Simple Synthesis of Some 2-Substituted Melatonin Derivatives

Abstract

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).

Synthesis of New 2,3-Dihydroindole Derivatives and Evaluation of Their Melatonin Receptor Binding Affinity

“…Selective nitrile reduction in the presence of cyclic amide was also achieved using NaBH 4 in methanol in the presence of catalytic amounts of anhydrous NiCl 2 . We have previously shown that the addition of acetic anhydride to the reduction mixture could obtain 2-chloromelatonin 7d [ 26 ] with good yield ( Scheme 6 ). In this work, we demonstrated that the same reduction followed by one-pot acylation can be used in the case of 2-oxindole derivatives and other anhydrides ( Scheme 6 ).…”

“…The following isatin derivatives were obtained by N -alkylation using previously described procedure [ 28 ]: N -methylisatin 1e , N -benzylisatin 1f , N -methyl-5-methoxyisatin 1g , N -benzyl-5-methoxyisatin 1h , N -methyl-5-bromoisatin 1i , N -methyl-6,7-dimethylisatin 1j . The following compounds were obtained as previously described: cyano(2-oxoindolin-3-ylidene)acetic acid 2a [ 25 ], cyano(2-oxo-5-methoxy-indolin-3-ylidene)acetic acid 2b [ 24 ], cyano(2-oxo-5-bromoindolin-3-ylidene)acetic acid 2c [ 23 ], 2-(2-oxo-2,3-dihydro- 1H -indol-3-ylidene)acetonitrile 3a , [ 25 ] 2-(1-methyl-2-oxo-2,3-dihydro- 1H -indol-3-ylidene)acetonitrile 3e [ 24 ], 2-(5-methoxy-1-methyl-2-oxo-2,3-dihydro- 1H -indol-3-ylidene)acetonitrile 3g [ 29 ], 2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3′-indol]-3-carbonitrile ( 6a ) [ 19 ], 5′-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3′-indol]-3-carbonitrile ( 6b ) [ 19 ], 2-chloromelatonin 7d [ 26 ].…”

A Putative New Melatonin Binding Site in Sheep Brain,MTx: Preliminary Observations and Characteristics

“…The following ones belong to the MLT compound library of Les Laboratoires Servier. Their respective syntheses were previously reported as indicated in the following list: S 22153 (Legros et al, 2019); SD 1883 (Legros et al, 2019); SD 1918 (Legros et al, 2014b); S 27128 (Leclerc et al, 2002); S 22958 (Leclerc et al, 1998); S 73229 (Lozinskaya et al, 2011);S 70643 (Ettaoussi et al, submitted manuscript);andSD 1671 (Harth e et al, 2003). All compounds were dissolved in DMSO at a stock concentration of 10 mM and stored at À20 C.…”

Superacid‐Catalyzed Trifluoromethylthiolation of Aromatic Amines

“…To this end, the reactivity of a series of model druglike molecules was evaluated under our optimized reaction conditions (Scheme ). The direct synthesis of the vinburnine SCF 3 analogue 4 and a precursor of the trifluoromethylthiolated analogue of melatonin 6 were selectively achieved . To evaluate the ability to extend our strategy to aromatic steroids, the protected 4‐methylphenol model substrate 7 was submitted to the optimized reaction conditions and led to the exclusive formation of 8 in 64 % yield.…”