F ethyl chloroformate with all the methyl or benzyl derivative proved detrimental towards the conversion. Using our optimized procedure with ethyl chloroformate and 2 equiv of base, we were capable to isolate ten in 71 yield following 2.five h at space temperature; see entry 1 in Table two. We then applied our catalytic procedure to various pyridine analogues and obtained the corresponding 1,2-dihydropyridines 11-14 in 72-96 yield, entries 2-5. The coppercatalyzed ynamide addition to activated pyridines and quinolines commonly shows quantitative conversion, but the yield on the preferred 1,2-dihydro-2-(2-aminoethynyl)heterocycles is in some circumstances compromised by concomitant formation of noticeable amounts from the 1,4-regioisomer. With pyridine substrates we observed that the ratio of the 1,2versus the 1,4-addition solution varied involving 3:1 and 7:1 unless the para-position was blocked, when solvents (acetonitrile, N-methylpyrrolidinone, acetone, nitromethane, tetrahydrofuran, chloroform, and dichloromethane) and temperature changes (-78 to 25 ) had literally no impact around the regioselectivity but impacted the conversion of this reaction.(S,Sp)-Taniaphos Formula 19 The 1,2-dihydropyridine generated from 4methoxypyridine swiftly hydrolyses upon acidic workup and cautious chromatographic purification on basic alumina gave ketone 15 in 78 yield, entry 6. It truly is noteworthy that the synthesis of functionalized piperidinones which include 15 has come to be increasingly critical resulting from the use of these versatile intermediates in medicinal chemistry.Price of 2-Bromo-4-fluorophenol 18a We were pleased to seek out that our system also can be applied to quinolines.PMID:23865629 The ynamide addition to quinoline gave Nethoxyarbonyl-1,2-dihydro-2-(N-phenyl-N-tosylaminoethynyl)quinoline, 16, in 91 yield, entry 7 in Table two. In contrast to pyridines, the reaction with quinolines apparently occurs with higher 1,2-regioselectivity and no sign of your 1,4-addition solution was observed. Finally, four,7-dichloro- and 4-chloro-6methoxyquinoline have been converted to 17 and 18 with 82-88 yield and 19 was obtained in 95 yield from phenanthridine, entries 8-10. In analogy to metal-catalyzed nucleophilic additions with alkynes, we believe that side-on coordination in the ynamide to copper(I) increases the acidity in the terminal CH bond. Deprotonation by the tertiary amine base then produces a copper complex that reacts with the electrophilic acyl chloride or activated N-heterocycle and regenerates the catalyst, Figure three. The ynamide additions are sluggish in the absence of CuI. We found that the synthesis of aminoynone, two, from 1 and benzoyl chloride is pretty much full after 10 h, but much less than 50 ynamide consumption and formation of unidentified byproducts had been observed when the reaction was performedNoteTable two. Copper(I)-Catalyzed Ynamide Addition to Activated Pyridines and QuinolonesaIsolated yield.with no the catalyst. NMR monitoring with the catalytic ynamide addition for the activated quinoline ring showed quantitative conversion to 1,2-dihydro-2-aminoethynylquinoline, 16, within 20 min, whereas no solution was isolated when the reaction was carried out in the absence of CuI for two.five h. In conclusion, we’ve got created the very first catalytic addition of a readily available ynesulfonamide to aliphatic and aromatic acyl chlorides. A slightly modified procedure has been successfully made use of for regioselective 1,2-addition of ynamides to pyridines and quinolines. Each reactions happen under mild conditions and give unprecedented access to a variety of 3aminoynones and 1,2-dihyd.