4,6-Dichloro-2-(methylthio)pyrimidine: FAQs & Lab Guide

4,6-Dichloro-2-(methylthio)pyrimidine is a versatile halogenated pyrimidine building block widely used in pharmaceutical and agrochemical research as a key intermediate for constructing substituted pyrimidine scaffolds via selective nucleophilic aromatic substitution.

CAS Number

6294-89-9

Molecular Formula

C₅H₄Cl₂N₂S

Molecular Weight

195.07 g/mol

Appearance

White to off-white crystalline solid

Key Reactive Sites

C-4 and C-6 chloro substituents; C-2 methylthio group

Primary Application

Pharmaceutical and agrochemical intermediate; heterocyclic synthesis building block

Chemical Identity and Physical Properties

4,6-Dichloro-2-(methylthio)pyrimidine (CAS 6294-89-9) is a dihalogenated pyrimidine derivative bearing a methylthio (–SCH₃) group at the 2-position and chloro substituents at the 4- and 6-positions. Its molecular formula is C₅H₄Cl₂N₂S with a molecular weight of approximately 195.07 g/mol. At room temperature it is typically a white to off-white crystalline solid with a characteristic organosulfur odor. The compound is sparingly soluble in water but dissolves readily in common organic solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, and dimethylformamide. These physicochemical attributes make it straightforward to handle in standard synthetic workflows.

Reactivity and Synthetic Applications

The defining feature of 4,6-Dichloro-2-(methylthio)pyrimidine is its capacity to undergo sequential or selective nucleophilic aromatic substitution (SNAr) reactions. The electron-withdrawing ring nitrogen atoms activate the C-4 and C-6 chloro positions toward displacement by a broad range of nucleophiles including amines, alcohols, and thiols under mild conditions. The C-2 methylthio group is less reactive toward direct SNAr but can be oxidized to a sulfoxide or sulfone to enhance its leaving-group ability, or it can serve as a handle for transition-metal-catalyzed cross-coupling reactions.

This orthogonal reactivity profile allows chemists to introduce up to three different substituents in a controlled manner, making this scaffold particularly valuable in medicinal chemistry for the rapid construction of diverse pyrimidine libraries targeting kinases, dihydrofolate reductase inhibitors, and other therapeutically relevant enzymes. In agrochemical research it serves as a precursor to herbicides and fungicides based on the pyrimidine core.

Storage, Handling, and Safety

Store 4,6-Dichloro-2-(methylthio)pyrimidine in a tightly sealed container in a cool, dry, and well-ventilated area, away from light and moisture. Refrigerated storage (2–8 °C) is recommended for long-term stability. The compound should be handled in a fume hood with appropriate personal protective equipment including chemical-resistant gloves, safety glasses, and a lab coat, as it is a skin, eye, and respiratory irritant. Consult the Safety Data Sheet (SDS) for full hazard classification and emergency procedures before use. Waste disposal must comply with local regulations governing halogenated organic compounds.

Purity, Specifications, and Quality Assurance

Aladdin Scientific supplies 4,6-Dichloro-2-(methylthio)pyrimidine (SKU D110314) with purity verified by HPLC and/or GC analysis. Research-grade material is typically ≥97% pure, which is suitable for the vast majority of synthetic and biological screening applications. The product is characterized by standard analytical techniques including NMR spectroscopy and mass spectrometry, and a certificate of analysis (CoA) is available for each lot. Researchers requiring higher purity for sensitive assays should contact technical support to discuss available options or additional purification strategies such as recrystallization from ethanol or heptane.

Ordering and Technical Support

4,6-Dichloro-2-(methylthio)pyrimidine is available from Aladdin Scientific under SKU D110314 in multiple pack sizes to suit screening-scale through preparative-scale needs. Orders can be placed directly through the Aladdin Scientific website or by contacting your regional sales representative. For technical inquiries regarding reactivity, compatibility with specific reaction conditions, or custom synthesis requirements, the Aladdin Scientific technical team is available via the website's support portal. Bulk pricing and institutional account options are available upon request.

Frequently asked questions

What nucleophiles can react with 4,6-Dichloro-2-(methylthio)pyrimidine, and at which positions?

Primary and secondary amines, alkoxides, and thiols readily displace the chloro groups at C-4 and C-6 via nucleophilic aromatic substitution. Mono-substitution can often be achieved by controlling stoichiometry and temperature, while excess nucleophile drives bis-substitution. The C-2 methylthio group is comparatively inert to SNAr under mild conditions but can be activated by prior oxidation to the sulfone.

How should I select conditions for mono- versus bis-substitution at C-4 and C-6?

For mono-substitution, use one equivalent of nucleophile at low temperature (0 °C to room temperature) in a polar aprotic solvent such as DMF or THF with a mild base like triethylamine. C-4 is generally more electrophilic than C-6 due to the influence of the ring nitrogens, so selective mono-substitution at C-4 is often achievable. For bis-substitution, use two or more equivalents of nucleophile and allow the reaction to warm to room temperature or above.

What is the recommended storage condition and shelf life of D110314?

The product should be stored in a sealed container at 2–8 °C, protected from light and moisture. Under these conditions the compound is expected to remain stable for an extended period. Always check the certificate of analysis for the specific lot expiry date and inspect the material for discoloration or clumping before use.

Is 4,6-Dichloro-2-(methylthio)pyrimidine compatible with aqueous reaction conditions?

The compound has limited water solubility and the chloro groups can undergo slow hydrolysis under aqueous acidic or basic conditions, which may reduce yield and complicate purification. For best results, reactions should be conducted in anhydrous organic solvents. If aqueous conditions are required, keep reaction times short, control pH carefully, and use a co-solvent to improve substrate solubility.

Can the methylthio group at C-2 be used for further functionalization?

Yes. The methylthio group can be oxidized to the corresponding sulfoxide or sulfone using reagents such as mCPBA or oxone, greatly increasing its leaving-group ability for subsequent SNAr with nitrogen or oxygen nucleophiles. Alternatively, the methylthio group can participate in palladium-catalyzed cross-coupling reactions, providing access to C-2 aryl or heteroaryl-substituted pyrimidines.

References

1. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. General reference for pyrimidine reactivity and SNAr chemistry.
2. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. General mechanistic reference for nucleophilic aromatic substitution.
3. Aladdin Scientific Product Page: 4,6-Dichloro-2-(methylthio)pyrimidine, SKU D110314. Certificate of Analysis available on request.

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