A general A³: coupling reaction based on functionalized alkynes

Abstract

Recebido em 15/1/13; aceito em 16/4/13; publicado na web em 17/7/13 A range of hydroxypropargylpiperidones were efficiently obtained by a one-pot three-component coupling reaction of aldehydes, alkynols, and a primary amine equivalent (4-piperidone hydrochloride hydrate) in ethyl acetate using copper(I) chloride as a catalyst. The developed protocol proved to be equally efficient using a range of aliphatic aldehydes, including paraformaldehyde, and using protected and unprotected alkynols.Keywords: hydroxypropargylamine; multicomponent reaction; A 3 -coupling. INTRODUCTIONConnecting organic fragments that have desired functionalities by short and inexpensive synthetic routes is one of the most exciting and challenging tasks for organic chemists, and it requires a high level of creativity and elegance.Recently, multicomponent reactions have been receiving significant attention, because multiple carbon-carbon and carbonheteroatom bonds can be generated in a single step, allowing for the straightforward construction of intricate organic compounds. Recent developments in this area have been very impressive, and procedures involving seven 1 and even eight 2 components have been reported.The three-component coupling of aldehydes, amines, and alkynes (A 3 -coupling) is a very efficient method for forming propargylamines by C-H activation.3 A 3 -coupling is more practical than the other methods available for preparing this class of compounds, because no moisture-sensitive stoichiometric organometallics, such as Grignard or organolithium reagents, are involved. It is also applicable to various substrates. This transformation can be catalyzed by a large number of transition-metal salts, including copper, 4 19 It is interesting to note that, although the use of various amines and aldehydes in this method has been described, the number of alkynes used has been limited. Non-functionalized alkynes, such as phenylacetylene and trimethylsilylacetylene, have been used most frequently, but the A 3 -coupling of alkynols, to prepare functionalized allenols, has recently been described. 20In 2006, Gommermann and Knochel described the use of an A 3 -coupling silylated adduct in the asymmetric synthesis of (S)-(+)-coniine. 21 We know of only a few examples of unprotected alkynols being used in the A 3 -coupling reaction, and all of them, except for ones we have previously reported, 22 have been limited to aromatic aldehydes. 23,24 A general procedure for the preparation of hydroxypropargylamines would be very desirable because these chemicals are direct precursors for alkaloids. The desired carbon skeleton could be achieved in a one-pot process using an A 3 -coupling-type protocol and using the correct functionalities for cyclization to form five-and six-(and higher) ring alkaloid systems.In 2006, Carreira reported using 4-piperidone hydrochloride hydrate as a secondary amine source in an A 3 -coupling reaction. 25The authors demonstrated that using this amine source allowed the A 3 -coupling adducts (tertiary amines) to be easily con...

Reações de acoplamento-A3 visando a síntese da desoxicastanospermina e swainsonina

“…Há poucos relatos do uso de alquinóis nesse tipo de reação, 49 a maioria dos quais descrevendo o emprego de aldeídos aromáticos para formação de iminas ou sais de imínio. Devido a esta escassez de exemplos, estudos foram desenvolvidos no grupo de pesquisa do Prof. Alcindo A.Dos Santos visando a síntese de hidroxipropargilaminas derivadas de alquinóis e aldeídos alifáticos 50. Os estudos de preparação dessa classe de compostos foram iniciados partindo-se de álcoois protegidos, que após reação de acoplamento e…”