Synthesis, Reactions and Medicinal Uses of Pyrimidine

Pyrimidine

Synthesis

Using phosphorus pentasulfide and triethylamine in chloroform, N,N-di-formyl aminomethyl aryl ketones are converted to 5-aryl thiazoles.


Hantzsch synthesis - Condensation is achieved by combining a α -halocarbonyl compound with either thioamide or thiourea. The reaction of sodium pentasulfide with formamide produces thioamide when it is conducted at room temperature.


Thioformamide, when combined with chloroacetaldehyde, yields unsubstituted thiazoles.


Gabriel synthesis - Synthesis of the 2, 5, and 2, 5-substituted thiazoles is achieved by reacting the α-acylamino ketones with phosphorus pentasulfide.

from thioamides - 2-Chloroxiranes can be substituted with thioamide to give thiazole derivatives.


Cook – Heilborn's synthesis - To form 5-amino thiazoles, dithioacids or esters of α-aminonitriles are used together with carbon disulfide, carbon oxysulfide, and isothiocyanates.


Tcherniac’s synthesis - By hydrolyzing thiocyanic ketones or treating them with sulfur compounds, 2-substituted thiazoles can be formed.


Using copper and potassium thiocyanate (KSCN), oxime-to-anhydride condensation gives thiazoles under mild conditions.

Reactions

At position-1 of thiazole, there is an atom of sulfur of the thiophene type and at position-3 there is an atom of nitrogen of the pyridine type. The chemical reactivity of imidazole is similar to that of oxazole and imidazole.

Protonation - Nitrogen provides a lone pair of electrons for protonation of thiazoles at the N3 position. It has the most electron-deficiency at position-2, almost neutral at position-4, and slightly electron-rich at position-5 in the thiazole ring.

N – alkylation - Thiazolium cations are formed by reacting thiazoles with alkyl halides. The positive charge of this cation is primarily on the sulfur atom, resulting in resonance stabilization.


Electrophilic substitution reaction - Using these resonance structures, we can explain all electrophilic and nucleophilic reactions of thiazoles.



Aromatic 4- and 5-double bonds undergo electrophilic substitution depending on the nature of the substituent occupying the 2-position. A sulfur atom may act as an electron donor when it is adjacent to a carbon atom.

At N3 atom - N3 atoms have a less reactive electron loan pair. Thiazoles are therefore slower in the process of N-alkylation.

Nitration - In acidic media, thiazolium (N - protonated) cations are formed during the attack. Thiazolium rings are considerably less reactive towards electrophilic attacks due to the protonated nitrogen of the ion. A thiazole cannot be nitrated in an oleum even at 160°C, proving that it is rather difficult to nitrate.

Sulphonation and halogenation - The electrophile prefers to attack the C5 position of the thiazole ring. If the C5 position is already substituted, electrophiles cannot attack any other position. Electrophiles are able to attack C5-position even under mild conditions due to electron-donating substituent at C2-position. For example,



Reduction - It is also resistant to the chemical reduction of metals in hydrochloric acid. Platinum is also highly resistant to hydrogenation by catalysis. By reducing with activated Raney nickel, a thiazole ring is desulfurized, leading to decomposition of the intermediate.

Oxidation - The most common way to oxidize the thiazole ring is through permanganate, chromic acid, selenium dioxide, or concentrated nitric acid.

Condensation reaction - When 2-methyl thiazole and 2-amino thiazole are combined with aromatic aldehydes, heterocycles are formed.

Medicinal Uses

Vitamins like thiamine, riboflavin, and folic acid contain pyridinium rings. Among the diverse biological activities of pyrimidine derivatives are antiviral, anticancer, antifungal, antimalarial, sedative, hypnotic, anticonvulsant, anthelmintic, and antithyroid properties.

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