-
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
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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