ARENBERG DOCTORAL SCHOOL

FACULTY OF SCIENCE

Application of heterogeneous catalysis for

the activation of triple bonds: from batch to
continuous-flow
activation

Prabhat Ranjan

Supervisor: Dissertation presented in partial

fulfilment of the requirements for the
Prof. Dr. Erik Van der Eycken
degree of Doctor of Science (PhD):
Chemistry

February 2021
i
Application of heterogeneous catalysis
for the activation of triple bonds: from
batch to continuous-flow
Prabhat Ranjan

Supervisor:
Prof. Dr. Erik V. Van der Eycken

Members of the
Examination Committee:
Prof. Dr. Bart Goderis Dissertation presented in
Prof. Dr. Thierry Verbiest partial fulfilment of the
Prof. Dr. Tom Van Gerven requirements for the
Prof. Dr. Tatjana Vogt degree of Doctor of Science
Prof. Dr. Victor Sebastián (PhD): Chemistry

February 2021

ii
© 2020 Prabhat Ranjan
Uitgegeven in eigen beheer, Prabhat Ranjan, KU Leuven, Science, Engineering and
Technology, Arenberg Doctoral School, Celestijnenleen, 3001, Heverlee, Belgium.

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iii
“Nearly everything you do is of no importance,
but it is important that you do it.”
Mahatma Gandhi

iv
 Acknowledgements
First and above all, I praise God, the almighty, for providing me with
this opportunity and granting me the capability to proceed successfully.
This thesis is made possible due to the assistance and guidance of
several people. I would therefore like to offer my sincere thanks to all
of them.
I wish to express my sincere appreciation to my supervisor, Prof. Dr.
Erik Van der Eycken, for being a guide in this journey from fresh
master student to an experienced doctoral student. Without your
valuable scientific suggestions, the goal of this project would not have
been realized.
I am also grateful to the examination committee, Prof. Dr. Bart
Goderis, Prof. Dr. Tatjana Vogt, Prof. Dr. Thierry Verbiest, Prof.
Dr. Tom Van Gerven and Prof. Dr. Victor Sebastián, who provided
me with valuable suggestions to improve the content of this thesis.
In my professional network, I would like to thank all Professors and
ESRs from the COSMIC team for improving my knowledge in various
fields other than chemistry. Besides your scientific knowledge, I have
enjoyed your company during our meetings. I would like to specially
thank Prof. Tom Van Gerven for organizing very informative and
inspiring training sessions during COSMIC meetings.
I thank Prof. Dr. Wim de Borggraeve for his valuable scientific
suggestions. I thank Roberta Manno for great collaborative research
work. Dear Camilla and Alessio, I thank you for your kindness and all
the help you provided during my stay in Cordoba. The time I spent with
you guys is one of the most beautiful memories of my PhD (especially
Camilla’s Pizza!). Special thanks go to Mohammed Noorul Hussain
for his continuous endless support as a friend at every point of my PhD
life. I will also never forget your lessons on flow chemistry.

v
At this point, I would like to thank all the LOMAC members for
providing me with a friendly environment. I thank Upendra Sharma
for his guidance, Guilong Tian, He Yi and Liangliang Song for
assisting me in the lab during my initial period. I would also like to
thank my mentor Pavel Fedoseev for giving me necessary help and for
giving me his guitar. With special kindness, I would like to thank
Guglielmo Coppola, Gerardo Manuel Ojeda Carralero, Su Chen,
Chao Liu, Xu Xianjun and Monical Oliva for creating a friendly,
motivating and inspiring working environment. I really enjoyed our lab
dinners, Chinese hot-pots, barbeques and all our small get together
parties.
Serena Pillitteri you are always right. I can’t win in any discussion
because you know everything. I can’t thank you enough for your
endless support in lab or outside the lab. I can’t forget your delicious
lunch without salt and oil which always made my day. I just wanted to
thank Prof. Katia Martina for sending you in LOMAC and allowing
us to meet and be friends.
Warm thankfulness goes to members of LOSH group: Ermal Ismalaj,
Joachim Demaerel, Vidmantas Bieliūnas and Carlotta Borgarelli
for scientific discussions with coffee.
I also wish to thank Karel Duerincks and Bart Van Huffel for all the
NMR spectra measurements, Ann Petre for her kindness and help in
understanding all the bureaucratic requirements.
Word fail me to express my appreciation to my family. All my
achievements are due to continuous support and blessing of my parents,
my brothers and my sisters in law. I would like to express my deep
sense of gratitude to my brother Dr. Anupam Kumar from whom I
have learned everything. Our simple conversions at different stages of
my life like ‘you can never be bored of studying’, ‘everyone has the

vi
same ability, don’t let yourself down’ gave me strength and motivation
to reach this stage. Thanks to my big brother Ashutosh Kumar for
encouraging me to pursue my PhD in KU Leuven and for the constant
support (including my pocket money ). Thanks to my niece Adu,
always cheering me up with her smile and dances.
In last I wish to thank all my friends from Banaras Hindu University
and Indian Institute of Technology, India. Kartikeya and Rishabh,
without you I could not have enjoyed the amazing European trips and
late night conversations. Rahul, thanks for your help in my studies
(especially in the understanding of physics), and for being like a big
brother to me. I thank Rajat, Rajvendra, Rajendra, Ashutosh,
Pratap, Piyush and Abhinay for being my good friends.
Thanks Chiara for your Italian lessons and chocolates.
Finally, I thank the Marie Curie fellowship for financial support.

To all the people in the list and also to all the people that I have
forgotten to mention at this point

Thank you

vii
Summary

In this work, the application of heterogeneous catalysis, i.e. polymer-

supported phosphine, metal nanoparticles and metal nanoclusters, was
investigated to construct a diverse range of heterocyclic molecules
through the activation of triple bonds. The work aimed to render the
activation of triple bonds more environmentally friendly and cost-
efficient by applying reusable heterogeneous catalysts under batch as
well as in continuous flow. An “umpolung Michael addition” was
reported to synthesize three-dimensional polyheterocyclic structures
employing a nucleophilic phosphine catalyst. Next, silver nanoparticles
and nanocluster were used to mainly generate 5-membered
heterocycles. Silver nanoclusters (Ag NCs) were used to construct C-
N, C-O and C-C bonds. The activity of silver clusters was higher for
the hydroamination (C-N bond) of the propargylguanidines and for the
synthesis of 2-phenylbenzofuran (C-O bond) as compared to
previously reported nano-based catalysts. The Ag NCs were also
reactivated by hydrogen peroxide to regain their catalytic activity. The
stability of metal nanoclusters was investigated under different reaction
conditions. Metal nanoparticles and nanoclusters were characterized by
HRTEM, XPS, and MP-AES to understand the effect of reaction
conditions on the morphology of the catalysts. Interestingly, no
appreciable leaching was detected by MP-AES under the applied
reaction conditions.

viii
Samenvatting

Tijdens dit doctoraatsonderzoek werd de toepassing van heterogene

katalysatoren, i.e. polymeer-gedragen fosfine, metaalnanopartikels en
metaalnanoclusters onderzocht, voor de synthese van verschillende
heterocyclische molecules via activering van een drievoudige binding
van het substraat. Het was de bedoeling om de activering van
drievoudige bindingen milieuvriendelijker en kostefficiënter te maken,
dit door gebruik te maken van herbruikbare heterogene katalysatoren
onder “batch” en “continuous flow” condities. Een “umpolung Michael
addition” werd uitgewerkt voor de synthese van driedimensionale
polyheterocyclische structuren gebruik makende van een nucleofiele
katalysator. Vervolgens werden zilver nanopartikels en zilver
nanoclusters gebruikt om 5-ring heterocyclische verbindingen te
maken. Zilver nanoclusters (Ag NCs) werden gebruikt om C-N, C-O
en C-C bindingen te vormen. In vergelijking met reeds vroeger
beschreven nano-gebaseerde katalysatoren, is de activiteit van
zilverclusters hoger voor de hydroaminering (C-N binding) van
propargylguanidines en voor de synthese van 2-fenylbenzofuraan (C-
O binding). De Ag NCs werden gereactiveerd met waterstofperoxide
om hun katalytische activiteit te herwinnen. De stabiliteit van de
metaalnanoclusters werd onder verschillende reactiecondities
onderzocht. Om het effect van de reactiecondities op de morfologie van
de katalysatoren te begrijpen, werden de nanopartikels en nanoclusters
gekarakteriseerd door middel van HRTEM, XPS en MP-AES. Het is
zonder meer een pluspunt dat onder de toegepaste reactiecondities,
geen “bloeden” van de katalysatoren kon worden gedetecteerd met
MP-AES.

ix
List of abbreviations

APTES (3-Aminopropyl)triethoxysilane
Ar aryl
Boc tert-butyloxycarbonyl
Cy cyclohexyl
DABCO 1,4-diazabicyclo[2.2.2]octane
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DMAP 4-Dimethylaminopyridine
EWG electron withdrawing group
FDA U.S. Food and Drug Administration
HRTEM high resolution transmission electron microscopy
Agilent microwave plasma atomic emission
MP-AES
spectrometers
NC nanocluster
NP nanoparticle
PMP para-methoxybenzyl
PMP para-methoxyphenyl
XPS X-Ray photoelectron spectroscopy

x
Table of Contents
Summary ............................................................................................ iii
Samenvatting.......................................................................................ix
List of abbreviations ............................................................................x
1. Introduction ................................................................................11
1.1 Phosphine Organocatalysis ................................................12
1.2 Nucleophilic Phosphine Catalysis of Alkynes ...................13
1.2.1 Phosphine-catalyzed isomerization of alkynes to
dienes 14
1.2.2 Phosphine-catalyzed α-umpolung addition ................17
1.3 Silver catalysis ...................................................................22
1.4 Heterogeneous Catalysis ....................................................27
1.4.1 Nanosilver Catalysis ..................................................28
1.4.2 Silver cluster catalysis ................................................31
1.5 Flow Chemistry..................................................................33
2 Objectives of this Work .............................................................37
3 Metal-Free Dearomatization: Direct access to Spiroindol(en)ines
in Batch and Continuous-Flow ..........................................................39
3.1 Introduction ........................................................................40
3.2 Results and Discussion ......................................................41
3.3 Conclusion .........................................................................49
4 Heterogeneously catalysed synthesis of imidazolones via
cycloisomerization of propargylic urea using Ag and Au/Al SBA-15
systems ...............................................................................................51
4.1 Introduction ........................................................................52
4.2 Results and Discussion ......................................................54
4.3 Conclusion .........................................................................66
5 Continuous Microwave-Assisted Synthesis of Silver
Nanoclusters Confined in Mesoporous SBA-15: Application in
Alkyne Cyclizations. ..........................................................................67
5.1 Introduction ........................................................................68

xi
 5.2 Results and discussion .......................................................71
5.2.1 Synthesis of Ag-NCs and Ag-NCs/SBA-15 ..............71
5.3 Conclusion .........................................................................83
6 Conclusions and Perspectives ....................................................85
7 Safety Aspects and Environmental Considerations ...................89
8 Experimental Part.......................................................................90
9 References ................................................................................127
10 Curriculum Vitae .................................................................138

xii
1. Introduction

Over the past decades, sustainable chemistry is gaining ample attention

due to the escalating environment issues. In general, sustainable
chemistry emphasizes the use of resources in such a manner, so that
can be replaced naturally.1 In this regards, heterogeneous catalysis
represents an important pillar for the sustainable and green production
of bulk chemicals. Heterogeneous catalysts are not only offering bulk
production of chemicals, but they can also reduce the waste production
by increasing the reaction selectivity.2 Heterogeneous catalysis has
been widely explored in various fields, as e.g. in chemical
transformations, in oil refining, and in waste water treatment.3 In recent
years, the development in heterogeneous catalysis also led to the
production of fine chemicals and bio-active heterocyclic scaffolds.
Among other chemical transformations, cycloisomerization has
surfaced as valuable synthetic approaches to develop highly complex
structures from simple scaffolds. The cycloisomerization of molecules
contacting unsaturated bonds like alkynes has been reported as a
sustainable approach to furnish poly-(hetero)cyclic scaffolds.
Moreover, continuous flow-reactors (packed-bed flow reactors) offer
an extra added value in heterogeneous catalysis over homogeneous
catalysis.
Considering this preface, the aim of this thesis is to elaborate
innovative approaches towards the synthesis of heterocyclic scaffolds,
providing a green and sustainable synthetic tool through the
combination of heterogeneous catalysis and flow chemistry.

11
1.1 Phosphine Organocatalysis
Nucleophilic phosphine catalysis, often classified as Lewis base
catalysis, remains a compelling area of interest for organic chemists.
The peculiar behaviour of nucleophilic phosphine catalysis towards
activated (electron-deficient) carbon-carbon multiple bonds has been
exploited in many organic transformations. One of the salient features
of this type of activation is the formation of  -phosphonium -
carbanion species, also known as zwitterionic species.

Figure 1: An α-carbanion β-phosphonium zwitterion.

The first physical evidence of such zwitterionic species was reported

by Horner in 1955. He was able to isolate the zwitterionic species (1-
1), formed from triethyl- and triphenylphosphine in the presence of
ethenemalononitrile (Scheme 1).4 Significant advancement in this field
surfaced after the synthesis of dialkyl-2-methylenepentadioates,
employing phosphine catalysis by Rauhut and Currier in 1963.5
Approximately two years later, the widely-known Morita reaction was
reported. In this reaction, a Horner zwitterion adds to an aldehyde to
eventually form -hydroxymethylated acrylates and acrylonitriles.
This transformation is catalyzed by tricyclohexylphosphine (Scheme
1).6 In 1972, Baylis and Hillman documented the amine-catalyzed
Morita reaction as a patent. This reaction is now recognized as Morita-
Baylis-Hillman (MBH) reaction.7

The vast development in the field of nucleophilic phosphine catalysis

today provides a reliable means to prepare synthetic intermediates as
well as natural products, ligands for catalysis, and materials. 8–13 These

12
novel phosphine catalyzed carbon-carbon bond formation approaches,
have attracted ample attention from a large number of research groups
and pharmaceutical companies, leading to a paroxysm in the reporting
of new reaction modes. The observed advancement in phosphine
catalysis could be attributed to several desirable features: (1) highly
efficient reaction processes, (2) formation of complex molecular
architectures from simple starting materials, (3) low waste production
and simple post-reaction workup, and (4) easy scale-up and reusability.

Scheme 1: Early history of phosphine chemistry.

1.2 Nucleophilic Phosphine Catalysis of Alkynes

Over the last decades, the activation of triple bonds has attracted keen
interest among the scientific community. In this regard, the encounter
of activated alkynes and a nucleophilic phosphine catalyst can provide
a wide scope for organic transformations. These reactions can best be
treated under two main categories: 1) isomerization of activated
alkynes to form conjugated dienes, 2) nucleophilic addition reactions,
which can be further sub-characterized into Michael addition and α-
umpolung addition. Moreover, a ring-forming reaction can also take
place to construct many heterocycles through a single or double
Michael addition, depending on the type of nucleophiles.

13
1.2.1 Phosphine-catalyzed isomerization of alkynes to dienes
The first phosphine catalyzed isomerization of carbon-carbon multiple
bonds was reported by Trost in 1992.14 The reaction starts with the
facile nucleophilic addition of PPh3 to the alkyne 1-2, resulting in the
spontaneous formation of vinyl phosphonium enoate 1-3 (Scheme 2).
Subsequently, a proton transfer creates the intermediate 1-4, which
exists in resonance with the anion 1-5, and after another proton transfer,
the vinylogous phosphonium ylide 1-6 is generated. The vinylogous
phosphonium ylide 1-6 equilibrates with the intermediate 1-7, ensuing
the formation of the intermediate 1-8 after proton transfer. Subsequent
elimination of phosphine delivers the diene 1-9 with good efficiency.

Scheme 2: Proposed mechanism of alkyne isomerization.

Trost conducted a series of experiments on the isomerization of

activated alkynes,14 and found that alkynes bearing a ketone moiety are
more reactive than esters, and even more than amides. The observed
reactivity can directly be correlated with the electron-withdrawing
ability of different functional groups. Higher temperature and acidic

14
additives were needed for the efficient isomerization of less reactive
alkynes (Scheme 3). However, the absence of acetic acid is required
for the selective isomerization of an alkynone in the presence of an
alkynamide. In this particular case, the less nucleophilic
triphenylphosphine is essential to reduce oligomeric products.

Scheme 3: Early examples of alkyne isomerization.

In 1993, Gua and Lu reported an efficient approach for the

isomerization of less-reactive alkynes by replacing the less
nucleophilic phosphines with a more nucleophilic tributylphosphine
(Scheme 4).15 Moreover, this acid-free methodology could be
amenable to compounds carrying acid-sensitive functionalities.

After Lu’s report, Rychnovsky and Kim introduced mild reaction

conditions for the isomerization of activated-alkynes by using phenol
as an additive.16 The inclusion of phenol facilitates the proton transfer
steps without hydrolyzing other functional groups like silyloxy and
acetal groups.

15
 Scheme 4: Isomerization of less reactive alkynes.

In 2011, Toy and co-workers reported a more sustainable way to

achieve the isomerization of various alkynoates and alkynones by
employing solid-supported phosphines (Scheme 5).17,18 The authors
synthesized phosphine and a phenol group containing bifunctional non-
cross-linked polystyrene polymer for the isomerization of alkynoates
and alkynones. Remarkably, the polystyrene polymer containing only
the phosphine group alone, delivered low or no yield of the desired
product, while the newly developed bifunctional polystyrene
organocatalyst was very efficient for the isomerization of alkynoates
and alkynones. Moreover, solid-supported phosphines could provide a
great opportunity in flow-chemistry by using a solid packed-bed
reactor.

Scheme 5: Solid-supported phosphine-catalyzed alkyne isomerization.

16
1.2.2 Phosphine-catalyzed α-umpolung addition
In 1997, Trost reported another class of reactions on activated alkynes,
known as α-umpolung addition.19 He documented the synthesis of α-
dehydroamino acids by nucleophilic addition of phthalimide and
sulfonamides as pronucleophiles at the α-position of alkynoates. The
general mechanism of this reaction is shown in Scheme 6. The reaction
starts with the addition of phosphine to the alkynoate to generate the
vinyl phosphonium enoate A, followed by α-umpolung addition of a
nucleophile to generate the ylide B. Subsequent proton shift and
elimination of phosphine delivers the desired product.

Scheme 6: Phosphine catalyzed α-umpolung addition.

About a decade later, in 2005, Taran and co-workers described a highly

efficient α-umpolung addition of activated carbon pronucleophiles to
alkynoates using tributylphosphine as catalyst (Scheme 7).20,21

Scheme 7: α-Umpolung addition of carbon pronucleophiles.

17
Moreover, the reaction was also feasible in the presence of a free
hydroxyl moiety. The author also mentioned that tributylphosphine
could not deliver the desired product in case of non-substituted (R=H)
alkynoates. After a year, Gouverneur and co-workers reported an
intramolecular version of the α-umpolung addition of oxygen
pronucleophiles to activated alkynes to generate derivatized
tetrahydrofuran-3-ones (Scheme 8a).22 The same group reported an
interesting example of a 5-exo-dig cyclization in case of phosphine
catalyzed α-umpolung addition of an oxygen pronucleophile to
activated alkynes.23 This result was in contrast with the 6-endo-dig
cyclization observed with the same substrates employed in gold
catalysis (Scheme 8b).

Scheme 8: α-Umpolung addition of oxygen pronucleophiles.

In 2012, Peczuh and co-workers disclosed an interesting example of an

intramolecular α-umpolung pathway to construct 3-oxanones and 3-

18
oxepanones.24 In this transformation, the reaction starts with the
opening of the alkynyl hemiketal (1-10a 1-10b) followed by the
nucleophilic attack of phosphine to generate intermediate 1-11.
Subsequent proton transfer generates a keto-phosphonium species (1-
12) which proceeds through an intramolecular attack of oxygen to form
the zwitterionic intermediate 1-13. The electrophilic nature of this
carbon is attributed to the electron-withdrawing nature of the adjacent
phosphonium ion. Successive proton transfer and elimination of
catalytic phosphine generate the desired product 1-14 (Scheme 9).

Scheme 9: α-Umpolung addition of oxygen pronucleophiles.

In this study, the authors observed the formation of a complex dimeric

product in the case of terminal alkynes (R = H) through a hetero-Diels-
Alder reaction (Scheme 10, entry 1). On the other hand, for the
synthesis of 3-oxanones, a sterically demanding phenyl substituent
must be positioned at the alkyne terminal to obtain the efficient
intramolecular α-umpolung addition (Scheme 10, entry 2).

19
 Scheme 10: Synthesis of spiroketal derivative and 3-oxanone.

In 2018, Sasai and co-workers reported the synthesis of hydroindole-

2-carboxylates and hydrobenzofuran-2-carboxylates via a phosphine-
catalyzed dual umpolung domino Michael procedure.25 The reaction
follows the general intermolecular α-umpolung pathway similar to the
Michael reaction to generate the desired product in high diastereomeric
ratio (Scheme 11).

20
 Scheme 11: Synthesis of hydroindole-2-carboxylates and hydrobenzofuran-2-
carboxylates.

Since phosphine catalysis has widely been exploited in the

activation of triple bonds, we decided to employ this catalytic
model for the dearomatization of indoles to generate
spiroindol(en)ines. The spiroindol(en)ines are rigid three-dimensional
structures bearing potential bio-active characteristics. The synthesis of
these scaffolds has been heavily investigated but there are still many
challenges to solve, such as regioselectivity and rearrangement of the
final products to regain aromaticity.
In order to provide an innovative synthetic pathway to achieve their
synthesis, we decided to employ immobilized phosphine as a
heterogeneous catalyst in a packed-bed flow reactor. Chapter 3 will
describe our research in this area and the benefits over previous
approaches towards the synthesis of spiroindol(en)ines.

21
1.3 Silver catalysis
The triple bond activation towards nucleophilic attack by metal and
non-metal catalysts has become one of the prevalent strategies in
modern chemistry to achieve different organic transformations. Such
fundamental reactions are not only providing a molecular building
block,26 but they also serve the goal of broadening the existing
chemical space, by leading to a large variety of complex molecular
architectures that can be of great interest for medicinal chemistry.27 The
selective interaction between a transition metal and an alkyne is
referred to as alkynophilicity. Silver, which possesses the electronic
configuration [Kr] 4d105s1, has emerged as a powerful catalyst for
alkyne transformations. Similar to gold, silver can also form a series of
salts with a variety of counter-anions, and can function as a - and/or
-Lewis acid.28 In addition, the d10 electronic configuration of silver
favours the interaction of an alkyne through a -bond interaction, as
explained in the case of Au catalysis.29–31 There are mainly two
pathways to achieve the activation of alkynes by silver metal, as shown
in Figure 2. In the case of a non-terminal alkyne, the coordination of
silver to the -system of the alkyne leads to the formation of a silver-
-complex A, which facilitates the formation of C-X bonds (X = C, N,
O, halogen, P, etc.) by the nucleophilic attack. Another reaction path in
the case of terminal or silylated alkynes can involve the formation of
silver acetylide (Figure 2, B) via deprotonation/desiliconization in the
presence of base. This intermediate B can further react with
nucleophiles/electrophiles.32,33

22
 Figure 2: Activation of the triple bond by a silver catalyst.

In this subsection, reactions catalyzed by homogeneous silver(I) and

heterogeneous silver, including nano-metals and nano-clusters, will be
presented. The general mechanism for the silver catalyzed addition of
a nucleophile to a triple bond is presented in Scheme 12. The addition
of nucleophiles to Ag-activated alkynes is possible in both inter- and
intramolecular way.

Scheme 12: General mechanism of the silver catalyzed addition of a nucleophile.

In this regard, the use of N-based nucleophiles has surfaced as a

convenient way to generate N-containing heterocycles via
intramolecular hydroamination of alkynes. The use of silver in this type
of reactions has been widely investigated over the last two decades. In
1999, Muller and co-workers reported the intramolecular
hydroamination of 6-aminohex-1-yne by using AgBF4 and
[Ag(Triphos)]BF4 as active catalysts (Scheme 13).34 Later on, the same

23
group performed several experiments on the same reaction to
understand the effect of counter-anions. In this systematic study, they
revealed the difference in the reaction rate in the presence of different
counter-anions of cationic-silver. Highest reaction rates were observed
with counter-anions derived from sulfonic acid (-OTs, -OTf), medium
rates were found for CF3CO2-, NO3- and the non-coordinating ions
(ClO4-, BF4-, PF6-). The lowest rates were observed for the more basic
anions (CH3CO2-, PhCO2, and CO32-).35

Scheme 13: Intramolecular hydroamination of 6-aminohex-1-yne.

About a decade later, Helquist and co-workers published a silver-

phenanthroline complex catalyzed intramolecular hydroamination of a
variety of primary aminoalkynes (Scheme 14).36 As compared to
AgOTf, a higher yield was achieved with [Ag(phen)]OTf. This result
can be attributed to the ability of the phenanthroline ligand to stabilize
the catalytically active metal centre during the reaction. In addition,
being air- and moisture stable, this catalytic system complements the
previous protocols because of its easy recyclability.

24
 Scheme 14: Intramolecular hydroamination of 5-phenyl-4-pentyn-1-amine using
[Ag(phen)]OTf catalyst.

Moreover, the silver catalyzed activation of propargylamine

derivatives has been extensively studied because of the possibility to
construct a library of medicinally relevant compounds. In 2010, Van
der Eycken and co-workers reported an efficient one-pot synthesis of
double protected imidazolidin-2-imines by employing
propargylamines, S-methylisothioureas and AgNO3 (Scheme 15).37
The reaction starts with the in situ formation of the propargyl guanidine
from S-methylisothioureas and propargylamines. This intermediate
further undergoes 5-exo-dig cycloisomerization to generate the desired
product. Subsequent hydrolysis of imidazolidin-2-imines by TFA in
DCM followed by aromatization, resulted in the formation of 2-
aminoimidazoles. This protocol was utilised for the synthesis of
trisubstituted 2-aminoimidazole alkaloids. In addition, the ability of 2-
aminoimidazoles to act as biofilm inhibitors was disclosed in this
study.

25
 Scheme 15: Silver catalyzed synthesis of bis-protected imidazolidin-2-imines.

In 2011, Van der Eycken and co-workers reported another efficient

silver catalyzed one-pot synthesis of imidazole-2-ones.38 The authors
performed the insitu generation of propargyl ureas via addition of

26
propargylamines to isocyanates followed by the silver catalyzed
cycloisomerization of the resulting ureas (Scheme 16). Harsher
reaction conditions were required in the case of the cycloisomerization
of propargyl ureas derived from internal N-alkyl propargylamines and
aromatic isocyanates as compared to the propargyl ureas derived from
terminal propargylamines, due to the higher steric hindrance of the
internal alkynes.

Scheme 16: Synthesis of imidazole-2-ones.

1.4 Heterogeneous Catalysis

A catalytic reaction can be defined as true heterogeneous when the
phases of reactants and catalyst are different, as in solid/liquid,
gas/liquid or solid/gas phases.39 Therefore, if the catalyst is solid or
immobilized on solid supports, and the reactants are dissolved in the
solvent (liquid phase), we can ascribe these reactions as true
heterogeneous reactions. Heterogeneous catalysis is one of the most
flourishing areas of research at the time because it provides a better
platform for green and sustainable development. Moreover,
heterogeneous catalysis provides many advantages over homogeneous
catalysis, like the possibility of catalyst recycling, continuous
processing, and ease of separation. In particular, the chance of

27
contamination is minimal (in heterogeneous catalysis), thus providing
a better chance to potential drug candidates to fulfil FDA requirements.
There are mainly two different approaches in heterogeneous catalysis:
1) immobilization of homogeneous catalysts, and 2) supported
nanoparticles. Over the last 30 years, major research in heterogeneous
catalysis has been focused on designing catalysts, especially
nanomaterials or nanoclusters, and their support on different materials.
In this subsection, nanomaterials, and in particular silver
nanoparticles(NPs) and clusters(NCs), will be discussed.

1.4.1 Nanosilver Catalysis

The thriving field of research in nanoparticle catalysis has been a centre
of attraction due to the high demand in chemical industries.40 This is
mainly due to the advantageous properties that nanoparticles show,
such as large available surface area per unit mass and shape-dependent
properties. In recent years, a fruitful multidisciplinary collaboration
between researchers from organic chemistry and nanoscience fields has
brought many novel approaches to build small to complex molecular
scaffolds.
In particular, extensive studies have been focused on nanoparticles (i.e.
Ag, Au, Pt, etc.) catalyzed activation of the triple bonds. The activation
of triple bonds towards nucleophilic attack has been established as an
efficient approach to construct complex molecules from simple starting
materials. The activation of triple bonds is made possible by means of
these overall neutral nanoparticles, because they possess a cationic
character near to the low-coordinated metal atoms, like at the corners
or at the edges. This cationic character is directly related to the Lewis
acidity of transition-metals, such as Au or Ag.41

28
Among other metal-based nanoparticles, silver nanoparticles play a key
role in catalysis.42,43 Nanosilver catalysts are also well suited for
industrial applications because of their relatively low price as
compared to gold-, platinum-, and palladium-based heterogeneous
catalysts. Every year a myriad of reports are surfacing but very few of
them are focused on organic transformations. An important example of
a nanosilver-catalyzed cyclization of 2-(1-hydroxy-3-arylprop-
2ynyl)phenols was reported by Yao and co-workers in 2010. In
addition to carbon black supported silver nanoparticles, they also
reported the crucial role of a phosphine ligand for the cyclization of 2-
(1-hydroxy-3-arylprop-2ynyl)phenols (Scheme 17).44

Scheme 17: Cyclization of 2-(1-hydroxy-3-arylprop-2ynyl)phenols.

In 2013, Safaei-Ghomi and co-workers reported the synthesis of

benzofurans by utilizing the easily available AgI nanoparticles. The
first step involves the formation of an iminium ion from
salicylaldehydes and amines, followed by the attack of silver acetylide
to generate A3-coupling products. Next, AgI nanoparticles activate the
triple bonds of the A3-coupling product to facilitate the nucleophilic

29
attack of the hydroxyl group of the salicylaldehyde. The subsequent
protodemetalation and aromatization of the intermediate leads to the
desired benzofurans (Scheme 18).45

Scheme 18: Synthesis of benzofurans.

In 2016, Van der Eycken and co-workers disclosed a silver

nanoparticle-catalyzed synthesis of 3-spiroindolenines via
46
dearomatization of indoles (Scheme 19). The authors presented a
wide scope with good functional group tolerance under mild reaction
conditions. In the case of non-terminal alkynes, the authors reported
mixtures of endo and exo products. Moreover, the catalyst was stable
after 10 catalytic cycles without any loss in catalytic activity.
Interestingly, the authors also investigated the stability of this catalytic
system in terms of size of nanoparticles at different temperatures. No
changes were observed up to 40°C by TEM microscopy, but crystal
ripening above 40°C was detected.

30
 Scheme 19: Silver nanoparticle-catalyzed synthesis of 3-spiroindolenines

1.4.2 Silver cluster catalysis

Nanoclusters (NCs)47 are aggregates of atoms with a diameter lower
than 2 nm. These ultra-small NCs show size-specific optical and
catalytic properties. Moreover, the accessible active sites increase in
the nanocluster scale (diameter <2 nm), showing different coordination
numbers at edges or corners. These nanoclusters also have different
properties as compared to their bulk materials and can easily be altered
by the addition of a single atom. Due to their smaller size compared to
Nps, they show a discrete electronic structure and molecule-like
properties instead of showing collective Plasmon resonance effect.
Henceforth, as a result of their unique molecule-like discrete energy
levels and rich unsaturated active sites, NCs are good catalysts for
organic transformations.48,49 In addition to their important role in
chemical industries, these NCs can also be a good model to study the
structure-activity relationships and reveal catalytic reaction
50
mechanisms. The importance of this field can be understood by the
following benefits of NCs over nanoparticles (Figure 3):
1) The nature of the cluster can precisely be tuned by the number,
type, and position of atoms. Therefore, the catalytic structure-
activity relationship is easier to investigate.

31
 2) Monodispersity and well-defined structure in the case of NCs
are auspicious for the study on catalytic reaction paths. On the
contrary, nanoparticles show different catalytic abilities at
different positions (i.e. facet, edge, kink, and corner sites).
Difficulties therefore arise when studying the catalytic reaction
pathways from the perspective of experimental and theoretical
simulations.
3) The surrounding environment of NCs can be easily recognized.
This helps to study the surface/interface effect. Moreover, NC
catalysts have the ability to fill the gap between homogeneous
and heterogeneous catalysis.

The synthesis of atom precise Ag NCs has gained much attention in the
research field of cluster synthesis, but surprisingly fewer attempts have
focused on the utilization of Ag NCs in organic transformations. In
2009, Satsuma and co-workers reported the first Ag NCs catalyzed C-
C cross-coupling reaction of secondary and primary alcohols.51 The
reaction starts with the dehydrogenative oxidation of primary and
secondary alcohols with the generation of a silver hydride species.
Afterwards, the insitu generated aldehydes and ketones undergo cross-

32
aldol condensation to give  unsaturated ketones. Finally, selective
transfer hydrogenation of  unsaturated ketones with silver hydride
species delivers the final product (Scheme 20). Moreover, silver-
particle size of less than 2 nm showed structure-based reactivity. The
observed structure-sensitivity is due to the presence of more
coordinatively unsaturated silver atoms at the corner sites of NCs.
These unsaturated silver atoms are essential for the rate-determining C-
H cleavage of alkoxide species during the dehydrogenative oxidation.

Scheme 20: C-C cross-coupling reaction of secondary and primary alcohols.

1.5 Flow Chemistry

Flow-reactors52–54 are one of the most important pillars in modern
chemistry. As compared to the traditional batch reactors, they provide
many advantages, like safety, improved mass and energy transfer and
easy scale-up. Although in academia the benefits of flow reactors are
not very viable, they become more preeminent in chemical industry due
to the high efficiency of these reactors.55 An important and significant
difference between flow and batch conditions is that, under continuous-
flow, the product leaves the reactor immediately, avoiding thermal
strain to heat-sensitive products. Moreover, the better heat and mass
transfer enable to shorten the reaction times.
Flow reactors are widely exploited in homogeneous56 as well as
heterogeneous catalysis. In particular, in heterogeneous catalyzed flow

33
reactions, packed-bed reactors are commonly used. An early example
of a packed-bed reactor was reported by Toste, Somorjai and co-
workers (Scheme 21). They demonstrated that the use of leaching-
stable supported palladium NPs is amenable for the synthesis of
benzofurane in a packed-bed flow reactor.57 They were also able to keep
the catalytic activity high by employing PhICl2 as an oxidant under
continuous flow conditions.

Scheme 21: Packed-bed reactor for Pd NP-catalyzed benzofurane formation.

Another interesting example of a packed bed reactor was reported by

Wiles and Watts in 2012 (Scheme 22).58 They employed polystyrene
beads supported gallium triflate catalytic system to perform the
Strecker reaction.

Scheme 22: Packed-bed reactor for three-component Strecker reaction.

In 2013, Lanari, Vaccaro and co-workers employed polystyrene-

supported triphenylphosphine (PS-TPP) catalytic system in a packed-
bed reactor for the synthesis of cyanohydrin trimethylsilyl ethers using

34
a wide range of ketones/aldehydes and trimethylsilyl cyanide
(TMSCN) (Scheme 23).59

Scheme 23: Packed-bed reactor for the solvent-free continuous flow preparation of a
cyanohydrin trimethylsilyl ether.

In 2017, Nguyen and co-workers introduced an innovative approach

for the selective phosphine-mediated C(sp3)-C(sp3) coupling.60 In their
methodology, the authors employed a sequential injection of the
different reagents, which eventually passed through the packed-bed
column to deliver the final desired product. The employment of
polymer-supported triphenylphosphine in a packed-bed reactor
reduced the laborious purification procedures to eliminate phosphine
oxide.

Scheme 24: Triphenylphosphine resin mediated C(sp3)-C(sp3) coupling.

An important aspect regarding polymer-supported catalysts is the

extent of swelling, which is not equal in every solvent. If the polymer

35
swells too much, it can block the flow of the reactants in the packed-
bed reactor.61 On the other hand, swelling is necessary for the activity
of the catalysts. An extensive optimization is therefore often required
to find a balance between a good solvent for the polymeric material and
a good solvent for the reaction.
In this thesis, polystyrene-supported triphenylphosphine (PS-TPP) and
mesoporous silica (SBA-15) were employed in packed bed flow
reactors.

36
2 Objectives of this Work

Triple C≡C bond containing organic molecules are versatile synthons

in organic synthesis, as they can be selectively transformed into various
important scaffolds using suitable catalytic systems. The growing
demand for fine chemicals for the pharmaceutical industry has led to a
huge load on the metal-based homogenous catalyst utilization.
Therefore, to synthesize fine chemicals sustainably and economically,
efficient catalytic systems are highly desirable. In this regard,
heterogeneous catalysis has the potential to be used as an effective
catalytic system for the production of these fine chemicals in a
sustainable manner.
The main focus of this work is therefore to develop a new synthetic
approach to construct C-O, C-C and C-N bonds through triple bond
activation and heterogeneous catalysis. The first objective (Chapter 3)
will be the selective generation of spiroindolines and spiroindolenines
employing polymer-supported phosphine in packed-bed reactors to
facilitate the process and to reduce the overall cost of production. In
the second part (Chapter 4 and 5), we will exploit metal oxide
supported nanoparticles and nanoclusters, especially silver, towards the
activation of triple bonds for nucleophilic attack. Besides the
application of heterogeneous catalytic systems in organic
transformations, we will also compare the activity of Ag NCs with
homogenous silver catalysts.
The reactivation of nanometal catalysts plays a prior role in the
reusability of these catalysts. In this thesis, a simple approach to
reactivate the catalyst under batch, as well as continuous flow
conditions, will be discussed as well.

37
Beyond the scope of this work is an in-depth analysis of the mechanism
involved in the organic transformations on the surface, at the edge or
corners of the nanoparticles.

38
3 Metal-Free Dearomatization: Direct
access to Spiroindol(en)ines in Batch and
Continuous-Flow

Reproduced with permission from:

Ranjan, P.; Ojeda, G. M.; Sharma, U. K.; Van der Eycken, E. V. Chem.
- A Eur. J. 2019, 25, 2442–2446. DOI: 10.1002/chem.201805945
Author contributions: PR designed the project, carried out the
experiments; GMO performed the experiments; PR, GMP, UKS and
EVVdE wrote the manuscript.

39
3.1 Introduction
Dearomatization62 is a robust strategy to synthesize three-dimensional
rigid molecular scaffolds from simple planar aromatic molecules. The
synthesis of spiroindol(en)ines and related spirocarbocycles through
dearomatization of indole and substituted phenols has captured the
close attention of chemist due to their widespread presence in various
natural products and biologically relevant molecules.63,64 Henceforth,
greener and atom economical syntheses of these structures have
become imperative for synthetic chemists.65-69 Several simple Lewis or
-acidic catalysts were employed in the last decades for the synthesis
of spiroindolenines through dearomatization of indole at the C-3
position, including nano-metal catalysts.70 In addition, a number of
alternative methods for the synthesis of spiroindolenines have also
been developed in the last decade, viz. the intramolecular version of the
Prins cyclization,71 a radical-oxidation72 and acid-catalyzed reactions.73
However, several synthetic procedures are often limited by exo/endo
selectivity issues and side reactions such as reopening of the spiro-ring
through 1,2-migration to restore the aromaticity, particularly prevalent
with spiroindolenines. Apart from these reports, an umpolung Michael-
type synthesis of spiroindol(en)ines with catalytic Lewis base (LB) is
still elusive. The uniqueness of nucleophilic phosphine catalysis has
already resulted in a plethora of reports in the last two decades 74 after
seminal work appearing in the 1960s.75 In 1997, Trost described the
phosphine-catalyzed -umpolung Michael reaction of alkyl esters with
sulfonyl amine or phthalimide to achieve -amino carbonyl
compounds (Figure 4).19 The reaction proceeds through several
intermediates, of which intermediate II could be trapped with different
nucleophiles.

40
 Figure 4: Our approach to obtain the spirocyclization.

With our enduring interest in spiroindol(en)ines,76 we planned to trap

the intermediate II through an intramolecular nucleophilic attack of the
C-3 position of the indole (Figure 4). This unique approach of LB-
catalyzed umpolung reaction could lead to highly functionalized
spiroindol(en)ines and related spirocarbocycles under mild reaction
conditions.

3.2 Results and Discussion

We commenced our investigation on the dearomatization of
propargylic amide 2-1a, derived from tryptamine and propargylic acid,
with triphenylphosphine as nucleophilic catalyst. In the presence of a
catalytic amount of phosphine, we observed the regioselective
formation of the six-membered spiroindolenine as the major product.
In view of recent reports on the phosphine-catalyzed conjugate addition
on electron-deficient acetylenes, we started optimizing our
reaction.14,77 Various potential LB catalysts were investigated under
different reaction conditions using amide 2-1a as substrate (Table 1).

41
 Table 1: Optimization of reaction conditions for the synthesis of spiroindolenines.a

Entry Catalyst Solvent t (h) T (°C) Yieldb (%)

1 PPh3 Toluene 5 30 10
2 PPh3 Toluene 5 80 40
3 PPh3 DCM 5 30 12
4 PPh3 EtOAc 3 80 78
5 PPh3 EtOH 3 80 84
6 P(p-MeOPh)3 EtOH 3 80 87c
7 P(n-Bu)3 EtOAc 2 80 <30
8 P(n-Bu)3 EtOH 1.2 80 <30
9 Me2PPh EtOH 3 80 10
10 (CF3Ph)3P EtOH 3 80 50
11 P(p-FC6H4)3 EtOH 3 80 -
12 P(OPh)3 EtOH 3 80 -
13 P(p-Tol)3 EtOH 3 80 trace
14 DMAP EtOH 4.5 80 -
15 DBU EtOH 8 80 -
16 Quinuclidine EtOH 12 80 -
17 DABCO EtOH 3 80 -

a
Reaction conditions: 2-1a (0.10 mmol), and catalyst (20 mol%), ethanol (0.3M). bDetermined by 1H-NMR
using 1,3,5-trimethoxybenzaldehyde as an internal standard. cIsolated yield.

The initial investigation was carried out using toluene as solvent with
20 mol% of triphenylphosphine at 30°C showing a slight conversion
(Table 1, entry 1). On raising the temperature to 80°C, we observed the
formation of 2-2a with 40% yield (entry 2). Considering the previous
reports, the product yield was increased to 78% (entry 4) by using the
more polar ethyl acetate as solvent. To further increase the yield of the
desired product 2-2a, we planned to use protic solvents like alcohols,
as we reasoned that they could increase the concentration of

42
intermediate II, via rapid proton transfer to intermediate I (Figure 4).
This should favour the attack through the C-3 position of the indole.
To our delight, 2-2a was obtained in 84% yield when EtOH was used
as solvent (entry 5). Ethanol has the potential to assist [1,2]-proton shift
in intermediate III (Figure 4).78 Also, we assumed that the rapid
protonation of intermediate I might avoid the chance of self-
oligomerization.5,14 In an attempt to further enhance the yield we
screened different phosphines. With tris(4-methoxyphenyl)phosphine
(p-MeOPh)3P under our optimized reaction conditions, the yield
increased to 87% (entry 6).25 On the contrary, electron-rich PBu3 and
PMe2Ph afforded very low yields (entries 7-9). More electron-deficient
P(p-FC6H4)3 gave only 50% yield of the desired product 2-2a (entry
10), whereas (CF3Ph)3P, P(OPh)3 and P(p-Tol)3 totally met with failure
(entry 11-13). When various amine Lewis bases such as DMAP, DBU,
quinuclidine and DABCO were used, no desired product was observed
(entry 14-17).79 Thereafter, we investigated the effect of the reaction
concentration as well as the amount of triphenylphosphine. The yield
of the reaction showed a concentration dependency up to 0.3 M and
became almost invariant at higher concentrations. A similar pattern
was observed for catalyst loading where yield remained identical past
20 mol% of the catalyst. With the optimized conditions in hand, we
explored the substrate scope for the formation of 6-membered
spiroindolenines (Table 2). Substrates bearing different electron-
donating benzyl groups on the amide nitrogen successfully gave the
desired spiroindolenines with good product yields (2-2a~2-2d, Table
2). The methoxy- and alkyl-substituted (2-2f; 5-OMe, 2-2o; 5-Me)
indolenines were each formed in high yields. Pleasingly, halogen
substitution in indole substrates (2-2e; 6-F, 2-2g; 6-Br, 2-2h; 5-Br, 2-
2i; 7-Cl and 2-2j; 6-Cl) showed only small influence on the efficiency
of the reaction (Table 2). The tryptophan-derived propargylic amide as

43
well as the substrate derived from propargylic amine failed to give the
desired products (2-2k and 2-2p, Table 2).

Table 2: Substrate scope for spiroindolenine formation.a

a
Reaction conditions: 2-1 (0.40 mmol), and catalyst (20 mol%), ethanol (0.3M). PClB = para-chlorobenzyl,
PFB = para-fluorobenzyl, PMB = para-methoxybenzyl. 2-2g~2-2j) at 85°C for 6h; 2-2k at 90°C for 24h; 2-
2h* P(p-MeOPh)3 (20 mol%) at 85°C for 4h; 2-3e at 85°C for 6h; 2-3g~2-3h) at 80°C for 2h.

Next, we employed this protocol to form 5-membered spiroindolenines

assuming that the exo-dig cyclization was also preserved in this case.
Propargylic amides bearing electronically different substituents on the
amide-nitrogen were successfully transformed into the desired
products (2-3a~2-3h, Table 2). An additional halogen substituent on the

44
indole (4-Br, 5-Br) resulted in higher yields (2-3b and 2-3c, Table 2).
The electron-donating 5-OMe substituent was behaving as in the higher
analogous 2-2f (2-3d, Table 2). Interestingly, the substrate bearing a
strong electron-withdrawing nitro-group gave 57% yield (2-3e, Table
2).46 Notably, when indole-based Ugi-adducts were treated with 20
mol% of triphenylphosphine, they gave the tricyclic products (2-3g and
2-3h, Table 2).76a These results inspired us to explore the methodology
on some phenol-containing propargylic amides to deliver
spirocarbocycles (Table 3). With the Ugi four-component reaction, the
free hydroxyl-containing substrates (2-4a~2-4d) were synthesized
conveniently. Here, the post-MCR reaction proceeded with an ipso
attack on the alkyne, followed by Michael addition to form the tricyclic
products (2-5a~2-5d, Table 3) in moderate to good yields.80 As
expected, the methoxy-substituted substrate did not result in product
formation (2-5e, Table 3).

Table 3: Substrate scope for spiroindolenine formation.a

a
Reaction conditions: 2-4 (0.10 mmol), and catalyst (20 mol%), ethanol (0.3M).
2-4c: at 85 °C for 6 h. 2-4e: at 85 °C for 24h.

45
Encouraged by the above results, we evaluated the reaction of a
propargylic amide bearing a -proton (alkyl substituted alkynes) under
our optimized conditions. The ether appeared to be the major product,
resulting from nucleophilic attack of the alcoholic solvent on the -
position (Scheme 25).81 Interestingly, this could be regarded as a
remote C-H functionalization. The reaction required a longer time as
compared to the spiro-cyclization. Formation of the ether instead of
spiro-product might be due to the rapid isomerization of intermediate
2-6a to form the cyclic zwitterion 2-6b (Scheme 25). To favour
intermediate 2-6a we tried different types of phosphines such as DPPP
(1,3-bis(diphenylphosphino)propane) and P(NMe2)3 to decrease the
acidity of the proton.82 However, all efforts failed to give the desired
spiro-product. To avoid the isomerization in the allenoate product, we
tried phenyl substituted propargylic amide in a range of polar and non-
polar solvent but unfortunately, we could not achieve the desired
spirocyclization.

Scheme 25: Remote C-H functionalization

To develop a reusable catalytic-system, we moved our attention

towards the application of polymer-supported triphenylphosphine.
Under our optimized conditions in batch, 40% yield of 2-2a was
accessed after 18h. This gave us the starting point to further optimize
the reaction conditions in a packed bed continuous flow reactor.

46
Moreover, in comparison with batch conditions, the employment of a
continuous–flow reactor, in this case, bypasses the tedious work of
recovering the catalyst after each reaction (Scheme 26).83 A 0.1M
solution of 2-1a in a mixture of toluene/ethanol (1:1) was passed
through a 3 mm diameter packed bed reactor with 120 mg of polymer-
bound catalyst (loading 3 mmol/g, corresponding to 94 mg of
triphenylphosphine) at a flow rate of 0.025 mL/min. After optimization
the reaction worked very efficiently, resulting in 88 % of 2-2a. We
observed that the combination of toluene and ethanol provided optimal
swelling of the catalyst without affecting the selectivity of the reaction.
The extra added value of this approach can be accounted for the
possibility to perform the gram-scale synthesis of 2-2a, where we
obtained 79% of the pure product in one step without performing
multiple reactions and extractions.

Scheme 26: Spirocyclization of propargylamides under continuous-flow conditions

with a packed bed reactor using polymer-supported triphenylphosphine.

A plausible mechanism is described in Scheme 27. The catalytic cycle

starts with the Michael addition of PPh3 to propargylamide 2-1a to
generate a phosphonium intermediate 2-1b, followed by protonation
resulting in the intermediate 2-1d. Thereafter, 2-1d undergoes
umpolung Michael addition at the -position, which is induced by the
electron-withdrawing ability of the phosphonium entity. The resultant

47
ylide 2-1e undergoes proton transfer and elimination of phosphine from
2-1f generating the final product 2-2a.

Scheme 27: Proposed mechanism for phosphine-catalysed alkyne hydroarylation.

48
Figure 5: 31P-NMR experiments at various reaction times (top), 31P-NMR recorded
after the addition of triphenylphosphine oxide (bottom).

To gain more insight, we followed the 31P NMR spectrum in ethanol

for 2-2a (Figure 5). The reaction was performed in an NMR-tube and
31
the P NMR spectra were recorded at various reaction times. The
formation of closely associated downfield peaks to triphenylphosphine
might support the formation of intermediates 2-1b/2-1d during the
catalytic cycle. Besides, no decrease in the intensity of the
triphenylphosphine peak was observed and no formation of
triphenylphosphine oxide could be detected, confirming the
regeneration of the catalyst.

3.3 Conclusion
In summary, we have developed a phosphine catalyzed “anti-Michael
addition” on alkynes to form the spiroindolines and spiroindolenines in
batch as well as continuous-flow heterogeneous conditions. Over 28
examples of structurally and functionally diverse products were
successfully synthesized. This nucleophilic catalysis enables a wide
scope of six- and five-membered spiroindolenines as well as ipso-

49
cyclized products with yields ranging from 56% to 98%. Moreover,
triphenylphosphine catalysed nucleophilic activation of alkynes
allowed us to form the exo-product regioselectively. This new
activation method should enable the mild synthesis of these
biologically relevant molecules more sustainably.

50
4 Heterogeneously catalysed synthesis of
imidazolones via cycloisomerization of
propargylic urea using Ag and Au/Al SBA-
15 system

Adapted with permission from:

Zuliani, A.#; Ranjan, P.#; Luque, R.; Van Der Eycken, E. V. ACS
Sustain. Chem. Eng. 2019, 7, 5568–5575; DOI:
10.1021/acssuschemeng.9b00198. Copyright 2019 Americal Chemical
Society. (#Shared first author)
Author contributions: PR designed the project, carried out the
experiments; AZ prepared the catalyst and performed the experiments;
PR, AZ, RL and EVVdE wrote the manuscript.

51
4.1 Introduction
Imidazolones are well-known compounds widely used in industries for
the preparation of different chemicals, agrochemicals and
pharmaceuticals. Indeed, due to the existence of tautomeric forms, they
can easily interact with biopolymers and receptors present in living
systems which account for the different biological activities.84 Some
substituted imidazolones were found to be herbicides, insecticidal,
antifungal, anti-inflammatory and antitumor agents while others
showed cardiotonic, antioxidant, vasodilator and enhancing-memory
properties.85-88 For example, in 2008 Congiu and co-workers reported
imidazole-2-one derivatives as active anti-tumoral against human
cancer cells.89 More recently, some other imidazolone derivatives were
demonstrated to show high hypertensive activity by molecular
modelling approaches.90 Imidazolones have been also proved to be
novel ligands for the synthesis of catalytically active complexes with
transition metals. Ong and co-workers reported the hydroamination of
aminoalkenes with zirconium complexes supported on imidazolones.91
As a result, the preparation of substituted imidazolones is gaining more
attention day by day. The most studied methods for the preparation of
imidazolones include the synthesis from acyloins and ureas;87 the
intramolecular cyclization of ureidoacetals, ureidoxazinanes and
ureido ketones;92 or the transformations of imidazole derivatives such
as imidazolidine-diones or imidazole-oxides.93 During recent years, the
synthesis of substituted imidazolones from ureas, specifically from
propargylureas, have gained more attention due to the large availability
of the starting materials propargylureas and isocyanates.94 In fact,
diverse type of propargylamines can be synthesized in one-pot
reactions through A3-coupling of alkynes, amines and aldehydes,
which are starting material of low economic impact. However, the
cycloisomerization of propargylic ureas normally requires the

52
utilization of strong bases, such as KOH or NaOH, limiting the
applicability in terms of safety and waste/by-products production, and
environmental impacts.95,96 In some previous works we have
synthesized several substituted imidazolones starting from propargylic
ureas, operating in toluene and employing silver and gold
homogeneous catalysts avoiding the use of strong bases and highly
toxic chemicals.97,38 The homogeneous catalytic conditions were
selected as they offer better selectivity and high reactivity avoiding
mass transfer limitations, which decrease the overall time of reaction.
However, the utilization of homogeneous catalysts entails some
inherent disadvantages including the metal contamination in the final
product and the high cost of production due to the impossible recovery
of the precious metals.98,98 In addition, the U.S. Department of Health
and Human Services Food and Drug Administration classified toluene
as Class 2 solvent and its utilization should be limited in the
pharmaceutical industry.100
Herein, in order to switch the reaction to greener conditions, different
sustainable and efficient paths for the catalysed cycloisomerization of
propargylic ureas were investigated. Initially, the study of the reaction
was accomplished in toluene and acetonitrile, substituting gold and
silver homogeneous catalysts with heterogeneous systems based on
gold and silver nanoparticles supported on AlSBA-15. In general,
metal-nanoparticles supported on solids allow the exploitation of
nanocatalysis, at the boundary between homogeneous and
heterogeneous catalysis, with the simplified recovery of the
material.99,101 In the last years, different mesoporous materials have
been studied as supports for the stabilization of gold and silver
nanoparticles and mesoporous silica materials emerged due to the
abundance of Si-OH bonds on the surface, which can stabilize the metal
nanoparticles.102-104 Specifically, SBA-15 emerged for its outstanding

53
characteristics.105 To the best of our knowledge, no report on similar
works were found in the literature. The catalysts were prepared through
environmentally friendly paths, including solventless ball milling
techniques and fast microwave-assisted synthesis. Triphenylphosphine
was used as a mild additive to increase the reaction yield without any
leaching effects. Sequentially the solvents were substituted with
ethanol, which is classified as Class 3 solvent by the U.S. FDA (less
toxic and of lower risk to human health).100 Finally, a new methodology
for the cycloisomerization of propargylic ureas using only water as
solvent and synthesis promoter was developed. In order to sensibly
accelerate all the reactions, the synthesis was carried out under
conventional and microwave heating. In fact, microwave heating offers
the possibility to perform experiments in an extremely effective, safe,
rapid, and highly reproducible way.106,107 The results indicated that
heterogeneous catalyst in toluene promoted most N-cyclization
reactions, while ethanol favoured the cyclization of propargylic ureas
characterized by more electron-withdrawing groups. Finally, water-
mediated reactions favoured the cyclization of propargylic ureas
containing electron donor compounds in the structure.

4.2 Results and Discussion

Heterogeneous catalyzed reactions in toluene and acetonitrile. The
first studies were carried out to switch the catalysed cycloisomerization
of propargyl ureas from homogeneous to heterogeneous conditions.
Gold and silver nanoparticles supported on AlSBA-15 (2% metal load),
which showed good activity in previous work for the synthesis of
spiroindolenines, were selected as catalysts.46 The catalysts were
prepared by both mechanochemical methods and microwave-assisted
synthesis. On the one hand, mechanochemistry emerged as a promising
solventless technology where the kinetic energy is transferred to the

54
milled material achieving the breaking of chemical bonds and/or
creating new surfaces by fractures.108 In recent years, this method has
allowed the simple, clean, versatile and highly reproducible
preparation of advanced materials such as MOFs, supported
nanometals and metal oxides for diverse applications in catalysis or
related advanced technologies (e.g. electrochemistry).109-111 The
preparation of the catalysts via mechanochemistry involved two simple
steps: the grinding of AlSBA-15 with the metal precursors, and the
sequential calcination at high temperature under different atmospheres
in order to generate the metals (oxide) nanoparticles strongly attached
on the surface of AlSBA-15.112 On the other hand, microwave
techniques show several advantages, including shorter times, the
possibility to obtain higher yields, different selectivities, and the
potential to accomplish reactions/chemistries that don’t take place
under conventional heating conditions.113,114 Furthermore, microwave-
assisted methods have emerged for providing scaled-up processes
without suffering thermal gradient effects, leading to an important
advancement in the synthesis of nanomaterials.115 In the present work,
the catalysts were prepared by a unique easy step, were a homogeneous
mixture of the metal precursors and AlSBA-15 in ethanol, were quickly
heated under microwave irradiation. The rapid heating allowed the fast
precipitation of the metal precursors, which was reduced by ethanol,
forming the nanoparticles on the SBA surface.46 Mesoporous silica
SBA-15 was selected as supporting material for gold and silver
nanoparticles because of the abundance of Si-OH bonds on the surface,
which can stabilize the nanoparticles.116 In addition, SBA-15 features
unique properties including large surface areas (up to 1000 m2/g),
controllable thick walls, small pore sizes (4–30 nm), and high thermal
and mechanical stability.117 Lastly, aluminium can be easily inserted
into the structure of SBA-15, forming AlSBA-15 with enhanced

55
Lewis-acidic, ion-exchanging, and catalytic properties.118 The
employed catalysts were fully characterized in previous reports.
Specifically, XRD, SEM, TEM, XPS, surface area analysis and thermal
stability analysis can be found in the literature.46 As an example, Figure
6 depicts a TEM image of BM-2%Ag@AlSBA-15 in which silver
nanoparticles can be observed inside and outside the channels of
AlSBA-15.

Figure 6: TEM of BM-2%Ag@AlSBA-15. Reprinted with permission from F.

Schröder, U. K. Sharma, M. Mertens, F. Devred, D. P. Debecker, R. Luque, E. V.
Van der Eycken, ACS Catal. 2016, 6, 8156–8161. Copyright 2016 American
Chemical Society.

Scheme 28: Plausible mechanism for the formation of 2-imidazole.

Initially, the experiments of cycloisomerization of propargylic urea

were carried out using terminal propargylic urea 3-1 synthesized by

56
tosyl isocyanate and N-methylpropargylamine (Table 4). Ball-milling
synthesized catalysts BM-2%Ag@AlSBA-15 and BM-
2%Au@AlSBA-15 were firstly employed. The proposed general
reaction mechanism is illustrated in Scheme 28. The first aim consisted
in the determination of the selectivities and in the comparison of these
results with those reported using homogeneous catalysts. The
cycloisomerization of propargylic ureas derived from tosyl isocyanate
was selected as a model reaction. As shown in Table 4, the reaction
was first run with 2.5 mol % of catalyst in toluene, obtaining 47% yield
of imidazolidin-2-one 3-1a with 20 % of migrated double bond product
imidazole-2-one 3-1b (Table 4, entry 1). The result was close to the
previous report, in which the synthesis of imidazolidin-2-one was
successfully promoted by PPh3AuCl (Table 4, entry 16) in
homogeneous conditions.97 Furthermore, increasing the amount of
BM-2%Au@AlSBA-15 employed improved the formation of 3-1a
(Table 4, entry 2).

Table 4: Optimization of the reaction conditions.

Entry Mol % Solvent T [°C] t[h] Yield % (a/b) e

1a 2.5 Au Toluene 40 3 47/20

2a 5 Au Toluene 40 3 78/20

3a 5 Au Toluene 40 2 70/20

4a 5 Au Toluene 40 1 20/0

5a 5 Au Toluene 80 1 60/36

6a 5 Au ACN 40 0.5 17/0

57
 7a 5 Au ACN 40 1 22/0

8b 1.5 Ag Toluene 40 1 85/0

9b 2.0 Ag Toluene 40 1 96/0

10b 2.5 Ag Toluene 40 1 97/0

11b 5 Ag Toluene 40 2 97/0

12b 5 Ag Toluene 80 1 98/0

13b 2.5 Ag ACN 40 2 87/0

14b 2.5 Ag ACN 40 1 80/0

15c 10 Ag ACN 80 4 66/0

16d 5 Au CDCl3 50 22 40/6

All reactions were run with 3-1 (72 μmol, 0.5 ml solvent) in a screw-cap vial. a) BM-2%Au@Al-SBA15. b)
BM-2%Ag@Al-SBA15. c) AgOTf. d) AuPPh3Cl. e) Reaction yield.

The decrease of the reaction time resulted in a decrease of the yield

with more selectivity to the formation of imidazolidin-2-one (Table 4,
entries 3, 4). This can be explained in terms of kinetic vs.
thermodynamic stability: kinetically favourable product 3-1a was
dominating over thermodynamically stable 3-1b in short reaction time.
The use of ACN as an alternative solvent was not as effective as
compared to toluene (Table 4, entries 6, 7). Sequentially, BM-
2%Au@AlSBA-15 was replaced by BM-2%Ag@AlSBA-15 (Table 4,
entries 8-14), a cheaper catalyst. Interesting, a smaller amount of BM-
2%Ag@AlSBA-15 was needed to obtain higher yields and selectivity,
as compared to the gold catalyst (Table 4, entries 8, 9, 10). Indeed, 2.5
mol % of catalyst and 1h of reaction were found to be the best
conditions to obtain 97% yield of imidazolidin-2-one 3-1a with 0%
production of migrated119 double bond imidazole-2-one 3-1b (Table 4,
entry 10 compared with 11). The above results showed the higher

58
metallic character of Ag@AlSBA-15 over Au@AlSBA-15. In fact,
XPS measurement of Au@AlSBA-15 showed the existence of some
Au3+ ( band at 85.7 and 89.4 eV) species with mostly Au(0) while XPS
measurement of Ag@AlSBA-15 exhibited mainly metallic silver not
oxidic.46 The switch to acetonitrile (ACN) provided good selectivity
and excellent yields of 3-1a (Table 4, entry 13, 14). However, the silver
mirror was noticed inside the NMR tube, demonstrating the leaching
of silver with acetonitrile.120 As a consequence, ACN was considered
inappropriate for the reaction. Positively, no silver mirror was observed
in the NMR tube using toluene.

Sequentially, based on the optimized conditions of using 2.5% mol

BM-2%Ag@AlSBA-15 in toluene, the reaction was attempted using
phenyl isocyanate. As shown in Table 5, the high reaction yields and
selectivities obtained with propargylic ureas 3-1 (Table 4) were never
observed, despite increasing the reaction time up to 17 h and the
temperature up to 80°C (Table 5, entry 1, 2, 3 and 4).

Table 5: Cycloisomerization of propargylic ureas derived from phenyl isocyanate.

Entry Additive pKa T [°C] t[h] Yield % (a/b)a

1 / 40 1 0

2 / 40 3 0

3 / 40 17 0/17

4 / 80 17 0/41

5 PPh3(1 equiv) 7.6b 40 3 0/70

59
 6 PPh3(0.5 equiv) 80 3 0/86

7 PPh3(0.5 equiv) 80 2.5 0/86

8 DABCO(0.5 equiv) 8.2b 80 3 0/10

9 DMAP(0.5 equiv) 80 3 10/0

10 Et3N(0.5 equiv) 10.7 c 80 3 0/0

All reactions were run with 3-2 (72 μmol, 0.5 ml toluene) in a screw-cap vial, BM-2%Ag@Al-SBA15 (2.5
mol %). a) Reaction yield was determined by the NMR-integration method. b) Basicity measurement in
acetonitrile. c) Determined in water for deprotonation of conjugate acid.

Aiming to increase the reaction yield, some additive were tested. Based
on previous results, the effect of triphenylphosphine was investigated
in combination with the new heterogeneous conditions.97 Using 1
equivalent of triphenylphosphine and operating at 40ºC, a major
selectivity to imidazole-2-one was observed (Table 5, entry 5). As
triphenylphosphine is a well-known ligand for gold and silver, the
possible leaching of BM-2%Ag@AlSBA-15 was evaluated by hot
filtration test. To execute this test, the catalyst was removed from the
reaction mixture after 30 min of ongoing stirring under the investigated
reaction conditions (35% conversion). Fresh triphenylphosphine was
subsequently introduced to avoid any loss and the reaction was
continued for other 6h. No appreciable conversion by NMR was
observed, in good agreement with an identical Ag-loading in the
catalyst before/after removal from the reaction mixture. These findings
were a good indication of the heterogeneous nature of the reaction. The
utilization of triphenylphosphine was subsequently tested at 80°C
lowering the reaction time. The best condition led to the synthesis of
product 3-2b with 86% yield operating at 80ºC for 2h 30’ (Table 5,
entry 7). In order to gain more insights, other Lewis bases were tested
as an additive (Table 5, entry 8, 9, 10). However, no improvement in
the reaction yield was observed. These results may point to a unique

60
and efficient electron-donating effect of the phosphorus of
triphenylphosphine, which upon coordination to Ag nanoparticles led
to Ag species with an improved “metallic” character correlated to an
improved reactivity for the investigated chemistry. This electron-
donating effect is well documented in the literature for homogeneous
catalysts and metals but firstly approached here as stabilizing effect for
heterogeneous catalysts.121
With the new optimized conditions, the reaction was successively ran
using other substituted propargylic ureas, as shown in Table 6. The
reaction was remarkably more efficient with nitro-phenyl isocyanate
derived ureas as compared to aryl-substituted ureas (Table 6, entries 1,
2 and 3). The observed low activity may be due to the free rotation of
the benzyl group, which can be responsible for steric hindrance.38 The
reaction with non-terminal alkynes under same optimized condition,
resulted in less than 20% conversion. This was expected due to the
steric hindering substituent on the triple bond.76d Sequentially, catalyst
loading and reaction time were increased, resulting in 56% yield (Table
6, entry 6).

Table 6: Optimization of substituted propargylic ureas.

Entry R R1 R2 R3 T [°C] t[h] Yield % (a/b)a

1 p-NO2C6H5 Me H H 40 1 0/90

2 Bn Me H H 40 6 0/10

3 Bn Me H H 80 6 0/22

4 p-Tol Me H H 80 3 0/73

61
 5 Ph Bn Pr Ph 80 3 0/14

6b Ph Bn Pr Ph 80 4 0/56

All reactions were run with 3-3 (72 μmol, 0.5 ml toluene) in a screw-cap vial using BM-2%Ag@AlSBA15 . Bn
= Benzyl group. a) Reaction yield was determined by the NMR-integration method. b) Catalyst = 10 mol % ,
1 ml toluene.

Due to the high loading of the catalysts, the last reaction conditions
(Table 6, entry 6) were selected for the comparison of nanocatalysts
synthesized by ball milling and microwave-assisted techniques (Table
7).

Table 7: Comparison of microwave and ball-milled synthesized catalysts for the

cycloisomerization of propargylic urea.

a
Entry Catalyst Yield %

1 BM- 2%Ag@AlSBA-15 56

2 MW- 2%Ag@AlSBA-15 35

3 BM-2%Au@AlSBA-15 <5

4 MW-2%Au@AlSBA-15 <5

All reactions were run with 3-3 (72 μmol, 1 ml toluene) in a screw-cap vial. a Reaction yield was determined
by the NMR-integration method. Catalyst = 10 mol %, temp. = 80 °C, time = 4h.

Gold nanocatalysts were found to be almost inactive for the reaction

(Table 7, entries 3 and 4). Considering silver catalysts, the ball-milling
synthesized one was more active than MW-2%Ag@AlSBA-15.
Despite this lowest activity, it has to be highlighted that the microwave-
assisted synthesis was much more favourable compared to the
synthesis of nanocatalysts prepared by ball-milling. In fact, BM-
catalysts needed longer time of preparation, resulting by the sum of the
10’ of ball milling and the several hours of muffle treatment for the

62
calcination. Instead, nanocatalysts prepared by microwave-assisted
techniques were prepared only through a one easy reduction step of 5’
irradiation in the microwave reactor. However, in order to obtain the
higher yields, the ensuing trials were carried out using BM-
2%Ag@AlSBA-15.

Switching to ethanol. In order to accomplish the reaction in greener

conditions, the synthesis was switched from toluene to ethanol, which
is classified as Class 3 solvent by U.S. FDA.100 Following the same
logical evolution accomplished in the first part of the research, the
reactions were initially carried out without any additive, operating
under conventional heating conditions, using propargyl urea 3-4
synthesized by tosyl isocyanate and N-methylpropargylamine (Table
8).

Table 8: Cycloisomerization of propargylic ureas derived from tosyl isocyanate in

EtOH.

Entry Mol % T [°C] t[h] % Yield (a/b) c

1a 2.5 Au 80 14 27/32

2a 5 Au 80 14 44/32

3b 2.0 Ag 40 1 97/0

4b 1.5 Ag 40 0.5 93/0

5b 1.0 Ag 40 0.5 80/0

6b 1.5 Ag 40 0.16 78/0

All reactions were run with 3-4 (72 μmol, 0.5 ml ethanol) in a screw-cap vial. a) BM-2%Au@Al-SBA15 b) BM-
2%Ag@Al-SBA15. c) Reaction yield was determined by the 1H-NMR-integration method.

63
The best results were observed using 2 wt% BM-Ag@AlSBA-15
catalysts and operating at 40 °C for 30 min. (Table 8, entry 4), finding
the same results observed in toluene (Table 4, entry 10). In order to
evaluate the effect of triphenylphosphine in ethanol, different trials
were carried out. As summarized in Table 9, no cyclization occurred
when triphenylphosphine was added.122,123

Table 9: Effect of polar solvent EtOH on cycloisomerization of propargylic ureas

derived from phenyl isocyanate with PPh3 as an additive.

Entry Additive T [°C] t[h] Yield % (a/b)

1 40 6 -

2 PPh3(0.5 equiv) 40 3 -

3 PPh3(0.5 equiv) 80 3 -

All reactions were run with 3-5 (72 μmol, 0.5 ml solvent) in a screw-cap vial with BM-2%Ag@Al-SBA15.

Developing the conditions for the water-mediated reaction. All

obtained results were combined aiming to carry out the reaction in
water. All the reactions were run in the microwave using only H2O as
solvent and promoter of the reaction. As reported by Mohan and co-
workers,124 water can act as a mediator for the construction of different
heterocycles. The possible mechanism is shown in Scheme 29.

64
 Scheme 29: Possible mechanism for the water-mediated formation of 2-imidazole.

As summarized in Table 10, different trails have been carried out,

varying reaction time, temperature, and structure of propargylic ureas.
The best results were obtained operating at 130°C for 20 min.. The
outcomes clearly showed that water was favouring the cyclization of
propargylic ureas containing electron donor compounds. As shown in
Table 10, entry 4, the best conditions allowed the preparation of
substituted imizadolones with 72% yield in 20 min..

Table 10: Cycloisomerization of different propargylic ureas in water under

microwave irradiation.

Entry R T [°C] t[min.] Yield % (a/b)

1 Ph 80 20 /

2 Ph 100 20 0/10

3 Ph 120 20 0/50

4 Ph 130 20 0/72

65
 5 Ph 130 5 0/8

6 Ph 130 10 0/30

7 p-FC6H4 130 20 0/66

8 Bn 130 20 0/3

9 p-NO2C6H4 130 20 0/68

All reactions were run with 3-6 (72 μmol, 0.5 ml water) in a screw-cap vial.

4.3 Conclusion
In conclusion, Ag and Au heterogeneous catalysts were explored for
the cycloisomerization of propargylic ureas. Several scopes were
studied highlighting the reaction mechanism in the selected different
paths, where heterogeneous catalyst in toluene promoted N-cyclization
reactions, ethanol favoured the cyclization of propargylic ureas
characterized by more electron-withdrawing groups and water-
mediated reactions favoured the cyclization of propargylic ureas
containing electron donor compounds in the structure. In contrast to
previous studies, the newly developed paths offer the possibility to
accomplish the cycloisomerization reaction more economically, using
recoverable heterogeneous catalysts and avoiding the utilization of any
strong base. In addition, all the reactions were carried out under
conventional and microwave heating, emphasizing the possibility of
microwave technique to reduce the reaction time.

66
5 Continuous Microwave-Assisted
Synthesis of Silver Nanoclusters Confined in
Mesoporous SBA-15: Application in Alkyne
Cyclizations.

Adapted with permission from:

Manno, R.#; Ranjan, P.#; Sebastian, V.; Mallada, R.; Irusta, S.; Sharma,
U.K.; Van Der Eycken, E. V.; Santamaria, J. Chem. Mater. 2020, 32,
2874–2883; DOI: 10.1021/acs.chemmater.9b04935. Copyright 2019
Americal Chemical Society. (#Shared first author)
Author contributions: PR performed the catalytic reactions; RM
prepared the catalysts; RM, VS, RM and SI analysed the catalysts; RM,
PR, VS, RM, SI, UKS, EVVdE and JS wrote the manuscript.

67
5.1 Introduction
The high demand for fine chemicals and the dependency of their
production on expensive and non-recoverable homogenous catalysis
has led to an active search for alternative heterogeneous catalysts,
especially nanostructured materials. In the last decade, due to vast
developments in characterization techniques, researchers have been
capable of studying the catalytic reaction from nanoparticles, down to
nanoclusters and even single-atom level.125 Also, significant advances
have been made in the synthesis of well-defined nanostructured
materials. Specifically, noble metal clusters (NCs) with sizes
approaching the Fermi-wavelength of an electron (<1 nm) have
received much attention in the past year, due to their widespread use in
the field of catalysis, biology and medicine.47,49,51,126,127 Silver-based
nanocatalysts exhibit high selectivity and reactivity for a wide range of
organic reactions, such as the reduction of nitroaromatics or carbonyl
compounds, the deoxygenation of epoxides or the oxidation of
alcohols, silanes and olefins. Silver can often be used as an alternative
to more expensive metals commonly used (Pt, Pd or Au), and this has
spurred interest in the development of high efficient silver-
nanocatalysts.128 Silver nanoclusters have been intensively investigated
since the early work by Ershov and co-workers129 generating a wide
library of synthesis procedures, particularly about Ag-NCs stabilized
by anion templates130 or thiolate groups.131,132 The works of Belloni and
Mostafavi133-135 were of extreme interest to further investigate the
mechanism of Ag nucleation in a poly acrylic acid (PAA) template by
γ-irradiation. The hydrated electrons generated by the energy of
irradiation activated the reduction of Ag(I), which were then
complexed by the COO- anionic groups of the polymer.
Several investigations have focused on the analysis of the effects of
alternative energy sources. For example, Diez and co-workers136

68
revealed the reductive power of visible-light at room temperature to
synthesize fluorescent Ag-NCs in a template of PMMA. The ratio
Ag/PMMA and the solvent adopted strongly influenced the properties
of the resulting clusters, especially in terms of number of atoms and
electroluminescence properties. Instead, UV-irradiation reduced the
synthesis time down to 20 min for Ag-NCs with a structure Agn+ with
n in a range from 2 to 8 atoms.137-139 In addition, Suslick introduced an
innovative sonochemical method, observing high fluorescence Ag-
NCs after 60 min of sonication in a template of PMMA (MW=4500).140
However, a remarkable reduction of the synthesis time (to 70s) was
obtained by microwave irradiation,141 resulting in homogeneous size
distribution of Ag-NCs with an average diameter of 2 nm which was
used for selectively sensing Cr3+. The speed of microwave heating may
represent an efficient alternative energy source to reduce induction
times and control the nucleation of small clusters with more accuracy.
Furthermore, its combination with continuous flow microfluidics may
help to improve the control of the temperature gradient, increasing the
rates of heating and mixing, but also enabling a fast quench, stopping
further nucleation events.142 To the best of our knowledge, there is no
report about the design of new reactors able to produce small Ag-NCs
combining the advantages of continuous flow and microwave heating.
In this work, we will present a novel flow micro-reactor, designed to
obtain a high control of the mixing, MW heating and quenching stages.
As reported by Santamaria and co-workers,143 MW heating enhanced
the heating rate and the synthesis yield in a microfluidic reactor for the
synthesis of Ag-NPs, while reducing unwanted wall fouling due to
selective heating. In this work, the final aim is to obtain stable Ag-NCs
and for this, accurate control of the subsequent cooling phase is
essential to avoid subsequent agglomeration, and inhomogeneous
growth of the Ag-NCs synthesized.

69
Finally, the catalytic activity of the supported NCs has been tested. The
activity of Ag atoms is largely reported for alkynylation, cycloaddition
and cycloisomerization of functionalized alkynes. Its high activity is
strictly connected with its d10 electronic configuration which allowed
the formation of π-complexes.144 Silver salts have been reported as
excellent catalysts for the synthesis of biologically relevant molecule
viz. furoquinolines,145 imidazolones,146 spiroindolines,147 o-
148
alkynylbenzohydroxamic acid cycloisomerizations, cycloaddition of
propargylamines,149 2-aminoimidazole alkaloids37 and so on. Despite
the high yield and selectivity usually observed, a high concentration of
silver-salts has been used, with many drawbacks related to their
recovery after the reaction. Small supported metal clusters,
characterized by a M(n+m)m+ structure, represent an innovative and more
efficient alternative, not only due to the high surface to volume ratio,
but also due to the population of highly active uncoordinated atoms that
usually surround the metal core structure.150 Therefore, to facilitate the
catalytic use of the Ag-NCs synthesized in this work, we have
supported them on SBA-15, a mesoporous silica substrate with a high
surface area.151-154 The substrate was amino-functionalized to increase
the electrostatic attraction with PAA and enable a high dispersion of
Ag-NCs in the wide channels, guaranteeing good reactant
accessibility.155-157 Herein, we were able to activate alkynes in diverse
substrates followed by the formation of C-N, C-O and C-C bonds
employing our newly developed Ag-NCs that showed superior
performance compared with traditionally adopted Ag-salts and Ag-
NPs.

70
5.2 Results and discussion
5.2.1 Synthesis of Ag-NCs and Ag-NCs/SBA-15
First, the synthesis of Ag-NCs was conducted in a batch-type reactor
at different reaction times (70s, 35s and 17s). Electron microscopy
images analysis of resulting Ag-NCs shows that the irradiation time
strongly influences the size distribution of the Ag-NCs (Figure 7).

Figure 7: TEM analysis for batch synthesis of Ag NCs at respectively 70s (a), 35s (b)
and 17s (c).

The mean size and standard deviation increases as the irradiation time
is extended from 17s to 70s, obtaining the most monodisperse
distribution of Ag-NCs (1.6±0.7 nm) at the shortest irradiation time
(17s). This achievement slightly improves some previous results
reducing the average size distribution, halving the synthesis time and
improving the size deviation.141 However, as reported in Figure 8a, the
switching off of MW did not lead to a fast cooling of the system, in fact
a temperature higher than 50°C was recorded for more than 300s which
may promote subsequent aggregation of Ag atoms, and size evolution
of the clusters. For this reason, we designed a continuous flow reactor
to rapid quench the reaction after the heating step, minimizing the
further evolution of the metallic nanoclusters. The microfluidic reactor
allowed to reach the reaction temperature of (71.7±8.7) °C in a 17s
heating step and a fast quench to a temperature of 4°C in a 21s cooling
stage (Figure 8d). The tighter control of heating and cooling in the flow
reactor yielded a reduction of the average diameter from the batch type-

71
reactor (1.6±0.7) nm to the continuous type-reactor (1.2±0.3) nm
(Figure 8b and 8e respectively). Interestingly, the Ag-NCs size
distribution was remarkably reduced around 60% when we used the
continuous microfluidic platform. Furthermore, HR-STEM analysis of
clusters confirmed the absence of a crystalline structure.135,139 As
reported in Figure 8c and 8f, a clear difference in the color of the
solution was observed between the two synthesis procedures. In detail,
Belloni and Mostafavi133,134 analyzed the mechanism of clusters
formation by γ-irradiation with a detailed STM analysis. The
carboxylate group in PAA had a dual function: anchoring of clusters
like a ligand and protecting them from coalescing through to
electrostatic repulsion. The clusters may present a structure like
Ag(4+m)m+, with silver atoms and silver ions stabilized by the
carboxylate groups of the polyelectrolyte.158,159

Figure 8: a) Experimental temperature profile for the batch-type reactor measured

with an optical fiber in three different points as indicated in the optical image; b) Size
distribution of Ag-NCs (N=679) produced by a batch-type reactor; c) UV-Vis
Spectroscopy of Ag-NCs produced in a batch-type reactor, synthesis time 17s. Inset,
optical image of resulted Ag-NCs (dilution in the quartz cuvette 0.5 ml of sample in 2.5
ml of DW); d) Temperature profile in a continuous-flow reactor measured by an IR
Camera (red points), Comsol Multiphysics® (blue line) and an optical fiber (black
point); e) Size distribution of Ag-NCs (N=412) produced in a microfluidic system; f)
UV-Vis Spectroscopy of Ag-NCs produced in the continuous microfluidic system. Inset,
optical image of resulted Ag-NCs (dilution in the quartz cuvette 0.5 ml of sample in 2.5
ml of DW).

72
Based on their analysis, it may be plausible to associate a structure of
Ag42++PA- to the pink colloidal solution, obtained with continuous
flow synthesis, and of larger species to blue complexes, reported for
batch reactions.129,158 The differences between the plasmonic resonance
peaks confirmed the absence of larger crystallized Ag-NPs and the
synthesis of Ag-NCs.139,160 The control of synthesis conditions is
usually challenging and has a strong effect on the resulting
nanomaterials. This issue is even more critical in fast kinetic
reactions,161 such as the one considered in this work. The microfluidic
synthesis of nanomaterials can enhance the controllability and
reproducibility of the resulting Ag-NCs due to the excellent control at
the mixing and reaction levels.161 Figure 9 depicts representative TEM
images of the Ag-NCs obtained at different synthesis runs under a
residence time of 17s. Remarkably, the synthesis of Ag-NCs using the
microfluidic system presents good reproducibility and comparable
interbatch nanoparticle size distributions (Figure 9).

Figure 9: TEM and HRSTEM analysis for SBA15 grafted with APTES (a),
unsupported Ag NCs (b), SBA15-APTES with three different loading of Ag NCs: 0.18
wt.% (c), 0.62wt.% (d) and 0.96wt.% (e).

Next, the improved clusters synthesized by continuous synthesis were

stabilized through deposition on a mesoporous substrate, ensuring a

73
long lifetime and their use for heterogeneous catalysis. Figure 10
depicts the HRSTEM analysis of the Ag-NCs supported on SBA-15.
No size alterations were observed after the deposition at different Ag
loadings (Figure 11). Furthermore, Ag-NCs were homogeneously
dispersed on the SBA-15 channels, occupying the external and the
internal surfaces of the porous substrate. Interestingly, N2 adsorption
analysis evidenced a decrease of 33 % of pore volume as a result of the
deposition. In spite of this, the analysis of type IV isotherms obtained
after deposition (Figure 10c) showed that the average pore size was still
higher than 9.0 nm with an average pore volume of 0.59 cm3/g. This
means that the functionalized mesoporous support can be used as a
suitable catalyst, since the substrates to be used in this work present a
molecule size lower than 2 nm. Finally, XPS analysis confirmed the
co-presence of 50% of Ag(0), that presumably forms the core of Ag-
NCs, and 50% of Ag(I), complexed by the polycarboxylate group of
PAA (Figure 10d).

Heterogeneously catalyzed reaction

As reported in our previous work by Ermolat’ev et al.37 silver salts may

represent an excellent catalyst for hydroamination of
propargylguanidines. Mechanistically, silver (I) –catalyzed activation
of the triple bond followed by nucleophilic attack of nitrogen and
subsequent proto-demetallation offered the desired product in good
yield. Unlike crystallized nanoparticles, Ag-NCs present a high
concentration of uncoordinated atoms, as shown in Figure 10d. The
optimized surface to volume ratio combined with the presence of Ag(I)
and Ag(0) presents a favourable situation to increase its catalytic
activity. In view of recent reports on silver catalysis, we started
optimizing our reaction in standard solvents commonly used for silver
and gold catalysis.

74
Figure10: (a) and (b) HRSTEM analysis Ag-NCs/SBA-15 (0.96 %wt) evidencing the
homogeneous distribution of the metallic clusters inside and outside of the pores. The
grafting of SBA-15 at first with APTES and subsequent with Ag-NCs is evidenced by
the reduction of pore diameter, which still continues to be higher than 9.0 nm, allowing
its catalytic application (c). XPS test evidenced the presence of Ag(0) and Ag(I) (d).

Figure 11: Reproducibility analysis of size distribution for three different synthesis of
Ag NCs/APTES-SBA-15.

To our delight Ag-NCs (0.15 mol % in overall Ag content) gave 4-2a

in 90% yield (Table 11, entry 2). Among the tested solvents, DCM
worked well (Table 11, entries 2, 3 and 4). Strikingly, a slight increase
in the temperature resulted in a 99% yield of 4-2a after 3h (Table 11,
entry 5). This is remarkable, since compared with the traditionally used
silver salts, the catalyst loading is about 33 times lower (compared to
AgNO3)162 and about 7 times lower compared to the Ag-NCs used by
Duan and co-workers.149 In the term of metal loading, 0.96 wt% of
silver loading was optimal to achieve the highest yield as compared to

75
0.62 wt% and 0.16 wt% of silver loading (Table 11, entries 6 and 7).
This result evidenced that a major density of the clusters on the porous
substrate (reported in Figure 11) may increase the stochastic
probability of the substrate to reach the active site.
Table 11: Optimization studies of propargylguanidine cyclization, catalyzed by Ag-
NCs.a

Mol
t Conv Yield
Entry Solvent T (°C)
(h) (%)e (%)e
% Ag

1 - DCM 40 12 <5 <5

2b 0.15 DCM 40 2 90 90

3b 0.15 DCE 40 2 50 50

4b 0.15 Toluene 40 3 85 83

5b 0.15 DCM 50 3 100 99

6c 0.15 DCM 50 3 84 81

7d 0.15 DCM 50 3 53 53
a
Reaction conditions: All reactions were run with 4-1a (0.12 mmol) in the indicated solvent (1.2 mL) in a screw
cap vial. b 0.96 wt% Ag-NCs@SBA-15. c 0.62 wt% Ag-NCs@SBA-15. d 0.16 wt% Ag-NCs@SBA-15. e
Conversion and yield were determined by the NMR-integration method using 3,4,5-trimethoxybenzaldehyde as
an internal standard.

Stability against leaching: In the case of our Ag-NCs leaching could

be due to the diffusion of Ag-ions from the support to the solvent. To
verify the stability of the catalyst a hot-filtration test was performed by
removing the catalyst after 90 min of reaction. As reported in Figure
12a , no further conversion was observed after the removal of the
catalyst, confirming the heterogeneous nature of the reaction.
Furthermore, the catalytic activity remained higher than 90% even after

76
4 cycles and no leaching of the Ag content could be detected by MP-
AES analysis (Table 12).

Figure 12: Leaching test analysis for Propargylguanidine cyclization. a) Hot-

filtration test after 90 minutes of reaction. b) Activity tested up to 4 cycles.

Table 12: Catalyst loading determination of fresh and used catalyst by MP-AES.

Fresh Catalyst Used Catalyst

[Ag] wt% (0.62+0.03)% (0.61+0.02)%

Finally, to verify the possible alterations in size distribution HRTEM

analysis was performed on the recovered catalyst used for the reaction
at different temperatures and in different solvents. As reported in
Figure 13, no relevant variations of size distribution were observed
confirming the absence of modifications on the catalyst itself. The
substrate scope for the hydroamination of propargylguanidines,
employing the optimized conditions, was subsequently investigated
and listed in Table 13. High yields were observed for all the substrates
analysed at 50°C in 3h, except for the case of 4-2f and 4-2g.

77
 Figure 13: HRSTEM analysis for Ag NCs/SBA-15 catalyst after reaction. a) and b)
after reaction at 50°C for 3h in DCM, c) and d) after reaction at 50°C for 3h in
Toluene.

Referring to the previous reports by Stratakis163 and our group73d this

was predictable due to the sterically hindered substituents on the
internal triple bond. To overcome this issue and further explore the
potential applicability of our Ag-NCs avoiding prolonged reaction
times of batch reaction, we applied our chemistry to continuous-flow
setup to achieving good conversion with the substrates 4-1f and 4-1g,
which resulted increased in yields up to 40% and 42% respectively
(Scheme 30). This could be rationalized as a consequence of the
instability of the final product at the reaction temperature. Thus, under
continuous flow conditions, the strong reduction in contact time (from
hours to minutes) would minimize the thermal strain and increase the
yield to the desired product.

78
 Table 13: Scope of the reaction by Ag-NCs catalysts in batch conditions.a

Product Product Time Temperature Yield (%)

no. (h) (°C)

4-2a 3 50 99

4-2bb 3 50 50

4-2c 3 50 80

4-2d 3 50 70

4-2e 3 50 92

4-2fb 3 50 <5

79
4-2gb 3 50 <5

a
Reaction conditions: All reaction were run with substrate 4-1 (0.32 mmol) in DCM (3.2 mL) and Ag-NCs (0.15
mol %, 0.96 wt% Ag-NCs@SBA-15) in a screw cap vial. b Ag-NCs (0.3 mol %, 0.96 wt% Ag-NCs@SBA-15).

Scheme 30: Comparison of the Ag-NCs catalyzed hydroamination of internal alkyne

substrates 4-1f and 4-1g in batch and continuous-flow with a packed-bed reactor.

To further extend the applicability of our catalyst, we examined the

synthesis of 2-phenylbenzofuran by employing Ag-NCs, which is
usually performed under homogeneous catalysis or with Pt-, Pd- and
Au-NCs.57,164,165 In line with the literature we assumed that the
activation of the triple bond by Ag-NCs would result in O-
cyclization.166,167 We observed low yield with AgNO3, AgOAc and
Ag2O, respectively of 15%, 5% and 5% (Table 14, entries 1, 2 and 3).
Furthermore, no conversion was observed with larger silver
nanoparticles previously used for the synthesis of imidazolones (Table
14, entry 4). On the contrary, Ag-NCs gave a nearly quantitative
conversion of 4-3a (Table 14, entry 5). Satisfyingly, increasing the
temperature to 70°C reduced the reaction time to 3h (Table 14, entry
7). Somorjai and co-workers57 have reported same reaction with 4
mol% of Pd40/SBA-15 but we were also able to achieve the same
conversion with the lower amount of Ag-NCs (1.5 mol %) at lower
reaction temperature (Table 14, entry 7). A slight deactivation of the
catalyst was observed after each application, diminishing the yield to
80
20% after the third cycle, as reported in figure14. We assumed that this
result might be due to the reduction of Ag(I) to Ag(0), which we
confirmed by XPS analysis after the reaction (Figure 14b).

Figure14: a) Reusability activity tested up to 4 cycles, with a H2O2 regeneration step.

b) XPS Analysis after 3 cycles, where it is possible to notice the complete reduction of
Ag. c) HR-STEM after the H2O2 treatment.

In an attempt to reactivate the catalyst, we used the H2O2 etching

reaction in water to increase the surface of Ag(I) ions.168,169 We
observed that this procedure effectively restore the catalytic activity,
giving 90% yield of 4-4a after the oxidation step (Figure 14a).
Furthermore, HRSTEM analysis confirmed that the morphology of the
catalyst remained almost invariable after H2O2 treatment (Figure 14c).
Finally, the stability of the catalyst was evaluated under continuous-
flow conditions at three different temperatures, 50°C, 80°C and 90°C.
As reported in Figure 15a, the catalyst was stable up to 7h of continuous
use, giving a conversion of 90% at 50°C. Although deactivation was
observed at higher temperatures, the catalyst could be completely
reactivated after H2O2 treatment. Furthermore, the continuous supply
of the fresh reactant and removal of product in a continuous flow
reactor diminished the chance of the catalyst deactivation induced by
product poisoning. For a better understanding of the reaction kinetics,
an activation energy of 6.99 kcal/mol was determined by measuring the
rate of reaction at a different temperature under batch conditions, as

81
reported in Figure 15b. This value was about three times lower in
comparison to Pd40/SBA-15.57

Table 14: Optimization of the cyclization of 2-(phenylethynyl)phenol catalyzed by

different Ag catalysts.a

Yieldb
Cat. T t
Entry Type of Catalyst (Conv)
(mol%) (°C) (h)
(%)

1 AgNO3 5 50 24 15(15)

2 AgOAc 5 50 24 5(5)

3 Ag2O 5 50 24 5(5)

4c Ag-NPs@SBA-1562 5 50 24 0(0)

5 Ag-NCs/SBA-15 1.5 30 20 91 (91)

6 Ag-NCs/SBA-15 1.5 50 6 93 (95)

7 Ag-NCs/SBA-15 1.5 70 3 93 (100)

a
Reaction conditions: All reactions were run with substrate 4-3a (0.05 mmol) in toluene (1 mL) in a screw cap
vial. bConversion and yield were determined by the GC-MS using hexamethylbenzene as an internal standard,c
Ag-NPs@SBA15 = 2 wt %62

Figure15: a) Continuous flow reaction of 2-(phenylethynyl)phenol cyclization at

different heating time, 50°C, 80°C and 95°C respectively. b) Determination of the
activation energy.

82
Encouraged by the above results, we used these Ag-NCs on post-MCR
spirocyclizations. In particular, we used Ag-NCs on
dearomatization/ipso-cyclization of substrate 4-5a because of the lower
selectivity reported with triphenylphosphine in our previous report.147
We conducted this reaction in DCM at 50°C for 12h (Scheme 34). To
our delight, Ag-NCs gave a high and selective conversion of 70% for
4-6a, without traces of product 4-6b which is a further confirmation of
the peculiar reactivity and applicability of Ag-NCs.170

Scheme 31: Spirocyclization of phenol based propargylamide 4-5a by Ag-NCs.a

a
Reaction condition: Reaction was run with substrate 4-5a (0.1 mmol) in DCM (1 mL) and Ag-NCs (0.3 mol
%, 0.96 wt% Ag-NCs@SBA-15) in a screw cap vial.

5.3 Conclusion
The innovative design of a microfluidic system for the synthesis of Ag
NCs including y-mixing section of reagents, MW heating during
reaction and fast quenching in ice bath, allowed to precisely control all
the synthesis steps, resulting in homogeneous AgNCs, that were further
stabilized in SBA-15 porous support, Ag-NCs/SBA-15 catalyst. The
small clusters with a dimension lower than 2 nm were homogeneously
distributed on the porous hexagonal channels of the mesoporous
substrate, as confirmed by HRSTEM analysis. The resulting catalysts
presented good accessibility for the substrates employed, could be
easily separated and recycled and were stable (in terms of particle size)
under the reaction conditions employed. The catalytic test evidenced
the high performances of cyclization of alkyne bonds for Ag-NCs, due
to the formation of π-complexes. The cycloisomerization of
propargylguanidine resulted in the formation of C-N bonds, with a

83
yield of 99% in less than 3h at 50°C. Furthermore, a reduction of 30
times of the metal loading was obtained in comparison to commonly
used Ag salts. Also, a clear advantage was observed for the cyclization
2-(phenylethynyl)phenol in comparison to the application of Ag-salts
and bigger nanoparticles. This extraordinary enhancement of catalytic
activity for Ag-NCs should be assigned to a good π-accepting
behaviour due to the co-presence of Ag(0) and Ag(I). This is also
supported by the fact that, for the cases where deactivation was
observed, a complete reactivation of the catalyst was possible through
H2O2 treatment that induced the partial oxidation of Ag(0). Finally, the
activity of the clusters was also confirmed for the formation of C-C
bonds in an important spirocyclization reaction. The catalyst designed
in this work is able to activate alkynes in diverse substrates followed
by the formation of C-N, C-O and C-C bonds.

84
6 Conclusions and Perspectives

The new synthetic approaches to construct C-O, C-C and C-N bonds
developed in this work, utilizing triple bond activation and
heterogeneous catalysis with the aid of continuous-flow reactors,
complement the existing array of synthetic approaches toward the
formation of these bonds. In the case of temperature-sensitive products,
packed-bed reactor proved to be a convenient tool to increase the
selective formation of the desired product by proving minimal thermal
strain (low residence time). These new sustainable synthetic tools led
to the synthesis of important biological scaffolds including
spiroindolines, spiroindolenines and imidazoles with good functional
group tolerance.

For the first time, the phosphine catalysis has been established to allow
the regioselective formation of 6 and 5-membered spiroindolenines as
well as various spirocyclic scaffolds (Chapter 3). The catalytic system
was recyclable up to 22 times under continuous flow-conditions
without showing any leaching. Notably, excellent regioselectivity was
found without the formation of any side-products.

The utilization of metal nanoparticles and nanoclusters in the formation

of C-C, C-N and C-O bonds was presented in Chapter 4 and 5
respectively. The special effect of triphenylphosphine as an additive
has been well demonstrated to enhance the activity of Ag NPs in the
cycloisomerization of propargylic ureas derived from phenyl
isocyanate. In contrast to Ag-based homogeneous catalysis, the effect
of phosphine as an additive to enhance the catalytic activity of Ag NPs
themselves is not very well explored. This heterogeneous catalytic

85
system provided mild conditions to access imidazoles without any
chance of metal contamination.
In Chapter 4, the use of Ag NCs was successfully reported for the
cycloisomerization of propargylguanidine, leading to the formation of
C-N bonds. In this transformation, Ag NCs proved superior to silver
salts towards the activation of the alkyne bond followed by a
cycloisomerization reaction. Also, higher reactivity was observed for
the cyclization 2-(phenylethynyl)phenol in comparison to the
application of Ag-salts and bigger nanoparticles. This extraordinary
enhancement of the catalytic activity of Ag-NCs was due to the co-
presence of Ag(0) and Ag(I) that led to good π-accepting behaviour.
This is also supported by the fact that, for the cases where deactivation
was observed, a complete reactivation of the catalyst was possible
through a H2O2 treatment, that induced the partial oxidation of Ag(0).
The control of regioselectivity in the spirocyclization of
indoles is still a flourishing field of research. The selective 6-exo and
7-endo spirocyclization can be achieved from the same starting
material designing the appropriate catalyst. This type of regioselective
switching has only been reported utilizing homogeneous Au and Ag
catalysis172, particularly with terminal alkynes, and this leaves the field
worth exploring.

Scheme 32: The regioselective synthesis of 6- and 7-membered spiroindolenines.

To achieve the same reactivity as presented in Scheme 32, a dual

catalytic system combining different loading of Au and Ag NCs on the
same metal oxide support can be envisioned. Dual catalysis can indeed

86
open the path to control the regioselectivity in the synthesis of
spiroindolenines to achieve the formation of these privileged
structures. The substrate scope can also be extended to 5-exo and 6-
endo spirocycles, as shown in Scheme 33.

Scheme 33: The regioselective synthesis of 5- and 6-membered spiroindolenines.

Another interesting application involves the utilization of CO2

in cycloaddition reactions employing Ag NCs, as shown in Scheme 34.
CO2 capture and its utilization in the organic synthesis is gaining ample
attention in the research community. Thus, the use of heterogeneous
Ag NCs can be a valuable tool to synthesize different heterocyclic
molecules like oxazolidinones.

Scheme34: General mechanism for the synthesis of oxazolidinones by CO2 capture.

In general, heterogeneous catalysis has the potential to offer

many advantages over homogenous catalysis. In the case of metal
nanoclusters, the catalytic activity can be easily tuned by controlling

87
shape and size of metal nanoclusters. In order to provide a better
understanding of this flourishing topic and to enhance its utilisation,
strong collaboration among various fields such as material chemistry
(catalyst preparation), chemical engineering (understanding of flow
and scale-up), organic chemistry (application) and computational
chemistry (mechanistic investigation) becomes necessary.

88
7 Safety Aspects and Environmental
Considerations

Safety in a research lab is a very important aspect when working with

any kinds of chemicals. Standard safety equipment such as lab coat,
safety glasses and gloves should always be worn. Considering the high
demand of gloves during COVID-19, the gloves should be only used
while working with chemicals. During the use of common lab
equipment such as door knobs, drawers and rotavaps gloves should not
be worn. Furthermore, it is always necessary to work under the fume
hood with proper ventilation. The height of the front sash should be
optimal to maintain the proper ventilation. In this work, special safety
consideration was taken for the synthesis of Ugi-adducts, which need
isocyanides as starting materials. Isocyanides are indeed very smelly
and toxic, resulting in allergies after skin contact. Therefore they
should only be handled in a fumehood. All disposable syringes, glass
and gloves exposed to isocyanides should be washed in the fumehood
and all the wastes should be treated with water before throwing them
away. When removing the solvents of reaction mixtures involving
isocyanides, rotary evaporators in closed fumehoods should be used.
All the solid catalysts used in this work are either adsorbed or
covalently bonded to the supporting material. Therefore, no special
precautions were taken.
It should also be noted that improper use of common solvents and
materials may bring certain danger. For example, chronic exposure to
DCM is presumably carcinogenic, while long-term exposure to silica
gel may result in chronic silicosis.

89
8 Experimental Part

2.4.1 General Experimental Methods and Data

All components as well as reagents and solvents were used as
received without further purification, unless stated otherwise. Reagents
and solvents were bought from Sigma Aldrich and TCI and if
applicable, kept under argon atmosphere. Technical solvents were
bought from VWR International and Biosolve, and were used as
received. Product isolation was performed using silica (60, F254,
Merck™), and TLC analysis was performed using Silica on aluminum
foils TLC plates (F254, Supelco Sigma-Aldrich™) with visualization
under ultraviolet light (254 nm and 365 nm) or appropriate TLC
staining. IR spectra were recorded on Bruker Alpha FT-IR
spectrometer. The IR data is presented for the maximal peaks. 1H (300
13
MHz, 400MHz and 600 MHz), C (100MHz) NMR spectra were
recorded on ambient temperature using a Bruker-Avance 400. 1H NMR
spectra are reported in parts per million (ppm) downfield relative to
CDCl3 (7.26 ppm) and all 13C NMR spectra are reported in ppm relative
to CDCl3 (77.2 ppm). NMR spectra uses the following abbreviations to
describe the multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
p = pentet, h = hextet, hept = heptet, m = multiplet, dd = double doublet,
td = triple doublet. Known products were characterized by comparing
to the corresponding 1H NMR and 13
C NMR from literature. High-
resolution mass spectra were acquired on a quadrupole orthogonal
acceleration time-of-flight mass spectrometer (Synapt G2 HDMS,
Waters, Milford, MA). Samples were infused at µl/min and spectra
were obtained in positive (or: negative) ionization mode with a
resolution of 15000 (FWHM) using leucine enkephalin as lock mass.
The morphology of the porous nanorods was evaluated by nitrogen

90
adsorption at 77 K in a Micrometrics ASAP 2020 and by Transmission
Electron Microscopy. For nitrogen adsorption analysis, the samples
were out-gassed at 26.7 Pa and 383 K for 5h before the measurement.
BJH method was applied to the adsorption branch of the N2 adsorption-
desorption isotherm to determine the pore diameter (MPD) and pore
size distribution. The specific surface area was calculated from the
adsorption isotherm using the Brunauer Emmett Teller (BET) method
in the range of relative pressure 0.06-0.19. The analysis was performed
to evaluate the influence of amine-functionalization and subsequent
Ag-NCs grafting on specific surface area and pore volume distribution.
Electron microscopy analysis was conducted to characterize the
synthesized mesoporous SBA-15 nanorods, the Ag-NCs and the Ag-
NCs/SBA-15 nanorods. The synthesized SBA-15 nanorods were
observed by Transmission Electron Microscopy (TEM) in a FEI
TECNAI T20 microscope with a maximum energy of 200 keV. A 10μL
suspension of the SBA-15 nanorods was pipetted onto a Formvar TEM
copper grid having a continuous carbon film. After complete
evaporation, the sample was analyzed by TEM. A FEI Titan™ (80–300
kV) microscope at an acceleration voltage of 300 kV was adopted for
the characterization of Ag-NCs. A 10 μL suspension of the Ag-NCs
was dropped onto a holey carbon TEM grid. Elemental analysis was
carried out with an EDS detector which allows performing EDS
experiments in the scanning mode. These two microscopes belong to
the Laboratory of Advanced Microscopies (LMA) at the Institute of
Nanoscience of Aragon (INA), University of Zaragoza. The Silver
content on the mesoporous channels of SBA-15 nanorods was
determined by Microwave Plasma Atomic Emission Spectroscopy
(MP-AES) (Agilent 4100 MP-AES). A representative analysis was
carried out by digesting 30 mg of the catalyst with the addition of 5 mL
of nitric acid (HNO3) and hydrochloric acid (HCl) in a volume ratio of

91
1:3, the mixture was heated at 200°C for 20 min in a microwave oven
(Milestone Ethos Plus). The digested sample was diluted with Milli-Q
water obtaining a final volume of 30 ml. After centrifugation (12000
rpm * 20 min), the supernatant was filtered (by hydrophilic syringe
filters of 0.2 µm) to discard any fragmented particle.
UV-Vis Spectroscopy (Agilent 8453 UV-Visible Spectrophotometer)
was adopted to measure the surface plasmon resonance (SPR) of silver-
NCs. This technique is a useful approach to differentiate at bulk scale
the presence of either nanoclusters and or nanoparticles.6 The
spectrophotometric test was performed diluting 500 µL of sample into
2.5 mL of deionized water. Finally, the presence of Agm+nm+ species
was verified by X-ray photoelectron spectroscopy (XPS), performed
with an Axis Supra spectrometer (Kratos Tech). The samples were
mounted on a sample rod placed in the pretreatment chamber of the
spectrometer and then evacuated at room temperature. The spectra
were excited by a monochromatized AlKα source at 1486.6 eV and
subsequently run at 12 kV and 10 mA. Survey spectrum was measured
at 160 eV pass energy and for the individual peak regions, spectra were
recorded with pass energy of 20 eV. Analysis of the peaks was
performed with the CasaXPS software using a weighted sum of
Lorentzian and Gaussian component curves after Shirley background
subtraction. The binding energies were referenced to the internal C1s
standard at 284.9 eV.

2.4.2 Synthesis of starting material

Synthesis of tryptamine derivatives65

92
In 50 mL round-bottom flask tryptamine (1 equiv.) and benzaldehyde
(1.2 equiv.) and Na2SO4 were dissolved in MeOH. After 12h of stirring
at, sodium tetrahydroborate (0.6 equiv.) was added to the reaction
mixture portionwise under cooling. The mixture was stirred for 2-3h.
The solvent was removed in vacuo and the reaction quenched with
saturated NaHCO3, then diluted with EtOAc and water. The organic
layer was separated and washed with water, brine and dried over
Na2SO4. Crude was further purified by silica gel column with
EtOAc/Heptane/Et3N = 1/1.9/0.1 to 2/0.9:0.1 to give the desired
product.

In an oven-dried small round bottom flask propiolic acid (0.9 equiv.)

was dissolved in DCM under cooling. After 5 min of stirring,
triethylamine (3 equiv.) and N-benzyl-2-(1H-indole-3-yl) ethamine
were added in the above solution under cooling. After 5 to 10 min of
stirring 2,4,6- tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(T3P, 1 equiv.) were added to the reaction mixture portion-wise under
cooling. After stirring for 1-4h (based on TLC), the mixture was diluted
with DCM and then washed with water (10 ml x 3), and the organic
layer extracted with ethyl acetate (20 ml x 3). The crude further was
purified by silica gel column with EtOAC/heptane = 1:2 to 1:1 to give
desired product.

Synthesis of substituted tryptamines171

93
In an oven-dried small round bottom flask 1‐(Dimethylamino)‐2‐
nitroethylene (1 equiv.) was dissolved in trifluoroacetic acid (0.6
M). After 5 min. stirring, the corresponding indole (31.2 equiv.) was
dissolved in normal grade dichloromethane (1 M) and added dropwise
to the above solution. The reaction mixture was stirred at room
temperature for 1h. Afterwards, the resultant solution was quenched
with water and extracted with DCM (50 x 3). The combined organic
layer was dried over Na2SO4 and the solvent was removed under
reduced pressure. The crude product was further purified by silica gel
column with EtOAC/heptane = 1:2 to 1:1 to give intermediate product.

In a flame-dried two-neck round bottom flask LiAlH4 (6 equiv.) was

added under inert atmosphere followed by addition of dry THF (0.5
M). After 5 min. stirring at room temperature, the resultant solution
was cooled to -78 °C. In another flask above intermediate product was
dissolved into dry THF (0.5 M) and the resultant solution was added
into LiAlH4 solution dropwise via syringe-pump with flow-rate 1
mL/min.. The resultant solution was stirred for 48 hours. Afterwards,
the solution was cooled at 0 °C and H2O and NaOH (15% aq. solution)
was added respectively. The solution was filtered on glass-filter with
2-3 times washing with DCM. The resultant filtrate was dried under
reduced pressure to afford crude product. Further, the crude product
was further purified by silica gel column with 80:18:2
CHCl3:MeOH:NH4OH to give desired substituted tryptamine.

Synthesis of Ugi substrates

94
In an oven-dried round bottom flask, aldehyde (1 equiv.) was dissolved
into 0.5 M MeOH with appropriate amine (1 equiv.). The mixture was
continued to stir at room temperature. After 2h propiolic acid (1 equiv.)
and appropriate isocyanide (1 equiv.) was added subsequently and left
for another 20h at room temperature. The reaction was quenched by
NaHCO3 and the organic layer was extracted with EtOAc. The organic
layer was dried over Na2SO4 and crude was purified by silica gel
column with EtOAC/heptane = 1:1 to 2:1 to give the desired product.

2.4.3 General procedure for the synthesis of spiroindolenines in

batch

In oven-dried 10 mL screw-cap vial triphenylphosphine (20.9 mg, 0.08

mmol, 0.2 equiv.) and N-(2-(1H-indol-3-yl)ethyl)-N-
benzylpropiolamide (140 mg, 0.4 mmol, 1 equiv.) was dissolved in 0.3
M dry ethanol. After 3h of heating at 80 °C, the mixture was diluted
with DCM. The solvent was evaporated and the crude product was
purified by column chromatography on silica (EtOAc : Heptane = 1 : 2
to 1: 1). After isolation, compounds 2-2b, 2-2g, 2-2l, 2-2n and 2-3f
were found to slowly trimerize. TFA was added to shift the equilibrium
to the monomer.73b

2.4.4 General procedure for the synthesis of spiroindolenines in

flow
For injecting the sample onto the reactor a Nexus 6000 pump was used
together with a 1.5 ml sample loop for the injection of the reaction
mixture. Before reaction, the flow was stabilized at each different flow

95
rate at the required reaction temperature with help of 20 psi back
pressure regulators at the end of the setup. The catalyst was filled into
the reactor (3mm × 50 mm) followed by sand and cotton wool
respectively. The reactor was sealed employing stainless steel micro-
sieve on both ends. In Case of lower catalyst loading, the catalyst was
mixed with silica to avoid any gap inside the reactor. A mixture of
toluene/dioxane and ethanol were used for a better swelling of the
resin-based triphenylphosphine.

Note: Blank test was performed with silica under same reaction
condition to rule out any possibility to participate in the reaction.

2.4.5 Optimization of product 2-2a in continuous flow.a

96
 Entry Conc. T Solvent Flow Res. Time Yieldd
(M) (°C) (mL/min.) (min.) (%)
1 0.15 80 Ethanol 0.2 2 16
2 0.15 80 Ethanol 0.1 5 23
3 0.15 80 Ethanol 0.07 8 25
4 0.2 80 Ethanol 0.1 4 21
5 0.08 80 Ethanol + Dioxane 0.2 1 34
6 0.08 80 Ethanol + Dioxane 0.15 4 36
7 0.08 80 ACN 0.1 13 13
8 0.08 90 Ethanol + Toluene 0.1 10 60
9 0.05 80 Ethanol 0.1 3 27
10b 0.15 90 Ethanol + Toluene 0.1 6 50
11b 0.1 90 Ethanol + Toluene 0.05 17 78
12b 0.1 90 Ethanol + Toluene 0.025 40 88
13c 0.1 90 Ethanol + Toluene 0.025 14 67
a
Catalyst loading = 350 mg, Ethanol: Toluene = 1:1, Ethanol: Dioxane = 1:1, bCatalyst loading = 120 mg,
Ethanol: Toluene = 1:1. cCatalyst loading = 200 mg dyield was determined by NMR. TPP-resin
triphenylphosphine: 100-200 mesh, 3 mmol/g loading [ sigma-aldrich]

Deactivation experiment: In order to define whether the packed bed

needed to be refilled frequently due to possible catalyst deactivation, a
gram-scale experiment was performed with 2-1a (0.1 M) as substrate
under optimized condition. Sample loop (1.5 mL) was refilled
continuously 22 times to convert 1.0 g of substrate. All samples were
collected together and purified by column chromatography on silica
with isolated yield 79 %. Furthermore, reaction with 0.5 g 2-1a was
carried out with same cartage with isolated yield 75.6%. After 22
cycles comparable yields were observed, indicating that catalyst
activity does not decrease during the reaction and that the reactor is
operationally stable under optimized conditions.

2.4.6 Deuterium Labelling Experiments

97
In oven-dried 10 mL screw-cap vial triphenylphosphine (3.5 mg, 0.013
mmol, 0.2 equiv.) and N-(2-(1H-indol-3-yl)ethyl)-N-
benzylpropiolamide (20 mg, 0.06 mmol, 1 equiv.) was dissolved in
0.3M EtOAc and 10 equiv. of D2O or 0.3M ethanol-d6. After 3 h of
heating at 80 °C, the solvent was evaporated. The crude product was
then dissolved in CDCl3 for 1H-NMR. The incorporation of 2 deuterium
atoms in the final product suggests that the intermediate 2-1e (Scheme
27) has a relatively long lifetime to allow the H/D exchange with the
solvent, which successively supports our proposed mechanism.

The deuterated product was synthesized from the previous step. The
deuterated product was dissolved in EtOAc with 10 equiv. of H2O or
EtOH in a 10 ml vial. The reaction was heated at 80°C after addition
of PPh3. After 3h, a small amount of Na2SO4 was added and the solvent
evaporated under vacuum. Scrambling of deuterium was analyzed by
1
H-NMR. We used the deuterated product to confirm the reversibility
of the reaction. We could not observe any proton scrambling.

2.4.7 Spectroscopic data of the starting material

N-(2-(1H-indol-3-yl)ethyl)-N-benzylpropiolamide
(2-1a').65 1H NMR (300 MHz, Chloroform-d) δ 8.10
(d, J = 13.5 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.40 – 7.27 (m, 4H), 7.25
– 7.14 (m, 3H), 7.12 (d, J = 7.0 Hz, 1H), 6.97 (dd, J = 14.2, 2.0 Hz,
1H), 4.63 (d, J = 13.3 Hz, 2H), 3.81 – 3.73 (m, 1H), 3.65 – 3.56 (m,
1H), 3.10 (s, 0H), 3.07 – 2.92 (m, 3H); 13C NMR (101 MHz, Acetone)

98
δ 205.35, 153.20, 152.96, 137.44, 137.09, 136.82, 128.71, 128.56,
128.09, 127.72, 127.58, 127.52, 127.50, 127.40, 122.86, 122.55,
121.36, 121.33, 118.70, 118.63, 118.42, 118.29, 111.91, 111.40,
111.35, 79.39, 79.34, 76.41, 76.24, 52.53, 49.04, 47.26, 45.24, 29.57,
29.38, 29.19, 29.00, 28.80, 28.61, 28.42, 24.72, 22.87.

N-(2-(1H-indol-3-yl)ethyl)-N-(4-
chlorobenzyl)propiolamide (2-1b'); 1HNMR (300
MHz, Chloroform-d) δ 8.29 (s, 1H), 8.23 (s, 1H),
7.55 – 7.47 (m, 2H), 7.35 (dd, J = 8.0, 3.4 Hz, 3H),
7.26 (d, J = 8.5 Hz, 2H), 7.25 – 7.12 (m, 2H), 7.16 – 7.02 (m, 7H), 6.94
(dd, J = 9.8, 2.3 Hz, 3H), 4.57 (s, 2H), 4.52 (s, 2H), 3.80 – 3.72 (m,
2H), 3.61 – 3.54 (m, 2H), 3.11 (s, 1H), 3.07 – 2.93 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 153.96, 153.55, 136.38, 136.30, 134.95, 134.59,
133.86, 133.57, 129.62, 128.94, 127.19, 127.16, 122.39, 122.23,
119.46, 112.43, 111.77, 111.42, 79.15, 79.08, 76.01, 75.69, 75.67,
52.69, 48.84, 47.39, 45.27, 31.00, 24.88, 23.03. HRMS (ESI)
calculated for C20H17ClN2O [M+H]+: 337.1102; found: 337.1111.
N-(2,6-
dichlorobenzyl)-N-(2-(5-methoxy-1H-indol-3-
1
yl)ethyl)propiolamide (2-1c'); H NMR (300
MHz, Chloroform-d) δ 7.98 (d, J = 28.2 Hz, 1H),
7.39 – 7.29 (m, 2H), 7.25 – 7.13 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 6.97
– 6.87 (m, 1H), 6.82 (td, J = 8.6, 2.4 Hz, 1H), 5.21 (s, 1H), 5.10 (s, 1H),
3.86 (d, J = 7.8 Hz, 3H), 3.67 – 3.52 (m, 1H), 3.52 – 3.37 (m, 1H), 3.22
(s, 1H), 3.06 – 2.92 (m, 1H), 2.88 – 2.79 (m, 1H); 13C NMR (151 MHz,
CDCl3) δ 154.00, 153.43, 136.96, 131.44, 131.28, 130.82, 130.18,
130.01, 128.84, 128.71, 127.66, 123.08, 122.90, 112.47, 112.23,
112.00, 111.87, 111.82, 100.46, 100.35, 79.34, 78.29, 76.48, 75.95,

99
55.95, 48.46, 48.00, 44.91, 42.62, 25.24, 23.07.; HRMS (ESI)
calculated for C21H18Cl2N2O2 [M+H]+: 401.0818; found: 401.0815.

N-(2-(1H-indol-3-yl)ethyl)-N-(4-
methoxybenzyl)propiolamide (2-1d'). 1H NMR (300
MHz, Chloroform-d) δ 8.17 (d, J = 15.7 Hz, 1H), 7.52
(d, J = 7.8 Hz, 1H), 7.35 (dd, J = 7.5, 3.8 Hz, 1H), 7.13 (dd, J = 14.0,
8.6 Hz, 4H), 6.96 (dd, J = 13.0, 2.3 Hz, 1H), 6.85 (dd, J = 8.7, 3.9 Hz,
2H), 4.56 (d, J = 14.3 Hz, 2H), 3.83 – 3.71 (m, 4H), 3.63 – 3.54 (m,
2H), 3.12 (s, 0.5H), 3.07 – 2.91 (m, 2.5H).

N-benzyl-N-(2-(6-fluoro-1H-indol-3-
yl)ethyl)propiolamide (2-1e'). 1H NMR (300 MHz,
Chloroform-d) δ 8.21 (s, 0.45H), 8.14 (s, 0.49H), 7.41
(dd, J = 8.6, 5.2 Hz, 1H), 7.37 – 7.27 (m, 3H), 7.20 (td, J = 7.8, 1.9 Hz,
2H), 7.03 (ddd, J = 9.7, 5.3, 2.3 Hz, 1H), 6.95 (d, J = 2.1 Hz, 0.5H),
6.87 (dddd, J = 13.4, 8.7, 3.5, 2.2 Hz, 1.5H), 4.63 (d, J = 17.0 Hz, 2H),
3.87 – 3.72 (m, 1H), 3.67 – 3.50 (m, 2=1H), 3.12 (s, 1=0.5H), 3.06 –
2.87 (m, 2.5H); 13C NMR (151 MHz, CDCl3) δ 160.81, 159.24, 153.89,
153.59, 136.31, 136.03, 128.84, 128.75, 128.25, 128.05, 127.78,
127.58, 123.90, 122.63, 122.61, 122.34, 122.32, 119.45, 119.38,
119.15, 119.09, 112.78, 112.10, 108.26, 108.22, 108.09, 108.06, 97.76,
97.61, 97.59, 97.43, 78.94, 78.76, 76.11, 75.81, 53.34, 48.65, 47.86,
45.25, 24.66, 22.93. HRMS (ESI) calculated for C20H17FN2O [M+H]+:
321.1397; found: 321.1389.

N-benzyl-N-(2-(5-methoxy-1H-indol-3-
yl)ethyl)propiolamide (2-1f'): 1H NMR (300 MHz,
Chloroform-d) δ 7.99 (s, 1H), 7.34 – 7.27 (m, 3H),
7.24 – 7.17 (m, 3H), 7.01-6.93 (m, 2H), 6.88 – 6.83 (m, 1H), 4.64 (d,

100
J = 13.1 Hz, 1H), 3.85 (d, J = 3.0 Hz, 3H), 3.80 – 3.75 (m, 1H), 3.62-
3.57 (m, 1H), 3.11 (s, 1H), 3.03 – 2.93 (m, 2H); 13C NMR (151 MHz,
CDCl3) δ 154.08, 154.07, 153.83, 153.57, 136.42, 136.15, 131.52,
131.38, 128.79, 128.73, 128.71, 128.27, 127.98, 127.72, 127.70,
127.64, 127.58, 127.57, 127.55, 123.02, 122.79, 112.56, 112.52,
112.31, 112.06, 111.97, 111.80, 100.50, 100.31, 78.82, 78.65, 76.19,
75.96, 55.97, 55.90, 53.34, 48.56, 47.85, 45.18, 24.81, 23.03. HRMS
(ESI) calculated for C21H20N2O2 [M+H]+: 333.1597; found: 333.1605.

N-benzyl-N-(2-(6-bromo-1H-indol-3-
yl)ethyl)propiolamide (2-1g'); 1H NMR (400
MHz, Chloroform-d) δ 8.19 (d, J = 28.4 Hz, 1H), 7.51 (dd, J = 7.4,
1.6 Hz, 1H), 7.40 – 7.27 (m, 4H), 7.25 – 7.16 (m, 3H), 6.94 (dd, J =
19.0, 2.3 Hz, 1H), 4.63 (d, J = 22.2 Hz, 2H), 3.75 (dd, J = 8.2, 6.4 Hz,
1H), 3.57 (dd, J = 8.6, 6.5 Hz, 1H), 3.12 (s, 1H), 2.97 (dt, J = 22.2,
7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 153.89, 153.59, 137.12,
137.03, 136.22, 135.94, 128.85, 128.76, 128.55, 128.22, 128.06,
127.79, 127.63, 127.57, 126.98, 126.18, 123.03, 123.00, 122.73,
122.71, 122.67, 122.65, 119.91, 119.63, 115.63, 115.59, 114.31,
114.16, 112.83, 112.79, 112.14, 112.11, 79.06, 79.02, 78.87, 78.84,
76.04, 75.72, 53.35, 48.63, 47.85, 45.24, 24.51, 22.79.

N-benzyl-N-(2-(5-bromo-1H-indol-3-
yl)ethyl)propiolamide (2-1h'); 1H NMR
(400 MHz, Chloroform-d) δ 8.11 (d, J = 17.0
Hz, 1H), 7.66 (s, 0.5H), 7.56 (m, 0.5), 7.39-7.29(m, 3H), 7.28 – 7.20
(m, 5H), 7.00 (d, J = 2.4 Hz, 0.5H), 6.93 (d, J = 2.4 Hz, 0.5H), 4.67 (s,
1H), 4.62 (s, 1H), 3.79 – 3.66 (m, 1H), 3.61 – 3.52 (m, 1H), 3.12 (s,
0.5H), 3.01 – 2.86 (m, 2.5H); 13C NMR (101 MHz, Acetone) δ 137.38,
137.03, 135.42, 129.34, 128.75, 128.58, 128.12, 127.77, 127.62,

101
127.44, 124.62, 124.28, 123.96, 120.96, 120.86, 113.22, 113.17,
111.80, 111.64, 111.24, 79.42, 79.24, 78.31, 76.32, 76.19, 52.50,
48.71, 47.08, 45.09, 24.32, 22.57; HRMS (ESI) calculated for
C23H16N3O [M+H]+: 380.0597; found: 381.0593.
N-benzyl-N-(2-(7-chloro-1H-indol-3-
yl)ethyl)propiolamide (2-1i'). 1H NMR (400
MHz, Acetone-d6) δ 10.37 (s, 0.5H), 10.31 (s,
0.5H), 7.59 – 7.50 (m, 1H), 7.36 (q, J = 7.7, 7.1
Hz, 1.5H), 7.33 – 7.26 (m, 3.5H), 7.24 (dd, J = 10.4, 2.4 Hz, 1H),
7.16 (dd, J = 7.5, 4.0 Hz, 1H), 7.02 (td, J = 7.8, 5.1 Hz, 1H), 4.81 (s,
1H), 4.68 (s, 1H), 3.91 (s, 0.4H), 3.87 – 3.78 (m, 1.6H), 3.62 – 3.54
(m, 1H), 3.12 – 3.05 (m, 1H), 2.99 – 2.92 (m, 1H).; 13C NMR (101
MHz, Acetone) δ 22.82, 24.58, 45.18, 47.25, 48.91, 52.57, 76.16,
76.35, 79.43, 79.54, 112.82, 113.38, 116.31, 116.36, 117.40, 117.53,
119.69, 119.75, 120.88, 120.91, 123.80, 124.17, 127.43, 127.58,
127.75, 128.10, 128.58, 128.73, 129.41, 133.61, 137.01, 137.37,
153.05, 153.24.; HRMS (ESI) calculated for C20H17ClN2O [M+H]+:
337.1102; found: 337.1109.

N-benzyl-N-(2-(6-chloro-1H-indol-3-
yl)ethyl)propiolamide (2-1j'). 1H NMR (400
MHz, Acetone-d6) δ 10.20 (d, J = 19.8 Hz,
1H), 7.55 (dd, J = 12.4, 8.4 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.37 (d, J =
7.2 Hz, 1H), 7.34 – 7.27 (m, 4H), 7.18 (dd, J = 9.6, 2.1 Hz, 1H), 7.02
(dt, J = 8.5, 2.1 Hz, 1H), 4.81 (s, 1H), 4.67 (s, 1H), 3.91 (s, 0.4H), 3.86
– 3.78 (m, 1.6H), 3.59 – 3.53 (m, 1H), 3.10 – 3.04 (m, 1.2H), 2.97 –
2.90 (m, 1.7H).; 13C NMR (101 MHz, Acetone) δ 22.66, 24.42, 45.19,
47.19, 48.92, 52.54, 76.16, 76.34, 79.38, 79.47, 111.16, 111.20,
111.73, 112.29, 119.09, 119.16, 119.52, 119.64, 123.69, 124.06,
126.29, 126.84, 127.42, 127.57, 127.74, 128.09, 128.57, 128.73,

102
137.03, 137.13, 137.38, 153.00, 153.21.; HRMS (ESI) calculated for
C20H17ClN2O [M+H]+: 337.1102; found: 337.1111.
N-(2-(1H-indol-3-yl)ethyl)-N-
1
cyclohexylpropiolamide (2-1l'). H NMR
(300 MHz, Chloroform-d) δ 8.23 (s, 0.4H), 8.15
(s, 0.6H), 7.27 – 7.23 (m, 1H), 7.14 (d, J = 2.4 Hz, 0.6H), 7.04 (d, J =
2.4 Hz, 0.4H), 6.98 (dd, J = 7.0, 2.4 Hz, 1H), 6.86 (ddd, J = 8.8, 3.6,
2.4 Hz, 1H), 3.93 – 3.74 (m, 4.4H), 3.71 – 3.59 (m, 1.2H), 3.30 (dd, J
= 19.5, 7.1 Hz, 2H), 3.16 – 2.91 (m, 0.6H), 3.10 (s, 0.6H), 3.05-2.98
(m, 2H), 2.94 (s, 0.5H), 1.78 – 1.60 (m, 6H), 1.32 – 1.06 (m, 3H), 1-
0.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 23.01, 24.89, 25.83, 26.32,
30.76, 30.84, 36.21, 37.10, 46.39, 50.89, 55.82, 76.25, 76.28, 78.05,
78.14, 78.75, 78.79, 100.34, 100.46, 111.68, 112.09, 112.36, 112.48,
122.78, 123.09, 127.67, 127.74, 131.40, 131.54, 153.76, 153.98.;
HRMS (ESI) calculated for C20H24N2O [M+H]+: 309.1961; found:
309.1971.
N-cyclohexyl-N-(2-(5-methoxy-1H-indol-3-
yl)ethyl)propiolamide (2-1m'). 1H NMR (300
MHz, Chloroform-d) δ 8.31 (d, J = 19.7 Hz, 1H),
7.63 (dd, J = 15.1, 7.7 Hz, 1H), 7.45 – 7.28 (m, 1H), 7.27 – 7.06 (m,
2H), 7.00 (dd, J = 7.9, 2.4 Hz, 1H), 3.91 – 3.76 (m, 1H), 3.72 – 3.58
(m, 1H), 3.30 (dd, J = 19.0, 7.1 Hz, 2H), 3.15 – 2.94 (m, 2.5H), 2.91
(s, 0.5H) 1.76 – 1.58 (m, 6H), 1.30 – 1.11 (m, 3H), 0.99-0.86 (m, 2H)
; 13C NMR (75 MHz, CDCl3) δ 22.93, 24.90, 25.83, 26.33, 30.75, 30.84,
36.21, 37.07, 50.93, 55.78, 76.21, 78.13, 78.78, 111.38, 111.95,
112.63, 119.36, 122.04, 122.16, 122.35, 127.28, 127.31, 136.30,
136.37, 153.76, 153.82.; HRMS (ESI) calculated for C21H26N2O2
[M+H]+: 339.2066; found: 339.2068.

103
 N-(2-(1H-indol-3-yl)ethyl)-N-
1
pentylpropiolamide (2-1n'). H NMR (300
MHz, Chloroform-d) δ 8.69 (s, 0.45H), 8.58 (s,
0.54H), 7.27 – 7.18 (m, 1H), 7.13 (d, J = 2.4 Hz,
0.59H), 7.03 (d, J = 2.4 Hz, 0.56H), 6.95 (t, J = 2.6 Hz, 1H), 6.88 –
6.79 (m, 1H), 3.90 – 3.76 (m, 4H), 3.69 – 3.59 (m, 1H), 3.42 (dt, J =
22.1, 7.5 Hz, 2H), 3.11 – 2.93 (m, 3H), 1.56 (p, J = 7.3 Hz, 2H), 1.27
(dt, J = 8.8, 6.4 Hz, 4H), 0.90 (d, J = 2.4 Hz, 1H), 0.87 (d, J = 2.4 Hz,
1H), 0.85 (d, J = 2.5 Hz, 1H).; 13C NMR (151 MHz, CDCl3) δ 153.90,
153.54, 153.50, 131.72, 131.58, 127.73, 127.66, 123.36, 123.04,
112.29, 112.19, 112.17, 112.14, 111.92, 111.33, 100.46, 100.34, 78.54,
78.25, 77.39, 77.18, 76.97, 76.31, 76.25, 55.97, 55.93, 55.89, 49.78,
49.63, 46.01, 45.20, 29.08, 28.73, 28.51, 27.16, 25.15, 23.37, 22.44,
22.33, 14.01, 13.98; HRMS (ESI) calculated for C19H24N2O2 [M+H]+:
313.1910; found: 313.1915.
N-benzyl-N-(2-(5-methyl-1H-indol-3-
yl)ethyl)propiolamide (2-1o'). Mp. 143-151°C;
1
H NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H),
7.54 (d, J = 7.9 Hz, 1H), 7.46 – 7.31 (m, 5H), 7.18 (d, J = 7.9 Hz, 1H),
6.92 (s, 1H), 6.31 (s, 1H), 5.16 (s, 1H), 5.04 (d, J = 14.3 Hz, 1H), 4.65
(d, J = 14.3 Hz, 1H), 3.70 – 3.61 (m, 1H), 3.61 – 3.53 (m, 1H), 2.32 (s,
3H), 2.19 – 2.11 (m, 1H), 2.00 – 1.90 (m, 1H); 13C NMR (151 MHz,
CDCl3) δ 172.90, 162.82, 152.38, 141.13, 136.89, 136.79, 135.14,
129.28, 128.86, 128.54, 128.48, 127.89, 123.45, 122.74, 121.45, 77.29,
77.08, 76.87, 60.90, 51.26, 44.89, 28.94, 21.46; HRMS (ESI)
calculated for C21H20N2O [M+H]+: 317.1648; found: 317.1653.

104
 N-((4-bromo-1H-indol-3-yl)methyl)-N-(4-
chlorobenzyl)propiolamide (2-3b'). Mp. 143-151°C;
1
H NMR (300 MHz, Chloroform-d) δ 8.50 (d, J = 15.3
Hz, 1H), 7.39 – 7.27 (m, 2H), 7.23 (d, J = 2.0 Hz, 1H),
7.18 – 7.08 (m, 3H), 7.03 (q, J = 8.1 Hz, 2H), 5.28 (d, J = 1.1 Hz, 1H),
5.04 (d, J = 0.9 Hz, 1H), 4.80 (s, 1H), 4.62 (s, 1H), 3.11 (d, J = 2.0 Hz,
1H); 13C NMR (151 MHz, CDCl3) δ 154.26, 153.98, 137.80, 137.37,
135.02, 134.99, 133.43, 133.36, 129.60, 128.79, 128.77, 128.68,
128.45, 126.28, 125.23, 125.13, 124.44, 124.30, 124.23, 123.43,
123.13, 113.69, 113.66, 111.87, 110.86, 110.82, 110.74, 79.21, 79.06,
76.07, 75.91, 50.92, 46.66, 45.00, 39.57, 30.95. HRMS (ESI)
calculated for C19H14BrClN2O2 [M+H]+: 401.0051; found: 401.0054.

N-((5-bromo-1H-indol-3-yl)methyl)-N-(4-
chlorobenzyl)propiolamide (2-3c'). 1H NMR (300
MHz, Chloroform-d) δ 8.39 (s, 0.5H), 8.30 (s, 0.5H),
7.75 – 7.65 (m, 1H), 7.38 – 7.31 (m, 2H), 7.29 (d, J
= 1.6 Hz, 1.3H), 7.25 – 7.22 (m, 0.4H), 7.21 – 7.15 (m, 1H), 7.15 –
7.09 (m, 2H), 4.85 (s, 1H), 4.65 (d, J = 8.1 Hz, 2H), 4.50 (s, 1H), 3.32
(s, 0.5H), 3.13 (s, 0.5H); 13C NMR (151 MHz, CDCl3) δ 207.0, 153.5,
153.4, 135.0, 134.7, 134.6, 134.4, 133.8, 133.5, 129.5, 129.0, 128.8,
128.7, 128.5, 128.2, 125.7, 125.6, 125.5, 124.9, 121.7, 121.5, 113.5,
113.4, 112.9, 112.7, 110.2, 110.0, 80.4, 79.3, 75.9, 75.8, 50.4, 45.4,
43.3, 37.6, 31.8, 30.9. HRMS (ESI) calculated for C19H14BrClN2O2
[M+H]+: 401.0051; found: 401.0058.

N-benzyl-N-((5-methoxy-1H-indol-3-
yl)methyl)propiolamideM (2-3d'). 1H NMR (300
MHz, Chloroform-d) δ 8.22 (d, J = 27.2 Hz, 1H),
7.44 – 7.34 (m, 2H), 7.32 – 7.24 (m, 3H), 7.22 (d, J = 1.7 Hz, 1H), 7.17

105
– 7.04 (m, 2H), 6.89 (ddd, J = 8.5, 5.5, 2.5 Hz, 1H), 4.88 (s, 1H), 4.68
(d, J = 4.0 Hz, 2H), 4.55 (s, 1H), 3.84 (d, J = 2.3 Hz, 3H), 3.30 (s,
0.5H), 3.10 (s, 0.5H); 13C NMR (151 MHz, CDCl3) δ 154.40, 153.60,
153.36, 136.29, 136.11, 131.52, 131.27, 129.03, 128.87, 128.69,
128.37, 128.28, 128.16, 127.92, 127.60, 127.52, 127.27, 126.98,
125.19, 124.67, 124.63, 113.17, 113.04, 112.25, 112.01, 110.39,
110.35, 110.04, 109.99, 100.71, 100.55, 79.90, 78.93, 76.38, 76.07,
55.77, 50.69, 45.65, 43.49, 37.58.

N-benzyl-N-((4-nitro-1H-indol-3-
yl)methyl)propiolamide (2-3e'). 1H NMR (400 MHz,
Chloroform-d) δ 9.43 (s, 1H), 7.95 (d, J = 7.9 Hz,
0.6H), 7.83 (d, J = 7.9 Hz, 0.6H), 7.71 (d, J = 8.1 Hz, 0.5H), 7.62 (d, J
= 8.1 Hz, 0.5H), 7.42 – 7.26 (m, 3H), 7.26 – 7.09 (m, 4H), 5.15 (s, 1H),
4.92 (s, 1H), 4.84 (s, 1H), 4.67 (s, 1H), 3.18 (s, 0.5H), 3.03 (s, 0.5H);
13
C NMR (101 MHz, CDCl3) δ 154.60, 136.14, 135.90, 128.79, 128.72,
128.13, 127.95, 127.76, 127.31, 126.73, 121.25, 120.81, 118.35,
118.30, 118.18, 117.95, 111.70, 110.13, 79.36, 78.82, 76.06, 75.81,
64.40, 52.75, 48.02, 47.02, 42.45, 31.89, 29.03, 22.70, 14.12.; HRMS
(ESI) calculated for C19H13BrN3O [M+H]+: 356.1011; found:
356.0990.

N-((1H-indol-3-yl)methyl)-N-
benzylpropiolamide (2-3f').46 1H NMR (300 MHz,
Chloroform-d) δ 8.35 (d, J = 29.1 Hz, 1H), 7.66 (ddd,
J = 8.0, 2.5, 1.2 Hz, 1H), 7.45 – 7.19 (m, 7H), 7.19 – 7.06 (m, 2H), 4.91
(s, 1H), 4.69 (d, J = 5.2 Hz, 2H), 4.54 (s, 1H), 3.27 (s, 0.5H), 3.09 (s,
0.5H). 13C NMR (101 MHz, CDCl3) δ 153.57, 153.49, 136.50, 136.26,
136.08, 128.86, 128.67, 128.27, 127.90, 127.58, 127.50, 126.78,
126.49, 124.65, 123.93, 122.61, 122.50, 120.10, 120.05, 119.36,

106
118.94, 111.49, 111.23, 110.53, 110.34, 79.99, 78.98, 77.34, 77.02,
76.71, 76.25, 76.06, 50.79, 45.76, 43.55, 37.60.

N-benzyl-N-(2-(tert-butylamino)-1-(4-
hydroxyphenyl)-2-oxoethyl)propiolamide (2-4a').
1
H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.90
(s, 0.4H), 7.71 (s, 0.5H), 7.18 – 6.98 (m, 4H), 6.91
(ddd, J = 18.8, 6.8, 1.5 Hz, 2H), 6.77 (dd, J = 7.1, 2.1 Hz, 1H), 6.67 –
6.58 (m, 1H), 6.56 – 6.47 (m, 1H), 6.00 (s, 0.4H), 5.82 (s, 0.5H), 4.97
(d, J = 17.3 Hz, 0.5H), 4.77 (d, J = 15.8 Hz, 0.4H), 4.65 (s, 0.4H), 4.55
(d, J = 17.3 Hz, 0.5H), 4.38 (s, 0.5H), 4.20 (d, J = 15.7 Hz, 0.4H), 3.34
13
(s, 0.6H), 1.98 (s, 0.5H), 1.24 (s, 4H), 1.19 (s, 5H); C NMR (151
MHz, CDCl3) δ 166.01, 159.81, 135.73, 132.86, 129.36, 128.01,
127.54, 127.12, 126.93, 125.34, 124.82, 114.15, 77.27, 77.06, 76.85,
67.73, 55.41, 46.25, 30.90, 30.86, 15.28; HRMS (ESI) calculated for
C22H24N2O3 [M+H]+: 365.1859; found: 365.1861.

N-benzyl-N-(2-(tert-butylamino)-1-(4-hydroxy-3-
methoxyphenyl)-2-oxoethyl)propiolamide (2-4b'). 1H
NMR (300 MHz, DMSO-d6) δ 9.06 (s, 0.4H), 8.96 (s,
0.5H), 7.93 (s, 0.41H), 7.72 (s, 0.54H), 7.18 – 6.98 (m,
3H), 6.98 – 6.86 (m, 1H), 6.84 – 6.73 (m, 1H), 6.69 – 6.50 (m, 1H),
5.98 (s, 0.45H), 5.79 (s, 0.53H), 4.97 (d, J = 17.3 Hz, 0.55H), 4.81 (d,
J = 15.8 Hz, 0.46H), 4.68 (s, 0.47H), 4.52 (d, J = 17.3 Hz, 0.54H), 4.41
(s, 0.54H), 4.15 (d, J = 15.8 Hz, 0.44H), 3.52 (d, J = 11.4 Hz, 3H), 1.24
(d, J = 15.0 Hz, 9H).; 13C NMR (151 MHz, DMSO) δ 169.03, 168.94,
154.75, 154.62, 147.57, 147.32, 147.02, 146.91, 138.81, 138.78,
128.06, 127.89, 127.12, 126.67, 126.48, 126.44, 126.12, 125.52,
122.74, 122.33, 115.52, 115.35, 114.64, 114.34, 83.69, 82.22, 77.23,
76.42, 65.05, 61.40, 55.79, 55.70, 51.01, 50.79, 50.44, 47.76, 40.40,

107
40.27, 40.13, 39.99, 39.85, 39.71, 39.57, 28.79.; HRMS (ESI)
calculated for C23H26N2O4 [M+H]+: 395.1965; found: 395.1963.

N-benzyl-N-(2-(cyclohexylamino)-1-(4-
hydroxyphenyl)-2-oxoethyl)propiolamide (2-4c'). 1H
NMR (400 MHz, DMSO-d6) δ 9.47 (s, 0.4H), 9.39 (s,
0.6H), 8.13 (d, J = 7.7 Hz, 0.4H), 7.94 (d, J = 7.9 Hz,
0.6H), 7.07 (ddd, J = 22.3, 10.9, 8.0 Hz, 4H), 6.92 (dd, J = 17.8, 7.7
Hz, 2H), 6.81 – 6.75 (m, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 8.3
Hz, 1H), 6.02 (s, 0.46H), 5.82 (s, 0.57H), 4.97 (d, J = 17.3 Hz, 0.59H),
4.76 (d, J = 15.6 Hz, 0.47H), 4.64 (s, 0.42H), 4.57 (d, J = 17.3 Hz,
0.62H), 4.38 (s, 0.53H), 4.24 (d, J = 15.7 Hz, 0.48H), 4.10 (d, J = 5.3
Hz, 1H), 3.59 (m, 1H), 3.17 (d, J = 3.9 Hz, 1H), 1.62 (p, J = 20.6, 18.3
Hz, 6H), 1.11 (dtd, J = 42.5, 23.0, 10.8 Hz, 6H).; 13C NMR (151 MHz,
DMSO) δ 168.43, 168.41, 157.77, 157.64, 154.77, 154.35, 138.62,
138.47, 131.33, 130.99, 128.13, 127.93, 127.15, 126.73, 126.49,
125.76, 125.07, 115.58, 115.31, 83.65, 82.35, 77.13, 76.35, 64.62,
60.84, 50.28, 49.07, 48.31, 48.20, 47.59, 40.39, 40.25, 40.11, 39.97,
39.83, 39.69, 39.56, 32.60, 32.57, 32.51, 25.63, 24.98, 24.92, 24.88, -
10.35.; HRMS (ESI) calculated for C24H26N2O3 [M+H]+: 391.2016;
found: 391.2017.

N-benzyl-N-(1-(4-hydroxy-3-methoxyphenyl)-2-
oxo-2-((2,4,4-trimethylpentan-2-
yl)amino)ethyl)propiolamide (2-4d'). 1H NMR (300
MHz, DMSO-d6) δ 9.39 (s, 1H), 7.74 (s, 0.46H), 7.52
(s, 0.52H), 7.19 – 6.84 (m, 4H), 6.99 – 6.93 (m, 1H), 6.92 – 6.86 (m,
1H), 6.75 (dd, J = 6.9, 2.8 Hz, 1H), 6.69 – 6.57 (m, 1H), 6.57 – 6.45
(m, 1H), 6.07 (s, 0.49H), 5.83 (s, 0.53H), 4.97 (d, J = 17.4 Hz,
0.56H), 4.76 (d, J = 15.8 Hz, 0.5H), 4.63 (s, 0.45H), 4.58 (d, J = 17.4

108
Hz, 0.52H), 4.38 (s, 0.52H), 4.25 (d, J = 15.7 Hz, 0.5H), 1.96 (d, J =
14.7 Hz, 0.55H), 1.80 (d, J = 14.6 Hz, 0.52H), 1.46 (dd, J = 14.5, 9.4
Hz, 1H), 1.33 (s, 1.5H), 1.29 – 1.13 (m, 3H), 1.19 (s. 1.5H), 0.89 (d, J
= 19.3 Hz, 9H).; 13C NMR (151 MHz, DMSO) δ 168.67, 168.56,
157.65, 157.50, 154.63, 154.17, 138.73, 138.52, 131.45, 131.10,
128.11, 127.87, 127.15, 126.68, 126.47, 126.41, 126.08, 125.25,
115.50, 115.20, 83.70, 82.29, 77.24, 76.40, 64.71, 60.96, 54.91,
54.68, 50.97, 50.87, 50.28, 47.68, 40.41, 40.27, 40.14, 40.00, 39.86,
39.72, 39.58, 31.79, 31.72, 31.66, 31.60, 29.55, 29.47, 29.02, 28.89.;
HRMS (ESI) calculated for C26H32N2O3 [M+H]+: 421.2485; found:
421.2482.

Spectroscopic data of the products

1'-benzyl-3'-methylenespiro[indole-3,4'-
piperidin]-2'-one (2-2a).65 1
H NMR (300 MHz,
Chloroform-d) δ 8.12 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H),
7.43 – 7.29 (m, 6H), 7.26 (s, 0.5H), 7.27 – 7.20 (m,
0.5H), 7.21 (d, J = 0.8 Hz, 0.5H), 7.22 – 7.15 (m, 0.5H), 7.16 (s, 0.5H),
6.32 (d, J = 1.1 Hz, 1H), 5.13 (d, J = 1.1 Hz, 1H), 4.88 (d, J = 14.4 Hz,
1H), 4.78 (d, J = 14.4 Hz, 1H), 3.75 – 3.42 (m, 1H), 2.18 – 1.92 (m,
1H).; 13C NMR (101 MHz, CDCl3) δ 186.2, 158.2, 157.4, 139.7, 139.1,
137.4, 134.1, 131.9, 130.8, 127.8, 127.3, 126.9, 123.0, 123.0, 121.4,
117.8, 117.5, 114.2.
1'-(4-chlorobenzyl)-3'-methylenespiro[indole-
3,4'-piperidin]-2'-one (2-2b). MP: 72.2 °C vmax/cm-1
2926, 1650, 1597, 1486, 1343, 1240, 1088, 731 ; 1H
NMR (300 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.67 (d,
J = 7.7 Hz, 1H), 7.42 (d, J = 1.3 Hz, 0.2H), 7.40 (d, J =

109
1.3 Hz, 0.5H), 7.38 (t, J = 2.0 Hz, 0.8H), 7.35 (s, 3.6H), 7.32 (d, J =
2.6 Hz, 0.5H), 7.29 – 7.22 (m, 1.5H), 7.19 – 7.14 (m, 1H), 6.31 (d, J =
1.0 Hz, 1H), 5.13 (d, J = 1.0 Hz, 1H), 4.85 (d, J = 14.4 Hz, 1H), 4.72
(d, J = 14.4 Hz, 1H), 3.67 – 3.51 (m, 2H), 2.14 – 1.97 (m, 2H);13C NMR
(101 MHz, CDCl3) δ 28.95, 44.94, 50.88, 60.80, 113.78, 116.63,
121.25, 123.09, 125.11, 125.15, 125.22, 128.33, 128.37, 129.01,
129.17, 129.47, 129.58, 129.76, 129.85, 133.19, 133.24, 133.97,
134.05, 134.58, 134.63, 140.30, 150.66, 150.77, 159.32, 159.71,
160.11, 160.50, 162.99, 174.44; HRMS (ESI) calculated for
C20H17ClN2O [M+H]+: 337.1102; found: 337.1112.
1'-(2,6-dichlorobenzyl)-5-methoxy-3'-
methylenespiro[indole-3,4'-piperidin]-2'-one (2-
2c). MP: 146.7 °C , vmax/cm-1 2996, 1650, 1603, 1429,
1241, 786, 766; 1H NMR (400 MHz, Chloroform-d)
δ 8.02 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.26
(t, J = 8.0 Hz, 2H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H), 6.82 (d, J = 2.5 Hz,
1H), 6.34 (s, 1H), 5.28 (d, J = 14.3 Hz, 1H), 5.19 (d, J = 14.3 Hz, 1H),
5.11 (s, 1H), 3.81 (s, 3H), 3.49 – 3.30 (m, 2H), 2.11 – 1.93 (m, 2H);
13
C NMR (151 MHz, CDCl3) δ 171.62, 162.49, 159.06, 148.24, 142.82,
136.94, 134.81, 131.42, 130.00, 128.76, 123.55, 122.26, 113.53,
109.19, 61.21, 55.75, 45.67, 43.52, 29.49; HRMS (ESI) calculated for
C21H18Cl2N2O2 [M+H]+: 401.0818; found: 401.0811.
1'-(4-methoxybenzyl)-3'-methylenespiro[indole-
3,4'-piperidin]-2'-one (2-2d). MP: 114.7 °C, vmax/cm-1
2928, 1649, 1604, 1509, 1449, 1249, 1157, 1027, 756;
1
H NMR (300 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.66
(d, J = 7.7 Hz, 1H), 7.38 (d, J = 1.3 Hz, 1H), 7.32 (d, J =
8.6 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.94 – 6.88
(m, 2H), 6.30 (d, J = 1.1 Hz, 1H), 5.11 (d, J = 1.1 Hz, 1H), 4.81 (d, J =
14.2 Hz, 1H), 4.70 (d, J = 14.2 Hz, 1H), 3.82 (s, 3H), 3.66 – 3.49 (m,

110
2H), 2.04 (ddd, J = 9.6, 6.9, 5.4 Hz, 2H).; 13C NMR (151 MHz, CDCl3)
δ 173.72, 162.72, 159.31, 154.66, 141.04, 134.93, 129.78, 129.75,
128.80, 128.73, 126.88, 122.91, 122.68, 121.93, 114.20, 114.19,
114.16, 77.25, 77.04, 76.83, 61.20, 55.32, 55.24, 50.59, 44.72, 29.14.;
HRMS (ESI) calculated for C21H20N2O2 [M+H]+: 333.1597; found:
333.1591.
1'-benzyl-6-fluoro-3'-methylenespiro[indole-
3,4'-piperidin]-2'-one (2-2e). Mp. 82.7°C; vmax/cm-1
2923, 1648, 1596, 1489, 1448, 1256, 727, 698; 1H
NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.48 – 7.28 (m, 6H),
7.09 (dd, J = 8.3, 5.2 Hz, 1H), 6.93 (td, J = 8.7, 2.4 Hz, 1H), 6.31 (d, J
= 1.0 Hz, 1H), 5.12 (d, J = 1.1 Hz, 1H), 4.89 (d, J = 14.3 Hz, 1H), 4.74
(d, J = 14.4 Hz, 1H), 3.65 – 3.50 (m, 2H), 2.13 – 1.95 (m, 2H).; 13C
NMR (151 MHz, CDCl3) δ 175.67, 164.00, 162.61, 162.37, 156.23,
156.15, 136.63, 136.61, 136.59, 134.64, 128.87, 128.33, 128.31,
127.90, 123.27, 123.20, 123.11, 113.67, 113.52, 109.76, 109.60, 77.34,
77.13, 76.91, 60.89, 51.20, 51.18, 44.92, 29.13.; HRMS (ESI)
calculated for C20H17FN2O [M+H]+: 321.1397; found: 321.1401.
1'-benzyl-5-methoxy-3'-methylenespiro[indole-
3,4'-piperidin]-2'-one (2-2f); vmax/cm-1 2927, 1650,
1
1595, 1484, 1430, 1212, 1030, 726, 699; H NMR
(400 MHz, Chloroform-d) δ 8.00 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 8.5,
2.0 Hz, 1H), 7.43 – 7.27 (m, 5H), 6.88 (dt, J = 8.5, 2.2 Hz, 1H), 6.72
(t, J = 2.1 Hz, 1H), 6.33 (d, J = 1.6 Hz, 1H), 5.14 (d, J = 1.6 Hz, 1H),
4.94 (d, J = 14.3 Hz, 1H), 4.70 (d, J = 14.3 Hz, 1H), 3.74 (d, J = 1.8
Hz, 3H), 3.68 – 3.50 (m, 2H), 2.12 – 1.95 (m, 2H).; 13C NMR (151
MHz, CDCl3) δ 171.62, 162.78, 159.06, 148.15, 142.75, 136.75,
134.98, 128.88, 128.35, 127.82, 123.32, 122.30, 113.51, 109.10, 61.29,
55.72, 51.26, 44.82, 29.31.; HRMS (ESI) calculated for C21H20N2O2
[M+H]+: 333.15974; found: 333.1605.

111
 1'-benzyl-6-bromo-3'-
methylenespiro[indoline-3,4'-piperidin]-2'-one
(2-2g). vmax/cm-1 3270, 2922, 1647, 1593, 1472, 1450,
1240, 726, 698; 1H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H),
7.81 (d, J = 1.7 Hz, 1H), 7.44 – 7.25 (m, 6H), 7.01 (d, J = 7.9 Hz, 1H),
6.33 (d, J = 0.9 Hz, 1H), 5.12 (d, J = 1.0 Hz, 1H), 4.90 (d, J = 14.3 Hz,
1H), 4.73 (d, J = 14.3 Hz, 1H), 3.67 – 3.50 (m, 2H), 2.14 – 1.94 (m,
2H). 13C NMR (151 MHz, CDCl3) δ 175.18, 162.52, 156.09, 139.94,
136.56, 134.24, 129.78, 128.90, 128.36, 127.95, 125.37, 123.81,
123.39, 122.22, 61.20, 51.23, 44.86, 28.96.
1'-benzyl-5-bromo-3'-methylenespiro[indoline-
3,4'-piperidin]-2'-one (2-2h). vmax/cm-1 3313, 2923,
1
1649, 1600, 1480, 1446, 1245, 728, 698; H NMR
(300 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.53 – 7.51 (m, 2H), 7.42 –
7.33 (m, 5H), 7.29 (t, J = 1.2 Hz, 1H), 6.35 (d, J = 0.9 Hz, 1H), 5.15
(d, J = 1.0 Hz, 1H), 4.98 (d, J = 14.3 Hz, 1H), 4.69 (d, J = 14.4 Hz,
1H), 3.65 – 3.50 (m, 2H), 2.16 – 2.08 (m, 1H), 2.03 – 1.92 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 174.02, 162.40, 153.56, 143.06, 136.53,
134.09, 131.93, 128.98, 128.29, 128.15, 127.96, 126.11, 123.49,
123.25, 120.79, 61.54, 51.23, 44.78, 28.83.
1'-benzyl-7-chloro-3'-methylenespiro[indoline-
3,4'-piperidin]-2'-one (2-2i). vmax/cm-1 3311, 2923,
1698, 1647, 1490, 1451, 1346, 1251, 1027, 756, 733,
698; Mp. 47.5°C; 1H NMR (600 MHz, Acetone-d6) δ
8.41 (s, 1H), 7.48 – 7.42 (m, 3H), 7.41 (t, J = 7.6 Hz, 2H), 7.36 – 7.33
(m, 1H), 7.32 – 7.24 (m, 2H), 6.19 (d, J = 1.5 Hz, 1H), 5.04 (d, J = 1.5
Hz, 1H), 4.95 (d, J = 14.4 Hz, 1H), 4.70 (d, J = 14.4 Hz, 1H), 3.76 (ddd,
J = 13.0, 7.8, 5.0 Hz, 1H), 3.68 (ddd, J = 13.2, 6.6, 5.1 Hz, 1H), 2.22
(ddd, J = 13.5, 6.6, 5.0 Hz, 1H), 2.14 (ddd, J = 13.4, 7.8, 5.2 Hz, 1H).
13
C NMR (151 MHz, Acetone) δ 205.22, 205.21, 175.55, 161.67,

112
151.63, 143.92, 137.59, 135.65, 128.95, 128.61, 128.20, 128.13,
127.43, 126.13, 121.59, 121.13, 63.01, 50.39, 44.67, 29.33, 29.20,
29.08, 28.95, 28.82, 28.69, 28.56.; HRMS (ESI) calculated for
C20H17ClN2O [M+H]+: 337.1102; found: 337.1098.
1'-benzyl-6-chloro-3'-methylenespiro[indoline-
3,4'-piperidin]-2'-one (2-2j). vmax/cm-1 3300, 2922,
1647, 1596, 1486, 1449, 1345, 1318, 1241, 1028, 956,
887, 732; H NMR (600 MHz, Acetone-d6) δ 8.39 (s, 1H), 7.64 (s, 1H),
1

7.44 (d, J = 7.1 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.2 Hz,
1H), 7.30 (s, 2H), 6.18 (d, J = 1.5 Hz, 1H), 5.02 (d, J = 1.5 Hz, 1H),
4.93 (d, J = 14.4 Hz, 1H), 4.71 (d, J = 14.4 Hz, 1H), 3.74 (ddd, J =
13.0, 7.8, 5.0 Hz, 1H), 3.66 (ddd, J = 13.1, 6.6, 5.1 Hz, 1H), 2.21 – 2.02
(m, 2H). 13C NMR (151 MHz, Acetone) δ 205.26, 176.36, 161.73,
156.64, 140.48, 137.58, 135.81, 133.57, 128.63, 128.20, 127.46,
126.40, 124.00, 121.64, 121.07, 61.52, 50.41, 44.71, 29.38, 29.26,
29.13, 29.00, 28.87, 28.74, 28.67, 28.61.; HRMS (ESI) calculated for
C20H17ClNO [M+H]+: 337.1102; found: 337.1118.
1'-(cyclohexylmethyl)-3'-methylenespiro[indole-
3,4'-piperidin]-2'-one (2-2l). vmax/cm-1 3307, 2920,
2849, 1649, 1594, 1486, 1448, 1241, 726; 1H NMR (300
MHz, Chloroform-d) δ 9.44 (s, 1H), 7.97 – 7.82 (m, 1H),
7.80 – 7.65 (m, 2H), 7.67 – 7.53 (m, 1H), 6.50 (s, 1H), 5.29 (s, 1H),
3.94 (ddd, J = 14.5, 10.5, 4.1 Hz, 1H), 3.83 (q, J = 4.9 Hz, 1H), 3.65 –
3.54 (m, 1H), 3.49 – 3.37 (m, 1H), 2.73 – 2.57 (m, 1H), 2.32 (dt, J =
14.1, 4.1 Hz, 1H), 1.85 – 1.66 (m, 6H), 1.32 – 1.20 (m, 3H), 1.08 (t, J
= 11.9 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 153.83, 153.78, 136.41,
136.33, 127.33, 127.30, 122.38, 122.18, 122.07, 121.98, 119.36,
118.65, 118.38, 112.62, 111.93, 111.46, 111.33, 78.77, 78.19, 77.30,
77.09, 76.87, 76.57, 76.22, 55.78, 50.95, 50.27, 46.45, 37.08, 36.22,

113
30.85, 30.77, 26.35, 26.33, 25.84, 25.83, 24.91, 22.95; HRMS (ESI)
calculated for C20H24N2O [M+H]+: 308.1888; found: 309.1966.
1'-(cyclohexylmethyl)-5-methoxy-3'-
methylenespiro[indole-3,4'-piperidin]-2'-on (2-
2m). vmax/cm-1 2920, 1652, 1597, 1483, 1471,
1447, 1240, 797, 730; 1H NMR (300 MHz,
Chloroform-d) δ 8.04 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 6.91 (dt, J =
8.5, 2.3 Hz, 2H), 6.83 (s, 1H), 6.26 (d, J = 2.0 Hz, 1H), 5.04 (d, J = 2.0
Hz, 2H), 3.82 (d, J = 2.0 Hz, 3H), 3.68 (t, J = 6.2 Hz, 2H), 3.42 (h, J =
7.5, 6.6 Hz, 2H), 2.08 (q, J = 6.4, 5.5 Hz, 2H), 1.85 – 1.63 (m, 6H),
1.35 – 0.97 (m, 6H).; 13C NMR (75 MHz, CDCl3) δ 25.80, 26.33, 29.66,
30.89, 30.95, 31.06, 36.07, 46.54, 46.74, 54.63, 55.27, 55.55, 55.58,
55.77, 56.08, 61.26, 109.10, 109.16, 113.28, 113.35, 121.73, 122.06,
122.24, 122.95, 123.02, 134.84, 143.10, 148.17, 159.01, 162.77,
171.34, 171.68, 171.81, 172.16, 206.88.; HRMS (ESI) calculated for
C21H26N2O2 [M+H]+: 339.20669; found: 339.2081.
5-methoxy-3'-methylene-1'-pentylspiro[indole-
3,4'-piperidin]-2'-one (2-2n). vmax/cm-1 2927, 1652,
1596, 1485, 1466, 1430, 1213, 1029, 730; 1H NMR
(300 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.64 (d, J =
8.5 Hz, 1H), 6.93 (dd, J = 8.6, 2.5 Hz, 1H), 6.84 (d, J
= 2.5 Hz, 1H), 6.29 (s, 1H), 5.07 (s, 1H), 3.82 (s, 3H), 3.75 – 3.65 (m,
2H), 3.69 – 3.41 (m, 2H), 2.27 – 2.03 (m, 2H), 1.68 (p, J = 7.3 Hz, 2H),
1.39 – 1.31 (m, 5H).; 13C NMR (101 MHz, CDCl3) δ 172.26, 162.64,
160.68, 160.29, 160.16, 159.91, 159.52, 133.41, 124.81, 121.72,
116.86, 113.98, 109.74, 100.00, 77.35, 77.04, 76.72, 60.80, 55.86,
48.75, 45.51, 29.71, 29.40, 29.15, 26.80, 22.45, 22.38, 13.96.; HRMS
(ESI) calculated for C19H24N2O2 [M+H]+: 313.1910; found: 313.1915.

114
 1'-benzyl-5-methyl-3'-methylenespiro[indole-
3,4'-piperidin]-2'-one (2-2o). Mp. 128°C; vmax/cm-1
2929, 1649, 1605, 1487, 1447, 1344, 1248, 699, 481;
1
H NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.54 (d, J = 7.9 Hz,
1H), 7.46 – 7.31 (m, 5H), 7.18 (d, J = 7.9 Hz, 1H), 6.92 (s, 1H), 6.31
(s, 1H), 5.16 (s, 1H), 5.04 (d, J = 14.3 Hz, 1H), 4.65 (d, J = 14.3 Hz,
1H), 3.70 – 3.61 (m, 1H), 3.61 – 3.52 (m, 1H), 2.32 (s, 3H), 2.19 – 2.11
(m, 1H), 2.00 – 1.90 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 172.90,
162.82, 152.38, 141.13, 136.89, 136.79, 135.14, 129.28, 128.86,
128.54, 128.48, 127.89, 123.45, 122.74, 121.45, 77.29, 77.08, 76.87,
60.90, 51.26, 44.89, 28.94, 21.46; HRMS (ESI) calculated for
C21H20N2O [M+H]+: 317.1648; found: 317.1659.
4-bromo-1'-(4-chlorobenzyl)-4'-
methylenespiro[indole-3,3'-pyrrolidin]-5'-one (2-3b).
Mp. 93.4°C; vmax/cm-1 3277, 2957, 2921, 2852, 1684,
1
1440, 1290, 1088, 799, 728; H NMR (300 MHz,
Chloroform-d) δ 7.93 (s, 1H), 7.57 (dd, J = 7.7, 0.9 Hz, 1H), 7.40 –
7.34 (m, 1.5H), 7.32 (d, J = 2.4 Hz, 1.5H), 7.29 (d, J = 3.8 Hz, 2H),
7.27 (s, 0.8H), 7.23 (s, 0.2H), 6.13 (s, 1H), 4.98 (s, 1H), 4.76 (d, J =
14.6 Hz, 1H), 4.60 (d, J = 14.6 Hz, 1H), 3.83 (d, J = 10.7 Hz, 1H), 3.49
(d, J = 10.6 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 173.12, 166.27,
156.89, 139.27, 134.48, 134.07, 133.79, 130.76, 130.72, 130.01,
129.03, 120.60, 118.49, 117.52, 117.50, 77.26, 77.05, 76.83, 61.38,
46.85, 46.84, 46.82, 44.61, 44.59, 44.58; HRMS (ESI) calculated for
C19H14BrClN2O1 [M+H]+: 401.0051; found: 401.0059.
5-bromo-1'-(4-chlorobenzyl)-4'-
methylenespiro[indole-3,3'-pyrrolidin]-5'-one (2-3c).
Mp. 113.6°C; vmax/cm-1 2958, 2922, 2853, 1680, 1471,
1258, 1258, 1088, 1014, 798, 728; 1H NMR (300 MHz,
Chloroform-d) δ 7.92 (s, 1H), 7.51 (d, J = 1.8 Hz, 2H), 7.37 (d, J = 8.5

115
Hz, 2H), 7.31 (dd, J = 1.4, 0.7 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1.3H), 7.25
(s, 0.7H)., 4.9 (s, 2H), 4.67 (s, 4H), 3.57 (d, J = 10.4 Hz, 2H), 3.45 (d,
J = 10.4 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 172.41, 165.95,
154.13, 142.74, 137.22, 134.26, 133.88, 132.23, 129.76, 129.29,
125.39, 122.94, 121.20, 118.71, 60.58, 48.19, 46.86, 29.69.; HRMS
(ESI) calculated for C19H14BrClN2O1 [M+H]+: 401.0051; found:
401.0043.
1'-benzyl-5-methoxy-4'-methylenespiro[indole-
3,3'-pyrrolidin]-5'-one (2-3d). Mp. 107.4°C; 1H
NMR (300 MHz, Chloroform-d) δ 1H NMR (400
MHz, Chloroform-d) δ 7.82 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.34 (q,
J = 7.1, 6.6 Hz, 5H), 7.27 (s, 1H), 6.87 (dd, J = 8.5, 2.5 Hz, 1H), 6.71
(d, J = 2.4 Hz, 1H), 6.05 (s, 1H), 4.97 (s, 1H), 4.70 (d, J = 1.8 Hz, 2H),
3.77 (s, 3H), 3.57 (d, J = 10.4 Hz, 1H), 3.43 (d, J = 10.4 Hz, 1H).; 13C
NMR (101 MHz, CDCl3) δ 170.47, 166.26, 159.43, 148.54, 142.59,
138.46, 135.55, 128.99, 128.37, 128.12, 121.96, 117.98, 113.82,
108.05, 77.35, 77.03, 76.71, 60.37, 55.73, 48.74, 47.46.; HRMS (ESI)
calculated for C20H18N2O2 [M+H]+: 319.1440; found: 319.1436.
1'-benzyl-4'-methylene-4-nitrospiro[indole-3,3'-
pyrrolidin]-5'-one (2-3e). Mp. 121.2°C; 1H NMR (300
MHz, Acetone-d6) δ 8.30 (s, 1H), 8.16 (d, J = 8.3 Hz,
1H), 8.02 (dd, J = 7.7, 0.9 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.54 – 7.14
(m, 5H), 5.80 (s, 1H), 4.81 (d, J = 14.9 Hz, 1H), 4.77 (s, 1H), 4.69 (d,
J = 14.9 Hz, 1H), 3.86 (d, J = 10.5 Hz, 1H), 3.69 (d, J = 10.5 Hz, 1H).;
13
C NMR (101 MHz, Acetone) δ 205.28, 175.49, 165.59, 159.50,
144.14, 136.77, 136.32, 135.41, 130.85, 128.60, 128.17, 127.52,
127.19, 122.12, 114.13, 61.70, 46.85, 45.25, 29.56, 29.37, 29.18,
28.99, 28.79, 28.60, 28.41; HRMS (ESI) calculated for C19H15N3O3
[M+H]+: 334.1186; found: 334.1194.

116
 2-benzyl-5-(tert-butyl)-8-methoxy-1-
methylene-1,2,5a,6-
tetrahydropyrrolo[3',4':3,4]pyrrolo[2,3-b]indole-
3,4(3aH,5H)-dione (2-3g): 1H NMR (300 MHz, Chloroform-d) δ 7.43
– 7.32 (m, 2H), 6.99 (t, J = 8.6 Hz, 2H), 6.61 (d, J = 8.3 Hz, 1H), 6.29
(d, J = 8.3 Hz, 2H), 6.21 (d, J = 2.2 Hz, 1H), 5.46 (d, J = 4.3 Hz, 1H),
5.32 (s, 1H), 5.19 (d, J = 14.3 Hz, 1H), 4.54 (d, J = 14.4 Hz, 1H), 4.46
(s, 1H), 3.78 (s, 1H), 3.72 (s, 3H), 1.44 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 163.57, 161.40, 161.13, 150.12, 146.34, 131.75, 131.71,
130.70, 130.62, 124.38, 122.80, 120.68, 115.64, 115.43, 106.26, 96.75,
85.00, 77.36, 77.05, 76.73, 65.70, 55.40, 55.16, 52.46, 44.50, 28.03.
5-isopropyl-2-(4-methoxybenzyl)-1-
methylene-1,2,5a,6-
tetrahydropyrrolo[3',4':3,4]pyrrolo[2,3- b]indole-
3,4(3aH,5H)-dione (2-3h): 1H NMR (400 MHz, Chloroform-d) δ 7.35
(d, J = 8.2 Hz, 2H), 7.14 – 7.07 (m, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.74
(q, J = 7.5 Hz, 2H), 6.66 (d, J = 7.9 Hz, 1H), 6.26 (d, J = 1.2 Hz, 1H),
5.32 (d, J = 3.0 Hz, 1H), 5.23 (d, J = 14.0 Hz, 2H), 4.65 (s, 1H), 4.47
(d, J = 14.3 Hz, 1H), 4.12 (dq, J = 13.8, 6.9 Hz, 1H), 3.93 (s, 1H), 3.77
(d, J = 1.0 Hz, 3H), 1.28 (dd, J = 6.9, 5.6 Hz, 7H).
3-benzyl-5-(tert-butyl)-1-methylene-3,3a,5a,6-
tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-
trione (2-5a). Mp.; 1H NMR (300 MHz, Chloroform-d)
δ 7.36-7.30 (m, 5H), 6.41 (d, J = 10.1 Hz, 1H), 6.37 (s,
1H), 6.05 (d, J = 10.1 Hz, 1H), 5.57 (s, 1H), 5.35 (d, J = 14.7 Hz, 1H),
4.57 (d, J = 14.7 Hz, 1H), 4.25 (d, J = 5.5 Hz, 0.5H), 4.21 (d, J = 5.5
Hz, 0.5H), 3.83 (s, 1H), 3.08 (d, J = 5.5 Hz, 0.5H), 3.03 (d, J = 5.5 Hz,
0.5H), 2.34 (dd, J = 15.5, 11.9 Hz, 1H), 1.40 (s, 9H); 13C NMR (151
MHz, CDCl3) δ 195.36, 169.08, 164.95, 145.72, 145.11, 135.41,
128.95, 128.88, 128.66, 128.04, 127.41, 119.89, 77.26, 77.04, 76.83,

117
61.96, 59.47, 55.36, 46.11, 45.51, 45.17, 28.01, 27. HRMS (ESI)
calculated for C22H24N2O3 [M+H]+: 365.1859; found: 365.1869
3-benzyl-8-methoxy-1-methylene-3,3a,5a,6-
tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-
trione (2-5b). Mp. 224.2 °C ; vmax/cm-1 3299, 2963,
1679, 1404, 1156, 729, 696, 640; 1H NMR (400 MHz,
Chloroform-d) δ 7.41 – 7.27 (m, 5H), 6.35 (s, 1H), 5.56 (s, 1H), 5.36
(d, J = 14.7 Hz, 1H), 5.27 (s, 1H), 4.56 (d, J = 14.7 Hz, 1H), 4.18 (dd,
J = 11.9, 5.4 Hz, 1H), 3.82 (s, 1H), 3.52 (s, 3H), 3.14 (dd, J = 15.6, 5.4
Hz, 1H), 2.46 (dd, J = 15.6, 11.9 Hz, 1H), 1.38 (s, 9H).; 13C NMR (151
MHz, CDCl3) δ 189.96, 169.51, 165.23, 149.96, 146.58, 135.55,
128.88, 128.70, 128.04, 119.45, 113.77, 77.26, 77.05, 63.34, 58.74,
55.33, 55.29, 46.14, 45.56, 45.39, 27.93.; HRMS (ESI) calculated for
C23H26N2O4[ M+H]+: 395.1965; found: 395.1966
3-benzyl-8-methoxy-1-methylene-3,3a,5a,6-
tetrahydro-1H-pyrrolo[2,3-c]indole-2,4,7(5H)-
trione (2-5b’). Mp. 246.5 °C ; vmax/cm-1 3271, 3071,
2963, 2923, 1669, 1440, 1428, 1206, 883, 859, 730,
594; 1H NMR (300 MHz, Chloroform-d) δ 7.42 – 7.19 (m, 3H), 6.61
(dd, J = 9.8, 2.7 Hz, 2H), 6.21 (d, J = 9.8 Hz, 1H), 6.15 (s, 1H), 5.77
(d, J = 2.6 Hz, 1H), 5.45 (s, 1H), 5.28 (d, J = 14.7 Hz, 1H), 3.99 (d, J
= 14.6 Hz, 1H), 3.63 (s, 3H), 3.63 (s, 1H), 1.29 (s, 9H).; 13C NMR (101
MHz, CDCl3) δ 180.14, 166.39, 165.64, 152.04, 148.16, 148.13,
140.17, 135.13, 129.04, 128.82, 128.29, 127.70, 127.65, 119.16,
119.13, 113.58, 77.35, 77.04, 76.72, 65.08, 55.00, 52.32, 48.66, 46.28,
28.55; HRMS (ESI) calculated for C23H26N2O4 [M+H]+: 395.1965;
found: 395.1963.

118
 2-benzyl-N-cyclohexyl-4-methylene-3,8-dioxo-
2-azaspiro[4.5]deca-6,9-diene-1-carboxamide
(2-5c). Mp. 185.1 °C ; vmax/cm-1 3292, 2927, 2857,
1672, 1618, 1513, 1446, 1380, 1225, 696, 528; 1H
NMR (300 MHz, Chloroform-d) δ 7.37 – 7.29 (m, 3H), 7.20 (dd, J =
7.2, 2.3 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.82 (s, 1H), 6.71 (d, J = 8.6
Hz, 2H), 6.06 (d, J = 1.5 Hz, 1H), 5.46 (d, J = 14.7 Hz, 1H), 5.29 (d, J
= 1.5 Hz, 1H), 4.77 (s, 1H), 3.97 (tt, J = 12.1, 3.5 Hz, 1H), 3.58 (d, J =
14.7 Hz, 1H), 2.15 (tdd, J = 25.3, 12.9, 4.4 Hz, 2H), 1.80 (d, J = 14.4
Hz, 3H), 1.62 (t, J = 13.1 Hz, 2H), 1.42 – 1.03 (m, 4H).; 13C NMR (151
MHz, CDCl3) δ 164.76, 160.78, 157.02, 136.99, 135.11, 129.09,
128.72, 128.33, 128.29, 127.16, 116.37, 106.00, 77.37, 77.16, 76.95,
63.05, 59.17, 47.52, 29.89, 27.81, 26.53, 26.13, 25.40, 22.83.; HRMS
(ESI) calculated for C24H26N2O3 [M+H]+: 391.2016; found: 391.2009.
2-benzyl-4-methylene-3,8-dioxo-N-(2,4,4-
trimethylpentan-2-yl)-2-azaspiro[4.5]deca-6,9-
diene-1-carboxamide (2-5d). Mp. 230 °C ; vmax/cm-1
2967, 1704, 1673, 1401, 1217, 1112, 898, 741, 696,
612; 1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.24
(m, 5H), 6.38 (d, J = 10.4 Hz, 2H), 6.05 (d, J = 10.1 Hz, 1H), 5.56 (s,
1H), 5.34 (d, J = 14.6 Hz, 1H), 4.58 (d, J = 14.7 Hz, 1H), 4.26 (dd, J =
11.8, 5.4 Hz, 1H), 3.82 (s, 1H), 3.10 (dd, J = 15.4, 5.4 Hz, 1H), 2.62
(d, J = 14.8 Hz, 1H), 2.37 (dd, J = 15.4, 11.8 Hz, 1H), 1.47 (s, 3H),
1.40 (s, 3H), 1.33 (d, J = 14.8 Hz, 1H), 0.92 (s, 9H).; 13C NMR (151
MHz, CDCl3) δ 195.43, 169.05, 164.96, 146.02, 145.49, 135.44,
128.94, 128.68, 128.02, 127.11, 120.22, 77.25, 77.04, 76.83, 62.04,
60.02, 59.96, 50.42, 46.56, 45.38, 44.78, 31.56, 29.10, 26.76.; HRMS
(ESI) calculated for C26H32N2O3 [M+H]+: 421.2485; found: 421.2479.

119
 (E)-N-(2-(1H-indol-3-yl)ethyl)-N-benzyl-4-
1
methoxybut-2-enamide (2-7b). H NMR
(400 MHz, Chloroform-d) δ 8.46 (s, 0.56H), 8.36 (s, 0.40H), 7.56 (dd,
J = 15.0, 7.8 Hz, 1H), 7.30 (dt, J = 13.8, 7.4 Hz, 3H), 7.23 (d, J = 12.6
Hz, 2H), 7.13 (tt, J = 17.4, 7.9 Hz, 3.5H), 6.96 – 6.81 (m, 1.5H), 6.55
– 6.36 (m, 1H), 4.66 (s, 1.2H), 4.50 (s, 0.8H), 4.06 (dd, J = 4.3, 2.0 Hz,
0.8H), 3.92 (dd, J = 4.3, 2.0 Hz, 1.2H), 3.71 (t, J = 7.7 Hz, 0.8H), 3.59
(t, J = 7.4 Hz, 1.2H), 3.31 (d, J = 4.6 Hz, 3H), 3.05 (t, J = 7.7 Hz, 0.8H),
2.97 (t, J = 7.4 Hz, 1.2H).; 13C NMR (101 MHz, CDCl3) δ 166.74,
166.66, 142.12, 141.78, 137.74, 137.13, 136.46, 136.38, 128.86,
128.69, 128.64, 128.15, 127.64, 127.44, 127.40, 127.15, 126.67,
122.64, 122.24, 122.08, 121.88, 120.47, 120.20, 119.44, 119.25,
118.80, 118.32, 112.96, 112.93, 111.80, 111.77, 111.52, 111.31, 71.58,
71.52, 58.59, 51.96, 49.29, 47.85, 34.18, 25.25, 23.60. HRMS (ESI)
calculated for C22H24N2O2 [M+H]+: 349.19104; found: 349.1913.

4.3.1 Optimization of heating time in batch synthesis for

synthesis of Ag NCs
Batch synthesis was conducted in CEM Microwave Discover®

Cavity with 200W for 70s, 35s and 17s. As reported in figure S1,

the decrease of the irradiation time strongly influenced the size

distribution of the Ag NCs, recording an optimum point at 17s

with an average particle diameter of (1.6±0.7) nm. Furthermore,

comparing the results with a previous work of S. Liu et al., optical

and morphological properties of Ag clusters are strictly

dependent on the polyelectrolyte adopted. In fact, PMAA-Ag

120
clusters presented a red transparent color. Instead PAA-Ag were

dispersed in a blue transparent suspension, as reported in figure

S1.

Figure 6: TEM analysis for batch synthesis of Ag NCs at respectively 70s (a), 35s (b)
and 17s (c).

N2 adsorption analysis

Table 2: N2 adsorption details for APTES/SBA-15 and Ag

NCs/APTES/SBA-15

Sample SBET (m2g-1) Vt (cm3g-1) DBJH (nm)

APTES / SBA-15 317 0.89 9.3

Ag NCs / APTES / SBA-15 255 0.59 9.2

4.3.2 General procedure for synthesis of starting material

Propargylamine (0.3 mmol), 1,3-bis(tert-butoxycarbonyl)thiourea
(DBTU, 115 mg,0.41 mmol, 1.35 equiv), and diisopropylethylamine
(112 mg, 0.9 mmol, 3 equiv) were dissolved in anhydrous MeCN
(2mL). After stirring at room temperature, it was cooled to 0 °C
followed by addition of EDCI (115 mg, 0.6 mmol, 2 equiv). Then
reaction was stirred at RT overnight. The reaction mixture was
transferred into 250 mL funnel and diluted with EtOAc (50 mL), and

121
washed with water (3×100 mL), followed by brine and dried over
anhydrous Na2SO4. The solvent was evaporated under vacuum
followed by column chromatography on silica using 20% EtOAc in
heptane as eluent (Rf 0.25-0.3).

4.3.3 General procedure for synthesis of product

Batch reaction: A proper amount of Ag-NCs was mixed with 0.32
mmol of N-propargylguanidine 1 (synthesis procedure reported in S.I.)
in DCM (3.2 mL), previously dispersed at 50°C until complete
dissolution. The reaction vial was immersed in an oil bath preheated at
set-point temperature and stirred at 500 rpm. After the reaction time,
the reaction mixture was centrifuged and the catalyst was washed three
times with DCM. The resulting organic layer was evaporated under
reduced pressure, and the residue was purified by silica gel column
chromatography.

Flow reactions: A Nexus 6000 pump was used together with a 1.5 mL
sample loop for the injection of the reaction mixture onto the reactor.
Before reaction, the flow was always stabilized at each flow rate at the
required reaction temperature with the help of 20 psi back pressure
regulator placed at the end of the setup. The catalyst was filled into the
reactor (5 mm × 40 mm) followed by sand and cotton wool
respectively. The reactor was sealed employing stainless steel micro-
sieve on both ends. The volume of the reaction was collected until TLC
gave no visible spot anymore for the starting material. After each
reaction, the reactor was cleaned with the appropriate solvent and one
reactor filling was used up to 4-5 reactions.

4.3.4 Spectroscopic data for the starting material

122
(Z)-1-([1,1'-biphenyl]-4-ylmethyl)-2,3-bis(pivaloyloxy)-1-(prop-2-
yn-1-yl)guanidine

1
H NMR (300 MHz, Chloroform-d) δ
10.04 (s, 1H), 7.58 (dd, J = 7.7, 3.8 Hz,
4H), 7.41 (dt, J = 20.8, 7.8 Hz, 5H), 4.84
(s, 2H), 4.18 (d, J = 2.5 Hz, 2H), 2.35 –
2.29 (m, 1H), 1.51 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 167.59,
166.59, 136.94, 135.70, 134.35, 133.54, 130.08, 129.09, 128.98,
128.58, 128.25, 127.41, 127.35, 126.79, 125.86, 125.03, 67.98, 67.92,
66.91, 66.86, 63.82, 51.09, 42.69, 42.61, 32.39, 32.33, 18.78, 18.68,
13.70. HRMS (ESI) calculated for C27H33N3O4 [M+H]+: 463.24708;
found: 464.2530

(Z)-1-(4-methoxybenzyl)-2,3-bis(pivaloyloxy)-1-(prop-2-yn-1-
yl)guanidine:

1
H NMR (400 MHz, Chloroform-d) δ 10.00 (s,
1H), 7.24 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.4
Hz, 2H), 4.72 (s, 2H), 4.11 (s, 2H), 3.80 (s,
3H), 2.30 (d, J = 2.5 Hz, 1H), 1.53 – 1.45 (m,
18H). 13C NMR (101 MHz, CDCl3) δ 162.54, 159.37, 155.46,
152.67, 150.73, 149.83, 129.90, 127.55, 114.15, 77.92, 73.50,
55.36, 50.95, 37.07, 28.24, 28.12. HRMS (ESI) calculated for
C22H31N3O5 [M+H]+: 417.22635; found: 418.2330.

(Z)-1-benzyl-2,3-bis(pivaloyloxy)-1-(prop-2-yn-1-yl)guanidine:

123
 1
H NMR (400 MHz, Chloroform-d) δ 10.01 (s, 1H),
7.40 – 7.22 (m, 5H), 4.82 (d, J = 21.6 Hz, 2H), 4.14
(t, J = 2.4 Hz, 2H), 2.30 (d, J = 2.5 Hz, 1H), 1.50 (s,
18H). 13
C NMR (101 MHz, CDCl3) δ 170.21,
162.45, 138.07, 135.15, 129.43, 129.03, 128.91, 128.72, 128.35,
128.23, 128.07, 106.00, 80.04, 54.02, 53.53, 50.66, 28.44, 28.31,
28.09. HRMS (ESI) calculated for C21H29N3O4 [M+H]+: 387.21579;
found: 388.2219.

(Z)-1-(cyclohexylmethyl)-2,3-bis(pivaloyloxy)-1-(prop-2-yn-1-
yl)guanidine:

1
H NMR (300 MHz, Chloroform-d) δ 9.83 (s,
1H), 4.33 – 4.25 (m, 2H), 3.40 (d, J = 7.0 Hz,
2H), 2.28 (d, J = 2.5 Hz, 1H), 1.76 – 1.60 (m,
8H), 1.48 (s, 18H), 1.20 (s, 2H), 1.00 – 0.82 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 162.55, 159.45, 155.64, 153.27,
150.66, 149.53, 137.22, 91.63, 84.26, 78.85, 77.96, 73.38, 50.85,
50.04, 35.81, 35.70, 30.70, 30.64, 28.51, 28.39, 28.34, 28.29, 28.19,
26.50, 26.45, 25.88. HRMS (ESI) calculated for C21H35N3O4 [M+H]+:
393.26273; found: 394.2691.

Spectroscopic data for products

tert-butyl (E)-2-((tert-butoxycarbonyl)imino)-3-methyl-5-
methyleneimidazolidine-1-carboxylate:

1
H NMR (400 MHz, Chloroform-d) δ 5.19 (q, J = 2.2
Hz, 1H), 4.46 (q, J = 2.0 Hz, 1H), 4.08 (t, J = 2.4 Hz,
2H), 2.94 (s, 3H), 1.56 (s, 8H), 1.50 (s, 9H).

Analytical data: Ermolat&apos;Ev, D. S.; Bariwal, J.

B.; Steenackers, H. P. L.; De Keersmaecker, S. C. J.; Van Der Eycken,
E. V. Angew. Chemie - Int. Ed. 2010, 49 (49), 9465–9468.

124
tert-butyl (E)-3-([1,1'-biphenyl]-4-ylmethyl)-2-((tert-
butoxycarbonyl)imino)-5-methyleneimidazolidine-1-carboxylate:

1
H NMR (400 MHz, Chloroform-d) δ
7.56 (t, J = 7.4 Hz, 5H), 7.44 (t, J = 7.6
Hz, 2H), 7.34 (dd, J = 11.0, 7.6 Hz, 3H),
5.17 (q, J = 2.3 Hz, 1H), 4.63 (s, 2H), 4.40
(q, J = 2.1 Hz, 1H), 3.93 (d, J = 2.3 Hz, 2H), 1.56 (d, J = 16.8 Hz, 18H).
13
C NMR (101 MHz, CDCl3) δ 159.46, 152.99, 149.53, 141.00, 140.70,
137.03, 134.27, 128.92, 127.62, 127.54, 127.19, 91.88, 84.55, 79.21,
48.65, 48.28, 28.52, 28.24, 28.21. HRMS (ESI) calculated for
C27H33N3O4 [M+H]+: 463.24708; found: 464.2538

tert-butyl(E)-2-((tert-butoxycarbonyl)imino)-3-(4-
methoxybenzyl)-5-methyleneimidazolidine-1-carboxylate:

1
H NMR (300 MHz, Chloroform-d) δ 7.18 (d, J =
8.6 Hz, 2H), 6.89 – 6.81 (m, 2H), 5.15 (q, J = 2.4
Hz, 1H), 4.52 (s, 2H), 4.37 (q, J = 2.2 Hz, 1H), 3.86
(t, J = 2.5 Hz, 2H), 3.79 (d, J = 0.7 Hz, 3H), 1.57
(s, 9H), 1.53 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 159.74, 159.34,
152.71, 149.57, 137.41, 129.90, 127.51, 114.50, 91.42, 84.44, 78.99,
55.45, 48.62, 48.21, 28.64, 28.29. HRMS (ESI) calculated for
C22H31N3O5 [M+H]+: 417.22635; found: 418.2330.

tert-butyl(E)-3-benzyl-2-((tert-butoxycarbonyl)imino)-5-
methyleneimidazolidine-1-carboxylate:

1
H NMR (300 MHz, Chloroform-d) δ 7.37 – 7.28
(m, 4H), 7.24 (m, 1H), 5.16 (q, J = 2.5 Hz, 1H), 4.58
(s, 2H), 4.38 (q, J = 2.1 Hz, 1H), 3.88 (t, J = 2.4 Hz,
1.5H), 3.85 (t, J = 2.4 Hz, 0.5H), 1.57 (s, 9H), 1.52
(s, 9H). C NMR (101 MHz, CDCl3) δ 170.17, 162.41, 152.59, 149.77,
13

125
138.05, 135.13, 128.88, 128.19, 128.04, 105.96, 81.92, 79.98, 53.99,
50.63, 30.95, 28.28, 28.06, 28.04. HRMS (ESI) calculated for
C21H29N3O4 [M+H]+: 387.21579; found: 388.2220.

tert-butyl(Z)-2-((tert-butoxycarbonyl)imino)-3-
(cyclohexylmethyl)-5-methyleneimidazolidine-1-carboxylate:

1
H NMR (300 MHz, Chloroform-d) δ 5.16 (q, J = 2.4
Hz, 1H), 4.43 (q, J = 2.1 Hz, 1H), 4.04 (t, J = 2.4 Hz,
2H), 3.20 (d, J = 7.1 Hz, 2H), 1.64 (dtd, J = 17.9, 6.5,
5.9, 3.4 Hz, 4H), 1.54 (s, 9H), 1.48 (s, 9H), 1.34 –
1.22 (m, 4H), 1.18 – 1.10 (m, 2H), 0.96 (s, 1H). 13C NMR (75 MHz,
Chloroform-d) δ 159.25 , 153.01 , 149.58 , 137.57 , 91.24 , 84.26 ,
78.71 , 51.18 , 50.36 , 36.09 , 32.01 , 30.94 , 29.08 , 28.65 , 28.29 ,
26.54 , 25.93 , 22.76 , 14.06 . HRMS (ESI) calculated for C21H35N3O4
[M+H]+: 393.26273; found: 394.2686.

126
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10 Curriculum Vitae

Prabhat Ranjan
Born in 1994 in Gorakhpur, India

Education
2017 – Present: Ph.D. in Organic Chemistry (Marie Curie fellow,
ITN Project COSMIC), KU Leuven, Leuven, Belgium).
Supervisor: Prof. Erik Van der Eycken, Laboratory of Organic and
Microwave-Assisted Chemistry (LOMAC), Department of Chemistry

Research Focus:
 Application of heterogeneous catalysis in organic synthesis under
batch and continuous-flow conditions.
 Photoredox functionalization of small heterocyclic molecules
under batch and continuous-flow conditions.
 January 2020: Visiting researcher in the framework of
COSMIC project at MAEM (Microwave Energy Application
and Management), Leuven, Belgium.
Supervisor: Dr. Vincent Goovaerts

Research Focus: Gram-scale three-component reactions under

microwave irradiation using a multimode microwave reactor
developed by MEAM.

 March 10th 2019 – May 12th 2019: Visiting researcher in the

framework of COSMIC project at the University of Turin, Italy.
Supervisors: Prof. Giancarlo Cravotto and Dr. Katia Martina,
Department of Science and Pharmaceutical Technology
Research Focus: Investigation of the combined effects of
ultrasounds and microwaves on alkyne cyclisation catalysed by
supported metal nanoparticles.

 April 9th 2018 – May 30th 2018: Visiting researcher in the

framework of COSMIC project at The University of Cordoba,
Spain
Supervisor: Prof. Rafael Luque, Department of Organic
Chemistry

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 Research Focus: Selective hydrogenation of triple bonds under
both microwave irradiation and continuous flow conditions using
nanoparticles related catalysts.
 2014-2016: M.Sc. in Chemistry (Specialization in Organic
Chemistry, 1st position out of 10 students) at Indian Institute of
Technology, Roorkee, India; CGPA 8.36/10.
Supervisor: Prof. K. R. Justin Thomas, Department of Chemistry
Research Focus: Synthesis of bi-polar tri/tetra substituted
carbazoles derivatives for OLED applications.
 2011-2014: B.Sc in Chemistry (Honours), Banaras Hindu
University, Uttar Pradesh, India; CGPA 7.86/10.

Publications and Conferences

 Ranjan, P.; Pillitteri, S.; Coppola, G.; Oliva, M.; Majnoni

d’Intignano, T.; Van der Eycken, E. V.; Sharma, U. K. Unlocking
the accessibility of alkyl radicals from boronic acids through
hydrogen-bond directed organophotoredox activation.
Manuscript in preparation, (Shared First Author)

 Manno, R.; Ranjan, P.; Sebastian, V.; Irusta, S.; Mallada, R.; Van
der Eycken, E. V.; Santamaria, J. One-Pot synthesis of supported
Ag nanoclusters by simultaneous cooling-microwave heating:
application alkynes cyclization. Manuscript in preparation,
(Shared First Author)

 Song, L.; Manno, R.; Ranjan, P.; Sebastian, V.; Irusta, S.;
Mallada, R.; Van Meervelt, L.; Santamaria, J.; Van der Eycken, E.
V. Preparation of Cu cluster catalysts by simultaneous cooling-
microwave heating: application in radical cascade annulation.
Nanoscale Adv., 2021, doi: 10.1039/D0NA00980F

 Chen, S.; Ranjan, P.; Voskressensky, L. G.; Van der Eycken,

E.V.; Sharma, U. K. Recent developments in transition-metal
catalyzed direct C–H alkenylation, alkylation, and alkynylation of
azoles. Molecules 2020, 25, 4970,
doi:10.3390/molecules25214970, (IF: 3.26).

 Sharma, U.K.; Ranjan. P.; Van der Eycken, E.V.; You, S.L.
Sequential and direct multicomponent reaction (MCR)-based

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 dearomatization strategies, Chem. Soc. Rev., 2020, Just accepted
10.1039/D0CS00128G (I.F: 42.84)

 Ranjan, P.; Pillitteri, S.; Van der Eycken, E.V.; Sharma, U. K.,
Photochemical methods for deuterium labelling of organic
molecules, Green Chem., 2020, just accepted doi:
10.1039/D0GC02901G, (IF: 9.48).

 Chen, S.; Ranjan, P.; Ramkumar, N.; Meervelt, L. Van; Van der
Eycken, E. V.; Sharma, U.K. Ligand enabled palladium–catalysed
through‐space C‐H bond activation via a carbopalladation/1,4‐Pd
migration/C‐H functionalization sequence. Chem. A Eur. J. 2020,
chem.202001582, doi:10.1002/chem.202001582. (IF: 4.85)

 Manno, R.; Ranjan, P.; Sebastian, V.; Mallada, R.; Irusta, S.;
Sharma, U.K.; Van der Eycken, E. V.; Santamaria, J. Continuous
microwave-assisted synthesis of silver nanoclusters confined in
mesoporous SBA-15: application in alkyne cyclizations. Chem.
Mater. 2020, 32, 2874–2883,
doi:10.1021/acs.chemmater.9b04935. (Shared First Author),
(IF: 9.56)

Journal Front cover Chemistry of material Issue 7, 2020.

 Zuliani, A.; Ranjan, P.; Luque, R.; Van der Eycken, E. V.

Heterogeneously catalyzed synthesis of imidazolones via
cycloisomerizations of propargylic ureas using Ag and Au/Al
SBA-15 systems, ACS Sustainable Chem. Eng. 2019, 7, 5568-
5575. (Shared First Author). (IF: 7.63) (Shared First Author)

 Ranjan, P.; Ojeda, G.M.; Sharma, U.K.; Van der Eycken, E. V.

Metal-free dearomatization: direct access to spiroindol(en)ines
in batch and continuous-flow. Chem. A Eur. J. 2019, 25, 2442–
2446, doi:10.1002/chem.201805945. (IF: 4.85)

Journal cover picture Chemistry-A European Journal Issue 10,

2019.

 Ojeda, G.M.; Ranjan, P.; Fedoseev, P.; Amable, L.; Sharma,

U.K.; Rivera, D.G.; Van Der Eycken, E. V. Combining the Ugi-
azide multicomponent reaction and rhodium(III)-catalyzed
annulation for the synthesis of tetrazole-isoquinolone/pyridone
hybrids. Beilstein J. Org. Chem. 2019, 15, 2447–2457,
doi:10.3762/bjoc.15.237. (IF: 2.53)

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 Conferences and Presentations
 December 2019: Ranjan, P.; Ojeda, G.M.; Sharma, U.K.; Van
der Eycken, E. V. Leaching stable phosphine‐based
heterogeneous catalyst for dearomatization: direct access to
spiroindol(en)ines from batch to continuous‐flow.
Oral Presentation at Merk Organic Chemistry Symposium,
Blankenberge, Belgium.

 May 2019: Ranjan, P.; Ojeda, G.M.; Sharma, U.K.; Van der
Eycken, E. V. Leaching stable phosphine‐based heterogeneous
catalyst for dearomatization: direct access to spiroindol(en)ines
from batch to continuous‐flow.
Oral Presentation at IPIC 2 (The Second International Process
Intensification Conference), Leuven, Belgium.

 December 2018: Ranjan, P.; Ojeda, G.M.; Sharma, U.K.; Van

der Eycken, E. V. Metal-Free Dearomatization: Direct access to
Spiroindol(en)ines in Batch and Continuous-Flow.
Poster Presentation at Merk Organic Chemistry
Symposium, Blankenberge, Belgium.

 July 2018: Participation in the 16th Belgian Organic

Synthesis Symposium.

 September 2017: Participation in the COSMIC Summer

School at KU Leuven, Belgium.
Topic: Ultrasound and Microwave for Chemical Processing -
Ultrasound and Microwave Technologies.

141
142
Figure 8: Journal front cover Chemistry of Materials.

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“For, each man can do best and excel in only that
thing of which he is passionately fond, in which he
believes, as I do, that he has the ability to do it, that
he is in fact born and destined to do it.”
Homi J Bhabha

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