2-Chloro-6-aminopyrazine
[CAS# 33332-28-4]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrazines
• Name: 2-Chloro-6-aminopyrazine
• Synonyms: 6-chloropyrazin-2-amine
• Molecular Formula: C₄H₄ClN₃
• Molecular Weight: 129.55
• CAS Registry Number: 33332-28-4
• EC Number: 636-487-7
• SMILES: C1=C(N=C(C=N1)Cl)N

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Melting point: 150 - 152 °C (Expl.)
• Boiling point: 282.8±35.0 °C 760 mmHg (Calc.)^*
• Flash point: 124.8±25.9 °C (Calc.)^*
• Index of refraction: 1.618 (Calc.)^*

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

Safety Data

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

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Serious eye damage	Eye Dam.	1	H318
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

2-Chloro-6-aminopyrazine is a heteroaromatic compound in which a pyrazine ring is substituted with a chlorine atom at position 2 and an amino group at position 6. Its molecular formula is C₄H₄ClN₃, with a molecular weight of approximately 127.55 g/mol. The pyrazine ring is a six-membered nitrogen-containing aromatic system with nitrogen atoms at positions 1 and 4, which influence the electron density and reactivity of the ring. The chloro substituent is electron-withdrawing and provides a site for nucleophilic substitution, while the amino group is nucleophilic and capable of hydrogen bonding, increasing polarity and reactivity.

Synthesis of 2-chloro-6-aminopyrazine generally involves selective halogenation and amination of pyrazine derivatives. One approach is the chlorination of pyrazine precursors at position 2, followed by introduction of the amino group at position 6 through nucleophilic substitution of a suitable leaving group or via reduction of a nitro intermediate. Reaction conditions, including choice of solvent, temperature, and reagents, are carefully controlled to achieve regioselective functionalization and to avoid overhalogenation or undesired side reactions.

Chemically, the amino group at position 6 is nucleophilic and can participate in acylation, alkylation, or condensation reactions, while the chloro group at position 2 can undergo nucleophilic substitution, including palladium-catalyzed cross-coupling reactions. The electron-withdrawing effect of the chlorine atom modifies the electronic distribution of the ring, influencing the reactivity of adjacent positions. The pyrazine ring itself is relatively electron-deficient compared to benzene, which affects the regioselectivity of further substitution reactions.

2-Chloro-6-aminopyrazine is typically a solid at room temperature and exhibits solubility in polar organic solvents such as ethanol, dimethylformamide, and acetone. It is stable under ambient conditions but should be stored away from strong acids or bases that could react with the amino group or promote hydrolysis of the chloro substituent. The combination of a reactive amine and a halogenated heteroaromatic ring provides multiple sites for chemical modification while maintaining the integrity of the aromatic core.

In practical applications, 2-chloro-6-aminopyrazine is widely used as an intermediate in the synthesis of pharmaceutical compounds, agrochemicals, and heterocyclic derivatives. Its amino and chloro functionalities enable selective derivatization and cross-coupling reactions, allowing the preparation of substituted pyrazine scaffolds with tailored electronic and steric properties. The molecule serves as a versatile building block for the design of bioactive compounds, ligands, and other functionalized heterocycles.

Overall, 2-chloro-6-aminopyrazine combines a nitrogen-rich aromatic core with reactive functional groups, providing a flexible platform for synthetic transformations. Its predictable chemical behavior, selective reactivity, and structural versatility make it a valuable intermediate in heterocyclic chemistry and applied organic synthesis.

References

2011. Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing. Journal of Medicinal Chemistry, 54(24).
DOI: 10.1021/jm2007326

2008. Identification of N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design. Journal of Medicinal Chemistry, 51(16).
DOI: 10.1021/jm800382h