4-Bromo-2-fluoro-N-methylbenzamide
[CAS# 749927-69-3]

Identification

• Classification: Organic raw materials >> Amino compound >> Amide compound
• Name: 4-Bromo-2-fluoro-N-methylbenzamide
• Molecular Formula: C₈H₇BrFNO
• Molecular Weight: 232.05
• CAS Registry Number: 749927-69-3
• EC Number: 808-257-8
• SMILES: CNC(=O)C1=C(C=C(C=C1)Br)F

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Boiling point: 284.8±30.0 °C 760 mmHg (Calc.)^*
• Flash point: 126.1±24.6 °C (Calc.)^*
• Solubility: water: Slightly soluble (2.1 g/L) (25 °C), Calc.
• Index of refraction: 1.546 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H317-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P272-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P333+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Skin sensitization	Skin Sens.	1	H317

Discovery and Applications

4-Bromo-2-fluoro-N-methylbenzamide is a halogenated aromatic amide in which a benzene ring is substituted with a bromine atom at the fourth position, a fluorine atom at the second position, and an N-methylamide group. The combination of electron-withdrawing halogens and the amide functionality gives the molecule distinct chemical reactivity and makes it a versatile intermediate in organic synthesis. The presence of bromine and fluorine on the aromatic ring allows selective functionalization through nucleophilic substitution or cross-coupling reactions, while the N-methylamide group provides stability and additional synthetic handles for derivatization.

The compound is typically prepared via acylation of the corresponding 4-bromo-2-fluoroaniline with methyl chloroformate or by direct coupling of the amine with activated carboxylic acid derivatives under controlled conditions. Halogenated aniline precursors are obtained through regioselective halogenation of substituted benzene derivatives, which ensures that the desired substitution pattern is preserved during subsequent acylation steps. Reaction conditions are carefully optimized to minimize side reactions, including over-halogenation or hydrolysis of the amide. The final product is usually isolated as a crystalline solid or an oil, depending on the purification and solvent used.

In organic synthesis, 4-bromo-2-fluoro-N-methylbenzamide is mainly used as a building block for the preparation of more complex aromatic and heteroaromatic compounds. The bromine atom allows palladium-catalyzed cross-coupling reactions, such as Suzuki or Buchwald–Hartwig couplings, enabling the introduction of aryl, alkyl, or heteroaryl groups at a defined position. The fluorine atom remains largely inert under many reaction conditions but can modulate the electronic properties of the aromatic system, influencing the reactivity of neighboring functional groups and the physicochemical properties of the resulting molecules. These characteristics make the compound particularly useful in designing drug-like molecules where halogenation and amide functionalities are strategically employed.

In medicinal chemistry, derivatives of 4-bromo-2-fluoro-N-methylbenzamide have been investigated as intermediates in the synthesis of potential bioactive molecules, including kinase inhibitors, enzyme modulators, and receptor ligands. The specific substitution pattern on the benzene ring allows precise placement of functional groups that can interact with biological targets, while the amide functionality contributes to hydrogen bonding and conformational stability. Fluorination at the ortho position can influence lipophilicity, metabolic stability, and binding affinity, which are critical parameters in lead optimization processes.

The compound is also used in materials chemistry and chemical methodology research. Its halogenated aromatic core can participate in the preparation of polymers, dyes, or functionalized surfaces where controlled substitution and electron-withdrawing groups are desirable. Additionally, it serves as a model substrate for studying halogen-specific effects in cross-coupling chemistry, including reactivity trends, selectivity, and catalyst efficiency. The N-methylamide group provides a convenient site for derivatization without disrupting the halogenation pattern, enabling systematic investigations of structural modifications.

Physically, 4-bromo-2-fluoro-N-methylbenzamide is a solid with moderate solubility in polar organic solvents such as dichloromethane, ethyl acetate, and dimethylformamide. It is generally stable under ambient laboratory conditions but should be protected from strong nucleophiles and high temperatures to prevent hydrolysis or decomposition. Proper storage ensures that the compound retains its chemical integrity for use in multistep synthetic sequences.

Overall, 4-bromo-2-fluoro-N-methylbenzamide is a strategically functionalized aromatic amide that serves as a versatile intermediate in both synthetic and medicinal chemistry. Its combination of halogen substituents and the N-methylamide functionality allows selective transformations and derivatizations, making it a valuable building block for the preparation of diverse functional molecules and bioactive compounds.

References

2022. Recent Advances in the Synthesis and Medicinal Chemistry of SF5 and SF4Cl Compounds. Synthesis, 54(19).
DOI: 10.1055/a-1845-9291