electron transfer.
2.2.1 The Leaving Group: Oxidative Fragmentation
The only consideration remaining of our envisioned one-pot cascade was determining the structure
of the starting anilide 52. Specifically, we needed to identify a suitable leaving group (LG) that would
be stable enough to facilitate cross-dehydrogenative cyclisation step (52 to 53) yet labile enough to
undergo spontaneous oxidative fragmentation post-cyclization to generate methine radical 54 (step
53 to 54) — accordingly viewed as a delayed radical precursor. Recent literature highlighted several
fragmenting groups that would be suitable for such radical fragmentations (Scheme 15).
Scheme 15: Plausible delayed radical precursors.
Me
O
H
deformylation
Me
dehalogenation
N
Me
O
-
O
H
decarboxylation
N
Me
Ph
N
Me
Ph
O
OH
-H+, -e,
+e, -Cl
N
O
Me
Cl
-H+, -e-, -CO2
a.
b.
c.

27
This includes (but not limited to a) deformylations86,87
b) dehalogenations,88–90
and c)
decarboxylations91,92
We were particularly intrigued by the carboxylic acid fragment as we considered it to be more readily
available and easy to prepare. Furthermore, its use within the cascade sequence is more
environmentally friendly relative to the other options. Additionally, they have been successfully
employed with great ease as traceless handles in generating c-centred radicals mediated by; transition
metal catalysis,93
metal-free catalysis94
or photoredox catalysis,95
making them a versatile and
attractive option for our proposed cascade sequence.
2.3 Proposed Mechanism
We were confident with our design rationale and proceeded to propose a plausible pathway for an
oxidative cyclisation-decarboxylation-dimerization cascade sequence (Scheme 16).
Scheme 16: Proposed mechanistic pathway features the carboxylate-derived delayed radical precursor.
N
Me
O
Et
OH
O
N
Me
O
O
OH
Et
N
Me
O
O
OH
Et
N
Me
O
O
OH
Et
N
Me
O
Et
N
Me
O
N
Me
O
Et
Et
CO2
58
59
61
59’
60
62
N
Me
O
Et
OH
O
57
N
Me
O
Et
OH
O
57’
-e-
OX
-H+, -e-
OX
-H+
-H+
base
-e-
OX
homocoupling
-H+

28
Enolisation of β-oxoacid 57, generates enolate 57’, which in the presence of a suitable oxidant,
undergoes SET oxidation generating acyclic radical 58, which subsequently undergoes homolytic
aromatic substitution to generate the cyclohexadiene radical 59. Oxidation of 59 yields a Wheland-
type cyclohexadiene cation 59’, which can effectively lose a proton to give the oxoindoline-3-
carboxylic acid 60.85,96–99
Related oxidative radical decarboxylation of 60 via a SET generates the
methine radical 61, which subsequently undergoes a perfectly predicted homocoupling to yield the
desired product – bisoxindole 62.100–103
2.4 Reaction Route Development
In this context, we identified β-oxoacid 57 as our model starting material which could be conveniently
prepared in two steps. The first step involves a peptide coupling reaction between commercially
available N-methyl aniline 63 and a half-malonic acid ester 65. We chose to use Mukuiyama’s reagent
64 as a coupling reagent of choice for this coupling reaction due to its mild and efficient nature and its
ease of use during the post-reaction work-up and purification steps. Mukuiyama’s reagent 64 contains
a pyridinium complex, which acts as an activating agent to promote the formation of an activated
intermediate with the half-malonic acid ester 65. This intermediate undergoes nucleophilic attack by
N-methyl aniline 63 to form the desired peptide linkage in the β-oxoester product 66.104,105
The hydrolysis of the ethyl ester group in the resulting β-oxoester 66 was carried out using LiOH.H2O,
which proceeds through an SN2 mechanism in good yields. In the process of lithium-mediated
hydrolysis, the coordination of lithium to the ester carbonyl group and the heteroatom at the α or β
position leads to the formation of a five- or six-membered chelate. This coordination results in an
increase in the reactivity of the ester carbonyl group, which facilitates the subsequent attack by the
hydroxide ion. This attack leads to the formation of a carboxylate intermediate, which, upon
protonation, ultimately generates the desired β-oxoacid 57.106–108
Scheme 17: Synthesis of the model 𝛽-oxo-acid 57.

29
The successful hydrolysis of the ester was confirmed using NMR spectroscopy. Specifically, the
disappearance of the ethyl ester signals were observed in both 13
C and 1
H NMR spectra. The yield of
the hydrolysis reaction was found to be 91%, indicating a high efficiency of the process. Overall, this
synthetic approach provides a straightforward and efficient method for the preparation of β-oxoacid
starting materials for use in subsequent cascade reactions.
With the model acid 57 in hand, we turned our attention to the desired oxidative cyclisation
decarboxylative dimerization cascade sequence. The results of the optimisation studies are
summarised in (Table 1).
Table 1: Reaction optimisation studies for the oxidative cyclisation dimerization cascade sequence.
entry catalyst (equiv.) oxidant(equiv.) solvent yield 62 (%)a
yield 67 (%)a
1 Cu(OAc)2.H2O (0.10) air PhMe - trace
2 Cu(OAc)2.H2O (0.50) air ACN - trace
3 Mn(OAc)3.2H2O
(0.10)
air PhMe 31 26
4 Mn(OAc)3.2H2O
(0.50)
air ACN 37 11
5d
Mn(OAc)3.2H2O
(0.50)
(NH4)2S2O8(3) THF - -
6b Mn(OAc)3.2H2O (3) - PhMe 56 -
7b Cu(OAc)2.H2O (3) - PhMe 10 29
8 Fe(OAc)2 (0.10) K2S2O8(1.5)/NaI(0.30) DMSO - -
a
Isolated yields as a 1:1 mixture of separable meso:±-D,L-diastereomers. B
under argon. C
with tBuOK base. D
starting material recovered.
E
at vigorous reflux 110 ℃
N
Me
O
Et
OH
O
N
Me
O
OH
Et
N
Me
O
N
Me
O
Et
Et
‘conditions’
solvent, reflux
48 hr
57 62
67

30
Inspired by independent reports by Taylor and Kündig, we decided to use copper salts to initiate the
studies of our envisaged cascade sequence. Our goal was to develop sustainable processes that
utilized molecular oxygen as a terminal oxidant to regenerate the catalytic amount of the active
catalyst since the overall cascade sequence was net oxidative. In the event, our initial attempts using
both 10 mol% and 50 mol% Cu(OAc)2.H2O failed to produce any desired product (entries 1 and 2). We
then switched to Mn(OAc)3.2H2O and we were able to attain the desired bisoxindole 62 in a promising
31% yield (as a 1:1 mixture of diastereomers), along with the formation of hydroxyoxindole 67 in 26%
yield (entry 3). However, increasing the amount of Mn(OAc)3.2H2O to 50 mol% did not significantly
improve the yield (entry 4). This result revealed an inherent challenge associated with utilising O2 as
a terminal oxidant, which is a competitive trapping of the methine radical by O2. This resulted in the
formation of hydroxyoxindole 67, which was significant and led to the near 1:1 ratio with desired
product 62 (Scheme 18).
Scheme 18: Formation of hydroxyl oxindole via methine radical interception.
Given the significant competition between homocoupling and O2 trapping by the methine radical, we
decided to switch to anaerobic conditions with a stoichiometric amount of ammonium persulfate as
a terminal oxidant, despite this being contrary to our preference and need for a greener process.
However, using this approach did not yield any improved results (entries 5).
Reflecting on our lead result (entry 3) we opted to use only Mn(OAc)3.2H2O under anaerobic
conditions (entry 6), with three equivalents to account for our 3 oxidation steps; thus, while seemingly
stoichiometric.
N
Me
O
Et
OH
O
N
Me
O
O
OH
Et
N
Me
O
Et
57
61
N
Me
O
Et
N
Me
O
Et
68
O OH
OH
‘’conditions’’
solvent, reflux
O2
60
67
OX
-2e-, -2H+
-H+,e-, -CO2
OX

31
However, strictly speaking, overall all the catalyst loading amounted to 1 equiv. per step as the
reaction had three requisite oxidation steps, resulting in 56% yield (entry 6) without the formation of
the side product. We were satisfied with the outcome as the oxidative cyclisation, decarboxylation
dimerization cascade sequence formed three bonds in one step.
In contrast, attempts to use Cu(OAc)2.2H2O did not improve the chemistry (entry 7) and conditions
reported by Zhao also did not result in higher yields (entry 8).109
Admittedly, this was consistent with
some literature reports supporting the use of manganese salts as superior oxidants for free radical
cyclisation reactions compared to closely related transition metal salts.110
Kochi’s studies have shown that solvents can significantly affect the stability of the manganese
trinuclear complex, thereby impacting its oxidising efficiency.111
In this context, we investigated the
effects of different solvents on our cascade sequence (Table 4). Dichloromethane (entry 1), only gave
a trace amount of desired dimeric product 62, as indicated on the TLC plate with reference to a
standard, likely due to its low reflux temperature. When we switched to solvents with higher boiling
temperatures, such as acetonitrile the yield of the bisoxindole 62 improved to 64% together with a
36% yield of the hydroxyloxindole 67 (entry 2).
However, both DMF and mesitylene afforded lower yields (entries 3 and 4), while THF gave a
significant improvement, resulting in a yield of 71%. Ultimately, the optimum conditions were found
by employing THF under vigorously refluxing conditions at 110 ℃, which resulted in an 81% yield of
bisoxindole 62 (entry 5).
Table 2: Solvent optimisation studies for the oxidative cyclisation dimerization cascade sequence.
entry solvent yield 62 (%)a
yield 67 (%)a
1 DCM trace -
2 ACN 64 36
3 DMF 24 30
4 Mesitylene trace 36
5 THF 72(81e
)
a
Isolated yields as a 1:1 mixture of separable meso:±-D,L-diastereomers. b
under argon. C
with tBuOK base.d
starting material recovered.
e
at vigorous reflux 110 ℃
N
Me
O
Et
OH
O
N
Me
O
OH
Et
N
Me
O
N
Me
O
Et
Et
Mn(OAc)3.2H2O (3 equiv.)
solvent, reflux, 48 hr
57 62 67

32
2.4.2 Substrate Scope
With our optimal conditions at hand, we moved on to explore the substrate scope, as depicted in
(Figure 12).
Figure 12: Substrate scope.
Our optimal conditions were found to be suitable for a wide array of substrates. Alkyl groups, including
long-chain variations (R3
), were well tolerated producing bisoxindoles 62a and 62c in 81% and 93%
yield, respectively. Protecting the nitrogen (R2
) with the benzyl group gave the N-benzyl-protected
bisoxindole 62c in 91% yield. Modifications on the aromatic rings we also well tolerated including
halides, and electron-donating groups 62e–62i in excellent yields of 85%−96%. Pleasing yields of
65%−95% were also observed as disubstituted and electron-withdrawing substituents were also
obtained, 62j–62l.
The reaction yielded a ca. 1:1 mixture of separable meso and (±)-dl diastereomers, in agreement with
literature reports that (±)-dl is less polar than the meso diastereomer. This information was
instrumental in assigning stereochemistry.75,78
In a 3:7 EtOAc:hexane solvent system, with reference
to our model substrate 62a, we observed that the meso and (±)-dl had Rf values of 0.24 and 0.59,
respectively.
R1
N
R2
O
R3
R1
N
R2
O
R3
N
Me
O
Et
62a
81%
Mn(OAc)3.2H2O (3.0 equiv.)
THF , 110 ℃.
argon, 48 h
N
Me
O
Me
62g
90%
N
Me
O
Me
62h
85%
N
Me
O
62f
91%
N
Me
O
Me
62d
93%
Me
Obtained as a ~1:1 mixture of separable meso:(±)-dl diastereomers.
N
Me
O
Me
62e
88%
62k
78%
N
Me
O
Me
62j
95%
N
R2
O
R3
O
OH
Me
MeO
F
Br
Cl
F
F
N
Me
O
Me
F
Br
N
Bn
O
Me
62c
92%
N
Me
O
Me
62i
96%
N
Me
O
62b
93%
N
Me
O
Me
62l
65%
O
Me
OMe
R1
57 62

33
Both diastereomers were visible under short UV light and had a characteristic distinct deep purple
colour after staining with anisaldehyde stain (5% anisaldehyde in EtOH) and heating with a heat gun.
Due to the large difference in Rf values, the diastereomers could easily be separated by standard
column chromatography without the need for specialised equipment. (Figure 13).
Figure 13: TLC plates for meso:(±) and -dl diastereomers run in 3:7 EtOAc:hexane. a.) Under UV light, b.) After
staining with anisaldehyde.
Figure 14 depicts the proton and carbon spectra of the dl isomer (62a), which possesses a total of 24
protons and 11 carbons. These counts align with the expected signals and are consistent with the
proposed structure C22H24N2O2. The 1
H NMR spectrum reveals four distinct peaks in the aromatic
region, ranging from 7.05 to 6.40 ppm, with a ratio of 2:1:1. This splitting pattern in the oxindole core
serves as a distinguishing feature. The 13
C NMR spectrum confirms this pattern, as the signals at 128.1,
123.3, 121.7, and 107.2 ppm exhibit cross-peaks in the HSQC spectrum. Notably, the broad singlet
peak at 11.1 ppm in 1
H NMR and a downfield 172.8 pp in 13
C NMR, corresponding to the carboxylic
acid proton, is absent, indicating decarboxylation. Additionally, a singlet peak at 3.06 ppm, with a 3:1
integration ratio, confirms the presence of N-methyl protons. Two quartets of doublets are observed
at 2.79 and 2.34 ppm, in a 1:1 ratio, which was expected given the diastereotopic nature of the protons
beta to the carbonyl group. Furthermore, a downfield triplet at 0.40 ppm corresponds to the methyl
group. It is worth mentioning that the observed signals in the dl isomer appear downfield, which can
be attributed to steric compression adjacent to a quaternary centre.
a.) Under shortwave UV
light 254nm.
b.) After staining with Anisaldehyde
and gentle heating.
(±)-dl
meso

34
Figure 14: 1H and 13C NMR spectra for the (±)-dl diastereomer of the model product.
In Figure 15, the meso isomer (62d) exhibits the same proton and carbon count as the dl isomer. It
displays four separate signals in the aromatic region, specifically at 7.15, 6.81, 6.61, and 6.47 ppm,
which cross-peak to the corresponding carbon signals (128.4, 124.0, 121.6, and 107.7) in the carbon
spectrum. Similar to the dl isomer, the carboxylic acid peak is absent in both the proton and carbon
NMR spectra. However, a notable difference is observed in the aromatic protons: the meso dimer
shows four distinct signals, whereas the dl isomer exhibited three signals.

35
The chemical shifts in the dl isomer are slightly more downfield compared to the meso isomer,
although falling within similar ranges. The N-methyl and aliphatic signals in the meso isomer appear
in ranges similar to those in the dl isomer, specifically at 2.87, 2.68, 2.02, and 0.36 ppm, respectively.
The integration values for these peaks are six, two, two, and six, respectively.
Figure 15: 1H and 13C NMR spectra for the meso diastereomer.

36
2.4.3 Failed Substrates
The scope had its clear limitations and some of the substrates that we failed to access are depicted
below. (Figure 16).
Figure 16: Unsuitable substrates.
Products 62m (i and ii), as well as their corresponding cyclic oxindoles, were not isolated, presumably
due to the persistent radical effect, a phenomenon in which radicals are long-lived and do not self-
terminate or react with other species,112–114
which presumably hinders the desired cyclization.
Additionally, the steric bulk of the boronic ester group might have hindered the biradical coupling,
leading to the non-isolation of desired product 62m iii. Surprisingly, the undimerized oxindole was
not obtained, and the starting acid was not recovered in all cases. In these cases it is possible that
degradation via further decarbonylation could have occurred, however the corresponding aniline was
also not isolated. Meanwhile, products 62m (iv-vi) could not be synthesized due to challenges
associated with the synthesis of the starting β-oxoacids. We were unable to access the corresponding
starting β-oxoesters via standard enolate chemistry.
2.5 Complementary Approach – Deformylation Strategy
Given the success of the oxidative cyclisation decarboxylation dimerization strategy, we went on to
develop an analogous oxidative cyclisation deformylation dimerization approach which similarly
provided access to bisoxindoles and assisted in overcoming some of the aforementioned limitations.
Particularly, with reference to accessing the starting precursors. Indeed, the use of deformylation
approaches to generate carbon-centred radicals features well in the literature (Scheme 19).86,87

37
Scheme 19: Proposed analogous deformylation approach.
NOTE: Investigation of this approach was primarily handed over to another student in the group, but
for completeness of this thesis, a brief overview will be provided as I contributed fairly substantially to
these results.
The synthesis of the β-oxoanilides as shown in (Scheme 20), involves a peptide coupling reaction
followed by an independent titanium-mediated formylation step with methyl formate. Notably, these
β-oxoanilides exhibit remarkable stability, withstanding storage for up to 6 months when refrigerated
and up to a week on the benchtop.
Scheme 20: Synthesis of the starting β-oxoanilide.
2.5.1 Substrate Scope – Starting from β-oxoanilide
After establishing an efficient synthetic route of our alternative starting β-oxoanilide, we subjected it
to our optimal conditions; Mn(OAc)3.2H2O (3 equiv.), THF, reflux, gave the desired bisoxindole 62 in
86% yield. When reverting to our second best conditions; utilising Mn(OAc)3.2H2O (3 equiv.), ACN,
reflux gave the product was obtained in an outstandingly 92% yield. As before, a 1:1 mixture of
separable diastereomers was obtained (Scheme 21).

38
Scheme 21: Bisoxindole synthesis attempts via deformylation approach.
We then proceeded to investigate the substrate scope of the deformylation approach, while also
observing any notable differences in performance compared to the decarboxylative approaches
(Figure 17).
Figure 17: Substrate scope starting from aldehyde starting material.
The deformylation approach proved to be amenable to a wide array of substrates, with the model
substrate 62a giving an exceptional 92% yield.
R1
N
R2
O
R3
R1
N
R2
O
R3
N
Me
O
Et
62a
92%
Mn(OAc)3.2H2O (3.0 equiv)
ACN, reflux, argon, 48 h
N
Me
O
Me
62g
80%
N
Me
O
Me
62h
60%
N
Me
O
62f
84%
N
Me
O
Me
62d
79%
Me
Obtained as a ~1:1 mixture of separable meso:(±)-dl diastereomers.
62k
59%
N
Me
O
Me
62j
88%
N
R2
O
R3
O
H
Me
MeO
F
Br
F
F
N
Me
O
Me
F
Br
N
Bn
O
Me
62c
92%
N
Me
O
Me
62r
71%
F3C
N
Me
O
62s
70%
Me
O2N
N
Me
O
62o
60%
N
Me
O
62n
82%
N
Me
O
62p
90%
BnO
N
Me
O
62q
59%
Br
R1
Ph
68 62

39
Modifications to the alkyl sidechain were well tolerated 62(n – q), including cylopentyl, long chain
aromatic, O-benzyl protected and alkyl bromides, yielding bisoxindoles in good to excellent 59–92%
yield. The N-benzyl-protected nitrogen bisoxindole 62c was obtained in 92% yield and the especially
valuable substrate as in principle debenzylation would lead to the free N-H which is highly desirable
in medicinal chemistry and novel HPI cores. Aromatic variations with halogens, electron-withdrawing
and donating and notably handles which can easily be functionalised, such as -NO2, -OMe were also
endured, providing products 62d, 62f, 62r, 62s, 62g and 62h in 70–84% yield. Disubstitution on the
aromatic rings was also well-tolerated with, bisoxindoles 62j and 62k being obtained in 88% and 59%
yields, respectively.
2.5.2 Unsuitable Substrates – Starting from β-oxoanilide
The deformylation approach similarly had its own clear limitations. These are summarised in Figure
18.
Figure 18: Products not obtained starting from aldehydes.

40
Failure to obtain bisoxindole 62m vii did not come as a surprise. Cyclopropanes have long been
employed as radical clock probes in radical chemistry.115
Scheme 22: Telescoped radical-mediated cyclopropane scission.
Due to high ring strain within the cyclopropane ring, they tend to undergo scission whenever a radical
is placed adjacent to the ring, as shown in Scheme 22. Following SET oxidation of aldehyde 70, the
resultant radical 70’ undergoes cyclopropane scission due to the proximity of the radical to the
cyclopropane ring resulting in radical 71. This leads to the formation of the formal dienamide following
similar SET oxidation. This was consistent with similar reports by Taylor, who also observed similar
cyclopropane scission in cyclopropyl-anilides99
This is also supportive of the existence of radical 70’ in
our proposed mechanism which then undergoes homolytic aromatic substitution (Scheme 24).
We also encountered difficulties in obtaining bisoxindoles 62m (viii–x) via the deformylation
approach. We attributed this to the persistent radical effect, a phenomenon in which radicals are long-
lived and do not self-terminate or react with other species,112–114
presumably in this instance resulting
in no cyclization. Similarly, products 62l, and 62m (iv–vi) could not be synthesized due to challenges
associated with the synthesis of the starting β-oxoanilides, as we were unable to formylate the
corresponding starting anilides using standard enolate chemistry. However, it is worth noting that
bisoxindole 64l could potentially be obtained by debenzylation of bisoxindole 62c.
Similarly, with the decarboxylative approach further investigations are underway in Petersen Labs to
provide a more concise explanation to the scope’s limitations.
Looking at both decarboxylative and deformylative approaches there aren’t significant differences
between the two approaches as they are relatively complementary to each other.

41
A specific point of difference was encountered during our work, was the inability to, synthesise
bisoxindole 62l, due to our inability to access the starting aldehyde. However, this limitation was
complemented by the decarboxylative approach, which allowed us to obtain the same bisoxindole in
65% yield.
2.6 Plausible Mechanistic Pathway and Mechanistic Evidence
A plausible reaction mechanism for the decarboxylative strategy is shown in (Scheme 23). The
proposed mechanism for the decarboxylative approach involves SET oxidation of carboxylic acid 57 by
the first equivalent of MnIII
, generating radical 58 while the metal catalyst is reduced to MnII
.110,116
The
resultant acyclic radical 58 endures homolytic aromatic substitution yielding radical 59, a cyclo-
hexadiene radical, which undergoes a second SET oxidation by a second equivalent MnIII
metal catalyst
yielding cyclohexadiene cation 59’, which loses a proton to give the cyclic oxindole 60.85,99,117
Following
deprotonation of carboxylic oxindole 60, a third and final oxidative SET process generates methine
radical 61 with concomitant loss of CO2,118–120
which subsequently dimerises to afford bisoxindole 62.
Scheme 23: Proposed reaction mechanism starting from β-oxoacid and TEMPO trapping experiment.
N
Me
O
Et
OH
O
N
Me
O
O
OH
Et
N
Me
O
O
OH
N
Me
O
O
OH
Et
N
Me
O
Et
N
Me
O
N
Me
O
Et
Et
N
Me
O
Et
OH
O
Ph
N
Me
O
Et
O
O H
O
N
Me
Me
Me
Me
TEMPO
N
Me
O
O
Me
74
45%
homocoupling
-CO2
-H+
Mn
SET
Mn
SET
Mn
SET
CDC
Mn
SET
57 58 59 59’
60
61
62
73
-H+, e- -e-
-H+, e-
H
Et

42
In the event of carrying out the reaction in the presence of TEMPO, the reaction failed to produce the
desired dimer 62 but instead, ketoamide 74 was isolated in 45% yield. We propose that occurred via
trapping of radical 58 by TEMPO to produce adduct 73 which subsequently decarboxylates to give the
ketoamide 74 in 45% yield. The trapping of radical 58 by TEMPO provides strong evidence towards the
existence of radical 58 which directly supports our proposed mechanism (Scheme 23).
Starting from the β-oxoanilide similar set of events occurs for the deformylative route (Scheme 24).
The main difference from the acid mechanism is the generation of the methine radical 61 from
aldehyde 68. We envisaged this to go via known polynuclear metal complex deformylations.87
Alternatively we considered an unconventional pathway which would oxidise the oxindoline
carbaldehyde 77 to oxindoline carboxylic acid 60 (Scheme 23 above) with subsequent deprotonation
and decarboxylation to generate the methine radical 61. However, under such circumstances, this
would equate to four requisite oxidation steps, and given that we employed three equivalence of
metal oxidant, in theory, it would incline a maximum theoretical yield of 75%. Since we had yields
above this threshold, this suggested otherwise and we considered this pathway to be doubtful.
Conversely, our proposed mechanistic pathway is not conclusive (Scheme 24).
Scheme 24: Plausible mechanism starting from aldehyde with TEMPO trapping experiments.
N
Me
O
Et
H
O
N
Me
O
O
H
Et
N
Me
O
O
H
Et
N
Me
O
Et
N
Me
O
N
Me
O
Et
Et
N
Me
O
Et
H
O
N
Me
O
O
Me
74
33%
-H+
Mn
SET
SET
Mn
SET
CDC
68 75 76 76’ 77
61 78’
81
N
Me
O
HO
O
Et
78
Mn OH
MnIII
N
Me
O
O
O
Et MnII
N
Me
O
Et
79
O
N
Me
Me
Me
Me
N
Me
O
Et OH
TEMPO
67
19%
Ph
N
Me
O
H
O
80
Et
O
N
Me
Me
Me
Me
Ph
N
Me
O
O
Et
O
N
Me
Me
Me
Me O
MnII
-HCO2H
-HCO2H
TEMPO
62
-H+,e- -e-
-H+,e-
N
Me
O
O
H
H
Et

43
Carrying out the reaction in the presence of TEMPO using β-oxoanilide starting material, we did not
obtain the desired bisoxindole 62. Instead, we isolated a ketoamide 74 as a major product in 33% yield
along with a hydroxy oxindole 67 in 19%. These results further support the proposed mechanism
involving the existence of acyclic radical 75 and the methine radical 61 (Scheme 24).
2.7 Application Towards Synthesis of the Dimeric Hexahydropyrrolo[2,3-B]Indole Core
To further demonstrate the utility of our developed cascade sequence, we aimed to complete the
total synthesis of (±)-folicanthine 12. Inspired by previous work by Ghosh,76
our retrosynthetic analysis
commenced with the recognition of dimeric methoxy carbamate protected diamine intermediate 82
which could be reductively cyclised to yield the alkaloid (±)-folicanthine 12. The protected bisoxindole
diamine intermediate 82 can be traced back to functional group interconversion starting from a
suitable bisoxindole 83, which could be synthesised using our oxidative cyclisation-deformylation-
dimerization cascade sequence of the formyl phenyl-butanamide 84.
We envisaged formylation of anilide 85 for efficient synthesis of the formyl phenyl-butanamide 84 for
the key dimerization reaction. Anilide 85 could be prepared by peptide coupling of the commercially
available N-methylaniline 61 and 𝛾-butyric acid 86 possessing a suitable group which could endure the
synthetic route, and easily be functionalised at a later stage (Scheme 25).
Scheme 25: Our retrosynthetic plan for the total synthesis of (±)-folicanthine.

44
Looking back at our substrate scope, we proposed that di(bromoethyl) bisoxindole 62q, obtained
previously, could be converted to azides 87 and 88 (Scheme 26), providing a late-stage advanced
intermediate.121
Reagents and conditions: a.) DIPEA, DCM, 0 ℃–rt. b.) Methyl formate, TiCl4, DCM for 30 mins then NEt3. c.) Mn(OAc)3.2H2O ACN, reflux 48h,
argon. d.) NaN3, DMF/H2O (4:1), 60 ℃–rt. 3 h. e.) Red-Al PhMe, reflux 16h, argon. f.) PPh3, THF, rt. g.) Moc-Cl, aq, sat NaHCO3, 0 ℃–rt 6h.
Scheme 26: Formal synthesis of (±)-folicanthine.
Azidation of the di(bromoethyl) bisoxindole 62q efficiently furnished the di(azidoethyl) bisoxindoles
87 and 88 in 71 and 69% yield for the meso and (±)-dl respectively. However, independent attempts
at direct reductive cyclisation of 87 and 88 following reports by Hayashi and co-workers were
unsuccessful.122
Instead we followed a similar protocol to that reported by Bisai which involved
independent Staudinger reduction of meso and dl di(azidoethyl) bisoxindoles to give the free amine,
which was subsequently protected by Moc in situ to give MOC-protected meso and (±)-dl-dimers 90
and 91, gratifyingly completing the formal synthesis as per Bisai’s procedure.76

45
2.8 Conclusion and Outlook
We have developed a mild and efficient Mn(OAc)3·2H2O mediated one-pot protocol for synthesising
bisoxindoles via an oxidative-dehydrogenative cyclisation-fragmentation-dimerization cascade
sequence.
The fragmentation step can proceed via decarboxylation when employing carboxylic acids as starting
materials or via deformylation when aldehydes are used. These starting acyclic materials are simple,
cheap, and easy to access and store. Both approaches are applicable to a wide array of substrates with
broad functional group tolerance. There aren’t many clear-cut differences between using aldehydes
versus carboxylic acids as starting materials, however, overall, they complement each other. This work
marks the first use of novel/delayed radical precursors which generate synthons for a cascade
sequence at a later stage. Furthermore, it represents the first formation of three consecutive bonds
in one step and the first example of 3,3’-disubstituted bisoxindole synthesis from simple acyclic
precursors.
Mechanistic studies, such as TEMPO trapping experiments, were supportive of the proposed reaction
mechanism as our proposed radical intermediates were trapped to form TEMPO adducts, which
supported their existence in our plausible mechanistic pathway. Further utility of this reaction was
demonstrated in its application to the formal synthesis of (±)-folicanthine. This reaction also opens
new reactivity channels, particularly the use of the delayed radical precursor in forging complex
natural product motifs.
The current methodology employs three equivalents of oxidant, albeit one equivalent per each
requisite step. However, developing a room-temperature alternative would be desirable. Additionally,
there is a need to address the issue of diastereoselectivity since the current method affords a mixture
of 1:1 meso: (±)-dl diastereomers, which limits its synthetic usefulness. Additional mechanistic studies
to better understand the mechanism will be a topic of future work, particularly the order of events in
the oxidative-dehydrogenative cyclisation-fragmentation-dimerization cascade sequence and also to
have an understanding if the single electron transfers during oxidations from transition metal occur
via inner sphere or outer sphere mechanism.
Lastly, a diverse library of cyclotryptamine alkaloids is envisaged to be constructed via this method
and screened for biological activity — specifically relevant to the African disease burden of TB and
malaria.

46
Part 2: Synthetic Approaches for the Construction of the Quinolin-2-
one Scaffold
This work was published in Organic and Biomolecular Chemistry (Munashe Mazodze, C.;
F. Petersen, W. Silver-Catalysed Double Decarboxylative Addition–Cyclisation–Elimination Cascade
Sequence for the Synthesis of Quinolin-2-Ones. Org. Biomol. Chem. 2022, 20, 3469-3474).123

47
Chapter 3
3.1 Introduction
Inspired by our success utilizing a delayed acyl radical precursor (Chapter 2), we aimed to extend this
cascade strategy to furnish a more complex and rigid dimeric 6-6 ring system 96, via a similar oxidative
radical cyclization dimerization sequence (Scheme 27).
Scheme 27: Envisaged oxidative double decarboxylative addition cyclization dimerization sequence for the
formation of 6-6 ring systems.
We envisioned that the key monomeric methine radical species 95 could similarly be produced
following a radical decarboxylation of the quaternary quinolinone 94, which could be generated via a
decarboxylative addition-cyclization sequence of oxamic acid 92 (through the formation carbamoyl
radical 92’) and an acrylic acid 93.
The oxidative generation of such carbamoyl radicals from their corresponding oxamic acids is well
documented in the pioneering studies by Minisci (Scheme 28).124,125 The use of oxamic acids has
distinct advantages. They are non-toxic, readily available, and bench-stable precursors that are easier
to store and handle than their counterparts; acyl and oxylcarbonyls are susceptible to decarboxylation
and decarbonylation, respectively.126

48
Scheme 28: Oxamic acids preparation from oxalyl chloride monoesters (97–98) and carbamoyl radical
generation from oxamic acid (99–100).
Oxamic acids can be easily prepared by direct coupling ofcommercially available oxalic acid monoester
derivatives and amines. The resulting oxamic ester intermediate can then be hydrolysed under basic
conditions to give the oxamic acid (as shown in Scheme 28). The acids are easily purified by simple
acid/base chemistry, allowing for the production of diverse precursors through only amine
modification without the need for lengthy and tedious purification processes.127
Accordingly, our model N-aryl oxamic acid 102 was prepared via nucleophilic acyl substitution reaction
between N-methylaniline 63 and methyl chloro-oxoacetate 100, in the presence of triethylamine as a
base, yielding oxamic acid ester 101 in 98% yield (Scheme 29).128
Base hydrolysis of the oxamic ester
101 with KOH or CsOH in THF/H2O solution, followed by purification via acid-base extraction afforded
the desired oxamic acid 102 in 86% yield.
In an alternative preparation, oxamic acid 102 could be synthesized by a low-temperature reaction
between N-methylaniline 63 and oxalyl chloride 103, followed by NaOH quench at 0 ℃, leading to the
direct access of oxamic acid 102 in 54% yield, excluding the need to proceed via the ester. Both
methods gave high-quality and structurally diverse oxamic acids in good to high yields.
NH
R1
R2
N
R1
R2
O
O
OR3
N
R1
R2
O
O
OH
N
R1
R2
O
oxidation
-H+, -e-, -CO2
Oxamic ester
Base
KOH
R3 = Me/Et
oxamic acid carbamoyl radical
97
98
99 100
Cl
O
O
OR3

49
Scheme 29: Synthetic approaches of our model starting oxamic acids.
To test the viability of our proposed 6-6 dimerization, we subjected the freshly prepared oxamic acid
102 and methacrylic acid 103 to our stoichiometric Mn(OAc)3.H2O (3 equivalents) conditions, as the
overall transformation would similarly require three requisite sequential oxidation steps. In the event,
the monomeric 2-quinolone 105 was isolated in 52% yield, and the envisaged dimer 104 was not
detected (Scheme 30). While initially disappointed, we recognized this as an opportunity to further
develop this chemistry, given the biological importance of the 2-quinolone scaffold (Chapter 1).
Scheme 30: One pot oxidative double decarboxylative addition cyclization dimerization sequence attempts.
The preferential isolation of monomeric structure instead of dimeric product can presumably be
rationalized to two main factors when comparing dimeric structure 104 and monomeric structure 105
(Scheme 31). Firstly, dimeric structure 105 contains a labile C4-C4’ bond that links all vicinal
quaternary stereogenic centres.

50
The formation of such bonds is a formidable synthetic challenge, and with increasing ring sizes in the
presence of such adjacent quaternary stereogenic centres, the bond becomes less stable and
consequently, its formation becomes less likely (Scheme 31).
Scheme 31: Dimeric vs monomeric quinoline structure formation.
Secondly, looking at the rates of reactivity between the formation of monomeric structure 105 and
dimeric structure 104, it is anticipated that intramolecular elimination is faster than intermolecular
dimerization due to pronounced steric clashes when methine radical 106 attempts to homocouple.
Additionally, 2-quinolones are known to exist in tautomeric form with 104.129
which gives extra
stability given the existence of an extended 𝜋-system. Consequently, monomeric structure 105 is the
preferred product over dimeric 104.129
The proposed mechanistic sequence of events is shown in Scheme 32. First, oxamic acid 102
undergoes a radical decarboxylation to generate carbamoyl radical 108,124,130
which in the presence
of methacrylic acid 103 undergoes an addition-cyclization sequence to form a dihyroquinolin-2-one
109. This then undergoes a second decarboxylation generating a methine radical 106 followed by a
third and final oxidation and loss of a proton to give the unexpected 2-quinolone product 105.126,131,132

51
Scheme 32: Proposed mechanistic pathway towards formation of monomeric quinoline-2-one.
The unexpected quinolin-2-one product 105 was confirmed with 1
H and 13
C NMR spectroscopy
(Figures 19).
The characterisation of 1,4-dimethylquinolin-2(1H)-one 105 shows a total of 10 protons consistent
with its molecular formula C12H11NO. In the aliphatic region, a singlet peak integrating for 3 protons is
observed for the N-methyl group at 3.65 ppm, and a doublet peak is observed at 2.41 ppm for the
lactam methyl group. A singlet peak is observed at 6.55 ppm for the lactam double bond. In the
aromatic region, a triplet peak is observed at 7.22 ppm for 2 protons, and a doublet and a double
doublet between are observed, which together integrate for a single proton at 7.53 and 7.65 ppm
respectively. These resonances are consistent with the expected unsubstituted 1,4-dimethylquinolin-
2-one. 13
C NMR spectrum shows 11 carbons, including downfield peaks at 162.1 ppm for the amide
carbonyl, 139.7 and 121.9. ppm for the 2-quinolone double bond. These spectroscopic data are
agreement in with those previously reported.17

52
Figure 19: 1H and 13C NMR of the unexpected 2-quinolone product.

53
3.2 The 2-Quinolone Scaffold
2-Quinolone, also known as quinolin-2-one, is a nitrogen-containing heterocycle, existing as a major
tautomer in equilibrium with 2-hydroxylquinoline. The tautomeric nature of quinolin-2-one was first
studied and established by Bastonova in 1952.129
This N-heterocycle is not only ubiquitous, but a
privileged motif, commonly found in secondary metabolites such as natural products and artificial
products such as pharmaceutical drugs133,134
and fluorescent materials (Figure 20).135,136
Figure 20: Structures and tautomerism of quinolin-2-one and its roles in synthetic chemistry and related
disciplines.
Furthermore, the 2-quinolone skeleton and its closely related analogues, such as 3,4-
dihydroquinolone, have been heavily employed as building blocks, scaffolds, or fragments, which
allows for generation of complex, diverse and novel library of quinolin-2-one derived compounds
relevant to chemical biology and medicinal chemistry.137
2-Quinolone is a two-ring fused nitrogen containing heterocyclic compound, consisting of a benzene
ring and a six membered aromatic lactam, whose nitrogen is joined to the benzene ring. The internal
amide of 2-quinolone exists as a fixed cis form of the lactam amide group and can hydrogen bond with
peptides, nucleic acids or water molecules cementing their relevance in medicinal chemistry and
chemical biology.
Notably, amide bonds in natural products exist predominantly in the trans form, (expect for 10% of
prolines which exists in cis form), because trans form amides are known to be thermodynamically
more stable than their cis equivalents.

54
Thus, the internal cis conformation of quinolin-2-one is a rare an intriguing structural feature, which
renders the moiety to show unique and distinctive features, different from other skeletons like
naphthalene, coumarins, naphthoquinones which lack the amide bond.138,139
The benzene ring of 2-quinolone can interact with aromatic rings of peptides or nucleic acids through
– stacking for non-covalent interactions.140
These are factors of unique structural features which
can be tuned by a medicinal chemist to their own advantage. Relevant to medicinal chemistry,
quinolin-2-one derivates have shown good and superior ADMET properties, this is because biologically
the amide bond of quinolin-2-one, cannot be cleaved enzymatically. Thus, it decomposes between the
C—N bond between the nitrogen and atom and the benzene ring, which shows excellent metabolic
stability in living organisms. This makes quinolin-2-one derived compounds relevant and calls for
innovative strategies to forge such molecules.141
3.2.1 Current Synthetic Strategies for 2-Quinolone Synthesis
The formation of 2-quinolones is generally placed into two broad synthetic approaches through
principal disconnections: a.) either between the carbonyl group and the double bond — achieved
through insertion into alkenes or alkynes;142–145
b.) or between the aryl and the double bond —
through an arylation approach (Scheme 33). 146–149
Scheme 33: Approaches towards the synthesis of quinolin-2-one.
Other notable approaches include the ring expansion of isatins150–152
and the oxidation of quinoline
salts.153

55
Interestingly, our current approach fits into a different category, namely, a double disconnection at
both the aromatic and carbonyl groups, formally enabling the direct insertion of a C(sp2
)–H/C(sp2
)–H
olefin moiety into a formamide derivative precursor (Figure 21).
Figure 21: The double disconnection approach.
To the best of our knowledge, the first report using this type of ‘double disconnection’ approach to
producing 2-quinolones was reported by Donald et al in 2017 (Scheme 34).
Scheme 34: Redox neutral modular addition–cyclisation–elimination sequence of carbamoyl radicals to α-
choro acrylate Michael acceptors and the proposed mechanism as reported by Donald et al.19
N
R1
R3
O
R2
‘double disconnection’

56
They utilised, a redox neutral photoredox approach to access carbamoyl radicals 108 from N-
hydroxyphtalimido oxamides 110, which successfully underwent an addition cyclisation sequence
with α-choro acrylate-derived Michael acceptors 111 yielding 4-substituted-1-methylquinolin-2(1H)-
ones 112.154
In terms of energy efficiency, this approach is very useful as it does not require high temperatures,
which means the method can be applied to thermally sensitive substrates and the development of
asymmetric variants. However, the method had two major limitations. First, the use of the N-
phthalimido ester precursor resulted in the generation of phthalimide as an organic waste product
(MW = 146.13), reducing the overall atom efficiency of the process. Secondly, the use of
chloroacrylates and cyanoacrylates limits the generality of the method as they are not easily obtained,
and their synthesis often involves laborious synthetic approaches. This is presumably the main reason
for the limited scope presented, which included only 3 examples.
More recently, Feng and co-workers reported a closely related silver-catalysed protocol using oxamic
acid and vinyl sulphone starting materials (Scheme 35).155
The reaction was net oxidative and utilised
the well-known AgNO3/Na2S2O8 catalytic system.94,156,157
Scheme 35: Feng’s silver catalyzed tandem addition–cyclisation–elimination sequence of carbamoyl radicals to
vinyl sulphones and proposed mechanism.

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