3-Chloropyrazolo[1,5-a]pyridine: Handling & Synthesis Protocol

3-Chloropyrazolo[1,5-a]pyridine is a halogenated bicyclic heteroaromatic compound widely employed as a versatile building block in medicinal chemistry and cross-coupling reactions.

CAS Number

Not confirmed in source material — see review flags

Molecular Formula

C7H5ClN2

Molecular Weight

152.58 g/mol

SKU

C191640

Compound Class

Halogenated pyrazolopyridine heterocycle

Primary Application

Synthetic building block for cross-coupling and C–N bond-forming reactions

Compound Overview and Properties

3-Chloropyrazolo[1,5-a]pyridine belongs to the pyrazolo[1,5-a]pyridine family of fused bicyclic heterocycles. The compound consists of a pyrazole ring fused to a pyridine ring at the [1,5-a] positions, with a chlorine substituent at the 3-position of the pyrazole ring. This halogen substituent renders the molecule a highly reactive handle for metal-catalyzed cross-coupling transformations, nucleophilic aromatic substitution, and directed C–H functionalization strategies.

The electron-deficient aromatic system imparts useful physicochemical properties, including moderate lipophilicity and a planar scaffold that is frequently encountered in bioactive molecules targeting kinases and other enzyme classes. As an Aladdin Scientific reagent (SKU C191640), 3-Chloropyrazolo[1,5-a]pyridine is supplied for research use in heterocyclic synthesis, fragment-based drug discovery, and medicinal chemistry programs.

Safety, Storage, and Handling

Personal Protective Equipment (PPE): Always wear nitrile gloves, a laboratory coat, and safety goggles when handling 3-Chloropyrazolo[1,5-a]pyridine. Work in a well-ventilated fume hood to avoid inhalation of dust or vapors.

Storage Conditions: Store the compound in a tightly sealed container under cool, dry conditions, away from direct light and moisture. A storage temperature of 2–8 °C or room temperature under inert atmosphere (nitrogen or argon) is recommended until specific stability data are confirmed. Keep away from strong oxidizers and bases.

Waste Disposal: Dispose of all waste in accordance with local institutional and governmental regulations for halogenated organic compounds. Do not pour down the drain.

Note: Consult the Safety Data Sheet (SDS) provided by Aladdin Scientific for authoritative hazard classifications, first-aid measures, and transport information specific to SKU C191640.

Protocol: Palladium-Catalyzed Cross-Coupling Reactions

3-Chloropyrazolo[1,5-a]pyridine is well-suited for palladium-catalyzed coupling reactions (e.g., Suzuki–Miyaura, Buchwald–Hartwig) due to the activated C–Cl bond at the electron-deficient 3-position. The following is a generalized protocol; researchers should optimize conditions for their specific coupling partner.

1. Reagent Setup: In a dry Schlenk flask or sealed vial under inert gas (N₂ or Ar), weigh 3-Chloropyrazolo[1,5-a]pyridine (1.0 equiv), the appropriate coupling partner (boronic acid, amine, or other nucleophile, 1.2–1.5 equiv), and a palladium catalyst (e.g., Pd(PPh₃)₄ or Pd₂(dba)₃, 2–5 mol%).
2. Base and Solvent: Add an inorganic base (e.g., K₂CO₃ or Cs₂CO₃, 2.0 equiv) and degassed solvent (e.g., DMF, dioxane, or toluene/water mixture). The solvent system should be chosen based on substrate solubility and reaction precedent.
3. Reaction: Heat the mixture at 80–110 °C with stirring for 12–24 hours, monitoring progress by TLC or HPLC.
4. Workup: Allow to cool to room temperature. Dilute with ethyl acetate, wash sequentially with water and brine, dry over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure.
5. Purification: Purify the crude product by silica gel column chromatography using an appropriate eluent system (e.g., hexanes/ethyl acetate gradient).

Caution: All reaction conditions above are general guidelines. Specific yields, temperatures, and catalyst loadings should be validated experimentally. Consult primary literature for optimized protocols relevant to your substrate.

Applications in Medicinal and Heterocyclic Chemistry

The pyrazolo[1,5-a]pyridine core is a privileged scaffold in drug discovery, appearing in compounds with reported activity against a range of biological targets including kinases, phosphodiesterases, and receptor systems. The chlorine at the 3-position serves as a versatile synthetic handle enabling:

• Suzuki–Miyaura coupling: Introduction of aryl or heteroaryl groups to diversify the C-3 position.
• Buchwald–Hartwig amination: C–N bond formation to install amine substituents, useful for generating pharmacophores.
• Nucleophilic aromatic substitution (SNAr): Reaction with amines, thiols, or alkoxides under appropriate conditions due to ring activation.
• Directed metalation: The compound may also participate in directed ortho-metalation strategies for further functionalization.

These transformations make 3-Chloropyrazolo[1,5-a]pyridine a high-value intermediate in fragment-based drug design and lead optimization campaigns. Researchers are encouraged to consult current medicinal chemistry literature for specific biological evaluation data.

Quality, Purity, and Ordering Information

Aladdin Scientific supplies 3-Chloropyrazolo[1,5-a]pyridine under SKU C191640. The compound is intended for research use only and is not for human or veterinary therapeutic application.

Recommended Characterization: Upon receipt, researchers may wish to confirm identity and purity by ¹H NMR, HPLC (purity ≥ 95% is typical for research-grade material), and LC-MS. Storage and handling per the SDS and the guidelines in this protocol are recommended to maintain compound integrity.

To Order: Contact Aladdin Scientific or visit the product page for current pricing, available pack sizes, and delivery options. For bulk or custom synthesis inquiries, reach out to the Aladdin Scientific sales team directly.

Frequently asked questions

What is 3-Chloropyrazolo[1,5-a]pyridine used for in research?

3-Chloropyrazolo[1,5-a]pyridine is primarily used as a synthetic building block in medicinal chemistry and heterocyclic synthesis. The C-3 chlorine substituent enables palladium-catalyzed cross-coupling reactions (e.g., Suzuki–Miyaura, Buchwald–Hartwig), nucleophilic aromatic substitution, and other transformations to access diverse pyrazolopyridine derivatives for drug discovery programs.

How should 3-Chloropyrazolo[1,5-a]pyridine (C191640) be stored?

The compound should be stored in a tightly sealed container under cool, dry, and dark conditions, away from moisture and strong oxidizers. Storage under an inert atmosphere (nitrogen or argon) at 2–8 °C is generally recommended for long-term stability. Always consult the Aladdin Scientific SDS for definitive storage instructions.

Which palladium catalysts are recommended for cross-coupling with 3-Chloropyrazolo[1,5-a]pyridine?

Commonly used palladium catalysts for aryl chloride cross-coupling include Pd(PPh3)4, Pd2(dba)3 with a suitable phosphine ligand (e.g., XPhos, SPhos, or BINAP), and PdCl2(dppf). The optimal catalyst and ligand combination depends on the coupling partner and desired reaction conditions, and should be determined empirically. Consult primary literature for substrate-specific guidance.

Is 3-Chloropyrazolo[1,5-a]pyridine suitable for fragment-based drug discovery (FBDD)?

Yes. The pyrazolo[1,5-a]pyridine scaffold is a recognized privileged structure in medicinal chemistry with drug-like physicochemical properties. Its low molecular weight and the reactive 3-chloro handle make it a useful fragment for FBDD, enabling rapid diversification via cross-coupling to generate structure–activity relationship (SAR) data.

References

1. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. General reference for pyrazolopyridine 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. Buchwald, S. L. et al. Palladium-catalyzed amination of aryl halides and sulfonates. General reference for Buchwald–Hartwig amination methodology.
4. Aladdin Scientific. Product page: 3-Chloropyrazolo[1,5-a]pyridine, SKU C191640. https://www.aladdin-e.com

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