Di Erasmo Benedetta, Bazzica Edoardo, Brufani Giulia, Li Chao-Jun, Vaccaro Luigi
Laboratory of Green S.O.C. - Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy.
Department of Chemistry and FRQNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
ACS Sustain Chem Eng. 2025 Jul 25;13(30):12220-12231. doi: 10.1021/acssuschemeng.5c04668. eCollection 2025 Aug 4.
Alkylated phenols hold significant importance in industrial chemistry, as many pharmaceuticals and polymer additives are based on these scaffolds. However, synthesizing these products in a sustainable way is still challenging because stoichiometric amounts of Lewis acids to promote Friedel-Crafts reactions on benzene and phenol derivatives are often employed, together with drastic and unsafe reaction conditions. In this paper, we present a regioselective process to produce -alkylated phenols, with high atom- and step-economy that minimizes the formation of waste associated with it. The key role is pursued by the dual catalytic system palladium on carbon (Pd/C) and scandium trifluoromethanesulfonate (Sc-(OTf)), which together promote the partial hydrogenation of phenol to cyclohexenone, while the alcohol is oxidized to aldehyde. The so-formed partners couple in an aldol condensation promoted by Sc-(OTf), which is then rearomatized in the air atmosphere. Amylmetacresol (antiseptic) was successfully obtained with this protocol in a one-step synthesis for the first time. Moreover, this process permits the recovery and reuse of the Pd/C catalyst for up to 5 runs. This paved the way for the development of a gram scale-up flow protocol associated with this strategy in an innovative tube-in-tube setup.
烷基化酚在工业化学中具有重要意义，因为许多药物和聚合物添加剂都基于这些骨架结构。然而，以可持续的方式合成这些产品仍然具有挑战性，因为在苯和酚衍生物上促进傅克反应时，通常会使用化学计量的路易斯酸，同时反应条件剧烈且不安全。在本文中，我们提出了一种区域选择性方法来生产α-烷基化酚，该方法具有高原子经济性和步骤经济性，能将与之相关的废物生成降至最低。关键作用由双催化体系碳载钯（Pd/C）和三氟甲磺酸钪（Sc-(OTf)₃）发挥，它们共同促进苯酚部分氢化为环己烯酮，同时醇被氧化为醛。如此形成的反应物在Sc-(OTf)₃促进的羟醛缩合反应中偶联，然后在空气氛围中重新芳构化。首次通过该方案一步合成成功得到了戊基间甲酚（防腐剂）。此外，该过程允许Pd/C催化剂回收并重复使用多达5次。这为在创新的管中管装置中开发与该策略相关的克级放大流动方案铺平了道路。
