本篇研究以噁唑烷酮化合物與氰基甲酸乙酯藉由[3+2]環化加成反應合成一系列的雙取代和三取代咪唑化合物。以合成雙取代咪唑化合物而言，先將甘胺酸和苯甲醯氯進行親核性加成反應生成甲醯胺61，再以1-乙基3-(3-二甲氨基)碳二亞胺鹽酸鹽(EDCI)於二氯甲烷中反應半小時進行脫水反應生成噁唑烷酮68，立即加入氰基甲酸乙酯和三丁基磷(0.6當量)於室溫下反應兩至三小時，此一系列的雙取代咪唑化合物64a-k分離後的產率為32-40%。另外以苯甘胺酸和丙胺酸取代甘氨酸與苯甲醯氯反應生成甲醯胺62和63，再以EDCI脫水環化生成噁唑烷酮69和70，並以上述合成雙取代咪唑化合物的合成方法合成三取代咪唑化合物65a-k和66a-k，純化後收得的產率為31- 63%。結合兩者，我們展示了一系列利用一鍋式兩步驟藉由[3+2]環化加成反應生成可提供進行高通量藥物篩選平台的雙取代和三取代的咪唑化合物。 In the current study, we take advantage of oxazolidinone and ethyl formate to carry out [3+2] cycloaddition aimed at synthesizing a series of di- and tri-substituted imidazoles. Regarding the synthesis of di-substituted imidazoles, glycine was taken to couple with benzoyl chloride, followed by the dehydration mediated by 1-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride(EDCI) in DCM to generate oxazolidinone 68 in 30 mins. Without purification, ethyl formate and tributylphosphine (PBu3, 0.6 eq) were further added in the solution and the mixture was stirred at rt for 2 hr. As a result, a small library of di-substituted imidazoles 64a-k was successfully prepared with 32-40% isolated yields. As the synthesis of tri-substituted imidazoles, glycine was replaced with alanine and phenylglycine, both of which were converted into carboxamide 62 and 63 with benzoyl chlorides, followed by EDC-mediated cyclization to generate oxazolidinones 69 and 70 similar to that of oxazolidinone 68. Once again, ethyl formate and tributylphosphine (0.6 eq) were added to the solution and stirred for 2 hr that afforded desired tri-substituted imidazoles 65a-k and 66a-k with 31-63% isolated yields. In summary, we have demonstrated a sequential one-pot two-step synthesis of di- and tri-substituted imidazoles via [3+2] cycloaddition which could feasibly offer a valuable platform for high-throughput drug screening.
