Abstract
New chiral monoaza-15-crown-5 type macrocycles anellated to 3,4-O-isopropylidene-�-L- arabinopyranose ( 5a-b), to �-L-arabinopyranose ( 6) and to 3,4-O-benzyliden-�-L- arabinopyranose (11 ) have been synthesized. The cation binding ability of the new lariat ethers was evaluated by the picrate extraction method in liquid-liquid system. Some representatives of these crown ethers showed moderate asymmetric induction as chiral phase transfer catalysts, among them 11 with a benzylidene group proved to be the most efficient one inducing 64% ee in the Michael addition of 2-nitropropane to chalcone and 61% ee in the addition of diethyl acetamidomalonate to trans -�-nitrostyrene. An induction of 65% ee was observed in the epoxidation of a chalcone analogue with tert -butyl hydroperoxide in the presence of catalyst 5a.
Highlights
Interaction of E-isomers of aromatic 1-2 and quinoline amidoximes 3 with o-iodobenzyl bromide (11a) or 2-bromo-3-chloromethylpyridine (11b) in the system solid dry Cs2CO3/Pd2(dba)3/Xantphos leads to corresponding oxadiazepines 12-16 isolated in 23-60% yields by column chromatography (Scheme 1, Table 1, entries 1-5)
Cytotoxic activity of compounds 19 and 23 was tested in vitro on two monolayer tumor cell lines: MG-22A and HT-1080 (Table 2). These compounds were selected from a wide range of 3substituted 1,2,4-oxadiazepines because of high activity of corresponding quinoline and thiazole containing N-hydroxy-ω-(hetarylmethoxy or hetarylthio)alkanamidines, the synthesis and cytotoxicity of which were presented in our earlier work.11c Beside this, compounds 19 and 23 formally are masked amidoxime O-benzyl ethers
It was demonstrated that the system benzyl bromide/solid Cs2CO3/Pd2(dba)3/Xantphos/dioxane was an excellent for O-alkylation/N-arylation tandem reaction of oxime 26 leading to 2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one O-benzyl oxime (27) in 62% yield by one pot method
Summary
Seven-membered heterocycles are often present in the wide range of biologically active molecules.1 Several recent chemical review articles were dedicated to the synthesis and transformation of seven membered rings.2-6 two chapters on the chemistry of seven-membered rings with three heteroatoms at the positions 1, 2 and 4 have appeared.6,7 3,5,7Trisubstituted 4,7-dihydro-1,2,4-oxadiazepines have been prepared via a two step method starting from enones using NH2CONHOH/MeONa Me2SO4/KOH,8 and the intramolecular condensation of methyl 2-chloro-2-(phenylcarbamoylimidoylaminooxycyclopropyl)acetate in the presence of NaH in acetonitrile leading to 9-chloro-6-phenyl-5,7-diaza-4-oxaspiro[2,6]non-5-en8-one has been reported.9 Recently we published articles on palladium catalyzed synthesis of 3-substituted 1,2,4-oxadiazepines from (E)-O-(2-iodophenylmethyl)amidoximes.10 there are no general methods for the synthesis of benzo or pyridine fused substituted 1,2,4oxadiazepines directly from (E)-amidoximes. We report a novel and simple palladium-catalyzed one-pot method for the preparation of 2-substituted 1,5-dihydrobenzo[e][1,2,4]oxadiazepines directly from the corresponding Eamidoximes and o-iodobenzyl bromide (11a) or 2-bromo-3-chloromethylpyridine (11b) by Oalkylation/N-arylation tandem reaction. Interaction of E-isomers of aromatic 1-2 and quinoline amidoximes 3 with o-iodobenzyl bromide (11a) or 2-bromo-3-chloromethylpyridine (11b) in the system solid dry Cs2CO3/Pd2(dba)3/Xantphos leads to corresponding oxadiazepines 12-16 isolated in 23-60% yields by column chromatography (Scheme 1, Table 1, entries 1-5).12 Corresponding aromatic or quinoline nitriles were isolated as minor side-products as a result of palladium mediated deoximation under basic conditions.
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