Reactions and Synthesis Quinolines and Isoquinolines

Chapter 6

Quinolines and isoquinolines: Reactions and synthesis

Quinolines and isoquinolines: Benzo condensed pyridines

4a 4a 5 4 5 4 6 c 3 6 3 b c N 7 aN 2 7 b a 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 than pyridine E Major isomers shown E E N N Halogenation in the pyridine ring

HCl H Br Br Br Br2 N N N N H H 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 X: H, halogen etc Nu Nu + X N X N N 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 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 NH N 2 -2 H2O X X

H O

H NH N 2 - H2O [ox; - H2]

H "New" strategy H O O NH2 -2 H2O N X X

Synthesis - Isoquinolines

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

O NH N X X 2 - H2O - 2 EtOH

“Blue bonds” formed by FC type react.

"New" strategy

NH2 N - H2O C X R [ox] X X 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 CF N Cl 3 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 O HO OH HO O OH O O Tyr HO OH OH O OH Norlaudanosoline Noskapine O (analgetic, not addictive)

CH N 3

HO O OH Morfin

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