Chapter 6
Quinolines and isoquinolines:
Reactions and synthesis
N
N
N
Pyridine
Quinoline
Isoquinoline
Quinolines and isoquinolines:
Benzo condensed pyridines
4a
4
c
3
b
7
aN 2
8
1
8a
6
4a
5
Quinoline
Benzo[b]pyridine
(1-azanaphtalene)
6
5
4
3
c
b aN 2
7
8
1
8a
Isoquinoline
Benzo[c]pyridine
(2-azanaphtalene)
N
N
Quinoline
N
Isoquinoline
Quinolizinium
cations
chapt. 25
Reaction with electrophiles
Protonation on N
N
N
N
pKa 4.9
pKa 5.2
pKa 5.5
Electrophilic Ar subst
E
N
Benzene more electron rich
than pyridine
N
E
Major isomers shown
E
E
N
N
Halogenation in the pyridine ring
H Br
HCl
Br2
Br
N
N
N
H
Br
N
H
H Br
H
H Br
Br
Br
Br
- HBr
N
-H
N
H
H Br
HCl
Br2
Br
N
N
Reaction with nucleophiles
Exchange of H
Nu
N
N
N
Nu
N
Nu
Nu
c.f. react ! to N in pyridines
Nu
Nu
N
N
Exchange of halogen etc.
Reactivity towards Nu as
X
N
N
X
X=halogen
X
N
X
N
X
N
N
X
X: H, halogen etc
Nu
Nu
N
N
X
Nu
+X
F > Cl > Br > I
res. stab
anion
ANRORC (Add. of Nu., Ring Opening and Ring Closure)
Br
Br
Br
NaNH2
N
N
N
H NH2
H
NH
N
NH2
NH
NH2
NH2
N
H
Oxy- and Aminoderivatives - Tautomeri
-All - isomers amino (not imino)
-“One”-Isomers:
O
N
H
O
N
H
NH
O
Tautomeric Mixt.:
OH
N
O
NH
Quinoid struct.: Negative
Amide: Positive, c.f. pyridine
Synthesis - Quinolines
H
O
Chapt. 3
Strategy b, 6-membered rings
O
NH2
X
-2 H2O
N
X
H
O
H
NH2
- H2O
[ox; - H2]
H
"New" strategy
H
O
O
NH2
X
N
-2 H2O
N
X
Synthesis - Isoquinolines
Chapt. 3
Strategy b, 6-membered rings
X
EtO OEt
H
O
X
NH2
N
- H2O
- 2 EtOH
“Blue bonds” formed by FC type react.
"New" strategy
NH2
C
X
X
R
X
O
X: -Cl, H
- H2O
[ox]
N
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
N
HO
R
R=OMe: Quinine (Cinchonidine epimer at C-9)
N
R=H:
Quinidine (Cinchonine epimer at C-9)
Quinidine: Antiarytmic
Quinine: Antimalaria
N
HN
N
Cl
Chloroquine
HO
N
H
N
CF3
CF3
Mefloquine
Dihydroquini(di)ne and der.
Chiral ligands
Asym. dihydroxylation (Sharpless)
Isoquinoline alkaloids
N
O
N
O
Papaverine
(against spasms)
O
O
NH2
CO2H
NH
HO
HO
OH
O
NH
HO
HO
OH
O
OH
O
Noskapine
(analgetic, not addictive)
O
HO
CH3
OH
Morfin
S
Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors
O
HO
N
OH
O
O
O
O
H
N
H2N
OH
O
O
N
HO
O
OH
Norlaudanosoline
N
N
O
OH
Tyr
N
H
O
NH
H
N
O
Met-enkefalin
OH
Morfin
OH
Tyr N-terminal
in opiopeptides