4-(6-Bromopyridin-3-yl)morpholine: Properties & Applications

4-(6-Bromopyridin-3-yl)morpholine is a halogenated pyridine–morpholine hybrid building block widely employed in medicinal chemistry and drug discovery as a versatile intermediate for palladium-catalyzed cross-coupling reactions and the construction of biologically active heterocyclic scaffolds.

CAS Number

Not confirmed in source material

Molecular Formula

C9H11BrN2O

Molecular Weight

Approximately 243.10 g/mol

Key Functional Groups

Aryl bromide, morpholine nitrogen, pyridine ring

Primary Use

Synthetic building block for cross-coupling and heterocycle synthesis

Storage Condition

Store in a cool, dry place away from light (verify with SDS)

Chemical Structure and Key Properties

4-(6-Bromopyridin-3-yl)morpholine consists of a pyridine ring bearing a bromine substituent at the 6-position and a morpholine ring connected through the nitrogen atom at the 3-position. This arrangement creates a bifunctional molecule: the electrophilic aryl bromide site is available for metal-mediated coupling reactions, while the electron-donating morpholine moiety modulates the electronic character of the pyridine ring.

The morpholine ring contributes favorable physicochemical properties often sought in drug-like molecules, including moderate aqueous solubility, a basic nitrogen center, and conformational rigidity. The pyridine nitrogen further provides a hydrogen-bond acceptor, making the overall scaffold compliant with key parameters in medicinal chemistry design.

Note: Exact physical constants such as melting point, boiling point, and specific CAS number should be confirmed against the product specification sheet and certificate of analysis provided by Aladdin Scientific.

Synthesis and Cross-Coupling Reactions

The aryl bromide functionality in 4-(6-Bromopyridin-3-yl)morpholine makes it an ideal electrophilic partner in a range of transition-metal-catalyzed cross-coupling reactions. These include Suzuki–Miyaura coupling with aryl- or heteroarylboronic acids, Buchwald–Hartwig amination with primary or secondary amines, and Negishi or Kumada couplings with organozinc or organomagnesium reagents.

In Suzuki–Miyaura reactions, the compound typically reacts under standard palladium catalysis conditions (e.g., Pd(PPh₃)₄ or Pd(dppf)Cl₂) with aqueous base at elevated temperatures, enabling the rapid construction of biaryl or heteroaryl systems that are prevalent in pharmaceutical candidates. Buchwald–Hartwig amination further extends utility by allowing C–N bond formation directly at the brominated position.

The morpholine nitrogen is generally inert under these conditions, acting as a spectator group that simultaneously imparts drug-like character to coupling products. Researchers should optimize catalyst loading, base, and solvent system empirically, as substrate-specific conditions may vary.

Applications in Medicinal Chemistry and Drug Discovery

Pyridine–morpholine hybrids represent a privileged structural motif in medicinal chemistry. The combination of the electron-deficient pyridine ring and the electron-rich, conformationally defined morpholine ring is frequently encountered in kinase inhibitors, GPCR modulators, and other therapeutic targets. 4-(6-Bromopyridin-3-yl)morpholine serves as a ready-made fragment of this motif, enabling rapid analog synthesis through diversification at the bromide position.

The morpholine group confers several advantages in drug candidates: it can enhance aqueous solubility, reduce lipophilicity relative to purely carbocyclic analogs, and contribute to metabolic stability through conformational restriction. These attributes align with modern lead optimization strategies aimed at improving absorption, distribution, metabolism, and excretion (ADME) profiles.

Researchers engaged in fragment-based drug discovery (FBDD) or scaffold-hopping strategies may use this compound to introduce a defined pharmacophoric unit while retaining a synthetic handle for further elaboration. Its commercial availability from Aladdin Scientific (SKU: B196045) facilitates rapid library construction without the need for multi-step de novo synthesis.

Handling, Storage, and Safety Considerations

As with all brominated aromatic intermediates, 4-(6-Bromopyridin-3-yl)morpholine should be handled with appropriate personal protective equipment, including nitrile gloves, safety glasses, and a laboratory coat. Operations that generate dust or aerosols should be conducted in a fume hood.

The compound should be stored in a tightly sealed container in a cool, dry, and well-ventilated location, away from direct light and incompatible materials such as strong oxidizers and strong bases. Specific storage temperature recommendations and hazard classifications should be confirmed by consulting the product's Safety Data Sheet (SDS) available from Aladdin Scientific.

In the event of skin or eye contact, the affected area should be rinsed thoroughly with water and medical attention sought if irritation persists. Disposal must comply with local regulations governing halogenated organic waste.

Frequently asked questions

What cross-coupling reactions are compatible with 4-(6-Bromopyridin-3-yl)morpholine?

The compound is compatible with a broad range of palladium-catalyzed cross-coupling reactions, including Suzuki–Miyaura (with boronic acids), Buchwald–Hartwig (C–N bond formation), and Negishi couplings. The aryl bromide serves as the electrophilic coupling partner, while the morpholine group typically remains unreactive under standard catalytic conditions.

Why is the morpholine group valuable in drug discovery applications?

The morpholine ring is a widely used pharmacophoric element that improves aqueous solubility, provides a basic nitrogen center for salt formation and ADME optimization, and constrains molecular conformation. These properties collectively contribute to improved drug-likeness and bioavailability compared with purely lipophilic analogs.

How should 4-(6-Bromopyridin-3-yl)morpholine be stored to maintain stability?

The compound should be stored in a tightly sealed container under cool, dry, and dark conditions. Detailed storage temperature and stability data should be verified against the Aladdin Scientific product specification sheet and Safety Data Sheet (SDS), as conditions can vary by lot and formulation.

Is 4-(6-Bromopyridin-3-yl)morpholine suitable for fragment-based drug discovery?

Yes. Its relatively low molecular weight, well-defined pharmacophoric elements (aryl bromide handle, morpholine, pyridine), and commercial availability make it a practical starting fragment for FBDD or scaffold-hopping programs. The bromide serves as a synthetic vector for rapid diversification during hit-to-lead optimization.

References

1. General reference: Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions and Synthesis. Springer. (For cross-coupling reaction background.)
2. Roughley, S. D.; Jordan, A. M. The medicinal chemist's toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 2011, 54, 3451–3479. doi:10.1021/jm200187y
3. Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 6752–6756. (Context for morpholine ring saturation benefits.) doi:10.1021/jm901241e
4. Aladdin Scientific product page: 4-(6-Bromopyridin-3-yl)morpholine, SKU B196045. (Primary source for product specifications.)

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