Abstract: Objective: To compare the advantages and disadvantages of Mannich method and Lewis acid catalysis in the application of gramine synthesis. Methods: The effects of reaction material ratio（indole: acetic acid）, reaction time and reaction temperature on the yield of gramine synthesized by Mannich method, and the effects of reaction solvent, reaction time and catalyst on the yield of gramine synthesized by Lewis acid catalysis were investigated through orthogonal experiments. The effects of different substrates on the synthesis of gramine derivatives were also studied. Results: The result of Mannich method indicated that the yield could reach 88.5%
when n（indole）: n（acetic acid）= 1 : 2 for 12 hours at the temperature of 55 ℃. The optimal conditions for Lewis acid catalysis were using ethanol as the reaction solvent and ZnCl2 as the catalyst for 120 minutes, making the yield as much as 93.1%. Conclusion: Lewis acid catalysis synthesis of gramine is superior to Mannich method. The results showed that the larger the steric hindrance of the amines involved in the reaction, the lower the reaction yield was. The introduction of electron-donating groups on indole could increase the yield of the derivatives, while on the contrary, the introduction of electron-withdrawing groups would lead to lower yield.

Key words: gramine, derivatives, Mannich reaction, Lewis acid, synthesis