Study On Syntheses And Bioactivities Of Turpentine-based P-Menthane Amine Derivatives

Turpentine is an important renewable resource,which possess an unique bioactivity.Our country is a big country of turpentine production,but the deeply processed product categories of turpentine are not abundant and the high value-added green products of turpentine need to be developed.This study is committed to synthesize series of turpentine-based p-menthane amine derivatives which will lay the foundation for the development of green pesticide and medicine.In this thesis,N,N'-diacetyl-p-menthane-1,8-diamine was prepared from turpentine,then it was hydrolyzed to provide cis or trans-p-menthane-1,8-diamine and p-menth-3-en-1-amine.In the course of our investigation,we found two new compounds(menth-3-en-1-amine and N-acetyl-1,2-azacyclo-pmenthane).53 derivatives of amide,Schiff base and thiourea were synthesized from the above p-menthane amines via serial reactions.The structures of the new compounds were identified by FT-IR,ESI+-MS,HRMS,1H NMR and 13 C NMR,and bioactivities(antimicrobial activity,herbicidal activity and cytotoxicity)were measured.The main conclusions are as follows:1.Ritter reaction was first used to synthesize N,N'-diacetyl-p-menthane-1,8-diamine from turpentine and acetonitrile.The p-menthane-1,8-diamine was provided from hydrolyzation of N,N'-diacetyl-p-menthane-1,8-diamine with ethylene glycol as the solvent and sodium hydroxide as the catalyst in high temperature condition.The p-menthane-1,8-diamine(the purity more than 98%)was easily separated from the reaction mixture via distillation.This method effectively solved the disadvantages(such as low selectivity,difficult to separate and high toxicity)caused by the synthesis of p-menthane-1,8-diamine from Na CN or NaN3 and turpentine.The cis/trans-p-menthane-1,8-diamine were effectively separated via ammonium salt fractional crystallization.2.It was found an important reaction.First,N-acetyl-p-menth-3-en-1-amine was obtained when an acetamide was eliminated from the C-8 position of N,N'-diacetyl-p-menthane-1,8-diamine at the presence of acid.Next,N-acetyl-1,2-azacyclo-p-menthane was synthesized from N-acetyl-p-menth-3-en-1-amine via isomerization and cyclization and a novel p-menthane amine(p-menth-3-en-1-amine)was provided via the alkali hydrolyzation of N-acetyl-p-menth-3-en-1-amine.3.The amide and Schiff base derivatives of cis-p-menthane-1,8-diamine and p-menth-3-en-1-amine were syhthesized via amidation and imidization.The amide and Schiff base derivatives were in 53%-100% and 65%~99% yeilds,respectively.In addition,p-menth-3-en-1-isothiocyanate was obtained from p-menth-3-en-1-amine and phenyl chlorothionocarbonate via nucleophilic addition-elimination and pyrolysis in 97% yeild.Then,the corresponding thiourea derivatives were provided from the reaction between p-menth-3-en-1-amineand isothiocyanate or the reaction between p-menth-3-en-1-isothiocyanate and amine in 53%~98%yields.4.The study on the antimicrobial activity of p-menthane amines and some of their derivatives against Klebsiella pneumoniae,Staphylococcusaureus and Candida albicanshad showed:N-(5-nitro-2-thenoyl)-p-menth-3-en-1-amine(7g)had strongest antimicrobial activity against Klebsiella pneumoniaand the MIC was 0.44 ?g/mL.p-Menth-3-en-1-amine(5)and N,N'-bis(6-chloro-2-pyridylformyl)-cis-p-menthane-1,8-diamine(12h)had strongest antimicrobial activity against Staphylococcusaureusand the MIC was 56.25 ?g/mL.p-Menth-3-en-1-amine(5)and N-(5-chloro-2-thenoyl)-p-menth-3-en-1-amine(7h)had strongest antimicrobial activity against Staphylococcus aureus and the MIC was 112.5 ?g/mL.5.p-Menthane amines and their Schiff base derivatives had excellent herbicidal activities against ryegrass.N,N'-bis(4-chlorobenzylidene)-cis-p-menthane-1,8-diamine(13j)had highest herbicidal activities.The inhibitory activities of 13 j against ryegrass root and shoot growth were 310.0% and583.3% higher than that of glyphosate.The structure-activity relationship indicated that the cyclic olefinic bond of p-menth-3-en-1-amine was beneficial for the whole herbicidal activity.In addition,the introduction of a chlorine or bromine atom into the Schiff base derivatives containing a furan or benzene ring could significantly improve the herbicidal activity.6.The study of cytotoxicity had showed: p-Menthane amines and their derivatives had no obvious antitumor activity against MDA-MB-231,ES-2 and Hep G-2 and no toxic to normal cells(3T3 and HUVEC-C)for these compounds.These new compounds belonged to secure compounds.