HeterocycleLectures2011 2C12

Heterocyclic Chemistry
Professor J. Stephen Clark

Room C4-04 Email: stephenc@chem.gla.ac.uk
20112012
http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html
Recommended Reading
Heterocyclic Chemistry J. A. Joule, K. Mills and G. F. Smith
Heterocyclic Chemistry (Oxford Primer Series) T. Gilchrist
Aromatic Heterocyclic Chemistry D. T. Davies
Introduction
Course Summary
Definition of terms and classification of heterocycles

Functional group chemistry: imines, enamines, acetals, enols, and sulfur-containing groups
Intermediates used for the construction of aromatic heterocycles
Synthesis of aromatic heterocycles

Carbonheteroatom bond formation and choice of oxidation state
Examples of commonly used strategies for heterocycle synthesis
Pyridines
General properties, electronic structure
Synthesis of pyridines
Electrophilic substitution of pyridines
Nucleophilic substitution of pyridines
Metallation of pyridines
Pyridine derivatives
Structure and reactivity of oxy-pyridines, alkyl pyridines, pyridinium salts, and pyridine N-oxides
Quinolines and isoquinolines
General properties and reactivity compared to pyridine
Electrophilic and nucleophilic substitution quinolines and isoquinolines
General methods used for the synthesis of quinolines and isoquinolines
Course Summary (cont)

Five-membered aromatic heterocycles
General properties, structure and reactivity of pyrroles, furans and thiophenes
Methods and strategies for the synthesis of five-membered heteroaromatics
Electrophilic substitution reactions of pyrroles, furans and thiophenes

Strategies for accomplishing regiocontrol during electrophilic substitution
Metallation of five-membered heteroaromatics and use the of directing groups
Indoles
Comparison of electronic structure and reactivity of indoles to that of pyrroles
Fisher and Bischler indole syntheses
Reactions of indoles with electrophiles
Mannich reaction of indoles to give 3-substituted indoles (gramines)
Modification of Mannich products to give various 3-substituted indoles
1,2 and 1,3-Azoles
Structure and reactivity of 1,2- and 1,3-azoles
Synthesis and reactions of imidazoles, oxazoles and thiazoles
Synthesis and reactions of pyrazoles, isoxazoles and isothiazoles
4
Introduction
Heterocycles contain one or more heteroatoms in a ring
X
X
Y
carbocycle
X
Y
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 Six-Membered

Isoelectronic carbocycle
Heterocycles
4
3
2
5
1
1
pyridine
pyrylium
2 N
4
3
3 N
5
6
1
pyridazine
1
pyrimidine
1
pyrazine
3
2
2N
8
1
quinoline
1
8
isoquinoline
Classification Aromatic Five-Membered
Isoelectronic carbocycle
Heterocycles
1
furan
1
thiophene
pyrrole
3
3
5
3
5
1
oxazole
1
thiazole
imidazole
3
2N 1
2 N
2N
1
isoxazole
1
isothiazole
pyrazole
4
5
3
2
1
N
H
indole
Classification Unsaturated / Saturated

Unsaturated
aromatic dipolar resonance form

O
4()-pyrone
N
H
N
H
OH
2-pyridone
Saturated
O
O
ethylene oxide
N
H
THF
1,4-dioxan
pyrrolidine
dihydropyran
Functional Group Chemistry

Imine Formation
R3
R3
R3NH2 H
O
R1
R2
N
R1
H3O
R1
R2
R2
H
H
H
3
O
R1
R
R2
N
R1
H
OH
R2
H
3
N
R1
R3
N
OH2
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 cant lose a proton and an
enamine is formed

Enols and Enolates
O
OH
R1
keto form
enol form
O
R1
B
H
R
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
R O
OR
R OH
H
2
enol ether
OR
acetal
R2
H2O
R1
10
R

Enamines
R3
R3
N
H
R3
R3
N
R1
H
R2
R2
iminium ion
(Schiff base)
R3
R3
E
R2
enamine
R3
N
N
1
R2
R3
N
H
R1
R1
H2O
E
R1
R2
R1
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
11

Common Building-Blocks
O
OH
NH2
urea
NH
NH2
H2N
NH2
amides
carboxylic acids
H2N
NH
amidines
O
R1
NH2
guanidine
-diketones
O
R1
R2
O
OR2
-keto esters
Building-Blocks for Sulfur-Containing Heterocycles

O
1
P2S5
R
R
1
SH
R1
R2
S
thioketones
thiols
thioethers
Heterocycle synthesis requires:

CO or CN bond formation using imines, enamines, acetals, enols, enol ethers
CC 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)
12
General Strategies for Heterocycle Synthesis

Ring Construction
Cyclisation 5- and 6-membered rings are the easiest to form
CX bond formation requires a heteroatom nucleophile to react with a C electrophile
Y
conjugate addition
+
X
X, Y = O, S, NR
Manipulation of Oxidation State

[O]
[O]
H2
H2
hexahydro
tetrahydro
[O]
or
H2
X
dihydro
aromatic
Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation

13

Common Strategies
4+1 Strategy
X
X
H
N
N
NH3
2H2O
O
NH3
2H2O
N
H
N
H
Strategy can be adapted to incorporate more than one heteroatom

5+1 Strategy
X
X
H
[O]
NH3
2H2O
O O
H2
N
H
1,5-Dicarbonyl compounds can be prepared by Michael addition of enones
14

3+2 Strategy
3+3 Strategy
or
or
X
Examples
H2N
H2N
H2N
OH
H2N
OH
+ Hal
+
O
O
E
Hal = Cl, Br, I
NH2
NH2
OH
OH
15
Bioactive Pyridines
H
N
N
H
NH2
O
O
sulphapyridine
nicotine
Nicotine is pharmacologically active constituent of tobacco toxic and addictive

Sulphapyridine is a sulfonamide anti-bacterial agent one of the oldest antibiotics
NH2
O
Me
NH
Me
N
paraquat
isoniazide
Paraquat is one of the oldest herbicides toxic and non-selective

Isoniazide has been an important agent to treat tuberculosis still used, but resistance
16
is a significant and growing problem
Drugs Containing a Pyridine

MeO
OMe
OMe
S
N
H
N
H
Name: Aciphex
2008 Sales: $1.05 billion
2008 Ranking: 34 branded
Company: Eisai
Disease: Duodenal ulcers and acid reflux
Name: Nexium
Company: AstraZeneca
Disease: Acid reflux
H
N
S
O
O
NH
N
N
HN
N
N
O
Name: Actos
Company: Eli Lilly
Disease: Type 2 diabetes
Name: Gleevec
Company: Novartis
17
Disease: Chronic myeloid leukemia
Pyridines Structure
1.40
1.39
2.2 D
N
<
<
N 1.34
1.17 D
<
..
N
H
<
Isoelectronic with and analogous to benzene

Stable, not easily oxidised at C, undergoes substitution rather than addition
I Effect (inductive electron withdrawal)
M Effect
Weakly basic pKa ~5.2 in H2O (lone pair is not in aromatic sextet)
Pyridinium salts are also aromatic ring carbons are more + than in parent pyridine
etc.
N
H
18
Pyridines Synthesis
The Hantzsch synthesis (5+1)
O
Ph
Me
Me
Ph
Me NH3 pH 8.5 Me
O
Me
Me aldol condensation Me
Ph
Me
Ph
Me
Me
Michael addition Me
OO
Me
and dehydration
Ph
Me
O
Me
Me
Me
HNO3
oxidation
Me
O
Me
Me
Me
Ph
Me
Me
O
Me
H2N
Me
The reaction is useful for the synthesis of symmetrical pyridines

The 1,5-diketone intermediate can be isolated in certain circumstances
A separate oxidation reaction is required to aromatise the dihydropyridine
19
Pyridines Synthesis
From Enamines or Enamine Equivalents the Guareschi synthesis (3+3)
CN
CO2Et
CN
CO2Et
Me
CN
CN
H2N
O HN
2
K2CO3
Me
N
H
Me
K2CO3
Me
EtO2C
The -cyano amide can exist in the enol form
Me
73%
Using Cycloaddition Reactions (4+2)

CO2H
Me
CO2H
Me
CO2H
H+
Me
O
Me
Diels-Alder Me
cycloaddition
Me
CO2H
CO2H
HO
Me
H2O
Me
N
70%
Me
Me
Oxazoles are sufficiently low in aromatic character to react in the Diels-Alder reaction
20
Pyridines Electrophilic Reactions

Pathways for the Electrophilic Aromatic Substitution of Pyridines
E
N
The position of the equilibrium between the pyridine and pyridinium salt depends on
the substitution pattern and nature of the substituents, but usually favours the salt
21

Regiochemical Outcome of Electrophilic Substitution of Pyridines
H
E
N
E
H
H
E
N
E
H
H
H
H
Resonance forms with a positive charge on N (i.e. 6 electrons) are very unfavourable
The -substituted intermediate, and the transition state leading to this product, have
more stable resonance forms than the intermediates/transition states leading to the
22
/ products

Regiochemical Outcome of Electrophilic Substitution of Pyridinium Ions
H
E
E
E
N
E
H
Regiochemical control is even more pronounced in the case of pyridinium ions

In both pyridine and pyridinium systems, substitution is favoured but the reaction is
slower than that of benzene
23
Reaction will usually proceed through the small amount of the free pyridine available

N Substitution
MeI
NO2 BF4
N
BF4 NO2
Me
R
Cl
Cl
SO3, CH2Cl2
N
SO3
C Substitution
Reaction at C is usually difficult and slow, requiring forcing conditions
Friedel-Crafts reactions are not usually possible on free pyridines
24

Nitration of Pyridine
NO2
c-H2SO4, c-HNO3
300 C, 24 h
N
N
6% !
Use of Activating Groups

Me
Me
Me
NO2
c-HNO3, oleum
100 C
Me
Me
Me
Me
Me
H
Me
Me
Me
90%
Me
NO2
MeI
c-HNO3, oleum
100 C
Me
Me
Me
N
I
Me
Me
Me
N
I
Me
Me 70%
Multiple electron-donating groups accelerate the reaction

Both reactions proceed at similar rates which indicates that the protonation at N occurs
25
prior to nitration in the first case

Sulfonation of Pyridine
SO3H
H2SO4, SO3
(low yield)
N
HgSO4, H2SO4,
220 C
70%
N
HgSO3
Low yield from direct nitration but good yield via a mercury intermediate
Halogenation of Pyridine
Cl
N
33%
Br
Cl2, AlCl3,
Br2, oleum
100 C
130 C
N
N
86%
Forcing reaction conditions are required for direct halogenation

26
Pyridines Reduction
Full or Partial Reduction of Pyridines
R
N
H
H2, Pt,
Na-NH3,
AcOH, rt
EtOH
N
N
H
Na, EtOH
N
H
Pyridines generally resist oxidation at ring carbon atoms and will often undergo
side-chain oxidation in preference to oxidation of the ring
Full or partial reduction of the ring is usually easier than in the case of benzene
27
Pyridines Nucleophilic Reactions

Regiochemical Outcome of Nucleophilic Addition to Pyridines
H
N
Nu
Nu
Nu
Nu
H
Nu
Nu
N
Nu
Nu
Nu
H
N
N
H
Nu
N
H
Nu
Nu
Nitrogen acts as an electron sink

Substitution is less favoured because there are no stable resonance forms with the
negative charge on N
Aromaticity will is regained by loss of hydride or a leaving group, or by oxidation
28

Nucleophilic Substitution
X
Nu
Nu
N
X = Cl, Br, I, (NO2)
Nu = MeO , NH3, PhSH etc.
Favoured by electron-withdrawing substituents that are also good leaving groups

The position of the leaving group influences reaction rate ( > >> )
OEt
Cl
NaOEt
N
Cl
Cl
Cl
40
Cl
NO2
Relative rate
80
3 104
29
Pyridinium Ions Nucleophilic Reactions

Nu
Nu
N
R
N
X = Cl, Br, I, (NO2)
Nu = MeO , NH3, PhSH etc.
Conversion of a pyridine into the pyridinium salt greatly accelerates substitution

Substituent effects remain the same (, >> ) but now >
Cl O2N
Me
Me
NO2
Cl
Cl
N
Me
Relative rate
5 107
Cl
Me
Me
1.5 104
Cl
104
30
Pyridines Pyridyne Formation

Substitution via an Intermediate Pyridyne
Cl
NH2
H2N
NH2
NH2
NaNH2
H2N
H
benzyne
Cl
NH2
H
NH2
N
NH2
NaNH2
N
27%
N
44%
When very basic nucleophiles are used, a pyridyne intermediate intervenes

Pyridynes are similar to benzynes and are very reactive (not isolable)
31

Nucleophilic Attack with Transfer of Hydride
O2 (air)
PhLi, Et2O, 0 C
Ph
N
N
Li
Ph
HN
Li
LiNH2
H2O
H2
H2N
H
N
Li
NHX
H2N
LiNH2
X = H (NH3) / 2-aminopyridine
A hydride acceptor or oxidising agent is required to regenerate aromaticity

The reaction with LiNH2 is referred to as the Chichibabin reaction
32
Pyridines Metal-Halogen Exchange

Direct Exchange of Metal and a Halogen
X
Li
n-BuLi
n-Bu
X = Cl, Br, I
Halogenated pyridines do not tend to undergo nucleophilic displacement with alkyl

lithium or alkyl magnesium reagents
Metallated pyridines behave like conventional Grignard reagents
N Li
Br
Li
n-BuLi,
PhC
Ph
Et2O, 78 C
N
NH
Ph H2O
Ph
N
33
Pyridines Directed Metallation

Use of Directing Groups
Me
OMe
OMe
O
Li
I
O
t-BuLi,
O
I(CH2)2Cl
Et2O, 78 C
N
N
O
Li
90%
Ph
O
Me
Ni-Pr2
Ni-Pr2
LiTMP, 78 C
N
Ni-Pr2
Me
Li
N
Ph
Me
Me
N
LiTMP
NMe2
Directing groups allow direct lithiation at an adjacent position

A Lewis basic group is required to complex the Lewis acidic metal of the base
34
Oxy-Pyridines Structure
Oxy-Pyridines/Pyridones
OH
N
H
OH
N
H
zwitterion
O
1,3-dipole
O
N
H
OH
N
H
zwitterion
N
H
N
H
zwitterion
N
H
N
H
N
H
Subject to tautomerism
The , systems differ from the systems in terms of reactivity and structure
In the case, the equilibrium is highly solvent dependent, but the keto form is favoured
35
in polar solvents
Amino Pyridines Structure

Amino Pyridine Systems
etc.
N
H
NH
NH2
NH2
Contrast with oxy-pyridines

Amino pyridines are polarised in the opposite direction to oxy-pyridines
36
Oxy-Pyridines Reactions
Electrophilic Substitution
Br
OH
Br2, H2O, rt
N
OH
Br
Br
O
NO2
c-H2SO4, c-HNO3
100 C, 2 days
N
H
N
H
38%
Reactions such as halogenation, nitration, sulfonation etc. are possible

N is much less basic than that in a simple pyridine
Substitution occurs ortho or para to the oxygen substituent (cf. phenols)
37
Cl
PCl5
Cl
N
PCl3
PCl3
Cl
H
Cl
Cl
PCl4
Cl
N
Cl
PCl3
Cl
H Cl
O
PCl3
Replacement of the oxygen substituent is possible

In this case, the reaction is driven by the formation of the very strong P=O bond
38
Cycloaddition
O
Me
CO2Me
Me
Me
N
CO2Me
Me
Me
CO2Me
CO2Me
Oxy-pyridines have sufficiently low aromatic character that they are able to participate
as dienes in Diels-Alder reactions with highly reactive dienophiles
39
Alkyl Pyridines Deprotonation

Deprotonation with a Strong Base
CH3
CH2
CH
PhLi
etc.
O
R1
R2
OH
R1
R2
Deprotonation of and alkyl groups proceeds at a similar rate, but alkyl groups are
much more difficult to deprotonate
Bases are also potential nucleophiles for attack of the ring
40
Pyridinium Salts Reactions

Nucleophilic Attack with Reducing Agents
H
BH3
NaBH4,
Me
Me H
N
Me
BH3
EtOH
N
Me H
BH3
Me
N
Me
H Me
H3B
Nucleophilic attack is much easier (already seen this)

Deprotonation of alkyl substituents is easier (weak bases are suitable)
Ring opening is possible by attack of hydroxide
H
N
O2N
N
OH
O2N
OH O2N
etc.
41
NO2
NO2
NO2
Pyridine N-Oxides
N-Oxide Formation
RCO3H
N
O
Cl
O
O
meta-chloroperoxybenzoic acid (m-CPBA)
The reactivity N-oxides differs considerably from that of pyridines or pyridinium salts
A variety of peracids can be used to oxidise N but m-CPBA is used most commonly
N-Oxide formation can be used to temporarily activate the pyridine ring to both
nucleophilic and electrophilic attack
42
Pyridine N-Oxides
H
NO2
NO2
NO2
c-H2SO4,
N
c-HNO3,
100 C
The N-oxide is activated to attack by electrophiles at both the and positions

Nitration of an N-oxide is easier than nitration of the parent pyridine
Reactivity is similar to that of a pyridinium salt in many cases e.g. nucleophilic attack,
deprotonation of alkyl groups etc.
Removal of O
NO2
NO2
NO2
PPh3
N
O
PPh3
O
PPh3
PPh3
Deoxgenation is driven by the formation of the very strong P=O bond
43
Pyridines Synthesis of a Natural Product

Synthesis of Pyridoxine (Vitamin B6) Using the Guareschi Synthesis
EtO
O
Me
EtO
CN
H2N
O2N
CN
c-HNO3, Ac2O, 0 C
piperidine,
EtOH, heat
EtO
Me
N
H
90%
CN
Me
N
H
32%
PCl5, POCl3, 150 C
HO
EtO
EtO
NH2
OH
HO
Me
H2N
1. NaNO2, HCl, 90 C
N
2. 48% HBr (neat)

3. AgCl, H2O, heat Me
O2N
H2, Pd/Pt, AcOH
N
Me
40%
CN
N
40%
Cl
The final sequence of steps involves formation of a bis-diazonium salt from a diamine
Pyridoxine performs a key role as the coenzyme in transaminases
44
Bioactive Quinolines/Isoquinolines
H
Me
NEt2
HO
N
HN
H
MeO
MeO
quinine
chloroquine
Quinine is an anti-malarial natural product isolated from the bark of the Cinchona tree
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 muscle45
relaxant and a coronary vasodilator
Drugs Containing a Quinoline/Isoquinoline

S
CO2H
CO2Et
HO2C
N
Cl
Ph
N
H
O
Name: Singulair
Company: Merck
Disease: Asthma and allergies
Name: Quinapril
2008 Sales: $133 million
2008 Ranking: 84 generic
Company: N/A
Disease: Hypertension and heart failure
HO
N
HN
Cl
OH
Name: Hydroxychloroquine
Company: N/A
Disease: Malaria, lupus erythematosus, rheumatoid arthritis
46
Malaria
Approximately 500 million cases of malaria each year and 13 million deaths
Disease is caused by protazoan parasites of the genus Plasmodium (falciparum, vivax,
ovale and malariae)
Disease spread by the Anopheles mosquito (female)
Cinchona pubescens
47
Anopheles mosquito
Plasmodium monocyte
Quinolines Synthesis
Structure
N
N
pKa values (4.9 and 5.4) are similar to that of pyridine

Possess aspects of pyridine and naphthalene reactivity e.g. form N-oxides and
ammonium salts
Combes Synthesis (3+3)
MeO
Me
MeO
O
Me
Me
MeO
O
Me
H2O
NH2
MeO
Me
MeO
N
H
Me
MeO
c-H2SO4,
MeO
Me
MeO
Me
Me
MeO H
OH
O
H2O
N
MeO
23%
Me
N
H
MeO
N
H
Me
MeO
Me
48
Conrad-Limpach-Knorr Synthesis (3+3)
O
OEt
OH
O
Me
270 C
OEt
rt, H2O
NH2
N
H
Me
70%
Me
N
H
Me
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
O
O
Me
140 C, H2O
NH2
Me
Me
250 C, H2O
OEt
N
H
N
50% H
49
OH
Skraup Synthesis (3+3)
OH
H
H
H
130 C, H2SO4
NH2
N
H
N
H
OH
H2O
[O] (e.g. I2)

N
N
H
N
H
85%
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.
Me
O
Me
Me
Me
ZnCl2 or FeCl3,
NH2 EtOH, reflux
2. [O]
65%
50
Friedlander Synthesis (4+2)
Ph
Ph
O
O
NH2
H
O Me
Me
Me
c-H2SO4, AcOH
heat
N
H
NH2
H2O
Me
88%
N
OH
Me
H2O
Me
KOH aq., EtOH
0 C
Ph
Me
O
Me
Ph
Ph
Ph
71%
Me
Me
The starting acyl aniline can be difficult to prepare

Acidic and basic conditions deliver regioisomeric products in good yields
51
Isoquinolines Synthesis
Pomeranz-Fritsch Synthesis (3+3)
EtO
OEt
OEt
OEt H , EtOH
H2N
O
H2O
Bischler-Napieralski Synthesis (5+1)

MeCOCl
NH2
Pd-C, 190 C
P4O10, heat
NH
O
Me
Me
93%
Cyclisation can be accomplished using POCl3 or PCl5

Oxidation of the dihydroisoquinoline can be performed using a mild oxidant
52
Me
Isoquinolines Synthesis
Pictet Spengler Synthesis (5+1)
MeO
MeO
HCHO 20% aq.
MeO
NH2
20% HCl aq.
heat
100 C
N
H
MeO
MeO
MeO
[O]
NH
N
80%
NH
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
53
Quinolines/Isoquinolines
Electrophilic Reactions
*
Regiochemistry
N
N
Under strongly acidic conditions, reaction occurs via the ammonium salt
Attack occurs at the benzo- rather than hetero-ring
Reactions are faster than those of pyridine but slower than those of naphthalene
NO2
Nitration
fuming HNO3,
N
cH2SO4, 0 C
N
72%
N
8%
NO2
In the case of quinoline, equal amounts of the 5- and 8-isomer are produced
54
Electrophilic Reactions
Sulfonation
HO3S
30% oleum3,
>250 C
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
55
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
N
H
N
OMe
OMe
N
H
Li
[O]
N
MeO
56
Nucleophilic Reactions
H2O
n-BuLi
N
benzene, rt
[O]
NH
Li
H n-Bu
H n-Bu
n-Bu
Oxidation is required to regenerate aromaticity

Amination
H
KNH2, NH3 (l)
NH2
>45 C
65 C
N
K
NH2
KMnO4, 65 C
N
K
KMnO4, 40 C
NH2
50%
NH2
60%
thermodynamic product
57
Displacement of Halogen
NaOEt, EtOH
reflux
N
Cl
Cl
N
DMSO 100 C
OEt
OMe
Cl
NaOMe, MeOH
N
OEt
OMe
Cl
N
N
87%
58
The Reissert Reaction
KCN
PhCOCl
H
N
N
CN
Ph
CN
Ph
base, MeI
NaOH aq.
Me
N
Me
HO
Me
N
CN
Ph
CN
Ph
The proton adjacent to the cyano group is extremely acidic

The reaction works best with highly reactive alkyl halides
59
Isoquinolines Synthesis of a Natural Product

Synthesis of Papaverine
O
MeO
Me Me2CH(CH2)2ONO,
MeO
MeO
ZnCl2, HCl, rt
NaOEt, EtOH, rt
N
MeO
MeO
MeO
OH
75%
NH2
Cl
KOH aq., rt
H
MeO
MeO
xylene, heat
MeO
MeO
OMe
MeO
Na-Hg, H2O, 50 C
P4H10,
N
OMe
OH
NH
MeO
30%
NH
60%
OMe
MeO
OMe
MeO
OMe
MeO
Cyclisation is achieved by the Pictet-Grams reaction cf. the Bischler-Napieralski

reaction
60
Bioactive Furans, Pyrroles and Thiophenes

NO2
Me2N
S
O
N
ranitidine
NHMe
Ranitidine (Zantac, GSK) 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 (Toradol, Roche) is an analgesic and anti-inflammatory drug

Me
N
S
banminth
Pyrantel (Banminth, Phibro) is an anthelminthic agent and is used to treat worms in

61
livestock
Drugs Containing a Furan/Thiophene/Pyrrole

MeO2C
Cl
N
O2N
Name: Plavix
Company: Bristol-Myers Squibb
Disease: Stroke and heart attack risk
NH
O
Name: Nitrofurantoin
2008 Sales: $92 + 72 million
2008 Ranking: 119 and 149 generic
Company: N/A
Disease: Antibiotic for urinary tract infections
F
N
H
HO2C
O
S
Ph
HO
HO
N
NHPh
Name: Cymbalta
Company: Eli Lilly
Disease: Depression
Name: Lipitor
Company: Pfizer
Disease: Lowers LDL levels
62
Furans, Pyrroles and Thiophenes Structure

Structure
N
H
..
6 electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion

Resonance Structures
etc.
X
..
Electron donation into the ring by resonance but inductive electron withdrawal
1.43
1.44
1.35
1.42
1.37
1.37
0.71 D
1.55 D
1.38 N
1.37 O
0.52 D
1.71 S
1.68 D
O
1.87 D
1.57 D
N
H
O and S are more electronegative than N and so inductive effects dominate
63
Furans Synthesis
Paal Knorr Synthesis
R1
R2
O
R1
R2
R1
OH
R2
heat
H
H
R1
R2
R1
R2
R1
R2
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)
64
Furans Synthesis
Feist-Benary Synthesis (3+2)
Me
EtO2C
+ Me
EtO2C
Me
EtO2C
+
Me
Cl
Cl
Me
Cl
Me
NaOH aq., rt
Me
EtO2C
Me
EtO2C
OH
H2O
Me
Me
OH Me
H
EtO2C
Me
OH
Cl
isolable
The product prior to dehydration can be isolated under certain circumstances

Reaction can be tuned by changing the reaction conditions
65
Furans Synthesis
Modified Feist-Benary
I
O
EtO2C
+ Me
EtO2C
Me
+
Me
NaI, NaOEt,
EtOH
EtO2C
Me
O
O
Cl
Me
Me
EtO
EtO2C
EtO2C
EtO2C
H2O
Me
Me
Me
Me
Me
OH
O
Me
Iodide is a better leaving group than Cl and the carbon becomes more electrophilic
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
66
Thiophenes Synthesis
Synthesis of Thiophenes by Paal Knorr type reaction (4+1)
Me
Me
Me
Me
Ph
O
Ph
P4S10
Me
Me
Me
O
Me
Ph
Ph
O
Reaction might occur via the 1,4-bis-thioketone
67
Pyrroles Synthesis
Paal Knorr Synthesis (4+1)
Me
Me
O
Me
Me
Me
O HN
NH3, C6H6,
heat
Me
O H2N
H
H
Me
N
H
Me
R1
N
H
R2
R1
N
OH H
R2
Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole
68
Pyrroles Synthesis
Knorr Pyrrole Synthesis (3+2)
EtO2C
Me
EtO2C
Me
KOH aq.
MeO2C
H2N
Me
HO2C
NH2
Me
Me
N
H
53%
N
NH2
Me
Use of a free amino ketone is problematic dimerisation gives a dihydropyrazine

EtO2C
Me
EtO2C
Me
NaOH aq.
EtO2C
NH3 Cl
HO
Me
EtO2C
via
EtO2C
N
H
EtO2C
EtO2C
EtO2C
N
H
Me
or
NH2
O
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
69
Pyrroles Synthesis
Liberation of an Amino Ketone in situ by Oxime Reduction
EtO2C
Me
EtO2C
Me
Zn, AcOH
Me
or Na2S2O4 aq.
(sodium
dithionite)
N
Me
N
H
OH
Preparation of -Keto Oximes from -Dicarbonyl Compounds

H
O
NaNO2, H
OEt
(HNO2)
OEt
H2O
O
H
OEt
N
OEt
N
OH
70
Pyrroles Synthesis
One-Pot Oxime Reduction and Pyrrole Formation
O
CO2Et
O
EtO2C
CO2Et
OEt
Zn, AcOH
EtO2C
N
OH
Hantzsch Synthesis of Pyrroles (3+2)

O
EtO2C
CO2Et
Cl
H
+ Me
EtO2C
Me
+
Me
N
H
EtO2C
Me
O
O
Cl
Me
Me
NH2
NH
NH3 aq.
rt to 60 C
EtO2C
EtO2C
EtO2C
H2O
Me
Me
N
H
41%
Me
Me
N
H
OH
Me
Me
O
NH2
A modified version of the Feist-Benary synthesis and using the same starting materials:
an -halo carbonyl compound and a -keto ester
71
Furans, Pyrroles Thiophenes

Electrophilic Substitution Regioselectivity
H
E
E
X
H
E
E
X
H
E
E
H
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
NO2
X = NH 4:1
6:1
X=O
72
Furans Electrophilic Substitution

Nitration of Furans
AcONO2,
NO2
<0 C
(Ac2O, HNO3)
NO2
O
AcO
NO2
AcO
isolable
pyridine, heat
AcOH
NO2
O
NO2
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,
Br
0 C
O
Br
Br
Br
Br
H
O
80%
Br
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
73
Furans Electrophilic Substitution

Friedel-Crafts Acylation of Furan
O
Me
Ac2O, SnCl 4,
Ac2O, SnCl 4,
H3PO4 cat., 20 C
O
Me
O
:
6800:1
Me
Me
150 C
Me
Me
O
77%
Blocking groups at the positions and high temperatures required to give acylation
Vilsmeier Formylation of Furan
Me
Me
Me2NCO, POCl3,
0 to 100 C
O
O
H
76%
Mannich Reaction of Furans

CH2O,
Me2NH.HCl
O
CH2
NMe2
NMe2
O
66%
NMe2
74
Thiophenes Electrophilic Substitution

Nitration of Thiophenes
NO2
AcONO2
S
NO2
Reagent AcONO2 generated in situ from c-HNO3 and Ac2O
Halogenation of Thiophenes
Br
Br2, Et2O,
Br2, Et2O,
48% HBr,
Br 10 10 C
48% HBr,
25 5 C
Br
Occurs readily at room temperature and even at 30 C

Careful control or reaction conditions is required to ensure mono-bromination
75
Pyrroles Electrophilic Substitution

Nitration of Pyrroles
NO2
AcONO2
AcOH, 10 C
N
H
N
H
51%
NO2
N
H
13%
Mild conditions are required (c-HNO3 and c-H2SO4 gives decomposition)

Vilsmeier Formylation of Pyrroles
Me
Me
O
POCl3
N
Me
Me
OPCl2
N
Me
Cl
N
Me
H
K2CO3 aq.
Cl
N
H
Me
Cl
N
H
N
H
NMe2
N
H
NMe2
N
H
83%
Me
76
Pyrroles Porphyrin Formation

OH
OH2
OH
1
N
H
N
H
N
H
H
N
H
1
N
H
N
H
N
H
N
H
N
H
R1
R ,R =H
NH
HN
NH
HN
NH
NH
HN
NH
HN
no extended aromaticity
HN
18 -electron system
The extended aromatic 18 -electron system is more stable than that having four
isolated aromatic pyrroles
77
Porphyrin Natural Products
CO2H
N
HO2C
Fe
N
N
Mg
N
H2N
N
H
porphobilinogen
MeO2C
HO2C
CO2H
haem
O
O
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
78

Deprotonation
Metallation
n-BuLi
H
X
Bu
Li
>>
X = O pKa (THF)
X = NR pKa (THF)
X=S
pKa (THF)
35.6
39.5
33.0
Deprotonation of Pyrroles
R M
N
H
pKa (THF) 39.5
H
pKa (THF) 17.5
M
N
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
79

Directed Metallation
Control of Regioselectivity in Deprotonation
Y
Y
n-BuLi
Li
Bu
X
Li
Common directing groups: CO2H(Li), CH2OMe, CONR2, CH(OR)2
Synthesis of ,-Disubstituted Systems

Y
n-BuLi
E
n-BuLi
E2
E2
Use of a Trialkylsilyl Blocking Group

Y
Y
n-BuLi
X
SiMe3
Y
F
n-BuLi
Me3SiCl
X
SiMe3
80
Furans Synthesis of a Drug

Preparation of Ranitidine (Zantac) Using a Mannich Reaction
Me2NH.HCl,
O
furfural
CH2O, rt
Me2N
O
OH
OH
HS(CH2)2NH2,
c-HCl, heat
NO2
NO2
Me2N
NHMe
Me2N
O
N
ranitidine
MeS
NHMe
S
O
NH2
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
81
Indoles Bioactive Indoles

O
H
Me
X
CO2H
H
NMe2
O
NH2
N
H
O
S
MeNH
N
tryptophan
sumatriptan
X = OH lysergic acid
H
X = NEt2 lysergic acid diethyamide (LSD)
Tryptophan is one of the essential amino acids and a constituent of most proteins
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)
82
Indoles Lysergic Acid
The Beggars (The Cripples) by Pieter Breugel the Elder (1568)

Louvre Museum, Paris
83
Drugs Containing an Indole
H
N
NMe2
N
H
H
N
O
S
O
N
H
Name: Cialis O
Company: Eli Lilly
Disease: Erectile disfunction
Name: Imitrex
Company: GlaxoSmithKline
Disease: Migraine
NMe2
O
O
N
S
N
N
N
Ph
N
H
Name: Maxalt
Company: Merck
Disease: Migraine
N
H
Name: Relpax
Company: Pfizer
Disease: Migraine
84
Indoles Synthesis
Fischer Synthesis
R1
2
R
N
H
NH2
H2O
H or
Lewis acid
NH3
N
H
Ph
ZnCl2, 170 C
Ph
N
H
76%
H
Ph
Ph
NH
N
H
NH3
H
H
Ph
Ph
Ph
[3,3]
N
H
NH2
NH
NH2
A protic acid or a Lewis acid can be used to promote the reaction
NH2
NH2
85
Indoles Synthesis
Bischler Synthesis
H
O
Me
Me
polyphosphoric
Me
H2O
KOH aq.
acid (PPA), 120 C

N
64% H
O
CF3
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
O
CF3
93% O
CF3
86
Indoles Electrophilic Substitution

Nitration of Indoles
NO2
O2N
Me
c-H2SO4, c-HNO3
Me
0 C
PhCO2NO2, 0 C
Me
N
84% H
35% H
Polymerisation occurs when there is no substituent at the 2-position

Halogenation is possible, but the products tend to be unstable
O
Acylation of Indoles
O
Me
Ac2O, AcOH, heat
Me
NaOH aq., rt
N
-product!
N
O
60% H
Me
Ac2O, AcONa
Ac2O, AcOH, heat
N
O
Me
Acylation occurs at C before N because the N-acylated product does not react
87

Mannich Reaction
NMe2
CH2O, Me2NH,
H2O, heat 93%
H2O, 0 C
or AcOH, rt 68%
NMe2
H2C
N
H
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
NMe2 EtO2C
CO2H
CO2Et
CO2Et
NHAc
Na
N
H
NHAc
PhMe, heat
NH2
NaOH aq. then

N
90% H
H2SO4, heat
N
80% H
88

Synthesis of Other 3-Substituted Indoles from Gramine
MeSO4
NMe3
CN
CN
NaCN aq., 70 C
N
H2O
H2O
100% H
The nitrile group can be modified to give other useful functionality

CN
CO2H
NH2
LiAlH4
N
H
acid/base hydrolysis
N
H
N
H
89
Indoles Synthesis of a Drug

Synthesis of Ondansetron (Zofran, GSK) using the Fischer Indole Synthesis
O
ZnCl2, heat
H2O
NH
NHNH2
N
MeI, K2CO3
Me3N I
O
N
H
Me
Me
N
N
H
Me
Me2NH.HCl, CH2O
N
then MeI
Me
N
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
90
elimination of the ammonium salt
1,3-Azoles Bioactive 1,3-Azoles

MeHN
H2N
N
Me
Me
H
N
S
CN
N
O
MeO
S
N
O-methylhalfordinol
HO
vitamin B1 (thiamin)
Me
N
H
cimetidine
O-Methylhalfordinol is a plant-derived alkaloid

Vitamin B1 (thiamin) is essential for carbohydrate metabolism. Deficiency leads to
beriberi, a disease which is characterised by nerve, heart and brain abnormalities
Cimetidine (Tagamet, GSK) is an H2-receptor antagonist which reduces acid
secretion in the stomach and is used to treat peptic ulcers and heartburn
91
Drugs Containing a 1,3-Azole

NO2
H
N
H
N
S
N
NH2
N
N
N
Name: Mirapex
Company: Boehringer Ingelheim
Disease: Parkinson's disease
Name: Azathioprine
Company: N/A
Disease: Kidney transplant rejection
Cl
N
Ph
O
O
N
H
N
H
O
N
N
H
N
N
OH
NH
N
OH
Ph
Name: Norvir
2008 Sales: $0.31billion
Company: Abbott
Disease: HIV/AIDS
Name: Cozaar
Company: Merck
Disease: Hypertension
92
1,3-Azoles Synthesis
The Hantzsch Synthesis (3+2)
O
NH2
+ Me
+
Me
Me
Me
HO
O NH2
C6H6, heat
Cl
Me
H
N
Me
Me
Me
H2O
N
S
43%
Me
HO
N
S
Me
The reaction is particularly important for the synthesis of thiazoles

A thiourea can be used in place of a thioamide leading to a 2-aminothiazole
93
Cyclodehydration of -acylaminocarbonyl compounds
N
c-H2SO4, rt
Ph
Ph
Ph
O
Ph
O
H2O
Ph
Ph
H2O
Ph
O
72%
A particularly important strategy for the synthesis of oxazoles which is known as the
Robinson-Gabriel Synthesis
The starting -acylaminocarbonyl compounds are easily prepared
From Isocyanides
Ts
H
Ts
Me
K2CO3, MeOH
N
N
C
t-Bu
Ts = O2S
Ts
N
Me
Me
H
Me
t-Bu
t-Bu
Me
t-Bu
94%
Tosylmethylisocyanide (TOSMIC) is a readily available isocyanide

Route can be adapted to give oxazoles and thiazoles using an acid chloride or a
94
thiocarbonyl compound
Ph
1,3-Azoles Electrophilic Substitution

Nitration
N
O2N
O2N
N
c-HNO3,
1% oleum, rt
N
H
N
H
N2O4/BF3
rt 70 C
Me
+
O2N
Me
S
59%
90%
Me
S
27%
Imidazoles are much more reactive to nitration than thiazoles (activation helps)
Imidazoles usually nitrate at the 4-position and thiazoles tend to react at the 5-position
Oxazoles do not generally undergo nitration
Halogenation
Br
N
Br
N
Br2, AcOH,
Na2SO3 aq.,
NaOAc, rt
N
H
heat
Br
N
H
78%
Br
N
H
58%
Imidazoles are brominated easily and bromination at multiple positions can occur
Thiazole does not brominate easily but 2-alkylthiazoles brominate at the 5-position
95

Acylation
O
O
Ph
N PhCOCl, Et3N,
O
Ph
Ph
H2O
Ph
MeCN, rt
N
Me
Me
Me
Me
Ph
N
Me
71%
1,3-Azoles do not undergo Friedel-Crafts acylation because complexation between the

Lewis acidic catalyst and N deactivates the ring
Acylation can be accomplished under mild conditions via the N-acylimidazolium ylide
96
1,3-Azoles Nucleophilic Substitution

Displacement of Halogen
N
PhSNa, MeOH, rt
Cl
SPh
S
75%
There are many examples of displacement of halogen at the 2-position

2-Halothiazoles react rapidly with sulfur nucleophiles, and are even more reactive than
2-halopyridines
n-Pr
n-Pr
N
PhNHMe,
Ph
xylene, 155 C
n-Pr
Cl
n-Pr
96%
Me
2-Halo-1-alkylimidazoles and 2-halooxazoles will react with nitrogen nucleophiles

97
1,3-Azoles Metallation
Direct Deprotonation
N
1.
n-BuLi, THF, 78 C
then ZnCl2
N
Pd(PPh3)4
ZnCl 2. acid aq.
SO2NMe2
SO2NMe2
Br
N
N
H
90%
Direct deprotonation oxazoles, thiazoles and N-alkylimidazoles occurs preferentially at

either the 2- or 5-position
Transmetallation of the lithiated intermediate is possible
Metal-Halogen Exchange
OH
Ph
Br
N
Ph
1. t-BuLi (2 equiv.)
2. Ph2CO
N
H
N
H
64%
Metallation at the 4-position can be accomplished by metal-halogen exchange

In the case of imidazoles without substitution at the 1-position, two equivalents of base
98
are required
1,2-Azoles Bioactive 1,2-Azoles

CF3
O
NH
N
N
Me
Me
O
CF3
leflunomide
celecoxib SO2NH2
Leflunomide (Arava, Sanofi-Aventis) inhibits pyrimidine synthesis in the body and is

used for the treatment of rheumatoid arthritis and psoriatic arthritis
Celecoxib (Celebrex, Pfizer) is a non-steroidal anti-inflamatory (NSAID) used in the
treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and
menstrual symptoms
Celecoxib is a COX-2 inhibitor, blocking the cyclooxygenase-2 enzyme responsible
for the production of prostaglandins. It is supposed to avoid gastrointestinal problems
associated with other NSAIDs, but side effects (heart attack, stroke) have emerged
99
Synthesis of Pyrazoles/Isoxazoles from 1,3-Dicarbonyl Compounds and Hydrazines or
Hydroxylamines (3+2)
Me
Me
O
H2N
NH2
OEt
Me
H2NNH2,
NaOH aq., rt
Me
N
N
H
75%
EtO
OEt
OEt
HO
NH2
H2NOH.HCl
H2O, heat
N
O
84%
This is the most widely used route to pyrazoles and isoxazoles

The dicarbonyl component can be a -keto ester or a -keto aldehyde (masked)
When a -keto ester is used a pyrazolone/isoxazalone is formed
100
Synthesis of Isoxazoles by Cycloaddition of Nitrile Oxides to Alkynes or Enamines
(3+2)
Et
EtO2C
EtCNO
N
Et
Me
Me
N
N
Et
EtO2C
EtO2C
C
N
Me
EtO2C
N
O
70%
Me
Nitrile oxides react readily with alkenes and alkynes

Addition to an alkene generates an isoxazoline unless a leaving group is present
Ph
Cl
Ph
Ph
Et3N, Et2O, rt
N
HO
PhCCH
N
O
Ph
Ph
N
O
76%
Mono-alkyl/-aryl alkynes react to give 3,5-disubstituted isoxazoles but when the alkyne
possesses two substituents mixtures of 3,4- and 3,5-disubstituted isoxazoles are
usually produced
101

Nitration of Isoxazoles, Pyrazoles and Isothiazoles
O2N
c-HNO3, Ac2O,
N
c-H2SO4, 0 C
AcOH, rt
N
H
NO2
N
H
80%
70%
Pyrazoles and isothiazoles undergo straightforward nitration

1-Nitropyrazole is formed in good yield by treatment of pyrazole with the mild nitrating
reagent, acetyl nitrate
1-Nitropyrazole can be rearranged to give 4-nitropyrazole by treatment with acid at
low temperature
Me
Me
O2N
f-H2SO4,
N
O
c-HNO3,
0 70 C
N
O
40%
Isoxazole nitrates in very low yield, but 3-methylisoxazole is sufficiently reactive to

undergo nitration at the 4-position
102

Halogenation of Isoxazoles, Pyrazoles and Isothiazoles
H
Br Br
Br
Br
Br
Br2, NaOAc
N
N
H
N
H
N
H
Halogenation (iodination, bromination) of pyrazole leads to the 4-halopyrazole

Poor yields are obtained when attempting to halogenate isoxazole or isothiazole, but
bromination can be accomplished when an activating group is present as a substituent
O
Acylation
Me
Cl
N
N
Me
Ph
PhCOCl, AlCl3,
Cl
O
H
N
N
Me2NCHO, POCl3,
N
95 C
Me
95 C then H 2O
Me
Me
33%
Me
Only N-substituted pyrazoles can be C-acylated directly

Vilsmeier formylation produces the 4-formylpyrazole in modest yield
103
Direct Metallation of Isoxazoles, Pyrazoles and Isothiazoles
Ph
n-BuLi, THF,
n-BuLi, MeI
N
Me
Ph
78 C then CO 2
HO2C
Ph
Ph
N
S
88%
1-Substituted pyrazoles and isothiazoles can be lithiated and alkylated at the 5-position
1. n-BuLi, THF,
78 C
N
H
N
N
H
CH2O, EtOH, heat
N
N
2. PhNCO
3. HCl aq.
PhNH
N
N
H
79%
It is possible to temporarily protect the 1-position of pyrazole and then perform

sequential deprotonation and alkylation/acylation at the 5-position
104
Direct Metallation of 4-Bromopyrazoles
Br
Br
Br
CO2
n-BuLi, Et2O,
78 C
Li
N
SO2Ph
HO2C
SO2Ph
SO2Ph
65%
At low temperature, N-sulfonyl 4-bromopyrazoles can be lithiated at 5-position without

undergoing metal-halogen exchange
Metallation of 4-Bromopyrazoles by Metal-Halogen Exchange
OH
H
Br
Li
S
O
n-BuLi, THF,
N
N
H
78 C
N
N
N
39%
N
H
Li
Treatment of 4-bromopyrazole with two equivalents on n-butyllithium results in

N-deprotonation and exchange of lithium for bromine
2,5-Dilithiopyrazole reacts with carbon electrophiles to give the 4-substituted product
105
1,2-Azoles Side Chain Deprotonation

Deprotonation of 5-methylisothiazole and 5-methylisoxazole
3-O2NC6H4CHO,
Me
N
S
O2N
Ac2O, piperidine
150 C
N
S
42%
A weak base can be used to deprotonate 5-methylisothiazole and 5-methylisoxazole

In this case above, dehydration of the initial product occurs in situ
Surprisingly, 3-methylisothiazole does not deprotonate as easily as 5-methylisothiazole
and the same effect is found in isoxazoles
Me
Me
CH2CHCH2Br
n-BuLi, THF,
Me
Me
78 C
Li
80%
Metal-halogen exchange can be used to avoid deprotonation of alkyl groups

Me
Br
Me
Br2
Me
N
O
Me
N
O
1. n-BuLi, THF,
78 C
2. CO2
3. HCl aq.
HO2C
Me
Me
N
O
106
1,2-Azoles Synthesis of a Drug

Synthesis of Celecoxib (Celebrex, Pfizer)
Me
CF3
CF3
N
N
Me
O
Me
F3C
N
N
NH2NH2
celecoxib SO2NH2
SO2NH2
SO2NH2
A regioisomeric mixture is formed requiring separation and disposal of the side product
Me
CF3
F3C
CF3
OSO2Ph
N
N
HN
N
Me
Et3N, THF, EtOAc
5 10 C
SO2NH2
SO2NH2
72%
SO2NH2
107
1,3-Dipolar cycloaddition of a nitrile imine offers a regioselective alternative route

HeterocycleLectures2011 2C12

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HeterocycleLectures2011 2C12

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Heterocyclic Chemistry

Professor J. Stephen Clark

Definition of terms and classification of heterocycles

Synthesis of aromatic heterocycles

Course Summary (cont)

Electrophilic substitution reactions of pyrroles, furans and thiophenes

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

Classification Aromatic Six-Membered

Classification Aromatic Five-Membered

Classification Unsaturated / Saturated

aromatic dipolar resonance form

Functional Group Chemistry

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

Functional Group Chemistry

Functional Group Chemistry

Functional Group Chemistry

Building-Blocks for Sulfur-Containing Heterocycles

Heterocycle synthesis requires:

General Strategies for Heterocycle Synthesis

Manipulation of Oxidation State

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

General Strategies for Heterocycle Synthesis

Strategy can be adapted to incorporate more than one heteroatom

1,5-Dicarbonyl compounds can be prepared by Michael addition of enones

General Strategies for Heterocycle Synthesis

Hal = Cl, Br, I

Nicotine is pharmacologically active constituent of tobacco toxic and addictive

Paraquat is one of the oldest herbicides toxic and non-selective

Drugs Containing a Pyridine

Isoelectronic with and analogous to benzene

The reaction is useful for the synthesis of symmetrical pyridines

The -cyano amide can exist in the enol form

Using Cycloaddition Reactions (4+2)

Pyridines Electrophilic Reactions

Pyridines Electrophilic Reactions

Pyridines Electrophilic Reactions

Regiochemical control is even more pronounced in the case of pyridinium ions

Pyridines Electrophilic Reactions

Pyridines Electrophilic Reactions

Use of Activating Groups

Multiple electron-donating groups accelerate the reaction

Pyridines Electrophilic Reactions

Forcing reaction conditions are required for direct halogenation

Pyridines Nucleophilic Reactions

Nitrogen acts as an electron sink

Pyridines Nucleophilic Reactions

Nu = MeO , NH3, PhSH etc.

Favoured by electron-withdrawing substituents that are also good leaving groups

Pyridinium Ions Nucleophilic Reactions

Nu = MeO , NH3, PhSH etc.

Conversion of a pyridine into the pyridinium salt greatly accelerates substitution

Pyridines Pyridyne Formation

When very basic nucleophiles are used, a pyridyne intermediate intervenes

Pyridines Nucleophilic Reactions

A hydride acceptor or oxidising agent is required to regenerate aromaticity

Pyridines Metal-Halogen Exchange

Halogenated pyridines do not tend to undergo nucleophilic displacement with alkyl

Pyridines Directed Metallation

Directing groups allow direct lithiation at an adjacent position

Amino Pyridines Structure

Contrast with oxy-pyridines

Reactions such as halogenation, nitration, sulfonation etc. are possible

Replacement of the oxygen substituent is possible