Preparation and Chemical Properties of 5-Dialkylaminomethylhydantoins and 2-Thio-Analogues

Abstract

In connection with our studies on synthetic applications of a new type of amino acid b-aminoalanines 1 [7][8][9][10] and our search for biologically active compounds, we have already reported that the compounds 1 are useful starting materials to prepare 5-dialkylaminomethylhydantoins (3: XϭO, YϭCH) via cyclization of corresponding urea derivatives 2, which are easily prepared by the addition of a primary amino group in compounds 1 to aryl isocyanates. 7) We carried out further preparation of new analogues of 5-dialkylaminomethylhydantoins and 2-thio-analogues. In this paper, we report the synthesis of these new derivatives 3 and the chemical properties observed in the synthesized compounds.The desired compounds 3 were obtained in good yields by cyclization of the corresponding urea derivatives 2 prepared by condensation of aryl(thio)isocyanates with b-aminoalanines 1 (Chart 1). Since purification of the intermediates urea derivatives (2b and 2h-j) was difficult, compound 3b and the 2-thio-analogues 3h-j were prepared by a "one-pot" procedure (1→3) without further purification of the corresponding intermediate urea derivatives. The results of the reaction stages (1→2 and 2→3) are summarized in Tables 1 and 2, respectively. The structures of these new products were established by spectroscopic and elemental analyses. All of the assignments were confirmed by two-dimensional (2D) -NMR spectroscopic analysis.By treatment with a large excess amount of H 2 O, deamination (elimination of dialkylamines 5) of 2-thiohydantoin derivative 3b took place to give 5-methylene-2-thiohydantoin 4b (Chart 2). This behavior was easily confirmed by 1 H-NMR spectroscopic analysis. Thus, by 2 ) is also confirmed by the 13 C-NMR spectrum. We observed that this deamination of 2-thiohydantoin 3b to give 5-methylene-2-thiohydantoin 4b proceeded more easily than that of corresponding hydantoin (3a→4a) 7) through the above NMR experiments. 5-Methylene-2-thiohydantoin analogue 4b could be isolated in good yield (76%, see Experimental). Throughout our repeated trials for the isolation of compound 4b, we found that 5-methylene-2-thiohydantoin is not a stable species at elevated temperatures (over 80°C in solution), giving unknown polymerized products. Methylenehydantoin 4a or the 2-thio-analogue 4b (by retro-Michael addition of 3a or 3b) is formed probably via a 6-membered tautomeric intermediacy state (A) (shown in Chart 2).In 1 H-NMR spectra of 5-methylene-2-thiohydantoin 4b, the N-H proton of the hydantoin ring was easily deuterated by treatment with D 2 O. Interestingly, two 5-methylene protons were further deuterated smoothly at room temperature. This result obviously indicates that 5-methylene-2-thiohydantoin 4b exists in an equilibrium state through keto-enol tautomerism of a thioamido functionality conjugated with a 5-methylene group in the 2-thiohydantoin ring (4b-I → ←4b-II → ←4b-III → ←4b-IV) (see Chart 3). The 5-dialkylaminomethylhydantoin system 3 may exist as many constituted tautomers that are in equilibrium with each other and ...

Synthesis of New 5-Substituted Hydantoins and Symmetrical Twin-Drug Type Hydantoin Derivatives

“…[16][17][18][19][20] As starting materials for further derivatizations in this series, 5-methylene hydantoins 4a-c were obtained from elimination (deamination) reactions of the corresponding 5-dialkylaminomethyl-hydantoins (3) 17) (Chart 1) (see Experimental).…”

“…The results are summarized in Tables 1 and 2. It is thought that the tautomeric isomer B of 5-methylene hydantoin in solution (A B) 17,19) is a crucial intermediate for the formation of 5,5-disubstituted hydantoins (11)(12)(13)(14), as shown in Chart 2. When using an excess amount of an amine, a considerable amount of ring-opened urea derivatives 15-17 was isolated as a predominant reaction product (Chart 2).…”

“…[10][11][12][13][14][15] Our previous studies on a bioisosteric replacement of the oxazolidinone ring in linezolid by a hydantoin nucleus provided a few interesting antibacterial leads. [16][17][18][19][20] Among previously targeted hydantoin derivatives, some derivatives including a twin-drug type symmetrical hydantoin derivative 20,21) showed significant antibacterial activity against Gram-positive organisms (Staphylococcus aureus). This finding of new antibacterially active molecules constructed on a hydantoin scaffold encouraged us to develop further modifications of this class of compounds.…”

Antibacterial Activity of 5-Dialkylaminomethylhydantoins and Related Compounds

“…In this article, additional synthetic applications of baminoalanines [9][10][11] to some new hydantoins and biological evaluation of the hydantoin-related derivatives for antibacterial activity with gram-negative (E. coli) and gram-positive (S. aureus) strains are described.…”

“…10,11) The hydantoin derivatives (3) described in this paper were prepared in a manner similar to that reported previously. Synthesis of the compounds (2, 3a, 3b, 3d-3j, 3n, 3p-3t, 4, 5) has already been reported.…”