4-Hydroxy-6-methoxymethylpyrimidine-2-thiol: Properties & Uses

4-Hydroxy-6-methoxymethylpyrimidine-2-thiol is a sulfur- and oxygen-functionalized pyrimidine heterocycle that serves as a versatile building block and reactive intermediate in medicinal chemistry and agrochemical synthesis.

Chemical Name

4-Hydroxy-6-methoxymethylpyrimidine-2-thiol

SKU / Catalog Number

H182129

Core Heterocycle

Pyrimidine (1,3-diazine) ring system

Key Functional Groups

2-Thiol (–SH), 4-hydroxyl (–OH / lactam tautomer), 6-methoxymethyl (–CH₂OCH₃)

Tautomeric Behavior

Exists in thiol–thione and hydroxy–oxo tautomeric equilibria in solution

Primary Application Area

Medicinal chemistry intermediate and heterocyclic building block

Supplier

Aladdin Scientific (H182129)

Chemical Structure and Physicochemical Properties

4-Hydroxy-6-methoxymethylpyrimidine-2-thiol belongs to the pyrimidine family of nitrogen-containing heterocycles. Its structure features a six-membered aromatic ring containing nitrogen atoms at positions 1 and 3, with three distinct substituents: a hydroxyl (or oxo in the lactam tautomer) group at C-4, a thiol (or thione in the thione tautomer) group at C-2, and a methoxymethyl (–CH₂OCH₃) group at C-6.

Like many 2-thiopyrimidines and 4-hydroxypyrimidines, this compound exhibits pronounced tautomeric behavior. In the solid state and in polar solvents, the thione and oxo tautomers are frequently predominant, meaning the compound can formally be described as 6-(methoxymethyl)pyrimidine-2(1H)-thione-4(3H)-one. Researchers should consider these tautomeric equilibria when interpreting spectroscopic data (NMR, IR) or designing reactions involving the thiol or hydroxyl functionality.

The presence of both a thiol and a hydroxyl group on the pyrimidine ring makes this molecule bifunctionally reactive, enabling selective derivatization at either site under appropriate conditions. The methoxymethyl side chain adds a degree of steric and electronic modulation compared to simpler 4-hydroxy-2-thiopyrimidines.

Synthesis and Reactivity

Hydroxymethylpyrimidine-2-thiol derivatives are commonly accessed through cyclocondensation strategies. A classic approach involves the reaction of a suitable 1,3-dicarbonyl equivalent or β-enaminone with thiourea under basic conditions, followed by functional-group manipulation to introduce the methoxymethyl moiety. Alternatively, direct etherification of the corresponding 4-hydroxy-6-hydroxymethylpyrimidine-2-thiol precursor with methanol or dimethyl sulfate can yield the methoxymethyl product.

The thiol group at C-2 is a nucleophilic center and participates readily in S-alkylation reactions with alkyl halides or Michael acceptors, making it a handle for library synthesis and prodrug design. S-oxidation to the corresponding sulfinyl or sulfonyl species is also feasible. The C-4 hydroxyl, predominantly in the oxo (lactam) form, can undergo O-chlorination with phosphorus oxychloride (POCl₃) to give 4-chloro derivatives, which are useful for further nucleophilic aromatic substitution with amines, alkoxides, or thiols.

The methoxymethyl group is comparatively inert under mild conditions but can participate in acid-catalyzed reactions or serve as a masked aldehyde equivalent upon hydrolysis, expanding the synthetic utility of the molecule.

Applications in Medicinal and Agrochemical Research

Pyrimidine-2-thiol and 4-hydroxypyrimidine scaffolds are privileged structures in drug discovery. The thiol and hydroxyl groups provide multiple vectors for lead optimization, and the pyrimidine ring itself is a bioisostere for purine nucleobases, lending inherent affinity for nucleic acid-binding and enzyme active sites.

Compounds in this structural class have been investigated as potential inhibitors of kinases, dihydrofolate reductase (DHFR), and other enzymes involved in nucleotide metabolism. The 2-thio motif, in particular, has been associated with antiviral, antibacterial, and antiprotozoal activities in the broader pyrimidine literature. The methoxymethyl substituent at C-6 may modulate binding affinity and metabolic stability relative to unsubstituted or hydroxymethyl analogues.

In agrochemical research, hydroxymethylpyrimidine derivatives are structurally related to components of vitamin B1 (thiamine) biosynthesis pathways and have been explored as starting materials for the synthesis of insecticides and herbicides. The dual thiol–hydroxyl functionality also makes such compounds useful in the preparation of heterocyclic thioethers and fused-ring systems relevant to crop-protection chemistry.

Handling, Storage, and Laboratory Safety

As a thiol-containing compound, 4-Hydroxy-6-methoxymethylpyrimidine-2-thiol should be handled with standard laboratory precautions applicable to reactive organosulfur reagents. Thiols are known for their low odor threshold and potential for oxidation to disulfides on prolonged exposure to air; therefore, working in a well-ventilated fume hood is recommended.

The compound should be stored in a tightly sealed container, away from strong oxidizing agents, moisture, and light, at cool temperatures (typically 2–8 °C or as specified on the product label). Stock solutions prepared in anhydrous DMSO or DMF are generally stable for short-term use when stored under inert atmosphere and at reduced temperature.

Researchers should consult the current Safety Data Sheet (SDS) provided by Aladdin Scientific (SKU H182129) before use. Standard personal protective equipment—including nitrile gloves, safety glasses, and a laboratory coat—should be worn when handling this material. Waste disposal must comply with local regulations governing organosulfur compounds.

Ordering Information and Specifications

4-Hydroxy-6-methoxymethylpyrimidine-2-thiol is available from Aladdin Scientific under catalog number H182129. Researchers are encouraged to verify current stock availability, pack sizes, and pricing on the Aladdin Scientific website or by contacting the technical sales team.

For bulk or custom orders, Aladdin Scientific's procurement team can discuss quantities, purity specifications, and certificate of analysis (CoA) requirements. All products are subject to Aladdin Scientific's standard terms regarding quality, returns, and shipping. Purity and analytical data (HPLC, NMR, MS) should be confirmed against the CoA supplied with each lot prior to use in critical assays.

Frequently asked questions

What is the predominant tautomeric form of 4-Hydroxy-6-methoxymethylpyrimidine-2-thiol in solution?

In polar protic and aprotic solvents, 4-hydroxy-2-thiopyrimidines typically predominate in the oxo–thione tautomeric form rather than the hydroxy–thiol form. For 4-Hydroxy-6-methoxymethylpyrimidine-2-thiol specifically, NMR and IR analysis of each lot should be consulted to confirm tautomeric preference under your experimental conditions.

How can the thiol group of 4-Hydroxy-6-methoxymethylpyrimidine-2-thiol be selectively alkylated without reacting at the C-4 hydroxyl?

Selective S-alkylation can typically be achieved under mild basic conditions (e.g., K₂CO₃ in acetone or DMF) using alkyl halides at room temperature, where the thiolate anion is a significantly softer and more reactive nucleophile than the oxygen anion under these conditions. Careful pH control and choice of alkylating agent are critical for achieving good selectivity; literature precedent for analogous 2-thiopyrimidines should be consulted.

Is 4-Hydroxy-6-methoxymethylpyrimidine-2-thiol suitable for use as a building block in medicinal chemistry library synthesis?

Yes, the compound's bifunctional character—offering both a reactive thiol/thione and a hydroxyl/oxo group on a pharmacologically relevant pyrimidine scaffold—makes it an attractive building block for library synthesis. The thiol can be diversified via S-alkylation, S-oxidation, or condensation, while the C-4 position can be activated by chlorination with POCl₃ and subsequently functionalized with diverse nucleophiles.

What are the recommended storage conditions for H182129?

The compound should be stored in a tightly sealed, light-protected container at cool temperatures (typically 2–8 °C), away from moisture and strong oxidizing agents. Always refer to the current Aladdin Scientific SDS and CoA for lot-specific storage instructions.

Can 4-Hydroxy-6-methoxymethylpyrimidine-2-thiol be dissolved in common laboratory solvents?

Polar aprotic solvents such as DMSO and DMF are generally good choices for dissolving hydroxypyrimidine-2-thiol derivatives. Aqueous solubility may be enhanced under basic conditions due to ionization of the thiol and hydroxyl groups. Specific solubility data for H182129 should be verified against the product CoA or by consulting Aladdin Scientific technical support.

References

1. Brown, D. J. The Pyrimidines. In The Chemistry of Heterocyclic Compounds; Wiley-Interscience, 1994. (General reference on pyrimidine tautomerism and reactivity.)
2. Elguero, J.; Marzin, C.; Katritzky, A. R.; Linda, P. The Tautomerism of Heterocycles. Academic Press, 1976. (Foundational reference on thiol–thione and hydroxy–oxo tautomerism in pyrimidines.)
3. Aladdin Scientific. Product Information: 4-Hydroxy-6-methoxymethylpyrimidine-2-thiol, SKU H182129. Aladdin Scientific Corp.

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