Jan-Feb 2007 Studies with Azoles and Benzoazoles: A Novel Simple Approach for Synthesis of 3-Functionally Substituted 3-Acylindoles 109 Ramadan Maawad Abdel-Motaleb a , Abdel-Moneim Abdel-Salam Makhloof a Hamada Mohamed Ibrahim a and Mohamed Hilmy Elnagdi *b a Chemistry Department; Faculty of Science; Fayoum University; Fayoum; A. R. Egypt. b Chemistry Department; Faculty of Science; Cairo University; Giza; A. R. Egypt E-mail: Shelmy@ access.com.eg Received April 25, 2006 N H ROC O COCH 3 O N NHAr CN N H R = CH 2 CN Ar N=N Cl + - O N H N N NH 2 X Ar ClCH 2 X ClCOCH 2 Cl Nu + Cl O N H N H Nu O N H R O 3-Substituted acylindoles 8 are obtained via refluxing carboxylic acids with indole in acetic anhydride solutions. The formed 3-substituted acylindole 8a is readily converted into 4-aminopyrazol-3-ylindoles 20, and into 22. Indole reacts with chloroacetyl chloride to yield: 3-chloroacetylindole 9 which could also be utilized for synthesis of a number of 3-substituted indoles. J. Heterocyclic Chem., 44, 109 (2007). 3-Substituted indoles are important heterocycles both in nature as well as pharmaceuticals [1,2]. For example tryptophane 1 and indole-3-acetaldoxime 2 participate in vital biological processes [3] while sumatriptan 3 is used for migraine treatment [4]. Fortunately 3-substituted indoles can be readily obtained by reacting indole with electrophiles under mild conditions. Thus indole readily couples at C-3 with aromatic diazonium salts [5], while C-3 acylation is conducted with acid chlorides in pyridine [6], N-acylation of indoles is generally conducted in the presence of bases [7]. In conjunction to our interest [8] in utilizing functionally susbstituted heteroaromatic ketones as precursors to functionally substituted heteroaromatics, a recent report [9] on synthesis of 3-indolyl-3- oxopropanenitrile 8a via refluxing indole with acetic anhydride and cyanoacetic acid has attracted our attention as it represents a new general synthetic route to functionally substituted acylindoles that seemed interesting as precursors to other 3-substituted indoles. We were further stimulated to utilize 8a as precursors to heteroaromatics by Slatt et al. report on the utility of 8a for synthesis of substituted indoles and heteroaryl indoles [10]. That would be of interest for biological activity evaluation. It has been found that refluxing indole 7 with organic acids 4a-e, which were preheated at 85°C for 10 minutes with acetic anhydride affords 8a-e in excellent yields. We believe that initially the organic acid is converted into the organic acid anhydride 5 or at least the mixed anhydride 6. This, being more electrophillic than acetic anhydride, reacts with indole to yield the functionally substituted acyl derivatives 8a-e. It is of value to report that compound 8d existed as indicated from 1 H nmr as an equilibrium mixture of both keto and enol form as expected for 1,3 diketone. On the other hand mixing indole 7 with chloroacetyl chloride in dioxane afforded the chloroacetylindole 9, hence, the utility of Lewis acid catalyst to promote activity as recently reported seemed to be of no value [11]. The chloroacetyl- indole 9 could be readily converted into 8a on treatment with potassium cyanide and into 10 on treatment with ammonium thiocyanate. 3-Chloroacetylindole has recently claimed to be formed from reaction with zinc salt of indole with chloroacetyl chloride in presence of ZnCl 2 [12]. However the product reported in literature is most likely an N-acetyl indole 11 as it is different in every respect from our product whose spectral data confirm that it is 3-chloroacetylindole 9 (Scheme 1). Treatment of 9 with benzotriazole 12 in toluene/triethylamine afforded a N H MeHNO 2 S N Me Me N H NH 2 COOH 1 3 2 N H NOH