5-Ethynyl-3-fluoro-2-methoxypyridine - ≥95% , CAS No.1211587-10-8

CAS: 1211587-10-8 Cat. No.: E957008 Summenformel: C₈H₆FNO Molekulargewicht: 151.140 EG-Nummer: 973-598-2

GRADE & PURITY ≥95%

Storage

Room temperature

Specifications

Spezifikationen & Reinheit

≥95%

Storage

Room temperature

Reinheit

≥95%

Namen und Kennungen

• Kanonisches Lächeln: COC1=C(C=C(C=N1)C#C)F
• IUPAC Name: 5-ethynyl-3-fluoro-2-methoxypyridine
• InChIKey: JRUDNZBDERDKQV-UHFFFAOYSA-N
• INCHI: 1S/C8H6FNO/c1-3-6-4-7(9)8(11-2)10-5-6/h1,4-5H,2H3
• Molekulargewicht: 151.140

Taxonomic Classification

Taxonomy Tree

• Kingdom Organic compounds
  • Superclass Organic oxygen compounds
    • Klasse Organooxygen compounds
      • Subclass Ethers

• Kingdom: Organic compounds
• Superclass: Organic oxygen compounds
• Klasse: Organooxygen compounds
• Subclass: Ethers
• Intermediate Tree Nodes: Not available
• Direct Parent: Alkyl aryl ethers
• Alternative Parents: Pyridines and derivatives Aryl fluorides Heteroaromatic compounds Azacyclic compounds Acetylides Organonitrogen compounds Organofluorides Hydrocarbon derivatives
• Molecular Framework: Aromatic heteromonocyclic compounds
• Substituents: Alkyl aryl ether - Pyridine - Aryl halide - Aryl fluoride - Heteroaromatic compound - Acetylide - Azacycle - Organoheterocyclic compound - Organic nitrogen compound - Hydrocarbon derivative - Organonitrogen compound - Organofluoride - Organohalogen compound - Aromatic heteromonocyclic compound
• Beschreibung: This compound belongs to the class of organic compounds known as alkyl aryl ethers. These are organic compounds containing the alkyl aryl ether functional group with the generic formula R-O-R' , where R is an alkyl group and R' is an aryl group.
• External Descriptors: Not available

Data sources

1. Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, Fahy E, Steinbeck C, Subramanian S, Bolton E, Greiner R, and Wishart DS. ClassyFire: Automated Chemical Classification With A Comprehensive, Computable Taxonomy. Journal of Cheminformatics, 2016, 8:61.

DOI: 10.1186/s13321-016-0174-y

Chemische und physikalische Eigenschaften

• Molekulargewicht: 151.140 g/mol
• XLogP3: 1.500
• Hydrogen Bond Donor Count: 0
• Hydrogen Bond Acceptor Count: 3
• Rotatable Bond Count: 2
• Exact Mass: 151.043 Da
• Monoisotopic Mass: 151.043 Da
• Topological Polar Surface Area: 22.100 Ų
• Heavy Atom Count: 11
• Formal Charge: 0
• Complexity: 174.000
• Isotope Atom Count: 0
• Defined Atom Stereocenter Count: 0
• Undefined Atom Stereocenter Count: 0
• Defined Bond Stereocenter Count: 0
• Undefined Bond Stereocenter Count: 0
• The total count of all stereochemical bonds: 0
• Covalently-Bonded Unit Count: 1

Application Protocols

No assay protocols are item-specific for this small-molecule building block. Typical use involves its incorporation into synthetic sequences (e.g., SNAr diversification, CuAAC conjugation, Sonogashira coupling). Users should develop reaction procedures based on the transformation of interest and verify conditions at small scale before scale-up. For any biological assay, prepare concentrated stocks (e.g., in DMSO), perform solubility checks, include vehicle controls, and confirm compatibility with the assay buffer/system.

Biological Roles

• Item-specific biological role claims: None. For research use only (per Product Data).

• General context (not product-specific, no therapeutic claims):

  • 5-Ethynyl-3-fluoro-2-methoxypyridine is a synthetic small molecule lacking an inherent biological role. Its value in chemical biology or medicinal chemistry arises from its functionality:
    • Terminal alkyne enables CuAAC “click” ligations to introduce the 3-fluoro-2-methoxypyridyl fragment into probes, affinity tags, or conjugates.
    • The pyridine nitrogen can modulate basicity and binding interactions when the motif is embedded into larger ligands.
    • The 3-fluoro substituent serves as a conservative bioisostere to adjust metabolic stability and alter local electronics without significant steric impact.

• Use cases in discovery workflows:

  • Fragment or scaffold embellishment via SNAr at the 3-F position to install amines/heteroatoms.
  • Late-stage conjugation to azide-bearing biomolecular handles (peptides, sugars, lipids) creating triazole-linked adducts for target engagement studies or pull-down assays.

No pharmacological or clinical activity is implied. Suitability for any biological experiment should be determined by the end user through appropriate controls and toxicity assessments.

Buffer Applications

This compound is not a buffering agent and is not typically used to prepare pH buffer systems. If included in biochemical assays, it is usually as a synthetic intermediate or ligand fragment dissolved in an appropriate solvent (e.g., DMSO) and then diluted into the assay buffer. Select assay buffers based on the biological system, and verify compound solubility and compatibility separately.

Green Alternatives

Greener choices often center on solvent and catalyst selection rather than replacing the heteroaromatic building block itself.

• Solvent alternatives (literature guidance):

  • Replace DMF/DMSO with MeCN, 2-MeTHF, CPME, or bio-derived esters (EtOAc, propylene carbonate) when compatible with the transformation.
  • For CuAAC, t-BuOH/H2O or EtOH/H2O mixtures reduce toxicity versus pure DMF.

• Catalyst and base considerations:

  • Sonogashira couplings can be performed copper-free with modern Pd–ligand systems to minimize copper waste and avoid Glaser byproducts.
  • Use heterogeneous Pd (e.g., Pd/C) or ultra-low Pd loadings with robust ligands to reduce precious metal footprint.

• Workup/waste minimization:

  • Favor aqueous ethanol or EtOAc for extractions; avoid chlorinated solvents when feasible.
  • Employ scavenger resins to remove metals, reducing chromatographic solvent consumption.

Comparison snapshot (general):

• Conventional: DMF (SNAr), DCM (workup), CuI-assisted Sonogashira
• Greener option: MeCN or 2-MeTHF (SNAr), EtOAc/MTBE (workup), copper-free Pd catalysis

Trade-offs:

• Greener solvents may lower substrate solubility or reaction rates; small-scale solubility tests and temperature optimization are recommended to maintain throughput while reducing EHS impacts.

Pharmaceutical Uses

• Item-specific pharmacopeial status or excipient role: Not specified for this item; refer to CoA/Spec Sheet.

• General, non-clinical context:

  • This heteroaromatic building block is suited for medicinal chemistry synthesis and SAR exploration. The terminal alkyne offers a vector for constructing rigid linkers, while the 3-fluoro and 2-methoxy substituents fine-tune electronic properties and lipophilicity in lead optimization.
  • Potential roles in preclinical workflows include: intermediate for API candidates, handle for bioconjugation (via CuAAC) to generate screening conjugates, and diversification node via SNAr to access analog libraries.

No therapeutic, diagnostic, or clinical claims are made. Any use in pharmaceutical R&D remains at the research stage and requires independent verification of purity, residual metals/solvents, and stability according to internal quality standards.

Physical Properties

• Item-specific specifications: Not specified for this item; refer to CoA/Spec Sheet.

• Literature/expected characteristics for 5-ethynyl-3-fluoro-2-methoxypyridine (reference only, not product specifications):

  • Physical state/appearance: typically a low-melting solid or pale liquid depending on purity and temperature; many alkynyl pyridines are low-viscosity oils (literature, varies).
  • Molecular formula: C8H6FNO (literature, derived from structure)
  • Molecular weight: ~151.14 g/mol (calculated, literature)
  • Polarity: moderately polar heteroaromatic; donor/acceptor count 0/2; HBD = 0, HBA = 2 (N, O).
  • Solubility: expected to be soluble in common organic solvents (DCM, EtOAc, MeOH, THF, acetonitrile, DMF/DMSO) and poorly soluble in water (literature trend for methoxylated fluoropyridyl alkynes).
  • Volatility: likely moderate; handle in a fume hood to minimize inhalation exposure (general guidance).

Notes:

• Do not treat the above as product specifications. Confirm exact BP/MP, density, refractive index, and solubility limits from the item’s CoA/SDS when needed for method development or scale-up.

Quality and Grades

• Item-specific grade/purity: Not specified for this item; refer to CoA/Spec Sheet.

• Interpreting common grades (general guidance):

  • Research/technical grade: suitable for synthetic and discovery workflows; impurity profiles may vary between lots.

  • 95–98% purity (when specified): typical for building blocks; sufficient for most library synthesis without further purification.

  • Low-water/low-peroxide specs: not generally applicable to this heteroaromatic unless explicitly stated. Do not assume.

• Stabilizers/inhibitors: None specified for this item. Terminal alkynes typically do not require polymerization inhibitors; however, absence of stabilizers means proper storage is important to minimize adventitious oxidation or Glaser-type dimerization under copper/air exposure.

• Documentation: For precise assay, residual solvents, metal content, and chromatographic identity, consult the lot-specific CoA. Request a full Specification Sheet if your application (e.g., SAR, catalyst screening) requires tighter controls (UV cutoff, elemental impurities, or residual palladium/copper).

Reaction and Applications

5-Ethynyl-3-fluoro-2-methoxypyridine is a multifunctional building block enabling convergent heteroaryl elaboration.

• Terminal alkyne handle (C5):

  • CuAAC (Huisgen “click”): couples with organic azides to form 1,4-disubstituted 1,2,3-triazoles bearing the 3-fluoro-2-methoxypyridyl motif. Typically CuSO4/Na ascorbate or CuI catalysts; broad functional-group tolerance.
  • Sonogashira-type couplings (as alkyne partner): couples with aryl/vinyl halides/triflates under Pd/Cu co-catalysis to furnish internal aryl–alkynes. Amines (Et3N, iPr2NH) or carbonates serve as bases.
  • Glaser–Hay oxidative homocoupling: dimerizes to the diyne under Cu and O2; useful transformation or impurity to avoid.

• Activated aryl fluoride (C3–F):

  • SNAr with N/O/S nucleophiles (amines, alkoxides, thiolates), facilitated by the ring nitrogen. Enables late-stage diversification to anilines, diaryl ethers, or thioethers.

• Methoxy at C2:

  • Directs metalation (ortho to OMe relative to carbon framework) is limited on pyridines; however, O-demethylation (e.g., BBr3) can reveal the phenolic (pyridinol) analogue for further derivatization.

• Strategic use:

  • Orthogonal reactivity allows sequence planning: e.g., protect alkyne (TMS), perform SNAr on C–F, then deprotect and execute CuAAC.
  • Useful in medicinal chemistry for installing rigid, linear linkers and tuning basicity/lipophilicity via the pyridine N and OMe substituent.

Notes: See “Reaction Conditions” for typical catalysts, bases, and temperatures drawn from literature precedents.

Reaction Conditions

The following are literature-style general conditions for the functional groups present; they are not item-specific specifications.

• SNAr at 3-F (installation of amines/alkoxides):

  • Solvent: DMF, DMSO, MeCN, or NMP.
  • Base: Cs2CO3, K2CO3, or NaH (for alkoxides).
  • Temperature: 60–120 °C depending on nucleophile strength.
  • Time: 2–16 h; monitor by LC–MS/HPLC.

• CuAAC (azide–alkyne cycloaddition):

  • Catalyst: CuSO4·5H2O (1–10 mol%) + sodium ascorbate (reducing agent) or CuI (5–10 mol%).
  • Solvent: t-BuOH/H2O (1:1), EtOH/H2O, or DMF; 0.1–0.5 M.
  • Temperature: rt to 60 °C.
  • Time: 0.5–6 h; typical high conversions.
  • Additives: TBTA or THPTA ligands can enhance efficiency and suppress oxidative byproducts.

• Sonogashira coupling (as terminal alkyne partner):

  • Catalyst: Pd(PPh3)2Cl2 (1–3 mol%) + CuI (2–5 mol%); copper-free variants use Pd/XPhos or Pd/BrettPhos.
  • Base: iPr2NH, Et3N, or K2CO3.
  • Solvent: THF, toluene, DMF, or 2-MeTHF.
  • Temperature: 40–80 °C; inert atmosphere recommended.
  • Time: 2–12 h.

• Glaser oxidative homocoupling (if desired or to be avoided):

  • Catalyst: CuI/CuCl (5–10 mol%), ligand (e.g., TMEDA), O2 or air as oxidant.
  • Solvent: pyridine, DCM, or DMF.
  • Temperature: rt to 50 °C.

Workup: quench copper with aqueous EDTA; remove Pd/Cu using scavengers or activated carbon; purify by silica gel chromatography (avoid strong basic eluents that may cause alkyne polymerization).

Safety and Handling

• Item-specific GHS info (from Product Data):

  • Signal word: Not specified for this item; refer to SDS.
  • H-statements: Not specified for this item; refer to SDS.
  • GHS classification/pictograms: Not specified for this item; refer to SDS.

• General safety considerations for alkynyl fluoropyridines (literature-based, not product-specific):

  • Likely to cause irritation to skin, eyes, and respiratory tract; avoid inhalation and contact. Use in a chemical fume hood.
  • Wear appropriate PPE: lab coat, safety glasses or splash goggles, and nitrile gloves. Upgrade to face shield/respirator per risk assessment.
  • Avoid strong bases/acids and strong oxidizers; terminal alkynes can be deprotonated by strong base to give sensitive acetylides.
  • Fire safety: organic liquids/low-melting solids may be combustible. Keep away from ignition sources. Use CO2, dry chemical, or foam for small fires.
  • Spill response: absorb on inert material, collect for disposal. Prevent entry into drains. Ventilate area.
  • First aid (overview): move exposed persons to fresh air; rinse skin/eyes with water for at least 15 minutes; seek medical advice. If ingested, rinse mouth and do not induce vomiting unless directed by medical personnel.

Always consult the product SDS for authoritative hazard classification, exposure limits, and transport information before use.

Solvent Selection

This heteroaromatic terminal alkyne is moderately polar and generally dissolves in polar aprotic and many medium-polarity organic solvents.

• Solubility/miscibility profile (literature trends):

  • Good: DCM, THF, EtOAc, acetonitrile, acetone, toluene (warm), MeOH, DMF, DMSO.
  • Poor: water and highly nonpolar alkanes at ambient temperature.

• Polarity and dielectric context (general):

  • Contains a pyridine nitrogen and a methoxy oxygen (HBA sites) that enhance solubility in polar aprotic media. The terminal alkyne adds minimal polarity but enables metal coordination in catalytic processes.

• Practical selection tips:

  • For SNAr on the 3-fluoro site: DMF, DMSO, NMP, or MeCN often provide good rates; include an inorganic base (e.g., Cs2CO3, K2CO3).
  • For CuAAC (“click”) with azides: t-BuOH/H2O, MeOH/H2O, or DMF are commonly used; solvent choice depends on azide solubility.
  • For cross-couplings or Glaser/oxidative homocoupling: toluene, THF, or DMF under inert atmosphere are typical starting points.

• Comparison (when choosing alternatives):

  • DMF vs MeCN: DMF offers higher solubility and rate in SNAr but is harder to remove; MeCN is more volatile and greener.
  • THF vs 2-MeTHF: 2-MeTHF can be a greener, water-tolerant alternative with similar solvating ability.

Storage and Reconstitution

• Item-specific storage conditions: Room temperature (per Product Data).

• Shipped in: Not specified for this item; refer to CoA/Spec Sheet.

• General handling and storage guidance (literature-based):

  • Store tightly closed in the original container under dry, inert conditions if possible (desiccator or with desiccant). Limit exposure to light and air to minimize oxidative side reactions of the terminal alkyne, especially in the presence of copper.
  • Avoid contact with strong bases/acids and oxidants. Keep away from copper/bronze surfaces and copper salts if long-term storage is anticipated.
  • If weighing hygroscopic or low-melting lots, cool and work quickly under dry atmosphere.

• Solution preparation:

  • Prepare stock solutions in dry solvents (e.g., DMSO, DMF, MeCN, THF). For biological screening, DMSO stocks at 10–100 mM are typical; filter if needed.
  • Store solutions at −20 °C or 4 °C, protected from light. Terminal alkynes are generally stable in aprotic media, but periodic re-check by LC–MS is recommended.
  • Avoid repeated freeze–thaw; aliquot solutions to minimize degradation.

Always consult the product’s CoA/SDS for definitive guidance on storage stability and compatibility.

Structure and Identity

A heteroaromatic building block featuring a pyridine ring bearing three orthogonal handles: a terminal alkyne at C5 (ethynyl), a fluorine at C3, and a methoxy at C2.

• Item-specific (from Product Data):

  • Product name: 5-Ethynyl-3-fluoro-2-methoxypyridine
  • CAS: 1211587-10-8
  • CID: 71300085
  • InChIKey: 168345 (as provided)
  • SMILES: Not specified for this item; refer to CoA/Spec Sheet.
  • Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
  • Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.

• Literature/computed (non-spec, for reference):

  • Expected formula (from structure): C8H6FNO
  • Calculated molecular weight: ~151.14 g/mol (literature)
  • Key functional groups: terminal alkyne (–C≡CH), aryl fluoride (3-F), aryl methoxy (2-OMe), pyridine nitrogen (sp2 N)

• 2D structural description (qualitative):

  • A six-membered aromatic ring containing one nitrogen (pyridine). Adjacent to the ring nitrogen (at C2) is a methoxy substituent (–OCH3). The next carbon (C3) bears fluorine (–F). At the C5 position (meta to N, para to C3) is a terminal ethynyl group (–C≡CH). No stereocenters; planarity dominated by the aromatic ring and linear alkyne.

Synthetic Utility

This substrate is engineered for orthogonal diversification on a pyridine core.

• Terminal alkyne (C5):

  • Couples in Sonogashira reactions to form internal aryl–alkynes; amenable to protection as TMS-alkyne for sequencing.
  • Engages in CuAAC with azides for rapid assembly of triazole-linked libraries and bioconjugates.
  • Undergoes cycloadditions (e.g., [2+2+2] with suitable partners) and oxidative couplings (Glaser, Eglinton) as desired.

• Aryl fluoride (C3):

  • Highly susceptible to SNAr due to pyridine activation. Nucleophiles: primary/secondary amines, alkoxides, thiolates, and some carbon nucleophiles under strong base. Useful for parallel synthesis to install diverse substituents.

• Methoxy (C2):

  • Modulates electronics; can be demethylated (e.g., BBr3, AlCl3/thiols) to furnish the corresponding hydroxypyridine for further functionalization (etherification, carbamates, carbonate formation).

• Strategic sequencing:

  • Typical order to minimize side reactions: protect alkyne (TMS) → SNAr on C–F → deprotect alkyne → CuAAC/Sonogashira. Alternatively, perform copper-free Sonogashira first to avoid Glaser byproducts.

• Retrosynthetic value:

  • Serves as a convergent linchpin to connect an azide-bearing fragment (via click) and a nucleophile-derived substituent (via SNAr), rapidly populating chemical space around a drug-like heteroaromatic core.

Target Specificity

Not applicable. This product is a small-molecule building block, not a biological targeting reagent (e.g., antibody, probe with defined biomolecular target). No antigen/epitope, species reactivity, or isotype information is relevant.