Methyl nitroacetate and 3-nitropropionate in the synthesis of hexahydropyrimidines and piperidines

Abstract

Treatment of methyl nitroacetate and 3-nitropropionate with formaldehyde and primary amines underMannich reaction conditions gives 5-nitrohexahydropyrimidines. In the case of methyl nitroacetate both the 5-nitrohexahydropyrimidine and isomeric 3,5-di(methoxycarbonyl)-1-methyl-3,5-dinitropiperidines are formed.The reaction of primary amines and formaldehyde with compounds containing a mobile hydrogen atom on a carbon atom is widely used in organic synthesis as a convenient method for preparing tetrahydro-1,3-oxazines, hexahydropyrimidines [1, 2], and also 3-aza-[3-6] and 3,7-diazabicyclo[3,3,1]nonanes [3,[7][8][9][10][11][12][13][14][15]. Members of this class of compounds show high physiological activity and are used in medical practice as antimicrobial, antiviral, antitumor and other medicinal agents [10][11][12]16]. It is known that nitro-substituted heterocyclic compounds show increased antibacterial activity [1], can behave as sources of nitric oxide [17] in the human organism, and they are of interest both as chemotherapeutic agents and as intermediates in organic synthesis. Hence 5-[2-(methoxycarbonyl)ethyl]-1,3-dimethyl-5-nitrohexahydropyrimidine shows clear antiarrythmic activity [18] and trinitrohexahydropyrimidine (containing a glutaric acid fragment) is a convenient synthon for preparing immunologically active peptide conjugates [19] used in immunoenzymic analysis.Condensation with a nitro compound has shown promise in the synthesis of novel, practically important polyfunctional six-membered nitrogen heterocycles. According to literature data the course of the reaction of aliphatic mononitroalkanes with formaldehyde and primary amines depends on the structure of the starting reagents, their ratio, the temperature, and the nature of the solvent and it can occur to form amines, diaminopropanes, tetrahydrooxazines, and hexahydropyrimidines [1,2]. It has been shown previously that the reaction of methyl 4-nitrobutanoate with methylamine hydrochloride and CH 2 O occurs in 40% yield to give 5-nitro-5-[2-(methoxycarbonyl)ethyl]-1,3-dimethyl-hexahydropyrimidine and it is formed exclusively via the CH 2 NO 2 fragment of the starting nitrobutanoate [18].

Nitro-Mannich Reaction

“…This methodology was later expanded by Shakirov et al to include reaction of methyl nitroacetate. 42 Similar reactions have also been reported by Cichra and Adolph. 43 Hirst et al showed that similar chemistry could be used for synthesis of 5-nitro-tetrahydro-1,3-oxazines 25 (Scheme 14).…”

“…Using an additional equivalent of formaldehyde the nitrodiamine intermediates 24 underwent cyclization via condensation with formaldehyde to form the 5-nitro-hexahydro-1,3-pyrimidines 23 . This methodology was later expanded by Shakirov et al to include reaction of methyl nitroacetate . Similar reactions have also been reported by Cichra and Adolph …”