Synthesis of Thienopyrimidines

Synthetic approaches to the construction of thienopyrimidines are sufficiently well developed. Three possible types of annulation of thiophene to the pyrimidine ring and, correspondingly, three isomeric thienopyrimidines are known thieno[2,3- 7]pyrimidine (1), thieno[3,2-J]pyrimidine (2), and thieno[3,4-c]-pyrimidine (3). The structures and the conventional numbering of these heterocyclic systems are shown below. 

The known approaches to the synthesis of thienopyrimidines can be divided into two main groups construction of the pyrimidine ring by intramolecular cyclization of thiophene derivatives and thiophene ring closure in pyrimidine derivatives. 

One of the most popular approaches to the synthesis of thienopyrimidinediones 4 is based on the pyrimidine ring closure in thienylureas 5. 

Hereinafter, A is the thiophene ring bearing substituents at positions 2 and 3 or 3 and 4 thienopyrimidine structure 4 is thiophene analogously annulated to the pyrimidine ring the ester group is most widely used as the COX group. 

Although intermediate thienylureas were not isolated, their transient formation is quite probable (1990PS181, 1991SL57). 

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In recent years, procedures were devised for the synthesis of thienopyrimidines using recyclization of derivatives of thieno[2,3-J]oxazinones (2002JCR(S)5, 2002MI2, 2002JCR(S)0149), thieno[3,2-<7]oxazines (1998P775), and pyrano[3,4-<7lpy-rimidines (1999P858). 

As earlier, procedures for the synthesis of thienopyrimidines by thiophene ring closure starting from the available pyrimidine are used much more rarely than the pyrimidine ring closure, because the appropriately substituted pyrimidines are less readily accessible. In this section, data are systematized according to the types of reactions giving rise to the thiophene ring. 

Generally, the synthesis of thienopyrimidines using the Claisen, Thorpe-Ziegler, and Friedlaender condensations can be represented by the following scheme ... 

Alternative approaches to the synthesis of thienopyrimidines by thiophene ring closure are also documented. For example, the thio-Claisen rearrangement of prop-argyl sulfide 137 (X = S) affords thienopyrimidinediones 138 the rearrangement of sulfoxide 137 (X = SO) gives the corresponding formyl derivative 138 (R2 = CHO) (1989JHC1851). 

DEPC promoted the condensation reaction of thiophene carboxylic acid (37) and hydroxyethanol amine to give amide 38 in 63% yield.16 Amide 38 is a key intermediate used in the synthesis of thienopyrimidines. 

In 2011, Jiang and coworkers reported the research and development of a new class of immunosuppressive agents that is useful for preventing graft rejection after organ transplantation. In the synthesis of thienopyrimidines, they employed direct amination of the tautomerizable heterocycle using BOP in the presence of DBU in MeCN (11JMC655). 

Pyrimidine-fused Systems.—o-Aminothiophencarboxylic acid derivatives have been extensively used for the synthesis of thienopyrimidine derivatives. Thus the mercapto-derivatives (464) have been synthesized by... 

Synthesis, chemistry, and biological properties of thienopyrimidines 96AHC(65)235, 96AHC(66)193. 

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>. 

The Thorpe-Ziegler reaction has been employed in the synthesis of thieno[3,4-t4pyritnidines by providing the thiophene 421. Heating this compound under reflux in formic acid leads to a series of thienopyrimidines 422 (Equation 157) <2002IZK854>. 

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>. 

An interesting synthesis of a condensed thienopyrazine resembling the preparation of a condensed thienopyrimidine (Scheme 103) is shown in Scheme 109 (80H(14)651, 81JHC739). Starting with 2-amino-3-cyanothiophene the 2-(l-pyrrolyl)-3-thienylcarboxylic acid (369) could be obtained in two steps, first by condensation with 2,5-dimethoxytetrahydrofuran... 

The synthesis of 2-thia-3,5,6,7,9-pentaazabenz[cr/ azulenes, in which thienopyrimidine is/>m -anulated (SP) with the 1,2,4-triazepine moiety, has been described <2002TL695>. 

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 next contribution, by Y. A. Ibrahim, A. H. M. Elwahy, and A. M. Kadry of Cairo and Zagazig Universities, Egypt, covers the synthesis, reactions, and biological activity of thienopyrimidines. It represents the first comprehensive account of these derivatives. 

The present review analyzes results of studies on the synthesis, chemical transformations, and biological activities of thienopyrimidines published primarily over the last 10-15 years. 

Another procedure for the synthesis of pyrimidines 119 involves alkylation of 5-ethoxycarbonylpyrimidine-4(3//)-thiones 121 with chloroacetic acid derivatives. In this case, thienopyrimidines 118 were prepared without isolation of intermediate pyrimidines 119 (1988GEP258012, 1988SL201, 1990SL75). 

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. 

Varvounis, G., Giannopoulos, T., Synthesis, Chemistry, and Biological Properties of Thienopyrimidines, 66, 193. 

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