CO-301 HeterocycIic

Chemistry
Convenor
Dr. Fawaz AIdabbagh
http://www.nuigalway.ie/chemistry/level2/staff/f_aldabbagh/Fawaz.htm
Cytotoxin- nhibits DNA-topoisomerase enzymes
Happy Tree
(China)
Definition: HeterocycIic 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 non-
aromatic
Significance - Two thirds of aII organic compounds are aromatic
heterocycIes. Most pharmaceuticaIs are heterocycIes.
ExampIes
Quinine
Pfizer: Viagra
Treatment of malaria for 400 years (Peru)
Erectile dysfunction

Me
HMe

C
H
H
Ovarian & Iung cancer
GSK - Topotecan Pfizer - Irinotecan
Camptothecin AnaIogues
Treating stomach & intestinal ulcers
More soluble & less side-effects
hen s A Molecule Aromatic?
For a molecule to be aromatic it must:
Be cyclic
Have a 5-orbital on every atom in ring
Be planar
Posses 4n+2 p electrons (n = any integer)
benzene naphthaIene
+
cycIopropenyI cation
[14]-AnnuIene
Erich HckeI
Six Membered HeterocycIes: Pyridine

H
pyridine piperidine
Pyridine repIaces the CH of benzene by a atom (and a pair of eIectrons)
Hybridization = sp
2
with simiIar resonance stabiIization energy
Lone pair of eIectrons not invoIved in aromaticity

H
H H
H H
pyridine
8.5
7.1
7.5

#0
Pyridinium ion: pKa = 5.5
Piperidine: pKa = 11.29
diethyIamine : pKa = 10.28
Pyridine is a weak base
Pyridine is 6-eIectron deficient
EIectrophiIic aromatic substitution is
difficuIt
ucIeophiIic aromatic substitution is easy

Me I

Me
+
I
_
O
O
O
OH O
O
O
R X
O
R O
R
+
Pyr
+
Pyr
R
1
-OH
1
X = OAc, CI, Br
Pyridine as a nucleophile
Use Pyridine as a solvent to make esters

O
R
+
AcyI pyridinium ion
Reactive intermediate
E.g.
DMAP (DimethyIAminoPyridine)

CH
3
C H
3

O
2
+
i
i
i, HO
3
, H
2
SO
4
Whereas acyIations "cataIyzed" by pyridine are
normaIIy carried out in pyridine as the reaction
soIvent. OnIy smaII amounts of DMAP are required
to do acyIations
Attempted EIectrophiIic Aromatic Substitution

AICI
3

R
O
+
ii
ii
ii, AlCl
3
, RCOCl
_
Unreactive, Stable
How can we nitrate pyridine?

O
O
2

O
O O

O
O
2

O
2
O PPh
3

O
H
O
O
+
_
H
2
O
2
, AcOH
Pyridine -oxide
HO
3
, H
2
SO
4
+
_
85%
+
_
+
+
_
PPh
3
+
75%
+
+
_
e now have an activating and protecting group
Mechanism
Third Period ; n
2
= 3
2
= 9 orbitaIs
Ar [Ne]; 3s
2
, 3p
x
2
, 3p
y
2
, 3p
z
2
3d
0
3d
0
3d
0
3d
0
3d
0
n = 3
ucIeophiIic Substitution at 2- and 4-positions of
pyridine is most favoured
CI
CI
u
u
_
_
u
CI
SPh
PhSH, Et
3
93%
E.g.

Br
Br

H
2
Br
H
3
(aq)
65%
Five Membered HeterocycIes: PyrroIe

H
H
H
H
H
PyrroIe
6.5
6.2

#0
Aromatic: Thus, 66 eIectrons
Sp
2
hybridised and pIanar
Lone pair tied up in aromatic ring
PyrroIe is 6-eIectron excessive
Thus, EIectrophiIic Aromatic Substitution is Easy
ucIeophiIic Substitution is DifficuIt

H
O
H
O
H Me
2

SO
2
Ph

SO
2
Ph
Me
O

H
Me
O

H
O
2

H
O
2
+
1. POCI
3
2. a
2
CO
3
, H
2
O
59%
Ac
2
O, AICI
3
rt
aOH (aq)
82%
AcOO
2
, AcOH/ -10 C
+
51% 13%
EIectrophiIic Aromatic Substitution preferred at the 2-position
ormal acidic nitration causes polymerization
ViIsmeier Reaction
EIectron-withdrawing group aIIows substitution at the 3-position

H
H
H

H

H
H
H

H
H
+
+
+
reaction continues to give poIymer
Organic Synthesis with PyrroIe shouId avoid strong acids

H
CI

H
CI CI
CI
CI
80%
80%
i; 1 X SO
2
CI
2
, Et
2
O
ii; 4 X SO
2
CI
2
, Et
2
O
i
ii
IndoIe
Lysergic acid (LSD) Strychnine
IndoIe AIkaIoids

H
IndoIe

H
CHO
ViIsmeier
55%
Aromatic due to 10 6-eIectrons
Benzene part is non-reactive
lectrophilic aromatic substitution
occurs at the 3-position
OCOH
2

OMe
H
H
2
Me
O
O
Mitomycin C
Other Five Membered HeterocycIes

H
S O
PyrroIe
Thiophene Furan
The Ieast aromatic:
The O atom is too eIectronegative
Can give addition, as weII as substitution products when
reacted with E
+
Less reactive than pyrroIe,
but substitution aIways at 2-
position
More aromatic than Furan
EIectrophiIic Substitution, not addition
Least reactive
%hiophene has similar reactivity to benzene
Avoid concentrated mineraI acids or strong Lewis acids, e.g. AICI
3
EIectrophiIic Aromatic Substitution of Thiophene
S
S
O
H
O
H Me
2
S
S
O
2
S
S
CI
S
CI
CI
+
1. POCI
3
2. a
2
CO
3
, H
2
O
68%
HO
3
, AcOH, Ac
2
O / -10 C
85%
43%
SO
2
CI
2
, heat
10%
S
S
O
O
O
O
O
O
O
O
O
O
+
ZnCI
2
, 100 C
+
ZnCI
2
, 0 C
83%
95%
Some Reactions of Furan
O
O
Br
Br
Br
Br
O
OMe
MeO
H H
CHO OHC

O
Ph
3
P
OHC
CHO
CHO
OHC
Br
2
, CCI
4
Br
2
, MeOH
H
+
, H
2
O
+
_
not a clean reaction
Furan is more reactive than thiophene
Addition product
HydroIysis of acetaI
Wittig reaction
Furan is easiIy cIeaved to dicarbonyIs
Furan is a source of 1,4-dicarbonyIs in Organic Synthesis
O
OMe
MeO
H H
O
O
H H
O
R H
O R H
O R H
R H
O O R R
O
# #
O
O
R R
cis-butenedioI
(too unstabIe to isoIate)
H
+
, H
2
O
acetal acetal
+
1
1 1
1
- H
2
O
acetaI
aIdehyde
+ 2 x aIcohoI
H
+
, H
2
O
acid-catalysed
The DieIs-AIder Reaction
Otto DieIs
Kurt AIder
obIe Prize in 1950
O
O
O
O
O
O
+
100 C
benzene
100%
Diene
46 system
dienophiIe
26 system 4+26 cycIoaddition
lectron rich
lectron poor
O
H
O
H
+
30 C
100%
H
H
O
O
OMe
OMe
H
H
CO
2
Me
CO
2
Me
H
H
O
OMe
O
MeO
H
H
CO
2
Me
CO
2
Me
+
+
%he configuration of the dienophile is retained
Always reacts via the cis-diene
O
O
O
O
O
O
H
H
H
H
O
O
O
+
25 C
100%
endo product
(100%)
Under kinetic controI
O
O
O
O
Thermodynamic
exo-product forms as the
temperature is raised
endo-product
Furan readiIy undergoes the DieIs-AIder reaction with maIeic anhydride
More stable due to less steric reasons
Aromaticity prevents thiophene from taking part in the DieIs-AIder reaction
S
O
O
X
S
O
O
X
X
+
- SO
2
%his sulfone is not aromatic & very reactive
Five-membered Rings with Two or More itrogens
DiazoIes

H
ImidazoIe PyrazoIe
midazole is more basic than pyridine, but more acidic than pyrrole

H
H

H
H

+
_
_
ImidazoIe + H
+
ImidazoIe - H
+
aOH
Properties: Very stable cation and anion of imidazole is formed
pKa = 14.5
(imidazoIe)
pKa = 16.5
(pyrroIe)
- H
2
O
Histidine
Is one of the essentiaI amino acids.
A reIativeIy smaII change in ceIIuIar pH can resuIt in a change in its charge
Some aturaI ImidazoIe Compounds
Important Iigand to many metaIIoproteins
histidine carboxylase
histamine
Carnosine
Dipeptide in high concentrations in the brain & muscles
- mproves social interactions & treatment of autism
Body neurotransmitter & local immune response
Synthesis of 2- and 5-itroimidazoIe Antibiotics

CPh
3

CPh
3
O
2

H
O
2
(i) (ii) (iii)
(i) ClCPh
3
, NEt
3
(ii) Bu-Li, n-PrONO
2
(iii) HCl (aq), MeOH
30%
2-Nitroimidazole, "azomycin
5-Nitroimidazoles, "metronidazole is used to treat anaerobic protozoan infections

H
Me

H
Me
O
2

Me
O
2

OH

Me
OH
O
2

+
Two tautomeric forms
metronidazole inactive
(i)
(i) HNO
3
, H
2
SO
4
80%
5
4
TriazoIes

H
1,2,3-TriazoIe
1,2,4-TriazoIe
eakly basic like pyridine, but more acidic than imidazole
pKa = 10.3
TetrazoIes
Only one isomer now possible

H
R

H
R

H
R

R
_
_
etc
pKa ~ 5 ~ RCOOH

O
O
Me
O
CI
H

O
Me
O
CI

H
ndomethacin
Tetrazole derivative
TetrazoIes are used in drugs as repIacements for CO
2
H
Anti-arthritis drug
- Non steroidal anti-inflammatory drug
reduces fever, pain, stiffness, delays
premature labour & other uses
Indomethacin

H
Me
2

H
C

O
CI
H
98%
Me
2
H, CH
2
=O
aC
a
3
, H
4
CI, LiCI
DMF, 100 C
Synthesis of Indomethacin
Bioreductive Anti-Tumour Agents
OCOH
2

OMe
H
H
2
Me
O
O

O
OR
O
O

Me

O
O

Tr
O
O
( )
n
C
50
1.0 aM
C
50
0.001 aM
Mitomycin C
E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211
K. Fahey, F. AIdabbagh, %etrahedron Lett., 2008, 49, 5235
PyrroIo[1,2-a]benzimidazoIe (PBI)
M. Lynch, S. Hehir, M. P. Carty, F. AIdabbagh, Chem. ur. J. 2007, 13, 3218
S. Hehir, L. O'Donovan, M. P. Carty, F. AIdabbagh, %etrahedron 2008, 64, 4196
1
10
L. O'Donovan, F. AIdabbagh, Chem. Commun., 2008, 5592.
Hypersensitive to Fanconi Anemia
More selective to hypoxia
Targeting Hypoxic CeIIs
Mitomycin C (MMC)
SET - activation
O
O

H
2
Me
OCOH
2
OMe
H
O
O

H
2
Me
OCOH
2
H
OMe
O
O

H
2
Me
H
2
DA
O
O

H
2
Me
OCOH
2
OMe
H
H
2
Me
OCOH
2
OMe
OH
OH
H
H
2
Me
OH
OH
H
2
DA
+ 2 e
-
+ 2 H
+
CY P450 reductase
Two eIectron activation
DT-diaphorase
.
+ 1 e
-
- 1 e
-
- 1 e
-
1
10
A alkylation
S. E. WoIkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477
steps
A alkylation
Measuring the Effect of FACD2 Expression on CeII ViabiIity
H
OMe
OCOH
2
O
O
H
2
Me

OMe
OMe
Tr
, PD20i ceIIs (Iack FACD2)
, PD20:RV (express FACD2)
K. Fahey, L O'Donovan, M. Carr, M. P. Carty, F. AIdabbagh, ur. J. Med Chem. 2010, 45, 1873-1879
0
20
40
60
80
100
0 2 4 6 8 10
Concentration (x 10
-3
aM)
C
e
I
I

V
i
a
b
i
I
i
t
y

%