Chapter 6

Quinolines and isoquinolines:

Reactions and synthesis

N
N N
Pyridine Quinoline Isoquinoline

Quinolines and isoquinolines:

Benzo condensed pyridines

4a 4a
5 4 5 4
6 c 3 6 3
b c
7 aN 2 7 b aN 2
8 1 8 1
8a 8a
Quinoline Isoquinoline
Benzo[b]pyridine Benzo[c]pyridine
(1-azanaphtalene) (2-azanaphtalene)
 N N
N
Quinoline Isoquinoline Quinolizinium
cations

chapt. 25

Reaction with electrophiles

Protonation on N

N
N N

pKa 5.2 pKa 4.9 pKa 5.5

Electrophilic Ar subst

E
Benzene more electron rich
N N
E
than pyridine
Major isomers shown
E
E
N N
Halogenation in the pyridine ring

HCl H Br
Br2 Br Br
N N N
H H N
H
H Br H Br
Br

Br Br
- HBr

N N
-H H
H Br

HCl
Br
Br2

N N

Reaction with nucleophiles

Exchange of H
Nu
N N
N N Nu
Nu
Nu

c.f. react ! to N in pyridines

Nu
Nu

N N

Exchange of halogen etc.

Reactivity towards Nu as
X X

N
N X N N X N
X
X=halogen
 Nu X: H, halogen etc
Nu
+X
N X N N Nu F > Cl > Br > I
X

res. stab
anion

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

Br Br Br
NaNH2
N N N

H NH2 NH2
H

NH NH2
N
NH N
NH2
H

Oxy- and Aminoderivatives - Tautomeri

-All - isomers amino (not imino)

-One-Isomers:

NH
N O N
H H
O

Tautomeric Mixt.:
OH O

N NH

Quinoid struct.: Negative

Amide: Positive, c.f. pyridine
 Synthesis - Quinolines
H
Chapt. 3 O
Strategy b, 6-membered rings
O
NH2 -2 H2O N

X X

H
O

H
NH2 - H2O N
[ox; - H2]

H
"New" strategy
H
O

NH2 O -2 H2O N
X X

Synthesis - Isoquinolines

Chapt. 3
Strategy b, 6-membered rings
EtO OEt
H

O NH2 N
X X - H2O
- 2 EtOH

Blue bonds formed by FC type react.

"New" strategy
NH2 N
- H2O
C X R
X X [ox]
O
X: -Cl, H
 Alkaloid natural products

N
N
Quinoline Isoquinoline

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

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

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

Quinidine: Antiarytmic
Quinine: Antimalaria

HO
N N
HN H

N CF3
N Cl
CF3
Chloroquine
Mefloquine

Dihydroquini(di)ne and der.

Chiral ligands
Asym. dihydroxylation (Sharpless)
 Isoquinoline alkaloids N

O
Papaverine
(against spasms)
N
O
O

NH2 O

CO2H NH HO O
NH N
HO O
HO OH
O
OH O O
Tyr
HO OH OH O
OH
Norlaudanosoline
Noskapine O
(analgetic, not addictive)

CH3
N

HO O OH
Morfin

S
Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors
O
HO
N N
N H
O
OH O NH
H H
O N N
O
H2N O
HO O
OH
OH Met-enkefalin
Morfin Tyr N-terminal
OH in opiopeptides