C-F Borylation of Unsaturated Fluorocarbons

该项目的总体目标是开发将环境持久性氟碳化合物转化为可用于合成的活性化学构件的方法。目标1（第1 - 12个月）。尽管频哪醇硼烷、双（频哪醇）二硼烷、邻苯二酚硼烷和双（邻苯二酚）二硼烷在合成中有广泛的应用，但含两个取代基的硼试剂的研究还不够。我们提出了通过胺-硼烷前驱体的催化脱氢来开发一系列胺稳定的硼二氢化物。配体前体将通过商业起始材料的Buchwald-Hartwig偶联来合成。[1]在与BH3配位之后，我们将研究第2组和第3组预催化剂以实现这些底物的还原环化，从而提供一种迄今无法获得的硼二氢化物的新途径。[2 - 5]目标2（第13 - 24个月）。上述新试剂将用于氢氟烯烃的C-F硼化。我们将寻找能够通过选择性加成消除反应操作的催化剂。基于目前未发表的机理分析，从组中，三个早期过渡金属催化剂作为出发点。所有这些都包含以下设计特征：（i）溶解和动力学稳定Cp配体，（ii）亲电早期TM，以促进β-氟化物消除，（iii）单个反应性氢化物位点，能够对不饱和体系进行氢化。[6 - 8]目标3（第25 - 36个月）。了解控制区域选择性和化学选择性的因素随着新催化反应的发展，我们将研究其机理。这将通过（i）分离活性中间体和催化剂静止状态并测试其反应性，（ii）竞争和机理探针实验，包括适用的D-标记实验，（iii）动力学分析和（iv）DFT研究（与计算小组合作）来实现。我们将质疑我们的添加-消除过程的假设，以及它是否真的在我们开发的条件下运行。我们将试图了解控制催化的区域选择性和化学选择性的步骤。如果这些步骤是在催化剂或底物的控制下，我们将设计额外的实验，看看我们是否可以切换反应的区域化学。备份计划：如果我们不能获得二氢化硼试剂，我们将研究已建立的二氢化铝络合物BDIAlH2以达到相同的目的。我们还可以研究新的含氟结构单元在合成中的应用，特别是在交叉偶联中。根据所提出的反应的化学选择性和区域选择性，我们还可以考虑开发手性催化剂，如柄型手性催化剂，以尝试生成对映体纯的产物。[9]参考文献：[1] Feng和同事，J. Med. Chem. 2015，1846。[2]（a）Hill和同事，Chem.Commun. 2010，46，7587;（B）Hill和同事，Chem. Eur. Chem. J. 2010，16，8505;（c）Hill和同事，Chem.Commun. 2013，49，1960. [3]（a）Rummin和同事，Chem.Commun. 2014，50，9536;（B）Rummin和同事，Organometallics，2015，DOI：10.1021/acs.organomet.5b00607。[4]Chen和同事，ACS Catalysis，2013，3，521. [5]（a）Sabo-Etienne及其同事，Angew。化学成分：Int.Ed.2012，51，3646;（B）Sabo-Etienne和同事，Chem.Eur. J. 2015，21，13080中所述。[6]（a）Lentz和同事，Angew。化学成分：Int.Ed.2010，49，2933;（B）Lentz和同事，Chem.Eur. J. 2012，18，10701中所述。[7]琼斯和他的同事们，J。Soc.2002，124，8681。[8]Andersen和同事，J. Am. 2005，127，7781中所述。[9]Buchwald和同事，J. Am. 1992，114，7562中所述。

The overall goal of the project is to develop methods to convert environmentally persistent fluorocarbons into reactive chemical building blocks that can be used in synthesis. Objective 1 (Months 1-12). Catalytic Generation of Boron Dihydrides Despite the extensive application of pinacolborane, bis(pinacol)diborane, catecholborane and bis(catechol)diborane in synthesis related boron reagents containing two hydrides are understudied. We proposed to develop a series of amine stabilised boron dihydrides by catalytic dehydrogenation of amine-borane precursors. The ligand precursors will be synthesized by Buchwald-Hartwig coupling of commercial starting materials.[1] Following coordination to BH3, we will investigate group 2 and 3 pre-catalysts to effect the dehydrogenative cyclisation of these substrates to provide a new route to hitherto inaccessible boron dihydrides.[2-5]Objective 2 (Months 13-24). Catalytic C-F Borylation of Fluoroalkenes The new reagents described above will be applied in the C-F borlyation of hydrofluoroolefins. We will hunt for catalysts capable of operating by a selective addition elimination reaction. Based on current unpublished mechanistic analysis from the group, three early transition metal catalysts are proposed as a starting points. All contain the following design features (i) solubilising and kinetically stabilising Cp ligands, (ii) electrophilic early TM to promote beta-fluoride elimination, (iii) a single reactive hydride site capable of hydrometallation of unsaturated systems.[6-8]Objective 3 (Months 25-36). Mechanistic Studies Understanding factors that control Regioselectivity and Chemoselectivity Following the development of the new catalytic reaction we will study the mechanism. This will be achieved by (i) isolating reactive intermediates and catalyst resting states and testing their reactivity, (ii) competition and mechanistic probe experiments including where applicable D-labelling experiments, (iii) kinetic analysis and (iv) DFT studies (in collaboration with a computational group). We will question our hypothesis of an addition-elimination process and whether or not this is truly operating under the conditions that we develop. We will seek to understand the steps that control the regio- and chemoselectivity of catalysis. If these steps are under catalyst or substrate control, we will aim to design additional experiments to see if we can switch the regiochemistry of the reaction. Backup Plans: Should we not be able to access the boron dihydride reagents we will investigate the established aluminium dihydride complexes BDIAlH2 to the same end. We can also investigate the application of the new fluorine containing building blocks in synthesis and specifically in cross-coupling.. Depending on the chemo- and regioselectivity of the proposed reaction we can also think about developing chiral catalysts such as ansa-metallocences to try and generate enantiomerically pure products.[9] References: [1] Feng and coworkers, J. Med. Chem. 2015, 1846. [2] (a) Hill and coworkers, Chem. Commun. 2010, 46, 7587; (b) Hill and coworkers, Chem. Eur. J. 2010, 16, 8505; (c) Hill and coworkers, Chem. Commun. 2013, 49, 1960. [3] (a) Crimmin and coworkers, Chem. Commun. 2014, 50, 9536; (b) Crimmin and coworkers, Organometallics, 2015, DOI: 10.1021/acs.organomet.5b00607. [4] Chen and coworkers, ACS Catalysis, 2013, 3, 521. [5] (a) Sabo-Etienne and coworkers, Angew. Chem., Int. Ed. 2012, 51, 3646; (b) Sabo-Etienne and coworkers, Chem. Eur. J. 2015, 21, 13080. [6] (a) Lentz and coworkers, Angew. Chem., Int. Ed. 2010, 49, 2933; (b) Lentz and coworkers, Chem. Eur. J. 2012, 18, 10701. [7] Jones and coworkers, J. Am. Chem. Soc. 2002, 124, 8681. [8] Andersen and coworkers, J. Am. Chem. Soc. 2005, 127, 7781. [9] Buchwald and coworkers, J. Am. Chem. Soc. 1992, 114, 7562.