Webb Daniel A, Alsudani Zeid, Xu Guolin, Gao Peng, Arnold Leggy A
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee Milwaukee Wisconsin 53211 USA
Sigma-Aldrich Co. LLC 6000 N. Teutonia Ave. Milwaukee WI 53209 USA.
RSC Sustain. 2023 Jul 17;1(6):1522-1529. doi: 10.1039/d3su00005b. eCollection 2023 Sep 7.
The synthesis of 5,5'-bis(trifluoromethyl)-2,2'-bipyridine using 2-bromo-5-(trifluoromethyl) pyridine was achieved at 50 °C using palladium acetate, tetrabutylammonium iodide (TBAI), potassium carbonate, and isopropanol in Cyrene™ (dihydrolevoglucosenone), a bio-renewable "green" solvent formed by a two-step process from cellulose. Improvements were achieved with 50% of γ-valerolactone (GVL) in Cyrene™ resulting in a 95% yield and 99% product purity without the use of column chromatography or recrystallization. At 80 °C, the reaction was completed within 1 h. Full conversion with 1 mol% instead of 15 mol% of palladium acetate was observed within 10 h. We showed that the formed 2,2'-bipyridine product significantly accelerated the reaction probably due to the stabilization of the catalytic species. The addition of TBAI was essential for the rapid homocoupling, however, 20 mol% of TBAI was sufficient to reach full conversion of 2-bromo-5-(trifluoromethyl) pyridine within 6 h at 80 °C. Another improvement was observed with the substitution of isopropanol by 1,4-butanediol achieving full conversion within 6 h. 2-Bromopyridines with electron withdrawing substituents in the 6, 5, 4 ring position reacted under these conditions. 2-Bromopyridines with an electron donating substituent reacted slower. Overall, we demonstrated that the 50% GVL in Cyrene™ blend is a superior "green" and less toxic alternative to dimethylformamide for the reductive homocoupling reaction. Using a quantitative scoring for twelve principles of green chemistry (DOZN™), we found significant improvements that were mediated by higher yield (atom economy), shorter heating time and lower reaction temperature (energy efficiency), safer solvent (hazardous chemical synthesis), and safer chemistry (accident prevention).
以2-溴-5-(三氟甲基)吡啶为原料，在50℃下，使用醋酸钯、碘化四丁基铵（TBAI）、碳酸钾和异丙醇，在由纤维素经两步法形成的生物可再生“绿色”溶剂Cyrene™（二氢左旋葡萄糖酮）中合成了5,5'-双(三氟甲基)-2,2'-联吡啶。在Cyrene™中加入50%的γ-戊内酯（GVL）可提高产率，无需柱色谱或重结晶即可实现95%的产率和99%的产物纯度。在80℃下，反应在1小时内完成。在10小时内观察到使用1 mol%而非15 mol%的醋酸钯可实现完全转化。我们表明，形成的2,2'-联吡啶产物可能由于催化物种的稳定而显著加速了反应。TBAI的添加对于快速均偶联至关重要，但20 mol%的TBAI足以在80℃下6小时内使2-溴-5-(三氟甲基)吡啶完全转化。用1,4-丁二醇替代异丙醇可在6小时内实现完全转化，这是另一个改进。在这些条件下，在6、5、4环位置带有吸电子取代基的2-溴吡啶会发生反应。带有供电子取代基的2-溴吡啶反应较慢。总体而言，我们证明了Cyrene™中50%的GVL混合物是用于还原均偶联反应的比二甲基甲酰胺更优的“绿色”且毒性更低的替代品。通过对绿色化学的十二条原则进行定量评分（DOZN™），我们发现由于更高的产率（原子经济性）、更短的加热时间和更低的反应温度（能源效率）、更安全的溶剂（危险化学合成）以及更安全的化学过程（事故预防），实现了显著的改进。
