C-F Borylation of Unsaturated Fluorocarbons

该项目的总体目标是开发方法，将环境持久性氟碳化合物转化为可用于合成的活性化学成分。目标1(1-12个月)。研究了在合成含两种氢化物的相关硼试剂中，尽管频碳硼烷、双(频那醇)二硼烷、儿茶酚硼烷和双(儿茶酚)二硼烷广泛应用于硼二氢化合物的催化生成。我们建议通过胺-硼烷前驱体的催化脱氢反应来开发一系列胺稳定的硼二氢化合物。配体前体将通过商业原料的Buchwald-Hartwig偶联来合成。[1]在与BH3配位后，我们将研究第2和第3族预催化剂，以实现这些底物的脱氢循环，为迄今无法获得的硼二氢化合物提供一条新的途径。[2-5]目标2(13-24个月)。氟烯烃的催化C-F硼化上述新试剂将用于氢氟烯烃的C-F硼化反应。我们将寻找能够通过选择性加成消除反应进行操作的催化剂。基于该小组目前未发表的机理分析，提出了三种早期过渡金属催化剂作为出发点。它们都包含以下设计特征：(I)溶解和动力学稳定的CP配体，(Ii)促进β-氟化物消除的亲电早期TM，(Iii)能够使不饱和体系湿法金属化的单一反应氢化物中心。[6-8]目标3(25-36个月)。机理研究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休眠状态并测试它们的反应性，(Ii)竞争和机械探针实验，包括适用的D-标记实验，(Iii)动力学分析和(Iv)密度泛函研究(与计算小组合作)来实现。我们将质疑我们关于加法-消除过程的假设，以及这是否真的在我们发展的条件下运行。我们将试图了解控制催化的区域和化学选择性的步骤。如果这些步骤是在催化剂或底物控制下进行的，我们将致力于设计额外的实验，看看我们是否可以改变反应的区域化学。后备计划：如果我们无法接触到二氢化硼试剂，我们将为同样的目的调查已建立的二氢化铝络合物BDIAlH2。我们还可以研究新的含氟构筑块在合成中的应用，特别是在交叉偶联中的应用。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ANSA-金属配位，以尝试并产生对映体纯的产物。参考文献：[1]冯及其同事，J.Med。化学。2015年，1846年。[2](A)希尔和同事，化学。交警。2010年，46,7587；(B)希尔和同事，化学。欧元。J.2010，16,8505；(C)希尔和同事，化学。交警。2013年、49年、1960年。[3](A)Crimmin和同事，Chem。交警。2014年，50,9536；(B)Crimmin和同事，有机金属学，2015年，DOI：10.1021/acs.Organomet.5b00607。[4]陈和同事，ACS催化，2013，3,521。[5](A)Sabo-Etienne和同事，Angew。Int.Chem.艾德。2012年，51,3646人；(B)Sabo-Etienne和同事，Chem。欧元。J.2015年，21年，13080。[6](A)Lentz和同事，Angew。Int.Chem.艾德。2010年，49,2933；(B)Lentz和同事，化学。欧元。J·2012，18,10701。[7]琼斯和同事，J.Am化学。SoC。2002年，124,8681。[8]安德森及其同事，J.Am化学。SoC。2005年，127,7781。[9]布赫瓦尔德及其同事，J.Am化学。SoC。1992年、114、7562年。

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.