5-(1-Cyanocyclopropyl)-2-fluorophenylboronic Acid: Lab Guide

5-(1-Cyanocyclopropyl)-2-fluorophenylboronic acid is a multifunctional arylboronic acid building block bearing both a strained cyanocyclopropyl pharmacophore and an ortho-fluoro substituent, making it a versatile reagent for transition-metal-catalyzed cross-coupling reactions and medicinal chemistry synthesis.

Product Name

5-(1-Cyanocyclopropyl)-2-fluorophenylboronic acid

SKU

C180613

Molecular Formula

C10H9BFNO2

Key Functional Groups

Boronic acid (–B(OH)₂), nitrile (–CN), cyclopropyl ring, aryl fluoride

Primary Application

Suzuki–Miyaura cross-coupling; medicinal chemistry fragment synthesis

Storage Recommendation

Store in a cool, dry place away from moisture and light; seal tightly after use

Chemical Identity and Structural Features

5-(1-Cyanocyclopropyl)-2-fluorophenylboronic acid (Aladdin SKU: C180613) is an arylboronic acid characterized by three distinct structural elements: (1) a boronic acid group at the 1-position of the phenyl ring, enabling participation in palladium-catalyzed cross-coupling reactions; (2) an ortho-fluorine substituent at the 2-position, which influences the electronic density of the ring and provides a handle for further functionalization or metabolic stability in drug candidates; and (3) a 1-cyanocyclopropyl group at the 5-position, combining ring strain with the electron-withdrawing nitrile to create a pharmacophore widely exploited in CNS and protease-targeted drug discovery programs.

The strained cyclopropane ring adjacent to the nitrile group is known to enhance the electrophilic character of the nitrile carbon while conferring conformational rigidity. The combination of fluorine and the cyanocyclopropyl group renders this compound a high-value intermediate for the preparation of drug-like molecules with favorable lipophilicity and metabolic profiles.

Handling, Safety, and Storage Guidelines

Personal Protective Equipment (PPE): When handling this compound, wear appropriate PPE including nitrile gloves, safety glasses or goggles, and a laboratory coat. Work in a well-ventilated fume hood to minimize inhalation exposure to any dust or aerosols generated during weighing.

Storage: Store the reagent in a tightly sealed container in a cool, dry location away from direct light and moisture. Boronic acids are susceptible to hydrolysis and oxidation under ambient conditions; exposure to atmospheric humidity can lead to formation of the corresponding boroxine or boric acid, reducing the effective purity of the compound. Desiccant storage is recommended for long-term preservation.

Stability considerations: The cyanocyclopropyl moiety is generally stable under standard laboratory conditions; however, the nitrile group may be reactive toward strong nucleophiles (e.g., amines under forcing conditions). Avoid contact with strong acids, strong bases, and strong oxidizing or reducing agents. Consult the Safety Data Sheet (SDS) provided by Aladdin Scientific before use.

Disposal: Dispose of waste in accordance with local institutional and governmental regulations for chemical waste. Do not dispose of down the drain without authorization.

Synthetic Applications and Reaction Protocols

Suzuki–Miyaura Cross-Coupling: The boronic acid group of C180613 enables it to serve as the organoboron partner in Pd-catalyzed Suzuki–Miyaura couplings with aryl or heteroaryl halides, triflates, and related electrophiles. Standard conditions employ a Pd(0) or Pd(II) precatalyst (e.g., Pd(PPh₃)₄, Pd(dppf)Cl₂, or third-generation Buchwald precatalysts), a mild inorganic base (e.g., K₂CO₃, Cs₂CO₃, or K₃PO₄), and a protic or mixed aqueous/organic solvent system (e.g., DMF/H₂O, dioxane/H₂O, or EtOH/H₂O) at temperatures typically ranging from 60–100 °C.

Protocol Outline (representative, not optimized):

1. Charge the aryl halide electrophile (1.0 equiv), C180613 (1.1–1.5 equiv), and base (2.0–3.0 equiv) into a Schlenk flask or sealed vial.
2. Add solvent (typically 0.1–0.5 M), degas by freeze-pump-thaw or sparging with inert gas (N₂ or Ar).
3. Add palladium catalyst (1–5 mol %) under inert atmosphere.
4. Heat at 80 °C with stirring until reaction completion (monitor by TLC or LC-MS).
5. Cool, dilute with ethyl acetate, wash with water and brine, dry over MgSO₄, filter, and concentrate. Purify by column chromatography.

Other Potential Transformations: The nitrile group is amenable to further elaboration, including hydrolysis to carboxylic acids or amides, reduction to amines, or conversion to tetrazoles via [3+2] cycloaddition with azides—reactions particularly relevant in medicinal chemistry for bioisostere introduction. The aryl fluoride may participate in nucleophilic aromatic substitution (SNAr) under appropriate conditions.

Quality, Purity, and Analytical Verification

Aladdin Scientific supplies C180613 with a specification for purity; researchers should consult the Certificate of Analysis (CoA) supplied with each lot for confirmed purity values, appearance, and other release criteria. Before use in sensitive synthetic sequences, it is good practice to verify reagent quality by one or more of the following techniques:

• ¹H and ¹¹B NMR spectroscopy: The boronic acid –B(OH)₂ protons are typically broad and may appear in the 6–9 ppm region or be absent in certain solvents due to fast exchange. ¹¹B NMR provides a direct diagnostic signal for sp²-hybridized boronic acids (typically δ ~28–33 ppm), distinguishing them from boronate esters or boric acid impurities.
• HPLC or LC-MS: Reverse-phase HPLC with UV detection (215 or 254 nm) provides purity assessment. LC-MS confirms molecular identity via the expected [M+H]⁺, [M−H]⁻, or [M+NH₄]⁺ adducts consistent with the molecular formula C₁₀H₉BFNO₂.
• Melting point: A sharp melting point consistent with the literature or CoA value is indicative of high purity.

If the reagent has been stored for an extended period or shows visual discoloration, re-verification of purity prior to use in critical experiments is strongly recommended.

Frequently asked questions

What are the recommended conditions for Suzuki–Miyaura coupling with C180613?

C180613 performs well under standard Suzuki–Miyaura conditions: a Pd catalyst such as Pd(PPh₃)₄ or Pd(dppf)Cl₂ (1–5 mol%), an inorganic base such as K₂CO₃ or Cs₂CO₃ (2–3 equiv), and a mixed aqueous/organic solvent (e.g., dioxane/H₂O or DMF/H₂O) at 80 °C under inert atmosphere. Reaction progress should be monitored by TLC or LC-MS.

How should C180613 be stored to maintain its purity over time?

Store C180613 in a tightly sealed container in a cool, dry location, protected from light and atmospheric moisture. Because boronic acids are susceptible to hydrolysis and conversion to boroxines, the use of a desiccant and inert-gas backfill upon opening is recommended for long-term storage. Always check the Certificate of Analysis and re-verify purity if the reagent has been stored for an extended period.

Can the nitrile group of C180613 be further functionalized after cross-coupling?

Yes. The nitrile (–CN) group on the cyanocyclopropyl moiety is amenable to a variety of downstream transformations including acid- or base-mediated hydrolysis to carboxylic acids or amides, catalytic reduction to primary amines, and [3+2] cycloaddition with azides to form tetrazoles, which are useful carboxylic acid bioisosteres in medicinal chemistry. The sequence of coupling followed by nitrile functionalization allows rapid diversification of the biaryl scaffold.

Why is the ortho-fluoro substituent significant for medicinal chemistry applications?

Fluorine substitution on aromatic rings is a well-established strategy in medicinal chemistry. An ortho-fluoro group can increase the metabolic stability of the molecule by blocking cytochrome P450-mediated oxidation at that ring position, modulate lipophilicity and membrane permeability, and influence the conformational preferences of the molecule through gauche interactions with adjacent groups. These properties collectively contribute to improved pharmacokinetic profiles of drug candidates.

References

1. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. doi:10.1021/cr00039a007
2. Hall, D. G. (Ed.) Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd ed.; Wiley-VCH: Weinheim, 2011.
3. Hagmann, W. K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359–4369. doi:10.1021/jm800219f
4. Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529–2591. doi:10.1021/jm1013693

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