A Review on Barbituric Acid and Its Derivatives: Synthesis, Reactions, and Bio-Applications

Abstract

Barbituric acid is a heterocyclic compound with various pharmacological and biological applications. This review paper provides a comprehensive overview of barbituric acid’s synthesis, reactions, and bio-applications, highlighting its multifaceted role in various fields. Many heterocyclic derivatives were formed based on barbituric acid, for instance, pyrano-fused pyrimidine derivatives, spiro-oxindole derivatives, chrome-based barbituric acid derivatives, and many more via the atom economic method, Michael addition reaction, Knoevenagel condensation reaction, etc. In the context of bio-applications, this review examines the production of a wide range of bioactive drugs like anti-histamine, anti-leprotic, sedative–hypnotic, anti-inflammatory, anti-urease, antiviral, anti-AIDS, antimicrobial, antioxidant, anticonvulsant, anesthetic agent, antitumor, and anticancer drugs using efficient multicomponent reactions. By showcasing the versatility and potential of this compound, it aims to inspire further research and innovation in the field, leading to the development of novel barbituric acid derivatives with enhanced properties and diverse applications, with coverage of the literature relevant up to 2024.

1. Introduction

Barbituric acid is a pyrimidine derivative that can also be named malonylurea or hydroxyuracil [1]. BA 1 (Figure 1) itself is not pharmacologically active but it can be considered as the parent constituent of barbiturate medication products. The combination of urea obtained from animals and malonic acid obtained from apples allowed Adolf von Baeyer to create the molecule in 1864 [2]. The pharmacological effects of barbiturates predominantly rely on the substituents attached to the C-5 atom of the pyrimidine ring [3]. There are several alkyl or aryl-barbiturates which serve as sedatives, anticonvulsants, hypnotics, and anti-hypertensives [4]. Barbituric acid and its variants are intriguing structural blocks in organic synthesis. They are known as 2,4,6-(1H,3-,5H)-pyrimidinetrione [5,6]. On the contrary, fused-cycle derivative synthesis results in compounds with either antidiabetic or anti-tuberculosis effects. In the colorimetric or heat detection process, the photophysical characteristics of BA derivatives have been used and promising dyes or fluorogenic samples have been reported [7,8,9]. The flexible characteristics of BA products prompted organic chemists to research their chemistry, and more recent developments have brought about effective multicomponent reactions [10,11].

Various reactions generate BA derivatives that have an extensive variety of pharmacological applications, such as anesthetics, anxiolytics, antimicrobials, antifungals, anticancer agents, and so on [12]. Knoevenagel condensation [13], one-pot multicomponent reactions (MCRs) [14,15], simple condensation [16], and thermal polymerization [17] have led to the synthesis of many synthetic drugs and chemotherapeutic agents obtained from BA/TBA. Knoevenagel condensation is a special case of an aldol condensation reaction in which organic compounds like BA, Meldrum’s acid, dimedone, and malononitrile undergo a nucleophilic addition reaction with a carbonyl group [18]. This classical approach is employed for the establishment of carbon–carbon connections but also has potential and functional features in medicinal chemistry and organic synthesis [19]. As materials for heterocyclic compound synthesis such as oxadiazafavin, asymmetric disulfide, and benzyl BA products, as well as dyes and other non-lined optics, several derivatives of 5-arylidene BA have received considerable interest [20]. The activity for the use of 5-arylmethylenepyrimidine-2,4,6-triones is based on a large spectrum of biological and pharmacological activities of 5-arylidene BA and TBA 7 [21]. Pyrano-fused pyrimidinones synthesized via MCRs and carrying uracil as a moiety exhibit pharmaceutical and biological properties [22]. 1-Ethyl-5-((E)-3-phenylallylidene)pyrimidine-2,4,6(1H,3H,5H)-trione 2, formed by the condensation reaction assisted by pyridine, is used as a therapeutic agent for lung cancer [23]. JNK activation omits lung cancer cells [24,25]. The pyridino [2,3-d] pyrimidine derivative formed by Knoevenagel condensation exhibits anticancer properties, due to the presence of an amino group, which enhances the chemical therapeutic agent’s capacity to penetrate the microorganism’s cell wall [26,27]. 1,3-Dimethyl barbituric acid, as a BA moiety, shows excellent luminescence properties, which are useful in making chemosensors and able to identify hydrazine in living cells [28]. 1,4-Dihydropyridine BA derivatives synthesize many pharmacologically active compounds, blocking the calcium channel [29]. They are used to treat cardiovascular diseases like hypertension. The ever-growing role of substituted chromenes and spiro-chromenes in medicinal chemistry is proven, with spiro[2-amino-4H-pyran-oxindole] 22 and BA as key moieties [30]. 5-(Phenyl-azo)thio, BA derivative 10, has been used as an anticancer agent against MCF-7 cells. It is proven that 10 exhibits antimicrobial properties against fungal species and also towards both Gram-positive and Gram-negative species [31]. Naphthoquinone BA-based derivatives are involved mainly in hypnotic drugs [32]. Additionally, these compounds show some sedative activities along with antioxidant properties [33]. 4-hydroxy-4H-chromene barbiturate 11 could be applied to medicinal chemistry, enabling researchers to synthesize many pharmacologically active compounds [34]. Pyrimido[4,5-b]quinoline-dione barbituric-based derivatives synthesized via MCR are useful in the pharmaceutical field. Some of these compounds are highly compatible with antimicrobial activity [35,36]. N,N′-Diethylthio barbituric enamine derivatives show anti-glycation properties with proteins. The enamine moiety serves various biological properties in enamine-based TBA [37]. TFM-based BA derivatives, as prospective building blocks of drug applicant synthesis in the pharmaceutical, agrochemical, and biomedical sectors, are organic compounds that have received considerable attention. Many drugs and agrochemicals containing CF₃ have now been introduced on the market [38]. Dihydropyrimido-[4,5-b]-quinolinetrione synthesized through MCR has been applied in, for instance, antitumor and antiviral drugs. There are many more pharmacological and biological properties [39]. Benzo [5,6] chromene-based BA derivatives formed through the MCR method, as well as chromene and its fused heterocyclic analogs, are key objectives in the synthesis of organic compounds that have biological and pharmaceutical characteristics [40]. Spiroindoline-based BA derivatives are widely present in a variety of natural and synthetic compounds with major biological activity [41]. Additionally, they exhibits antibacterial and antimicrobial properties [42].

Amobarbital 3 is a barbiturate analog (formerly known by the name amylobarbitone or sodium amytal). It has hypnotic sedative characteristics. It is an odorless, white, and slightly bitter crystalline powder, whose first synthesis was achieved in 1923 in Germany [43]. If amobarbital is used for a long period, it may cause physical and mental dependency. The removal of amobarbital mimics leads to life threats. Eli Lilly, the American corporation, had formerly created the Amytal product under the Amytal brand name with vivid blue or pink bullet capsules comprising 50, 100, or 200 mg [44].

In vitro research on stout thalamic sections showed that amobarbital operating through the stimulation of GABA receivers lowered resistance to inputs and lowered burning and tone firing in ventrobasal and intra-laminar neurons while improving blowing time and mean conductance in each chloride channel at the same [45]. In that study, amobarbital was used to prevent the transportation of mitochondrial electrons to the rat heart to re-establish mitochondrial function [46]. Research conducted in 1988 on amobarbital revealed that it enhances in vivo activity but is less effective at the benzodiazepine receptor compared to secobarbital and pentobarbital [47]. Amobarbital is considered to suppress, often to the point of uselessness, the consequences of hormonal birth control. The same applies to digitoxin and heart glucose, whether organically connected with phenobarbital or not [48]. Such adverse effects include confusion, a decline in reflexes, sleeplessness, slumbering, sloppiness, sweating, stunning, sleeping difficulty, irregular motions of the pupils, weightlessness, and sluggish breathing (severe) [49,50]. Phenobarbital 4, or Luminal, is a medicinal product in the form of a barbiturate, also known as phenobarbitone [51]. The World Health Organization suggests this in the treatment of epileptic patients in developed nations [52]. Phenobarbital is still widely used for neonatal and childhood seizures and for drug-resistant convulsive and nonconvulsive status epilepticus [53]. It is utilized or injected into the muscle intravenously via the mouth. The injectable type should be used for epilepsy treatment. Rarely, phenobarbital is used to treat and support sleeping problems, nausea, and medicinal withdrawals. It normally starts operating intravenously within five minutes and is delivered in half an hour. It lasts between four hours and two days. In addition, side effects include reduced awareness and reduced breathing effort [54]. Suicide risk is also increased. In those who have impaired liver or kidney function and for older adults, a reduced dosage is advised. As with other barbiturates, phenobarbital acts by increasing GABA inhibitor activity [55].

Phenobarbital is a BA derivative, introduced in 1912 and considered to be the oldest still extensively used anti-seizure drug. Phenobarbital, excluding absence seizures, is used in all forms of seizures. To treat partial startup seizures, phenobarbitals have a therapeutic benefit over carbamazepine. For generalized tonic–clonic seizures, carbamazepine has a therapeutic benefit compared with phenobarbital [56]. For some people, this dose may not have to be taken daily, especially once the dosage is stabilized for many weeks or months, and because of its extended active half-life (53–118 h), convolutions are successfully monitored. For its sedative and anticonvulsive effects, phenobarbital is also used as an alcohol detoxifying agent and for benzodiazepine detoxification. The related chlordiazepoxide (Librium) and oxazepam (Serax) benzodiazepine also mostly substitute detoxifier phenobarbital [57]. For insomnia and anxiety, phenobarbital is helpful. The main side effects of phenobarbital are sedation and hypnosis. Effects on the central nervous system are also normal, such as dizziness, nystagmus, and ataxia. It creates excitement and confusion in elderly patients, whilst it leads to paradoxical hyperactivity in infants. Barbiturate drugs in solid form are obtained by condensation between DEM and urea derivatives [58]. This popular method is used for the synthesis of phenobarbital but varies as to how the malonate derivative is achieved. The explanation for this distinction is that aryl halides in malonic ester synthesis do not normally undergo nucleophilic substitution, such as aliphatic organo-sulfates or halocarbons do [59]. Pentobarbital is a short-acting barbiturate that is commonly used in emergencies for sedatives, anesthetics, and seizure control [60,61]. It also has been used to treat insomnia for short periods but was eventually superseded by the medication family of benzodiazepines. Pentobarbital deaths from respiratory arrest are caused by heavy doses. It is used for veterinary euthanasia and by various US and federal governments to execute condemned criminals [62]. Oral (pill) pentobarbital has been discontinued commercially. Sedative, brief hypnotic, anesthetic, sleeplessness, and emergency convulsion treatment are typical pentobarbital applications. It is also used as an anesthetic by veterinarians [63]. Traumatic brain harm and coma induction are also utilized to decrease intracranial pressure in patients with Reye’s illness. In acute liver dysfunction patients, mannitol intractable is promoted for pentobarbital-induced coma [64,65].

BA, also known as malonylurea, is a versatile heterocyclic compound with a rich history in organic chemistry. Its unique structure, containing a pyrimidine ring, has attracted significant interest due to its diverse synthetic applications and biological relevance. In this comprehensive review, we delve into the synthesis methods, various reactions, and intriguing bio-applications of BA and its derivatives. From its role as a precursor in drug design to its use in coordination chemistry, BA continues to captivate researchers across disciplines.

2. Bio-Applications of Barbituric Acid and Its Derivatives

Barbituric acid is a chemical compound that has various bio-applications in the field of medicine and research. It serves as a fundamental component for the synthesis of barbiturates, a class of drugs that have historically been used as sedatives, hypnotics, and anticonvulsants [66]. Barbiturates work by depressing the central nervous system, promoting relaxation, inducing sleep, and reducing the occurrence of epileptic seizures [67]. In the past, BA derivatives were commonly used as general anesthetics to induce unconsciousness during surgical procedures. However, due to their potential for addiction and the development of safer alternatives, their use as anesthetics has significantly declined [68]. BA also finds applications in the realm of biochemical and pharmaceutical research. It serves as a fundamental material for the synthesis of various heterocyclic compounds [69], which are essential for the development of new drugs. Researchers utilize BA derivatives to explore and create compounds with potential therapeutic properties [70]. Furthermore, BA and its derivatives have been studied for their potential in photodynamic therapy (PDT). In PDT, light-sensitive compounds called photosensitizers are administered to target cells or tissues. Upon exposure to light of a specific wavelength, these photosensitizers produce reactive oxygen species, leading to localized cell death [71]. BA-based photosensitizers have shown promise in preclinical studies for applications in cancer treatment and other diseases [72].

BA derivatives have also been studied for their antioxidant properties. Oxidative stress, caused by an imbalance between the production of reactive oxygen species and the body’s antioxidant defenses, is implicated in various diseases and aging processes. Some BA derivatives have demonstrated antioxidant activity, which could potentially be utilized for therapeutic purposes [73]. Moreover, BA itself has been investigated for its antimicrobial properties. Studies have shown that BA exhibits inhibitory effects against certain bacteria and fungi. This antimicrobial potential may contribute to the development of novel antimicrobial agents or serve as a basis for further research in the field of antimicrobial drug discovery [74]. While the bio-applications of BA and its derivatives have evolved and shifted over time, they continue to be of interest in various areas of research and pharmaceutical development. Ongoing studies and advancements in medicinal chemistry and pharmacology will further uncover the potential applications and therapeutic benefits of BA and its derivatives in the future. From sedatives and anticonvulsants to antimicrobial agents and beyond, these BA derivatives exhibit a plethora of therapeutic potentials [75].

Barbituric acid, a derivative of urea, serves as the core structure for various pharmacologically active compounds, notably barbiturates. These derivatives are synthesized by substituting different functional groups on the BA molecule, leading to drugs with sedative, hypnotic, or anticonvulsant properties [63]. This class of compounds has been historically significant in medicine for its central nervous system depressant effects. Below is a breakdown of some important derivatives of BA in Table 1:

Through careful modification and structural variations, scientists have been able to harness their unique properties for various medical applications. In Scheme 1, we will explore some notable BA derivatives, their bio-applications, and key characteristics that make them valuable in medicine.

3. Synthesis of Barbituric Acid Derivatives

The synthesis of BA derivatives plays a crucial role in expanding the library of compounds available for various bio-applications. BA, a heterocyclic compound, serves as the starting point for the synthesis of these derivatives [102]. The process involves modifying the chemical structure of BA by introducing different substituents or functional groups to create compounds with desired properties and activities [103]. Synthetic strategies to produce BA derivatives vary depending on the specific target compound and the desired bio-application [104]. These synthesis methods often involve multi-step reactions, where intermediate compounds undergo various transformations to achieve the final desired derivative [105]. The ability to efficiently synthesize BA derivatives is vital for drug discovery, as it allows researchers to explore their potential in fields such as sedation, anticonvulsant therapy, and other areas of medicinal chemistry [106].

The reaction of BA derivatives encompasses a multitude of chemical transformations that modify the core structure to yield compounds with different properties. These reactions are typically carried out through functional group modifications, such as substitution [107], oxidation [108], reduction [109], and condensation [110], among others. The resulting derivatives often possess altered solubilities, stabilities, and pharmacological profiles compared to the parent BA compound.

One of the key reactions involving BA derivatives is the alkylation reaction, where alkyl groups are introduced at various positions on the pyrimidine ring. This reaction plays a crucial role in the synthesis of many barbiturate drugs, which are widely used as sedatives, hypnotics, and anticonvulsants [111]. By modifying the alkyl groups attached to the pyrimidine ring, researchers have been able to tailor the pharmacological properties of barbiturate drugs to achieve specific therapeutic effects [112]. In addition to alkylation, BA derivatives can undergo other important reactions, such as acylation [113], esterification [5], and ring-opening reactions [114]. These transformations enable the introduction of a wide range of functional groups, leading to the development of structurally diverse derivatives with enhanced or novel biological activities. The reactivity of BA derivatives also extends to their involvement in various condensation reactions [115]. For example, the reaction of BA derivatives with aldehydes or ketones can result in the formation of pyrimidinediones, which are important intermediates in the synthesis of pharmaceuticals, agrochemicals, and other bioactive compounds [116].

Overall, the reaction of BA derivatives is a fascinating area of study with far-reaching implications in the fields of medicinal chemistry, drug development, and chemical synthesis. By understanding and manipulating the reactivity of these derivatives, researchers continue to explore new avenues for the synthesis of novel compounds with potential therapeutic applications [117].

5-Arylidene BA derivative 40 was formed with substituted aldehyde 39 and BA 1 catalyzed by a reusable ionic liquid catalyst [TPPHSP]Br under EtOH–water reflux conditions. It was formed by the one-pot MCR method along with an eco-friendly catalyst [118]. Compound 40 (Scheme 2) has also been synthesized in excellent yield up to 94–99% by the catalyst [DABCO](SO₃H)₂(Cl)₂ under aqueous and refluxing conditions [119].

Another reaction of BA 1, which reacts with aldehyde 39 in the presence of Co₃O₄ nanostructure under aqueous medium, gave us the arylidene barbituric acid derivative 40 in excellent yield up to 89–91% (Scheme 3) [120]. The findings showed that Co₃O₄ catalysts are more efficient than others. These items can compete with existing catalysts and can potentially be utilized as a new contender. Synthetic materials may be used for catalytic purposes [121,122,123,124].

https://www.tandfonline.com/doi/abs/10.1080/00397911.2024.2363376 (accessed on 1 August 2024).

Diethyl malonate treated with sodium ethoxide, KI, and allyl bromide afforded compound 47, diethyl allyl-malonate, which was then treated with sodium ethoxide and urea to form compound 48. Further, after treating with HCl, 5-allylBA derivatives were obtained in good yields up to 80–94%. Afterward, the obtained compound 49 (Scheme 4) was recrystallized from ethanol to form a colorless solid [125].

A pyrazolo pyrano pyrimidine compound was formed (Scheme 5) by the reaction between hydrazine hydrate 50, ethyl acetoacetate 51, and BA 1, to form p-Cl-benzaldehyde 52, whereas TEDA/IMIZ-BAIL@UiO-66 catalyzed the reaction in excellent yields up to 93–97%. As shown in Scheme 5, the mentioned catalyst was very efficient and could be recycled again for further use without losing its reactivity. It was also considered a green chemistry method for the resultant compound 53. In this report, we already mentioned many applications of pyrimidine derivatives [126,127].

Compound 57 was formed (Scheme 6) via MCR by different catalysts; many of them were organically based in excellent yields up to 91–98%, but the reaction took place with an organic–inorganic hybrid catalyst. Pyrazole-fused pyrimidine was produced with the help of the following compounds: hydrazine hydrate 54, ethyl acetoacetate 51, aryl aldehyde 56, and amino-1,3-dimethyl uracil 55 catalyzed by a POM hybrid. The resultant compound 57 was utilized as an anticancer agent [128].

MCR methods were used to synthesize fused pyrimidine derivatives. Compound 60 was produced in excellent yields up to 94–97% (Scheme 7) by the reaction between aromatic aldehyde 56, BA 1, ammonium acetate 59, and phenyl-hydrazine under catalyst a. It was a five-component reaction and the resulting product was employed in the treatment of cancer [129].

Pyrano-based barbituric acid derivative 12 was obtained by reacting ethyl acetoacetate 51, benzaldehyde 39, and hydrazine 50 with BA in the presence of catalyst PBCMO-amine, which is a dendritic polymer, through a four-component reaction in excellent yields up to 97–99% [86]. The synthesized product has also been derived from a β-cyclodextrin catalyst (Scheme 8) [130].

Pyrano-fused pyrimidine 62 (Scheme 9) was obtained through one-pot MCR in excellent yields up to 96–98%. This reaction took place in PEG-400, which is non-toxic. The above scheme was a non-thermal, catalyst-free reaction that came under green chemistry. When ethyl acetoacetate 51 reacted with hydrazine hydrate 50, substituted BA and aryl aldehyde 39 formed the desired product, 62, applied in the pharmaceutical field [131].

The pyrano-based barbituric acid derivative 64 (Scheme 10) was produced in excellent yields up to 96–99% by the MCRs. BA reacted with malononitrile, substituted benzaldehyde, and synthesized a piano scaffold BA derivative catalyzed by nanocatalyst Fe₃O₄@PVA-Cu under aqueous conditions at room temperature. Due to the magnetic property of the employed catalyst, it was simply detached from the complex reaction blend and analyzed by FTIR or EDX methods [132]. The synthesized compound has also been derived from the catalyst Fe₃O₄@MCM-41@IL/Pd [133] under solvent-free conditions, as well as the nanocatalyst Schiff base complex [Zn-2BSMP]Cl₂ [134] in EtOH/H₂O at 40 °C with an ethylene glycol catalyst [92] and a nanocomposite SnO₂/SiO₂ catalyst [135] under CFL irradiation conditions at RT [136] or with verjuice under reflux conditions [137]. The resultant compound exhibits variant properties in pharmacology.

Heterocyclic compounds based on pyrimidine derivatives were produced through one-pot methods. Compound 67 was formed via aryl aldehyde 65, ethyl cyanoacetate 66, and BA 1 using nickel NPs@N-dopedTiO₂ under methanol solvent at 65 °C in excellent yields up to 95–98% (Scheme 11). The employed catalyst did not produce any undesirable by-products. Therefore, it could be utilized to synthesize many organic compounds. The resultant compound was examined by spectroscopic techniques [138].

Pyrano-fused pyrimidine derivatives were produced through intramolecular cyclization MCRs. Compound 68 was formed in excellent yields up to 94–97% when aryl aldehyde reacted with malononitrile and BA by ultrasound-assisted irradiation in ethanol under the Fe₃O₄@SiO₂@BenzIm-Fe[Cl]/ZnCl₂ catalyst. Desired heterocyclic component 68 (Scheme 12) possesses various pharmaceutical properties employed in day-to-day life [139].

Pyrano-fused barbituric acid derivatives were formed through an MCR method using different catalysts and solvents. Compound 71 (Scheme 13) was formed in excellent yields up to 93–98% under magnetized deionized water as the solvent and catalytic-free conditions using 1,3-DMBA and benzylidene malononitrile 70 as reactants [87,140].

Pyrano-pyrimidine derivative 64 was synthesized via a three-component reaction under the nanocatalyst Fe₂O₃@APTES@isatin-HSO₃, in a solvent mixture of ethanol/water (1:1), under a reflux environment. Compound 39-substituted benzaldehyde reacts with 1 BA, and 63 malononitrile to give 64 (Scheme 14) in excellent yields up to 95–98% under the influence of the nanocatalyst and solvent mixture [141].

BA 1 was used to synthesize naphthopyrano pyrimidine 74 (Scheme 15) in the presence of the catalyst LaMoFeO₃ at 100^o C in solvent-free conditions. When compound 2-naphthol 72 reacts with 1 and 73, it yields compound 74 under mild conditions with excellent yields up to 95–98% [142,143].

Substituted pyrimidinone derivatives were formed through intramolecular cyclization using verjuice as a catalyst under reflux conditions. The reaction between aryl aldehyde 65, BA 1 and substituted urea 75 generates pyrimidinone derivatives with good yields up to 91–95% (Scheme 16), which possess many biological properties [137].

Triazole-based barbituric acid derivatives were formed through MCR-employed MOF-based zinc terephthalate catalysts. When BA/TBA reacted with amino-based triazole 77 and aromatic aldehyde 56 to produce compound 78 (Scheme 17), the above reaction was enhanced by ultrasound irradiation at 40 °C along with solvent-free conditions to generate good yields up to 91–96%. The catalyst was characterized by spectroscopic techniques such as IR, UV, XRD, and SEM [144].

Pyrido-fused pyrimidine analogs were derived via MCR using the eco-friendly solvent EtOH under reflux conditions at 78 °C in excellent yield of 92–94%. Compound 81 (Scheme 18) was formed by BA 1, substituted aldehyde 79, malononitrile 63, and pyrrolidine 80, whereas compound 81 exhibited anti-inflammatory and antioxidant properties [145].

Nucleoside-bearing heterocyclic compound 83 (Scheme 19) was formed via one-pot MCR using BA 1, benzaldehyde 56, malononitrile 63, and adenosine 82 using the catalyst DBU-Functioned MCM-41-CNSH and covered nanosized hematite in the absence of solvent at 80 °C in excellent yields up to 95–98%. The resultant compound has many biomedicinal applications due to its nucleoside-bearing heterocyclic component [146].

Pyrido pyrimidine derivatives 84 (Scheme 20) were formed through the MCR method in excellent yields up to 96–99%. When amino-uracil 55 reacted with aromatic aldehyde 39 and 1,3-DMBA, the compound 84 was obtained, which exhibits numerous biological activities. The formation of the desired compound was catalyzed by the heterogeneous catalyst MWCNTs@L-His-Cu complex, which shows proficient reusable activity and could be easily separated from the product obtained [147].

Pyrido-pyrimidine derivative 88 (Scheme 21) was produced in excellent yields up to 93–97% by condensing thio-barbituric acid 85, substituted amines 86, and vanillin 87. The reaction took place in a water bath, which is an environmentally friendly solvent. Therefore, it came under green chemistry [148].

In Scheme 22, the formation of compound 13, which is a pyrimidine derivative, is obtained by reacting substituted aryl amine 89, substituted aldehyde 39, and BA 1 with catalyst GOx (carbon catalyst) at 100 °C for 4 h in excellent yields up to 96–98% through a one-pot three-component reaction [35].

Compound 91 (Scheme 23) was synthesized through a four-component reaction by reacting D-glucosamine 90, benzaldehyde 39, BA 1, and malononitrile 63 using catalyst p-toluene sulfonic acid and solvent EtOH at 50 °C with excellent yields up to 93–97% [149].

Substituted chromeno-based barbituric acid derivatives (Scheme 24) were synthesized via MCR catalyzed by trisodium citrate dihydrate in EtOH under aqueous conditions. 4-Hydroxycoumarin 92 reacted with substituted benzaldehyde 39 along with substituted BA 93 to form compound 94 in excellent yields up to 95–98%. The above reaction was assisted by ultrasound irradiation, and the trisodium citrate dihydrate catalyst is non-toxic and environmentally friendly and could be reused [150].

Chromeno-based pyrimidine derivative 96 (Scheme 25) was obtained through the MCR in excellent yields up to 94–99% between aromatic aldehyde 65, orcinol 95, and BA 1 under heterogeneous catalyst Fe₃O₄@SiO₂@BenzIm-Fe[Cl]/ZnCl₂. The resultant compound was further analyzed by spectroscopic methods like FTIR and X-ray diffraction. Additionally, compound 96 showed many biological applications such as anti-inflammatory, antitumor, anti-HIV, antiviral, etc. [139].

MCR methods were used to synthesize many heterocyclic derivatives (Scheme 26), many of which were employed in pharmaceuticals. Benzochromeno-pyrimidine 99 was formed by β-naphthol 97 and substituted aldehydes 39, and BA/TBA 98 was catalyzed by MWCNTs@NHBu/PTA in the absence of solvent at 100 °C in excellent yields up to 97–99% [151].

In Scheme 27, compound 101, a 4-OH-4H-chromene barbituric acid derivative, is formed when chalcones 100 react with BA 1. This reaction is catalyzed by 30 mol% L-Proline in water at 30 °C, yielding excellent results of 95–98% [152].

Pyrimidine derivative 23 was synthesized in Scheme 28 by reacting BA 1 with aromatic aldehyde 56 and dimedone derivative 102, under the catalyst TBAI in an aqueous medium at RT, with excellent yields up to 94–97%. The reaction took place in constant potential electrolysis assembled with platinum plates acting as electrodes [97,153].

In Scheme 29, the formation of compound 104, a benzo-[5,6]-chromene-based barbituric acid derivative, was achieved in excellent yields up to 95–97%, when a reaction took place between β-naphthol 97, PhOx-monohydrate 103, and substituted BA 98 with catalyst potassium phthalimide-N-oxyl. Afterward, tautomerism of compound 104 took place in DMSO solvent leading to the generation of 105 and 106, products of chromene [39,154,155].

In Scheme 30, chromeneno-pyrimidines 109 were produced by the reaction of barbituric derivative 93, methylarenes 107, and dimedone derivatives 108 via one-pot MCR in the presence of lemon juice as the catalyst and an oxidant (TBHP) with excellent yields up to 92–98%. This transition included the creation of metal-free C–C bonding by activating methylarenes under moderate reaction conditions [156].

A one-pot electrochemical method lacking harmful chemicals or solvents was used to produce spirocyclic-based barbituric acid 111 with high-potential antibacterial activity. In Scheme 31, caffeic acid 110 reacted with BA derivatives 98 to produce spiro-based barbituric acid derivatives in excellent yields up to 93–99% through an electrochemical procedure. Electrooxidation of caffeic acid took place to afford the desired compound, whereas the BA derivative acted as a nucleophile [157].

In the above scheme, when substituted ketimines 112 reacted with BA-based olefins 113, they synthesized TFM-dispiro-barbituric acid derivative 114 (Scheme 32) via a Michael cycloaddition reaction in the company of a squaramide catalyst in excellent yields up to 93–97%. In the meantime, the TFM group increases the combination flexibility between pharmaceutical drugs by occupying an adjacent carbon to nitrogen bond [158].

Spirooxindole-based barbituric acid derivatives were formed through a three-component MCR. 1,3-dimethyluracils 115 reacted with isatin 116, substituted BA or 1,3-indanedione-formed BA derivatives 118 and 119, catalyzed in excellent yields up to 97–99% by BAIL@UiO-66 under ultrasonic irradiation in EtOH at RT (Scheme 33). The above-used heterogeneous catalyst was very efficient and reusable, and productivity was proficient [159].

Naphthalene-fused spiro-barbituric acid derivative 122 was formed through a highly efficient multicomponent reaction (Scheme 34) in excellent yields up to 92–98%. Vinyl malononitrile 121 reacted with 1,3-DMBA 69 and substituted aldehyde 120 to afford the desired component 122, employing a DABCO-based cationic surfactant along with aqueous conditions at ambient temperature. The above reaction was assisted by ultrasonic irradiation. Compound 122, bearing a spiro scaffold, made this product of greater potential in the medicinal field [160].

When isatin derivatives 123 reacted with 1,3-DMBA 69 and pyridinium salts of phenacyl 124, they formed compound 125 in excellent yields up to 95–98%, which exhibited biological activities under ambient conditions and in EtOH solvent at 50 °C (Scheme 35). The employed catalyst recovered easily and was reused without losing its efficiency [161].

Spirooxindole-BA derivatives were synthesized via a Knoevenagel reaction using alkyl amines 86, nitro ethylene 126, isatin 116, and BA 1 using EtOH as the solvent or H₂O with reflux conditions (Scheme 36) in excellent yields up to 93–98%. The spirooxindole scaffold was used due to its pharmacological activities with pyrimidine derivatives as pharmacophores. Therefore, compound 127 showed various biological properties due to the spirooxindole moiety [162].

Spirooxindole motif BA derivatives (Scheme 37) were formed through one-pot MCRs with substituted BA 1, isatin 128, and malononitrile 129, catalyzed by SnO₂-NPs in EtOH solvent at RT with excellent yields up to 94–97%. Synthesized product 130 showed antibacterial and antimicrobial activities [163].

Spiro-fused pyran BA derivatives are efficiently formed through MCRs with nanocomposite graphene quantum dots. When substituted, isatin 116 reacted with malononitrile 129 and BA/1,3-DMBA 61 at RT in aqueous conditions, which produced spiro-pyran derivatives in excellent yields up to 96–99% (Scheme 38), showing pharmaceutical and biological properties [164]. The obtained product was also derived from a CuO/ZnO@N-GQD heterogeneous catalyst [30].

As shown in Scheme 39, spiro-pyrimidine barbituric acid 134 was synthesized by using aryl amine 133, isatin 132, and BA 1 via three-component reactions under aqueous conditions in excellent yields up to 94–98%. Compound 134 was used as an anti-urease agent in agriculture and also demonstrated antimicrobial properties [165].

In Scheme 40, the production is shown of compound 137 with the involvement of BA 1 as one of the reactants via three-component reactions. In the following reaction, substituted aldehyde 135 reacted with 3-aminobutenenitrile 136 and BA 1, forming product spiro-pyrimidine derivative 137 under NH₂OH and L-proline catalysts with excellent yields up to 94–99% [166].

Compound 139, a spiro-pyrimidine derivative, was formed by the reaction of aromatic aldehyde 135, benzo-1,3-dioxol-5-amine 138, and BA 1 under acidic medium in excellent yields up to 93–98%. The reaction in Scheme 41 is environmentally benign and shows higher efficiency [167].

In Scheme 42, compound 22, a spiro-fused heterocyclic compound, was synthesized via three-component reactions that took place between BA 1, urea 140, and substituted aldehydes 141 under catalyst gel-entrapped ZnCl₂ at RT with excellent yields up to 96–98%. Without significant changes in the catalyst, the polymer gel-entrapped catalyst can again be employed [96].

Spirooxindole BA derivative 145 was synthesized via a three-component reaction under catalyst p-TSA and ethanol along with reflux conditions (Scheme 43). When compound 142 reacted with tricyclic isatin 143, pyrazole-5-amines 144 and a spirooxindole barbituric acid derivative 145 were formed in excellent yields up to 95–98% [168].

In Scheme 44, dihydropyridine derivatives 149 were obtained from the three-step reaction in excellent yields up to 95–99%. Initially, 2,6-dimethyl-4-pyrone 146 reacted with BA or 1,3-DMBA in the presence of Ac₂O, which produced compound 147, followed by a reaction with 1-hexadecylamine acetonitrile, which formed compound 148. The resulting compound 149 was synthesized by reacting compound 148 with 4-dimethylaminobenzaldehyde and piperidine in the presence of dimethyl sulfoxide as a catalyst and DMSO as a solvent. It was used for the design and synthesis of SSAC materials [169].

Dihydropyrido pyrimidine derivatives were synthesized by MCRs in which dihydro pyrimidine derivative 150 reacted with ethyl acetate 151 and amino sulfonamide 152 to afford sulfonamide-bearing pyrimidine derivative 153 at 80 °C in EtOH with excellent yields up to 94–98% (Scheme 45) [170].

1,4-Dihydropyrimidine derivatives 154 formed in excellent yields up to 96–99% through substituted aromatic aldehyde 39, 2 moles of BA 1, and ammonium ethanoate 59 under EtOH solvent at 50 °C, catalyzed using an MNP-NPBG-SA nanocomposite catalyst mentioned in Scheme 46. All the desired components revealed many biological applications [171].

1,4-dihydropyrimidine derivatives bearing a barbituric acid moiety were formed with the reaction of substituted aldehyde 39, 2 moles of BA 1, and aromatic amine 155 under the influence of EtOH at 50 °C, along with nanocomposite MNP-NPBG-SA catalyst (Scheme 47) in excellent yields up to 95–99%. The resultant compounds were utilized in pharmaceuticals and bio-based industries [165].

In Scheme 48, the pyrimidine derivative 159 is formed through a one-stage process, achieving excellent yields of 93–99% in the presence of a (3-MSimCl) catalyst as an acidic ionic liquid with a four-component reaction of 4-hydroxybenzaldehyde 157, pentane diketone 158, primary amine 86, and BA 1 [172].

1,4-Dihydropyrimidine derivative 162 was synthesized using BA 1 by a one-pot four-component reaction under the nano-fibrillated catalyst cellulose–sulfuric acid (Scheme 49). When aryl aldehyde 160, aromatic amines 161, dimedone 102, and BA 1 reacted together, dihydropyrimidine derivative 162 was formed through refluxing with an employed catalyst in excellent yields up to 94–98% [173].

Pyrimidine derivatives 165 were formed through the condensation of 1,2-DMBA 69 with aromatic aldehyde catalyzed by methylamine in excellent yields up to 95–99% (Scheme 50). The obtained product 165 showed in vitro antibacterial properties against aeruginosa bacteria and was characterized by spectroscopic methods [12].

2-Arylbenzo-imidazo-[2,1-b]-thiazole 168 was produced via a one-pot MCR using I₂ in DMSO solvent. It was produced in excellent yields up to 94–98% by a three-component reaction involving aryl acetylene 166, 2-aminobenzothiazole 167, and 1,3-DMBA 69 under DMSO solvent, catalyzed by I₂ at 110 °C. The derived component was a medicinally significant molecule. The reaction was assisted by MW heating (Scheme 51) [174].

DPT 170 was formed with 7-(dimethylamino)-4,5-dihydronaphtho[1,2-b]thiophene-2-carbaldehyde 169 as a starting material. When 6-amino-1-tetralone reacted with methyl iodine and K₂CO₃ under DMF, it formed a compound with an amino scaffold. Afterward, the resulting compound reacted with Na₂S along with Cl-acetaldehyde and K₂CO₃ at 60 °C, forming compound 169. Compound 169 again reacted with BA 1 to synthesize the DPT probe in excellent yields up to 97–99% (Scheme 52). It is a novel fluorescent probe that can be used for the detection of hydrazine in SH-SY5Y neuroblast cells. Additionally, it does not show any cytotoxicity and exhibits great biocompatibility [175].

2-Acetamido-4-arylthiazol-5-yl derivative 173 was synthesized with excellent yield up to 97–99% via a one-pot MCR, in which arylglyoxals 171 and acetyl thiourea 172 reacted together with BA 1 under reflux conditions with Et₃N in the presence of ethanol (Scheme 53), which have several claims in dermatology, organic synthesis, and the therapeutic industry [176].

1,3-Bis-OH-Me-barbituric acid derivative 175 was used as a catalyst to form sulfa-based barbituric acid derivative 176 through the Williamson reaction. Initially, theamide derivative 174 reacted with compound 175 to yield compound 176 in excellent yields up to 94–99%, which exhibits antimicrobial activity towards Pseudomonas aeruginosa and Staphylococcus aureus-type bacteria [4]. FTIR and ¹H-NMR methods were used for the verification of the synthesized product obtained in Scheme 54.

Compound 177 was formed with the help of 1 mole of 1,3-DMBA reacted with a substituted aldehyde in the presence of a dimedone catalyst at RT and aqueous conditions. On the other hand, substituted aryl aldehyde reacted with 2 moles of 1,3-DMBA, which afforded compound 178 with excellent yields up to 94–96%, which is also a BA derivative, with two BA moieties presented in keto form, while compound 177 is depicted in enol form in excellent yields up to 96–98% (Scheme 55). The derived compounds exhibited antioxidant properties and were analyzed by spectroscopic methods [177].

Silane-based chemosensor 184 was formed to determine silver ions. It was a four-step process. Initially, substituted aldehyde 179 reacted with 3-bromopropyne 180 to afford compound 181 under the influence of K₂CO₃, DMF solvent, and stirring for more than 16 h. Afterward, compound 181 reacted with 1,3-DMBA under aqueous conditions and formed compound 182 followed by the formation of compound 183 under AzPTES and Cu(PPh₃)Br in the presence of ET₃N along with THF solvent at 60 °C (Scheme 56). Finally, compound 184, a silatrane-based chemosensor, was obtained in excellent yields up to 94–97%, with the help of triethanolamine to undergo transesterification, whereas KOH acted as the base and toluene as the solvent. Nowadays, it is used for the detection of silver ions in the human body [178].

Contamination in food samples and water is detected by many chemosensors developed by scientists. Oligo-thiophene-based chemosensor 189 was developed for the tracing of cyanide ions in water and food samples. It was produced by the reaction between 2-bromothiophene 185, 2-thienylmanesium bromide 186, 5-(thiophene-3-yl)-2,2′-bithiophene 187 and 5-(5-(thiophene-2-yl)thiophen-2-yl)thiophene-2-carbaldehyde 188 to synthesize 1,3-dimethyl-5-((5-(5-(thiophen-2-yl)thiophen-2-yl)thiophen-2-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione 189 chemosensors using 1,3-DMBA and EtOH solvent in excellent yields up to 95–98%, mentioned in Scheme 57; the addition of cyanide ions resulted in a blue shift and color change. Additionally, compound 189 exhibited low cytotoxicity towards the live-cell permeability, thus suitable for the in vivo detection of cyanide ions [179].

A curcumin–barbituric acid derivative was produced by substituting aromatic aldehyde 39 when reacted with BA 1 and curcumin 190, catalyzed by a CoFe₂O₄@OCMC@Cu(BDS) nanocomposite under reflux conditions in excellent yields up to 94–99% (Scheme 58). It was examined by various spectroscopic methods like FTIR, ¹³C-NMR, and X-ray diffraction. The resultant compound 191 shows good biological properties [180].

A dibenzothiophene-barbituric acid derivative chemosensor was produced with AIE effects for the detection of cyanide ions. It followed two steps; firstly, dibenzothiophene 192 was treated with catalyst Cl₂CHOMe in the presence of TiCl₄, which formed compound 193. Afterward, compound 193 reacted with BA 1 in EtOH at 80 °C (Scheme 59) forming a DBT fluorescence probe in excellent yields up to 97–98%, utilized in the medical field and the industrial sector for the verification of cyanide ions. The DBT probe could detect cyanide ions in the aqueous phase; additionally, BA acted as EWG and DBT as EDG [181].

Hydroxyalkyl-containing 5-(1H-1,2,3-triazol-4-ylmethylidene) barbiturates 197 were formed via a three-component reaction in excellent yields up to 95–99% (Scheme 60). Firstly, 4-OH-alkynal 195 reacted with trimethylsilylazide to form triazole-based carbaldehyde 196 intermediates through a cycloaddition reaction. Afterward, intermediate compound 196 went through Knoevenagel condensation with BA/1,3-DMBA to afford the desired components 197, which bear two pharmacophores [182].

A TPEB fluorescent probe was formed using substituted aldehyde 198 and BA 1 with EtOH solvent under reflux conditions in excellent yields up to 97–99% (Scheme 61). It was used for the detection of cyanide ions; additionally, it exhibits AIE characteristics in DMSO solvent when mixed with water. The synthesized probe 199 can be utilized for the qualitative detection of acidity in samples [183].

In Scheme 62, a synthetic route for 1,2,3-triazole–(thio)-based BA derivative 206 is described [184]. A 4-hydroxy-3-methoxybenzaldehyde 200 and bromoethyne 201 were stirred at RT for 3 h to form 4-(ethynyloxy)-3-methoxybenzaldehyde 202, while K₂CO₃ was present at dimethylformamide. Benzyl azides, on the other hand, are pro situ-induced by a reaction in the presence of NEt₃ between benzyl bromides 204 and NaN₃. 1,2,3-Triazole derivatives 205 were obtained at RT for 16–24 h through a reaction between benzyl azides 203, compound 202, sodium ascorbate, and CuSO₄·5H₂O. Compounds 205 were them reacted with BA 1 or TBA acid in EtOH to form the desired compound 206 in excellent yields up to 94–99% [184,185,186,187,188].

Initially, compounds 207 and 208 formed an intermediate 1,3-diphenyl barbituric acid 209 using trichloromethane reagent. Afterward, for 4 h, a mixture of 9-phenylcarbazole-3-carbaldehyde 210 and 1,3-diphenyl barbituric acid 209 was refluxed into the EtOH-produced CB-Ph derivative 211 in excellent yields up to 95–99%, which exhibited AIE effects (Scheme 63) [189].

Firstly, compound 212 reacted with compound 213 to form the intermediate compound 214, which was then again used for further reaction. For 4 h, a blend of 214 and 1,3-DMBA acid 69 was refluxed under EtOH to produce a CB-Me BA derivative (Scheme 64). Lastly, compound 215, CB-Me, was obtained in ethanol under reflux conditions in excellent yields up to 97–99% [190,191,192,193,194].

In Scheme 65, when compound 216 reacted with cinnamaldehyde 217 with the aid of pyridine, it gave 1-ethylpyrimidinetrione 218 in the presence of ethyl alcohol solvent at RT in excellent yields up to 95–98%. The obtained compound showed potent cytotoxicity to lung cancer cells and also had pronounced antitumor effects. Overall, we can say that it was helpful as a therapeutic agent for lung cancer [25].

In Scheme 66, when vanillin 218 reacted with a catalyst, i.e., several secondary amines or methanal, it formed substituted aldehyde 219; moreover, when urea or thiourea 75 catalyzed diethyl malonate in the presence of ethanol and NaOEt, it gave us the substituted BA 61 [28]. Further, when compounds 219 and 61 reacted together, compound 220, a barbituric derivative, was formed, catalyzed by methylene in the presence of EtOH, with excellent yields up to 96–98%.

In Scheme 67, the reaction of substituted BA 221 with acetic anhydride in the presence of DMF solvent for 2 h at 90 °C made compound 222, which appeared as solid yellow crystals. Further, compound 222 reacted with various amines in EtOH under RT to obtain TBA ethylamine derivative 223 in excellent yields up to 97–99% [89].

In Scheme 68, pyrano[2,3-d]pyrimidine dione 225 was formed with high yield up to 90% by reacting substituted barbituric acid 224 with substituted benzaldehyde 39 and malononitrile 63 in the presence of the nanocatalyst SBA-Pr-SO₃H in solvent-free conditions at RT in excellent yields up to 96–98%. These derivatives showed good urease inhibitory activity [195].

Two novel OH-calamine derivatives were synthesized by the Knoevenagel condensation reaction following hydroxylation reactions between H₂O₂, BA 1, and citral or cinnamaldehyde (Scheme 69). The BA group has two carbonyl groups flanked by an aldehyde-condensing reaction group, such as citral and cinnamaldehyde, that is easily involved in the Knoevenagel condensation reaction. In addition, two-N imides may be used on the ring of BA to fix chlorine for N-halamines. The Knoevenagel condensation reaction resulted in BA derivatives cit-bar 227 and cin-bar 230 in excellent yields up to 95–99% [196].

Knoevenagel condensation reactions of BA 1 with 3-NBA or 3-TFMB in an aq. medium in the absence of a catalyst and at RT (Scheme 70) gave compound 40. On the other side, we observed that condensation in formic acid by stirring two equivalents of BA 1 with 3-NBA or 3-TFMB for 30 min gave compound 232 in excellent yields up to 94–98% [78].

In Scheme 71, pyrimidine derivative 234 was synthesized by reacting phenylglyoxal monohydrate 103 and substituted BA 69 in the presence of potassium phthalimide-N-oxyl 233 by reflux under aqueous medium in excellent yields up to 96–99% [39].

In Scheme 72, a three-component reaction formed compounds 236 and 237 by reacting phenylglyoxal monohydrate 103, 1,3-DMBA 69, and benzamide 235, which generated the desired trisubstituted oxazole via a fluid-assisted grinding process in excellent yields up to 95–98% [197].

In Scheme 73, when TAA 239 undergoes oxidation in the presence of I₂ in DMSO at 110 °C for 4–5 h, an NPQ-fused pyrrole 240 is produced in excellent yields up to 94–98% via a three-component reaction [33].

In Scheme 74, the formation of compound 240, named NPQ-fused pyrroles, was achieved when acetophenone 241 reacted with 1,3-DMBA 69 and substituted naphthoquinone 239 in the presence of I₂ and DMSO solvent in excellent yields up to 96–98%. Oxidative cyclization of acetophenone 241 took place [35]. The obtained product showed many biological properties.

NPQ-bonded pyrrole 240 tied with a BA 1 moiety through a three-component reaction in iodine-mediated MeOH solvent in excellent yields up to 94–98% (Scheme 75). Arylglyoxals 103, when reacted with 1,3-DMBA 69 and amino-tethered naphthoquinone 239, formed the desired product, which is medicinally important [33].

In Scheme 76, thermal polymerization of BA 241 formed photocatalytic material 242 without using metal in excellent yields up to 95–97% [17]. The polycondensation reaction of BA was defined as the primary building block by precipitating trimmer units. The synthesized photocatalyst 242 could remove Rh-B with higher efficiency.

In Scheme 77, BA 1 undergoes polymerization, with compound 246, named melem, acting as the precursor to give product 247 in excellent yields up to 97–98%. The intermediate product melem 246 could be used as a precursor for co-polymerization with BA 1 during the thermal polymerization of polymetric carbon nitride with great molecular weight. The polymerization of melem 246 and BA 1 thus permits the insertion of CO groups into the polymetric carbon nitride matrix, which results in enhanced pH oxidation of water through the encouraged use of polymetric carbon nitride photocatalyst radiation [198].

In Scheme 78, chemosensor 250 was easily synthesized by condensations of 7-DEAC 249 and BA 1 in excellent yields up to 96–99%, which was successfully used with excellent efficiency to detect hypochlorite and hydrazine. It took place with anhydrous acetic acid and was dissolved in EtOH [199].

In Scheme 79, the behavior of 5-ylidene barbituric acid 251 was observed in reactions with carbon and nitrogen nucleophiles at active exocyclic double bonds [39]. Pyrimidine derivatives 252–258 were produced with yields ranging between 75 and 95 percent when heating compound 251 with active methylene compounds, e.g., cyano-acetamide, malononitrile, and ethyl cyanoacetate, in ethanol and very few drops of TMA for 1–3 h.

Substituted BA 93 reacted with dialkyl-acetylene-dicarboxylates 259 and trialkyl phosphine 260 or tri-alkoxy phosphine 261 to yield zwitterionic salts of barbiturates 262 or thiobarbiturates 263 in excellent yields up to 95–99% (Scheme 80) [99].

The first approach included Pinner’s benzyl cyanide reaction, which produced an ethyl ester for phenylacetic acid [200]. This ester was subsequently transformed with diethyl-oxalate by Claisen cross-condensation, which gave phenyloxobutandioic acid diethyl ester. When the substance is heated, carbon monoxide evaporates quickly and diethyl phenyl malonate develops [201]. Malonic ester formation using EtBr yields α-phenyl-α-ethylmalonic ester 268. Lastly, phenobarbital 269 formed in excellent yields up to 95–98% via condensation reaction (Scheme 81) [202].

The second alternative was with the diethyl carbonate to form α-phenyl cyanoacetic ester 270 in the presence of a solid base (Scheme 82) [203,204]. This ester was alkylated using ethyl bromide, which gave the α-phenyl-α-ethyl cyanoacetic ester 271 from the intermediate nitrile anion [205,206]. After condensation with urea, this substance was further transformed into a 4-imino derivative 272. The resulting substance ultimately provided phenobarbital 273 by acid hydrolysis in excellent yields up to 96–98% [207].

From our above survey, we concluded that BA derivatives represent a fascinating class of compounds with diverse applications. These derivatives exhibit intriguing properties and find application in various fields, including medicinal chemistry, material science, and biochemistry. Researchers have explored a range of transformations to modify the BA scaffold, and this table provides valuable insight into the yields obtained during these synthetic endeavors.

4. Conclusions

Numerous research studies have explored the synthesis of diverse heterocyclic compounds containing BA as a functional group, alongside its manifold biomedicinal applications. The medicinal properties of BA mainly depend on the side groups attached to the pyrimidine ring. The discussion on reactions has highlighted the remarkable transformation potential of BA, leading to formed products exhibiting strong antibacterial, cytotoxic, xanthine oxidase inhibitory, and urease inhibitory properties. The proposed methods for synthesizing various derivatives such as pyranopyrimidines, benzochromenopyrimidines, chromeno-pyranopyrimidines, spiroxyindoles, oxospiro-tricyclic furopyrimidines, and pyrimidine-based mono- and bicyclic pyridines were examined. The various reactions explored, including condensations, substitutions, oxidations, and reductions, further emphasize the compound’s significance in synthetic chemistry and its potential to yield compounds with altered properties.

Author Contributions

Data collection and manuscript preparation, N.K.; conceptualization, M.K.; investigation, H.H.; writing—original draft, N.K. and H.S.S.; writing—review and editing, N.K., M.K., H.H. and P.K.B.; supervision, M.K. and H.S.S. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

The authors are grateful to Chandigarh University, Gharuan, for providing other financial assistance for research. Authors Haesook Han and Pradip K. Bhowmik are also thankful to the UNLV University for providing all the necessary support.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

BA	barbituric acid
MCR	multicomponent reaction
TBA	thio-barbituric acid
PDT	photodynamic therapy
MOF	metal–organic framework
TBHP	tert-butyl hydroperoxide
RT	Room Temperature
EtOH	ethanol
1,3-DMBA	1,3-dimethyl barbituric acid

Footnotes

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Schemes and Table

Figure 1. General structure of barbituric acid.

Scheme 1. Some biologically potent derivatives of barbituric acid.

Scheme 2. Formation of 5-arylidene barbituric acid derivative. Reagents and conditions: a—[TPPHSP]Br, EtOH-H2O, reflux conditions.

Scheme 3. Formation of 5-arylidene barbituric acid under Co3O4 nanostructure. Reagents and conditions: a—Co3O4 nanocatalyst, aqueous medium, reflux conditions.

Scheme 4. Formation of 5-allyl barbituric acid. Reagents and conditions: a—sodium ethoxide, KI, allyl bromide; b—sodium ethoxide, urea; c—HCl.

Scheme 5. Formation of pyrazolo-pyrano-pyrimidine 53 via MCR method. Reagents and conditions: a—TEDA/IMIZ-BAIL@UiO-66, refluxed.

Scheme 6. Formation of pyrazole-based barbituric acid derivative via four-component reaction. Reagents and conditions: a—(Na[Nd(pydc-OH)(H2O)4]3}[SiW12O40].

Scheme 7. Formation of pyrazole-based barbituric acid derivative via five-component reaction. Reagents and conditions: a—(Na[Nd(pydc-OH)(H2O)4]3}[SiW12O40].

Scheme 8. Formation of pyrano-based barbituric acid derivative via MCR. Reagents and conditions: a—PBCMO-amine catalyst and BA, 15 min.

Scheme 9. Formation of pyrano-fused pyrimidines through MCR. Reagents and conditions: a—PEG-400 solvent.

Scheme 10. Formation of pyrano-based barbituric acid derivative. Reagents and conditions: a—Fe3O4@PVA-Cu, H2O, room temp.

Scheme 11. Formation of pyrano-based pyrimidine derivative. Reagents and conditions: a—Ni NPs@N-dopedTiO2, MeOH solvent, 65 °C.

Scheme 12. Formation of pyrano-fused pyrimidine derivative. Reagents and conditions: a—Fe3O4@SiO2@BenzIm-Fe[Cl]/ZnCl2, ethanol, H2O, ultrasound irradiation.

Scheme 13. Formation of pyrano-fused pyrimidine derivative. Reagents and conditions: MDW medium, catalyst-free conditions.

Scheme 14. Pyrano-pyrimidine derivative 64 synthesized via a three-component reaction. Reagents and conditions: a—Fe2O3@APTES@isatin-HSO3; b—EtOH/H2O (1:1) in reflux conditions.

Scheme 15. Naphthopyrano pyrimidine 74 was synthesized through a three-component reaction using BA 1. Reagents and conditions: a—LaMoFeO3 at 100 °C under solvent-free conditions.

Scheme 16. Formation of pyrimido-based pyrimidinone derivative. Reagents and conditions: a—verjuice with reflux conditions.

Scheme 17. Formation of pyrimido-triazole-based barbituric acid derivative via three-component reaction. Reagents and conditions: a—Zn(BDS)-MOF.

Scheme 18. Formation of pyrido-fused pyrimidine derivative. Reagents and conditions: a—EtOH, reflux conditions.

Scheme 19. Formation of pyrido-based barbituric acid derivative using nucleoside. Reagents and conditions: a—DBU-F-MCM-41-CNSH reagent at 80 °C.

Scheme 20. Formation of pyrido-pyrimidine derivative via one-pot MCR. Reagents and conditions: a—MWCNTs@L-His/Cu2+, reflux conditions.

Scheme 21. Formation of pyrido-pyrimidine derivatives through one-pot synthesis. Reagents and conditions: took place in a water bath.

Scheme 22. Formation of pyrido-pyrimidine derivative 13, with BA as a reactant, by the three-component reaction. Reagents and conditions: a—GOx (carbon catalyst) at 100 °C for 4 h.

Scheme 23. Pyrido-pyrimidine derivative 91 synthesized with the involvement of compound 31. Reagents and conditions: a—p-toluene sulfonic acid, solvent EtOH at 50 °C.

Scheme 24. Chromeno-based barbituric acid derivative via three-component reaction. Reagents and conditions: a—trisodium citrate dihydrate as a catalyst, EtOH, H2O, 35–60 min.

Scheme 25. Formation of chromeno-based pyrimidine derivative. Reagents and conditions: a—Fe3O4@SiO2@BenzIm-Fe[Cl]/ZnCl2, ethanol, H2O, ultrasound irradiation.

Scheme 26. Formation of benzochromeno-based barbituric acid derivatives. Reagents and conditions: a—MWCNTs@NHBu/PTA, solvent-free conditions at 100 °C.

Scheme 27. Formation of a chromeno-based barbituric acid derivative via Michael addition reaction. Reagents and conditions: a—L-Proline (30 mol%) in H2O at 30 °C.

Scheme 28. Formation of a chromeno-based pyrimidine derivative 23. Reagents and conditions: a—TBAI in an aqueous medium at RT.

Scheme 29. Formation of a benzo-[5,6]-chromene-based barbituric acid derivative. Reagents and conditions: a—potassium phthalimide-N-oxyl catalyst under aqueous medium and reflux conditions.

Scheme 30. Formation of chromeneno-pyrimidines, 109. Reagents and conditions: a—lemon juice as a catalyst and TBHP as oxidant.

Scheme 31. Spirocyclic-based barbituric acid derivative 8 formed via an electrochemical reaction.

Scheme 32. TFM-dispiro-barbituric acid derivatives formed through Michael [3+2]-cycloaddition reaction. Reagents and conditions: quinine catalyst, CH2Cl2, RT for 1 h.

Scheme 33. Formation of spirooxindole-barbituric acid derivatives 118 and 119. Reagents and conditions: a—BAIL@UiO-66, EtOH, RT, ultrasonic irradiation.

Scheme 34. Formation of spiro-naphthalene-based barbituric acid derivative. Reagents and conditions: a—[C-18-Dabco][Br], H2O, ultrasound irradiation.

Scheme 35. Formation of spirooxindole-based barbituric acid derivative. Reagents and conditions: a—MgO@PMO-IL catalyst, EtOH, 50 °C.

Scheme 36. Formation of spirooxindole-based barbituric acid derivative through Knoevenagel condensation. Reagents and conditions: a—EtOH, H2O at RT with reflux conditions.

Scheme 37. Formation of spirooxindole-based barbituric acid derivatives. Reagents and conditions: a—SnO2 NPs, EtOH at RT.

Scheme 38. Formation of spiro-fused pyran derivatives. Reagents and conditions: a—CuO/ZnO@N-GQD nanocatalyst, H2O, RT.

Scheme 39. Formation of spiro-pyrimidine-based barbituric acid derivative via three-component reactions. Reagents and conditions: aqueous conditions at room temperature.

Scheme 40. Formation of spiro-pyrimidine derivative 137 via three-component reactions. Reagents and conditions: a—NH2OH, b—L-Proline.

Scheme 41. Formation of spiro-pyrimidine-based barbituric acid derivative 139 by three-component reaction. Reagents and conditions: acetic acid as an acidic medium in EtOH.

Scheme 42. Formation of spiro-based heterocyclic compound 22 was synthesized by three-component reactions. Reagents and conditions: a—gel-entrapped ZnCl2 at RT.

Scheme 43. Formation of spirooxindole barbituric acid derivative 145. Reagents and conditions: a—p-TSA, ethanol along with reflux conditions.

Scheme 44. Dihydropyridine BA derivative 149 was formed using BA/TBA as an intermediate. Reagents and conditions: a—BA or 1,3-DMBA, Ac2O; b—1-hexadecylamine acetonitrile; c—4-dimethylaminobenzaldehyde, piperidine, DMSO.

Scheme 45. Formation of dihydropyrido-pyrimidine-based barbituric acid derivatives. Reagents and conditions: EtOH, 80 °C.

Scheme 46. Formation of 1,4-dihydropyrimidine-based barbituric acid derivatives. Reagents and conditions: a—MNP-NPBG-SA, ethanol, 50 °C.

Scheme 47. Formation of 1,4-DHP barbituric acid derivative. Reagents and conditions: a—nanocomposite MNP-NPBG-SA, ethanol, 50 °C.

Scheme 48. Formation of dihydropyrimidine derivative 159 via four-component reaction. Reagents and conditions: a—(3-MSimCl), acidic ionic liquid.

Scheme 49. Formation of 1,4-dihydropyrimidine derivative 162 via four-component reaction. Reagents and conditions: a—Z-nanofibrillated cellulose sulfuric acid, reflux conditions.

Scheme 50. Synthesis of pyrimidine derivative 165 via condensation reaction. Reagents and conditions: a—acetic anhydride; b—substituted phenyls and methylamine, where R can be 2-ClC6H4, 4-Me2NC6H4, 4-HOC6H4, naphthalen-1-yl.

Scheme 51. Formation of benzothiazole-fused imidazole barbituric acid derivative. Reagents and conditions: a—I2/DMSO, 110 °C, and reflux conditions.

Scheme 52. DPT, compound 170 synthesis. Reagents and conditions: BA 1, 60 °C.

Scheme 53. Formation of thiazole-based barbituric acid 5 via MCR. Reagents and conditions: BA 1, refluxed with Et3N, where Ar-4ClC6H4, 4-CH3C6H4, 4-BrC6H4, 4-CH3OC6H4, 4-FC6H4.

Scheme 54. Sulfa drug-based barbituric acid derivative was formed via the Williamson reaction.

Scheme 55. Barbituric acid derivatives 177 and 178 are formed by one-pot MCR. Reactions and conditions: a—dimedone catalyst, 1,3-DMBA; b—2 moles of 1,3-DMBA with H2O and RT.

Scheme 56. Formation of silatrane-based chemosensor bearing BA moiety. Reagents and conditions: a—K2CO3, DMF, 16 h stirring; b—1,3-DMBA, H2O; c—AzPTES, Cu(PPh3)Br, ET3N, THF at 60 °C; d—KOH, toluene, triethanolamine.

Scheme 57. Synthesis of oligo-thiophene-based barbituric acid derivative chemosensor. Reagents and conditions: a—Mg, THF; b—THF, substituted thiophene; c—POCl3, DMF; d—1,3-DMBA, EtOH.

Scheme 58. Formation of curcumin–barbituric acid derivative. Reagents and conditions: a—CoFe2O4@OCMC@Cu(BDS), reflux conditions.

Scheme 59. Formation of dibenzothiophene-based barbituric acid derivative. Reagents and conditions: a—Cl2CHOMe, TiCl4; b—BA, EtOH, 80 °C.

Scheme 60. Formation of hydroxyalkyl-containing barbiturates. Reagents and conditions: a—Me3SiN3, H2O, EtOH; b—BA/1,3-DMBA, -H2O.

Scheme 61. Formation of TPEB probe bearing BA motif. Reagents and conditions: a—EtOH, reflux conditions.

Scheme 62. Formation of compound 206 BA derivative. Reagent and conditions: a—K2CO3, C3H7NO, RT; b—NaN3, NEt3, RT; c—C6H7NaO6, CuSO4·H2O; d—ethanol, piperidine and R = 2,4-dichloro, 3-Br; X = O, S.

Scheme 63. Formation of CB-Ph derivative 211. Reagents and conditions: a—trichloromethane; b—EtOH under reflux conditions.

Scheme 64. Synthesis of CB-Me derivatives 215. Reagents and conditions: a—POCl3; b—EtOH with reflux conditions.

Scheme 65. Synthetic pathway of compound 218 barbituric acid derivative. Reagents and conditions: pyridine, EtOH solvent at RT.

Scheme 66. Formation of barbituric acid derivative 220. Reagents and conditions: a—different secondary amines, methanal; b—diethylmalonate, NaOEt with ethanol; c—methylene with EtOH.

Scheme 67. Synthetic pathway of TBA ethylamine derivative. Reagents and conditions: a—acetic anhydride reagent and DMF; b—substituted amines, methanol, under RT.

Scheme 68. Formation of TFM-BA derivative. Reagents and conditions: a—Me3SiCl, Et3N, DCM for 2 h at RT; b—sodium ethoxide; c—HCl.

Scheme 69. Knoevenagel condensation reaction in which Cit-Bar and Cin-Bar derivatives are synthesized. Reagents and conditions: a—H2O; b—H2O2; c—ethanol; d—H2O2.

Scheme 70. Formation of compounds 40 and 232 via Knoevenagel condensation. Reagents and conditions: R = NO2, CF3.

Scheme 71. Formation of compound 234 via Knoevenagel condensation reaction. Reagents and conditions: potassium phthalimide-N-oxyl 233 in aqueous medium with reflux conditions.

Scheme 72. Formation of oxazole-based barbituric acid derivatives 236 and 237 via a three-component reaction of BA. Reagents and conditions: liquid-assisted grinding for 25 min.

Scheme 73. Formation of compound 240, NPQ-fused pyrroles, via three-component reaction. Reagents and conditions: a—I2 reagent under DMSO solvent.

Scheme 74. Formation of NPQ-fused pyrroles 240. Reagents and conditions: a—I2 reagent in DMSO at 110 °C.

Scheme 75. Formation of compound 74 via three-component reaction. Conditions and reagents: a—I2, MeOH at 65 °C.

Scheme 76. Formation of a crystalline trimer of BA 242 via a thermal condensation reaction. Reagents and conditions: removal of water molecule undergoing condensation reaction.

Scheme 77. Thermal polymerization reaction pathway with melem 246 as a precursor.

Scheme 77. Thermal polymerization reaction pathway with melem 246 as a precursor.

Scheme 78. Formation of chemosensor 250 via the condensation reaction. Reagents and conditions: a—HOAC, EtOH solvent under reflux conditions.

Scheme 79. 5-arylidene barbituric acid reacted with different nucleophile moieties bearing carbon and nitrogen.

Scheme 80. Zwitterionic salts of TBA/BA are formed via a multicomponent reaction.

Scheme 81. Synthesis of phenobarbital by Pinner’s benzyl cyanide reaction.

Scheme 82. Synthesis of phenobarbital with the involvement of diethyl carbonate.

Table 1

Some important derivatives of barbituric acid.

S. No.	Barbituric Acid Derivative	Structure	Application	Reference
1	1-Ethyl-5-(E)-3-phenylallylidene) pyrimidine-2,4,6(1H,3H,5H)-trione	[Image omitted. Please see PDF.]	Effective antitumor compound, used for lung cancer	[76]
2	Barbitone	[Image omitted. Please see PDF.]	Shows hypnotic properties	[77]
3	Phenobarbitone	[Image omitted. Please see PDF.]	Shows anticonvulsant properties	[78]
4	Hexobarbitone	[Image omitted. Please see PDF.]	Shows anesthetic properties	[79]
5	1,3-Dimethyl barbituric acid derivative	[Image omitted. Please see PDF.]	Shows anti-proliferative activity toward cancer cell line	[80,81]
6	Thio-barbituric acid derivative	[Image omitted. Please see PDF.]	Shows in vitro inhibitory activity	[82]
7	5-Bezylidene-2-thioxodihydropyrimidinone	[Image omitted. Please see PDF.]	Shows in vitro inhibitory activity against PARP1	[83]
8	5-Salicylidene barbituric acid	[Image omitted. Please see PDF.]	Shows antimicrobial, antioxidant, and anticancer activities	[84]
9	5-(Phenyl-azo)thio barbituric acid	[Image omitted. Please see PDF.]	Shows effective antimicrobial activities against fungal species	[85]
10	4-Hydroxy-4H-chromene barbiturates	[Image omitted. Please see PDF.]	Shows various medical applications	[34]
11	Pyrazolopyranopyrimidinone barbituric acid derivative	[Image omitted. Please see PDF.]	Anti-inflammatory, anticancerous, and antimicrobial; also applied in agrochemicals	[86]
12	Pyrimido[4,5-b] quinolinone-2,4-diones	[Image omitted. Please see PDF.]	Shows antimicrobial properties	[35,87]
13	5-Benzylidene barbituric acid derivative	[Image omitted. Please see PDF.]	Shows antibacterial, anti-leprotic, sedative–hypnotic, and anticonvulsant activities	[88]
14	N,N′-Diethylthio barbituric enamine	[Image omitted. Please see PDF.]	Shows anti-glycation activity	[89]
15	TFM-based Barbituricacid	[Image omitted. Please see PDF.]	Used in pharmaceuticals and agrochemicals	[38]
16	Pyrimidine-fused barbituric acid derivative	[Image omitted. Please see PDF.]	Exhibits antitumor, antioxidant, and antiviral activities	[90]
17	Chromene-based barbituric acid derivative	[Image omitted. Please see PDF.]	Shows biological and pharmaceutical possessions	[91]
18	Pyrano[2,3-d] pyrimidine derivatives	[Image omitted. Please see PDF.]	Anti-allergic, anti-hypertensive, cardiotonic, bronchodilator, anti-bronchitic, and antitumor activities	[92]
19	Spiro-based barbituric acid derivative	[Image omitted. Please see PDF.]	Used as an anti-urease, shows antimicrobial and antifungal properties, also used in the agricultural field	[42,93]
20	Disubstituted spiro-fused barbituric acid derivative	[Image omitted. Please see PDF.]	Antibacterial, antifungal and antiviral	[94,95]
21	Spiro-based heterocyclic barbituric acid derivative	[Image omitted. Please see PDF.]	Applied in the formation of natural products and used in the medicinal field	[96]
22	Chromeno-fused pyrimidine barbituric acid derivative	[Image omitted. Please see PDF.]	Shows pharmaceutical and various biological activities	[97]
23	Naphthopyranopyrimidine-based barbituric acid	[Image omitted. Please see PDF.]	Anti-hypertensive, antibacterial, antimicrobial, antitumor	[98]
24	Phosphonate-based barbituric acid	[Image omitted. Please see PDF.]	Used as a therapeutic drug and in insecticides as well as pesticides	[99]
25	1-[anilino (phenyl) methyl]-pyrimidine-2,4,6-trione	[Image omitted. Please see PDF.]	Shows antimicrobial properties, anti-corrosive properties	[100]
26	Spiro oxindole-dihydropyridine-based barbituric acid	[Image omitted. Please see PDF.]	Used in the treatment of hypertension and angina pectoris	[101]

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