Protection by acylation in the selective alkylation of heterocycles
Protection by acylation in the selective alkylation of heterocycles
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杂环选择性烷基化中的酰化保护
DOI：
10.1021/jo00832a031
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发表时间：
1970
影响因子：
3.6
通讯作者：
R. Kendall
中科院分区：
文献类型：
--
作者：
R. A. Olofson;R. Kendall
描述了使用不同的酰基（乙酰基、苯甲酰基、乙氧羰基）保护基作为在多氮杂环中通常不受欢迎的位置上实现排他性烷基化的辅助剂。新合成路线的实例包括由4-苯基咪唑无异构体合成1-乙基-5-苯基咪唑，总收率86%（1-甲基化合物的最佳文献产率为7%加上异构体），以77%产率从1，2，4-三唑制备4-甲基-1，2，4-三唑（其它方法：10和31%加上异构体和其它烷基化产物），以52%产率从1，2，4-三唑得到4-异丙基-1，2，4-三唑，和以89%产率从苯并三唑得到1-乙基苯并三唑（最佳文献产率：37%+36%2异构体）.在多氮杂芳族化合物中，烷基化一个特定的环氮原子的困难仍然是杂环化学中的一个主要问题。有时，通过在闭环之前将N-烷基引入体系中的方法来制备所需的物质，可以避免这种麻烦，但通常这种合成方法是不可用的。如果实验者幸运的话，在特定情况下，他可以通过改变烷基化剂来完成所需的烷基化，至少以小的产率（fie.，从硫酸甲酯到重氮甲烷），通过首先将底物转化成其去质子化的金属盐，或者通过改变溶剂和温度，但是到目前为止，这个问题还没有找到通用的解决方案。即使实验者确实得到了一些所需的产物，他也必须设计出将其与其异构体、二烷基化阳离子副产物和任何剩余的起始原料分离的程序。历史上，这种一般类型的问题已经通过选择性封闭有害的反应位点来克服。这一领域的情况并非如此，主要是因为人们相信：（a）引入保护基也会遇到同样的选择性困难，（B）最容易除去的封闭基团会使化合物强烈失活，从而抑制下一步形成N-烷基阳离子。最近发展的强氧鎓 1和羧鎓 2离子烷基化剂大大减轻了这一最后的缺点。我们认为，这些烷基化方法与简单的酰化保护方法相结合，将从根本上消除上述困难。详细地说，我们提出了一个三步法（方案I），其中杂环首先通过经典方法（I-II）酰化，然后用氧鎓或羧鎓离子试剂（II-III）烷基化。
The use of different acyl (acetyl, benzoyl, carbethoxy) protecting groups as aids in accomplishing exclusive alkylation at normally unfavored positions in polynitrogen heterocycles is described. Examples of the new synthetic scheme include the isomer-free preparation of l-ethyl-5-phenylimidazole from 4-phenylimidazole in 86% overall yield (best literature yield for 1-methyl compound is 7% plus isomer), 4-methyl-l, 2, 4-triazole from 1, 2, 4-triazole in 77% yield (other methods: 10 and 31% plus isomer and other alkylation products), 4-isopropyl-l, 2, 4-triazole from 1, 2, 4-triazole in 52% yield, and 1-ethylbenzotriazole frombenzotriazole in 89% yield (best literature yield: 37% plus 36% 2 isomer).The difficulties involved in alkylating a specific ring nitrogen atom in a polynitrogen heteroaromatic com-pound in which alkylation atanother nitrogen is preferred still constitute a major problem in heterocyclic chemistry. Sometimes the trouble may be circumvented by preparing the required substance by a method in which the N-alkyl group is incorporated into the system prior to closure of the ring, but often such syn-theses are unavailable. If the experimenter is lucky he may then, in specific cases, accomplish the desired alkylation, at least in small yield, by changing the alkylating agent (fie., from methyl sulfate to diazo-methane), byfirst convertingthe substrate into its de-protonated metal salt, or by varying solvent and temperature, but as yet this problem has found no general solution. Even if the experimenter does obtain some of the required product, he must then devise procedures for separating it from its isomers, the dialkylated cation by-products, and anyremaining starting material. Historically, problems of this general type have been overcome by the selective blocking of the offending reaction site. Such has not been the case in this area primarily because it has been believed (a) that the in-troduction of the protecting group would be subject to the same selectivity difficulties, and (b) that most easily removableblocking groups wouldstrongly de-activate the compound and thus inhibit the next step in which an N-alkyl cation would be formed. The re-cent development of the powerful oxonium1 and car-boxonium2 ion alkylating agents has substantially mitigated the final objection, and we suggest that these alkylation methods in combination with simple acyla-tion as the method of protectionwill lead to the essen-tial eliminationof the difficulties above. In detail, we propose a three-step process (Scheme I) in whichthe heterocycle is first acylated by classical procedures (I II), then alkylated with an oxonium or carboxonium ion reagent (II—