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
