Aminouracil and aminothiouracil as versatile precursors for a variety of heterocyclic systems

Heterocycles, particularly pyrimidine derivatives, which are present in many natural products and many interesting synthetic compounds, are the most diverse class of organic compounds and have significant chemical, biomedical and industrial applications. Uracil, a pyrimidine derivative, constitutes a promising structure in widespread natural products and many of its derivatives exhibited significant pharmacological properties. They have been widely used as starting materials for the synthesis of a huge number of biologically important nitrogen-containing heterocycles. This review casts light on various methods for the construction of different heterocyclic systems utilizing aminouracil and aminothiouracil as versatile precursors. The heterocyclic systems mentioned in this review are categorized according to the type of the heterocyclic systems.


Introduction
Heterocyclic compounds are being used in several areas, including agrochemistry, medicine, polymer science, and various industries.They have gained significant interest in the design of biologically active molecules and are of great importance for the chemistry of life since their structural subunits occur in many natural products such as vitamins, hormones, and antibiotics.They play an active role in numerous medical applications as antiviral, anti-bacterial, anti-inflammatory, anti-fungal, and anti-tumor medications.Heterocyclic compounds are also used as sanitizers, developers, antioxidants, corrosion inhibitors, copolymers, and dyestuffs.2][3][4][5][6][7][8] They generally show superior pharmaceutical effects compared to non-nitrogen analogues.][11][12] In addition, nitrogen-containing heterocycles play a significant role in coordination chemistry. 13mong various nitrogen-containing heterocycles, pyrimidine derivatives constitute an interesting subclass.They are present in many natural products, such as vitamin B1 (thiamine), and many interesting synthetic compounds, such as barbituric acid and veronal, which are used as hypnotic agents. 14,15They demonstrated a wide variety of biological properties, including antibacterial [15][16][17] , antifungal 15,18 , antileishmanial 19 , antiinflammatory 20 , analgesic 21 , antihypertensive 22,23 , antipyretic 24 , antiviral 25 , antidiabetic 26 , antiallergic 27 , antioxidant 28,29 , antihistaminic 30 , herbicidal 31 , and anticancer activities 32,33 .Uracil is a very important representative of the pyrimidines.It is one of the five nucleobases and constitutes a promising structure in widespread natural products 34 .Uracil derivatives are interesting molecules in the area of drug discovery 35 since they exhibit significant pharmacological applications as antiviral 36 , anticancer, cytotoxic 37 , antimycobacterial 38 , anti-inflammatory 39 , antitumor 34,40 , and antibacterial 41 .Moreover, some uracil derivatives showed antithrombotic 42 , antidotal 43 and potent inhibitors of interleukin-8-induced neutrophil chemotaxis 44 .Some uracils, particularly 6-aminouracils and their corresponding thiouracil derivatives, have been widely used as starting materials for the synthesis of a huge number of biologically important nitrogen-containing heterocycles [45][46][47][48] .
In continuation of our interest in reviewing various synthetic approaches to heterocyclic systems, this review highlights various synthetic methods used for the preparation of different heterocyclic systems utilizing aminouracil and aminothiouracil as versatile precursors.Depending on the size of the heterocyclic ring as well as the location and number of heteroatoms, heterocyclic compounds mentioned are arranged in this review.The review will cover the literature in this field from 2015-2020.A few of the recent reviews [49][50][51][52][53][54][55][56] on this subject appear not to have paid sufficient attention to fused uracil systems in an ordered manner with respect to the ring system.

Table 9 .
% Yields of compounds 61a-i i 86 Some aminouracil derivatives 3 and 6 reacted with a variety of chalcones 62 under different conditions to give pyrido[2,3-d]pyrimidines 63 successfully in good yields.It is worth mentioning that some of the reported compounds in (Table 10) have shown various bioactivities.

Table 10 .
% Yields of compounds

Table 21 .
% Yields of compounds 104a-h The latter compounds were then cyclized through Vilsmeier-Haack reaction to give compounds 106a-d in good yields (Scheme 47).

Table 27 .
% Yields of compounds 127a-k Heating of the latter compound in DMF and in the presence of trimethylamine, provided hexahydropyrimido[4,5-g]pteridine 129 in 92% yield.The latter compound showed moderate anti-microbial activity against the Gram-positive Bacillus subtilis (Scheme 60).