室温下苯甲酸直接脱羧合成苯酚，简便可放大！
文摘
科学
2024-10-05 20:57
四川
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点击上方蓝色文字进行关注酚类化合物普遍存在于天然产物、药物、农用化学品和功能聚合物中，还可以作为有机合成中的多用途合成中间体。因此，开发简单、高效地制备苯酚的实用方法是有机化学中的一个重要研究课题。目前由各种芳基前体合成苯酚的策略主要包括以下几点：- 在过渡金属的辅助下，C−X键以氧化还原中性的方式转化为C−O键；
与芳基卤化物和芳基金属不同，苯甲酸是稳定的，对水分和空气不敏感，易于获得，具有广泛的结构多样性，也可以从生物质平台中提取。因此，非常需要一种简单有效的方法将苯甲酸转化为苯酚。与其他芳基前体相比，将苯甲酸转化为酚类（即脱羧氧化）将更具挑战性，因为脱羧过程的能量势垒很高。芳香族脱羧功能化的已知方法通常需要专门的底物（即邻位取代的苯甲酸）或非常高的温度。本期小编将给大家一种简便、可放大、安全的苯甲酸直接合成苯酚的新方法，还无需金属催化。受到经典Hofmann降解的启发，该降解通过芳基[1, 2]-迁移将伯苯甲酰胺1转化为苯胺2（下图a）。因此，当找到合适的离去基团时，类似的[1, 2]-迁移也可能进行（下图b，3到4），从而构建所需的芳香族C−O键。在这一假设的指导下，作者在各种条件下评估了常见的卤素氧化剂，这些氧化剂都未能形成C−O键（下图b，反应1）。近些年研究较多的NHPI酯5，即使在路易斯酸或Brønsted酸的辅助下也不能迁移得到6。考虑到O−O键（35 kcal/mol）明显弱于N−O键，苯甲酸通过缩合转化为各种过氧衍生物。在多种条件下评估了这些过氧衍生物的迁移反应性。最后发现，过氧苯甲酸7和过氧苯甲酸叔丁酯8都不能顺利迁移，而过氧苯甲酸间氯苯甲酸酯10，在室温（约25°C）下，即可有效迁移，以88%的产率得到目标迁移产物11。
该反应的底物适用性也相当不错，并且可以进行较大规模的反应（12-14），苯环上的氯、溴、碘、酰胺、呋喃、吲哚和硝基都可以很好地兼容，具体底物例子可以见下图。此外，肉桂酸也能顺利得到相应的烯基酯（51，53）。
当取代的芳香酸比间氯苯甲酸更缺电子时，则需要在酸诱导的重排之前将底物转化为对称的过氧化二苯甲酰基，如F（54）、CF3（55）、NO2（56）、磺酰胺（57）、砜（58）和含氮杂环（59−60），都可以在标准TfOH/DCM条件下得到相应的苯酚（下图）。值得注意的是，57和59都直接来源于药物分子丙磺舒和ataluren。可扩展性和与不同官能团的兼容性清楚地确立了这种新型芳香族脱羧氧化方案的多功能性和稳健性。值得注意的是，这种方法仍有一些局限性。因为这种方法需要过氧化物活化和强酸，所以对氧化剂和强酸敏感的苯甲酸不是合适的底物作者还将该反应作为关键合成步骤合成了γ分泌酶抑制剂。运用该方法，先将3,5-二氯苯甲酸62转化为3,5-二氯苯酚63，后续再经两步偶联得到γ分泌酶抑制剂68。为了进一步证明这种芳香脱羧氧化的合成价值，作者还展示了不对称六芳基苯（HAB）的合成。HABs是化学和材料中重要的分子结构，引起了人们的广泛关注。目前的HABs相关研究主要基于对称HABs，因为不对称HABs的合成非常具有挑战性。以苯甲酸脱羧氧化为苯酚作为关键步骤，继而可以在酚羟基邻位引入卤素，再偶联，即可顺利得到六芳基苯。机制研究表明，关键的迁移步骤涉及游离碳正离子（96）而不是自由基中间体。该方法是一个在室温下用简单的有机试剂从苯甲酸直接制备苯酚的有效而实用的策略。这种方法与各种官能团和杂环相容，并且可以很容易地放大。考虑到苯甲酸的丰富性和酚类化合物的实用性，小编认为该方法有望在有机合成中得到广泛应用。大家不妨尽快一试。A round-bottom flask (100.0 mL) was charged with benzoic acid (12.0 mmol, 1.0 equiv),
dry DCM (50.0 mL) and catalytic amount of DMF (8.0 drops). The reaction mixture
was cooled to 0 ℃ and stirred for 5 minutes. Then, (COCl)2 (1524.0 L, 1.5 equiv) was
added dropwise to the reaction mixture and stirred at 25 ℃ for 8 h. The resulting
mixture was concentrated under reduced pressure to afford acid chloride quantitatively
which was used directly without further purification for the next step. To a solution of acid chloride (1.0 equiv) and K2CO3 (4968.0 mg, 3.0 equiv) in dry
DCM (50.0 mL), 75% m-CPBA (3037.0 mg, 1.1 equiv) was added and the reaction mixture was stirred at 25 ℃ for 4 h. Then water (100.0 mL) was added, the organic
layer was separated and the aqueous layer was extracted with EtOAc (3 × 50.0 mL).
After that, the organic layer was dried over Na2SO4 and concentrated under reduced
pressure to afford diacyl peroxides which was used directly without further purification
for the next step. Diacyl peroxides (1.0 equiv), CF3SO3H (0.8 equiv) were added into dry DCM (50.0
mL) in a reaction flask with a septum (100.0 mL), which was evacuated and back-filled
with high-purified N2 for three times prior to use. The reaction was stirred at 25 ℃ for
4 h. Then, the resulting solution was concentrated under vacuo to provide the
corresponding phenol ester. To the reaction flask (100.0 mL) containing phenolic ester,
a magnetic stir bar, K2CO3 (3.0 equiv) and CH3OH (40.0 mL) were added, which was
then evacuated and back-filled with high-purified N2 for three times prior to use. The
reaction mixture was stirred at 25 ℃ and monitored by TLC until the phenolic ester
was fully consumed. The reaction mixture was acidified by addition of 1 M aqueous
HCl to pH = 3-5. The solution was concentrated to about 10% or less of its volume
under reduced pressure. The remaining suspension was dissolved in EtOAc (60.0 mL)
and transferred into a separatory funnel containing saturated aqueous NaHCO3 (20.0
mL) and H2O (20.0 mL) . The organic layer was collected, and the aqueous layer was
further extracted with EtOAc (3 × ca. 40.0 mL). The combined organic layers were
dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to
dryness. The residue was purified by chromatography on silica gel to afford the phenol
derivatives. 点了在看![]()
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