4-Chloro-2-Methoxypyrimidine: Properties, Uses & FAQs

4-chloro-2-methoxypyrimidine is a halogenated heteroaromatic building block widely employed in medicinal chemistry and drug discovery as a versatile electrophilic intermediate for nucleophilic aromatic substitution and cross-coupling reactions.

IUPAC Name

4-chloro-2-methoxypyrimidine

Molecular Formula

C5H5ClN2O

Molecular Weight

144.56 g/mol

CAS Number

3680-71-5

Appearance

White to off-white crystalline solid

Recommended Storage

Cool, dry place; protect from moisture and light

SKU

C176663

What Is 4-Chloro-2-Methoxypyrimidine?

4-Chloro-2-methoxypyrimidine (CAS 3680-71-5, MW 144.56 g/mol, molecular formula C₅H₅ClN₂O) is a halogenated pyrimidine derivative bearing a chloro substituent at the 4-position and a methoxy group at the 2-position of the pyrimidine ring. The electron-withdrawing nitrogen atoms of the pyrimidine core activate the carbon–chlorine bond toward nucleophilic aromatic substitution (S_NAr), making the C-4 chloride an excellent leaving group under mild conditions. Simultaneously, the 2-methoxy group can serve as a masked leaving group or directing element in further synthetic elaboration, providing two distinct handles for sequential functionalization. The compound is a white to off-white crystalline solid at room temperature and is commercially available as Aladdin product C176663.

Applications in Synthesis and Drug Discovery

4-Chloro-2-methoxypyrimidine is a privileged heterocyclic building block in pharmaceutical and agrochemical research. Its primary utility lies in S_NAr reactions, where amines, thiols, and alkoxides can displace the 4-chloro group to furnish 4-amino-, 4-thio-, or 4-alkoxypyrimidine products, respectively. These transformations typically proceed under mild heating with or without base in polar solvents such as DMF, NMP, or ethanol.

The compound also participates in transition-metal-catalyzed cross-coupling reactions. Under palladium catalysis (e.g., Suzuki–Miyaura, Buchwald–Hartwig conditions), the C-4 chloride can be coupled with arylboronic acids or amines to deliver biaryl or diarylamino pyrimidine scaffolds that appear frequently in kinase inhibitor programs. The methoxy group at C-2 is hydrolyzable under acidic conditions to give the 2-hydroxypyrimidine (pyrimidinone) tautomer, providing access to additional diversity.

In medicinal chemistry, pyrimidine cores substituted at the 2- and 4-positions are found in numerous bioactive molecules, including kinase inhibitors, antiviral agents, and antimicrobial compounds, making 4-chloro-2-methoxypyrimidine a valuable starting material for library synthesis and lead optimization.

Handling, Safety, and Storage Guidelines

Personal Protective Equipment: Handle 4-chloro-2-methoxypyrimidine with standard laboratory precautions. Wear appropriate gloves (nitrile recommended), safety glasses, and a lab coat. Work in a well-ventilated fume hood to minimize inhalation of dust or vapors.

Storage: Store the compound in a tightly sealed container in a cool, dry location away from moisture, light, and incompatible materials such as strong oxidizers and strong bases. Refrigeration (2–8 °C) is recommended for long-term stability. Avoid repeated freeze-thaw cycles once opened.

Disposal: Dispose of waste material in accordance with local, regional, and national regulations for halogenated organic compounds. Do not pour down the drain. Consult the Safety Data Sheet (SDS) for complete hazard information before use.

Note: Specific GHS hazard classifications, R/S phrases, and flash point data should be verified against the current SDS provided with the product lot.

Purity, Quality Specifications, and Analytical Methods

Research-grade 4-chloro-2-methoxypyrimidine (Aladdin C176663) is supplied at high purity suitable for synthetic and screening applications. Purity is typically assessed by one or more of the following techniques:

• HPLC (High-Performance Liquid Chromatography): The primary method for purity determination, often reported as area percentage at UV 254 nm.
• NMR Spectroscopy (¹H and ¹³C): Confirms structural identity and the absence of major impurities; characteristic signals include the aromatic ring protons and the methoxy singlet.
• GC (Gas Chromatography): An alternative purity method suitable for volatile organic compounds.
• Elemental Analysis or HRMS: Used for definitive molecular formula confirmation.

Customers requiring lot-specific certificates of analysis (CoA) including purity data, NMR spectra, and batch release test results should contact Aladdin Scientific technical support or download the CoA from the product page.

Ordering, Availability, and Technical Support

Product SKU: C176663 — 4-Chloro-2-methoxypyrimidine is available through Aladdin Scientific. Multiple pack sizes may be available to suit both small-scale discovery and larger preparative needs; please check the current product listing for up-to-date stock and pricing information.

Custom Quantities: For bulk orders or custom packaging requirements, contact the Aladdin Scientific sales team directly. Volume pricing may apply.

Technical Inquiries: For questions regarding reactivity, compatibility with specific reaction conditions, or co-reagent recommendations, contact Aladdin Scientific technical support. Our team can assist with selection of complementary building blocks, coupling partners, and catalysts available in the Aladdin catalog.

Returns and Quality Issues: If you receive a product that does not meet the stated specifications, please contact customer service within the stated return window with your order number and lot number. Aladdin Scientific is committed to product quality and customer satisfaction.

Frequently asked questions

What reactions is 4-chloro-2-methoxypyrimidine typically used for?

4-Chloro-2-methoxypyrimidine is most commonly used in nucleophilic aromatic substitution (SNAr) reactions, where the C-4 chloride is displaced by amines, thiols, or alkoxides to produce substituted pyrimidines. It also serves as a coupling partner in palladium-catalyzed reactions such as Suzuki–Miyaura and Buchwald–Hartwig couplings for the construction of more complex heterocyclic scaffolds.

Can the methoxy group at the 2-position be removed or further functionalized?

Yes. The 2-methoxy group can be hydrolyzed under acidic aqueous conditions to afford the corresponding 2-hydroxypyrimidine (pyrimidinone) tautomer. In principle, the methoxy can also act as a leaving group in a second SNAr step under forcing conditions with strongly nucleophilic reagents, enabling sequential double functionalization of the pyrimidine ring. Specific conditions should be optimized for each nucleophile.

How should 4-chloro-2-methoxypyrimidine be stored to maintain stability?

The compound should be stored in a tightly sealed container in a cool, dry place away from moisture and direct light. Refrigeration at 2–8 °C is recommended for long-term storage. Exposure to moisture may promote hydrolysis of the C–Cl bond over time, so desiccant-protected storage is advisable, especially after opening.

What solvents are compatible with 4-chloro-2-methoxypyrimidine for SNAr reactions?

Common solvents for SNAr reactions with this compound include polar aprotic solvents such as DMF, DMSO, and NMP, which facilitate nucleophile reactivity and substrate solubility. Protic solvents like ethanol or isopropanol are also used, particularly when amine nucleophiles are employed and when milder conditions are desired. Solvent choice should be matched to the nucleophile and base used.

Is a Certificate of Analysis (CoA) available for lot C176663?

Yes, lot-specific Certificates of Analysis for Aladdin product C176663 are available. You can download the CoA directly from the product page on the Aladdin Scientific website using your lot number, or contact Aladdin Scientific customer service to request a copy.

References

1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed.; Wiley-Interscience: New York, 1992. (General reference for SNAr reactions of activated halopyrimidines.)
2. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. (General reference for pyrimidine chemistry and reactivity.)
3. Aladdin Scientific product listing: 4-Chloro-2-methoxypyrimidine, SKU C176663. https://www.aladdin-e.com (accessed 2024).

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.