CM4103 Heterocycles
Heteroaromaticity:
Ring system containing at least one heteroatom (O, N, S) can be described as
heterocyclic.
Heterocycles can be aromatic (eg pyridine) or non-aromatic (eg piperidine).
Main focus of this course will be on aromatic heterocycles.
N
N
H
pyridine
piperidine
Pyridine can be seen as replacing a CH unit in benzene with an sp2
hybridised N atom. N has a lone pair instead of H, but this is not involved in
six  electron cloud.
What about pyrrole?
Etc.
N
H
N
H
pyrrole
Again N atom is sp2 hybridised with the lone pair of electrons in p orbital at
right angles to the ring. Delocalisation of this lone pair leads to aromaticity.
Different types of heterocycles
N
N
H
Indole
O
Oxazole
N
H
Imidazole
S
Thiazole
N
N
N
O
O
Isoxazole
Isothiazole
N
N
H
Pyrazole
N
N
N
N
N
O
S
Oxadiazole
N
N
N
Thiadiazole
N
N
N
N
N
O
Oxatriazole
N
N
N
N
H
Triazole
S
Thiatriazole
N
H
Tetrazole
O
O
coumarin
O
O
chromone
Revision – Imine formation
REACTION WITH NITROGEN NUCLEOPHILES - 1° AMINES FORMATION OF IMINES:
CH3
:
:
O
N
C
+ H2NCH3
CH3
+ H2O
C
CH3
CH3
CH3
Imine aka Schiff base
Mechanism:
+
H3O
R
H
R
+
H2O
C
C
C
+
NH2R
HO
H
R
:
O
+
OH
NHR
C
H
:NH2 R
Proton
transfer
R
H
- H2O
H
R
N
- H+
C
R
H
R
N+
C
R
H
Question: Imine formation is acid catalysed as illustrated above but will not
proceed if more than a catalytic trace of acid is present. Can you guess
why?
Imine linkage present in many heterocycles – cyclisation of amino and
carbonyl groups. Enamine type linkage also important in the synthesis of
heterocycles.
R
N
R
O
R
OH
R
NH 2
NH 2
N
H
R
O
R
OH
R
S
R
OH
OH
SH
R
O
R
O
OH
OH
Substituted Heterocycles
(a) Introduce substituents after the heterocycle has been formed.
(b) Incorporate substituents at the same time as formation of the cyclic ring.
Many drugs are heterocyclic molecules – quite polar and interact with
receptors and active sites of enzymes.
E.g. Anti-migraine drugs – indoles modeled on Serotonin.
NH2
HO
N
H
Serotonin
N
H
Pyrrole
S
Thiophene
Heterocycles also important in materials – conducting polymers
(polypyrroles). Pyrrole polymerises easily and decomposes. Only when it is
substituted can it be stabilized and properties exploited.
Light emitting diodes – substituted thiophenes.
Dipolar Cycloadditions
1,3 Dipolar cycloadditons used to synthesise 5 membered heterocycles
including fused heterocycles.
a
b
d
b
c
c
a
e
d
e
I
4  electron system undergoing
cycloaddition with 2  electron system
a
b
b
c
c
a
d
e
d
e
II
Isoelectric with Diels-Alder reaction.
Mechanism: - Concerted pericyclic reaction
- Highly sterospecific
- Some regioselectivity (orientation of 2 components relative to
each other).
Intramolecular 1,3-dipolar cycloaddition reactions – leads to formation of
fused heterocycles.
a
-
b
d
c
e
b
c
a
d
e
Frontier-Orbital Analysis works well for 1,3-dipolar cycloadditions.
Need to identify HOMO and LUMO of dipolar species.
Can have octet stabilized and non-octet stabilized 1,3-dipoles:
a
b
c
a
b
c
Many synthetically useful 1,3-dipoles have a lone pair of electrons on b. Can
write a resonance form where electrons are transferred to a and therefore it is
octet stabilized.
H2C
C
H
CH2
H2C
C
H
CH2
Allyl anion is a model system and is isoelectronic
with 1,3 - dipole
1,3 dipolar cycloadditions are thermally allowed processes.
1,3- dipoles
Some are reactive intermediates and to use them synthetically they must be
generated from the precursor in the presence of a ‘trap’.
reagent
Precursor
a
b
c
d
e
d
e
5 membered
heterocycles
(Dipolarophile)
Other 1,3 - dipoles are stable species
C
N
O
C
N
N
C
N
C
C
N
C
O
N
C
N
Nitrile Oxides
N
C
Nitrile Imines
Nitrile Ylides
N
N
N
N
N
N
Azides
N
N
O
N
N
O
Nitrous oxide
C
N
N
C
N
N
C
N
N
Diazoalkanes
Very few non-octet stabilized 1,3 dipoles – vinyl nitrenes
N
N
General synthesis of 1,3 - dipoles
C
N
X
(X = C, N, O)
R
N
Cl
X
NEt3
R
C
N
X
H
H
- H+
R
R
C
N
X
R
O
H
N
H
R
Cl2 (g)
O
N
CHCl3
- 10 oC
H
Cl
O
H
Nitrile Oxide Precursor
O
PCl5
R
R
N
NHNHR1
Cl
NR1
H
Nitrile imine precursor
O
R
PCl5
R
N
NHCH
C
Cl
H
Nitrile ylide precursor
octet
N
N
stabilised
O
O
Nitrones
Generally stable compounds
Synthesis:
1.
OH
O
+
N
HN
OH
O
2.
N
mCPBA
N
Oxidation of imines
Not a reliable method because you may also get production of
the corresponding oxaziridine
O
N
Carbonyl Ylides
In the majority of cases they are not stable and are generated as reactive
intermediates.
O
C
O
C
Can be used to generate tetrahydrof uran type molecules
O
O
+
C
From a synthetic point of view substituted tetrahydrofurans
would attract more interest than THF.
Synthesis:
1. Electrocyclic ring opening of epoxides
O
O
C
EWG
EWG
In order to be successful the EWG is required to stabilise the carbanion.
This reaction can occur under photochemical or thermal conditions.
2. Addition of a carbene or carbenoid to the O of an aldehyde or ketone
O
O
C
For intramolecular reactions the yields can be very low
This reaction works better for an intramolecular type reaction.
O
O
X
Regioselectivity
R
C
N
O
Methyl acrylate
EWG
CO2Me
2 potential 5-membered outcomes due to the dif fering
orientations of the dipole relative to the alkene.
R
N
O
N
R
O
or
CO2Me
MeO2C
Look at Frontier Orbitals for the 2 species.
The majority of cycloadditons are HOMO (dipole) controlled
HOMO (dipole) + LUMO (alkene)
Substituents influence the magnitude of the orbital coef ficients
Major product above is:
R
N
O
CO2Me
Ph
N
N
N
N
Ph
Ph
C
C
N
N
This reaction isn't synthetically
usef ul
N
+
H
Ph
N
Ph
H
N
H
50%
Ph
50%
Regioisomers
The utility of dipolar cycloaddition reactions is limited to some extent by the
possibility of formation of regioisomers.
Intramolecular Cycloaddition
-
Entropically favoured (S# small)
Fused bicyclic heterocycles
Target
N
N
O
O
(CH3)3
CO2Me
CO2Me
Intramolecular reactions remove the problems
of regioselectivity.
Y
N
O
X
N
O
Z
CO2Me
X=C
X is sometimes called a disposable tether.
CO2Me
1,3- Oxazoles
R2
N
R3
R1
O
Most common method of synthesis is the Robinson-Gabriel Reaction
R2
R2
N
R3
O
N
R1
R3
HO
enol ether portion
R1
O
Hemiketal
In the f orward reaction the hemiketal should readily
undergo dehydration.
The driving force for the reaction is the thermodynamic
stability of the 5-membered aromatic heterocycle.
R2
R2
N
R3
HO
O
N
R1
R3
HO
R1
O
R2
H+ catalysed cyclisation
of an amidoketone (ketoamide)
NH
R1
O
R3
O
Starting material
The reaction is so efficient that any common mineral acid can be used for
the cyclisation e.g. H2SO4, CF3CO2H.
R2
NH
R1
O
H
R3
O
Cyclisation step works very well but access to the amidoketone
is a problem.
These type of molecules are not stable because they dimerise - theref ore
they are isolated as the amino hydrochloride.
O
O
Br
R3
1. Na N3
HCl. H2N
2. H2/Pd-C
HCl
R2
R3
R2
O
AcOH Br2
Goes through enol intermediate
R1
O
Cl
O
R
3
H
N
R1
R3
R2
O
R2
Synthesis can be scaled up successfully, but R2 and R3 can be limiting.
If R3 is an aromatic ring, tBu group - no enol formed on that side of the
molecule.
Dehydration can also be achieved using phosphorus oxychloride (POCl3)
and thionyl chloride (SOCl2).
H
R2
R1
R2
R3
N
Cl
Cl
O
O
R3
N
S
O
R1
O
S
O
Cl
Cl
R2
R
1
R3
N
Cl
OH
- HCl
R2
N
R1
O
R3
R2
N
R1
O
R3
Cl
O
1,3- Thiazoles and Imidazoles
R2
R2
N
R3
N
R1
S
R3
R1
N
H
In principle the Robinson-Gabriel Reaction should also work
for the synthesis of these compounds. In practice it doesn't work very well.
R2
R2
NH
NH
R1
O
S
R3
R3
-ketothioamide
R
HN
-amidine ketone
O
S
R2
1
R1
O
N
H
P4S10
Toluene
R
1
R2
N
H
Conversion of an amide to a thioamide. However can't selectively do this
in the presence of another carbonyl group.
R2
R2
NH
N
1
O
R
R3
HN
-amidine ketone
R1
O
R3
2 tautomeric forms
H 2N
Hantsch Thiazole Synthesis
R2
R2
O
N
R3
R1
S
N
+
R3
-halocarbonyl compound
- HCl
R2
HO
R2
H
N
Thioamide
Na2CO3
EtOH
HN
R1
O
R3
S
H
R1
S
Cl
S
R1
R3
Never isolated
- H2O
R2
N
R3
S
R1
Note that S is a much more potent nucleophile than N and attacks the halocarbonyl compound. This is the best general synthesis of thiazoles
although there are other more specific ones available.
Imidazole Synthesis
R2
R2
O
O
N
R3
+
R1
N
H
R1
H
R3
O
1,2 diketone
Aldehyde
NH4 OAc
aq EtOH
R2
NH
NH
+
R1
H
R3
R2
H
H 2N
N
R3
NH
H
R2
H2N
R1
HN
N
R1
N
R3
- NH3
R2
R2
N
N
H
R3
N
R1
R3
N
H
H
R1
Isoxazoles, Pyrazoles and Isothiazoles
N
N
N
N
H
O
S
1,3-dipolar cycloadditions
1
C
N
O
R2
C
C
R3
R
R1
R2
R3
N
O
Retrosynthetic Analysis:
R1
R2
R3
N
X
R1
R2
N
R3
OH
R1
R2
N
R3
O
XH
XH
X = O, NH, S
1. NH2OH
R1
R2
2. NH2NH2
3. NH2SH - far too unstable
O
R3
O
Isoxazole synthesis:
H
O
O
O
H
OH
- H 2O
N
O
O
N
H2N
OH
H
H
OH
H
H
- H 2O
N
N
HO
O
O
Pyrazole Synthesis
O
O
+
H2N
NH2
N
N
H
Unsymmetrical diketones leads to regioisomers
O
R2
O
+
R
1
3
R
R2
H2N
R3
R2
R3
+
OH
R1
N
O
R1
O
N
Isothiazole Synthesis
Cl
NH
NH2
Cl
NH
S
S
N
NH2
H
H
-H
S
H
NH
N
- HCl
Cl
N
S
H
N
H
S
NH2
N
H
Isothiazole
H
Benzoheterocycles
O
N
H
Benzofuran
S
Indole
Benzothiophene
OH
R
R
O
O
enol ether
hemiketal
R
O
OH
H
Intramolecular condensation
Addition type dehydration process
FGI
OH
O
FG I
O
OH
Dehydration to produce
unsaturation
O
Benzofuran Synthesis
Method 1
Br
OH
K2CO3/acetone
O
Claisen
rearrangement
O
(i) O3
(ii) Zn.H2O
(iii) H3O
OH
Heat
180 oC
OH
OH
O
O
Method 2
OH
OH
O
O
H
Br
H
O
O
OH
NaH
THF
O
H
H
H
OH
H
O
O
OH
- H2O
O
O
O
Indoles
N
N
H
H
Indole - 10  electron aromatic system
Other major resonance
contributor to electronic structure
NH2
Indole Alkaloids
- Tryptophan
- Serotonin
HO
N
H
Anti-Migraine Drugs target Serotonin receptors but not those targeted
by Prozac and other anti-depressant drugs
O
NMe2
O
S
N
H
N
O
N
H
N
H
Sumatriptan (GSK)
O
S
Triptans: majority are substituted
indoles
Ph
N
H
Eletriptan (Pfizer)
Fischer Indole Synthesis
O
Ph
N
H
NH2
- H 2O
N
H
N
Ph
AcOH
or
ZnCl2
Ph
N
H
Cyclisation Mechanism
H
H
H
N
H
N
N
H
Ph
N
Ph
H
H
-H
H
NH
NH2
Ph
N
H
NH
Ph
NH2
N
H
Ph
- NH3
Ph
N
H
Moody-Rees Reaction
3
2
4
1
N
N5
H
H
A vinyl nitrene
6 e- in N valence shell
[1,5] Sigmatropic
rearrangement of H
Characteristic reaction of vinyl
nitrenes is a cyclisation reaction
- Electrocyclic ring closure
N
H
CO2R (EWG)
N
H
Cyclisation of vinyl azides
CO2R
Heat
CO2R
Xylene
(156 oC)
- N2
N3
N
H
O
CO2R
H
CO2R
NaOMe
+
N3
MeOH
N3
Reaction proceeds via the anion of the ester
CO2
N3
Azido esters available by reacting bromides
with azides
CO2R
CO2R
Na N3
DMSO
Br
N3
Moody Rees reaction is a cascade of reaction
R
N
N
N
R
N
+ N2
Generation of a nitrene
O
O
Cl
Na
NO2
NO2
CH3
H2/Pd-C
O
- H 2O
N
H
NH2
CH3
Metallation Reactions of Heterocycles
- Ways to introduce substituents after the ring has f ormed
and/or exchange of substituents.
- Metallation refers to any process where a carbon- metal bond
(ionic or covalent) is formed.
(C-M)
C M
- There are 3 types of metallation reaction commonly applied
1.
C
H
acid
C M
+ M X
+
X
H
+
X
Y (X Y )
X is a base
The simplest version is an acid-base reaction
2.
C
X
C M
+ M Y
X = Br, I (Doesn't work for F and not very well for Cl)
3.
R
RZnX + MgCl2
MgX + ZnCl2
Transmetallation reaction
- Quite often the metallation requires a heteroatom next to a multile bond.
H
X
C
Y
Y = O, N, S
X
C
Y
X=O
- Process works very well if the neighboring atom is O.
- The reagent is organolithium as Li has a high affinity for O.
RLi (n-BuLi, sec-BuLi, t-BuLi). In practice, organic chemists most often use t-BuLi.
Conditions: THF, -78 oC.
Sometimes an additive is necessary for successful metallation reactions
Most common additive is tetramethylethylenediamine (TMEDA)
N
N
Li
In solution these species often exist as tetramers or hexamers. In THF, they tend
to aggregate (RLi)n n = 4 or 6.
Sometimes we get a tetrahedral type structure
R
Li
Li
R
Li
R
Li
R
The existence of aggregates can effect the rate of reaction (they may pref er to
stick together than react - decrease in rate of reaction).
Additives such as TMEDA can break up the aggregate
The O atom of THF can also play a role in breaking up
aggregates.
O
O
H
O
RLi
Proton easily removed using organolithium
reagent to form an organometallic species.
Li
Anion chemistry of 1,3-azoles
N
N
RLi
Li
H
X
N
E
X
X = O, N, S
E
X
It may be more diff icult if there is
no O in the vicinity of the reaction
Example:
N
N
1. n-BuLi
2. CH3CHO
3. HCl/H2O
O
O
OH
N
N
RLi
X
N
Li
X
Li
X = O, N, S
X
E
N
E
X
Example:
N
N
1. n-BuLi
2. MeI
S
S
Anion chemistry of 1,2-azoles
O
RLi
(CO2Et)2
Li
N
N
S
N
EtO
S
S
RLi
MeI
Li
N
O
N
N
N
Ph
N
Ph
N
Ph
Not applicable to isoxazole chemistry
Ph
Ph
Ph
RLi
N
Ph
Li
O
Ph
+ PhCN
N
O
O
Li
Ynolate
Generation of reactive intermediates
Ph
C
C
N
O
O
RLi
Ph
Li
C
N
O
C
O
PhCH2Cl
Ph
N
O
Anion chemistry of Indole
Reaction on nitrogen
N
H
RLi
or
NaH
MeI
N
N
Li or Na
RMgBr
Br
N
N
H
MgBr
Reaction at the C3 position
Deprotonation at C2 when the nitrogen is blocked
RLi
Li
E
E
N
Me
N
Me
N
Me
Metallation of C-halogen bonds
C
Br
THF
+ t-BuLi
C Li
- 78 oC
(additive ?)
+ t-BuBr
O
Br
HO
Li
t-BuLi
1. CO2
N
N
O
2. H3O
N
O
O
Synthetic equivalent of
HO
C
O
(Bu)3Sn
Li
Cl
Ph
Sn(Bu)3
Pd(PPh3)4
N
Ph-I
N
O
N
O
O
(Stille reaction)
OMe
MeO
OMe
B
Li
N
MeO
B
Ph
Pd(PPh3)4
OMe
N
O
O
Ph-Br
aq NaOH
(Suzuki coupling)
ClZn
Li
ZnCl2
N
O
N
O
Applications in Pd(0)
catalysed reactions
N
O
Electrophilic substitution reactions
1,3-azoles not very reactive towards electrophilic attack
- Deactivating effect of pyridine-like nitrogen
N
X
1,2-azoles have also reduced reactivity towards electrophilic attack
- Electrophilic substitution occurs at C4
Br
Br
Br
H
Br
-H
Br2
N
N
O
N
O
O
Indoles easily undergo electrophilic substitution - they are electron rich heterocycles
- They react preferentially at C3 position
E
E
E
H
-H
N
H
N
H
N
H
NMe 2
CH2O
N
H
HNMe2
AcOH
(Mannich Reaction)
N
H