1-Cyclopropylnaphthalene
[CAS 25033-19-6]

Identification

• Classification: Organic raw materials >> Aryl compounds >> Naphthalenes
• Name: 1-Cyclopropylnaphthalene
• Synonyms: 1-Naphthylcyclopropane
• Molecular Formula: C₁₃H₁₂
• Molecular Weight: 168.23
• CAS Registry Number: 25033-19-6
• EC Number: 690-694-7
• SMILES: C1CC1C2=CC=CC3=CC=CC=C32

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 296.4±7.0 °C 760 mmHg (Calc.)^*
• Flash point: 135.2±8.9 °C (Calc.)^*
• Index of refraction: 1.663 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS09 Warning
• Risk Statements: H410
• Safety Statements: P273-P391-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410

chemBlink Chemical Story

1-Cyclopropylnaphthalene, CAS 25033-19-6, is an aromatic hydrocarbon used primarily as an organic and pharmaceutical intermediate. Its molecular formula is C₁₃H₁₂ and its molecular weight is 168.23. Structurally, it consists of a naphthalene system bearing a cyclopropyl group at the 1-position. The molecule is therefore built from two very different carbon frameworks: a large, flat fused aromatic system and one of the smallest possible carbon rings.

Naphthalene consists of two fused benzene rings and provides a rigid, hydrophobic aromatic surface. Cyclopropane, by contrast, is a three-membered ring whose carbon-carbon bonds are forced into an unusual geometry. Combining these two motifs produces a compact arylcyclopropane that has attracted interest both as a subject of fundamental organic chemistry and as a building block in medicinal chemistry.

Cyclopropane is particularly interesting because its bonding cannot be understood simply as a miniature version of an ordinary cycloalkane. The approximately 60-degree internal angles are far from the preferred tetrahedral geometry of an sp³ carbon atom. The carbon-carbon bonds consequently have unusual orbital character, often described in terms of bent or "banana" bonds. Despite this ring strain, cyclopropanes can be sufficiently stable to survive many synthetic transformations.

Arylcyclopropanes have therefore been studied for decades as systems in which a strained three-membered ring interacts electronically with an aromatic group. Classic spectroscopic studies of cyclopropyl aromatic compounds examined how cyclopropane substitution changes ultraviolet absorption and electronic behavior. These investigations helped establish that a cyclopropyl group is not simply equivalent to a conventional saturated propyl substituent.

For medicinal chemists, cyclopropane offers another advantage: it places three carbon atoms into a compact, conformationally restricted structure. Replacing a flexible alkyl group with cyclopropyl can change molecular shape, lipophilicity, metabolic susceptibility, and the way a molecule occupies a hydrophobic binding pocket. Cyclopropyl groups have consequently become common structural motifs in modern drug discovery.

1-Cyclopropylnaphthalene provides a particularly clear pharmaceutical example because it is an established intermediate in the synthesis of lesinurad. Lesinurad was developed as a uricosuric agent targeting urate transport, particularly URAT1, a transporter involved in the renal reabsorption of uric acid.

The relationship is structurally direct. The cyclopropylnaphthalene portion of CAS 25033-19-6 is not merely a temporary synthetic aid. It survives through subsequent transformations and becomes the 4-cyclopropylnaphthalen-1-yl portion of the lesinurad molecule. In this case, a relatively simple hydrocarbon intermediate already contains a substantial part of the final drug's hydrophobic molecular architecture.

Published synthetic routes show how the simple starting material is progressively elaborated. 1-Cyclopropylnaphthalene can first undergo regioselective nitration to give 1-cyclopropyl-4-nitronaphthalene. Reduction of the nitro group then produces 4-cyclopropylnaphthalen-1-amine. Subsequent functional-group transformations introduce the nitrogen- and sulfur-containing structures required for the triazole portion of the lesinurad framework.

This sequence illustrates an important concept in synthetic planning. When a final molecule contains a difficult structural motif, chemists often build that motif into an early intermediate and preserve it through the remaining steps. Here, the cyclopropyl group is already attached to naphthalene before the much more elaborate heterocyclic and sulfur-containing portions are constructed.

The synthesis of 1-cyclopropylnaphthalene itself has been approached in several ways. Published chemistry includes coupling of naphthalene derivatives with cyclopropyl organometallic or organoboron reagents. A reported route to lesinurad, for example, couples 1-bromonaphthalene with cyclopropylmagnesium bromide under nickel catalysis to produce 1-cyclopropylnaphthalene. Other literature describes palladium-catalyzed coupling of 1-bromonaphthalene with cyclopropylboronic acid.

These reactions demonstrate another important feature of cyclopropane chemistry: under properly selected catalytic conditions, the strained three-membered ring can be transferred intact. The goal is not to open the ring but to preserve it while establishing a new bond between the cyclopropyl carbon and the aromatic system.

The medicinal significance of the resulting cyclopropylnaphthalene motif extends beyond a single manufacturing route. Research on URAT1 inhibitors derived from lesinurad has continued to examine the contribution of the 1-cyclopropylnaphthalene core. Reviews of this field describe this hydrophobic region as an important part of molecular recognition, and analog studies have retained or modified the motif while searching for compounds with altered potency and safety profiles.

This does not mean that 1-cyclopropylnaphthalene itself has the pharmacological activity of lesinurad. CAS 25033-19-6 is a synthetic intermediate, not the finished uricosuric drug. The additional heterocyclic, sulfur-containing, halogenated, and carboxylic-acid functionality of lesinurad is essential to the properties of the complete molecule.

The distinction is chemically instructive. Some pharmaceutical intermediates carry temporary groups that disappear completely before the drug is finished. Others, like 1-cyclopropylnaphthalene, contribute a recognizable molecular fragment that survives almost unchanged. Following such an intermediate through a synthetic route is therefore like watching one piece of the final molecular architecture appear early and remain visible while the rest of the drug is assembled around it.

1-Cyclopropylnaphthalene is a simple hydrocarbon, containing no nitrogen, oxygen, sulfur, or halogen. Yet its combination of a rigid aromatic surface and a strained three-membered carbon ring made it useful in the construction of a much more complex pharmaceutical molecule. It demonstrates a central principle of medicinal chemistry: sometimes an important pharmacophore begins not as a complicated functional molecule, but as a carefully chosen piece of molecular shape.

References

1. PubChem. 1-Cyclopropylnaphthalene, CID 14668693. CAS 25033-19-6. Molecular formula C₁₃H₁₂; molecular weight 168.23.
https://pubchem.ncbi.nlm.nih.gov/compound/14668693

2. Hahn, R. C.; Howard, P. H.; Kong, S. M.; Lorenzo, G. A.; Miller, N. L. (1969). "Cyclopropyl Aromatic Chemistry. I. Ultraviolet Spectra of Certain Cyclopropyl Aromatic Systems." Journal of the American Chemical Society, 91, 3558-3566.

3. Lemhadri, M.; Doucet, H.; Santelli, M. (2006). Palladium-catalyzed coupling chemistry involving cyclopropylboronic acid. Synthetic Communications, 36, 121-128.

4. WO 2011/085009 A2. Ardea Biosciences. Synthetic processes and forms related to lesinurad, including preparation and use of 1-cyclopropylnaphthalene.

5. Chen, J. et al. (2021). "Recent Updates of Natural and Synthetic URAT1 Inhibitors and Novel Screening Methods." Evidence-Based Complementary and Alternative Medicine, 2021, 5738900.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8572588/