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A simple strategy for the synthesis of some 2-substituted melatonin derivatives using p-anisidine as starting material is reported. The key step is a chemoselective reduction of a cyano group in the presence of an appropriate acid anhydride by hydrogenation over Adams' catalyst or with sodium borohydride in the presence of catalytic amounts of anhydrous nickel(II) chloride. The 2-substituted melatonin derivatives were obtained in six or seven steps from inexpensive p-anisidine in 9-13% overall yield.Melatonin (N-acetyl-5-methoxytryptamine) is the principle neurohormone secreted by the pineal gland. 1 Its medicinal use is restricted due to low selectivity and too broad spectrum of action. The search for melatonin analogues with greater selectivity is very important. Two subtypes (Mel1a and Mel1b) of human melatonin receptors are known. A recent molecular modeling study 2a and additional experimental data 2b have shown that melatonin derivatives with bulky substituents at position 2 exhibited a greater affinity for Mel1b melatonin receptors than for Mel1a receptors. In the case of halogens, 2-bromomelatonin 3 is more selective and exhibits a greater affinity for Mel1b receptors than 2-iodomelatonin, a useful ligand for both melatonin receptor subtypes. 2-Chloromelatonin, proposed to have a much greater selectivity, has been previously mentioned as a low-yield product of direct chlorination of melatonin. 4 In this study, we report a simple strategy for the synthesis of 2-chloromelatonin and 2-oxo-2,3-dihydromelatonin, and derivatives, in good overall yield.Cyano compound 2 was prepared as a mixture of stereoisomers via Knoevenagel condensation of 5-methoxyisatin (5-methoxyindoline-2,3-dione, 1) with cyanoacetic acid using the method of Pietra 5 (Scheme 1). It has been previously reported that hydrogenation of compound 2 in the presence of palladium on carbon led to a selective reduction of the carbon-carbon double bond. 6 We have found that the use of the less expensive reduction system zinc dust-aqueous hydrochloric acid resulted in a high yield of compound 3. The key compound for further synthesis, (5-methoxy-2-oxoindolin-3-yl)acetonitrile (4), was prepared via decarboxylation of acid 3 in 2-ethoxyethanol (Scheme 1).Cyano compound 4 was hydrogenated using Adams' catalyst (PtO 2 ) in a mixture of acetic acid and acetic anhydride at room temperature and atmospheric pressure. 2-Oxo-2,3-dihydromelatonin (5) was obtained in high yield (Scheme 2). Scheme 2(2-Chloro-5-methoxy-1H-indol-3-yl)acetonitrile (6) was prepared by refluxing (5-methoxy-2-oxoindolin-3-yl)acetonitrile (4) in phosphorus oxychloride (Scheme 3).

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