5-Bromo-2-chloro-4-methoxypyrimidine: FAQs & Lab Guide

5-bromo-2-chloro-4-methoxypyrimidine is a trisubstituted pyrimidine building block bearing two orthogonal electrophilic leaving groups and a methoxy activating group, making it a versatile intermediate for selective nucleophilic aromatic substitution and cross-coupling reactions in medicinal and agrochemical synthesis.

CAS Number

89793-12-4

Molecular Formula

C5H4BrClN2O

Molecular Weight

223.45 g/mol

Key Functional Handles

C-2 chloro, C-5 bromo, C-4 methoxy

Primary Use

SNAr reactions, Pd-catalyzed cross-coupling (Suzuki, Buchwald-Hartwig), pharmaceutical intermediate synthesis

Aladdin SKU

B176822

What Is 5-Bromo-2-chloro-4-methoxypyrimidine and Why Is It Useful?

5-Bromo-2-chloro-4-methoxypyrimidine (CAS 89793-12-4, Aladdin SKU B176822) is a polyhalogenated pyrimidine derivative in which the aromatic ring carries a bromine atom at position 5, a chlorine atom at position 2, and a methoxy group at position 4. The electron-deficient pyrimidine core, reinforced by the two halogen substituents, renders the ring highly activated toward nucleophilic aromatic substitution (SNAr).

The compound is widely employed as a bifunctional building block in medicinal chemistry and agrochemical research because the C-2 chloro and C-5 bromo positions display distinct reactivity profiles. Under mild SNAr conditions, the C-2 chloro group is preferentially displaced by heteroatom nucleophiles (amines, alcohols, thiols) due to the greater activation provided by both flanking ring nitrogens. The C-5 bromo bond, by contrast, is an excellent handle for palladium-catalyzed cross-coupling reactions such as Suzuki-Miyaura, Negishi, and Buchwald-Hartwig amination, enabling carbon-carbon or carbon-heteroatom bond formation with high chemoselectivity. The C-4 methoxy group can itself be displaced under forcing conditions or converted to other functionality, providing a third site for diversification.

This combination of orthogonal reactivities makes 5-bromo-2-chloro-4-methoxypyrimidine an efficient scaffold for the rapid assembly of structurally diverse pyrimidine libraries used in drug discovery programs targeting kinases, GPCRs, and other therapeutically relevant protein classes.

Physical Properties, Purity, and Analytical Specifications

5-Bromo-2-chloro-4-methoxypyrimidine is typically encountered as a white to off-white crystalline solid at room temperature. Key physicochemical parameters are summarized below:

• Molecular formula: C₅H₄BrClN₂O
• Molecular weight: 223.45 g/mol
• CAS Registry Number: 89793-12-4
• Appearance: White to off-white solid
• Purity (typical): ≥97% by GC or HPLC

Researchers should verify purity by ¹H NMR and GC or HPLC analysis upon receipt, particularly when the compound is used in sensitive multi-step sequences where trace impurities can erode yields or complicate purification. The methoxy singlet and the characteristic C-5 pyrimidine proton singlet are diagnostic resonances in the ¹H NMR spectrum.

Note: Specific melting point, boiling point, and logP values are not confirmed in the current source material and should be verified against the supplier's Certificate of Analysis (CoA) or primary literature before reporting.

Handling, Storage, and Safety Considerations

As an organohalogen compound, 5-bromo-2-chloro-4-methoxypyrimidine should be handled with standard laboratory precautions appropriate for reactive halogenated heterocycles:

• Personal protective equipment: Wear nitrile gloves, lab coat, and safety glasses. Use in a well-ventilated fume hood.
• Storage: Store in a tightly sealed container under dry, inert atmosphere (argon or nitrogen) at 2–8 °C or room temperature in a cool, dry location away from moisture, light, and incompatible materials (strong bases, oxidizers). Confirm recommended storage temperature on the product CoA.
• Hygroscopicity: The compound may be sensitive to moisture over prolonged exposure; handle under inert atmosphere when possible and re-seal promptly after use.
• Waste disposal: Dispose of according to local regulations for halogenated organic waste.

Researchers should consult the Safety Data Sheet (SDS) provided by Aladdin Scientific for complete hazard classifications, first-aid measures, and regulatory information before working with this compound. Specific GHS hazard classifications and H/P statements should be taken directly from the SDS rather than inferred from structure alone.

Synthetic Applications and Reaction Guidance

Selective SNAr at C-2 (chloro displacement): The C-2 position is activated by both adjacent ring nitrogen atoms and is selectively reactive toward primary and secondary amines, alkoxides, and thiolates under mild conditions (often 0 °C to room temperature, polar aprotic or protic solvent). A base such as triethylamine, DIPEA, or K₂CO₃ is typically employed to neutralize the generated HCl. This selectivity allows mono-functionalization at C-2 while preserving the C-5 bromo handle for subsequent metal-catalyzed steps.

Pd-catalyzed cross-coupling at C-5 (bromo): The aryl bromide at C-5 undergoes standard Suzuki-Miyaura coupling with aryl or heteroaryl boronic acids/esters, Buchwald-Hartwig amination with secondary amines, and Negishi coupling with organozinc reagents. Common catalyst systems include Pd(PPh₃)₄, Pd(dppf)Cl₂, or XPhos/Pd-G2 precatalyst, with aqueous K₂CO₃ or Cs₂CO₃ as base for Suzuki reactions.

Methoxy group manipulation: The C-4 methoxy group can be cleaved under acidic conditions (e.g., HBr or BBr₃) to reveal the hydroxypyrimidine, or can participate in transetherification or further SNAr-type substitution with strong nucleophiles under forcing conditions.

Sequential functionalization strategy: A common two-step library synthesis approach involves (1) selective C-2 SNAr with an amine nucleophile to introduce a nitrogen substituent, followed by (2) Suzuki coupling at C-5 to install a (hetero)aryl group, generating 2-amino-5-aryl-4-methoxypyrimidine scaffolds of medicinal interest.

Specific reaction conditions, yields, and literature precedents for individual transformations should be verified in primary synthetic literature; no specific yields are claimed here.

Ordering, Availability, and Quality Assurance at Aladdin Scientific

SKU: B176822 — 5-Bromo-2-chloro-4-methoxypyrimidine is available from Aladdin Scientific. Researchers and procurement personnel can place orders directly through the Aladdin Scientific website or by contacting customer service.

Quality assurance: Each lot is accompanied by a Certificate of Analysis (CoA) documenting purity (GC/HPLC), appearance, and relevant analytical data. Customers are encouraged to request a CoA at the time of order or lot-specific data upon request.

Packaging and quantities: Multiple pack sizes may be available to suit both small-scale discovery research and larger preparative needs. Contact Aladdin Scientific for bulk pricing and availability.

Returns and concerns: If you receive material that does not meet specification, please contact Aladdin Scientific customer service promptly with your order number and lot number. Our returns and refund policy is available on the Aladdin Scientific website.

Storage upon receipt: Store as directed on the CoA immediately upon receipt to maintain product integrity throughout its shelf life.

Frequently asked questions

What is the difference in reactivity between the C-2 chloro and C-5 bromo positions of 5-bromo-2-chloro-4-methoxypyrimidine?

The C-2 chloro group is flanked by both pyrimidine nitrogen atoms, making it highly activated toward nucleophilic aromatic substitution (SNAr) with heteroatom nucleophiles such as amines and alkoxides, often proceeding under mild conditions. The C-5 bromo group is the preferred handle for palladium-catalyzed cross-coupling reactions (e.g., Suzuki, Buchwald-Hartwig) due to the favorable oxidative addition kinetics of aryl bromides with Pd(0) catalysts. This orthogonal reactivity allows sequential, chemoselective functionalization of each position independently.

How should 5-bromo-2-chloro-4-methoxypyrimidine be stored to maintain stability?

The compound should be stored in a tightly sealed container under a dry, inert atmosphere (nitrogen or argon) in a cool, dry location, away from moisture, light, and incompatible reagents such as strong bases and oxidizers. Refrigerated storage (2–8 °C) is commonly recommended for halogenated pyrimidine derivatives; confirm the exact recommended conditions on the Aladdin Scientific Certificate of Analysis for lot B176822. Always reseal the container promptly after use to minimize exposure to atmospheric moisture.

Can the methoxy group at C-4 be removed or converted to other functional groups?

Yes, the C-4 methoxy group can be cleaved under acidic conditions — for example, using hydrobromic acid or boron tribromide (BBr3) — to afford the corresponding 4-hydroxypyrimidine (pyrimidinone tautomer), which may itself serve as a versatile intermediate. The methoxy group can also be displaced by strong nucleophiles under forcing SNAr conditions, or subjected to transetherification. The specific conditions required are more forcing than those needed for C-2 chloro displacement, so selectivity is achievable in sequential functionalization strategies. Researchers should consult primary literature for optimized protocols for each transformation.

Is 5-bromo-2-chloro-4-methoxypyrimidine suitable for Suzuki-Miyaura coupling, and what catalyst systems are recommended?

Yes, the C-5 aryl bromide of 5-bromo-2-chloro-4-methoxypyrimidine is well-suited for Suzuki-Miyaura coupling with aryl and heteroaryl boronic acids or boronate esters. Commonly used catalyst systems include Pd(PPh3)4, Pd(dppf)Cl2, and bulky phosphine-based precatalysts such as XPhos Pd G2, with K2CO3 or Cs2CO3 as base in aqueous dioxane, DME, or THF. The C-2 chloro group typically remains unreacted under standard Suzuki conditions, enabling chemoselective functionalization at C-5. Specific conditions should be optimized based on the boronic acid coupling partner and reaction scale.

How do I confirm the identity and purity of the received batch of 5-bromo-2-chloro-4-methoxypyrimidine?

Identity can be confirmed by 1H NMR (look for a singlet for the C-5 ring proton and a singlet for the OCH3 group at approximately δ 4.0 ppm), 13C NMR, and/or mass spectrometry (MS). Purity is best assessed by GC or reverse-phase HPLC with UV detection; the CoA provided by Aladdin Scientific for SKU B176822 will report the lot-specific purity value and analytical method. If the CoA is not included in the shipment, contact Aladdin Scientific customer service with your lot number to obtain a copy.

References

1. March, J.; Smith, M. B. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed.; Wiley: Hoboken, NJ, 2013. (General reference for SNAr reactions and cross-coupling chemistry.)
2. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chemical Reviews 1995, 95 (7), 2457–2483. doi:10.1021/cr00039a007
3. Hartwig, J. F. Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification of Aryl Halides. Accounts of Chemical Research 2008, 41 (11), 1534–1544. doi:10.1021/ar800098p
4. Aladdin Scientific. Certificate of Analysis, SKU B176822, 5-Bromo-2-chloro-4-methoxypyrimidine. (Lot-specific document; request from Aladdin Scientific customer service.)

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