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.
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.
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.
(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.
(4) Pictet-Gams modification: In this method, β-phenylethylamine is replaced by β-hydroxy-β-phenylethylamine which is heated with cyclization catalyst, POCl3.
(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.,
(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 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.
(b) Oxidation: Isoquinoline is resistant to oxidation. If vigorous conditions are employed, isoquinoline undergoes ring cleavage to give degradation products.
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.
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