Amidation of 1-bromo-3,5-dimethyladamantane catalyzed with manganese compounds and complexes

Abstract

One of the most important compounds containing adamantane moiety are amides like 1-acetamido-3,5dimethyladamantane, whose deprotection gives 1amino-3,5-dimethyladamantane, the constituent of Memantine drug. Memantine is unique pharmaceutical preparation effective for the treatment of Alzheimer's disease and other CNS disorders at an early stage. It helps to normalize the psychic activity of human: it improves memory and ability to concentrate, reduces fatiguability, depression symptoms, and restores neuromuscular system disorders [1][2][3][4][5].Typically 1-bromo-3,5-dimethyladamantane I is used for laboratory and industrial synthesis of various N-(adamant-1-yl)amides by Ritter method [6,7]. Known methods for producing N-(adamant-1-yl)acylamides include reacting 1-bromoadamantane with formamide and acetamide at elevated temperature (185±195°C) [8], or in the presence of the stoichiometric amount of silver sulfate as the catalyst [9]. Yields of amides in both cases do not exceed 45%.Considering the practical importance of N-(3,5-dimethyladamantane-1-yl)amides, we aimed at developing a new effective method for their preparation using metal complex catalysts. We have recently shown that the Mn-catalyzed reaction of 1-bromoadamantane with carboxylic acid amides produced N-(adamantan-1-yl)amides in yields of 70-90% [10].In the present work, we found that manganese compounds and complexes catalyzed amidation of 1bromo-3,5-dimethyladamantane I with carboxylic acid amides. The reactions were carried out as described previously [10]. The interaction of 1-bromo-3,5-dimethyladamantane I with formamide, acetamide, propionamide, and benzamide in the presence of Mn 2 (СО) 10 [or MnCl 2 , MnBr 2 , Mn(OAc) 2 , Mn(acac) 3 ] resulted in the formation of the corresponding N-(3,5-dimethyladamant-1-yl)amides II-V in 78-99% yield. At the same time the nature and the structure of the organic amide had no significant effect on the selectivity of the reaction and the yield of adamantylamide (Scheme 1).In summary, the Mn-containing catalysts made it possible to perform amidation of 1-bromo-3,5-dimethyladamantane I with organic amides in a single step in a solvent-free conditions.[Mn] = MnCl 2 , MnBr 2 , Mn(OAc) 2 , Mn(acac) 3 , Mn 2 (CO) 10 ; R = H (II), CH 3 (III), C 2 H 5 (IV), Ph (V). + RCONH 2 [Mn] 3 mol % 120−130 o C, 2−3 h, 78−100% NHCOR Br I I I −V Scheme 1.