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