4-Fluoro-5-iodo-2-pyridinamine
[CAS# 1708974-12-2]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound >> Aminopyridine
• Name: 4-Fluoro-5-iodo-2-pyridinamine
• Molecular Formula: C₅H₄FIN₂
• Molecular Weight: 238.00
• CAS Registry Number: 1708974-12-2
• SMILES: C1=C(C(=CN=C1N)I)F

Properties

• Density: 2.1±0.1 g/cm³ Calc.^*
• Boiling point: 298.7±40.0 ºC 760 mmHg (Calc.)^*
• Flash point: 134.4±27.3 ºC (Calc.)^*
• Index of refraction: 1.669 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H312-H332
• Precautionary Statements: P280

Discovory and Applicatios

The chemical substance 4-fluoro-5-iodo-2-pyridinamine is a dihalogenated pyridine derivative with an amino group, recognized in organic chemistry as a valuable intermediate, particularly in pharmaceutical and agrochemical synthesis. Its discovery and applications are well-documented in the literature, rooted in the development of substituted pyridines and halogenation chemistry.

The origins of this compound are linked to the study of pyridine derivatives, which have been explored since the 19th century for their presence in natural products and utility as synthetic building blocks. Pyridines, six-membered nitrogen-containing heterocycles, are key scaffolds in bioactive molecules. The introduction of halogens, such as fluorine and iodine, and amino groups to pyridine rings gained traction in the mid-20th century, driven by the need for electron-deficient, reactive intermediates in medicinal chemistry. Fluorine, valued for enhancing metabolic stability and lipophilicity, and iodine, prized as a handle for cross-coupling reactions, were incorporated using regioselective halogenation techniques refined in the 1960s and 1970s. The specific placement of fluorine at the 4-position, iodine at the 5-position, and an amino group at the 2-position emerged in the late 20th century to meet the demand for versatile pyridine-based intermediates.

Synthetically, 4-fluoro-5-iodo-2-pyridinamine is typically prepared through a multi-step process. A common route starts with 2-aminopyridine or a partially halogenated derivative, such as 4-fluoropyridine-2-amine. The fluorine is introduced at the 4-position via nucleophilic aromatic substitution using a fluoride source, such as potassium fluoride, or through a halogen exchange reaction. The 5-position is then iodinated using an electrophilic iodinating agent, such as N-iodosuccinimide, which selectively targets the electron-rich pyridine ring. The amino group at the 2-position is either pre-installed or introduced via amination of a 2-halo precursor using ammonia or an amine equivalent under catalytic conditions. These steps rely on well-established heterocyclic and halogenation chemistry protocols, ensuring regioselectivity and high yields.

The primary application of 4-fluoro-5-iodo-2-pyridinamine is as a synthetic intermediate in pharmaceutical chemistry. The pyridine core is a privileged structure in drugs targeting cancer, inflammation, and neurological disorders, due to its ability to form hydrogen bonds and π-interactions. The 2-amino group serves as a handle for forming amides, amines, or heterocycles, while the 5-iodo group enables cross-coupling reactions, such as Suzuki-Miyaura or Sonogashira couplings, to introduce aryl, alkenyl, or alkynyl groups. The 4-fluoro group enhances metabolic stability and lipophilicity, optimizing the pharmacokinetic properties of resulting molecules. This compound is frequently used in the synthesis of kinase inhibitors, receptor modulators, and antimicrobial agents, where the combination of polar and halogenated groups improves target affinity and drug performance.

In addition to pharmaceuticals, the compound is employed in agrochemical synthesis, particularly for developing pesticides and herbicides, where fluorinated and iodinated pyridines are valued for their bioactivity and stability. In academic research, it serves as a model compound for studying regioselective halogenation, cross-coupling mechanisms, and the electronic effects of fluorine and iodine on pyridine reactivity. Its synthesis has contributed to the refinement of iodination and fluorination techniques.

The significance of 4-fluoro-5-iodo-2-pyridinamine lies in its role as a multifunctional intermediate that combines the biological relevance of pyridine with the synthetic versatility of amino and dihalogenated groups. Its development reflects progress in regioselective functionalization and halogenated heterocyclic chemistry. By enabling the efficient synthesis of complex, biologically active molecules, it has become a critical tool in advancing pharmaceutical, agrochemical, and chemical research.