格式试剂及其制备和应用

格氏试剂也叫格林尼亚试剂，是法国化学家维克多•格林尼亚于1900年左右发现的，它是一种分子内含卤化镁的有机金属化合物。格式试剂是一种很强的亲核试剂，原因是其分子内含有碳负离子。格氏试剂的研发初衷是为了延长碳链，但是反应进行的很慢；接着又发现格式试剂在加成反应上的作用，进而被广泛的使用。格氏试剂在有机合成上的用途十分广泛，因此市场上有多种在售的格氏试剂。

格氏试剂是极强的路易斯碱，极易夺取其他物质的质子氢，因此无论是制备还是储存，都应该绝对无水，乙醇，氨，端炔等含有活泼质子的物质。

格式试剂的制备方法：用卤代烃和镁屑在无水THF，乙醚和甲叔醚中制得，反应需要引发。制备格式试剂的注意事项：

1，一般使用镁屑，不建议使用镁粉。因为镁粉易氧化，而且会使反应十分剧烈，不好控制。镁屑的处理方法：①用砂纸将镁条表面的氧化膜打磨掉，然后将镁条剪成镁屑；②用1N的盐酸洗涤镁屑，然后再用水洗，乙醇洗，最后用乙醚洗，真空条件下干燥，惰性气体保护备用；③新买的镁屑可以直接使用，效果还很不错。

2，直接购买的卤代物一般可以直接使用；如果卤代物是自己合成的，在使用前尽量做一下无水处理。反应所用溶剂一般为干燥的THF，甲叔醚或乙醚，市场上都能买到。反应所用的搅拌子和瓶子尽量做一下干燥处理。

3，反应所用的引发剂为：碘，碘甲烷，二溴乙烷，三甲基氯硅烷等，有些时候也用现成的格式试剂来做引发剂。

4，底物活性：底物（以溴苯为例）上供电子基团越多，格式试剂越难做，而生成的格式试剂的稳定性就越高；相反，底物上拉电子基团越多，格式试剂越易做，而生成的格式试剂的稳定性就越差，多为自身偶联的副产物。底物（以溴苯为例）溴邻位有卤素原子时，得到的格式试剂的稳定性很差；一般来说，苄基和烯丙基类的格式试剂的稳定性也很差。

5，基本操作步骤举例：向插有温度计的干燥的三口瓶中依次加入镁屑(1.1mmol)、引发剂碘(5%mmol)和搅拌子，在氮气保护下加入无水THF和1/10的溴苯的THF溶液，用电吹风加热反应体系，当体系颜色由红色变为白色时，停止加热，待温度冷却到50度时，缓慢滴加溴苯的THF溶液，保持温度在50度左右，加完后将体系置于50度油浴锅搅拌1h。反应液冷却至室温，待用。

格式试剂的应用

格式试剂可以和醇，末端炔，醛，酮，酯，酰卤，腈， Weinreb酰胺，环氧乙烷，卤代烷，二氧化碳等发生反应。下面将简单举一些实例：

1：和醛，酮反应                                                                  

格式试剂和醛、酮的加成反应是一个被广泛应用的制备醇类化合物的方法。

[TetrahedronLetters, 2014, vol. 55, # 41, p. 5591 - 5594]

Procedure：To a 0 °C solution of pyrimidine-2-carbaldehyde(23.1 mmol) in THF (25 mL) under N₂ was added ethyl magnesiumbromide (0.5 M in THF, 27.5 mmol) dropwise over 15 min. After stirring at 0 °Cafter 30 min, the mixture was allowed to warm with the ice bath to rt and stirredat rt for 3.5 hr. The resulting reaction mixture was treated with saturatedaqueous NH₄Cl solution (15 mL) followed by water (35 mL), extractedwith EtOAc (2 × 10 mL). (2.17 g, 68% yield)

[Journalof Medicinal Chemistry, 2013, vol. 56, # 2, p. 460 - 470]

Procedure：To a solution of ketone (1.0 eq) in anhydrousTHF was added dropwise a solution of an appropriate Grignard reagent (2.0−3.0eq) under an N₂ at −78 °C. The reaction was stirred at the sametemperature for another 1 h, and subsequently warmed to room temperature. Afterbeing stirred for 15 h, the reaction was quenched with saturated aqueous NHCl₄(5 mL), extracted with EA (3 × 10 mL), dried over MgSO4, and concentrated invacuo. The residue was purified by flash chromatography on silica gel to yieldthe corresponding alcohol.

2：和酯反应

Procedure：Phenyl magnesium bromide (3 M solution inether; 100 ml.) was added dropwise to a solution of methyl 5-methylisoxazole-3-carboxylate(20.2 g) in anhydrous THF (300 ml.) at -10⁰C under a nitrogenatmosphere. The reaction mixture was stirred at -10⁰C for 5 mins,then allowed to warm up to rt and stirred for 18 hours. The reaction mixturewas poured into cold 1 M HCI (300 ml.) and extracted with ether. The combinedorganic extracts were washed with NaHCO₃, water, and brine, dried(MgSO4), filtered and evaporated in vacuo to give(5-methyl-isoxazol-3-yl)-diphenyl-methanol (37.21 g, 98percent) as a waxy solid.

3：和炔反应

[Synthesis(Germany), 2017, vol. 49, # 1, art. no. SS-2016-Z0504-OP, p.209 - 217]

Procedure：A suspension of CuI (494 mg, 0.5 equiv) intoluene (6 mL) was cooled to -78 °C. Then, propargyl alcohol (300 μL, 1.0equiv) and PhMgBr (15.6 mL, 1.0 Min THF, 3.0 equiv) were added, and the mixturewas warmed to room temperature overnight. After the addition of NH4Cl solution(2 mL), the layers were separated, and the aqueous layer was extracted withEtOAc (3 × 10 mL). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated. The crude product was purified by FC to givie thedesired alcohol as a light yellow oil.

4：和Weinreb酰胺反应

[Organic Letters, 2019, vol. 21, # 6, p.1857 - 1862]

Procedure:To a solution of prepared Grignard reagent (1M, 45 mL) in THF was added S1 (5.0g, 30 mmol) in THF (10 mL) at 0 °C dropwise. The reaction mixture was stirredat room temperature for 5 h and quenched with saturated NH₄Cl (20mL). Diethyl ether was used to extract the product from the aqueous layer (3×50mL). The combined organic layer was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to afford thecrude product S2.

5：Kumada coupling reaction

[Tetrahedron, 2010,vol. 66, # 29, p. 5451 - 5458]

A round bottom flask was charged with arylbromide (1 mmol), Pd₂(dba)₃·CHCl₃ (1 mol %), ligand A/B (2 mol%), toluene (2 mL), then a THF solution of ArMgBr (2 mmol) was added dropwiseat room temperature with stirring. The reaction mixture was stirred at 55 ⁰Cfor 10h. After the mixture had been cooled to room temperature, the reactionwas quenched with water. The aqueous phase was extracted with CH₂Cl₂and the combined organic layers were dried with Na₂SO₄,filtered and concentrated, the residue was purified by flash column chromatography.