Combination of transition metal-catalyzed (hydro)formylation and organocatalysis for the tandem synthesis of diindolylmethanes, porphyrins and BODIPY fluorescent dyes

二吲哚甲烷类、卟啉类和BODIPY类化合物是一类重要的具有广泛用途的化合物。然而，已建立的以醛为起点的这些化合物的合成有几个缺点：醛并不总是可以在商业上获得，因此它们经常不得不通过额外的步骤进行制备。许多醛对氧化也非常敏感，因此很难处理。此外，使用TFA等酸作为催化剂可以排除敏感底物。最后但并非最不重要的是，在酸性反应介质中也可能发生不希望发生的副反应，如聚合反应。这是一个缺点，特别是在目前的合成方法中，需要用高稀释度来弥补这一缺点。本研究项目将采用串联反应方法：通过甲酰化反应，如铑催化的氢甲酰化或钯催化的甲酰化反应，在反应容器中直接从可接触和稳定的底物如烯烃或芳基卤化物生成醛。在第二步反应中，原位生成的醛与芳基亲核试剂通过Friedel-Craft反应进行反应。有机催化剂，如芳基硫脲，用于通过氢键激活醛的羰基。这可以使反应条件比以前的酸催化反应温和得多。除了烯烃和芳基卤化物外，(氢)甲酰化反应还将使用烯烃、炔烃和卤乙烯基化合物作为底物。在优化了反应条件后，将用不同的吲哚化合物合成一个广泛的二吲哚甲烷文库。使用吡咯作为芳基亲核试剂，将生成二吡咯甲烷作为中间体。如果吡咯中的第二个亲核位置被封闭，BODIPY化合物可以通过添加氧化剂、碱和BF3·OEt2来获得。然而，如果第二个亲核位置是可到达的，那么就形成了卟啉原，它们可以通过氧化转化为卟啉。因此，含有不同烯烃、烯、炔以及芳基和乙烯基卤化物的各种吡咯将被用来生成广泛的BODIPY和卟啉。此外，计划将前面描述的方法应用于合成更复杂的产品。一个具有巨大应用潜力的例子是以苯乙烯为起始原料合成手性BODIPY化合物。在这里，立体中心必须通过对映选择性氢甲酰化来建立。最后，将对生成的二吲哚甲烷进行生物活性研究，同时对卟啉和BODIPY进行光学性质测试。

Diindolylmethanes, porphyrins and BODIPYs are important classes of compounds with a large number of applications. However, the established synthesis of these compounds starting from aldehydes has several drawbacks: aldehydes are not always commercially available, so they often have to be prepared in an additional step. Many aldehydes are also extremely sensitive to oxidation and therefore difficult to handle. Furthermore, the use of acids such as TFA as catalysts can preclude sensitive substrates. Last but not least, undesirable side reactions such as polymerizations can also occur in the acidic reaction medium. This is a disadvantage especially in the synthesis of porphyrins which has to be compensated by high dilution in current methods.This research project will pursue a tandem reaction approach: via formylation reactions, such as rhodium-catalyzed hydroformylation or palladium-catalyzed formylation, the aldehydes will be generated directly in the reaction vessel from accessible and stable substrates such as alkenes or aryl halides. In the second reaction step, the in situ generated aldehydes react with aryl nucleophiles via Friedel-Crafts reaction. Organocatalysts, such as arylthioureas, are used to activate the carbonyl group of the aldehyde via hydrogen bonds. This could allow for much milder reaction conditions than the previous ones with acid catalysis. In addition to alkenes and aryl halides, allenes, alkynes and vinyl halides will also be used as substrates for the (hydro)formylation reactions. After optimization of the reaction conditions, an extensive library of diindolylmethanes will be synthesized using various indoles. Using pyrroles as aryl nucleophiles, dipyrromethanes will be generated as intermediates. If the second nucleophilic position in the pyrrole is blocked, BODIPY compounds are accessible by addition of an oxidizing agent, a base, and BF3•OEt2. However, if the second nucleophilic position is accessible, then porphyrinogens are built, which can be converted into porphyrins by oxidation. Therefore, various pyrroles with diverse alkenes, allenes, alkynes, as well as aryl and vinyl halides will be used to generate a wide range of BODIPYs and porphyrins. Furthermore, it is planned to apply the previously described methods for the synthesis of more complex products. An example with great application potential is the synthesis of chiral BODIPY compounds starting from styrenes. Here, the stereocenter has to be built up via enantioselective hydroformylation. Finally, the produced diindolylmethanes will be investigated for biological activity while the porphyrins and BODIPYs will be tested for optical properties.