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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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2,3-Dihydroindoles are promising agents for the synthesis of new compounds with neuroprotective and antioxidant properties. Usually, these compounds are obtained by direct reduction of the corresponding indoles containing acceptor groups in the indole ring for its activation. In this work, we propose a synthetic strategy to obtain new 2,3-dihydroindole derivatives from the corresponding polyfunctional 2-oxindoles. Three methods were proposed for reduction of functional groups in the 2-oxindole and 2-chloroindole molecules using various boron hydrides. The possibility of chemoselective reduction of the nitrile group in the presence of an amide was shown. The proposed synthetic strategy can be used, for example, for the synthesis of new analogs of the endogenous hormone melatonin and other compounds with neuroprotective properties.

Melatonin is a pineal hormone that has a capacity to lower intraocular pressure; it exhibits neuroprotective and antioxidant properties that make it possible to use melatonin in the therapy of glaucoma. Analogs of melatonin having affinity to melatonin receptors are promising candidates for application as antiglaucomatous drugs. Chemical modification of the melatonin structure can in-crease efficiency, bioavailability and selectivity of these analogs. We have designed and synthe-sized a number of new 2-oxindole derivatives – ligands of melatonin MT3 subtype receptors that displayed ability to lower intraocular pressure in normotensive rabbits and high antioxidant activity against hydroxyl radical and superoxide anion-radical. The antioxidant activity of new ligands was several times higher than one of melatonin that makes them prospective therapeutic tools for the diseases that include oxidative stress. The maximal hypotensive effect of analogs was comparable to that of melatonin itself but prolonged. Combination of these properties gives an opportunity of using the presented melatonin analogs in complex therapy of glaucoma.

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