手性过渡金属配合物催化下非官能化烯烃的不对称卤胺化反应

Functionalization of un-activated C=C double bonds is one of the most important reactions in organic synthesis. In the presence of a suitable catalyst, the reaction converts unfunctionalized olefins to important organic and pharmaceutical intermediates through (di)hydroxylation, (di)amination, aminohydroxylyation or epoxidation of C=C double bonds. .Vincinal haloamine compounds are important intermediates for organic synthesis and drug synthesis, and a variety of nitrogen-containing compounds can also be prepared from these intermediates. In addition, they also appear as important subunits in some natural products and antitumor agents. Direct functionalization of C=C double bond with halogen and amino group is the most straightforward method for the synthesis of this type of important compounds. Most of the current studies focused on alpha, beta-unsaturated and related substrates, and only a few works were reported for haloamination of unfunctionalized olefins. These reported methods utilized palladium-copper or palladium-copper-carbonate multi-metal systems, and relatively harsh conditions were normally required..Very recently, we found that several 4-penten-1-amine substrates were able to undergo chloroamination in the presence of CuCl2. The reactions were easy to perform, and all the operations could be carried out at room temperature in open air..Based on our preliminary results and our understanding of steric and electronic effects on the activation of unfunctionalized olefins, the proposed study will use 4-penten-1-amine and related compounds as model substrates, chiral transition metal complexes as catalysts, to study the asymmetric haloamination and related reactions of unfunctionalized olefins. Catalysts with different Lewis acidity and different steric and electronic properties will be designed and synthesized, and their performance for selective activation and functionalization of unactivated C=C double bonds will be investigated. The effects of the d electron configurations of transition metals on their catalytic performance will be studied, and new methods for asymemtric synthesis of chiral amines and related compounds will be developed. .Our preliminary study indicated that in the presence of a transition metal complex, a C-M intermediate was first formed during the functionalization of C=C double bond, and subsequent cleavage of the C-M bond with different reagents would give different nitrogen-containing compounds. In this regard, the proposed study would provide new and efficient routes to different products from a single substrate. .The final goal of the proposed study is to design new chiral catalysts and to realize the asymmetric functionalization of unfunctionalized olefins under mild conditions.

非活化碳碳双键的官能化是有机合成中一类重要反应。它以非官能化烯烃为原料，通过碳碳双键上的各种反应，将简单烯烃转化成重要的有机合成中间体。邻卤胺化合物是有机合成及药物合成的重要中间体，使用氨基和卤素同时对碳碳双键官能化是制备这类化合物最直接的手段之一。目前这类反应大多集中在alpha,beta-不饱和化合物等反应活性较高的底物，而对非官能化烯烃的研究则相对较少。.本研究基于我们对非官能化烯烃反应的理解，以4-戊烯胺等非官能化烯烃为模型底物、手性过渡金属配合物为催化剂进行非官能化烯烃的不对称卤胺化反应。通过改变催化剂的Lewis酸性及配体的空间电子因素，研究在氨基等配位性基团存在下碳碳双键的选择性活化，研究过渡金属d电子结构对其催化能力的影响，以及不同条件下反应中间体金属-碳键的断裂方式，扩展非活化烯烃的官能化反应，发展重要手性含氮化合物的不对称合成新方法。

在项目的执行期间，我们根据申请书中的研究方案，对手性过渡金属配合物催化下非官能化烯烃的不对称卤胺化反应进行了系统研究。在项目实施过程中我们首先研究了影响反应的关键因素，包括不同催化剂/反应促进剂对C=C双键的活化情况比较，不同空间/电子因素的底物对反应活性的影响，以及不同的Lewis酸催化剂/促进剂对反应的影响等。通过研究我们发现，不同的过渡金属对反应有不同的影响。其中铜、锰等催化剂的反应活性较好，铬、铁、钴、镍等催化剂的反应活性较低，锌催化剂则倾向于发生氢胺化反应。在对铜、锰的催化剂进行研究时我们发现，手性配体如双噁唑啉配体等在不对称溴胺化反应有上佳的表现，反应的ee值最高可达95%以上。在研究中，我们发现使用催化量的单质碘也可实现非官能化烯烃的卤胺化反应。在反应过程中加入过硫酸钾等氧化剂可实现碘的再生，使用不同的亲核试剂如氯离子或溴离子则可得到氯胺化或溴胺化的产物。同样，高价碘如醋酸碘苯在活化C=C双键时也有较好的表现。使用醋酸碘苯作为反应的促进剂，可实现非官能化烯烃的氟胺化、氯胺化、溴胺化和碘胺化反应，产率高，后处理容易。在研究催化量高价碘催化的分子内卤胺化反应时我们发现，使用间氯过氧苯甲酸作为氧化剂，可实现环氧化-分子内开环的串联反应，最后得到2-羟甲基吡咯烷或2-羟甲基哌啶类化合物。我们还研究了硼化合物对反应的影响。结果表明，不同的硼化合物可发生不同类型的反应。在醋酸碘苯存在下，三氟化硼可作为氟源进行氟胺化反应。在没有醋酸碘苯存在时，三氟化硼可作为Lewis酸促进非官能化烯烃的氢胺化反应。而三氯化硼则直接作为反应物参与反应。从这一发现出发，我们发展了一类新型的环化反应，即分子内硼胺化反应。在研究中，我们还对其他化合物的卤胺化反应进行研究，制备了一系列含卤素的噁唑啉类化合物。截至到目前为止，在Angew Chem Int Ed, JOC, Adv Synth Catal等国际刊物发表研究论文15篇，另有多篇文章正在整理中。