(R)-4,4,4-Trifluoro-3-hydroxy-3-methylbutan-2-one
[CAS# 2875067-31-3]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Ketones
• Name: (R)-4,4,4-Trifluoro-3-hydroxy-3-methylbutan-2-one
• Synonyms: (3R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one
• Molecular Formula: C₅H₇F₃O₂
• Molecular Weight: 156.10
• CAS Registry Number: 2875067-31-3
• SMILES: CC(=O)[C@](C)(C(F)(F)F)O

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Boiling point: 152.6±35.0 °C 760 mmHg (Calc.)^*
• Flash point: 46.1±25.9 °C (Calc.)^*
• Index of refraction: 1.364 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Danger
• Risk Statements: H225-H315-H319
• Safety Statements: P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235
• Transport Information: UN 1993

Discovery and Applications

(R)-4,4,4-Trifluoro-3-hydroxy-3-methylbutan-2-one is a chiral, fluorinated α-hydroxy ketone compound with the molecular formula C₅H₇F₃O₂. It features a trifluoromethyl group (-CF₃) at the terminal carbon (C-4), a hydroxyl group and a methyl group both bonded to the same carbon (C-3), and a ketone function at the C-2 position. The compound possesses a stereocenter at the C-3 carbon, and the (R)-enantiomer refers to the absolute configuration according to the Cahn-Ingold-Prelog rules.

This compound belongs to the class of α-hydroxy ketones, which are useful synthetic intermediates in asymmetric synthesis and medicinal chemistry. The presence of a trifluoromethyl group imparts strong electron-withdrawing effects, altering both the physical properties and chemical reactivity of the molecule. The CF₃ group also enhances metabolic stability and influences the compound's lipophilicity, characteristics often sought in drug development.

(R)-4,4,4-Trifluoro-3-hydroxy-3-methylbutan-2-one is typically synthesized via asymmetric aldol reactions, where a fluorinated precursor undergoes enantioselective carbon-carbon bond formation catalyzed by chiral auxiliaries, metal complexes, or organocatalysts. Another synthetic route includes enantioselective reduction of corresponding keto-esters or oxo-compounds using chiral catalysts such as oxazaborolidines or enzymes, yielding high enantiomeric purity of the desired (R)-enantiomer.

The compound is primarily used as a chiral building block in the synthesis of fluorinated pharmaceuticals, agrochemicals, and fine chemicals. The hydroxy and ketone groups offer handles for further functionalization, including esterification, oxidation, reductive amination, and formation of cyclic derivatives such as oxazolines and lactones. Its fluorinated structure is particularly valuable in the design of fluorine-containing drug candidates where specific pharmacokinetic and binding properties are required.

In asymmetric synthesis, it may also serve as a precursor for the construction of more complex chiral molecules, including β-hydroxy acids, α-fluoro alcohols, and heterocycles. The ability to selectively incorporate fluorine atoms and chiral centers in one molecule makes it a strategically important intermediate in synthetic organic chemistry.

Physically, (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one is typically a colorless to pale yellow liquid or low-melting solid, depending on purity and storage conditions. It is soluble in common organic solvents such as dichloromethane, methanol, and ethyl acetate. The compound is sensitive to moisture and heat and should be stored under inert atmosphere at low temperatures to prevent racemization or decomposition.

Due to its ketone and hydroxyl functionalities, the compound may exhibit keto-enol tautomerism in solution, though the presence of the electron-withdrawing CF₃ group tends to stabilize the keto form. In NMR and IR spectroscopy, the compound shows characteristic shifts for the hydroxyl proton, carbonyl group, and CF₃ group, facilitating structural confirmation and purity assessment.

In summary, (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one is a valuable chiral fluorinated α-hydroxy ketone used as a building block in asymmetric synthesis and drug development. Its unique structure offers multiple reactive sites for chemical transformation and contributes to the design of fluorinated compounds with desirable biological and physicochemical properties.

References

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