Chapter 6

Quinolines and isoquinolines:

Reactions and synthesis

Pyridine

N

Quinoline

N

Isoquinoline

N

Quinolines and isoquinolines:

Benzo condensed pyridines

N

QuinolineBenzo[b]pyridine(1-azanaphtalene)

abc

1

2

3

4

4a

56

7

8

8a

N

IsoquinolineBenzo[c]pyridine(2-azanaphtalene)

abc

12

3

4

4a

56

7

8

8a

Quinoline

N

Isoquinoline

N

Quinoliziniumcations

N

chapt. 25

N NN

pKa 5.2 pKa 4.9 pKa 5.5

Reaction with electrophiles

Protonation on N

Electrophilic Ar subst

N

E

N

N

E

N

Major isomers shown

E

E

Benzene more electron rich

than pyridine

Halogenation in the pyridine ring

N

HCl

Br2

NH

N

H Br

H

Br Br

N

H Br

H Br

H

- H

Br

N

Br

H

H Br

N

Br

- HBr

N

HCl

Br2

N

Br

Reaction with nucleophiles

N

Nu

N Nu

N

Nu

N

Nu

N

Nu

N

Nu

c.f. react ! to N in pyridines

Exchange of H

Exchange of halogen etc.

N

X

N X N

X

X=halogen

Reactivity towards Nu as

N NX

X

ANRORC (Add. of Nu., Ring Opening and Ring Closure)

Nu

N N

Nu

XN NuX

+ X

res. stabanion

X: H, halogen etc

F > Cl > Br > I

N

Br

N

Br

H NH2

N

Br

HNH2

N

NH2

H

NaNH2

NH

NH

N

NH2

Oxy- and Aminoderivatives - Tautomeri

-All - isomers amino (not imino)

-“One”-Isomers:

Tautomeric Mixt.:

NH

O NH

O

NH

O

N

OH

NH

O

Quinoid struct.: NegativeAmide: Positive, c.f. pyridine

Synthesis - Quinolines

X X

Chapt. 3Strategy b, 6-membered rings

NH2

O

O

H

-2 H2O N

NH2

O

H

- H2O

[ox; - H2]

NH

NH2

O

O

H

H

N-2 H2O

X X

"New" strategy

Synthesis - Isoquinolines

O NH2

OEtEtO

H

- H2O

- 2 EtOH

N

NH2

O

X R

X: -Cl, H

- H2O [ox]

N

“Blue bonds” formed by FC type react.

X X

Chapt. 3Strategy b, 6-membered rings

X X

"New" strategy

C

Quinoline

N

Isoquinoline

N

Alkaloid natural products

•Largets class of secondary metabolites, >6500 compds known

•Contains N, most compds basic (alkaline), often heterocyclic

•Often highly toxic

•Found in certain higher plants (seldom in bacteria)

•Little is known regarding why alkaloids are produced

•Biosynthesis from amino acids

Quinoline alkaloids

Cinchona pubescens (Kinatre) from South America

N

R

HO N

H

R=OMe: Quinine (Cinchonidine epimer at C-9)

R=H: Quinidine (Cinchonine epimer at C-9)

Quinidine: Antiarytmic

Quinine: Antimalaria

N CF3

CF3

HONH

Mefloquine

N Cl

HNN

Chloroquine

Dihydroquini(di)ne and der.

Chiral ligands

Asym. dihydroxylation (Sharpless)

Isoquinoline alkaloids

Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors

OOHHO

N

Morfin

O

OH

N

OH

H2N

OH

HN

HN

O

O

O

NH

HO

NH

O

O

S

Met-enkefalin

Tyr N-terminalin opiopeptides

N

O OHHO

NCH3

Morfin

NH

OHHO OH

OH

Norlaudanosoline

NH

OH

OH

HO

HON

O

O

O

O

O OO

N

O

O

O

O

Papaverine(against spasms)

NH2

HO

CO2H

Tyr

Noskapine(analgetic, not addictive)