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Mitsunobu反应是有机合成中非常重要的一个反应，最常用的活化试剂就是三苯基膦（PPh3）和偶氮二甲酸二乙酯（DEAD）。经过多年的研究和发展，由底物醇出发形成了一大类合成应用，如醇的构型反转，成醚，成碳杂键，甚至形成新的碳碳键，称之为Mitsunobu 反应。这类反应被广泛应用在有机合成，特别是天然产物的合成中。
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但是Mitsunobu反应对于空间位阻较大的醇和酸性较弱的亲核试剂都不能取得相对较高的收率，甚至有时候完全不能发生反应。在遇到这些情况时，建议试一下Tsunoda试剂。
图片来源：化学空间
Tsunoda试剂由Tsunods等人在1994年首先报道，利用三丁基膦与氯乙腈反应形成的季鏻盐进一步与正丁基锂反应，最终获得CMBP (cyanomethylene tributylphosphorane) 试剂。之后，Tsunoda课题组研究发现，CMBP试剂能够顺利将Mitsunobu反应的底物应用范围扩展至各类二级醇以及pKa≥12的弱酸 (如N-甲基对甲苯磺酰胺，N-苄基三氟甲基乙酰胺)【Tetrahedron Lett. 1994, 35, 5081–5082】。
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CMBP作为活化试剂，在室温条件下反应产率由于经典的DEAD-TPP条件，但是效果不如TMAD-TBP条件。CMBP的优点是稳定性好，可以加热到100℃进行反应。
图片来源：化学空间
后续他们利用三甲基膦替代三丁基膦制备得到的CMMP, 活性更高，反应收率进一步提高，亲核试剂的pKa范围扩展至11~23。【Tetrahedron Lett. 1996, 37, 2459；Chem. Pharm. Bull. 2003, 51, 474】。Tsunoda试剂可以合成传统的Mitsunobu反应无法合成的各种环状化合物、环醚和环状脂肪胺等等。CMBP与CMMP都称为Tsunoda试剂。Tsunoda试剂具有较高的热稳定性，能够获得更高的收率以及更为广泛的底物适用范围。
反应操作：氩气保护下，将醇 (1 mmol)和HA (1.5 mmol)溶于干燥的苯(5 mL，建议用甲苯代替)，加入CMBP (1.5 mmol)，加热至100℃反应24小时。浓缩，柱层析纯化。
反应机理
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【Tetrahedron Lett. 1996, 37, 2459】![]()
Typical experimental procedure:1) (Cyanomethylene)tributylphosphorane (262 L, 1.00 mmol) was added to a solution of (tetrahydrofuran-3-yl)methanol (51 mg, 0.50 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (97 mg, 0.5 mmol) in degassed 1,4-dioxane (2 mL) sealed in a microwave tube at rt under nitrogen. The solution was heated to 150 °C for 30 min in the microwave reactor and cooled to rt.2) 1-Bromo-4-methoxybenzene (94 mg, 0.50 mmol), potassium carbonate (207 mg, 1.50 mmol) and [1,1'-Bis (diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (40.8 mg, 0.05 mmol) were added to the solution. The tube was sealed, evacuated and backfilled with nitrogen. Degassed water (1 mL) was added under nitrogen. The resulting mixture was stirred at 120 °C for 20 min. The reaction mixture was diluted with EtOAc (25 mL) and water (15 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (15mL). The combined organic layers were washed with saturated brine (15 mL). The organic layer was dried with MgSO4, filtered and evaporated to afford the crude product. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5µ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% by volume NH3OH (28-30% in H2O)) and MeCN as eluents to afford 4-(4-methoxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole (89 mg, 69 %) as a beige solid.【Tetrahedron Letters 2018，59，1708–1710】
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【Tetrahedron Lett. 1996, 37, 2463】
参考资料：
一、Mitsunobu反应
二、https://cn.chem-station.com/reactions/2020/10/tsunoda%e8%af%95%e5%89%82.html
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