Cytotoxin- Inhibits DNA-topoisomerase enzymes
Happy Tree
(China)
CO-301 Heterocyclic
Chemistry
Convenor
Dr. Fawaz Aldabbagh
http://www.nuigalway.ie/chemistry/level2/staff/f_aldabbagh/Fawaz.htm
Definition:
Heterocyclic compounds are organic
compounds that contain a ring structure containing atoms
in addition to carbon, such as sulfur, oxygen or nitrogen,
as the heteroatom. The ring may be aromatic or nonaromatic
Significance – Two thirds of all organic compounds are aromatic
heterocycles. Most pharmaceuticals are heterocycles.
Examples
Pfizer: Viagra
Quinine
Treatment of malaria for 400 years (Peru)
Erectile dysfunction
H
NHMe
N
N
N
H
Me
NC
N
Treating stomach & intestinal ulcers
Camptothecin Analogues
Pfizer - Irinotecan
GSK - Topotecan
Ovarian & lung cancer
More soluble & less side-effects
When Is A Molecule Aromatic?
• For a molecule to be aromatic it must:
•
•
•
•
Be cyclic
Have a p-orbital on every atom in ring
Be planar
Posses 4n+2 p electrons (n = any integer)
benzene
naphthalene
Erich Hückel
+
[14]-Annulene
cyclopropenyl cation
Six Membered Heterocycles: Pyridine
N
pyridine
N
H
piperidine
Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)
Hybridization = sp2 with similar resonance stabilization energy
Lone pair of electrons not involved in aromaticity
1H
Pyridinium ion: pKa = 5.5
Piperidine: pKa = 11.29
diethylamine : pKa = 10.28
NMR: d
H 7.5
H 7.1
H
H
N
pyridine
H 8.5
Pyridine is a weak base
Pyridine is -electron deficient
Electrophilic aromatic substitution is
difficult
Nucleophilic aromatic substitution is easy
Pyridine as a nucleophile
Me I
N
N+ I
Me
_
Use Pyridine as a solvent to make esters
O
+
R
O
Pyr
R1-OH
1
R
X
O
R
X = OAc, Cl, Br
N+
E.g.
O
OH
O
+
O
Pyr
O
O
O
R
Acyl pyridinium ion
Reactive intermediate
DMAP (DimethylAminoPyridine)
H3C
Whereas acylations “catalyzed” by pyridine are
normally carried out in pyridine as the reaction
solvent. Only small amounts of DMAP are required
to do acylations
N
CH3
N
Attempted Electrophilic Aromatic Substitution
i
NO2
i
N+
H
N
N
i, HNO3, H2SO4
Unreactive, Stable
O
ii
ii
N+
_
AlCl3
N
ii, AlCl3, RCOCl
R
N
How can we nitrate pyridine?
NO2
H2O2, AcOH
HNO3, H2SO4
N+
_
O
Pyridine N-oxide
N
N+
_
O
85%
We now have an activating and protecting group
_
O N O
+
O
+
O N H
Mechanism
N+
_
O
NO2
N+
O
NO2
PPh3
N+
_
O
+
N
75%
O PPh3
Third Period ; n2 = 32 = 9 orbitals
Ar [Ne]; 3s2, 3px2, 3py2, 3pz2 3d0 3d0 3d0 3d0
3d0
n=3
Nucleophilic Substitution at 2- and 4-positions of
pyridine is most favoured
_
Nu
N
Cl
Nu
N
_
E.g.
Cl
N
PhSH, NEt3
N
Cl
N
SPh
93%
Br
Br
N
NH2
Br
NH3 (aq)
N
65%
Nu
Five Membered Heterocycles: Pyrrole
Aromatic: Thus, 6 electrons
1H
NMR: d
Sp2 hybridised and planar
Lone pair tied up in aromatic ring
H
H
H 6.2
N
H
Pyrrole
H 6.5
Pyrrole is -electron excessive
Thus, Electrophilic Aromatic Substitution is Easy
Nucleophilic Substitution is Difficult
Electrophilic Aromatic Substitution preferred at the 2-position
NO2
AcONO2, AcOH/ -10 C
N
N
H
H
NO2
+
N
H
13%
Normal acidic nitration causes polymerization 51%
Vilsmeier Reaction
O
+
N
1. POCl3
2. Na2CO3, H2O
H
H
NMe2
N
H
H
O
59%
O
O
Me
Ac2O, AlCl3
rt
N
SO2Ph
Me
NaOH (aq)
N
N
SO2Ph
H
82%
Electron-withdrawing group allows substitution at the 3-position
Organic Synthesis with Pyrrole should avoid strong acids
H
H+
H
N
H
N+
N
H
H
H
H
reaction continues to give polymer
N
N+
H
H
i
i; 1 X SO2Cl2, Et2O
Cl
N
N
H
H 80%
Cl
Cl
ii; 4 X SO2Cl2, Et2O
ii
N
H
Cl
N
Cl
H 80%
Indole
Aromatic due to 10 -electrons
Benzene part is non-reactive
N
H
Electrophilic aromatic substitution
occurs at the 3-position
CHO
Indole
Vilsmeier
N
N
H
H
Indole Alkaloids
O
OCONH2
H2 N
OMe
N
Me
Lysergic acid (LSD)
55%
Strychnine
NH
O
Mitomycin C
Other Five Membered Heterocycles
N
H
S
O
Thiophene
Furan
Least reactive
The least aromatic:
The O atom is too electronegative
Pyrrole
More aromatic than Furan
Less reactive than pyrrole,
but substitution always at 2position
Electrophilic Substitution, not addition
Can give addition, as well as substitution products when
reacted with E+
Thiophene has similar reactivity to benzene
Electrophilic Aromatic Substitution of Thiophene
Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3
HNO3, AcOH, Ac2O / -10 C
NO2
S
S
85%
O
+
S
1. POCl3
2. Na2CO3, H2O
H
H
NMe2
S
68%
O
Cl
SO2Cl2, heat
S
S
43%
Cl
S
10%
Cl
Some Reactions of Furan
ZnCl2, 100 C
O
+
S
S
O
O
83%
ZnCl2, 0 C
O
+
O
O
O
Furan is more reactive than thiophene
O
O
O
95%
Br
Br
Br2, MeOH
Br2, CCl4
Br
O
not a clean reaction
Br
MeO
O
H
OMe
O
H
Addition product
Wittig reaction
H+, H2O
OHC
CHO
Ph3P
+
Hydrolysis of acetal
O
_
OHC
CHO
Furan is easily cleaved to dicarbonyls
OHC
CHO
MeO
H
H+, H2O
OMe
O
O
O
H
H
H
cis-butenediol
(too unstable to isolate)
acetal
acetal
O
R
+
H
aldehyde
O R1
1
H O R
H
- H2O
1
R O
R
+ 2 x alcohol
1
O R
H
acetal
acid-catalysed
H+, H2O
R
O
R
O
O
R
R
Furan is a source of 1,4-dicarbonyls in Organic Synthesis
The Diels-Alder Reaction
O
O
100 C
+
O
Diene
4 system
O
benzene
O
100%
dienophile
2 system
O
4+2 cycloaddition
Otto Diels
Electron rich
Electron poor
O
O
+
H
30 C
H
100%
Kurt Alder
Noble Prize in 1950
The configuration of the dienophile is retained
O
H
H
CO2Me
OMe
+
OMe
H
CO2Me
H
O
Always reacts via the cis-diene
O
H
CO2Me
H
+ MeO
OMe
H
CO2Me
H
O
O
H
O
25 C
+
O
O
H
O
100%
O
H
H endo product
O (100%)
O
O
Under kinetic control
Furan readily undergoes the Diels-Alder reaction with maleic anhydride
O
endo-product
Thermodynamic
exo-product forms as the
temperature is raised
O
O
O
More stable due to less steric reasons
Aromaticity prevents thiophene from taking part in the Diels-Alder reaction
O
S O
O
- SO2
+
S
O
X
X
X
This sulfone is not aromatic & very reactive
Five-membered Rings with Two or More Nitrogens
N
Diazoles
pKa = 14.5
(imidazole)
pKa = 16.5
(pyrrole)
N
N
N
H
H
Pyrazole
Imidazole
Imidazole is more basic than pyridine, but more acidic than pyrrole
H
H
N+
N
Imidazole + H+
Imidazole - H+
N
N
H
H
N
NaOH
- H2O
N
_
N
_
N
Properties: Very stable cation and anion of imidazole is formed
Some Natural Imidazole Compounds
Histidine
Important ligand to many metalloproteins
Is one of the essential amino acids.
A relatively small change in cellular pH can result in a change in its charge
Body neurotransmitter & local immune response
histamine
histidine carboxylase
Dipeptide in high concentrations in the brain & muscles
- Improves social interactions & treatment of autism
Carnosine
Synthesis of 2- and 5-Nitroimidazole Antibiotics
2-Nitroimidazole, “azomycin”
N
N
(i)
N
(ii)
NO2
N
N
N
H
CPh3
CPh3
(i) ClCPh3, NEt3
N
(iii)
NO2
N
30%
H
(iii) HCl (aq), MeOH
(ii) Bu-Li, n-PrONO2
5-Nitroimidazoles, “metronidazole” is used to treat anaerobic protozoan infections
O2N
N
H
N
(i)
N
Me
O2N
O
80%
N
N
Me
4
N
+
O2N
5
Me
N
Me
N
H
Two tautomeric forms
OH
(i) HNO3, H2SO4
metronidazole
OH
inactive
Weakly basic like pyridine, but more acidic than imidazole
Triazoles
H
H
N
N
Tetrazoles
N
N
N
H
N
N
N
N
N
N
N
H
1,2,4-Triazole
1,2,3-Triazole
pKa = 10.3
Only one isomer now possible
H
N
R
N
N
N
N
R
N
N
N
pKa ~ 5 ~ RCOOH
H
N
R
N
N
N
H
R
N
N
N
N
N
_
_
N
R
N
N
etc
Tetrazoles are used in drugs as replacements for CO2H
H
O H
N N
N
N
O
Me
O
Me
N
N
O
O
Cl
Indomethacin
Indomethacin
Cl
Tetrazole derivative
Anti-arthritis drug
- Non steroidal anti-inflammatory drug –
reduces fever, pain, stiffness, delays
premature labour & other uses
Synthesis of Indomethacin
NMe2
Me2NH, CH2=O
CN
NaCN
N
N
H
N
98%
H
H
N N
N
N
H
NaN3, NH4Cl, LiCl
N N
N
N
H
DMF, 100 C
N
H
N
O
Cl
Bioreductive Anti-Tumour Agents
O
10
H2N
O
OCONH2
O
N
OMe
N
1
N
Me
OR
NH
N
Me
O
O
Mitomycin C
Pyrrolo[1,2-a]benzimidazole (PBI)
IC50 ≈ 1.0 µM
O
O
E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211
K. Fahey, F. Aldabbagh, Tetrahedron Lett., 2008, 49, 5235
More selective to hypoxia
O
N
N
N
N
( )n
IC50 ≈ 0.001 µM
Hypersensitive to Fanconi Anemia
N
Tr
O
L. O’Donovan, F. Aldabbagh, Chem. Commun., 2008, 5592.
M. Lynch, S. Hehir, M. P. Carty, F. Aldabbagh, Chem. Eur. J. 2007, 13, 3218
S. Hehir, L. O’Donovan, M. P. Carty, F. Aldabbagh, Tetrahedron 2008, 64, 4196
Targeting Hypoxic Cells
Mitomycin C (MMC)
SET - activation
O
10
H2N
OCONH2
OMe
O
+ 1 e-
H2N
- 1 e-
Me
OCONH2
N
Me
NH
O
steps
OMe
1
N
O
- 1 e-
NH
O.
DNA
H2N
N
Me
NH2
O
DNA alkylation
CY P450 reductase
Two electron activation
O
H2N
OMe
N
Me
OH
OCONH2
+ 2 e-
NH
H2N
+ 2 H+
O
H2N
OMe
N
Me
OH
OH
OCONH2
NH
DNA alkylation
DNA
N
Me
OH
DT-diaphorase
S. E. Wolkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477
NH2
Measuring the Effect of FANCD2 Expression on Cell Viability
100
Cell Viability %
O
80
H2 N
60
Me
OCONH2
OMe
N
NH
O
40
OMe
N
20
N
N
0
0
2
4
8
6
10
OMe
-3
Concentration (x 10 µ M)
●, ● PD20i cells (lack FANCD2)
▲, ▲ PD20:RV (express FANCD2)
K. Fahey, L O’Donovan, M. Carr, M. P. Carty, F. Aldabbagh, Eur. J. Med Chem. 2010, 45, 1873-1879
Tr