3-Fluoro-4-morpholinophenylboronic Acid | CAS 279262-09-8 | ≥95%

3-Fluoro-4-morpholinophenylboronic acid (3-fluoro-4-morpholin-4-ylphenylboronic acid) combines three medicinal-chemistry-relevant features in one building block: a boronic acid handle for Suzuki–Miyaura cross-coupling, a morpholine ring that can contribute hydrogen-bond-acceptor character and aqueous-solubility tuning, and a meta-fluorine that adds a metabolically stable C–F bond, a 19F NMR handle, and a positional element for blocking or redirecting oxidative aromatic metabolism in suitably designed analogues. The para-morpholino substituent is an electron-donating arylamino group, while the meta-fluorine is inductively electron-withdrawing relative to the boronic acid (Hammett σ_m(F) ≈ +0.34); together these substituents give a functionalised, electron-rich arylboronic-acid scaffold whose handling may require supplier-recommended inert and refrigerated storage. The 3-fluoro-4-morpholinophenyl fragment is a privileged structural motif in medicinal-chemistry scaffold design, including morpholine-containing kinase-inhibitor series in the PI3K/AKT/mTOR pathway, but its specific binding role depends on the coupled heteroaryl core, substitution pattern, and full molecular context.

The product may contain small amounts of the cyclic anhydride 3-fluoro-4-morpholinophenylboroxine; under aqueous or basic coupling conditions the two forms re-equilibrate and the impact on yield is minor.

Applications and Reactions

• Suzuki–Miyaura coupling: couples with aryl, heteroaryl, and alkenyl halides or pseudohalides under Pd catalysis to install the 3-fluoro-4-morpholinophenyl fragment onto biaryl, heterobiaryl, and styrenyl scaffolds. The compound is particularly useful for coupling with chloro-, bromo-, and iodo-substituted nitrogen heterocycles such as pyrimidines, pyridines, pyrazines, triazines, and pyridopyrimidines, giving morpholino-fluoroaryl-substituted heteroaromatic products in a convergent step.
• Medicinal-chemistry scaffold synthesis: the 3-fluoro-4-morpholinophenyl fragment is useful for constructing heteroaryl-linked arylmorpholine libraries by Suzuki–Miyaura coupling, including morpholine-containing kinase-inhibitor scaffold research in the PI3K, AKT, and mTOR family. In such kinase-oriented contexts, the morpholine oxygen frequently serves as the hydrogen-bond acceptor toward the conserved hinge-region backbone amide of the ATP-binding pocket, with the morpholine nitrogen tethering the ring to the aryl scaffold; in products derived from this boronic acid, the precise binding role depends on the coupled heteroaryl core, substitution pattern, and full molecular context.
• Substituent positioning and electronic profile: the 4-morpholino substituent is an electron-donating arylamino group (strong π-donation via the nitrogen lone pair), while the 3-fluoro substituent is inductively electron-withdrawing relative to the boronic acid (σ_m ≈ +0.34). This combination delivers a morpholine-containing aryl fragment that can contribute hydrogen-bond-acceptor character, solubility-tuning potential through the morpholine oxygen, an aryl-F 19F NMR reporter for tracking the fragment in reaction monitoring or biological assay work, and a fluorinated ring position that can be used to block or redirect oxidative aromatic metabolism in suitably designed analogues.
• Protodeboronation and condition sensitivity: class-level arylboronic-acid chemistry. Arylboronic-acid stability under aqueous-basic coupling conditions is substituent-, pH-, base-, concentration-, and temperature-dependent, and electron-rich aminated arylboronic acids should not be assumed to tolerate prolonged warm aqueous-basic exposure without condition optimisation. For 3-fluoro-4-morpholinophenylboronic acid, mild base systems, controlled aqueous content, moderate temperatures, and limited reaction times are sensible starting points for Suzuki optimisation; slow-release formats such as MIDA boronates or trifluoroborates can be considered when extended coupling conditions are required.
• Chan–Lam coupling: class-level arylboronic-acid chemistry. The boronic acid can serve as the aryl donor in copper-mediated C–N, C–O, and C–S bond formation under aerobic conditions, transferring the 3-fluoro-4-morpholinophenyl group to suitable amines, anilines, amides, phenols, alcohols, or thiols. Reaction rates and selectivity depend on the copper source, ligand, base, solvent, and nucleophile class.
• Petasis borono-Mannich reaction: class-level arylboronic-acid chemistry. Arylboronic acids can act as aryl donors in three-component reactions with an amine and an aldehyde, glyoxylic acid, or α-hydroxy aldehyde partner to give arylated amines, α-aryl glycine derivatives, or β-amino alcohol scaffolds. For 3-fluoro-4-morpholinophenyl transfer, conditions should be checked against the selected carbonyl and amine partners unless a substrate-specific example is cited.
• Protected boronate ester forms: the corresponding pinacol ester ((3-fluoro-4-morpholinophenyl)boronic acid pinacol ester, CAS 873431-46-0) is commercially documented and provides a protected boronate form for handling and Suzuki–Miyaura coupling workflows. Other slow-release boron formats, including MIDA boronates and potassium organotrifluoroborates, are class-level protection strategies that can improve shelf stability and enable controlled-release coupling behaviour; preparation of 3-fluoro-4-morpholinophenyl variants of these formats should be confirmed against substrate-specific procedures when required.

Further Reading

For comprehensive protocols on boronic acids, esters, protodeboronation, boroxine content, and reagent selection, refer to NorrChemica's Lab Journal guide: Choosing Your Boron Source for Suzuki–Miyaura Coupling.