Catalyzed Methods to Synthesize Pyrimidine and Related Heterocyclic Compounds

Abstract

This review covers articles published in the period from 2010 to mid-2022 on synthetic advances in the formation of pyrimidine and related heterocyclic compounds. Special emphasis has been given to the different types of cycloadditions, taking into account the number of their components and leading to the formation of the pyrimidine ring. Due to the large number of publications on the Biginelli reaction and related reactions, this will be dealt with in a separate review in the near future.

1. Introduction

Compounds with pyrimidine rings and analogs have attained considerable interest in the last years because of their properties [1,2,3,4,5]. In this review, we focus on the latest syntheses of these compounds, emphasizing those that use cyclization reactions and cycloadditions of two or more components. We are interested in those pyrimidines and analogous compounds such as pyrimidinones, pyrimidinethiones and other pyrimidine-related scaffolds. The synthesis of pyrimidines with substituted or decorated rings is only considered when the principal functionalization is included in the starting components and is involved in the cyclization or cyclocondensation processes. Works whose primary objective is to modify the substitution of an already formed pyrimidine ring are not described.

In addition, we consider those less well-known reactions with the formation of new rings by expansion or contraction of other types of rings. In this review, we analyze the synthetic aspect of these compounds as a principal point of view. Their biological and medical applications have been well described in a plethora of reviews in the last years [6,7,8,9,10,11,12]. We summarize the published findings reported mainly from 2010 to mid-2022. It is worth noting the growing number of emerging publications in this field in the last years [13]. Owing to the number of reports about pyrimidine derivatives, we apologize to researchers whose important publications might be left out.

The multicomponent approach (MCR) is especially appealing to form the pyrimidine core and other heterocyclic compounds [14,15,16]. Much diversity can be readily achieved simply by varying the reacting components. The two most known multicomponent reactions to form N-containing heterocycles are Hantzsch’s (1881) [17] dihydropyridine synthesis and Biginelli’s (1893) [18] 3,4-dihydropyrimidin-2(1H)-one synthesis to form pyrimidine frameworks. These reactions were reported a long time ago; however, after years with much interest [19] and later with a discreet number of publications, the Biginelli reaction has been intensively studied in the last two decades [20,21]. The principal reason is the large number of applications of synthesized dihydropyrimidinone and related compounds [22]. Most of the applications of these products are in the field of biochemistry and medicine [23,24]. More information on the Biginelli-type reaction will be given in a following review. We now focus on other types of strategies for forming the pyrimidine core.

2. Strategies to Compose the Pyrimidine Core

By analyzing the pyrimidine framework, one can consider diverse options of cycloadditions to form pyrimidine rings. We distinguish them considering the number of components and the atomic composition of each of the fragments. The corresponding reactions are revised below. Figure 1 depicts the numbers of the schemes corresponding to each type, where the reactions are described.

2.1. Two-Component Cycloadditions

The usefulness of these strategies to form the pyrimidine core can be found in the literature [25]. As a matter of fact, in the period considered in this review, a large number of examples have been reported starting from two components [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65]. In the following schemes, information is given on those reactions which can be included in this group. The classification has been made according to the four types considered in Figure 1, for two-component reactions, starting with the one with the largest components [5+1].

2.1.1. [5+1] Cycloadditions

The [5+1] annulation of enamidines 2 with N,N-dimethylformamide dialkyl acetals 4 has been described. This process leads to the synthesis of tri- and tetrasubstituted pyrimidine derivatives 3 under catalyst- and solvent-free reaction conditions (Scheme 1) [26]. These intermediate enamidines 2 were prepared from functionalized silanes, organolithium compounds and two nitriles. Furthermore, the [5+1] annulation of enamidines using orthoesters 5 with a catalytic amount of ZnBr₂ was also considered, yielding polysubstituted pyrimidines (Scheme 1) [26].

The diversity of two-or-more-component pyrimidine syntheses starting from alkynes has been well documented [27]. Some examples are described below.

2.1.2. [4+2] Cycloadditions

An original route to prepare multifunctionalized pyrimidines involved in the in situ generation of ketimines from alkynes and sulfonyl azides. Thus, the synthesis of a novel class of sulfonamide pyrimidine derivatives 10 via a copper-catalyzed tandem reaction of trichloroacetonitrile, 1,1,3,3-tetramethylguanidine (6), sulfonyl azides and terminal alkynes 7 has been described with high yields (up to 87%) [28]. The intermediates 8 and 9 via a [4+2]-A condensation gave the targeted pyrimidines 10 (Scheme 2).

A methodology [4+2]-A to prepare 2-trifluoromethylpyrimidines 14 has been developed based on a cyclization reaction of 2-trifluoromethyl 1,3-diazabutadienes 13 [29]. These intermediates were prepared by the condensation of trifluoroacetamidine 11 and amide acetals 12 or with chloromethaniminium salt derived from N,N-dimethylbenzamide with phosphorus oxychloride. The cycloaddition reactions of these 2-trifluoromethyl-1,3-diazabutadienes 13 with dimethyl acetylenedicarboxylate and phenylacetyl chloride provided 2-trifluoromethylpyrimidine derivatives 14 and 15 in a regular to moderate overall yield (Scheme 3).

A particular case of [4+2] cycloaddition involves triazines using a Diels–Alder-type reaction. Recently, a review on triazines, their syntheses and inverse electron-demand Diels–Alder reactions, focusing on the application of obtaining heterocycles with nitrogen, has been published [30]. As an example of their usefulness, a series of 4,5 disubstituted-or 4-monosubstituted-pyrimidine 18 was obtained by an organocatalytic inverse electron-demand Diels–Alder reaction of a variety of ketones 16 with 1,3,5-triazine 17 through enamine catalysis. Good yields and high levels of regioselectivity were reported (Scheme 4) [31].

More recently, a similar strategy, but with TFA-catalyzed reactions of electron-deficient 1,3,5-triazines 19 and aldehydes/ketones 16, was described [32]. Highly functionalized pyrimidines 20 were obtained as products in fair-to-good yields. The reaction mechanism was carefully studied by the combination of experimental and computational studies. The reactions involved a cascade of stepwise inverse electron-demand hetero-Diels–Alder reactions, followed by retro-Diels–Alder reactions and the elimination of water. Both Diels–Alder reactions required TFA. The yields were higher when cyclic ketones were used. (Scheme 5).

Amidines are another group of compounds that can be used in cyclization reactions of two or more components. Substituted amidines are useful intermediates in the synthesis of many heterocyclic compounds, not only for pyrimidines. Consequently, several reviews have been devoted to the application of amidines as condensation agents to form heterocyclic rings [33,34].

Amidines can react with malononitrile dimer in a [4+2]-B cyclocondensation, as reported by Aly’s group [35]. The reaction occurred via an amination process followed by cyclization to give racemic 6-aminopyrimidine compounds 23, which were catalyzed with piperidine in DMF. Amidine compounds 21 that have aryl groups with electron-donating or electron-withdrawing substituents on the benzene ring were selected to examine their respective effect on the course of the reaction. The yield was higher in the case of electron-donating substituents, p-methoxy (89%), than for the withdrawing nitro group (70%) (Scheme 6).

An enantioselective rhodium-catalyzed [4+2]-B cycloaddition was performed from α,β-unsaturated imines 24 and isocyanates 25, obtaining pyrimidinones 26 with a high enantioselectivity and moderate-to-good yields. The reaction was catalyzed by a phosphoramidite–Rh complex, affording a substitution pattern complementary to that of Biginelli adducts (Scheme 7) [36].

An [4+2]-B condensation starting from β-enaminones was described by Campagne´s group [37]. These authors achieved, with (Z)-selectivity, several N-Cbz-β-enaminones 29 through a novel base-catalyzed isomerization from propargylic N-hydroxylamines 28. The use of NaOH as a base was crucial to improve the yield of the reaction. The role of the R² substituent was also important. In fact, for R² = ^tBu, Ph, p-Tol, a propargylic by-product was formed in significant proportion. The usefulness of these enaminones was to obtain 2,4,6-trisubstituted pyrimidines 30, as they could be condensed with various carboxamides, under basic conditions, in gram scale, in moderate-to-good yields (Scheme 8).

Later, amino acid-derived carboxamides were also employed in this reaction, providing chiral pyrimidine derivatives 34 and 35 in modest yields. The obtained pyrimidines were studied with NMR and DFT methods (Scheme 9) [38].

Anderson and Boger [39] published a systematic study of the inverse electron-demand Diels–Alder reactions of 1,2,3-triazines. The study revealed not only that the reactivity may be predictably modulated by a C-5 substituent (R = CO₂Me > Ph > H), but also that the application of this methodology is broadened to heterocyclic ring systems as pyrimidine derivatives. In this case, from 1,2,3-triazines, pyrimidine formation follows a [4+2]-B cycloaddition. In a subsequent work, amidines were found to undergo a powerful cycloaddition to 1,2,3-triazines bearing electron-donating substituents at C5, to provide 2,5-disubstituted pyrimidines 42 in excellent yields (42–99%) (Scheme 10) [40]. Even selected ynamines and enamines were capable of cycloadditions with 36, but not with 37 or 38, to provide other trisubstituted pyridines in modest yields (37–40% and 33%, respectively).

2.1.3. [3+3] Cycloadditions

We cannot deal with the synthesis of pyrimidines by [3+3] cycloaddition without describing the classical Pinner reaction [41]. This synthesis entails the condensation of 1,3-dicarbonyl compounds, formerly ketones, with amidines (Scheme 11).

A modified Pinner reaction is described by Vidal et al. with a β-keto ester instead of 1,3-diketone. The procedure was improved under ultrasound (US) irradiation. Fully substituted pyrimidines were obtained by tosylation of the free hydroxyl of the obtained pyrimidine derivatives, which allowed further Suzuki cross-coupling reactions (Scheme 12) [42].

Other variations of the original reaction have been described [43]. Thus, using 1,3-dicarbonyl equivalents as precursors, several syntheses of pyrimidines have been reported using a Pinner-like synthesis. Cho’s group [44] condensed β-bromo-α,β-unsaturated ketones with benzamidine or acetamidine under Cu⁰ catalysis to provide the corresponding pyrimidines in fair yields. Most of the samples were fused pyrimidines, which do not fall within the scope of this study. Previously, this group carried out the same synthesis with β-bromo-α,β-unsaturated carboxylic acids [45]. One remarkable modification was the use of unsaturated ketones instead of the dicarbonyl compound [46]. Thus, a [3+3] annulation–oxidation sequence between α,β-unsaturated ketones and benzamidine hydrochloride was performed using green and recyclable choline hydroxide as both a catalyst and a reaction medium. Strong bases, such as NaOH, KOH and CsOH, catalyzed the reaction better than weak inorganic bases, to give substituted pyrimidine 50 in excellent yields. However, the optimal reaction conditions required the use of choline hydroxide as a catalyst, as well as reaction medium at 60 °C (Scheme 13) [46].

Another variation was carried out by Hu et al., who reported [47] a [3+3] cycloaddition of polysubstituted 5-aminopyrimidines 52 from α-azidovinyl ketones 51 and amidines 39 in the presence of a base (K₂CO₃) in anhydrous DMF (Scheme 14).

Amidines were also condensed via [3+3] annulation with 2,2,2-trichloroethyliden-acetophenones 53, easily available from chloral and acetophenones, providing novel 2,6-diaryl-6-hydroxy-4-trichloromethyl-1,4,5,6-tetrahydropyrimidines 54 in good yields.

On the other hand, new intermediate 2,4-diaryl-6-trichloromethyl-1,6-dihydropyrimidines 55 were formed by dehydration and found able to undergo base-induced chloroform elimination to give 2,4-diarylpyrimidines 56 (Scheme 15) [48].

A bromoenone was used to afford trifluoromethylated pyrimidines 59 through the treatment of fluorinated 2-bromoenones 57 with aryl- and alkylamidines 34 [49]. The formation of a pyrimidine core proceeded via an aza-Michael addition–intramolecular cyclization–dehydrohalogenation/dehydration sequence. The influence of the trifluoromethyl group was demonstrated to be necessary to achieve selectively the target heterocycles in high yields (up to 99%) under mild conditions. With other substituents, imidazoles were obtained (Scheme 16).

Another modification was described by Chu et al. [50], starting from a variety of saturated carbonyl compounds: ketones, aldehydes and esters 60. The condensation was promoted by FeSO₄ and 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), selectively favoring β-functionalization. A mechanism initiated by TEMPO reduction via complexed Fe(II) with ketones was proposed. The total sequence included the formation of intermediate enamine and finished with a β-TEMPO elimination, followed by cyclization. The Fe(II) catalytic complex, formed in situ, could be recycled. More than forty pyrimidinic derivatives were obtained (some of them with condensated rings), sixteen of which were of type 61 (Scheme 17) [50].

Subsequently, a condensation with a special type of unsaturated ketone, a substituted chromone, was carried out by Yu et al. [51]. The strategy was based on a transition metal-free synthesis of 3-trifluoromethyl chromones via tandem C-H bond trifluoromethylation and chromone annulation reactions of o-hydroxyphenyl enaminones. The addition of K₂S₂O₈ made the use of any transition metal catalyst or additive unnecessary. The 3-trifluoromethyl chromone products were successfully used for the synthesis of 3-trifluoromethyl pyrimidines through reactions with guanidine/amidine substrates (Scheme 18).

[3+3] cycloadditions have also been carried out from fluorinated building blocks. Thus, an efficient microwave-assisted cyclization reaction was developed to provide faster and efficient access to new fluoroalkyl pyrimidines 66 and 68 from fluorinated acetoacetates, malononitrile, various amidines and fluoroalkyl amino reagents (Scheme 19) [52].

Very recently, in 2022, Xiang and Yang reported [53] a photoredox-catalyzed amination of o-hydroxyarylenaminones with tert-butyl [(perfluoropyridin-4-yl)oxy]carbamate, a versatile amidyl radical precursor. This method allows 3-aminochromones to be obtained under mild conditions, with an additional application in the synthesis of a series of amino pyrimidines (Scheme 20) [53].

Not many examples of bis-pyrimidines are found in the literature. With the aim of obtaining new biological active pyrimidine derivatives 75, 76 and 77, Dabholkar and Ansari [54] proposed this synthesis starting from bis-α,β-unsaturated esters 74 and carbamide C, thiocarbamide (T) and guanidine (G) as efficient substrates under ultrasound (US) irradiation in aqueous media (Scheme 21).

The effectiveness of the cyclization reactions involving alkynes and nitrogen compounds for the synthesis of pyrimidines, using a variety of promoters and catalysts, has been demonstrated. More specifically, the Cu(II)-catalyzed cycloaddition reaction of alkynes is considered a powerful tool for the construction of pyrimidines using nitrogen-containing molecules, such as amidines, guanidines and sulfonyl azides [27]. Müller and colleagues [55] planned a versatile copper-catalyzed synthesis of 2,6-disubstituted pyrimidones 79 from terminal alkynes 7, CO₂ and amidine hydrochloride 34 in DMF. Although the total reaction involved three components, the formation of a pyrimidine ring can be considered a [3+3] cycloaddition strategy. After an initial carboxylation/methylation of terminal alkynes to produce the methyl arylpropiolates 78, a Michael addition cyclocondensation led to pyrimidones 79 with moderate-to-good yields (Scheme 22) [55].

Lin et al. [56] described the use of Cu(II) triflate (20 mol%) as an efficient catalyst to synthesize 2,4-disubstituted or 2,4,6-trisubstituted pyrimidines 83 from propargyl alcohols and amidine. The synthesis started with a Cu(II) activation of propargyl alcohol 80, followed by a [3+3] addition combined with ring closure in a 6-endo-dig mode. The authors proposed the initial formation of the propargyl cation 81, which triggers the attack on amidine to complete the pyrimidine skeleton, as a key step of the reaction mechanism. A subsequent aromatization by oxidation was the last step leading to pyrimidines 83 (Scheme 23) [56].

A series of 4-iminopyrimidines 86 using the strategy of [3+3]-A cycloaddition was synthesized from intermediate β-alkynyl-N-sulfonyl ketenimines 85 with a copper catalyst. The sequence started with the reaction of butadiynes 84 and sulfonylazides and continued with the addition of hydrazides or imidamides (Scheme 24) [57]. The best reaction conditions to first form ketenimine 85 with subsequent cycloaddition were with CuCl (10 mol%) as a catalyst with NEt₃ in DCE at room temperature. Although three components are involved in this reaction, in two sequential steps, the atoms of the starting azide are not integrated in the pyrimidine core in the cycloaddition (Scheme 24) [57].

Sharma et al. [58] took advantage of the Selectfluor’s ability to regioselectively functionalize a variety of methylthio-substituted β-enaminones 87, which were transformed into α-fluoro-β-enaminones in acetonitrile. The resulting crude reaction was condensed with guanidinium nitrate under basic conditions. The corresponding 6-aryl- or 6-alkylamines-2-amino-5-fluoropyrimidines 88 were obtained in good overall yields (Scheme 25) [58].

Sulfur derivatives are frequently compounds of interest in biomedical applications. With the aim of obtaining sulfur-functionalized pyrimidines, a practical microwave-assisted protocol for the synthesis of 2,6-disubstituted pyrimidinones 91 was developed. It was based on a domino Michael addition/cyclocondensation reaction between substituted thioureas/guanidines and acetylencarboxylates (Scheme 26). Following this strategy, the subsequent synthesis of not easily accessible N-DABO (dihydro-alkoxyl-benzyl-oxopyrimidine) derivatives was reported [59].

A direct and single-step procedure towards substituted pyrimidine and pyridine derivatives via Lewis-acid-promoted [3+3] annulation between 3-ethoxycyclobutanones and enamines or amidines is presented. These 3-ethoxycyclobutanones act as 1,3-di-carbonyl surrogates. Choosing the right reaction conditions, diverse substituted pyrimidine 95 and pyridine derivatives 94 were obtained in good-to-high yields with a wide substrate scope (Scheme 27) [60].

A new [3+3] strategy was carried out by El-Sayed et al. [61], preparing pyrimidine derivatives via an epoxy ketone. Pyrimidinic compounds 98 and 99 were synthesized starting from unsaturated carbonyl compound 96, which, with hydrogen peroxide, yielded epoxy ketone 97. After a reaction with urea or thiourea by epoxide opening, the corresponding derivatives 98 were formed. Compound 99 was prepared by the treatment of epoxy ketone with thiosemicarbazide. The anticancer activity of these derivatives was studied against the MCF-7 human breast cancer cell line (Scheme 28) [61].

Modified nucleobases and nucleic acids have found many biological and pharmaceutical applications. Burgula et al. [62] have reported a [3+3] green procedure for the single-step preparation of a series of uracil and cytosine nucleobases 100 and 101. Uracil analogs 100 were synthesized through the treatment of the respective β-ketoesters or β-aldehydoesters 102 with urea, whereas the cytosine derivatives 101 were obtained from benzoylacetonitriles 103 or N,N-diethylamide precursors (Scheme 29). A Lewis acid catalyst (BF₃:Et₂O) and MW irradiation improved the reaction, with higher yields and lower reaction times. The crystal structures of 5-isopropyl-6-methyluracil and 6-phenyluracil were also determined.

A good synthetic design was reported by Tejedor and García-Tellado [63] to obtain pyrimidine derivatives 105 with an oxy-functionalized acetate chain at the ring. Amidines 32 with electrophilic diynes 104 interacted in two consecutive aza-Michael additions, followed by a second domino process involving sequential [H]-shift and a [3,3]-sigmatropic rearrangement, giving pyrimidine derivatives 105 (Scheme 30).

Hosamani et al. reported the MW-assisted synthesis of 3-(2-(4-fluorobenzyl)-4-(substituted phenyl) pyrimidin-6-yl)-2H-chromen-2-ones 108 [64]. The reactions proceeded through a [3+3] cyclic condensation of substituted chalconated coumarins 106 with 2-(4-fluorophenyl) acetamidine hydrochloride 107 in DMF. Improved yields and shortened reaction times, when using MW irradiation compared to conventional heating, were observed (Scheme 31). Although we do not focus on the biological activities of the compounds in this review, this work is of interest because it evaluates the role of the substituents in the pharmacological activities and it evaluates the obtained products against cancer lines.

Very recently, in 2022, the effective and accessible synthesis of (E,E)-4,6-bis(styryl)-pyrimidines was carried out with TFA as a catalyst and water as a solvent. The pyrimidine ring formation was achieved from acetylacetone and urea by [3+3] cycloaddition. A subsequent aldol condensation with differently substituted aromatic aldehyde gave the desired (E,E)-4,6-bis(styryl)-pyrimidines 110 in moderate-to-good yields (Scheme 32) [65].

2.2. Three-Component Cycloadditions

There is a plethora of three-component condensations leading to pyrimidine and related products. We start by describing an example of a [4+1+1] reaction and continue with [3+2+1] reactions.

2.2.1. [4+1+1] Cycloadditions

Yuan et al. [66] developed a base-promoted formal [4+1+1] annulation of aryl aldehyde 109, N-benzyl arylamidines 111 and DMSO to access to a series of 2,4,6-triaryl pyrimidines 112 in moderate-to-good yields, with molecular O2 as the sole eco-friendly oxidant (Scheme 33). It is to be noted that DMSO served as a methine source, which was promoted by a base rather than either a Lewis acid or electrophile. A detailed mechanism was proposed.

2.2.2. [3+2+1] Cycloadditions

One of the classical multicomponent strategies for synthesizing dihydropyrimidines is the Biginelli three-component condensation (type [3+2+1]-A, Figure 1) of an aldehyde, an α-keto ester and a urea or thiourea that gives a 3,4-dihydropyrimidin-2(1H)-(thi)one [18]. Due to the vast information and literature on this type of multicomponent reaction (MCR), we will soon provide a further review of this reaction. Now, we detail other strategies, although a number of them may be considered by other authors as modifications of the Biginelli reaction.

Thus, in the following, we look at other possibilities with the [3+2+1] combination that differ from the classical Biginelli reaction. In pyrimidine synthesis, the in situ oxydation of alcohols to provide the formyl component in MCRs is a good option. Thus, a comparative study of nickel-catalyzed syntheses of pyrimidines via the dehydrogenative multicomponent coupling of alcohols and amidines using two types of nickel complex catalysts has been reported [67]. Catalyst I dehydrogenates alcohols via a two-electron hydride transfer pathway, while in the presence of II, the dehydrogenation of alcohols proceeds via a one-electron hydrogen atom transfer (Scheme 34).

With the aim of obtaining 2-(N-alkylamino)pyrimidines, heterocycles widely found in various pharmaceutically drugs, a new ruthenium-catalyzed synthesis was reported in a [3+2+1] fashion [68]. The method consisted of a new cooperative ruthenium-complex-catalyzed, multicomponent tandem synthesis of 2-(N-alkylamino)pyrimidines directly from guanidine salt and alcohols. The reactions proceeded through the dehydrogenation of alcohols, followed by C–C coupling and sequential C–N coupling with guanidine and primary alcohol, with the elimination of three equivalents of hydrogen gas. Several Ru catalysts were tested, Ru catalyst I (2 mol %) being that which provided the best results (Scheme 35). The viability of this method was demonstrated through the preparative-scale synthesis of a few products. Mechanistic studies and DFT calculations were subsequently performed (Scheme 35) [68].

A series of [3+2+1] three-component annulations of amidines 39, ketones and N,N-dimethylaminoethanol 120 to obtain pyrimidine derivatives 121 was reported. This productive and eco-friendly method showed the oxidation of N,N-dimethylaminoethanol through C(sp³)−H activation to provide one carbon donor to be the principal action. It is worth mentioning, in this strategy, the good tolerance to many important functional groups in air, with improvements to the existing methods of 4-aliphatic pyrimidine formation (Scheme 36) [69].

2.2.3. [2+2+2] Cycloadditions

A copper acetate-catalyzed tandem Blaise/Pinner-type reaction with nitriles and a Reformatsky reagent was performed to obtain pyrimidinones 125. Nitrile 122 reacted with Reformatsky reagent 123 to form a Blaise intermediary 124, and then, a second nitrile 122 was added to complete the targeted ring (Scheme 37) [70].

The multicomponent condensation [2+2+2] (C-C+N-C+N-C) of oxygenated arylacetic acids with electron-donating trimethoxybenzene provided o-diaryl pyrimidines in acetonitrile at 60 °C. On the other hand, electron-withdrawing nitroarylaldehydes followed the annulation route (C-C-C-C+C+N) to give 1-aryl isoquinolinones. The uses of various metal triflates and reaction conditions were investigated in these one-pot reactions, highlighting bismuth triflate Bi(OTf)₃, which acted in mild conditions in open vessels (Scheme 38). The reaction mechanisms were proposed [71].

Gold complexes have been used to catalyze different cycloadditions to give pyrimidines. Karad and Liu reported the intermolecular [2+2+2] cycloaddition of ynamides 129 (R² = Ms, Ts) with nitriles to give 4-aminopyrimidines 130 [72]. The reaction conditions were studied in detail, indicating that the use of Ph₃PAuNTf₂ (5 mol%) in DCE at 75 °C was the best option to obtain the products in good yields (Scheme 39).

A zirconium-mediated reaction of silyl-butadiynes with two molecules of aryl nitriles was described, which provided rapid access to polysubstituted pyrimidines 132 in a regioselective manner and in a one-pot fashion. On the other hand, employing aliphatic nitriles resulted in the coupling of only one nitrile, leading to the formation of enynyl ketones after hydrolysis. The reaction was extended to a zirconocene–monoyne complex, which underwent similar reactions with nitriles to form highly substituted pyrimidines (Scheme 40) [73].

In a similar strategy [2+2+2], Low et al. reported the synthesis and reactivity of Zr complexes Zr(IV)L(THF)₃, which display a two-electron-reduced anthracene moiety. Mechanistic studies suggest that selectivity to form pyrimidines 133 originates from the preferred formation of an azazirconacyclopentadiene intermediate, which reacts preferentially with nitriles over alkynes (Scheme 41) [74]. Previously, Sato et al. reported a similar synthesis catalyzed by NbCl₅ [75].

In the following synthesis of diversely functionalized pyrimidines with a [2+2+2] strategy, the cyclization of ketones with nitriles was carried out under basic conditions with a copper catalyst. The reaction proceeded via a pathway involving the nitriles acting as electrophiles, with consecutive C–C bonds and two C–N bond formations. The method shows a broad substrate scope and a good tolerance for many important functional groups (Scheme 42) [76].

Babaoglu et al. described a sequential three-component, one-pot reaction sequence for the formation of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates following a [2+2+2] strategy (Scheme 43) [77].

Jadah and Singh planned an oxidative annulation promoted by K₂S₂O₈, involving anilines, aryl ketones and DMSO as a methine (=CH-) equivalent. In the process, a sulfenium ion was formed. This methodology was applied to the synthesis of 4-arylpyrimidines 139 from aryl ketones, via the activation of acetophenone–formamide conjugates 141. The proposed mechanism is depicted in Scheme 44 [78].

2.3. Four-Component Cycloadditions

A regioselective, iridium-catalyzed [3+1+1+1] synthesis of alkyl or aryl pyrimidines 142 from amidines and up to three (different) alcohols was carried out. The reaction proceeded via a sequence of condensation and dehydrogenation steps, which gave rise to selective C–C and C–N bond formations. PN5P–Ir–pincer complexes (cat. [Ir]) efficiently catalyzed the regioselective process. A total of thirty-eight different pyrimidines were synthesized in isolated yields of up to 93% (Scheme 45). The authors pointed out that the combination of this novel protocol with established methods for converting alcohols to amidines could allow the selective assembly of pyrimidines from four alcohol building blocks and two equivalents of ammonia [79]. Later, a similar approximation using an Mn complex stabilized by a PN5P–pincer ligand (cat. [Mn]) as a catalyst gave pyrimidines from amidines and up to three (different) alcohols. The consecutive four-component reaction combines the concept of borrowing hydrogen or hydrogen auto transfer with dehydrogenation–condensation to permit selective C–N and C–C bond formation, as in the previous work (Scheme 45) [80].

Using β-cyclodextrin (β-CD) as a catalyst, pyrimidine derivatives were synthesized from a variety of substituted phenyl and heterocyclic aldehydes in aqueous medium. The advantage of this [3+1+1+1] method is that β-CD is a recyclable, inexpensive, economically viable, non-toxic and readily available material. Thus, the reaction of a series of aromatic aldehydes with ammonium acetate and 1,3-diketones afforded a series of pyrimidine derivatives 143. The method worked well with both electron-withdrawing and electron-releasing substituents in the aromatic groups, giving pyrimidines 143 in good-to-excellent yields (Scheme 46 [81].

2,4,6-Triarylpyrimidines 144 were synthesized via a simple, one-pot, four-component [2+2+1+1] annulation among aryl methyl ketones, benzaldehydes, aromatic nitriles and hydroxylamine under microwave irradiation and solvent-free conditions in good-to-excellent yields (Scheme 47) [82].

Guo et al. [83] designed an effective four-component reaction methodology for the synthesis of pyrimidine carboxamides 145 from three different starting compounds: amidines, styrene and N,N-dimethylformamide (DMF). Regarding this Pd-catalyzed oxidative process, the versatility of DMF as a dual synthon ought to be mentioned, providing both a one-carbon atom and amide synthons. These roles were proven by isotope labeling experiments, which showed the usefulness of this reaction from easily available starting materials (Scheme 48) [83].

2.4. Pseudo Five-Component Cycloadditions

[2+1+1+1+1] Cycloadditions

Ding et al. reported a [C-C+C+N+C+N] multicomponent cyclocondensation between methyl aryl ketone, two equivalents of aromatic aldehyde and two of ammonium acetate to give pyrimidines 146. That is to say, five components were involved in the ring formation, but with only three different molecules. Thus, the authors called it a pseudo five-component reaction. The process was catalyzed by triflic acid (Scheme 49) [84].

2.5. Miscellaneous

In this section, we have highlighted several reactions due to their peculiarity. For example, a multifunctionalized pyrimidine 149 was synthesized from 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (147) through the treatment with Ph₃P. An intermediate spirocycle 148 was obtained with a 66% yield, and its degradation with BnEt₃NCl (0.5 equiv.) afforded 4,5,6-trichloropyrimidine-2-carbonitrile (149) in an 81% yield. Rational mechanisms to explain the intermediate and product formation were proposed (Scheme 50) [85].

A straightforward synthesis of pyrimidines 153 or 154 via Au(III) or Au(I)/Lewis-acid-catalyzed cascade reactions of propargyl alcohols 150 with 3-amino-benzo[d]isoxazoles 151 has very recently been carried out. The propargyl amine intermediates 152 were readily generated in situ via oxophilic activation by Au(III) or a Lewis acid. After the intermediate cyclization/1,2-H or group migration/aromatization, the desired products were delivered. The selective migratory aptitude was dependent on the steric and electronic properties of the propargylic groups used (Scheme 51) [86].

Dofe et al. reported a convenient and facile methodology for the synthesis of a new series of pyrazole and pyrimidine derivatives 156 from chromenones 155 and thiourea under ultrasound irradiation. With regard to pyrimidine derivatives, they have been synthesized in better yields and shorter reaction times compared with the conventional method (Scheme 52) [87].

Pyrimidine N-oxides 158 were prepared from β-keto enamides 157 and hydroxylamine hydrochloride by a reaction in r.t. for 5–19 days or at 70–75 °C for 4.5–6.5 h under MW irradiation. The required β-keto enamides 157 were prepared by the MCR of nitriles, trichloroacetic acid and lithiated methoxyallene. N-oxides 158 were obtained in moderate-to-excellent chemical yields (28–61% and 71–96%), together a pyridine side product (2%). The acetylation of the methyl group of the pyrimidine N-oxides 158 was achieved with Ac₂O at 130 °C through Boekelheide rearrangement to provide the acetylated 159 (Scheme 53) [88].

3. Conclusions

The MCR is a valuable synthetic approach to obtain new pyrimidine derivatives and related compounds, not only by using the Biginelli reaction. Catalysis is of great value in this type of reaction, and a large number of new catalysts have been developed. New perspectives for known catalysts have also been discovered. In addition, the use of various technologies, such as microwave and ultrasound irradiation, also helps to improve reaction conditions and yields. In general, in the period of time considered in this review, increasingly more importance has been given to eco-friendly reactions.

Author Contributions

Conceptualization, M.-S.P.-G.; methodology, M.-S.P.-G. and M.A.; writing—review and editing, M.-S.P.-G., M.A., S.C.-L., M.D.-F., F.S. and J.-J.Q.; supervision, M.-S.P.-G. and M.A.; project administration, M.-S.P.-G. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Not applicable here.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

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Figure and Schemes

Figure 1. Formation of pyrimidine core from diverse numbers of components.

Scheme 1. Synthesis of tri- and tetrasubstituted pyrimidine derivatives 3.

Scheme 2. Synthesis of sulfonamide pyrimidines 10 from trichloroacetonitrile, 1,1,3,3-tetramethylguanidine (6), sulfonyl azides and terminal alkynes 7.

Scheme 3. Synthesis of 2-trifluoromethylpyrimidines 14 and 15.

Scheme 4. Synthesis of pyrimidines 18 from ketones 16 and triazines 17.

Scheme 5. Synthesis of pyrimidines 20 from substituted triazines 19 and ketones 16.

Scheme 6. Synthesis of pyrimidines 23 from amidines and malononitrile dimer.

Scheme 7. Synthesis of pyrimidinones 27 from α,β-unsaturated imines 24 and isocyanates 25.

Scheme 8. Synthesis of pyrimidines 30 from β-enaminones 29.

Scheme 9. Synthesis of pyrimidines 34 and 35 from amino acid-derived carboxamides.

Scheme 10. Inverse electron-demand Diels–Alder reactions of 1,2,3-triazines 36–38 with amidines 39.

Scheme 11. Classical Pinner synthesis.

Scheme 12. Modified Pinner reaction with β-keto esters 45 and amidines 39.

Scheme 13. Synthesis of pyrimidines 50 from unsaturated ketones 48 and amidine 49.

Scheme 14. Synthesis of 5-aminopyrimidines 52 from α- azidovinyl ketones 51 and amidines 39.

Scheme 15. Synthesis of 2,4-diarylpyrimidines 56 from 2,2,2-trichloroethyliden-acetophenones 53 and amidines 39.

Scheme 16. Synthesis of trifluoromethylated pyrimidines 59 from bromoenones 57 and aryl- and alkylamidines 39.

Scheme 17. Iron-catalyzed synthesis of pyrimidines 61 from carbonyl derivatives 60 and amidines 39.

Scheme 18. Synthesis of F3C-functionalized pyrimidines 63 from chromones 62.

Scheme 19. Synthesis of fluoroalkyl pyrimidines 66 and 68 under MW irradiation.

Scheme 20. Synthesis of 3-aminochromones 71 and amino pyrimidines 72.

Scheme 21. Synthesis of bis-pyrimidines 75, 76 and 77 under US irradiation.

Scheme 22. Copper-catalyzed synthesis of 2,6-disubstituted pyrimidones 79 with MW.

Scheme 23. Mechanistic proposal for Cu(II)-catalyzed tandem synthesis of pyrimidines 83.

Scheme 24. Copper-catalyzed synthesis of 4-iminopyrimidines 86.

Scheme 25. Sequential synthesis of 4-amino-5-fluoropyrimidines 88.

Scheme 26. Microwave-assisted tandem Michael addition–cyclocondensation to form sulfur-functionalized pyrimidines 91.

Scheme 27. Synthesis of pyrimidines 94 and 95 from 3-ethoxycyclobutanones 92.

Scheme 28. Synthesis of oxo and thio pyrimidine derivatives 98 and 99 via epoxyde 97.

Scheme 29. Green synthesis of uracil and cytosine analogs (100 and 101).

Scheme 30. Synthesis of functionalized pyrimidines from electrophilic diynes 104 and amidines 39.

Scheme 31. MW-assisted synthesis of fluorinated coumarin–pyrimidine hybrid molecules 108.

Scheme 32. Synthesis of (E,E)-4,6-bis(styryl)-pyrimidines 110.

Scheme 33. Base-promoted synthesis of 2,4,6-triaryl pyrimidines 112 from aryl aldehyde 109, N-benzyl arylamidines 111 and DMSO.

Scheme 34. Nickel-catalyzed syntheses of pyrimidines 115 from alcohols and amidines.

Scheme 35. Synthesis of 2-(N-alkylamino)pyrimidines 119 directly from guanidine salt and alcohols.

Scheme 36. Copper-mediated synthesis of 4-aliphatic pyrimidines 121 from ketones, amino alcohol 120 and amidines 39.

Scheme 37. Zinc-mediated synthesis of pyrimidinones 125 from nitriles 122 and ethyl bromoacetates 123.

Scheme 38. Bismuth-mediated synthesis of pyrimidinones 128 from arylacetic acids 126 with trimethoxybenzene 127.

Scheme 39. Gold-complex-mediated synthesis of 4-aminopyrimidines 130 by [2+2+2] cycloaddition of alkynes 129 with nitriles 122.

Scheme 40. Zirconium-mediated synthesis of polysubstituted pyrimidines 132 with silyl-butadiynes or other alkynes 131 and with two molecules of aryl nitriles 122.

Scheme 41. Zirconium-mediated synthesis of polysubstituted pyrimidines 133 with alkynes 131 and two molecules of nitriles 122.

Scheme 42. Copper-catalyzed synthesis of pyrimidines 134 from ketones and nitriles 122.

Scheme 43. Indium-mediated Blaise-type synthesis of pyrimidines 138 via the reaction of bromomalonates 135 with nitriles 136 and isocyanates 137.

Scheme 44. Synthesis of pyrimidines 139 and proposed mechanism from aryl ketones 140.

Scheme 45. Iridium- or manganese-mediated four-component synthesis of pyrimidines 142 from amidines and alcohols.

Scheme 46. β-cyclodextrin (β-CD)-catalyzed synthesis of pyrimidine derivatives 143 from a variety of substituted phenyl and heterocyclic aldehydes in aqueous medium.

Scheme 47. Synthesis of 2,4,6-triarylpyrimidines 144 by [2+2+1+1] annulation from aryl methyl ketones, benzaldehydes, aromatic nitriles and hydroxylamine under MW irradiation.

Scheme 48. Pd-catalyzed synthesis of pyrimidine carboxamides 145 from amidines, styrene and N,N-dimethylformamide (DMF).

Scheme 49. Synthesis of pyrimidines 146 via the multicomponent cyclocondensation between methyl aryl ketone, two equivalents of aromatic aldehyde and two of ammonium acetate.

Scheme 50. Ph3P-mediated pyrimidine 149 synthesis from 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (147).

Scheme 51. Gold-mediated pyrimidine 153 and 154 synthesis from propargyl alcohols 150 with 3-amino-benzo[d]isoxazoles 151.

Scheme 52. Synthesis of pyrimidines 156 from chromones 155 and thiourea under ultrasound irradiation.

Scheme 53. Synthesis of pyrimidine N-oxides 158 from β-keto enamides 157 and hydroxylamine hydrochloride under MW irradiation.

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