HETEROCYCLIC CHEMISTRY (CHM 4207)

SYNTHESIS, REACTIONS AND APPLICATIONS OF ISO-

QUINOLINES

UMARU MUSA YAR’ADUA UNIVERSITY KATSINA

COURESE LECTURER: DR. N. MANSIR
2. BENZOPYRIDINES (ISO-QUINOLINES)
Synthesis and Reactions of Iso-quinolines

Application of the Iso-quinoline Ring System in Drug delivery

 SYNTHESIS AND REACTIONS OF ISO-QUINOLINES

 Introduction
 General Physical and Chemical Properties Isoquinoline
 Reactions with Electrophiles
 Reduction and Reactions with Nucleophiles
 Synthesis of Isoquinoline Bischler-Napieralski Synthesis
 Picket-Spengler Synthesis
 The Pomeranz-Fritsch Synthesis

Introduction

Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline.

Isoquinoline and quinoline are benzo-pyridines, which are composed of a benzene ring fused to a
pyridine ring. The nitrogen in iso-quinoline is on position 2 while the nitrogen is on position 1 in
quinoline (Figure 3). In a broader sense, the term isoquinoline is used to make reference to
isoquinoline derivatives. 1-Benzylisoquinoline is the structural backbone in naturally occurring
alkaloids including papaverine and morphine. The isoquinoline ring in this natural compound
derives from the aromatic amino acid tyrosine.

Fig. 3: Structures of Quinoline and Isoquinoline

General Physical and Chemical Properties Isoquinoline

Isoquinoline is a colorless hygroscopic liquid at room temperature with a penetrating, unpleasant

odour. Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes
to platelets and have a low solubility in water but dissolve well in ethanol, acetone, diethyl ether,

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carbon di-sulphide, and other common organic solvents. It is also soluble in dilute acids as the
protonated derivative. Being an analog of pyridine, isoquinoline is a weak base, with a pKb of 5.1.
It protonates upon treatment with strong acids, such as HCl to form salts. It forms adducts with
Lewis acids, such as BF3. Isoquinoline is closely related to quinoline in physical and chemical
properties. Modifications are only as a result of the different position of the nitrogen atom relative
to the carbocyclic ring.

1.1 Reactions with Electrophiles

Isoquinoline like quinoline is protonated and alkylated at the nitrogen atom and undergoes
electrophilic substitution in the benzene ring. Sulphonation with oleum gives mainly the 5-
sulphonic acid, but fuming nitric acid and concentrated sulphuric acid at 0˚C produce a 1:1 mixture
of 5- and 8-nitroisoquinolines. Bromination in the presence of aluminium trichloride at 75˚C gives
a 78% yield of 5-bromoisoquinoline (Scheme 15).

Scheme 15: Reactions of Iso-quinolines with Electrophiles

Reduction and Reactions with Nucleophiles

Nucleophilic addition takes place at C-1 and this is considerably enhanced if the reaction is carried
out upon an iso-quinolinium salt. Reduction with lithium aluminium hydride {tetrahydroaluminate
(III)} in THF (tetrahydrofuran) for example gives a 1,2-dihydroisoquinoline. These products
behave as cyclic enamines and if iso-quinolium salts are reacted with sodium borohydride
[tetrahydroboronate(III)] in aqueous ethanol, further reduction to 1,2,3,4-tetrahydroisoquinolines
is effected through protonation at C-4 and then hydride transfer from the reagent to C-3 (Scheme
16).
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Scheme 16: Reduction of Isoquinoline

The cyanide anion adds to C-1 in 2-benzoylisoquinolinium salts in water/DCM (dichloromethane),

forming Reissert compounds; then, just like their quinoline counterparts, the adducts can be
deprotonated by a base with the loss of the N-substituent and the formation of a 1- cyano-
isoquinoline (Scheme 17).

Scheme 17: Reaction of Isoquinoline with Nucleophiles

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Synthesis of Iso-quinolines

Isoquinoline was first isolated from coal tar in 1885 by Hoogewerf and van Dorp. They isolated it
by fractional crystallization of the acid sulphate. Weissgerber developed a more rapid route in
1914 by selective extraction of coal tar; exploiting the fact that isoquinoline is more basic than
quinoline. Isoquinoline can then be isolated from the mixture by fractional crystallization of the
acid sulphate. Although isoquinoline derivatives can be synthesized by several methods, relatively
few direct methods deliver the unsubstituted isoquinoline. The Pomeranz-Fritsch reaction provides
an efficient method for the preparation of isoquinoline. The biological properties of many
derivatives have ensured the development of a number of syntheses providing access to all types
of iso-quinolines, both natural and manmade. Three important routes are the Bischler-Napieralski,
Pictet-splenger and Pomeranz-Fritsch methods.

Bischler-Napieralski Synthesis

This method is very useful for the construction of 1-substituted 3,4- di-hydro-isoquinolines, which
if necessary can be oxidized to isoquinolines. A β-phenyl ethylamine (1-amino-2-phenylethane) is
the starting material, and this is usually performed by reaction of an aromatic aldehyde with
nitromethane in the presence of sodium methoxide, and allowing adduct to eliminate methanol and
give a β-nitrosytrene (1-nitro-2-phenylethene). This product is then reduced to β-phenyl
ethylamine commonly by the action of lithium aluminium hydride (Scheme 18). Once prepared,
the β-phenyl ethylamine is reacted with an acyl chloride and a base to give the corresponding
amide (R1 = H) and then this is cyclized to a 3,4-dihydroisoquinoline by treatment with either
phosphorus pentoxide or phosphorus oxychloride. Finally, aromatization is accomplished by
heating the 3,4-dihydroisoquinoline over palladium on charcoal (Scheme 19)

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Scheme 18: Synthesis of β-phenyl ethylamine

Scheme 19: Bischler-Napieralski Synthesis of Isoquinoline

Alternatively, a β-methoxy-β-phenyl ethylamine can be used to circumvent the oxidation step after
the conventional Bischler-Naperialski cyclisation. Here, when treated with the phosphorus reagent
the amide (R1 = OMe) undergoes both cyclisation and the elimination of methanol to give the
isoquinoline (R=H) directly. This is known as the Pictet-Gams modification of the Bischer-
Napieralski synthesis.

Picket-Spengler Synthesis

A β-phenyl ethylamine is treated with an aldehyde in the presence of dilute acid; ring closure
occurs by a reaction of Mannish type reaction and the tetra-hydro-isoquinoline formed is
dehydrogenated on palladium (Scheme 20).

Scheme 20: Picket-Spengler Synthesis

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The Pomeranz-Fritsch Synthesis

Whereas both the previous two routes depend upon a cyclisation of the benzene ring to what
becomes C-1 of the heterocycle, the key step in the Pomeranz-Fritsch synthesis is the formation
of a bond to C-4. A benzaldehyde is the starting material, and it is reacted with an amino-
acetaldehyde di-alkyl acetyl to form an imine, which is then cyclized directly under relatively
severe acidic conditions (e.g. conc. H2SO4 at 100˚C) to give the isoquinoline. Although the
Pomeranz-Fritsch ring-closure conditions permit the cyclisation of unsubstituted imines, the
reaction is accelerated greatly if electron-donating groups are present in the benzene ring (Scheme
21).

Scheme 21: Pomeranz-Fritsch Synthesis

Through slight modification the Pomeranz-Fritsch synthesis can be made particularly useful for
the preparation of 1,2-dihydroisoquinolines. The imine is first reduced with sodium borohydride
in 98% ethanol to the corresponding benzyl amine, prior to cyclisation, by treatment with 6M
hydrochloric acid. When electron-donating groups (such as a methoxyl) are present in the aromatic
unit of the benzyl amine, the ring closure step occurs at room temperature to give a 1,2-
dihydroisoquinoline. As 1,2-dihydroisoquinolines are unstable in air, it is customary to carry out
the reaction under an atmosphere of oxygen-free nitrogen.

An advantage of the modified Pomeranz-Fritsch synthesis is that the 1,2-dihydroisoquinolinium

salts can be reacted in situ with electrophiles, yielding 3,4-dihydroisoquinolinium salts that react
with nucleophiles at C-3. Such a ‘single pot’ procedure can be used to form complex 1,2,3,4- tetra-
hydro-isoquinolines.

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 Application of the Iso-quinoline ring system in drug synthesis

1 Papaverine

2 Morphine

3 Other Applications of Isoquinolines

4 Isoquinoline and Parkinson’s disease

Introduction

Isoquinolines are very important because of their derivatives. A large proportion of which are
alkaloids, show useful biological effects. Indeed, the medicinal properties of the plants that
biosynthesize these alkaloids have been recognized for centuries, long before the nature of the
compounds responsible was known. Papaverine and morphine are found in the latex from poppy
seed capsules. Papaverine is a vasodilator while morphine is an analgesic agent. Antihypertensive
agents such as debrisoquine, quinalapril and quinalaprilat all contain the isoquinoline ring system.

1. Papaverine

Papaverine is an opium alkaloid that is a vasodilator used primarily in the treatment of visceral
spasm, vasospasm (especially those involving the heart and the brain), and occasionally in the
treatment of erectile dysfunction. While both are found in the opium poppy, papaverine differs in
both structure and pharmacological action from the analgesic (morphine-related) opium alkaloids
(opioids).

Fig. 4: Structure of Papaverine

Scheme 22: Synthesis of Papaverine Based on the Bischler-Napieralski Procedure

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2. Morphine (MS Contin, MSIR, Avinza, Kadian, Oramorph, Roxanol)

Morphine is a benzyl isoquinoline alkaloid with two additional ring closures. It is a potent opiate
analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804
by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in
1827, which at the time was a single small chemists' shop. It was more widely used after the
invention of the hypodermic needle in 1857. It took its name from the Greek god of dreams,
Morpheus.

Morphine is the most abundant alkaloid found in opium, the dried sap (latex) derived from
shallowly slicing the unripe seedpods of the opium, or common edible, poppy, Papaver
somniferum. Morphine was the first active principle purified from a plant source and is one of at
least 50 alkaloids of several different types present in opium, Poppy Straw Concentrate, and other
poppy derivatives. In clinical medicine, morphine is regarded as the gold standard, or benchmark,
of analgesics used to relieve severe or agonizing pain and suffering. Like other opioids, such as
oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central
nervous system (CNS) to relieve pain. Unlike many other opioids, morphine is an opiate and a
natural product. Morphine has a high potential for addiction; tolerance and psychological
dependence develop rapidly, although physiological dependence may take several months to
develop.

Fig. 5: Structure of Morphine

3 Other Applications of Isoquinolines

a) Anesthetics; di-methisoquin is one example (shown below).

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 Fig. 6: Structure of Di-methisoquine

b) Antihypertension agents, such as quinapril, quinapirilat, and debrisoquine (all derived from
1,2,3,4-tetrahydroisoquinoline).

c) disinfectants, like N-lauryl-iso-quinolinium bromide (shown below), which is prepared by

simple N-alkylation of isoquinoline.

Fig. 8: Structure of N-lauryl-iso-quinolinium Bromide

Bis-benzyl-iso-quinolinium compounds are compounds similar in structure to tubocurarine. They

have two iso-quinolinium structures, linked by a carbon chain, containing two ester linkages.

3.4 Isoquinolines and Parkinson’s Disease

Parkinson's disease, a slowly progressing movement disorder, is thought to be caused by certain

neurotoxins. A neurotoxin called MPTP (1[N]- methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the
precursor to MPP+, was found and linked to Parkinson's disease in the 1980s. The active
neurotoxins destroy dopaminergic neurons, leading to parkinsonism and Parkinson's disease.
Several tetra-hydro-isoquinoline derivatives have been found to have the same neurochemical
properties as MPTP. These derivatives may act as neurotoxin precursors to active neurotoxins.

Other Uses:

• Isoquinolines are used in the manufacture of dyes, paints, insecticides and antifungals. It is also
used as a solvent for the extraction of resins and terpenes, and as a corrosion inhibitor.