4-Bromo-5-methoxy-1H-indazole: Handling & Synthesis Protocol

4‐bromo‐5‐methoxy‐1H‐indazole is a halogenated, methoxy-substituted indazole heterocycle widely employed as a versatile building block in medicinal chemistry and cross-coupling reactions.

Chemical Name

4-Bromo-5-methoxy-1H-indazole

Molecular Formula

C₈H₇BrN₂O

Molecular Weight

227.06 g/mol

Key Functional Groups

Aryl bromide, methoxy group, NH-indazole

Primary Application

Medicinal chemistry intermediate; Pd-catalyzed cross-coupling substrate

Recommended Storage

Cool, dry place; protect from light and moisture; sealed container

Materials and Safety Precautions

Before handling 4-bromo-5-methoxy-1H-indazole (Aladdin SKU: B172450), ensure the following personal protective equipment (PPE) is in place: nitrile gloves, laboratory coat, and safety goggles. Work in a well-ventilated fume hood at all times.

Materials required:

• 4-Bromo-5-methoxy-1H-indazole (B172450)
• Appropriate anhydrous solvents (e.g., DMF, DMSO, THF, or MeOH depending on downstream application)
• Analytical balance (0.1 mg readability)
• Amber glass vials or sealable glass containers
• Inert gas line (nitrogen or argon) for moisture-sensitive operations
• Standard organic chemistry glassware

Safety notes: As with all organobromine compounds, treat this reagent as potentially irritating to skin, eyes, and respiratory tract. Consult the Safety Data Sheet (SDS) before use. Dispose of waste in accordance with local regulations for halogenated organic compounds.

Storage and Handling Protocol

Proper storage of 4-bromo-5-methoxy-1H-indazole is essential to maintain reagent integrity over time.

1. Storage temperature: Store at room temperature (15–25 °C) in a cool, dry location away from direct light. Long-term storage at 2–8 °C in a desiccated environment is recommended to maximize shelf life.
2. Container integrity: Keep the container tightly sealed under an inert atmosphere (N₂ or Ar) when not in use, especially after the first opening, to prevent moisture absorption and potential oxidation of the indazole NH.
3. Weighing procedure: Tare an appropriate amber glass vial on an analytical balance. Transfer the desired quantity of compound using a clean, dry spatula. Re-seal the stock container immediately under inert gas.
4. Dissolution: For most synthetic applications, dissolve 4-bromo-5-methoxy-1H-indazole in anhydrous DMF or DMSO (typical solubility: readily soluble). For protic conditions, methanol or ethanol may be used. Always prepare fresh stock solutions where possible.
5. Avoid: Prolonged exposure to air, moisture, and strong light. Do not store near strong oxidizers or bases.

Protocol: Use in Palladium-Catalyzed Cross-Coupling Reactions

The aryl bromide functionality of 4-bromo-5-methoxy-1H-indazole makes it an excellent electrophilic partner in transition-metal-catalyzed cross-coupling reactions, including Suzuki–Miyaura, Buchwald–Hartwig, and Sonogashira couplings.

General Suzuki–Miyaura Coupling Procedure (representative):

1. In a flame-dried Schlenk flask under argon, combine 4-bromo-5-methoxy-1H-indazole (1.0 equiv), arylboronic acid (1.2–1.5 equiv), and Pd(PPh₃)₄ or Pd(dppf)Cl₂ (2–5 mol%).
2. Add anhydrous base (e.g., K₂CO₃ or Cs₂CO₃, 2–3 equiv) and a degassed solvent mixture (e.g., DMF/H₂O, 4:1, or dioxane/H₂O, 4:1).
3. Stir at 80–100 °C for 12–16 hours under inert atmosphere. Monitor reaction progress by TLC or HPLC.
4. Upon completion, cool to room temperature, dilute with ethyl acetate, wash with brine, dry over Na₂SO₄, filter, and concentrate in vacuo.
5. Purify the product by silica gel column chromatography using an appropriate gradient (e.g., hexanes/EtOAc).

Note: Reaction conditions should be optimized for each specific coupling partner. The NH of the indazole may require N-protection (e.g., SEM or Boc) in certain reaction conditions to avoid side reactions.

Quality Control and Characterization

To confirm the identity and purity of 4-bromo-5-methoxy-1H-indazole (B172450) upon receipt and before use, the following analytical techniques are recommended:

• TLC: Run on silica gel plates with an appropriate solvent system (e.g., 3:1 hexanes/EtOAc). Visualize under UV light (254 nm).
• HPLC: Assess purity by reverse-phase HPLC (C18 column, acetonitrile/water gradient with 0.1% TFA). Target purity ≥95% for synthetic applications.
• ¹H NMR (400 MHz, DMSO-d₆ or CDCl₃): Expect signals consistent with an NH indazole proton (broad, δ ~13 ppm), aromatic protons, and a methoxy singlet (δ ~3.9 ppm). Confirm absence of extraneous peaks.
• ¹³C NMR: Cross-reference with calculated or literature values for the indazole core carbons, the C-Br carbon, and the OCH₃ carbon.
• Mass Spectrometry (ESI or APCI): Confirm molecular ion [M+H]⁺ consistent with MW 227.06; note the characteristic isotope pattern of one bromine atom (M:M+2 ≈ 1:1).

Record all characterization data in a laboratory notebook and retain batch-specific CoA data provided by Aladdin Scientific for audit and reproducibility purposes.

Frequently asked questions

What solvents are recommended for dissolving 4-bromo-5-methoxy-1H-indazole?

4-Bromo-5-methoxy-1H-indazole is readily soluble in polar aprotic solvents such as DMF and DMSO, and also dissolves well in common organic solvents including THF, dichloromethane, and methanol. For cross-coupling reactions, degassed DMF or dioxane are typically preferred.

Does the NH group of the indazole interfere with cross-coupling reactions?

The free NH of 4-bromo-5-methoxy-1H-indazole can potentially coordinate to palladium catalysts or act as a proton source, which may reduce yields in some coupling reactions. N-protection using groups such as SEM-Cl or Boc anhydride prior to cross-coupling is advisable when side reactions are observed. Alternatively, N-alkylation conditions can be explored depending on the synthetic target.

How should 4-bromo-5-methoxy-1H-indazole be stored to maximize shelf life?

Store 4-bromo-5-methoxy-1H-indazole in a tightly sealed container under an inert atmosphere (nitrogen or argon) in a cool, dry, and dark location. For long-term storage, keeping the compound at 2–8 °C in a desiccator is recommended. Avoid repeated freeze-thaw cycles and exposure to moisture or strong light.

What is the typical purity of Aladdin's 4-bromo-5-methoxy-1H-indazole (B172450)?

Aladdin Scientific's 4-bromo-5-methoxy-1H-indazole (B172450) is supplied at research-grade purity. Please refer to the batch-specific Certificate of Analysis (CoA) available on the product page for the exact purity value. For critical synthetic applications, independent HPLC purity verification is recommended.

References

1. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. (General reference for indazole chemistry)
2. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. doi:10.1021/cr00039a007
3. Aladdin Scientific. Product Page: 4-Bromo-5-methoxy-1H-indazole, SKU B172450. Accessed 2024.

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