CO-301 Heterocyclic Chemistry

ConvenorDr. Fawaz Aldabbagh

http://www.nuigalway.ie/chemistry/level2/staff/f_aldabbagh/Fawaz.htm

Cytotoxin- Inhibits DNA-topoisomerase enzymes

Happy Tree(China)

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 non-aromatic

Significance – Two thirds of all organic compounds are aromatic heterocycles. Most pharmaceuticals are heterocycles.

Examples

Quinine

Pfizer: Viagra

Treatment of malaria for 400 years (Peru)Erectile dysfunction

N

N

Me

N NHMe

NNC

H

H

Ovarian & lung cancer

GSK - TopotecanPfizer - Irinotecan

Camptothecin Analogues

Treating stomach & intestinal ulcers

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

+

cyclopropenyl cation[14]-Annulene

Erich Hückel

Six Membered Heterocycles: Pyridine

N NH

pyridine piperidine

Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)Hybridization = sp2 with similar resonance stabilization energyLone pair of electrons not involved in aromaticity

N

HHH

H H

pyridine

8.5

7.17.5

1H NMR: Pyridinium ion: pKa = 5.5Piperidine: pKa = 11.29diethylamine : pKa = 10.28

Pyridine is a weak basePyridine is -electron deficientElectrophilic aromatic substitution is difficultNucleophilic aromatic substitution is easy

N

Me I

NMe

+ I_

O

O

O OH O

O

O

R X

O

R OR

+ Pyr

+PyrR1-OH 1

X = OAc, Cl, Br

Pyridine as a nucleophile

Use Pyridine as a solvent to make esters

N

O R

+

Acyl pyridinium ionReactive intermediate

E.g.

DMAP (DimethylAminoPyridine)

N

N CH3CH3

NNH

N

NO2

+

ii

i, HNO3, H2SO4

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

Attempted Electrophilic Aromatic Substitution

NNAlCl3

N

R

O

+

iiii

ii, AlCl3, RCOCl_

Unreactive, Stable

How can we nitrate pyridine?

N NO

NO

NO2

NO

O N O

NO

NO2

N

NO2

O PPh3

NO

N HO

O

+_

H2O2, AcOH

Pyridine N-oxide

HNO3, H2SO4

+_

85%

+_

+

+_

PPh3 +

75%

+

+_We now have an activating and protecting group

Mechanism

Third Period ; n2 = 32 = 9 orbitalsAr [Ne]; 3s2, 3px

2, 3py2, 3pz

2 3d0 3d0 3d0 3d0 3d0

n = 3

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

N Cl N ClNu

N Nu_

_Nu

N Cl N SPh

PhSH, NEt3

93%

E.g.

N

BrBr

N

NH2BrNH3 (aq)

65%

Five Membered Heterocycles: Pyrrole

NH

H

H

H

H

Pyrrole

6.5

6.2

1H NMR: Aromatic: Thus, 6 electrons

Sp2 hybridised and planarLone pair tied up in aromatic ring

Pyrrole is -electron excessiveThus, Electrophilic Aromatic Substitution is Easy

Nucleophilic Substitution is Difficult

N

HN

H O

HO

H NMe2

N

SO2Ph

N

SO2Ph

Me

O

N

H

Me

O

N

H

N

H

NO2 N

H

NO2

+1. POCl32. Na2CO3, H2O

59%

Ac2O, AlCl3rt

NaOH (aq)

82%

AcONO2, AcOH/ -10 C+

51% 13%

Electrophilic Aromatic Substitution preferred at the 2-position

Normal acidic nitration causes polymerization

Vilsmeier Reaction

Electron-withdrawing group allows substitution at the 3-position

N

H

N

H

H

H N

H

N

H

H

H N

H

H++

+

reaction continues to give polymer

Organic Synthesis with Pyrrole should avoid strong acids

NH

NH

Cl

NH

NH

ClCl

ClCl

80%

80%

i; 1 X SO2Cl2, Et2O

ii; 4 X SO2Cl2, Et2O

i

ii

Indole

Lysergic acid (LSD) Strychnine

Indole Alkaloids

NH

IndoleNH

NH

CHOVilsmeier

55%

Aromatic due to 10 -electronsBenzene part is non-reactiveElectrophilic aromatic substitution occurs at the 3-position

OCONH2

N

OMe

NH

NH2

Me

O

O

Mitomycin C

Other Five Membered Heterocycles

NH

S O

PyrroleThiophene Furan

The least aromatic:The O atom is too electronegative

Can give addition, as well as substitution products when reacted with E+

Less reactive than pyrrole, but substitution always at 2-position

More aromatic than Furan

Electrophilic Substitution, not addition

Least reactive

Thiophene has similar reactivity to benzene

Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3

Electrophilic Aromatic Substitution of Thiophene

S SO

HO

H NMe2

S S NO2

S S Cl S Cl

Cl

+1. POCl32. Na2CO3, H2O

68%

HNO3, AcOH, Ac2O / -10 C

85%

43%

SO2Cl2, heat

10%

S SO

O

O

O

O OO

O

O

O

+ZnCl2, 100 C

+ZnCl2, 0 C

83%

95%

Some Reactions of Furan

OO

Br

Br

Br

Br O

OMeMeO

H H

CHOOHC

OPh3P

OHCCHO

CHOOHC

Br2, CCl4 Br2, MeOH

H+, H2O

+ _

not a clean reaction

Furan is more reactive than thiophene

Addition product

Hydrolysis of acetal

Wittig reaction

Furan is easily cleaved to dicarbonyls

Furan is a source of 1,4-dicarbonyls in Organic Synthesis

O

OMeMeO

H H

O OH H

O

R H

O RH

O RH R H

O O RR

OR R O OR R

cis-butenediol(too unstable to isolate)

H+, H2O

acetal acetal

+1

1 11 - H2O

acetalaldehyde + 2 x alcohol

H+, H2O

acid-catalysed

The Diels-Alder Reaction

Otto Diels

Kurt Alder

Noble Prize in 1950

O

O

O

O

O

O

+100 C

benzene

100%Diene

4 systemdienophile2 system 4+2 cycloaddition

Electron richElectron poor

O

H

O

H+30 C

100%

H

H

O

O

OMe

OMe

H

H

CO2Me

CO2Me

H

H

O

OMe

O

MeO

H

H

CO2Me

CO2Me

+

+

The configuration of the dienophile is retained

Always reacts via the cis-diene

O

O

O

O

O

O

H

H

HH

OO

O

+25 C

100%

endo product(100%)

Under kinetic control

OO

O

O

Thermodynamicexo-product forms as the

temperature is raisedendo-product

Furan readily undergoes the Diels-Alder reaction with maleic anhydride

More stable due to less steric reasons

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

SO

OX

S OO

XX

+- SO2

This sulfone is not aromatic & very reactive

Five-membered Rings with Two or More Nitrogens

Diazoles

N

N

H

NN

HImidazolePyrazole

Imidazole is more basic than pyridine, but more acidic than pyrrole

N

N

H

H

N

NH

H

N

N

N

N

+

_

_

Imidazole + H+

Imidazole - H+NaOH

Properties: Very stable cation and anion of imidazole is formed

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

- H2O

Histidine

Is one of the essential amino acids.A relatively small change in cellular pH can result in a change in its charge

Some Natural Imidazole Compounds

Important ligand to many metalloproteins

histidine carboxylase

histamine

CarnosineDipeptide in high concentrations in the brain & muscles- Improves social interactions & treatment of autism

Body neurotransmitter & local immune response

Synthesis of 2- and 5-Nitroimidazole Antibiotics

N

N

H

N

N

CPh3

N

N

CPh3

NO2 N

N

H

NO2

(i) (ii) (iii)

(i) ClCPh3, NEt3 (ii) Bu-Li, n-PrONO2(iii) HCl (aq), MeOH

30%

2-Nitroimidazole, “azomycin”

5-Nitroimidazoles, “metronidazole” is used to treat anaerobic protozoan infections

N

N

H

Me N

N

H

Me

O2N O

N

N

Me

O2N

OH

N

N

Me

OH

O2N+

Two tautomeric forms

metronidazole inactive

(i)

(i) HNO3, H2SO4

80% 5

4

Triazoles

NN

N

H

NN

NH

N

NN

H

N

NNH

1,2,3-Triazole1,2,4-Triazole

Weakly basic like pyridine, but more acidic than imidazole

pKa = 10.3

Tetrazoles Only one isomer now possible

NN

NN

H

RN

N

NNH

R

NN

NN

H

RN

N

NN

R NN

NN

R_

_

etc

pKa ~ 5 ~ RCOOH

N

O

OMe

O

Cl

H

N

OMe

O

Cl

NN

NNH

IndomethacinTetrazole derivative

Tetrazoles are used in drugs as replacements for CO2H

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

Indomethacin

NH

NH

NMe2

NH

CN

NH

NN

NN

H

N

NN

NN

O

Cl

H

98%

Me2NH, CH2=O NaCN

NaN3, NH4Cl, LiCl

DMF, 100 C

Synthesis of Indomethacin

Bioreductive Anti-Tumour AgentsOCONH2

N

OMe

NH

NH2

Me

O

O

N

N

O

OR

O

O

N

Me

N

N

O

O

N

N N Tr

O

O

( )n

IC50 ≈ 1.0 µM

IC50 ≈ 0.001 µM

Mitomycin C

E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211K. Fahey, F. Aldabbagh, Tetrahedron Lett., 2008, 49, 5235

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

M. Lynch, S. Hehir, M. P. Carty, F. Aldabbagh, Chem. Eur. J. 2007, 13, 3218S. Hehir, L. O’Donovan, M. P. Carty, F. Aldabbagh, Tetrahedron 2008, 64, 4196

1

10

L. O’Donovan, F. Aldabbagh, Chem. Commun., 2008, 5592.

Hypersensitive to Fanconi AnemiaMore selective to hypoxia

Targeting Hypoxic Cells

Mitomycin C (MMC)

SET - activation

O

ON

NH2

Me

OCONH2

OMe

NH

O

ON

NH2

Me

OCONH2

NH

OMe

O

ON

NH2

MeNH2

DNA

O

ON

NH2

Me

OCONH2

OMe

NH N

NH2

Me

OCONH2

OMe

OH

OHNH N

NH2

Me

OH

OH NH2

DNA+ 2 e-

+ 2 H+

CY P450 reductase

Two electron activation

DT-diaphorase

.

+ 1 e-

- 1 e-

- 1 e-1

10

DNA alkylation

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

steps

DNA alkylation

Measuring the Effect of FANCD2 Expression on Cell Viability

N NH

OMe

OCONH2O

O

NH2

Me

N

N

OMe

OMe

N Tr

●, ● 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

0

20

40

60

80

100

0 2 4 6 8 10

Concentration (x 10-3µ M)

Cel

l Via

bilit

y %