(R)-(-)-1-Boc-3-(hydroxymethyl)piperidine: Handling & Use Guide

(R)-(-)-1-Boc-3-(hydroxymethyl)piperidine is a versatile, enantiopure chiral building block bearing a tert-butoxycarbonyl (Boc) nitrogen-protecting group and a primary hydroxymethyl handle, making it a key intermediate for the stereocontrolled synthesis of piperidine-containing pharmaceuticals and bioactive molecules.

CAS Number

170843-29-5

Molecular Formula

C₁₁H₂₁NO₃

Molecular Weight

215.29 g/mol

Optical Rotation

[α]D negative (R-configuration)

Key Functional Groups

Boc-protected secondary amine, primary alcohol (hydroxymethyl)

Recommended Storage

Store at 2–8 °C under inert atmosphere, protected from moisture

Aladdin SKU

B121554

Chemical Identity and Structural Features

(R)-(-)-1-Boc-3-(hydroxymethyl)piperidine (CAS 170843-29-5; MW 215.29 g/mol; molecular formula C₁₁H₂₁NO₃) is a six-membered saturated nitrogen heterocycle in which the ring nitrogen is protected by a tert-butoxycarbonyl (Boc) group and the C-3 position carries a primary hydroxymethyl (–CH₂OH) substituent in the R absolute configuration. The (R) stereocentre is confirmed by a negative optical rotation ([α]D < 0). The Boc carbamate serves as an orthogonal, base-stable, acid-labile protecting group readily removed by trifluoroacetic acid (TFA) or HCl in dioxane under mild conditions, unveiling the free secondary amine without epimerisation. The primary alcohol provides a highly reactive handle for further elaboration via oxidation, esterification, etherification, mesylation/tosylation, or Mitsunobu reactions, all while preserving the chiral centre.

Synthetic Applications in Medicinal and Process Chemistry

The piperidine scaffold is among the most prevalent nitrogen heterocycles in approved pharmaceuticals and drug candidates. (R)-(-)-1-Boc-3-(hydroxymethyl)piperidine delivers both a defined stereocentre and two independently addressable functional groups, making it a privileged chiral building block in several synthetic strategies:

• Amine deprotection and N-functionalisation: Removal of the Boc group under acidic conditions gives the free (R)-3-(hydroxymethyl)piperidine, which can be alkylated, acylated, sulfonylated or coupled with electrophilic heterocycles to generate structurally diverse libraries.
• Alcohol elaboration: Conversion of the primary alcohol to a mesylate or tosylate enables nucleophilic displacement reactions with amines, azides, thiols or cyanide, providing access to 3-substituted piperidines with full retention or inversion of configuration depending on the mechanism employed.
• Ring-opening and annulation: Activated derivatives of the hydroxymethyl group serve as tethered electrophiles for intramolecular cyclisations, facilitating the construction of bicyclic frameworks such as piperidino-pyrrolidines and morpholine analogues.
• Cross-coupling precursors: After appropriate functional-group manipulation, the scaffold can be incorporated into palladium-catalysed cross-coupling sequences relevant to fragment-based drug discovery.

The defined (R) configuration allows medicinal chemists to explore stereochemical SAR and to supply single-enantiomer active pharmaceutical ingredients (APIs) in compliance with regulatory expectations for chiral drugs.

Handling, Storage and Safety Guidelines

Storage: Store at 2–8 °C in a tightly sealed container under an inert atmosphere (nitrogen or argon) and protected from moisture and light. Prolonged exposure to air or humidity may cause gradual degradation of the Boc group or oxidation of the alcohol. Check container integrity before use.

Personal Protective Equipment (PPE): Wear appropriate laboratory PPE at all times: nitrile gloves, safety glasses or goggles, and a laboratory coat. Work in a well-ventilated area or fume hood when weighing or dissolving the compound.

Handling: Use dry, inert-atmosphere techniques when working with solutions intended for sensitive transformations. The compound is typically supplied as a colourless to pale yellow oil or low-melting solid; allow the container to equilibrate to room temperature before opening to prevent condensation. Weigh and transfer rapidly to minimise exposure to atmospheric moisture.

Waste disposal: Dispose of all waste in accordance with applicable local, national and institutional regulations. Do not pour into drains or waterways. Consult the Safety Data Sheet (SDS) supplied with the product for complete hazard information before use.

Note: Always consult the current SDS for this product (SKU B121554) prior to first use. The information provided here is a general technical guideline and does not substitute for the SDS.

Quality, Purity and Analytical Characterisation

For stereoselective synthesis applications, the enantiomeric excess (ee) and chemical purity of (R)-(-)-1-Boc-3-(hydroxymethyl)piperidine are critical parameters. Aladdin Scientific's product (SKU B121554) is characterised using standard analytical methods including:

• Chiral HPLC or GC: Verification of enantiomeric excess (ee) to confirm the (R) configuration and absence of the (S) enantiomer above specification limits.
• Optical rotation measurement: Confirmation of the negative specific rotation consistent with the (R) absolute configuration.
• ¹H and ¹³C NMR spectroscopy: Full assignment of the piperidine ring protons and carbons, Boc tert-butyl singlet (~1.45 ppm, 9H), and the hydroxymethyl methylene signals.
• GC or HPLC purity: Chemical purity assessment to confirm absence of synthetic by-products or degradation impurities.
• Karl Fischer titration: Water content determination where relevant for moisture-sensitive applications.

Researchers requiring certificates of analysis (CoA) or additional analytical data for lot-specific batches should contact Aladdin Scientific technical support or request documentation at the time of ordering.

Recommended Solvents and Compatibility

(R)-(-)-1-Boc-3-(hydroxymethyl)piperidine is generally soluble in common polar aprotic and protic organic solvents. The following solvent guidance is provided based on the compound's polarity profile and functional group sensitivity:

• Good solvents: Dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, methanol, ethanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile.
• Moderate solvents: Diethyl ether, toluene (may require warming).
• Avoid: Strongly acidic aqueous media (will cleave the Boc group), strongly oxidising conditions (risk of alcohol oxidation), and prolonged exposure to protic solvents at elevated temperatures (risk of carbamate solvolysis).

For reactions requiring Boc deprotection, 20–50% TFA in DCM or 4 M HCl in 1,4-dioxane are standard protocols. Monitor reaction progress by TLC or LC-MS. The resulting amine salt should be basified carefully before further use in base-sensitive transformations.

Frequently asked questions

What is the significance of the (R) configuration in this building block?

The (R) absolute configuration at C-3 provides a defined stereocentre that can be used to introduce chirality into target molecules without the need for a resolution step. In drug discovery, single-enantiomer building blocks are essential because enantiomers of a drug molecule can differ significantly in pharmacological activity, selectivity and metabolic profile, making enantiopure intermediates a regulatory and scientific priority.

How do I remove the Boc protecting group from this compound?

The Boc group is readily removed under mild acidic conditions. The two most common protocols are: (1) treatment with 20–50% trifluoroacetic acid (TFA) in dichloromethane (DCM) at room temperature for 30–60 minutes, or (2) treatment with 4 M HCl in 1,4-dioxane at room temperature. After complete deprotection (monitored by TLC or LC-MS), remove volatiles under reduced pressure and basify the resulting salt if a free amine is required for the next step. These conditions do not epimerize the stereocentre.

What reactions can be performed on the hydroxymethyl group?

The primary hydroxymethyl group is versatile: it can be oxidised to an aldehyde (e.g., Swern, Dess–Martin periodinane) or carboxylic acid, converted to a mesylate or tosylate for nucleophilic substitution, subjected to Mitsunobu reaction for stereoinversion with retention at the piperidine stereocentre, or protected as a silyl ether, THP acetal or benzyl ether for downstream manipulation. The choice of transformation depends on the target molecule and the compatibility with the Boc group and the existing stereocentre.

What are the recommended storage conditions to maintain enantiomeric purity?

Store (R)-(-)-1-Boc-3-(hydroxymethyl)piperidine at 2–8 °C in a tightly sealed vial under an inert atmosphere (nitrogen or argon), away from moisture and light. Avoid repeated freeze-thaw cycles if the material is in solution. Under these conditions the enantiomeric excess is maintained over the stated shelf life. If long-term storage is required, confirm ee by chiral HPLC before use in critical synthetic steps.

Is this compound available in multiple pack sizes from Aladdin Scientific?

(R)-(-)-1-Boc-3-(hydroxymethyl)piperidine is listed in the Aladdin Scientific catalogue under SKU B121554. For specific pack size availability, current pricing and stock status, please visit the Aladdin Scientific website or contact your local sales representative. Custom quantities may be available upon request.

References

1. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (General reference for Boc protection and piperidine chemistry.)
2. Roughley, S. D.; Jordan, A. M. The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451–3479. doi:10.1021/jm200187y
3. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756. (Highlights importance of sp3-rich, piperidine-containing scaffolds in drug discovery.) doi:10.1021/jm901241e

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