5-Benzyloxyindole is an organic compound with CAS 1215-59-4 and molecular formula C18H15NO. It is a white to light yellow solid, usually in a crystalline form. Has a certain aromatic odor, but no obvious taste. This odor mainly comes from the benzene ring in its molecular structure. Its molecular structure contains benzene rings and nitrogen heterocycles, thus exhibiting distinct organic compound characteristics in appearance. It has good solubility and can be dissolved in most organic solvents, such as alcohols, ethers, ketones, etc.
However, its solubility in water is relatively low. It does not have significant conductivity and can therefore be considered a non-conductive material. This is related to the lack of freely movable electrons in its molecular structure. Stable at room temperature and pressure, but may undergo decomposition or oxidation reactions under certain conditions. For example, in the presence of strong acids or bases, their molecular structure may undergo fragmentation or transformation. It has broad application value in fields such as medicine, biotechnology, and organic synthesis.
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C.F |
C15H13NO |
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E.M |
223 |
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M.W |
223 |
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m/z |
223 (100.0%), 224 (16.2%), 225 (1.2%) |
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E.A |
C, 80.69; H, 5.87; N, 6.27; O, 7.17 |
5-Benzyloxyindole (5-Benzyindole) is an indole compound with a unique chemical structure, which has shown extensive application value in chemical synthesis, pharmaceutical research and development, materials science and other fields.
Chemical synthesis field
Regional and stereoselective catalytic reactions&Metal free catalytic reaction
5-Benzyindole can be used as a key reagent to participate in regioselective and stereoselective catalytic reactions. For example:
Morpholine catalyzed C-3 alkynylation reaction: Under mild conditions, 5-benzyindole undergoes direct C-3 alkynylation reaction with α, β - unsaturated aldehydes under morpholine catalysis, producing alkynylation products with specific stereoisomers. This reaction is of great significance in the total synthesis of natural products and the construction of drug molecules.
Debenzylation reaction under silica palladium catalytic system: In the silica palladium catalytic system, 5-benzyindole can serve as a selective debenzylation reagent for protecting groups, achieving exposure of hydroxyl groups at specific positions and providing a key step for the synthesis of complex molecules.
5-Benzyindole can also be used in metal free catalytic reactions, such as:
Friedel Crafts alkylation reaction: As a reagent, 5-benzyindole can participate in Friedel Crafts alkylation reaction under metal free conditions to generate arylalkylation products. This reaction condition is mild and avoids the use of metal catalysts, which is in line with the development trend of green chemistry.
Synthesis of protein kinase C (PKC) inhibitors
5-Benzyindole is an important intermediate for the synthesis of protein kinase C (PKC) inhibitors. PKC is a type of serine/threonine protein kinase that participates in various physiological processes such as cell proliferation, differentiation, and apoptosis. By modifying the structure of 5-benzyindole, PKC inhibitors with specific selectivity and activity can be designed for the treatment of diseases such as tumors and inflammation.
Synthesis of Indole/Quinoline Thiohydroxyamide Derivatives
5-Benzyindole can also be used to synthesize indole/quinoline thiolamide derivatives. These compounds have unique biological activities, such as antibacterial, antiviral, anti-tumor, etc., and are an important direction for drug development. 5-Benzyindolee, as a key intermediate, can be used to construct a library of derivatives with specific structures through thiohydroxy acid amidation reaction, providing a material basis for drug screening.
Pharmaceutical research and development field
Synthesis of 5-hydroxytryptophan (5-HTP)
5-Benzyindole is a key intermediate for the synthesis of 5-hydroxytryptophan (5-HTP). 5-HTP is a precursor substance of serotonin (5-HT) in the human body, which has sedative, antidepressant, and sleep improving effects. Through chemical synthesis methods, 5-HTP can be efficiently prepared using 5-benzyindole as the raw material, meeting the needs of the pharmaceutical and health product fields.
Research and development of anti-tumor drugs
5-Benzyindole and its derivatives have potential application value in the development of anti-tumor drugs. Research has shown that certain indole compounds can inhibit tumor cell proliferation, induce tumor cell apoptosis, inhibit tumor angiogenesis, and so on. By modifying the structure of 5-benzyindole, drug molecules with higher anti-tumor activity and selectivity can be designed.
Research on the treatment of neurological diseases
5-Benzyloxyindole also has potential applications in the treatment of neurological diseases. For example, serotonin (5-HT) is an important neurotransmitter involved in regulating various physiological functions such as mood, sleep, and appetite. 5-HTP, as a precursor of 5-HT, can improve neurological function by supplementing 5-HT levels. Therefore, 5-benzyindole has significant value in the development of drugs for depression, anxiety, and sleep improvement.
Research on drug metabolism and pharmacokinetics
5-Benzyindole can also be used as a model compound for studying the metabolic pathways and pharmacokinetic properties of drugs. By tracking its absorption, distribution, metabolism, and excretion processes in the body, the mechanism of action and sources of toxicity of drugs can be revealed, providing scientific basis for drug optimization and clinical application.
Materials Science Field
Synthesis of functional polymer materials
5-Benzyindole can be used to synthesize polymer materials with specific functions. For example, by introducing it into the polymer main chain or side chain, polymer materials with photoresponsiveness, electrical responsiveness, or biocompatibility can be constructed. This type of material has broad application prospects in fields such as smart sensors, biomedical materials, optoelectronic devices, etc.
5-Benzyindole can also be used for the preparation of nanomaterials. For example, it can serve as a template or stabilizer to guide the growth and assembly of nanoparticles, forming nanostructures with specific morphology and size.This type of nanomaterial has potential application value in fields such as catalysis, sensing, biological imaging, and drug delivery.
Preparation of nanomaterials&Surface modification materials
5-Benzyindole can also be used for the preparation of surface modification materials.
By fixing it on the surface of the material, the surface properties and functions of the material can be changed. For example, modifying 5-benzyindole on metal or polymer surfaces can improve the material's biocompatibility, corrosion resistance, and wear resistance. This type of surface modification material has important application value in fields such as medical devices, biosensors, and tissue engineering.
Agricultural field&Spices and essence
In the field of agriculture, 5-benzyindole and its derivatives may have plant growth regulatory effects. Research has shown that certain indole compounds can promote plant growth and development, improve plant stress resistance and yield. By modifying and optimizing its structure, plant growth regulators with higher activity and selectivity can be designed, providing new technological means for agricultural production.
Analyze chemical standards
5-Benzyindole has unique aroma characteristics and can be used in the synthesis of spices and essence. By adjusting its structure or mixing with other flavor molecules, essence products with specific fragrance and durability can be prepared, which are widely used in cosmetics, food, daily necessities and other fields.
5-Benzyindole can also be used as an analytical chemical standard for calibration and quality control of instruments such as chromatography and mass spectrometry. Its high purity and stability make it an important reagent in the field of analytical chemistry.
Classification of Synthetic Routes and Process Selection
5-Benzyloxyindole (CAS: 1215-59-4) is a core protected intermediate for 5-hydroxytryptamine and tryptamine pharmaceuticals. Its synthetic methods are mainly divided into two categories: the short one-step benzylation route and the long Fisher indole cyclization route.
For laboratory-scale preparation, the Williamson etherification route using 5-hydroxyindole as the starting material is preferred due to fewer steps and high reaction selectivity.
For industrial mass production, the four-step cyclization route starting from m-cresol is widely adopted, featuring cheap and easily accessible raw materials and superior scale-up stability.
This paper elaborates on the general laboratory benzylation synthetic process, focusing on side reaction suppression and post-treatment purification protocols, with an overall yield ranging from 85% to 90%.
Standard Experimental Procedures
Pretreatment of Anhydrous System
Fully dry the reaction vessel and purge with nitrogen three times to exclude water vapor. Charge 1 equivalent of 5-hydroxyindole into a three-necked flask, add anhydrous N,N-dimethylformamide (DMF) and stir until complete dissolution.
Subsequently add 1.3 equivalents of solid anhydrous potassium carbonate, and stir at room temperature for 1 hour to complete deprotonation of phenolic hydroxyl groups, affording a suspension of potassium phenoxide. Excess potassium carbonate neutralizes hydrogen chloride generated in the reaction and maintains a weakly alkaline system to prevent substrate hydrolysis.
Temperature-Controlled Benzylation Substitution Reaction
Cool the reaction system to 0–5 °C via an ice-water bath, then slowly add dropwise 1.1 equivalents of benzyl chloride over no less than 2 hours, keeping the temperature below 10 °C throughout the addition. After dropwise addition, remove the ice bath, heat the mixture to 65 °C, and stir at constant temperature for 8 hours.
Monitor the reaction progress by thin-layer chromatography (TLC) with petroleum ether-ethyl acetate (3:1) as the developing solvent; terminate the reaction once the raw material spot completely disappears. High temperatures aggravate the formation of N-benzylated byproducts, so the temperature must never exceed 80 °C.
Quenching, Extraction and Concentration
Cool the reaction mixture to room temperature, then slowly pour it into 10 times its volume of ice water for quenching, resulting in precipitation of a large amount of crude solid. Collect the solid via suction filtration, extract the filtrate with ethyl acetate twice, and combine the organic phases with the filter cake crude product. Wash sequentially with saturated brine and pure water to remove residual DMF and inorganic salts. Dry the combined organic phase over anhydrous sodium sulfate for 4 hours, then remove the solvent by rotary evaporation under reduced pressure at 45 °C to obtain a pale yellow crude solid.
Purification by Recrystallization
Purify the crude product via recrystallization using an ethanol-water mixed solvent system: dissolve the crude solid in hot anhydrous ethanol under heating, slowly add deionized water dropwise until slight turbidity appears, cool to induce crystallization, filter at low temperature, and dry under vacuum at 40 °C to afford pure white acicular 5-benzyindole with purity ≥99.2% and single-step yield of 86%–89%. For samples with high impurity content, secondary recrystallization or short silica gel column chromatography can be performed to remove trace N-benzylindole impurities.
Critical Process Control and Side Reaction Avoidance
Anhydrous control: DMF must be dehydrated with molecular sieves, and benzyl chloride should be stored in a sealed container. Trace water drastically reduces reaction selectivity and leaves unreacted 5-hydroxyindole as residual impurity.
Alkaline system selection: Strong bases such as NaH and NaOH are prohibited. Strongly alkaline environments simultaneously activate indole N-H bonds, pushing the proportion of N-alkylation impurities above 15%.
Gradient temperature control: Conduct dropwise addition at low temperature and hold the reaction at moderate temperature. Rapid temperature rise easily triggers self-polymerization of benzyl chloride and produces benzyl ether tar impurities.
Solvent recovery: Recover DMF by vacuum distillation; after drying and dehydration, the recovered DMF can be recycled to reduce waste discharge and raw material costs.
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