Gold-catalysed cycloisomerisation reactions of 2-(2-propynyl)pyridine N-oxides leading to indolizinones

Masahito Murai, Sachie Kitabata, Kazuhiro Okamoto, Kouichi Ohe
2012 Chemical Communications  
Gold(I)-catalysed tandem oxygen-transfer/cycloisomerisation reacion of 2-(2-propynyl)pyridine N-oxides provides an atomeconomical route to indolizinone frameworks. 10 Indolizinones, the structure of which are closely related to that of indolizines which exhibit strong anti-inflammatory, anti-HIV, and anti-leukemia, have been exploited as privileged structural motifs in the development of biologically active molecules. 1 Development of efficient and selective 15 constructions of these
more » ... s with different substitution patterns from readily available starting materials under mild conditions remains an important task in synthetic chemistry. In this regard, transition metal-catalysed cycloisomerisation reaction of heteroatom-functionalized alkynes has received 20 considerable attention, since they provide a wide variety of complexed heterocycles with high atom-efficiency. 2 - Alkyne metal complexes are key intermediates capable of undergoing a wide range of reactions. Perhaps most commonly, they induce the addition of internal nucleophiles 25 with a suitable length of tethers leading to zwitterion (or metallocarbenoid) intermediates. A variety of oxygen species may serve as the nucleophiles: carbonyl (C=O), 2,3 epoxides, 2,4 amine N-oxides (R 3 N + O  ), 5 nitrones, 6 nitro, 7 and sulfoxides (R 2 S=O) 8 have been employed with various transition-metal 30 catalysts. In line with our recent interests in the development of facile and efficient cycloisomerisation reactions leading to heterocycles, 9 we applied oxygen transfer from pyridine Noxide 10 to alkynes activated with transition metals A to the generation of zwitterions B or metallocarbenoids C (Scheme 35 1). 11 Since resulting metallocarbenoids C possess reactive pyridyl groups, they might be further converted into nitrogencontaining heterocycles. Herein, we wish to report goldcatalysed cycloisomerisation of 2-(2-propynyl)pyridine Noxides leading to indolizinones via acyl[(2-pyridyl)methyl]-40 carbenoid complexes. 12 We reported the atom-economical generation of (2furyl)carbene complexes using carbonyl-ene-yne compounds as their precursors. 13 In the course of our continuing studies on such reactive intermediates, we have found the novel method for the 45 generation of carbene complexes bearing a pyridyl group from pyridine N-oxides having alkyne moieties. When, pyridine N-50 55 Scheme 1 Transition Metal-induced Oxygen-transfer in Pyridine N-Oxides Involving an Alkyne Moiety. 60 oxide 1a was treated with 5 mol% of AuCl(P t Bu 3 )/AgSbF 6 in ClCH 2 CH 2 Cl at rt (Scheme 2), -pyridylenone 2 (E:Z = 92:8) and indolizinone 3a were obtained in 59% and 41% yields, respectively. The relative stereochemistry of 3a was established 65 by X-ray crystallography. 14 When the reaction was carried out at 50 °C, the total yield of 2 was decreased to 25%, whereas the yield of 3a was raised up to 75%. These results indicate that 3a might be formed by the cycloisomerisation of 2 under the reaction conditions. 70 75 Scheme 2 Gold(I)-catalysed Cycloisomerisation of 1a. 80 This interesting result stimulated us to optimize conditions for the cycloisomeriszation of 1a leading to indolizinone 3a. The results are summarized in Table 1 . First, reactions of 1a in the presence of other gold catalysts were examined. While reactions were generally sluggish in the presence of neutral gold catalysts, 85 such as AuCl, AuCl 3 , and AuCl(P t Bu 3 ) (entries 1-3), cationic gold species prepared in situ from the reaction of equimolar amounts of gold and silver salts exhibited much higher catalytic activity (entries 4-5). The combination of AuCl(P t Bu 3 )/AgSbF 6 was the catalyst of choice for this cycloisomerisation and the yield of 3a 90 was improved to 86% when the reaction temperature was increased to 80 °C (entry 6). Furthermore, we found that reducing the catalyst loading to 2 mol% did not influence the selectivity and efficiency of the reaction (entry 7). 15 The use of
doi:10.1039/c2cc32628k pmid:22728547 fatcat:pd5o44opkzc7zhdeyhnhvajibi