Pyridine and derivatives, Synthesis

Ref:
Heterocyclic chemistry, Raj K Bansal
The Chemistry of Heterocycles Eicher, Hauptmann, and Speicher
Heterocyclic chemistry, Joule and Mills
Six-Membered Heterocycles
pyridine Pyridinium ion isoelectronic
with benzene
parent compounds
of six-membered
neutral heterocycles
with one heteroatom 2H-pyran
and the maximum
number of pyrylium ion
noncumulative double pyran
bonds.
4H-pyran

2H- thiopyran

thiopyrylium ion
thiopyran
4H- thiopyran
 π-electron density is lowest on the 2, 4, and 6 C-atoms and highest on the N-atom

• electronegative nitrogen
• inductive effect of nitrogen causes a polarization in the σ - bond framework
• resonance structures with negative charge on nitrogen are more stable
• a permanent polarisation of the π - electron system
• permanent dipole towards the nitrogen atom
• partial positive charges on the carbons of the ring, located on the α - and γ – positions
• “ electron – poor” molecules
Synthesis of pyridine derivatives

From 1,5 - Dicarbonyl Compounds and Ammonia

1,5-Dicarbonyl compounds

• accessible by Michael addition of enolates or enamines to α,β-unsaturated carbonyl compounds

or by ozonolysis of a cyclopentene precursor

• undergo cyclocondensation with NH3 to afford 1,4-dihydropyridines whose dehydrogenation leads to pyridines
 dehydrogenation leads to pyridines

If R = CH2R’ intramolecular cyclocondensation with hydroxylamine helps because

aldol condensation N-hydroxy intermediate, by H2O elimination , gives the product directly
competes with 1,4-
dihydropyridine formation
Synthesis of pyridine derivatives

From 1,5 - Dicarbonyl Compounds and Ammonia

oxidation

dehydration
Michael addition
of enolates to α,β-unsaturated carbonyl compounds
(masked as the Mannich product)
Syntheses of pyridine
From unsaturated 1,5 - Dicarbonyl Compounds and Ammonia

glutaconic dialdehyde
syntheses of pyridine derivative
From unsaturated 1,5 - Dicarbonyl Compounds and Ammonia

One pot synthesis of 2,2 ′,6 ′,2 ′′-Terpyridine

from 2 - acetylpyridine, dimethylformamide dimethylacetal (DMFDMA) and ammonia

the first step is

Conjugate Addition by the
dimethylaminomethylenation of
enolate of the starting ketone
the ketone methyl group
and elimination of HNMe2.
Condensation the ketone with
formamide

dimethylformamide dimethylacetal
(DMFDMA)
Formylating agent
Methylating agent
Syntheses of 4 – pyridones

4 – pyridones from bis –enamines and primary amines

bis - enamines obtained

directly from ketones Conjugate Addition by MeNH2
by condensation on both and elimination of HNMe2.
sides of the carbonyl group
with DMFDMA

dimethylformamide dimethylacetal
(DMFDMA)
Formylating agent
Methylating agent
 Hantzsch synthesis
• four-component domino reaction,
• two molecules of a β-dicarbonyl compound and an aldehyde are condensed with NH3
• Give 1,4-dihydropyridines which can be dehydrogenated to give highly substituted pyridines

nitric acid, nitrous acid, or other oxidants such as ceric ammonium nitrate (CAN), cupric nitrate etc can be used as
the oxidating agent
Symmetrically substituted pyridines

Reaction scheme can be considered

in any of these pathways
Hantzsch synthesis of Symmetrically substituted pyridines
 Hantzsch synthesis of unsymmetrically substituted pyridine
Two different β-dicarbonyl compounds ( 1,3 dicarbonyl compounds) used as starting material

Hantzsch synthesis conducted in two stages,

 by making the aldol condensation product separately,
 then reacting with ammonia and a different 1,3 - dicarbonyl compound or an enamino - ketone
Application of Hantzsch synthesis

A B

Condensation between ammonia aldol condensation product of a different Conjugate addition of A on B

and a 1,3 - dicarbonyl compound , 1,3 - dicarbonyl compound and an aldehyde Deprotonation/protonation
Imine then enamine NH2 condensation with carbonyl group
The Hantzsch protocol is of considerable scope

β-enaminones can replace one

molecule of β-dicarbonyl compound
β-enaminones can combine with enones
(three-component condensation)
(two-component condensation),
Syntheses of pyridine derivatives
From 1,3 - Dicarbonyl Compounds

cyclization with NH3, primary amines, or hydroxylamine to give pyridine or pyridine derivatives

1,3-diketone Pentene-1,5-dione derivative

Knoevenagel condensation

formation of 3-acylpyridines
Synthesis of pyridine derivatives

From 1,3 - Dicarbonyl Compounds and 3 - amino enones or 3-amino acrylate

3-amino enones or 3-amino acrylates can be

prepared by the reaction of ammonia
with a 1,3 - diketone
or a 1,3-keto ester

The simplest 1,3 - dicarbonyl compound,

malondialdehyde, is unstable,
its acetal enol ether is used
 Syntheses of pyridine derivatives

3-cyano -2- pyridones result if cyanoacetamide is used instead of an amino enone (Guareschi Synthesis)