3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline
[CAS# 641571-11-1]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline
• Synonyms: 1-(3-Amino-5-trifluoromethylphenyl)-4-methylimidazole
• Molecular Formula: C₁₁H₁₀F₃N₃
• Molecular Weight: 241.21
• CAS Registry Number: 641571-11-1
• EC Number: 688-269-6
• SMILES: CC1=CN(C=N1)C2=CC(=CC(=C2)N)C(F)(F)F

Properties

• Density: 1.4$+/-$0.1 g/cm³ Calc.^*
• Boiling point: 379.8$+/-$42.0 $degree$C 760 mmHg (Calc.)^*
• Flash point: 183.5$+/-$27.9 $degree$C (Calc.)^*
• Index of refraction: 1.553 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS06;GHS07;GHS09 Danger
• Risk Statements: H301-H302-H315-H318-H319-H335-H411
• Safety Statements: P261-P264-P264+P265-P270-P271-P273-P280-P301+P316-P301+P317-P302+P352-P304+P340-P305+P351+P338-P305+P354+P338-P317-P319-P321-P330-P332+P317-P337+P317-P362+P364-P391-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Serious eye damage	Eye Dam.	1	H318
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319

Discovery and Applications

3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline is a heteroaromatic compound featuring an aniline group substituted with an imidazole ring and a trifluoromethyl group on a benzene ring. This type of compound is significant in medicinal chemistry and chemical research due to its potential hydrogen-bonding, π–π interactions, and electronic modulation provided by the trifluoromethyl group. The imidazole moiety acts as a basic nitrogen-containing heterocycle capable of forming hydrogen bonds, while the trifluoromethyl group is highly electron-withdrawing, which can influence acidity, lipophilicity, and metabolic stability of derivatives. Structurally, the molecule consists of a benzene ring with a trifluoromethyl group at the 5-position, an aniline amino group at the 1-position, and a 4-methyl-imidazole attached through the nitrogen at the 3-position. The imidazole ring is planar and aromatic, allowing for hydrogen bonding and π-stacking interactions, while the aniline group provides nucleophilicity and can participate in further derivatization such as acylation, sulfonylation, or diazotization. The trifluoromethyl substituent increases electron deficiency on the aromatic ring, affecting reactivity in electrophilic or nucleophilic aromatic substitutions and enhancing chemical and metabolic stability. The synthesis of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline is generally carried out through nucleophilic aromatic substitution or palladium-catalyzed cross-coupling reactions. A suitable 3-halo-5-(trifluoromethyl)aniline derivative is reacted with 4-methylimidazole under controlled conditions to form the N-aryl linkage. Reaction conditions are optimized to avoid over-substitution or degradation of sensitive functional groups, producing a high-purity target compound suitable for further chemical transformations. In medicinal chemistry, this compound can serve as a building block for bioactive molecules targeting enzymes, receptors, or nucleic acid structures. The imidazole ring is a common pharmacophore in histidine analogs, enzyme inhibitors, and ligands for metal-binding sites. The trifluoromethyl group improves binding affinity, lipophilicity, and metabolic resistance, while the aniline provides a site for further functionalization to modulate pharmacokinetic properties. This combination of heterocycles and functional groups allows for the design of molecules with high specificity and desirable drug-like properties. Beyond pharmaceutical applications, 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline is a versatile intermediate in organic synthesis. The aniline group enables acylation, sulfonation, or coupling reactions, while the imidazole and trifluoromethyl groups can influence selectivity in multi-step syntheses. This versatility allows chemists to construct heterocyclic libraries, fluorinated aromatic compounds, and functionalized scaffolds for chemical biology or material science applications. Overall, 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline is a multifunctional heteroaromatic compound with hydrogen-bonding, electron-withdrawing, and nucleophilic properties. Its combination of imidazole, aniline, and trifluoromethyl groups makes it a valuable scaffold and intermediate for medicinal chemistry, organic synthesis, and the development of bioactive compounds.

References

2023. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. Science.
DOI: 10.1126/science.abo7201

2023. A novel imidazole-based azo molecule: synthesis, characterization, quantum chemical calculations, molecular docking, molecular dynamics simulations and ADMET properties. Journal of Molecular Modeling.
DOI: 10.1007/s00894-023-05625-1