Synthesis Of Multi-Functionalized Benzofurans Via One-Pot Domino Oxidation/[3+2] Cyclization Reactions Of A Hydroquinone And Ynamides

Ynamides are a sub-sets of nitrogen-substituted alkynes and acted as multifunctional synthons.Over the past decades,ynamides,as powerful building blocks,have been involved in the transition-metal catalyzed reactions for construction of diverse functionalized molecules including important pharmacophores.In this thesis,we systematically summarized the development of the methods for the synthesis of ynamides that used commonly,as well as transition-metal(Cu,Pd,Rh,Au)catalyzed reactions of ynamides.And multi-sites substituted amino-functionalized benzofurans were concisely accessed via one-pot domino oxidation/[3+2] cyclization of a hydroquinone ester and easily accessible ynamides under mild conditions in a relatively short time was reported.In this thesis,the complicated benzofurans were able to be efficiently synthesized all from simple and inexpensive starting materials in two steps.It is worth to mention that ynamides used here were all easily prepared in one step via copper-catalyzed oxidative cross coupling of corresponding simple amides and terminal alkynes.Silver oxide and magnesium sulfate were then added to a solution of methyl 2,5-dihydroxybenzoate in diethyl ether to give the desired hydroquinone ester.The ynamides and the hydroquinone ester were further reacted at room temperature,using scandium trifluoromethanesulfonate as a catalyst,in 5 minutes to obtain the desired products.Specifically:(1)Reaction of methylamine and 4-toluene sulfonyl chloride with phenylacetylene,4-ethynylanisole,1-heptyne or triisopropylsilylacetylene formed ynamide derivatives(1a～1d),which were reacted with oxidized hydroquinone ester(2b)to give 2-((N,4-dimethylphenyl)sulfonamido)-5-hydroxy-3-phenylbenzofuran-4-carboxylate(3a),2-((N,4-dimethylphenyl)sulfonamido)-5-hydroxy-3-(4-methoxyphenyl)-benzofuran-4-carboxylate(3b),2-((N,4-dimethylphenyl)-sulfonamido)-5-hydroxy-3-pentylbenzofuran-4-carboxylate(3c)and 2-((N,4-dimethylphenyl)-sulfonamido)-5-hydroxy-3-(triisopropylsilyl)benzofuran-4-carboxylate(3d),respectively;(2)Ynamide derivatives(1e and 1f)were synthesized by reaction of2-azetidinone with phenylacetylene/1-heptyne.Oxidized hydroquinone ester(2b)were reacted with ynamide derivatives(1e and 1f)to give methyl5-hydroxy-2-(2-oxoazetidin-1-yl)-3-phenylbenzofuran-4-carboxylate(3e)and methyl5-hydroxy-2-(2-oxoazetidin-1-yl)-3-pentylbenzofuran-4-carboxylate(3f);(3)Reaction of methyl indole-3-carboxylate with 1-heptyne or phenylacetylene formed ynamide derivatives(1g and 1h),which were reacted with oxidized hydroquinone ester(2b)to give 1-(5-hydroxy-4-(methoxycarbonyl)-3-pentylbenzofuran-2-yl)-1H-indole-3-carboxylate(3g)and 1-(5-hydroxy-4-(methoxycarbonyl)-3-phenylbenzofuran-2-yl)-1H-indole-3-carboxylate(3h),respectively.Compounds 1f,1g and3a～3h were characterized by NMR spectroscopies and mass spectrometry.