N-Ethylation of substituted ethyl 1H-indole-2-carboxylates with iodoethane and potassium carbonate gave substituted ethyl 1-ethyl-1H-indole-2-carboxylates. The later compounds on treatment with a range of aryl amines with varying structural complexity, gave the desired ethyl 1H-indole-2-carboxamide analogues.J. Heterocyclic Chem., 42, 217 (2005).In the search for new potential and safer antiarrhythmic agents, the present study focuses on the synthesis of selected novel ethyl 1H-indole-2-carboxamide analogues. A variety of antiarrhyhtmic agents (e.g. procainamide, disopyramide, lidocaine, tocainide, and flecanide) [1][2][3][4][5][6][7][8][9][10][11][12][13], containing amide functional groups have shown interesting antiarrhythmic activity [14][15][16][17][18][19][20][21].In view of the wide range of structural diversity of compounds possessing antiarrhythmic activity, efforts to determine a definitive structure have not been too successful. Even some of the more common antiarrhythmic drugs were synthesized for different purposes, when interestingly; upon routine pharmacological screening and clinical trials their antiarrhythmic activity was revealed.The first extensive reviews on the structure activity relationships of antiarrhythmic drugs were by Conn [22]. These investigations indicated that most antiarrhythmic drugs possess a tertiary amine group that appears to be a key component for activity. The aromatic ring system is important and this moiety, is usually connected to the tertiary amine via a hydroxy substituted alkyl chain typically an ester or an amide group, although methoxy groups substituted on the aromatic ring may enhance activity [23][24].Our approach into a new series of some selected analogues is based on the synthesis, chemistry and pharmacological activity of a variety of ethyl 1-ethyl-1H-indole-2-carboxamide analogues. Since the interest in amides have been growing steadily over the years for more targeted biological action [25][26][27][28][29]. This prompted us to design and evaluate a series of novel amides. Scheme 1 illustrates the synthetic approach chosen for the preparation of the amides.The first step involved the reaction of substituted ethyl 1H-indole-2-carboxylates (1a-c, Scheme 1) with iodoethane in the presence of potassium carbonate for the preparation of the desired substituted ethyl 1-ethyl-1H-indole-2-carboxylates (2a-c, Scheme 1). This reaction was exploited following initial experiments to ascertain whether it was necessary to protect the nitrogen atom. It became obvious during these studies in view of the very low yields, that protection of the nitrogen atom in the ring was most probably required to prevent any interaction during the synthesis of the desired amides.Surprisingly, there was no precedence found for this kind of reaction especially with the indole nucleus and the substituents adopted herein. However, the reaction was found to proceed smoothly and afforded the corresponding ethyl 1-ethyl-1H-indole-2-carboxylates (2a-c Scheme 1) albeit in low yields (39% -44%). Att...
