INDOLE: Synthesis and Medicinal Importance
Lecture- 1: Heterocyclic Chemistry
MSc final year
Govt Raza PG College Rampur
Email : mkhcdri@gmail.com
Dr Mohd Kamil Hussain
Asst. Professor
Department of Chemistry

Indole is an aromatic heterocyclic organic compound. It has a bicyclic
structure, consisting of a six-membered benzene ring fused to a five-
membered nitrogen-containing pyrrole ring. Compounds that contain
an indole ring are called indoles.
The indole nucleus is a fundamental constituent of a number of
natural and synthetic products with different biological activities
Although indole moiety is very small but is fascinated by
scientists because of the diverse biological activities by not only
indole but its various substituted derivatives as well.
 Indole alkaloids form a very large group of physiologically active and
pharmacologically important molecules example:brucine, reserpine,
yohimbine, vincamine, strychinine etc
N
H
Indole

Due to its wider applications in pharmaceutical industries, they will
replace many existing heterocyclic based pharmaceuticals.
Now days, many drugs are in the world market, while several
hundred are in clinical trials.
indoles
Anti hypertensive drugs
Anti depressant drugsAnti psychotic agents
NSAIDS
Anti emetic drug
Analgesic drug
Anti asthmatic drug
Anti viral drug.Anti arrhythmic drug
B-blocker drug
ToxinsInhibitor of RNA Polymerase-11 Agonist for the cannabinoid receptor
Non- Nucleoside reverse transcriptase inhibitor
Opioid agonist
Sexual dysfunction.
Anti Cancer drug

Vincristine VINBLASTINE VinorelbineVindesin
Vinca alkaloids are a set of anti-mitotic and anti-microtubule agents that
were originally derived from the Catharanthus roseus.
They are a class of cell-cycle-specific cytotoxic drugs that work by
inhibiting the ability of cancer cells to divide: Acting upon tubulin, they
prevent it from forming into microtubules, a necessary component for
cellular division.
Vinca alkaloids are now produced synthetically and used as drugs in
cancer therapy and as immunosuppressive drugs. These compounds include
vinblastine, vincristine, vindesine, and vinorelbine.

VINCAMINE
Anti-hypertensive drugs
PINDOLOL
nonselective beta blocker with partial beta-
adrenergic receptor agonist activity
OXYPERTINE
Antipsychotic agent
RESERPINE
Anti-hypertensive drugs & antipsychotic
ATEVIRIDINE
Anti-HIV
Strychnine
toxin

YOHIMBINE
Stimulant and aphrodisiac effects
DOLASETRON
Serotonin 5-HT3 Receptor antagonist
ZAFIRLUKAST
an oral leukotriene receptor antagonist LTRA) for
the maintenance treatment of asthma
ARBIDOL
antiviral treatment for influenza
infection
Lysergic acid

PROMANULLIN
Amatoxin
BUCINDOLOL
Non selective beta blocker with additional weak
alpha-blocking properties
Delavirdine
non-nucleoside reverse transcriptase inhibitor
MITRAGYNINE
Opioid agonist
PERICINE
Opioid agonist

The Fischer indole synthesis:
It consists of heating the phenyl hydrazones of an aldehyde or a ketone with ZnCl2,H2SO4 ,
BF3etherate,or polyphosphoric acid to about 1800C
The reaction of a (substituted) phenylhydrazine with an aldehyde or ketone initially forms a
phenylhydrazone which isomerizes to the respective enamine (or 'ene-hydrazine'). After
protonation , a cyclic [3,3]-sigmatrpic-rearrangement occurs producing an imine. The resulting
imine forms a cyclic aminoacital (or aminal), which under acid catalysis that eliminates NH3,
resulting in the energetically favorable aromatic indole.

The Japp-Klingemann reaction
is a chemical reaction used to synthesize hydrazones from β-keto-acids (or β-keto-esters) and aryl
diazonium salts.The hydrazone products of the Japp-Klingemann reaction are most often used as
intermediates in synthesis of more complex organic molecules. For example, a phenylhydrazone
product can be heated in the presence of strong acid to produce anindole via the Fischer indole
synthesis.
The Leimgruber-Batcho indol synthesis
is an efficient method of sythesizing indole and substituted indoles. Originally disclosed in a
patent in 1976, this method is high-yielding and can generate substituted indoles.

Resonating structure of Indole
N N
H
N
HH
Low energy iminium str High energy
orthoquinonoid str
The most reactive position on indole for electrophilic aromatic substitution is
C-3, which is 1013 times more reactive thanbenzene
 Electrophilic Substitution in indole occurs at position- 3, but if this is already
occupied then on the 5 & 7 position.
The basicity of indoles corresponds approx.to that of pyrrole.
Although the indole N-1 nitrogen atom has a lone pair ofelectrons, indole is not
basic like amines and anilines because the lone pair is delocalised and contributes
to the aromatic system.
Strong bases like sodiumhydride or butyl lithium and water-free conditions are
needed for completedeprotonation.

N
H
N
H
SO3H
SO3inpyridine
N
H
NO2
C
2H
5NO
2
C
2H
5O
Na
N
H
Br or I or Cl
Br2 or I2 or
SO2Cl2
N
H
CHO
HCHO
/ HCl
N
H
CHO
Me2NCHO/POCl3
N
H
CH2N(CH3)2
HCHO
(Me) 2
NH
N
H
N
H
Sn / HCl
H2
/ Ni250 0
c
gramin-nat pdt
isolated from grasses
indoline

Multicomponent reaction of 2-substituted indoole
Multicomponent reactions between 2-substituted indoles , benzaldehyde and Meldrum’s acid in the
presence of one equivalent of triethylamine affording stable, crystalline adduct salts 1.On heating
witth t-BuOH it gives acid-ester 2.
When in situ formed azides 3 prepared from 2, were heated in toluene, a diastereomeric mixture of
spirocyclic pyrrolidinone-indolines 5 was isolated via 4 resulting from a Curtius rearrangement,
followed by a thermal spirocyclisation process.
N
H
R
CHO
O
OO
O
+
N
H
R
O
O
O
OEt3NH
N
H
R
COOtBu
COOH
N
H
R
COOtBu
CON3
N
H
R
COOtBu
N
C
O
N
H
NH
R
O
OtBuO
N
H
R
COOtBu
NHCO2Bn
2
34
5
6
t-BuOH
DPPA
Et3N
BnOH,Et3N
Et3N
1
ARKIVOC 2004 (vii) 208-222

The indole scaffold is a prominent and privileged structural motif found in numerous natural
products and various synthetic compounds. Recently, a large number of indole-containing
compounds have revealed remarkable pharmacological activity and their utility as therapeutic
agents has attracted considerable attention from chemists, Subsequently, the development of
efficient methods that allow rapid access to functionalized indoles with different substitution
patterns (at C-2, C-3, N-atom and aromatic ring, constitutes an emerging area.
Angew.Chem. 2005, 44, 606, J.Am.Chem.Soc. 2005, 127, 5342
Novel Synthetic Approaches Toward Substituted Indole Scaffolds

one-pot, three-component procedure for the synthesis of 2,3-substituted indoles
based on Cacchi´s protocol.
This regiospecific procedure consisted of a Pd domino indolization involving a consecutive Pd-
catalyzed Sonogashira coupling followed by aminopalladation and reductive elimination starting
from 2-iodo-N-trifluoroacetylanilide 1, a suitable acetylene 2 and bromoarene 3. The
Senanayake group optimized the reaction conditions as shown in Scheme. the use of
trifluoroacetyl as protecting group in 1 was shown to be advantageous (readily hydrolyzable);
addition of bromobenzene at the beginning simplified the procedure and enhanced the reaction
rate; DMF as solvent combined with K2CO3 as base, and a temperature of 60 ºC gave better
results
J.Chem.Soc.PerkinTrans.1 2000, 1045
R1 = H, CO2Me, CN
R2 = Ph, 4-MePh
R3 = Ph, 4-MeOPh, 4-CO2MePh,
2-NO2Ph

The Larock group of the Iowa State University reported on the synthesis of 3-iodoindoles 4 via
Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines 1 with terminal acetylenes 2 and subsequent
electrophilic cyclization of 3. Due to the high reactivity of N,N-dialkyl-o-iodoanilines towards the
Sonogashira coupling, a wide variety of substituted anilines and alkynes were used (with aryl, vinyl, alkyl
and silyl groups). However, the authors reported that substituents on the triple bond of 3 affect the yield
of the following cyclization step, since increased conjugation enhances the reaction rate and also increases
the product yield. In addition, while electron-withdrawing groups enhanced cyclization, (strong)
electron-donating groups slowed the reaction and led to lower yields.
The authors reported an interesting feature; when there are two different N-alkyl groups, the less-
hindered group is more easily removed. Additionally, this procedure allows further
derivatization/functionalization at C-3, since 4 might be used for cross-coupling reactions.
J.Org.Chem. 2006, 71, 62
R1 = H, 4-NO2 ,4-Me, 4-CO2Et, 4-
CO2Me
R2 = Ph, t-Bu, n-Hexyl,
R4 = Me, n-Bu, Ph

The Lautens group of the University of Toronto described a modular synthesis of 2-
substituted indoles via a palladium-catalyzed coupling. This methodology involved an
intramolecular Buchwald-Hartwig C-N/intermolecular Suzuki-Miyaura C-C coupling of o-
gem-dihalovinylanilines with an organoboron reagent catalyzed by Pd(OAc)2/S-Phos in the
presence of K3PO4.H2O. Interestingly, the free aniline furnished the desired indole directly and
in good yield. The strategy reported by the authors showed a wide range of applicability in
terms of substituents, in particular for the challenging 4-substituted indoles. Better results
were obtained for X = Cl. Moreover, the authors expanded the reaction scope to obtain 1,2,3-
trisubstituted indoles by switching the order of addition of the two boronic acids.
Org. Lett. 2005, 7, 3549 ,J. Org. Chem.,Vol. 72, No. 4, 2007
,
R1 = H, 3-Me, 3-F, 4-F, 4-CF3, 4-CO2Me, 4-OBn
R2-‘B’ = Aryl/HetAryl/Alkyl/ Vinyl Boronic acid/ester
R3 = H, CF3, Me X = Br, Cl

NH
R4
R1
X
X
R3
N
R3
R4
R2
R1
N
R4
R1
R
N
R4
R1 R
N
R1
N
O
R
Cbz
C-N/ Suzuki
Pd/L
C-N/ Heck
Pd/L
C-N/ Sonogashira
Pd/ Cu/L
C-N/C-N
Cu/L
Org. Lett. 2005, 7, 3549
Org. Lett. 2006, 8, 4203
Org. Lett. 2007, 9, 2955.
Org. Lett. 2006, 8, 653.
Recently, Lautens group have reported a Pd-catalyzed indole synthesis via a C- N/Suzuki
or C-N/Heck or C-N Sonogashira combinations and a Cu-catalyzed double C-N bond
formation

Zn(OTf)2 –Catalyzed Cyclization.
The Liu group of the National Tsing-hua University published a new indole synthetic approach
, using anilines 1 as starting material with the appropriately substituted propargyl alcohols 2 as the
source of the C-2―C-3 unit. This method proved to be very effective in the preparation of several
indoles 3 in good to high yields ,since Zn(OTf)2 has the advantage of activating not only the C-2-
addition of the alcohol but also the subsequent cyclization step. The mechanism elucidated by the
authors proposed that the isomerization of the α-amino ketone intermediate occurs through a 1,2-
nitrogen shift, thus explaining the observed chemoselectivity.
J. Org. Chem. 2006, 71, 4951

Rearrangement of Azirines viaThermolysis
D. Taber and W. Tian of the University of Delaware have reported on the synthesis of indole 3.via
the thermal rearrangement of azirines 2 that are readily available from the ketones 1 (Neber
reaction) via the corresponding activated oxime. The rearrangement occurred at temperatures
ranging from 40 ºC up to 170 ºC. The authors suggest that the cyclization mechanism proceeds
by a π-participation of the aromatic ring followed by reorganization, before the new C-N bond is
formed.
(J.Am.Chem.Soc. 2006, 128, 1058
R1 = H, 2-Br, 4-Br
R2 = Me, n-Octyl , R3 = H, Ph
Activationof Oxime: 1> For monoarylacyclic ketones—MsCl/Et3
2>For diaryl ketones—DIAD/n-Bu3P orPh3P

The Nicholas and Penoni groups of the University of Oklahoma and of the Università degli Studi
dell’Insubria, respectively, have reported on a pathway to N-methoxyindoles via an alkylative
cycloaddition reaction .. The authors performed a one-pot procedure for the preparation of several
substituted N-methoxyindoles 3 using as starting materials the readily available nitrosoarenes 1 and the
alkyne 2 (Scheme 6). Both electron-poor and electron-rich nitrosoarenes gave good product yields and
regioselectivity for the 3-position was observed. The authors obtained higher yields for 2-substituted
nitrosoarenes 1when compared to 4-substituted nitrosoarenes 1. Additionally, this method constitutes a
formal synthesis of the corresponding indole (NH) since the latter can be formed by reduction of 3.
J. Org. Chem. 2006, 71, 823
N-Methoxyindoles via Alkylative Cycloaddition of Nitrosoarenes with Alkynes

Concise Total Synthesis of(+)-cis-Trikentrin A and (+)-Herbindole
A via Intermolecular Indole Aryne Cycloaddition
The trikentrins were isolated by Capon from the marine spongeTrikentrion flabelliforme
and display antibacterial activity.The more recently discovered herbindoles by Scheuer from the
Australian spongeAxinella sp. possess both cytotoxic and antifeedant properties.The interesting
biological profiles of these molecules combined with their uncommon structural motifs make them
attractive targets for total synthesis.
Trikentrion flabelliforme
N
H
(+)-cis-Trikentrin
N
H
Herbindole A
N
H
Herbindole B
Axinella sp
Org.Lett., 11, 2009,201-204

An efficient nine-step total synthesis of the annulated indole natural products ((+)-cis-
trikentrin A and (+)-herbindoleA was accomplished via an intermolecular Diels-Alder
cycloaddition using indole aryne (indolyne) methodology as the key step.
This strategyprovides rapid access into the trikentrins and the related herbindoles and
represents the first application of this methodology to natural products total synthesis.
The required 6,7-indolyne precursor was readily constructed by means of the Bartoli indole
synthesis with substituted nitrobenzenes and vinyl magnesium bromide.
cis-Trikentrin A: Bartoli Indole Synthesis
Diazotization of 2 with t-BuONO followed by bromination catalyzed by CuBr2 was carried out to
afford the o-dibromide 3.
Application of the Bartoli indole synthesis (CH2CHMgBr, ;THF, -40 °C) proceeded
uneventfully and gave the desired indole 4.
The NH group of the indole was then protected as itsTBS group (KHMDS,TBSOTf,THF, -78 °C).
NH2 NH2
NO2
Br
NO2
Br N
H
Br
Br N
Br
Br
TBS
1 Ac2O,
2 HNO3
3 NaOH
DCE, H2O
50-80 0
C, 96%
CuBr2 cat, Br2
t-BuONO
MeCN, 500
C
82%
MgBr,2 eq
THF, -40 0
C
52%
KHMDS
TBSOTf
THF, -78 0
C
73%
1
2 3 4
5

N
Br
Br
TBS
5
N
TBS
N
TBS
OH
HO
N
TBS
CHO
OHC
N
H
CH(EtS)2
(SEt)2HC
N
H
Me
Me
6
7
8
910
n-BuLi , -780C-RT
PhMe, 77%
OsO4 ,NMO
THF/H2O, 88%
NaIO4
THF/H2O
88%
EtSH,BF3.OEt2
-78 0C-RT
91%
Ni (R)
EtOH,
85%
(+)-cis-Trikentrin A
With the desired indole 5 in hand, metal-halogen exchange with n-BuLi in the presence of
cyclopentadiene resulted in desired cycloadduct 6 in an 77%.
Osmylation of 6 followed by oxidative cleavage of the diol 7 afforded the dialdehyde 8
Finally, 8 was converted into its corresponding dithioacetal 9 with concomitant desilylation
in 91% yield. Raney nickel reduction afforded in nine steps synthetic ((+)-cis trikentrin

Mitragyne speciosa
The Opioid Agonistic Indole Alkaloid Mitragynine
OMe
N
N
H
O
O
O
H
H
OMe
N
H
N
H
O
O
O
H
H
OH
Mitragynine
7-Hydroxy Mitragynine
Mitragynine was isolated from Mitragyne speciosa and has been employed as a substitute forin the
treatment of pain in Thailand. Mitragynine itself is a full opioid agonist and primarily acted on u- and δ-
opioid receptors. Interestingly the methoxyl functional group was found essential for the analgesic activity
Pharm. J. 1907, 78, 453, Life Sci. 2006, 78, 2265, Org. Lett., 9, 2007,3491

Total Synthesis of the Opioid Agonistic Indole Alkaloid Mitragynine
OMe
N
H
N
H
O
O
O
H
H
Mitragynine
OMe
I
NHBoc
N
N
TMS
EtO
OEt
OMe
N
N
N
EtO
OEt
BoC
TMS
OMe
N
H
COOEt
NH2
OMe
N
H
NH2
O
O
9-Stapes
+
Pd(OAc)2 ,K2CO3
LiCl , DMF,100 0
C
6 hr,
2N Aq HCl, THF
1NaOH, EtOH
2 Triphosgene
THF,45 0
C
PhCH2OH
Et2O/HCl, 24 hr
1 2 3
4
5
4-methoxy-D-tryptophan ester
the Larock heteroannulation process between Boc-protected
2-iodo-3- ethoxyaniline1 and theTMS alkyne 2 gave the N-
Boc-protected indole derivative 3.
The hydrolysis of the3 was accompanied by concomitant loss
of the indole2-silyl group of .This smoothly took place in
aqueous 2 N HCl inTHF to provide 4-methoxy-D-tryptophan
ethyl ester 4 in a single step in 91% yield. 3 was hydrolyzed in
ethanolic NaOH solution and then converted into the benzyl
ester 5.

Indole-3-carbinol (I3C) is a compound found in high concentrations in Brassica family
vegetables, including broccoli, cauliflower, Brussels sprouts, collard greens, kale and cabbage.
As a nutritional supplement, I3C has received attention in recent years as a promising
preventive and treatment agent for breast and other types of cancers, and may have beneficial
effect in the management of Herpes simplex virus (HSV) and human papilloma virus (HPV).
I3C Down-Regulates ERα. Protein Levels without Altering ERβ Protein Levels in MCF7
T47D Human Breast Cancer Cells and Pleiotropic Effects on Multiple Signaling
Pathways in Prostate Cancer Cells.
Indole-3-Carbinol ( I3C)I3C
Alternative Medicine Review, 2005, 10, 337-341,Mol Endocrinol, 2006, 20,3070–3082 Cancer Res 2007; 67, 7815
,

N
H
OH
N
H
O
H
NH3,Ca THF,
N
H
O
H
8 hHCHO
N
H
N
-33°C; 2 h
NaOMe
1 EtOH,Aq H2O2
2 aq NaOH,Et2O
N
H
1 POCl3 DMF 2 NaBH4,EtOH
J.Org.Chem. 1996 , 61, 1493, Chemico-Biological Interactions 2010 186 255–266
Synthesis of Indole

Anticancer Agent 5,6,11,12,17,18,23,24-Octahydrocyclododeca[1,2-b:4,5-
b’:7,8-b’’:10,11-b’’’] tetraindole (Ctet).
Macrocyclic condensation products of indole and simple aldehydes
N
H
HN
N
H
NH
H
N
HN
NH
NH
37% HCHO, MeOH, 96% H2SO4, reflux, 2 h.
HCHO HCHO
Dark Dark
Mixture of CTr & CTet
CTr CTet
CTet is a potent inhibitor of DNA synthesis in both estrogen receptor positive (MCF-7) and
estrogen receptor negative (MDA-MB-231) human breast cell lines (IC50 = 1.20 ± 0.04 μM and
1.0 ± 0.1 μM, respectively).
Molecules 2010, 15, 4085-4093,Tetrahedron 1970, 26, 3347–3352, Cancer Res 2007; 67, 7815
dx.doi.org/10.1021/jm2013425 | J. Med. Chem 2012

5-Hydroxy Tetraindole Induces G2 Arrest and Apoptosis in Human Breast Cancer Cells
H
N
H
N
N
H
OHHO
HO
N
H
OH
Anti proliferative activity against
breast adenocarcinoma
(MCF 7and MDA-MB-231) cells
Induces G2 arrest in cell cycle
with a distinctive increase in the
expression of cyclin B1 and
phospho-cdc2
Induces apoptosis through externalization of membrane
phosphatidylserine, DNA fragmentation, and activation of
caspase-3.
IC50 (MDA-MB-231) 0.45 ± 0.03 μM (MCF-7) 0.88 ± 0.04 μM
J. Med. Chem. 2012, 55, 1583−1592

H
N
H
N
N
H
OHHO
HO
N
H
OH
CHO
CHO
+
H
N
OH
I2 / MeCN
2h,RT,89%
4-Hydroxy tetraindole bearing an aromatic central core structure, was prepared in
satisfactory yields by addition reactions of terephthalaldehyde with indole in the presence
of catalytic amounts of molecular iodine at room temperature .
x.doi.org/10.1021/jm2013425 | J. Med. Chem.2012
Easy is
the Best