Heterocyclic Chemistry

Introduction
• Heterocycles contain one or more heteroatoms in a ring

Z
X X X

Y Y
carbocycle heterocycles − X, Y, Z are usually O, N or S

• Aromatic, or partially or fully saturated – this course will focus on aromatic 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 Five-Membered
Heterocycles
3 4 3 4 3 4

2 1 5 2 5 2 5
N 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
 Bioactive Furans, Pyrroles and Thiophenes
NO2
Me2N S
O
NHMe
N

ranitidine H

• Ranitidine is one of the biggest selling drugs in history. It is an

H2-receptor antagonist and lowers stomach acid levels – used to treat stomach ulcers

O
CO2H
N
Ph

ketorolac

• Ketorolac is an analgesic and anti-inflammatory drug

Me

S
N

banminth
• Pyrantel is an anthelminthic agent and is used to treat worms in
livestock
Drugs Containing a Furan/Thiophene/Pyrrole
MeO2C Cl
O

N
N NH
N
O2N
S O
O
Name: Plavix Name: Nitrofurantoin

Disease: Stroke and heart attack risk Disease: Antibiotic for urinary tract infections

N
H
HO2C
O
HO Ph
S
HO N
NHPh

Name: Cymbalta Name: Lipitor O

Disease: Depression Disease: Anti Asthma

 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 R2 R1 R2 R1 R2
O O 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”)
Me O
EtO2C O δ+ Me EtO2C O Me EtO2C

δ+ Cl
Me O Cl Me O Cl Me O

NaOH aq., rt

OH Me OH
EtO2C Me EtO2C Me H
OH EtO2C Cl
−H2O

Me Me
O O Me O
isolable

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

• Reaction can be tuned by changing the reaction conditions
 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 Synthesis (“4+1”)

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

NH3, C6H6,
heat
H
H

Me Me R1 R2 R1 R2
N N N
H H OH H

• Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole
 Furans, Pyrroles Thiophenes –
Electrophilic Substitution
Electrophilic Substitution – Regioselectivity
−H
α E E E
E
X X H X H X H X
E

E E E
E H H
−H
β
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

NO2
AcONO2

NO2
X X 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 H O H N
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
Br2, dioxan, −HBr
0 °C Br Br Br
Br
O Br O H H O H O
Br 80%
Br

• 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, SnCl 4, Ac2O, SnCl 4,
O
H3PO4 cat., 20 °C 150 °C
Me Me Me Me
O O O O
Me
α:β
β 6800:1 77%

• Blocking groups at the α positions and high temperatures required to give β 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 NMe2 O NMe2 O
H
66% NMe2
74
 Thiophenes – Electrophilic Substitution
Nitration of 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 °C Br
S S S

• 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
NO2
N N 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

H K2CO3 aq.
H H
Cl
N Cl Me N N N
H H NMe2 H NMe2 H O
N 83%
H Me