Tetracyclines.  VI.  Some new aspects in the chemistry of oxazolones and their sulfur analogs

Muxfeldt, Hans; Behling, Jochen.; Grethe, Guenter; Rogalski, Werner

doi:10.1021/ja00995a029

Cited by 31 publications

(7 citation statements)

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“…Similar results (Scheme 2) are found in the literature for other carbonyl compounds including 1,3-dihydroindol-2-one (4, oxindole), 5 a,b-unsaturated ketones, 6,7 3-phenylisoxazol-5-one (5), 8 benzofuran-2(3H)one (6), 9 pyrazol-5-one (7), 10 and 2-phenyl-3-thiazolin-5one (8). 11 The use of catalysts (AlCl 3 , TsOH and KF/alumina) has been reported for other similar substrates, in particular oxindole, with good results for a limited number of examples. We envisaged using a large diversity of the library ligand sets; however, the microwave-assisted synthesis would not be viable for a two-dimensional library consisting of several hundred compounds.…”

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confidence: 98%

First Example of Lewis Acid Catalyzed 3-Substituted 5-Arylidene-1-methyl-2-thiohydantoin Formation

Gregg¹,

Earley²,

Golden³

et al. 2006

Synthesis

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A survey of Lewis acids was conducted to facilitate the formation of arylidenethiohydantoins. The use of indium(III) triflate shows significant advantages in facilitating this reaction. In most examples, the Lewis acid promoted catalysis gave shorter reaction times, higher conversion, and better purity profiles as compared to the traditional uncatalyzed reactions.The 3-substituted 5-arylidene-1-methyl-2-thiohydantoin moiety 3 is known to be a biologically active heterocycle in areas of antimycobacterial, 1 antiviral 2 and potentially anticonvulsant indications. 3 As part of our efforts to generate libraries of medicinally relevant compounds, we set out to prepare a focused library of approximately 400 compounds elaborating this interesting core. Most recently Nielsen 4 reported the preparation of a small 28-member library of 3-substituted 5-arylidene-1-methyl-2-thiohydantoins 3 via microwave-mediated and traditional reflux conditions with good results. Our initial approach for the preparation of 3-substituted 5-arylidene-1-methyl-2-thiohydantoins involved the direct condensation of aldehydes with 3-substituted 1-methyl-2-thiohydantoins 2 in the presence of an organic base and a solvent such as toluene or 1,4-dioxane (Scheme 1). Our observations showed that, in general, uncatalyzed reactions give modest to good yields of 40% to 80% with unhindered aldehydes and that sterically hindered aldehydes typically gave very poor results. Similar results (Scheme 2) are found in the literature for other carbonyl compounds including 1,3-dihydroindol-2-one (4, oxindole), 5 a,b-unsaturated ketones, 6,7 3-phenylisoxazol-5-one (5), 8 benzofuran-2(3H)-one (6), 9 pyrazol-5-one (7), 10 and 2-phenyl-3-thiazolin-5-one (8). 11 The use of catalysts (AlCl 3 , TsOH and KF/alumina) has been reported for other similar substrates, in particular oxindole, with good results for a limited number of examples. We envisaged using a large diversity of the library ligand sets; however, the microwave-assisted synthesis would not be viable for a two-dimensional library consisting of several hundred compounds. Hence we sought to develop a reaction protocol which generated the target 3-substituted 5-arylidene-1-methyl-2-thiohydantoins 3 in good yield for a wide variety of R and R¢ groups. We herein report our findings for the protocol validation phase of our compound library synthesis. A number of potential Lewis acid catalysts were surveyed to efficiently and reproducibly generate a library of previously unreported 3-substituted 5-arylidene-1-methyl-2-thiohydantoins 3. Scheme 1 General synthetic sequence for the preparation of 3-substituted 5-arylidene-1-methyl-2-thiohydantoins.

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confidence: 98%

First Example of Lewis Acid Catalyzed 3-Substituted 5-Arylidene-1-methyl-2-thiohydantoin Formation

Gregg¹,

Earley²,

Golden³

et al. 2006

Synthesis

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“…A further structural unit used was the methyl N-tert-butyl-3-oxoglutaramate (6); this compound was obtained (m. p. 65-66 "C) from dimethyl 3-oxoglutarate with tert-butylamine and p-toluenesulfonic acid in boiling dioxane. Addition of (5) and (6) to a boiling mixture of tetrahydrofuran and ether containing one equivalent of sodium hydride yields, analogously to reactions described prev i o u~l y [~~, a mixture of stereoisomers and tautomers (7). The structure of this mixture follows from analytical data, the IR spectrum (h,,,,,=3.30, 5.71, 5.95, and 6.30pm in CHC13) and the UV spectrum [h,,,(~)=227 (31 400), 278 (16000), and 326nm (3700) in 0.01 N methanolic NaOH].…”

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confidence: 86%

Total Synthesis of Anhydroaureomycin

Muxfeldt

Döpp

Kaufman

et al. 1973

Angew. Chem. Int. Ed. Engl.

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“…Trimethyl and triethyloxonium tetrafluoroborates, in particular, have been widely employed for the methylation and ethylation of sensitive or weakly nucleophilic functional groups, including the amide group. 10 The oxygen atom of amides can be alkylated by oxonium salts to give salts of N-alkyliminoethers. 11 N-Substituted 2-phenylacetamides (ethyl, n-propyl, i-propyl, n-butyl, cyclohexyl) were treated with trimethyloxonium tetrafluoroborate under ambient conditions (Scheme 5) and the products were analysed by GC.…”

Section: Alkylation With Trialkyloxonium Saltsmentioning

confidence: 99%