Synthesis of 1-[3-(Hetaryl)allyl]morpholines as Potential Anticholinesterase Agents
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hesis of 1-[3-(Hetaryl)allyl]morpholines as Potential Anticholinesterase Agents N. M. Chernova,*, P. I. Ezhova, R. V. Shutova, and I. P. Yakovleva a St.
Petersburg State Chemical Pharmaceutical University, St. Petersburg, 197376 Russia *e-mail: [email protected] Received May 26, 2020; revised May 26, 2020; accepted June 7, 2020
Abstract—A number of new pyrazole and pyrimidine derivatives containing an allylmorpholine fragment were obtained by reactions of chromone-containing allylmorpholines with 1,2- and 1,3-binucleophiles (hydrazine, guanidine, acetamidine). The syntheses were carried out under mild conditions (ethanol, room temperature), and the target products were isolated with high yields. The obtained compounds are of interest as potential cholinesterase inhibitors. Keywords: chromone, allylamine, morpholine, pyrazole, pyrimidine, anticholinesterase activity
DOI: 10.1134/S1070363220090054 Chromones currently occupy an important place in the chemistry of heterocyclic compounds [1, 2] due to broad spectrum of biological activity, including the role of the chromone system as the basis of secondary plant metabolites (for example, flavonoids). Of special interest is the reactivity of chromone derivatives, which has a high synthetic potential. Thus, chromones are capable of acting as precursors of azoles [3], azines [4] and other heterocyclic systems [5, 6]. Earlier we have developed an approach to the synthesis of chromone-containing allylmorpholines 1 [7], which showed anticholinesterase activity, which makes these structures promising for use in the therapy of neurodegenerative diseases. On the other hand, the chromone system of 1 can be used to construct other heterocyclic systems. The hetarylallylmorpholines thus obtained can potentially also act as cholinesterase inhibitors. Anticholinesterase drugs often have common structural motifs. In particular, they include an aromatic system in combination with a cyclic amine fragment as
a hydrogen bond acceptor [8]. An example is Donepezil (Scheme 1). The most effective approach to the design of chromone-based heterocyclic compounds are reactions with 1,2- and 1,3-N,N-binucleophiles [9]. At the first stage, we investigated the reaction of chromones 1a–1e with hydrazine, a representative of 1,2-binucleophilic reagents (Scheme 2). The reaction proceeded under mild conditions (ethanol, room temperature) with a small (20 mol %) excess of hydrazine and led to pyrazolecontaining allylmofrolines 2a–2e in moderately high yields (73–87%, Table 1). This synthesis is a variant of Knorr’s synthesis, in which chromone containing a masked β-dicarbonyl system acts as a donor of a three-carbon fragment in the construction of the pyrazole ring. Presumably, the reaction begins with a nucleophilic attack by hydrazine at position 2 of chromone, followed by the ring closure through position 4.
Scheme 1.
1620
SYNTHESIS OF 1-[3-(HETARYL)ALLYL]MORPHOLINES
1621
Scheme 2.
Scheme 3.
Under similar conditions, the reaction of chromonecontaining allylmorpholines 1a–1e wit
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