5-(Benzyloxy)indole: Properties, Uses & FAQs

5-(Benzyloxy)indole is a synthetically versatile indole building block in which the C-5 hydroxyl is protected as a benzyl ether, enabling selective functionalization of the indole nucleus in complex molecule synthesis.

Chemical Name

5-(Benzyloxy)indole

CAS Number

13112-31-7

Molecular Formula

C₁₅H₁₃NO

Molecular Weight

223.27 g/mol

Protecting Group Strategy

Benzyl ether protection of 5-hydroxyindole; removable by hydrogenolysis

Appearance

White to off-white crystalline solid

Aladdin SKU

B406873

What Is 5-(Benzyloxy)indole and Why Is It Used?

5-(Benzyloxy)indole (CAS 13112-31-7) is a protected form of 5-hydroxyindole in which the phenolic hydroxyl group at the 5-position of the indole ring is masked as a benzyl ether. This protection strategy is widely adopted in multi-step organic synthesis because it prevents unwanted reactions at the hydroxyl site—such as O-alkylation, oxidation, or interference with nucleophilic coupling reactions—while the indole C-2 and C-3 positions remain available for electrophilic or transition-metal-catalysed functionalisation.

The compound serves as a key intermediate in the preparation of 5-hydroxyindole-containing natural products, pharmaceutical analogues, and fluorescent probes. After the desired transformations are complete, the benzyl protecting group can be cleanly removed by catalytic hydrogenolysis (e.g., Pd/C, H₂, EtOH) under mild conditions to reveal the free 5-hydroxyindole moiety without disturbing most other functional groups.

Physicochemical Properties and Handling

5-(Benzyloxy)indole is a white to off-white crystalline solid with the molecular formula C₁₅H₁₃NO and a molecular weight of 223.27 g/mol. It is sparingly soluble in water but dissolves readily in common organic solvents such as dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, and methanol. Its indole NH is mildly acidic and can participate in hydrogen-bonding interactions, influencing its solubility and reactivity profile.

Standard laboratory safety precautions apply: wear appropriate personal protective equipment (gloves, lab coat, eye protection), work in a well-ventilated area or fume hood, and avoid inhalation of dust. Consult the Safety Data Sheet (SDS) provided by Aladdin Scientific for complete hazard information before use.

Storage and Stability

For long-term stability, 5-(Benzyloxy)indole should be stored in a tightly sealed container at room temperature (15–25 °C) in a cool, dry location away from light. Protection from moisture and strong oxidising agents is recommended. Under these conditions the compound is expected to be stable for an extended period; however, periodic quality checks by TLC or HPLC are advisable for stocks held longer than 24 months.

When removed from storage, allow the container to equilibrate to room temperature before opening to prevent condensation on the product, which can accelerate degradation. Working solutions in organic solvents should be prepared fresh or stored under inert atmosphere at reduced temperature.

Key Synthetic Applications

The benzyloxy group at C-5 renders the indole ring electron-rich, facilitating electrophilic substitution reactions preferentially at C-3 (and secondarily at C-2). This selectivity makes 5-(Benzyloxy)indole a useful precursor for the synthesis of tryptamine and tryptophan analogues bearing a 5-hydroxy or 5-alkoxy group, which are relevant to the study of serotonin receptor pharmacology.

The compound also finds use as a starting material in Pictet–Spengler reactions, Fischer indole synthesis variants, and palladium-catalysed cross-coupling reactions at C-2 or through N-functionalisation. Following deprotection, the released 5-hydroxyindole unit can be further elaborated via O-alkylation, O-acylation, or oxidative cyclisation to access structurally diverse indole scaffolds found in bioactive natural products.

Ordering and Quality Information

5-(Benzyloxy)indole is available from Aladdin Scientific under SKU B406873. Aladdin Scientific provides a Certificate of Analysis (CoA) with each lot, detailing purity (typically assessed by HPLC or GC), appearance, melting point, and NMR data where applicable. Researchers requiring a specific purity grade or custom pack size are encouraged to contact Aladdin's technical sales team.

For procurement, the compound can be ordered directly through the Aladdin Scientific online portal. Bulk quantities may be available upon request; lead times and pricing are confirmed at the time of order. All shipments comply with applicable regulations for chemical transport.

Frequently asked questions

What is the difference between 5-(Benzyloxy)indole and 5-hydroxyindole?

5-Hydroxyindole bears a free phenolic hydroxyl group at the C-5 position, which can interfere with many synthetic transformations through O-alkylation, oxidation, or competing nucleophilicity. 5-(Benzyloxy)indole is simply the benzyl-protected form of 5-hydroxyindole: the hydroxyl is converted to a benzyl ether (–OBn), which is stable to a broad range of reaction conditions. The free phenol is regenerated quantitatively by catalytic hydrogenolysis (Pd/C, H₂) under mild conditions.

How should 5-(Benzyloxy)indole be dissolved for use in reactions?

The compound dissolves readily in polar aprotic solvents (DMF, THF, acetonitrile), chlorinated solvents (DCM, chloroform), and ethyl acetate. It has limited solubility in water. For most synthetic applications, prepare a stock solution in the chosen reaction solvent immediately before use, or store solutions under nitrogen or argon at 0–4 °C to minimise potential degradation.

Can the benzyl group in 5-(Benzyloxy)indole be removed selectively without reducing other functional groups?

Catalytic hydrogenolysis (Pd/C, 1 atm H₂, EtOH or MeOH) is the standard method for removing benzyl ethers and is compatible with most functional groups, including esters, amides, and aryl halides under optimised conditions. However, it will also reduce alkenes, alkynes, and other easily hydrogenolysable groups, so careful optimisation of conditions is necessary when such groups are present in the molecule. Alternative deprotection methods, such as Lewis acid-mediated cleavage (e.g., BCl₃) or transfer hydrogenation (ammonium formate/Pd/C), may offer complementary selectivity.

What analytical methods are used to confirm the identity and purity of 5-(Benzyloxy)indole?

Identity is typically confirmed by ¹H NMR and ¹³C NMR spectroscopy, which reveal the characteristic indole NH signal, aromatic proton patterns, and the benzylic –OCH₂– singlet near δ 5.1 ppm. Purity is routinely assessed by HPLC (reverse-phase C18 column) or GC. Mass spectrometry (ESI-MS or EI-MS) provides confirmation of the molecular ion at m/z 223. Melting point measurement offers a quick purity check; literature values should be confirmed on the CoA supplied with each batch.

Is 5-(Benzyloxy)indole suitable for use in Pictet–Spengler reactions?

Yes. 5-(Benzyloxy)indole is well-suited for Pictet–Spengler condensations with aldehydes or ketones in the presence of a Brønsted or Lewis acid catalyst, yielding 1,2,3,4-tetrahydro-β-carboline derivatives bearing the 8-benzyloxy substituent (corresponding to the 5-position of the indole precursor). These products are relevant as scaffolds in the synthesis of alkaloid natural product analogues. After cyclisation, the benzyl group can be removed to provide the corresponding 8-hydroxy-β-carboline.

References

1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th ed.; Wiley-Interscience: Hoboken, NJ, 2007.
2. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012.
3. Aladdin Scientific Certificate of Analysis for 5-(Benzyloxy)indole, SKU B406873.

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