Recent advances in the application of acetophenone in heterocyclic compounds synthesis

Abstract

Acetophenone is an interesting synthon in the most organic reactions. Acetophenone has been utilized in the synthesis of many heterocyclic compounds. Acetophenone and most of its derivatives are commercially available or readily accessible and hence are ideal synthon for multicomponent reactions including the three- and four-component reactions. Also, the biological activities of some compounds were studied. Herein, we want to review the application of the acetophenone as starting material in the synthesis of various heterocyclic compounds including fused and five-, six-, seven-membered rings via multicomponent reactions.

Graphic abstract

Introduction

Acetophenone is a useful precursor in the organic reactions for the synthesis of heterocyclic compounds [1,2,3,4]. There are several methods for the preparation of acetophenone 2; one of them comprises the reaction of aryl triflates 1 with a mixture of SnMe₄, Pd(0) and CO (balloon) in the presence of Et₃N in DMF at 60 °C (Scheme 1) [5,6,7,8].

Scheme 1

Synthesis of acetophenone 2

Acetophenone and its derivatives use in the organic reactions, including in (pseudo)-two-, three- and four-component reactions [9,10,11,12]. Furthermore, acetophenone is the main constituent of many natural compounds. For example, the three new acetophenone derivatives were isolated from the leaves of Acronychiaoligophlebia [13, 14]. Recent studies have demonstrated the antifungal activities of some naturally occurring acetophenone derivatives. For example, xanthoxylin isolated from Melicope borbonica leaves exhibited the antifungal activity against Candida albicans and Penicillium expansum; 4-hydroxy-3-(isopentent-2-yl) acetophenone, from Helichrysum sp., showed antifungal activity against Cladosporium herbarum (Fig. 1) [7, 15]. We have already published the synthesis of heterocyclic compounds via multicomponent reactions [16,17,18,19,20,21,22,23,24]. Based on previously published articles, in the review, we will try to highlight the applications of acetophenone as starting materials in the synthesis of various heterocycles.

Fig. 1

Medicinally significant natural products containing acetophenone

Acetophenone reactions

Acetophenones have been applied in the structure of different types of heterocyclic frameworks. In this review, a range of heterocyclic compounds from acetophenone involving: five-, six-, seven-membered through three-, four-component reactions, are presented.

Synthesis of five-membered rings

Five-membered rings containing O atom

Initially, intermediate compounds 4 were prepared in excellent yields via the Claisen condensation of acetophenones 2 with methyl 2-methoxytetrafluoropropionate 3. 5-Aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones 5 were generated via intramolecular cyclization of intermediate compounds 4 in the presence of H₂SO₄ and SiO₂ as a catalyst (Scheme 2) [25].

Scheme 2

Synthesis of 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-one 5

Various 2,3-substituted-butyrolactones 8 have been prepared by three-component reaction of acetophenone 2, aryl bromides 6 and dimethyl itaconate 7 in MeCN as a solvent at 60 °C in the excellent yield (Scheme 3) [26].

Scheme 3

Synthesis of various 2,3-substituted–butyrolactones 8

A novel copper-catalyzed domino reaction of acetophenone derivatives 2, α,β-unsaturated dicarboxylate 9 and diethyl zinc 10 produced lactones 11 in the high yield, the role of diethyl zinc was as an alkyl Michael donor (Scheme 4) [27].

Scheme 4

Synthesis of lactones 11

A large number of furo[3,2-c]coumarin derivatives 13 were obtained via three-component reaction of acetophenone derivatives 2 and two moles of various coumarins 12 in the presence of molecular iodine in DMSO at 80 °C (Scheme 5) [28].

Scheme 5

Synthesis of furo[3,2-c]coumarin derivatives 13

Five-membered rings containing N atom

Rad-Moghadam et al. [29] developed a sequential tandem reaction for the synthesis of new series of oxindolyl-7-deazapurine derivatives 16 via the novel cyclocondensation reaction between acetophenones 2, isatins 14 and 6-amino-uracils 15 in ethanol under reflux (Scheme 6). 5-(2-Oxoindolin-3-yl)-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione and its derivatives 16 were evaluated for their antimicrobial activities [29].

Scheme 6

Synthesis of 2-oxoindolin-3-yl-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-diones 16

The one-pot reaction of substituted acetophenone 2, pyridine 17, acetic acid 18 and molecular iodine 19 in the presence of ceric ammonium nitrate (CAN) as a catalyst was carried out for the synthesis of 1-iodoindolizines 20 in 45–56% yields (Scheme 7) [30].

Scheme 7

Synthesis of 1-iodoindolizines 20

Yahyavi et al. [31] prepared the synthesis of 2,3-disubstituted-chromeno[4,3-b]pyrrole-4(1H)-ones 31 or 32 via multicomponent reactions of phenylglyoxals 28, active methylene compounds 29 and 4-amino coumarin 30 (Scheme 8).

Scheme 8

Synthesis of 2,3-disubstituted-chromeno[4,3-b]pyrrole-4(1H)-ones 25 or 26

The synthesis of pyrrole derivatives 29 was accomplished with good yield using acetophenone 2 and trimethylacetaldehyde 27 and TosMIC in LiOH·H₂O at room temperature (Scheme 9) [32]

Scheme 9

Synthesis of pyrrole derivatives 29

In 2018, Mishra et al. [33] developed the synthesis of pyrroles via multicomponent reaction of acetophenone, 4-hydroxycoumarin and amino chromones in the presence of I₂ as a catalyst in DMSO. The products confirmed with high yield in a short time (Scheme 10).

Scheme 10

Synthesis of pyrroles 32

Five-membered rings containing two hetero atoms

The synthesis of 1,3-oxathiolane 34 has been developed via the carbonyl group protection of acetophenone 2 using mercaptoethanol 33 in the presence of Tin(IV) hydrogen phosphate [Sn(HPO₄)₂ H₂O] nanodisks as an efficient heterogeneous catalyst at room temperature (Scheme 11) [34]. Alinezhad et al. [35] performed this reaction with N-bromosaccharin (NBSac) as a catalyst and obtained the product. Two different methods for the synthesis of this product are compared in Table 1.

Scheme 11

Synthesis of 1,3-oxathiolane 28

Table 1 Different reported strategies for the synthesis of 1,3-oxathiolane 34 in CH₂Cl₂ as solvent at room temperature

Initially, 1-(substituted methylbenzoyl)-3-arylthioureas 37 were prepared via condensation of benzoyl chlorides 34 potassium thiocyanate 36 in acetone that followed by reaction of suitably substituted anilines 38. Next cyclization of 1-aroyl-3-arylthioureas 39 with acetophenone 2 in the presence of bromine and triethyl amine to afford 2-aroylimino-3-aryl-4-phenyl-1,3-thiazolines 40 (Scheme 12) [36].

Scheme 12

Synthetic route to 2-aroylimino-3-aryl-4-phenyl-1,3-thiazolines 40

A probable mechanism for the preparation of compounds 47 was shown in Scheme 13. Initially, the reaction of acetophenones 2 with anhydrous chloral 41 gave trichloroethylidene acetophenones 42. According to the peculiar mechanism of this reaction, the 2,2-dichlorovinylacetophenones 42 were generated in high yields. These, 2,2-dichlorovinylacetophenones 44 reacted with hydroxylamine 45 to create oxime intermediates 46 which was treated with aqueous sodium hydroxide to afford novel 3-aryl-5-dichloromethyl-2-isoxazolines 47 (Scheme 13) [37].

Scheme 13

Synthesis of novel 3-aryl-5-dichloromethyl-2-isoxazolines 47

Synthesis of trisubstituted isoxazoles 49 via the reaction of acetophenone 2 and ethyl nitroacetate 48 was carried out at in the presence of I₂/CuO as a catalyst in DMSO at 70 °C (Scheme 14) [38]. Many of these compounds were evaluated for the biological activities, such as antibacterial, antiviral, anticancer and antithrombotic activities [38].

Scheme 14

Synthesis of trisubstituted isoxazoles 49

In 2014, Wang et al. [39] synthesized 4,5-dihydropyrazole derivatives 52 via one-pot three-component condensation of acetophenones 2, arylacetylenes 50 and hydrazines 51 in the presence of KOtBu/DMSO (Scheme 15).

Scheme 15

One-pot synthesis of 5-benzyl-4,5-dihydropyrazoles 52

Yang et al. have established trisubstituted isoxazoles 54 via an efficient one-pot two-component reaction of acetophenone 2 and α-nitroketones 53 in DMSO at 70 °C in the presence of the I₂/CuO as a catalyst (Scheme 16) [38].

Scheme 16

Synthesis of isoxazoles 54

A novel series of coumarin-substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes 57 were synthesized through an efficient, one-pot multicomponent reaction of acetophenones 2, 3-(2-bromoacetyl) coumarins 55 and thiosemicarbazide 56 utilizing Vilsmeier–Haack reaction condition with good yields (Scheme 17) [28].

Scheme 17

Synthesis of coumarin-substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes 57

Amer et al. [40] performed three-component reaction via condensation of acetophenones 2, triazole 58 and N,N-dimethylformamide-dimethylacetal (DMF-DMA) 59 in ortho-phosphoric acid as a solvent to obtain the target products 60 (Scheme 18). Triazolethiones possess various biological activities including anticancer, antiviral, anti-inflammatory, antiproliferative, antifungal, antidepressant and antioxidant.

Scheme 18

Synthesis of coumarin-substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes 60

Three-component condensation reaction of acetophenone derivatives 2, thiosemicarbazide 56, various aldehydes 61 and N-bromosuccinimide (NBS) 56 as a substrate instead of haloacetophenones in the presence of (KIT-6) mesoporous silica-coated magnetite nanoparticles as catalyst at room temperature was carried out by Nikpassand et al. [41] to achieve a series of benzothiazole derivatives 57 in the high yield (Scheme 19).

Scheme 19

Synthesis of benzothiazole 62

The synthesis of 1,3-dioxolanes 64 has been developed through the acetalization reaction of various acetophenone 2 and glycerol 63 in the presence of FeCl₃·6H₂O in tetrahydrofuran (THF) at 60 °C in the excellent yield (Scheme 20) [42].

Scheme 20

Acetalization of glycerol with ketones catalyzed by FeCl₃ 6H₂O

Acetophenone derivatives 2 were reacted with thiourea 65 in the presence of HX/DMSO (X = Br or I) liquid system as the halogenating agent in EtOAc at 60 °C in which 2-aminothiazoles 66 and other analogous heterocyclic compounds were obtained in high yields (Scheme 21) (Table 2, entry 1) [43]. This reaction was also performed using N,N,N′,N′-tetrabromobenzene-1,3-disulfonamide [TBBDA], poly(N,N′-dibromo-N-ethylbenzene-1,3-disulfonamide) [PBBS] (TBBDA-MNPs@SiO₂-Pr-AP) [44] and I₂/CuO [45] as a catalyst. The efficiency of various conditions in the synthesis of 2-aminothiazoles 66 is compared in Table 2.

Scheme 21

Synthesis of 2-aminothiazoles 66

Table 2 Different reported methods for the synthesis of compounds 66

Liu et al. [48] described the synthesis of 2-aryl benzothiazole 69 via one-pot reaction of acetophenone 2, aniline derivatives 67 and elemental sulfur 68 in the presence of iodine as catalyst (Scheme 22).

Scheme 22

Synthesis of 2-aryl benzothiazole 69

Alanthadka et al. [49] accomplished the one-pot reaction of acetophenone 2 and benzylamine 70 in the presence of N-heterocyclic carbene as a catalyst and under the solvent-free condition for the synthesis of imidazoles 71 (Scheme 23).

Scheme 23

Synthesis of imidazoles 71

In 2019, Han et al. [50] applied poly(vinylbenzyltrimethylammonium hydroxide) resin (Amberlite 717) as a catalyst in the reaction of acetophenone 2 and ethylene glycol 72 for the synthesis of α-bromoacetal 73 in excellent yield (Scheme 24).

Scheme 24

Synthesis of α-bromoacetal 73

Khan et al. [51] synthesized various products including benzoxazole, benzothiazole and benzimidazole 74 via an interesting cyclization of acetophenone 2 and 2-amino aniline derivatives 73 in the presence of SeO₂ as a catalyst at 100 °C (Scheme 25).

Scheme 25

Synthesis of various compounds including benzoxazole, benzothiazole and benzimidazole

Farmani et al. [52] recorded the three-component reaction of acetophenone 2, aldehydes 75 and thiosemicarbazide 56 in the presence of tetrabutylammonium hydroxide as catalyst under microwave irradiation for the synthesis of 4,5-dihydro-1H-pyrazole-1-carbothioamides 76 (Scheme 26).

Scheme 26

Synthesis of 4,5-dihydro-1H-pyrazole-1-carbothioamides 76

Synthesis of six-membered rings

Six-membered rings containing O atom

The multicomponent reaction between acetophenone derivatives 2, α-naphthol 77 and triethylorthobenzoate 78 catalyzed by bis[7-tert-butyl-2-anilinotropone]Ti complex in refluxing toluene afforded a new series of 2-(4-aryl)-4-ethoxy-4-phenyl-4H-benzo[h]chromene derivatives 79 (Scheme 27) [53].

Scheme 27

Synthesis of 2-(4-aryl)-4-ethoxy-4-phenyl-4H-benzo[h]chromene derivatives 79

4-Phenacylidene flavenes 81 were synthesized by Bhattacharjee et al. [54] via the one-pot pseudo-three-component reaction between acetophenones 2 and salicylaldehydes 80 with a ratio of 2:1, respectively, in the presence of 20 mol% of bromodimethylsulfonium bromide (BDMS) as a catalyst in acetonitrile at room temperature (Scheme 28).

Scheme 28

Synthesis of 4-phenacylidene flavene derivatives 81

Reddy et al. [55] described an efficient method for the synthesis of pyrano[3,2-c]chromen-5(4H)-ones 82 via one-pot three-component reaction of acetophenone 2, aldehydes 75 and 4-hydroxy-2H-chromen-2-one 12 without using catalyst and solvent under microwave irradiation (Scheme 29).

Scheme 29

Synthesis of pyrano[3,2-c]chromen-5(4H)-ones 82

2-Amino-4-(3-methoxynaphthalen-2-yl)-6-phenyl-4H-pyran-3-carbonitrile 85 was synthesized via a three-component reaction of acetophenone 2, malononitrile 83 and 2-methoxyquinoline-3-carbaldehyde 84 in the presence of NaOH as a catalyst in ethanol (Scheme 30) [56].

Scheme 30

Synthesis of pyrano[3,2-c]chromen-5(4H)-ones 85

Sharifi et al. [57] applied a green method for the synthesis of chromene derivatives 88 via reaction of acetophenone 2, 4-hydroxycoumarin 86 and aldehydes 87 in the presence of KF/clinoptilolite nanoparticles (KF/CP-NPs) under solvent-free conditions at 50 °C with high yield in low time (Scheme 31).

Scheme 31

Synthesis of chromene derivatives 88

The bis(2-anilinotropone) Ti complex was applied as a catalyst for the synthesis of 1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f] chromenes 90 via multicomponent reaction of acetophenone derivatives 2, β-naphthol 89, and triethyl orthobenzoate 78 under refluxing in toluene as a solvent (Scheme 32) [58].

Scheme 32

Synthesis of 1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f] chromenes 90

Six-membered rings containing N atom

2-Chloronicotinonitriles 91 were synthesized by sequential cyclization and aromatization under Vilsmeier-Haack reaction of acetophenones 2 and malononitrile 83 (Scheme 33) [59].

Scheme 33

Synthesis of 2-chloronicotinonitriles 91

A plausible mechanism of this reaction is shown in Scheme 34. Initially, acetophenones 2 underwent Vilsmeier–Haack reaction in the presence of POCl₃ and DMF to afford chloromethyleneiminium salt intermediates 92. Malononitrile 83 was added on the chloromethyleneiminium salt intermediates 93 to give intermediate 94. As a result, by intramolecular cyclization, elimination of dimethylamine, 1,3-shift of the chlorine atom and by aromatization, respectively, afforded 2-chloropyridines 96 (Scheme 34) [59].

Scheme 34

A plausible mechanism for the synthesis of 2-chloropyridines 96

Synthesis of aminothieno[2,3-b]pyridine derivatives 99 was reported by the reaction of acetophenone derivatives 2 and 2-amino-3-thiophenecarbonitriles 98 in the presence of a catalytic amount of ytterbium (III) triflate (Yb(OTF)) under microwave irradiation (Scheme 35) [60]. Thieno[2,3-b]pyridine derivatives have important structures in many alkaloids and biologically active natural products [60].

Scheme 35

Synthesis of aminothieno[2,3-b]pyridine derivatives 99

Two series of heterocyclic compounds including 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and their isosteric 2-oxopyridine derivatives 102 were synthesized by the multicomponent reaction of the 4-bromo acetophenone 2, aromatic aldehyde 74, malononitrile or ethyl cyanoacetate 100 and ammonium acetate 101 in ethanol under reflux condition (Scheme 36) [61].

Scheme 36

Synthesis of 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles 102

In the first step, ortho-nitro-chalcones 104 were obtained by the Claisene Schmidt condensation of acetophenone 2 and 2-nitrobenzaldehydes 75. Next 2-substituted-1,2,3,4-tetrahydroquinolines 103 has been achieved by the one-pot reductive intramolecular cyclization of ortho-nitro-chalcones with gaseous hydrogen in the presence of a Pd/C as a catalyst and CH₂Cl₂ as a solvent (Scheme 37) [62].

Scheme 37

Synthesis of tetrahydroquinolines 104

Safari et al. [46] reported in 2011 the Hantzsch condensation of acetophenones 2, aromatic aldehydes 75, ammonium acetate 101 and dimedone 75 in the presence of a catalytic amount of Co nanoparticles at ambient temperature to produce C5-unsubstituted 1,4-dihydropyridines 107 in 30–97% yields (Scheme 38). In another study, Ray et al. developed a one-pot synthesis of C5-unsubstituted 1,4-dihydropyridines 107 using ammonium carbonate (NH₄)₂CO₃ 106 as nitrogen source at room temperature under solvent-free conditions (Table 3, entry 2) [47].

Scheme 38

Synthesis of 1,4-dihydropyridines 107

Table 3 Comparison of different conditions in the synthesis of 1,4-dihydropyridines 107 at room temperature

Kowsari et al. [63] investigated the synthesis of quinoline 108 via the condensation reaction of acetophenone 2 with isatin 14 in the presence of the basic ionic liquid (BIL) based on imidazolium cation under ultrasonic irradiation in aqueous media with excellent yields (Scheme 39). Quinolines are the main constituents of many natural products, and also the quinoline nucleus plays an important role as an intermediate to design many pharmacologically active compounds [63].

Scheme 39

Synthesis of quinoline compounds 104

A series of 2,4,6-triphenylpyrdine 110 was synthesized through a one-pot multicomponent reaction of acetophenone derivatives 2, ammonium acetate 101 and alcohols 109 using 1-methylimidazolium nitrate in 1-butyl-3-methylimidazolium tetrafluoroborate [Hmim]NO₃-[Bmim]BF₃ as a binary task-specific ionic liquid under microwave irradiation (Scheme 40) [64].

Scheme 40

Synthesis of 2,4,6-triphenylpyrdine 110

A family of 2-amino-3-cyanopyridine derivatives 113 was synthesized by Jun Tang et al. [65] via a four-component reaction of acetophenones 2, aldehydes 75, malononitrile or ethyl cyanoacetate 111 and ammonium acetate 112 using [Yb(PFO)₃] as a catalyst under refluxing in EtOH (Scheme 41). This reaction was also developed using different catalysts including MgO [66], graphene oxide [67], [Bmim][BF₄] [68], PEG-400 [69], Fe₃O₄@SiO₂@(CH₂)₃-urea-benzimidazole sulfonic acid [70], SrFe₁₂O₁₉ [71], (Fe₃O₄@TiO₂@O₂PO₂(CH₂)NHSO₃H) [72], morpholine tags [73], catalyst free along with Ultrasound-promoted method and Cu@imineZCMNPs [74, 76]. A comparison of different catalysts is demonstrated in Table 4.

Scheme 41

The one-pot synthesis of 2-amino-3-cyanopyridines 113

Table 4 Comparison of different conditions in the synthesis of 2-amino-3-cyanopyridines 113

A series of novel 1-benzyl-2-butyl-4-chloroimidazole embodied 4-azafluorenone hybrids 116 was synthesized in excellent yields via one-pot condensation of acetophenone derivatives 2, ammonium acetate 101, 1,3-indanedione 114 and 1-benzyl-2-butyl-4-chloroimidazole-5-carboxaldehyde 115 under refluxing DMF in 77–86% yields (Scheme 42) [77].

Scheme 42

Synthesis of 4-azafluorenone hybrids 116

2,4,6-Triarylpyridines 117 were synthesized via a multicomponent reaction of acetophenone 2, aldehyde 75 and ammonium acetate 101 under different conditions (Scheme 43). According to Table 5 various catalysts including wet 2,4,6-trichloro-1,3,5-triazine (Wet-TCT) [78], ZnO [79], pentafluorophenylammoniumtriflate (PFPAT) [80], ZrOCl₂ [81], nanotitania-supported sulfonic acid (N-TSA) [82], silica vanadic acid [SiO₂–VO(OH)₂] (SVA) [83], Fe₃O₄@TiO₂@O₂PO₂(CH₂)₂NHSO₃H [72], chitosan-supported oxo-vanadium (CSVO) [84], MgAl₂O₄ [85], HNTf₂ [86] and PPA-SiO₂ [87] were reported to be effective in this reaction.

Scheme 43

Synthesis of 2,4,6-triarylpyridines 117

Table 5 Comparison of different conditions in the synthesis of 2,4,6-triarylpyridines 117

The multicomponent reaction of acetophenone 2, phenylacetic acids 118 and ammonium acetate 101 in the presence of VNU-22 {[Fe₃(BTC)-(BPDC)₂]·11.97H₂O} was accomplished by Doan et al. [88] (Scheme 44).

Scheme 44

Synthesis of 2,4,6-triarylpyridines 119

The tandem reaction of acetophenone derivatives 2 and simple nicotinamide salts 120 was carried out for the synthesis of substituted 2,7-naphthyridin-1(7H)-ones 121 in the high yield (Scheme 45) [89].

Scheme 45

Synthesis of substituted 2,7-naphthyridin-1(7H)-ones 121

A series of quinoline derivatives 124 was synthesized by Friedländer reaction of acetophenone derivatives 2, 2-bromobenzaldehydes 122 and aqueous ammonia 123 as the nitrogen source in the presence of CuBr as a catalyst in high yields (Scheme 46) [90].

Scheme 46

Synthesis of quinoline derivatives 124

Sarmah et al. [91] developed an efficient method for the synthesis of pyrido[2,3-d]pyrimidine derivatives 126 by the multicomponent aza-Diels–Alder reaction of acetophenones 2, aromatic aldehydes 75 and uracil analogues 125 in the presence of Na₂CO₃ in DMF at 153 °C (Scheme 47).

Scheme 47

Synthesis of pyrido[2,3-d]pyrimidines 126

Alinezhad et al. [92] in 2014 utilized Cu-doped ZnO nanocrystalline powder (10 mol%) in water/ethanol (50:50) as a solvent at room temperature to obtain indeno[1,2-b]pyridines 127 by multicomponent reaction of acetophenones 2, aldehydes 75, ammonium acetate 101 and 1.3-indandione 114 in 1.5-2 h (Scheme 48). Tapaswi et al. applied Ceric ammonium nitrate (CAN) as a catalyst in this reaction and obtained the products in good yields (Table 6, entry 2). This reaction was performed without any catalyst and obtained the products in good yields (Table 6, entry 3, 4).

Scheme 48

Synthesis of indeno[1,2-b]pyridines 127

Table 6 Comparison of the efficiency of various catalysts in the synthesis of indeno[1,2-b]pyridines 127

Tamaddon et al. [96] established the reaction of acetophenones 2, aldehydes 75, malononitrile 83 and urea 128 for the synthesis of 2-amino-3-cyanopyridines 129 using urease as the catalyst in the water at 70 °C in the high yield (Scheme 49).

Scheme 49

Synthesis of 2-amino-3-cyanopyridines 129

Baluja et al. [97] described the synthesis of dihydropyridine derivatives 132 via condensation reaction of different substituted acetophenones 2, ammonium acetate 101, 4-hydroxy-3-methoxybenzaldehyde 130 and ethyl cyanoacetate 131 in refluxing dioxane (Scheme 50).

Scheme 50

Synthesis of dihydropyridine derivatives 132

2-Phenyl pyridine 134 was synthesized via the cyclization of acetophenone 2 with 1,3-diamino propane 133 using palladium acetate in THF as a solvent (Scheme 51) [98]. Pyridine and its derivatives were evaluated for pharmaceuticals including etoricoxib (selective COX-II inhibitor), PMBI (antimalarial), topoisomerase type II inhibitor and zibotentan (endothelial antagonist) [98].

Scheme 51

Synthesis of 2-phenyl pyridine 134

Ladraa et al. [99] prepared a simple and convenient method for the synthesis of 3-cyanopyridine derivatives 136, 137 from the reaction of acetophenone derivatives 2, active methylene compounds 83, ammonium acetate 101 and 2-chloroquinolin-3-carbaldehydes 135 in the presence of PPh₃ as a catalyst at room temperature (Scheme 52).

Scheme 52

Synthesis of 3-cyanopyridine derivatives 136, 137

The synthesis of various nitroarenes 139 has been developed through three-component ring transformation (TCRT) of acetophenone 2, ammonium acetate as nitrogen source 101 and dinitropyridone 139 in EtOH at 60 °C without using any catalyst (Scheme 53) [100].

Scheme 53

Synthesis of nitroarenes 139

An efficient and environment-friendly procedure has been described for the preparation of substituted cyanopyridines 141 via four-component reaction of acetophenones 2, aromatic aldehydes 75, malononitrile 83 and sodium alkoxide 140 (molar ratio 1:1:1:1.3) in ethanol or methanol under MW (Scheme 54) [76].

Scheme 54

Preparation of substituted cyanopyridines 141

A series of 2-substituted-1,8-naphthyridine derivatives 143 was synthesized by Friedlander condensation reaction of acetophenone derivatives 2 and 2-amino nicotinealdehyde 142 in refluxing methanol/water in the presence of potassium hydroxide as catalyst (Scheme 55) [101].

Scheme 55

2-Substituted-1,8-naphthyridine derivatives 143

The reaction of acetophenone 2, alkyl amines 144 and malononitrile 145 was performed in the presence of KF/basic alumina as a catalyst for the synthesis of [1, 6] naphthyridines 146 [102] (Scheme 56).

Scheme 56

Synthesis of [1, 6] naphthyridines 146

The condensation reaction of acetophenone 2 and aniline derivatives 67 in the presence of CH₃SO₃H as a catalyst in DMSO solvent for the synthesis of quinolines 147 was reported by Jiang and co-works (Scheme 57) [103].

Scheme 57

Synthesis of quinolines 147

The quinoline derivatives 148 were obtained from the three-component reaction of acetophenone 2, aldehyde 75 and aromatic anilines 67 in the presence of CeO₂–TiO₂ under solvent-free conditions (Scheme 58) [104].

Scheme 58

Synthesis of quinoline derivatives 148

Six-membered rings containing two hetero atoms

2-Methyl-2-phenyl-1,3-dithiane derivatives 150 were synthesized via the protection of acetophenone derivatives 2 with 1,3-propanedithiol 149 using the catalytic amount of yttrium triflate Y(OTf)₃ as a catalyst at room temperature (Scheme 59) [105]. The protection of carbonyl compounds played an important role during multistep syntheses in organic, medicinal, carbohydrate and drug design chemistry.

Scheme 59

Synthesis of 2-methyl-2-phenyl-1,3-dithiane derivatives 150

Wang et al. [106] studied a simple and efficient method for the synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-(1H)-ones 151 via the Biginelli-like three-component reactions of acetophenone 2, aldehyde 75 and urea 128 in the presence of FeCl₃.6H₂O under refluxing in MeCN (Scheme 60). This reaction was also performed using a variety of catalysts such as MnO₂-CNTs [107], MnO₂ [107], TiO₂-MWCNTs [108], Na-atomazed [109], sulfonic acid functionalized silica (SBA-Pr-SO₃H) [110] and ionic liquid N,N,N′,N′-tetramethylethylenediaminium-N,N′-disulfonic acid hydrogen sulfate [TMEDSA][HSO₄]₂ [111] under different conditions. The efficiency of various conditions for this reaction is compared in Table 7.

Scheme 60

Synthesis 5-unsubstituted 3,4-dihydropyrimidin-2-(1H)-ones 151

Table 7 The efficiency comparison of various catalysts in the synthesis of compound 151

The three-component condensation reaction of acetophenone 2, aromatic aldehydes 75 and thiourea 65 in the presence of inexpensive and efficient ceric ammonium nitrate (CAN) as a catalyst in PEG-400 was carried out by Singh et al. [112] to obtain 1,3-thiazine 152 with excellent yield (Scheme 61). 1,3-Thiazine and its derivatives were described as an inhibitor of Gram-negative bacteria and operated via inhibition of 4-diphosphocytidyl-2-C methyl-D-erythritol (IspE) kinase [112].

Scheme 61

Synthesis of 1,3-thiazines 152

Magar et al. [113] synthesized 4,5,8 a-triarylhexahydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-diones 153 with good-to-excellent yields via six-component reactions between acetophenone 2, aromatic aldehyde 75 and urea 128 in the presence of sulfated tin oxide (STO) as a reusable catalyst in ethanol at 60 °C (Scheme 62). Pyrimido pyrimidines have wide biological activities, such as antitumor, anti-inflammatory, antifungal and antibacterial activities [113].

Scheme 62

Synthesis of 4,5,8 a-triarylhexahydropyrimido[4,5-d]pyrimidine-2,7(1H,3H)-diones 153

A probable mechanism for the synthesis of substituted 2-aminopyrimidines 159 was shown in Scheme 58. Initially, condensation of acetophenone 2 with 3-hydroxybenzaldehyde 154 gave chalcone 155 and then reacted with carbamoyl chlorides 156 to generate carbamates intermediate 157 which can be reacted with guanidine hydrochloride 158 in the presence of NaH in N, N-dimethylformamide (DMF) to produce 2-amino pyrimidines 159 (Scheme 63) [114].

Scheme 63

Preparation of 2-aminopyrimidines 159

Thienothiophene-fused pyrimidine derivatives 161 were synthesized through the heterocondensation of acetophenone derivatives 2 with symmetric thieno[2,3-b]thiopheneo-aminonitrile 160 under the reflux condition in ethanol for 2 h (Scheme 64) [115]. Thieno[2,3-b]thiophene ring skeleton and its derivatives possess a wide range of biological activities such as antiviral, antibacterial and anticancer activities [115].

Scheme 64

Synthesis of thienothiophene-fused pyrimidine derivatives 161

Jadhav et al. synthesized the quinoxalines 164 which was generated by the reaction of acetophenone 2, succinamide 162 and aromatic amine 163 in the presence of I₂ in poly-ethylene glycol-400/water (2:1) as green solvent under microwave irradiation (Scheme 65) [116].

Scheme 65

Synthesis of quinoxalines 164

Aldol condensation of acetophenones 2 and aldehydes 75 gave intermediate chalcones 165 which were reacted with various compounds 166 to give pyrimidine derivatives 167 in 79–95% yields (Scheme 66) [117].

Scheme 66

Synthesis of pyrimidine derivatives 167

The reaction of acetophenone 2 and 2-aminobenzamidine 168 with the presence of SeO₂ as a catalyst for the synthesis of quinazolinone 169 was published by Khan et al. [51] (Scheme 67).

Scheme 67

Synthesis of quinazolinone 169

A class of 3-cyanoimidazo[1,2-a]pyridines 172 was achieved via three-component reaction of acetophenones 2, 2-aminopyridines 170, and benzyl cyanide 171 by using an MCM-41-anchored l-proline⁻ copper(I) complex [MCM-41-l-Proline-CuI] as a catalyst at 120 °C in high yields (Scheme 68) [118].

Scheme 68

Synthesis of 3-cyanoimidazo[1,2-a]pyridines 172

Synthesis of seven-membered rings

1-H-1,5-Benzodiazepine 174 was synthesized in good yields by the condensation of acetophenone 2 and phenylenediamine 173 in glycerol as a solvent in the catalyst-free condition (Scheme 69) [119]. As shown in Table 8, MIL-100 (v) [120], and amorphous mesoporous iron aluminophosphate (FeAlP-550) [121] were also used as catalysts in this reaction. Benzodiazepines and their derivatives have wide pharmacological properties such as anticonvulsant, analgesic, hypnotic, sedative and anti-depressive agents [121].

Scheme 69

Synthesis of 1,5-benzodiazepine 174

Table 8 Comparison of the efficiency of various catalysts in the synthesis of 1,5-benzodiazepine 174

Synthesis of fused heterocycle rings

A series of 5,7-diaryl-4,7-dihydrotetrazolo[1,5-a] pyrimidine derivatives 176 was obtained through the three-component reaction of acetophenones 2, aryl aldehydes 75 and 2-aminotetrazole 175 in the presence of N, N, N′, N′-tetrabromobenzene-1,3-di sulfonamide (TBBDA) as a catalyst under the solvent-free condition at 100 °C [122]. AlCl₃ was used for the synthesis of 5,7-diaryl-4,7-dihydrotetrazolo[1,5-a] pyrimidine derivatives (Table 9, entry 2) [123]. According to Table 9, the best condition was in the presence of N, N, N′, N′-tetrabromobenzene-1,3-di sulfonamide (TBBDA) as a catalyst under solvent-free at 100 °C (Scheme 70) [122].

Table 9 Comparison of different conditions in the synthesis of 5,7-diaryl-4,7-dihydrotetrazolo[1,5-a] pyrimidine derivatives 176

Scheme 70

One-pot synthesis of 5,7-diaryl-4,7-dihydrotetrazolo[1,5-a] pyrimidine derivatives 176

A class of pyrimido[1,2-a]benzimidazole derivatives 178 was synthesized from the multicomponent reaction of acetophenone derivatives 2, benzaldehyde derivatives 75 and heterocyclic amines 177 in the presence of H-ferrierite zeolite in short time and high yield (Scheme 71) [89].

Scheme 71

Synthesis of pyrimido[1,2-a]benzimidazole derivatives 178

Tris-dihydrotetrazolo[1,5-a]pyrimidine 180 was synthesized via a three-component reaction of acetophenone 2, 5-aminotetrazole 175 and trialdehyde (A15) 179 in the presence of N, N, N′, N′-tetrabromobenzene-1,3-disulfonamide (TBBDA) as a catalyst under solvent-free conditions in the excellent yield (Scheme 72) [122].

Scheme 72

Synthesis of tris-dihydrotetrazolo[1,5-a]pyrimidines 180

Qiao et al. [124] explained the synthesis of fused pyrazoles 183 through an efficient one-pot reaction of acetophenone 2, 2-phenylethynyl benzaldehyde 181 and hydrazine 182 in the presence of NaOMe under refluxing methanol (Scheme 73). The pyrazoles and their derivatives are an important class of bioactive heterocycles that display pharmaceutical properties, including anticancer agent, antipsychotic, auxin transport inhibitor and insecticidal activities.

Scheme 73

Synthesis of fused pyrazoles 183

The two-component condensation reaction of acetophenone 2 and 2-aminopyridine 173 in the presence of I₂-NH₄OAc in chloroform as a solvent was carried out by Kour et al. [125] to achieve 2-arylimidazo[1,2-a]pyridines 184 in high yield (Scheme 74).

Scheme 74

Synthesis of 2-arylimidazo[1,2-a]pyridines 184

Pyrrolo[1,2-a]quinoxalines 186 were prepared via a three-component reaction of acetophenone derivatives 2, o-phenylenediamine 173 and 2-alkoxy-2,3-dihydrofuran 185 in the presence of boron trifluorideetherate as a catalyst (Scheme 75) [126].

Scheme 75

Synthesis of pyrrolo[1,2-a]quinoxalines 186

Suresh et al. [127] worked on the multicomponent reaction of acetophenone 2, 5-aminotetrazole 175 and dimethylformamidedimethylacetal 187 in the presence of 1-butyl-3-methylimidazolium hydrogen sulfate [Bmim]HSO₄ ionic liquid to obtain fused tetrazolo[1,5-a]pyrimidine derivatives 188 in high yields (Scheme 76).

Scheme 76

Synthesis of fused tetrazolo[1,5-a]pyrimidine derivatives 188

A new series of nitrogen bridgehead [1, 2, 4] triazolo[5,1-c] [1, 2, 4] triazepine derivatives 190 was synthesized by Moustafa’s group via one-pot three-component reaction of acetophenone derivatives 2, aromatic aldehydes 75 and polyfunctionaltriazole 189 using alcoholic sodium hydroxide solution (Scheme 77) [128].

Scheme 77

Synthesis of [1, 2, 4]triazolo[5,1-c][1, 2, 4]triazepine derivatives 190

Gálvez et al. [129] reported in 2018 two-component reaction between 4-chloro acetophenone 2 and 5-chloro-2-(1H-pyrazole-5-yl)aniline 191 in acetic acid at room temperature to produce 8-chloro-5-(4-chlorophenyl)-5-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline 192 (Scheme 78).

Scheme 78

Synthesis of pyrazolo[1,5-c]quinazoline 192

The synthesis of thieno[2,3-d]pyrimidin-4-amines 195 was reported by Shi et al. [130] through a four-component reaction between acetophenone 2, formamide 193, malononitrile 83 and S₈ 194 in the presence of Na₂HPO₄ as a catalyst at 200 °C (Scheme 79).

Scheme 79

Synthesis of thieno[2,3-d]pyrimidin-4-amines

Sum et al. [131] synthesized a wide range of 1,2,3-triaroylindolizines 197 in excellent yield via the reaction of acetophenone 2 and pyridine derivatives 196 in the presence of CuBr₂ as a catalyst at 90 °C (Scheme 80).

Scheme 80

Synthesis of 1,2,3-triaroylindolizines 197

Ramesh et al. [132] accomplished the synthesis of the indolizine derivatives 199 via the reaction of acetophenone 2 and 1-(1-cyano-2,2-bis(methylthio)vinyl)pyrdin-1-ium 198 in the presence of NaH at 65 °C in high yield (Scheme 81).

Scheme 81

Synthesis of the indolizine derivatives 199

Synthesis of 2-arylbenzo[d]imidazo[2,1-b] thiazoles 202 was followed by a three-component reaction of acetophenone 2, 2-aminobenzothiazoles 200 and barbituric acids 201 in the presence of I₂ in DMSO (Scheme 82) [133].

Scheme 82

Synthesis of 2-arylbenzo[d]imidazo[2,1-b] thiazoles 202

The synthesis of 3-sulfenylimidazo[1,2-a]pyridines was studied by Hu et al. For the synthesis of 3-sulfenylimidazo[1,2-a]pyridines, the multicomponent reaction of acetophenone, 2-aminopyridine and 4-methylbenzenesulfonohydrazide was accomplished (Scheme 83) [134]

Scheme 83

Synthesis of 3-sulfenylimidazo[1,2-a]pyridines 204

Various pyridazino[4,5-b]quinolone skeletons 207 were synthesized in 40–65% yields via three-component reaction of acetophenone 2, anilines 67, enaminones 205 and hydrazine 206 in the presence of I₂ as a catalyst at 100 °C (Scheme 84) [135].

Scheme 84

Synthesis of pyridazino[4,5-b]quinolone skeletons 207

Conclusions

In this review, different types of reactions which included acetophenone as a starting material have been studied. Also, we tried to highlight the application of acetophenone as a synthon in the synthesis of various heterocyclic systems.