Synthesis of cytisine derivatives of coumarins

Abstract

New substituted 4-chloromethylcoumarins that were used as alkylating agents to modify cytisine were synthesized by Pechmann condensation.A series of 4-(12-cytisylmethyl)coumarins containing pharmacophores of the natural heterocycles coumarin and cytisine in a single molecule was prepared. The alkylation gave the best results if diisopropylethylamine was used as the base.In continuation of research on the modification of natural compounds, we decided to investigate the alkaloid (-)-cytisine from seeds of Cytisus laburnum L. and Thermopsis lanceolata R.Br. Cytisine is of great interest to many researchers because of its effect on the ganglionic nervous system and its use in medicine as a respiratory analeptic [1]. A variety of N-alkyl derivatives of cytisine has been synthesized [2-4], among which are compounds with analgesic, antihypertensive, and inotropic activities [3]. According to the patent literature [5], N-methyl derivatives also possess anti-inflammatory and hypoglycemic activities.Therefore, the search for methods of modifying cytisine is very timely. The combination into one molecule of two natural heterocyclic compounds can lead to the production of compounds with new types of physiological activity. Considering this, we selected substituted 4-chloromethylcoumarins, which are used to synthesize compounds with antimicrobial [6] and antiinflammatory [7] properties, as alkylating agents for modifying cytisine. 1, 12: R 1 = R 2 = R 4 = H, R 3 = CH 3 ; 2, 13: R 1 = R 3 = R 4 = H, R 2 = CH 3 ; 3, 14: R 1 = R 2 = H, R 3 = OH, R 4 = CH 3 4, 15: R 1 = R 2 = H, R 3 = R 4 = CH 3 ; 5, 16: R 1 = R 4 = H, R 2 = Cl, R 3 = CH 3 ; 6, 17: R 1 = R 4 = H, R 2 = OH, R 3 = CH 3 7, 18: R 1 = R 3 = CH 3 , R 2 = R 4 = H; 8,19: R 1 = R 3 = H, R 2 = R 4 = CH 3 ; 9, 20: R 1 = R 3 = R 4 = H, R 3 = CH 2 CH 3 10, 21: R 1 = R 4 = H, R 2 R 3 = CH 2 CH 2 CH 2 ; 11, 22: R 1 = R 4 = H, R 2 = R 3 = CH 3 Several synthetic methods for 4-chloromethylcoumarins are known. These include the reaction of phenols with 4-chloroacetoacetic ester in H 2 SO 4 (Pechmann condensation) [8-10], chlorination of coumarin-4-acetic acid in AcOH [11], and reaction of 4-hydroxymethylcoumarins with PCl 5 in benzene [8,12]. Based on the literature, we selected the Pechmann condensation for preparing 4-chloromethylcoumarins 1-11.

Water Soluble Coumarin Quaternary Ammonium Chlorides: Synthesis and Biological Evaluation

“…Synthesis and Characterization of Compounds 4-Chloromethylcoumarin derivatives (1a-1c) were prepared according to the literature. [20] The target CQACs were synthesized by the reactions of 1a -1c and pyridine or tertiary amines and obtained in good yields of 47-94 %. Synthesis and structures of CQACs are given in Scheme 1.…”

Inhibition of paraoxonase 1 by coumarin‐substituted N‐heterocyclic carbene silver(I), ruthenium(II) and palladium(II) complexes

“…These compounds were synthesized by the procedure described by Frasinyuk et al . Crude products were recrystallized from ethanol instead of dioxane.…”

Synthesis and biological activity of 3,4-dihydropyrimidin-2-thione aminomethylene derivatives based on the alkaloid cytisine

“…Among these, compounds with types of biological activity that are uncharacteristic of cytisine itself are constantly being discovered. Until now many cytisine derivatives with various heterocylic groups such as coumarin [2,3]; 1,2,3-triazole [4]; 1,2,4-thiadiazole [5]; 1,3-thiazoline [6]; 2,5-dimercapto-1,3,4-thiadiazole [7]; barbituric acid [8]; pyridine [9]; 1,4-dihydropyridine [10]; and phenothiazine [11] were prepared.The Mannich reaction, which is widely used in organic chemistry to synthesize a variety of practically important compounds, is a convenient method for preparing new N-derivatives of cytisine in addition to the broadly used nucleophilic substitution and addition reactions of cytisine [2][3][4][5][6][7][9][10][11].The starting synthons for preparing new N-heterocyclic cytisine derivatives were 3,4-dihydropyrimidin-(1H)-2-thione derivatives, which were obtained via three-component condensation using a Biginelli reaction. The number of publications on the chemistry of 4-aryl-3,4-dihydropyrimidin-2-ones and 4-aryl-3,4-dihydropyrimidin-2-thiones has recently increased significantly in the scientific literature.…”

“…The Mannich reaction, which is widely used in organic chemistry to synthesize a variety of practically important compounds, is a convenient method for preparing new N-derivatives of cytisine in addition to the broadly used nucleophilic substitution and addition reactions of cytisine [2][3][4][5][6][7][9][10][11].…”

“…Among these, compounds with types of biological activity that are uncharacteristic of cytisine itself are constantly being discovered. Until now many cytisine derivatives with various heterocylic groups such as coumarin [2,3]; 1,2,3-triazole [4]; 1,2,4-thiadiazole [5]; 1,3-thiazoline [6]; 2,5-dimercapto-1,3,4-thiadiazole [7]; barbituric acid [8]; pyridine [9]; 1,4-dihydropyridine [10]; and phenothiazine [11] were prepared.…”