3-bromo-4-methoxy-pyridine - Reagent grade

Cat. No.: B482412

GRADE & PURITY Reagent Grade

Storage

Room temperature

Specifications

Specifiche e purezza

Reagent grade

Condizioni di conservazione di stoccaggio

Room temperature

Grado

Reagent Grade

Application Protocols

Not applicable.

• No validated bioassay protocols (e.g., WB, IHC, IF, FC) or dilutions are associated with this small-molecule building block. For synthetic applications, refer to the Reaction Conditions and Synthetic Utility sections for representative procedures and optimization guidance.

Biological Roles

Applicability

• This compound is a synthetic heteroaryl building block. It is not a biomolecule and has no established endogenous biological role.

General context (literature/knowledge)

• Pyridine-containing motifs are widespread in bioactive small molecules due to their ability to modulate basicity, hydrogen-bonding, and metabolic stability. Substituted pyridines often serve as bioisosteres of phenyl groups in medicinal chemistry SAR.
• The methoxy substituent can influence lipophilicity and metabolic O-dealkylation pathways after incorporation into larger molecules, while the ring nitrogen can engage as a weak hydrogen-bond acceptor or coordinate to metalloenzymes in designed ligands.

Use in research workflows

• 3-Bromo-4-methoxypyridine serves primarily as a divergence point for preparing analog libraries. Installation of diverse substituents at C3 via coupling or metalation enables rapid exploration of binding and ADME properties in lead optimization.
• The scaffold may also be used to build ligands for coordination chemistry studies where a pyridyl donor is required.

Important note

• No medical, diagnostic, or therapeutic uses are implied or supported for this catalog item. It is provided strictly for research and laboratory use, as indicated in the Product Data. Any biological activity of derivatives must be established experimentally and independently.

Buffer Applications

Not typically applicable.

• 3-Bromo-4-methoxypyridine is a neutral organic building block and is not used as a buffering agent. It lacks an appropriate conjugate acid–base pair with a useful buffering window in aqueous media at practical concentrations.

Practical guidance

• If aqueous handling is required (e.g., for extractions or biphasic couplings), employ a suitable external buffer such as phosphate (pH 6–8) or carbonate (pH 9–11) systems compatible with your reaction/catalyst. Verify that the chosen buffer and pH do not sequester or poison catalysts (e.g., Pd/Ni) via coordination to the pyridine nitrogen.
• For silica chromatography, adding 0.1–1% triethylamine to the eluent can mitigate streaking due to interactions of the basic nitrogen with acidic silanols, but this is not buffering in the aqueous sense.

Green Alternatives

Context

• As a solid heteroaryl building block, inherent “green” considerations focus on the choice of solvent, base, and catalyst system rather than on replacing the substrate. Below are greener process options frequently compatible with heteroaryl bromide couplings.

Greener choices (literature/guidance)

• Solvents: Replace dioxane, DMF, and NMP where feasible.
  • 2-MeTHF or CPME: Comparable to THF/dioxane for Pd couplings; better EHS profile and easier separations due to lower water miscibility.
  • Toluene or anisole: Acceptable for many Buchwald–Hartwig systems with biaryl phosphines; lower toxicity compared with chlorinated solvents.
  • Water/ethanol mixtures: Effective for some Suzuki reactions using water-tolerant catalysts and bases.
• Catalysts and loading:
  • Use highly active Pd precatalysts (e.g., Pd-PEPPSI, Buchwald precatalysts) to reduce Pd loading to ppm levels; facilitates metal removal and lowers cost/E-footprint.
  • Nickel catalysis: For some couplings, Ni can substitute for Pd, reducing critical metal usage; requires optimization on heteroaryl bromides to manage competitive pathways.
• Bases:
  • Preference for inorganic bases with favorable EHS profiles (K3PO4, K2CO3) over strong, hazardous bases (NaOtBu) when compatible with the coupling manifold.

Comparison snapshot (general)

• Traditional: Pd(PPh3)4 in dioxane/DMF, 80–100 °C, 1–2 mol% Pd.
• Greener: Buchwald precatalyst (0.05–0.2 mol% Pd) in 2-MeTHF/H2O with K3PO4 at 60–80 °C.

Note

• Evaluate solvent substitution for solubility and catalyst stability; heteroarenes can bind metals differently versus carbocyclic substrates.

Pharmaceutical Uses

Scope

• This product is not an excipient and is not intended for administration. It has no pharmacopeial monograph status indicated in the Product Data.

Relevance in pharmaceutical R&D (general)

• Substituted pyridines are common scaffolds in medicinal chemistry. 3-Bromo-4-methoxypyridine serves as a versatile intermediate to prepare structure–activity relationship (SAR) analogs via cross-coupling or metalation, enabling rapid diversification at the C3 position while preserving a para-methoxy handle for later modification (e.g., demethylation to a phenol and subsequent derivatization).
• Typical roles include: heteroaryl core installation into candidate molecules, linker attachment in PROTAC-like constructs (after further functionalization), or fragment elaboration in FBLD workflows.

Manufacturing/process context

• For routes adopting this intermediate, considerations include catalyst selection for efficient heteroaryl oxidative addition, metal removal strategies to meet ICH Q3D, and solvent selection aligned with ICH Q3C.
• If used in GMP settings as a starting material or intermediate, full traceability and control of elemental impurities, residual solvents, and identity/purity must be established via a validated specification and CoA. None of these specifications are provided here and must be defined by the user’s quality system.

Regulatory note

• No clinical or therapeutic claims are made or implied. Supplied strictly for research and laboratory synthesis.

Physical Properties

Item-specific specs

• Appearance, BP/MP, density, refractive index, water/peroxide/metal content, UV cutoff: Not specified for this item; refer to CoA/Spec Sheet.

Literature/general properties (for guidance only; not item specifications)

• Molecular formula: C6H6BrNO (literature)
• Molecular weight: ~188.02 g/mol (literature)
• Physical state: Typically an organic solid or low-melting solid/oil for halo-methoxypyridine isomers; exact form for this item is not specified.
• Solubility: Expected to be soluble in common organic solvents (e.g., dichloromethane, ethyl acetate, THF, toluene, acetonitrile) and sparingly soluble to poorly soluble in water, consistent with heteroaryl bromides.
• Volatility: Low to moderate vapor pressure relative to low-MW solvents; handle in a fume hood to minimize inhalation exposure.
• Acid/base behavior: The ring nitrogen is weakly basic (pyridine-type); the overall molecule can form salts upon protonation under strong acidic conditions. No titratable acidic proton.

Practical notes (general)

• Purification: Often amenable to silica gel chromatography; the pyridine nitrogen can interact with silica—adding a small amount of triethylamine to eluent can sharpen bands.
• Drying: If needed for air/moisture-sensitive reactions (e.g., metalation), dry under high vacuum over P2O5 or molecular sieves. Avoid strong heat unless a validated BP/MP is known.

Always verify exact physical constants for your lot via the CoA or internal characterization before process design.

Quality and Grades

Item-specific quality

• Grade: Reagent Grade (per Product Data).

What Reagent Grade generally implies (general guidance)

• Intended for laboratory synthesis and analytical work where high purity is required but not necessarily at the ultra-trace impurity levels demanded by HPLC/LC–MS solvents or semiconductor grades.
• Typical expectations include low levels of non-volatile residue and controlled organic/elemental impurities suitable for most synthetic operations and method development.

Clarifications and best practices

• Trace specifications: Exact limits for water, residual solvents, metals, and stabilizers are Not specified for this item; refer to CoA/Spec Sheet for lot-specific values.
• Suitability for catalysis: For Pd-catalyzed cross-couplings or sensitive organometallic steps, users often further purify (e.g., short plug on basic alumina/silica) or pre-check by test coupling to ensure consistent performance.
• UV absorbance: If using as a reference standard or for photophysical studies, verify UV–Vis background from CoA; Reagent Grade does not guarantee low UV cutoff specifications.
• Stabilizers/inhibitors: None stated in Product Data; if your process is sensitive to trace acid/base, test acidity/basicity and consider brief bulking with triethylamine or filtration through neutral alumina to remove trace HBr/phenolic impurities if detected.

Documentation

• For GMP or regulated workflows, retain the CoA, SDS, and any internal QC data (NMR, GC/LC, MS). Aladdin can provide lot-level documentation upon request.

Reaction and Applications

Overview

• 3-Bromo-4-methoxypyridine is a versatile electrophilic heteroaryl bromide used to access 3-substituted 4-methoxypyridines through cross-coupling, metalation, and substitution manifolds. The pyridine nitrogen and para-methoxy substituent together modulate oxidative addition and regioselectivity in downstream transformations.

Representative applications (literature/general)

• Cross-coupling platforms:
  • Suzuki–Miyaura: Coupling with aryl/alkenyl/alkyl boron reagents to build libraries of 3-substituted 4-methoxypyridines. Pd(0) catalysts with dialkylbiaryl phosphines (e.g., SPhos/XPhos) often promote oxidative addition on heteroaryl bromides at mild temperatures.
  • Buchwald–Hartwig amination: Installation of amines at C3; BrettPhos or RuPhos ligands can be effective with secondary/primary amines. The ring N may require ligand/base tuning to prevent catalyst inhibition.
  • Stille/Negishi/Kumada: Useful for challenging sp2–sp2 couplings or for installing alkyl fragments via organozinc/magnesium partners.
• Directed metallation / halogen–lithium exchange:
  • n-BuLi or i-PrMgCl·LiCl (Turbo Grignard) enables halogen–metal exchange at low temperature; trapping with electrophiles (carbonyls, CO2, electrophilic fluorinating reagents) affords functionalized 3-substituted derivatives.
• C–H functionalization of the ring (post-coupling): The methoxy group can serve as a removable/modulating group; demethylation (e.g., BBr3) to the phenolic pyridinol can open access to further O-functionalization.
• Heterocycles in discovery: This scaffold appears in agrochemical and medicinal chemistry SAR campaigns as a bioisosteric pyridine core; the bromide allows rapid diversification for analog generation.

Practical notes

• Ensure rigorous exclusion of moisture/air for organometallic steps; for couplings, degas solvents and consider catalyst pre-activation when working with basic heteroarenes.

Reaction Conditions

General literature conditions (guidance; optimize per system)

• Suzuki–Miyaura coupling (C3):
  • Catalyst: Pd2(dba)3 (1–2 mol%) + SPhos/XPhos (2–4 mol%) or Pd-PEPPSI (0.1–0.5 mol%).
  • Base: K3PO4 (2–3 equiv) or K2CO3.
  • Solvent: 1,4-dioxane/H2O (3:1), 2-MeTHF/H2O, or toluene/H2O.
  • Temperature/time: 60–90 °C, 2–16 h.
  • Notes: Aqueous co-solvent accelerates transmetalation; heteroaryl bromides often couple readily at C3.
• Buchwald–Hartwig amination:
  • Catalyst: Pd2(dba)3 (1 mol%) with BrettPhos or RuPhos (2 mol%), or Buchwald precatalysts (0.5–1 mol%).
  • Base: NaOtBu or K3PO4 (depending on amine nucleophilicity).
  • Solvent: Toluene, dioxane, or tert-amyl alcohol.
  • Temperature/time: 80–110 °C, 4–18 h.
  • Notes: The pyridine N can coordinate Pd; biaryl phosphines mitigate inhibition.
• Negishi/Stille couplings:
  • Catalyst: Pd(PPh3)4 (1–3 mol%) or PdCl2(dppf) (2 mol%).
  • Solvent: THF or DMF.
  • Temperature: 50–80 °C.
• Halogen–lithium exchange (C3):
  • Reagent: n-BuLi (1.1–1.3 equiv) at −78 to −40 °C in anhydrous THF.
  • Quench: Electrophiles (RCHO, R2CO, DMF for formylation, CO2 for carboxylation).
  • Notes: The ring N can coordinate Li; rapid trapping minimizes rearrangements.
• Grignard formation:
  • Activators: Iodine or 1,2-dibromoethane to initiate Mg insertion in THF; alternatively, i-PrMgCl·LiCl enables halogen–magnesium exchange at −20 to 0 °C.

Analytics and workup

• Monitor by GC/LC–MS. For basic heteroarenes, add 1–5% Et3N to chromatography eluents to reduce tailing. Chelating scavengers (SiliaMetS, Thiol resins) aid Pd removal to trace levels.

Safety and Handling

Item-specific hazard data

• GHS signal word, hazard statements, pictograms, and classification: Not specified for this item; refer to the product SDS.

General safety information for halo-methoxypyridines (literature/guidance; defer to SDS)

• Likely hazards: May cause skin/eye irritation and respiratory tract irritation. Many aryl bromides are harmful if swallowed and may be hazardous to aquatic life. Treat as combustible organic material.
• Peroxides: Not an ether solvent; peroxide formation is not a typical concern.
• Incompatibilities: Strong oxidizers, strong acids/bases (particularly under heating), and reactive metals. During strong base metalation (e.g., with BuLi), exclude moisture/air rigorously.
• PPE: Lab coat, nitrile gloves, splash goggles. For weighing or transfers, work in a certified chemical fume hood.
• First aid (overview): Eye/skin contact—rinse with water for at least 15 minutes; remove contaminated clothing. Inhalation—move to fresh air; seek medical attention if symptoms persist. Ingestion—rinse mouth; do not induce vomiting; get medical advice.
• Fire safety: Use CO2, dry chemical, or foam. Combustion may produce HBr, NOx, and CO/CO2; firefighters should wear SCBA.
• Spill/cleanup: Contain and absorb with inert material; collect in halogenated organic waste. Decontaminate area with appropriate solvent while maintaining ventilation.

Storage guidance (item-specific + general)

• Product Data indicates storage at room temperature. Keep tightly closed in a dry, well-ventilated place; protect from light and sources of ignition. Segregate from oxidizers. Always consult the SDS for authoritative safety measures.

Solvent Selection

Applicability

• This product is a heteroaryl building block, not a solvent. Solvent selection here refers to choosing media for reactions or handling of 3-bromo-4-methoxypyridine.

Solubility/miscibility profile (general)

• Good solubility in chlorinated solvents (DCM, chloroform), ethereal solvents (THF, CPME), aromatics (toluene, xylene), and polar aprotics (acetonitrile, DMF, DMAc, NMP). Poor water solubility expected.

Choosing solvents by transformation

• Pd-catalyzed cross-couplings (Suzuki/Negishi/Stille): 1,4-dioxane, toluene, THF, Me-THF, CPME, or mixed aqueous polar aprotics (DMF/H2O, dioxane/H2O). Water co-solvent improves boronate transmetalation in Suzuki.
• Buchwald–Hartwig amination: Toluene, dioxane, tert-amyl alcohol, or polar aprotics (DMF/DMAc) depending on ligand/base system.
• Lithiation/metal–halogen exchange: Anhydrous THF, MTBE, or toluene at −78 to 0 °C under inert atmosphere.
• Nucleophilic substitutions on the ring are generally disfavored; SNAr is unlikely at C3 with Br on a methoxy-substituted pyridine, so coupling/metalation media are preferred.

Practical tips

• The basic ring nitrogen can coordinate metals and acids; traces of base (e.g., Et3N) in chromatography solvents can minimize tailing.
• For scale-up, consider greener media (2-MeTHF, CPME, propylene carbonate) where compatible with catalyst and base; avoid DCM/NMP where possible for EHS reasons.
• If preparing analytical solutions, acetonitrile or methanol often provide clear baselines for LC/UV; verify stability and absorbance as needed.

Storage and Reconstitution

Item-specific storage

• Storage Conditions: Room temperature (per Product Data). Keep container tightly closed in a dry, well-ventilated area. Store away from incompatible materials (strong oxidizers) and ignition sources.
• Shipped In: Not specified for this item; refer to CoA/Spec Sheet.
• Appearance: Not specified for this item; refer to CoA/Spec Sheet.

General handling and solution preparation (guidance)

• Atmosphere: For air/moisture-sensitive transformations (e.g., metalation), handle under inert gas (N2/Ar). Routine weighing can be done quickly in ambient air with fume hood ventilation.
• Solution prep: Dissolves in common organic solvents such as DCM, THF, toluene, acetonitrile, DMF, and ethyl acetate. Prepare stock solutions in dry, oxygen-free solvent if using in Pd/Ni catalysis or with organometallic reagents.
• Concentration/stability: Prepare only what is needed for immediate use; prolonged storage of solutions can lead to gradual degradation or solvent contamination. Store any retained solutions in sealed vials under inert gas at 2–8 °C when feasible.
• Freeze–thaw: Not typically applicable; if the material is a low-melting solid or oil, minimize thermal cycling to preserve quality.

Disposal

• Dispose of residues and solutions as halogenated organic waste according to institutional and local regulations.

Documentation reminder

• For exact stability limits, assay/purity, and any lot-specific recommendations, consult the CoA and SDS for this item.

Structure and Identity

Item-specific (from Product Data)

• SKU: B482412
• Product Name: 3-bromo-4-methoxy-pyridine
• Grade: Reagent Grade
• Storage conditions: Room temperature
• Research Use Note: For research use only
• CAS, CID, InChIKey, SMILES: Not specified for this item; refer to CoA/Spec Sheet.

Literature/computed identifiers (for reference; not item-specific)

• Preferred IUPAC name (literature): 3-bromo-4-methoxypyridine
• Molecular formula (literature): C6H6BrNO
• Molecular weight (literature): ~188.02 g/mol
• Example SMILES (literature): COc1cc(Br)cnc1

Structural features (general description)

• Ring system: A six-membered aromatic heteroaromatic ring (pyridine) containing one ring nitrogen (sp2), para to a methoxy substituent and meta to a bromine substituent.
• Functional groups: Electron-deficient pyridine ring (aza-arene), aryl bromide (good cross-coupling handle), and an anisole-like methoxy substituent (weakly electron-donating by resonance/inductive effects modulated by the ring N).
• Regiochemistry: Substituents at the 3- (bromo) and 4- (methoxy) positions relative to the ring nitrogen at position 1. The combination of a σ-withdrawing ring N and a para-OMe gives a distinctive reactivity profile in metal-catalyzed couplings and directed metallations.
• 2D description: A planar pyridine where the methoxy group projects from C4 and bromine from C3; the ring nitrogen can act as a Lewis base/ligand, potentially coordinating to transition metals or bases during reactions.

Note: Exact identifiers for the supplied item (CAS, InChIKey, etc.) are not specified here; consult the product CoA/Spec Sheet for definitive identity data.

Synthetic Utility

Key functional elements

• Aryl bromide at C3: Reliable electrophile for Pd/Ni-catalyzed cross-couplings (Suzuki, Buchwald–Hartwig, Negishi, Stille, Kumada). Facilitates rapid construction of C–C and C–N bonds.
• Pyridine nitrogen: Modulates electronic properties and can coordinate to catalysts/bases, influencing oxidative addition rates and regioselectivity. Provides a handle for salt formation in purification if protonated.
• Para-methoxy group: Donating substituent that can be demethylated (e.g., BBr3, AlCl3/thiols) to the corresponding phenolic pyridinol, enabling further O-alkylation/acylation or serving as a directing group in some metalations.

Strategic uses (literature)

• Divergent library synthesis: Start from 3-bromo-4-methoxypyridine, install varied substituents at C3 via coupling, then modulate the OMe group (e.g., demethylate → O-acylate → carbonate/urethanes) to explore SAR.
• Metal–halogen exchange: Generate 3-lithiated or 3-magnesium species under cryogenic conditions, then trap with electrophiles (aldehydes/ketones, CO2, electrophilic halogen sources) to access densely functionalized heteroarenes not easily obtained via direct coupling.
• Annulation/heterocycle fusion: Post-coupling intramolecular cyclizations can furnish bicyclic N-heteroarenes where the pyridyl nitrogen acts as a nucleophile or ligand.

Practical considerations

• Base choice in couplings (K3PO4, Cs2CO3, NaOtBu) strongly affects rates with heteroaryl substrates; screen alongside ligand families (dialkylbiaryl phosphines, NHCs).
• The basic nitrogen can retard oxidative addition; proton sponge additives or ligand selection that tolerates Lewis basic sites can mitigate this. Pre-complexation of the substrate is typically unnecessary but degassing and rigorous exclusion of adventitious sulfur/phosphorus impurities are beneficial.

Target Specificity

Not applicable.

• This product is a small-molecule building block and does not have biological target specificity, antigen/epitope information, clone/isotype, or species reactivity. No antibody or biochemical target data are provided in the Product Data.