Current Organic Chemistry, 2009, 13, 0000-0000 1 3-Acetylindoles: Synthesis, Reactions and Biological Activities Mohamed A. Metwally,a Saad Shaaban,a Bakr F. Abdel-Wahabb and Gamal A. El-Hiti*c a Department of Chemistry, Faculty of Science, University of Mansoura, P.O. Box 23, Mansoura, Egypt b Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt c School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK Abstract: This review deals with synthesis and reactions of 3-acetylindoles as well as their biological activities. The data published over the last few years on the methods of synthesis and chemical properties of 3-acetylindoles are reviewed here for the first time. 1. INTRODUCTION perchloric acid [10,11], silicon tetrachloride and tin tetra- chloride [12]. 3-Acetylindole derivatives have been in the centre of at- Ac tention of researchers over many years due to the high prac- tical value of these compounds, in the first place, the unusu- AcCl or Ac2O ally broad spectrum of biological activities. For example, 4- N R R N (1H-indol-3-yl)-2-hydroxy-4-oxobut-2-enoic acid was useful H H as anti-HIV agent, other compounds derived from 1, R = H, Cl, OMe 2 3-acetylindoles used in the treatment of gastrointestinal, car- diovascular and CNS disorders, and also used as HIV-1 inte- Scheme 1. Ac Ac AcCl KOH N AlCl3 N MeOH/H2O N H R R 2a O O 3 R = Me, CH2Cl, Ph 4 Scheme 2. grase inhibitors. Despite this importance, 3-acetylindoles Treatment of 1-acylindoles (3) with acetyl chloride in the have not been previously reviewed. The main purpose of this presence of AlCl3 as a catalyst gave the corresponding 1- review is to present a survey of the literature on 3- acyl-3-acetylindoles 4 (Scheme 2) in 76-97% yields. Hy- acetylindole's chemistry and provides useful and up-to-date drolysis of 4 (R = Me) with KOH in aqueous MeOH pro- data for medicinal chemists. duced 3-acetylindole (2a; Scheme 2) [13]. Ethyl indole-2-carboxylates (5) were reacted with acetic 2. METHODS OF SYNTHESIS acid in the presence of trifluoroacetic anhydride (TFAA) and 2.1. Friedel-Crafts Acetylation phosphoric or polyphosphoric acid (PPA) to produce ethyl 3- acetylindole-2-carboxylates 6 (Scheme 3) [14]. 3-Acetylindoles (2) were prepared by Friedel-Crafts ace- Friedel-Crafts acetylation of 1-(phenylsulfonyl)indoles tylation of indoles (1) with acetyl chloride (AcCl) or acetic (7) with acetic anhydride or acetyl chloride in the presence anhydride (Ac2O) in the presence of a catalyst (Scheme 1). of aluminium chloride gave 3-acyl-1-(phenylsulfonyl)indoles Various catalysts were used in acetylation of indoles, such as 8 (Scheme 4). Base hydrolysis converted 8 to 3-acylindoles 9 diethyl aluminium chloride [1,3], PPh3-HClO4 (TPP) [4], (Scheme 4) in 79-96% yields [15]. Indium trichloride and indium triflate [5], tin tetrachloride Heating N-acetoacetylindole (10) with acetic anhydride [6], AlCl3 [7], zinc chloride [8], vinyl acetate or styrene [9], afforded 1-acetoacetyl-3-acetylindole (11; Scheme 5) which on hydrolysis with 5% NaOH gave 2a in ca. 13% yield [16]. Treatment of methyl N-alkyl-2-indole carboxylates 12 *Address correspondence to this author at the School of Chemistry, Cardiff with a mixture of trifluoroacetic anhydride, glacial acetic University, Main Building, Park Place, Cardiff CF10 3AT, UK; Tel: --------- acid and 85% H3PO4 in acetonitrile gave the corresponding -; Fax: ------------; E-mail: methyl N-alkyl-3-acetyl-2-indole carboxylates 13 (Scheme 1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. 2 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. Ac R1 R1 AcOH CO2Et CO2Et TFAA/H3PO4 N N R R 5 R = H, PhCH2, R1 = H, Cl, OMe 6 Scheme 3. Ac Ac Ac2O or AcCl base R R R N AlCl3 N N O O H S S O O Ph Ph 7 8 9 R = H, 6-OMe, 5-OMe, 5-F Scheme 4. Ac Reaction of an equimolar mixture of 2,4,4,5,5- pentamethyldioxolanium perchlorate and indole (1a) in ace- Ac2O tic acid followed by hydrolysis with 5% HCl gave 2a in 51% N N yield [19]. Ac Ac 2.2. Grignard Reactions O O 10 11 Addition of 2-(benzyloxy)acetyl chloride (17) to (1H- indol-3-yl)magnesium iodide (16) in diethyl ether afforded Scheme 5. 3-benzyloxyacetylindole (18; Scheme 8). Reduction of 18 with Raney Ni in absolute ethanol gave 2-hydroxy-1-(1H- 6) which on alkaline hydrolysis gave the corresponding N- indol-3-yl)ethanone (19; Scheme 8) in 68% yield [20]. alkyl-3-acetyl-2-indole carboxylic acids 14 (Scheme 6) [17]. Ac Ac O O O TFAA/AcOH KOH CO2Me CO2Me CO2H O N H3PO4/MeCN O N O N R R R 12 R = Me, Et 13 14 Scheme 6. O O MgI O OH O Et2O Raney Ni + O EtOH N Cl N N H H H 16 17 18 19 Scheme 8. Treatment of indole (1a) with acetic anhydride in the Reaction of indole (1a) with ethylmagnesium iodide in presence of formic acid afforded 3-(1-acetyl-1-hydroxyethyl) dry ether followed by reaction with acetyl chloride produced indole (15; Scheme 7). Photolysis of 15 at room temperature a mixture of 2a and 1,3-diacetylindole (20; Scheme 9) [21]. under nitrogen for 48 h gave 2a in 77% yield [18]. OH Ac Ac Me Ac 1, EtMgI Ac2O/HCO2H + N 2, AcCl N N H H N N Ac H H 1a 2a 20 1a 15 Scheme 9. Scheme 7. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 3 2.3. Hydrolysis of diacyl-4,5-dihydroimidazole or 3- Ac Ac acetoacetylindole Raney Ni Hydrolysis of both N,N'-diacyl-4,5-dihydroimidazole (21; Fig. 1) or 3-acetoacetylindole (22; Fig. 1) gave 2a N N H [22,23]. OH Ac 24 2a N O Scheme 11. Me N Me Ac 2.6. Fisher Indole Synthesis O N N Heating 3-(2-phenylhydrazono)butan-2-one (25), which H H could be obtained from diacetyl and PhNHNH2.HCl, in 21 22 polyphosphoric acid afforded 2a in 52% yield (Scheme 12) [26]. Fig. (1). Ac Me Ac 2.4. Rearrangement of 2-acetylindole PPA 2-Acetylindole (23) was rearranged to produce 2a, but in N N N very low yield, when treated with polyphosphoric acid at 100 H H °C (Scheme 10) [24]. 25 2a Ac Scheme 12. PPA Ac 2.7. From Dichlorocarbene N 100 °C N H H Addition of monochlorocarbene to indole (1a) followed 23 2a by rearrangement and hydrolysis produced 2a (Scheme 13) [27]. Scheme 10. 2.8. From Halobenzene Derivatives 2.5. Reduction of 1-hydroxymethyl-3-acetylindole Palladium catalyzed cross-coupling reaction of 3-methyl- Hydrogenation of 1-hydroxymethyl-3-acetylindole (24) 4-(tributylstannyl)isoxazole with 2-iodonitrobenzene fol- over Raney Ni in EtOH gave 2a in 82% yield (Scheme 11) lowed by reductive cyclization gave 2a [28]. Treatment of [25]. 2-bromoanilines (26) with but-3-en-2-one (27) in the pres- ence of palladium(II) chloride afforded 28 (Scheme 14). A Cl H H CHCl H Cl N N N - HCl N H H H 1a Cl Cl H Ac Cl H2O H N N N H H 2a Scheme 13. Ac Br O Br Ac PdCl2 Pd R + R R Me NH2 N N H H 26 27 28 2 R = H, 3-CO2Me, 4-CO2Me, 5-CO2Me, 5-OMe Scheme 14. 4 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. R2O O Me Me BF4 MeC(OEt)3 R1 R1 R1 PhC(OMe)3 N N N R R R 29 R, R1 = H, Me, Ph; R2 = Me, Et 30 31 Scheme 15. Ac Li COMe Cu2O MeO + NC NC N O H 32 33 2a Scheme 16. palladium (0)-assisted cyclization of 28 led to the formation Ac Ac of 3-acetylindoles 2 [29]. AlCl3 2.9. From 1,1,1-triethoxyethane N N H Acylation of 2-substituted indoles 29 with 1,1,1-triethoxyethane or 1-(trimethoxymethyl)benzene and in presence of HBF4 proceeded with high regioselectivity to 36 2a give acylindole tetrafluoroborates 30 (Scheme 15) in 45-95% Scheme 18. yields. Base catalyzed hydrolysis of 30 gave 3-acetylindoles Ac Ac 31 in the yields of 95-98% [30,31]. KF/Al2O3 2.10. From (2-isocyanobenzyl)lithium N or TBAF N Treatment of (2-isocyanobenzyl)lithium (32) with methyl H SO2CH3 but-3-enoate afforded 1-(2-isocyanophenyl)propan-2-one (33), which on treatment with cuprous oxide gave 37 2a 3-acetylindole (2a; Scheme 16) [32]. Scheme 19. 2.11. From Thioketals 2.13. From Amide Derivatives Treatment of thioketals 34 with an acidic catalyst such as 3-Acetylindole (2a) was synthesized from reaction of in- Dowex 50W in the presence of paraformaldehyde under mild dole with acetamide in the presence of phosphorus oxychlo- conditions afforded 3-acetylindoles 35 (Scheme 17) in rea- ride [37]. 6-Benzyloxy-3-acetylindole (38) was obtained sonable yields [33]. from reaction of 5-benzyloxyindole with a mixture of N,N- dimethylacetamide and phosphorus oxychloride (Scheme 20) S [38]. S Ac 2.14. From Diketone Diazonium Salts Dowex 50W, acetone The Rh(II) acetate catalyzed reaction of 3-diazo-1-(indol- paraformaldehyde N N 3-yl)propane-1,2-dione (39) produces 2a in 70% yield R R (Scheme 21). The reaction involves a Wolff rearrangement [39]. 34 R = H, Ac 35 Scheme 17. 3. PROPERTIES 2.12. Debenzylation or Desulfonylation The melting point of 3-acetylindole (2a) is 189-90 °C [40], the spectrophotometrical determination of pKa value of Debenzylation of 1-benzyl-3-acetylindole (36) using 3-acetylindole was 13.79 in 50% aq. MeOH, while, the pKb aluminium chloride in benzene or anisole gives 2a (Scheme values of 2a and 3-acetyl-N-methylindole were -1.74 and - 18) [34]. 1.53, respectively. Protonation of acylindoles took place on Desulfonylation of 1-[1-(methylsulfonyl)-1H-indol-3- the carbonyl group [41]. IR, UV, and NMR spectral data and yl]ethanone (37) proceeded using KF/Al2O3 or TBAF in dipole moments indicated that 3-acetylindole exist as an THF under reflux conditions to produce 2a (Scheme 19) equilibrium mixture of s-cis and s-trans conformers with the [35,36]. latter predominant [42,43]. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 5 Me O Me Me Cl Ph O N Me N C Cl P Cl + Me Me O POCl2 N Cl O H Cl2OP Me O Me N Me N Me O H Ph O Ph N N Me Me N Me Ac Ph O Ph O NaOH N N H H 38 Scheme 20. O While, treatment of 2a with lithium borohydride in THF O O N Me under reflux conditions gave 3-ethylindole (42; Scheme 24) N [46]. Also, reduction of 2a with diborane gave 3-ethylindole Rh(CH3COO)2 (42; Scheme 24) [47]. O N N Me Et H H 39 2a LiBH4 Scheme 21. or B2H6 N N H H 4. REACTIONS 2a 42 4.1. Reactions of Acetyl Group Scheme 24. 4.1.1. Reduction Reduction of 1-[1-(phenylsulfonyl)-1H-indol-3-yl]etha- none (43) with sodium borohydride in trifluoroacetic acid Reaction of 3-acetylindole (2a) with propanol and under nitrogen gave 3-ethyl-1-(phenylsulfonyl)-1H-indole NADPH in phosphate buffer and MgCl2 (pH 7.1) afforded (44; Scheme 25) [15]. (R)-1-(1H-indol-3-yl)ethanol (40; Scheme 22) [44]. The al- O cohol dehydrogenase from Lactobacillw kefir simultaneously Me Et catalyzed carbonyl reduction of 2a into (R)-1-(1H-indol-3- yl)ethanol (40) [45]. NaBH4 O HO N CF3CO2H N Me Me O O S S O O propanol Ph Ph 43 44 NADPH N N H H Scheme 25. 2a 40 4.1.2. Oxidation Scheme 22. Oxidation of 3-acetylindole (2a) with selenium dioxide in Treatment of 2a with lithium borohydride gave 1-(1H- pyridine or potassium permanganate gave 2-(1H-indol-3-yl)- indol-3-yl)ethanol (41) along with starting material being 2-oxoacetic acid (45; Scheme 26) [48]. recovered (Scheme 23). O O HO O O Me Me Me OH LiBH4 SeO2 or KMnO4 N N N N H H H H 2a 45 2a 41 Scheme 23. Scheme 26. 6 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. Me Br HN N O Me O Me N NH2 O N Me NH HN N N H H N H 46 47 48 Scheme 27. I O O Me N+ N+ F Cl . (BF4)22- N I2 N H H 2a 49 Scheme 28. O R N OEt O O O O N OH OEt RNHNH2 O aq. NaOH O N N N H H H 52 50 51 R = H, Ph Scheme 29. OMe O X OMe Me O OH X O N LHMDS N + N N EtO THF N N H N N HN N 2 X = H, Cl, F 53 54 Scheme 30. 4.1.3. Halogenation indol-3-yl)-2,4-dioxobutanoate (50). Cyclization of 50 with hydrazines gave the corresponding ethyl 3-(1H-indol-3-yl)- Topsentin-A (48) was prepared according to Scheme 27. 1H-pyrazole-5-carboxylates 51 (Scheme 29). Hydrolysis of Treatment of 2-bromo-1-(1H-indol-3-yl)ethanone (46), pre- 50 with aqueous sodium hydroxide afforded 4-(1H-indol-3- pared from bromination of 2a, with 1,1-dimethyl hydrazine yl)-2,4-dioxobutanoic acid (52; Scheme 29) [51,52]. gave 2-(2,2-dimethylhydrazinyl)-1-(1H-indol-3-yl)ethanone (47) which rearranged to produce 48 (Scheme 27) [49]. 3-Acetylindoles 2 were coupled with ethyl 1-(4- methoxybenzyl)-1H-tetrazole-5-carboxylate (53) in the pres- 1-(1H-Indol-3-yl)-2-iodoethanone (49) was prepared by ence of LHMDS to provide the corresponding 1-(1H-indol- reaction of 2a with elemental iodine in methanol as a solvent 3-yl)-3-hydroxy-3-(1-(4-methoxybenzyl)-1H-tetrazol-5- and in the presence of 1-(chloromethyl)-4-fluoro-1,4- yl)prop-2-en-1-ones 54 (Scheme 30) [53]. diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) as iodina- tion mediator (Scheme 28) [50]. 4.1.5. Mannich Reaction 4.1.4. Claisen Condensation Reaction of 2a with treptamine hydrochloride and para- formaldehyde gave 1-(1H-indol-3-yl)-3-(phenethylamino) 3-Acetylindole (2a) condensed with diethyl oxalate in propan-1-one hydrochloride (55; Fig. 2) as Mannich adduct. sodium methoxide at room temperature to give ethyl 4-(1H- Also its reaction with N-phenyl piperazines gave 1-(1H- 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 7 R O O H . HCl N N N N N H H 55 56 R = OMe, Cl Fig. (2). Ar Ar N N O O N N N H N Ac CH2O O F F 57 58 Scheme 31. OH Me NH O O NR2 N N H H 59 60 Fig. (3). indol-3-yl)-3-(4-arylpiperazin-1-yl)propan-1-ones 56 (Fig. Me 2) [54,55]. CN N Me Me Mannich reaction of 1-(4-fluorobenzoyl)-3-acetylindole N (57) with 1-arylpiperazine and paraformaldehyde in ethanol CN Ph as a solvent gave the corresponding Mannich bases identified O as 1-[1-(4-fluorobenzoyl)-1H-indol-3-yl]-3-(piperazin-1-yl) N N propan-1-ones 58 (Scheme 31) [56]. H H Mannich reaction of 2a, paraformaldehyde and l-nore- 61 62 phedrine in 2-propanol as a solvent afforded 3-(1-hydroxy-1- phenylpropan-2-ylamino)-1-(1H-indol-3-yl)propan-1-one Fig. (4). (59; Fig. 3) [57]. Also, Mannich reaction of 2a with formal- dehyde and alicyclic amines in ethanol as a solvent afforded 4.1.7. Reformatsky Reaction the corresponding 3-substituted amino-1-(1H-indol-3-yl) 3-Acetyl-1-methylindole (63) was treated with ethyl propan-1-one 60 (Fig. 3: R2 = 1-pyrrolidonyl, 1-piperidinyl, bromoacetate and Zn to give ethyl 3-(1-methyl-3- 4-morpholinyl, etc) [58]. indolyl)crotonate (64) as the only product (Scheme 32) [61]. 4.1.6. Knoevenagel Reaction Me Me O Base-catalyzed ring closure reaction of 2a with O malononitrile in the presence of high concentration of di- Zn EtO methylamine afforded 2-[1-(1H-indol-3-yl)ethylidene] N BrCH2CO2Et N malononitrile (61; Fig. 4) [59]. While, the solid state con- densation of 2a with 5-methyl-2-phenylpyrazolidin-3-one Me Me 63 64 afforded 4-[1-(1H-indol-3-yl)ethylidene]-3-methyl-1-phenyl- 1H-pyrazol-5(4H)-one (62; Fig. 4) [60]. Scheme 32. 8 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. O Me Cl O PCl5/DMF 40% NaOH/dioxane N PhCH2NMe3Cl N N H H H 2a 65 66 Scheme 33. O O Me Me Me Me MeONa MeOH N N N N H H H H 2a 67 Scheme 34. 4.1.8. Vilsmeier Reaction hydrochloride under alkaline conditions (Scheme 37) [66,67]. Treatment of 2a with the Vilsmeier complex, phosphorus pentachloride and DMF, gave 3-chloro-3-(1H-indol-3- O Me O yl)acrylaldehyde (65) which on treatment with 40% NaOH and PhCH2NMe3Cl in dioxane as a solvent afforded 3- Ar ethynyl-1H-indole (66; Scheme 33) [62]. + ArCHO N 4.1.9. Decarbonylation H N H Treatment of 2a with sodium methoxide in methanol for 2a 73 13 h at 210 °C gave 3-methylindole, skatole (67) by cleavage and realkylation (Scheme 34) [63]. Scheme 37. 1-(2-Methyl-1H-indol-3-yl)ethanone (68) was trans- 4.1.12. Reaction with Aldehydes formed into 2,3-dimethylindole (69) by action of sodium metal in methanol (Scheme 35) [64]. 3-Acetylindole (2a) condensed with various aromatic al- dehydes to afford the corresponding chalcones 73 (Scheme O Me 38) [58,68-71]. Me O Na/MeOH Me O Me Me N N Ar H H + ArCHO 68 69 N H N Scheme 35. H 2a 73 4.1.10. Grignard Reaction 2-(1H-Indol-3-yl)propan-2-ols 71 were synthesized from Scheme 38. N-protected 3-acetylindoles (70) by reaction with methyl Aldol condensation of 2a and polymer supported 75 in magnesium bromide in THF as a solvent (Scheme 36) [65]. THF in the presence of potassium carbonate for 48 h under O Me reflux conditions produced 76 (Scheme 39). Compound 75 Me HO was first obtained from reaction of 5-(3-formyl-4- Me nitrophenoxy)pentanoic acid (74) and hydroxyethyl polysty- MeMgBr/THF rene in the presence of DIPC and DMAP in DCM at room temperature for 22 h (Scheme 39). Reduction of 76 followed N N by cyclization in the presence of hydrated SnCl2 in a mixture R R of DCM and EtOH under reflux conditions for 4 h afforded 70 71 the corresponding quinoline-N-oxide 77 (Scheme 39). Treat- Scheme 36. ment of 77 with TiCl3 at room temperature afforded quino- line derivative 78. Reaction of 78 with amines in the pres- 4.1.11. Reaction with Hydroxylamine ence of AlMe3 at room temperature afforded the correspond- ing 5-(2-(1H-indol-3-yl)quinolin-6-yloxy)pentanamides (79) 1-(1H-Indol-3-yl)ethanone oximes 72 were synthesized (Scheme 39) [72]. from reactions of 3-acetylindoles 70 with hydroxylamine 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 9 P P OH O O NO2 NO2 NO2 O O 2a O OH H N O CHO O CHO O 74 75 76 O O O -O N+ N O P O P HN 77 O HN 78 O O N NHR HN O 79 Scheme 39. HO N O O Me CHO O NH O LDA, THF 1, MsCl, Et3N, THF + N N N 2, NaOH, H2O N CHO H H H 2a 80 81 82 Scheme 40. OEt O CN Ph Me N NC CHO KOH N Ph + EtOH EtO N NH2 N H HN 83 2a 84 Scheme 41. Reaction of 3-acetylindole (2a) and oxazole-4- 4.1.13. Reaction with DMF/DMA carbaldehyde (80) in the presence of LDA in dry THF pro- duced 3-hydroxy-1-(1H-indol-3-yl)-3-(oxazol-4-yl)propan-1- Treatment of 2a with dimethylformamide/dimethylacetal one (81) which on sequential treatment with MsCl/Et3N and (DMF/DMA) gave the corresponding N-methylated product aq. NaOH gave 5-(1H-indol-3-yl)-1H-pyrrole-2-carbalde- 85 (Fig. 5; R = H) in 85% yield. While, 85 (Fig. 5; R = Me) hyde (82; Scheme 40) [73]. was obtained in 71% yield when 2a was treated with ondensation of 6-amino-2-ethoxy-5-formyl-4-phenyl- DMF/dimethylformamide-di-tert-butylacetal. Treatment of nicotinonitrile (83) with 3-acetylindole (2a) under catalytic 85 with guanidine in 2-propanol and in the presence of so- alkaline conditions gave 2-ethoxy-7-(1H-indol-3-yl)-4- dium methoxide gave 86 (Fig. 5) in 74% yield when R = H phenyl-1,8-naphthyridine-3-carbonitrile (84), the expected and 44% yield when R = Me [75,76]. Friedlaender product (Scheme 41) [74]. 10 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. H2N H Me N N O N N Me O N N N R R N N 85 86 90 Fig. (5). Fig. (8). 4.1.14. Reaction with Isatins 4.1.17. Reaction with Hydrazines, Thiosemicarbazides, Am- Condensation of 5-bromoisatin and 2a gave 3-[2-(1H- ides and Hydrazides indol-3-yl)-2-oxoethyl]-5-bromo-3-hydroxyindolin-2-one (87; Fig. 6) [77]. Thiosemicarbazone derivatives 91 were obtained from direct condensation of 2a with substituted semi and/or thiosemicarbazides in refluxing ethanol (Scheme 43). Also, 91 can be obtained from reaction of 2a with hydrazine hy- NH drate to produce 92 followed by reaction with iso and/or O thiocyanates (Scheme 43) [83]. HO Reaction of 2a with hydrazine gave 4-(2-aminophenyl) Br pyrazole (93; Fig. 9) [84-87]. It was found that condensation O of 2a with thiosemicarbazides in ethanol afforded the corre- N sponding products 94 (Fig. 9) [88]. H (6-tert-Butyl-3-pyridazinyl)hydrazine reacted with 2a in 87 toluene and in the presence of a catalytic amount of Fig. (6). 4-methylbenzenesulfonic acid to afford 3-[1-[2-(6-tert- butylpyridazin-3-yl)hydrazono]ethyl]-1H-indole (95; Fig. 9) Treatment of isatins with 3-acetylindole (2a) afforded the [89]. corresponding indolylcinchoninic acids 88 (Scheme 42) [78- 3-Dimethylamino-1-(1H-indol-3-yl)propenone (96), pre- 80]. pared from reaction of 3-acetylindole (2a) with di- 4.1.15. Reaction with 1,2-ethanthiol methoxymethyl/dimethylamine, undergoes cyclocondensa- tion with guanidine carbonate to produce 4-(1H-indol-3-yl)- 3-(2-methyl-1,3-dithiolan-2-yl)-1H-indole (89; Fig. 7) pyrimidin-2-ylamine (97; Scheme 44) [90]. was prepared from reaction of 2a with 1,2-ethanthiol [81]. OH O O Me O R2 R2 R1 + O N NH N N H H R1 2a R1 = H, Me, Ph; R2 = H, Me, Br 88 Scheme 42. Me S Treatment of acid hydrazides 98 with 2a gave the corre- sponding hydrazones 99 (Scheme 45) [91]. S 4.1.18. Reaction with Heterocycles N H The iodination-alkylation between 2a and 4-tert- 89 butylpyridine afforded the corresponding pyridinium iodide Fig. (7). 100. Reductive cyclization of 100 with lithium aluminum hydride in THF followed by acidification gave 101 (Scheme 4.1.16. Reaction with Hexamethylenetetramine 46). Hydrogenation of 101 in ethanol over palla- dium/charcoal gave cis-2-tert-butyl-1,2,3,4,6,7,12,12b- One-step condensation of hexamethylenetetramine with octahydroindolo[2,3-a]quinolizine (102; Scheme 46) along 2a in acetic acid gave 7-(3-indolyl)-1,3,5-triazaadamantane with traces of its trans-isomer [92]. (90; Fig. 8) [82]. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 11 Me S Me N N N N N (CH2)n X NH2 H N HN But H N N N N H H H 93 94 X = NMe2, NEt2, 1-pyrrolidinyl…etc; n = 2, 3 95 Fig. (9). H NH H2N N NH2 . H2CO3 N Me H2N N N Me NH O 96 97 Scheme 44. H NH O NHNH2 O Me O N N R R + Me N N Ph H N Ph 98 R = H, Me 2a 99 Scheme 45. O I- N+ N N 1, LiAlH4/THF H2 2, H+ N Pd/C N N H H H H H 100 101 102 Scheme 46. N Ph O O I- HN N+ O NH 103 104 Fig. (10). Reaction of 2a with isoquinoline gave 2-[2-(3-indolyl)-2- O O NC oxoethyl]isoquinolinium iodide (103; Fig. 10) [93]. While, Me Me EtO P CN treatment of isoquinoline with 2a and benzoyl chloride gave the corresponding isoquinoline derivative (104; Fig. 10) OEt CN [94]. LiCN N N H H 4.1.19. Reaction with Organophosphorous Compounds 2a 105 Treatment of 3-acetylindole (2a) with diethyl phosphoro- cyanidate and lithium cyanide gave the corresponding 3-(1- cyanoethyl)-1H-indole-2-carbonitrile (105; Scheme 47) [95]. Scheme 47. 12 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. CN CN R R CO2Me NaH N N CN CO2Me Me Me NH2 106 107 R = Me, CO2Me Scheme 48. Treatment of 2-cyano-3-indoleacetonitrile (106) with Treatment of 3-[(benzylthio)vinyl]indole (111), synthe- acetylene carboxylates afforded the corresponding 1-amino- sized from 3-thioacetylindole (110) on treatment with NaH 4-cyanocarbazoles 107 (Scheme 48) [95]. and benzyl chloride in THF, with dimethyl but-2-ynedioate Also, it was found that reaction of 2a with diethyl cyano- gave dimethyl 4-(benzylthio)-9H-carbazole-1,2-dicarboxy- phosphonate in the presence of lithium cyanide can produce late (112; Scheme 49) [98]. diethyl 2-cyano-3-(1-cyanoethyl)-1H-indol-1-yl-1-phospho- 4.1.22. Miscellaneous Reactions nate (108; Fig. 11) [95,96]. Me The N-protected diazoacetylindole 114 was readily syn- CN thesized from 113 using the modified diazo transfer proce- dure (Scheme 50). Rhodium(II) acetate catalysed decomposi- CN tion of 114 in boiling acetonitrile gave tert-butyl 3-(2- N methyloxazol-5-yl)-1H-indole-1-carboxylate (115), which on O treatment with sodium methoxide in methanol/THF gave 5- P EtO (1H-indol-3-yl)-2-methyloxazole (116; Scheme 50) [99,100]. OEt 108 (S)-1-[5-(1H-Indol-3-yl)oxazol-2-yl]-N,N-dimethyl-2- Fig. (11). phenylethanamine (117; Fig. 14) was synthesized by aza- Wittig reaction of (S)-N-phthaloylphenylalanyl chloride and 4.1.20. Allylation iminophosphorane derived from
-azidoacetylindole [101]. Allylation of 2a with allylboronic acid under standard Two-step reaction of 3-acetylindole (2a) and 3-(1,1- conditions gave homoallylic amine (109; Fig. 12) which can ethylenedioxyethyl)pyridine gave 1-((12bS)-1,2,3,4,6,7,12, easily isolated in high yield through simple acid–base extrac- 12b-octahydroindolo[2,3-a]quinolizin-3-yl)ethanone (118; tion [97]. Fig. 14) [102]. Me Rhodanine derivative, (E)-2-[5-[1-(1H-indol-3-yl)ethyl- H2N idene]-4-oxo-2-thioxothiazolidin-3-yl]acetic acid (119; Fig. 14), was prepared from condensation of rhodanine-3-acetic acid with 2a in the presence of 1,8-diazabicyclo[5.4.0]undec- 7-ene [103]. N H Treatment of the dianion of 3-acetylindole 120 with ben- 109 zophenone and diethylmalonic dichloride resulted in the Fig. (12). production of 4-(diphenylmethylene)-6,6-diethylcyclo- 4.1.21. Reaction with Lawesson’s Reagent oct[cd]indole-3,5,7(1H,4H,6H)-trione (121; Scheme 51) [104]. Reaction of 2a with Lawesson’s reagent gave 1-(1H- indol-3-yl)ethanethione (110; Fig. 13) [98]. 4.2. N-Substitution S Me 4.2.1. N-Alkylation Alkylation of 2a with alkyl halides (MeI, EtI, H2C=CHCH2Br, PhCH2 Br) in the presence of lithium cya- N nide in THF as a solvent afforded the corresponding N-alkyl H 110 indoles 122 (Fig. 15) [105,106]. Fig. (13). H S Ph N MeO2C CO2Me S N CO2Me H CO2Me 111 112 Scheme 49. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 13 N2 O O Me LiHMDS, THF, -78°C N CF3CO2CH2CF3, MsN3, Et3N N Boc Boc 113 114 Me Me N N O O Rh(OAc)2 MeONa MeCN N THF/MeOH N H Boc 115 116 Scheme 50. Me S S O N N N O OH O NMe2 O N H Me N H H N H 117 118 119 Fig. (14). O- Ph -O Et O Ph Me Et Ph Ph Ph O Ph HO O O O Cl Me O Ph2CO + H+ O Cl 2 Li+ N N - H+ N N H 120 121 Scheme 51. Ac presence of 4-acetamidobenzenesulfonyl azide, gave ethyl 2- diazo-3-(1-methyl-1H-indol-3-yl)-3-oxopropanoate (123; Scheme 52) [107,108]. N N-Alkylation of 2a with the appropriate 2-bromoalkyl R chloride (n = 1, 2) gave the corresponding chloro derivatives 122 R = Me, Et, H2C=CHCH2, PhCH2 124, which gave the corresponding azides 125 on reaction with sodium azide in DMSO (Scheme 53). Heating 125 in Fig. (15). bromobenzene at 180 °C, in a sealed metal reactor, afforded Acylation of 3-acetyl-1-methylindole (63) with ethyl 126 (Scheme 53) [109,110]. cyanoformate followed by diazo transfer reaction, in the N2 O O Me CO2Et 1, LHMDS, THF, DMPU, EtO2CCN 2, ArSO2N3, Et3N, MeCN N N 63 Me 123 Me Scheme 52. 14 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. Ac Ac Ac Ac NaH/DMF NaN3, DMSO PhBr + BrCH2(CH2)nCl NH N N N N H Cl N3 ( )n ( )n ( )n 2a 124 125 126 Scheme 53. Ac Ac HO O Cl RONa/ROH OH N + AcO N AcO OAc O OH 127 128 129 Scheme 54. The synthesis of ribofuranosylindole (129; Scheme 54) Hydrolysis of 2-[(3-acetyl-1H-indol-1-yl)methoxy]ethyl involved alkylation of the sodium salt of 3-acetylindole 127, acetate (130), prepared from condensation of 2a with (2- obtained from 2a on treatment with NaH in MeCN, with 1- acetoxyethoxy)methyl bromide, gave 1-{1-[(2-hydroxy- chloro-2,3,5-tri-O-acetyl-D-ribose (128). Removal of pro- ethoxy)methyl]-1H-indol-3-yl}ethanone (131; Scheme 55) tecting group was easily achieved on treatment with sodium [112]. alkoxide [111]. N-Alkylation of 3-acetylindoles 2 with benzyl bromides Treatment of 2a with formalin in the presence of Na- gave the corresponding N-benzyl indoles 132 (Scheme 56). HCO3 afforded 1-hydroxymethyl-3-acetylindole (24; Fig. Reaction of 132 with diethyl oxalate in THF or dry sodium 16) [25]. ethoxide afforded ethyl 4-(1-benzyl-1H-indol-3-yl)-2- Ac hydroxy-4-oxobut-2-enoate (133) which on hydrolysis with NaOH/MeOH furnished the corresponding acids 134 (Scheme 56) [1]. N Condensation of 2a with bromobenzene under the Ull- mann conditions (copper (II) oxide catalyst and DMF as the OH solvent) gave 1-(1-phenyl-1H-indol-3-yl)ethanone (135; Fig. 24 17) [113]. Also, N-(4-fluorophenyl)-3-acetylindole (136; Fig. Fig. (16). 17) was synthesized from 2a and 1-fluoro-4-iodobenzene by Ac Ac MeONa Me MeOH N O N OH O O O 130 131 Scheme 55. O Ac Ac R' Br EtO2C OEt N NaH/THF R N NaH or EtONa R H 2 132 R' HO HO CO2Et CO2H O O NaOH/MeOH R N R N R' R' 133 R = H, OMe, Cl; R' = H, F 134 Scheme 56. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 15 Ac Ac Ac Ac N N N N Me N Me 135 136 137 138 F Fig. (17). an analogous Ullmann condensation procedure using copper N-Acetylation of 2a with hex-4-enoyl chloride afforded metal powder as the catalyst [114]. the corresponding amide which was converted to tetracyclic Reaction of 2a with bis(dimethylamino)methane in the silyl enol ether 143 that readily hydrolyzed to give the corre- presence of succinic anhydride and potassium carbonate af- sponding ketone 144 (Scheme 58) [99]. forded 1-{1-[(dimethylamino)methyl]-1H-indol-3-yl}etha- 4.2.3. N-Amination none (137; Fig. 17) [115]. While, N-vinyl-3-acetylindole (138; Fig. 17) was prepared from reaction of 2a with 3-Acetylindole (2a) was converted to 1-amino-3- 1-bromo-2-chloroethane in the presence of 18-crown-6 and acetylindole (145) via N-amination with NH2Cl in the pres- powdered potassium hydroxide in toluene [116]. ence of sodium hydride [118]. Also, amination of 2a with H2NOSO3H in anhydrous DMF containing KOH gave 145 4.2.2. N-Acylation (Fig. 19) [119]. Acylation of 2a with acyl halides in the presence of lith- Ac ium cyanide in THF afforded the corresponding N-acyl in- doles 4 (Fig. 18) [105]. Ac N NH2 145 N Fig. (19). R 4.24. N-Silylation O Silylation of 2a with tert-butylchlorodimethylsilane gives 4 R = Me, Et, Ph N-silylated derivative 146 (Fig. 20) [120]. Fig. (18). Ac N-Acylation of 2a with pent-4-ynoic acid generates 1-(3- acetyl-1H-indol-1-yl)but-3-yn-1-one (139). Compound 139 was readily converted to methoxime derivative 140, which N cyclized to give 1-methyl-4H-indolo[3,2,1-ij][1,6]naphthy- But Si ridin-6(5H)-one (141; Scheme 57). Compound 141 was de- Me Me hydrogenated to give 1-methyl-6H-indolo[3,2,1-ij][1,6] 146 naphthyridin-6-one (142; Scheme 57) [117]. Fig. (20). Me Me Me N OMe Ac N N MeONH2.HCl toluene 30% Pd/C C5H5N N sulfolane N N N 95% EtOH O O O O 139 140 141 142 Scheme 57. O TMSO O Ac 1, Cl Et3N H H N 2, TMSOTf N H N 3, 270 °C 2a O 144 O 143 Scheme 58. 16 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. CO2Me NHTs O O N Me I Me S Me Tl(CF3CO2)3 1, Me3SnSCH2CO2Me CuI/I2 2, TsNHNH2, 97% N N N H H H 2a 147 148 CO2Me CONH2 S Me S Me NaH NH3/MeOH N N H H 149 150 Scheme 59. Ac Ac NO2 NO2 Ac O2N N O2N N N N H H H H 151 152 153 154 Fig. (21). NO2 Ac NH2 N2Cl Ac Ac TiCl3 HCl KI MeOH NaNO2 N N N H H H 154 155 156 O OMe O OMe I Me Ac O S Ac S HS OMe NH4OAc N Pyridine-MeOH MeOH N N H H H 157 158 159 Scheme 60. 4.3. Ring Reactions Cu2+, Al3+, and Fe2+ salts yielded 3-nitroindole (153; Fig. 21), 3-acetyl-4-nitroindole (154; Fig. 21) and 3-acetyl-6- 4.3.1. Halogenation nitroindole (152; Fig. 21), respectively [123]. 3,5-Dihydro-3-methyl-2H-thiopyrano[4,3,2-cd]indole-2- Catalytic reduction of 3-acetyl-4-nitroindole (154) with carboxamide (150) was prepared starting from 2a through TiCl3 in methanol gave 4-amino-3-acetylindole (155) which intermediates 147, 148 and 149 via multi-steps reaction gave the corresponding diazonium salt 156 on treatment with (Scheme 59) [121]. nitrous acid at low temperature (Scheme 60) [124]. Treat- ment of 156 with KI gave the corresponding 4-iodo deriva- 4.3.2. Nitration tive 157 (Scheme 60) [123]. Compound 158 was produced 3-Acetylindole (2a) reacted regioselectively with from 157 via displacement of iodine at position 4 with thio- NO2BF4 in the presence of SnCl4 to produce 3-acetyl-5- acetate. Treatment of 158 with ammonium acetate in acetic nitroindole (151; Fig. 21) or 3-acetyl-6-nitroindole (152; acid afforded dehydrochuangxinmycin (159), the dehydrate Fig. 21), depending on the temperature of the reaction [122]. derivative of the antibiotic alkaloid chuangxinmycin, in ex- Nitration of 2a in the presence of acetonitrile solvates of cellent yield (Scheme 60) [123]. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 17 4.3.4. Acetylation 4-[5-Chloro-1-(2,6-difluorobenzyl)-1H-indole-3- carbonyl]-3-hydroxyfuran-2(5H)-one (169; Fig. 25) is useful Acetylation of 2a with AcCl/AlCl3 in PhNO2/CH2 Cl2 as HIV-1 integrase inhibitor [131]. 3-bromo-4-(4-oxo-3,4- gave mainly 3,5-diacetylindole (160) together with some dihydro-1H-carbazol-9(2H)-yl)benzamide (170; Fig. 25) is 3,6-diacetylindole (161) and 3,7-diacetylindole (162), re- useful as antiproliferative agent [55,132]. spectively (Fig. 22) [124]. F Ac Ac Ac Ac NH2 Br N O N Ac N N H H H Cl F Ac N 160 161 162 O O O Fig. (22). 4.3.5. Thallation HO O Thallation of 2a gave 163, which on treatment with KI 169 170 gave 1-(4-iodo-1H-indol-3-yl)ethanone (164; Scheme 61) [125]. Fig. (25). F3COC COCF3 Tl I 1-[3-(1H-Indol-3-yl)-5-aryl-4-(phenyldiazenyl)-4,5- Ac Ac dihydro-1H-pyrazol-1-yl]ethanones 171 (Fig. 26) showed KI anti-inflammatory activity [69]. Ph N N H H N N Ar 163 164 Scheme 61. N N Ac HN 4.4. Photolysis Irradiation of 2a in ethanol gives a mixture of 171 Ar = Ph, 4-HOC6H4, 4-Me2NC6H4, 3-MeOC6H4 4-acetylindoles (165), 6-acetyl indoles (166) and 2-acetylindoles (23), respectively (Fig. 23) by Fries type Fig. (26). rearrangement [126]. 4-(1H-Indol-3-yl)-2-(4-methoxyphenyl)-2,3-dihydro- Ac benzo[b][1,4]thiazepine (172; Fig. 27), N-{[(4-(1H-indol-3- yl)-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]thiazepin- 3-yl]methyl}aniline (173; Fig. 27) and 3-[(3-chlorophenyl) Ac diazenyl]-4-(1H-indol-3-yl)-2-(4-methoxyphenyl)-2,3-dihy- Ac N N N drobenzo[b][1,4]oxazepine (174; Fig. 27) are useful as an- H H H 165 166 23 tipsychotic agents [133]. Fig. (23). 1-(1H-Indol-3-yl)-3-hydroxy-3-(1-(4-methoxybenzyl)- 1H-tetrazol-5-yl)prop-2-en-1-ones (175; Fig. 28) are useful as HIV-1 Integrase Inhibitors [53]. 5. MEDICINAL APPLICATIONS Ribofuranosylindole 128 (Scheme 54) was found to be 4-(5-Chloro-1H-indol-3-yl)-2-hydroxy-4-oxobut-2-enoic useful as potential antiviral agents [111]. 1-(1-Methyl-1H- acid (167; Fig. 24) is useful as anti-HIV agent [127-129], indol-3-yl)-3-(4-arylpiperazin-1-yl)propan-1-ones 176 (Fig. while indole derivative 168 (Fig. 24) is used as modulators 28) showed moderate antagonism at the 5-HT3 receptor [55]. of ghrelin receptor [130]. 1-(1-(4-Fluorobenzoyl)-1H-indol-3-yl)-3-(piperazin-1- Ac O OH Cl O OH N OMe F N N H O 167 168 Fig. (24). 18 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. H H N H N N N N N N S N NH O S Cl MeO MeO MeO 172 173 174 Fig. (27). OMe N N Ar X HO O O N N N N N N H Me 175 X = H, Cl, F 176 Fig. (28). R2 N N O R1 O H Me N Me Bu HO N O O N O NH H 177 178 179 R1 = H, Me; R2 = cycloalkyl, substituted alkyl, alkanoyl, substituted alkanoyl Fig. (29). Pr Me O O HN OH HO O O N NH H N N N H H 180 181 Me 182 Fig. (30). yl)propan-1-ones 58 (Scheme 31) were found to be useful as The mineral acid salts of 3-pyridazinylhydrazone 95 (Fig. 5-hydroxytryptamine and dopamine receptor modulators in 9) was found to be active as antiviral agents and agrochemi- mice [56]. 3-(1H-indol-3-yl)butanoic acid (177; Fig. 29) or cal fungicides [90]. Indolmycin derivatives 179 (Fig. 29) its salts are useful for control of bacterial wilt (caused by showed antibacterial activity [136]. Pseudomonas solanacearum) [134]. While, the oxalate salt Rhodanine derivative 119 (Fig. 14) was found to be use- of 3-(1-butylpiperidin-4-yl)-1-(3,4-dihydro-2H-[1,3]oxazino ful as blood platelet aggregation inhibitors [103]. 3-(1- [3,2-a]indol-10-yl)propan-1-one (178; Fig. 29) was found to hydroxy-1-phenylpropan-2-ylamino)-1-(1H-indol-3-yl)pro- be useful as 5-HT4 receptor antagonists in the treatment of pan-1-one (180; Fig. 30) was found to be useful for treat- gastrointestinal disorders, cardiovascular disorders and CNS ment of heart disease at 0.1-500 mg oral doses [57]. disorders [135]. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 19 3-[2-(1H-Indol-3-yl)-2-oxoethyl]-5,6-dihydropyridin- [17] Sechi, M.; Derudas, M.; Dallocchio, R.; Dessì, A.; Bacchi, A.; 2(1H)-one (181; Fig. 30) was isolated from the marine Sannia, L.; Carta, F.; Palomba, M.; Ragab, O.; Chan, C.; Shoe- maker, R.; Sei, S.; Dayam, R.; Neamati, N. Design and synthesis of sponge Halichondria melanodocia with some applications novel indole
-diketo acid derivatives as HIV-1 integrase inhibi- [137]. While, N-[2-hydroxy-2-(1-methyl-1H-indol-3- tors. J. Med. Chem., 2004, 47, 5298-5310. yl)ethyl]butyramide (182; Fig. 30) was found to be a potent [18] Ryang, H.-S.; Sakurai, Preparation and photolysis of acyloins. inhibitors of lipid peroxidation in rat liver microsomes [138]. Acylation of pyrroles and indole. H. J. Chem. Soc., Chem. Com- mun., 1972, 77. [19] Dorofeenko, G.N.; Mezheritskaya, L.V.; Vasserman, A.L. Synthe- CONCLUSION sis of ketones by the reaction of 2-substituted dioxolanium salts with aromatic compounds. Russ. J. Gen. Chem., 1971, 41, 713; The chemistry of 3-acetylindol has exhibited promise on Chem. Abstr., 1972, 75, 35591. a number of fronts; the full evaluation of its utility in hetero- [20] Suvorov, N.N.; Kholodkovskaya, K.B.; Preobrazhenskaya, M.N. cycles synthesis was not sufficiently investigated. The aim of Indole derivatives. XXIII. 3-Indolylethylene glycol. Chem. Hetero- this review was to demonstrate the wide synthetic applica- cycl. Compd. Engl. Transl., 1965, 2, 265-270; Chem. Abstr., 1966, tion of 3-acetylindole in organic synthesis. 63, 38963. [21] Baker, J.W. Syntheses in the indole series. Part II. Derivatives of - keto--3-indolylpropionic acid. Chem. Soc., 1964, 461-463. REFERENCES [22] Bergman, J.; Goonewardena, H.; Sjoeberg, B. The N,N'-diacyl-4,5- [1] Barreca, M.L.; Ferro, S.; Rao, A.; De Luca, L.; Zappalà, M.; Mon- dihydroimidazolium ion as an electrophile. Heterocycles, 1982, 19, 297-300. forte, A.-M.; Debyser, Z.; Witvrouw, M.; Chimirri, A. Pharma- cophore-based design of HIV-1 integrase strand-transfer inhibitors. [23] Bergman, J. A simple synthesis of 3-acetoacetylindoles. Acta Chem. Scand., 1968, 22, 1063-1066; Chem. Abstr., 1970, 70, 3724. J. Med. Chem., 2005, 48, 7084-7088. [2] Wynne, J.H.; Lloyd, C.T.; Jensen, S.D.; Boson, S.; Stalick, W.M. [24] Chastrette F., Fischer [indole] synthesis and rearrangements of acetylindoles. Bull. Soc. Chim. Fr., 1970, 1151-1157. 3- Acylindoles via a one- pot , regiosel ect iv e Friedel- Craft s rReact ion. Synthesis, 2005, 2277-2282. [25] Preobrazhenskaya, M.N.; Orlova, L.M.; Alekseeva, L.M.; Suvorov, N.N. 1-Hydroxymethyl-3-acylindoles. Mendeleeva, 1967, 12, 697- [3] Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh K.; Yoshino, H. A general method for acylation of indoles at the 3-position with 698; Chem. Abstr., 1969, 69, 59026. [26] Chang, M.C.; Hsing, C.I.; Ho, T.S. Synthesis of 2-acetylindole and acyl chlorides in the presence of dialkylaluminum chloride. Org. Lett., 2000, 2, 1485-1487. its rearrangement into 3-acetylindole. Huaxue Xuebao, 1966, 32, 64-67; Chem. Abstr., 1967, 65, 56697. [4] Nagarajan, R.; Perumal, P.T. Electrophilic substitution of indoles catalysed by triphenyl phosponium perchlorate: synthesis of 3- [27] Pal, B.; Giri, V.S.; Jaisankar, P. First indium trichloride catalyzed self-addition of indoles: one-pot synthesis of indolylindolines. acetylindoles and bis-indolylmethane derivatives. Synth. Commun., 2002, 32, 105-109. Catal. Commun., 2005, 6, 711-715. [28] Uchiyama, D.; Yabe, M.; Kameyama, H.; Sakamoto, T.; Kondo, [5] Nagarajan, R.; Perumal, P.T. InCl3 and In(OTf)3 catalyzed reac- tions: synthesis of 3-acetyl indoles, bis-indolylmethane and in- Y.; Yamanaka, H. Synthesis and reactions of 4-tributylstannyl-3- methylisoxazole. Heterocycles, 1996, 43, 1301-1304. dolylquinoline derivatives. Tetrahedron, 2002, 58, 1229-1232. [6] Ottoni, O.; Neder, A.V.F.; Dias, A.K.B.; Cruz, R.P.A.; Aquino, [29] Kasahara, A.; Izumi, T.; Murakami, S.; Yanai, H.; Takatori, M. Synthesis of 3-substituted indoles by a palladium-assisted reaction. L.B. Acylation of indole under Friedel-Crafts conditions: an im- proved method to obtain 3-acylindoles regioselectively. Org. Lett., Bull. Chem. Soc. Jpn., 1986, 59, 927-928. [30] Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Condensed 2001, 3, 1005-1007. heteroaromatic ring systems. XVII. Palladium-catalyzed cycliza- tion of -(2-halophenyl)amino substituted
,-unsaturated ketones [7] Yang, C.; Patel, H.H.; Ku, Y.-Y.; Shah, R.; Sawick, D. The use of Lewis acid in the reaction of zinc salts of indoles and acyl chloride. Synth. Commun., 1997, 27, 2125-2132. and esters to 2,3-disubstituted indoles. Synthesis, 1990, 215-218. [31] Pfeuffer, L.; Sody, E.; Pindur, U. Preparation of 3-acylindoles. [8] Bergman, J.; Venemalm, L. Acylation of the zinc salt of indole. Tetrahedron, 1990, 46, 6061-6066. Triethyl orthoacetate and trimethyl orthobenzoate as effective acy- lating agents. Chemiker-Zeitung, 1987, 111, 84; Chem. Abstr., [9] Hart, G.; Liljegren, D.R.; Potts, K.T. 3-Acetylindole. J. Chem. Soc., 1961, 4267-4268. 1989, 108, 21653. [32] Pfeuffer, L.; Mueller, J.; Pindur, U. Reactions of electron-rich [10] Dorofeenko, G.N. Catalytic acetylation of some aromatic and het- erocyclic compounds in the presence of perchloric acid. Russ. J. heterocycles with derivatives of carboxylic ortho acids. Part 6. Re- action pathways and synthetic applications of 3- Gen. Chem., 1961, 31, 994-997; Chem. Abstr., 1962, 55, 130623. [11] Dorofeenko, G.N. Simple method for the preparation of some aro- indolylmethylethoxycarbenium tetrafluoroborates. Chimia, 1985, 39, 143-144; Chem. Abstr., 1987, 104, 68719. matic and heterocyclic ketones. Mendeleeva, 1960, 5, 354-355; Chem. Abstr., 1962, 54, 118161. [33] Ito, Y.; Kobayashi, K.; Saegusa, T. Indole syntheses with o-tolyl isocyanide. 3-Acylindoles and 2-substituted indoles. J. Org. Chem., [12] Yur'ev Y.K.; Elyakov, G.B. Tetraacyl hydroxy silanes in organic synthesis. VI. Silicoanhydrides of monobasic organic acids in syn- 1979, 44, 2030-2032. [34] Giri, V.S.; Sankar, P.J. Convenient procedure for dethioketalisation thesis of ketones of indole and pyrrole series. Russ. J. Gen. Chem., 1956, 26, 2350-2353; Chem. Abstr., 1960, 51, 25465. in nitrogen heterocycles. Synth. Commun., 1993, 23, 1795-1800. [35] Watanabe, T.; Kobayashi, A.; Nishiura, M.; Takahashi, H.; Usui, [13] Shner, V.F.; Sladkova, T.N.; Turchin, K.F.; Suvorov, N.N. Indole derivatives. 131. Reaction of 1-acylindoles with acetyl and T.; Kamiyama, I.; Mochizuki, N.; Noritake, K.; Yokoyama, Y.; Murakami, Y. Synthetic studies on indoles and related compounds. chloroacetyl chloride under Friedel-Crafts reaction conditions. Chem. Heterocycl. Compd. Engl. Transl., 1989, 3, 328-330. XXVI. The debenzylation of protected indole nitrogen with alumi- num chloride. Chem. Pharm. Bull., 1991, 39, 1152-1156. [14] Murakami, Y.; Tani, M.; Suzuki, M.; Sudoh, K.; Uesato, M.; Ta- naka, K.; Yokoyama, Y. Synthetic studies on indoles and related [36] Yasuhara, A.; Sakamoto, T. Deprotection of N-sulfonyl nitrogen- heteroaromatics with tetrabutylammonium fluoride. Tetrahedron compounds. XII. A simple general method for the C-3 acylation of ethyl indole-2-carboxylates. Chem. Pharm. Bull., 1985, 33, 4707- Lett., 1988, 39, 595-596. [37] Sabitha, G.; Abraham, S.; Reddy, B.V.S.; Yadav, J.S. Microwave- 4716. [15] Ketcha, D.M.; Gribble, G.W. A convenient synthesis of 3- assisted selective cleavage of sulfonates and sulfonamides in dry media. Synlett, 1999, 1745-1746. acylindoles via Friedel Crafts acylation of 1- (phenylsulfonyl)indole. A new route to pyridocarbazole-5,11- [38] Anthony, W.C. Novel synthesis of heterocyclic ketones. J. Org. Chem. 1960, 25, 2049-2053. quinones and ellipticine. J. Org. Chem., 1985, 50, 5451-5457. [16] Perekalin, V. V.; Slavachevskaya, N. M. Reactions of diketene. II. [39] Yanez, E.C.; Almanza, R.C. Rhodium(II) catalyzed Wolff rear- rangement of a carbenoid derived from an indolyl diazopropanedi- Reaction of diketene with indole and its oxygen-containing deriva- tives. Zhurnal Obshchei Khimii, 1954, 24, 2164; Chem. Abstr., one. Revista de la Sociedad Quimica de Mexico, 2004, 48, 46-48; Chem. Abstr., 2004, 141, 349998. 1959, 50, 1452-1458. 20 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. [40] Colwell, W.T.; Horner, J.K.; Skinner, W.A. Synthesis of N- [59] Dunkel, S.; Hess, U.; Reck, G. Synthesis of cyano-substituted di- containing heterocyclic compounds possessing physiological activ- and tetrahydropyridines in DIMCARB (dimethylamine CO2 ad- ity. United States Department of Commerce, Office of Technical duct). J. Prakt. Chem., 1997, 339, 414-419. Services, PB Report, 1964; Chem. Abstr., 1966, 62, 66385. [60] Du, D.-M.; Meng, S.-M.; Wang, Y.-M.; Meng, J.-B.; Zhou, X.-Z. [41] Vereshchagin, A.L.; Pogodaeva, N.N.; Semenov, A.A. Acid-base Solid state reaction of aromatic ketones with heteroaromatics. Chin. properties of indolylglyoxal and some acetylindoles. Chem. Het- J. Chem., 1995, 13, 520-524. erocycl. Compd. Engl. Transl., 1987, 12, 1621-1624; Chem. Abstr., [61] Baron, M.; De Cointet, P.; Bauduin, G.; Pietrasanta, Y.; Pucci, B. 1989, 108, 204157. Synthesis of 4-(3-indolyl)-2,5-dihydro-2-furanones. Bull. Soc. [42] Kost, A.N.; Minkin, V.I.; Budylin, V.A.; Kolodyazhnyi, Y.V.; Chim. Fr., 1979, 369-372. Druzhinina, V.V.; Yurovskaya, M.A. Steric structure of 3- [62] Suvorov, N.N.; Kamenskii, A.B.; Smushkevich, Yu. I.; Livshits, acylindoles. Chem. Heterocycl. Compd. Engl. Transl., 1982, 12, A.I. Synthesis and reactions of indol-3-ylacetylene. Zhurnal Or- 1647-1652; Chem. Abstr., 1984, 98, 125032. ganicheskoi Khimii, 1977, 13, 197; Chem. Abstr., 1978, 86, [43] Tsukerman, S. V.; Pivnenko, N. S.; Bugai, A. I.; Lavrushin, V. F. 139745. Configuration of 3-formyl- and 3-acetylindole and their N-methyl [63] Powers, J.C. General cleavage reaction of 3-substituted indoles. derivatives. J. Struct. Chem. 1971, 12, 443-446; Chem. Abstr. 1972, Tetrahedron Lett., 1965, 11, 655-658. 75, 82237. [64] Alberti, C. Transformation of indolylmethyl ketones into homologs [44] Wong, C.H.; Bradshaw, C.W. Stereospecific interconversion of of indole. Gazz. Chim. Ital., 1973, 67, 238-243. trialkylsilylethynyl
-alcohols and the corresponding ketone using [65] Witty, D.R.; Walker, G.; Bateson, J.H.; O'Hanlon, P.J.; Cassels, R. the alcohol dehydrogenase of Lactobacillus kefir. US Pat., 1993, Structure-activity dependency of new bacterial tryptophanyl tRNA 5225339; Chem. Abstr., 1994, 119, 115519. synthetase inhibitors. Bioorg. Med. Chem. Lett., 1996, 6, 1375- [45] Zhang, J.; Jiang, L.; Liu, Z. Synthesis of 1-(3'-indolyl)-3- 1380. substituted-phenyl-2-propen-1-ones. Ziran Kexueban, 1991, 21, [66] Yurovskaya, M.A.; Druzhinina, V.V.; Budylin, V.A.; Yu. Bundel, 115-117; Chem. Abstr., 1993, 116, 6364. G.; Yufit, D.S.; Struchkov, Y.T. Structure of oximes of 3- [46] Ames, D.E.; Bowman, R.E.; Evans, D.D.; Jones, W.A. New thia- acylindoles. Chem. Heterocycl. Compd. Engl. Transl., 1983, 2, zole derivatives. J. Chem. Soc., 1956, 1984. 226-229; Chem. Abstr., 1984, 99, 5473. [47] Biswas, K.M.; Jackson, A.H. Diborane as a reducing agent-II: The [67] Albini, F.M.; Oberti, R.; Caramella, P. The oximation of some 3- reduction of indole and pyrrole carbonyl derivatives. Tetrahedron, acylindoles. A convenient entry to 3-acylaminoindoles. J. Chem. 1968, 24, 1145-1162. Res. (S), 1983, 1, 4-5. [48] Beebe, X.; Nilius, A.M.; Merta, P.J.; Soni, N.B.; Bui, M.H.; Wag- [68] Piozzi, F.; Fuganti, C. Reaction between 3-acetylindole and aro- ner, R.; Beutel, B.A. Synthesis and SAR evaluation of oxadia- matic aldehydes. Annali di Chimica (Rome), 1966, 56, 1248-1258; zolopyrazines as selective Haemophilus influenzae antibacterial Chem. Abstr., 1968, 67, 73473. agents. Bioorg. Med. Chem. Lett., 2003, 13, 3133-3136. [69] Rani, P.; Srivastava, V.K.; Kumar, A. Synthesis and antiinflamma- [49] Braekman, J. C.; Daloze, D.; Stoller, C. Synthesis of topsentin-A, a tory activity of heterocyclic indole derivatives. Eur. J. Med. Chem., bisindole alkaloid of the marine sponge Topsentia genitrix. Bull. 2004, 39, 449-452. Soc. Chim. Belg., 1987, 96, 809-812; Chem. Abstr., 1989, 109, [70] Manna, F.; Chimenti, F.; Bolasco, A.; Bizzarri, B.; Filippelli, W.; 73723. Filippelli, A.; Gagliardi, L. Anti-inflammatory, analgesic and anti- [50] Jereb, M.; Stavber, S.; Zupan, M. Direct
-iodination of aryl alkyl pyretic 4,6-disubstituted 3-cyano-2-aminopyridines. Eur. J. Med. ketones by elemental iodine activated by 1-chloromethyl-4-fluoro- Chem., 1999, 34, 245-254. 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate). Synthesis, [71] El-Ahl, A.A.S.; Afeefy, H.; Metwally, M.A. Rapid entry to highly 2003, 853-858. substituted 4,5-dihydronicotinonitriles. Rev. Roum. Chim., 1997, [51] Gorbunova, V.P.; Suvorov, N.N. Indole derivatives. LXXXIX. 42, 1049-1053; Chem. Abstr., 1999, 129, 122546. Synthesis of some indole diketo esters and indolylpyrazoles pre- [72] Ruhland, T.; Kuenzer, H. Structurally diverse 2,6-disubstituted pared from them. Chem. Heterocycl. Compd. Engl. Transl., 1973, quinoline derivatives by solid-phase synthesis. Tetrahedron Lett., 11, 1519-1522; Chem. Abstr., 1975, 80, 70640. 1996, 37, 2757-2760. [52] Barrett, C.B.; Beer, R.J.S.; Dodd, G.M.; Robertson, A. J. Chem. [73] Reeves, J.T.; Song, J.J.; Tan, Z.; Lee, H.; Yee, N.K.; Senanayake, Soc., 1957, 4810. C.H. A general synthesis of substituted formylpyrroles from ke- [53] Pais, G.C.G.; Zhang, X.; Marchand, C.; Neamati, N.; Cowansage, tones and 4-formyloxazole. Org. Lett., 2007, 9, 1875-1878. K.; Svarovskaia, E.S.; Pathak, V.K.; Tang, Y.; Nicklaus, M.; Pom- [74] Quintela, J.M.; Peinador, C.; Gonzalez, L.; Iglesias, R.; Parama, A.; mier, Y.; Burke, T.R. Structure activity of 3-aryl-1,3-diketo- Alvarez, F.; Sanmartin, M.L.; Riguera, R. Piperazine N-substituted containing compounds as HIV-1 integrase inhibitors. J. Med. naphthyridines, pyridothienopyrimidines and pyridothienotriazines: Chem., 2002, 45, 3184-3194. new antiprotozoals active against Philasterides dicentrarchi. Eur. J. [54] Romeo, G.; Materia, L.; Pittala, V.; Modica, M.; Salerno, L.; Sira- Med. Chem., 2003, 38, 265-275. cusa, M.; Russo, F.; Minneman, K. P. New 1,2,3,9-tetrahydro-4H- [75] Rossignol, E.; Youssef, A.; Moreau, P.; Prudhomme, M.; Anizon, carbazol-4-one derivatives: analogues of HEAT as ligands for the F. Synthesis of aminopyrimidylindoles structurally related to me-
-1-adrenergic receptor subtypes. Bioorg. Med. Chem., 2006, 14, ridianins. Tetrahedron, 2007, 63, 10169-10176. 5211-5219. [76] Simon, G.; Couthon-Gourves, H.; Haelters, J.-P.; Corbel, B.; Ker- [55] Srinivas, P.; Subramanian, A.R.; Raghavan, S.A.V.; Jagadeesh varec, N.; Michaud, F.; Meijer, L. Towards the syntheses of N-H Babu, R.; Gupta, C.N. V.H.B.; Sridhar, N.; Veeranjaneyulu, A.; and N-alkylated derivatives of meridianins. J. Heterocyclic Chem., Parimoo, P. Structural modification from agonists to antagonists in 2007, 44, 793-801. the synthesis of new 5-hydroxytryptamine (5-HT3) receptor an- [77] Popp, F.D.; Donigan, B.E. Synthesis of 3-hydroxy-3- tagonists and preliminary in-vitro pharmacological evaluation on phenacyloxindole analogs. J. Pharm. Sci., 1979, 68, 519-520. guinea-pig ileum. Pharm. Pharmacol. Commun., 1999, 5, 95-101. [78] Nguyen M.T. Synthesis and reactions of analogs of atophan con- [56] Srinivas, P.; Subramanian, A.R.; Raghavan, S.A.V.; Jagadeesh taining the indole ring system. II. Synthesis of 2-(3- Babu, R.; Gupta, C.N. V.H.B.; Sridhar, N.; Veeranjaneyulu, A.; indolyl)cinchoninic acids. Tap Chi Hoa Hoc, 1983, 21, 27-29; Parimoo, P. Synthesis and pharmacological evaluation of Chem. Abstr., 1985, 100, 138919. arylpiperazinyl Mannich bases of 1-(4-fluorobenzoyl)-3- [79] Holmes, R.E. Cinchoninic acid derivatives. US pat., 1975, acetylindole as 5-hydroxytryptamine and dopamine receptor modu- 3870712; Chem. Abstr., 1976, 83, 9822. lators in mice. Pharm. Pharmacol. Commun., 1998, 4, 539-43. [80] Holmes, R. E. Cinchoninic acid derivatives. US pat., 1974, [57] Posselt, K.; Thiele, K. Indole aminoketones. US pat., 1975, 3799929; Chem. Abstr., 1975, 81, 13402. 3859305; Chem. Abstr., 1976, 83, 43189. [81] Andrieu, L.; Bitoun, J.; Fatome, M.; Granger, R.; Robbe, Y.; Terol, [58] El-Gendy, A.A.; Ismail, M.A.H.; El-Ansary, A.; Abdou, N.A. A.; Fernandez, J.P. Potential radioprotecting indole derivatives. I. ynthesis of some derivatives of 3-acetylindole of potential biologi- Chemistry. Eur. J. Med. Chem., 1974, 9, 449-452. cal activity. Bull. Fac. Pharm. Cairo Univ., 1990, 28, 47-51; Chem. [82] Shkulev, V.A.; Saakian, I.B.; Agadzhanyan, Ts. Ye. Synthesis and Abstr., 1993, 117, 90076. transformations of polyhedral compounds. 16. Synthesis and sev- eral reactions of 7-aroyl- and 7-heteroyl-1,3,5-triazaadamantanes. 3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 21 Chem. Heterocycl. Compd. Engl. Transl., 1952, 11, 1565-1571; multiple anion capture reactions of 1,3-dianions. Eur. J. Org. Chem. Abstr., 1994, 119, 116600. Chem., 2001, 8, 1511-1517. [83] Kassem, E.M.; Mandour, A.H. Some 3-indole derivatives with [105] Kurihara, T.; Fujimoto, T.; Harusawa, S.; Yoneda, R. Simple N- evaluation of their antimicrobial activity. Egypt. J. Chem.,1999, 42, alkylation and N-acylation of 3-acetylindole and 3- 387-401. indolecarboxaldehyde. Synthesis, 1987, 396-397. [84] Alberti, C. Reactions of involving nuclear opening and closing in [106] Ottoni, O.; Cruz, R.; Alves, R. Efficient and simple methods for the the heterocyclic series. VI. Specific effects of hydrazine hydrochlo- introduction of the sulfonyl, acyl and alkyl protecting groups on the ride and alkaline reagents on the hydrazine hydrate transformation nitrogen of indole and its derivatives. Tetrahedron, 1998, 54, of -acetylindoles to pyrazoles. Gazz. Chim. Ital., 1957, 87, 751- 13915-13928. 61. [107] Baum, J.S.; Shook, D.A.; Davies, H.M.L.; Smith, H.D. Diazotrans- [85] Alberti, C. Reactions involving nuclear opening and closing in the fer reactions with p-acetamidobenzenesulfonyl azide. Synth. Com- heterocyclic series. V. Course of the -acetylindole-pyrazole trans- mun., 1987, 17, 1709-1716. formation as a function of the experimental conditions. Gazz. Chim. [108] Davies, J.R.; Kane, P.D.; Moody, C.J.; Slawin, A.M.Z. Control of Ital., 1957, 87, 736-750. competing N
H insertion and Wolff rearrangement in dirho- [86] Alberti, C. Reactions involving nuclear opening and closing in the dium(II)-catalyzed reactions of 3-indolyl diazoketoesters. Synthesis heterocyclic series. III. Formation of 4-(o-aminophenyl) pyrazoles of a potential precursor to the marine 5-(3-indolyl)oxazole Mar- by the action of hydrazine hydrate on -acylindoles with butyric, tefragin A. J. Org. Chem., 2005, 70, 5840-5851. isobutyric, and isovaleric substituents. Gazz. Chim. Ital., 1957, 87, [109] de la Mora, M.A.; Cuevas, E.; Muchowski, J.M.; Cruz-Almanza, R. 720-728. Synthesis of tricyclic 2-aminoindoles by intramolecular 1,3-dipolar [87] Alberti, C. Transformations of indolyl methyl ketones into ho- cycloaddition of 1--azidoalkylindoles. Tetrahedron Lett., 2001, mologs of indole. II. Gazz. Chimi. Ital., 1939, 69, 568-583. 42, 5351-5353. [88] Siatra-Papastaikoudi, T.; Tsotinis, A.; Raptopoulou, C.P.; Sambani, [110] Artis, D.R.; Cho, I.-S.; Jaime-Figueroa, S.; Muchowski, J.M. Oxi- C.; Thomou, H. Synthesis of new alkylaminoalkyl thiosemicarba- dative radical cyclization of (
-iodoalkyl)indoles and pyrroles. zones of 3-acetylindole and their effect on DNA synthesis and cell Synthesis of (-)-monomorine and three diastereomers. J. Org. proliferation. Eur. J. Med. Chem., 1995, 30, 107-114. Chem., 1994, 59, 2456-2466. [89] Abdulla, R.F. Preparation of antiviral pyridazinyl hydrazones. US [111] Almerico, A.M.; Lauria, A.; Diana, P.; Barraja, P.; Cirrincione, G.; pat., 1987, 4670437; Chem. Abstr., 1988, 107, 96730. Dattolo, G. Glycosidopyrroles. Part 4. 1--D-Ribofuranosyl- [90] Fischer, P.M.; Wang, S.; Meades, C.K.; Andrews, M.J.I.; Gibson, pyrroles and indoles as potential antiviral agents. Arkivoc, 2000, D.; Darren, K. Preparation of 4-(1H-Indol-3-yl)-pyrimidin-2- 486-496. ylamine Derivatives as Protein Kinase Inhibitors and Their Use in [112] Almerico, A.M.; Barraja, P.; Diana, P.; Cirrincione, G.; Mingoia, Therapy. PCT Int. Appl. WO, 2006, 2006075152; Chem. Abstr., F.; Musiu, C.; Perra, G.; Putzolu, M.; Marongiu, M.E. Glycosi- 2006, 145, 167275. dopyrroles Part 3. Effect of the benzo-condensation on acyclic de- [91] Nguyen M.T.; Phan V.C. Synthesis of derivatives of atophan and rivatives: 1-(2-hydroxyethoxy)-methylindoles as potential antiviral analogous compounds. Tap San Hoa Hoc, 1979, 17, 25-31; Chem. agents. Farmaco, 1998, 53, 409-414. Abstr., 1981, 93, 46375. [113] Khan, M.A.; Rocha, E.K. Arylindoles. I. Synthesis of some N- [92] Gribble, G.W.; Nelson, R.B. Conformational requirements for the arylindoles. Chem. Pharm. Bull., 1977, 25, 3110-3114. existence of Bohlmann bands in the infrared spectra of indolo [2,3- [114] Subramanian, A.R.; Raghavan, S.A.V.; Veeranjaneyulu, A.; Ja- a]quinolizidines. I. Cis- and trans-2-tert-butyl derivatives. J. Org. gadeesh, R.; Babu, Gupta, C.N.V.H.B.; Parimoo, P.; Srinivas, P.A. Chem., 1973, 38, 2831-2834. A facile synthesis of N-(4-fluorophenyl)-3-acetylindole. Hetero- [93] Liljegren, D.R.; Potts, K.T. Simple synthesis of the yohimbine ring cycl. Commun., 1998, 4, 437-440. skeleton from 3-acetylindole. Proc. Chem. Soc., 1960, 340-341; [115] Love, B.E. Facile synthesis of N-dialkylaminomethyl-substituted Chem. Abstr., 1962, 55, 38054. heterocycles. J. Org. Chem., 2007, 72, 630-632. [94] Stupnikova, T.V.; Skorobogatova, Z.M. 1- [116] Abele, E.; Dzenitis, O.; Rubina, K.; Lukevics, E. Synthesis of N- Aroylmethylisoquinolines. Chem. Heterocycl. Compd. Engl. and S-vinyl derivatives of heteroaromatic compounds using phase- Transl., 1979, 12, 1662-1664; Chem. Abstr., 1981, 92, 110813. transfer catalysis. Chem. Heterocycl. Compd., 2002, 38, 682-685. [95] Kurihara, T.; Hanakawa, M.; Wakita, T.; Harusawa, S. Reaction of [117] Snyder, S.A.; Vosburg, D.A.; Jarvis, M.G.; Markgraf, J.H. In- 3-acylindoles with diethyl phosphorocyanidate. A facile synthesis tramolecular hetero Diels–Alder routes to -carboline alkaloids. of 2-cyano-3-indoleacetonitriles. Heterocycles, 1985, 23, 2221- Tetrahedron, 2000, 56, 5329-5335. 2224. [118] Hynes, J.; Doubleday, W.W.; Dyckman, A.J.; Godfrey, J.D.; [96] Kurihara, T.; Hanakawa, M.; Harusawa, S.; Yoneda, R. Synthesis Grosso, J.A.; Kiau, S.; Leftheris, K. N-Amination of pyrrole and and cycloaddition reaction of 2-cyano-3-indoleacetonitriles. Chem. indole heterocycles with monochloramine (NH2Cl). J. Org Chem., Pharm. Bull., 1986, 34, 4545-4553. 2004, 69, 1368-1371. [97] Dhudshia, B.; Tiburcio, J.; Thadani, A.N. Diastereoselective allyla- [119] Somei, M.; Matsubara, M.; Natsume, M. Preparation of N- tion and crotylation of N-unsubstituted imines derived from ke- aminoheterocycles and their reactions. Hukusokan Kagaku To- tones. Chem. Commun., 2005, 44, 5551-5553. ronkai Koen Yoshishu, 8th 1975, 219-223; Chem. Abstr., 1977, 84, [98] Murase, M.; Hosaka, T.; Koike, T.; Tobinaga, S. Sulfur-assisted 164705. synthesis of functionalized carbazoles. Chem. Pharm. Bull., 1989, [120] Langer, P.; Doering, M.; Seyferth, D. Regioselective reactions of 37, 1999-2001. ambident dianions. Part 6. Synthesis of medium-sized rings, spiro- [99] Moody, C.J.; Doyle, K.J.; Elliott, M.C.; Mowlem, T.J. Synthesis of annulated oxazacycles, and 1-amino-3-siloxy dienes based on re- heterocyclic natural products: Model studies towards diazonamide. gioselective reactions of ambident dianions. Synlett, 1999, 135-137. Pure App. Chem., 1994, 66, 2107-2110. [121] Brown, M.J.; Carter, P.S.; Fenwick, A.E.; Fosberry, A.P.; Ham- [100] Danheiser, R.L.; Brisbois, R.G.; Kowalczyk, J.J.; Miller, R.F. An precht, D.W.; Hibbs, M.J.; Jarvest, R.L.; Mensah, L.; Milner, P.H.; annulation method for the synthesis of highly substituted polycyclic O'Hanlon, P.J.; Pope, A.J.; Richardson, C.M.; West, A.; Witty, aromatic and heteroaromatic compounds. J. Am. Chem. Soc., 1990, D.R. Antimicrobial natural product chuangxinmycin and Some 112, 3093-3100. synthetic analogues are potent and selective inhibitors of bacterial [101] Fresneda, P.M.; Castaneda, M.; Blug, M.; Molina, P. Iminophos- tryptophanyl tRNA synthetase. Bioorg. Med. Chem. Lett., 2002, 12, phorane-based preparation of 2,5-disubstituted oxazole derivatives: 3171-3174. synthesis of the marine alkaloid almazole C. Synlett, 2007, 324- [122] Ottoni, O.; Cruz, R.; Krammer, N.H. Regioselective nitration of 3- 326. acetylindole and its N-acyl and N-sulfonyl derivatives. Tetrahedron [102] Mandal, S.B.; Pakrashi, S.C. Synthesis of (±)-deplancheine. Het- Lett., 1999, 40, 1117-1120. erocycles, 1987, 26, 1557-1562. [123] Murase, M.; Koike, T.; Moriya, Y.; Tobinaga, S. Nitration of 3- [103] Niigata, K.; Kageyama, T.; Yoneda, T. Rhodanine derivatives. Jpn. acylindoles in the presence of metal acetonitrile solvates and syn- Kokai Tokkyo Koho JP, 1986, 61056175; Chem. Abstr., 1987, 105, thesis of the antibiotic alkaloid chuangxinmycin. Chem. Pharm. 42785. Bull., 1987, 35, 2656-2660. [104] Langer, P.; Doring, M.; Gorls, H. Regioselective synthesis of het- [124] Hino, T.; Torisawa, Y.; Nakagawa, M. The acetylation of 3- erospirocyclic isobenzofuranones and medium-sized lactones by acylindoles. Chem. Pharm. Bull., 1982, 30, 2349-2356. 22 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al. [125] Hollins, R.A.; Colnago, L.A.; Salim, V.M.; Seidl, M.C. Thallation- indol-3-yl)carbonyl]-3-hydroxyfuran-2(5H)-ones,
-diketo acid iodination studies of heterocyclic systems. J. Heterocycl. Chem., analogs as HIV-1 integrase inhibitors. Arch. Pharm., 2007, 340, 1979, 16, 993-996. 292-298. [126] Somei, M.; Natsume, M. Photochemical rearrangements for the [132] Hanson, G.J.; Barta, T.E.; Geng, L. Preparation of indole and car- syntheses of 3-, 4-, and 6-substituted indoles. Tetrahedron Lett., bazole derivatives as antiproliferative agents. PCT Int Appl, WO, 1973, 27, 2451-2454. 2007, 035620; Chem. Abstr., 2007, 146, 379821. [127] Fujishita, T.; Yoshinaga, T. Preparation of indole derivatives with [133] Bajaj, K.; Srivastava, V.K.; Lata, S.; Chandra, R.; Kumar, A. Syn- antiviral activity. PCT Int. Appl. WO, 1999, 9950245; Chem. thesis of some new benzothiazepinyl- and benzoxazepinyl indoles Abstr., 2000, 131, 271806. as antipsychotic agents. Indian J. Chem., 2003, 42B, 1723-1728. [128] Burke, T.R.; Zhang, X.; Pais, G.C.G.; Svarovskaia, E.; Pathak, [134] Matsuda, K.; Toyoda, H.; Yoshida, T.; Harada, S.; Sakamoto, H.; V.K.; Marchand, C.; Pommier, Y. Aroyl(hydroxy)propenoic acids Ishiguro, Y. Indole derivative for control of bacterial wilt. Jpn. Ko- as HIV integrase inhibitors. PCT Int. Appl. WO, 2003, 049695; kai Tokkyo Koho JP, 1995, 07228502; Chem. Abstr., 1996, 123, Chem. Abstr., 2003, 139, 36342. 332733. [129] Selnick, H.G.; Hazuda, D.J.; Egbertson, M.; Guare, J.P.; Wai, J.S.; [135] Francis, K.D.; Mary, G.L.; Raymond, M.K. 5-HT4 Receptor an- Young, S.D.; Clark, D.L.; Medina, J.C. Preparation of nitrogen- tagonists. PCT Int Appl WO, 1994, 9427987; Chem. Abstr., 1996, containing 4-heteroaryl-2,4-dioxobutyric acids useful as HIV inte- 122, 187597. grase inhibitors. PCT Int Appl WO, 1999, 9962513; Chem. Abstr., [136] Dirlam, J.P. Antibacterial 2-amino-oxazolinones and process there- 2000, 132, 22866. fore. US pat., 1986, 4584385; Chem. Abstr., 1988, 106, 5006. [130] Burstein, E.; Eeg Knapp, A.; Olsson, R.; Eskildsen, J.; Ek, F. Bi- [137] Gopichand, Y.; Schmitz, F.J. Two novel lactams from the marine cyclic nitrogen compounds as modulators of ghrelin receptor and sponge Halichondria melanodocia. J. Org. Chem., 1979, 44, 4995- their preparation, pharmaceutical compositions and use in the 4997. treatment of diseases. PCT Int Appl WO, 2007, 079239; Chem. [138] Iakovou, K.; Varvaresou, A.; Kourounakis, A.P.; Stead, K.; Abstr., 2007, 147, 166196. Sugden, D.; Tsotinis, A. Design, synthesis and biological evalua- [131] Ferro, S.; Barreca, M.L.; De Luca, L.; Rao, A.; Monforte, A.M.; tion of novel beta-substituted indol-3-yl ethylamido melatoninergic Debyser, Z.; Witvrouw M.; Chimirri, A. A. New 4-[(1-benzyl-1H- analogues. J. Pharm. Pharmaco., 2002, 54, 147-156.