Synthesis Reactions and Medicinal Uses of Pyrazole: Five membered heterocyclics containing two nitrogen atoms in the adjacent 1,2-position are designated as pyrazoles. When two heteroatoms are present in a 1, 3-position, they are named pyrazole.
Pyrazole was discovered by Buchner in 1889. It is a colorless solid having m.p. of 70°C. Pyrazoles have been used as antioxidants in fuels and are a basic skeleton in food colorant, tartrazine, and drugs like phenylbutazone, celecoxib, stanozolol, etc. It is a weak base.
Chemical Synthesis of Pyrazole
(i) Pyrazole may be synthesized by reacting acetylacetone with either hydrazine or phenylhydrazine.
(ii) Pyrazole itself can be formed by the reaction of hydrazine with propargyl aldehyde.
(iii) An iron-catalyzed reaction of diarylhydrazones and vicinal diols gives 1, 3-substituted pyrazoles.
(iv) An α, β-unsaturated aldehydes/ketones readily react with hydrazine salts in an I2 – mediated reaction to give substituted pyrazole.
(v) An α, β-ethylene carbonyl derivative reacts easily with hydrazine to give substituted pyrazole.
Chemical Reactions of Pyrazole
The N-atom at position-1 is unreactive. It can lose its proton (H atom) easily in the presence of the base and offers the site of substitution reaction. The N-atom at position-2 with two electrons is basic and therefore reacts easily with electrophiles. The combined electron richness of both N-atoms reduces the charge density at C3 and C5, making C4 available for electrophilic attack. Deprotonation at C3 can occur in the presence of a strong base, leading to ring-opening.
(i) The N1 atom easily loses its proton with a strong base. The resulting nucleophile on nitrogen can afterward react with an electrophile
(ii) Scorpionate (tridentate ligand) formation: Pyrazole reacts with potassium borohydride to form a tridentate ligand known as scorpionate.
(iii) The free –NH group of pyrazole can be easily alkylated using alkyl halides, diazomethane, or dimethylsulfate.
Excess of alkylating agent causes quaternization. Acylation on the free –NH group can be readily done using acetyl chloride in the presence of a weak base such as pyridine.
(iv) The electrophilic substitution in pyrazole occurs readily at position-4.
(v) As all the 3 carbons and 2 nitrogen atoms in pyrazole are having good electron density (electron-rich), pyrazole does not undergo nucleophilic substitution reactions under the usual reaction conditions.
(vi) Oxidation reaction: The pyrazole ring is remarkably stable to the action of the oxidizing agent but the side chain may be oxidized.
(vii) Reduction reaction: Unsubstituted pyrazole is relatively stable to catalytic and chemical reductive conditions. Pyrazole derivatives may undergo reduction under a variety of conditions. e.g.,
Applications in Drug Synthesis
Pyrazole derivatives are used for their analgesic, antipyretic, anti-inflammatory (e.g., antipyrine, phenylbutazone, celecoxib), antibacterial, tranquilizing, anticancer, and antidiabetic activities.
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