Below is synthesis procedure for preparing 3-(2-methoxybenzoyl)indole (an RCS-2 precursor) from indole, using 2-methoxybenzoyl chloride. I’ve tailored it based on bbgate jwh-018 precursor original procedure for clarity and auditability by we would like to discuss adjustments, feasibility and reaction time with an experienced chemist.
3-(2-Methoxybenzoyl)indole Synthesis From Indole
To synthesize 3-(2-methoxybenzoyl)indole as a precursor for RCS-2 via Friedel-Crafts acylation of indole with 2-methoxybenzoyl chloride.
Materials:
- Indole: 100 g (~0.85 moles, MW = 117.15 g/mol)
- Dichloromethane (DCM): 300 mL + 200 mL
- Aluminum chloride (AlCl₃): 114 g (~0.85 moles, MW = 133.34 g/mol)
- 2-Methoxybenzoyl chloride: 145 g (~123 mL, ~0.85 moles, MW = 170.59 g/mol, density ~1.18 g/mL)
- Cold water: 3 L (for quenching)
Equipment:
- 2 L round-bottom flask
- Magnetic stirrer or overhead stirrer
- Ice bath (ice water or chilled brine)
- Beaker (for preparing 2-methoxybenzoyl chloride solution)
- Glass rod (for crushing crystals)
- Large vessel (≥3 L) for quenching
- Filtration setup (e.g., Buchner funnel)
Let's go !
1. **Preparation of Indole Solution
Pour 100 g of indole into a 2 L flask. Add 300 mL of dichloromethane (DCM) and stir the mixture until the indole is completely dissolved.
2.
Place the flask in an ice bath (ice water or chilled brine) and cool the reaction mixture to 0-10°C while stirring.
3. **Addition of Aluminum Chloride
Gradually add 114 g of aluminum chloride (AlCl₃) to the flask with constant stirring. Continue stirring until the AlCl₃ is fully dissolved. (Note: This step may generate some heat; maintain the temperature at 0-10°C.)
4. **Preparation of 2-Methoxybenzoyl Chloride Solution
Measure 145 g (~123 mL) of 2-methoxybenzoyl chloride into a beaker. Add 200 mL of DCM and mix thoroughly to form a homogeneous solution. (Note: 2-Methoxybenzoyl chloride is a liquid at room temperature—no heating is required, unlike 1-naphthoyl chloride.)
5. Acylation Reaction
Slowly add the 2-methoxybenzoyl chloride/DCM solution from the beaker into the flask, maintaining the reaction temperature at 0-10°C. Stir continuously during the addition to ensure even mixing.
6. **Reaction Completion
After the addition is complete, continue stirring the reaction mixture at 0-10°C. Monitor for solid precipitate formation, which indicates product crystallization. Allow the mixture to stir for 4–6 hours initially—check for significant precipitation. If crystallization appears incomplete, extend stirring overnight (up to 12–16 hours) until crystallization is finished.
7. **Crystal Processing
Once a solid precipitate forms, crush the crystals in the flask using a glass rod to break up any large clumps.
8. **Quenching
Pour the reaction mixture in small portions, with constant stirring, into a vessel containing 3 L of cold water. The raw 3-(2-methoxybenzoyl)indole will precipitate and settle at the bottom of the vessel.
9. **Product Isolation
Separate the 3-(2-methoxybenzoyl)indole precipitate from the water (e.g., by filtration or decanting).
**Note**: The raw product can be dried and used as is, but for higher purity, recrystallization is recommended (e.g., from a suitable solvent like ethanol or toluene—consult a chemist for optimization).
Yield and Characterization:
- Expected product: 3-(2-methoxybenzoyl)indole (MW = 251.28 g/mol).
- Theoretical yield: ~213 g (based on 0.85 moles), though practical yields may vary (50–80% typical for Friedel-Crafts reactions, depending on conditions and reagent quality).
- Appearance: Likely a white to off-white solid
3-(2-Methoxybenzoyl)indole Synthesis From Indole
To synthesize 3-(2-methoxybenzoyl)indole as a precursor for RCS-2 via Friedel-Crafts acylation of indole with 2-methoxybenzoyl chloride.
Materials:
- Indole: 100 g (~0.85 moles, MW = 117.15 g/mol)
- Dichloromethane (DCM): 300 mL + 200 mL
- Aluminum chloride (AlCl₃): 114 g (~0.85 moles, MW = 133.34 g/mol)
- 2-Methoxybenzoyl chloride: 145 g (~123 mL, ~0.85 moles, MW = 170.59 g/mol, density ~1.18 g/mL)
- Cold water: 3 L (for quenching)
Equipment:
- 2 L round-bottom flask
- Magnetic stirrer or overhead stirrer
- Ice bath (ice water or chilled brine)
- Beaker (for preparing 2-methoxybenzoyl chloride solution)
- Glass rod (for crushing crystals)
- Large vessel (≥3 L) for quenching
- Filtration setup (e.g., Buchner funnel)
Let's go !
1. **Preparation of Indole Solution
Pour 100 g of indole into a 2 L flask. Add 300 mL of dichloromethane (DCM) and stir the mixture until the indole is completely dissolved.
2.
Place the flask in an ice bath (ice water or chilled brine) and cool the reaction mixture to 0-10°C while stirring.
3. **Addition of Aluminum Chloride
Gradually add 114 g of aluminum chloride (AlCl₃) to the flask with constant stirring. Continue stirring until the AlCl₃ is fully dissolved. (Note: This step may generate some heat; maintain the temperature at 0-10°C.)
4. **Preparation of 2-Methoxybenzoyl Chloride Solution
Measure 145 g (~123 mL) of 2-methoxybenzoyl chloride into a beaker. Add 200 mL of DCM and mix thoroughly to form a homogeneous solution. (Note: 2-Methoxybenzoyl chloride is a liquid at room temperature—no heating is required, unlike 1-naphthoyl chloride.)
5. Acylation Reaction
Slowly add the 2-methoxybenzoyl chloride/DCM solution from the beaker into the flask, maintaining the reaction temperature at 0-10°C. Stir continuously during the addition to ensure even mixing.
6. **Reaction Completion
After the addition is complete, continue stirring the reaction mixture at 0-10°C. Monitor for solid precipitate formation, which indicates product crystallization. Allow the mixture to stir for 4–6 hours initially—check for significant precipitation. If crystallization appears incomplete, extend stirring overnight (up to 12–16 hours) until crystallization is finished.
7. **Crystal Processing
Once a solid precipitate forms, crush the crystals in the flask using a glass rod to break up any large clumps.
8. **Quenching
Pour the reaction mixture in small portions, with constant stirring, into a vessel containing 3 L of cold water. The raw 3-(2-methoxybenzoyl)indole will precipitate and settle at the bottom of the vessel.
9. **Product Isolation
Separate the 3-(2-methoxybenzoyl)indole precipitate from the water (e.g., by filtration or decanting).
**Note**: The raw product can be dried and used as is, but for higher purity, recrystallization is recommended (e.g., from a suitable solvent like ethanol or toluene—consult a chemist for optimization).
Yield and Characterization:
- Expected product: 3-(2-methoxybenzoyl)indole (MW = 251.28 g/mol).
- Theoretical yield: ~213 g (based on 0.85 moles), though practical yields may vary (50–80% typical for Friedel-Crafts reactions, depending on conditions and reagent quality).
- Appearance: Likely a white to off-white solid
