在本論文中，我們利用手性氧釩催化劑搭配氧化劑TBHP生成並引導自由基在醇類溶劑中對乙烯基芳烴進行不對稱的1,2-烷氧基硫基化反應。在七種雜芳硫醇自由基試劑之初步檢測，挑選出鏡像選擇性最佳的2-巰基苯並噁唑進行後續研究。經過十一種柳醛C-3與C-5取代的手性氧釩催化劑以及一系列反應濃度、溫度、溶劑與氧化劑的優化，確立最佳化的反應條件。在八種醇類溶劑的測試後，確立反應對甲醇、乙醇、正丙醇、正丁醇與異戊醇等一級醇類溶劑的通用性；並以甲醇與五十種鄰、間、對不同單取代、雙取代以及苯並/雜芳並的乙烯基芳烴及三種不同取代基的2-巰基苯並噁唑進行搭配，在大部分的例子中可得到高度的立體選擇性（>80%）與中等（~60%）至良好（~80%）的產率，產率可高達92%，ee值可高達96%。我們推測了產物與副產物可能的反應機制，並搭配理論計算進行反應中間體與過渡態的鏡像選擇性探討，最終我們也利用X光單晶繞射儀確立一代表性產物的絕對立體化學。

In this thesis, we utilized chiral vanadyl catalysts to facilitate the asymmetric 1,2-alkoxy-sulfenylation of vinylarenes via a radical pathway in alcohol solvents, employing TBHP as the oxidant. Among seven heteroarylthio radical precursors screened initially, 2-mercaptobenzoxazole was selected for further investigation due to its superior enantioselectivity. Through optimization involving eleven chiral vanadyl catalysts and a series of parameters including reaction concentration, temperature, solvent, and oxidant, optimal reaction conditions were established. After being tested with eight alcohol solvents, the generality of the reaction towards primary alcohol solvents was confirmed. Utilizing methanol and fifty different vinylarenes, along with 2-mercaptobenzoxazole with various substituents, resulted in high enantioselectivity (>80%) with moderate (~60%) to good yields (~80%) in most cases, with yields reaching up to 92% and ee values up to 96%. Possible reaction mechanisms for the products and by-products were proposed, and the enantioselectivity of reaction intermediates was explored through theoretical calculations. Finally, the absolute stereochemistry of the products was confirmed using X-ray single-crystal diffraction analysis.

中文摘要 -------------------------------------------------I
Abstract------------------------------------------------II
謝誌----------------------------------------------------III
目錄----------------------------------------------------IV
式目錄--------------------------------------------------VII
圖目錄---------------------------------------------------X
表目錄---------------------------------------------------XI
縮寫對照表----------------------------------------------XII
第一章、緒論---------------------------------------------1
第一節、烯類雙官能基化反應--------------------------------1
1.芳香硫酚在烯烴雙官能基化之反應（外消旋）----------------2
2.芳香硫酚在烯烴雙官能基化之反應（手性）------------------11
第二節、氧釩催化劑在不對稱催化反應之應用-------------------17
第三節、氧釩催化劑生成並引導自由基對烯烴進行不對稱1,2-烷氧基芳硫化反應之困境------------------------------------------------------29
1.目前已知的不對稱研究皆經由鋶三員環中間體----------------29
2.1,2-氫基烷硫基化的背景反應----------------------------29
3.硫化物的氧化副產物------------------------------------31
第四節、研究動機-----------------------------------------33
第二章、結果與討論---------------------------------------34
第一節、不同硫醇自由基試劑探討----------------------------34
第二節、反應條件優化與催化劑檢測--------------------------37
第三節、醇類溶劑通用性檢測--------------------------------46
第四節、苯乙烯衍生物通用性檢測----------------------------50
1.單取代苯乙烯衍生物檢測---------------------------------50
2.雙取代苯乙烯衍生物檢測---------------------------------55
3.芳香雜環乙烯衍生物檢測---------------------------------57
4.2-巰基苯並噁唑取代基效應檢測---------------------------60
第五節、反應機制-----------------------------------------62
第六節、探討反應中間體之鏡像選擇性的建立-------------------67
第七節、後續應用-----------------------------------------71
第八節、結論---------------------------------------------73
第三章、分析儀器、實驗步驟與光譜數據-----------------------74
第一節、分析儀器-----------------------------------------74
第二節、實驗步驟與光譜數據--------------------------------76
1.初始反應條件嘗試--------------------------------------76
2.不同硫醇自由基試劑探討之通用步驟------------------------78
3.反應條件優化與催化劑檢測通用步驟------------------------88
4.醇類溶劑與苯乙烯衍生物檢測通用步驟----------------------106
5.後續應用之步驟----------------------------------------163
參考文獻--------------------------------------------------166
附錄壹、核磁共振光譜圖-------------------------------------S1
附錄貳、X-ray 單晶繞射結構解析數據-------------------------S141

1. Bao, X.; Li, J.; Jiang, W.; Huo, C. Radical-Mediated Difunctionalization of Styrenes. Synthesis 2019, 51, 4507−4530.
2. Kharasch, N.; Buess, C. M. Derivatives of Sulfenic Acids. II. Characterization of Olefins with 2,4-Dinitrobenzenesulfenyl Chloride. J. Am. Chem. Soc. 1949, 71, 2724−2728.
3. Taniguchi, N. Copper-Catalyzed 1,2-Hydroxysulfenylation of Alkene Using Disulfide via Cleavage of the S-S Bond. J. Org. Chem. 2006, 71, 7874−7876.
4. Huang, J.; Li, X.; Xu, L.; Wei, Y. Three-Component Oxychalcogenation of Alkenes under Metal-Free Conditions: A Tetrabutylammonium Tribromide-Catalyzed System. J. Org. Chem. 2023, 88, 3054−3067.
5. Yuan, Y.; Chen, Y.; Tang, S.; Huang, Z.; Lei, A. Electrochemical oxidative oxysulfenylation and aminosulfenylation of alkenes with hydrogen evolution. Sci. Adv. 2018, 4, eaat531.
6. Wang, Y.; Deng, L.; Mei, H.; Du, B.; Han, J.; Pan, Y. Electrochemical oxidative radical oxysulfuration of styrene derivatives with thiols and nucleophilic oxygen sources. Green Chem. 2018, 20, 3444−3449.
7. Zhou, S.-F.; Pan, X.; Zhou, Z.-H.; Shoberu, A.; Zou, J.-P. Air Oxidative Radical Hydroxysulfurization of Styrenes Leading to β‑Hydroxysulfides. J. Org. Chem. 2015, 80, 3682−3687.
8. Chen, Z.; Xue, F.; Liu, T.; Wang, B.; Zhang, Y.; Jin, W.; Xia, Y.; Liu, C. Synthesis of β-hydroxysulfides via visible-light-driven and EDA complex-promoted hydroxysulfenylation of styrenes with heterocyclic thiols in EtOH under photocatalyst-free conditions. Green Chem. 2022, 24, 3250−3256.
9. Hong, J. E.; Jung, Y.; Jang, D. M. M.; Kim, S.; Park, J.; Park, Y. Visible-Light-Induced Organophotocatalytic Difunctionallization: Open-Air Hydroxysulfurization of Aryl Alkenes with Aryl Thiols. J. Org. Chem. 2022, 87, 7378−7391.
10. Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. Catalytic Asymmetric Thiofunctionalization of Unactivated Alkenes. J. Am. Chem. Soc. 2011, 133, 15308−15311.
11. Denmark, S. E.; Chi, H. M. Lewis Base Catalyzed, Enantioselective, Intramolecular Sulfenoamination of Olefins. J. Am. Chem. Soc. 2014, 136, 8915−8918.
12. Denmark, S. E.; Hartmann, E.; Kornfilt, D. J. P.; Wang, H. Mechanistic, crystallographic, and computational studies on the catalytic, enantioselective sulfenofunctionalization of alkenes. Nat. Chem. 2014, 6, 1056−1064.
13. Liu, X.-D.; Luo, Y.; Huo, X.; Luo, H.-Y.; Cao, R.-F.; Chen, Z.-M. Chiral Sulfide/Phosphoric Acid Cocatalyzed Enantioselective Intermolecular Oxysulfenylation of Alkenes with Phenol and Alcohol O-Nucleophiles. CCS Chem. 2022, 4, 3342−3354.
14. Liu, X.-D.; Ye, A.-H.; Chen, Z.-M. Catalytic Enantioselective Intermolecular Three-Component Sulfenylative Difunctionalizations of 1,3-Dienes. ACS Catal. 2023, 13, 2715−2722.
15. Liu, X.; An, R.; Zhang, X.; Luo, J.; Zhao, X. Enantioselective Trifluoromethylthiolating Lactonization Catalyzed by an Indane-Based Chiral Sulfide. Angew. Chem. Int. Ed. 2016, 55, 5846−5850.
16. Liang, Y.; Zhao, X. Enantioselective Construction of Chiral Sulfides via Catalytic Electrophilic Azidothiolation and Oxythiolation of N‑Allyl Sulfonamides. ACS Catal. 2019, 9, 6896−6902.
17. Hon, S.-W.; Li, C.-H.; Kuo, J.-H.; Barhate, N. B.; Liu, Y.-H.; Wang, Y.; Chen, C.-T. Catalytic Asymmetric Coupling of 2-Naphthols by Chiral Tridentate Oxovanadium(IV) Complexes. Org. Lett. 2001, 3, 869−872.
18. Barhate, N. B.; Chen, C.-T. Catalytic Asymmetric Oxidative Couplings of 2-Naphthols by Tridentate N-Ketopinidene-Based Vanadyl Dicarboxylates. Org. Lett. 2002, 4, 2529−2532.
19. Pawar, V. D.; Bettigeri, S.; Weng, S.-S.; Kao, J.-Q.; Chen, C.-T. Highly Enantioselective Aerobic Oxidation of α-Hydroxyphosphonates Catalyzed by Chiral Vanadyl(V) Methoxides Bearing N-Salicylidene-α-aminocarboxylates. J. Am. Chem. Soc. 2006, 128, 6308−6309.
20. Weng, S.-S.; Shen, M.-W.; Kao, J.-Q.; Munot, Y. S.; Chen, C.-T. Chiral N-salicylidene vanadyl carboxylate-catalyzed enantioselective aerobic oxidation of α-hydroxyesters and amides. Proceed. Natl. Acad. Sci. USA 2006, 103, 3522−3527.
21. Yang, W.-C.; Weng, S.-S.; Ramasamy, A.; Rajeshwaren, G.; Liao, Y.-Y.; Chen, C.-T. Vanadyl species-catalyzed complementary β-oxidative carbonylation of styrene derivatives with aldehydes. Org. Biomol. Chem. 2015, 13, 2385−2392.
22. Fenton, H. J. H. LXXIII.−Oxidation of tartaric acid in presence of iron. J. Chem. Soc., Trans. 1894, 65, 899−910.
23. Chen, C.-T.; Su, Y.-C.; Lu, C.-H.; Lien, C.-I.; Hung, S.-F.; Hsu, C.-W.; Agarwal, R.; Modala, R.; Tseng, H.-M.; Tseng, P.-X.; Fujii, R.; Kawashima, K.; Mori, S. Enantioselective Radical Type, 1,2-Oxytrifluoromethylation of Olefins Catalyzed by Chiral Vanadyl Complexes: Importance of Noncovalent Interactions. ACS Catal. 2021, 11, 7160−7175.
24. Chen, C.-T.; Chang, Y.-C.; Tseng, P.-X.; Lein, C.-I.; Hung, S.-F.; Wu, H.-L. Asymmetric Synthesis of Trifluoroethyl-Based, Chiral 3-benzyloxy-1- and -2-phenyl-quinazolinones of Biomedicinal Interest by Radical Type Cross-Coupling to Olefins. Int. J. Mol. Sci. 2023, 24, 513.
25. Chen, C.-T.; Hung, S.-F.; Tsai, B.-Y.; Chen, T.-C.; Lein, C.-I.; Tseng, P.-X.; Chang, Y.-C.; Chuang, C.-W.; Agarwal, R.; Hsu, C.-W.; Shimizu, Y.; Fujii, R.; Mori, S. Asymmetric Cross Couplings of Trifluoromethyl Radical to Vinylarenes with N-Hydroxy-oxazinediones and Subsequent Aerobic Oxidative Homocoupling of 2-Naphthols Catalysed by Chiral Vanadyl Complexes. Adv. Synth. Catal. 2024, 366, 248−261.
26. Chuang, C.-W.; Huang, G.-R.; Hung, S.-F.; Hsu, C.-W.; Liu, Y.-H.; Hwang, C.-H.; Chen, C.-T. Enantioselective Radical-Type 1,2-Alkoxy-Phosphinoylation to Styrenes Catalyzed by Chiral Vanadyl Complexes. Angew. Chem. Int. Ed. 2023, 62, e202300654.
27. Choudhuri, K.; Mandal, A.; Mal, P. Aerial dioxygen activation vs. thiol–ene click reaction within a system. Chem. Commun. 2018, 54, 3759−3762.
28. Yue, H.-L.; Klussmann, M. Acid-Catalyzed Oxidative Addition of Thiols to Olefins and Alkynes for a One-Pot Entry to Sulfoxides. Synlett 2016, 27, 2505−2509.
29. Nakajima, K.; Kojima, M.; Fujita, J. Asymmetric oxidation of sulfides to sulfoxides by organic hydroperoxides with optically active Schiff base-oxovanadium (IV) catalysts. Chem. Lett. 1986, 15, 1483−1486.
30. Sun, J.; Zhu, C.; Dai, Z.; Yang, M.; Pan, Y.; Hu, H. Efficient Asymmetric Oxidation of Sulfides and Kinetic Resolution of Sulfoxides Catalyzed by a Vanadium-Salan System. J. Org. Chem. 2004, 69, 8500−8503.
31. Yu, G.; Ou, Y.; Chen, D.; Huang, Y.; Yan, Y.; Chen, Q. Air-Induced Disulfenylation of Alkenes: Facile Synthesis of Vicinal Dithioethers. Synlett 2019, 31, 83−86.
32. Nakajima, K.; Kojima, M.; Tsuchimoto, M.; Yoshikawa, Y.; Fujita, J. Isomerization of a Diastereomeric Oxovanadium(IV) Complex Containing an Unsymmetrical Tetradentate Schiff Base Ligand Catalyzed by Oxovanadium(V) Species. Chem. Lett. 1994, 9, 1593−1596.
33. Parsaee, F.; Senarathna, M. C.; Kannangara, P. B.; Alexander, S. N.; Arche, P. D. E.; Welin, E. R. Radical philicity and its role in selective organic transformations. Nat. Rev. Chem. 2021, 5, 486−499.
34. Kupwade, R. V. A Concise Review on Synthesis of Sulfoxides and Sulfones with Special Reference to Oxidation of Sulfides. J. Chem. Rev. 2019, 1, 99−113.
35. Mao, S.; Li, Q.; Yang, Z.; Li, Y.; Ye, X.; Wang, H. Design, synthesis, and biological evaluation of benzoheterocyclic sulfoxide derivatives as quorum sensing inhibitors in Pseudomonas aeruginosa. J. Enzyme Inhib. Med. Chem. 2023, 38, 2175820.