How to make pyridines: the Hantzsch pyridine synthesis 1191

Zinc in acetic acid (Chapter 24) reduces the oxime to the amine and we can start the synthesis by
doing the conjugate addition and then reducing the oxime in the presence of the keto-diester.
MeO2C MeO2C
MeO2C
MeO Zn, HOAc
Me
+ Me
CO2Me O
CO2Me
Me Me CO2t-Bu
Me CO2t-Bu N
O HO N H
O
This reaction forms the required pyrrole in one step! First, the oxime is reduced to an amine; then
the amino group forms an imine with the most reactive carbonyl group (the ketone) in the keto-
diester. Finally, the very easily formed enamine cyclizes on to the other ketone.

MeO2C MeO2C
MeO2C

Me Me
Me
MeO2C O
CO2Me O
Me CO2t-Bu Me CO2t-Bu
Me + CO2t-Bu
N
N
O H2N H
H

This pyrrole synthesis is important enough to be given the name of its inventorit is the Knorr P
pyrrole synthesis. Knorr himself made a rather simpler pyrrole in a remarkably efficient reaction. Standard heterocyclic syntheses
See if you can work out what is happening here. tend to have a name associated
EtO2C Me with them and it is simply not
CO2Et 1. 0.5 NaNO2, HOAc worth while learning these
Me 87% yield names. Few chemists use any but
2. 0.5 Zn, HOAc the most famous of them: we will
O Me CO2Et
N mention the Knorr pyrrole
H synthesis, the Hantzsch pyridine
synthesis, and the Fischer and
Reissert indole syntheses. We
How to make pyridines: the Hantzsch pyridine synthesis did not mention that the
synthesis of furans from 1,4-
The idea of coupling two keto-esters together with a nitrogen atom also works for pyridines except dicarbonyl compounds is known
that an extra carbon atom is needed. This is provided as an aldehyde and another important differ- as the FeistBenary synthesis,
and there are many more like this.
ence is that the nitrogen atom is added as a nucleophile rather than an electrophile. These are fea- If you are really interested in
tures of the Hantzsch pyridine synthesis. This is a four-component reaction that goes like this. these other names we suggest
R you consult a specialist book on
R Hantzsch
pyridine heterocyclic chemistry.
EtO2C CO2Et synthesis EtO2C CO2Et
O H
L
Arthur Hantzsch, 18571935, the fiery
O stereochemist of Leipzig, is most
N O famous for the work he did with Werner
NH3 at the ETH in Zurich where in 1890 he
suggested that oximes could exist in
You are hardly likely to understand the rationale behind this reaction from that diagram so lets cis and trans forms.
explore the details. The product of the reaction is actually the dihydropyridine, which has to be oxi-
dized to the pyridine by a reagent such as HNO3, Ce(IV), or a quinone.
R R

EtO2C CO2Et EtO2C CO2Et

O H
pH 8.5

O O EtOH N
NH3 H
the dihydropyridine
1192 44 . Aromatic heterocycles 2: synthesis

PThe mechanism of
the Hantzsch
pyridine synthesis
Several of these steps
could be done in
different orders but the
essentials are:
aldol reaction
between the aldehyde
and the keto-ester
Michael (conjugate)
addition to the enone
addition of ammonia
to one ketone
cyclization of the
imine or enamine on
to the other ketone
R R
EtO2C
The reaction is very simply carried out by mixing the components in the right proportions in
ethanol. The presence of water does not spoil the reaction and the ammonia, or some added amine,
ensures the slightly alkaline pH necessary. Any aldehyde can be used, even formaldehyde, and yields
of the crystalline dihydropyridine are usually very good.
This reaction is an impressive piece of molecular recognition by small molecules and writing a
detailed mechanism is a bold venture. We can see that certain events have to happen. The ammonia
has to attack the ketone groups, but it would prefer to attack the more electrophilic aldehyde so this
is probably not the first step. The enol or enolate of the keto-ester has to attack the aldehyde (twice!)
so let us start there.
R R R R
H
EtO2C EtO2C EtO2C EtO2C
O H O OH
O O O O
This adduct is in equilibrium with the stable enolate from the keto-ester and elimination now
gives an unsaturated carbonyl compound. Such chemistry is associated with the aldol reactions we
discussed in Chapter 27. The new enone has two carbonyl groups at one end of the double bond and
is therefore a very good Michael acceptor (Chapter 29). A second molecule of enolate does a conju-
gate addition to complete the carbon skeleton of the molecule. Now the ammonia attacks either of
the ketones and cyclizes on to the other. As ketones are more electrophilic than esters it is to be
expected that ammonia will prefer to react there.
R R
CO2Et CO2Et EtO2C CO2Et EtO2C CO2Et
EtO2C
NH3

O O O N
O O O
H
the dihydropyridine
The necessary oxidation is easy both because the product is aromatic and because the nitrogen
atom can help to expel the hydrogen atom and its pair of electrons from the 4-position. If we use a
quinone as oxidizing agent, both compounds become aromatic in the same step. We will show in
Chapter 50 that Nature uses related dihydropyridines as reducing agents in living things.
DDQ
DichloroDicyano
Quinone CN CN CN
O CN O CN HO CN
H atom transferred with
its bonding electrons

R H Cl O Cl OH Cl OH
H
EtO2C CO2Et Cl Cl Cl
aromatic benzene ring formed
R
R
N EtO2C CO2Et
H H EtO2C CO2Et
the dihydropyridine
N
N
H
aromatic pyridine ring formed

The Hantzsch pyridine synthesis is an old discovery (1882) which sprang into prominence in the
1980s with the discovery that the dihydropyridine intermediates prepared from aromatic aldehydes
are calcium channel blocking agents and therefore valuable drugs for heart disease with useful effects
on angina and hypertension.
 How to make pyridines: the Hantzsch pyridine synthesis 1193

various substituents P
R in various positions R These drugs inhibit Ca2+ ion
transport across cell membranes
and relax muscle tissues
EtO2C CO2Et EtO2C CO2Et selectively without affecting the
O H
pH 8.5 working of the heart. Hence high
blood pressure can be reduced.
O Pfizers amlodipine (Istin or
O EtOH N
Norvasc) is a very important
NH3 H
drugit had sales of 1.6 billion
calcium channel blocker dollars in 1996.
drug for heart disease

So far, so good. But it also became clear that the best drugs were unsymmetricalsome in a trivial
way such as felodipine but some more seriously such as Pfizers amlodipine. At first sight it looks as
though the very simple and convenient Hantzsch synthesis cannot be used for these compounds.
Cl O O
S
Ph O
Cl Cl
MeO2C CO2Et MeO2C CO2Et

O
N N NH3
H H
felodipine amlodipine

Clearly, a modification is needed in which half of the molecule is assembled first. The solution lies
in early work by Robinson who made the very first enamines from keto-esters and amines. One half
of the molecule is made from an enamine and the other half from a separately synthesized enone. We
can use felodipine as a simple example.
Cl Cl

Cl
Cl Cl
MeO2C CHO MeO2C Cl

base MeO2C CO2Et

O O

N
CO2Et CO2Et H
NH3
felodipine
O H2N

Other syntheses of pyridines

The Hantzsch synthesis produces a reduced pyridine but there are many syntheses that go directly to
pyridines. One of the simplest is to use hydroxylamine (NH2OH) instead of ammonia as the nucleophile.
Reaction with a 1,5-diketone gives a dihydropyridine but then water is lost and no oxidation is needed.
H H
H2N OH

HCl
R1 O O R2 EtOH R1 N R2 R1 N R2
OH
H
1194 44 . Aromatic heterocycles 2: synthesis

The example below shows how these 1,5-diketones may be quickly made by the Mannich
(Chapter 27) and Michael (Chapter 29) reactions. Our pyridine has a phenyl substituent and a fused
saturated ring. First we must disconnect to the 1,5-diketone.
3
4 2
2 CN
+ H2N OH

N Ph 5 O O 1 Ph

Further disconnection reveals a ketone and an enone. There is a choice here and both alternatives
would work well. a b
a b

O O Ph O O Ph O O Ph

It is convenient to use Mannich bases instead of the very reactive unsaturated ketones and we will
continue with disconnection a.
elimination Me2N Mannich Me2NH
+
O Ph O Ph CH2O O Ph
The synthesis is extraordinarily easy. The stable Mannich base is simply heated with the other
ketone to give a high yield of the 1,5-diketone. Treatment of that with the HCl salt of NH2OH in
EtOH gives the pyridine directly, also in good yield.

Me2N 160 C H2N OH

+
HCl
O O Ph O O Ph EtOH N Ph
100% yield 94% yield

O Another direct route leads, as we shall now demonstrate, to pyridones. These useful compounds
are the basis for nucleophilic substitutions on the ring (Chapter 43). We choose an example that puts
NH2 a nitrile in the 3-position. This is significant
O
because the role of nicotinamide in living things
CN CN
N (Chapter 50) makes such products interesting to aldol
nicotinamide make. Aldol disconnection of a 3-cyano pyridone
starts us on the right path. R N O R N O
If we now disconnect the H H
CN bond forming the enam-
ine on the other side of the ring O
O
we will expose the true starting CN CN
CN
materials. This approach is
+
unusual in that the nitrogen enamine
atom that is to be the pyridine R N O H2N O
H R O cyanoacetamide
nitrogen is not added as ammo-
nia but is already present in a
molecule of cyanoacetamide.
The keto-aldehyde can be made by a simple Claisen ester condensation (Chapter 28) using the
enolate of the methyl ketone with ethyl formate (HCO2Et) as the electrophile. It actually exists as a
stable enol, like so many 1,3-dicarbonyl compounds (Chapter 21).
O
O
O Claisen
H +
H R O EtO H
R O
R O ethyl formate
 Pyrazoles and pyridazines from hydrazine and dicarbonyl compounds 1195

In the synthesis, the product of the Claisen ester condensation is actually the enolate anion of the
keto-aldehyde and this can be combined directly without isolation with cyanoacetamide to give the
pyridone in the same flask.
O CN
CN
HCO2Et
+
R O NaOEt R N O
H2N O
R O H P
If dehydration occurred first, only
What must happen here is that the two compounds must exchange protons (or switch enolates if the Z-alkene could cyclize and the
you prefer) before the aldol reaction occurs. Cyclization probably occurs next through CN bond major product, the E-alkene,
formation and, finally, dehydration is forced to give the Z-alkene. would be wasted.

O O OH
OH CN
CN CN

+ + R N O
CN CN R N O
R O R O R O H2N O H
H

H2N O H2N O

In planning the synthesis of a pyrrole or a pyridine from a dicarbonyl compound, considerable

variation in oxidation state is possible. The oxidation state is chosen to make further disconnection
of the carbon skeleton as easy as possible. We can now see how these same principles can be applied
to pyrazoles and pyridazines.

Pyrazoles and pyridazines from hydrazine and dicarbonyl

compounds
Disconnection of pyridazines reveals a molecule of hydrazine and a 1,4-diketone with the
proviso that, just as with pyridines, the product will be a dihydropyrazine and oxidation will be
needed to give the aromatic compound. As with pyridines, we prefer to avoid the cis double bond
problem.
R R R
1
2 CN FGA
N NH2 O O
N NH2 O O
4
R R R
P
As an example we can take the cotton herbicide made by Cyanamid. Direct removal of hydrazine The herbicide kills weeds in
would require a cis double bond in the starting material. cotton crops rather than the
cotton plant itself!
N OMe O OMe
N O
2 CN
F 3C F 3C

Cyanamid cotton herbicide reject cis alkene as starting material

If we remove the double bond first, a much simpler compound emerges. Note that this is a keto-
ester rather than a diketone.