Palladium-catalyzed stereoselective C-F bond activation of gem-difluoroalkenes and copper-mediated trifluoromethylation of α-diazo compounds

Ph.D.Organofluorine compounds have gained increasing importance in medicine and material science. This is because the properties and reactivities of organic molecules can often be dramatically altered in the presence of fluorinated moieties. Therefore, there is a growing demand for the development of more efficient and selective methods to access fluorinated molecules. This thesis is divided into three parts detailing two palladium-catalyzed and one copper-mediated methods for the synthesis of novel fluorine-containing compounds.The first chapter describes a palladium-catalyzed Sonogashira process for the stereoselective synthesis of conjugated monofluoroenynes via the reaction of gem-difluoroalkenes with terminal alkynes. (Q. Ma, Y. Wang, G. C. Tsui, Angew. Chem. Int. Ed. 2020, 10.1002/anie.202002219.) This represents the first example of metal-catalyzed C-F bond alkynylation of gem-difluoroalkenes. In which, NaI as an additive plays a key role in the suppression of side reactions. Both NOE study and X-ray crystallography were used to confirm the E-configuration of the monofluoroenyne products. The successful preparation and crystallization of a key Pd complex provided direct evidence for the C-F bond insertion by Pd as a viable mechanistic pathway.The second chapter discusses a palladium-catalyzed stereoselective hydrodefluorination of gem-difluoroalkenes. (Q. Ma, C. Liu, G. C. Tsui, Org. Lett. 2020, 10.1021/acs.orglett.0c01813.) Hydrosilanes were used as the hydrogen source, with mild reaction conditions various monofluoroalkenes were obtained in good to high yields with excellent E-selectivity. The excellent level of stereocontrol presumably stems from an ester-directed C-F bond oxidative addition process. And a novel yield-enhancing effect of adding catalytic organic azide is also revealed. The formation of thermostable Si-F bond between Pd-F complex and hydrosilanes should be an important driving force to promote this reaction.The third chapter discloses a copper-mediated trifluoromethylation of α-diazoesters and α-diazoketones using fluoroform-derived CuCF3. (Q. Ma, G. C. Tsui, Org. Chem. Front. 2019, 6, 27- 31.) Reaction conditions are mild and easy to handle, allowing the synthesis of a series of α-trifluoromethyl esters and ketones in one-step from α-diazo carbonyl compounds. The ultimate CF3 source is the inexpensive, nontoxic, industrial waste fluoroform. Synergistic effect of using 1,4-dioxane as co-solvent and pyridine as promoter is revealed.有機氟化合物在藥物化學和材料科學領域的重要性日益凸顯。這是由於含氟官能團通常能夠顯著地改變有機分子的基本屬性和反應活性。因此，發展高效且具有選擇性的方法用以合成新型含氟分子具有很重要的意義。本論文分為三章，其中前兩章討論鈀催化的選擇性碳氟鍵活化，第三章介紹銅介導的三氟甲基化反應。第一章闡述了一例鈀催化Sonogashira 類型的反應。以偕二氟烯烴和末端炔烴為原料，立體選擇性地合成多種共軛單氟烯炔衍生物，這是基於偕二氟烯烴，金屬催化的碳氟鍵炔基化首次報導。反應中，添加物碘化鈉在抑制副反應方面起了關鍵性的作用。通過 NOE 研究和晶體結構測定，最終確定共軛單氟烯炔產物的構型為 E 式。關鍵的反應中間體鈀碘配合物被成功製備並分離表徵，其晶體結構信息表明金屬鈀對碳氟鍵進行了直接的插入。第二章討論了一例鈀催化，基於偕二氟烯烴的立體選擇性氫化脫氟反應。該反應條件溫和且產率優良，以矽氫試劑作為氫源，成功製備多種E式的單氟烯烴。優異的立體選擇性控制可能歸功於酯羰基的導向作用，此外，本工作中還發現催化量的有機疊氮化合物對反應有顯著的促進作用。中間體鈀氟配合物和矽氫試劑反應形成熱力學穩定的矽氟鍵，是該催化反應的重要驅動力。第三章介紹了一例銅介導的三氟甲基化反應。用三氟甲烷製備銅三氟甲基化試劑，反應條件溫和且方便操作，以重氮羰基化合物為原料經一步轉化，成功合成一系列的三氟甲基酯以及三氟甲基酮。最終的三氟甲基源是便宜無毒的工業廢氣，三氟甲烷。文中，1，4-二氧六環作為共溶劑和吡啶作為促進劑的協同作用被詳細討論。Ma, Qiao.Thesis Ph.D. Chinese University of Hong Kong 2020.Includes bibliographical references.Abstracts also in Chinese.Title from PDF title page (viewed on February 18, 2022)