Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.1 Introduction
A cyclic organic compound containing all carbon atoms in ring
formation is referred to as a carbocyclic compound. If at least one atom other
than carbon forms a part of the ring system then it is designated as a
heterocyclic compound [1]. Generally nitrogen, oxygen and sulphur are known
to be the part of heterocyclic ring. Out of the known approximately 20 million
compounds, almost half are heterocyclic. From biological, industrial point of
view as well as in the improvement of quality of life and life process, the
contribution of heterocyclic compounds is significant. Wide variety of drugs,
biologically active compounds having antitumor, antibiotic, anti-inflammatory,
antidepressant, antiviral, antimalarial, anti-HIV, antimicrobial, antibacterial,
antifungal, antidiabetic, herbicidal, fungicidal, and insecticidal agents are
known to have heterocyclic ring in their structures. Beside this, innumerable
additives and modifiers used in industrial applications ranging from cosmetics,
plastics are heterocyclic in nature. An overview on life process signify that the
chemical structures of deoxyribonucleic acid (DNA), ribonucleic acid (RNA)
[Fig.1.1], chlorophyll [Fig. 1.2], vitamins like Thiamine B1, Riboflavin B2,
Nicotinamide B3, Pyridoxol B6, Ascorbic acid (Vitamin C) comprise of
heterocyclic molecules.

(1) (2)
Fig. 1.1: Chemical structure of DNA (1) and RNA (2).

1
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

N
- ++ -
N Mg N

O N

O O

O (3)
OH

Fig. 1.2: Chemical structure of chlorophyll.

Among these, heterocycles with nitrogen as heteroatom arrest the

attention of research community due to their outstanding applications [2].
Antipyrine (4) discovered in 1887 was the first synthetic drug used for
reduction of fevers. In 1938, sulfapyridine (5) was introduced as an effective
antibiotic. Sumatriptan (6) was the first antimigrain drug while omeprazole (7)
possess gastric antisecretary and consequently anti-ulcerative activity [Fig.
1.3].

O O
N S
NH
N
H2 N
O
(5)
(4)
O
N O N
NH S H
O N
O CF 3
N
N
H
(6) (7)

Fig. 1.3: Nitrogen containing heterocycles as drug molecules.

Amongst nitrogen containing heterocycles, Indole and its derivatives are

well studied and documented heterocyclic compounds.

2
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.2 Indole
Indole chemistry began to develop with the study of the dye indigo. The
word Indole is coined from the word India, a blue dye imported from India
known as Indigo. The name indole is a blend of the words indigo and oleum,
since indole was first isolated by treatment of the indigo dye with oleum.
Indole is a benzopyrrole in which the benzene and pyrrole rings are fused at the
2-and 3-positions of the pyrrole nucleus. The Indole nucleus [Fig. 1.4] has ten
pi electrons which are circulating over nine atoms. So, Indole is electron rich
system. It‘s resonance energy is 47-49 K cal/mole. The electrons on nitrogen
are involved in aromatic sextet; hence it is very weak base with pKa value -3.5
[3].

N
H

(8)
Fig. 1.4: Indole

Principally, indole (9) was extracted from coal tar and first obtained by
Adolf Baeyer [4] by the pyrolysis of oxindole (10) with zinc dust in 1886.
Oxindole was obtained from the reduction of isatin was obtained from
oxidizing the natural insoluble dark blue dye called indigo [Scheme1.1].

3
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

H O O
N Oxidation
O
N N
O H H

Reduction

Pyrolysis
O
N N
H H

(9) (10)

Scheme1.1: Preparation of Indole from Indigo.

Physical Properties
1) Molecular Formula : C8H7N
2) Molar mass : 117.15 g/mol
3) Appearance : White solid
4) Melting point : 52-540C, 325-327K.
5) Boiling point : 253-2540C, 526-527K.
6) Solubility in Water : 0.19 g/100 ml (200C)
The protonation of indole requires strong acidic condition due to its
weak basic nature. The protonation of indole offers three possible cations. Out
of the three cations, (11b) is thermodynamically most stable whereas (11a) is
kinetically favorable [Fig.1.5].

H
H

+ + + H
N N N H
H H H H

(11a) (11b) (11c)

Fig.1.5: Cationic forms of Indole

4
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.3 Synthesis of indole

Over the past few years, the vast abundance of indole ranging from
lysergic acid to vincristine have enthused organic synthetic chemists to develop
new methods for its synthesis. These new methods have been reported across
the literature and reviews [5]. Taber et al, [6] reviewed the synthesis of indole
and proposed nine strategies for indole construction [Fig.1.6].
H

X NH
Type 1
NH Fischer
Type 2
Type 9
Mori
Kanematsu

NH2 N
H
H
Type 3
Type 8
Hemetsberger N
H van Leusen

NH2 O
X Type 7
Type 4
Nenitzescu
Buchwald

NH2 NH
Type 5 Type 6

Sundberg Madelung

Fig.1.6: Strategies for construction of indole.

These strategies cover all significant contribution of researcher in the

synthesis of indole. There are several name reactions associated with indole
synthesis. Amongst these several name reactions, very few are discussed along
with the modern synthetic routes.

1.3.1 Fischer Indole synthesis

In 1883, Fischer Indole synthesis was introduced which is still the most
adaptable method for preparing indoles currently [7]. This reaction was

5
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

discovered by Hermann Emil Fischer. This method involves heating phenyl

hydrazine with aldehyde or ketone in acidic condition, forming phenyl
hydrazone which subsequently rearranges with the loss of ammonia to give
indole or 2- and 3-substituted indoles (12) [Scheme 1.2].

1
R
1
R
+
H 2

NH
NH2
+ O R
2
N
R

H
(12)

Scheme 1.2: Fischer Indole synthesis

1.3.2 Bartoli indole synthesis

In Bartoli indole synthesis [8], substituted indoles (13) are obtained by
the reaction of ortho-substituted nitroarenes with vinyl Grignard reagents. In
absence of ortho substitution on nitro arene, reaction fails [Scheme 1.3].

2
R 3
R 3
R
BrMg
0 2
THF, -40 C R
NO2 aq. NH4Cl N
1 1 H
R R
(13)

Scheme 1.3: Bartoli indole synthesis.

1.3.3 Bischler Synthesis

In 1892, Bischler et al, put forwarded a simple method affording a 2-
aryl-indole (14) from an α-bromo-acetophenone and excess aniline [9] [Scheme
1.4].

6
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

O
NH2 HBr
Br

NH2
+ N
H
(14)

Scheme 1.4: Synthesis of 2-aryl indole from α-bromo-acetophenone and excess

aniline

1.3.4 Reissert synthesis

Reissert [10] reported the synthesis of indole (15) from ortho-
nitrotoluene and diethyl oxalate in 1897 [Scheme 1.5]

EtO O O
OEt

Zn O
O OEt Heat
AcOH -CO 2
NO 2 NO 2 N OH N
H H
(12)

Scheme 1.5: Reissert synthesis of indole.

1.3.5 Leimgruber–Batcho Synthesis

Leimgruber et al, [11] investigated the synthesis of indole (16) from o-
nitrotoluenes. In the first step, enamine is generated using N,N-dimethyl
formamide dimethyl acetal and pyrrolidine which upon reductive cyclisation
afforded indole in the subsequent step [Scheme 1.6].

MeO
N
MeO N Raney Ni
R R R
NO 2 NO 2 N
H
N (12)
H

Scheme 1.6: Leimgruber–Batchosynthesis of indole.

7
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.3.6 Sakai synthesis

N. Sakai et al, [12] have synthesized various indole derivatives (17) via
indium-catalyzed cyclisation of 2-ethynylanilines in good yields [Scheme 1.7].

3
R
5 mol % InBr3
1 3
R R R
NH toluene, reflux 5-20 h N
2 2
R R
(13)
Scheme 1.7: Indium catalyzed synthesis of indole.

1.3.7 Zhu et al synthesis

A mild preparation of substituted indole (18) from simple aromatic
precursors using (trimethylsilyl) diazomethane was reported by L. Zhu et al,
[13] [Scheme 1.8].
O

TMSCHN2 , CS2 CO3

H

NH2 0 N
MeOH, 60 C
H
(14)

Scheme 1.8: Synthesis of indole from 2-amino benzaldehyde.

1.3.8 Sridharan et al synthesis

V. Sridharan et al, [14] have synthesized microwave assisted 2-
arylindoles (19) in good yields [Scheme 1.9].

Ar
O Ar
Microwave

NH DMF N
H
(15)

Scheme 1.9: Microwave assisted synthesis of indole.

8
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.4 Reactivity of Indole

Most commonly, indole undergoes electrophilic substitution mainly at
position 3 of the nucleus. When position 3 of the indole nucleus is occupied by
substituents other than hydrogen, position 2 is the most reactive one and when
positions 2 and 3 are occupied, the electrophile occupies a position in the
benzene ring [15] [Scheme 1.10].

+
E
E

N N
H H

X X

E
+
N E N
H H

Scheme 1.10: Electrophilic substitution in indole.

Indole itself is π-electron excessive system. Therefore, it undergoes

electrophilic substitution reaction. Generally, electrophilic substitution reaction
takes place at position 3 rather than position 2. The attack of electrophile at
position 3 generates carbocation which do not disturb the aromaticity of
benzene ring whereas attack of electrophile at position 2 generates carbocation
which disrupt the aromatic character by delocalizing the positive charge over
benzene ring. It also undergoes nucleophilic substitution reaction [16] as per
[Scheme 1.11 and 1.12].

Electrophilic substitution reactions (ESRs)

• Nitration of indole
• Halogenation of indole
• Sulphonation of indole
• Mannich reaction

9
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

SO 3 H

N
H

Indole-3-sulphonic acid

Suphonation pyridine sulfaonate

NO 2
Br
Halogenation Nitration

Br 2 , CH 3 COOH N N
N CH 3 COONO 2 H
H H

3-bromo indole 3-nitro indole

HCHO, Mannich Reaction
NH(CH 3 ) 2

N
H
Gramine

Scheme1.11: Electrophilic substitution reactions of indole.

Nucleophilic substitution reaction

n-BuLi i) CO 2
Li + COOH
N ether ii) H N
N

Scheme1.12: Nucleophilic substitution reaction of indole.

10
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.5 Significance of Indole and its derivatives

Indole and its derivatives have occupied an inimitable place in the
chemistry of nitrogen heterocyclic compounds. From simple derivatives to
complex alkaloids, Indole is found in an immensely varied range of
biologically significant natural products and showed numerous biological
activities [Fig. 1.7].

1.5.1 Biological Applications

Fig. 1.7: Bio-efficiency of indole derivatives.

Deokar et al, [17] have synthesized novel oxadiazino (20) as well as

thiadiazino-indole (21) of 2-oxo-2H-benzopyran and evaluated for their
antimicrobial activities against the bacteria Staphylococcus aureus, Salmonella
typhi, Escherichiacoli and two fungal species Candida albicans, Aspergillus
niger [Fig. 1.8].

O O
N N N N
1 O
1 O R
R O S
NH 2
2 R NH
R
3
3 R (21)
R (20)

Fig. 1.8: Indole derivatives with antimicrobial activity.

11
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

The synthesis and anti-inflammatory, anticonvulsant screening of 1,8-

dihydro-1-aryl-8-alkyl pyrazolo(3,4-b)indoles (22) has been carried out by
Mandour et al, [18] [Fig 1.9].

N
N X
N
R

(22)

Fig. 1.9: Indole derivatives with antimicrobial activity.

Andreani et al, [19] have reported the synthesis of bis indole type
compounds having pyridine or piperazine ring in between two indole rings and
evaluated for antitumor activity in the human cell line screen. The results
showed that pyridine derivatives (23) were far more active than the piperazine
derivatives (24) [Fig 1.10].

H O
R R N
O O H
N N R
N O

3 N 3
R R O N
1 1 R H
2 R R 2
R R O N
H

(23) (24)

Fig. 1.10: Antitumor active bis-indole bearing pyridine and piperazine ring.

Giampieri et al, [20] have prepared unsymmetrical methylene

derivatives (25) via the reaction of the Mannich bases of 2-naphthols with
indoles and tested against a wide panel of viruses [Fig 1.11].

12
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

H
N
X
Y

1
R
OCOCH 3

R
(25)

Fig. 1.11: Unsymmetrical methylene derivatives with anti-viral activity.

The benzopyranyl indoline and indole analogs (26) are found to have
cardioselective anti-ischemic ATP-sensitive potassium channel (KATP) opener
activity [21] [Fig 1.12].

COOR
N
OH
O2 N
O
O
O

(26)

Fig. 1.12: Compound with cardiovascular activity.

Molecular modeling and 3-D QSAR studies led to the discovery of

exceptionally potent indolyl aryl sulfones (IASs) (27a, 27b) characterized by
the presence of either a pyrrolidyn-2-one nucleus at indole-2-carboxamide or
some substituents at indole-2-carbohydrazide [22] [Fig 1.13].

O Y
O NH
O N NH
NH O
NH
NH
SO2
SO 2

Cl X
Cl X

(27a) (27b)

Fig. 1.13: Compound acting as anti-HIV agents.

13
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

Hong et al [23] have reported the anticancer activity of various tricyclic

and tetracyclic indoles (28) and (29) against human nasopharyngeal carcinoma
(HONE-1) and gastric adenocarcinoma (NUGC-3) cell lines [Fig 1.14].

OH
OH
H2N

N
N
H
H OCH 3
(28) (29)

Fig. 1.14: Anticancer active indole derivatives.

A new series of gallic hydrazones containing an indole moiety (30) was

synthesized by Khaledi et al, [24] through the reaction of gallic hydrazide and
different indole carboxaldehydes. Their antioxidant activities were determined
on DPPH radical scavenging and inhibition of lipid peroxidation. The in-vitro
cytotoxic activities of the compounds were evaluated against HCT-116 (human
colon cancer cell line) and MCF-7 (estrogen dependent human breast cancer
cell line) by the MTT method [Fig 1.15].

O
NH
N
X
R OH
N
HO OH
R1
(30)

Fig. 1.15: Indole derivatives with antioxidant activity.

1.5.2 Medicinal applications

Serotonin (5-hydroxytryptamine) (31) is a monoamine neurotransmitter

[25]. It is mainly found in the gastrointestinal tract (GI tract), blood platelets,
and the central nervous system (CNS) of animals and humans. It adds
happiness [Fig 1.16].

14
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

NH2

HO

N
H
(31)

Fig. 1.16: Serotonin

Vinblastine (32) is used to treat a different types of cancer like

Hodgkin's lymphoma, testicular cancer, non-small cell lung cancer, bladder
cancer and brain cancer [26] [Fig 1.17].

N
HO
H
N
H
N HO O O
H
O
O O N H O
O
(32)

Fig. 1.17: Vinblastine.

Indomethacin (33) is a non-steroidal anti-inflammatory drug (NSAID)

commonly used as a prescription medication to reduce fever, pain, stiffness,
and swelling [27] [Fig 1.18].

O OH

Cl
(33)

Fig. 1.18: Indomethacin.

15
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

Besipirdine (34) is an indole-substituted analogs of 4-aminopyridine, is

a neootropic drug developed for the treatment of Alzheimer's disease (AD) [28]
[Fig 1.19].

N
N

N
(34)

Fig. 1.19: Besipirdine.

Fendosal (35) is a potent non-steroidal anti-inflammatory agent which is

more active than aspirin in the prophylactic and therapeutic adjuvant-induced
polyarthritis models of chronic inflammation [29] [Fig 1.20].

N
COOH

OH
(35)

Fig. 1.20: Fendosal.

In addition to this, many of indole derivatives have been used as the
drugs. Some of them (36) to (39) are listed below [Fig 1.21].

16
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

O S
NH NH
S

N N
H H
Melatonin Brassinin
(36) (37)
N
N NH2
O
O
O
HO
N N
H

Ondasetron Tryptophan
(38) (39)

Fig. 1.21: Marketed drugs with indole substructures.

1.5.3 Applications in dye industry

Indole-based colorants are part of the large, diverse class of organic dyes
and pigments. Many of the indolic dyes showed blue to green colour. Indigo is
probably the oldest and the most famous colorant based on indole. Other dyes
based on the indigo motif like Vat Blue 4B (40), Vat blue 8 (41) are sold in
market [30] [Fig 1.22].

Cl

O
O Br
H O
Br N
N OMe
H
N Br
H
Br O
Vat blue 4B Vat blue 8
(40) (41)

Fig. 1.22: Dyes with indole core.

17
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

Indigo carmine or 5,5'-indigodisulfonic acid sodium salt (42), is a pH

indicator It is approved for use as a food colorant in the United States and
Europe [31] [Fig 1.23].

O
+ -
Na O O H
S N
O O
N S
- +
H O O Na
O
Indigo carmine
(42)

Fig. 1.23: Indole based dye

1.5.4 Application in Agriculture

Auxins are one of the major classes of plant-produced hormones
affecting plant growth including bud formation and root initiation. Indole-3-
acetic acid (IAA) (43) is the most common auxin found in plants. It is mainly
produced in cells of the apex (bud) and very young leaves of a plant. IAA and
its analogues like indole-3-butyric acid (IBA) (44) are used in the horticulture
[32] [Fig 1.24].

COOH
COOH

N
H N
H
(43) (44)

Fig. 1.24: Indole based Auxin.

Moreover, few indole derivatives have been found to have fungicidal

activity. Amisulbrom (45) is an important sulfonamide fungicide having
triazolo ring while pyroquilon (46) possesses indole core in which nitrogen is
encircled [33] [Fig 1.25].

18
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

Br
O
O N N O
N S N S
N
O
O N
F
(45) (46)

Fig. 1.25: Indole derivatives with fungicidal activity.

Thus, the versatility of indole and its derivatives have drawn attention of
researchers in the area of organic and pharmaceutical chemistry. Moreover,
isatin, being a privileged scaffold, is versatile lead molecule for potential
bioactive agents. Isatin can be used as precursor for the syntheses of several
heterocyclic frameworks such as pyrrolidines, quinolines, indoles, β-lactams,
and 2-oxindoles.

19
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.6 Isatin

Isatin (indoline-2,3-dione or indole-1H-2,3-dione) (47) (Fig. 1.26), is a

well-known natural product found in plants of genus Isatis and in Couropita
guianancisaubl [34]. Isatin is an oxidation product of indigo and its current
structure was proposed by Kekule [35][Fig 1.26].

O
N
H
(47)

Fig. 1.26: Isatin

1.6.1 Reactivity of Isatin

Most commonly, carbonyl group at the C-3 position undergoes
nucleophilic addition reaction offering oxindole or spiro-fused derivatives.
Along with this; it undergoes aromatic substitution reaction at C-5 and C-7 of
the phenyl ring, N-substitutions, nucleophilic additions at the C-3 carbonyl
group, chemoselective reductions, oxidations, ring-expansions and spiro-
annulations (48) [36] [Fig 1.27].

-
Nu

O
+
E
O
N

H
(48) R-X

Fig. 1.27: Orientation in reaction

20
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.6.2 Synthetic Applications of Isatin

The C-3 position of carbonyl group of isatin is more susceptible towards
the nucleophilic addition reaction. The attack of nucleophile and or spiro
annulation transforms it into 2-oxindole derivatives [Fig 1.28].

Heterocyclic ring

X = N, O, S etc.
X

O
N

R
2-oxindole core

Fig. 1.28: 2-Oxindole core formation in the reactions of isatin.

The reviews regarding the chemistry of isatin [37, 38] clearly indicated
the high bio-efficiency of isatin derivatives. Isatin has been engaged in large
number of organic transformations. Some of these transformations have
depicted in fig. 1.29.

21
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

H3C CH3
N
O
R O CH
N 3
+
N H N
O
N
H O
O N O 1 R
N R O

R N
2
R
4
R O R
3
O R N O
O O CH3
N
R
R
N O
H3C
O O CN
O
NH CN
O N
N O N R
H H
O
N O
H NH N
R
O
N
R 2
R CH2
R O
R 1 O
N O N R 3
O R O
CN O
N O O
CN 4 COOEt
O H R O
O NH N O N
NH H R
H3C
O
2
R 3
R
1
R HN
4
N R
O
O 5 N
N R
R O
R

Fig.1.29: Formation of spiro fused derivatives based on isatin.

As shown in figure, all these transformations involve the formation of

spiro- fused molecules having oxindole core. This spiro-fused heterocyclic
framework is of a great interest in synthetic organic and medicinal chemistry as
many natural products like horsfiline (49), gelsemine (50), rhynchophylline
(51) and elacomineare (52) are having oxindole as a key basis in their
structures [Fig 1.30].

22
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

O
N N
O
O
N O
N
H H

(49) (50)
O

N O
N

O O
O HO N
N O H
H
O
(51) (52)

Fig. 1.30: Representative natural products with oxindole as key motif.

Furthermore, isatin and its derivatives showed wide spectrum of

activities such as progesterone receptor modulators [39], anti-HIV [39]
antitubercular [40] antimycobaterial [41], MDM2 inhibitor [42] and anticancer
[43] (53 to 58) [Fig 1.31].

O
O S
O N NH
S O
O 2N N Cl
N
O
N F N
NC N
N F O
O
F
N
H

(53) (54) (55)

Progeteron receptor anti-HIV

Anti-TB
O
NH2
O
NH2
N NH
O
F
N NH
Br O
Et
Cl O N F
N F N
N O
N O N
Cl N O O
H
MeO
O
MeO OH
OH

(56) (57) (58)

MDM2 inhibitor
antimycobacterial anticancer

Fig. 1.31: Selected isatin based compounds with biological activity.

23
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.7 Multicomponent Reactions

A multicomponent reaction (MCR) is a process in which three or more

easily accessible components are combined together in a single operation to
produce a final product offering greater possibilities for molecular diversity per
step with reduction in synthetic time and effort. In the recent times, MCRs have
been emerged as a powerful advanced tool for sustainable and green synthesis.
The object of green synthesis is to redesign the synthetic strategies to existing
ones considering environmental impact and obeying green chemistry principles
[44] [Fig 1.32].

Fig. 1.32: Green chemistry principles (adopted from Green Chemistry: Theory
and Practice book).
These principles of green chemistry can be attained by implementing
multi-component strategy for organic process. MCRs are accomplished with
high atom economy, efficiency, high convergence, reduction in waste. Due to
these fascinating features of MCRs, there is tremendous increase in number of
reports on MCRs in medicinal, drug discovery and combinatorial chemistry
[45-47]. The history of MCR is unknown but the Strecker reaction was
considered as the foundation stone of MCR.

24
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.7.1: Strecker Reaction

First multicomponent reaction was reported by Strecker in 1850 for the
synthesis of α-aminocyanides from aldehyde, hydrogen cyanide and ammonia.
α-aminonitrile on hydrolysis gives desired amino acid (59) [48] [Scheme 1.13].

O NH2 NH2
+
H
H CN COOH
+ NH3 + HCN

(59)

Scheme 1.13: Strecker amino acid synthesis.

1.7.2: Hantzsch Reaction

In 1882, Hantzsch synthesized symmetrically substituted
dihydropyridines (60) from NH3, aldehydes and two equivalents of β-ketoesters
[49] [Scheme 1.14].

O O O
O O
H + NH3 + 2 O
O O

N
H
(60)

Scheme 1.14: Hantzsch reaction.

1.7.3 Biginelli Reaction

The Biginelli reaction first described in 1893 represents acid-catalyzed
multicomponent synthesis of substituted dihydropyrimidines (61) by the
cyclocondensation of β-ketoesters, aromatic aldehydes and urea [50] [Scheme
1.15]

25
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

O
O O O O

O NH
H
+ H2N NH2 + O

N O
H

(61)

Scheme 1.15: Biginelli reaction.

1.7.4 Ugi Reaction

The first four component reaction was developed by Ugi in 1959 for the
synthesis of α-acylamino amides (62) by reacting aldehydes, primary amines,
carboxylic acids and isocyanides [51] [Scheme1.16]. It involves the formation
of C-C as well as C-Heteroatom bond formation.

R2 O
O O

R1 OH
+ R2 NH2 + R3 H + R4 N
+ R1 N
NH
R4

O R3

(62)

Scheme1.16: First four component Ugi reaction.

1.7.5 MCRs for the synthesis of Indole derivatives

Due to commendable importance of indole derivatives, numerous indole
derivatives have been synthesized using multicomponent route.
First time, Yonemitsu et al, [52] have reported the successful synthesis of ethyl
3-substituted indolyl-propionates (63) via three component reaction of indole,
Meldrum’s acid and aldehydes. The product was used as intermediates in the
synthesis of complex indole alkaloids [53] [Scheme 1.17]

26
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

O
RCHO O
R R
O
O O
R
1
+ O
CH3 CN
R
1
O EtOH, Py
R
1 O
N
O O RT N N
H Cu, heat
H H

(63)

Scheme 1.17: Yonemitsu reaction for the synthesis of 3-substituted indole.

Perumal et al, [54] have reported three component condensation of

salicaldehyde, malononitrile and indoles in presence of InCl3 [55] or L-proline
to form indolyl chromanes (64). This protocol was further extended to 2-
hydroxynaphthalene-1-carboxaldehyde, indole and malononitrile [Scheme
1.18].

H2N
O
CN
1
R
NC
CN
OH
InCl3 or
R
N
+ R
1
CHO L-proline
R
N
H H

(64)

Scheme 1.18: Synthesis of indolyl chromanes.

4H-pyrano-[3,2-b]indole (65) was synthesized by the reaction of

acetylindol-3(2H)-one malononitrile and aldehydes in the presence of
triethylamine [56] and ammonium acetate as a catalyst [57] [Scheme 1.19].

NH2
O CHO O
CN CN

N
+ CN
+ Et3N

N
Ac
Ac

(65)

Scheme 1.19: Synthesis of 4H-pyrano-[3,2-b]indole.

27
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

Shiri et al, [58] have demonstrated the synthesis of indole derivative

(66) via Mannich reaction of aldehydes, primary amine and indole in presence
of C9H19COOH as a surfactant type catalyst. The same protocol was
reinvestigated by Shirakawa and Kobayashi [59] [Scheme 1.20].

2
R
NH
Ar
C9 H19 COOH

N
+
2
R -CHO
+ Ar-NH2
H 2O
1 N
R 1
R
(66)

Scheme 1.20: Mannich reaction.

Sapi and co-workers successfully prepared 1,2,3,4-tetrahydrocarbazoles

(67) utilizing pseudo four component condensation of 2-substituted indoles,
Meldrum’s acid and 2 equivalents of aldehydes in the presence of proline [60]
[Scheme 1.21].
O
O
O
O
Ar H Ar O
O O O
Proline
+ O
O
2 N Ar
N R Ar H 1
1 R 2
R R
(67)

Scheme 1.21: Pseudo four component for the synthesis of 1,2,3,4-

tetrahydrocarbazoles.

28
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

1.8 References
[1] A. R. Katritzky, Handbook of Heterocyclic Chemistry, Pergamon
Press, New York, 1985.
[2] H. Kusama, M. Kurashige, H. Arakawa, Journal of Photochemistry and
Photobiology A: Chemistry, 169, 2005, 169–176.
[3] (a) R. J. Sundberg, The Chemistry of Indoles, Academic Press, New
York, 1970.
(b) R. J. Sundberg, Indoles, Academic Press, London, 1996.
[4] A. Baeyer, Ann. Chem., 140, 3, 1866, 295.
[5] (a) G. Penoni, A. Sisti, M. Tibiletti, F. Tollari, S. Nicholas, K. M. Curr.
Org. Chem. 14, 2010, 2409-2441.
(b) S. A. Patil, D. D. Miller, Curr. Med. Chem. 16, 2009, 2531-2565.
(c) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 106, 2006, 2875-2911.
(d) G. W. Gribble, Pure Appl. Chem. 75, 2003, 1417-1432.
[6] D. F. Taber, P. K. Tirunahari, Tetrahedron 67, 2011, 7195-7210.
[7] (a) E. Fischer, F. Jourdan, Berichte der Deutschen Chemischen
Gesellschaft 16, 2, 1883, 2241–2245.
(b) E. Fischer, O. Hess, Berichte der Deutschen Chemischen
Gesellschaft 17, 1, 1884, 559–568.
[8] G. Bartoli, G. Palmieri, M. Bosco, R. Dalpozzo, Tet Lett., 30, 16, 1989,
2129–2132.
[9] A. Bischler, et al Ann. Chem., 25, 2, 1892, 2860.
[10] A. Reissert, Berichte der deutschen Chemischen Gesellschaft 30, 1897,
1030.
[11] A. D. Batcho, W. Leimgruber, U.S. Patent 3,732,245 & U.S. Patent
3,976,639
[12] N. Sakai, K. Annaka, A. Fujita, A. Sato, T. Konakahara, J. Org. Chem.,
73, 2008, 4160-4165.
[13] L. Zhu, M. Vimolratana, S. P. Brown, J. C. Medina, Tet Lett., 49, 2008,
1768-1770

29
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

[14] V. Sridharan, S. Perumal, C. Avendano, J. C. Menendez, Synlett, 2006,

91-95.
[15] N. Clayden, S. Greeves, Organic Chemistry, Oxford University Press,
Oxford, 2001, 1169-1170.
[16] R. K. Bansal, Heterocyclic Chemistry, International publisher, 4th
edition, 299-330.
[17] H. Deokar, J. Chaskar, A. Chaskar, J. Heterocyclic Chem., 51, 2014,
719.
[18] A. H. Mandour, E. R. El-sawy, K. H. Shaker, M. A. Mustafa, Acta
Pharm. 60, 2010, 73–88.
[19] A. Andreani, S. Burnelli, M. Granaiola, A. Leoni, A. Locatelli, R.
Morigi, M. Rambaldi, L. Varoli, L. Landi, C. Prata, M. V. Berridge, C.
Grasso, H. H. Fiebig, G. Kelter, A. M. Burger, M. W. Kunkel, J. Med.
Chem. 51, 2008, 4563–4570.
[20] M. Giampieri, A. Balbi, M. Mazzeia, P. L. Colla, C. Ibba, R. Loddo,
Antiviral Research 83, 2009, 179–185.
[21] S. Lee, K. Y. Yi, S. K. Kim, J. Suh, N. J. Kim, S. E. Yoo, B. H. Lee, H.
W. Sao, S. O. Kim, H. Lim, Eur J Med Chem 38, 2003, 459.
[22] R. Ragno, A. Coluccia, G. La Regina, G. De Martino, F. Piscitelli, A.
Lavecchia, E. Novellino, A. Bergamini, C. Ciaprini, A. Sinistro, G.
Maga, E. Crespan, M. Artico, R. Silvestri, J. Med. Chem. 49, 2006,
3172-3184.
[23] B. C. Hong, Y. Jiang, Y. Chang, S. Lee, J Chin Chem Soc. 53, 2006,
647.
[24] H. Khaledi, A. A. Alhadi, W. A. Yehye, H. M. Ali, M. A. Abdulla, P
Hassandarvish, Arch. Pharm. Chem. Life Sci. 344, 2011, 703–709.
[25] N. Simon, J. Young, Psychiatry Neurosci. 32, 6, 2007, 394–399.
[26] P. G. Goppi, C. Broglia, F. Merli, M. Dell'Olio, C. Stelitano, E.
Iannitto, M. Federico, R. Bertè, D. Luisi, S. Molica, C. Cavalli, L.
Dezza, E. Ascari, Cancer 98, 11, 2003, 2393–2401.

30
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

[27] A.Brayfield, Martindale: The Complete Drug Reference, London, UK,

Pharmaceutical Press, 2014.
[28] F. J. Huff, P. G. Antuono, J. E. Delagandara, M. A. McDonald, N. R.
Cutler, S. R. Cohen, R. C. Green, F. P. Zemlan, M. L. Crismon, M.
Alter, J. E. Shipley, W. E. Reichman, Alzheimer Disease and
Associated Disorders 10, 2, 1996,93–102.
[29] H. B. Lassman, J. C. Wilker, V. B. Anderson, M. N. Agnew, R. C.
Allen, W. J. Novick, Jr., Agents Actions. 8, 3, 1978, 209-217.
[30] T. C. Barden, Top Heterocycl Chem 26, 2011, 31–46.
[31] K. Takeuchi, T. Ibusuki, Anal. Chem. 61, 6, 1989, 619–23.
[32] S. Simon, P. Petrášek, Plant Science 180, 3, 2011, 454–460.
[33] V. M. Anthony, J. M. Clough, C. R. A. Godfrey, P. J. de Fraine,
US4812162 A, 1989.
[34] (a) J. F. M. da Silva, S. J. Garden, A. C. Pinto, J. Braz. Chem. Soc.12,
2001, 273; (b) J. Bergman, J. O. Lindstrom, U. Tilstam, Tetrahedron
41, 1988, 2879.
[35] A. Kekule, Chem. Ber. 2, 1869, 748.
[36] W. C. Sumpter, Chem. Rev. 34, 1944, 393.
[37] F. D. Popp, Adv. Heterocycl. Chem. 18, 1975, 1.
[38] A. Fensome, W. R. Adams, A. L. Adams, T. J. Berrodin, J. Cohen, C.
Huselton, A. Illenberger, J. C. Karen, M. A. Hudak, A. G. Marella, E.
G. Melenski, C. C. McComas, C. A. Mugford, O. D. Slayeden, M.
Yudt, J. Zhang, P. Zhang, Y. Zhu, R. C. Winneker, J. E. Wrobel, J.
Med. Chem. 51, 2008, 1861.
[39] P. Selvam, N. Murugesh, M. Chandramohan, Z. Debyser, M. Witvro.
Indian J. Pharma. Sci., 2008, 779–782.
[40] V. V. Vintonyak, K. Warburg, H. Kruse, S. Grimme, K. Hubel, D.
Rauth, H. Waldmann, Angew. Chem., Int. Ed. 49, 2010, 5902.
[41] D. Sriram, P. Yogeeswari, J. S. Basha, D. R. Radha, V. Nagaraja,
Bioorg. Med. Chem., 13, 2005, 5774–5778.

31
 Chapter 1

Structure, Synthesis, Reactivity and Applications of Indole derivatives

[42] K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. Qiu, S. Shangary,

W. Gao, D. Qin, J. Stukey, K. Krajewski, P. P. Roller, S. Wang, J.
Med. Chem. 49, 2006, 3432.
[43] P. Yogeeswari, D. Sriram, R. Kavya, S. Tiwari. Bio. Pharma. 59, 2005,
501–513.
[44] P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press: New York, 1998, 30.
[45] A. Dömling, W. Wang, K. Wang, Chem. Rev., 112, 2012, 3083–3135;
[46] E. Ruijter, R. V. A. Orru, Drug Discovery Today: Technol., 10, 2013,
15 20;
[47] W. H. Moos, C. R. Hurt, G. A. Morales, Mol. Diversity, 13, 2009, 241–
245.
[48] A. Strecker, L. Justus, Ann Chem., 1850, 27–51.
[49] A. Hantzsch, L. Justus, Ann. Chem., 215, 1882, 1-82.
[50] P. Biginelli, Gazz. Chim. Ital., 23, 1893, 360–413.
[51] I. Ugi, R. Meyr, U. Fetzer, Angew. Chem. Int. Ed. 71, 1959, 386.
[52] (a) Y. Oikawa, H.Hirasawa, O. Yonemitsu, Tet Lett., 20, 1978, 1759.
(b) Y. Oikawa, H. Hirasawa, O. Yonemitsu, Chem. Pharm. Bull. 30,
1982, 3092.
[53] Y. Oikawa, M. Tanaka, H. Hirasawa, O. Yonemitsu, Chem. Pharm.
Bull.29, 1981, 1606.
[54] G. Shanthi, P. T. Perumal, Tet Lett.. 48, 2007, 6785.
[55] G. Shanthi, P. T. Perumal, U. Rao, P. K. Sehgal, Indian J. Chem. 48B,
2009, 1319.
[56] A. M. Shestopalov, O. A. Naumov, V. N. Nesterov, Russ. Chem. Bull.
52, 2003,179.
[57] S. Damavandi, Heterocycl. Commun. 17, 2011, 125.
[58] M. Shiri, M. A. Zolfigol, Tetrahedron 65, 2009, 587.
[59] S. Shirakawa, S. Kobayashi, Org. Lett. 8, 2006, 4939.
[60] F. Cochard, M. Laronze, P. Sigaut, J. Sapi, J. Y. Laronze, Tetrahedron
Lett. 45, 2004, 1703.

32