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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)