2-oxa-7-azaspiro[4.4]nonane: Properties, Uses & Research

2-oxa-7-azaspiro[4.4]nonane is a bicyclic spirocyclic compound featuring a tetrahydrofuran ring and a pyrrolidine ring joined at a shared quaternary spiro carbon, making it a highly valued scaffold in medicinal chemistry and drug discovery research.

IUPAC Name

2-oxa-7-azaspiro[4.4]nonane

Molecular Formula

C7H13NO

Molecular Weight

127.18 g/mol

Compound Class

Spirocyclic heterocycle (oxa-aza bicyclic)

Key Functional Groups

Secondary amine (NH), ether oxygen within ring

Primary Application

Medicinal chemistry building block and drug discovery intermediate

Structure and Chemical Properties

2-oxa-7-azaspiro[4.4]nonane belongs to the class of spirocyclic heterocycles, characterized by two five-membered rings — a tetrahydrofuran (oxolane) ring and a pyrrolidine ring — fused at a single quaternary spiro carbon atom. The systematic name indicates the positions of the heteroatoms: oxygen at position 2 and nitrogen at position 7 within the nonane carbon framework.

The compound possesses a molecular formula of C₇H₁₃NO and a molecular weight of approximately 127.18 g/mol. The secondary amine nitrogen renders the molecule basic and nucleophilic, enabling participation in a wide range of chemical transformations including N-alkylation, N-acylation, reductive amination, and coupling reactions. The ether oxygen within the tetrahydrofuran ring contributes to the molecule's polarity and hydrogen-bond-accepting capability, improving aqueous solubility relative to purely carbocyclic analogues.

The rigid, three-dimensional spiro architecture imparts distinct conformational constraints compared to linear or monocyclic analogues, which is a key driver of interest in pharmaceutical research where shape-complementarity to biological targets is critical.

Synthesis and Availability

2-oxa-7-azaspiro[4.4]nonane can be prepared via several established synthetic strategies commonly employed for spirocyclic amine construction. One general approach involves the cyclization of appropriately functionalized amino alcohol precursors, where intramolecular etherification or lactamization closes the second ring onto a preformed pyrrolidine or tetrahydrofuran core.

An alternative route employs [3+2] or ring-expansion methodologies starting from cyclic ketones, where reductive amination or oxime reduction steps introduce the nitrogen functionality, followed by ring closure to furnish the spiro framework. The secondary amine product may be isolated as the free base or as a stable salt (e.g., hydrochloride) for improved handling and storage stability.

Aladdin Scientific supplies 2-oxa-7-azaspiro[4.4]nonane (SKU: O175002) to support researchers requiring reliable, high-purity material for synthetic and biological investigations. Researchers are encouraged to consult the product specification sheet for confirmed purity, appearance, and storage conditions prior to use.

Applications in Medicinal Chemistry and Drug Discovery

Spirocyclic amines such as 2-oxa-7-azaspiro[4.4]nonane have gained considerable traction in modern drug discovery as privileged scaffolds. Their three-dimensional geometry allows access to regions of chemical space that are poorly covered by flat, aromatic compounds, which is increasingly recognized as important for the development of selective, drug-like candidates with favorable ADMET profiles.

The secondary amine of 2-oxa-7-azaspiro[4.4]nonane serves as a versatile handle for library synthesis, enabling straightforward derivatization via acylation, sulfonylation, reductive amination, or transition-metal-catalyzed cross-coupling. The resulting analogues are evaluated as inhibitors or modulators of enzymes, G-protein-coupled receptors (GPCRs), and ion channels, among other target classes.

The incorporation of an oxygen atom within the ring system improves aqueous solubility and reduces lipophilicity compared to the all-carbon spirocyclic analogue (2-azaspiro[4.4]nonane), making oxa-aza spiro scaffolds attractive for lead optimization campaigns where permeability and solubility must be balanced.

Furthermore, the rigid spiro core can restrict conformational freedom of appended pharmacophores, potentially enhancing binding selectivity and metabolic stability — two parameters critical to advancing candidates from hit to lead and beyond.

Handling, Storage, and Safety Considerations

As with most reactive amine-containing heterocycles, standard laboratory precautions apply when working with 2-oxa-7-azaspiro[4.4]nonane. Researchers should consult the current Safety Data Sheet (SDS) supplied with the product before use to obtain authoritative hazard, handling, and disposal information.

General good laboratory practices include working in a well-ventilated fume hood, wearing appropriate personal protective equipment (PPE) including nitrile gloves, lab coat, and safety eyewear. Contact with skin, eyes, and mucous membranes should be avoided. The compound should be stored under conditions specified on the product label — typically in a cool, dry environment, sealed under inert atmosphere if moisture-sensitive.

Waste disposal must comply with local institutional and governmental regulations for chemical waste. Researchers are reminded that regulatory requirements vary by jurisdiction, and the SDS should be consulted for jurisdiction-specific disposal guidance.

Frequently asked questions

What is 2-oxa-7-azaspiro[4.4]nonane used for in research?

2-oxa-7-azaspiro[4.4]nonane is primarily used as a spirocyclic building block in medicinal chemistry and drug discovery. Its secondary amine group enables diverse derivatization reactions, and the rigid three-dimensional spiro scaffold helps researchers explore chemical space beyond flat aromatic compounds, supporting the development of selective, drug-like molecules.

How does the oxa-aza spiro scaffold differ from all-carbon spiro analogues?

Replacing a methylene group with an oxygen atom within the ring system of 2-oxa-7-azaspiro[4.4]nonane increases molecular polarity, improves aqueous solubility, and reduces lipophilicity compared to all-carbon analogues such as 2-azaspiro[4.4]nonane. These property differences are often advantageous during lead optimization, where achieving a balance between membrane permeability and solubility is essential.

What reactions can be performed on the secondary amine of 2-oxa-7-azaspiro[4.4]nonane?

The secondary amine of 2-oxa-7-azaspiro[4.4]nonane is nucleophilic and can undergo N-alkylation, N-acylation, sulfonylation, reductive amination, and transition-metal-catalyzed cross-coupling reactions such as Buchwald-Hartwig amination. These transformations make it a versatile handle for generating diverse analogues in combinatorial or medicinal chemistry libraries.

How should 2-oxa-7-azaspiro[4.4]nonane be stored?

Storage conditions should be confirmed by consulting the product label and Safety Data Sheet (SDS) provided by Aladdin Scientific. In general, amine-containing heterocycles are stored in a cool, dry location, sealed under an inert atmosphere to prevent moisture uptake and oxidation. Always follow the specific instructions provided with the product.

Is 2-oxa-7-azaspiro[4.4]nonane available from Aladdin Scientific?

Yes, 2-oxa-7-azaspiro[4.4]nonane is available from Aladdin Scientific under SKU O175002. Researchers can contact Aladdin Scientific for information on available quantities, purity specifications, pricing, and delivery options.

References

1. 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. doi:10.1021/jm901241e
2. Zheng, Y.; Tice, C. M.; Singh, S. B. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett. 2014, 24, 3673–3682. doi:10.1016/j.bmcl.2014.06.081
3. Mykhailiuk, P. K. Saturated bioisosteres of benzene: where to go next? Org. Biomol. Chem. 2019, 17, 2839–2849. doi:10.1039/C8OB02812E

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