6-Chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine
[CAS# 1383624-01-8]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridazine
• Name: 6-Chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine
• Molecular Formula: C₁₄H₁₁ClN₄O₂
• Molecular Weight: 302.72
• CAS Registry Number: 1383624-01-8
• SMILES: CCC1=C(C=C(C=C1)C2=CN3C(=N2)C=CC(=N3)Cl)[N+](=O)[O-]

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Solubility: water: |Insoluble (4.5E^-3 g/L) (25 ºC), Calc.
• Index of refraction: 1.697 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P280-P301+P312-P302+P352-P305+P351+P338

Discovory and Applicatios

6-Chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine is a fused bicyclic heteroaromatic compound belonging to the imidazopyridazine family. It contains an imidazole ring fused to a pyridazine ring, forming a rigid aromatic system. At position 6 of the bicyclic core a chlorine atom is present, while position 2 bears a substituted phenyl ring, on which an ethyl group occupies the 4-position and a nitro group occupies the 3-position. The molecular structure therefore combines a halogen, a nitroaromatic ring, and a nitrogen-rich fused heterocycle, giving rise to a highly functionalized framework suitable for synthetic elaboration.

This compound traces its origins to research on substituted imidazopyridazines, which were first systematically explored in the mid-twentieth century due to their structural similarity to biological heterocycles. As synthetic methodologies evolved, chemists discovered numerous ways to modify this ring system to influence physicochemical and biological properties. During these investigations, electrophilic aromatic substitution and metal-catalyzed coupling strategies were developed to functionalize both the heterocyclic core and the pendant phenyl ring. Introduction of heteroatoms and electron-withdrawing substituents, such as chlorine and nitro groups, became standard approaches for tuning reactivity, acidity, solubility, and metabolic stability. The compound 6-chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine emerged from this body of synthetic work as part of efforts to construct libraries of fused heterocycles bearing diverse substituent patterns.

Compounds in the imidazopyridazine series are regarded as privileged structures in medicinal chemistry. They have been investigated as starting points for the development of kinase inhibitors, antiparasitic agents, and anti-inflammatory candidates. The bicyclic system is planar and electron-deficient, while the attached phenyl ring permits further electronic diversification. The presence of the nitro group can strengthen electron withdrawal and influence hydrogen-bonding interactions once reduced or derivatized. The chloro substituent can support cross-coupling chemistry or serve as a recognition element in target binding. The ethyl group contributes hydrophobic bulk, altering lipophilicity and molecular shape. Together, these features make 6-chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine a useful scaffold in the preparation of analogues for structure–activity relationship investigations.

Regarding synthesis, the heterocyclic core is often constructed through cyclization processes starting from aminopyridazine precursors. A common strategy employs condensation between a 3-amino-6-chloropyridazine derivative and an aldehyde, followed by cyclodehydration to generate the fused bicyclic ring. Alternative approaches use transition-metal catalysis to assemble the framework via C-N or C-C bond formation. Once the core is generated, electrophilic or nucleophilic substitutions may introduce chlorine at the desired position. The nitrophenyl substituent is typically incorporated earlier as a functionalized aldehyde or haloarene, allowing the imidazole ring to form in the presence of the nitro group. The ethyl substituent may be introduced by alkylation of an appropriate precursor prior to ring fusion. Protecting group strategies are sometimes required to preserve the nitro group or avoid unwanted rearrangements under cyclization conditions.

Application of this compound mainly lies in exploratory research. Its rigid bicyclic system enables predictable π-stacking and directional interactions in biological environments, making it amenable to optimization for potency and selectivity. In many studies involving heteroaromatic scaffolds, analogues of imidazo[1,2-b]pyridazine derivatives are synthesized and screened to evaluate their binding to enzymes or receptors. The nitro group may later be converted into amine, amide, heterocycle, or other functional groups, which broadens the range of chemical transformations available. The chloro substituent can be displaced in palladium-catalyzed reactions to introduce diverse substituents at position 6, enabling systematic investigation of steric and electronic effects. Such strategies have positioned molecules of this structural class as intermediates and reference compounds for the development of potential therapeutic agents.

Historically, the growing availability of reliable cross-coupling methods, milder nitration procedures, and improved oxidative cyclizations facilitated the expansion of this chemical class. As a result, substituted imidazopyridazines, including derivatives like 6-chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine, continue to serve as versatile building blocks for medicinal, synthetic, and mechanistic studies. Their combination of aromatic rigidity, heteroatom content, and functional group diversity ensures ongoing relevance in heterocyclic chemistry.

References

Garrido A, Vera G, Delaye P-O, Enguehard-Gueiffier C (2021) Imidazo[1,2-b]pyridazine as privileged scaffold in medicinal chemistry: An extensive review. European Journal of Medicinal Chemistry 226 113867 DOI: 10.1016/j.ejmech.2021.113867



Kusakabe K-I, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y (2015) Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity. Journal of Medicinal Chemistry 58(4) 1760–1775 DOI: 10.1021/jm501599u