Synthesis of Hexahydropyrimidines and 1,2,3,4-Tetrahydropyridines by Reaction of Ethyl Benzoylacetate with Formaldehyde
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hesis of Hexahydropyrimidines and 1,2,3,4-Tetrahydropyridines by Reaction of Ethyl Benzoylacetate with Formaldehyde and Primary Amines D. R. Kireevaa,* and A. I. Kamalovaa a
Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, Ufa, 450054 Russia *e-mail: [email protected] Received June 15, 2020; revised June 28, 2020; accepted July 4, 2020
Abstract—The reaction of ethyl benzoylacetate with formaldehyde and primary amines in boiling pyridine or methanol afforded new 1,2,3,4-tetrahydropyridine derivatives and substituted hexahydropyrimidines. Keywords: ethyl benzoylacetate, hexahydropyrimidine, tetrahydropyridine, diethyl 2,4-dibenzoylpentanedioate, debenzoylation, one-pot synthesis, multicomponent reactions
DOI: 10.1134/S1070428020100103 Six-membered nitrogen heterocycles of the hexahydropyrimidine and 1,2,3,4-tetrahydropyridine series exhibit a broad spectrum of biological activity. Hexahydropyrimidines were found to show antitumor [1], cytotoxic [2–4], antibacterial [5, 6], antiviral [7], and nootropic activities [8]. Tetrahydropyridine derivatives possessing antimalarial [9], antibacterial [10], insecticidal [11], and analgesic activities [12] have been reported. Tetrahydropyridines are also promising as potential anti-Alzheimer and anti-Parkinson drugs [13, 14]. In recent time, one-pot multi-component methods for the synthesis of 1,2,3,4-tetrahydropyridine [15, 16] and hexahydropyrimidine derivatives [17–20] have attracted much interest. The present work was aimed at synthesizing a series of substituted 1,2,3,4-tetrahydropyridines and some hexahydropyrimidine derivatives using ethyl benzoylacetate (1) as starting material. We previously proposed a procedure for the synthesis of analogous compounds on the basis of ethyl acetoacetate [21, 22] and showed
that hexahydropyrimidine derivatives containing an amino acid fragment exhibit pronounced cytotoxicity [3]. With the goal of extending the range of biologically active compounds we examined the reaction of ester 1 with formaldehyde and primary amines. The amine components were methylamine (2a), propylamine (2b), butylamine (2c), and benzylamine (2d). The reactions were carried out by heating the reactants at a 1–formaldehyde–amine ratio of 1:15:2 in boiling methanol for 5 h (Scheme 1). Ethyl benzoylacetate (1) reacted with 33% aqueous formaldehyde and 25.2% aqueous methylamine in boiling methanol gave 30% of ethyl 1,3-dimethylhexahydropyrimidine5-carboxylate (3a). Apart from compound 3a, diethyl 3-benzoyl-1-methyl-6-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (4a) was formed as minor product (16%). It should be noted that products like 4 were not detected previously in analogous reactions [22]. Keto ester 1 reacted with formaldehyde and propylamine (2b) or butylamine (2c) in a similar way. In the
Scheme 1. O O
O + CH2O
Ph
+ RNH2
MeOH, Δ, 5 h
OEt
1
OEt
+ R
2a–2c
N
N
R
3a–3c, 30–54%
R = Me (a), Pr (b), Bu (c).
1733
O
O
Ph OEt
EtO Ph
N
O
R 4a–4c, 11–16%
1734
KIREEVA, KAMALOVA Scheme 2. O 1
+ CH2O
+ Ph
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