基于钯催化碳氢键活化反应合成磺胺类药物活性单元的研究

Sulfonamides have been extensively used as pharmaceutical and pesticidal agents because of their diverse biological properties. Moreover, sulfonamide moiety is also a very important functional group which is closely linked to pharmaceutical activity. Recently, we have developed an efficient methodology for the synthesis of 1,1’-biaryl 2-sulfonamides based on Pd-catalyzed regioselective arylation of aryl sulfonamides by employing sulfonylamino acid moiety as a novel bidentate directing group. Based on these results, we hypothesized to synthesize series of novel sulfonamide substrates with a sulfonamide as a linker by using an amino acid moiety as a novel bidentate directing group. Firstly, we are mainly focusing on the development of palladium-catalyzed direct sp3 C-H bond functionalizations of alkyl sulfonamides to afford a series of aliphatic sulfonamides with various substituents. Meanwhile, mechanistic studies will be carried out to probe the details of this C-H activation.Subsequently, we will explore the palladium-catalyzed enantioselective direct sp3 C-H bond functionalizations of alkyl sulfonamides for the synthesis of enantiopure alkyl sulfonamides. Secondly, we will study the palladium-catalyzed C-H alkylation of aryl sulfonamides with three-membered heterocycles. Besides, the direct acylation, carbonylation and the formation of carbon-heteroatom bond via palladium-catalyzed C-H activation of arylsulfonamides were also investigated, to afford the 2-substituted aryl sulfonamides, which are as a promising scaffold for the synthesis of benzosultams. Furthermore, we will study the palladium-catalyzed oxidative annulation via C-H/N-H functionalization cascade reactions of alkenyl sulfonylamino acids with aryl halides, alkenes or alkynes. Finally, employing ortho-iodo aryl sulfonamides as substrates, we will develop an efficient protocol to prepare structurally complicate benzosultam skeletons based on palladium-catalyzed intramolecular Heck/C-H activation domino reaction. Meanwhile, many novel and efficient organic synthetic methodologies could be well developed as well in this regard.

磺酰胺类化合物在医药和农药上都具有广泛的生物活性，磺酰胺片段也是一类重要的药效基团。最近，申请人研究了钯催化的磺酰氨基酸双齿配位导向的碳氢键活化芳基化反应合成联苯类磺酰胺重要片段。在此工作基础上，我们拟以小分子氨基酸为原料，设计合成一系列含磺酰氨基酸双齿配位基团的烷基、烯基、芳基磺酰氨基酸化合物。首先，以烷基磺酰氨基酸为底物，重点研究钯催化的sp3C-H键活化官能化反应，合成一系列不同官能团的脂肪族磺酰胺类衍生物。其次，我们对其机理进行探索，尝试研究其不对称sp3C-H键活化反应在手性磺酰胺合成中的应用。再次，以烯基、芳基磺酰氨基酸为底物，研究钯催化的碳氢键活化烷基化、酰基化、羰基化、碳-杂键形成及其一锅发串联成环等反应，提供一系列合成苯并磺内酰胺药物的多功能合成模块的新方法。最后，研究基于钯催化的碳氢键活化多米诺反应构筑多环苯并磺内酰胺新母核，藉此亦可丰富和发展新型高效的有机合成方法学。

磺酰胺类化合物在医药和农药上都具有广泛的生物活性，磺酰胺片段也是一类重要的药效基团。我们研究了铑催化苯磺酰胺的邻位C-H活化炔基化反应，合成一系列邻炔基苯磺酰胺类化合物。并且，当炔基保护基是TES或TMS时，可发生炔基化和关环串联反应合成苯并六元环磺内酰胺化合物。我们探索了铱催化苯磺酰胺的邻位C-H活化胺基化反应研究，成功实现了C-H活化胺基化反应，合成了一系列邻氨基苯磺酰胺类化合物。此外，在机理研究上我们也做了相关的探索，研究发现分子动力学同位素效应 (KIE=2.6)，表明C-H键的断裂可能是催化循环的决速步。我们探索了银盐催化下芳基羧酸的脱羧、分子内的碳氢键芳基化反应，合成一种联苯类磺内酰胺衍生物。我们研究了过渡金属铑、铱催化4-苯基-1(2H)-酞嗪酮及其衍生物的C-H键活化炔基化、氨基化及酰基化反应，研究发现通过控制添加六氟锑酸银，可以实现4-苯基-1(2H)-酞嗪酮选择性单炔化和双炔化反应，合成了一系列相关的单/双功能化的衍生物。我们研究了电化学方法氧化和可见光驱动的去氢N-S键偶联反应，合成了一系列噻二唑及2-苯基苯并[d]异噻唑类衍生物。同时，我们研究了电化学氧化脱羧偶联合成芳基炔基砜衍生物。最后，我们研究铜催化下芳基磺酰胺与芳基硫酚或苯酚的C-S和C-O键偶联反应，合成一类含邻位硝基的芳基硫醚和对应的联苯醚。我们研究了邻羟基查尔酮为底物，在过渡金属钯催化下与芳基碘在水相中进行heck偶联、关环串联反应得到4-芳基黄酮类衍生物。该方法使用原料价廉、易得；且该催化反应可在水中进行，符合绿色化学。. 综合上述结果，本研究为芳基磺酰胺类化合物的合成打下坚实的工作基础。同时对药物分子设计提供了重要的启示性线索。项目资助发表核心论文16篇，授权发明专利1项目，待发表1篇。培养硕士生7名，其中5名已经取得硕士学位，2名在读。项目投入经费39万元，实际支出29.1594万元。剩余经费9.8406万元，剩余经费计划用于本项目研究后续支出。