鈀金屬催化麥可加成反應-烯丙基化反應於活化烯類：合成三取代之異㗁唑酮

Pd-Catalyzed Michael Addition-Allylation Reaction on Activated Olefins-Synthesis of Trisubstituted Isoxazolones

黎軒安(Xuan-An Li)

指導教授 ： 劉緒宗

國立臺灣大學/理學院/化學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202003177

摘要

異㗁唑酮常存在於許多天然物、生物活性分子中，該結構於醫藥領域中，顯現出廣泛之應用。
本篇論文中闡述了以胺甲酸烯丙酯1-2在零價鈀金屬催化下，進行脫羧反應後，對亞苄基異㗁唑酮3進行1,4-加成反應。於室溫下且短時間中，合成出中等至不錯產率之對應之異㗁唑酮產物4，為具有單一位置選擇性的β-Michael加成N-烯丙基化之反應。在官能基容忍度測試部分，發現更換亞苄基異㗁唑酮3苯環上的對位取代基為Hammett對位取代基常數 (σp) 小於0者時，產率明顯下降，說明了對位推電子之官能基降低了此種活化烯類之親電性，致使反應性不佳。作為親核基與親電子基來源之胺甲酸烯丙酯1-2的測試方面，根據實驗結果，發現改變烯丙基上的取代對反應結果影響不大，而作為親核基之氮上則必具備羰基，推論為親核基與親電基在脫羧後，需先與鈀金屬生成含氮、氧原子之二-π-烯丙基鈀金屬中間體，才可加成於亞苄基異㗁唑酮3上，否則將生成對應的烯丙基胺副產物。最後根據以上實驗結果與過往文獻，提出了此反應的反應中間體與推測之反應機構。
除以上探討外，產物4結構中的苯甲醯胺基團，能夠在酸性、高溫的條件下脫離，生成帶正電之親電子基中間體，作為一個強Michael受體，與耐酸性環境之不同親核基進行加成，合成出對應產物5以及6，藉此擴展反應中適用之親核基。

關鍵字

烯丙基化 ； 脫羧 ； 鈀金屬 ； 1,4-加成反應 ； 異㗁唑酮

並列摘要

Isoxazolone derivatives possess biological properties and demonstrate a wide range of applications to medicinal chemistry, such as antibacterials and inhibitors. In this study, a palladium(0)-catalyzed protocol has been developed for the synthesis of trisubstituted isoxazolones 4. In the presence of Pd(PPh3)4, reactive nucleophile and electrophile, generated in situ from allyl carbamate 1-2 via palladium-mediated decarboxylation, proceed Michael addition-allylation with arylideneisoxazolones 3 smoothly at ambient temperature to yield the corresponding β-amino N-allyl isoxazolones 4, exhibiting a specific regioselectivity.
The electronic property of para substituents in arylideneisoxazolones 3 has a great influence on the reactivity of activated olefins. Hammett plot analysis reveals the yield of product decreases as the para substituents of the arylideneisoxazolones 3 being electron-donating. Moreover, the carbonyl group on allyl carbamates 1-2 is indispensable to the synthesis of trisubstituted isoxazolones 4. The carbonyl group on N-nucleophile could retard the formation of side product by coordinating to π-allylpalladium. On the basis of these results and reported cases, a plausible mechanism involving an amphiphilic oxazabis-π-allylpalladium intermediate was proposed.
Further investigation shows that isoxazolones 4 undergo acid-promoted amido-elimination followed by a Michael addition of acid-tolerant nucleophiles to afford multifunctionalized isoxazolones 5-6 in good to excellent yield at an elevated temperature.

並列關鍵字

allylation ； decarboxylation ； palladium ； 1,4-addition ； isoxazolone

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