Been demonstrated41,42. Herein, we report mild and scalable situations for the very chemo-, regio-, and stereoselective synthesis of enamines (“direct hydroamination”) and alkylamines (“reductive hydroamination”) products from alkynes, employing a single copper catalyst technique.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptNat Chem. Author manuscript; obtainable in PMC 2015 July 01.Shi and BuchwaldPageResults and discussionDirect hydroamination: development and scope To assess the feasibility from the outlined alkyne hydroamination (Fig. 1b, A), we treated 1,2diphenylacetylene (1a) with N,N-dibenzyl-O-benzoylhydroxylamine (2a, 1.2 equiv.) and an excess of diethoxymethylsilane (3) within the presence of two mol copper acetate in addition to a range of phosphine ligands. Several ligands could possibly be made use of to carry out the direct hydroamination reaction, and the resulting enamine 4a was efficiently produced as a single geometric isomer, as determined by 1H NMR analysis (Table 1, entries 1?). Though copper catalysts depending on two,2-bis(diphenylphosphino)-1,1-binaphthalene (BINAP, L1), 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, L2) or 4,4-bi-1,3benzodioxole-5,5-diylbis(diphenylphosphane) (SEGPHOS, L3) were effective in this context, the catalyst determined by five,5-bis[di(three,5-di-tert-butyl-4methoxyphenyl)phosphino]-4,4-bi-1,3-benzodioxole (DTBM-SEGPHOS, L4) was discovered to become one of the most effective and generally applicable. We then evaluated the substrate scope of this reaction and, as shown in entries 5?, a diverse array of aryl-substituted internal alkyne substrates could possibly be converted for the corresponding (E)-enamines four with total stereoselectivity (4b?e; 80?9 ). Notably, sterically hindered amines, which were problematic substrates for previously reported hydroamination reactions of FGFR1 medchemexpress alkynes43, may very well be successfully transformed utilizing the existing conditions (4b and 4d). A lot more importantly, direct hydroamination of unsymmetrical internal alkynes occurred with excellent regioselectivity (4c?e; 19:1). In addition, we located that a 1,2-dialkylacetylene was left intact below these conditions (4e) and pharmaceutically critical heterocycles, like morpholine (4c), thiophene (4d), Adenylate Cyclase Species piperidine (4e), and pyrimidine (4e) were well-tolerated. When the direct hydroamination of terminal alkynes to construct monosubstituted enamines was not successful, the existing process represents a rare example of a highly regio- and stereoselective hydroamination of internal alkynes for the building of dialkyl enamines43. Reductive hydroamination: development and scope As previously described, we were hopeful that the addition of a protic additive could divert this reaction from direct alkyne hydroamination for the outlined reductive hydroamination by selective protonation of the formed vinylcopper intermediate (Fig. 1c). Certainly, inclusion of methanol as an additive beneath the reaction circumstances in Table 1 resulted in formation of your preferred reductive hydroamination product 5a in moderate yield, as well as a considerable volume of enamine 4a (18 ) and stilbene (17 ) as side products (Table two, entry 1). Luckily, an evaluation of alcohol additives revealed that ethanol was a appropriate proton source, which minimized the formation of those side solutions to afford benzylamine 5a in great yield and higher enantioselectivity (entry 2, 92 yield, 89 e.e.). Interestingly, in contrast towards the direct alkyne hydroamination protocol for enamine formation, L4 was u.
