此反應(yīng)相比傳統(tǒng)的疊氮化物-炔環(huán)加成反應(yīng)而言，此反應(yīng)無需疊氮化合物及金屬鹽，原料廉價易得環(huán)境友好，更加安全，更加適合工藝生產(chǎn)。目前，該反應(yīng)已經(jīng)逐漸應(yīng)用于各類天然產(chǎn)物的化學(xué)選擇性修飾與部分生物活性分子的合成。早在2010年，Roger Hanselmann等人就報道了利用此反應(yīng)進(jìn)行公斤級反應(yīng)用于合成macrolide的重要中間體。

反應(yīng)機(jī)理

反應(yīng)實(shí)例

(1-{(1S,2R)-2-[4-(2-Aminopyrimidin-5-yl)-phenyl]-1-fluoromethyl-2-methoxy-ethyl}-1H-[1,2,3]triazol-4-yl)-acetic Acid Ethyl Ester, 17. To a suspension of 11 (3.2 kg, 9.16 mol) in ethanol (11.2 L) was added N,N-diisopropylethylamine (9.9 L,56.8 mol) within 30 min at 0-15 °C. A solution of 10 (4.42kg, 12.1 mol) in MeCN (4.8 kg) was added over 1.5 h at below25 °C. The reaction was held at 20-25 °C for 1 h and thenwarmed to 35 °C and held for 8 h. The reaction mixture wassplit into three parts, and each was diluted with ethyl acetate(9.5 L). Each portion was cooled to 0-5 °C and extracted with1 M HCl (3 × 7.8 L). The combined aqueous extracts werebasified to pH 11 with 50% aqueous NaOH solution (2 kg) at0-5 °C. The cold aqueous solution was extracted with ethylacetate (2 × 9.5 L), and the combined organic extracts wereevaporated. The oil from all three workup portions werecombined, taken up in ethanol (16 L), and concentrated on arotary evaporator, yielding 17 (5.88 kg containing 2.84 kg ethanol, 80%) as an oil. An analytical sample was obtained by crystallizing the dry residue from ethyl acetate.

【Org. Process Res. Dev. 2010, 14, 152–158】