Recent applications of aminouracil in multicomponent reactions

6-Aminouracil and its derivatives are versatile heterocyclic compounds and are frequently employed to synthesize a wide array of fused uracils annulated with other heterocyclic rings which can serve to address biological and pharmacological targets. Multicomponent reactions (MCRs) are important in the synthesis of natural products and pharmaceuticals by forming heterocyclic molecular frameworks with generally high atom-economy in a single reaction step. This review embraces various modern synthetic strategies, summarizing recent research developments providing fused 6-aminouracil derivatives and to highlight the progress based on MCRs between 2015 and 2020.


Introduction
][13] One of the primary starting materials and as a privileged scaffold, 6-aminouracil is a widespread subunit in various complex molecules, and their derivatives remain of great interest in organic chemistry.Since this molecule can act as both nucleophile and electrophile, it is of interest to many chemists.At position 3, the most significant nucleophilic activity is observed.This compound can be easily used to prepare fused annulated compounds with other materials and polycyclic compounds with biological targets such as pyrido-, pyrrolo-and pyrimido-pyrimidines. [14][15][16] These derivatives have presented a remarkably broad spectrum of pharmacological and biological activities , such as antimicrobial [17][18][19] and anticancer, [20][21][22] and they are employed as anticoagulant, 22,23 antifungal, [24][25][26] antiviral, [27][28][29] antitumor, 30,31 antioxidant, 32,33 anti-inflammatory agents, 34,35 HIV protease inhibitors, [36][37][38] antiallergics, 39 and tyrosine kinase inhibitors. 40o prepare new heterocyclic molecules, in particular compounds with pharmaceutical and biological activities, chemists always try to prepare such compounds using the least amount of energy and in the shortest time.In recent years, one-pot multicomponent reactions (MCRs) have made it possible to achieve this goal by simultaneously combining several substances, accompanied by the breaking and formation of several bonds.For a rapid and green methodology in modern organic synthesis to prepare molecular diversity and complexity from simple and readily available substrates, organic and medicinal chemists can use one-pot (MCR) processes as powerful and productive synthetic tools.][43][44][45][46][47][48] Herein, in continuation of studies towards the synthesis of heterocyclic scaffolds via multicomponent reactions, [49][50][51][52] and because the 6-aminouracil is frequently used as a starting material in synthesizing these compounds.This review is devoted to recent applications of 6-aminouracil and its derivatives in synthesizing diverse heterocyclic compounds based on MCRs from 2015 to 2020.

Synthesis of Pyrido-pyrimidine Compounds
A green and sustainable approach for the preparation of a series of pyrido [2,3-d]pyrimidine derivatives via three-component reaction of 6-aminouracil derivatives (2), with malononitrile (3) and various aromatic aldehydes (1) in the presence of a novel nanocrystalline MgO with high efficiency was reported by Mokhtary et Scheme 1. Efficient one-pot synthesis of pyrido [2,3-d]pyrimidines catalyzed by nanocrystalline MgO. 53 a follow-up investigation in 2015, the Mohammadi Ziarani group found a green procedure for the three-component synthesis of pyrido [2,3-d]pyrimidine derivatives in water. 55For this purpose, the single-pot, three-component condensation reaction of 6-aminouracil (2), various aromatic aldehydes (1), and malononitrile (3) in the presence of sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) as a highly active nanoporous heterogeneous acid catalyst proceed rapidly in solvent-free at 60 °C in good to excellent yields (Scheme 2).They studied the biological activities of desired products found, and some of them shown antimicrobial activities against some fungi and Gram-positive and -negative bacteria.
One of the exciting candidates for solid supports in catalytic reactions is SBA-15 (Santa Barbara Amorphous-15), a mesoporous nanocatalyst.This nanocatalyst has high thermal stability, high surface area, fine pore size distributions, well ordered hexagonal arrays of cylindrical channels, thick silica walls, large pore size, and the appreciable number of silanol groups at the surface of its channels.To improve its physical and chemical properties, this efficient and practical support can be improved.In acid-catalyzed reactions, the acidification of SBA-15 can increase its acidic properties as an efficient, heterogeneous, and reusable catalyst. 57padhyay et al. demonstrated a convenient and economical new approach for electosynthesizing biologically important pyrido [2,3-d]pyrimidine derivatives via a one-pot three-component reaction.A wide variety of aromatic aldehydes (1) and dimedone (5) or malononitrile (3) and 6-aminouracil derivatives (2)  undergo this reaction to afford these heterocycles' high yields (Scheme 3). 57In this reaction, sodium bromide is used as a supporting electrolyte in an undivided cell with a constant current and ethanol as a solvent.In electrochemistry, the electron acts as the sole reagent, so it does not require acid, nor base, nor catalyst, nor an electrogenerated base (EGB) to conduct good efficiency reactions.The literature mentioned the advantages of the electrosynthesis method as being mild reaction conditions, decreased energy requirements, atom economy, and reduction byproducts, and can be used in a wide range of oxidation and reduction reactions.

Scheme 2.
One-pot synthesis of pyrido [2,3-d]pyrimidine derivatives using sulfonic acid functionalized SBA-15. 55Scheme 3. One-pot three-component synthesis of fused pyridines via electrochemical approach. 57e authors suggested that a plausible reaction mechanism included the following steps (Scheme 4).The solvents or catalysts help to activate the electrophile by the acidic moiety or the nucleophiles by the basic moiety and play an important role in forming anion methylene actives malononitrile (3), the dehydration, and tautomerization process.The Knoevenagel condensation between aldehyde (1) and prepared anion of methylene actives or malononitrile (3)   (6).
In 2016, 58 using a one-pot Knoevenagel-Michael addition pathway, the group of Hashmi has developed the synthesis of pyrido [2,3-d]pyrimidine derivatives (8).In this method, the reaction of substituted aromatic aldehydes (1), cyanoacetamide (7) and 6-aminouracil (2) in N,N-dimethylformamide (DMF) in the presence of 4-dimethyl aminopyridine (DMAP) as organo-catalyst under ultrasonic irradiation has been used to prepare the final product (Scheme 5).It is interesting to note that the reaction proceeded in good to excellent yields (81-93%) with no significant variation in the yield of the product among the substrates tested.Nowadays, sono-promoted transformations are recognized as a powerful and green method; therefore, they are widely used to increase the reaction rates and product efficiency of organic compounds.Usually, ultrasonic-assisted organic synthesis (UAOS) accelerates the reaction time, reduces the induction period, and enhances the efficiency of catalysts, which has prominent effects on the chemical reaction.[2,3-d]pyrimidine derivatives. 58 the last decades, the combination of electro synthetic and multicomponent reactions (EMCRs) has been used extensively to synthesize biologically active scaffolds and have become important research fields in medicinal, combinatorial, and organic chemistry.Kazemi-rad et al. developed a new 7-aminopyrido [2,3d]pyrimidine-6-carbonitrile derivatives, the electrocatalytic multicomponent transformation reaction of 6aminouracils (2), aromatic aldehydes (1) and malononitrile (3) in ethanol in an undivided cell in the presence of potassium bromide as an electrolyte in short reaction times and good to high yields (Scheme 6) (70-86%). 59Scheme 6. Synthesis of Pyrido [2,3-d]pyrimidines. 59avahershenas and Khalafy represented one-pot three-component reaction of various arylglyoxals (9), malononitrile (3), and 1,3-dimethyl-6-aminouracil (2) gave the desired main products polyfunctionalized pyrido [2,3-d]pyrimidine-6-carbonitrile derivatives (11) in the presence of urea as a cheap and readily accessible organocatalyst in EtOH:H2O (1:1) at 60 °C in good to excellent yields (Scheme 7). 60Scheme 7. One-pot three-component reaction of polyfunctionalized pyrido [2,3-d]pyrimidine derivatives. 60hammadpoor-Baltork et al. studied an efficient one-step reaction of aromatic aldehydes (1), 1,3dimethyl-6-aminouracil (2) and carbonitriles catalyzed by APTADPHS-nSiO2 (triazine diphosphonium hydrogen sulfate ionic liquid supported on functionalized nanosilica) as a reusable catalyst under microwave irradiation and solvent-free conditions that gave fused heteroaromatic1,3-dimethyl-5-aryl-7-(pyridine-3(2)(4)yl)pyrimidine-2,4(1H,3H)-diones in moderate to good yields (Scheme 8). 61Besides, synthesizing the bisderivatives of pyridylpyrimidines was also efficiently obtained by using dinitriles and dialdehydes.Without any significant loss of its activity can be reused the catalyst at least several times.The easy recovery, reusability, and excellent activity of the catalyst, and easy workup are other noteworthy advantages of this method.
Pyrido [2,3-d]pyrimidines are considered highly important heterocyclic compounds which exhibit a wide variety of biological activities.In another study reported by Aryan and co-workers, the deep eutectic solvents (DESs) was utilized as a media to synthesize a series of diverse pyrido [2,3-d]pyrimidine derivatives.A straightforward and efficient multicomponent synthesis of a small library of diverse pyrido [2,3-d]pyrimidine derivatives was reported through the three-component reaction of aromatic aldehydes (1), active methylene compound (malononitrile (3), methyl acetoacetate (20) or ethyl cyanoacetate (19)), and aminouracil (2, Scheme 10). 63The products were obtained within relatively short reaction times in good to excellent yields in the presence of in situ prepared choline chloride/urea (1:2) deep eutectic solvents (DESs) as media and promoters.Recently, the use of DESs has received extensive attention as a green solvent alternative to harmful organic solvents and ionic liquids due to the unique properties such as low production price, low toxicity, negligible vapor pressure, and high biodegradability.This new solvent class, in addition to providing a reaction medium, has in some cases been used as a reactant or even a catalyst for a variety of several synthetic methods.The beneficial factors of this method are simple purification and the ability to reuse deep eutectic solvent.Also, antibacterial and antifungal activities were observed for all compounds synthesized in vitro.

Scheme 8. Multicomponent synthesis of pyridylpyrimidines and their bis-derivatives catalyzed by APTADPHS-nSiO2. 61
Scheme 9. General procedure for the preparation of pyrido [2,3-d]pyrimidines. 62heme 10.Synthesis of various pyrido [2,3-d]pyrimidine derivatives through a multicomponent reaction. 63 2018, an efficient one-pot, three-component condensation reaction synthesis of 6,8adihydropyrido [2,3-d]pyrimidine derivatives (24) was accomplished through the condensation of (phenylsulfonyl)acetonitrile (23), aromatic aldehydes (1), and 6-aminouracil (2) in glycerol at 80 o C without using any toxic solvent under mild reaction conditions in good to excellent yields (88-95%) by Shaterian et al. (Scheme 11). 64The method covers domino condensation-cyclization Knoevenagel-Michael addition.The reaction was performed in glycerol as a solvent that is commercially available, cheap, and non-toxic.It could also be successfully recovered and recycled at least for five runs without significant loss in activity.

© AUTHOR(S)
Scheme 15.Three-component synthesis of fused indenopyridines. 68nsoor and his groups developed a mild, facile and straightforward one-step condensation method for the synthesis of privileged of 5-aryl-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido [2,3-d]pyrimidine-2,4,6-trione derivatives (29) from aromatic aldehydes (1),1,3-indanedione (28) and 6-aminouracil (2) in the presence of the catalyst, β-cyclodextrin-propyl sulfonic acid (β-CD-PSA) under solvent-free conditions (Scheme 16). 69he hydrophobic cavity of CDs (cyclodextrin) has unique supramolecular properties, so this widespread use of CDs in various organic synthesis areas is of particular interest to chemists.Many kinds of literature have been reported that β-cyclodextrin based polyurethane has been used as an efficient phase transfer and reusable catalyst without significant loss of activity to prepare heterocyclic scaffolds via multicomponent synthesis. 69review of articles and research has shown that due to phosphorus pentoxide's unique properties and synthetic capabilities, P2O5 can be used in organic conversions like in olefin dimerization, Beckmann rearrangement, the formation of 1,1-diacetates and the tetrahydropyranylation of alcohols.A clean and efficient P2O5 mediated procedure for the three-component reaction of synthesis of pyrido[2,3-d:6,5d]dipyrimidines derivatives (30) from aromatic aldehydes (1), barbituric acid (29)/thiobarbituric acid (24), and 1,3-dimethyl-6-aminouracil (2) was developed by Anbhule et al. in ethanol with good yields (Scheme 17). 70tudies on the biological activities of these synthetic compounds showed that all prepared compounds have antituberculosis activity activities against the H37RV strain of Mycobacterium tuberculosis.
In this research, they were prepared a new multi-walled carbon nanotubes (MWCNTs) catalyst through Cu(II) immobilization on L-histidine functionalized (MWCNTs@L-His/Cu(II)).It should be noted that the catalyst can be separated from the reaction medium and reused several times without a significant loss of activity.Scheme 18. Synthesis of pyrido [2,3-d:5,6-d']dipyrimidine derivatives in the presence of MWCNTs@L-His/Cu(II). 71 The group of Pravin 72 discovered a highly efficient regioselective reaction for synthesizing pyrimidinefused tetrahydropyridines (34, 35, 36) tethered through a three-component reaction of α,β-unsaturated aldehydes (26), cyclic 1,3-dicarbonyls, and 6-aminouracils (2) had been demonstrated in the presence of FeCl3•6H2O as catalyst under microwave irradiation (Scheme 19).Besides, they prepared a two-component pyrimidine-fused pyridine by replacing cyclic 1,3-diketones and keeping all other conditions the same.
In supramolecular and host-guest chemistry, some of the most useful host molecules are the cyclodextrins (CDs).They are torus-shaped cyclic oligosaccharides with the ability to form host-guest complexes through a hydrophobic interior cavity.Substrates are bound to form desired products, often in a highly selective fashion.The formation of complexes depends on the size, shape, and hydrophobicity of the guest molecule.The used β-cyclodextrin catalyst was recuperated and the process was repeated several times, devoid of considerable loss of catalytic activity, a crucial green synthesis parameter. 74heme 20.Synthesis of pyrido [2,3-d]pyrimidine trione framework. 73

Synthesis of Pyrrolo-pyrimidine Compounds
The one-pot condensation of the one-pot reaction of 1,3-dimethylbarbituric acid (29) and arylglyoxal (9) with aminouracil 2 in the presence of TBAB (5 mol%) in ethanol at 50 °C for the synthesis of the novel an efficient method for the synthesis of pyrrolo [2,3-d]pyrimidine derivatives (63), has also been investigated by Javahershenas and Khalafy (Scheme 36). 90n another study, this group reported an efficient procedure for the reaction of arylglyoxals (9) with 6amino-1,3-dimethyluracil (2) and 4-hydroxycoumarin (33), in the presence of L-proline in acetic acid under reflux conditions, affording polyfunctionalized pyrrolo [2,3-d]pyrimidine derivatives (64) in high yields (Scheme 37). 91cheme 36.Three-component synthesis of polyfunctionalized fused pyrroles. 90heme 37. Three-component synthesis of pyrrolopyrimidine. 91e mechanism proposed by the authors is as follows: to form the final product, first through a Knoevenagel condensation reaction of 4-hydroxycoumarin with aryglyoxal under loss of a water molecule leads to the formation of intermediate C. The organo-catalyst L-proline helps to attack by activating arylglyoxal.Then, by Michael addition 6-aminouracil (2) to intermediate C, followed by intramolecular heterocyclization through condensation.The proposed mechanism is shown in Scheme 38.

Synthesis of 6-Aminouracil Arylmethane Derivatives
Brahmachari and Banerjee reported a simple, facile, and convenient, practical method for the one-pot synthesis of biologically relevant alkyl/aryl/heteroaryl-substituted bis(6-aminouracil-5-yl)methane scaffolds (67).(Scheme 40). 93They have demonstrated an elegant and efficient approach for the synthesis by using ceric ammonium nitrate (CAN) as a commercially available and eco-friendly catalyst via a pseudo-threecomponent condensation reaction aldehydes (1) and 6-aminouracils (2) in aqueous ethanol at room temperature.
Typical experimental procedure for synthesizing bifunctional thiourea-based organocatalyst I: First, 4amino-1-benzyl piperidine (0.5mmol) was dissolved in 2 mL dichloromethane and cooled to 0 o C.Then, 2piperidinoethyl isothiocyanate (0.5 mmol) was added into the reaction mixture and stirred at room temperature until completion of the reaction, as judged by TLC.The reaction mixture was cooled, and the solid was filtered off and washed with ethanol to afford the desired bifunctional thiourea-based organocatalyst.
The plausible mechanism for the formation of tri-substituted methane derivatives ( 69) is schematically presented in Scheme 42.The hydroxy group in 4-position of 4-hydroxycoumarin (33) is vital for the reaction; aldehyde initially reacts with 4-hydroxycoumarin (33) via aldol condensation followed by dehydration to give intermediate A. Since 6-amino-1,3-dimethyluracil (2) is a softer nucleophile than 4-hydroxycoumarin (33), the former will undergo a 1,4-addition reaction preferentially.Then the third component undergoes Michael AUTHOR(S) addition followed by tautomerization to provide the corresponding tri-substituted methane derivatives (69).The basic functionalities present in catalyst activates nucleophiles and the C=O group by a double hydrogen bonding interaction.When aminouracil cyclization did not occur, this may be due to the presence of a carbonyl group (amide) conjugated to the enamine moiety of compound (2), which reduces the nucleophilicity of the amino group.Scheme 41.Synthesis of tri-substituted methane derivatives. 94heme 42.Plausible reaction mechanism.
The Brahmachari group 95 also developed another synthetic protocol for efficiently synthesized a new series of biologically-interesting diverse and functionalized 5-((1H-indol-3-yl)(aryl)methyl)-6-aminopyrimidine-2,4(1H,3H)-dione derivatives (74) through the one-pot three-component coupling reaction of substituted aromatic aldehydes (1), 6-aminouracil derivatives (2), and indoles (73) in the presence of sulfamic acid as a low-cost and eco-friendly catalyst in the water at room temperature under mild reaction conditions (Scheme 43).It was shown that this versatile synthon could be used as intermediates to generate a series of pharmaceutically active heterocycles such as the target molecules in high yields.

Conclusions
Researchers' significant attention has been paid to the design and development of the synthesis of numerous heterocyclic compounds containing nitrogen atoms in the central core due to valuable pharmaceutical and biological activities.A topic of intense research throughout the areas of medicinal and biomolecular chemistry is the synthesis of new uracil derivatives.This review has highlighted the recent progress of the multicomponent functionalization of 6-aminouracil as a significant starting material and a vital nucleus in synthesizing complex heterocyclic scaffolds with ease ecologically viable fashion.In fact, in modern organic synthesis, these MCRs have rigorously proven to be brilliant, powerful tools for synthesizing diverse and complex molecular systems, including various heterocyclic and natural products in a single one-pot operational step.It is needless to mention that there remains a vast opportunity to develop and design various sustainable strategies to perform the reaction under mild conditions, in high efficiency, and selectivity and greenness of the respective procedures.The authors apologize for the research which has not been mentioned in this review for one reason or another.This review has tried to summarize the latest research on the application of 6-aminouracil in multicomponent reactions to synthesize a variety of novel substituted heterocyclic compounds between 2015 and 2020.

Acknowledgements
The author is grateful for the support of this work from the University of Urmia.

Scheme 38 . 92 ©
Scheme 38.The proposed mechanism for the one-pot three-component reaction.

Table of Contents
followed by eliminating water to afford intermediate (B or B').Subsequent Michael-type addition of 6-aminouracil derivative (2) to intermediate (B or B') gives the intermediate C or C'.Cyclization of intermediate followed by dehydration affords the corresponding intermediate (E or E`).This intermediate undergoes oxidation to give final product (4) or