Quinolines and isoquinolines 1209

CO2H

O2C S HO2C S Me
HO2C S S
1. FeSO4,
Me NH4OH
CHO
2. HCl, CH2N2
NO2 OMe NO2 N N
H H
Me2N OMe chuangxinmycin
di th l t l f DMF

Quinolines and isoquinolines

5 4 5 4
We move from benzo-fused pyrroles to benzo-fused pyridines and 3 3
6 6
meet quinoline and isoquinoline. Isoquinolines will feature as ben-
zylisoquinoline alkaloids in Chapter 51 and their synthesis will most- 7 2 7 N2
N
ly be discussed there. In this section we shall concentrate on the 8 1 8 1
quinolines. quinoline isoquinoline
Quinoline forms part of the structure of quinine, the malaria
remedy found in cinchona bark and known since the time of the N
Incas. The quinoline in quinine has a 6-MeO substituent and a side
OH
chain attached to C4. In discussing the synthesis of quinolines, we H R
will be particularly interested in this pattern. This is because the
MeO MeO
search for anti-malarial compounds continues and other quinolines
with similar structures are among the available anti-malarial drugs.
We shall also be very interested in quinolones, analogous to pyri- N N
dones, with carbonyl groups at positions 2 and 4 as these are useful quinine the quinoline in quinine
antibiotics. A simple example is pefloxacin which has a typical 6-F
and 7-piperazine substituents. O
O
F CO2H

N N
N O N O N
H H H MeN Et

2-pyridone 2-quinolone 4-quinolone a quinolone antibiotic, pefloxacin

When we consider the synthesis of a quinoline, the obvious disconnections are, first, the C–N
bond in the pyridine ring and, then, the C–C bond that joins the side chain to the benzene ring. We
will need a three-carbon (C3) synthon, electrophilic at both ends, which will yield two double bonds
after incorporation. The obvious choice is a 1,3-dicarbonyl compound. O

C=N C–C
+
N imine NH2 O NH2 O

The choice of an aromatic amine is a good one as the NH2 group reacts well with carbonyl com-
pounds and it activates the ortho position to electrophilic attack. However, the dialdehyde is malonic
dialdehyde, a compound that does not exist, so some alternative must be found. If the quinoline is
substituted in the 2- and 4-positions this approach looks better.
R O

C=N C C
R
+
N R imine NH2 R O
1210
R
O
NH2
P
The ugly name of the Skraup
reaction appropriately applies to
the worst ‘witch’s brew’ of all the
heterocyclic syntheses. Some
workers have added strange
oxidizing agents such as arsenic
acid, iron (III) salts, tin (IV) salts,
nitrobenzenes of various
substitution patterns, or iodine to
make it ‘go better’.
R R
+
NH2
44 . Aromatic heterocycles 2: synthesis
The initially formed imine will tautomerize to a conjugated enamine and cyclization now occurs
by electrophilic aromatic substitution.
O O O
R R R
+
NH2 R O N R N R
H
R R R
H OH
O
N R N R N R
H H
The enamine will normally prefer to adopt the first configuration shown in which cyclization is
not possible, and (perhaps for this reason or perhaps because it is difficult to predict which quinoline
will be formed from an unsymmetrical 1,3-dicarbonyl compound) this has not proved a very impor-
tant quinoline synthesis. We shall describe two more important variants on the same theme, one for
quinolines and one for quinolones.
In the synthesis of pyridines it proved advantageous to make a dihydropyridine and oxidize it to a
pyridine afterwards. The same idea works well in probably the most famous quinoline synthesis, the
Skraup reaction. The diketone is replaced by an unsaturated carbonyl compound so that the quino-
line is formed regiospecifically.
The first step is conjugate addition of the amine. Under acid catalysis the ketone now cyclizes in
the way we have just described to give a dihydroquinoline after dehydration. Oxidation to the aro-
matic quinoline is an easy step accomplished by many possible oxidants.
O R R
HO R
R H H [O]
N N N N
H H H
Traditionally, the Skraup reaction was carried out by mixing everything together and letting it rip.
A typical mixture to make a quinoline without substituents on the pyridine ring would be the aro-
matic amine, concentrated sulfuric acid, glycerol, and nitrobenzene all heated up in a large flask at
over 100 °C with a wide condenser.
R R
PhNO2
HO OH
+
OH H2SO4, >100 °C
NH2 N
glycerol
The glycerol was to provide acrolein (CH2=CH·CHO) by dehydration, the nitrobenzene was to
act as oxidant, and the wide condenser...? All too often Skraup reactions did let rip—with destructive
results. A safer approach is to prepare the conjugate adduct first, cyclize it in acid solution, and then
oxidize it with one of the reagents we described for pyridine synthesis, particularly quinones such as
DDQ.
H O
R R
O R H DDQ
acrolein N N N
H H
 Quinolines and isoquinolines 1211

An important use of the traditional Skraup synthesis is to make 6-methoxy-8-nitroquinoline from

P
an aromatic amine with only one free ortho position, glycerol, the usual concentrated sulfuric acid, Arsenic has a bad reputation
and the oxidant arsenic pentoxide. Though the reported procedure uses 588 grams of As2O5, which because it is traditionally used by
might disconcert many chemists, it works well and the product can be turned into other quinolines by poisoners. If arsenic gets into
reduction of the nitro group, diazotization, and nucleophilic substitution (Chapter 23). living things it is indeed very
poisonous—about 6 mg per kg is
MeO MeO needed to kill an animal.
As2O5 However, many other compounds
HO OH are equally toxic, but you just
+
NH2 OH N have to avoid eating them.
H2SO4, >100 °C
NO2 glycerol NO2
70% yield

The more modern style of Skraup synthesis is used to make 8-quinolinol or ‘oxine’. ortho-Amino-
phenol has only one free position ortho to the amino group and is very nucleophilic, so acrolein can
be used in weak acid with only a trace of strong acid. Iron(III) is the oxidant with a bit of boric acid
for luck, and the yield is excellent. oxine complex of copper

CHO

NH2 N N
HOAc
OH Fe2(SO4)3, (HO)3B OH 90% yield
trace H2SO4 O Cu O
N
This compound is important because it forms unusually stable metal complexes with metal ions
such as Mg(II) or Al(III). It is also used as a corrosion inhibitor on copper because it forms a stable
layer of Cu(II) complex that prevents oxidation of the interior.

Quinolones also come from anilines by cyclization to an ortho position

The usual method for making quinolone antibiotics is possible because they all have a carboxylic
acid in the 3-position. Disconnection suggests a rather unstable malonic ester derivative as starting
material.
O
CO2H C–N and C–C EtO2C CO2Et
3
+
N enamine and NH2 CHO
Friedel–Crafts
H
In fact, the enol ether of this compound is easily made from diethyl malonate and ethyl orthofor-
mate [HC(OEt)3]. The aromatic amine reacts with this compound by an addition–elimination
sequence giving an enamine that cyclizes on heating. This time there is no worry about the geometry
of the enamine.
EtO2C CO2Et EtO2C CO2Et
HC(OEt)3 PhNH2
EtO2C CO2Et
Ac2O EtO PhHN

O O O

CO2Et CO2H F CO2H

heat NaOH

H2O
N N N N
H H MeN O
For examples of quinolone antibiotics we can choose ofloxacin, whose synthesis is discussed in ofloxacin
detail in Chapter 23, and rosoxacin whose synthesis is discussed overleaf. Both molecules contain the
1212 44 . Aromatic heterocycles 2: synthesis

O same quinolone carboxylic acid framework, outlined in black, with another heterocyclic system at
CO2H position 7 and various other substituents here and there.
To make rosoxacin two heterocyclic systems must be constructed. Workers at the pharmaceutical
company Sterling decided to build the pyridine in an ingenious version of the Hantzsch synthesis
N using acetylenic esters on 3-nitrobenzaldehyde. The ammonia was added as ammonium acetate.
N Et Oxidation with nitric acid made the pyridine, hydrolysis of the esters and decarboxylation removed
rosoxacin
the acid groups, and reduction with Fe(II) and HCl converted the nitro group into the amino group
required for the quinolone synthesis.
CO2Me CO2Me
CO2Me

OHC NO2 NO2 HNO3 NO2

NH2
NH3 CO2Me HN N
CO2Me CO2Me N

Now the quinolone synthesis can be executed with the same reagents we used before and all that
remains is ester hydrolysis and alkylation at nitrogen. Notice that the quinolone cyclization could in
theory have occurred in two ways as the two positions ortho to the amino group are different. In
practice cyclization occurs away from the pyridine ring as the alternative quinolone would be impos-
sibly crowded.
O O
EtO2C CO2Et
CO2Et CO2H

NH2 EtO
N N
N H
N N Et

Since quinolones, like pyridones, can be converted into chloro-compounds with POCl3, they can
be used in nucleophilic substitution reactions to build up more complex quinolines.
O Cl NHR
MeO POCl3 MeO RNH2 MeO

N R N R N R
H
Because isoquinolines are dealt with in more detail in Chapter 51, we will give just one important
P
synthesis here. It is a synthesis of a dihydroisoquinoline by what amounts to an intramolecular
This dehydrogenation is the
reverse of palladium-catalysed
Vilsmeier reaction in which the electrophile is made from an amide and POCl3. Since, to make the
hydrogenation. isoquinoline, two hydrogen atoms must be removed from carbon atoms it makes more sense to use a
noble metal such as Pd(0) as the oxidizing agent rather than the reagents we used for pyridine syn-
thesis.
NH2
RCOCl POCl3 [O]

HN R N N

O R R

More heteroatoms in fused rings mean more choice in

synthesis
The imidazo-pyridazine ring system forms the basis for a number of drugs in human and animal
medicine. The synthesis of this system uses chemistry discussed in Chapter 43 to build the pyridazine
ring. There we established that it was easy to make dichloropyridazines and to displace the chlorine