γ
PYRIDINES
4
3 β
β 5
α 6
Synthesis of Pyridines
2 α
N
1
From 1,5-dicarbonyl and ammonia (c.f. chapt. 3)
1,5-dicarbonyl
X
H
X
NH3
H
X=N: NH3
- 2 H2O
HO N
H OH
OO
N
From 1,3-dicarbonyl and enamine (c.f. chapt. 3)
H
H
X
X
O
H2N
O
OH
H
H
±H
O
OH
H
O
NH
±H
NH2
From 2 equivs. 1,3-dicarbonyl , aldehyde and ammonia - Hantzsch Synthesis
O
C
X
X
H
O
O H
H
O
O
O
NH3
Various syntheses from other heterocycles
O
O
O
ox
-3 H2O
N
H
Dihydropyridine
N
Symmetri
γ
PYRIDINES
4
3 β
β 5
α 6
N
2 α
1
Reaction with electrophiles - react. on N:
•Protonation
•Nitration
E
Nu
E-Nu +
N
N
•Sulfonation
E
•Amination
Mild, not acidic
N
electrophile
F
•Halogenation
•Alkylation
•Acylation
N
N
N
N
OTf
ROH
Ac2O
N
DMAP
O2N
N
O
AcO
N
BF4
O S O
O
Reaction with electrophiles - react. on C:
Electrophilic Aromatic Substitution
Electron defficient / Poor nucleophiles
Difficult
Electrophiles may react at N
•Nitration
•Sulfonation
•Halogenation
N
N
}
Not:
•FC alkylation
•FC acylation
React. in 3-pos.
N
N
N
Nitration
N
KNO3 / H2SO4
24 h, 300 oC
N
H
N
NO2 BF4
6%
R
N
R
NO2
R=Cl
Cl
Bakke:
O
N
O
N
Na O
S
O OH
O
O
N
O
N
NO2
N
NO2
NO3
OSO2H
H
NO2
H
OSO2H
N H
Pyridinium kation
activated for Nu-attack
- HOSO2H
NO2
4
[1,5]-sigmatropic rearrang.
3
2
H
5
1
H
5
1
BF4
N
NO2
R=H
NO2
N
68%
N
Cl
Possible intermediates
Sulfonation
conc. H2SO4
cat. HgSO4
N
220 oC
SO3H
N
Hg-SO4H
70%
N
SO3H
N
N
HgSO4
- HgO
Halogenation
X2
PdCl2
POX3
N
H
O
N
X
Br2 / conc. H2SO4
or Cl2 / AlCl3
N
Via:
N
Cl Pd Cl
N
X
N
X=Br; 66%
X=Cl; 33%
N
Reaction with Nucleophiles
Nu
Nu
N
a)
X
N X
N
Nu
a) X=H
b) X=Good leaving group
+X
X=H, Substitution with “hydride” transfer
Nu: NaNH2 - amination - Chichibabin reaction
Nu: BuLi, PhLi etc - alkylation / arylation
Nu: NaOH - “hydroxylation” - NB! High temp
b)
}
Attack in the 2-pos (not 4-pos)
X=LG, Displacement of good leaving group
X: Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR
X
Nu
Nu
N
Nu
N
X
Via Pyridyne
Br
Nu
X Nu
N
N
N
NaNH2, But OK
R2NH
NaNH2, But OK
R2NH
N
N
N
NR2
NR2
+
N
Br
N
Nu
N
Metallation and Reactions with Electrophiles
D
D
MeONa / MeOD
Termodynamic
165 oC
N
N
1
D
N
:
N
9
:
12
K
N
BuLi / ButOK
low temp
+
N
N
Kinetic
Bu-Li
N
K
Ortho directing subst.
Cl
Cl
LDA
N
Cl
Li
N
E
E
N
Metal - Halogen Exchange
Br
N
E
1) BuLi
Br
2) E
- 90 oC
1) BuLi
N
Br
2) E
- 78 oC - 78 oC - r.t.
E
N
Br
Direct Reactions with Electrophiles: Additions, Substitutions
Some examples (c.f. react. with ArLi)
HO R
R'
O
N
1) O
SnR3
R R'
2) H+/H2O
R3SnX
N
Li
SiR3
R3SiX
N
N
DMF
O
1) ArCN
Ar
+
2) H /H2O
N
ZnX2
N
Br
ZnX
I2
N
I
N
N
Pd-Catalyzed Coupling reactions
a) On metallated pyridines
Ar-X
cat. "Pd"
Met
Ar
N
Met = -SnR3; Stille coupling
Met= -B(OR)2; Suzuki
Met= -ZnX; Negishi
N
b) On halopyridines
X
Ar-Met
cat. "Pd"
Ar
N
N
R
X
R
cat. Pd, CuX, R3N
N
Reactivity
Met = -SnR3; Stille coupling
Met= -B(OR)2; Suzuki
Met= -ZnX; Negishi
X
X
N
Sonogashira coupling
X
N
N
N
X=I>X=Br/OTf>X=Cl
R
X
R
cat. Pd, Base
Heck coupling
N
N
Br
N
R
N
RR'NH,
cat. "Pd", Base
N
R'
Hartvig - Buchwald
Radical Reactions
a) Reactions with C-radicals: Minisci React.
Nucleophilic radical
R-CO2H
AgNO3 / (NH4)2S2O8
R
Alkyl radical
R
N
H
N
H
R
H
ox.
CO2
N
R
O
Reactivity: Pyridinum cation > neutral pyridine
2-pos. > 4-pos. > >3-position
H
H2SO4, But OOH, FeSO4
R
R
R=Alkyl, Aryl, -NR2
Acyl radical
(aldehyd / formamid)
b) Generation of / Reaction on pyridylradicals
Intramolecuar cyclisations
X
N
Bu3SnH, AIBN
Br
N
N
O
Bu3SnH, AIBN
N
Reductions
Ph(Me)SiH2
cat. Cp2TiMe2
Na, NH3 (l)
N
H
N
Si
H
Ph
Me
N
H2, Pt
AcOH
N
H
Photochemistry
hν (254 mn)
H
H
N
N
t1/2 = 2 min
Oxy-, Thio- and Aminopyridines
Structure - Tautomerism
2-Pyridone
3-Hydroxtpyridine
4-Pyridone
OH
O
N
N
H
HO
HO
N
O
N
H
N
O
O
H2N
XH
N
?
N
N
H
N
H
HN
N
H
HN
X
?
N
H
HX
N
X
N
H
N
H
X=O: one / hydroxy
X=NR: imino / amino
X=S: thione (6-membered rings) /
thiol (5 membered)
Reactions on Pyridones - With Electrophiles
o/p-directing
E
E
OH
OH
N
N
OH
OH
E
N
N
E
H
OH
N-protonation as pyridine
N
H
E
N
H
O
N
OH
o/p-directing
N
H
O
E
N
H
O
H
H
N O
N O
H
H
O-protonation as amides
Reactions on Pyridones - Deprotonation - O or N-substitution
Ambident anion
N
H
O
Me3SiNHSiMe3
(HMDS)
Base
N
O
pKa≈11
N
O
N
OR
N
H
O
R-X
N
Δ
R-X
and / or
N
R
O
Reactions on Pyridones - Replacement of Oxygen
O
Cl
N
O
P
Cl
O
Cl
N
H
Cl
H
O
P
Cl
Cl
Cl O
P
O
Cl
Cl
N
H
B
Triflate
(CF3SO2)2O
Base
N
H
O
Pd-cat. couplings etc
N
OSO2CF3
N
Cl
O
SiMe3
N
R
O
Thiopyridones
O
Cl
N
R Base
S
N
H
S
O
R'MgX
O
'R
R
R
ketone
Useful synthetic
intermedites
O
N
R'
NHProt
S
R
+
H2N
R'
Prot
O
Prot
O
O
N
H
NHProt
R
Peptide
O
N
OH
n
S
O
heat
N
H
N
H
S
O
O
n
S
O
n
Lactone
Aminopyridines
N
H
NH2
N
H
NH2
H
H
N
NH2
H
H
NH2
N
NH2
N NH2
H
pKa 7.2
N
H
pKa 9.1
NH2
H
N
NH2
NH3
H
N
H
pKa 6.6
N
H
pKa -1.5
O
H2O
NH2
N
NaNO2, acid
N2
N
N
H
F
HF
HBr
Br2
N
Br
N
Alkyl- and Vinylpyridines
Base
N
N
CH2
CH3
E
Nu-H
N
N
N
N
CH2E
N
CH2
Quartenary Pyridinium Salts
N
R
N
R
Add of: -hydrides
-dithionite
-organometallics
-stab. carbanions
etc. etc.
N
R
Nu
H Nu
N
R
Nu
H
and / or
N
R
PhMgBr
CuI
N
R
H Ph
N
R
Cleav. of R
Ox.
Ph
N
R: -SiMe2But
-SO2R
-CO2R
Nu
O
O
NH2
N
O
O
O P O
O
OH
O P O HO
O
N N
O
HO
N
NH2
N
HO
NH2
Co-enz.
NAD+
N
N
Nicotine
NH2
N
+ Sub + H
NADH
Hydride add. to NAD+, SubH2 oxidized
N
CO2H
[ox]
+ Sub-H2
NAD+
Nicotine amide: Vit. B3
Adenine: Vit. B4
N
H H O
O
N
HN
Nicotinic acid
Isoniazide
Antituberculosis drug
NH2
Mn2+ /O
N
H H O
Active acyl radical
O formed in vivo
N
O
H O
NH2
N
NADH co-enzyme
in enzyme involved in cell wall
component synth
NH2
N
Inactive der. of co-enz
Pyridine N-oxides
HO OH
N
N
OH
+ OH
N
+ H2O
N
O
(or peracid etc)
+
PPh3
+ POPh3
N
O
N
N
O
O
2.22D
N
N
N
N
N
Neg. charge i α,γ pos.
4.25D
N
O
N
O
N
O
N
O
N
O
More activated for electrophilic
and nucleophilic attack
H E
E
N
O
N
E
N
Electrophilic Ar. subst
O
H
O
E
N
N
OH
O
KNO3 / H2SO4
24 h, 300 oC
N
NO2
N
H
N
6%
c.f. Electrophilic Ar. subst on pyridine /
puridinium cation
H NO2
fum. HNO3
conc. H2SO4
100 oC
N
H NO2
N
O
O
N
O
Rearrangements
Ac2O
N
N
O
OAc
OAc
N
OAc
H
OAc -AcOH
hydrolysis
N
N
H
OAc
Ac2O
N
O
CH3
N
OAc
H
C
H2
OAc
N
O
O
N
O
O
O
NO2
N
O
66%