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)

N NPyridazine1,2-Diazine

NN

Pyrimidine1,3-Diazine

N

N

Pyrazine1,4-Diazine

N NCinnoline

N NPhtalazine

NN

Quinazoline

N

NQuinoxaline

N N N N N NN N

NN

NN

NN

NN

N

N N

N

N

N

N

N

Only C-5 in pyrimidineNOT elctron def.

Reactions with electrophiles

N NNN

N

NpKa 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+

N N

N NR

HH

[ox]N N R

N NH

[ox]N N

R H R

NN

1) R-Met2) 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:

NNX N N N N

XX N

NX N

X

NXNN

XNN

X

PyrimidinesClose in reactivity

Pyridazines Pyrazines Pyridines

NN Cl

NMe3 NN NMe3

Nu

Better leav. group

NN Nu

rel.soft

Pd-cat. couplings

NN

Cl

Cl

BrR-SnBu3,cat. Pd

NN

R

Cl

BrR-SnBu3,cat. Pd

NN

R

Cl

RR-SnBu3,cat. Pd

NN

R

R

R

NN

Cl

Cl

IR-SnBu3,cat. Pd

NN

Cl

Cl

R NN

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

NN

NLi (LiTMP) N

N

LiE N

N

E

ex. Bu3SnCl, TMS-Cl

NN

LiNN

H N

N

N N

LiTMPN N

Li

N

N

LiTMP N

N

LiUnstable

NN

X

Bu3SnCu

Bu3SnSnBu3cat. Pd

NN

SnBu32-, 4- or 6-halo

halo in all pos.

Stille coupl.

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

Radical reactions (Minisci)

N N

"R "N N

R

NN

"R " NN

RX

X=H+ N

NR

"R "X=Br

NN

RBr

Cycloadditions (DA)

N N

N

N- N2

NN NN N

-HCN

H

H N

N

N

NN

-HCN

H

H

Oxydiazines

Structure - Tautomerism

HN N

ON NH

ONNH

OHN

N

ONNH

O

NN OH

NH

N

O

HNNH

O

OR R=H: Uracil

R=Me: Thymindione

δ+

δ+

δ-

δ-HN N

H

O

O HN N

O

OHδ+δ+ δ

+

δ-

δ-

δ-

δ- δ+

React. with E-files

More electron rich, reacts easier with E-files than diazines“OH” o/p directing

HNNH

O

O

O

Barbitursyre: Trione

NN

O

OR

R

Cl

R=H, Me

PhSHpyridine

NN

O

OR

R

SPh

React. with Nu-files

NN

O

OR

R HCNHCN HCN

NN

O

OR

R CN

NN

O

OR

R Br

BenzenoidNot activated for Nu-attack

CN

≈ Michael add.

NN

O

O

R

R

BrH

CN

HN

N

O

OR

R HBrH

CN

O

- HBrN

N

O

OR

R

CN

≈ Michael add.

N

CN

H

Nu Ar subst

More complex mech.:

NNO

Cl

R

HS Microtubuli

HNN

H S

OR

MIcrotubuli

Cl

Undheim - Metaphase Inhibitors

Prophase Metaphase Anaphase Telophase

N-Deprotonation / Alkylation

HN N

O BaseRX

N N

O

RHN

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. NH4SO4Δ

NN

TMSO

TMSO

R

O X

ORRO

RO

cat. Lewis acid

β-ribosideRO RO

ORO

HNN

O

O

R

α-ribosideRO RO

ORO

NHN

O

O

R

+

O-silylation / N-alkylation

O

ORRO

RO O

ORRO

RO

SN1

N-Deprotonation / AlkylationN-alkylation / C-alkylation

HNNH

O

O Me

BaseRX HN

N

O

OR

Me

BaseH2C=O

HNNH

O

O MeOH HN

N

O

O MeOH

Hemiaminal - unstablec.f. hemiacetal

NNO

Cl

H

Base NNO

ClNNO

Cl

RX

NNO

Cl

R

NNO

ClR+

Ambident anion

N-alkylation / O-alkylation

HNNR

O

O

1) RLi / LDA2) E+

HNNR

O

O

EKinetic

HNNR

O

O ETermodyn.

C-Deprotonation / Metallation

Excess base Because of NH

RO RO

O

NLiN

O

O

R

LiOR

Replacement of oxygen

Halogenation

N OH

POCl3base N Cl

R-Metcat Pd N R

Nu

N Nu

c.f. Pyridones

HNNH

O

O O

R≠H: Barbiturate

RH

POCl3base N

N

Cl

Cl Cl

R NaOH (aq) HNNH

O

O Cl

R HNNH

O

O Nu

R

Uracil derivativesClSO2CH3base

HNNH

O

O OSO2CH3

R H2 / cat HNNH

O

O

R

Oxo thio

N OH

P4S10base N S

H

Cycloadditions

RNNR

O

ONO

R

RNNR

O

O

H

HON

React. with 1,3-dipol

Cancer

RNNR

O

O O R

Dienophile in DA

RNNR

O

O

O R

H

H

RNNR

O

ONR

NR

O

O

hν RNNR

O

O NR

NRO

O

H

H

H

HPhotochemical

[2+2] + isomers

OO O

R

R'

HN

N

O

O

OO O

R

R'

HN

N

NNO

O NH2

ONNNH2

O

hν

Psoralenes - Psoriasis

AminodiazinesExists as aminodiazines (not imino…)-NR2 electron donor: Stronger bases-NR2 electron donor: Participates easier in E-fil Ar subst.Diazotation reactionsDimroth rearrangement

HNNO NH

N

2-OxopurineGeir Andresen

HNN NH2O

Cytosine

HNO3 H2SO4 HN

N NH2O

NO2

E-fil Ar Subst(nitration)

H2/cat HNN NH2O

NH2CH(OEt)3cat H+

NNNH2

CH3IN

NNH2

CH3 OHN

NNH2

CH3

HOH HN

NNH2

CH3O - H2O N

NNHCH3

Dimroth

Synthesis of Pyridazines

O O

H2NNH2

NH

NHOH

HO-2 H2O [ox] N N

Cycloadditions

Carbonyl condensations

NN

NN - N2 N N

NN NN

+

NN

NN NPhPhN

O

O

O

O

KOHMeOH

NPhN N

O

O

SR

R

OO

2 +

BrBr

BrBr

BrBr

N NR

NN

H HBrBr

HR

Diazoalkane

NH

NBr Br

RH N

HN- HBr

Br

R N NBr

RMeLi

-H+

Synthesis of Pyrimidines

OO

HNHNH2 -2 H2O

NN

Carbonyl condensations etc.

NH2

NO

ORCO - ROH

HNN

O

O

Cycloadditions

N NN N

NNN

N- HCN+

N

N

H2NHN

N N

NO

RR

NH2OR

ORO

-ROH-H2O

Bioactive PyrimidinesDNA bases

Double α-helix

Base pairs

HN

N

O

O

Thymine

N

N

NH2

O

Cytosine Adenine

N

N N

NNH2

Guanine

HN

N N

NO

H2N

Anticancer comp.N

N

NH2

OO

HO

HOF

F

N

N

NH2

OO

HO

HOOH

Cytarabine (ARA-C)Gemcitabin

HN

NH

O

O

F

5-FU

Antivirals

HN

NO

O

O

HO

N3

AZT

N

NO

O

NH2

HO

ddC

HN

NO

O

O

HO

N

NO

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 PyrazinesCarbonyl condensations etc.

Bioactive Pyrazines/Pyridazines: Pteridines

NH2

OH

H2N

OH+

N

N-2 H2O [ox]

O

O

H2N

H2N

H

H+

N

N-2 H2O [ox]

Bacteria synthesize folic acid

NN N

N

Pteridine

H2N SN

ON

O O

H

H2NO

OHHN

N NH

N NH

CO2HO

H2N

HNN N

H

HN N

H

O

H2N

ONH

CO2HCO2H

NN

NH2

H2N OCH3

OCH3

OCH3

PABA Tetrahydrofolic acid

TrimetoprimSulfa drug

HNN N

N NH

O

H2N

ONH

CO2HCO2H

Folic acidVit. B9

HNN

O

O N

N

OHOH

OH

OHRiboflavineVit. B2 N

N N

N NNH2

H2N

ONH

CO2HCO2H

MethotrexateAnticancer drugFolic acid antagonist

Me