BENZO CONDENSED PYRIDINES: QUINOLINES AND ISOQUINOLINES

N

QuinolineBenzo[b]pyridine(1-azanaphtalene)

abc

123

44a

56788a

N

IsoquinolineBenzo[c]pyridine(2-azanaphtalene)

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12

34

4a5

6788a

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 NH

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

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

Quinidine: AntiarytmicQuinine: Antimalaria

N CF3CF3

HO NH

Mefloquine

N Cl

HN N

Chloroquine

Dihydroquini(di)ne and der.Chiral ligandsAsym. dihydroxylation (Sharpless)

Isoquinoline alkaloidsCurare - Pilgift - Søramerikanske indianereBland. Av flere alkaloider med muskeslammende effektFlere plantekilder bl.a. Chondodendron tomentosum

MeO NMe

MeO

MeO NHMe

MeO

MeO

MeO

MeO

MeO

MeO

OMe

O

OO

O

MeO

O

HO

OOH

OMe

NR

Me

NMe

Me

R=H: TubocurarinR=Me: Wrong struct.

N N

Ex. Mivacurium kloridMuscle relax, anesthesia

Cl

N O O N

O

OCl

Esterase

Cl

N OHHO N

O

OCl

HOOH

Succinsyrekolin

Suksametonium, Curacit® “Nesset”

Isoquinoline alkaloids

Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors

O OHO

N CH3

O OHHO

N CH3

H3CO OO

N CH3

H3C CH3

Thebaine Morfin

NH

OHHO OH

OH

Norlaudanosoline

NH

OH

OH

HO

HO N

O

O

O

OO O O

N

O

O

O

O

Papaverine(against spasms)

NH2

HO

CO2H

Tyr

Noskapin(not analgetic,not adiction)

O OHHO

N

Morfin

O

OHN

OH

H2N

OH

HN H

NO

OO

NH

HO

NH

O

O

S

Met-enkefalin

Tyr N-terminalin opiopeptides

N N N

pKa 5.2 pKa 4.9 pKa 5.5

Protonation Electrophilic Ar. Subst.

N

E

N

NE

N

Major isomers shownE

E

Halogenation in the Pyridine Ring

N

HClBr2

N H

Br

NH Br

H

Br BrN

H Br

H BrH

- H

N

Br

HH Br

- HBr

N

Br

N

HClBr2

N

Br

Nucleophilic Addition - Nucleophilic Ar. Subst.

N

Nu

N NuN

Nu

NNu

N

Nu

NNu

NX

N X N

X

X=halogen

Reactivity towards Nu as N NX

X

Nu-radicals (Minisci react.)attacks in the same pos.

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

NHNH

NNH2

NBr NaNH2

NBr

H NH2

NBr

H NH2

NNH2

H

NuN N

NuX N NuX + X a) X=H

b) X=Good leaving group

Oxy- and Aminoderivatives - Tautomeri

-All - isomers amino (not imino)

-“One”-Isomers:

NH

O NH

O

NHO

Tautomeric Mixt.:

NOH

NHO

Quinoid struct.: NegativeAmide: Possitive

Synthesis - Quinolines

NH2

OO

H

-2 H2O N NH2

OH

- H2O [ox]

NH

Synthesis - Isoquinolines

NH2

OO

HH

N-2 H2O

O NH2

OEtEtOH

- H2O- 2 EtOH

NNH2

OX R

X: -Cl, H

- H2O [ox]

N