Co 301 Hetero Cyclic Chemistry

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

+

cyclopropenyl cation

[14]-Annulene

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 1

Pyridinium ion: pKa = 5.5 Piperidine: pKa = 11.29 diethylamine : pKa = 10.28

H NMR: δ H 7.5 H 7.1

H H

N pyridine

H 8.5

Pyridine is a weak base Pyridine is π-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

X

+

O

Pyr

R1-OH

1

R

O

R

X = OAc, Cl, Br

N+

E.g.

O

O O

OH +

Pyr

O

O O

R

Acyl pyridinium ion Reactive intermediate

DMAP (DimethylAminoPyridine)

H3 C

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

i N+ H

NO2

N

N

i, HNO3, H2SO4

Unreactive, Stable

ii N+ _ AlCl3

N ii, AlCl3, RCOCl

O

ii

R N

How can we nitrate pyridine? H2O2, AcOH

NO2

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

Nucleophilic Substitution at 2- and 4-positions of pyridine is most favoured Nu N

_

Cl

Nu N _

Cl

N

PhSH, NEt3

E.g. N

Cl

N

SPh

93%

Br Br N

NH2 Br

NH3 (aq) N 65%

Nu

Five Membered Heterocycles: Pyrrole

Aromatic: Thus, 6π electrons 1

H NMR: δ

H H

H 6.2

N H Pyrrole

H 6.5

Sp2 hybridised and planar Lone pair tied up in aromatic ring

Pyridine is π-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 π-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

H 2N

OMe N

Me

Lysergic acid (LSD)

Strychnine

55%

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 + S

S

O

O

83%

ZnCl2, 0 C

O

+ O

ZnCl2, 100 C

O

O

O Furan is more reactive than thiophene

O

O

O

95%

Br

Br Br2, MeOH

Br2, CCl4 Br

Br O not a clean reaction H+, H2O

MeO

O

H

Wittig reaction OHC

CHO

Hydrolysis of acetal

Ph3P +

O

_

OMe O

H

Addition product

OHC CHO

Furan is easily cleaved to dicarbonyls OHC

CHO

The Diels-Alder Reaction O

O 100 C

+

O

Diene 4π system

O

benzene

O

100%

dienophile 2π system

O

4+2π 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

O

100%

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 steric reasons

Aromaticity prevents thiophene from taking part in the Diels-Alder reaction

O O +

S O

X

S O

- SO2

X X

This sulfone is not aromatic & very reactive

Five-membered Rings with Two or More Nitrogens

N

Diazoles

N

pKa = 14.5 (imidazole) pKa = 16.5 (pyrrole)

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

- H 2O

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

•

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

80%

N

O2N

O N Me

O2N

5

Me

N

4

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

N

N

H

1,2,4-Triazole

1,2,3-Triazole

pKa = 10.3

Only one isomer now possible N R

H

N

N

N

R

N

N N N

H N R

N

N

N H

N

N

N N N H

N R

N _

_ N

N

N N

pKa ~ 5 ~ RCOOH

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

Cl Tetrazole derivative

Anti-arthritis drug - Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses

Bioreductive Anti-Tumour Agents O

10

H2N

O

OCONH2 N

OMe

O

N

1

N

Me

OR NH

N

Me

O

O

Mitomycin C IC50 ≈ 1.0 µM O

O

Pyrrolo[1,2-a]benzimidazole (PBI) 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 1

N

Me

NH

O + 1 e-

H2N

- 1 e-

Me

O

OCONH2 steps

OMe 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 O

OH

OCONH2 -

NH

+2e + 2 H+

H2N

DT-diaphorase

H2N

OMe N

Me OH

OH

OCONH2

NH

DNA alkylation

DNA N

Me OH

S. E. Wolkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477

NH2