Development of Methods for Regioselective Introduction of Difluoromethylene Unit Using Difluorocarbene Ryo Takayama February 2018 1 Development of Methods for Regioselective Introduction of Difluoromethylene Unit Using Difluorocarbene Ryo Takayama Doctoral Program in Chemistry Submitted to the Graduate School of Pure and Applied Sciences in Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy in Science at the University of Tsukuba 2 Contents Chapter 1. General Introduction Chapter 2. Introduction of Difluoromethylene Unit into Thiocarbonyl Compounds 2-1. S-Selective Difluoromethylation of Thiocarbonyl Compounds 2-1-1. Introduction 2-1-2. Synthesis of S-Difluoromethyl Thioimidates 2-1-3. Mechanistic Study 2-1-4. Comparison with the Reported Methods for the Generation of Difluorocarbene 2-1-5. Conclusion 2-2. Difluoromethylidenation of Dithioesters: Synthesis of Sulfur-Substituted Difluoroalkenes 2-2-1. Introduction 2-2-2. Synthesis of Sulfanylated Difluoroalkenes 2-2-3. Mechanistic Study 2-2-4. Comparison with the Reported Methods for the Generation of Difluorocarbene 2-2-5. Conclusion 2-3. Experimental Section 2-4. References 3 Chapter 3. Introduction of Difluoromethylene Unit into Dienol Silyl Ethers 3-1. Regioselective Difluorocyclopropanation of Dienol Silyl Ethers 3-1-1. Introduction 3-1-2. Regioselective Difluorocyclopropanation: Synthesis of Vinylated Difluorocyclopropanes 3-1-3. Conclusion 3-2. Metal-Free Synthesis of α,α-Difluorocyclopentanone Derivatives via Regioselective Difluorocyclopropanation/VCP Rearrangement of Dienol Silyl Ethers 3-2-1. Introduction 3-2-2. Metal-Free Synthesis of 5,5-Difluorocyclopent-1-en-1yl Silyl Ethers 3-2-3. Advantages of the Organocatalytic Synthesis 3-2-4. Conclusion 3-3. Synthesis of Fluorinated Cyclopentenones via Regioselective Difluorocyclopropanation of Dienol Silyl Ethers 3-3-1. Introduction 3-3-2. Preparation of 1-Fluorovinyl Vinyl Ketones 3-3-3. Fluorine-Directed and Fluorine-Activated Nazarov Cyclization: Regioselective Synthesis of α-Fluorocyclopentenones 3-3-4. Effect of Fluorine Substituent in Nazarov Cyclization 3-3-5. Conclusion 3-4. Experimental Section 3-5. References Chapter 4. Conclusions List of Publications Acknowledgement 4 Chapter 1. General Introduction 1-1. Biologically Useful Properties of Fluorine Compared with fluorine-free compounds, organofluorine compounds often exhibit unique behavior due to specific properties of fluorine substituents. For example, organofluorine compounds have weak intermolecular forces, generated by electronic polarization of molecules, because C–F bond is stable and electronic polarization is hardly to generate due to the strong electronegativity of fluorine. Because of this behavior, compounds with fluorine atoms have low boiling points. In addition, due to the strong electron-withdrawing property of fluorine, fluorine interacts with positive species such as a proton. Furthermore, being the second smallest substituent next to hydrogen, fluorine has been recognized as a mimic of hydrogen. Thus, organofluorine compounds are considered to be important in pharmaceutical, agrochemical, and functional material sciences. Among fluorinated compounds, difluoromethylene (-CF2-) or difluoromethylidene (=CF2) group containing compounds have attracted particular attention in the fields of pharmaceuticals and agrochemicals. For example, Flomoxef bearing a difluoromethylsulfanyl group exhibits antimicrobial activity (Figure 1).[1] Difluoroalkene 1 shows anticancer activity and dermatological activity, while difluorocyclohexanone 2 exhibits antimalarial activity.[2,3] Figure 1. Bioactive Compounds Bearing the Difluoromethylene or Difluoromethylidene Moiety 5 1-2. Synthetically Useful Properties of Fluorine From a synthetic point of view, there are several useful properties in fluorinated compounds. A fluorine substituent acts as an electron-withdrawing group because fluorine atom is most electronegative. When a fluorine atom is connected to a π-system, it can also act as an electron- donating group. This is because fluorine is on the same row as that of carbon in the periodical table, and thus donation of lone pairs of fluorine atom occurs efficiently. Because of this property, a fluorine substituent generally stabilizes an anion, whereas it destabilizes the anion at the α-position connected to a π-system. Likewise, it stabilizes the α-cation and destabilizes the β-cation (Figure 2). Figure 2. Properties of Fluorine Substituents. 1-3. Fluorine Installation Methods There are roughly two methods for the synthesis of difluoromethylene compounds. They are (i) direct introduction of fluorine substituents and (ii) introduction of building blocks containing fluorine substituents. As the background of this thesis, examples of these strategies are provided below. Although fluorine molecule (F2) or xenon difluoride (XeF2) had been used as electrophilic agent for direct fluorination, recently more stable, storable, and easily handled agents have been developed. For example, N-fluoropyridinium salt 3, chloromethyl-4-fluoro-1,4-diazoniumbicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™), and N-fluorobenzenesulfonimide (NFSI) are widely used as electrophilic fluorinating agents (eq. 1–3, Scheme 1).[4–6] In these reactions, nucleophiles, such as 6 dienyl ester, enol, and vinyllithium, attack the electrophilic fluorine equivalents mentioned above. Scheme 1. Electrophilic Fluorine Introduction Apart from electrophilic fluorination, fluorination proceeds via nucleophilic attack of a fluoride ion to electrophilic substances. Pyridinium fluoride, potassium (alkali metal) fluoride, and N,N- diethylaminosulfur trifluoride (DAST) are often selected as the reagents (eq. 4–6, Scheme 2).[7–9] 7 Scheme 2. Nucleophilic Fluorine Introduction Although these direct nucleophilic and electrophilic fluorination methods are widely used, they suffer from drawbacks relating to the requirements of time-consuming processes (carbon-skeleton construction and fluorine installation) as well as the use of expensive fluorinating reagents. Introduction of a difluoromethylene unit using building blocks is useful, because diverse building blocks with a difluoromethylene unit have been developed until now. There are three kinds of one-carbon difluoromethylene sources: difluorocarbene, difluoromethyl cation (equivalent), difluoromethyl anion (equivalent), and difluoromethyl radical. Difluorocarbene, generated from chlorodifluoromethane and sodium hydroxide, reacts with indole to give 1-difluoromethylindole in 50% yield (eq. 7, Scheme 3).[10] On treatment with sulfonium salt 4, which acts as difluoromethyl cation equivalent, sodium p-toluenesulfonate provides difluoromethyl p-toluenesulfonate in 77% yield (eq. 8).[11] When benzaldehyde is treated with difluoromethyl phenyl sulfone, nucleophilic attack of difluoro(phenylsulfonyl)methide proceeds to give alcohol 5 in 65% yield (eq. 9).[12] 1- Pentene reacts with dibromodifluoromethane in the presence of a catalytic amount of copper(I) chloride to afford the radical addition product 6 in 57% yield (eq. 10).[13] 8 Scheme 3. Introduction of a Difluoromethylene Unit Using One-carbon Building Blocks There are several two- or more-carbon building blocks that allow to introduce a difluoromethylene or difluoromethylidene unit. For example, when benzaldehyde is treated with ethyl bromodifluoroacetate in the presence of zinc metal, the Reformatsky reaction proceeds, which allows installation of a carbonylated difluoromethylene unit (C2 unit introduction, eq. 11, Scheme 4).[14] Difluorovinylborane 7, generated from 2,2,2-trifluoroethyl tosylate, reacts with benzoyl chloride in the presence of a cupper salt to afford difluorovinylated ketone 8 in 78% yield (C2 unit introduction, [15] eq. 12). When 2-phenyl(trifluoromethyl)propene is treated with butyllithium, SN2’-type reaction proceeds to afford disubstituted difluoroalkene 9 in 93% yield (C3 unit introduction, eq. 13).[16] The difluorinated diene 11, prepared from trifluoromethyl ketone 10, reacts with benzaldehyde or 9 benzylideneaniline to produce the ring-fluorinated heterocycles 12 and 13 in 64% and 60% yields, respectively (C4 unit introduction, eq. 14 and 15).[17] Scheme 4. Introduction of Difluoromethylene Units Using Two- or More-carbon Building Blocks As shown above, the methods using fluorinated building blocks are of use because introduction of fluorine substituents and construction of carbon skeleton are carried out at the same time. I have focused on fluorinated one-carbon building blocks, especially the simplest difluorocarbene, which 10 can be applied to the synthesis of various difluoromethyl, difluoromethylene and difluoromethylidene compounds. Among one-carbon building blocks, difluorocarbene has particularly high and versatile reactivities. In spite of the merits, difluorocarbene has not been used widely, because the conditions for its generation are too severe to apply to a wide variety of compounds. Treatment of phenol with chlorodifluoromethane in the presence of excess amounts of sodium hydroxide afforded difluoromethoxybenzene in 65% yield (eq. 16, Scheme 5).[18] First, deprotonation of chlorodifluoromethane proceeds by sodium hydroxide. Then α-elimination of the generated chlorodifluoromethyl anion proceeds to form difluorocarbene. Finally, phenoxide, generated from phenol and sodium hydroxide, reacts with the generated difluorocarbene and protonation affords the difluoromethylated compound. This method requires the strong base. There is a reductive