Thienopyrimidin-4 -ones

To synthesize 2-methyl-3-substituted thienopyrimidin-4-ones 178, a two-step reaction was applied. o-Aminoesters 189 (Y = Me) were reacted with acetic anhydride in the presence of 4-dimethylaminopyridine to give methyl 3-acetylaminothiophene-2-carboxylates 196. These were then cyclized by heating with primary amines to the thieno[3,2-d]pyrimidin-4-ones 197 (91GEP295381 92PHA577). 

Thienopyrimidin-4-one-2( 1H )-thiones 217 were prepared by two slightly different methods. Reaction of o-aminoesters 189 with thiophosgene gave the isothiocyanates 216 which were heated with a variety of a-aminoes-... 

In another example of a tandem displacement/annulation sequence, Neidlein and co-workers reported the reaction of ethyl 2-mercaptoacetate with chlorocyanopyrimidine 47 <00S255>. Thienopyrimidine 48 was produced in high yield through this one-pot procedure. 

Surprisingly, only one example of the synthesis of thieno[3,4-,7 pyrimidines has been described starting from a pyrimidine ring. In CHEC-II(1996) <1996CHEC-II(7)229>, substituted 5-cyanouracils, upon reaction with elemental sulfur, led to the formation of compounds in this class. Now the use of a 5-cyanopyrimidino-2-thione 419 under similar conditions (Equation 156) leads to the thienopyrimidine 420 <1997HC0151>. 

There is one example of annulation of a pyrimidine ring to a saturated thiophene ring. Ketone 477 is condensed with. J-ethylthiourea HBr at room temperature in water over 18 h. The product is the reduced thienopyrimidine 478 (Equation 179) <1994NN1 B5>. 

One example of the synthesis of a thienopyrimidine commencing with a pyrimidine precursor appeared in 2006. Thus, 4-chloro-5-cyano-6-aryl-2-methylthiopyrimidines react with either ethyl (or f-butyl) 2-mercaptoacetate to afford 5-amino-4-aryl-2-methylthiothieno[2,3-,y]pyrimidine-6-carboxylic acids <2006JMC3888>. 

The thienopyrimidin-4(3f/)-ones 135 were converted into the corresponding 4-chloro derivatives 136 almost exclusively by heating with phosphoryl chloride containing A,N-dimethylanilme as catalyst. The 4-chloro compounds 136 were then treated with a variety of aliphatic and aromatic amines to afford the corresponding 4-alkyl or aryl aminothieno... 

Since the publication of the monograph chapter on thienopyrimidines (84M1), only one paper has appeared on the synthesis of thieno[2,3-djpyrimidines from pyrimidines. 

The third chapter in the present volume is by Drs. Ryabukhin, Korzha-vina, and Suzdalev (Rostov University, Russia), who have provided the first specialized review of l,3-thiazin-4-ones. Professor Varvounis and Dr. Giannopoulos (Ioannina, Greece) cover recent developments in the synthesis, chemistry, and biological properties of the thienopyrimidines in the fourth chapter of this volume. 

Another procedure is based on the use of iminothienothiazinethiones 29 as the starting substrates. For example, their reactions with one equivalent of methyl iodide afforded compounds 96, which underwent recyclization into thienopyrimidines 97 under the action of amines. Two equivalents of methyl iodide gave di(methyl-thio)thienopyrimidines 98 (1993JCR(S)302). 

In the case of Y = C02Et, the reaction affords 5-hydroxy thienopyrimidines, which exist predominantly as the oxo form (118). Pyrimidines 119 starting compounds can be prepared by two methods. One of them involves substitution of the mercaptoacetic acid residue for the chlorine atom in 4-chloro-5-ethoxycarbonylpy-rimidines 120. Pyrimidines 119 are then cyclized in the presence of bases to thieno[2,3-<7]pyrimidin-5-ones 118 (1988JHC959, 1993INP13664). 

Analysis of the data on the chemistry of isomeric thienopyrimidines published over the last 10-15 years shows that this class of heteroaromatic compounds, which are structural analogs of natural compounds of the purine class, attracts increasing interest of chemists and biochemists. In the first half of the 21st century, new approaches to the synthesis of derivatives of these fused heterocyclic systems will be, undoubtedly, extensively developed. These derivatives are not only of theoretical interest but also possess a broad spectrum of practical use, primarily, due to various biological activities. Of the approaches to their synthesis, multicomponent cascade heterocyclization, which allows one to construct various functionalized thienopyrimidines and their fused analogs in one technologically and ecologically safe step, holds the most promise. 

---