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To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem

Overview on the chemistry of 1-(4-substituted aminophenyl) ethanones Part(I) Moustafa. A. Gouda, *1, 2 Mohamed H. Helal, 3, 4 Ahmed Ragab, 3 Ghada G. El-Bana, 5 Mohammed A. Salem, 3, 6 1Department of Chemistry, Faculty of Science and Arts, Ulla, Taibah University, KSA 2Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, 35516, Mansoura, Egypt 3Department of Chemistry, Faculty of Science, Al-Azhar University, 11284 Nasr City, Cairo, Egypt 4Department of Chemistry, Faculty of Arts and Science, Northern Border University, Rafha, KSA. 5 laboratory Department, Blood Bank, Student hospital, Mansoura University, El-Gomhoria Street, 35516, Mansoura, Egypt 6Department of Chemistry, Faculty of Arts and Science, King Khalid University, Mohail Assir, KSA [email protected]*, [email protected], [email protected]. Abstract: This review presents a systematic and comprehensive survey of the method of preparation and the chemical reactivity of 1-(4-substituted-aminophenyl) ethanones. The target compounds are important intermedi-ates for the synthesis of a variety of synthetically useful and novel heterocyclic systems with different ring sizes such as thiophene, oxazole, triazole, pyrimidine, pyridine, quinolone, coumarin, imidazopyrimidine, pyridoimidazole and triazolo[1,5-a] pyridine. Keywords: 1-(4-Substitutedaminophenyl)ethanones, Heterocyclic, Thiazole, Pyridine, 2- aminothiophenes Introduction There is no review summarizing the literature on the synthesis and chemistry of 1-(4- substitutedaminophenyl)ethanones. This review therefore aims to cover the work on the synthesis and reaction of 1-(4-substitutedaminophenyl) ethanone. 4-Aminophenylethanone, 1 has been a key starting material for the synthesis of formyl-substituted 5-aryl-2,2'-bithiophenes as new precursors for nonlinear optical (NLO) materials [1], 4-amino-5,6-diaryl-furo[2,3-d]pyrimidines as potent glycogen synthase kinase-3 inhibitors [2], 1-phenyl-3-{4-[(2E)-3-phenylprop-2- enoyl]phenyl-thiourea and urea derivatives with anti-nociceptive activity [3], and methane analogues of rofecoxib [4]. Furthermore, 4-Phenylmorpholine derivatives are showing anti-inflammatory [5, 6], central nervous system [5], and antimicrobial activities [5], antidiabetic [7], antiemetic [8], platelet aggregation inhibitors, antihyperlipo-proteinemics [7], bronchodilators, growth stimulats [9], and [10]. Synthesis

Hydrolysis of 1-ethynyl-4-nitrobenzene 2 with water in presence of AuBr3 [11], 2, 2, 2- trifluoroethanol [12], or cetyltrimethylammonim / isopropyl gave 4- aminoacetophenone 1[13]. Furthermore, treatment of N-(4-acetylphenyl)-acetamide 3 with aqueous sodium hydroxide in afforded 4-aminoacetophenone [14] (Scheme 1). Moreover, reaction of triisopropylsilyl- 4-acetylphenylcarbamate 4 with tetrabutyl ammonium fluoride in tetrahydrofuran [15]. Also, hydrolysis of 5, 5, 6, 6, 7,7, 8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 12-heptadecafluoro-2-methyl-dodecan-2-yl-4- acetylphenylcarbamate 5 with trifluoroacetic acid in [16].

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To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem

In addition, hydrolysis of (E)-1-(4-((4-(3, 3, 4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 10- heptadecafluorodecyl)phenyl(phenyl) methylene amino)-phenyl)ethanone 6 or 1-(4- (diphenylmethylene-amino) phenyl) ethanone 7 with hydrogen chloride in tetrahydrofuran afforded 4-aminoacetophenone 1 (Scheme 1) [17, 18].

Reagents and conditions: (i) H2O /AuBr3 (ii) H2O / 2, 2, 2-trifluoroethanol (iii) H2O /cetyltrimethylammonim bromide/ (iv) NaOH(aq) /MeOH,(v) tetrabutyl ammonium fluoride in tetrahydrofuran (vi) trifluoroacetic acid / dichloromethane(vii) hydrogen chloride/ tetrahydrofuran. Scheme 1. Synthesis of 4-aminoacetophenone Treatment of 2, 2, 2-trichloroethyl- 4-acetylphenylcarbamate 8 with indium and ammonium chloride in [19], or tert-butyl-4-acetylphenylcarbamate 9 [20], with water gave compound 1. Also, hydrolysis of 1-(4-(tert-butyldimethylsilylamino) phenyl)ethanone 10 with silica gel in ethanol/water [21], or 1-(4-(triethylsilylamino) phenyl) ethanone 11 with water afforded compound 1[22] (Scheme 2). Acid catalyzed hydrolysis of 1-(4-aminophenyl)-1-methoxyethanol 12 with phosphate buffer in water or 4-(1,1-dimethoxyethyl) -mine 13 with hydrogen chloride in water afforded the 4-amino- 1[23] (Scheme 3). Tao, C.-Z. et al., [24] reported a catalytic method to synthesized 4-aminoacetophenones from the 1-(4-bromo(iodo) phenyl)ethanones 14 under mild conditions using 2,2,2-trifluoroacetamide was used as ammonia surrogate, thus stirring of 1-(4-bromo (iodo)phenyl)ethanones with 2,2,2-trifluoroacetamide in the presence of CuI/N,N'-dimethyl ethylenediamine as catalyst in methanol/ water achieved the 4-aminoacetophenone (Scheme 2). Furthermore, Thakur, K. G. et al., report the using of CuI/D- glucosamine as an efficient catalyst for synthesis of 4-aminoacetophenone 1, thus, cross-coupling reaction between 1-(4-bromo(iodo)-phenyl)ethanones 14 and aqueous ammonia in presence of CuI, D-glucosamine and carbonate in a mixture of /water afforded the 4- aminoacetophenone [25] (Scheme 2).

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The cross-coupling reaction between 1-(4-bromo(iodo)phenyl)-ethanone 14 and aqueous ammonia was efficiently catalyzed by the sulfonato–Cu (salen) complex in water with high yields, thus Coupling of 1-(4-bromophenyl)ethanone 14 or 1-(4-iodophenyl) ethanone 14 with aqueous ammonia in water in the presence of sodium hydroxide and in the presence of N,N'-bis(5- sulfonatosalicylidene)-1,2-diaminoethane]-copper disodium as acatalyst afforded the aminoacetophenone 1 [26] (Scheme 2). The copper(I) bromide/1-(5, 6, 7, 8- tetrahydroquinolin-8-yl)-2-methylpropan-1-one (CuBr-L3) combination catalyzed the cross- coupling reactions between 1-(4-bromo(iodo)phenyl)ethanone 14 and aqueous ammonia in dimethylsulfoxide in the presence of with high yields to produce compound 1 at room temperature or under mild conditions [27]. Furthermore coupling of 4- iodoacetophenone 14 with tetramethylstannane and in presence of tris-(o-tolyl) and tris(dibenzylideneacetone)dipalladium (0) in dimethylsulfoxide gave 1[28] (Scheme 2).

H Cl N Cl O O Cl H N O CH3 O O CH H3C 3 O 8 CH3 H3C O 9 H C X i 3 H C ii H CH3 3 O N Si CH3 CH 14 vi,vii,viii,ixor.x H C 3 iii 3 H3C 10 v O H3CO NH2 NH 2 H3C H3C 1 ii CH3 OCH3 H O N CH 13 Si 3 iv H C HO H3C 3 NH2 11 H3C OCH3 12

Reagents and conditions: (i) indium, ammonium chloride in ethanol (ii) H2O (iii), silica gel EtOH/H2O

(iv) H2O / phosphate buffer (v) H2O /HCl (vi) a-NH2COCF3.CuI, b-CH3OH/H2O, (vii) a-(2R,3S,4R,5S)-

3-amino-6-(hydroxymethyl)-tetrahydro-2H-pyran-2,4,5-triol,CuI, K2CO3/CH3COCH3, H2O,(viii) N,N'- bis(5-sulfonato-salicylidene-1,2-diaminoethane]copper disodium salt, ammonia, sodium hydroxide

/ H2O (ix) copper(I) bromide/1-(5,6,7,8-tetrahydroquinolin-8-yl-2-methylpropan-1-one, ammonia,

K3PO4 / H2O/dimethyl sulfoxide (x) tetramethylstannane/carbomonoxide. Scheme 2. Synthesis of 4-aminoacetophenone. Reduction of 1-(4-nitrophenyl)ethanone 15 with hydrogen in methanol [29], ethanol [30], di sodium ethylenediamine tetra acetic acid and iron(II) sulfate/ water [31], NiRh3 in ethylacetate [32], ethylacetate [33], tetrahydrofuran [34], afforded the 4-aminoacetophenone. Furthermore, 4- aminoacetophenone 1 was prepared via reduction of 1-(4-nitrophenyl)ethanone 15 with sodium tetrahydroborate/tin (ll) chloride in ethanol, [35] hydrazine hydrate in ethanol [36], or tris(triphenyl- phosphine)-ruthenium(II) chloride, and zinc in 1,4-dioxane [37] (Scheme 3). Carole Guyon et al., [38] reported that reduction of 1-(4-nitrophenyl)ethanone 15 by hypophosphites catalyzed by Pd/C under biphasic 2-MeTHF/water solvent mixture afforded 4- aminoacetophenone 1 in addition to 4-ethylaniline 16 as a co-product [38] (Scheme 3).

Furthermore, hydrogenation of 4-nitroacetophenone (4-NAP) 15 and 4-aminoacetophenone (4- AAP) 1 was examined over rhodium/silica catalysts. The reactions were carried out using isopropanol as a solvent under arrange of temperatures (303–333 K) and pressures (1–5 barg). It was observed that 1-(4-nitrophenyl)ethanone 15 underwent rapid hydrogenation of the NO2

23 To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem group to form 1-(4-aminophenyl)-ethanone 1, followed by hydrogenation of the carbonyl group to give 1-(4-aminophenyl)ethanol 16, before ring saturation to give 1-(4-aminocyclohexyl)ethanol 17 and 4-ethylbenzenamine 18. Under selected conditions high selectivity and yield to either 1- (4-aminophenyl)ethanone 1 (99%) or 1-(4-aminophenyl)-ethanol 16 (94%) was achievable [39] (Scheme 3).

Reagents and conditions: (i) H2, methanol (ii) H2, ethanol (iii), H2, disodiumethylene- diaminetetraacetic acid/ FeSO4/H2O (iv) H2, NiRh3 / ethylacetate (v) H2 / ethylacetate (vi) H2 / tetrahydrofuran/ H2O (vii) sodium tetrahydroborate/tin (ll) chloride/ethanol (viii) hydrazine hydrate / ethanol (ix) tris(triphenyl-phosphine)-ruthenium(II) chloride, potassium hydoxide, zinc /1,4- dioxane (x) Pd/C, NaH2PO2.H2O, 2-MeTHF, H2O, sonication (xi) H2/ rhodium/silica/ isopropanol. Scheme 3. Synthesis of 4-aminoacetophenone. Treatment of 1-(4-azidophenyl)ethanone 20 with ammonium hydroxide [40], samarium diiodide in tetrahydrofuran [41], BnEt3N]2MoS4 in water/cetonitrile [42], MoO2[S2CNEt2]2 and phenylsilane in [43] , sodium sulfide in methanol [44] , or ammonium formate and zinc in methanol [45], gave 4-aminoacetophenone 1(Scheme 4). Reaction of (E)-1-(4- aminophenyl)ethanone oxime 21 with toluene-4-sulfonic acid in neat [46], sodium periodate and silica gel in [47], perchloric acid, dihydrogen peroxide, potassium bromide and hexaammonium heptamolybdate tetrahydrate in water,[48] sulfuric acid in 1,4-dioxane and water [49], afforded 4-aminoacetophenone 1(Scheme 4). Oxidation of 1-(4-aminophenyl)ethanol 22 with silica-supported Jones reagent in dichloromethane[50], N-bromosuccinimide and cycloheptaamylose in methanol/ water [51], tert -butyl hydrogen peroxide, and Co(0.137)Fe3O4(0.863) in water [52], tert -butyl hydrogen peroxide in water [53], Fe2O3 and

24 To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem hydrogen peroxide in water, [54], or phen, iron (III) acetylacetonate and in toluene [55], gave 4-aminoacetophenone 1(Scheme 4). Moreover reduction of bisacetyl 23 with aminomethyl polysterene resin formic acid salt, zinc in methanol [56], or polystyrene-CH2-NH3(+)HCO2(-) and magnesium in methanol [57] afforded 4- aminoacetophenone 1(Scheme 4). Oxidation of 4-(2-methyl-1,3-dithian-2-yl)benzenamine 24 with dihydrogen peroxide, iodine and sodium lauryl sulfate in water [58], 2, 4, 4, 6-tetrabromo- 2,5-cyclohexadien-1-one and dihydrogen peroxide in water / [59], or tetrabutyl ammonium fluoride in tetrahydrofuran [60], afforded 4-aminoacetophenone 1(Scheme 4). Friedel-Crafts acetylation of aninline 25 with acetyl chloride in presence of Zinc metal gave 1[61]. Furthermore, Fries rearrangement of N-phenylacetamide 26 with aluminium trichloride under microwave irradiation[62], ytterbium trifluoromethane-sulfonate and lithium perchlorate in nitromethane [63], or zinc (II) chloride in acetic anhydride [64], achieve compound 1(Scheme 4).

S S OH CH3 CH3 H2N 24 NH2 H2N 22 xviii, xix or xi,xii,xiii,xiv or xv 25 xxi xx O O N OH i,ii,iii,iv,v,or vi vii,viii,ix or x CH CH CH3 3 3 H N H N N3 O 2 1 2 20 xxii,xxiii or xxiv 21 H3C xvi or xvii H N CH3

N N O 26 23 O

H3C

Reagents and conditions: (i) NH4OH, (ii) samarium diiodide/ tetrahydrofuran, (iii) [BnEt3N]2MoS4 / water, acetonitrile, (iv) MoO2[S2CNEt2]2, phenylsilane / toluene, (v) methanol/ sodium sulfide, (vi) ammonium formate, zinc/ methanol, (vii) toluene-4-sulfonic acid, (viii) sodium periodate, silica gel in solid, (ix) perchloric acid, dihydrogen peroxide, potassium bromide, hexaammonium heptamolybdate tetrahydrate in water, (x) sulfuric acid in 1,4-dioxane, water, (xi) silica-supported Jones reagent in dichloromethane, (xii) N-Bromosuccinimide, cycloheptaamylose in methanol, water, acetone, (xiii) tert -butyl hydrogen peroxide, Co(0.137)Fe3O4(0.863) in water, (xiv)tert - butyl hydrogen peroxide in water, (xv) Fe2O3, hydrogen peroxide in water(xvi) aminomethyl polysterene resin formic acid salt, zinc in methanol, (xvii) polystyrene-CH2-NH3(+)HCO2(-), magnesium in methanol, (xviii) dihydrogen peroxide, iodine, sodium lauryl sulfate in water, (xix), 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one, dihydrogen peroxide in water, acetonitrile (xx) 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one, dihydrogen peroxide in water, acetonitrile, (xxi) CH3COCl/Zn (xxii), AlCl3 (xxiii), ytterbium trifluoromethanesulfonate, lithium perchlorate in nitromethane (xxiv), acetic anhydride/ zinc(II) chloride.

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Scheme 4. Synthesis of 4-aminoacetophenone 1. 1-(4-Morpholinophenyl)ethanone 29 was synthesized from 4-floroacetophenone 27 by using classical neucleophilic substitution of morpholine 28 with 4-floroacetophenone 27 in dimethyl sulphoxide and in the presence of potassium carbonate [65] (Scheme 5). Furthermore, Soni, R. et al., prepared asires from aminoacetophenone 29, 33-35 via heating of p-fluoroacetophenone 27 with aqueous amine in a sealed pressure tube [66] (scheme 5).

Scheme 5. Synthesis of 4-aminoacetophenones 29 and 33-35. REACTIVITY 4-aminoacetophenones 1, 29 and 33-35 are difunctional compounds possessing nucleophile and electrophilic properties. Typical electrophile position is CO (C1).

Furthermore, C2 of CH3 and N at position 3 could act as nucleophiles. These chemical properties have been used to design different heterocyclic moieties such as oxazole, pyrazole, thiophene, thiazole, pyridine, diazepine, oxazepine, and pyrimidine (Fig. 1). 1 3 2 R O N C CH3 R Fig. 1: Reactivity of 4-aminoacetophenones 1, 29 and 33-35. Reduction A symmetric transfer hydrogenation (ATH) of 4-aminoacetophenone 29 and 33-35 under aqueous conditions using tethered Ru(II)/η6-arene/diamine catalysts gave the corresponding 36a- d (scheme 6) [66].

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Scheme 6. Asymmetric reduction of ketones 29, 33-35 with tethered Ru(II)/TsDPEN catalysts Halogenation Bromination of p-aminoacetophenone 1 with in acetic acid afforded the dibromoaniline 37 in 74% yield. Subsequently diazotation of 37 in the presence of Cu powder in refluxing EtOH gave 3, 5-dibrominateted acetophenone 38.This, brominated by bromine in Et2O at rt to the corresponding 39, which was substituted by sodium azide at 0 0C in MeOH to the azide 40. Compound 40 was reacted with 4-(ethylsulfonyl)-2-isocyanato-1-methoxybenzene 41 in the presence of PPh3 in DCM at rt to give the oxazole 42 and urea derivative 43 as a side product. Final products 46 and 47 were synthesized from aminoxazole 42 each in one step by either Stille reaction with Bu3Snpy-2-yl 44 or Suzuki reaction with (HO)2Bpy-3-yl 45, respectively. Both coupling reactions were carried out in the presence of (PPh3)4Pd. Compound 49 was prepared in two independent Stille coupling reaction steps. First aminoxazole 42 was transformed to compound 48 with Bu3Snpy-2-yl 45 and subsequently 48 converted to compound 49 by reaction of 48 with Bu3Snpy-3-yl 45[67] (scheme 7).

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Reagents and conditions: (i) Br2, AcOH (ii) NaNO2, Cu powder/EtOH (iii), Br2, Et2O (iv) NaN3, MeOH (v) PPh3 in DCM (vi) Bu4NBr, (PPh3)4Pd (vii) (viii) Bu4NBr, (PPh3)4Pd / py-2-ylSnBu3. Scheme 7. Synthesis of pyridine derivatives 46-49. Chen, J. M. reported a facile one-pot preparation of polystyrene-supported (dichloroiodo) benzene (loading of -ICl2 up to 1.35 mmol/g) 51 from polystyrene, iodine, and bleach, which use

28 To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem inchlorination of 4-aminoacetophenone 1 giving 1-(4-amino-2- chlorophenyl)ethanonehydrochloride 52 [68] (scheme 8).

Reagents and conditions: (i)a- I2, I2O5, H2SO4, PhNO2, CCl4 reflux, 24 h, b- NaOCl (5%), HCl, H2O, rt, 0 12 h, (ii) a- Py, CH2Cl2, 0 C, 3 h, b- HCl, dioxane. Scheme 8. Synthesis of 1-(4-amino-2-chlorophenyl) ethanonehydrochloride 52. Thiazole derivative 53 was achieved via the condensation of ethanone derivative 29 with thiourea in presence of iodine, acetylation of 2- aminothiazole 53 with acetic anhydride on refluxing afforded N, N-(diacetyl)aminothiazole 54, furthermore, condensation of compound 53 with 4- methylbenzaldehyde in refluxing ethanol and in the presence of a catalytic amount of piperidine resulted in the formation of the imino derivative 55[69] (scheme 9). O Ar Ar S ii S CH Ar S iii N 3 N NH2 N CH3 N N O 53 54 55 i

O N N Ar = O CH3 O 29

Reagents and conditions: (i) I2, thiourea, fusion, (ii) acetic anhydride,(iii) 4-methylbenzaldehyde, piperidine /ethanol,reflux. Scheme 9. Synthesis of 2-aminothiazole s 54 and 55. Acylation Bai, H. et. al., synthesized Fluorescent polarity probe 58 for identifying bovine serum albumin, starting by acetylation of 1 with acetyl chloride in dichloromethane followed by Claisene Schmidt condensation of the formed N-(4-acetylphenyl)acetamide 56 with 6-(diethylamino)-2-oxo-2H- chromene-3-carbaldehyde 57 in ethanol in the presence of pyrrolidine [70] (scheme 10).

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O

O O

i H3C N 1 O CH3 ii H O H3C N O H Et O N Et 56 N Et H 58 Et O O 57

Reagents and conditions: (i) CH3COCl/CH2Cl2 (ii) EtOH/pyrrolidine. Scheme10. Synthesis of synthesized Fluorescent polarity probe 58 Brembilla, A. et al., prepared poly 3,4-diamino-styrene 66, in seven steps via, acetylation of p- aminoacetophenone 1 with acetic anhydride, nitration of the formed N-(4- acetylphenyl)acetamide 56 with nitric acid to the nitro derivative 59, this hydrolyzed with dil. H2SO4 to the 4-amino-3-nitro-acetophenone 60, reduction of 60 with sodium boronhydride to the ethanol 61 which, dehydrated with hexamethylphosphoramide to the corresponding aminonitrostyrene 62, reduction of 62 with sodium sulphide gave the diaminostyrene 63, compound 63 was prepared in another rout via reduction of the 3,4-diaminoacetophenone 64 with sodium boronhydride , followed by dehydration of the formed 1-(3,4-diaminophenyl)1- ethanol 65, with hexamethylphosphoramide. Polymerization of the diamimostyerne 63 gave the desired poly diaminostyrene 66 [71] (scheme 11).

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Reagents and conditions: (i) Ac2O, (ii) HNO3, (iii) dil.H2SO4, (iv) NaBH4, (v) H MPT,

(vi) Na2S.9H2O, (vii) polymerization on mass, solution, suspension or emulsion. Scheme 11. Synthesis of poly 3,4-diamino-styrene 66 2-aminoacetophenone 1 was converted to 2-hydroxyacetophenone 67 by acetylation, bromination and hydroxylation with . Subsequent reaction with malononitrile in the presence of diethylamine led to furan 68 which was treated with triethylorthoformate, followed by amination and cyclization with sodium ethoxide, giving 4-amino-5-(4-acetamidophenyl)- furo[2,3-d]pyrimidine 69. After removal of the acetyl group, 70, was treated with various isocyanates to provide the corresponding urea derivatives 71[72] (scheme 12).

1 1 1 1 71a; R = 2-F-5-CF3-Ph, 71b; R = 3, 5-Di- CF3-Ph, 71c; R = 3-Phenoxy-Ph, 71d; R = 3- CF3-Ph, 71e 1 1 1 1 ; R = 2-Cl-5- CF3-Ph, 71f; R = 2-F-5-OMe-Ph, 71g ; R = 1-naphthyl, 71h; R = 2-naphthyl. Reagents and conditions: (i) Ac2O/toluene, (ii) Br2, AcOH, (iii) potassium formate, NaHCO3, EtOH/H2O,(iv) malononitrile, Et2NH, DMF (v) HC(OEt)3, Ac2O, (vi) NH3, EtOH/THF (vii) NaOEt, EtOH/THF, (viii) 2M

KOH, EtOH/H2O, (ix) isocyanates/ THF. Scheme 12. Synthesis of furo[2,3-d]pyrimidine 71. Aly, M. R. E. S., et al., synthesized 4'-(N-oleoylamido)chalcones 74-77 as oleoyl estroneanalogues for screening mainly as potential antiobesity agents, thus 4-aminoacetophenone 1 was treated with oleoyl chloride 72 in Et3N to afford substrate 73. Claisene Schmidt condensation of 73 with a set of aromatic aldehydes, afforded the desired chalcones 74-77[73] (Scheme 13).

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76a; R'=H, 76b; R'=OCH3, 76c; R'= CH3, 76d; R'= Cl, 76e; R'=NO2; 76f; R'=H, 76g; R'=H, 76h; R'=H. Reagents and conditions: (i) DCM, Et3N, (ii) Aldehyde, Et2O/EtOH, NaOH, rt. Scheme 13. Synthesis of 4'-(N-oleoylamido)chalcones 74-77. N-(4-acetylphenyl)-2,2,2-trifluoroacetamide 78 was obtained by refluxing p-aminoacetophenone 1 with excess amount of TFA in p-xylene, bromination of 78 with NBS in the presence of p- toluenesulfonic acid (p-TsOH) in acetonitrile afforded the corresponding N-(4-(2- bromoacetyl)phenyl)-2,2,2-trifluoroacetamide 79. This, reacted with thioureas 80 a,b under microwave conditions in isopropyl alcohol or conventionally in absolute ethanol afforded N-(4- (2-thiazol-4-yl)phenyl)-2,2,2-trifluoroacetamide derivatives 81[74](Scheme 14). Compound 79 undergoes cyclocondensation upon treatment with 2-aminothiazole 82 or 2-aminobenzothiazole 83, in ethanol or isopropyl alcohol, under thermal conditions and microwave irradiation to afford the corresponding imidazo[2,1-b]thiazole derivative 84, 2,2,2-trifluoro-N-(4-(imidazo[2,1- b]benzthiazol-6-yl)phenyl)-acetamide derivative 85 [74] (Scheme 14). Simillary, N-(4-(2- bromoacetyl)phenyl)-2,2,2-trifluoro-acetamide 79 with 2-amino-5-trifluoro-methy1,3,4- thiazdiazole 86 under thermal conditions as well as microwave irradiation in isopropyl alcohol afforded the corresponding 2,2,2-trifluoro-N-(4-(2-(trifluoromethyl) imidazo[2,1-b][1,3,4]- thiadiazol-6-yl)phenyl)acetamide 87 [74] (Scheme 14).

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81a; R=NH2, 81b; R=NHCH3, 81c; R= NHPh, 81d; R= Me .Reagents and conditions: (i) TFA/ xylene,

(ii) NBS , p-TsOH/CH3CN(iii) thioureas 80a,b and thioacetamide 80c, MW, isopropyl alcohol or EtOH , heat. Scheme 14. Synthesis of thiazole 81 and 84, 85, 87 derivatives. Furthermore, N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoro-acetamide 79 was allowed to react with some 2-aminopyridine 88a and 2-aminopyrimidine 88b under thermal as well as microwave conditions which, led to the formation of the targeted 89a and imidazopyrimidines 89b, respectively, as shown in [74] (Scheme 15). Attempts were made to obtain the 3-acylimidazo [1,2-a]pyrimidine 91 via the alternative one pot three component reaction of N- (4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroaceta-mide 79, 2-aminopyridine 88a, and dimethylformamide dimethylacetal 92 under solvent free conditions. The reaction afforded the non-carbonyl analog imidazopyrimidines 89a,b as shown in Scheme 15 [74].

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Reagents and conditions: (i) MW, isopropyl alcohol or EtOH , heat. (ii) MW/ solvent free. Scheme 15. Synthesis of imidazopyrimidine and pyridoimidazole derivative 89a,b. The carbonyl analog of the targeted 91 could be synthesized by the reaction of N, N-dimethyl-N'-(pyridin-2-yl)formimidamide 90 with N-(4-(2-bromoacetyl)phenyl)- 2,2,2- trifluoroacetamide 79 under microwave irradiation or in refluxing ethanol [74] (Scheme 16).

Reagents and conditions: (i) MW, isopropyl alcohol or EtOH , heat. Scheme 16. Synthesis of imidazopyrimidine 91 Moreover, 4-amino-3-mercapto-1, 2, 4-triazole derivatives 93a, b were reacted with 79 in isopropyl alcohol under microwave irradiation or in anhydrous ethanol under reflux afforded novel S-triazolo[3,4-b]thiadiazines 94a,b [74] (Scheme 17). Also, 2-amino-1,2,4-triazole 95 and N-(4-(2- bromoacetyl)phenyl)-2,2,2-trifluoroacetamide 79 was irradiated in isopropylalcohol under microwave or refluxed in ethanol to afforded the novel N-(4-(7H-imidazo[2,1-c][1,2,4]triazol-5- yl)phenyl)-2,2,2-trifluoroacetamide 96 [74] (Scheme 17).

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Reagents and conditions: (i) MW, isopropyl alcohol or EtOH , heat. Scheme 17. Synthesis of S-triazolo[3,4-b]thiadiazines 94a,b and imidazo[2,1-c][1,2,4]triazole 96. Sulphonation Doherty, E. M. et al., prepared 4-methylsulfonylamino) 97, from commercially available 4-aminoacetophenone 1 which, converted to the corresponding amines 98, via reductive amination of 4-aminoacetophenone 97, condensation of 98 with 4-tert-butylbenzylisothiocyanate 99 afforded the corresponding thiourea analogue 100 [75] (Scheme 18).

Reagents and conditions: (i) CH3SO2Cl, pyridine, (ii) NH2OH, pyridine, (iii) H2, Pd-C, HCl, MeOH (iv)

4-t-BuBnNCS75, CH2Cl2. Scheme 18. Synthesis of thiourea analogue 100.

Zarghi, A.,et al. [4] prepared a number of 3,4-diaryl-2(5H)furanones 104 by reaction of 4- aminoacetophenone 1 with methanesulfonyl chloride in dichloromethane in the presence of triethylamine followed by bromination of the formed 4-(methylsulfonamido) acetophenone 97 using bromine in in the presence of AlCl3 to the bromoacetyl derivative 101, condensation of 101 with 4-substituted-phenylacetic acid 102 in acetonitrile in the presence of triethylamine to give the phenacyl phenylacetate product 103, and cyclization of the esters 103,

36 To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem using NaH in DMSO [4] (Scheme 19). A series of sulfonamide chalcone derivatives 108 were synthesized via reaction of 1 with 2, 5-dichlorobenzene-1-sulfonyl chloride 105 in dichloromethane in the presence of triethylamine, followed by Claisen–Schmidt condensation of the formed sulfonamide 106 with various aryl aldehyde 107 in ethanol in the presence of sodium hydroxide [76] (Scheme 19). Furthermore, Claisen–Schmidt condensation of 4- (methylsulfonamido) acetophenone 97 with a para-substituted-benzaldehyde 109 in presence of sodium hydroxide as a catalyst afforded the 1,3-diphenylprop-2-en-1-ones 110 [77] (Scheme 19).

104a; R=H, 104b; R=OCH3, 104c; R= CH3, 104d; R= Cl, 104e; R=Br; 104f; R=F. 108a; R'=2,4- diOMeC6H3, 108b; R'=4-FC6H4, 108c; R'= 3,4-OCH2OC6H3, 108d; R'= 4-ClC6H4, 108e; R'=2,4-diClC6H3, 108f; R'=2,4-diFC6H3. 108g; R'= 3,4,5-triOMeC6H2 , 108h; R'= C6H5, 108i ; R'=4-MeC6H4 ,108j; R'= 4- OMeC6H4. 108k; Ar=C6H5, 108l; Ar=4-FC6H4, 108m; Ar =4-Me C6H4, 108n; Ar= 4-OMeC6H4. Reagents and conditions: (i) CH3SO2Cl, TEA/CH2Cl2 (ii) Br2 / CHCl3 / AlCl3 (iii) CH3CN / TEA (iv) NaH/ DMSO, (v) TEA/CH2Cl2, (vi) NaOH/ EtOH. Scheme 19. Synthesis of 3-(4-substituted-phenyl)-2(5H) furanone product 104 sulfonamide chalcone derivatives 108 and 110. Alkylation The N-aryl substituted (triazol) imidazol-1-ylmethylphenylamines 117a,b and 118a,b were prepared via a three step procedure involving a Suzuki coupling, thus, the treatment of 4- acetylphenylboronic acid 111 with aniline 112a and 2-naphthylamine 112b or the coupling of

37 To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem compound 1 with aryl boric acids 113 in presence of CuOAc/ pyridine gave the 4-aminophenyl ketones 114 (Scheme 20). Subsequent, reduction of 114 with NaBH4, MeOH/dioxane to the alcohols 115 and finally condensation of alcohols 115 with (triazol-1-yl) 2SO 116a in K2CO3/CH3CN or imidazole 116b in CDI/ CH3CN [78] (Scheme 20).

Reagents and conditions: (i) CuOAc, pyridine, 4 A ˚ molecular sieves, CH2Cl2, rt, 3 days; (ii) NaBH4, MeOH/dioxane, rt, 1–18 h; (iii) (triazol-1-yl)2SO 116a, K2CO3, CH3CN, rt, 4 days; (iv) CDI, imidazole 0 116b, CH3CN, 65 C, 1 h. Scheme 20. Synthesis of N-aryl substituted triazol- and imidazol-1-ylmethylphenylamines 117a, b and 118a, b. Cao, D. et. al., synthesized a novel, V-shaped fluorene derivative branched from triphenylamine via Cu-mediated Ullmann condensation and subsequent Pd-catalyzed Heck coupling reaction. thus coupling of 9,9-diethyl-2,7-diiodo-9H-fluorene 119 with 1 in presence of copper bronze/K2CO3 in 1, 2-dichlorobenze afforded N,N-Bis(7-iodo-9,9-diethyl-9H-fluorene-2-yl(-4- acetylaniline 120 which, coupled with N-phenyl-N-(4-vinylphenyl)benzenamine 121 in presence of reaction of tri-o-tolylpho-sphine, palladium(II) acetate, triethylamine in DMF afforded the target molecule 122[79] (Scheme 21).

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I O

CH3 N N H3C CH3 O

CH3 CH 3 ii N CH3

CH I N 3 120 CH3

i 121

I I + 1

H C CH3 3 N 119

122

Reagents and conditions: (i) copper bronze, K2CO3, 18-crown-6, 1, 2-dichlorobenze reflux; (ii) tri- o-tolylphosphine, palladium(II) acetate, triethylamine, reflux. Scheme 21. Synthesis of V-shaped fluorene derivative branched 122 from triphenylamine. N-(4-Acetylphenyl)-2-bromoacetamide 124 was prepared through treatment of p-aminoaceto- phenone 1 with bromoacetyl bromide 123 in the presence of potassium carbonate. Heating at reflux of the 1, 2, 4-triazole-3-thiol derivatives 125 [80], with N-(4-acetylphenyl)-2- bromoacetamide 124 in acetonitrile in the presence of TEA afforded the corresponding 2-((4H- 1,2,4-triazol-3-yl)thio)-N-(4-acetylphenyl)acetamides 126, which converted to the corresponding oximes 127 upon reacting with hydroxamine in boiling ethanol 127 [81] (Scheme 22).

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Reagents and conditions: (i) K2CO3/H2O/CHCl3, (ii) TAE/CH3CN, (iii) NH2OH.HCl /EtOH,127a; R=allyl, Ar =Ph, 127b; R=allyl, Ar = 4-OCH3C6H4, 127c; R=allyl, Ar =3,4-diOCH3C6H3, 127d; R=allyl, Ar =3,4,5-triOCH3C6H2, 127e; R= Et, Ar =Ph; 127f; R=Et, Ar = 4-OCH3C6H4, 127g; Et, Ar =3,4- diOCH3C6H3, 127h; R=Et, Ar =3,4,5-triOCH3C6H2 ,127i; R= Ph, Ar =Ph, 127j; R=Ph, Ar = 4-OCH3C6H4, 127k; R=Ph, Ar = 3,4-diOCH3C6H3, 127l; R=Ph, Ar = 3,4,5-triOCH3C6H2. Scheme 22. Synthesis of 1, 2,4-triazole derivatives. Treatment of 128 with 4-aminoacetophenone 1 afforded 4-(4-acetylanilino)-8- methoxy(hydroxy)-2-phenylquinoline 129 which, reacted with NH2OR' to give exclusively (E)- oximes 130 [82] (Scheme 23). Furthermore, 4-aminoacetophenone 1 condensed with 4-chloro-7- trifluoromethylquinoline 131 in boiling ethanol to give the corresponding aminoquinoline derivative 132, that also, reacted with hydroxylamine hydrochloride in ethanol to form the corresponding oxime 133 [83] (Scheme 23). In addition, Chen, Y. L. et. al., prepared a series from 4-anilinofuro[2,3-b]quinoline derivatives 136 via reaction of 3,4-dichloro-7- methoxy(hydroxy)furo[2,3-b]quinoline 134 with 4-aminoacetophenone 1, and declorination of the formed 1-[4-(3-chloro-7-methoxyfuro[2,3-b]quinolin-4-ylamino)phenyl]ethanone 135 via reaction with hydrogen in the presence of Pd/C in methanol [84] (Scheme 23).

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130a; R=OMe, R' =H, 130b; R=OH, R' = Me, 136a; R=OMe, 136b; R=OH. Reagents and conditions: (i) EtOH, Reflux, (ii) NH2OR', K2CO3, EtOH, reflux, (iii) EtOH, H2O, HCl reflux, (iv) H2, Pd/C, MeOH,CH2Cl2 . Scheme 23. Synthesis of quinoline derivatives 130,133 and 136. Sharma, M. et. al. synthesized a new series of N-acetyl and N-formyl-pyrazoline derivatives 141 and 142 were synthesized by reaction of 4,7-dichloroquinoline 137 with 4-aminoacetophenone 1 in EtOH, then, Claisene Schmidt condensation for the formed 4-(7-chloroquinolin-4-ylamino) acetophenone 138 with different aromatic aldehydes 139 in KOH/ MeOH and cyclocondensation reaction of the obtained [(7-chloroquinolin-4-yl)amino]chalcones 140 with hydrazine hydrate in acetic acid or hydrazine hydrate in formic acid respectively [85] (Scheme 24). Moreover, Sharma, M. synthesized amino linked pyrimidines 146 via reaction amino linked chalcones 144 with guanidine hydrochloride 145 in the presence of NaH in DMF [86] (Scheme 24).

Ar O HN HN N vi Ar N NH 145 2 Cl N Cl N 144 146

ArCHO v 143 O O HN HN CH3 ii R Cl Cl N 139 N 138 140

iii i. 1 or iv O N Cl HN N R'

Cl N Cl N

137 R 141,142

141a; R=Br, R' =H, 141b; R=Cl, R' = H, 141c; R=OMe, R'=H, 141d; R=3,4,5-triOMe, R'=H; 142a; R=Br, R' =CH3,142b; R=Cl, R' = CH3, 142c; R=OMe, R'= CH3, 142d; R=3,4,5-triOMe, R'= CH3; 146a; Ar =Ph 146b; Ar = 4-OCH3C6H4, 146c Ar = 4-OCH3C6H4 , 146d Ar=3,4,5-triOCH3C6H2, 146e; Ar =2,3,4- triOCH3C6H2, 146f; Ar =2,3-diOCH3C6H2, 146g; Ar =2,5-diOCH3C6H2,146h; Ar = 4-ClC6H4 ,146i; Ar = 2-ClC6H4, 146j; Ar = 4-SCH3C6H4, 146k; Ar = 4-i-pr-C6H4, 146l; Ar = 3-BrC6H4, 146m; Ar = 2-BrC6H4, 146n; Ar = 3-NO2C6H4 , 146o; Ar = 3-pyridinyl, 146p; Ar =2-furyl. Reagents and conditions: (i) EtOH,

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reflux (ii) KOH, MeOH, reflux (iii) a-NH2NH2.H2O/HCOOH, reflux (iv) NH2NH2.H2O.AcOH, (v) 10% NaOH /MeOH. (vi) guanidine hydrochloride, NaH / DMF. Scheme 24. Synthesis of N-acetyl and N-formyl-pyrazoline derivatives 141 and 142 and aminopyrimidines 146. Refluxing of 9-chloroacridine 147, with p-aminoacetophenone 1 gave 1-(4-(acridine-9-ylamino) phenyl)ethanone 148. This reacted with various aldehydes 149 to achieve Chalcone substituted 9-anilinoacridines 150 a-j which cyclized with urea to afford the corresponding oxazine substituted 9-anilinoacridines 151a-j [87] (Scheme 25). O O HN HN ii R CH3

RCHO N N 149 150 148 iii NH2

i. 1 O N HN Cl R

N N 147 151

151a; R =Ph 151b; R = 4-OH-3-OCH3C6H3, 151c R = 3-NO2C6H4, 151d, R =4-NO2C6H4 151e; R =3,4- diOCH3C6H2, 151f; R = 4-ClC6H4 ,151b; R = 2-ClC6H4, R=CH3. Reagents and conditions: (i) 2-BuOH, (ii) EtOH /10% NaOH (iii) urea. Scheme 25. Synthesis of oxazine substituted 9-anilinoacridines 151a-j. Kraege S. et. al., found that combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2), thus the substituted 4-chloroquinazolines 157 and 158 were prepared via reaction of anthranillic acid 152 with formamide and anthranillic acid 153 with aromatic aldehyde 154, followed transformed into 4-anilinoquinazolines 159 and 160 by reaction with 4-aminoacetophenone 1. Finally, Claisene Schmidt condensation of the ketones 159 and 160 with different benzaldehydes 161 and 162, using LiOH. H2O as a catalyst, led to formation of the desired quinazoline-chalcones 163 and 164[88] (Scheme 26).

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1 2 5 6 1 2 5 6 1 2 5 6 163a; R , R = H; R , R = OCH3, 163b; R , R = H; R = OCH3, R = H, 163c; R , R = OCH3; R , R = OCH3, 1 2 5 6 3 4 5 6 3 4 5 6 163d; R , R = OCH3; R = OCH3, R = H, 164a; R , R = H; R , R = OCH3, 164a; R , R = H; R = OCH3, R = 3 4 5 6 3 4 5 6 3 4 3 5 6 H, 164a; R , R = H; R = H, R = OCH3, 164a; R , R = H; R = H, R = H, 164a; R , R = OCH ; R , R = 3 4 5 6 3 4 5 6 3 4 OCH3, 164a; R , R = OCH3; R = OCH3, R = H, 164a; R , R = OCH3; R = H, R =OCH3, 164a; R , R = 5 6 0 OCH3; R , R = H. Reagents and conditions: (i) fusion, 150 C; (ii) DMF, I2, K2CO3; (iii) POCl3, 9 h, 0 reflux, (iv) isopropanol, reflux, (v) LiOH. H2O, MeOH, microwave (120 W, 100 C), 30 min. Scheme 26. Synthesis of quinazoline-Chalcones 163 and 164.

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Triazine analogs 167 were formed by nucleophilic substitution of cyanuric chloride 165 with p- aminoacetophenone 1 in acetone at room temperature followed by treatment with of the formed triazine 166 appropriate secondary amines using K2CO3 in dry DMF[89] (Scheme 27). The acetophenones 167a and 167b were further reacted with 3, 4, 5-trimethoxy benzaldhyde 168 under Claisen-Schmidt condition resulting in the Chalcone derivatives 169a and 169b. Furthermore cyclization of Chalcones with hydrazine hydrate in glacial acetic acid resulted in the pyrazoline derivatives 170a and 170b [89] (Scheme 27). The enaminones 171a and 171b were prepared from the reaction of 167a and 167b with DMF-DMA. Compounds 171a and 171b were then reacted with hydrazine hydrate or hydroxylamine hydrochloride in absolute ethanol to afford 172a, b and 173a, b respectively. Additionally, a series of diarylpyrazoles 175 was prepared via the reaction of enaminone 171a and 171b with appropriate phenylhydrazine hydrochlorides 174 in absolute ethanol to yield the pyrazoles 175a-d [89] (Scheme 27).

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1 1 1 175a; R = piperdinyl. R =H, 175b; R= morphinyl, R = H, 175c; R=piperidinyl, R = SO2CH3, 175d; 1 R=morphinyl, R =SO2CH3. Reagent and Conditions: (i) Acetone, 1 h, RT; (ii) various amines, K2CO3, DMF, (iii) methanol, KOH, (iv) hydrazine hydrate, glacial acetic acid, reflux (v) DMF-DMA, (vi) hydrazine hydrate, absolute ethanol, reflux (vii) hydroxylamine HCl, EtOH, reflux (viii)phenyl hydrazine HCl derivatives, EtOH, reflux. Scheme 27. Synthesis of diarylpyrazoles 175a-d. Reductive amination Mathew, S. C., et al., developed a novel protocol for the synthesis of adenosyl fentanyl 183 via reductive amination of 1-phenethylpiperidine-4-one 176 with 4-aminoacetophenone 1, next the formed secondary amine was subjected to propionylation to provide 178; further reductive amination of 178 with ammonium acetate and sodium cyanoborohydride gave amine 179. Coupling between the amine 179 and acid 180 gave 182, which undergo acetal deprotection by using aqueous trifluoroacetic acid to give adenosyl fentanyl 183[90] (Scheme 28).

Reagent and Conditions: (i) NaBH(OAc)3, AcOH, DCE, rt; (ii) propionyl chloride, Et3N, DCM, reflux, (iii) NH4OAc, NaBH3CN, MeOH, 50 °C, (iv) BOP, Et3N, THF (v) H2O/TFA. Scheme 28. Synthesis of adenosyl fentanyl 183. Vilsmeier–Haack–Arnold (VHA) Vilsmeier–Haack–Arnold (VHA) reaction of 4-aminoacetophenone 1 gave β-chloroβ- arylacroleins 184. Compound 184 was converted to the arylthienyl-ethanones 185 through condensation with sodium sulfide Na2S.9H2O, in DMF in the presence of and K2CO3 at 60 0C. The second VHA reaction on arylthienyl-ethanones 185 gave compounds 186. Finally,

45 To Chemistry Journal Vol 7 (2020) ISSN: 2581-7507 https://purkh.com/index.php/tochem condensation of compound 186 with sodium sulfide, using the same experimental conditions described above gave the bisthiophenes 187 [1] (Scheme 29). Mannich reaction Mannich reaction of 1, with Formaldehyde and 5-phenyl-4-(phenylamino)-4H-1, 2, 4- triazole-3-thiol 188 in ethanol afforded the corresponding Mannich base 189 [91] (Scheme 29). O CH3 Cl Cl S ii iii S CHO CHO

H2N H2N 184 185 H N N N 2 186 Ph N SH i O NH i Ph O N N 188 CH3 S 1 S H Ph S H2N iv N NH Ph 189 187

Reagent and Conditions: (i) POCl3 / DMF / 60 °C, (ii) Na2S.9 H2O / DMF , ClCH2COCH3 / K2CO3, (iii) Na2S.9 H2O / DMF,ClCH2CHO / K2CO3 , (iv) CH2O/ EtOH . Scheme 29. Synthesis of 5-formyl-5'-(4-substituted-phenyl)-2, 2'-bithiophenes 187 and Mannich base 189.

Conclusion The data considered in this review evident that many of 4-aminoacetophenones are used as a key intermediate for synthesis of some heterocyclic compounds which, possess a wide range of pharmacological properties . References. [1] Herbivo, C.; Comel, A.; Kirsch, G.; Raposo, M. M. M. Tetrahedron, 2009, 65(10), 2079-2086.. [2] Miyazaki, Y.; Maeda, Y.; Sato, H.; Nakano, M.; Mellor, G. W. Bioorg. Med. Chem. Lett., 2008, 18, 1967-1971. [3] dos Santos, L.; Lima, L. A.; Cechinel-Filho, V.; Corrêa, R.; de Campos Buzzi, F.; Nunes, R. J. Bioorg. Med. Chem. Lett., 2008, 16, 8526-8534. [4] Zarghi, A.; Rao, P. P.; Knaus, E. E. Bioorg. Med. Chem. Lett., 2007, 15, 1056-1061. [5] Panneerselvam, P.; Nair, R. R.; Vijayalakshmi, G.; Subramanian, E. H.; Sridhar, S. K. Eur. J. Med. Chem., 2005, 40, 225-229. [6] Dorn, C. P.; Hale, J. J.; Mac Coss, M.; Mills, S. G. U.S. patent 5691336: 82; C. A. 1997, 128, 48231 [7] Manfred, R.; Michael, M.; Robert, S.; Wolfgang, G. 1H and 13C NMR spectra of N-substituted morpholines. Eur. pat. appl. Ep. 334146. C. A. 1989, 112, 178999.

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