Warkentin John
Department of Chemistry, McMaster University, Hamilton, Ontario, Canada.
Acc Chem Res. 2009 Jan 20;42(1):205-12. doi: 10.1021/ar800072h.
2,5-Dihydro-1,3,4-oxadiazoles with heteroatom substituents at C-2 (also known as corresponding Delta(3)-1,3,4-oxadiazolines) are very useful materials for the thermal generation of acetoxy(alkoxy)-, dialkoxy-, alkoxy(aryloxy)-, diaryloxy-, alkoxy(alkylthio)-, bis(alkylthio)- and alkoxy(amino)-carbenes. Such carbenes are relatively nucleophilic and react with a variety of electrophilic functional groups. This Account reviews our work to prepare 2,5-dihydro-1,3,4-oxadiazoles and apply them to the synthesis of other target molecules. Carbenes bearing alkoxy substituents at the carbene carbon can be looked upon as acetals of carbon monoxide. Their reactions with electron-deficient alkenes or alkynes can afford acetals of cyclopropanones or cyclopropenones. Although such products may be formed by concerted cycloaddition, initial formation of one bond to produce zwitterions is likely in some cases. In addition, the reactions of these molecules with carbonyl compounds could involve acetals of alpha-lactones as intermediates. Although we have isolated some acetals of cyclopropanones, we have not isolated the other intermediates. However, some of the products we observe probably resulted from these intermediates. For example, dimethoxycarbene reacts with maleic anhydrides to generate six-membered rings by apparent carbonyl addition followed by an acyloxy group transfer. Similarly, dimethoxycarbene reacts with thiocarbonyl compounds, such as xanthates, by apparent carbonyl addition and transfer of the alkylthiyl group to the erstwhile carbene carbon. Reaction of ROC:(OR)' with an alcohol R''OH or a phenol should generate chiral (racemic) orthoformates. Similarly, reaction of alkoxy(alkylthiyl) carbenes with alcohols could generate chiral (racemic) dialkyl thiyl orthoformates. 2,5-Dihydro-1,3,4-oxadiazoles are particularly useful for synthetic applications because they are easily prepared and reasonably stable, thermal sources of bis(heteroatom)carbenes. Such carbenes react with a variety of electrophilic functional groups, often with rearrangement of initial products. Those products, many of them new, could be used as starting materials toward other synthetic targets. Isolation of products from the reaction is relatively simple because the coproducts of thermolysis of the oxadiazoles are primarily N(2) and a ketone, such as acetone. Thus, 2,5-dihydro-1,3,4-oxadiazoles should be part of every synthesis chemist's toolbox.
在C-2位带有杂原子取代基的2,5-二氢-1,3,4-恶二唑（也被称为相应的Δ³-1,3,4-恶二唑啉）是用于热生成乙酰氧基（烷氧基）-、二烷氧基-、烷氧基（芳氧基）-、二芳氧基-、烷氧基（烷硫基）-、双（烷硫基）-和烷氧基（氨基）-卡宾的非常有用的材料。这类卡宾具有相对亲核性，能与多种亲电官能团发生反应。本综述介绍了我们制备2,5-二氢-1,3,4-恶二唑并将其应用于合成其他目标分子的工作。在卡宾碳上带有烷氧基取代基的卡宾可被视为一氧化碳的缩醛。它们与缺电子烯烃或炔烃的反应能生成环丙酮或环丙烯酮的缩醛。尽管此类产物可能通过协同环加成形成，但在某些情况下，最初形成一个键以产生两性离子可能是反应的起始步骤。此外，这些分子与羰基化合物的反应可能涉及α-内酯的缩醛作为中间体。虽然我们已经分离出了一些环丙酮的缩醛，但尚未分离出其他中间体。然而，我们观察到的一些产物可能是由这些中间体产生的。例如，二甲氧基卡宾与马来酸酐反应，通过明显的羰基加成随后进行酰氧基转移生成六元环。类似地，二甲氧基卡宾与硫代羰基化合物（如黄原酸酯）反应，通过明显的羰基加成并将烷硫基转移到原来的卡宾碳上。ROC:(OR)'与醇R''OH或酚反应应生成手性（外消旋）原酸酯。同样，烷氧基（烷硫基）卡宾与醇反应可生成手性（外消旋）二烷基硫代原酸酯。2,5-二氢-1,3,4-恶二唑对于合成应用特别有用，因为它们易于制备且相当稳定，是双（杂原子）卡宾的热来源。这类卡宾与多种亲电官能团反应，初始产物常常会发生重排。那些产物，其中许多是新的，可作为合成其他目标物的起始原料。从反应中分离产物相对简单，因为恶二唑热解的副产物主要是N₂和一种酮，如丙酮。因此，2,5-二氢-1,3,4-恶二唑应成为每位合成化学家工具箱中的一部分。
