Rapid Access to α-Alkoxy and α-Amino Acid Derivatives through Safe Continuous-Flow Generation of Diazoesters
Rapid Access to α-Alkoxy and α-Amino Acid Derivatives through Safe Continuous-Flow Generation of Diazoesters
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DOI：
10.1002/chem.201101590
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发表时间：
2011-08-01
影响因子：
4.3
通讯作者：
Hayes, Christopher J.
中科院分区：
文献类型：
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作者：
Bartrum, Hannah E.;Blakemore, David C.;Hayes, Christopher J.
尽管重氮化合物具有广泛的合成潜力（XÀH插入、叶立德形成、环丙烷化、环加成等），[1]对其制备、分离和使用相关危害的担忧阻碍了它们在学术和工业实验室中的充分利用。一些重氮化合物是可商购的（例如重氮乙酸乙酯和重氮乙酸丁酯、TMS-重氮甲烷和重氮二甲酮），[2]，但仍然需要安全、方便地获得更广泛的有用官能化重氮物质。 [3]重氮转移可用于获取 α-重氮羰基，但这只能部分解决与重氮物质相关的安全问题，因为仍然需要使用同样危险的叠氮基重氮转移试剂。 [4]理想地，如果重氮物质可以就地产生和消耗，从而完全避免危险重氮化合物的处理，这将是有益的。 Ley,[5] Jamison,[6] Kappe,[7] 和其他人 [4, 8–10] 最近的工作表明，高反应性重氮和叠氮化合物可以在实验室规模的连续流动反应器中使用，以实现许多非常有用的合成转化，而且我们自己实验室的工作实际上已经表明，重氮乙酸乙酯可以用于流动获取 β-酮酯。 [11]因此，我们想知道是否有可能在流动条件下实际生成 α-重氮羰基化合物，然后直接在进一步的合成操作中使用这些材料，从而最大限度地减少与任何潜在危险材料的接触。实际上，我们是否可以开发一种连续流重氮发生器，然后演示其用于通过 OÀH 和 NÀH 插入制备一系列有用的 α-烷氧基 (3a–i) 和 α 氨基酸 (4a–i) 衍生物（方案 1）？
Despite the wide synthetic potential of diazo compounds (XÀH insertion, ylide formation, cyclopropanation, cycloaddition etc.),[1] concerns over the hazards associated with their preparation, isolation, and use have hindered their full exploitation in both academic and industrial laboratories. A few diazo compounds are commercially available (eg ethyl and butyl diazoacetate, TMS-diazomethane and diazodimedone),[2] but safe and convenient access to a wider range of useful functionalized diazo species is still desirable.[3] Diazo transfer can be used to access α-diazocarbonyls, but this only partially addresses the safety concerns associated with the diazo species, as the use of equally hazardous azidebased diazo-transfer reagents is still required.[4] Ideally, it would be beneficial if the diazo species could be generated and consumed in situ so that handling of the hazardous diazo compound is avoided altogether. Recent work by Ley,[5] Jamison,[6] Kappe,[7] and others [4, 8–10] has shown that highly reactive diazo and azido compounds can be used in lab-scale continuous-flow reactors to achieve a number of very useful synthetic transformations, and indeed work from our own laboratory has shown that ethyl diazoacetate can be used in-flow to access β-keto esters.[11] We therefore wondered if it was possible to actually generate α-diazocarbonyl compounds under flow conditions and then use these materials directly in further synthetic manipulations, thus minimizing exposure to any potentially hazardous material. In effect, could we develop a continuous-flow diazo generator and then demonstrate its use to prepare a range of useful α-alkoxy (3a–i) and αamino acid (4a–i) derivatives through OÀH and NÀH insertion (Scheme 1)?