室温下将羧酸还原为醛

chem 3796 0
一直以来,没有简单易操作的直接还原羧酸得到醛的方法。想将羧酸还原到醛,传统的还原剂无法将还原停留在醛这一步,最常规的方法就是先将羧酸还原到醇,然后用一些常见的氧化反应(Dess-Martin高碘烷氧化,Swern氧化反应,PCC(Pyrindium Chlorochromate)氧化等等)重新将醇氧为醛。

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图片来源:StrategicApplications of Named Reactions in Organic Synthesis

或者先将羧酸转化为Weinreb酰胺然后在还原,由于Weinreb酰胺和金属还原试剂(DIBALH或LAH)的加成物由于酰胺上N-甲氧基的存在形成一个五元环的螯合物相对稳定,使反应不再继续。还原Weinreb酰胺得到醛时,DIBAL的产率通常高于LAH。

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还有就是将羧酸转化为酰氯,利用Rosenmund还原,通过降低催化剂的活性来源控制还原停留在醛。酰氯也可以用金属还原试剂在低温下还原,控制还原停留在醛,但是这种控制成功率较低,很多情况下都会还原到醇。另外酯利用DIBALH在-78℃还原也是类似的情况,很难控制。

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Synthesis 1976, 767–768】


另外还可以将羧酸衍生为硫代酸酯,通过Fukuyama还原反应还原为醛,但是味道限制了此反应的应用。如果将羧酸转化为腈再进行还原就更加曲折了。

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近期,中科院兰州化学物理研究所刘超教授团队联合武汉大学戚孝天教授团队在《Angewandte Chemie International Edition》上发表了一种直接将羧酸还原为醛的新方法。在三氟甲磺酰基吡啶鎓盐促进下,室温下利用频哪醇硼烷快速可控的还原羧酸到醛。他们开创性的利用三氟甲磺酰基吡啶鎓盐将羧酸转化为酰基吡啶中间体,利用频哪醇硼烷将酰基吡啶中间体还原为醛。并且他们通过理论研究表明,还原酰基吡啶中间体比醛需要更低的活化自由能。此方法条件温和,易于操作,底物应用范围广,底物手性保持不易消旋,此方法的另一个一个优点就是可以用于连续流动化学进行规模化合成。

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反应的底物应用范围极广,芳香羧酸,脂肪羧酸都适用此条件,手性氨基酸还原后还能保持很高的ee值。

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反应机理

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利用密度泛函理论计算,对这一机理进行了验证。

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反应操作

Synthesis of Tf-DMAP, Tf-DPAP and Tf-MPLP

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Into a solution of DMAP (61.1 g, 500.0 mmol.) in DCM (800.0 mL) was added(CF3SO2)2O (101.0 mL, 600.0 mmol, 1.2 equiv) at 0 oC. After addition, the mixture was warmed to room temperature and stirred for 4 h. The crude product was precipitated from the solution. After filtration, the solid was washed with DCM (400 mL × 4), then dried under reduced pressure to give the pure product as a white powder (191.9 g, 95%). The synthesis of Tf-DPAP and Tf-MPLP were similar to that of Tf-DMAP.

Synthesis of Tf-PPDP

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Into a solution of 4-piperidin-1-ylpyridine (32.4 g, 200.0 mmol, 1.0 equiv.) in DCM (300.0 mL) was added (CF3SO2)2O (40.4 mL, 240.0 mmol, 1.2 equiv.) at 0 oC. After addition, the mixture was warmed to room temperature and stirred for 4h. Upon completion, 200 mL of n-hexane was added and the crude product precipitated out of solution. After filtration, the solid was washed with hexane (100 mL × 2), then dried under reduced pressure to give the pure product as a white powder (84.3 g, 95%).

General Procedure:

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To a 25 mL Schlenk tube equipped with a magnetic stirring bar, carboxylic acid (0.3 or 1.0 mmol, 1.0 equiv), base (1.6 or 1.8 equiv) and DCM (2.0 ~ 5.0 mL) were added under a dry nitrogen atmosphere. Then the Tf-PPDP (1.7 equiv) and HBpin (1.1 ~ 1.8 equiv) were added to the reaction mixture. After the reaction was stirred for 10 min, the crude mixture was quenched by H2O and extracted by DCM (3 x 3.0 mL). The combined organic layers were dried over anhydrous Na2SO4. After the solvent was removed under reduced pressure, the resulting residue was purified by flash column chromatography on silica gel and eluted with petroleum ether/ethyl acetate to afford the desired aldehydes.


参考资料

Triflylpyridinium Enables Rapid and Scalable Controlled Reduction of Carboxylic Acids to Aldehydes using Pinacolborane,

Angewandte Chemie International Edition, 2023, 62, e202215168;  doi.org/10.1002/anie.202215168

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