PYRIDINES 4 β 5 3 β - Universitetet i oslo · Synthesis of Pyridines X X O O H H H2N ±H NH H OH...
Transcript of PYRIDINES 4 β 5 3 β - Universitetet i oslo · Synthesis of Pyridines X X O O H H H2N ±H NH H OH...
PYRIDINES
N1
2
34
5
6 α
β
γ
α
β
X X
1,5-dicarbonyl
X=N: NH3H
O O
NH3
NHHO OH
H
- 2 H2O N
From 1,5-dicarbonyl and ammonia (c.f. chapt. 3)
Synthesis of Pyridines
X X OO
HH
H2N ±HNH
HOH
O
H
NH2
OH
O
H
±H
From 1,3-dicarbonyl and enamine (c.f. chapt. 3)
X X
C
From 2 equivs. 1,3-dicarbonyl , aldehyde and ammonia - Hantzsch Synthesis
OO
H
OO
H
NH3
O
NH-3 H2O
H OO
Dihydropyridine
oxN
OO
Symmetri
Various syntheses from other heterocycles
PYRIDINESN1
2
34
5
6 α
β
γ
α
β
Reaction with electrophiles - react. on N:•Protonation•Nitration•Sulfonation•Amination•Halogenation•Alkylation•Acylation
NE
NE
Mild, not acidicelectrophile
Nu E-Nu + N
NF OTf
NO2N BF4
NS OOO
N
N
DMAP
Ac2ON
N
O AcO
ROH
Reaction with electrophiles - react. on C:Electrophilic Aromatic Substitution
DifficultElectron defficient / Poor nucleophiles
Electrophiles may react at N
•Nitration•Sulfonation•Halogenation
Not:•FC alkylation•FC acylation} React. in 3-pos.
N N N N N
Nitration
NKNO3 / H2SO424 h, 300 oC N
HN
NO2
6%N RR
NO2 BF4
NNO2
BF4R=H
R=Cl
N ClCl
NO2
Bakke:
H12
345 H
51
[1,5]-sigmatropic rearrang.
NN O NO
O
O
O NNO2
NO3
Pyridinium kationactivated for Nu-attack
SO
O OH
Na
NOSO2HH
NO2N H
OSO2H
NO2H
- HOSO2H
N
NO2
68%
Sulfonation
N
conc. H2SO4cat. HgSO4
N
SO3H
70%220 oC
Possible intermediates
Halogenation
Pd ClCl
N
NVia:
NNHgSO4
N
Hg-SO4H
N
SO3H
- HgO
N
Br2 / conc. H2SO4or Cl2 / AlCl3
N
X X=Br; 66%X=Cl; 33%
X2PdCl2
N XNH
OPOX3
Reaction with Nucleophiles
a) X=H, Substitution with “hydride” transferNu: NaNH2 - amination - Chichibabin reactionNu: BuLi, PhLi etc - alkylation / arylationNu: NaOH - “hydroxylation” - NB! High temp } Attack in the 2-pos (not 4-pos)
NuN N
NuX N NuX + X
a) X=Hb) X=Good leaving group
b) X=LG, Displacement of good leaving groupX: Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR
N XNu
N Nu NNu
N
X Nu
N
X Nu
Via PyridyneN
Br NaNH2, ButOKR2NH
N N
NaNH2, ButOKR2NH Br
NuN
N
NR2
N
NR2+
Metallation and Reactions with Electrophiles
N
MeONa / MeOD165 oC N N ND
DD
1 : 9 : 12
Termodynamic
N Bu-Li
NBuLi / ButOK
low temp N NK
K
Kinetic+
Ortho directing subst.
N
ClLDA
N
ClLi E
N
ClE
N Br
Br
Metal - Halogen Exchange
1) BuLi- 78 oC
2) E- 78 oC - r.t. N Br
E1) BuLi2) E- 90 oCN E
Br
Direct Reactions with Electrophiles: Additions, Substitutions
N
Li
R R'O1)
2) H+/H2O
N
HO RR'
DMFN
O
1) ArCN
2) H+/H2O N
OAr
Br
N
I2
N
I
R3SnX
R3SiX
ZnX2
N
SnR3
N
SiR3
N
ZnX
Some examples (c.f. react. with ArLi)
Pd-Catalyzed Coupling reactionsa) On metallated pyridines
N
Met Ar-Xcat. "Pd"
N
Ar Met = -SnR3; Stille couplingMet= -B(OR)2; SuzukiMet= -ZnX; Negishi
b) On halopyridines
N
X Ar-Metcat. "Pd"
N
Ar Met = -SnR3; Stille couplingMet= -B(OR)2; SuzukiMet= -ZnX; Negishi
N
XR
cat. Pd, CuX, R3N
N
RSonogashira coupling
N
X cat. Pd, Base
NHeck coupling
R R
N
RR'NH, cat. "Pd", Base
NHartvig - Buchwald
Br NR
R'
N X N
X
N
X
Reactivity
X=I>X=Br/OTf>X=Cl
Radical Reactions
a) Reactions with C-radicals: Minisci React.
b) Generation of / Reaction on pyridylradicals
NH
R
Nucleophilic radical
NH
RH
ox.
N R
Reactivity: Pyridinum cation > neutral pyridine 2-pos. > 4-pos. > >3-position
R-CO2HAgNO3 / (NH4)2S2O8
CO2
RAlkyl radical
HO
R
R=Alkyl, Aryl, -NR2
(aldehyd / formamid)
H2SO4, ButOOH, FeSO4 OR
Acyl radical
N
X Bu3SnH, AIBN
NN
Br Bu3SnH, AIBNN
Intramolecuar cyclisations
Reductions
N
NH
NSi PhMe
HNH
H2, PtAcOH
Ph(Me)SiH2cat. Cp2TiMe2Na, NH3 (l)
Photochemistry
N
HH
N
t1/2 = 2 min
hν (254 mn)
X=O: one / hydroxyX=NR: imino / aminoX=S: thione (6-membered rings) / thiol (5 membered)
NHX NH
X
?
N
XH
NH
X?
NH2N NH
HNNH
HN
NHO NH
O N
HO
N NH
OH O
NH
ONH
O
2-Pyridone 3-Hydroxtpyridine 4-Pyridone
Structure - Tautomerism
Oxy-, Thio- and Aminopyridines
Reactions on Pyridones - With Electrophiles
N
OH
H
E o/p-directing
NH
OH
N
EOH
N
OH
N
OH
E E
N-protonation as pyridine
NH
O
N OHo/p-directing
NH
O
E
NH
O
E
NH
O H NH
O H
O-protonation as amides
Reactions on Pyridones - Deprotonation - O or N-substitution
NH
O
pKa≈11
BaseN O N O
R-X
Ambident anion
N O N O RR
and / or
NH
O
Me3SiNHSiMe3(HMDS)
Δ N O SiMe3R-X
N OR
Reactions on Pyridones - Replacement of Oxygen
N OH
(CF3SO2)2OBase
N OSO2CF3
Pd-cat. couplings etc
Triflate
N OPO
ClCl
Cl
HNH
O PO
ClCl
Cl
NH
Cl
O PO
ClCl
B
N Cl
Thiopyridones
N SH
ClOR Base
N SOR
Useful synthetic intermedites
R'MgX'ROR
ketone
N SO
RNHProt + H2N
ProtR'
ONH
O
RNHProt
R'Prot
O
Peptide
N SO
OHn
NH
SO
O
heat
n
N SH
O n
O
Lactone
Aminopyridines
N NH2
H
N NH2H
NH
NH2
pKa 7.2
H
NH
NH
NH
pKa 9.1
HNH2
NH2
NH2
NH
NH2
N
NH2
HpKa 6.6
HN
NH3
HpKa -1.5
N
NH2 NaNO2, acid
N
N2
H2O
HF
HBrBr2
NH
O
N
Br
N
F
Alkyl- and Vinylpyridines
N CH3
Base N CH2
N CH2
E
N CH2E N NNu-H
N Nu
Quartenary Pyridinium Salts
NR
NR
NR
Nu
NR
NuH
and / or NR
H Nu
Add of: -hydrides -dithionite -organometallics -stab. carbanions etc. etc.
NR
PhMgBrCuI
NR
H Ph Cleav. of ROx.
N
PhR: -SiMe2But -SO2R -CO2R
Co-enz.NAD+
N
ONH2
+ Sub-H2
NAD+
N
ONH2
NADH
H H
+ Sub + H
Hydride add. to NAD+, SubH2 oxidizedNicotine amide: Vit. B3Adenine: Vit. B4
N
ONH2
NADH co-enzymein enzyme involved in cell wallcomponent synth
H H
NO
HN NH2
IsoniazideAntituberculosis drug
NO
Mn2+ /O
Active acyl radical formed in vivo
N
ONH2
HO
N
Inactive der. of co-enz
N
ONH2
O
OHHO
OPOP
OO
O OO
ON
HOHO
N
NN
NH2
N
N
Nicotine
[ox]N
CO2H
Nicotinic acid
Pyridine N-oxides
N N N N N2.22D
4.25DNO
NO
NO
Neg. charge i α,γ pos.
NO
NO
More activated for electrophilic and nucleophilic attack
NHO OH
(or peracid etc)
NOH
+ OH NO
+ H2ONO
+ PPh3N
+ POPh3
N
O
NO
NKNO3 / H2SO424 h, 300 oC N
HN
NO2
6%
NO
fum. HNO3conc. H2SO4
100 oC NO
NO2
66%NO
H NO2
NO
H NO2
NO
E NO
E
NO
H E
H
NOH
NO
E
c.f. Electrophilic Ar. subst on pyridine / puridinium cation
Electrophilic Ar. subst
NO
Ac2ONOAc
OAc NOAc
HOAc -AcOH N OAc
hydrolysisNH
O
Rearrangements
NO
CH3Ac2O
NOAc
OAcCH2H N
O O N OO