Diazines - Universitetet i oslo · Diazoalkane N H N Br Br R H H - HBr Br R N N Br R MeLi-H+ Synthesis of Pyrimidines O O NH H NH 2-2 H 2O N N Carbonyl condensations etc. NH 2 N O

Chapter 10 - 11

Diazines

Diazines

-Reacts less readily with electrophiles than pyridine

-Reacts easily with nucleophiles (additions / substitutions)

-Reacts with nucleophilic radicals (Minisci)

-Reacts as dienes in DA cycloadd. (less aromatic than pyridine)

NN

Pyridazine1,2-Diazine

N

N

Pyrimidine1,3-Diazine

N

N

Pyrazine1,4-Diazine

NN

Cinnoline

NN

Phtalazine

N

N

Quinazoline

N

N

Quinoxaline

NN

NN

NN

NN

N

N

N

N

N

N

N

N

N

N N

N

N

N

N

N

Only C-5 in pyrimidine

NOT elctron def.

Reactions with electrophiles

NN

N

N

N

N

pKa 2.3 pKa 1.3 pKa 0.65

-Protonation

-N-alkylation

-Ox. to N-oxides (H2O2, peracids)

-Pract. no E-fil Ar subst. (C-5 pyrimidine)

-Halogenation by add. / elim. mechanisms

c.f. pyridines

weaker bases than pyridine

Reactions with nucleophiles

Addition - Rearomatization

R-MgX

1) R-Li

2) H+

NN

NN

R

HH

[ox]

NN R

NN

H

[ox]

NN

R H R

N

N

1) R-Met

2) H+ N

N

R HH [ox] N

N

R

RMet: RLi, RMgX

[ox]: DDQ, KMnO41,2- add

1,4-add

Add. av NH2- (Chichibabin)

N

N

NH2 N

N

H NH2

- H

N

N

NH2

Easier than for pyridine

More difficult than for pyridine(less aromatic comp.)

Substitution on halodiazines

Nucleophiles:

-ammonia / amines

-thiolates

-malonates etc.

-water / alchohols / alchoxides

Leaving groups:

-halogen

-OMe

-SO2Me

Reactivity:

N

NXNN

NN

X

X N

NX N

X

NX

N

N

X

N

N

X

PyrimidinesClose in reactivity

Pyridazines Pyrazines Pyridines

N

N Cl

NMe3 N

N NMe3

Nu

Better leav. group

N

N Nu

rel.

soft

Pd-cat. couplings

N

N

Cl

Cl

BrR-SnBu3,cat. Pd

N

N

R

Cl

Br

R-SnBu3,cat. Pd

N

N

R

Cl

R

R-SnBu3,cat. Pd

N

N

R

R

R

N

N

Cl

Cl

IR-SnBu3,cat. Pd

N

N

Cl

Cl

R N

N

Cl R-SnBu3,cat. Pd

No react.

With hard Nu:

N

NCl

Ar-Li N

NAr

Ar-Li

N

NH

Cl Ar

[ox] N

NCl Ar

Metallation

N

N

NLi (LiTMP)

N

N

Li

EN

N

E

ex. Bu3SnCl, TMS-Cl

N

N

LiN

N

H N

N

NN

LiTMP

NN

Li

N

N

LiTMP N

N

Li

Unstable

N

N

X

Bu3SnCu

Bu3SnSnBu3cat. Pd

N

N

SnBu32-, 4- or 6-halo

halo in all pos.

Stille coupl.

Rel. stable, can be prepared without Pyr-Li as intermed.

Cycloadditions (DA)

NN

N

N

- N2

N

N NN N

-HCN

H

H N

N

N

N

N

-HCN

H

H

Oxydiazines

Structure - Tautomerism

HNN

O

NNH

O

N

NH

O

HN

N

O

N

NH

O

N

NOH

NH

N

O

HN

NH

O

O

RR=H: UracilR=Me: Thymin

dione!+

!+

!-

!-HN

NH

O

O HN N

O

OH

!+!+ !

+

!-

!-

!-

!- !+

React. with E-files

More electron rich, reacts easier with E-files than diazines

“OH” o/p directing

HN

NH

O

O

O

Barbitursyre: Trione

N

N

O

OR

R

Cl

R=H, Me

PhSHpyridine

N

N

O

OR

R

SPh

React. with Nu-files

N

N

O

O

R

RH

CN

HCN

HCN

N

N

O

O

R

R CN

N

N

O

O

R

R Br

Benzenoid

Not activated

for Nu-attack

CN

! Michael add.

N

N

O

O

R

R

Br

H

CN

H

N

N

O

O

R

RH

Br

HCN

O

- HBr

N

N

O

O

R

R

CN

! Michael add.

N

CN

H

Nu Ar subst

More complex mech.:

N-Deprotonation / Alkylation

HNN

O Base

RXNN

O

R

HN

NH

O

O

R

R=H: UracilR=Me: Thymin

BaseRX HN

N

O

O

R

R

BaseRX N

N

O

O

R

R

R

Me3SiSiMe3 (HMDS)

cat. NH4SO4!

N

N

TMSO

TMSO

R

O X

ORRO

RO

cat. Lewis acid

"-ribosideRO RO

ORO

HN

N

O

O

R

#-riboside

RO RO

ORO

NH

N

O

O

R

+

O-silylation / N-alkylation

O

ORRO

ROO

ORRO

RO

SN1

N-Deprotonation / Alkylation

N-alkylation / C-alkylation

HN

NH

O

O Me

Base

RXHN

N

O

O

R

Me

Base

H2C=O

HN

NH

O

O Me

OHHN

N

O

O Me

OH

Hemiaminal - unstable

c.f. hemiacetal

N

NO

Cl

H

Base N

NO

ClN

NO

Cl

RX

N

NO

Cl

R

N

NO

Cl

R+

Ambident anion

N-alkylation / O-alkylation

HN

NR

O

O

1) RLi / LDA

2) E+

HN

NR

O

O

E

Kinetic

HN

NR

O

O E

Termodyn.

C-Deprotonation / Metallation

Excess base

Because of NH

RO RO

O

NLi

N

O

O

R

LiO

R

Replacement of oxygen

Halogenation

N O

H

POCl3base

N Cl

R-Met

cat PdN R

Nu

N Nu

c.f. Pyridones

HN

NH

O

O O

R!H: Barbiturate

R

H

POCl3base N

N

Cl

Cl Cl

RNaOH (aq) HN

NH

O

O Cl

RHN

NH

O

O Nu

R

Uracil derivativesClSO2CH3base

HN

NH

O

O OSO2CH3

R H2 / cat HN

NH

O

O

R

Oxo ! thio

N O

H

P4S10base

N S

H

Cycloadditions

RN

NR

O

O

N

O

R

RN

NR

O

O

H

HON

React. with 1,3-dipol

Cancer

RN

NR

O

O O R

Dienophile in DA

RN

NR

O

O

O R

H

H

RN

NR

O

O

NR

NR

O

O

h!RN

NR

O

O NR

NR

O

O

H

H

H

H

Photochemical[2+2]

+ isomers

OO O

R

R'

HN

N

O

O

OO O

R

R'

HN

N

NNO

O NH2

ONN

NH2

O

h!

Psoralenes - Psoriasis

Aminodiazines

!Exists as aminodiazines (not imino…)

!-NR2 electron donor: Stronger bases

!-NR2 electron donor: Participates easier in E-fil Ar subst.

!Diazotation reactions

!Dimroth rearrangement

HN

NO NH

N

2-OxopurineGeir Andresen

HN

N NH2O

Cytosine

HNO3 H2SO4 HN

N NH2O

NO2

E-fil Ar Subst(nitration)

H2/cat HN

N NH2O

NH2

CH(OEt)3cat H+

N

N

NH2

CH3I

N

N

NH2CH3 OH

N

N

NH2CH3

HO

H HN

N

NH2CH3

O- H2O N

N

NH

CH3

Dimroth

Synthesis of Pyridazines

OO

H2NNH2

NH

NHOH

HO-2 H2O [ox] N

N

Cycloadditions

Carbonyl condensations

N

N

N

N - N2N

N

N

NN

N

+

N

N

N

N NPhPhN

O

O

O

O

KOH

MeOH

NPhN

N

O

O

S

R

R

O

O2 +

Br

Br

Br

Br

BrBr

N N

R

NN

H H

BrBr

H

R

Diazoalkane

NH

N

Br Br

R

HNH

N- HBr

Br

R NN

Br

R

MeLi

-H+

Synthesis of Pyrimidines

O

O

HNH

NH2-2 H2O

N

N

Carbonyl condensations etc.

NH2

N

O

OR

CO - ROH

HN

N

O

O

Cycloadditions

NN

NN

NN

N

N

- HCN+

N

N

H2N

HN

N N

N

O

RR

NH2

OR

O

RO

-ROH

-H2O

Bioactive Pyrimidines

DNA bases

Double !-helix

Base pairs

HN

N

O

O

Thymine

N

N

NH2

O

Cytosine Adenine

N

N N

N

NH2

Guanine

HN

N N

N

O

H2N

Anticancer comp.

N

N

NH2

O

O

HO

HO

F

F

N

N

NH2

O

O

HO

HO

OH

Cytarabine (ARA-C)Gemcitabin

HN

NH

O

O

F

5-FU

Antivirals

HN

N

O

O

O

HO

N3

AZT

N

N

O

O

NH2

HO

ddC

HN

N

O

O

O

HO

N

N

O

S

O

NH2

HO HIV (RT -inhibitors)

Barbiturates (old sedatives)

HN

NH

O

OO

i.e. Phenobarbital

HN

NH

O

OO

Barbituric acidpKa 4.0

Synthesis of Pyrazines

Carbonyl condensations etc.

Bioactive Pyrazines: Pteridines

NH2

O

H

H2N

O

H+

N

N

-2 H2O[ox]

O

O

H2N

H2N

H

H

+

N

N

-2 H2O[ox]

Bacteria synthesize folic acid

N

N N

N

Pteridine

H2N S

NON

OO

H

H2N

O

OH

HN

N NH

NNH

CO2HO

H2N

HN

N NH

HN

NH

O

H2N

O

NH

CO2H

CO2H

N

N

NH2

H2N OCH3

OCH3

OCH3

PABATetrahydrofolic acid

TrimetoprimSulfa drug

HN

N N

NNH

O

H2N

O

NH

CO2H

CO2H

Folic acid

Vit. B9

HN

N

O

O N

N

OH

OH

OH

OHRiboflavine

Vit. B2 N

N N

NN

NH2

H2N

O

NH

CO2H

CO2H

MethotrexateAnticancer drugFolic acid antagonist

Me