Current Organic Chemistry, 2009, 13, 0000-0000 1 1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. 3-Acetylindoles: Synthesis, Reactions and Biological Activities Mohamed A. Metwally, a Saad Shaaban, a Bakr F. Abdel-Wahab b 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 3-Acetylindole derivatives have been in the centre of at- tention of researchers over many years due to the high prac- tical value of these compounds, in the first place, the unusu- ally broad spectrum of biological activities. For example, 4- (1H-indol-3-yl)-2-hydroxy-4-oxobut-2-enoic acid was useful as anti-HIV agent, other compounds derived from 3-acetylindoles used in the treatment of gastrointestinal, car- diovascular and CNS disorders, and also used as HIV-1 inte- grase inhibitors. Despite this importance, 3-acetylindoles have not been previously reviewed. The main purpose of this review is to present a survey of the literature on 3- acetylindole's chemistry and provides useful and up-to-date data for medicinal chemists. 2. METHODS OF SYNTHESIS 2.1. Friedel-Crafts Acetylation 3-Acetylindoles (2) were prepared by Friedel-Crafts ace- tylation of indoles (1) with acetyl chloride (AcCl) or acetic anhydride (Ac 2 O) in the presence of a catalyst (Scheme 1). Various catalysts were used in acetylation of indoles, such as diethyl aluminium chloride [1,3], PPh 3 -HClO 4 (TPP) [4], Indium trichloride and indium triflate [5], tin tetrachloride [6], AlCl 3 [7], zinc chloride [8], vinyl acetate or styrene [9], *Address correspondence to this author at the School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK; Tel: --------- -; Fax: ------------; E-mail: perchloric acid [10,11], silicon tetrachloride and tin tetra- chloride [12]. N H R N H R Ac 2 AcCl or Ac 2 O 1, R = H, Cl, OMe Scheme 1. Treatment of 1-acylindoles (3) with acetyl chloride in the presence of AlCl 3 as a catalyst gave the corresponding 1- acyl-3-acetylindoles 4 (Scheme 2) in 76-97% yields. Hy- drolysis of 4 (R = Me) with KOH in aqueous MeOH pro- duced 3-acetylindole (2a; Scheme 2) [13]. Ethyl indole-2-carboxylates (5) were reacted with acetic acid in the presence of trifluoroacetic anhydride (TFAA) and phosphoric or polyphosphoric acid (PPA) to produce ethyl 3- acetylindole-2-carboxylates 6 (Scheme 3) [14]. Friedel-Crafts acetylation of 1-(phenylsulfonyl)indoles (7) with acetic anhydride or acetyl chloride in the presence of aluminium chloride gave 3-acyl-1-(phenylsulfonyl)indoles 8 (Scheme 4). Base hydrolysis converted 8 to 3-acylindoles 9 (Scheme 4) in 79-96% yields [15]. Heating N-acetoacetylindole (10) with acetic anhydride 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 with a mixture of trifluoroacetic anhydride, glacial acetic acid and 85% H 3 PO 4 in acetonitrile gave the corresponding methyl N-alkyl-3-acetyl-2-indole carboxylates 13 (Scheme R = Me, CH 2 Cl, Ph N O R N O R Ac KOH MeOH/H 2 O N H Ac 3 4 2a AcCl AlCl 3 Scheme 2.