Chemistry of Heterocyclic

Compounds

Dr. S. Sreenivasa M.Phil., Ph.D., D.Sc.

Associate Professor and Coordinator
Department of Studies and Research in Organic
Chemistry, Tumkur University, Tumkur – 572 103
Course Summary
 Introduction

• Heterocycles one or more a ring

contain heteroatoms in
X Z
X X

Y Y
carbocycl heterocycle X, Y, Z are usually O, N or S
e s

• Aromatic, or partially or saturated – this course will focus on

aromatic fully systems
• Heterocycles are important and a large proportion of natural products contain
them
•
Many pharmaceuticals and agrochemicals contain at least one heterocyclic unit
•
Heterocyclic systems are important building-blocks for new materials
possessing interesting electronic, mechanical or biological properties
Classification – Aromatic Six-Membered
Isoelectronic carbocycle Heterocycles
4 4
3 5 3 5
2 6 2 6
1
N O
1
X
pyridine
pyrylium

4 4 4
N
3 5 3 N 5 3 5
2 N 6 2 6 2 6
N N N
1 1 1
pyridazine pyrimidine pyrazine

4 5 4 5
3 6 3 6
2 7 2N 7
N
1 8 1 8
quinoline isoquinoline
 Classification – Aromatic Five-Membered
Isoelectronic Heterocycles
carbocycle 3 4 3 4 3 4
1
2 N 5 2 5 2 5
O S
H 1 1
pyrrole furan thiophene

3 4 3 4 3 4
N N N
2 1 5 2 5 2 5
N O S
H 1 1
imidazole oxazole thiazole

3 4 3 4 3 4

2N 1 5 2 N 5 2N 5
N O S
H 1 1
pyrazole isoxazole isothiazole

4
3 5
6
2 1
N 7
H
indole
 Classification – Unsaturated / Saturated
Unsaturated
O O

aromatic dipolar resonance form

O O

4( )-pyrone

N O N O N OH
H H
2-pyridone

Saturated
O

O O NH O

ethylene oxide THF 1,4-dioxan pyrrolidine

dihydropyran
 Functional Group Chemistry
Imine Formation

R3 R3
O R3NH2 H N N

R1 R2 H3O R1 R2 R1 R2

H H

H
H H H R3
H
O R 3
N OH N
3
R N OH2

R1 R2 R1 R2 R1 R2 R1 R2

• Removal of water is usually required to drive the reaction to completion

• If a dialkylamine is used, the iminium ion that is formed can’t lose a proton and an
enamine is formed
 Functional Group Chemistry
Enols and Enolates
O OH O B O O
H
R1 R1 E R1 H R1 R1
R2 R2 R2
R2 R2
keto form enol form enolate

• The enol form is favoured by a conjugating group R2 e.g. CO2R, COR, CN, NO2 etc.
• Avoid confusing enols (generated under neutral/acidic conditions) with
enolates (generated under basic conditions)
• Enolates are nucleophilic through C or O but react with C electrophiles through C
Enol Ethers R3O OR3

R1
R3OH
R3
OR 3
O R2
acetal

R1 H R1
R2
R2
H2O O
enol ether

R1

R2
 Functional Group Chemistry
Enamines
R3 R3 R3 R3 R3 R3
O N N N
H H H
R1 R1 H R1

R2 R2 R2
iminium ion enamine
(Schiff base)

R3 R3 R3 R3
N N H2O O

R1 E E E
R1 R 2 R1 R2
R2

• Analogues of enols but are more nucleophilic and can function as enolate equivalents
• Removal of water (e.g. by distillation or trapping) drives reaction to completion
• Enamines react readily with carbon nucleophiles at carbon
• Reaction at N is possible but usually reverses
 Functional Group Chemistry
Common Building-Blocks
O
O NH
R R R
OH NH2 NH2
carboxylic acids amides amidines

O NH O O O O

HN NH
H2N NH2 R
1 R2 1
R OR2
2 2
urea guanidine -diketones -keto esters

Building-Blocks for Sulfur-Containing Heterocycles

O
S
P2S5 R
1
R
2
R SH S
R1 R2 1 2
R R
thioketones thiols thioethers

• Heterocycle synthesis
requires:
C O or C N bond formation using imines, enamines, acetals, enols, enol ethers
C C bond formation using enols, enolates, enamines
• During heterocycle synthesis, equilibrium is driven to the product side because of
removal of water, crystallisation of product and product stability (aromaticity)
 General Strategies for Heterocycle Synthesis
Ring Construction
• Cyclisation – 5- and 6-membered rings are the easiest to form
• C X bond formation requires a heteroatom nucleophile to react with a C electrophile

Y Y

+ + conjugate addition

X +

X, Y = O, S, NR

Manipulation of Oxidation State

[O] [O]
[O]
H2 H2 or H2
X X X X X
hexahydro tetrahydro dihydro aromatic

• Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation

General Strategies for Heterocycle Synthesis
Common Strategies
“4+1” Strategy
X X

H
N N
NH3 NH3
2H2O 2H2O
N N
O O O O
H H
• Strategy can be adapted to incorporate more than one heteroatom

“5+1” Strategy

X X

NH3 [O]
2H2O
H2 N
O O
N
H
• 1,5-Dicarbonyl compounds can be prepared by Michael addition of enones
General Strategies for Heterocycle Synthesis
“3+2” Strategy “3+3” Strategy

or or
X X X X
X X

Examples

X H2N H2N O H2N OH

O +

+
X H2N O OH

+ Hal
+
O
+ Hal = Cl, Br, I
+ O
O

E E

NH2 NH2 OH OH
 Bioactive Quinolines/Isoquinolines
H
NEt2
Me

HO
N HN
H
MeO MeO

N
N
quinine chloroquine
• Quinine is an anti- natural product isolated the bark of the Cinchona tree
malarial from
• Chloroquine is a completely synthetic anti-malarial drug that has the quinoline system
found in quinine – parasite resistance is now a problem
MeO

N
MeO

OMe

OMe
papaverine
• Papaverine is an alkaloid isolated from the opium poppy and is a smooth muscle
relaxant and a coronary vasodilator
 Quinolines –
Structure
Synthesis
N
N
• pKa values (4.9 and 5.4) are similar to that of pyridine
• Possess aspects of and naphthalene reactivity e.g. form N-oxides and
pyridine ammonium salts
Combes Synthesis (“3+3”)
MeO Me MeO Me
O O MeO

O O
Me Me
H2O
NH2 N Me N Me
H
MeO MeO MeO

c-H2SO4,

MeO Me MeO MeO Me

Me OH
H
O

H2O
N
Me N Me N Me
H H
MeO MeO MeO
23%
 Quinolines –
Conrad-Limpach-KnorrSynthesis
Synthesis (“3+3”)

OEt OH O
O O
O
Me
OEt 270 °C
rt,
NH2 N Me Me N Me
H2O H 70%N H

• Very similar to the Combes synthesis by a -keto ester is used instead of a -diketone
• Altering the reaction conditions can completely alter the regiochemical outcome

Me Me Me
O O

O
Me OEt 250 °C,H2O
140 H2O
N °C, H2 N O N O N OH
H 50% H
 Quinolines –
Synthesis
Skraup Synthesis (“3+3”)
OH
H H
H
H
O O

130 °C, H2SO4

NH2 N N
H H

H OH

[O] (e.g. I2) H2O

N N N
85% H H
• Acrolein can be generated in situ by treatment of glycerol with conc. sulfuric acid
• A mild oxidant is required to form the fully aromatic system from the dihydroquinoline
1. O Me

Me Me
Me
ZnCl2 or FeCl3,
NH2 EtOH, reflux N
2. [O] 65%
 Quinolines –
Synthesis
Friedlander Synthesis (“4+2”)

Ph O Ph Ph
H
Me
O Me O Me Me
H2O
c-H2SO4, AcOH N
NH2
heat N Me 88% Me
H

Ph O Ph Ph
Me
O O
Me H2O
KOH aq., EtOH
NH2 0 °C N N
71%
OH H Me Me

• The starting acyl aniline can be difficult to prepare

• Acidic and basic conditions deliver regioisomeric products in good yields
 Isoquinolines – Synthesis
Pomeranz-Fritsch Synthesis (“3+3”)
EtO OEt
OEt

H2N OEt H , EtOH

O H2O N N

Bischler-Napieralski Synthesis (“5+1”)

MeCOCl P4O10, heat Pd-C, 190 °C

NH2 NH N N
O

Me Me Me
93%
• Cyclisation can be accomplished using POCl3 or PCl5
• Oxidation of the dihydroisoquinoline can be performed using a mild oxidant
 Isoquinolines – Synthesis
Pictet Spengler Synthesis (“5+1”)

MeO MeO MeO

HCHO 20% aq. 20% HCl
aq.
N
NH2
heat 100 °C N
H

MeO MeO MeO

[O]
N NH NH
80% H

• An electron-donating substituent on the carboaromatic ring is required

• A tetrahydroisoquinoline is produced and subsequent oxidation is required to give
the fully aromatic isoquinoline
 Quinolines/Isoquinolines –
Electrophilic Reactions
*
Regiochemistry

N
N H
H
*
• Under strongly acidic conditions, reaction occurs via the salt
ammonium
• Attack occurs at the benzo- rather than hetero-ring
• Reactions are faster than those of pyridine but slower than those of naphthalene

Nitration NO2

fuming HNO3,

N cH2SO4, 0 °C
N N
72% 8%
NO2

• In the case of quinoline, equal amounts of the 5- and 8-isomer are produced
 Quinolines/Isoquinolines –
Electrophilic Reactions
Sulfonation
HO3S
30% oleum3, >250
°C
N 90 °C N
N

SO3H 54% thermodynamic product

• Halogenation is also possible but product distribution is highly dependent on conditions

• It is possible to introduce halogens into the hetero-ring under the correct conditions
• Friedel-Crafts alkylation/acylation is not usually possible
 Quinolines/Isoquinolines –
Nucleophilic Reactions
Regiochemistry

N
N

• Attack occurs at hetero- rather than benzo-ring

• They are enerally more reactive than pyridines to nucleophilic attack

Carbon Nucleophiles
2-MeOC6H4Li H2O
Et2O, rt H OMe
HOMe
N N N
H
Li

[O]

MeO
 Quinolines/Isoquinolines –
Nucleophilic Reactions
n-BuLi H2O [O]
N benzene, rt N NH N
Li
H n-Bu H n-Bu n-Bu
• Oxidation is required to regenerate aromaticity

Amination H NH2

KNH2, NH3 (l) > 45 °C

65 °C
H
N N N
NH2
K K
KMnO4, 65 °C KMnO4, 40 °C

NH2

N NH2 N
50% 60%
thermodynamic product
 Quinolines/Isoquinolines
–
Nucleophilic Substitution
Displacement of Halogen

NaOEt, EtOH
reflux
Cl
N Cl N N OEt
OEt

OMe
Cl OMe
NaOMe, MeOH Cl

N DMSO 100 °C N N
87%
 Quinolines/Isoquinolines –
The Reissert Reaction
PhCOCl KCN
H
N N N
CN
CN
O Ph O Ph

base, MeI

NaOH aq.
M e Me
N Me N N
CN CN

HO Ph O Ph
O

• The proton adjacent to the cyano group is extremely acidic

• The reaction works best with highly reactive alkyl halides
Isoquinolines – Synthesis of a Natural
Product
Synthesis of Papaverine
O O O

MeO MeO MeO

Me Me2CH(CH2)2ONO, ZnCl2, HCl, rt
NH2
NaOEt, EtOH, rt N
MeO MeO OH MeO
75% O Cl

KOH aq., rt

H OH O OMe

MeO MeO MeO OMe

P4H10, Na-Hg, H2O, 50 °C
N xylene, heat O NH O NH
MeO MeO MeO

30% 60%

OMe OMe OMe

MeO MeO MeO

• Cyclisatio achieved by the Pictet-Grams reaction cf. the Bischler-Napieralski

n is reaction
 Bioactive Furans, Pyrroles and
Thiophenes Me2N S
NO2

O NHMe
N

ranitidine
H
• Ranitidine (Zantac®, GSK) is one of the selling drugs in history. It is an
biggest
H2-receptor antagonist and lowers stomach acid levels – used to treat stomach ulcers

O
CO2H
N
Ph
ketorolac

• Ketorolac (Toradol®, Roche) is an analgesic and anti-inflammatory drug

Me

S
N

banminth
• Pyrantel (Banminth®, Phibro) is an anthelminthic agent and is used to treat worms in
livestock
 Furans, Pyrroles and Thiophenes – Structure
Structure

X O N S
.. H

•6 electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion

Resonance Structures

etc.
X
X X X
.. +

• Electron donation into the ring by resonance but inductive electron withdrawal
1.44 Å 1.43 Å 1.42 Å
1.35 Å 1.37 Å 1.37 Å
0.71 D 1.55 D 0.52 D
1.37 Å O 1.38 Å N 1.71 Å S
H

1.68 D 1.57 D 1.87 D

O N S
H
• O and S are more electronegative than N and so inductive effects dominate
 Furans – Synthesis
Paal Knorr Synthesis

R1 R2 R1 R2
R1 R2
O
O O O O OH
H
H H

H heat
H
H

R1 R
2
R
1
O R
1
R
2
O

R
2 O OH2

• The reaction is usually reversible and can be used to convert furans into 1,4-diketones
• A trace of acid is required – usually TsOH (p-MeC6H4SO3H)
 Furans – Synthesis
Feist-Benary Synthesis (“3+2”)
MeO
EtO2C O+ Me EtO2C O Me EtO2C

+ Cl
Me O Cl Me O Cl Me O

NaOH aq., rt

OH
MeOH H
EtO2C Me Me
EtO2C
OH EtO2C Cl
H2O
Me
O Me
O Me O

isolable

• The product prior to dehydration can be isolated under certain circumstances

• Reaction can be tuned by changing the reaction conditions
 Furans – Synthesis
Modified Feist-Benary
I

EtO2C O+ Me EtO2C Me EtO2C Me

+ O O
Me O Cl Me O Me O
I
NaI, NaOEt,
EtOH

EtO
EtO2C EtO2C H
EtO2 C Me
H2O
M O
e
Me Me Me
O Me O
O

OH

• Iodide is a better leaving group than Cl and the carbon becomes

electrophilic
more
• The Paal Knorr sequence is followed from the 1,4-diketone onwards
• The regiochemical outcome of the reaction is completely altered by addition of iodide
 Thiophenes –
Synthesis
Synthesis of Thiophenes by Paal Knorr type reaction (“4+1”)
Me

Me Me
Me Ph
P4S10 S O
Me Ph
Me Me Ph
O O S

Me Ph
O S

• Reaction might occur via the 1,4-bis-thioketone

 Pyrroles – Synthesis
Paal Knorr (“4+1”)
Synthesis

Me Me Me Me Me Me
O H2N
O O O HN

NH3, C6H6,
heat
H
H

Me
N Me R1 1 2
H R R
N
2
R N
H OH H

• Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole
 Pyrroles – Synthesis
Knorr Synthesis (“3+2”)
Pyrrole EtO2C Me
EtO2C O Me
KOH aq.

MeO C O HO2C
NH N
2 2
H
53%

H2N O Me Me N

Me O NH2 N Me

• Use of a free amino ketone is problematic – dimerisation gives a dihydropyrazine

HO Me
EtO2C Me
EtO2C O Me EtO2C EtO2C O Me
NaOH aq.
via or
EtO2C EtO C O NH2 EtO C N
EtO C O NH Cl N
2 3 2 2
H H

• Problem can be overcome by storing amino carbonyl compound in a protected form

• Reactive methylene partner required so that pyrrole formation occurs more rapidly
than dimer formation
 Pyrroles – Synthesis
Liberation of an Amino Ketone in situ by Oxime Reduction
EtO2C Me
EtO2C O Me
Zn, AcOH
or Na2S2O4 aq.
Me
Me O N (sodium dithionite) N
H
O

Preparation of -Keto from -Dicarbonyl Compounds

Oximes H
O O O O
NaNO2, H
(HNO2)
OEt OEt

H2O N O

O O O O
H
OEt OEt

N N
OH O
 Pyrroles – Synthesis
One-Pot Oxime Reduction and Pyrrole Formation
O

O O CO2Et
EtO2C CO2Et
OEt
Zn, AcOH EtO2C
N N
H CO2Et
OH

Hantzsch Synthesis of Pyrroles (“3+2”) Cl

H
EtO2C O Me EtO2C EtO2C
+ Me Me

+ O O
Me O Cl Me NH2 Me NH

NH3 aq.
rt to 60 °C

EtO2C EtO2C
EtO2 C Me
H2O
Me
O
Me Me Me
N N OH Me NH2
H H
41%
• A modified version of the Feist-Benary synthesis and using the same starting materials:
an -halo carbonyl compound and a -keto ester
 Furans, Pyrroles Thiophenes
– Electrophilic Substitution
Electrophilic Substitution – Regioselectivity
H
E E E
XE
E
X H X H X H X

E E E
E H H
H

X X X X

• Pyrrole > furan > thiophene > benzene

• Thiophene is the most aromatic in character and undergoes the slowest reaction
• Pyrrole and furan react under very mild conditions
• -Substitution favoured over -substitution more resonance forms for intermediate and
so the charge is less localised (also applies to the transition state)
• Some -substitution usually observed – depends on X and substituents
NO2

AcONO2

X X NO2
X
X = NH 4:1
X=O 6:1
 Furans – Electrophilic Substitution
Nitration of Furans
AcONO2,
<0 °C NO2 AcO NO2
O (Ac2O, HNO3) O H O H N
H
NO2 AcO isolable
pyridine, heat
AcOH

NO2

NO2
O H O
• Nitration can occur by an addition-elimination process
• When NO2BF4 is used as a nitrating agent, the reaction follows usual mechanism

Bromination of Furans
HBr
Br2, dioxan, 0 °C
Br Br Br
Br
O O H H O H Br
O
Br
Br 80%

• Furan reacts vigorously with Br2 or Cl2 at room temp. to give polyhalogenated products
• It is possible to obtain 2-bromofuran by careful control of temperature
 Furans – Electrophilic Substitution
Friedel-Crafts Acylation of Furan
O

Me
Ac2O, SnCl4, Ac2O, SnCl4,
O
H3PO4 cat., 20 150 °C
Me Me Me O Me
°C O O
O : 6800:1 77%
Me

• Blocking groups at the positions and high temperatures required to give acylation

Vilsmeier Formylation of
Furan
Me Me

Me2NCO, POCl3,
O
0 to 100 °C
O
O

H
76%
Mannich Reaction of Furans
CH2O,
Me2NH.HCl
O O CH2 O NMe2 O
H
NMe2 66% NMe2
 Thiophenes Electrophilic
–
Nitration of
Substitution
Thiophenes
NO2
AcONO2

NO2
S S S

• Reagent AcONO2 generated in situ from c-HNO3 and Ac2O

Halogenation of Thiophenes
Br2, Et2O, Br2, Et2O,
48% HBr, 48% HBr,
Br Br 10 10 °C 25 5 Br
S S S
°C

• Occurs readily at room temperature and even at 30 °C

• Careful control or reaction conditions is required to ensure mono-bromination
 Pyrroles – Electrophilic Substitution
Nitration of Pyrroles
NO2

AcONO2
AcOH, 10 °C
N N NO2 N
H H H
51% 13%

• Mild conditions are required (c-HNO3 and c-H2SO4 gives decomposition)

Vilsmeier Formylation of Pyrroles

Me O Me OPCl2 Me Cl
POCl3 N N
N
Me H Me H Me H

K2CO3 aq.
H H H
Cl
N Cl Me N N N
H H H
H NMe2 NMe2 O
N 83%
H Me
 Pyrroles – Porphyrin Formation
OH
OH OH2
R1 N
N R2 N
R1 R R1 R
2 2
H H H

H R2
N N N N N
H R1 R2 H H R1 R2 H H N
R1
H

R1, R2 = H

NH HN NH HN NH N

NH HN NH HN N HN

no extended aromaticity 18 -electron system

• The extended aromatic 18 -electron system is more stable than that having four
isolated aromatic pyrroles
 Porphyrin Natural Products

CO2H

N N HO2C N N

Fe Mg
N
N N N N
H2N H

porphobilinogen

MeO2C O
HO2C CO2H O
O
haem C20H39 chlorophyll-a

• The pigment haem is found in the oxygen carrier haemoglobin

• Chlorophyll-a is responsible for photosynthesis in plants
• Both haem and chlorophyll-a are synthesised in cells from porphobilinogen
 Furans, Pyrroles Thiophenes –
Deprotonation
Metallation
n-BuLi

H Li
X X
>>
Bu
X=O pK (THF) 35.6
a

X = NR pKa (THF) 39.5

X=S pKa (THF) 33.0

Deprotonation of Pyrroles
R M M
H M
N N N
N
pKa (THF) 39.5
H
pKa (THF) 17.5 M

• Free pyrroles can undergo N or C deprotonation

• Large cations and polar solvents favour N substitution
• A temporary blocking group on N can be used to obtain the C-substituted compound
 Furans, Pyrroles Thiophenes –
Directed Metallation
Control Regioselectivity in Deprotonation
of
Y Y Li Y
n-BuLi Bu

H Li
X X X

Common directing groups: CO2H(Li), CH2OMe, CONR2, CH(OR)2

Synthesis of , ’-Disubstituted Systems

Y Y Y
n-BuLi n-BuLi
E1 E2
E1 E2 E1
X X X

Use of a Blocking Group

Trialkylsilyl
Y Y Y
Y

n-BuLi n-BuLi F
Me3SiCl
X E
 Furans, Pyrroles Thiophenes –
SiMe3
X E SiMe3
X
E
X
 Furans – Synthesis of a
Preparation Drug(Zantac®) Using a Mannich Reaction
Ranitidine
of

Me2NH.HCl,
CH2O, rt Me2N
O O O
O OH OH
furfural
HS(CH2)2NH2,
NO2 c-HCl, heat

NO2
MeS NHMe
Me2N S Me2N S
O
O
N NHMe
NH2
ranitidine H

• Furfural is produced very cheaply from waste vegetable matter and can be reduced to
give the commercially available compound furfuryl alcohol
• The second chain is introduced using a Mannich reaction which allows selective
substitution at the 5-position
• The final step involves conjugate addition of the amine to the , -unsaturated nitro
compound and then elimination of methane thiol
 Indoles – Bioactive Indoles O
H
Me
X N
CO2H NMe2 H

H OO
NH2 S
MeNH

N N N
H H X = OH
lysergic acid H
tryptophan sumatriptan X = NEt2 lysergic acid diethyamide (LSD)

• Tryptophan is one of the amino acids and a constituent of most proteins

essential
• Sumatriptan (Imigran®, GSK) is a drug used to treat migraine and works as an agonist
for 5-HT receptors for in the CNS
• LSD is a potent psychoactive compound which is prepared from lysergic acid, an
alkaloid natural product of the ergot fungus

NH2
HO

N
H
5-hydroxytryptamine (serotonin)
 Indoles – Synthesis
Fischer Synthesis
O
R1
R1
1 2
R R
H or
2
R Lewis acid
R2
NH2 H2 O N NH3
N N N
H H
H
Ph
ZnCl2, 170 °C
Ph
N
N N
H
76% H

H
H
Ph

Ph
NH
N N NH 3
H
H

H
Ph Ph Ph
[3,3]

NH2 NH2 NH2

N NH NH2
H H
• A protic acid or a Lewis acid can be used to promote the reaction
 Indoles – Synthesis
Bischler Synthesis
H
Me
O Me
O Me
polyphosphoric H2O
acid (PPA), 120 KOH aq.
N °C N N
64% H
O CF3 O CF3

• An -arylaminoketone is cyclised under acidic conditions

• The reaction also works with acetals of aldehydes

Me EtO OEt Me
(CF3CO)2O,
CF3CO2H, heat
N N

CF3
O CF3 93% O
 Indoles – Electrophilic
Nitration ofSubstitution
NO2
Indoles
O2N c-H2SO4, c-HNO3 PhCO2NO2, 0 °C
Me Me Me
0 °C
N N
N
H 35% H
84% H

• Polymerisation occurs when there is no substituent at the 2-position

• Halogenation is possible, but the products tend to be unstable

Acylation of Indoles O O
Me Me

Ac2O, AcOH, heat NaOH aq., rt

N N N
H -product! 60% H
O
Me
Ac2O, AcONa Ac2O, AcOH, heat

O
Me
• Acylation occurs at C before N because the N-acylated product does not react
 Indoles – Electrophilic
Substitution
Mannich Reaction
NMe2

CH2O, Me2NH, H2O, heat 93%

H2O, 0 °C or AcOH, rt 68%
N N N

H NMe2 H

H2C NMe2 (preformed) 95%

• A very useful reaction for the synthesis of 3-substituted indoles

• The product (gramine) can be used to access a variety of other 3-substituted indoles

Synthesis of Tryptophan from

Gramine
EtO2C CO2H
CO2Et

NMe2 EtO2C CO2Et

NHAc NH2
Na NaOH aq. then
NHAc
PhMe, heat H2SO4, heat N
N N
H 90% H 80% H
 Indoles – Electrophilic
Substitution
Synthesis of Other 3-Substituted Indoles from Gramine

MeSO4 NMe3 CN CN

NaCN aq., 70 °C

N N N
H2O H H2O H 100% H

• The nitrile group can be modified to give other useful functionality

CN CO2H
NH2
LiAlH4 acid/base hydrolysis

N N N
H H H
 Indoles – Synthesis of a Drug
Synthesis of Ondansetron (Zofran®, GSK) using the Fischer Indole Synthesis
O O
O O

ZnCl2, heat
H2O NH
NHNH2 N N
H H
N
M
e MeI, K CO
2 3
N
Me3N I

O N O O

Me
N
H Me2NH.HCl, CH2O
then MeI
N N N
Me Me Me

• Ondansetron is a selective 5-HT antagonist used as an antiemetic in cancer

chemotherapy and radiotherapy
• Introduction of the imidazole occurs via the , -unsaturated ketone resulting from
elimination of the ammonium salt
 Reference Books

• Heterocyclic Chemistry – J. A. Joule, K. Mills and G.

F. Smith
•
Heterocyclic Chemistry (Oxford Primer Series) – T.
• Gilchrist

Aromatic Heterocyclic Chemistry – D. T. Davies