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背景介绍
亚胺官能团在有机合成中是一个非常常见和常用的基团。手性N-亚磺酰基亚胺特别是在过去二十年中作为实用和立体选择性的助剂广泛出现。由Ellman及其同事开发的2种N-叔丁基亚磺酰基亚胺是用途最广泛、研究最深入的一类N-亚磺酰基亚亚胺。其合成方法有:
采用MgSO4或CuSO4作为脱水试剂。
Ti(OEt)4作为脱水试剂,该试剂对所有类型的醛的缩合都非常有效。重要的是,Ti(OEt)4能够转化不符合MgSO4或CuSO4条件的醛。
其他脱水试剂,如Cs2CO3、NaOH或KOtBu,Yb(OTf)3和KHSO4。
Ruano和Cid报道的在60°C下使用催化吡咯烷和4ÅMS在CH2Cl2中形成亚胺的通用方案。(J. Am. Chem. Soc. 2014, 136, 1082)
以上方法中,Ti(OEt)4方法使用最多,然而其缺点是需要在后处理过程中去除不溶性TiO2废物。而TiO2的过滤通常非常缓慢,并且在放大反应中可能变得令人望而却步。此外,Ti(OEt)4的使用还需要广泛的反应器清洁方案,以确保Ti残留物的完全去除。许多替代试剂的非均相体系是不可取的,因为这些系统可能导致反应器壁的蚀刻。因此,需要寻找一种替代试剂,最好满足以下几点:(1)不需要在反应后过滤不溶性物质;(2) 均相反应;(3) 对具有不同电子和空间性质的醛均可接受;(4)使用良性的和商业上可获得的原料。
本期小编就给大家介绍一种简单易得的试剂:B(OCH2CF3)3,即三(2,2,2-三氟乙基)硼酸酯,它可以促进叔丁基亚磺酰胺与醛甚至酮的缩合,也可以制备其他几种有价值的醛亚胺。(Org. Lett. 2015, 17, 2442−2445)
图片来源:Org. Lett.
反应在室温下即可进行,在水性后处理时,试剂B(OCH2CF3)3被水解以得到水溶性硼酸,并且不需要过滤不溶性试剂或副产物。N-亚磺酰基酮亚胺的形成在高温下也是可能的,可以作为制备这种类型的酮亚胺的Ti(OEt)4的第一种替代方案。值得注意的是,B(OCH2CF3)3是市售的,并且也可以由硼酸酐和三氟乙醇一步大规模制备得到。
哪些底物适用
该反应适用于贫电子(产物2a−c、3和5)和富电子芳香醛(产物4和7)。带有一个(产物6)或两个(产物7)邻位取代基的醛顺利转化为N-亚磺酰基亚胺。值得注意的是,先前报道的2,4,6-三甲氧基-苯基亚磺酰亚胺7的合成需要在THF中使用Ti(OEt)4回流。可以使用杂环(产物8)和α,β-不饱和(产物9)底物。B(OCH2CF3)3介导的缩合对烷基醛也是有效的,例如:与具有两个、一个或零个α-质子的醛反应生成N-亚磺酰基亚胺10−13,产率都很高。此外,先前仅通过使用Ti(OEt)4可获得的大位阻三甲基乙醛衍生的亚胺13也能在该条件下顺利得到。
实验操作
General Procedure for N-Sulfinyl Aldimine Formation. To a dry round bottom flask equipped with a football shaped magnetic stir bar was charged aldehyde (2.0 mmol, 1.0 equiv), (S)-tert-butanesulfinamide (291 mg, 2.4 mmol, 1.2 equiv) and THF (2.0 mL). The flask was sealed with a rubber septum and a nitrogen inlet needle was inserted in the septum. The reaction mixture was then treated dropwise with B(OCH2CF3)3 (0.43 mL, 2.0 mmol, 1.0 equiv) and the solution was stirred at rt for 2-6 h (until complete consumption of aldehyde by HPLC analysis at 220 nm). The reaction mixture was then diluted with EtOAc and the EtOAc solution was washed with saturated aqueous NaHCO3 solution followed by water. The organic phase was then dried over Na2SO4, filtered and concentrated to give the crude product. Purification by flash chromatography on SiO2 using hexanes/MTBE as eluent gave the pure product.
General Procedure for N-Sulfinyl Ketimine Formation. To a dry round bottom flask equipped with a football shaped magnetic stir bar was charged ketone (2.0 mmol, 1.0 equiv), (S)-tert-butanesulfinamide (364 mg, 3.0 mmol, 1.5 equiv) and THF (2.0 mL). The flask was equipped with a reflux condenser which was sealed with a rubber septum and a nitrogen inlet needle was inserted in the septum. The reaction mixture was then treated dropwise with B(OCH2CF3)3 (1.29 mL, 6.0 mmol, 3.0 equiv) and the solution was stirred at 55 °C for 48 h. The reaction mixture was cooled to rt and then diluted with EtOAc and the EtOAc solution was washed with saturated aqueous NaHCO3 solution followed by water. The organic phase was then dried over Na2SO4, filtered and concentrated to give the crude product. Purification by flash chromatography on SiO2 using hexanes/MTBE as eluent gave the pure product.
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