2-Bromo-4-methylquinoline: Properties, Synthesis & Applications

2-Bromo-4-methylquinoline is a halogenated quinoline derivative widely valued in synthetic and medicinal chemistry as a reactive building block for constructing pharmacologically relevant heterocyclic frameworks.

Molecular Formula

C₁₀H₈BrN

Molecular Weight

222.08 g/mol

CAS Number

4876-10-2

Appearance

Off-white to pale yellow crystalline solid

Key Functional Groups

Aryl bromide, quinoline nitrogen, 4-methyl substituent

Primary Use

Synthetic intermediate in medicinal and heterocyclic chemistry

Chemical Identity and Physical Properties

2-Bromo-4-methylquinoline (CAS 4876-10-2) is a brominated derivative of quinoline bearing a methyl group at the 4-position and a bromine atom at the 2-position of the bicyclic aromatic ring system. Its molecular formula is C₁₀H₈BrN, with a molecular weight of approximately 222.08 g/mol. The compound typically appears as an off-white to pale yellow crystalline solid at room temperature.

The quinoline core consists of a benzene ring fused to a pyridine ring, conferring aromatic stability and electron-deficient character at specific ring positions. The presence of bromine at the 2-position makes this carbon highly susceptible to nucleophilic substitution and transition-metal-catalyzed cross-coupling reactions, while the 4-methyl group can be further functionalized through oxidation, halogenation, or other transformations. These combined structural features make 2-Bromo-4-methylquinoline a multifunctional synthetic handle.

Synthesis and Key Reactions

2-Bromo-4-methylquinoline can be prepared from 4-methylquinoline (lepidine) through electrophilic or directed halogenation strategies, or alternatively via cyclization routes from appropriately substituted aniline and carbonyl precursors using methods such as the Doebner–Miller or Combes quinoline syntheses, followed by selective bromination at the 2-position.

As a synthetic intermediate, it participates in several important reaction classes:

• Palladium-catalyzed cross-coupling: Suzuki–Miyaura, Negishi, Stille, and Buchwald–Hartwig amination reactions exploit the C–Br bond to introduce aryl, alkenyl, alkyl, or amino groups at the 2-position, rapidly expanding molecular complexity.
• Nucleophilic aromatic substitution (SNAr): The electron-deficient ring nitrogen activates the 2-position toward displacement by nitrogen, oxygen, and sulfur nucleophiles under appropriate conditions.
• Functionalization of the 4-methyl group: Benzylic bromination, oxidation to aldehyde or carboxylic acid, or Knoevenagel-type condensations extend the utility of this substituent for library synthesis.

These reaction pathways collectively make 2-Bromo-4-methylquinoline a highly versatile node in synthetic planning for heterocyclic compound libraries.

Applications in Medicinal and Materials Chemistry

The quinoline scaffold is a privileged structure in medicinal chemistry, found in numerous bioactive natural products and approved drugs including antimalarials, antibacterials, and kinase inhibitors. 2-Bromo-4-methylquinoline serves as a key entry point to this chemical space, enabling rapid diversification through combinatorial and parallel synthesis approaches.

Researchers employ this compound as a starting material or intermediate in the synthesis of:

• Potential antimalarial agents, leveraging the well-established bioactivity of 4-substituted quinolines against Plasmodium species.
• Kinase inhibitor candidates, where the 2-amino or 2-aryl quinoline motif is frequently observed in ATP-binding site pharmacophores.
• Antimicrobial and antifungal compounds incorporating the quinoline nucleus.
• Fluorescent probes and organic electronic materials, where the rigid aromatic quinoline core contributes to favorable photophysical properties.

The 4-methyl group additionally provides a synthetic handle that is absent in simpler 2-bromoquinoline, enabling elaboration toward more complex target structures and improving physicochemical properties such as lipophilicity.

Handling, Storage, and Safety Considerations

As with all organobromine compounds and nitrogen heterocycles, appropriate laboratory safety precautions should be observed when working with 2-Bromo-4-methylquinoline. Users should consult the current Safety Data Sheet (SDS) provided by Aladdin Scientific prior to use.

General handling guidelines:

• Use in a well-ventilated fume hood to avoid inhalation of dust or vapors.
• Wear appropriate personal protective equipment (PPE) including nitrile gloves, laboratory coat, and safety glasses.
• Avoid contact with skin, eyes, and mucous membranes.

Storage: Store in a tightly sealed container in a cool, dry place away from light, heat, and incompatible materials such as strong oxidizers and bases. Recommended storage temperature is typically 2–8 °C or room temperature as specified on the product label; refer to the Aladdin Scientific product page for lot-specific storage conditions.

Disposal: Dispose of in accordance with local, regional, and national regulations governing halogenated organic waste.

Frequently asked questions

What makes 2-Bromo-4-methylquinoline useful in cross-coupling reactions?

The C–Br bond at the 2-position of the quinoline ring is reactive toward palladium-catalyzed cross-coupling protocols such as Suzuki–Miyaura, Negishi, and Buchwald–Hartwig amination. The electron-deficient nature of the quinoline nitrogen further facilitates oxidative addition of palladium into the C–Br bond, making this compound an efficient partner for generating 2-substituted quinoline libraries.

How does the 4-methyl group on this quinoline differ from a 4-unsubstituted analog?

The 4-methyl group provides an additional site for synthetic elaboration—including benzylic bromination, oxidation to an aldehyde or carboxylic acid, or condensation reactions—that is simply unavailable in 2-bromoquinoline itself. This extra handle enables access to more structurally complex targets and can also modulate the compound's physicochemical properties, such as increasing lipophilicity, which is relevant when optimizing drug candidates.

Can 2-Bromo-4-methylquinoline undergo nucleophilic aromatic substitution?

Yes. The quinoline ring is electron-deficient due to the ring nitrogen, which activates the 2-position toward nucleophilic aromatic substitution (SNAr). Nitrogen nucleophiles such as amines, as well as oxygen and sulfur nucleophiles, can displace the bromide under appropriate thermal or base-mediated conditions, providing an alternative to transition-metal catalysis for introducing heteroatom substituents.

What storage conditions are recommended for 2-Bromo-4-methylquinoline?

The compound should be stored in a tightly sealed container in a cool, dry location away from direct light and heat sources. Refer to the Aladdin Scientific product label and SDS for lot-specific recommendations, as storage conditions may range from room temperature to 2–8 °C depending on formulation.

References

1. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (Quinoline chemistry and cross-coupling reactions, textbook reference)
2. Manske, R. H. F.; Kulka, M. The Skraup Synthesis of Quinolines. Org. React. 1953, 7, 59–98. (General quinoline synthesis methods)
3. Kaur, R. et al. Quinoline: A Privileged Scaffold for the Design of Anti-infective Agents. Eur. J. Med. Chem. 2016, 123, 80–102. (Medicinal chemistry of quinoline derivatives)

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