5-Bromo-4-chloro-6-methyl-2-(methylsulfanyl)pyrimidine: Lab Guide
5-Bromo-4-chloro-6-methyl-2-(methylsulfanyl)pyrimidine: Lab Guide
5-bromo-4-chloro-6-methyl-2-(methylsulfanyl)pyrimidine is a multifunctional halogenated pyrimidine building block bearing orthogonal reactive sites—bromo, chloro, and methylthio substituents—that make it a versatile intermediate for constructing pharmacologically relevant heterocyclic scaffolds in medicinal and agrochemical research.
- CAS Number
- Verify with supplier certificate of analysis
- Molecular Formula
- C6H6BrClN2S
- Molecular Weight
- Approximately 253.55 g/mol (verify with CoA)
- Key Functional Groups
- C-5 bromo, C-4 chloro, C-6 methyl, C-2 methylsulfanyl
- Recommended Storage
- Cool, dry, dark conditions; check SDS for exact temperature
- Primary Applications
- Medicinal chemistry, heterocyclic synthesis, agrochemical research
Chemical Identity and Physical Properties
5-Bromo-4-chloro-6-methyl-2-(methylsulfanyl)pyrimidine belongs to the class of substituted pyrimidines, a six-membered aromatic heterocycle containing two nitrogen atoms at positions 1 and 3. Its structure features four distinct substituents on the pyrimidine ring: a bromine atom at C-5, a chlorine atom at C-4, a methyl group at C-6, and a methylsulfanyl (–SCH3) group at C-2. This unique combination of substituents imparts a rich palette of reactivity.
The molecular formula is C6H6BrClN2S, with a calculated molecular weight of approximately 253.55 g/mol. The compound is typically obtained as a solid. Exact melting point, solubility, and spectral data (NMR, MS) should be confirmed against the Aladdin Scientific certificate of analysis (CoA) supplied with each batch, as these values are batch-dependent and represent quality-release parameters.
Pyrimidine ring systems are planar and aromatic, conferring thermal stability and the ability to participate in π–π stacking interactions relevant to drug–target binding. The electron-withdrawing nitrogen atoms reduce electron density on the ring, activating electrophilic positions toward nucleophilic aromatic substitution (SNAr).
Reactivity and Synthetic Applications
The defining synthetic value of 5-bromo-4-chloro-6-methyl-2-(methylsulfanyl)pyrimidine lies in its three orthogonal electrophilic handles, each of which can be selectively manipulated under appropriate conditions:
- C-4 Chloro group: The chlorine at C-4, flanked by two ring nitrogen atoms, is highly activated toward SNAr with nitrogen, oxygen, and sulfur nucleophiles (e.g., amines, alcohols, thiols) under mild conditions. This position is typically the most reactive toward nucleophilic displacement.
- C-5 Bromo group: The aryl bromide is an excellent partner for palladium-catalyzed cross-coupling reactions including Suzuki–Miyaura (boronic acids/esters), Negishi (organozinc), Sonogashira (terminal alkynes), and Buchwald–Hartwig (amination) protocols, enabling introduction of diverse carbon or heteroatom fragments.
- C-2 Methylsulfanyl group: The –SCH3 moiety can be oxidized to the sulfoxide or sulfone to enhance its leaving-group ability, facilitating subsequent displacement by amines or other nucleophiles—a well-established strategy in pyrimidine medicinal chemistry. Alternatively, it can be retained as a bioisostere or pharmacophore element.
These orthogonal reactivities allow sequential, chemoselective functionalization, making this building block a strategic starting material for library synthesis and lead optimization in drug discovery programs targeting kinases, dihydrofolate reductase, and other therapeutically important enzymes that possess pyrimidine-binding pockets.
Handling, Safety and Storage Guidelines
Personal Protective Equipment (PPE): Always consult the current Safety Data Sheet (SDS) before use. As a general practice with halogenated heteroaromatic compounds, wear appropriate nitrile or neoprene gloves, a laboratory coat, and safety goggles. Work inside a well-ventilated fume hood to avoid inhalation of dust or vapors.
Storage: Store the compound in a tightly sealed container in a cool, dry location away from light, heat sources, and incompatible materials (strong oxidizers, strong bases). Specific recommended storage temperature should be confirmed from the product label or SDS provided with the shipment. Moisture ingress can hydrolyze reactive C–Cl bonds over time; the use of desiccants and inert atmosphere (argon or nitrogen) for opened containers is recommended.
Disposal: Dispose of all waste in accordance with applicable local, national, and institutional regulations for halogenated organic waste. Do not discharge into sewers or the environment.
First Aid: In case of skin or eye contact, rinse immediately with copious water and seek medical attention. Refer to the SDS for comprehensive first-aid measures specific to this compound.
Note: The SDS supplied by Aladdin Scientific (SKU B174943) is the authoritative safety reference and supersedes any general guidance provided here.
Quality Specifications and Analytical Characterization
Aladdin Scientific supplies 5-bromo-4-chloro-6-methyl-2-(methylsulfanyl)pyrimidine (SKU B174943) with a certificate of analysis (CoA) that documents batch-specific purity and analytical data. Researchers should request and review the CoA prior to use, particularly for sensitive applications such as asymmetric synthesis or biological assays where impurity profiles may affect results.
Typical analytical methods used for characterization include:
- Purity by HPLC: High-performance liquid chromatography provides quantitative purity assessment. Confirm the minimum purity specification on the current CoA.
- Structural confirmation by NMR: 1H and 13C NMR spectra confirm substitution pattern and absence of regioisomers. The C-6 methyl group and N-CH3S protons provide characteristic diagnostic signals.
- Mass Spectrometry (MS): The expected molecular ion exhibits a characteristic isotope pattern consistent with the presence of one bromine (M and M+2 in approximately 1:1 ratio) and one chlorine (further splitting), confirming elemental composition.
- Melting Point: Reported melting point should be verified against the CoA value as a routine identity check.
If additional characterization data are required for regulatory submissions or method validation, contact Aladdin Scientific technical support for custom analytical documentation options.
Applications in Drug Discovery and Agrochemistry
Pyrimidine is among the most privileged heterocyclic scaffolds in pharmaceutical and agrochemical research. The 2-methylsulfanyl-4,5-dihalopyrimidine motif present in this compound is recognized as a versatile platform for elaboration into bioactive molecules.
Pharmaceutical applications: Halogenated 2-(methylsulfanyl)pyrimidines serve as key intermediates in the preparation of kinase inhibitors, antimicrobial agents, and antiviral compounds. The sequential substitution strategy—first displacing the C-4 chloride with an amine to install selectivity-determining pharmacophores, then using palladium cross-coupling at C-5 to introduce aryl or heteroaryl groups—is a widely practiced route in medicinal chemistry. The C-2 methylsulfanyl can subsequently be oxidized and displaced to install additional diversity elements.
Agrochemical applications: Substituted pyrimidines are core structures in several classes of herbicides, fungicides, and insecticides. The electrophilic reactivity of this building block facilitates rapid analog synthesis for agricultural lead optimization programs.
Material science: Pyrimidine-containing compounds have also found use in the development of organic semiconductors and coordination polymers, where the nitrogen atoms serve as ligands for metal ions. This building block's mixed halide functionality may be exploited in the design of functional materials.
Researchers are encouraged to perform a literature search (e.g., SciFinder, Reaxys) using the CAS number of this compound to identify specific published synthetic routes that have used this building block.
Frequently asked questions
What makes C-4 chloro more reactive than C-5 bromo toward nucleophilic substitution?
The C-4 position is flanked by both ring nitrogen atoms (N-3 and the C-4–N-3 bond is adjacent to N-1 as well), making it highly electron-deficient and strongly activated toward SₙAr with nucleophiles such as amines. The C-5 bromo, while an excellent handle for palladium-catalyzed cross-coupling, is not as activated toward direct nucleophilic aromatic substitution under mild conditions. This chemoselectivity allows sequential functionalization of the two positions.
How should I handle the methylsulfanyl group if I want to replace it with an amine?
A well-established approach is to first oxidize the –SCH₃ group to the corresponding sulfoxide (using mCPBA or similar oxidant) or sulfone (using stronger oxidants such as Oxone® or H₂O₂), which substantially increases the leaving-group ability of the sulfur moiety. The resulting sulfoxide or sulfone can then be displaced by primary or secondary amines under relatively mild conditions. It is important to complete any desired C-4 or C-5 functionalization steps before or after this oxidation, depending on the desired sequence and compatibility of functional groups.
What solvents are recommended for dissolving this compound for reactions?
Common solvents for substituted pyrimidine reactions include dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, and dioxane, depending on the reaction type and nucleophile or catalyst employed. For SₙAr reactions with amines, DMF or DMSO at elevated temperatures is frequently used. For palladium-catalyzed cross-couplings, dioxane or THF with aqueous base is typical. Actual solubility data specific to this compound should be confirmed from the CoA or by experiment.
Is this compound stable at room temperature for long-term storage?
Halogenated pyrimidines can be susceptible to hydrolysis of the C–Cl bond under prolonged exposure to moisture and elevated temperature. For long-term storage, it is advisable to keep the compound sealed under an inert atmosphere (nitrogen or argon), with a desiccant, at the temperature specified on the product label or SDS. The Aladdin Scientific CoA will indicate the recommended storage conditions and shelf life for each specific batch.
Can I use this building block for Suzuki–Miyaura coupling at C-5?
Yes, the aryl bromide at C-5 is well-suited for Suzuki–Miyaura cross-coupling with aryl or heteroaryl boronic acids and esters under standard palladium catalysis conditions (e.g., Pd(PPh₃)₄ or Pd(dppf)Cl₂, base such as K₂CO₃ or Cs₂CO₃, aqueous dioxane or THF, 80–100 °C). Care should be taken to ensure that the chosen reaction conditions are compatible with the other functional groups present (C-4 Cl and C-2 SCH₃). Literature precedent for related substrates should be consulted for optimized protocols.
References
- Aladdin Scientific Certificate of Analysis, SKU B174943, 5-bromo-4-chloro-6-methyl-2-(methylsulfanyl)pyrimidine. Available from Aladdin Scientific upon request.
- Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. Chapter on nucleophilic aromatic substitution and heterocyclic chemistry.
- Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. Chapter on pyrimidine reactivity and synthesis.
- Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. doi:10.1021/cr00039a007
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