Int. J. Pharm. Investigation, 2024; 14(4):1052-1060.

https://www.jpionline.org Review Article

Indole Moiety in Organic Synthesis: A Comprehensive

Review of Methods and Mechanisms
Akanksha Porwal, A Rajendiran*, Parwz Alam, Himanshu Singh, Kratika Singh, Ayush Dubey
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, CSJM University, Kanpur (Formerly Kanpur University, Kanpur),
Uttar Pradesh, INDIA.

Correspondence:
ABSTRACT Mr. A Rajendiran
The indole moiety, a prevalent and versatile heterocyclic scaffold, plays a pivotal role in the
Assistant Professor, Department of
realm of organic synthesis, underpinning the structural basis of myriad natural products,
Pharmaceutical Chemistry, School
pharmaceuticals and advanced materials. This review comprehensively surveys the landscape
of methodologies for indole synthesis, highlighting the evolution of techniques from classical to of Pharmaceutical Sciences, CSJM
contemporary strategies. We investigate the Fischer Indole Synthesis, emphasizing its historical University, Kanpur, Uttar Pradesh, INDIA.
significance and mechanistic nuances and transition to discussing the Reissert Indole Synthesis, Email: [email protected]
detailing its unique contributions to the synthesis of indole derivatives. Furthermore, the review
explores advanced methodologies including metal-catalyzed reactions, C-H activation processes Received: 10-05-2024;
and green synthesis approaches, offering insights into their mechanisms, scope and limitations. Revised: 28-05-2024;
Through this review, we aim to provide a holistic overview of indole synthesis, furnishing Accepted: 09-07-2024.
researchers with a detailed understanding of its complex mechanisms and the broad utility
of the indole moiety in synthesizing biologically active compounds. The synthesis methods
reviewed not only underscore the chemical diversity and adaptability of indole chemistry but
also highlight ongoing challenges and future directions in the synthesis and transformation of
derivatives of indole. This comprehensive examination serves as a valuable resource for chemists
seeking to harness the indole scaffold's potential in novel synthetic applications.

Keywords: Indole Moiety, Organic Synthesis, Fischer Indole Synthesis, Reissert Indole Synthesis,
Metal-Catalyzed Reactions, C-H Activation.

INTRODUCTION
The indole moiety (Figure 1), characterized by a fused pyrrole chemistry endeavors aimed at combating various diseases.3,4 This
and benzene ring system, stands as a cornerstone in organic comprehensive review aims to provide a resource for researchers
chemistry due to its ubiquity in natural products and synthetic in organic chemistry, aiding in the exploration of indole's
compounds. This foundational role is underscored by the indole's potential for future scientific breakthroughs.5
participation in a variety of bioactive molecules, including
alkaloids, hormones and pharmaceuticals, showcasing its Historical Overview
significance across medicinal chemistry, material science and Early Discoveries and Synthesis Methods
beyond. The indole structure's intrinsic reactivity and versatility
enable the synthesis of complex molecules, providing a scaffold The foundation of indole chemistry can be traced back to the
for innovative drug design and development.1,2 late 19th and early 20th centuries when initial methods focused
on the rudimentary construction of the indole nucleus. One of
The significance of the indole moiety extends into the realm the earliest recognized methods in indole synthesis, the Fischer
of synthetic organic chemistry, where it serves as a critical indole synthesis, established in the late 1880s by Emil Fischer,
foundational element for the structure of complex natural provided a groundbreaking pathway for synthesizing indoles
products and synthetic compounds. Notably, the indole from phenylhydrazines and ketones or aldehydes under acidic
nucleus's incorporation into compounds often imparts desirable conditions.9 After the Fischer synthesis, various methodologies
pharmacological properties, making it a target for medicinal emerged, expanding the toolbox for indole synthesis. The
Leimgruber-Batcho indole synthesis (Figure 2), developed in
DOI: 10.5530/ijpi.14.4.115 the mid-20th century, offered an alternative for synthesizing
N-substituted indoles, demonstrating the evolving complexity
Copyright Information :
and efficiency of indole formation techniques.6 Moreover, the
Copyright Author (s) 2024 Distributed under
Creative Commons CC-BY 4.0
development of the Baeyer-Jackson method (Figure 3) and the
application of reductive cyclization processes further diversified
Publishing Partner : EManuscript Tech. [www.emanuscript.in]

1052 International Journal of Pharmaceutical Investigation, Vol 14, Issue 4, Oct-Dec, 2024
 Porwal, et al.: Indole Moiety in Organic Synthesis

the approaches towards indole synthesis, enabling the creation of efficient and versatile synthesis of substituted indole derivatives
a vast array of indole derivatives with varying substitutions.7 with unique substitution profiles.11
Throughout the 20th century and into the 21st, the exploration of Synthesis Methods
indole chemistry has continued to flourish, with newer methods
Fischer Indole Synthesis
such as C-H activation and functionalization directing the
forefront of indole synthesis research.8 These modern approaches The Fischer Indole Synthesis (Figure 4) stands as a pivotal
highlight the ongoing innovation within the field, emphasizing methodology within organic chemistry, offering a straightforward
regioselective and environmentally conscious strategies that route for the construction of indoles, a core structure found in
enhance the combination of complex derivatives of indole. many biologically active compounds and natural products. This
Today, the synthesis of indoles encompasses a wide spectrum of synthesis process, named after Emil Fischer who developed it in
methodologies, reflecting over a century of scientific inquiry and 1883, involves the cyclization of phenylhydrazines and ketones or
development aimed at harnessing the indole structure's intrinsic aldehydes under acidic conditions to yield indoles. This approach
reactivity and versatility for applications across medicinal has been fundamental in the synthesis of various complex indole
chemistry, material science and beyond. derivatives, showcasing its versatility and significance in synthetic
organic chemistry.9,12
Evolution of Indole Synthesis Techniques
Initially, the Fischer indole synthesis served as the cornerstone Over the years, the Fischer Indole Synthesis has evolved,
for indole formation, utilizing phenylhydrazines and ketones incorporating new insights into its mechanism and extending
or aldehydes under acidic conditions. This method laid the its application through the development of novel reaction paths
groundwork for the synthetic exploration of indoles, highlighting and conditions. Studies have focused on understanding the
their potential in organic synthesis.9 In recent years, the cyclization process in greater depth, leading to advancements
focus has shifted towards developing more sustainable and in the regioselective synthesis of indoles and enhancing the
efficient synthesis methods. Furthermore, modern synthesis efficiency and yield of these reactions.12 The introduction
techniques now employ catalytic systems and C-H activation/ of three-component coupling processes and the use of
functionalization-based methods, offering advancements in environmentally friendly catalysts and solvents have further
regioselective synthesis of functionalized indoles.8 These methods expanded the scope of this synthesis, enabling the creation of a
underscore the importance of indoles in pharmaceuticals, wide array of indole derivatives with diverse functional groups
demonstrating their versatility across various fields.10 Moreover, and biological activities.13,14
the development of modular strategies for constructing highly
strained tetracyclic structures showcases the potential for
Reissert indole synthesis
Reissert indole synthesis (Figure 5) is a well-regarded method
in the domain of organic chemistry for the construction of
indoles, which are crucial structures in many biologically active
molecules. This synthesis technique, alongside others, has
evolved significantly over the years, offering efficient routes to
various indole derivatives. For instance, methods such as the
Reissert-type reaction, which is catalyzed by chiral phosphoric
acid, have improved the synthesis and functionalization of
indoles., which affords enantioenriched indoles with strong
yields and elevated enantioselectivities under mild conditions.15
Figure 1: Structure of indole moiety.
Furthermore, a contemporary method involving continuous-flow

Figure 2: Leimgruber-Batcho Indole Synthesis (mid-20th century).

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 Porwal, et al.: Indole Moiety in Organic Synthesis

hydrogenation has been developed for the synthesis of substituted 3,3'-bis-indolylmethanes, highlighting its significant impact on
indole-2-carboxylic acid ethyl esters and aza-indole analogs, organic synthesis and medicinal chemistry.18
demonstrating the adaptability and progression of Reissert indole
synthesis in facilitating the preparation of indole derivatives Madelung synthesis
efficiently.16 Madelung synthesis (Figure 7) stands for synthesizing indole
derivatives, which are foundational structures in numerous
Bartoli indole synthesis natural products and pharmaceuticals. This synthesis process
Bartoli indole synthesis (Figure 6), named after its discoverer, involves a sequence of steps starting from ortho-substituted
offers a direct and versatile pathway to synthesize 7-substituted nitrobenzenes, leveraging reductive cyclizations to forge indole
indoles, which are challenging to obtain through classical indole cores efficiently. Notably, the process has been adapted to
synthesis methods. This approach employs vinyl magnesium solid-phase synthesis, enabling the generation of 2,3-substituted
halides and ortho-substituted nitroarenes, showcasing its indoles directly from resin-bound intermediates, showcasing
adaptability not only to heteroaromatic nitro derivatives but also the method's versatility and applicability in modern synthetic
to solid support applications, enhancing its utility in complex strategies.19 Additionally, a novel approach for synthesizing
molecule construction. For instance, the synthesis on solid 2,5-disubstituted-3-cyanoindoles demonstrates the Madelung
supports has been realized starting from Merrifield resin, leading synthesis' adaptability and potential in accessing structurally
to substituted methyl indole carboxylates with excellent purities, diverse indole scaffolds, previously challenging to achieve.20
demonstrating the method's compatibility with various functional
groups and the potential for streamlined synthetic processes.17 Larock indole synthesis
Furthermore, the synthesis's flexibility is evident in its application Larock indole synthesis (Figure 8) is an innovative method in
across different indole derivatives, including the construction of organic chemistry for creating indole derivatives, a cornerstone

Figure 3: Baeyer-Jackson Method and Reductive Cyclization.

Figure 4: Fischer Indole Synthesis (late 1880s).

Figure 5: Reissert indole synthesis.

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 Porwal, et al.: Indole Moiety in Organic Synthesis

structure in numerous biological compounds. Developed to reactions. This integration has significantly enriched strategies
address the need for a versatile synthesis approach, it uses for constructing diverse heterocyclic structures.23 Similarly, the
palladium catalysis to fuse 2-iodoaniline with internal alkynes, addition of nitrenes and carbenes to C-H bonds, catalyzed by
thus producing indoles with varying substitution patterns. The transition metals, has emerged as a robust method for forming
process distinguishes itself by its ability to handle a wide range C-C and C-N bonds, streamlining the synthesis of complex
of functional groups, showcasing its adaptability and efficiency.21 natural products through improved efficiency and selectivity.24
This method opens up avenues for synthesizing complex indolic
Mechanistic Insights
structures, such as tricyclic indoles, through intramolecular
reactions, demonstrating the broad applicability of the Larock Mechanisms of Classical Synthesis Methods
synthesis in crafting biologically relevant molecules.22
The classical methods of mechanism synthesis have been a
cornerstone in the development of complex mechanical systems,
Transition metal-catalyzed reactions
focusing on guiding movements and optimizing function through
Transition metal-catalyzed reactions have revolutionized precise design. These methods, incorporating principles from
the synthesis of heterocycles, enabling more efficient and kinematics and dynamics, allow for the creation of mechanisms
versatile pathways. The combination of multi-component that perform specific tasks with high efficiency. The synthesis of
reactions with transition metal catalysis has expanded the mechanisms, particularly for guiding or transforming motion,
repertoire of heterocyclic syntheses, traditionally dominated relies on understanding the physical principles that govern the
by classical carbonyl chemistry, to include processes that behavior of mechanical components under various conditions.
utilize organometallic catalysis for both domino and sequential For instance, the synthesis of guidance mechanisms involves

Figure 6: Reissert indole synthesis.

Figure 7: Madelung synthesis.

Figure 8: Larock indole synthesis.

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 Porwal, et al.: Indole Moiety in Organic Synthesis

Figure 9: C-2 Functionalization.

determining the optimal configuration of components to guide a of heterocyclic compounds through Vicarious Nucleophilic
point along a predetermined path, which can be achieved through Substitution (VNS), demonstrating their versatility and
the application of genetic algorithms or evolutionary techniques significance in synthetic chemistry.30 Understanding the
to find the most effective solutions.25,26 stereochemistry and factors affecting these substitutions is crucial
for designing efficient synthetic routes in organic synthesis.31
Catalytic Cycles in Transition Metal-Catalyzed
Syntheses Rearrangements and Ring-Closure Mechanisms
Catalytic cycles in transition metal-catalyzed syntheses play Rearrangements and ring-closure mechanisms play a crucial role
a pivotal role in modern organic chemistry, enabling the in organic synthesis, offering pathways to intricate structures
transformation of simple molecules into complex structures from simpler precursors. For instance, the transition from
through a series of well-orchestrated steps. These cycles often (3Z,5Z)-octa-1,3,5,7-tetraene to (1Z,3Z,5Z)-cycloocta-1,3,
involve the formation and cleavage of bonds in a manner that 5-triene showcases a ring-closure process where the Localization
is both efficient and selective. For example, Transition metal function of electrons and catastrophe theory highlight the
catalysis in multi-component heterocyclic synthesis has expanded mechanistic pathways, revealing bond formation and electron
the toolbox of chemists, enabling novel transformations that pair rearrangements.32 Similarly, Ring-Arrangement Metathesis
proceed through intricate catalytic cycles involving palladium, (RRM) emerges as a powerful synthetic method, combining
rhodium, ruthenium and copper catalysts.23 Moreover, transition metathesis transformations into a domino process for constructing
metal-catalyzed C-H amination reactions represent another complex structures through the interplay of ring-opening and
fascinating area where catalytic cycles facilitate the direct ring-closing metathesis.33
transformation of C-H bonds into C-N bonds, showcasing the
power of metals such as palladium in driving these transformations Functionalization of the Indole Ring
through specific mechanistic pathways.27 C-2 and C-3 Functionalization

Nucleophilic and Electrophilic Substitution Functionalization of the indole ring at the C-2 and C-3 positions
Mechanisms is pivotal in the synthesis of complex molecular structures.
The selective functionalization of these positions enables
Nucleophilic and electrophilic substitution mechanisms are
the creation of several different indole derivatives, thereby
fundamental in organic chemistry, driving the transformation
expanding the utility of indoles in medicinal chemistry. For C-2
of molecules through the replacement of atoms or groups
functionalization (Figure 9), a noteworthy method involves the Fe
by nucleophiles or electrophiles, respectively. Nucleophilic
(II)-catalyzed amination of aromatic C-H bonds via ring opening
substitution reactions involve a nucleophile, an electron-rich
of 2H-azirines, leading to the synthesis of 2,3-disubstituted
species, attacking an electrophilic center leading to the
indoles.34 Similarly, Two-vinylated indoles are produced when
displacement of a leaving group. This mechanism is prominent
indole-3-carboxylic acids are oxidatively vinylated with alkenes
in aliphatic compounds, where the type of mechanism (e.g., SN1
by palladium-catalyzed directed C-H functionalization and
or SN2 ) varies based on factors like the structure of the substrate,
decarboxylation.35 Another innovative approach includes the
the strength of the nucleophile and the solvent.28 Electrophilic
rhodium-catalyzed technique that demonstrates the wider range
substitution, on the other hand, typically occurs in aromatic
of functionalization beyond C-2 and C-3 sites for direct C-H
systems where the aromatic ring acts as a nucleophile, attacking
functionalization at the C4 position of unprotected indoles.36
an electrophile, leading to the substitution of a hydrogen atom
while preserving the aromaticity of the ring.29 These substitution For C-3 functionalization, cobalt(III)-catalyzed site-selective
reactions are not just limited to simple transformations but C-H alkynylation using hypervalent iodine-alkyne reagents
extend to complex organic syntheses, including the formation exemplifies the diverse functional group tolerance and provides

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 Porwal, et al.: Indole Moiety in Organic Synthesis

an efficient procedure for creating C-2 alkynylated indoles.37 limitations of traditional metal-catalyzed carbene transfer, which
Additionally, a Ru (II)-catalyzed C-H activation strategy allows typically requires N-protected indoles.43
for the addition of maleimide selectively to indole at the C-2
location, further demonstrating the ability to selectively target Selective Halogenation, Nitration and Sulfonation
indole's reactive sites.38 For selective halogenation (Figure 11), a controlled α-mono-
and α,α-di-halogenation of alkyl sulfones can be attained by
N-1 Functionalization employing Electrophilic Halogenation with Base Mediation,
N-1 functionalization of indoles (Figure 10) represents a highlighting the importance of solvent-electrophile interactions
significant area in synthetic chemistry, enabling the creation of for product control.44 Similarly, the palladium-catalyzed oxidative
diverse indole derivatives with varied biological activities. This C-H halogenation of S-unprotected sulfides, directed by pyridinyl
process involves the modification of the indole scaffold at the groups, prevents sulfur oxidation while forming C-X bonds,
nitrogen atom, which can significantly alter the chemical and demonstrating a method for synthesizing sulfanyl polyhalides
and polyaromatics with high selectivity.45
pharmacological properties of indole-based compounds.
In the realm of nitration, the halogen-directing effects in the
For instance, palladium-catalyzed reactions have become
sulfonation of halogens-toluenes reveal that halogen substituents
indispensable tools for the synthesis and functionalization of
predominantly direct the nitration to the para position over the
indoles, offering routes to a wide array of biologically active
methyl substituent, showcasing the subtle interplay of electronic
compounds. The versatility of palladium catalysis, tolerant of
effects in determining nitration patterns.46
various functionalities, makes it ideal for complex molecule
synthesis, including indole derivatization at the N-1 position.39 For sulfonation, the direct sulfonation of aromatic hydrocarbons
Similarly, N-alkoxycarbamoyl indoles' functionalization via and their halogen derivatives using various sulfur reagents is a
transition metal catalysis has been explored, with N-methoxy/ more straightforward approach than indirect methods. This
ethoxy/pivaloxy amide groups serving as effective directing method is pivotal for introducing sulfonic acid, sulfonyl chloride
groups for site-selective inert C-H functionalization, thereby and sulfonyl fluoride groups into aromatic systems, showing
enabling the synthesis of polycyclic indole frameworks.40 broad applicability and convenience.47

Moreover, the creation of metal-free conditions for the Applications in Organic Synthesis
functionalization of indoles, such as the bromo-amination via Natural Product Synthesis
1,3-migration of imides on indolyl(phenyl)iodonium imides,
underscores the growing interest in employing hypervalent The indole moiety, a prominent and structurally significant
iodine(III) for regioselective dual functionalization of C(sp2)-H.41 component, plays a crucial role in the process of creating natural
Additionally, the PIDA-driven oxidation C-C bond formation items, particularly alkaloids. This two-cycle arrangement,
from N-aryl enamines offers a straightforward approach to composed of a benzene ring fused to a pyrrole ring, is foundational
synthesizing functionalized indoles, demonstrating excellent in a myriad of bioactive compounds and pharmaceuticals. One
resistance to functional groups and low reaction temperatures.42 of the most classical and still relevant methods for synthesizing
indoles is the Fischer Indole Synthesis (FIS), which has been
Biocatalysis also provides a fresh avenue for the C-H widely utilized throughout the whole process of creating natural
functionalization directly of unprotected indoles, enabling products. This method illustrates the enduring value of FIS in
the synthesis of C3-functionalized derivatives. This approach, generating indole rings that form the core of many alkaloids and
utilizing engineered variants of myoglobin, bypasses the other biologically active compounds.48

Figure 10: N-1 Functionalization (Vilsmeier-Haack reaction with indole).

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 Porwal, et al.: Indole Moiety in Organic Synthesis

Figure 11: Selective Halogenation, Nitration and Sulfonation.

Furthermore, palladium-catalyzed reactions have become an Indole derivatives exhibit a broad spectrum of biological
effective synthesis technique. and functionalization of indoles. activity, such as antioxidant, antibacterial, antitubercular,
These methods have been instrumental in constructing the indole antiviral, anti-inflammatory, anticancer, anti-HIV, antidiabetic,
nucleus of many natural products, demonstrating the critical antimalarial and anticholinesterase properties. This wide range of
Palladium's involvement in catalysis in the modern synthesis activities has fueled research into synthesizing a variety of indole
of complex molecules.49 Recent advances have also showcased derivatives, driven by their significant therapeutic potential and
the synthesis of indole derivatives through green approaches, the pursuit of novel treatments for diverse medical conditions.52
emphasizing the importance of sustainable methodologies in
The importance of indole derivatives in the pharmaceutical
the construction of indole-based compounds. These methods
landscape is further highlighted by their role in Central Nervous
highlight the ongoing innovations in indole synthesis, contributing
System (CNS) disorders. Several marketed drugs for CNS
to the development of pharmaceuticals and the exploration
disorders, such as binedaline, amedalin, pindolol, siramesine and
of new biological activities.50 Indoles are also key scaffolds in
oxypertine, feature the indole moiety. This focus on CNS-active
multicomponent reactions, a testament to their utility in creating
indole derivatives emphasizes their critical role in addressing
diverse heterocyclic compounds. This approach has facilitated the
mental health conditions and neurological disorders, providing
design of novel polycyclic structures by incorporating multiple
a foundation for future drug development efforts targeting the
fused heterocyclic scaffolds, thereby expanding the chemical and
CNS.53
biomedical relevance of indole derivatives.51
Moreover, the medicinal significance of indoles is evident in the
Pharmaceutical Applications Structure-Activity Relationship (SAR) studies of various indole
Indole derivatives hold a pivotal position in pharmaceutical analogs, which have led to the discovery of new drug candidates to
chemistry because they engage in a variety of biological activities, address pharmacological conditions. Indole-derived compounds
making them essential components in the development of like vincristine (anticancer), reserpine (antihypertensive)
therapeutic agents. The versatility of the indole moiety allows and amedalin (antidepressant) exemplify the medicinal and
for its incorporation into a myriad of pharmacologically active pharmacological importance of the indole nucleus in improving
molecules targeting various diseases, including cancer, viral human health.54
infections, psychiatric disorders, hypertension, migraines,
arthritis and pain management. DISCUSSION
New advances in the production of derivatives of indole through The indole moiety, with its distinct bicyclic structure made out
green methodologies have further enhanced their pharmaceutical of a fused benzene ring to a pyrrole ring, occupies a venerable
applicability. These green approaches offer advantages such as position in the realm of organic synthesis. Its ubiquity in a vast
high yields, short reaction times, cost-effectiveness, efficiency array of natural products, pharmaceuticals and materials science
and environmental friendliness, addressing the limitations underscores its importance. Recent advances in indole chemistry
of conventional synthetic methods. The shift towards green have significantly expanded the toolbox for synthetic chemists,
chemistry underscores the commitment to sustainable practices enabling the construction of complex indole architectures with
in drug development and highlights the ongoing innovations in unprecedented efficiency and selectivity. This discussion delves
the synthesis of indole-based pharmaceuticals.50 into these advancements, spotlighting novel methodologies,

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 Porwal, et al.: Indole Moiety in Organic Synthesis

mechanistic insights and the burgeoning application of indoles in encompassed the historical significance and mechanistic
drug synthesis.55 intricacies of the Fischer Indole Synthesis and the unique
contributions of the Reissert Indole Synthesis to indole
Recent developments in Multicomponent Reactions (MCRs)
derivative synthesis. Moreover, advanced methodologies such
have unveiled new vistas for the synthesis of indole derivatives,
as metal-catalyzed reactions, C-H activation processes and
illuminating the path toward complex heterocyclic structures
green synthesis approaches were examined, shedding light on
with significant biological and pharmaceutical potential. The
their mechanisms, applicability and limitations. By offering a
integration of indoles in MCRs allows for the design of polycyclic
comprehensive overview, this review aims to equip researchers
molecules by incorporating multiple fused heterocyclic scaffolds,
with a profound comprehension of the complex mechanisms
aiming to yield new compounds of chemical and biomedical
underlying indole synthesis and the broad utility of indole moiety
relevance.51 Furthermore, the exploration of new synthetic
in creating biologically active compounds.
pathways, including contemporary iterations of traditional
syntheses, such as the Fischer, Nenitzescu and Reissert syntheses, ACKNOWLEDGEMENT
alongside novel approaches involving heterocycle conversions,
synthesis from o-alkynyl anilines and N-heterocyclic carbene We sincerely acknowledge the Honorable Vice-Chancellor of
catalysis, reflects the dynamic nature of indole synthesis research.58 CSJM University, Kanpur for the resources and substantial
support.
The advent of palladium-catalyzed reactions has marked a
significant milestone in indole chemistry, offering a flexible CONFLICT OF INTEREST
platform for the synthesis and functionalization of indoles. These
methodologies, known for their wide tolerance of functionalities, The authors declare that there is no conflict of interest.
facilitate the elaboration of complex molecules, thereby
ABBREVIATIONS
revolutionizing traditional synthetic strategies and significantly
reducing waste.49 Additionally, the utilization of chemistry of flow THF: Tetrahydrofuran; BuLi: Butyllithium; H3O+: Hydronium
in the synthesis of indole derivatives exemplifies the shift towards ion; Pd(OAc)2: Palladium (II) acetate; VNS: Vicarious Nucleophilic
more sustainable and efficient processes. Flow technology, Substitution; RRM: Ring-Rearrangement Metathesis; FeCl3: Iron
by enhancing reaction rates and selectivities, has become an (III) chloride; DMF: Dimethylformamide; POCl3: Phosphoryl
effective instrument. in the synthesis of pharmaceutically relevant chloride; PIDA: Phenyliodine(III)diacetate; FIS: Fischer
indoles.56 Indole Synthesis; SAR: Structure-Activity Relationship; MCRs:
Multicomponent Reactions.
The synthesis of indoles catalyzed by transition metals such
as copper, ruthenium, rhodium, palladium, or gold has been
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Cite this article: Porwal A, Rajendiran A, Alam P, Singh H, Singh K, Dubey A. Indole Moiety in Organic Synthesis: A Comprehensive Review of Methods and
Mechanisms. Int. J. Pharm. Investigation. 2024;14(4):1052-60.

1060 International Journal of Pharmaceutical Investigation, Vol 14, Issue 4, Oct-Dec, 2024