4-Bromo-2-chloropyrimidine
[CAS# 885702-34-1]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Bromopyrimidine
• Name: 4-Bromo-2-chloropyrimidine
• Molecular Formula: C₄H₂BrClN₂
• Molecular Weight: 193.43
• CAS Registry Number: 885702-34-1
• EC Number: 807-846-7
• SMILES: C1=CN=C(N=C1Br)Cl

Properties

• Density: 1.9±0.1 g/cm³ Calc.^*
• Boiling point: 291.6±13.0 °C 760 mmHg (Calc.)^*
• Flash point: 130.1±19.8 °C (Calc.)^*
• Solubility: Slightly soluble (9.7 g/L) (25 °C), Calc. (Expl.), Slightly soluble (9.7 g/L) (25 °C), Calc.
• Index of refraction: 1.588 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06;GHS07 Danger
• Risk Statements: H301+H311+H331-H315-H319-H335
• Safety Statements: P261-P262-P264-P264+P265-P270-P271-P280-P301+P316-P302+P352-P304+P340-P305+P351+P338-P316-P319-P321-P330-P332+P317-P337+P317-P361+P364-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

4‑Bromo‑2‑chloropyrimidine is a halogenated heterocyclic compound with molecular formula C₄H₂BrClN₂ and a molecular weight of about 193.43 g/mol. It features a pyrimidine ring substituted with a bromine atom at the 4-position and a chlorine atom at the 2-position.

This compound is primarily used as a building block or intermediate in organic synthesis, particularly in pharmaceutical chemistry. Its dual halogenation offers sites for regioselective functionalization. The C–Br bond (at the 4-position) and the C–Cl bond (at the 2-position) can be selectively engaged in cross‑coupling and nucleophilic substitution chemistry. Under Suzuki–Miyaura coupling conditions, for example, the more reactive bromine can be replaced with aryl or heteroaryl boronic acids to introduce carbon substituents. Transition‑metal catalysis further enables this type of transformation.

In addition, the chlorine at the 2-position is well-suited for nucleophilic aromatic substitution (SNAr), particularly because the pyrimidine ring is electron-deficient. This allows for the replacement of the chlorine with amines, oxygen nucleophiles, or other nucleophilic species. Such functionalizations make 4‑bromo‑2‑chloropyrimidine versatile for accessing a wide variety of substituted pyrimidine derivatives, which are common scaffolds in medicinal chemistry.

Synthesis of 4‑bromo‑2‑chloropyrimidine typically proceeds via halogenation of a 2‑hydroxypyrimidine precursor. The hydroxyl group is first brominated (e.g., by hydrobromic acid and an oxidant) to introduce the bromine at C‑4, and then converted to a chloro group using a chlorinating reagent such as phosphorus oxychloride (POCl₃) in the presence of a tertiary amine base. This two-step route is efficient and scalable.

Beyond its use in small-molecule drug discovery, the compound is also valuable for creating complex heterocyclic systems by leveraging its orthogonal reactivity: one can first substitute the bromine by cross-coupling, then later functionalize the chlorine. This sequential strategy is especially powerful in constructing libraries of molecules for medicinal chemistry screening.

From a physical standpoint, 4‑bromo‑2‑chloropyrimidine is reported to be slightly soluble in water and is commercially available at high purity (e.g., 98%). Appropriate safety measures are required, as the compound may cause skin and eye irritation and should be stored under inert atmosphere or at low temperature to preserve its integrity.

References

Schomaker JM, Buckwald PG, McDonald FR (2001) Arylation of halogenated pyrimidines via a Suzuki coupling. Journal of Organic Chemistry 66: 3920–3928. DOI: 10.1021/jo010573+

Cherng YJ, Chen CC, Chen CH, et al. (2002) Efficient nucleophilic substitution of halogenated pyrimidines under microwave irradiation. Tetrahedron 58: 123–132. DOI: 10.1016/S0040-4020(01)01182-6