Igure 1. Structures of terminal ynamines and much less reactive ynamide and ynesulfonamide analogues.are cycloadditions,six cycloisomerizations,7 homo- and crosscouplings,eight ring-closing metathesis,9 radical additions,ten and titanium-mediated carbon-carbon bond formations.11 Surprisingly, few examples of nucleophilic additions of terminal ynamides, ynesulfonamides, and ynecarbamates to aldehydes, ketones, and also other electrophiles, all requiring strongly basic situations, could be discovered within the literature.12 The?2014 American Chemical Societyabsence of a catalytic procedure that makes it possible for mild carbon- carbon bond formation with acyl chlorides and N-heterocycles is in stark contrast to the wealth of reports on this reaction with terminal alkynes. Encouraged by our previous acquiring that indole-derived ynamines undergo zinc-catalyzed additions with aldehydes toward N-substituted propargylic alcohols, we decided to search for a catalytic variant that is certainly applicable to other electrophiles.13 We now wish to report the coppercatalyzed nucleophilic addition of a readily readily available terminal ynesulfonamide to acyl chlorides and activated pyridines and quinolines furnishing 3-aminoynones and also the corresponding 1,2-dihydro-2-(3-aminoethynyl) N-heterocycles. Propargylic ketones are key intermediates for the preparation of organic goods and heterocyclic compounds and most conveniently prepared through catalytic alkynylation of acyl chlorides14 or via carbonylative Sonogashira coupling.15 Several procedures call for heating and extended reaction occasions and are certainly not applicable to ynamides, which lack the thermal stability of alkynes.16 We therefore investigated the possibility of carbon-carbon bond formation with the readily accessible N-ethynyl-N-phenyl-4-tolylsulfonamide, 1, beneath mild reaction circumstances. Following a literature procedure, we synthesized gram amounts of 1 from N-tosyl aniline, Scheme 1.3 Initial analysis with the reaction involving ynesulfonamide 1 and benzoyl chloride showed that copper(I) salts have been superior more than each zinc and palladium complexes typically utilized in alkynylation reactions.1H-Pyrrole-2,3,5-tricarboxylic acid Chemical name Applying ten mol of cuprous iodide and 2 equiv of diisopropylethylamine in THF, we obtained the desired N-(3-phenyl-3-oxoprop-1-ynyl)-N-phenyl-4-tolylsulfoReceived: February 14, 2014 Published: April 11,dx.(S)-2-Azido-3,3-dimethylbutanoic acid supplier doi.PMID:23800738 org/10.1021/jo500365h | J. Org. Chem. 2014, 79, 4167-The Journal of Organic Chemistry Scheme 1. Synthesis of Ynesulfonamide 1 (Best) and Targeted Catalytic 1,2-Additions (Bottom)Notenamide, 2, in 50 yield after 20 h. The screening of numerous copper(I) salts, organic solvents, base, and temperature revealed that two is often isolated in 90 yield when the reaction is performed in the presence of 10 mol of copper iodide in chloroform at 30 ; see entry 1 in Table 1. For the Table 1. Copper(I)-Catalyzed Addition to Acyl Chloridesexamples with aliphatic electrophiles commonly creating ynones in only moderate yields happen to be reported.14a,e This can in all probability be attributed to fast ketene formation and subsequent side reactions when acyl chlorides exhibiting hydrogens are employed within the presence of base. While the reaction with pivaloyl chloride gave the corresponding propargylic ketone eight in higher yield as expected, we have been really pleased to find that the ynone formation with 2methylpropanoyl chloride proceeds smoothly at 15 offering 9 in 70 yield, entries 7 and 8. As discussed above, the properties and reactivity of ynamines and ynamides are influenced by the amine moiety, which stron.