Synthesis and Reactions of Isoquinoline

Synthesis and Reactions of Isoquinoline: Isoquinoline is a colorless hygroscopic liquid having an unpleasant odor. Like quinoline, it is also a weak base. It was first isolated from coal tar by Hoogewerff and Dorp in 1885.

Synthesis and Reactions of Isoquinoline

Chemical Synthesis of Isoquinoline

(1) Pomeranz-Fritsch reaction: In this reaction, benzaldehyde is condensed with amino acetal to form an aryl aldimine. The aldimine is cyclized using a strong acid such as concentrated Sulfuric acid or phosphorous pentoxide.

Chemical Synthesis of Isoquinoline

The electron-donating groups (if present at 3 and/ or 5 positions in benzaldehyde) increase the rate of reaction while electron-withdrawing groups decrease the rate.

(2) Schlitttler – Muller Modification: When benzylamine condenses with glyoxal diethyl acetal, the resulting imine can be cyclized with acid to give 1-substituted isoquinoline. It is a modification of the Pomeranz-Fritsch reaction.

Chemical Synthesis of Isoquinoline

(3) Bichler-Napieralski synthesis: In this reaction, a β-phenylethylamine is acylated using acid-chloride/anhydride to form an amide. This amide can be cyclized with a loss of water using a Lewis acid (phosphoryl chloride or phosphorous pentoxide) to give 1-substituted-3, 4-dihydro isoquinoline. This intermediate can be readily dehydrogenated to isoquinoline using palladium, sulfur, or diphenyl disulfide.

Chemical Synthesis of Isoquinoline

(4) Pictet-Gams modification: In this method, β-phenylethylamine is replaced by β-hydroxy-β-phenylethylamine which is heated with cyclization catalyst, POCl3.

Chemical Synthesis of Isoquinoline

(5) Pictet-Spengler synthesis: When arylethanamines react with aldehyde, it gives imines. Under acid-catalyzed cyclization, the imine gets converted to 1, 2, 3, 4 – tetrahydroisoquinoline. If electron-donating substituents are present on the phenyl ring, ring closure (i.e., cyclization) occurs under very mild conditions. e.g.,

Chemical Synthesis of Isoquinoline

(6) Ozonolysis of indene: Indene when treated with ozone at –70°C, it provides homophthal-aldehyde. This dialdehyde is reduced followed by cyclization with dimethylsulfide in the presence of NH4OH.

Chemical Synthesis of Isoquinoline

Chemical Reaction of Isoquinoline

As with pyridine, isoquinoline is a weak base. It protonates to form salts upon treatment with strong acids. The lone pair of electrons available on N-atom and aromatic nature of isoquinoline compel it to behave similarly to quinoline in its chemical reactions. For example, like quinoline, 5- and 8-positions of isoquinoline are most susceptible to electrophile attack while the nucleophile attacks preferably at 1-position or 3-position if position-1 is already occupied.

(a) Reduction: Isoquinoline gives rise to different reduced products under the attack of different reducing agents.

Chemical Reaction of Isoquinoline

(b) Oxidation: Isoquinoline is resistant to oxidation. If vigorous conditions are employed, isoquinoline undergoes ring cleavage to give degradation products.

Chemical Reaction of Isoquinoline

Applications in Drug Synthesis

Isoquinoline is a core part of the structure of many drugs. These drugs include dimethisoquin (anesthetic), debrisoquine, quinapril (antihypertensive), papaverine (vasodilator), and many therapeutically active alkaloids like berberine, emetine, etc.

Make sure you also check our other amazing Article on : Synthesis and Reactions of Pyridine
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