6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine: Properties & Uses
6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine: Properties & Uses
6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine is a fluorinated bicyclic heterocyclic compound widely valued in medicinal chemistry and drug discovery as a versatile electrophilic building block bearing both a reactive chloro substituent and a electron-withdrawing trifluoromethyl group on the imidazo[1,2-a]pyridine scaffold.
- IUPAC Name
- 6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine
- Core Scaffold
- Imidazo[1,2-a]pyridine (bicyclic nitrogen-containing heterocycle)
- Key Functional Groups
- Chloro substituent at position 6; trifluoromethyl group at position 2
- SKU
- C692511
- Supplier
- Aladdin Scientific
- Primary Application
- Synthetic building block in medicinal chemistry and heterocyclic chemistry research
Chemical Structure and Key Features
6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine belongs to the imidazo[1,2-a]pyridine family of fused bicyclic heterocycles, in which an imidazole ring is annulated to a pyridine ring through the nitrogen at the 1-position of imidazole and the 2-position of pyridine. This fusion creates a planar, aromatic scaffold with two nitrogen atoms that confer significant basicity and the ability to participate in hydrogen bonding interactions with biological targets.
The compound carries two electronegative substituents: a chloro group at the 6-position of the pyridine ring and a trifluoromethyl (–CF₃) group at the 2-position of the imidazole ring. The –CF₃ group is strongly electron-withdrawing by induction, reducing electron density throughout the ring system and increasing metabolic stability relative to unsubstituted analogues. The 6-chloro substituent serves as a handle for further functionalization via cross-coupling reactions such as Suzuki–Miyaura, Buchwald–Hartwig, or nucleophilic aromatic substitution, making this compound a valuable synthetic intermediate.
Synthesis and Derivatization
Imidazo[1,2-a]pyridines are classically prepared by the condensation of 2-aminopyridine derivatives with α-haloketones or equivalent electrophilic partners under thermal or catalytic conditions. Introducing a trifluoromethyl group at the 2-position can be achieved either by using a trifluoromethyl-containing α-halocarbonyl precursor during the ring-forming step or by post-cyclization trifluoromethylation using reagents such as the Togni reagent or Umemoto's reagent.
The 6-chloro group on the pyridine ring is particularly amenable to palladium-catalyzed cross-coupling reactions, enabling the introduction of aryl, heteroaryl, alkyl, amino, or alkoxy groups to generate structurally diverse analogues for structure–activity relationship (SAR) studies. Nucleophilic aromatic substitution with amines or alkoxides can also displace the chloro group under appropriate activation conditions, broadening the synthetic utility of this building block.
Research and Medicinal Chemistry Applications
The imidazo[1,2-a]pyridine scaffold is a privileged structure in drug discovery, present in or related to several pharmacologically active compounds. Its balanced lipophilicity, planar geometry, and hydrogen-bond-acceptor nitrogen atoms make it well-suited for engaging enzyme active sites and receptor binding pockets. Fluorinated analogues, including trifluoromethyl-substituted variants, are particularly sought after because the –CF₃ group enhances membrane permeability, improves metabolic stability toward cytochrome P450-mediated oxidation, and can modulate pKa values of nearby ionizable groups.
6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine is employed as an electrophilic building block in combinatorial and medicinal chemistry libraries targeting a range of biological areas including kinase inhibition, CNS disorders, anti-infective research, and oncology. Researchers use it to rapidly generate focused compound libraries by exploiting the reactivity of the 6-chloro group, enabling efficient SAR exploration around the core scaffold.
Handling, Storage, and Safety Considerations
As with all halogenated and fluorinated organic compounds, appropriate laboratory safety precautions should be observed when handling 6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine. Personnel should wear suitable personal protective equipment (PPE) including gloves, safety glasses, and a lab coat. Operations generating dust or aerosols should be conducted in a well-ventilated fume hood.
The compound should be stored in a tightly sealed container in a cool, dry, and well-ventilated area, away from incompatible materials such as strong bases and strong oxidizing agents. Researchers should consult the Safety Data Sheet (SDS) provided with the product for comprehensive hazard information, first-aid measures, and disposal guidelines prior to use. Aladdin Scientific supplies this compound with full documentation to support safe laboratory practice.
Frequently asked questions
What makes the trifluoromethyl group important in this compound?
The trifluoromethyl (–CF₃) group is strongly electron-withdrawing, which increases the metabolic stability of the molecule by reducing susceptibility to cytochrome P450-mediated oxidative metabolism. It also enhances lipophilicity and membrane permeability, and can fine-tune the pKa of nearby functional groups, making it a highly valued motif in drug discovery campaigns.
How can the 6-chloro substituent be used in further synthesis?
The 6-chloro group can be functionalized through palladium-catalyzed cross-coupling reactions (e.g., Suzuki–Miyaura for arylation, Buchwald–Hartwig for amination) or via nucleophilic aromatic substitution with amines, alkoxides, or thiolates. These reactions enable the rapid generation of structurally diverse analogues for medicinal chemistry SAR studies.
What are the recommended storage conditions for C692511?
6-Chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (SKU: C692511) should be stored in a tightly sealed container under cool, dry, and well-ventilated conditions. Always refer to the product SDS supplied by Aladdin Scientific for specific temperature requirements and incompatibility information.
In what research areas is this compound typically used?
This compound is primarily used as a synthetic building block in medicinal chemistry, particularly for the construction of compound libraries targeting kinases, CNS-related proteins, infectious disease targets, and oncology pathways. Its privileged imidazo[1,2-a]pyridine scaffold and dual electrophilic/metabolically stable substituents make it attractive for lead optimization programs.
References
- Comprehensive Heterocyclic Chemistry III, Katritzky, A. R. et al. (Eds.), Elsevier, 2008. Chapter on imidazo[1,2-a]pyridines.
- Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018, 61, 5822–5880.
- Lauria, A. et al. Imidazo[1,2-a]pyridine: A privileged scaffold in drug discovery. Eur. J. Med. Chem. 2017, 126, 1034–1052.
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