Synlett 2020; 31(11): 1067-1072
DOI: 10.1055/s-0039-1690900
letter
© Georg Thieme Verlag Stuttgart · New York

Straightforward Three-Component Synthesis of N′,N′′-Disubstituted N-Alkyl-1,3,5-Triazinanes

a   Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation   Email: avkletskov@gmail.com
,
Antonio Frontera
b   Department of Chemistry, Universitat de les Illes Balears, Crta. de Valldemossa km 7.7, 07122 Palma de Mallorca (Baleares), Spain
,
Anna A. Sinelshchikova
c   Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky pr. 31, bld. 4, Moscow 119071, Russian Federation
,
Mikhail S. Grigoriev
c   Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky pr. 31, bld. 4, Moscow 119071, Russian Federation
,
a   Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation   Email: avkletskov@gmail.com
,
Mariya V. Grudova
a   Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation   Email: avkletskov@gmail.com
,
d   Medicinal Chemistry Center, Togliatti State University, 14 Belorusskaya St., 445020 Togliatti, Russian Federation
,
Sofia Presnukhina
e   Pharmaceutical Technology Transfer Center, Yaroslavl State Pedagogical University named after K. D. Ushinsky, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
,
Anton Shetnev
e   Pharmaceutical Technology Transfer Center, Yaroslavl State Pedagogical University named after K. D. Ushinsky, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
,
a   Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation   Email: avkletskov@gmail.com
› Author Affiliations
The publication has been prepared with the support of the RUDN University Program 5-100 and the Russian Foundation for Basic Research (project No 19-03-00807 A). A.F. thanks MICIU/AEI of Spain (projects CTQ2017-85821-R and RED2018-102331-T, FEDER funds) for financial support.
Further Information

Publication History

Received: 03 March 2020

Accepted after revision: 30 March 2020

Publication Date:
17 April 2020 (online)


Abstract

Efficient approaches towards the synthesis of various N-substituted 1,3,5-triazinanes based on a transformation of N-alkyl-1,5,3-dioxazepanes or on a domino reaction involving condensation of various amines, amides, and paraformaldehyde are described for the first time. Mg(ClO4)2 was shown to be one of the most potent additives for the condensation. The proposed approaches permit the synthesis of a broad spectrum of substituted sym-triazinanes in good yields with relatively easy workup. In the case of the multicomponent reaction, the approach allows the preparation of the target substances from simple and easily accessible reagents. The representatives of the resulting compounds were found to possess no antimicrobial or cytotoxic activity in in vitro bioassays.

Supporting Information

 
  • References and Notes

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  • 18 1,3,5-Triazinanes 46; Typical Procedure Method a (Multicomponent Approach) Paraformaldehyde (90 mg, 3.00 mmol; 94.3 mg, 3.14 mmol in the case of thiourea derivatives) (based of formaldehyde) and Mg(ClO4)2 (36 mg, 0.157 mmol) were added to a solution the appropriate amide (1.57 mmol) in CHCl3 (5 mL). The appropriate amine (0.8 mmol; 1.60 mmol in the case of thiourea) was then added, and the mixture stirred under reflux for 3 h in air or under argon. (A sealed vessel at 66 °С in oil bath was used in the case of t-BuNH2 or i-PrNH2. Refluxing for 4.5 h was required for derivative 6). The mixture was then cooled to r.t. and filtered through a thin layer of silica gel. In the case of compounds 4u and 4v, the reaction was quenched with hot acetone (25 mL), due to the low solubility of corresponding compounds in CHCl3, and filtered through a fritted glass filter with minimal porosity. The filtrate was concentrated to approximately 0.5–0.7 mL under reduced pressure, and Et2O (5 mL) was added. The resulting solution was cooled to –20 °C and the precipitate was collected by filtration, washed with a small amount of cold EtOH and dried, initially in air and then in a vacuum desiccator over P2O5. Workup for products 4l, 4p, and 4w after concentration of the filtrate included extraction of the crude viscous product with boiling hexane–Et2O (1:2), followed by slow evaporation of the resulting extract, initially at r.t. and then at 0 °C, resulting in slow precipitation of the products as white solids. The resulting solids were collected by filtration and dried in air and then in a vacuum desiccator over P2O5. Compound 5e precipitated from CHCl3. The crude product was collected by filtration, washed with acetone, and dissolved in EtOH. The solution was filtered through a fritted glass filter with minimal porosity, evaporated, and treated with CHCl3 (5 mL). The precipitate was collected by filtration and dried in air and then in a vacuum desiccator over P2O5. In the case of 3,5-di-tert-butyl-1,3,5-triazinane-1-carbaldehyde (6), 2.05 equivalents of the amine were used under the optimal conditions, as the use of equimolar combinations of formamide and tert-butylamine gave 6 in a lower yield. Pure compound 6 was obtained immediately after evaporation of the filtrate under reduced pressure. The use of an argon atmosphere did not generally affect the yields of the products, but did reduce the slight coloration of the reaction mixtures and the crude products. Typical Procedure Method b (from 1,5,3-Dioxazepanes) The appropriate 3-alkyl-1,5,3-dioxazepane (1.57 mmol) was added to the amide (1.57 mmol) and Sm(NO3)3·6H2O (71 mg, 0.16 mmol) in CHCl3 (5 mL), and the mixture was stirred for 36 h at r.t. CHCl3 (35 mL) was added and the mixture was washed twice with H2O in a separatory funnel. The organic layer was separated, dried (Na2SO4), and filtered through a thin layer of silica gel. Further workup of the filtrate was similar to that described in Method A. 1-(tert-Butyl)-3,5-bis[(4-chlorophenyl)sulfonyl]-1,3,5-triazinane (4a) White powder; yield: 274 mg (71%; Method a); 304 mg (79%; Method b); mp 185–186 ℃. IR (KBr): 3089, 3067 (CHarom), 2974 (alkyl), 1347, 1161 (SO2N) cm–1. 1H NMR (600.2 MHz, CDCl3): δ = 7.73 (app. d, J ≈ 8.6 Hz, 4 Harom), 7.49 (app. d, J ≈ 8.6 Hz, 4 Harom), 4.64 (s, 2 H, CH2), 4.16 (s, 4 H, 2CH2), 1.05 (s, 9 H, 3CH3). 13C NMR (150.9 MHz, CDCl3): δ = 139.87 (2 Cquat), 137.07 (2 Cquat), 129.57 (4 CHarom), 129.09 (4 CHarom), 62.56 (2 CH2), 60.89 (CH2), 54.23 (Cquat), 27.35 (3 CH3). MS (ESI): m/z = 494.0 [M + H, 37Cl, 37Cl]+, 493.1, [M + H, 35Cl, 37Cl]+, 492.1 [M + H, 35Cl, 35Cl]+. Anal. Calcd for C19H23Cl2N3O4S2: C, 46.34; H, 4.71; N, 8.53; S, 13.02. Found: C, 46.33; H, 4.59; N, 8.58; S, 12.94.
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