Unusual Effect of a Remote Substituent on Chlorination of Melatonin

Abstract

No information is available in the literature on methods for obtaining N-acetyl-2-chlorotryptamines, although the existence of 2-chloromelatonin is mentioned in [1]. The need to develop methods for synthesis of 2-halotryptamine derivatives is dictated by their high activity with respect to melatonin receptors [2][3][4]. We have established that electrophilic chlorination of melatonin by N-chlorosuccinimide (NCS) in THF at low temperatures and also by dichloroamine T (TsNCl 2 ) (for different substrate:reagent ratios) in an AcOH-THF mixture at 20°C and -15°C does not lead to formation of the 2-chloro derivative, and the reaction mixtures mainly contain unreacted melatonin and tarry byproducts. We unexpectedly found that using N-acetylmelatonin (N,N-diacetyl-5-methoxytryptamine) as the substrate allows us to successfully carry out the process of electrophilic chlorination at the 2 position by dichloroamine T in THF at -50°C. N H NAc 2 MeO TsNCl 2 N H NAc 2 Cl MeO N H NHAc Cl MeO AIBN, CCl 4NaOH NCS Introducing a second protective acetyl group allows us to carry out not only electrophilic chlorination but also radical chlorination of melatonin at the 2 position. In fact, we have shown that chlorination of N-acetylmelatonin by NCS under conditions favorable for the occurrence of free-radical processes (in CCl 4 in the presence of azobisisobutyronitrile (AIBN)) also leads to the 2-chloro derivative. Known attempts in the __________________________________________________________________________________________

Simple Synthesis of Some 2-Substituted Melatonin Derivatives

“…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.…”