二苯基苄基氧膦催化量实现Mitsunobu反应

前几天小编介绍了一篇后处理除去三苯氧膦的文章【 最新《Org. Process Res. Dev.》：三苯基氧膦后处理又出新方法！ 】，总之三苯氧膦给有机合成人员带来各种麻烦。然而非不巧的是，在合成中非常重要的一个反应----Mitsunobu反应的当量副产物就是三苯氧膦。Mitsunobu反应是一种双分子亲核取代反应（SN2反应）。1967年， Mitsunobu 报道了在三苯基膦（PPh₃）和偶氮二甲酸二乙酯（DEAD）作用下酸和醇缩合成酯的新方法。当底物为仲醇的时候，与羟基相连的碳原子的构型会发生翻转。经过多年的研究和发展，形成了一大类合成方法，可以用于手性醇的构型反转，制备各种酯，由醇直接制备胺，由醇制备醚，醇的硫代反应，醇的卤化反应等等，我们总称之为 Mitsunobu反应 。

说到 Mitsunobu反应 ，小伙伴们肯定立刻想到三苯基膦/DEAD(DIAD), 但是2019年《Science》上发表了一篇名为《Redox-neutral organocatalytic Mitsunobu reactions 》文章，通讯作者是诺丁汉大学化学系Ross M. Denton教授， Ross M. Denton教授团队开发的是一种不涉及氧化还原反应的有机催化的 Mitsunobu反应 。传统的 Mitsunobu反应 中涉及氧化还原反应，三苯基膦被氧化为三苯氧膦，DEAD被氧化为二烷氧酰基肼，而且都会化学当量参与反应。他们利用一种二苯基苄基氧膦作为催化剂，在加热条件下就可以实现Mitsunobu反应，反应产生的唯一副产物就是水。经过验证基本上可以实现各种类型的Mitsunobu反应，构型反转也非常有效。甚至可以实现传统Mitsunobu反应不能实现的脂肪醇的自身成醚反应。【 Science 365, 910–914 (2019)； DOI: 10.1126/science.aax335】

反应机理

五价有机膦催化剂的氧化态始终不变，作者推测它将被酸性前亲核试剂活化，并进行循环和脱水得到氧鏻盐 2，通过醇亲核开环得到常规中间体烷氧基鏻-亲核离子对 3。随后发生亲核取代应得到产物并再生膦氧化物 1，完成催化循环。这种方法没有氧化还原变化，水是唯一的副产物。反应以甲苯或者二甲苯为溶剂，使用Dean-Stark分水器共沸除水对催化循环至关重要，因为鏻盐中间体是动力学和热力学不稳定的，易发生水解。低Brønsted酸性的亲核试剂如苯甲酸很难促进催化作用

脂肪醇的成醚反应需要另外加入TfOH催化。

反应的底物验证：

反应操作

催化剂的制备也非常方便：

(2-methoxybenzyl)diphenylphosphine oxide (13) To a solution of diphenylphosphine oxide (8.43 g, 41.6 mmol) in THF (120 mL) was added NaH (2.50 g, 62.5 mmol of a 60% w/w dispersion in oil)in portions at 0 °C. The suspension was warmed to 18 °C, and after 30 minutes was re-cooled to 0 °C before 1-(bromomethyl)-2-methoxybenzene (S1) (10.0 g, 50.0 mmol) was added and the mixture was then warmed to room temperature and stirred for a further 1 hour. The reaction mixture was then quenched with water at 0 °C and extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. The crude organic residue was purified by trituration with Et2O to afford the title compound as an off-white solid. (11.05 g, 82%)。

(2-hydroxybenzyl)diphenylphosphine oxide To a solution of 13 (11.0 g, 34.3 mmol) in CH2Cl2 (75 mL) was added BBr3 (75 mL, 75 mmol of a 1.0 M solution in CH2Cl2) dropwise at 0 °C. The reaction mixture was warmed to ambient temperature and stirred for 16 hours, after which reaction was quenched by careful addition of H2O (50 mL). The pH of the aqueous layer was adjusted to pH 8 using sat. NaHCO3 (30 mL) before being extracted CH2Cl2 (3 × 75 mL). The combined organic extracts were washed with sat. NaHCO3 (75 mL), then brine (75 mL), dried over MgSO4 and concentrated in vacuo. The crude organic residue was purified by trituration with Et2O to afford the title compound as a white solid (8.95 g, 84%).

A suspension of alcohol (1.0 equiv.), 2,4-dinitrobenzoic acid (1.0 equiv.) and catalyst 1 (5-25 mol%) in xylenes (12.5 mL per mmol of alcohol) was heated to reflux in a Dean-Stark apparatus and stirred for 48 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc and washed with 1 M NaOH (aq) solution twice then brine. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was purified by flash column chromatography to afford the inverted ester product.*

*If desired, the catalyst can be recovered by flash column chromatography. The catalyst elutes with 1:1 EtOAc:petrol and is usually recovered with 50-90% yield (dependent on the substrate.)

General Procedure for N,N-bis-sulfonamidation

A suspension of dibenzenesulfonamide (297 mg, 1.00 mmol), alcohol (1.00 mmol) and catalyst 1(31 mg, 0.10 mmol) in xylenes (12.5 mL) was heated to reflux in a Dean-Stark apparatus and stirred for 48 hours. The reaction mixture was then concentrated in vacuo and purified by flash column chromatography to afford the N-substituted N,N-bis-sulfonamide.

A suspension of isoamyl alcohol (1.31 mL, 12.0 mmol), p-toluenesulfonic acid monohydrate (2.28 g, 12.0 mmol) and catalyst 1 (185 mg, 0.600 mmol) in toluene (75 mL) was heated to reflux in a Dean-Stark apparatus and stirred for 16 hours. Afterwards, the reaction mixture was cooled, 4-nitrophenol (2.00g, 14.4 mmol), caesium carbonate (4.69 g, 14.4 mmol) and DMF (30 mL) was added and the reaction was heated to reflux and stirred for 3 hours. The reaction mixture was concentrated, CH2Cl2 (300 mL) was added and the yellow precipitate was collected by filtration.* The filtrate was concentrated and the crude residue was purified by flash column chromatography (SiO2, 1:9 EtOAc/petrol) to afford 1-(isopentyloxy)-4-nitrobenzene as a colorless oil (2.16 g, 86%)

In a round bottom flask was added sequentially 1-decanol (190 μL, 1.0 mmol), catalyst 1 (30.8 mg, 100 μmol), toluene (12.5 mL), and trifluoromethanesulfonic acid (8.8 μL, 100 μmol). The flask was fitted with a Dean-Stark apparatus, the joints were sealed with Teflon tape, and the reaction mixture was heated to reflux and stirred for 30 hours. The reaction mixture was then cooled to room temperature. The volatiles were evaporated in vacuo, 1,1,2,2-tetrachloroethane (106 μL, 1.00 mmol) was added as a 1H NMR internal standard so that the yield could be determined (78% didecylether 12). The remaining mass balance was decanol and decyl triflate.

此方法明显的优点就是避免使用当量的三苯基膦和偶氮二羧酸酯，极大的方便了后处理纯化过程，但是反应需要高温回流除水，也是一个美中不足的地方。这种新的Mitsunobu反应模式对于我们在有机合成的路线选择上有了新的启发。

参考资料

Redox-neutral organocatalytic Mitsunobu reactions； Science 365, 910–914 (2019)； DOI: 10.1126/science.aax335