Burilov A.

Garifzyanov A.

Pudovik M.

Syakaev V.

Vagapova L.

Voronina J.

Mendeleev Communications

Kazan Federal University Digital Repository

Mendeleev Commun., 2018, 28, 398–400– 398 –MendeleevCommunications© 2018 Mendeleev Communications. Published by ELSEVIER B.V.  on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the  Russian Academy of Sciences.Pyrrolidine ring is included in many biologically active natural products,1 alkaloids, and compounds that exhibit antitumor,2 anti­bacterial,3 antimicrobal,4 neurotropic,5 anti­inflammatory and anti­HIV activities.6 The presence of a phosphonate group in biologically active molecules enhances their properties.7 In this context, phosphorylated pyrrolidine derivatives can be of particular interest. Effective inhibitors of HIV protease and dipeptidyl peptidase IV,8 thymidine phosphorylase,9 purine nucleoside phosphorylase,10 and 6­oxopurine phosphoribosyl transferase11 were discovered among them.Analysis of literature shows that effective syntheses of phospho­rylated pyrrolidines are scarce in spite of their biological potential. The known methods mainly include: (i) direct electrophilic or nucleophilic phosphorylation of heterocyclic system;12 (ii) ring closing of phosphoryl­functionalized substrates as a result of intramole­cular cyclization, cycloaddition13 and multi­component reactions.14 Most of the methods relate to the preparation of 1­phosphono­pyrroli dines or 2­ or 3­phosphoryl substituted pyrrolidines. In spite of this positive background, simple and effective  accesses to 2­aryl­sub stituted pyrrolidinylmethylphosphonates are lacking. At the same time, 2­aryl­substituted pyrrolidines are of interest as non­nucleoside HIV reverse transcriptase inhibitors (NNRTIs).15 Incorporation of phosphonate moiety into compounds possessing NNRTI activity may improve their solubility and bioavailability.16Assuming these facts, in the present work we aimed at developing novel synthesis of phosphorus­containing 2­aryl­substituted pyrro­lidines. Recently, we obtained such compounds by acid­catalyzed intra molecular cyclization of N­(4,4­diethoxy butyl) ureas in the presence of phenols as nucleophiles.17Here, the reaction of P­(4,4­diethoxybutylamino methyl)­P,P­di­p­tolylphosphine oxide 1 with polyatomic phenols 2a–c has been investigated for the first time in order to prepare phos­phorylated 2­aryl­substituted pyrrolidines. Previously unknown amino acetal 1† was synthesized by the reaction of 4,4­diethoxy­butyl amine with di­p­tolylphosphine oxide and paraformaldehyde in benzene in the presence of p­toluenesulfonic acid according to the Kabachnik–Fields reaction18 (Scheme 1).In the first experiments, amino acetal 1 reacted with 2­methyl­resorcinol 2a in chloroform at room temperature in the presence of trifluoroacetic acid giving a hardly separable mixture of products. The MALDI mass spectra of the reaction mixture revealed the signals at m/z 560 [M + H]+, corresponding to diaryl butylamine derivative, [4,4­bis(2,4­dihydroxy­3­methylphenyl)butylamino­methyl]di­p­tolylphosphine oxide, along with signal at m/z 435 [M + H]+ of the target product 3a. We have previously reported on the synthesis of diarylbutylamine derivative containing dihexyl­phosphorylmethyl group by the reaction of 2­methyl resorcinol Synthesis and structure of new 2-aryl-substituted  pyrrolidines containing phosphine oxide groupLiliya I. Vagapova,*a Julia K. Voronina,a Victor V. Syakaev,a Alexander R. Burilov,a Airat R. Garifzyanovb and Mikhail A. Pudovikaa A. E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of the Russian Academy of Sciences, 420088 Kazan, Russian Federation. Fax: +7 843 273 4872; e-mail: vagapovan@mail.rub Kazan Federal University, 420008 Kazan, Russian FederationDOI: 10.1016/j.mencom.2018.07.019HO OHRP NHHO OHRNPCF3COO–+R = Me, H, OHCF3COOHbenzeneHOMeMeOEtOEt OMeMe2-Aryl-substituted pyrrolidines containing phosphine oxide group have been obtained by the reaction of P-(4,4-diethoxy-butyl aminomethyl)-P,P-di-p-tolylphosphine oxide with poly-atomic phenols.† P-(4,4-Diethoxybutylaminomethyl)-P,P-di-p-tolylphosphine oxide 1. A mixture of di(p­tolyl)phosphine oxide (0.86 g, 3.74 mmol), 4,4­di­ethoxy butan­1­amine (0.6 g, 3.74 mmol), paraformaldehyde (0.11 g, 3.74 mmol) and TsOH (0.01 g) in benzene (50 ml) was heated under reflux in a flask equipped with a Dean–Stark trap for 6 h. When the +CH2O– H2OHO OHRHO OHRNP OCF3COO–CF3COOH / benzene3a–cMeMe2a–c12345678910111213141516+TsOH, benzeneHNHOOEtPOMeMe12345 Me67189111210H2NOEtOEta  R = Meb  R = Hc   R = OHHPOMe MeScheme 1

Synthesis and structure of new 2-aryl-substituted pyrrolidines containing phosphine oxide group

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Synthesis and structure of new 2-aryl-substituted pyrrolidines containing phosphine oxide group

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