Synthesis of heterocyclic scaffolds through 6-aminouracil-involved multicomponent reactions

Abstract

This review presents the advances in the use of 6-aminouracil as a starting material in the synthesis of various heterocyclic structures such as pyrido-, pyrrolo-, and pyrimido-pyrimidines, fused spirooxindole derivatives, etc. There is a wide range of multicomponent reactions that include 6-aminouracil in the synthesis of various organic compounds. This review aims at showing representative examples of these multicomponent reactions in recent years.

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Ghodsi Mohammadi Ziarani

Ghodsi Mohammadi Ziarani was born in Iran, in 1964. She received her B.Sc. degree in Chemistry from the Teacher Training University, Tehran, Iran, in 1987, her M.Sc. degree in Organic Chemistry from the same university, under the supervision of Professor Jafar Asgarin and Professor Mohammad Ali Bigdeli in 1991. She obtained her Ph.D. degree in asymmetric synthesis from Laval University, Canada under the supervision of Professor Chenevert, in 2000. She is a Full Professor in the Science faculty of Alzahra University. Her research interests include organic synthesis, natural products synthesis, synthetic methodology and applications of nano-heterogeneous catalysts in multicomponent reactions.

Narges Hosseini Nasab

Narges Hosseini Nasab was born in 1989 in Isfahan, Iran. She received her B.Sc. degree in chemistry from Payam Noor University, Shahin Shahr, Iran, in 2011 and her M.Sc. degree in organic chemistry from Alzahra University, Tehran, Iran in 2013. She is currently working towards her Ph.D. in organic chemistry at Kashan Univeristy, Kashan, Iran. Her research interests include synthesis of uracil based heterocyclic compounds and the application of nano-heterogeneous catalysts in organic synthesis and multicomponent reactions.

Negar Lashgari

Negar Lashgari was born in 1985 in Tehran, Iran. She received her B.Sc. degree in Applied Chemistry from the Teacher Training University, Tehran, Iran (2008) and her M.Sc. degree in Organic Chemistry at Alzahra University, Tehran, Iran (2011) under the supervision of Dr. Ghodsi Mohammadi Ziarani. She is currently working towards her Ph.D. in Nano-Chemistry at the University of Tehran under the supervision of Dr. Alireza Badiei and Dr. Ghodsi Mohammadi Ziarani. Her research field is synthesis and application of nano-heterogeneous catalysts in multicomponent reactions.

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1. Introduction

Uracil is one of the five nucleobases and therefore an important component of nucleic acids.¹ Its chemistry and that of its derivatives e.g. 6-aminouracil are very rich, as these molecules can act as both nucleophiles and electrophiles. Uracils are widespread in natural products and are of interest because of their biological properties.² Uracil is an important component in helping enzymes carry out different reactions and the making of polysaccharides. Because uracil helps enzymes carry out different reactions in cells, it is important in the drug industry with delivering drugs throughout the body. It has been found to be a common structural moiety of several bioactive compounds known for anti-inflammatory,^3,4 antimicrobial,⁵ analgesic,⁶ acaricidal,⁷ and anticancer activities.⁸ Uracil can be used as a hygienic quality index to determine microbial contamination of tomatoes. The presence of uracil indicates lactic acid bacteria contamination of the fruit.⁹ 6-Aminouracils are used as starting materials for the synthesis of heterocyclic frameworks of biological significance such as pyrido-, pyrrolo- and pyrimido-pyrimidines.^10–12 Recent literature shows resurgence of interest in the chemistry and bioactivity of 6-aminouracil derivatives leading to improvement in procedures of several already known reactions.^13–16

Worldwide demand for environmentally friendly chemical processes, requires the design of highly efficient chemical synthetic methods that provide maximum structural complexity and diversity with a minimum number of synthetic steps to assemble compounds with interesting structures and properties.¹⁷ The design of reactions involving more than two components, usually referred to as multicomponent reactions (MCRs), for synthesizing molecules with complex structures has become an important area of research in organic, medicinal, and combinatorial chemistry.^18,19 Multicomponent reactions are powerful tools for the rapid synthesis of highly complex scaffolds. This article aims to review the multicomponent reactions in which one of the starting materials is 6-aminouracil.

2. Synthesis of pyrido-pyrimidine compounds

Synthesis of a library of uracil fused spirooxindole derivatives 4 has been developed by Paul and Das involving PEG-OSO₃H mediated one-pot three-component domino coupling of 6-aminouracil 1, isatin 2, and 1,3-diketo compounds 3 (Scheme 1).²⁰ Acidic PEG-based catalyst showed a dual role in this reaction: as a catalyst to activate the substrate molecules and as a phase transfer catalyst to solubilize organic reactants in aqueous medium. It was observed that without adding PEG-OSO₃H, the reaction did not go to completion even after 24 h. The three-component reaction of isatin and 6-aminothiouracil with 1,3-indanedione, dimedone, or barbituric acid in distilled water in the presence of p-toluenesulfonic acid,²¹ in refluxing ethanol,²² and in the presence of ionic liquid N,N,N,N-tetramethylguanidinium triflate (TMGT_f)²³ was also reported. In another study, application of deep eutectic solvent (choline chloride–oxalic acid: 1 : 1) (DES) as catalyst and reaction medium catalyzed the reaction of aminouracils, isatins and cyclic carbonyl compounds to facilitate the synthesis of spiroheterocycles in excellent yields.²⁴

Scheme 1

The reactions of isatins 2, 6-aminouracil 1, and 2-hydroxynaphthalene-1,4-dione 5 could proceed smoothly in poly(ethylene glycol) 200/H₂O and spiroindeno[1,2-b]pyrido[2,3-d]pyrimidine compounds 6 were obtained (Scheme 2).²⁵ Furthermore, various benzaldehydes 7 could be applied to the reaction of 6-aminouracils 1 and benzo[a]phenazine 8 using AcOH as the reaction medium to successfully produce related uncyclized products 9.

Scheme 2

Naeimi et al. reported a three component one-pot reaction of 6-aminouracil 1, isatins 2 and anilinolactones 10 or tetronic acid 11 in the presence of manganese ferrite nanoparticles as a magnetic catalyst in water to produce a series of novel spiro-furo-pyrido-pyrimidine-indolines derivatives 12 and 13 (Scheme 3).²⁶ It was observed that by using anilinolactones in comparison with tetronic acid, the reaction time has decreased to 3 h.

Scheme 3

A multicomponent domino reaction involving 6-aminouracil 1, isatin 2, and acetyl acetone 14 catalyzed by L-proline for the synthesis of a library of spirooxindole derivatives with a pyrido[2,3-d]pyrimidine moiety 15 has been reported by Singh and coworkers (Scheme 4).²⁷ The first step of the reaction involves the nucleophilic addition reaction of L-proline with isatin which leads to the formation of the intermediate A which, in the next step, is attacked by 6-aminouracil to produce the intermediate C. The intermediate C finally reacts with the active methylene compound and undergoes Michael addition which leads to the formation of D, which further undergoes elimination of water to give the final product (Scheme 4).

Scheme 4

A green approach for the regioselective synthesis of novel isoxazoloquinolines 17 and spiroxindoles 18 via the cleavage of the isatin C–N bond followed by ring expansion reaction in one-pot manner has been established using p-toluenesulfonic acid as a catalyst (Scheme 5).²⁸ In this one-pot reaction, the course of the reaction was found to be dependent upon the nature of the group attached to the isatin ring nitrogen atom, under the same conditions.

Scheme 5

In a similar study, some new and known pyrido[2,3-d:6,5-d′]dipyrimidine derivatives 19 were synthesized by condensation reaction of 6-aminouracil 1 and different aldehydes 7 using nanocatalyst SBA-15-SO₃H under solvent-free conditions (Scheme 6).²⁹ Final NH₂ activation by SBA-15-SO₃H helped in the elimination of ammonia which was a driving force for obtaining the desired product. Dabiri and coworkers have also investigated the reaction of 6-amino-1,3-dimethyluracil 1 with aromatic aldehydes 7 to afford compounds 19 using [bmim]Br/p-TSA or microwave-assisted conditions.³⁰

Scheme 6

A series of pyridopyrimidine derivatives 22–24 were synthesized and evaluated for their ability to inhibit cyclic nucleotide synthesis in the presence of stable toxin of Escherichia coli. All compounds were synthesized from the reaction of 6-aminouracil derivative 1 with an aldehyde 7 and a 1,3-dicarbonyl compound 3, 20, and 21 (Scheme 7).³¹ Similarly, the reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of cyclic ketones or cyclic 1,3-diketones and the appropriate aromatic aldehydes afforded regioselectively a series of polycyclic pyrimido[4,5-b]quinoline and pyrido[2,3-d]pyrimidine derivatives in good yields.³²

Scheme 7

Bazgir and coworkers described a simple three-component one-pot cyclocondensation reaction of barbituric acids 3, aromatic aldehydes 7, and 6-aminouracils 1 for the synthesis of pyrido[2,3-d:6,5-d]dipyrimidines 25 in the presence of catalytic p-toluenesulfonic acid (p-TSA) (Scheme 8).³³ A possible mechanism for the formation of 25 is proposed in Scheme 8. It is reasonable to assume that 25 results from initial formation of a heterodiene A by standard Knoevenagel condensation of the barbituric acid 3 and aldehyde 7. Then, the subsequent Michael-type addition of the 6-aminouracil 1 to the heterodyne A, followed by cyclization affords the corresponding products 25. Application of ultrasound irradiation in this one-pot, three-component condensation was also investigated.³⁴ Replacement of barbituric acids with 2-hydroxynaphthalene-1,4-dione in this reaction leading to pyrimido[4,5-b]quinoline-tetraones in the presence of ionic liquids,³⁵ p-toluenesulfonic acid,³⁶ or nano ZnO³⁷ was also reported.

Scheme 8

Pyrido[2,3-d]pyrimidine-2,4,7-trione derivatives 27 have been synthesized via the one-pot, three-component reaction of 6-aminouracil 1, aromatic aldehydes 7, and 4-hydroxycoumarin 26 in the presence of catalytic amounts of sulfamic acid (Scheme 9).³⁸

Scheme 9

Khurana and coworkers have reported three-component reaction of 6-amino-1,3-dimethyluracil 1, aromatic aldehydes 7, and dimedone 3 in the presence of InCl₃ as a recyclable catalyst and water as the solvent to produce a variety of bioactive pyrimidine derivatives 29 (Scheme 10).³⁹ Similar procedures were also described using p-TSA,⁴⁰ TEBAC (triethylbenzylammonium chloride),^41,42 a mixture of acetic acid and ethylene glycol,^43,44 boiling acetic acid,⁴⁵ and magnetic nanoparticles supported silica sulfuric acid (Fe₃O₄@SiO₂–SO₃H)⁴⁶ as catalysts in this reaction. In another study, Shi and coworkers used ionic liquid 1-n-butyl-3-methylimidazolium bromide ([bmim]Br) as the reaction medium without any catalyst.⁴⁷ They observed that when an aliphatic aldehyde was treated with 1 and 3 in [bmim]Br, the desired product 29 was not obtained, but the uncyclized product 28 was achieved.

Scheme 10

A three-component reaction of 6-amino-1,3-dimethyluracil 1, acetyl acetone 14, and aromatic or aliphatic aldehydes 7 for the synthesis of dihydropyrido[2,3-d]pyrimidines 30 was reported by Agarwal and Chauhan (Scheme 11).⁴⁸ It was observed that as the reaction time was increased, oxidation of 30 took place and the oxidized products (31 and 32) were formed. The same group also reported this three-component reaction on solid support using microwave irradiation.⁴⁹ Later on, similar reactions were reported by employing thiourea dioxide⁵⁰ or in refluxing DMF.⁵¹ In the latter one, to gain deep understanding of the electronic structure, reactivity, and ring cyclization potential of uracil, quantum mechanical calculations were performed at the density functional theory (DFT) level using the Becke–Lee–Yang–Parr (BLYP) energy functional and the basis set DNP (double-numerical basis functions with polarization functions).

Scheme 11

One-pot three-component cyclocondensation of aromatic aldehydes 7, β-oxodithioesters 33, and 6-amino-1,3-dimethyluracil 1 in the presence of recyclable SiO₂–H₂SO₄ as an efficient and convergent route to dihydropyrimidinones 34 has been reported by Singh and coworkers (Scheme 12).⁵²

Scheme 12

Microwave-assisted three-component cyclocondensation of 6-aminouracils 1, benzaldehyde 7, and alkyl nitriles 35 afforded pyrido[2,3-d]pyrimidines 36 in high yields (Scheme 13).⁵³ Antiviral and cytotoxic activities of these derivatives were evaluated.⁵⁴ This reaction was also reported in the presence of other catalysts such as triethylbenzylammonium chloride (TEBAC),⁵⁵ [bmim]Br,⁵⁶ triethanolamine (TEOA),⁵⁷ ZrO₂ nanoparticles,^58,59 SBA-Pr-SO₃H⁶⁰ or under ultrasonic irradiation using tetra-n-butyl ammonium bromide (TBAB).⁶¹ Further synthetic utility of this reaction has been demonstrated by replacement of the alkyl nitriles 35 with benzoyl acetonitrile to give fused pyrido[2,3-d]pyrimidines without any catalyst.⁶²

Scheme 13

A one-pot procedure for preparation of some new condensed pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones 38 based on condensation of ninhydrin 37, alkyl cyanoacetate 35, and 6-aminouracil derivatives 1 has been reported by Azizian et al. (Scheme 14).⁶³ A reasonable mechanism for the formation of the product 38 is outlined in Scheme 14. The reaction occurs via an initial formation of alkyl cyano-(1,3-dioxoindan-2-ylidene)acetate A from the condensation of ninhydrin and alkyl cyanoacetate which is then subjected to nucleophilic attack followed by the loss of hydrogen cyanide to give aminoketone intermediate B. The intermediate B then undergoes cyclization to afford the product 38.

Scheme 14

Prajapati and coworkers have demonstrated a facile and efficient one-pot, three-component reaction strategy for the synthesis of structurally diverse 6,8a-dihydropyrido[2,3-d]pyrimidine derivatives 40 in good to excellent yields by three-component reactions involving sulfonyl acetonitrile 39, aromatic aldehydes 7, and 6-aminouracils 1 (Scheme 15).⁶⁴ It is assumed that Knoevenagel condensation product A is formed between alkylsulfonyl acetonitrile 39 and aromatic aldehyde 7 which then participates in Michael addition with 6-aminouracil 1 to form the Michael adduct B. Then the formed Michael adduct B undergoes intramolecular cyclization to produce intermediate C. A subsequent 1,3-proton shift of the intermediate C forms the final product 40.

Scheme 15

Hegab et al. isolated 1,3-dimethyl-5-aryl-1,6,7,8,9,10-hexahydrocyclohepta[5,6]pyrido[2,3-d]pyrimidine-2,4-diones 42 and the Schiff bases, 6-N-benzylidenamino-1,3-dimethyluracils 45, from the three-component reaction of cycloheptanone 41, 6-amino-1,3-dimethyluracil 1 and aromatic aldehydes 7 (Scheme 16).⁶⁵ Surprisingly, the angular regioisomers 43 and the Schiff bases 45 were also isolated. However, the three-component reaction of 6-amino-1,3-dimethyluracil 1, cycloheptanone 41, and 2-methoxybenzaldehyde 7h afforded only one product, 1,3-dimethylbenzo[4,5]pyrido[3,2-d]pyrimidine-3,4-dione 44.

Scheme 16

Some novel functionalized dihydropyrido[2,3-d]pyrimidines 47 were synthesized using a one-pot three-component reaction of 6-aminouracils 1, aryl aldehydes 7, and 3-cyano acetyl indole 46 using InCl₃ as catalyst (Scheme 17).⁶⁶

Scheme 17

The same group developed a protocol for the synthesis of hexahydropyrimido[4,5-b]-1,8-naphthyridine derivatives 49 and 50 by a one-pot three-component reaction of 2-cyano-3-(1H-indol-3-yl)-pent-2-enedinitrile or ethyl-2,4-dicyano-3-(1H-indol-3-yl)but-2-enoate derivative 48 with aryl aldehydes 7 and 6-aminouracil derivatives 1 (Scheme 18).⁶⁷ A probable mechanism is outlined in Scheme 18. The reaction might occur through initial formation of the Knoevenagel condensation product A, which undergoes Michael addition with the 6-aminouracil 1 to give intermediate B. Intermediate B undergoes intramolecular cyclization to give intermediate C, which participates in another intramolecular cyclization process followed by rearrangement to give the product 49. However, if an ester group is present in intermediate B, product 50 is formed via intermediate E. The mechanism of the reaction was confirmed by performing the reaction in two steps.

Scheme 18

Some spiro pyridopyrimidine derivatives 52–54 have been synthesized by condensation of 6-amino-1,3-dimethyluracil 1 with reactive cyclic ketones such as isatin derivatives 2, ninhydrin 37 and acenaphtoquinone 51 under classical or microwave-assisted solvent-free conditions (Scheme 19).⁶⁸

Scheme 19

Singh and coworkers successfully prepared densely functionalized pyrido[2,3-d]pyrimidines 56 utilizing condensation of 6-amino-1,3-dimethyluracil 1, aldehydes 7, and dialkyl acetylenedicarboxylates 55 in the presence of L-proline (Scheme 20).⁶⁹ The multicomponent process involves Knoevenagel condensation followed by [4 + 2] cycloaddition reaction. It is conceivable that initially 6-amino-1,3-dimethyluracil 1 undergoes proline catalyzed Knoevenagel condensation with aldehyde 7 to give the intermediate A. Once the intermediate A is formed, it undergoes spontaneous [4 + 2] cycloaddition with dialkyl acetylenedicarboxylate 55 to form the desired pyrido[2,3-d]pyrimidine 56.

Scheme 20

The reaction between triphenylphosphine 57 and electron-deficient dialkyl acetylenedicarboxylates 55 in the presence of 6-amino-1,3-dimethyluracil 1 to prepare phosphorus ylides 58–59 has been studied by Mohebat et al. (Scheme 21).⁷⁰

Scheme 21

The reaction of 6-aminouracils 1 with 2-oxoindolin-3-ylideneacetophenones 60 afforded pyriimido[5,4:5′,6′]pyido-[2,3-b]indole-2,4-diones 61 via a regiospecific Michael addition, followed by cyclization (Scheme 22). Alternatively, the reaction of 6-aminouracil 1 with 2-oxoindolin-3-ylidenemalononitrile 62 gave rise to regiospecific formation of spiro indolin-2-one-3,5′-pyrido[2,3-d]pyrimidines 63 in high yields (Scheme 23).⁷¹ The latter one could also be synthesized by one-pot reaction of isatin derivatives 2 with equimolar amounts of malononitrile 35 and 6-aminouracil 1.

Scheme 22

Scheme 23

When the three component of dicarboxaldehydes 64, 6-aminouracil 1, and dimedone 3 were treated in [bmim]Br, a series of bis(pyrimido[4,5-b]quinolin-2,4,6-trione) 65 were obtained in high yields (Scheme 24).⁴⁷

Scheme 24

Kajino and Meguro reported two methods for the synthesis of pyrido[2,3-d]pyrimidine derivatives 68 through Hantzsch synthesis: 6-aminouracils 1 were refluxed with 2-arylmethyleneacetoacetates 66 in an appropriate solvent to afford the desired products in good to excellent yields (method A). The 2-arylmethyleneacetoacetates 66 were prepared from arylaldehydes 7 and acetoacetates 67 by means of the Knoevenagel condensation. The pyridopyrimidines 68 were also prepared by the one-pot condensation of 1, 7 and 67 (method B) under conditions similar to those used for method A (Scheme 25).⁷²

Scheme 25

Dzvinchuk and Lozinskii investigated the reaction between p-(dimethylamino)benzaldehyde 7, 2-acylmethyl-1H-benzimidazoles 69, and 6-amino-1,3-dimethyluracil 1 in boiling acetic acid for the synthesis of 6-(1H-benzimidazol-2-yl)pyrido[2,3-d]pyrimidino-2,4(1H,3H)-diones 70 (Scheme 26).⁷³ The reaction proceeds in accordance with the Hantzsch reaction to form 1,4-dihydropyridine-bearing compounds A followed by aromatization as a result of cleavage of N,N-dimethylaniline.

Scheme 26

Dzvinchuk designed a three-component strategy for the synthesis of pyrido[2,3-d]pyrimidines 72 based on cyclocondensation reaction of p-(dimethylamino)benzaldehyde 7, 2-phenacylazaheterocycle 71, and 6-amino-1,3-dimethyluracil 1 in boiling acetic acid (Scheme 27).⁷⁴ The reaction proceeds through intermediates of type A.

Scheme 27

Balalaie and co-workers introduced an efficient protocol for the synthesis of hexahydropyrido[2,3-d]pyrimidine derivatives 75 by the cyclocondensation reaction of (arylmethylidene)pyruvic acids 74 and 6-aminouracils 1 in H₂O under reflux conditions (Scheme 28).⁷⁵ The acids 74 were synthesized by reaction of aromatic aldehydes 7 and pyruvic acid 73 in an aqueous MeOH solution of KOH.

Scheme 28

3. Synthesis of pyrimido-pyrimidine compounds

Dabiri and coworkers investigated the reaction of 6-amino-1,3-dimethyluracil 1, benzaldehydes 7, and urea 76 in the presence of a catalytic amount of acetic acid which afforded pyrimido[4,5-d]pyrimidine-2,4,7-trione derivatives 77 (Scheme 29).³⁰ In another studies, magnetic α-Fe₂O₃-MCM-41 mesoporous material functionalized by dual acidic ionic liquid (DAIL)⁷⁶ and nano-crystalline CuI⁷⁷ showed good catalytic performances in the one-pot synthesis of pyrimido[4,5-d]pyrimidine derivatives.

Scheme 29

Bazgir and coworkers have investigated a three-component one-pot process by condensation reaction of 6-amino-1,3-dimethyluracil 1, aromatic aldehydes 7, and 2-benzylisothiourea hydrochloride 78 in the synthesis of pyrimido[4,5,d]pyrimidine-2,4-(1H,3H,5H,8H)-dione derivatives 79 (Scheme 30).⁷⁸

Scheme 30

The reaction of 6-aminouracil 1 with primary aromatic or heterocyclic amines 80 and formaldehyde 81 or aromatic (heterocyclic) aldehydes 7, 82–83 in a molar ratio (1 : 1 : 2) gave the pyrimido[4,5-d]pyrimidin-2,4-dione ring systems 84–87 via a double Mannich reaction (Scheme 31).⁷⁹

Scheme 31

4. Synthesis of pyrrolo-pyrimidine compounds

Quiroga et al. reported a three component one-pot reaction of 6-aminouracil 1, dimedone 3 and arylglyoxal 88 to produce a series of unexpected several pyrrolo[2,3-d]pyrimidine derivatives 89 (Scheme 32).⁸⁰

Scheme 32

Some novel 5-arylamino-pyrrolo[2,3-d]pyrimidine derivatives 90 were synthesized via microwave-assisted three-component reaction of N,N-dimethyl-6-aminouracil 1, aryl glyoxal monohydrates 88 and aryl amines 80 (Scheme 33).⁸¹ The proposed mechanism shows that acetic acid acts as Brønsted acid promoter as well as solvent in the reaction process. First, the condensed compound A forms from the reaction of compounds 88 and 80 which undergoes nucleophilic addition to compound 1 in presence of acid to give intermediate B. The intermediate B then undergoes through an intramolecular cyclization process in presence of acid catalyst to produce the intermediate C, which subsequently eliminates water molecule to afford the desired product 90.

Scheme 33

Rad-Moghadam and Azimi developed a sequential tandem protocol for facile preparation of 2-oxoindolin-3-yl-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives 92 in one-pot via a cycloaddition reaction between acetophenones 91, isatins 2, and 6-amino-uracils 1 in refluxing ethanol (Scheme 34).⁸² The mechanistic pathway includes a sequence of reactions initiated by a quick nucleophilic addition of acetophenone onto isatin under piperidine catalysis to afford 3-hydroxy-3-aroylmethylindolin-2-one A. Upon addition of p-TSA to the reaction mixture, compound A undergoes dehydration to give the intermediate 3-aryloylmethylideneindolin-2-one B. This intermediate is comprised of an exocyclic alkenyl bond being polarized by the dominant electron-withdrawing impact of indolin-2-one moiety, whereupon it undergoes Michael addition preferably at the olefinic methine carbon atom. The Michael adduct C follows an intramolecular condensation to form the product 92. The products were evaluated in vitro for their antibacterial activities. Almost all of the obtained compounds exhibited good to excellent antibacterial activities against the tested strains.

Scheme 34

Spiro[pyrimido[4,5-b]quinoline-5,5′-pyrrolo[2,3-d]pyrimidine]-pentaone derivatives 93 can be prepared by condensation reaction of 6-amino-uracils 1 and isatins 2 in aqueous media (Scheme 35).⁸³ The products were evaluated in vitro for their antibacterial activities. Similarly, another reaction was reported by Dabiri and coworkers⁸⁴ in refluxing EtOH for 5–7 h affording products with 70–81% yield.

Scheme 35

5. Synthesis of 6-aminouracil arylmethane derivatives

In a careful study, Lintao et al. reported the first study on the synthesis of di(6-aminouracil-5-yl)-arylmethane 94 from uracils 1 and aldehyde 7 co-catalyzed by BF₃ and aniline in very good yields (Scheme 36).⁸⁵

Scheme 36

Application of ceric ammonium nitrate (CAN) as an eco-friendly catalyst in pseudo three-component condensation reaction between aldehydes 7 and 6-aminouracils 1 in aqueous ethanol at room temperature resulted in the formation of alkyl/aryl/heteroaryl-substituted bis(6-aminouracil-5-yl)methanes 95 (Scheme 37).⁸⁶ CAN as a Lewis acid activates aldehyde 7 and thus facilitates a nucleophilic attack by 6-aminouracil 1 to the electron-deficient carbonyl centre of 7 through electron-rich C-5 position, thereby generating an intermediate C, which then reacts with the second molecule of 1 under the influence of CAN in aqueous ethanol to afford the desired product 95. This reaction was also reported in water at room temperature⁸⁷ and also in the presence of glacial acetic acid and methanol at room temperature⁸⁸ or ethanol at 80 °C or microwave radiation at solvent free conditions.⁸⁹

Scheme 37

A series of 5-benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione 97 and 5,5′-(arylmethylene) bis[6-aminopyrimidine-2,4(1H,3H)-dione] derivatives 98 were synthesized via the three-component reactions of aromatic aldehydes 7, 6-aminouracils 1 and Meldrum's acid 96 in the presence of triethylbenzylammonium chloride (TEBAC) in aqueous media (Scheme 38).⁹⁰ It was observed that the structures of the products were affected by the electronic nature of substituents in aromatic aldehydes. When the aromatic aldehydes with electron-donoring groups were used, the products 97 were obtained. While the aromatic aldehydes with electron-withdrawing groups were used, the products 98 were obtained with excellent yields under the same reaction conditions.

Scheme 38

Synthesis of a series of tri-substituted methane derivatives 99–100 has been reported via a one-pot multicomponent reaction of aldehyde 7, 1,3-dimethyl-6-aminouracil 1 and 2-hydroxy-1,4-naphthoquinone 5/4-hydroxycoumarin 26 using a bifunctional thiourea-based organocatalyst in aqueous medium (Scheme 39).⁹¹ A plausible mechanism for the formation of tri-substituted methane derivatives has been proposed in Scheme 40. The aldehyde 7 initially reacts with 5 or 26 via aldol condensation followed by dehydration to give intermediate B. Then the third component undergoes Michael addition followed by tautomerization to provide the corresponding tri-substituted methane derivatives 99 or 100. The same authors also reported the three-component reaction of 4-hydroxycoumarin, aldehyde, and 1,3-dimethyl-6-aminouracil in the presence of a catalytic amount of L-proline in ethanol under reflux conditions.⁹²

Scheme 39

Scheme 40

6. Miscellaneous reactions

Synthesis of 8,12-dihydro-8,10-dimethyl-12-aryl-12H-naphtalo[1′,2′:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-diones 102 was accomplished by coupling of aldehydes 7, β-naphthol 101, and 6-amino-1,3-dimethyluracil 1 under solvent-free conditions (Scheme 41).⁹³ The reaction proceeds via the ortho-quinonemethide intermediate (o-QM) B, which was formed by the nucleophilic addition of 2-naphthol 101 to aldehyde 7. InCl₃ as Lewis acid plays a role in increasing the electrophilic character of the starting aldehyde and stabilizing the o-QM intermediate by the coordination of oxygen lone electron pair with In(III). Subsequent Michael addition of the o-QM B with 6-amino-1,3-dimethyluracil 1 provides the intermediate C that on subsequent intramolecular cyclization followed by deamination afforded the naphtho-pyranopyrimidines 102.

Scheme 41

The multicomponent reaction of 6-aminouracils 1, formaldehyde 81, and selected amines 80 allowed the direct synthesis of a tricyclic heterocyclic scaffold 103, 5,6,8,9-tetrahydro-4H,7H-2,5,6a,8,9a-pentaazaphenalene-1,3-diones, through consecutive Mannich-type and condensation reactions in excellent yields using EtOH or DMSO/H₂O as the solvents (Scheme 42).⁹⁴

Scheme 42

A multicomponent reaction of 6-aminouracil 1 with substituted salicylaldehydes 104 and acetyl-acetic ester 105 was discovered by Magedov and coworkers (Scheme 43).⁹⁵

Scheme 43

6-Aminouracil 1 was successively used to assemble with dimedone 3 and salicylaldehyde 104 using L-proline as a catalyst to generate substituted xanthene derivatives 107 in good yields (Scheme 44).⁹⁶ Later on, ZnO nanoparticles-mediated synthesis of these structures in water under thermal condition has been reported.⁹⁷

Scheme 44

A novel and feasible procedure for the construction of 5-alky/arylidenebarbituric acids 97 has been reported by Kalita et al. based on the three component domino reaction of 6-aminouracils 1, water and aldehydes 7, with water serving a dual role as both solvent and reactant (Scheme 45).⁹⁸ This tandem reaction involves an initial FeCl₃·6H₂O and water assisted amine hydrolysis of 6-aminouracil to barbituric acid followed by Knoevenagel condensation with aldehydes.

Scheme 45

7. Conclusion

The biological activities of 6-aminouracil derivatives make these compounds versatile synthetic targets as well as important structural units in medicinal and synthetic organic chemistry. Recent years have witnessed many fascinating applications of 6-aminouracil in design and synthesis of multiple heterocyclic frameworks with a wide variety of functional groups. 6-Aminouracil and its derivatives have been employed in the synthesis of pyrido-pyrimidines, pyrrolo-pyrimidines, pyrimido-pyrimidines, and 6-aminouracil arylmethane derivatives. Many synthetic compounds also exhibit potential antimicrobial activities. In this review we have tried to summarize the multicomponent reactions of 6-aminouracil as a useful skeletal motif for the preparation of an enormous variety of compounds of interest. We can still expect many further developments of this compound in synthetic chemistry.

Acknowledgements

We gratefully acknowledge for financial support of Alzahra University Research Council.

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