不用Click反应，也能制备三氮唑----Sakai对甲苯磺酰腙环化反应

α,α-二氯对甲苯磺酰腙与伯胺之间缩合环化制备1,4-二取代三氮唑的反应，称为Sakai对甲苯磺酰腙环化反应。该反应由日本Sagami化学研究中心的Sakai Kunikazu研究室在1986年首次报道【Bull. Chem. Soc. Jpn. 1986, 59, 179】。此反应不是一个很常用的反应，底物胺只能是伯胺，Ts腙也只能是α,α-二氯对甲苯磺酰腙，这些都限制了其广泛应用。原始的反应条件是两种底物在醇类溶剂中反应，但是底物胺需要过量，后来B. Westermann等人发现加入二异丙基乙胺可以将底物胺减少到一个当量。

此反应相比传统的叠氮化物-炔环加成反应而言，此反应无需叠氮化合物及金属盐，原料廉价易得环境友好，更加安全，更加适合工艺生产。目前，该反应已经逐渐应用于各类天然产物的化学选择性修饰与部分生物活性分子的合成。早在2010年，Roger Hanselmann等人就报道了利用此反应进行公斤级反应用于合成macrolide的重要中间体。

反应机理

反应实例

(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】