3-(1-Naphthoyl)indole Synthesis

Introduction

3-(1-Naphthoyl)indole is an important precursor in a huge row of synthetic cannabinoids such as JWH-018, JWH-019, AM-2201, AM-2232 and etc. This topic is dedicated to simple 3-(1-Naphthoyl)indole synthesis from indole and 1-Naphthoyl chloride.

Reagents:

• Indole (cas 120-72-9) 1000 g;
• Dichloromethane (CH2Cl2) 15 l;
• Tin(IV) chloride (SnCl4) 2000 ml;
• 1-Naphthoyl chloride (cas 879-18-5) 1627 g;
• Nitromethane (cas 75-52-5) 10 l;
• Distilled water 20 l;
• Ethyl acetate (EtOAc) 15 l;
• Sodium or magnesium sulphate (Na2SO4 or MgSO4);

Equipment and glassware:

• Batch reactor 50 l with a top stirrer;
• Ice bath;
• Vacuum source;
• Rotovap machine;
• Several buckets;
• Laboratory scale (1-1000 g is suitable);
• Funnel;
• Glass rod and spatula;
• Pyrex dish;

Reaction scheme:

Synthesis:

1. Tin(IV) chloride (SnCl4) 2000 ml is added in a single portion to an indole 1000 g solution in dichloromethane (CH₂Cl₂) 15 l in a batch reactor 50 l.
2. The mixture is stirred at room temperature for 30 min after an ice bath was removed. Then 1-naphthoyl chloride 1627 g is added to the reaction suspension in small portions, followed by nitromethane 10 l.
3. Then, the mixture is stirred for 2 h at room temperature.
4. Next, the reaction mixture is quenched with an ice cold water 20 l. The mixture is filtered in order to remove inorganic precipitates. Layers are separated.
5. The water layer is extracted with ethyl acetate (EtOAc) 15 l. EtOAc extract is combined with organic layer.
6. The organic phase is dried over sodium or magnesium sulphate (Na₂SO₄ or MgSO₄) and concentrated at reduced pressure. A crystalline solid 3-(1-Naphthoyl)indole product (cas 109555-87-5) is obtained.

Wiley, Jenny L., et al. "Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl) indoles: Steric and electronic effects of 4-and 8-halogenated naphthoyl substituents." Bioorganic & medicinal chemistry 20.6 (2012): 2067-2081. https://www.sciencedirect.com/science/article/pii/S0968089612000685