​Wohl–Ziegler反應利用NBS制備苄溴，生成的二溴代副産物，如何還原爲單溴代物，機理如何？

Wohl–Ziegler反應，NBS(N-溴丁二醯亞胺）在自由基引發條件下對烯烴的烯丙位或芳烴的苄位進行取代得到烯丙基溴或苄溴的反應。常見的自由基引發條件有：自由基引發劑（如AIBN, BPO)，加熱或光照。四氯化碳是最常用的溶劑。但是實際投反應時，常常發現生成二溴代甚至多溴代副産物，由於這些副産物和和單溴代産物極性相似，分離難度極大。有沒有一種方法將此類副産物直接轉化爲我們想要的單溴代産物？

其實早點2001年，中國科學院成都有機化學研究所鄧金根教授團隊和蘭州大學塗永強教授團隊就報道了利用亞磷酸二乙酯和二異丙基乙胺將多溴代苄轉化爲苄溴的高傚制備方法【Synthesis 2001, 2078】。衹需要加入NBS2兩倍到八倍儅量的亞磷酸二乙酯和二異丙基乙胺在THF中室溫下攪拌即可將多溴代産物轉化爲單溴代産物。

反應操作：NBS (10.8 g, 60 mmol) was added in three equal portions during 9 h to a solution of 1 (10 mmol) in refluxing CCl4 (60 mL), each addition being followed by a few milligrams of benzoyl peroxide. The mixture was cooled and filtered to remove the succinimide. The filtrate was washed with aq NaHCO3 solution (30 mL) and brine (30mL). After drying (Na2SO4), the solvent was evaporated under reduced pressure and the residue was dissolved in anhyd THF (20mL). To the resulting solution were added diethyl phosphite (15.4mL, 120 mmol) and i-Pr2NEt (20.8 mL, 120 mmol) at 0 °C under Ar with stirring. The mixture was gradually warmed to r.t. and stirred for 29 h (the reaction was monitored by 1H NMR). The mixture was poured into ice/water and extracted with Et2O (3 ¥ 40 mL). The organic layer was washed with 1 M HCl (except for 2e) and brine, dried (Na2SO4), filtered and evaporated to give the crude product. The pure product was obtained by silica gel column chromatography with petroleum ether (bp 60–90 °C) as eluent (Tables 1 and 2).

反應機理

此轉化機理其實可以蓡考Atherton-Todd反應，亞磷酸二酯在溫和的堿性條件下與四氯化碳的作用，把P-H鍵轉換成P-Cl鍵，制備得到氯磷酸二酯的反應。

蓡考此機理，衹是Atherton-Todd反應的底物四氯化碳換成了多溴代苄。

反應實例

2-(bromomethyl)-2'-phenyl-1,1'-binaphthalene (2)7,8: To a flame-dried round bottom flask was added SI-16 (6.28 g, 18.2 mmol, 1.0 equiv.), NBS (16.2 g, 91 mmol, 5.0 equiv.), AIBN (299 mg, 1.82 mmol, 0.1 equiv.) and cyclohexane (400 mL). The flask was then equipped with a water-cooled condenser and the reaction mixture was refluxed overnight. The reaction was then cooled to 23 ˚C and filtered through Celite with Et2O. The resulting solution was then diluted with H2O and extracted with Et2O (3x). The organic layers were combined and washed with saturated NaHCO3 (aq) , brine, dried with Na2SO4, and concentrated in vacuo. The crude material (12.33 g) containing a mixture of mono-brominated and di-brominated products was added to a round bottom flask and dissolved in THF (40 mL). The resulting solution was cooled to 0 ˚C followed by the addition of iPr2NEt (31.70 mL, 182 mmol, 10.0 equiv.) and diethyl phosphite (23.44 mL, 182 mmol, 10 equiv.). The reaction mixture was then warmed to 23 ˚C and stirred overnight. The reaction was then cooled to 0 ˚C and quenched with H2O, extracted with Et2O (3x), washed with brine, dried with Na2SO4, and concentrated in vacuo. The resulting reside was filtered through a silica plug using Et2O as the eluent and concentrated. The crude material was then purified via recrystallization from cyclohexane to afford the title compound as an off-white solid (6.29 g, 14.86 mmol, 82% over 2 steps). 

【Org. Lett. 2016, 18, 2883–2885】

2-bromomethyl-4-fluorobenzonitrile (3). N-bromosuccinimide (98.78 g, 0.555 mol) and 2,2'-azobisisobutyronitrile (6.08 g, 0.037 mol) was added to a solution of 4-fluoro-2-methylbenzonitrile (50 g, 0.37 mol) in dichloromethane (250 mL). The slurry was refluxed for 24 h under an atmosphere of nitrogen, filtered and washed with dichloromethane (100 mL). The filtrate was cooled to 0 °C, then diethyl phosphite (25.55 g, 0.185 mol) and diisopropylethylamine (9.56 g, 0.074 mol) was added. The solution was stirred at 0 °C for 1 h and at room temperature for another hour. Potassium carbonate solution (125 mL, 0.2 g/mL) was added, and the organic phase was separated and washed with water (50 mL × 2). Then the solution was concentrated to dryness to give the raw product of 3 as a brown oil (109.5 g), which was used in the next reaction without any purification.

【Org. Process Res. Dev. 2017, 21, 585–589】