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