Desulfurization of 2-Thioxo-1,2,3,4-tetrahydropyrimidin-4-ones with Oxiranes and 2-Haloacetonitriles

Abstract

A procedure was developed for the synthesis of tetrahydropyrimidine-2,4-diones by desulfurization of 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ones with oxiranes or 2-haloacetonitriles in polar solvents in the presence of a base.It is known that 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one derivatives differently react with different alkylating agents. In most cases, the reaction gives the corresponding 2-alkylsulfanylpyrimidin-6(1H)-ones or 2-alkylsulfanyl-1-alkylpyrimidin-4(1H)-ones, while 2-chloroacetic acid reacts with 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ones in an aqueous solution to afford tetrahydropyrimidine-2,4-diones.We found that 2-methyloxirane and 2-iodoacetonitrile are also capable of effecting desulfurization of 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one derivatives with formation of 1,2,3,4-tetrahydropyrimidine-2,4-diones (Scheme 1). The reactions were performed using the following base-solvent systems (which are typically used for alkylation of 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ones): K 2 CO 3 -DMFA, NaH-DMFA, NaOMe-MeOH, KOH-EtOH, and NaOH-H 2 O. The yield of the resulting pyrimidine-2,4-dione derivatives was quantitative, regardless of the base used.While studying desulfurization of 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ones Ia-Ie we showed that 2-phenyloxirane and 2-ethyloxirane also equally effective in this reaction, and the corresponding 1,2,3,4-tetrahydropyrimidine-2,4-diones IIa-IIe were formed in quantitative yield. Presumably, the reason is that the examined oxirane derivatives possess an endocyclic methylene group which is not shielded with respect to nucleophilic attack. Both protic polar solvents (H 2 O, MeOH, EtOH) and aprotic dimethylformamide ensured quantitative formation of pyrimidinediones IIa-IIe. This suggests that the solvent does not participate in the reaction with initially formed 2-[(2-hydroxyalkyl)sulfanyl]pyrimidinone and that oxirane acts as source of oxygen.Desulfurization of compounds Ia-Ie with 2-iodoacetonitrile (as well as with 2-bromo-and 2-chloroacetonitrile) resulted in quantitative formation of pyrimidinediones IIa-IIe only when the reaction was carried out in an alcoholic medium. The reaction in DMF in the presence of K 2 CO 3 was accompanied by strong tarring. Treatment of Ia-Ie with 2-iodoacetonitrile in aqueous sodium hydroxide afforded compounds IIa-IIe in a poor yield, and the conversion of initial 2-thioxopyrimidinones was not complete. These data indicate that the process should be performed in a protic solvent which is likely to promote cleavage of the initially formed 2-(cyanomethylsulfanyl) derivative. The low yield of pyrimidine-2,4-diones in the reaction in water may be due to heterogeneous conditions and concurrent hydrolysis of 2-iodoacetonitrile.It should be noted that the maximal yield of compounds II in the reactions with both substituted oxiranes and 2-haloacetonitriles was observed only when the amount of base was equal to or greater than equimolar. Reduction of the amount of base leads to proportional decrease in the conversion (accor...

A gene encoding a DUF523 domain protein is involved in the conversion of 2‐thiouracil into uracil

“…It was demonstrated that this reaction is pH‐dependent, the main product formed at pH 6.6 being pirimidinone riboside (H 2 U), whereas at pH 7.6, uridine is formed. Correspondingly, in case of 2‐thiouracil, the nucleophilic substitution of sulfur by oxygen takes place after the alkylation of the thiol group with 2‐haloacetonitryles or oxirane (Novakov et al ., ). For the desulfuration in which DUF523 proteins are involved, the scenario is yet unclear.…”

Novel synthetic route for 5‐substituted 6‐arylmethylluracils from 2,4,6‐trichloropyrimidines

“…The intermediates i were decarboxylated in strong acidic medium to afford 6‐arylpyrimidine‐2,4‐diols ii which are the enol forms of compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h (Scheme ). Compounds 5a,b,f have previously been prepared through desulfurization of the corresponding 2‐thiouracil derivatives [14–16]. Compounds 5a , 5b , 5c , 5d were brominated with N ‐bromosuccinimide in absolute ethanol in the presence of benzoyl peroxide at room temperature to give the 5‐bromouracil derivatives 6a , 6b , 6c , 6d (Scheme ).…”

“…5‐Bromo‐6‐arylmethyluracils were used as inhibitors of thymidine phosphorylase [11–13]. Uracil derivatives are known to be synthesized by refluxing the corresponding thiouracils with 10% aqueous chloroacetic acid [14–21]. Thiouracils are synthesized by the condensation of the appropriate β‐ketoester with thiourea in strong basic medium [14–21].…”

“…Uracil derivatives are known to be synthesized by refluxing the corresponding thiouracils with 10% aqueous chloroacetic acid [14–21]. Thiouracils are synthesized by the condensation of the appropriate β‐ketoester with thiourea in strong basic medium [14–21]. Lee and Kim [22] have reported the synthesis of 5‐alkyl‐6‐benzyluracil derivatives by the reaction of 5‐alkyl‐2,4,6‐trichloropyrimidines with various arylmethyl magnesium halides to afford the regioselectively 6‐arylmethyl‐2,4‐dichloropyrimidines as the major products.…”

Electrophilic Intramolecular Cyclization of 1-(N-alkenyl)-6-methylpyrimidine-2,4-diones

“…Commercially available materials were used without further purifications. 6-Methyluracil was produced by the oxidation of 6-methylthiouracil by 1,2propyleneoxide [15].…”