Development of Methods for Regioselective Introduction of Difluoromethylene Unit Using Difluorocarbene

Home , Difluorocarbene, Silyl ether

Development of Methods for Regioselective Introduction

of Difluoromethylene Unit Using Difluorocarbene

Ryo Takayama

February 2018

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

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

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

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

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]

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 method through a similar α-elimination process from a halodifluoromethyl anion. When α-methylstylene reacted with dibromodifluoromethane in the presence of zinc metal, difluorocyclopropane 14 was produced in 83% yield (eq. 17).[19] Furthermore, difluorocarbene is generated by using a nucleophilic agent. For example, when cyclohexene was treated with pheny(trifluoromethyl)mercury in the presence of sodium iodide, difluorocyclopropanation proceeded to give 15 in 83% yield (eq. 18).[20]

In this reaction, a plausible mechanism is as follows: Iodide ion attacks the mercury center to liberate trifluoromethyl anion, which undergoes α-elimination to generate difluorocarbene. Although this method is carried out under relatively mild conditions, a toxic mercury(II) reagent is required.

Therefore, it is not beneficial for organic synthesis.

Scheme 5. Conventional Generation Method of :CF2 I (Basic, Reductive, or Nucleophilic Method)

In addition, difluorocarbene can be generated by thermal decomposition of difluoromethylene compounds (difluorocarbene precursors). For example, treatment of cyclohexene with hexafluoropropylene oxide (HFPO) afforded difluorocyclopropane 16 in 35% yield (eq. 19, Scheme

6).[21] Ring opening of HFPO proceeds at high temperature to generate the corresponding carbonyl ylide, followed by liberation of difluorocarbene. Butyl 1-propenyl ether was treated with sodium chlorodifluoroacetate at 165 °C to afford difluorocyclopropane 17 in 53% yield (eq. 20).[22] This precursor is decomposed at high temperatures to eliminate carbon dioxide.

Scheme 6. Conventional Generation Method of :CF2 II (Thermal Decomposition Method)

Recently, several new methods for generating difluorocarbene have been developed (Figure

3).[23–37] The compounds shown at the top of Figure 3 are precursors which generate difluorocarbene under basic conditions. They generally require strong bases such as KOH or NaH. For example, in

2013, Hartwig reported difluoromethylation of phenol derivatives using difluoromethyl triflate (eq.

21, Scheme 7).[26] Treatment of phenol derivatives with difluoromethyl triflate in the presence of excess amount of KOH affords difluoromethoxyarenes in good yields.

The precursors shown at the middle of Figure 3 generate difluorocarbene using a nucleophilic agent as their activator. They have an electrophilic moiety consisting of heteroatoms. For example,

Hu et al. developed (bromodifluoromethyl)trimethylsilane (TMSCF2Br). Since then it has been 12 applied to various alkenes in the presence of a catalytic amount of tetraammonium bromide (TBAB)

[38] (eq. 22). In this reaction, bromide ion attacks on the silicon of TMSCF2Br to generate difluorocarbene.

Two precursors shown at the bottom of Figure 3 decompose at relatively high temperatures to evolve difluorocarbene. These carbene precursors are characterized by decomposition along with decarboxylation. In 2013, Xiao developed difluoromethylenephosphobetaine 18 as a difluorocarbene precursor (eq. 23).[37] Various alkenes were treated with 18 to afford the corresponding difluorocyclopropanes in good yields. This reagent can be used under milder conditions than those of the conventional thermal decomposition, but still it requires somewhat high temperatures for efficient difluorocarbene generation.

I focused on the difluorocarbene precursors using nucleophilic agents, which would achieve the generation of difluorocarbene under nearly neutral conditions and at low temperatures.

Figure 3. Recent Difluorocarbene Precursors.

Scheme 7. Recent Generation Method of :CF2

As exemplified above, the nucleophile-promoted generation of difluorocarbene is useful for introduction of a CF2 unit. However, these precursors had one serious problem, namely, overreaction of difluorocarbene. When ketone 19 was treated with TFDA in the presence of 10 mol% of sodium fluoride, enol difluoromethyl ether 20 was not obtained, but difluorocyclopropane 21 was formed as a sole product in 70% yield (eq. 24).[39] This result was probably because the generation of difluorocarbene was too fast compared to the formation of 20 and its concentration was too high. For this reason, the rate of difluorocarbene generation should be controlled to obtain 20.

To prevent the overreaction, the Ichikawa group adopted an organocatalyst, N-heterocyclic carbene (NHC), as an activator of TFDA. Since the substituents of NHC can be easily changed, it is considered possible to adjust its nucleophilicity to TFDA, that is, the generation rate of

14 difluorocarbene. In his group, the following reaction was carried out in order to confirm that NHCs controlled the generation rate of difluorocarbene. Indanone was treated with TFDA in the presence of various NHCs and sodium carbonate to form difluoromethyl ether 22 (Table 1).[40] In fact, 22 and the undesired difluorocyclopropane 23 were obtained in different yields depending on the employed

NHCs. This data confirmed that the suitable generation rate of difluorocarbene enabled to preventing the overreaction product 23. This difluoromethylation of indanone can be interpreted by the proposed mechanism shown in Scheme 8. First, 1,3-dimesitylimidazolylidene (IMes) attacks the silyl group of

TFDA to generate difluorocarbene through evolution of CO2, SO2, and fluoride ion. After indanone reacts with the generated difluorocarbene to form the ylide, a hydrogen at the α-position of the carbonyl group migrates to the difluoromethylene carbon, providing the desired difluoromethyl enol ether 22. The silylated NHC formed in the process is attacked by a fluoride ion released via decomposition of TFDA, thereby regenerating NHC.

Table 1. Effect of NHCs.

Scheme 8. Organocatalytic Generation of Difluorocarbene and Difluoromethylation.

I recognized the high potentiality of organocatalytic generation of difluorocarbene from TFDA to control the generation rate of difluorocarbene. So far, this concept was used only to prevent the abovementioned overreaction. In this doctoral thesis, thus, I aimed to achieve selective reactions utilizing the controlled generation of difluorocarbene. In other words, I expected that selective reactions would be affected at the most reactive position of the substrates by suppressing the overreaction of difluorocarbene under milder conditions. To generate difluorocarbene under milder conditions, the organocatalysts were optimized among heteroatom nucleophiles, which had a high affinity for the silyl group of TFDA. Often screening of the organocatalysts in difluoromethylation of thioamido 25a, I found 1,8-bis(dimethylamino)naphthalene (24, Proton sponge™) as a new activator of TFDA (eq. 25). Proton sponge efficiently activated TFDA at lower temperatures and under nearly neutral conditions. As a result, I achieved the following regioselective reactions that had been considered difficult to carry out because of the conventional harsh conditions for generating difluorocarbene.

In chapter 2, I achieved sulfur-selective difluoromethylation of thioamides in a regioselective reaction of difluorocarbene on heteroatoms (eq. 26). I believed that difluoromethylation of thiocarbonyl compounds, which were easily hydrolyzed in the presence of a strong base, would be possible because the organocatalyst and TFDA generated difluorocarbene under nearly neutral conditions.

When thiocarbonyl compounds 25, secondary thioamides and thiocarbamates, were treated with

TFDA in the presence of a catalytic amount of proton sponge, selective difluoromethylation proceeded on the sulfur atoms to give S-difluoromethylated compounds 26 in good yields. Here, the formation of the N-difluoromethylated compounds 27 were not observed. In this reaction, the attack of the sulfur in 25 onto difluorocarbene, followed by proton transfer gave the S-difluoromethylated compounds 26, because 25 had a high electron density on its sulfur atom. The sulfur-selectivity shows that the isomerization from 26 to 27 was suppressed by carrying out the reaction at a lower temperature than that of the conventional, thermal generation of difluorocarbene. This process provides an efficient approach to pharmaceuticals and agrochemicals bearing a difluoromethylsulfanyl group, starting from widely available thioamides and thiocarbamates.

In addition, I achieved an efficient synthesis of sulfur-substituted difluoroalkenes, using

17 dithioesters as thiocarbonyl compounds. For the synthesis of difluoroalkenes, a nucleophilic method

(Wittig type reaction), in which difluoromethylene ylides react with carbonyl compounds, is widely used. However, it cannot be applied to esters which have lower electrophilicity, because ylides hardly attack ester carbonyl carbons. Therefore, I examined an electrophilic method for difluoroalkene synthesis via the reaction of electron deficient difluorocarbene with thiocarbonyl compounds

(Barton–Kellogg type reaction, eq. 27).[41] In this protocol, nucleophilic attack of thiocarbonyl sulfur atoms should occur on an electrophilic carbene, therefore, it is considered that this electrophilic method might be applied to ester derivatives. In fact, I found that when dithioesters 28 were treated with difluorocarbene, the thiocarbonyl moieties underwent difluoromethylidenation to afford sulfur- substituted difluoroalkenes 30 in good yields.

On treatment with TFDA in the presence of a catalytic amount of proton sponge, a thiocarbonyl group of dithioesters 28 was converted to a difluorovinylidene group, providing sulfur-substituted difluoroalkenes 30, the promising synthetic intermediates, in 58–94% yields. In this reaction, alkenes

30 were formed by desulfurization of thiirane intermediates 29, which were generated by the reaction of dithioesters 28 with in situ generated difluorocarbene.

In chapter 3, as a regioselective reaction on carbon atoms, difluorocyclopropanation of dienol silyl ethers with difluorocarbene was investigated. Among two alkene moieties, the electron-rich alkene moiety with a siloxy group would selectively undergo difluorocyclopropanation. When dienol silyl ethers 31 were treated with TFDA in the presence of a catalytic amount of proton sponge, difluorocyclopropanation proceeded selectively at the alkene bearing a siloxy group as expected,

18 which afforded difluorocyclopropanes 32 in 75–96% yields (eq. 28). In this reaction, by conducting the reaction at a moderate temperature of 60 °C, the thermal ring-expansion of cyclopropanes 32 leading to cyclopentenes 33 (vinylcyclopropane rearrangement, Chapter 3, 3-2)[42] was suppressed and difluorocyclopropanes 32 were obtained efficiently.

In addition, I achieved the metal-free synthesis of difluorinated cyclopentenyl silyl ethers via regioselective difluorocyclopropanation followed by regioselective ring-expansion (eq. 29).

Difluorocyclopropanes 32 were obtained by regioselective difluorocyclopropanation of dienol silyl ethers 31 with difluorocarbene (Chapter 3, 3-1). When the reaction temperature was raised to 140 °C, thermal ring-expansion subsequently proceeded in a regioselective manner to afford cyclic enol silyl ethers 33, synthetic key intermediates of fluorine-containing cyclopentanones, in 66–90% yields. The key to efficient conversion to 33 was performing the difluorocyclopropanation and the VCP rearrangement at their own suitable temperatures. This is a method for the synthesis of fluorine- containing cyclopentanones which proceeds under metal-free conditions.

Furthermore, I achieved a regioselective Nazarov cyclization (the synthesis of fluorinated cyclopentenones) utilizing the α-cation stabilizing effect (+R effect, Figure 2) of fluorine substituent.

When the obtained cyclopropanes 32 (Chapter 3, 3-1) were treated with a catalytic amount of fluoride ion, elimination of the silyl group followed by ring opening proceeded to give 1-fluorovinyl vinyl ketones 34. Treatment of divinyl ketones 34 with a Lewis acid promoted a regioselective Nazarov cyclization. Here, in the cyclopentenyl cation intermediate A, the positive charge is localized at the

α-position of fluorine due to the α-cation stabilizing effect of a fluorine substituent. Successive deprotonation proceeded selectively near the positive charge to afford the fluorinated cyclopentenones 35 with a fluorovinyl moiety. Typically in the Nazarov cyclization, the rate- determining step is the process of 4π electrocyclization. Thus, I expected to accelerate the reaction by the stabilization of intermediate A caused by the α-cation stabilizing effect of fluorine.

When cyclopropanes 32 were treated with n-Bu4N SiF2Ph3 (TBAT, 20 mol%), 1-fluorovinyl

[43] vinyl ketones 34 were obtained in 53–77% yields. Next, when Me3Si B(OTf)4 was applied to 34, the Nazarov cyclization proceeded selectively and the expected cyclopentenones 35 were produced as a sole products (Scheme 9). Theoretical calculations (B3LYP/6-31G*) showed that in this Nazarov cyclization the position of deprotonation was controlled by the +R effect of fluorine, and the products

35 were obtained selectively under kinetic control. In addition, compared to that of a fluorine-free substrate, the reaction was accelerated by the fluorine substituent.

Scheme 9. Synthesis of Fluorinated Cyclopentenones via Regioselective Cyclopropanation.

In this doctoral thesis, I found that 1,8-bis(dimethylamino)naphthalene (Proton sponge™) acted as an efficient organocatalyst that activated TFDA and promoted generation of difluorocarbene under

20 mild conditions. As a result, the regioselective reactions of difluorocarbene were successfully achieved, which selectivities were difficult to be achieved under conventional, severe conditions for generating difluorocarbene. The following chapters show the details of these reactions.

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Chapter 2. Introduction of CF2 Unit to Thiocarbonyl Compounds

2-1. S-Selective Difluoromethylation of Thiocarbonyl Compounds

2-1-1. Introduction

Recently, the difluoromethyl group (CHF2 group) has received considerable attention in the field of pharmaceuticals and agrochemicals.[1] Since the difluoromethyl group acts as a proton donor and forms a hydrogen bond with its hydrogen atom,[2] it is regarded as a bioisostere of a hydroxyl group

(Figure 4).[3] Furthermore, introduction of fluoroalkyl groups, including the difluoromethyl group, often reduces Hildebrand’s δ value of molecules, and raises lipophilicity of the original molecules.[4,5]

Because of these practical advantages, the development of efficient methods for the synthesis of difluoromethylated compounds has been desired especially in recent years.

Figure 4. Difluoromethyl Group as a Bioisostere of Hydroxy Group.

Notably, the difluoromethylsulfanyl group (SCHF2 group) is included in various bioactive compounds (Figure 5). For example, flomoxef bearing a difluoromethylsulfanyl group exhibits antimicrobial activity,[6] and 2-difluoromethylsulfanyl-4,6-bis(isopropylamino)-1,3,5-triazine (SSH-

108) shows herbicidal activity.[7]

Figure 5. Useful Difluoromethylsulfanylated Compounds.

Difluoromethylation on S atoms of sulfur-containing functional groups is a straightforward method for the synthesis of difluoromethylsulfanylated compounds. However, the S- difluoromethylation has been limited to that of aromatic thiols. For example, Greaney reported difluoromethylation of benzenethiol.[8] p-Methoxybenzenethiol reacts with difluorocarbene, generated from sodium chlorodifluoroacetate in the presence of a base, to afford difluoromethylsulfanylbenzene 36 in 93% yield (eq. 30). The similar S-difluoromethylation of

[9] aromatic thiols with difluorocarbene was also achieved by Dolbier (precursor: HCF3), Hu

[10] [11] (PhS(O)(NTs)CF2H), and Segall (PO(OEt)2CF2Br).

To establish a method for the synthesis of difluoromethylsulfanylated compounds with broad substrate scope, I focused my attention on the use of thiocarbonyl compounds as substrates. In the

Ichikawa group, O-difluoromethylation of carbonyl compounds with difluorocarbene, leading to difluoromethyl ethers, was disclosed recently (Table 1).[12] I expected that thiocarbonyl compounds, specifically thioamides and thiocarbamates would react readily with electron-deficient difluorocarbene to afford the corresponding difluorosulfanylated compounds in a similar manner. In general, thiocarbonyl compounds are less stable than carbonyl compounds, and therefore, they have been scarcely utilized in organic synthesis. It was also expected that organocatalytic generation of difluorocarbene under mild conditions would expand the synthetic utility of thiocarbonyl compounds.

2-1-2. Synthesis of S-Difluoromethyl Thioimidates

In the classical difluoromethylation of secondary and primary amides with difluorocarbene under strongly basic conditions, no selectivity is observed because the ambident imidate anions B react with difluorocarbene on both oxygen and nitrogen centers (Scheme 10). In contrast, our group recently reported O-selective difluoromethylation of amides using the organocatalytically generated difluorocarbene.[13] Under the nearly neutral conditions, difluoromethylation of amides proceeded on their oxygen atoms having higher electron density, and O-difluoromethylated products

(difluoromethyl imidates) were obtained regioselectively. For example, treatment of amide 37 with

TFDA in the presence of a catalytic amount of triazolium salt 40 and sodium carbonate afforded O- difluoromethyl imidate 38 as a sole product in 80% yield. Thus, I expected S-difluoromethylation of thioamides, in which the oxygen atom of the amide carbonyl group was replaced with sulfur atom.

Scheme 10. Previous Work: O-Selective Difluoromethylation of Amides.

Formation of N-difluoromethylated products is a problem during difluoromethylation of thioamides. Particularly, when cyclic thiocarbamate 25b was treated with sodium chlorodifluoroacetate in the presence of potassium carbonate, S-difluoromethylated product 26b was obtained in 54% yield along with and 28% yield of N-difluoromethylated product 27b (eq. 31).[8]

It is considered that S-difluoromethylated compound 26b was formed at first, and transformed into N-difluoromethylated compound 27b in the presence of an excess amount of difluorocarbene at high temperatures. Thus, in order to obtain 26b selectively, it was required to reduce the reaction temperature. I expected to facilitate selective difluoromethylation of thioamides by the method for generating difluorocarbene with TFDA and proton sponge at lower temperatures, leading to the desired S-difluoromethylated product.

Optimization of the Catalyst

Optimization of the catalyst for S-difluoromethylation was performed by using 2-thiopyridone

25a as the model substrate (Table 2). First, dimesitylimidazolium and diphenyltriazolium salts 41 and

40 (NHCs), which were effective in the previous O-difluoromethylation, were examined.[12,13] In each case, 26a was obtained in 61% yield (Table 2, entries 1 and 2), and notably, N-difluoromethylated product 27a was not observed by 19F NMR analysis of the reaction mixture. In the generation of difluorocarbene from TFDA, organocatalysts act as nucleophiles that attack the trimethyl silyl group.

Thus, activity of triphenylphosphine was examined, and it afforded 26a albeit only in 28% yield

(Table 2, entry 3). Trialkylamines and pyridine derivatives provided 26a in 49–69% yields (Table 2, entries 4–10). Finally, it was found that aniline derivatives were more effective, and 1,8- bis(dimethylamino)naphthalene (proton sponge, 24) gave the highest yield of 26a (78%) at 50 °C in

10 min (Table 2, entries 11 and 12).

Table 2. Optimization of the Catalyst.

Synthesis of S-Difluoromethyl Thioimidates

The optimized conditions were applied to the synthesis of acyclic difluoromethylsulfanylated compounds (Table 3). The required thioamides 25c–h were prepared through the reported

28 thionation reaction of carboxamides with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-

2,4-disulfide (Lawesson’s reagent).[14] Treatment of amides 42c–h with Lawesson’s reagent afforded the desired thioamides 25c–h in 53–97% yields (Table 3, entries 1–6). The formation of thioamides

25c–h was confirmed by observing the stretching frequencies of C=S bond (1050–1250 cm–1) in infrared (IR) spectroscopy. Thiocarbamates 25i and 25j were prepared by the reaction of isothiocyanates 43i and 43j with alkoxides in 36% and 99% yields, respectively (eq. 32).

Table 3. Synthesis of Thioamides.

Thioamide 25c, derived from cyclohexanecarboxamide, underwent the expected difluoromethylation at 80 °C in 10 min to give the corresponding S-difluoromethylthioimidate 26c in quantitative yield as a 79:21 diastereomeric mixture (Table 4, entry 1). Not only cyclohexanethiocarboxamide but also thioacetamides bearing a phenyl (25d) and p-chlorophenyl

(25e) group on the nitrogen atom afforded the corresponding products 26d and 26e in 70% and 75%

29 yields, respectively (Table 4, entries 2 and 3, 80 °C). Thioamides derived from aromatic carboxamides also participated in S-difluoromethylation. Thioamides 25f–h afforded the expected thioimidates 26f–h in 51–85% yields (Table 4, entries 4–6, 80 °C). It was revealed that aliphatic thioamides were more reactive than aromatic thioamides, when the reactions were conducted at 50 °C.

Namely, electron-donating alkyl thioamides 25c–e afforded 26c–e in 47–71% yields at 50 °C (Table

4, entries 1–3), whereas the less electron-donating aryl thioamides 25f–h afforded 26f–h only in 12–

40% yields (Table 4, entries 4–6, 50 °C). This is probably due to the fact that the electron-deficient difluorocarbene favors the electron-rich aliphatic thioamides.

Thiocarbamates were more reactive than thioamides in S-difluoromethylation. Methyl thiocarbamate 25i was subjected to the organocatalyzed difluoromethylation. The reaction proceeded smoothly even at 50 °C in 10 min to give the expected S-difluoromethyl thioiminocarbonate 26i in

93% yield (Table 4, entry 7). Thiocarbamate 25j also afforded the corresponding thioiminocarbonate

26j in 97% yield (Table 4, entry 8, 50 °C).

As described above, the products were obtained as diastereomeric mixtures of syn/anti isomers.

Comparisons between the spectral data of the products and those in the literature revealed that they were S-difluoromethylated products. Namely, all the products, including minor products, exhibited

13C NMR signals at 158–172 ppm and IR absorption signals at 1618–1645 cm–1. The reported thioimidate 44 exhibits its 13C NMR signal at 170 ppm (C=N) and an IR absorption signal at 1630 cm1 (C=N stretching).[15] Thioamide 45 exhibits its 13C NMR signal at 203 ppm (C=S) and an IR absorption signal at 1247 cm1 (C=S stretching).[16] These data suggested that all the major and minor products had a C=N double bond and therefore were the S-difluoromethylated compounds.

Table 4. Selective Synthesis of S-Difluoromethyl Thioimidates.

2-1-3. Mechanistic Study

Catalytic Cycle and Reaction Mechanism

There are two candidates for the role of proton sponge: (1) a nucleophile or (2) a base. In the first possibility (proton sponge as a nucleophilic agent), there are two cases to act as (a) a carbon nucleophile and (b) a nitrogen nucleophile. In the case (a), the mechanism of TFDA activation can be depicted as in Scheme 4, path A. The nucleophilic attack of the aromatic carbon of proton sponge

24 occurs onto the trimethylsilyl group of TFDA, and the silylated proton sponge 46 is obtained with difluorocarbene generation. The desilylation of 46 proceeds with the simultaneous formation of fluoride ion to regenerate the catalyst 24. In the case (b), the nitrogen atom of 24 attacks TFDA, and an ammonium salt 47 is formed with difluorocarbene generation, as shown in Scheme 11, path B.

The eliminated fluoride ion in turn attacks the silyl group of 47, thereby catalyst 24 is regenerated.

Scheme 11. Possible Mechanism for TFDA Activation with Proton Sponge as a Nucleophile.

In the second possibility (proton sponge as a base), proton sponge captures a proton from a trace amount (1–2 mol%) of carboxylic acid, FSO2CF2CO2H contained in TFDA, which causes evolution of carbon dioxide and sulfur dioxide to generate difluorocarbene, leading to the formation of ammonium fluoride 48 (Scheme 12). The fluoride ion of 48 functions as an actual catalyst for the activation of TFDA.

Scheme 12. Possible Mechanism for TFDA Activation with Proton Sponge as a Base.

First, considering the possibility that proton sponge 24 acted as a carbon nucleophile (Scheme

4, path A), 1H NMR studies were performed (Figure 6). Under argon atmosphere, 24 was treated with

1 TFDA in benzene-d6 for 2 h at RT, and then H NMR of the reaction mixture was measured. The silylated 46’ (neutral form) in the literature[17] shows the 1H NMR signals of two singlets (derived from the dimethylamino groups) at 2.8 ppm, and two doublets and three double doublets (derived from the aromatic ring) at 6.9–7.6 ppm (Figure 6, left). However, such signals were not observed

(Figure 6, right).

Figure 6. 1H NMR Spectrum Data of 46’ and Observed Compound.

Next, considering the possibility that proton sponge acted as a nitrogen nucleophile (Scheme 11, path B), the effect of bulkiness on the nitrogens was examined. Thus, 1,8- bis(diethylamino)naphthalene 49, prepared from 1,8-diaminonaphthalene and ethyl iodide, was treated with TFDA. Decomposition of TFDA reached to completion within 30 min, whereas the original 24 required an hour. Namely, the decomposition rate of TFDA with the more bulky 49 was almost same as (or rather higher than) that with 24 (Scheme 13). Therefore, the possibility that proton sponge 24 acts as a nitrogen nucleophile is quite low.

Scheme 13. Comparison of Decomposition Rates of TFDA (with Ethylated 49 vs. Methylated 24).

Finally, the second possibility (proton sponge as a base) was examined. The ammonium salt 48 was prepared in situ from the carboxylic acid (FSO2CF2CO2H) and proton sponge. The generation of

48 was confirmed by 1H NMR spectroscopy, because spectral data of the ammonium salt 48 was in complete agreement with those in the literature.[18] Then, thiocarbamate 25i was treated with the obtained 48 to give S-difluoromethylthioimidate 26i in 97% yield (Scheme 14, middle). Since proton- free 24 was not involved in the obtained solution of 48 just before the addition of TFDA (confirmed by 1H NMR spectroscopy), ammonium fluoride 48 was considered to decompose TFDA. In the presence of proton sponge 24, 25i afforded 26i in quantitative yield (Scheme 14, bottom). Thus, the yield of 26i with ammonium salt 48 was nearby equal to that with 24, which strongly suggests that the salt 48 was the actual catalyst in this reaction.

Scheme 14. Actual Catalyst for the Generation of Difluorocarbene.

Conclusively, it is considered that 1,8-bis(dimethylamino)naphthalene 24 acts as a base. The proposed catalytic cycle and difluoromethylation mechanism is shown in Scheme 15.

Scheme 15. Proposed Catalytic Cycle and Reaction Mechanism.

2-1-4. Comparison with the Reported Methods for the Generation of

Difluorocarbene

To demonstrate the advantage of the organocatalyzed generation of difluorocarbene from TFDA, difluoromethylation of thioamides was performed using the reported methods for difluorocarbene generation (Scheme 16). As described above, thioamide 25c underwent S-difluoromethylation with

TFDA in the presence of proton sponge 24 to give thioimidate 26c in quantitative yield at 80 °C

(Scheme 16, top). In contrast, treatment of 25c with sodium chlorodifluoroacetate[19] at 80 °C did not give 26c (Scheme 16, middle) because higher temperatures were required for decomposition of this carbene source. Only when the reaction with sodium chlorodifluoroacetate was performed at 160 °C, thioimidate 26c was formed in 98% yield. Generation of difluorocarbene under strongly basic 35 conditions did not afford 26c (Scheme 16, bottom). Treatment of 25c with bromodifluoroacetophenone, which is analogous to the reported chlorodifluoroacetophenone,[20] in the presence of an excess amount of potassium hydroxide resulted in the partial decomposition of 25c and formation of 26c was not observed. As a result of these investigations, the organocatalytic generation of difluorocarbene from TFDA using proton sponge is particularly suitable for S- difluoromethylation of thioamides.

Scheme 16. Comparison with Other Methods for the Generation of Difluorocarbene.

S-Difluoromethylation of cyclic thiocarbamate 25k proceeded in a similar manner to give difluoromethylsulfanylated benzoxazole 26k in 83% yield (Scheme 17, top). Interestingly, Greaney and co-workers reported that the N-difluoromethylation of 25k with difluorocarbene, which was generated from sodium chlorodifluoroacetate in the presence of potassium carbonate, proceeded at much higher 95 °C for 14 h, which afforded only benzoxazol-2-thione 27k (N-difluoromethylation product) in 46% yield (Scheme 17, bottom).[8]

Scheme 17. S- and N-Difluoromethylation of Cyclic Thiocarbamate by Organocatalytic and Classical Generation of Difluorocarbene.

To examine how N-difluoromethylated product 27k was formed in Scheme 17, the reaction shown in eq. 33 was carried out. Isolated S-difluoromethylated product 26k was subjected to the conditions of sodium chlorodifluoroacetate. Although the yield was low, N-difluoromethylated product 27k was formed in 8% yield, suggesting that 26k was converted to 27k under the reaction conditions.

The following isomerization mechanism is conceivable (Scheme 18). First, excessively generated difluorocarbene is attached by the nitrogen atom of S-difluoromethylated product 26k. Next, proton transfer followed by elimination of difluorocarbene proceeds to generate N- difluoromethylated product 27k. Thus, it is likely that S-selective difluoromethylation was successfully achieved because the organocatalytic difluorocarbene generation from TFDA did not generate excess amount of difluorocarbene and furthermore the reaction was conducted at a lower temperature.

Scheme 18. Supposed Mechanism for Isomerization of 26k to 27k.

2-1-5. Conclusion

Organocatalytic generation of difluorocarbene from TFDA facilitated efficient S- difluoromethylation of thiocarbonyl compounds. Treatment of secondary thioamides with TFDA in the presence of proton sponge at 80 °C afforded S-difluoromethyl thioimidates selectively in good to excellent yields. Difluoromethylation of secondary thiocarbamates proceeded in a similar manner at

50 °C to afford S-difluoromethyl thioiminocarbonates in excellent yields. The starting thiocarbonyl compounds were readily prepared from carboxamides or isothiocyanates. Decomposition of these substrates was not substantially observed under the abovementioned mild reaction conditions. The mild conditions also realized high sulfur selectivity, leading to the formation of the difluoromethylsulfanylated products in high yields.

2-2. Difluoromethylidenation of Dithioesters: Synthesis of Sulfur-Substituted Difluoroalkenes

2-2-1. Introduction

1,1-Difluoro-1-alkene is an important structure in the both fields of medicinal[21] and synthetic chemistry.[22] Many difluoroalkenes with biological activity have been reported. For example, compound 1, 50, and 51 have antitubulin activity,[23] antiviral activity for HSV-1,[24] and insecticidal activity,[25] respectively (Figure 7). Furthermore, 1,1-difluoro-1-alkenes act as important synthetic intermediates. The Ichikawa group has reported a variety of cyclizations using 1,1-difluoroalkenes as intermediates until now. For instance, treatment of difluoroalkene 52 with sodium hydride promoted

5-endo-trig cyclization followed by elimination of fluoride ion to afford the fluorinated indole 53 in

84% yield (eq. 34).[26]

Figure 7. Useful Difluoroalkenylated Compounds.

The conventional methods for the synthesis of 1,1-difluoroalkenes involve the Wittig-type reactions with nucleophilic difluoromethylidenating agents, difluoromethylidene ylides (eq. 35).[27]

Recently other routes have been developed, i.e., (i) the transition metal catalyzed cross-coupling

39 reactions[28] and (ii) the β-fluorine eliminations from trifluoromethyl compounds[29] as well as (iii)

[30] [31] their SN2′-type and SN1′-type reactions.

It is expected that sulfur-substituted difluoroalkenes are utilized as a useful synthetic intermediates, because sulfur groups can be converted to the other beneficial substituents. For example, sulfur-substituted difluoroalkene 30 undergoes oxidation with mCPBA, followed by substitution with tin. Migita–Kosugi–Stille cross-coupling is carried out to introduce an aryl group to the difluoroalkene moiety (eq. 36).[32] However, it is difficult to apply the conventional methods to the synthesis of difluoroalkenes with a sulfur substituent. In Wittig-type reactions, the nucleophilic attack of ylides to ester analogs cannot be expected to occur because of the decreased electrophilicity of ester carbonyl groups. So far, sulfur-substituted difluoroalkenes 30 are synthesized under strongly basic conditions, using low-valent titanium. Treatment of trifluoroacetophenone of thiophenol in the presence of aluminum trichloride affords dithioacetal 54 in 92% yield, then treated with titanium tetrachloride and lithium aluminum hydride to afford 30a in 78% yield. (Eq. 37).[33]

I focused my attention on the synthesis of sulfanylated difluoroalkenes 30 via difluorothiiranes obtained from dithioesters and difluorocarbene (C1 unit). Actually, it was reported that thioketone 55

40 was treated with difluorocarbene, generated from trifluoromethyl(phenyl)mercury, leading to thiirane intermediate 56, which underwent desulfurization to give difluoroalkene 57 in 55% yield (Barton–

Kellogg-type reaction,[34] eq. 38).[35] In this reaction, the thiirane intermediates were efficiently generated, because the thiocarbonyl compounds had the higher electron density on the sulfur atoms.

Thus, I aimed to develop an efficient method for the synthesis of sulfur-substituted difluoroalkenes by studying electrophilic difluoromethylidenation of dithioesters with difluorocarbene. The catalytic generation of difluorocarbene (:CF2) from TFDA using proton sponge does not require toxic difluorocarbene precursor such as PhHgCF3, which has been used in the conventional methods. Thus,

I considered that this generation method of difluorocarbene would allow the electrophilic synthesis of sulfur-substituted difluoroalkenes, which would provide a more useful synthetic route (eq. 39).

2-2-2. Synthesis of Sulfanylated Difluoroalkenes

Optimization of Reaction Conditions

We first performed the electrophilic difluoromethylidenation using phenyl (28a) and methyl

(28b) benzenedithioates as model substrates (Table 5). Phenyl dithioate 29a was treated with TFDA

(2.0 equiv. over 5 min) in toluene in the presence of 5 mol% of proton sponge 24 at 40 °C (Table 5, entry 1). Although it seemed that decomposition of TFDA proceeded at this temperature, the expected thiirane intermediate 29a was generated only in 7% yield, and a considerable amount of the starting

41 dithioate 28a remained unchanged according to TLC analysis. In contrast, when the reaction was performed at 60 °C, 28a was converted into 29a and the sulfanylated difluoroalkene 30a in 40% and

46% yields, respectively (Table 5, entry 2). Performing the reaction at higher temperatures (90 °C,

Table 5, entry 3 or reflux, Table 5, entry 4) led to complete conversion of 29a, affording 30a in

84−90% yields, along with the undesired tetrafluorocyclopropane 58a in 2−5% yields. To prevent the overreaction to 58a, 28a was treated with TFDA at 60 °C for 30 min before rising the temperature

(Table 5, entry 5). After confirming that 28a was consumed completely by TLC analysis and that difluorocarbene had been generated absolutely, the reaction mixture composed by 29a and 30a was heated at 100 °C for 30 min. Thus, desired difluoroalkene 30a was isolated in 87% yield with high selectivity (method A).

Methyl dithioate 28b, which was more electron-rich substrate than 28a, had unexpectedly less reactivity than that of 28a for the formation of thiirane 29b. The reaction of 28b at 60 °C afforded the corresponding thiirane 29b in decreased total yield (29 + 30, 46%, Table 5, entry 6 vs. 86%, Table 5, entry 2). When the reaction was performed at reflux temperature (Table 5, entry 7), 29b was formed at least in 81% yield (30b + 58b), although forming the undesired tetrafluorocyclopropane 58b in

14% yield. In order to suppress the undesired cyclopropanation, the contact time of 30b with difluorocarbene was reduced. When addition of TFDA was completed within 1 min, the yield of 30b was improved up to 82% (Table 5, entry 8, method B).

Table 5. Optimization of Reaction Conditions.

Synthesis of Sulfanylated Difluoroalkenes: Substrate Scope

Various sulfanylated 1,1-difluoro-1-alkenes 30 were synthesized by the above described electrophilic difluoromethylidenation of dithioesters (Table 6). Phenyl dithioates 28a and 28c−f underwent difluoromethylidenation by method A to give the corresponding products 30a and 30c−f in 70−87% yields. Sterically demanding 28g and 28h underwent the reaction by method B to give the corresponding 30g and 30h in 94% and 80% yields, respectively. Dithioester 28i, bearing an m- chlorosubstituted phenyl group, also afforded the corresponding 30i by method B in 92% yield.

Alkanedithioate 28j and alkyl dithioates 28b and 28k−n afforded the corresponding products 30b and

30j−n by method B in 58−90% yields. In contrast, when thionoester 28o reacted under the conditions

43 that TFDA was dropped in 10 min in method B, 30o was obtained in 8% yield. Treatment of thioester

28p by method B did not afford the corresponding difluoroalkene 30d. From these results, it can be concluded that electron-deficient (specifically, S-arylated) and sterically less demanding dithioesters

(28a and 28c−f) require method A because of their high reactivity, whereas electron-rich (specifically

S-alkylated, 28b and 28j−o) or sterically demanding (28g and 28h) dithioesters and thionoester are less reactive for difluorocarbene and their cyclization can be performed by method B.

Table 6. Synthesis of Sulfanylated 1,1-Difluoro-1-alkenes.

There remains a possibility that the thiirane formation involves stepwise ylide formation and nucleophilic ring closure (Scheme 19, path B). As a fact, electron-rich dithioesters 28b and 28o showed low reactivity, which is explained by the slow nucleophilic ring closure from the intermediary difluoromethylene thiocarbonyl ylides.

Scheme 19. Proposed Reaction Mechanism.

2-2-3. Mechanistic Study

In general, desulfurization in the Barton–Kellogg reaction requires reducing agents such as phosphine. First, I assumed that the second molecule of difluorocarbene acted as reducing species.

Namely, difluoroalkenes were considered to be formed via addition of difluorocarbene on the sulfur atom of difluorothiiranes, followed by elimination of thiocarbonyl fluorides. To examine the desulfurization mechanism, I carried out the following investigation. When difluoromethylidenation of 28a was performed with 1.0 equiv of TFDA, 30a was obtained in 88% yield (eq. 40). This result suggests that the thiirane intermediates underwent desulfurization without the aid of the second molecule of difluorocarbene.

Next, I assumed that desulfurization proceeded spontaneously in a form of elemental sulfur. To confirm the formation of elemental sulfur, the reaction products were analyzed in detail after difluorovinylidenation of 28a. When 0.89 mmol of difluoroalkene 30a was obtained (89% yield),

24.9 mg of yellow crystalline material was isolated (eq. 41). Elemental analysis of this material

45 indicated that this sample was composed of 91.63% sulfur (0.71 mmol sulfur atom). Therefore, it was found that difluoroalkene 30 was formed by elimination of elemental sulfur from difluorothiirane intermediate 29.

In standard (non-fluorinated) Barton–Kellogg reactions, reducing agents are required for desulfurization. However, desulfurization from difluorothiirane 29 proceeded without the aid of other reagents. The instability of difluorothiirane was mentioned by Sharkey,[36] Mloston[35] et al.

According to Steudel, who studied the mechanism of desulfurization using quantum chemical calculations, it is considered that there are two kinds of desulfurization mechanisms from thiirane depending on its concentration.[37] When concentration of thiirane is low, unimolecular dissociation of the C–S bond of thiirane proceeds spontaneously (Scheme 20, path A). Conversely, when its concentration is high, two molecules of thiirane are involved in the bond dissociation (Scheme 20, path B). The rate-determining step in these desulfurization processes is the dissociation step of C–S bond. In the extrusion of sulfur from difluorothiirane 29, the diradical or zwitterion intermediates, generated by dissociation of the C–S bond of thiirane 29, are probably stabilized by fluorine substituents. Namely, the α-radical and α-cation of fluorine atom are stabilized by +R effect (donation of lone pairs) of fluorine, which the β-anion of fluorine atom is stabilized by –I effect (electron- withdrawing effect) of fluorine. Thus, rate-determining step is accelerated, and desulfurization of thiirane 29 readily proceeds.

Scheme 20. Proposed Mechanism of Extrusion of Sulfur.

2-2-4. Comparison with the reported methods for the generation of

difluorocarbene

To show the advantages of the electrophilic (Barton−Kellogg-type) difluoromethylidenation, I conducted the following comparative studies with Wittig-type difluoromethylidenation (Scheme 21,

22). Application of difluorovinylidenation (Barton–Kellogg-type reaction) of dithioester 28a with difluorocarbene afforded the desired sulfur-substituted difluoroalkene 30a in 87% yield (Table 6 and

Scheme 21, top). When the difluoromethylidenation with difluoromethylidene ylide was conducted with 28a, 30a was not obtained (Scheme 21, bottom). In contrast, although the electrophilic difluoromethylidenation was not suitable for aldehyde 61 (0% yield) (Scheme 22, top), 61 successfully underwent nucleophilic difluoromethylidenation to give the corresponding difluorostyrene 62 in 87% yield (Scheme 22, bottom).[38]

Scheme 21. Comparative Investigation on Difluoromethylation of Dithioester.

Scheme 22. Comparative Investigation on Difluoromethylation of Aldehyde.

2-2-5. Conclusion

In conclusion, electrophilic difluoromethylidenation of dithioesters was achieved using difluorocarbene, organocatalytically generated from TFDA. The reaction proceeded via thiirane intermediates following the Barton−Kellogg-type mechanism to afford various sulfanylated 1,1- difluoro-1-alkenes in good to excellent yields. This electrophilic difluoromethylidenation proved to be complementary to the conventional nucleophilic Wittig-type difluoromethylidenation of carbonyl compounds.

2-3. Experimental Section

2-3-1. General

Analysis

IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance

(ATR method). NMR spectra were recorded on a Bruker AVANCE 500 or a Jeol JNM ECS-400

1 13 spectrometer in CDCl3 at 500 or 400 MHz ( H NMR), at 126 or 100 MHz ( C NMR), and at 470 or

19 1 376 MHz ( F NMR). Chemical shifts were given in ppm relative to internal Me4Si (for H NMR: δ

13 19 = 0.00), CDCl3 (for C NMR: δ = 77.0), and C6F6 (for F NMR: δ = 0.0). High resolution mass spectroscopy (HRMS) was conducted with a Jeol JMS-T100GCV spectrometer (EI, TOF). Elemental analysis was performed with a Elementar Vario Micro Cube apparatus.

Reaction

All the reactions were conducted under argon. In difluoromethylidenation of dithioesters (Chapter 2, 2-2), all the reaction was performed using standard Schlenk techniques.

Purification

Silica gel 60 (spherical, Kanto Chemical) was used for column chromatography, and

Wakogel®B-F5 (Wako Pure Chemical Industries) was used for preparative thin-layer chromatography.

Solvents and Reagents

Toluene, tetrahydrofuran (THF), and N,N-dimethylformamide (DMF) were purchased from

Kanto Chemical Co., Inc. and dried by passing over a column of activated alumina followed by a column of Q-5 scavenger (Engelhard). Dimethyl sulfoxide (DMSO) and diethyleneglycol dimethyl ether (diglyme) were distilled from CaH2. Acetonitrile was distilled from CaH2 after it was pre-

49 distilled from P2O5. 2-Pyridinethione was purchased from Sigma-Aldrich, recrystallized from CHCl3.

1,8-Bis(dimethylamino)naphthalene (proton sponge), triazolium salt 40, 1,1,1,3,3,3-hexafluoro-2,2- di(p-tolyl)propane (internal standard for 19F NMR), Lawesson’s reagent, and isothiocyanate 43 were purchased from Tokyo Chemical Industry Co., Ltd. Trimethylsilyl 2,2-difluoro-2-

(fluorosulfonyl)acetate (TFDA) was prepared according to the literature.[39] 19F NMR analysis suggested that the prepared TFDA contained a small amount of the starting acid and that its purity was higher than 98% (mol/mol). Imidazolium salt 41 was prepared according to the literature.[40]

Unless otherwise noted, materials were obtained from commercial sources and used directly without further purification.

2-3-2. S-Selective Difluoromethylation of Thiocarbonyl Compounds (2-1)

Preparation of Thioamides and Thiocarbamates

2-Thiopyridone 25a and benzothioxazole 25k were purchased from Sigma–Aldrich Co. LLC.

Thioamides 25c–h and thiocarbamates 25i,j were prepared by the reported procedures, using commercially available 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (Lawesson’s reagent) for 25c–h [14] and commercially available isothiocyanates for 25i,j.[41]

N-(p-Methylphenyl)benzenecarbothioamide (25g)

Preparation of thioamide 25g is described as a typical procedure. To a THF solution (50 mL) of

Lawesson’s reagent (432 mg, 1.07 mmol) was added a solution of N-(p- methylphenyl)benzenecarboxamide (461 mg, 2.18 mmol) at room temperature. The reaction mixture was stirred and heated to 50 °C for 2.5 h. After cooling the resulting mixture to room temperature, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:AcOEt = 2:1) to give thioamide 25g (481 mg, 97% yield).

O-Methyl N-phenylthiocarbamate (25i)

Preparation of thiocarbamate 25i is described as a typical procedure. To a methanol solution (3 mL) of phenyl isothiocyanate (0.60 mL, 5.0 mmol) was added a methanol solution (1 mol/L, 10 mL) of sodium methoxide (10 mmol). The reaction mixture was stirred for 30 min at room temperature.

Concentrated hydrochloric acid was then added to adjust the pH of the crude mixture to 4–5. The resulting white precipitate was filtered with suction and washed with methanol. The filtrate was concentrated under reduced pressure to give thiocarbamate 25i (556 mg, 67% yield).

Synthesis of Difluoromethylsulfanylated Compounds (Typical Procedure)

(A) Synthesis of S-difluoromethyl thioimidates

Synthesis of S-difluoromethyl imidate 26c is described as a typical procedure. To a toluene solution (1.0 mL) of proton sponge 24 (4.1 mg, 0.019 mmol) was added thioamide 25c (42 mg, 0.19 mmol) at room temperature. The reaction mixture was stirred and heated to 80 °C, and TFDA (80 mL, 0.40 mmol) was added. After the resulting mixture was stirred for 10 min and cooled to room temperature, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:AcOEt = 10:1) to give thioimidate 26c (53 mg, quant).

(B) Synthesis of S-difluoromethyl thioiminocarbonates

Synthesis of S-difluoromethyl thioiminocarbonate 26j is described as a typical procedure. To a toluene solution (1.0 mL) of proton sponge 24 (4.3 mg, 0.020 mmol) was added thiocarbamate 25j

(46 mg, 0.21 mmol) at room temperature. The reaction mixture was stirred and TFDA (80 mL, 0.40 mmol) was added. The reaction mixture was heated to 50 °C, and stirred for 10 min. After cooling the resulting mixture to room temperature, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:AcOEt = 10:1) to give thioiminocarbonate 26j (56 mg, 97% yield).

Spectral Data of S-Difluoromethylated Products

S-Difluoromethyl N-phenylcyclohexanecarbothioimidate (26c)

The product 26c was obtained as an inseparable diastereomeric mixture. Spectral data of the

1 major isomer: H NMR (500 MHz, CDCl3): δ = 0.99–1.09 (m, 3H), 1.35 (td, J = 12.0, 12.0 Hz, 2H),

1.53 (d, J = 12.0 Hz, 1H), 1.65 (t, J = 12.0 Hz, 4H), 2.59 (t, J = 12.0 Hz, 1H), 6.66 (d, J = 7.4 Hz,

2H), 7.06 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 7.4 Hz, 2H), 7.49 (t, J = 55.7 Hz, 1H); 13C NMR (126 MHz,

19 CDCl3): δ = 24.9, 29.4, 30.4, 43.0, 119.2, 120.7 (t, J = 269 Hz), 123.6, 129.1, 148.6, 171.6; F =

–1 NMR (470 MHz, CDCl3): δ = 61.3 (d, J = 56 Hz); IR (neat): ν = 2931, 1628, 1596, 1448, 970 cm ;

+ HRMS (EI): m/z calcd. for C14H17F2NS [M] : 269.1050; found: 269.1050.

1 19 1 Characteristic H and F NMR signals of the minor isomer: H NMR (500 MHz, CDCl3): δ =

19 6.93 (t, J = 55.2 Hz); F NMR (470 MHz, CDCl3): δ = 69.1 (d, J = 55 Hz).

S-Difluoromethyl N-phenylethanethioimidate (26d)

The product 26d was obtained as an inseparable diastereomeric mixture. Spectral data of the

1 major isomer: H NMR (500 MHz, CDCl3): δ = 2.06 (s, 3H), 6.76 (d, J = 8.1 Hz, 2H), 7.11 (t, J = 8.1

13 Hz, 1H), 7.33 (t, J = 8.1 Hz, 2H), 7.68 (t, J = 55.4 Hz, 1H); C NMR (126 MHz, CDCl3): δ = 21.7,

19 119.8, 120.2 (t, J = 270 Hz), 124.2, 129.1, 148.8, 162.1; F NMR (470 MHz, CDCl3): δ = 60.9 (d, J

–1 = 55 Hz); IR (neat): ν = 2870, 1645, 1487, 1138, 1068 cm ; HRMS (EI): m/z calcd. for C9H9F2NS [M]+: 201.0424; found: 201.0421. A characteristic 19F NMR signal of the minor isomer: 19F NMR

(470 MHz, CDCl3): δ = 69.9 (d, J = 56 Hz).

S-Difluoromethyl N-(p-chlorophenyl)ethanethioimidate (26e)

The product 26e was obtained as an inseparable diastereomeric mixture. Spectral data of the

1 major isomer: H NMR (500 MHz, CDCl3): δ = 2.06 (s, 3H), 6.70 (d, J = 8.6 Hz, 2H), 7.29 (d, J =

13 8.6 Hz, 2H), 7.64 (t, J = 55.4 Hz, 1H); C NMR (126 MHz, CDCl3): δ = 21.7, 120.0 (t, J = 270 Hz),

19 121.2, 129.2, 129.3, 147.2, 163.2; F NMR (470 MHz, CDCl3): δ = 60.9 (d, J = 55 Hz); IR (neat): ν

–1 + = 2951, 1645, 1161, 1049, 694 cm ; HRMS (EI): m/z calcd. for C9H8ClF2NOS [M] : 235.0034; found: 235.0033.

1 19 1 Characteristic H and F NMR signals of the minor isomer: H NMR (500 MHz, CDCl3): δ =

19 7.14 (t, J = 55.6 Hz); F NMR (470 MHz, CDCl3): δ = 70.0 (d, J = 56 Hz).

S-Difluoromethyl N-phenylbenzenecarbothioimidate (26f)

The product 26f was obtained as an inseparable diastereomeric mixture. Spectral data of the

1 mixture (50:50): H NMR (500 MHz, CDCl3): δ = 6.72 (t, J = 56.3 Hz, 1H × 0.50), 6.73 (d, J = 7.6

Hz, 2H × 0.50), 6.97 (d, J = 7.8 Hz, 2H × 0.50), 7.04 (t, J = 7.4 Hz, 1H × 0.50), 7.21 (t, J = 7.4 Hz,

2H × 0.50), 7.25–7.32 (m, 5H × 0.50), 7.38 (d, J = 7.2 Hz, 1H × 0.50), 7.47 (t, J = 7.4 Hz, 2H × 0.50),

7.57–7.72 (m, 3H × 0.50), 7.75 (t, J = 55.0 Hz, 1H × 0.50), 7.87 (d, J = 7.4 Hz, 2H × 0.50); 13C NMR

(126 MHz, CDCl3): δ = 119.5, 120.3 (t, J = 265 Hz), 120.4 (t, J = 270 Hz), 120.9, 121.1, 124.0, 125.3,

128.0, 128.5, 128.8, 129.0, 129.1, 130.5, 131.5, 133.5, 136.6, 148.2, 148.9, 157.9, 162.6; 19F NMR

(470 MHz, CDCl3): δ = 60.5 (d, J = 55 Hz), 69.6 (d, J = 56 Hz); IR (neat): ν = 3062, 1618, 1593,

–1 + 1049, 762, 690 cm ; HRMS (EI): m/z calcd. for C14H11F2NS [M] : 263.0580; found: 263.0578. The GC peaks of the isomers were not isolated from each other on GC-HRMS analysis.

S-Difluoromethyl N-(p-methylphenyl)benzenecarbothioimidate (26g)

The product 26g was obtained as an inseparable diastereomeric mixture. Spectral data of the

1 mixture (63:37): H NMR (500 MHz, CDCl3): δ = 2.23 (s, 3H × 0.37), 2.37 (s, 3H × 0.63), 6.59 (d, J

= 8.0 Hz, 2H × 0.37), 6.68 (t, J = 56.3 Hz, 1H × 0.63), 6.85 (d, J = 8.2 Hz, 2H × 0.63), 6.96 (d, J =

8.2 Hz, 2H × 0.37), 7.21–7.26 (m, 2H), 7.29 (t, J = 7.4 Hz, 1H × 0.63), 7.35 (d, J = 7.4 Hz, 1H ×

0.37), 7.53–7.56 (m, 2H), 7.71 (t, J = 55.4 Hz, 1H × 0.37), 7.82 (d, J = 7.4 Hz, 2H × 0.63); 13C NMR

(126 MHz, CDCl3): δ = 20.9, 21.1, 119.5, 120.4 (t, J = 274 Hz), 120.4 (t, J = 270 Hz), 121.1, 128.2,

128.5, 129.0, 129.3, 129.5, 129.7, 130.4, 131.4, 133.6, 135.2, 136.6, 138.6, 145.5, 146.2, 157.5, 161.9;

19 F NMR (470 MHz, CDCl3): δ = 60.5 (d, J = 55 Hz), 69.5 (d, J = 56 Hz); IR (neat): ν = 2924, 1618,

–1 + 1506, 1072, 769 cm ; HRMS (EI): m/z calcd. for C15H13F2NS ([M] ): 277.0737; found: 277.0732.

The GC peaks of the isomers were not isolated from each other on GC-HRMS analysis.

S-Difluoromethyl N-(p-chlorophenyl)benzenecarbothioimidate (26h)

The product 26h was obtained as an inseparable diastereomeric mixture. Spectral data of the

1 mixture (55:45): H NMR (500 MHz, CDCl3): δ = 6.56–6.61 (m, 2H × 0.5), 6.65 (t, J = 56.3 Hz, 1H

× 0.5), 6.81–6.88 (m, 2H × 0.5), 7.05–7.10 (m, 2H × 0.5), 7.13–7.19 (m, 2H × 0.5), 7.22–7.28 (m,

2H × 0.5), 7.30–7.37 (m, 3H × 0.5), 7.47– 7.56 (m, 4H × 0.5), 7.73–7.81 (m, 2H × 0.5); 13C NMR

(126 MHz, CDCl3): δ = 120.1 (t, J = 271 Hz), 120.3 (t, J = 275 Hz), 121.0, 122.5, 128.0, 128.5, 128.7,

128.8, 129.0, 129.2, 130.5, 130.7, 131.7, 133.1, 136.4, 138.6, 146.7, 147.2, 158.8, 163.7; 19F NMR

(470 MHz, CDCl3): δ = 60.5 (d, J = 55 Hz), 69.5 (d, J = 56 Hz); IR (neat): ν = 2927, 1620, 1483,

–1 + 1076, 698 cm ; HRMS (EI): m/z calcd. for C14H10ClF2NS [M] : 297.0191; found: 297.0188. The GC peaks of the isomers were not isolated from each other on GC-HRMS analysis. 54

S-Difluoromethyl O-methyl N-phenylthioiminocarbonate (26i)

1 H NMR (500 MHz, CDCl3): δ = 4.04 (s, 3H), 6.85 (dd, J = 7.0, 1.0 Hz, 2H), 7.13 (tt, J = 7.0,

13 1.0 Hz, 1H), 7.32 (t, J = 7.0 Hz, 2H), 7.37 (t, J = 56.5 Hz, 1H); C NMR (126 MHz, CDCl3): δ =

19 56.9, 119.0 (t, J = 274 Hz), 121.2, 124.6, 129.2, 145.7, 152.6; F NMR (470 MHz, CDCl3): δ = 68.7

(d, J = 57 Hz); IR (neat): ν = 2951, 1645, 1161, 1049, 694 cm–1 ; HRMS (EI): m/z calcd. for

+ C9H9F2NOS [M] : 217.0373; found: 217.0371.

S-Difluoromethyl O-isopropyl N-(p-methoxyphenyl)thioiminocarbonate (26j)

1 H NMR (500 MHz, CDCl3): δ = 1.40 (d, J = 6.2 Hz, 6H), 3.78 (s, 3H), 5.36 (sept, J = 6.2 Hz,

1H), 6.78 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.32 (t, J = 57.0 Hz, 1H); 13C NMR (126 MHz,

19 CDCl3): δ = 21.6, 55.4, 73.7, 114.4, 119.4 (t, J = 277 Hz), 122.2, 139.2, 151.4, 156.7; F NMR (470

–1 MHz, CDCl3): δ = 66.6 (d, J = 57 Hz); IR (neat): ν = 2983, 1639, 1504, 1033, 769 cm ; HRMS (EI):

+ m/z calcd. for C12H15F2NO2S [M] : 275.0792; found: 275.0790.

2-(Difluoromethylsulfanyl)benzoxazole (26k)

Spectroscopic data of 1H and 19F NMR were in agreement with those in the literature.[8]

2-3-3. Difluoromethylidenation of Dithioesters: Synthesis of Sulfur-Substituted

Difluoroalkenes (2-2)

Preparation of Dithioesters

Aryl[42] and alkyl[43] dithiocarboxylates were prepared according to the literature.

Spectral Data of Dithioesters

Spectral data of dithioesters 28a,[42] 28b,[44] 28k,[44] and 28m[45] were in complete agreement with those in the literature.

Phenyl p-toluenedithiocarboxylate (28c)

1 H NMR (500 MHz, CDCl3): δ = 2.40 (s, 3H), 7.22 (d, J = 8.2 Hz, 2H), 7.47–7.52 (m, 5H), 8.03

13 (d, J = 8.2 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 21.6, 127.1, 129.1, 129.6, 130.3, 131.5, 135.5,

142.1, 143.7, 227.8. IR (neat): ν = 3060, 2854, 1599, 1439, 1180, 1051, 872, 816 cm–1; HRMS (EI):

+ m/z Calcd. for C14H12S2 [M] : 244.0380; found: 244.0381.

Phenyl p-methoxybenzenedithiocarboxylate (28d)

1 H NMR (500 MHz, CDCl3): δ = 3.88 (s, 3H), 6.91 (d, J = 8.9 Hz, 2H), 7.47–7.52 (m, 5H), 8.19

13 (d, J = 8.9 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 55.6, 113.5, 129.2, 129.5, 130.2, 131.5, 135.6,

137.6, 163.8, 225.8; IR (neat): ν = 3012, 2837, 1595, 1240, 1173, 1026, 870 cm–1; HRMS (EI): m/z

+ Calcd. for C14H12OS2 [M] : 260.0330; found: 260.0330. 56

Phenyl p-chlorobenzenedithiocarboxylate (28e)

1 H NMR (500 MHz, CDCl3): δ = 7.40 (dd, J = 6.7, 2.0 Hz, 2H), 7.46–7.54 (m, 5H), 8.05 (dd, J

13 = 6.7, 2.0 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 128.3, 128.6, 129.7, 130.5, 131.1, 135.4, 139.1, 142.7, 226.4; IR (neat): ν = 3060, 1583, 1481, 1441, 1398, 1219, 1049, 825 cm–1; HRMS (EI): m/z

+ Calcd. for C13H9ClS2 [M] : 263.9834; found: 263.9835.

Phenyl p-(trifluoromethyl)benzenedithiocarboxylate (28f)

1 H NMR (500 MHz, CDCl3): δ = 7.48–7.51 (m, 2H), 7.52–7.54 (m, 3H), 7.68 (d, J = 8.1 Hz,

13 2H), 8.14 (d, J = 8.1 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 123.7 (q, J = 273 Hz), 125.4 (q, J =

4 Hz), 127.2, 129.8, 130.6, 130.8, 133.5 (q, J = 33 Hz), 135.2, 147.1, 226.7; 19F NMR (470 MHz,

–1 CDCl3): δ = 99.9 (s); IR (neat): ν = 1406, 1325, 1219, 1115, 1045, 872, 835 cm ; HRMS (EI): m/z

+ Calcd. for C14H9F3S2 [M] : 298.0098; found: 298.0099.

Phenyl o-phenylbenzenedithiocarboxylate (28g)

1 H NMR (500 MHz, CDCl3): δ = 7.15 (dd, J = 7.5, 1.6 Hz, 2H), 7.36–7.43 (m, 8H), 7.46–7.50

13 (m, 3H), 7.56 (dd, J = 8.3, 1.3 Hz, 1H); C NMR (126 MHz, CDCl3): δ = 127.2, 127.4, 128.0, 128.1,

129.2, 129.5, 129.9, 130.2, 130.5, 131.6, 134.5, 138.5, 140.5, 146.3, 233.5; IR (neat): ν = 3057, 1473,

–1 + 1431, 1221, 1039, 860, 739, 698 cm ; HRMS (EI): m/z Calcd. for C19H14S2 [M] : 306.0537; found: 306.0537.

Phenyl o-chlorobenzenedithiocarboxylate (28h)

1 13 H NMR (500 MHz, CDCl3): δ = 7.27–7.32 (m, 2H), 7.38–7.41 (m, 2H), 7.49–7.51 (m, 5H); C

NMR (126 MHz, CDCl3): δ = 126.6, 128.0, 129.2, 129.7, 130.5, 130.2, 130.9, 134.7, 145.2, 228.8;

IR (neat): ν = 3059, 1475, 1425, 1282, 1219, 1080, 1041, 874 cm–1; HRMS (EI): m/z Calcd. for

+ C13H9ClS2 [M] : 263.9834; found: 263.9833.

Phenyl m-chlorobenzenedithiocarboxylate (28i)

1 H NMR (500 MHz, CDCl3): δ = 7.36 (t, J = 7.9 Hz, 1H), 7.46–7.48 (m, 2H), 7.51–7.54 (m,

13 4H), 7.95 (ddd, J = 7.9, 1.9, 1.9 Hz, 1H), 8.06 (t, J = 1.9 Hz, 1H); C NMR (126 MHz, CDCl3): δ = 125.0, 127.1, 129.6, 129.8, 130.5, 130.9, 132.2, 134.6, 135.3, 145.8, 226.4; IR (neat): ν = 3060, 1695,

–1 + 1562, 1475, 1412, 1219, 1045, 895 cm ; HRMS (EI): m/z Calcd. for C13H9ClS2 [M] : 263.9834; found: 263.9838.

Phenyl hexanedithioate (28j)

1 H NMR (500 MHz, CDCl3): δ = 0.91 (t, J = 7.0 Hz, 3H), 1.32–1.42 (m, 4H), 1.89 (tt, J = 7.5,

7.5 Hz, 2H), 3.07 (t, J = 7.5 Hz, 2H), 7.39–7.42 (m, 2H), 7.47–7.49 (m, 3H); 13C NMR (126 MHz,

CDCl3): δ = 13.9, 22.3, 30.91, 30.93, 51.3, 129.5, 130.2, 131.4, 134.9, 239.8; IR (neat): ν = 2954,

–1 + 2927, 2858, 1441, 1213, 904, 742, 687 cm ; HRMS (EI): m/z Calcd. for C12H16S2 [M] : 224.0693; found: 224.0690.

Methyl p-chlorobenzenedithiocarboxylate (28l)

1 H NMR (500 MHz, CDCl3): δ = 2.78 (s, 3H), 7.36 (dd, J = 6.7, 2.1 Hz, 2H), 7.96 (dd, J = 6.7,

13 2.1 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 20.7, 128.0, 128.5, 138.7, 143.1, 227.0; IR (neat): ν

–1 + = 2912, 1583, 1479, 1398, 1232, 1090, 1047, 823 cm ; HRMS (EI): m/z Calcd. for C8H7ClS2 [M] : 201.9678; found: 201.9676.

Benzyl p-chlorobenzenedithiocarboxylate (28n)

1 13 H NMR (500 MHz, CDCl3): δ = 4.58 (s, 2H), 7.20–7.38 (m, 7H), 7.95 (d, J = 8.6 Hz, 2H); C

NMR (126 MHz, CDCl3): δ = 42.4, 127.8, 128.1, 128.5, 128.7, 129.3, 134.7, 138.9, 142.8, 225.5; IR

–1 (neat): ν = 3028, 1583, 1481, 1227, 1045, 879, 827, 696 cm ; HRMS (EI): m/z Calcd. for C14H11ClS2 [M]+: 277.9991; found: 277.9987.

Synthesis of Sulfanylated Difluoroalkenes (Typical Procedure)

(A) The method for electron-deficient and sterically less hindered substrates

To a toluene solution (4 mL, 60 °C) of phenyl benzenedithiocarboxylate (28a, 115 mg, 0.499 mmol) and proton sponge (24, 5.6 mg, 0.030 mmol) was added TFDA (200 mL, 1.06 mmol) dropwise over 5 min. Gas evolution was observed and the solution was stirred for 30 min. After the solution was heated up to 100 °C and stirred for 30 min, saturated aqueous sodium hydrogen carbonate (10 mL) was added to quench the reaction at room temperature. Organic materials were extracted with

59 ethyl acetate three times and the combined extracts were washed with brine. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (hexane) to give difluoroalkene 30a (109 mg, 87% yield) as a colorless liquid.

(B) The method for electron-rich or sterically hindered substrates

To a refluxing toluene solution (2 mL) of methyl benzenedithiocarboxylate (28b, 43 mg, 0.26 mmol), proton sponge (24, 2.8 mg, 0.013 mmol), and 1,1,1,3,3,3-hexafluoro-2,2-di(p-tolyl)propane

(14 mg, 0.042 mmol) was added TFDA (100 mL, 0.531 mmol) dropwise over 1 min. The solution was stirred for 30 min. 19F NMR analysis based on an internal standard, 1,1,1,3,3,3-hexafluoro-2,2- di(p-tolyl)propane indicated that difluoroalkene 30b was obtained in 82% yield.

Spectral Data of Dithioesters

2,2-Difluoro-3-phenyl-3-(phenylsulfanyl)thiirane (29a)

Thiirane 29a was obtained as a mixture with difluoroalkene 30a. Thiirane 29a presented its 13C and 19F NMR signals that are similar to those of its derivative in the literature.[6] HRMS data of 29a was not obtained because of the rapid desulfurization under ionization conditions.

1 13 H NMR (500 MHz, CDCl3): δ = 7.19–7.31 (m); C NMR (126 MHz, CDCl3): δ = 63.4 (dd, J

= 11, 10 Hz), 120.5 (dd, J = 310, 310 Hz), 127.9, 128.6, 129.0, 129.1, 129.5, 130.5, 135.0, 135.3 (d,

19 J = 4 Hz); F NMR (470 MHz, CDCl3): δ = 63.0 (d, J = 106 Hz, 1F), 65.6 (d, J = 106 Hz, 1F); IR (neat): ν = 1323, 1234, 1140, 933, 737 cm–1.

1,1-Difluoro-2-phenyl-2-(phenylsulfanyl)ethene (30a)

Spectral data of difluoroalkene 30a met complete agreement with those in the literature.[31]

1,1-Difluoro-2-methylsulfanyl-2-phenylethene (30b)

1 H NMR (500 MHz, CDCl3): δ = 2.07 (s, 3H), 7.31 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.0, 8.0 Hz,

13 2H), 7.50 (d, J = 8.0 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 16.4, 91.0 (dd, J = 22, 21 Hz), 128.0,

128.5, 129.0 (dd, J = 3, 3 Hz), 131.9 (dd, J = 3, 1 Hz), 154.7 (dd, J = 301, 288 Hz); 19F NMR (470

MHz, CDCl3): δ = 81.8 (d, J = 24 Hz, 1F), 84.0 (d, J = 24 Hz, 1F); IR (neat): ν = 2925, 1695, 1265,

–1 + 1236, 1007, 912, 748, 741 cm ; HRMS (EI): m/z Calcd. for C9H8F2S [M] : 186.0315; found: 186.0317.

1,1-Difluoro-2-phenylsulfanyl-2-p-tolylethene (30c)

1 H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3H), 7.10–7.13 (m, 3H), 7.19 (dd, J = 7.4, 7.4 Hz,

13 2H), 7.22–7.24 (m, 2H), 7.42 (dd, J = 8.1, 1.5 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 21.1, 88.7

(dd, J = 21, 21 Hz), 126.3, 128.0, 128.5 (dd, J = 4, 4 Hz), 128.9, 129.1, 129.3 (d, J = 4 Hz), 134.6 (dd,

19 J = 2, 2 Hz), 137.9, 156.9 (dd, J = 305, 290 Hz); F NMR (470 MHz, CDCl3): δ = 85.2 (d, J = 14 Hz, 1F), 87.2 (d, J = 14 Hz, 1F); IR (neat): ν = 3076, 3028, 1684, 1265, 1009, 814, 735, 687 cm–1;

+ HRMS (EI): m/z Calcd. for C15H12F2S [M] : 262.0628; found: 262.0627.

1,1-Difluoro-2-p-methoxyphenyl-2-(phenylsulfanyl)ethene (30d)

1 H NMR (500 MHz, CDCl3): δ = 3.78 (s, 3H), 6.84 (d, J = 8.8 Hz, 2H), 7.12 (t, J = 6.8 Hz, 1H),

13 7.15–7.24 (m, 4H), 7.46 (d, J = 8.8 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 55.2, 88.5 (dd, J = 21,

21 Hz), 113.8, 124.3 (d, J = 4 Hz), 126.3, 128.0, 129.0, 129.9 (dd, J = 4, 4 Hz), 134.5, 156.7 (dd, J =

19 304, 290 Hz), 159.2; F NMR (470 MHz, CDCl3): δ = 83.1 (d, J = 16 Hz, 1F), 85.2 (d, J = 16 Hz,

1F); IR (neat): ν = 3060, 2836, 1684, 1606, 1510, 1242, 912, 744 cm–1; HRMS (EI): m/z Calcd. for

+ C15H12F2OS [M] : 278.0577; found: 278.0576.

1-p-Chlorophenyl-2,2-difluoro-1-(phenylsulfanyl)ethene (30e)

1 H NMR (500 MHz, CDCl3): δ = 7.12 (tt, J = 6.9, 1.8 Hz, 1H), 7.17–7.26 (m, 6H), 7.45 (dd, J =

13 8.6, 1.3 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 88.4 (dd, J = 22, 20 Hz), 126.6, 128.3, 128.6,

129.1, 130.0 (dd, J = 4, 4 Hz), 130.8 (d, J = 4 Hz), 133.8–133.9 (m), 157.0 (dd, J = 306, 291 Hz); 19F

NMR (470 MHz, CDCl3): δ = 86.1 (d, J = 11 Hz, 1F), 88.2 (d, J = 11 Hz, 1F); IR (neat): ν = 3074,

–1 + 1682, 1477, 1279, 1009, 933, 737, 688 cm ; HRMS (EI): m/z Calcd. for C14H9ClF2S [M] : 282.0082; found: 282.0087.

1,1-Difluoro-2-phenylsulfanyl-2-[p-(trifluoromethyl)phenyl]ethene (30f)

1 H NMR (500 MHz, CDCl3): δ = 7.15–7.19 (m, 1H), 7.21–7.25 (m, 4H), 7.56 (d, J = 8.3 Hz,

13 2H), 7.65 (d, J = 8.3 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 88.6 (dd, J = 22, 20 Hz), 123.9 (q, J

= 272 Hz), 125.4 (q, J = 4 Hz), 126.8, 128.4, 129.0 (dd, J = 4, 4 Hz), 129.2, 130.0 (q, J = 33 Hz),

19 133.7 (dd, J = 2, 2 Hz), 136.2 (d, J = 5 Hz), 157.5 (dd, J = 307, 292 Hz); F NMR (470 MHz, CDCl3):

δ = 87.4 (d, J = 8 Hz, 1F), 89.8 (d, J = 8 Hz, 1F), 100.1 (s, 3F); IR (neat): ν = 3066, 1682, 1319, 1273,

–1 + 1119, 1068, 1011, 841, 741 cm ; HRMS (EI): m/z Calcd. for C15H9F5S [M] : 316.0345; found: 316.0341.

1-(Biphenyl-2-yl)-2,2-difluoro-1-(phenylsulfanyl)ethene (30g)

1 13 H NMR (500 MHz, CDCl3): δ = 7.19–7.26 (m, 9H), 7.29–7.39 (m, 5H); C NMR (126 MHz,

CDCl3): δ = 88.9 (dd, J = 24 Hz), 127.1, 127.2, 127.4, 128.1, 128.6, 128.7, 128.9, 130.4, 130.7, 131.2,

131.3, 133.4 (dd, J = 2 Hz), 140.8, 142.2 (d, J = 2 Hz), 156.0 (dd, J = 300, 292 Hz); 19F NMR (470

MHz, CDCl3): δ = 83.3 (d, J = 15 Hz, 1F), 86.2 (d, J = 15 Hz, 1F); IR (neat): ν = 3060, 1697, 1475,

–1 + 1277, 1219, 1007, 914, 748 cm ; HRMS (EI): m/z Calcd. for C20H14F2S [M] : 324.0784; found: 324.0796.

1-o-Chlorophenyl-2,2-difluoro-1-(phenylsulfanyl)ethene (30h)

1 13 H NMR (500 MHz, CDCl3): δ = 7.13–7.25 (m, 6H), 7.33–7.35 (m, 3H); C NMR (126 MHz,

CDCl3): δ = 86.8 (dd, J = 25, 25 Hz), 126.6, 127.4, 128.9, 129.69, 129.72, 130.7, 131.5 (d, J = 3 Hz),

19 131.6, 132.9 (dd, J = 2, 2 Hz), 134.2, 156.2 (dd, J = 302, 292 Hz); F NMR (470 MHz, CDCl3): δ =

84.5 (d, J = 10 Hz, 1F), 89.3 (d, J = 10 Hz, 1F); IR (neat): ν = 1697, 1471, 1275, 1065, 1011, 750,

–1 + 688 cm ; HRMS (EI): m/z Calcd. for C14H9ClF2S [M] : 282.0082; found: 282.0081.

1-m-Chlorophenyl-2,2-difluoro-1-(phenylsulfanyl)ethene (30i)

1 H NMR (500 MHz, CDCl3): δ = 7.13 (tt, J = 7.0, 1.8 Hz, 1H), 7.19–7.24 (m, 6H), 7.39–7.41

13 (m, 1H), 7.53 (s, 1H); C NMR (126 MHz, CDCl3): δ = 88.4 (dd, J = 21, 21 Hz), 126.7, 126.9 (dd,

J = 4, 4 Hz), 128.1, 128.3, 128.7 (dd, J = 4, 4 Hz), 129.1, 129.6, 133.8 (dd, J = 2, 2 Hz), 134.2 (d, J

19 = 4 Hz), 134.3, 157.2 (dd, J = 307, 291 Hz); F NMR (470 MHz, CDCl3): δ = 86.9 (d, J = 10 Hz,

1F), 89.1 (d, J = 10 Hz, 1F); IR (neat): ν = 1683, 1475, 1282, 1217, 1012, 908, 732, 688 cm–1; HRMS

+ (EI): m/z Calcd. for C14H9ClF2S [M] : 282.0082; found: 282.0081.

1,1-Difluoro-2-(phenylsulfanyl)hept-1-ene (30j)

1 H NMR (500 MHz, CDCl3): δ = 0.86 (t, J = 7.0 Hz, 3H), 1.19–1.31 (m, 4H), 1.49 (dt, J = 7.4,

7.4 Hz, 2H), 2.14 (tt, J = 7.4, 2.5 Hz, 2H), 7.18–7.22 (m, 1H), 7.28–7.29 (m, 4H); 13C NMR (126

MHz, CDCl3): δ = 13.9, 22.3, 27.0 (dd, J = 2, 2 Hz), 28.1, 30.9, 86.7 (dd, J = 26, 16 Hz), 126.5, 128.8,

19 129.0, 134.2 (dd, J = 2, 2 Hz), 156.9 (dd, J = 297, 288 Hz); F NMR (470 MHz, CDCl3): δ = 80.6

(d, J = 27 Hz, 1F), 81.4 (d, J = 27 Hz, 1F); IR (neat): ν = 2929, 1709, 1477, 1259, 1126, 771, 739,

–1 + 688 cm ; HRMS (EI): m/z Calcd. for C13H16F2S [M] : 242.0941; found: 242.0941.

1,1-Difluoro-2-methylsulfanyl-2-p-tolylethene (30k)

1 H NMR (500 MHz, CDCl3): δ = 2.06 (s, 3H), 2.36 (s, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.38 (d, J

13 = 8.0 Hz, 2H); C NMR (126 MHz, CDCl3): δ = 16.3 (dd, J = 2 Hz), 21.2, 90.8 (dd, J = 22, 21 Hz),

154.5 (dd, J = 300, 288 Hz), 137.9, 129.2, 128.9 (dd, J = 3 Hz), 128.8 (d, J = 4 Hz); 19F NMR (470

MHz, CDCl3): δ = 81.4 (d, J = 26 Hz, 1F), 83.3 (d, J = 26 Hz, 1F); IR (neat): ν = 2924, 1691, 1510,

–1 + 1265, 1234, 1011, 931, 816 cm ; HRMS (EI): m/z Calcd. for C10H10F2S [M] : 200.0471; found: 200.0480.

.1-p-Chlorophenyl-2,2-difluoro-1-(methylsulfanyl)ethene (30l)

1 H NMR (500 MHz, CDCl3): δ = 2.07 (s, 3H), 7.36 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H);

13 C NMR (126 MHz, CDCl3): δ = 16.4, 90.3 (dd, J = 23, 20 Hz), 128.8, 130.3 (dd, J = 3, 3 Hz), 130.4

19 (dd, J = 4, 2 Hz), 133.9, 154.9 (dd, J = 302, 289 Hz); F NMR (470 MHz, CDCl3): δ = 82.8 (d, J =

22 Hz, 1F), 85.0 (d, J = 22 Hz, 1F); IR (neat): ν = 2925, 1685, 1488,1274, 1009, 912, 827, 742 cm–1;

+ HRMS (EI): m/z Calcd. for C9H7ClF2S [M] : 219.9925; found: 219.9930.

1-Benzylsulfanyl-2,2-difluoro-1-phenylethene (30m)

1 H NMR (500 MHz, CDCl3): δ = 3.62 (s, 2H), 7.14 (d, J = 7.2 Hz, 2H), 7.20–7.26 (m, 3H), 7.30 (t, J = 7.2 Hz, 1H), 7.36 (dd, J = 7.2, 7.2 Hz, 2H), 7.44 (d, J = 7.2 Hz, 2H); 13C NMR (126 MHz,

CDCl3): δ = 37.2 (dd, J = 2, 2 Hz), 89.1 (dd, J = 23, 21 Hz), 127.2, 127.9, 128.38, 128.43, 128.9,

129.1 (dd, J = 3, 3 Hz), 132.2 (d, J = 3 Hz), 137.3, 155.9 (dd, J = 303, 289 Hz); 19F NMR (470 MHz,

CDCl3): δ = 83.1 (d, J = 19 Hz, 1F), 85.4 (d, J = 19 Hz, 1F); IR (neat): ν = 2925, 1689, 1491, 1265,

–1 + 1234, 1007, 694 cm ; HRMS (EI): m/z Calcd. for C15H12F2S [M] : 262.0628; found: 262.0628.

1-Benzylsulfanyl-1-p-chlorophenyl-2,2-difluoroethene (30n)

1 H NMR (500 MHz, CDCl3): δ = 3.63 (s, 2H), 7.11–7.13 (m, 2H), 7.21–7.28 (m, 3H), 7.31–

13 7.36 (m, 4H); C NMR (126 MHz, CDCl3): δ = 37.3 (dd, J = 2, 2 Hz), 88.3 (dd, J = 23, 20 Hz), 127.3,

128.4, 128.7, 128.9, 130.3 (dd, J = 4, 4 Hz), 130.8 (d, J = 3 Hz), 133.8, 137.1, 156.0 (dd, J = 304,

19 290 Hz); F NMR (470 MHz, CDCl3): δ = 84.1 (d, J = 17 Hz, 1F), 86.4 (d, J = 17 Hz, 1F); IR (neat):

–1 + ν = 3032, 1685, 1491, 1275, 1090, 1010, 827 cm ; HRMS (EI): m/z Calcd. for C15H11F2S [M] : 296.0238; found: 296.0238.

1,1,2,2-Tetrafluoro-3-methylsulfanyl-3-phenylcyclopropane (58b)

1 13 H NMR (500 MHz, CDCl3): δ = 2.08 (s, 3H), 7.29 (d, J = 7.3 Hz, 2H), 7.36–7.44 (m, 3H); C

NMR (126 MHz, CDCl3): δ = 13.8, 45.5 (dddd, J = 13, 13, 11, 11 Hz), 106.0 (dddd, J = 313, 313, 12,

19 12 Hz), 128.7, 129.0, 130.1; F NMR (470 MHz, CDCl3): δ = 18.7 (dm, J = 165 Hz, 2F), 23.5 (dm,

J = 165 Hz, 2F); IR (neat): ν = 2927, 1489, 1217, 1157, 810, 748, 696, 565 cm–1; HRMS (EI): m/z

+ Calcd. for C10H8F4S [M] : 236.0283; found: 236.0278

2-4. References

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L. S.; Lindhardt, A. T.; Jensen, K. L.; Skrydstrup, T. J. Org. Chem. 2008, 73, 3404; Fujita, T.;

Suzuki, N.; Ichitsuka, T.; Ichikawa, J. J. Fluorine Chem. 2013, 155, 97; Ichitsuka, T.; Takanohashi, T.; Fujita, T.; Ichikawa, J. J. Fluorine Chem. 2015, 170, 29. [29] Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425; Miura, T.; Ito, Y.; Murakami, M.

Chem. Lett. 2008, 37, 1006; Hu, M.; He, Z.; Gao, B.; Li, L.; Ni, C.; Hu, J. J. Am. Chem. Soc.

2013, 135, 17302; Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS Catal. 2015, 5, 5947; Zhang, Z.;

Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang, J. Org. Lett. 2015, 17, 2474; Huang, Y.; Hayashi, T. J. Am. Chem. Soc. 2016, 138, 12340. [30] Hiyama, T.; Obayashi, M.; Sawahata, M. Tetrahedron Lett. 1983, 24, 4113; Begué, J.-P.;

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Chapter 3. Introduction of CF2 Unit to Dienol Silyl Ether

3-1. Regioselective Difluorocyclopropanation of Dienol Silyl Ethers

3-1-1. Introduction

Enol silyl ethers are electron-rich alkenes, and thus potentially react readily with difluorocarbene because of its electron-deficiency. However, difluorocyclopropanation of enol silyl ethers has been limited until recently[1] because of instability of these substrates under the harsh conditions required for conventional difluorocarbene generation.[2] In 2010, Amii and co-workers performed difluorocyclopropanation of enol silyl ethers under milder conditions using sodium bromodifluoroacetate as a difluorocarbene source, affording the corresponding difluorocyclopropanes in good yields (eq. 42).[3] Difluorocyclopropanation of enol silyl ethers was also reported by Dilman and Wang using (bromodifluoromethyl)trimethylsilane (eq. 43 and eq.

[4] [5] 44), and Mikami using Zn(CF3)2(DMPU)2 (eq. 45). Because of its mild conditions, I supposed that the difluorocarbene generation from TFDA using organocatalysts would facilitate the difluorocyclopropanation of enol silyl ethers.

Among enol silyl ethers, I specifically focused on vinylated derivatives: dienol silyl ethers.

These substrates have two alkene moieties, which have quite different electron density. I expected that regioselective difluorocyclopropanation of dienol silyl ethers would be achieved at the electron- rich alkene moiety bearing a siloxy group (eq. 46).

There are two potential problems in difluorocyclopropanation of dienol silyl ethers. These problems are related to decomposition of the products, vinylated difluorocyclopropanes. One is vinylcyclopropane–cyclopentene (VCP) rearrangement (Chapter 3, 3-2).[6] When fluorine-free vinylcyclopropanes are subjected to high temperatures, the isomerization to cyclopentenes is induced

(eq. 47). For instance, when vinylcyclopropane 63 is heated to 580 °C, cyclopentene (rearrangement product) 64 is obtained in 77% yield (eq. 48).[7] Disadvantageously, fluorine substituents lower the temperature required for this rearrangement. Vinylated difluorocyclopropane 65, bearing two fluorine substituents, is heated at 100 °C, leading to the corresponding difluorinated cyclopentene 66 in 99% yield (eq. 49).[8] Fluorine substituents increase the ring strain of the difluorocyclopropane moiety and lengthen the C–C bond distal to the fluorine substituents (Bent’s rule), which accelerates this unfavorable but regioselective isomerization.[9]

The other is a [1,5]-hydrogen shift (eq. 50). Particularly, fluorine-free vinylated cyclopropane

67 is heated to 230–240 °C, migration products 68 and 69 are obtained in good yields (eq. 51).[10]

Unfavorable acceleration by fluorine substituents is again observed in this isomerization. Vinylated difluorocyclopropane 70 undergoes the [1,5]-hydrogen shift even at 53–87 °C to give the corresponding product 71 in 95% yield (eq. 52).[11]

Therefore, to achieve the regioselective synthesis of vinylated difluorocyclopropanes, it is necessary to prevent these decomposition reactions (VCP rearrangement and [1,5]-hydrogen shift).

As mentioned in chapter 2, I achieved the generation of difluorocarbene from TFDA at low temperatures by using proton sponge as an organocatalyst. I thus expected that the difluorocyclopropanation of dienol silyl ethers would be realized by the abovementioned generation of difluorocarbene.

3-1-2. Regioselective Difluorocyclopropanation: Synthesis of Vinylated Difluorocyclopropanes

Optimization of Catalyst and Reaction Conditions

First of all, the organocatalyst was optimized to facilitate the desired difluorocyclopropanation of dienol silyl ethers (Table 7). Dienol silyl ether 31a, prepared from methyl styryl ketone, was treated with TFDA (2.0 equiv) in the presence of sodium fluoride (the original catalyst developed by Dolbier) in toluene at 80 °C (Table 7, entry 1). However, the desired vinylated difluorocyclopropane 32a was obtained only in 9% yield, presumably because difluorocarbene was hardly generated from TFDA at the temperature (i.e., lower than the optimized temperature, 105 °C). The N-heterocyclic carbene

(NHC) catalysts afforded 32a in higher yields (17% and 49%; Table 7, entries 2 and 3).

The catalytic activities of nitrogen nucleophiles (catalysts) for difluorocarbene generation were examined. Although pyridine and benzo[h]quinoline were not effective as catalysts (20% and 0% yields of 32a, respectively; Table 7, entries 4 and 5), 1,10-phenanthroline (10 mol%) showed higher activity to afford 32a in 58% yield (Table 7, entry 6). Aliphatic amines such as triethylamine and

N,N,N’,N’-tetramethylethylenediamine (TMEDA) exhibited less efficiency (47% and 38% yields, respectively; Table 7, entries 7 and 8). Finally, dienol silyl ether 31a afforded vinylated difluorocyclopropane 32a in the presence of 5 mol% of proton sponge 24 in 75% yield (Table 7, entry

9). Proton sponge 24 was active even at low temperatures. TFDA (1.5 equiv) was added dropwise to a toluene solution of dienol silyl ether 31a and 5 mol% of catalyst 24 at 50 °C or 60 °C over 10 min.

When the addition was finished, the reaction reached to completion to afford 32a in 74% and 77% yields, respectively (Table 7, entries 11 and 12). Under these temperatures, undesired [1,5]-hydrogen shift product was hardly obtained. In addition, doubly cyclopropanated product 73a was not observed by 1H and 19F NMR spectroscopy in all the entries. Thus, the expected regioselective difluorocyclopropanation of dienol silyl ethers was successfully achieved.

Table 7. Optimization of Catalyst and Reaction Conditions.

Synthesis of Vinylated Difluorocyclopropanes: Substrate Scope

Under the optimized conditions, various 1,1-difluoro-2-siloxy-2-vinylcyclopropanes were synthesized (Table 8). Electron-donating and electron-withdrawing groups, installed on the aromatic ring at the terminal position (R1), did not affect the reaction, and led to the corresponding products

32b and 32c in 79% and 83% yields, respectively (Table 8, entries 2 and 3). Substrate 31d bearing an alkyl substituent (i.e., isopropyl group) on the reacting alkene moiety (R3) afforded the corresponding cyclopropane 32d in 78% yield (Table 8, entry 4). The dienol silyl ether 31e bearing a butyl group as R1 substituent also produced 32e in 75% yield (Table 8, entry 5).

Difluorocyclopropanation of these dienol silyl ethers proceeded in a diastereospecific manner, with 31d and 31e (91:9 and 92:8 Z/E ratio) leading to 32d and 32e (82:18 and 92:8 d.r.), respectively.

The structures of their diastereomers were determined by NMR spectroscopy (HOESY, Figure 8).

Difluorocarbene is a singlet carbene, leading to the stereospecific outcome via the concerted cyclization

Figure 8. Structure Determination of 32d by 1H-19F HOESY.

Substrates bearing a methyl group (31f) and a bromo substituent (31g) at the internal position

(R2) afforded 32f and 32g in 92% and 96% yields, respectively (Table 8, entries 6 and 7). Not only dienol silyl ethers, but also enol silyl ethers underwent organocatalytic difluorocyclopropanation.

Enol silyl ether 31h, derived from acetophenone, afforded the corresponding cyclopropane 32h in

80% yield (Table 8, entry 8). Thus, the required difluorocyclopropanation of dienol silyl ethers 31 was successfully achieved by organocatalytic difluorocarbene generation from TFDA with proton sponge 24.

Table 8. Synthesis of Vinyldifluorocyclopropanes.

3-1-3. Conclusion

The regioselective difluorocyclopropanation of dienol silyl ethers was achieved. The key of the achievement is the milder reaction conditions realized by the proton sponge catalyst. The organocatalytic system efficiently suppressed the decomposition reactions of the produced vinylated difluorocyclopropanes (i.e., the VCP rearrangement and the [1,5]-hydrogen shift).

3-2. Metal-Free Synthesis of α,α-Difluorocyclopentanone Derivatives via Regioselective Difluorocyclopropanation of Dienol Silyl Ethers

3-2-1. Introduction

α,α-Difluorinated ketone is an important structure found in bioactive compounds and their synthetic intermediates. For example, an acyclic difluorinated ketone 74 acts as an agonist for a

[12] neurotransmitter GABAB receptor (Figure 9). α,α-Difluorocyclohexanone 2 exhibits anti-malarial activity.[13] In this context, α,α-difluorinated cyclopentanones seem to be promising compounds as pharmaceuticals, because a cyclopentanone framework is found in a variety of bioactive natural products. To date, fluorinated cyclopentanone derivatives have been mostly synthesized by fluorination of cyclopentanones.[14] However, these methods suffer from drawbacks relating to the requirement of time-consuming processes such as carbon-skeleton construction and fluorine installation, as well as the use of expensive fluorinating reagents.

The Ichikawa group has already reported the metal-catalyzed synthesis of α,α- difluorocyclopentanone derivatives based on the strategy of introducing a difluoromethylene unit (eq.

53).[15] The reaction involves sequential (i) nickel-catalyzed regioselective difluorocyclopropanation of dienol silyl ethers with a metal difluorocarbene complex and (ii) regioselective vinylcyclopropane/cyclopentene (VCP) rearrangement. This method is efficient because the introduction of fluorine substituents and the construction of the carbon skeleton are performed simultaneously. Thus, I attempted to apply the organocatalytic generation of difluorocarbene to this reaction (eq. 54). The advantages of this attempt are that the difluorocyclopropanation would proceed under milder conditions, and that the metal-free synthesis of α,α-difluorocyclopentanone derivatives [16] would be realized.

Figure 9. Useful Difluorinated Ketones for Pharmaceuticals.

3-2-2. Metal-Free Synthesis of 5,5-Difluorocyclopent-1-en-1yl Silyl Ethers

Optimization of Reaction Conditions

As mentioned in Chapter 3, 3-1, the standard VCP rearrangement requires high temperatures, whereas fluorine substituents accelerate the rearrangement. I first examined the temperature required for the VCP rearrangement of fluorinated substrates, using isolated difluoro(vinyl)cyclopropane 32a.

Cyclopropane 32a, prepared from dienol silyl ether 31a and difluorocarbene, was heated in p-xylene 81

(Table 9). The rearrangement took place even at 80 °C (Table 9, entries 1 and 2), which is much lower than the temperature required for the VCP rearrangement of fluorine-free substrates. It was found that the rearrangement proceeded within 30 min at 140 °C, affording 33a in quantitative yield (Table 9, entry 6).

Table 9. Optimization of Reaction Temperature for VCP Rearrangement

Next, the desired metal-free, one-pot difluorocyclopropanation/VCP rearrangement was investigated (Table 10). Since a trace amount of the corresponding acid remained in TFDA, decomposition (hydrolysis) of dienol silyl ethers 31 occurred at room temperature. Thus, TFDA (1.5 equiv) was added dropwise to the preheated p-xylene solution of dienol silyl ether 31a and proton sponge 24 (5 mol%). The difluorocyclopropanation/VCP rearrangement proceeded efficiently at

140 °C in a one-pot operation to afford cyclic enol silyl ether 33a in 83% yield (Table 10, entry 1).

When dienol silyl ether 31f was used as the substrate, the reaction proceeded under the same conditions to afford 33f in 81% yield (Table 10, entry 2). The yield of 33f was increased to 90% when

82 difluorocyclopropanation was performed at 60 °C, followed by VCP rearrangement at 140 °C (Table

10, entry 4).

Table 10. Optimization of Reaction Conditions for One-Pot Difluorocyclopropanation/VCP

Rearrangement

Substrate Scope

Under the optimized conditions, cyclic enol silyl ethers 33 with various substituents were synthesized (Table 11). Dienol silyl ethers 31b, 31c, 31i, and 31j, bearing electron-donating or

-withdrawing aryl groups or alkyl groups at the terminal position (R1), afforded the corresponding cyclic enol silyl ethers 33b, 33c, 33i, and 33j in 77–90% yields (Table 11, entries 2–5). Substrates 31f and 31g, bearing a methyl or a bromo substituent at the internal position (R2), afforded 33f and 33g in

90% and 83% yields, respectively (Table 11, entries 6 and 7). When dienol silyl ether 31k with a cyclohexene ring was used as the substrate, 33k possessing a [4.3.0]bicyclononane structure was obtained in 66% yield (Table 11, entry 8).

Substrates 31d and 31e, bearing an alkyl substituent (i.e., an isopropyl group and a butyl group, respectively) on the enol ether moiety (R3), also successfully participated in the reaction (Table 11,

83 entries 9 and 10). Dienol silyl ethers 31d and 31e (with Z/E ratios of 92/8 and 94/6, respectively) underwent the difluorocyclopropanation/VCP rearrangement, leading to the diastereoselective formation of 33d and 33e in 45% and 49% yields (with a trans/cis ratio of >99/<1 and >99/<1, respectively). The relative stereochemistry of the diastereomers was determined by NMR spectroscopy (NOE, Figure 10). VCP rearrangement of cyclopropanes 32d and 32e exclusively provided more thermodynamically stable trans-isomers, probably because the ring closure avoided steric hindrance during the rearrangement (Scheme 23). In addition, when the substrates 31d and 31e were employed, [1,5]-hydrogen shift products, siloxydienes 75d and 75e were also obtained in 7% and 11% yields, respectively.

Table 11. Metal-Free Synthesis of Cyclic Enol Silyl Ethers 33a–k.

Figure 10. Structure Determination of 33d by NOE.

Scheme 23. Exclusive Formation of Trans Cyclopentane Derivatives from 32d and 32e.

3-2-3. Advantages of the Organocatalytic Synthesis

Notably, the metal-free protocol for the synthesis of -difluorocyclopentanone derivatives is advantageous with respect to regioselectivity in the VCP rearrangement step. Whereas dienol silyl ethers 31g underwent metal-free difluorocyclopropanation/VCP rearrangement to give 33g as a single product (Table 11 and Scheme 24, top), treatment of 31g with TFDA in the presence of a catalytic amount of a Ni complex afforded 33g in 72% yield along with its structural isomer 4,4- difluorocyclopent-1-en-1-yl silyl ether 76g in 8% yield (Scheme 24, bottom).[15] Although the formation mechanism of 76g is uncertain, it could be generated by a formal [4 +1] cycloaddition[17] or by an oxidative addition of the C–C bond in difluorocyclopropane 33g, followed by ring expansion and reductive elimination. The advantage of the synthesis of 5,5-difluorocyclopent-1-en-1-yl silyl ethers 33 under metal-free conditions was thus demonstrated.

Scheme 24. Advantage of the Organocatalytic Synthesis of 5,5-Difluorocyclopent-1-en-1yl Silyl Ethers.

3-2-4. Conclusion

Regio- and stereoselective difluorocyclopropanation/VCP rearrangement sequence of dienol silyl ethers under the metal-free conditions was developed by using proton sponge as an organocatalyst. The key to achieve the efficient conversion was that the difluorocyclopropanation/VCP rearrangement was performed under the suitable temperature control.

This finding leads to efficient syntheses of biologically promising fluorinated cyclopentanone derivatives.

3-3. Synthesis of -Fluoroyclopentenones via Regioselective Difluorocyclopropanation of Dienol Silyl Ethers

3-3-1. Introduction

Cyclopentenone is an important structure included in various bioactive compounds (Figure 11). For example, cryptosporiopsin and dehydropentenomycin exhibit antibiosis activity.[18,19]

[20] Prostaglandin J2 shows anticancer activity. Importantly, biological activities of fluorine-substituted analogues have been studied for years, and antileukemic activity of 77 (fluorinated clavulone derivative) was reported.[21]

Figure 11. Bioactive Compounds with Cyclopentenone Skeleton.

The Nazarov cyclization[22] is one of the most useful methods for construction of cyclopentenone skeletons. In the Nazarov cyclization, 4π electrocyclization of pentadienyl cation intermediates, formed by the treatment of divinyl ketones with Brønsted acids or Lewis acids, proceeds to generate cyclopentenyl cations, and their deprotonation leads to the construction of cyclopentenone frameworks (Scheme 25). A drawback in the Nazarov cyclization in the difficulty in controlling the position of the double bond introduced to the products. The position generally depends on the thermodynamic stability of the products. Demmark controlled the position of the double bond in the

Nazarov cyclization, using β-cation stabilizing effect of silicon (eq. 55).[23] Controlling the position of the double bond was also achieved by using a tin (eq. 56)[24] or an alkoxy (eq. 57)[25] substituent.

In all cases, the generated cations are localized because of the stabilizing effect of these heteroatom substituents, and deprotonation proceeds regioselectively to afford the products.

Scheme 25. Reaction Mechanism of Nazarov Cyclization.

In the past years, the Ichikawa group has reported regioselective Nazarov cyclizations utilizing the β-carbocation destabilizing effect of fluorine (–I effect, Chapter 1, Figure 2). When 2,2- difluorovinyl vinyl ketone 78 is treated with trimethylsilyl trifluoromethanesulfonate (Me3SiOTf), 4π electrocyclization proceeds to generate a cyclopentenyl cation, in which the positive charge is localized at the δ position of the fluorine substituents, avoiding the β-cation destabilizing effect (eq.

58, canonical structure B).[26] Elimination of Ha adjacent to the localized positive charge proceeds to afford cyclopentenone 79 along with formation of Me3SiF. When 1-(trifluoromethyl)vinyl vinyl ketone 80 is treated with Me3SiOTf, a double bond is formed at the position distal to the 89 trifluoromethyl group because of the β-cation destabilizing effect of fluorine (eq. 59).[27]

However, in the abovementioned previous examples, the cyclopentenyl cation intermediates are destabilized, and thus rate enhancement of the rate-determining electrocyclization step is not expected.

To accelerate the Nazarov cyclization, stabilization of the formed cyclopentenyl cation is required. I expected that both positional control of the double bond and rate enhancement of the cyclization would be achieved by using the α-cation stabilizing effect of fluorine. Namely, I focused my attention on examination of the Nazarov cyclization of 1-fluorovinyl vinyl ketones (eq. 60). When divinyl ketones 34 is treated with a Lewis acid, the cyclopentenyl cation intermediate, expressed by E and F as canonical structures, would be generated. In this intermediate, it is considered that the positive charge is localized at the position α to the fluorine substituent, because the α-cation is stabilized by

+R effect of fluorine. Thus, the electrocyclization step would be accelerated and deprotonation of Ha would proceed, leading to the double bond formation at the position adjacent to the fluorine substituent to afford 35 (the fluorine-directed and -activated Nazarov cyclization).

To facilitate the Nazarov cyclization, I planned the following preparation of 1-fluorovinyl vinyl ketones (eq. 61). Divinyl ketones 34 would be synthesized by ring opening of vinylated difluoro(siloxy)cyclopropanes 32, which are obtained by the regioselective difluorocyclopropanation of dienol silyl ethers 32 with difluorocarbene (Chapter 3, 3-1). Thus, the synthesis of fluorine- containing cyclopentenones would be achieved by combining two selective reactions (regioselective difluorocyclopropanation and regioselective Nazarov cyclization).

3-3-2. Preparation of 1-Fluorovinyl Vinyl Ketones

The Nazarov precursors (i.e., 1-fluorovinyl vinyl ketones 34) were prepared by the ring opening of 1,1-difluoro-2-siloxy-2-vinylcyclopropanes 32 (Table 12), whose synthesis was described in the previous section (Chapter 3, 3-1). Treatment of vinylated difluorocyclopropane 32a with cesium fluoride at 60 °C in THF did not afford the desired 34a (72% recovery of 32a; Table 12, entry 1). Use of tetrabutylammonium fluoride (TBAF, 20 mol%) led to formation of the desired 34a at room temperature in 70% yield (Table 12, entry 2). Tetrabutylammonium difluorotriphenylsilicate (TBAT, n-Bu4N SiF2Ph3) as milder fluoride ion source than TBAF raised the yield of 34a to 94% (Table 12, entry 3). While tris(dimethylamino)sulfonium difluorotrimethylsilicate afforded a complex mixture

(Table 12, entry 4), tetrabutylammonium difluorotriphenylstannate was inactive even at 60 °C (97%

91 recovery of 32a; Table 12, entry 5).

Table 12. Catalyst (Fluoride Ion Source) Optimization.

Several 1-fluorovinyl vinyl ketones 34 were prepared by the abovementioned method (Table 13).

Cyclopropanes, bearing phenyl (32a), p-methylphenyl (32b), and p-chlorophenyl (32c) groups, underwent the ring opening to afford the corresponding divinyl ketones 34a–c in 53–76% yields

(Table 13, entries 1–3). Substrate 32e, bearing a butyl group on the cyclopropane moiety, did not afford the desired product 34e and decomposed under the TBAT and TBAF systems at 0 °C to RT

(Table 13, entries 4 and 5). On the basis of these results, the ring opening of 32e and 32d was conducted with water-deactivated TBAF at controlled temperatures to give 34e and 34d in 61% and

74% yields, respectively (Table 13, entries 6 and 7). Methylated and brominated vinylcyclopropanes

32f and 32g afforded the desired divinyl ketones 34f and 34g in 77% and 75% yields, respectively

(Table 13, entries 8 and 9)

Table 13. Preparation of 1-Fluorovinyl Vinyl Ketones.

3-3-3. Fluorine-Directed and Fluorine-Activated Nazarov Cyclization: Regioselective Synthesis of α-Fluorocyclopentenones

The Nazarov cyclization of 1-fluorovinyl vinyl ketones 34 was examined using Z-34e as a model substrate (Table 14). Treatment of Z-34e with 3 equiv of Me3SiOTf in HFIP–dichloromethane (1:1) led to hydroxycyclopentenone 81e (i.e., a hydrolyzed product of the desired fluorinated cyclopentenone 35e) in 57% yield (Table 14, entry 1). I assumed that the hydrolysis of 35e was caused by a trace amount of water present in HFIP. When the reaction was conducted in dichloromethane, no reaction was observed even under reflux, presumably due to the lack of cation-stabilizing effect of HFIP (Table 14, entry 2). Thus, I examined other Lewis acids to efficiently generate pentadienyl

93 cations. Utilization of BF3•OEt2 in dichloromethane was fruitless (Table 14, entry 3), whereas SnCl4 afforded the desired 35e in 41% yield (Table 14, entry 4). Eventually, I found that strong silylating

[28] agent Me3Si B(OTf)4 successfully induced the Nazarov cyclization to afford 35e in 89% yield within 15 min (Table 14, entry 5).

Table 14. Optimization of the Lewis Acid for Regioselective Nazarov Cyclization.

As expected, the Nazarov cyclization proceeded in a regioselective manner (Table 15). 1-

Fluorovinyl vinyl ketone 34a bearing a phenyl group at the terminal carbon atom (R1) afforded the corresponding 35a in 51% yield (Table 15, entry 1). The undesired isomer concerning the position of the double bond was not observed by 19F NMR and GC-MS analyses. An electron-donating methyl group (34b) and an electron-withdrawing chlorine substituent (34c) installed on the aromatic ring at the terminal position (R1) did not affect the reaction, and 35b and 35c were obtained in 57% and 74% yields, respectively (Table 15, entries 2 and 3). Divinyl ketones Z-34d, Z-34e, and E-34e bearing an alkyl substituent (i.e., isopropyl or butyl group) on the fluoroalkene moiety readily underwent cyclization on increasing the loading of the Lewis acid to afford 35d (88% yield; Table 15, entry 4) and 35e (79% and 70% yields; Table 15, 5 and 6), respectively. The Nazarov cyclization of cyclohexenyl ketone 34l allowed the construction of the bicyclic structure, and led to 35l in 79% yield

(Table 15, entry 7).

Table 15. Regioselective Synthesis of α-Fluorocyclopentenones.

The oxygenated cyclopentenone skeleton of 81 is included in cyclotenes, which are used as food additives with a caramellike flavor. Divinyl ketone 34f bearing a methyl group at an internal position

(R2) also underwent defluorinative Nazarov cyclization (eq. 62). When methylated ketone 34f was treated with Me3SiOTf (1.0 equiv) in HFIP–dichloromethane (1:1) at 0 °C, 2-hydroxycyclopent-2- en-1-one 81f was obtained in 68% yield. Thus, fluorine-directed and fluorine-activated Nazarov cyclization is a useful method for the synthesis of fluorinated cyclopentanone derivatives and their fluorine-free analogues.

3-3-4. Effect of Fluorine Substituent in Nazarov Cyclization

In order to elucidate the regioselectivity of the fluorine-directed Nazarov cyclization, the structures of key cyclopentenyl cation intermediates were analyzed by theoretical calculation (Figure

12). Figure 12 shows the calculated values for charges and Löwdin bond orders of the optimized model structures of cyclopentenyl cation intermediates (s-cis and s-trans forms) and their fluorine- free counterpart (blank).

The theoretical calculation indicated that the α-carbon atoms of the fluorine substituent (C1) have high positive charges [i.e., +0.362 (s-cis) and +0.354 (s-trans)], whereas the C3 carbon atoms have slightly negative charges [–0.032 (s-cis) and –0.064 (s-trans)]. These charge distributions were not found in the blank structure, in which C1 and C3 showed slightly negative and positive charges (

–0.015 and +0.027, respectively). Thus, positive charge was localized mainly on the α-carbons of the fluorine substituent.

Difference in bond orders were also observed. The Löwdin bond orders for C1–C2 bonds in s- cis and s-trans forms (1.28 and 1.26) were significantly lower than those for C2–C3 bonds (1.58 and

1.45), respectively. In contrast, the bond orders of the C1–C2 and C2–C3 bonds in the blank structure were nearly equal (1.39 and 1.38). These electronic and structural perturbations suggested that the fluorinated cyclopentenyl cations have a localized allyl cation structure, and thereby lead to regioselective deprotonation and selective formation of 2-fluorocyclopent-2-en-1-ones 35.

Figure 12. Calculated Properties of Cyclopentenyl Cation Intermediate (DFT, B3LYP/6-31G**).

The effect of fluorine substituents on the reactivity and selectivity of the Nazarov cyclization was experimentally investigated by using fluorinated (34m, X = F, Scheme 26) and fluorine-free (82,

X = H) substrates. A competition experiment demonstrated the acceleration by the effect of the fluorine substituent. A 1:1 mixture of 34m and 82 was treated with 1.0 equiv of Me3Si B(OTf)4 in dichloromethane at room temperature. Fluorinated 34m exclusively underwent the Nazarov cyclization to afford the corresponding product 35m in 89% yield as the sole product, whereas fluorine-free counterpart 82 did not react and was recovered in 92%. Thus, the fluorine substituent activated the substrates in the Nazarov cyclization through fluorine-stabilized cyclopentenyl cation intermediates.

Scheme 26. Effects of Fluorine Substituent 1: Activation.

Furthermore, when fluorine-free divinyl ketone 82 was separately treated with Me3Si B(OTf)4

(1.0 equiv), the Nazarov cyclization proceeded, albeit very slowly (eq. 63). It required 20 h for completion (i.e., 80 times slower than 34m) to give a regioisomeric mixture concerning the position of the double bond (83 and 83’ in 24% and 65% yields, respectively).

Theoretical calculations suggested that phenyl-non-conjugated cyclic intermediate G1, leading to 35m, is less stable than phenyl-conjugated G3 by 2.80 kcal/mol (Scheme 27, DFT, B3LYP/6-

31G**). Thus, the fluorine substituent governed the cyclization to exclusively afford the non- conjugated cyclopentenone 35m as a kinetic product, whereas fluorine-free substrate 82 afforded 83’ as a major product under the influence of the higher stability of phenyl-conjugated G4 by 3.16 kcal/mol.

Scheme 27. Effects of Fluorine Substituent 2: Direction.

3-3-5. Conclusion

The method for the synthesis of 2-fluorocyclopent-2-en-1-ones (α-fluorocyclopentenones) was developed by combining organocatalyzed difluorocyclopropanation of dienol silyl ethers and fluorine-directed and fluorine-activated Nazarov cyclization; the selective preparation of the Nazarov precursors (i.e., 1-fluorovinyl vinyl ketones) was facilitated through proton sponge-catalyzed generation of difluorocarbene from TFDA. The mild difluorocarbene generation allowed efficient preparation of 1,1-difluoro-2-siloxy-2-vinylcyclopropanes, whose ring opening afforded the required

Nazarov precursors. Regioselective synthesis of 2-fluorocyclopent-2-en-1-ones was achieved by the

Nazarov cyclization, accelerated and directed by the α-cation-stabilizing effect of a fluorine substituent. Treatment of the precursors with Me3Si B(OTf)4 readily induced the Nazarov cyclization and allowed the efficient synthesis of biologically promising α-fluorocyclopentenone derivatives.

3-4. Experimental Section

3-4-1. General

Analysis

IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance

(ATR method). NMR spectra were recorded on a Bruker AVANCE 500 or a Jeol JNM ECS-400

1 13 spectrometer in CDCl3 at 500 or 400 MHz ( H NMR), at 126 or 100 MHz ( C NMR), and at 470 or

19 1 376 MHz ( F NMR). Chemical shifts were given in ppm relative to internal Me4Si (for H NMR: δ

Reaction

All the reactions were conducted under argon.

Purification

Silica gel 60 (spherical, Kanto Chemical) and alumina (Aluminium Oxide 90 Active Basic, Merck KGaA for column chromatography) were used for column chromatography, and Wakogel®B- F5 (Wako Pure Chemical Industries) was used for preparative thin-layer chromatography.

Solvents and Reagents

Toluene, tetrahydrofuran (THF), and dichloromethane were purchased from Kanto Chemical

Co., Inc. and dried by passing over a column of activated alumina followed by a column of Q-5 scavenger (Engelhard). 1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) supplied by Central Glass Co., Ltd (purity 99.9%) was distilled from and stored over molecular sieves 3A. HFIP can be also purchased from commercial suppliers such as Sigma–Aldrich Co. LLC. p-Xylene was distilled from CaH2. 1,8-

100

Bis(dimethylamino)naphthalene (proton sponge), 1,1,1,3,3,3-hexafluoro-2,2-di(p-tolyl)propane

(internal standard for 19F NMR), and triazolium salt 40 were purchased from Tokyo Chemical

Industry Co., Ltd. Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) was prepared according to the literature.[29] 19F NMR analysis suggested that the prepared TFDA contained a small amount of the starting acid and that its purity was higher than 98% (mol/mol). Tetrabutylammonium difluorotriphenylsilicate (TBAT, n-Bu4N SiF2Ph3) was purchased from Sigma–Aldrich Co. LLC.

Trimethylsilylium tetrakis(trifluoromethanesulfo nyloxy)borate (Me3Si B(OTf)4) was prepared according to the literature.[28] imidazolium salt 41 was prepared according to the literature.[30] Unless otherwise noted, materials were obtained from commercial sources and used directly without further purification.

101

3-4-1. Regioselective Difluorocyclopropanation of Dienol Silyl Ethers (3-1)

Preparation of Dienol Silyl Ethers

Dienol silyl ethers 31a–k were prepared from the corresponding ketones and silyl triflate according to our previous paper.[15] Dienol silyl ether 31h was prepared according to the literature.[31]

Spectral Data of Dienol Silyl Ethers

Spectral data of dienol silyl ethers 31a–c and 31f and 31g were described in our previous paper.[15] Spectral data of 31h met complete agreement with those in literature.[32]

(1E,3Z)-3-[tert-Butyl(dimethyl)silyloxy]-5-methyl-1-phenylhexa-1,3-diene (31d)

1H NMR: δ = 0.16 (s, 6H), 1.00 (d, J = 6.5 Hz, 6H), 1.05 (s, 9H), 2.70–2.82 (m, 1H), 4.76 (d, J

= 9.8 Hz, 1H), 6.52 (d, J = 15.9 Hz, 1H), 6.64 (d, J = 15.9 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.30 (dd,

J = 7.5, 7.5 Hz, 2H), 7.36 (d, J = 7.5 Hz, 2H); 13C NMR: δ = −3.7, 18.5, 23.0, 25.2, 26.0, 124.3, 126.3,

127.07, 127.12, 127.8, 128.6, 137.3, 146.5; IR (neat): ν = 2956, 1614, 1254, 997, 839 cm–1; HRMS

+ (EI): m/z Calcd. for C19H30OSi [M] : 302.2066; Found: 302.2066

. (5Z,7E)-6-[tert-Butyl(dimethyl)silyloxy]dodeca-5,7-diene (31e)

1H NMR: δ = 0.11 (s, 6H), 0.82–0.93 (m, 6H), 1.00 (s, 9H), 1.25–1.41 (m, 8H), 1.99–2.13 (m,

4H), 4.65 (t, J = 7.2 Hz, 1H), 5.76 (dt, J = 15.0, 7.2 Hz, 1H), 5.80 (t, J = 15.0 Hz, 1H); 13C NMR: δ

= −3.6, 13.9, 18.5, 22.3, 22.5, 25.7, 25.96, 26.04, 31.7, 31.9, 32.0, 113.3, 128.7, 129.1, 148.1; IR

–1 + (neat): ν = 2927, 1624, 1464, 1254, 912, 742 cm ; HRMS (EI): m/z Calcd. for C18H36OSi [M] :

296.2535; Found: 296.2532. 102

Synthesis of Vinylated Difluorocyclopropanes

Typical Procedure for the synthesis of 1,1-difluoro-2-siloxy-2-vinylcyclopropanes (32).

Dienol silyl ether 31a (104 mg, 0.398 mmol) was added to a toluene solution (4 mL) of proton sponge (24, 3.7 mg, 0.017 mmol) and (CF3)2CTol2 (21 mg, 0.063 mmol) as standard at room temperature. The reaction mixture was stirred and heated at 60 °C. After TFDA (120 μL, 0.609 mmol) was added to the solution of 24 and 31a dropwise over 10 min, hexane (5 mL) and aqueous NaHCO3

(10 mL) were added to quench the reaction at room temperature. Organic materials were extracted with hexane for times. Combined extracts were dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexane) to give vinylated difluorocyclopropane 32a (94 mg, 76% yield) as a colorless oil.

Spectral Data of Vinylated Difluorocyclopropanes

Spectral data of 32a and 32h met complete agreement with those in our previous paper.[15]

1-[tert-Butyl(dimethyl)silyloxy]-2,2-difluoro-1-[2-(4-methylphenyl)ethenyl] cyclopropane (32b)

1H NMR: δ = 0.15 (s, 3H), 0.17 (s, 3H), 0.94 (s, 9H), 1.61–1.69 (m, 2H), 2.34 (s, 3H), 6.09 (d,

J = 15.9 Hz, 1H), 6.70 (d, J = 15.9 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H); 13C

NMR: δ = −3.8, 18.2, 21.2, 25.1 (dd, J = 9, 9 Hz), 25.8, 61.4 (dd, J = 12, 12 Hz), 112.7 (dd, J = 298,

298 Hz), 124.1, 126.3, 129.3, 131.2, 133.4, 137.8; 19F NMR: δ = 24.5 (dm, J = 155 Hz, 1F), 28.8 (dm,

J = 155 Hz, 1F); IR (neat): ν = 2929, 2858, 1450, 1221, 1200, 989, 912 cm–1; EA: Calcd. for

C18H26F2OSi: C 66.63%, H 8.08%; Found: C 66.39%, H 8.04%.

103

1-[tert-Butyl(dimethyl)silyloxy]-1-[2-(4-chlorophenyl)ethenyl]-2,2- difluorocyclopropane (32c)

1H NMR: δ = 0.15 (s, 3H), 0.17 (s, 3H), 0.94 (s, 9H), 1.65–1.73 (m, 2H), 6.10 (dd, J = 16.0, 1.5

Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H), 7.29 (m, 4H); 13C NMR: δ = −3.8, 18.2, 25.3 (dd, J = 8, 8 Hz),

25.8, 61.3 (dd, J = 10, 10 Hz), 112.6 (dd, J = 296, 296 Hz), 126.1 (dd, J = 4, 4 Hz), 127.6, 128.8,

129.9, 133.5, 134.7; 19F NMR: δ = 24.7 (dm, J = 156 Hz, 1F), 29.1 (dm, J = 156 Hz, 1F); IR (neat):

–1 ν = 2931, 2860, 1491, 1452, 1225, 989, 835 cm ; EA: Calcd. for C17H23ClF2OSi: C 59.20%, H 6.72%; Found: C 59.03%, H 6.78%.

1-[tert-Butyl(dimethyl)silyloxy]-2,2-difluoro-3-isopropyl-1-(2-phenylethenyl) cyclopropane (32d) (diastereomeric mixture, 1R*,3S*/1R*,3R* = 65:35)

1H NMR: δ (1R*,3S*-32d) = 0.14 (s, 3H), 0.17 (s, 3H), 0.94 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H), 1.26−1.34 (m, 1H), 1.90−1.99 (m, 1H), 6.24 (d, J = 16.0 Hz, 1H), 6.71 (d, J

= 16.0 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.32 (dd, J = 7.2 Hz, 7.2 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H);

δ (1R*,3R*-32d) = 0.20 (s, 3H), 0.21 (s, 3H), 1.00 (s, 9H), 1.05−1.07 (m, 3H), 1.11 (d, J = 6.4 Hz,

3H), 1.55−1.62 (m, 1H), 1.68−1.77 (m, 1H), 6.24 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 16.0 Hz, 1H), 7.25−7.43 (m, 5H); 13C NMR: δ (1R*,3S*-32d) = −4.72, −4.65, 18.5, 21.6, 22.2, 22.4 (d, J = 3 Hz), 26.0, 41.0 (dd, J = 8, 8 Hz), 62.1 (dd, J = 10, 10 Hz), 114.5 (dd, J = 310, 299 Hz), 126.3, 126.5, 127.7,

128.7, 130.4, 136.5; δ (1R*,3R*-32d) = −4.10, −4.07, 18.5, 21.4, 22.7, 24.2 (d, J = 4 Hz), 25.9, 43.6

(dd, J = 11, 5 Hz), 63.4 (dd, J = 11, 11 Hz), 114.8 (dd, J = 302, 302 Hz), 122.6, 126.3, 126.5, 128.7,

132.5, 136.7; 19F NMR: δ (1R*,3S*-32d) = 14.6 (d, J = 157 Hz, 1F), 32.3 (dd, J = 157 Hz, 18 Hz,

1F); δ (1R*,3R*-32d) = 16.4 (d, J = 157 Hz, 1F), 27.9 (dd, J = 157 Hz, 18 Hz, 1F); IR (neat): ν

(diastereomeric mixture, 1R*,3S*/1R*,3R* = 65:35) = 2960, 2931, 2858, 1446, 1254, 1219, 1192,

–1 + 1109, 935, 833, 769 cm ; HRMS (EI): m/z Calcd. for C20H30F2OSi [M−t-Bu] : 295.1329; Found: (1R*,3S*-32d) 295.1327, (1R*,3R*-32d) 295.1326. 104

1-Butyl-2-[tert-butyl(dimethyl)silyloxy]-3,3-difluoro-2-(hex-1-en-1-yl)cyclopropane (32e)

1H NMR: δ = 0.12 (s, 6H), 0.89–0.92 (m, 15H), 1.27–1.42 (m, 9H), 1.50–1.54 (m, 2H), 2.05 (dt,

J = 6.8, 6.8 Hz, 2H), 5.55 (d, J = 15.6 Hz, 1H), 5.79 (dt, J = 15.6, 6.8 Hz, 1H); 13C NMR: δ = −4.64,

−4.59, –3.4, 13.88, 13.94, 18.4, 20.0 (d, J = 4 Hz), 22.2, 22.4, 25.9, 25.9, 30.8, 31.2, 32.1, 32.8 (dd,

J = 9, 9 Hz), 61.5 (dd, J = 10, 10 Hz), 114.4 (dd, J = 309 Hz, 299 Hz), 126.5, 133.2; 19F NMR: δ =

14.8 (d, J = 155 Hz, 1F), 30.7 (dd, J = 155 Hz, 17 Hz, 1F); IR (neat): ν = 2929, 1456, 1219, 837, 773

–1 cm ; EA: Calcd. for C19H36F2OSi: C 65.85%, H 10.47%; Found: C 65.53%, H 10.45%.

1-[tert-Butyl(dimethyl)silyloxy]-2,2-difluoro-1-(1-methyl-2-phenylethenyl) cyclopropane (32f)

1H NMR: δ = 0.12 (s, 3H), 0.14 (s, 3H), 0.89 (s, 9H), 1.48 (ddd, J = 14.0, 7.2, 6.0 Hz, 1H), 1.76

(ddd, J = 14.0, 9.2, 4.8 Hz, 1H), 2.00 (s, 3H), 6.60 (s, 1H), 7.21–2.78 (m, 3H), 7.35 (dd, J = 9.0, 9.0

Hz, 2H); 13C NMR: δ = −4.1, 15.8, 17.9, 22.9 (dd, J = 9, 9 Hz), 25.5, 65.3 (dd, J = 11, 11 Hz), 112.5

(dd, J = 294, 294 Hz), 127.0, 128.2, 128.9, 129.8, 133.0, 136.8; 19F NMR: δ = 21.7 (dm, J = 155 Hz,

1F), 25.0 (dm, J = 155 Hz, 1F); IR (neat): ν = 2929, 2858, 1454, 1227, 1205, 1165, 912 cm–1; HRMS

+ (EI): m/z Calcd. for C18H26F2OSi [M] : 324.1721; Found: 324.1721.

105

1-(1-Bromo-2-phenylethenyl)-1-[tert-butyl(dimethyl)silyloxy]-2,2- difluorocyclopropane (32g)

1H NMR: δ = 0.19 (s, 6H), 0.91 (s, 9H), 1.63–1.70 (m, 1H), 1.77–1.83 (m, 1H), 7.12 (s, 1H),

7.33–7.41 (m, 3H), 7.63 (d, J = 7.6 Hz, 2H); 13C NMR: δ = −4.1, 18.0, 25.5, 26.4 (dd, J = 10, 10 Hz),

65.6 (dd, J = 11, 11 Hz), 113.0 (dd, J = 296, 296 Hz), 121.0, 128.3, 128.8, 129.1, 133.2, 134.4; 19F

NMR: δ = 25.9 (dm, J = 152 Hz, 1F), 29.7 (dm, J = 152 Hz, 1F); IR (neat): ν = 2929, 2857, 1446,

–1 + 1218, 1004, 957, 836 cm ; HRMS (EI): m/z Calcd. for C13H14BrF2OSi [M−t-Bu] : 330.9965; Found: 330.9961.

106

3-4-2. Metal-Free Synthesis of α,α-Difluorocyclopentanone Derivatives via Regioselective Difluorocyclopropanation/VCP Rearrangement of Dienol Silyl Ethers (3-2)

Synthesis of 5,5-Difluoropent-1-en-1-yl Silyl Ethers

Typical Procedure for the synthesis of 5,5-difluorocyclopent-1-en-1-yl silyl ethers (33)

Synthesis of 33a is described as a typical procedure. The mixture of proton sponge (24, 2.3 mg,

0.011 mmol), 1,1,1,3,3,3-hexafluoro-2,2-di(p-tolyl)propane (6.2 mg, 0.019 mmol), and dienol silyl ether 31a (52 mg, 0.20 mmol) in p-xylene (2 mL) was heated to 60 °C and TFDA (60 μL, 0.30 mmol) was added dropwise over 5 min. The resulting mixture was stirred at 60 °C for 15 min. The reaction mixture was heated at 140 °C for 30 min and then cooled to room temperature. The mixture was diluted with hexane (2 mL) and a saturated aqueous solution (10 mL) of sodium hydrogen carbonate was added. Organic materials were extracted with hexane three times. The combined extracts were dried over anhydrous sodium sulfate. The sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane) to afford 5,5-difluorocyclopent-1-en-1-yl silyl ether 33a as a yellow liquid (50 mg, 80% yield).

107

Spectral Data of 5,5-Difluorocyclopent-1-en-1-yl Silyl Ethers

Spectral data of 33a, 33b, 33c, 33f, 33g, 33j, and 33k showed complete agreement with those in our previous paper.[15]

1-[tert-Butyl(dimethyl)silyloxy]-5,5-difluoro-3-[4-(trifluoromethyl)phenyl]cyclopent-1-ene (33i)

1 H NMR (400 MHz, CDCl3): δ = 0.23 (s, 3H), 0.24 (s, 3H), 0.98 (s, 9H), 2.14 (dddd, J = 17.2,

16.0, 11.6, 4.0 Hz, 1H), 2.84 (dddd, J = 16.0, 16.0, 8.4, 8.4 Hz, 1H), 3.86–3.93 (m, 1H), 5.16 (d, J =

13 2.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H); C NMR (100 MHz, CDCl3): δ =

–4.8, –4.8, 18.2, 25.5, 40.5, 41.6 (dd, J = 25, 25 Hz), 114.3 (dd, J = 7, 7 Hz), 124.1 (q, J = 270 Hz),

125.7, 125.8, 126.8 (dd, J = 243, 243 Hz), 127.4, 148.1 (d, J = 5 Hz), 149.3 (dd, J = 25, 25 Hz); 19F

NMR (376 MHz, CDCl3): δ = 99.3 (s, 1F), 69.3 (dddd, J = 249, 17, 11, 8 Hz, 1F), 64.5 (dddd, J =

249, 16, 12, 3 Hz, 1F); IR (neat): ν = 2933, 2862, 1655, 1323, 1167, 1068, 835 cm–1; HRMS (EI):

+ m/z calcd. for C14H14F5OSi [M–t-Bu] : 321.0734; Found: 321.0732.

1-[tert-Butyl(dimethyl)silyloxy]-5,5-difluoro-4-isopropyl-3-phenylcyclopent-1-ene (33d)

1 H NMR (400 MHz, CDCl3): δ = 0.20 (s, 3H), 0.21 (s, 3H), 0.86 (d, J = 6.4 Hz, 3H), 0.97 (s,

9H), 1.04 (d, J = 6.4 Hz, 3H), 2.02–2.20 (m, 2H), 3.50–3.58 (m, 1H), 5.04 (dd, J = 1.8, 1.8 Hz, 1H),

7.21 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.30 (dd, J = 7.6, 7.6 Hz, 2H); 13C NMR (100 MHz,

CDCl3): δ = –4.9, –4.8, 18.2, 20.8, 21.5, 25.5, 27.9 (d, J = 5 Hz), 46.3 (d, J = 7 Hz), 58.5 (dd, J = 19,

19 Hz), 115.9 (dd, J = 9, 9 Hz), 126.7, 127.4 (dd, J = 247, 247 Hz), 127.7, 128.6, 144.4 (d, J = 5 Hz),

19 147.6 (dd, J = 23, 23 Hz); F NMR (376 MHz, CDCl3): δ = 52.1 (ddd, J = 251, 13, 4 Hz, 1F), 70.5

(ddd, J = 251, 19, 10 Hz, 1F); IR (neat): ν = 2958, 2931, 2860, 1660, 1365, 1188, 1011, 839 cm–1;

+ HRMS (EI): m/z calcd. for C16H21F2OSi [M–t-Bu] : 295.1330; Found: 295.1329.

108

3,4-Dibutyl-1-[tert-butyl(dimethyl)silyloxy]-5,5-difluorocyclopent-1-ene (33e)

1 H NMR (400 MHz, CDCl3): δ = 0.179 (s, 3H), 0.183 (s, 3H), 0.87–0.93 (m, 6H), 0.95 (s, 9H),

1.21–1.53 (m, 12H), 1.59–1.70 (m, 1H), 1.80–1.93 (m, 1H), 5.09 (br s, 1H); 13C NMR (100 MHz,

CDCl3): δ = –4.91, –4.85, 13.9, 14.0, 18.2, 22.9 (d, J = 5 Hz), 25.5, 28.0, 28.1, 29.5, 30.0, 35.0 (d, J

= 5 Hz), 42.2 (d, J = 7 Hz), 49.3 (dd, J = 22, 22 Hz), 115.2 (dd, J = 8, 8 Hz), 127.2 (dd, J = 245, 245

19 Hz), 147.0 (dd, J = 25, 25 Hz); F NMR (376 MHz, CDCl3): δ = 53.5 (ddd, J = 3, 11, 249 Hz, 1F),

69.8 (ddd, J = 11, 20, 249 Hz, 1F); IR (neat): ν = 2958, 2929, 2860, 1660, 1363, 1186, 1012, 839

–1 + cm . HRMS (EI): m/z calcd. for C15H27F2OSi [M–t-Bu] : 289.1799; Found: 289.1799.

1-[tert-Butyl(dimethyl)silyloxy]-2-bromo-4,4-difluoro-3-phenylcyclopent-1-ene (76g)

1 H NMR (500 MHz, CDCl3): δ = 0.280 (s, 3H), 0.283 (s, 3H), 1.01 (s, 9H), 2.85 (ddd, J = 16.5,

16.5, 7.5 Hz, 1H), 2.88–2.97 (m, 1H), 4.20 (dd, J = 20.0, 4.5 Hz, 1H), 7.19–7.20 (m, 2H), 7.32–7.38

13 (m, 3H); C NMR (126 MHz, CDCl3): δ = –4.0, –3.9, 18.1, 25.5, 43.3 (dd, J = 28, 28 Hz), 60.8 (dd,

J = 28, 23 Hz), 95.6 (d, J = 3 Hz), 124.4 (dd, J = 259, 254 Hz), 128.1, 128.5, 129.1, 133.8 (dd, J = 4,

19 4 Hz), 147.2 (dd, J = 7, 4 Hz); F NMR (470 MHz, CDCl3): δ = 65.5 (dddd, J = 227, 14, 8, 5 Hz,

1F), 75.2 (dddd, J = 227, 20, 18, 15 Hz, 1F); IR (neat): ν = 2925, 2856, 1662, 1327, 1255, 1117, 912,

–1 + 839 cm ; HRMS (EI): m/z calcd. for C17H23BrF2OSi [M] : 388.0670; Found: 388.0669.

109

3-[tert-Butyl(dimethyl)silyloxy]-4,4-difluoro-6-methyl-1-phenylhepta-2,5-diene (75d)

1 H NMR (400 MHz, CDCl3): δ = 0.14 (s, 6H), 0.91 (s, 9H), 1.79 (td, J = 3.2, 1.4 Hz, 3H), 1.84

(td, J = 2.8, 1.4 Hz, 3H), 3.50–3.58 (m, 2H), 5.03 (t, J = 1.8 Hz, 1H), 5.50 (tqq, J = 13.3, 1.4, 1.4 Hz,

13 1H), 7.19–7.43 (m, 5H); C NMR (126 MHz, CDCl3): δ = –4.7, 18.0, 25.5, 26.5, 29.7, 31.6 (t, J = 4

Hz), 111.3, 118.0 (t, J = 239 Hz), 120.7 (t, J = 28 Hz), 125.9, 128.2, 128.4, 141.1, 142.7 (t, J = 7 Hz),

19 146.0 (t, J = 30 Hz); F NMR (376 MHz, CDCl3): δ = 53.5 (br d, J = 13 Hz); HRMS (EI): m/z calcd.

+ for C16H21F2OSi [M–t-Bu] : 295.1330; Found: 295.1330.

7-[tert-Butyl(dimethyl)silyloxy]-6,6-difluorotrideca-4,7-diene (75e)

1 H NMR (400 MHz, CDCl3): δ = 0.14 (s, 6H), 0.91 (s, 9H), 0.95–1.01 (m, 6H), 1.21–1.53 (m,

8H), 2.06–2.17 (m, 4H), 4.93 (t, J = 8.0 Hz, 1H), 5.60–5.71 (m, 1H), 6.10 (dtt, J = 15.6, 9.6, 2.8 Hz,

13 1H); C NMR (100 MHz, CDCl3): δ = –4.7, 13.6, 14.0, 18.1, 21.7, 22.5, 25.2, 25.6, 30.1, 31.4, 33.8,

113.9, 117.7 (t, J = 240 Hz), 124.6 (t, J = 28 Hz), 136.1 (t, J = 10 Hz), 143.9 (t, J = 30 Hz); 19F NMR

(376 MHz, CDCl3): δ = 67.8 (ddd, J = 10, 6, 3 Hz); HRMS (EI): m/z calcd. for C15H27F2OSi [M– t-Bu]+: 289.1799; Found: 289.1798.

110

3-4-3. Syntheses of Fluorinated Cyclopentenones via Regioselective Difluorocyclopropanation of Dienol Silyl Ethers (3-3)

Preparation of 1-Fluorovinyl Vinyl Ketones

Typical Procedure for the synthesis of 1-Fluorovinyl vinyl ketones (34).

A THF solution (5 mL) of vinylated difluorocyclopropane 32a (240 mg, 0.774 mmol) was added to solid TBAT (83 mg, 0.15 mmol) at room temperatute. After the reaction mixture was stirred for 1 h, CH2Cl2 (5 mL) and aqueous NaHCO3 (5 mL) were added to quench the reaction at room temperature. Organic materials were extracted with CH2Cl2 four times. Combined extracts were dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexane/AcOEt 100:1 to 50:1) to give fluorovinyl vinyl ketone 34a (104 mg,

76% yield) as colorless crystals.

Spectral Data of 1-Fluorovinyl Vinyl Ketones

Spectral data of fluorine-free ketone 82 met complete agreement with those in literature.[33,34]

3 [35] Geometry of the fluoroalkene moiety of 34 was assigned based on their JFH values.

(E)-4-Fluoro-1-phenylpenta-1,4-dien-3-one (34a)

1H NMR: δ = 5.31 (dd, J = 14.5, 3.4 Hz, 1H), 5.71 (dd, J = 45.6, 3.4 Hz, 1H), 7.24 (dd, J = 15.5,

2.0 Hz, 1H), 7.38–7.50 (m, 3H), 7.63 (dd, J = 7.5, 2.0 Hz, 2H), 7.85 (d, J = 15.5 Hz, 1H); 13C NMR:

δ = 101.0 (d, J = 15 Hz), 119.2, 128.8, 129.0, 131.2, 134.3, 146.2 (d, J = 2 Hz), 160.6 (d, J = 269 Hz),

182.9 (d, J = 31 Hz); 19F NMR: δ = 44.5 (dd, J = 46, 15 Hz); IR (neat): ν = 3130, 1660, 1640, 1610,

–1 1360, 1070, 940 cm ; EA: Calcd for C11H9FO: C 74.99%; H 5.15%. Found: C 74.72%; H 5.20%.

111

(E)-4-Fluoro-1-(4-methylphenyl)penta-1,4-dien-3-one (34b)

1H NMR: δ = 2.39 (s, 3H), 5.28 (dd, J = 14.6, 3.3 Hz, 1H), 5.69 (dd, J = 45.6, 3.3 Hz, 2H), 7.19

(dd, J = 15.7, 2.0 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 15.7 Hz,

1H); 13C NMR: δ = 21.6, 100.7 (d, J = 16 Hz), 118.2, 128.8, 129.8, 131.6, 141.9, 146.3 (d, J = 2 Hz),

160.7 (d, J = 267 Hz), 182.9 (d, J = 31 Hz); 19F NMR: δ = 44.4 (dd, J = 46, 15 Hz); IR (neat): ν =

–1 + 3130, 1660, 1599, 742 cm ; HRMS (EI): m/z Calcd. for C12H11FO [M] : 190.0794; Found: 190.0792.

(E)-1-(4-Chlorophenyl)-4-fluoropenta-1,4-dien-3-one (34c)

1H NMR: δ = 5.29 (dd, J = 14.0, 4.0 Hz, 1H), 5.69 (dd, J = 46.0, 4.0 Hz, 1H), 7.19 (dd, J = 15.6,

2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H); 13C NMR:

δ = 101.1 (d, J = 16 Hz), 119.5, 129.3, 129.9, 132.7, 137.1, 144.6, 160.4 (d, J = 268 Hz), 182.6 (d, J

= 32 Hz); 19F NMR: δ = 44.3 (dd, J = 46, 14 Hz); IR (neat): ν = 3126, 1603, 1491, 1354, 912 cm–1;

+ HRMS (EI): m/z Calcd. for C11H8ClFO [M] : 210.0248; Found: 210.0245.

112

(1E,4Z)-4-Fluoro-6-methyl-1-phenylhepta-1,4-dien-3-one (34d)

1H NMR: δ = 1.11 (d, J = 6.7 Hz, 6H), 2.87–2.97 (m, 1H), 6.04 (dd, J = 35.1, 9.8 Hz, 1H), 7.23

(dd, J = 15.6, 2.0 Hz, 1H), 7.36– 7.44 (m, 3H), 7.61 (br d, J = 4.2 Hz, 2H), 7.80 (d, J = 15.6 Hz, 1H);

13C NMR: δ = 22.1 (d, J = 2 Hz), 24.7 (d, J = 3 Hz), 119.6, 126.4 (d, J = 12 Hz), 129.0, 128.6, 130.9,

134.5, 145.2 (d, J = 2 Hz), 154.4 (d, J = 261 Hz), 183.0 (d, J = 30 Hz); 19F NMR: δ = 31.0 (d, J = 35

–1 Hz); IR (neat): ν = 2964, 1646, 1606, 1334, 1205, 763 cm ; EA: Calcd for C14H15FO: C 77.04%; H 6.93%. Found: C 76.84%; H 6.93%.

(5Z,8E)-6-Fluorotrideca-5,8-dien-7-one ((Z)-34e)

1H NMR: δ = 0.92 (t, J = 7.2 Hz, 6H), 1.32–1.51 (m, 8H), 2.24– 2.31 (m, 4H), 6.09 (dt, J = 34.5,

7.9 Hz, 1H), 6.58 (dm, J = 15.3 Hz, 1H), 7.09 (dt, J = 15.3, 7.6 Hz, 1H); 13C NMR: δ = 13.76, 13.84,

22.30, 22.34, 24.8 (d, J = 4 Hz), 30.1, 30.5, 32.5, 120.1 (d, J = 12 Hz), 123.5, 150.7 (d, J = 2 Hz),

155.8 (d, J = 260 H), 182.9 (d, J = 30 Hz); 19F NMR: δ = 31.7 (d, J = 35 Hz); IR (neat): ν = 2958,

–1 + 2861, 1654, 1621, 1303, 983 cm ; HRMS (EI): m/z Calcd. for C13H21FO [M] : 212.1576; Found: 212.1563.

113

(5E,8E)-6-Fluorotrideca-5,8-dien-7-one ((E)-34e)

1H NMR: δ = 0.91 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H), 1.16–1.51 (m, 8H), 2.26 (dt, J =

7.2, 7.2 Hz, 2H), 2.53 (dt, J = 8.0, 7.2 Hz, 2H), 5.77 (dt, J = 22.8, 8.0 Hz, 1H), 6.58 (dm, J = 15.2 Hz,

1H), 7.06 (dt, J = 15.2, 7.2 Hz, 1H); 13C NMR: δ = 13.9, 22.3, 22.4, 25.19, 25.25, 30.2, 31.6, 32.5,

122.5 (d, J = 17 Hz), 125.2, 150.6 (d, J = 2 Hz), 153.7 (d, J = 257 Hz), 185.2 (d, J = 36 Hz); 19F

NMR: δ = 39.6 (dd, J = 23, 3 Hz); IR (neat): ν = 2929, 1641, 1616, 1362, 1219, 771 cm–1; HRMS

+ (EI): m/z Calcd. for C13H21FO [M] : 212.1576; Found: 212.1570.

(E)-4-Fluoro-2-methyl-1-phenylpenta-1,4-dien-3-one (34f)

1H NMR: δ = 2.16 (s, 3H), 5.38 (dd, J = 15.5, 3.5 Hz, 1H), 5.47 (dd, J = 46.0, 3.5 Hz, 1H), 7.34–

7.45 (m, 5H), 7.43 (s, 1H); 13C NMR: δ = 14.0, 102.4 (d, J = 17 Hz), 128.5, 128.9, 129.8, 135.1,

135.3, 141.4 (d, J = 5 Hz), 159.8 (d, J = 268 Hz), 189.5 (d, J = 28 Hz); 19F NMR: δ = 54.6 (dd, J =

–1 46, 16 Hz); IR (neat): ν = 3055, 1655, 1618, 1178, 1041 cm ; HRMS (EI): m/z Calcd. for C12H11FO [M]+: 190.0794; Found: 176.0793.

114

(Z)-2-Bromo-4-fluoro-1-phenylpenta-1,4-dien-3-one (34g)

1H NMR: δ = 5.47 (dd, J = 14.8, 4.0 Hz, 1H), 5.63 (dd, J = 45.2, 4.0 Hz, 1H), 7.50–5.59 (m, 3H),

7.85–7.88 (m, 2H), 7.93 (s, 1H); 13C NMR: δ = 104.3 (d, J = 16 Hz), 119.6, 128.5, 130.4, 130.8,

133.2, 142.7 (d, J = 7 Hz), 158.1 (d, J = 268 Hz), 182.2 (d, J = 31 Hz); 19F NMR: δ = 52.8 (dd, J =

45, 15 Hz); IR (neat): ν = 3032, 1672, 1595, 1219, 1122, 688 cm–1; HRMS (EI): m/z Calcd. for

+ C11H8BrFO [M] : 253.9743; Found: 253.9741.

(Z)-Cyclohex-1-en-1-yl 1-fluorobut-1-en-1-yl ketone (34l)[34]

1H NMR: δ = 1.08 (t, J = 7.6 Hz, 3H), 1.61–1.71 (m, 4H), 2.22– 2.31 (m, 6H), 5.87 (dt, J = 34.8,

7.6 Hz, 1H), 6.79 (td, J = 3.8, 1.6 Hz, 1H); 13C NMR: δ = 13.2, 17.9 (d, J = 5 Hz), 21.5, 21.9, 24.0,

26.0, 122.6 (d, J = 13 Hz), 137.4, 141.6 (d, J = 6 Hz), 155.7 (d, J = 262 Hz), 188.5 (d, J = 27 Hz); 19F

NMR: δ = 37.6 (dd, J = 35, 2 Hz); IR (neat): ν = 2937, 1655, 1649, 1381, 1282, 977 cm–1; EA: Calcd for C11H15FO: C 72.50%; H 8.30%. Found: C 72.21%; H 8.33%.

115

(1E,4Z)-4-Fluoro-1-phenylhepta-1,4-dien-3-one (34m)[34]

1H NMR: δ = 1.11 (t, J = 7.6 Hz, 3H), 2.33 (ddq, J = 7.6, 7.6, 2.1 Hz, 2H), 6.18 (dt, J = 34.7, 7.8

Hz, 1H), 7.23 (dd, J = 15.8, 2.1 Hz, 1H), 7.38–7.43 (m, 3H), 7.58–7.64 (m, 2H), 7.80 (d, J = 15.8 Hz,

1H); 13C NMR: δ = 13.0 (d, J = 2 Hz), 17.9 (d, J = 4 Hz), 119.6, 121.4 (d, J = 13 Hz), 128.6, 128.9,

130.8, 134.5, 145.1 (d, J = 2 Hz), 155.5 (d, J = 260 Hz), 182.7 (d, J = 31 Hz); 19F NMR: δ = 31.3 (d,

J = 35 Hz); IR (neat): ν = 2960, 1650, 1600, 1570, 1450, 1330, 1200, 1010, 760 cm–1; EA: Calcd for

C13H13FO: C 76.45%; H 6.42%. Found: C 76.32%; H 6.48%; HRMS (EI): m/z Calcd. for C13H13FO [M]+: 204.0950; Found: 204.0959.

116

Synthesis of Fluorinated Cyclopentenones

Typical Procedure for the synthesis of 1-fluorocyclopentenones (35).

A CH2Cl2 solution (4 mL) of fluorovinyl vinyl ketone 34a (101 mg, 0.573 mmol) was added to a CH2Cl2 solution (2 mL) of Me3Si B(OTf)4 (0.29 mol/L, 0.57 mmol) at room temperature. After the reaction mixture was stirred for 1 h, aqueous NaHCO3 (4 mL) was added to quench the reaction at room temperature. Organic materials were extracted with CH2Cl2 three times. Combined extracts were washed with aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by PTLC (SiO2, hexane/AcOEt 5:1) to give fluorocyclopentenone

35a (52 mg, 51% yield) as a colorless oil.

Synthesis of defluorinated cyclopentenones 81

Me3SiOTf (54.0 μL, 0.30 mmol) was added to a HFIP/CH2Cl2 solution (4 mL, 1:1) of fluorovinyl viny ketone 34f (55 mg, 0.30 mmol) at 0 °C. After the reaction mixture was stirred for 15 min, aqueous NaHCO3 (3 mL) was added to quench the reaction at 0 °C. Organic materials were extracted with CH2Cl2 three times. Combined extracts were washed with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by PTLC

(SiO2, hexane/AcOEt 5:1 to 1:1) to give hydroxycyclopentenone 81f (38 mg, 68% yield) as a pale yellow oil.

117

Spectral Data of Fluorinated Cyclopentenones

2-Fluoro-4-phenylcyclopent-2-en-1-one (35a)

1H NMR: δ = 2.40 (dd, J = 19.4, 1.8 Hz, 1H), 2.99 (dd, J = 19.4, 6.4 Hz, 1H), 4.03–4.09 (m, 1H),

7.00 (d, J = 2.8 Hz, 1H), 7.18 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.36 (dd, J = 7.3, 7.3 Hz,

2H); 13C NMR: δ = 38.7 (d, J = 6 Hz), 42.5 (d, J = 4 Hz), 126.9, 127.6, 129.1, 138.8 (d, J = 6 Hz),

140.9 (d, J = 2 Hz), 158.8 (d, J = 284 Hz), 198.3 (d, J = 19 Hz); 19F NMR: δ = 23.1 (d, J = 6 Hz); IR

–1 (neat): ν = 2929, 1732, 1648, 1340, 1078, 765, 701 cm ; EA: Calcd for C11H9FO: C 74.99%; H 5.15%. Found: C 74.91%; H 5.19%.

2-Fluoro-4-(4-methylphenyl)cyclopent-2-en-1-one (35b)

1H NMR: δ = 2.34 (s, 3H), 2.37 (dd, J = 19.3, 1.9 Hz, 1H), 2.97 (dd, J = 19.3, 6.6 Hz, 1H), 4.00–4.06 (m, 1H), 6.97 (d, J = 3.0 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H); 13C

NMR: δ = 21.0, 38.3 (d, J = 5 Hz), 42.6 (d, J = 5 Hz), 126.8, 129.7, 137.3, 137.9 (d, J = 2 Hz), 139.1

(d, J = 5 Hz), 158.7 (d, J = 283 Hz), 198.5 (d, J = 19 Hz); 19F NMR: δ = 22.8 (d, J = 6 Hz); IR (neat):

–1 + ν = 3020, 1730, 1217, 771, 746 cm ; HRMS (EI): m/z Calcd. for C12H11FO [M] : 190.0794; Found: 190.0794.

118

4-(4-Chlorophenyl)-2-fluorocyclopent-2-en-1-one (35c)

1H NMR: δ = 2.34 (dd, J = 19.4, 1.9 Hz, 1H), 2.99 (dd, J = 19.4, 6.7 Hz, 1H), 4.02–4.09 (m, 1H),

6.97 (d, J = 3.0 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H); 13C NMR: δ = 38.1 (d, J

= 5 Hz), 42.3 (d, J = 4 Hz), 128.3, 129.3, 133.5, 138.2 (d, J = 6 Hz), 139.4 (d, J = 2 Hz), 159.0 (d, J

= 284 Hz), 197.8 (d, J = 19 Hz); 19F NMR: δ = 23.8 (d, J = 6 Hz); IR (neat): ν = 3020, 1734, 1219,

–1 + 781, 762 cm ; HRMS (EI): m/z Calcd. for C11H8ClFO [M] : 210.0248; Found: 210.0249.

2-Fluoro-3-isopropyl-4-phenylcyclopent-2-en-1-one (35d)

1H NMR: δ = 1.05 (d, J = 7.0 Hz, 3H), 1.12 (dd, J = 7.0, 1.5 Hz, 3H), 2.35 (d, J = 19.0 Hz, 1H),

2.48 (sept, J = 7.0 Hz, 1H), 2.90 (dd, J = 19.0, 7.0 Hz, 1H), 3.91–3.96 (m, 1H), 7.17 (d, J = 7.3 Hz,

2H), 7.25–7.31 (m, 1H), 7.34 (d, J = 7.3 Hz, 2H); 13C NMR: δ = 19.7 (d, J = 3 Hz), 20.6 (d, J = 2

Hz), 28.4 (d, J = 2 Hz), 41.9 (d, J = 6 Hz), 42.3 (d, J = 4 Hz), 127.4, 127.6, 129.0, 140.8 (d, J = 2 Hz),

154.9 (d, J = 277 Hz), 160.3, 198.0 (d, J = 20 Hz); 19F NMR: δ = 19.4 (d, J = 5 Hz); IR (neat): ν =

–1 + 2971, 1724, 1658, 1456, 1315, 1070, 701 cm ; HRMS (EI): m/z Calcd. for C14H15FO [M] : 218.1107; Found: 218.1087.

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3,4-Dibutyl-2-fluorocyclopent-2-en-1-one (35e)

1H NMR: δ = 0.92 (t, J = 7.3 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H), 1.18–1.44 (m, 7H), 1.44–1.54

(m, 1H), 1.54–1.64 (m, 1H), 1.73– 1.82 (m, 1H), 2.09 (d, J = 18.9 Hz, 1H), 2.19–2.28 (m, 1H), 2.54

(dd, J = 18.9, 6.0 Hz, 1H), 2.53–2.62 (m, 1H), 2.69–2.75 (m, 1H); 13C NMR: δ = 13.7, 14.0, 22.7,

22.8, 28.7, 28.8, 28.9, 32.3, 38.3 (d, J = 2 Hz), 40.0, 154.8 (d, J = 275 Hz), 157.3 (d, J = 3 Hz), 197.6

(d, J = 19 Hz); 19F NMR: δ = 16.3 (d, J = 5 Hz); IR (neat): ν = 2937, 1656, 1386, 1282, 1164, 896

–1 + cm ; HRMS (EI): m/z Calcd. for C13H21FO [M] : 212.1576; Found: 212.1563.

9-Ethyl-8-fluorobicyclo[4.3.0]non-8-en-7-one (35l)

1H NMR: δ = 1.19 (t, J = 7.6 Hz, 3H), 1.28–1.46 (m, 3H), 1.50– 1.62 (m, 2H), 1.64–1.75 (m,

1H), 1.92 (dtd, J = 12.6, 6.2, 6.2 Hz, 1H), 1.98–2.05 (m, 1H), 2.26 (ddd, J = 15.2, 7.6, 2.1 Hz, 1H),

2.46 (dd, J = 12.5, 6.4 Hz, 1H), 2.60 (dq, J = 15.2, 7.6 Hz, 1H), 2.79–2.86 (m, 1H); 13C NMR: δ =

11.1 (d, J = 2 Hz), 19.6, 20.8, 21.0, 22.4, 27.2 (d, J = 3 Hz), 36.0 (d, J = 4 Hz), 43.4 (d, J = 5 Hz),

154.1 (d, J = 277 Hz), 157.6 (d, J = 3 Hz), 200.4 (d, J = 17 Hz); 19F NMR: δ = 14.0 (d, J = 4 Hz); IR

(neat): ν = 2962, 2933, 2875, 1722, 1688, 1461, 1380, 1355, 1116, 1022 cm–1; HRMS (EI): m/z Calcd.

+ for C11H15FO [M] : 182.1107; Found: 182.1115.

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3-Ethyl-2-fluoro-4-phenylcyclopent-2-en-1-one (35m)

1H NMR: δ = 1.05 (t, J = 7.6 Hz, 3H), 1.96–2.06 (m, 1H), 2.36 (d, J = 19.0 Hz, 1H), 2.47 (dq, J

= 15.2, 7.6 Hz, 1H), 2.92 (dd, J = 19.0, 6.7 Hz, 1H), 3.92 (dd, J = 6.1, 6.1 Hz, 1H), 7.15 (d, J = 7.3

Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.35 (dd, J = 7.3 Hz, 2H); 13C NMR: δ = 10.9 (d, J = 2 Hz), 19.9,

41.6 (d, J = 5 Hz), 42.1 (d, J = 4 Hz), 127.2, 127.5, 129.1, 140.3 (d, J = 2 Hz), 155.0 (d, J = 277 Hz),

156.9 (d, J = 4 Hz), 197.5 (d, J = 19 Hz); 19F NMR: δ = 16.8 (d, J = 5 Hz); IR (neat): ν = 2970, 1720,

–1 1665, 1360, 1110, 1060, 700 cm ; EA: Calcd for C13H13FO: C 76.45%; H 6.42%. Found: C 76.22%; H 6.46%.

121

3-5. Reference

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M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165; Baldwin, J. E.

Chem. Rev. 2003, 103, 1197–1212. [7] Hudlicky, T., Short, R. P. J. Org. Chem. 1982, 47, 1522. [8] Orr, D.; Percy, J. M.; Tuttle, T.; Kennedy, A. R.; Harrison, Z. A. Chem. Eur. J. 2014, 20, 14305. [9] Bent, H. A. Chem. Rev. 1961, 61, 275. [10] Nakamura, E.; Kubota, K.; Isaka, M. J. Org. Chem. 1992, 57, 5809. [11] Dolbier, W. R., Jr.; Sellers, S. F. J. Org. Chem. 1982, 47, 1. [12] Han, C.; Salyer, A. E.; Kim, E. H.; Jiang, X.; Jarrard, R. E.; Powers, M. S.; Kirchhoff, A. M.;

Salvador, T. K.; Chester, J. A.; Hockerman, G. H.; Colby, D. A. J. Med. Chem. 2013, 56, 2456.

[13] Fäh, C.; Hardegger, L. A.; Baitsch, L.; Schweizer, W. B.; Meyer, S.; Bur, D.; Diederich, F. Org.

Biomol. Chem. 2009, 7, 3947.

[14] Baudoux, J.; Cahard, D. Org. React. 2007, 69, 347; Nakano, T.; Makino, M.; Morizawa, Y.;

Matsumura, Y. Angew. Chem., Int. Ed. Engl. 1996, 35, 1019; Pravst, I.; Zupan, M.; Stavber, S.

Synthesis 2005, 2005, 3140; Meegalla, S. K.; Doller, D.; Liu, R.; Sha, D.; Lee, Y.; Soll, R. M.;

Wisnewski, N.; Silver, G. M.; Dhanoa, D. Bioorg. Med. Chem. Lett. 2006, 16, 1702.

[15] Aono, T.; Sasagawa, H.; Fuchibe, K.; Ichikawa, J. Org. Lett. 2015, 17, 5736–5739.

122

[16] Independently, ammonium bromide-catalyzed synthesis of α,α-difluorocyclopentanones with

(bromodifluoromethyl)trimethylsilane was conducted during the same period. See: Chang, J.;

Xu, C.; Gao, J.; Gao, F.; Zhu, D.; Wang, M. Org. Lett. 2017, 19, 1850.

[17] Fuchibe, K.; Aono, T.; Hu, J.; Ichikawa, J. Org. Lett. 2016, 18, 4502.

[18] Strunz, G. M.; Court, A. S.; Komlossy, J.; Stillwell, M. A. Can. J. Chem. 1969, 47, 2087. [19] Noble, M.; Noble, D.; Fletton, R. A. J. Antibiot. 1978, 31, 15. [20] Hirata, Y.; Hayashi, H.; Ito, S.; Kikawa, Y.; Ishibashi, M.; Sudo, M.; Miyazaki, H.; Fukushima,

M.; Narumiya, S.; Hayaishi, O. J. Biol. Chem. 1988, 263, 16619. Review: Straus, D. S.; Glass,

C. K. Med. Res. Rev. 2001, 21, 185.

[21] Iguchi, K.; Kaneta, S.; Tsune, C.; Yamada, Y. Chem. Pharm. Bull. 1989, 37, 1173.

[22] Nazarov, I. N.; Zaretskaya, I. I. Zh. Obshch. Chim. 1957, 27, 693. Review: Santelli-Rouvier, C.; Santelli, M. Synthesis 1983, 429; Pellissier, H. Tetrahedron 2005, 61, 6479. [23] Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642. [24] Peel, M. R.; Johnson, C. R. Tetrahedoron Lett. 1986, 27, 5947. [25] He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125, 14278. [26] Ichikawa, J. J. Org. Chem. 1995, 60, 2320 [27] Ichikawa, J. Synlett. 1998, 927. [28] Davis, A. P.; Jaspars, M. Angew. Chem. Int. Ed. Engl. 1992, 31, 470; Angew. Chem. 1992, 104,

475.

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123

[33] Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130, 4978. [34] 1-Fluorovinyl ketones 34l,m and fluorine-free vinyl ketone 82 were prepared according to the literature: Satoh, T.; Itoh, N.; Yamakawa, K. Bull. Chem. Soc. Jpn. 1992, 65, 2800. [35] Blanco, L.; Rousseau, G. Bull. Chem. Soc. Fr. 1985, 455.

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Chapter 4. Conclusions

It was found that 1,8-bis(dimethylamino)naphthalene (proton sponge™) efficiently activated trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) at lower temperatures and under nearly neutral conditions to generate difluorocarbene. On the basis of this finding, the following regioselective reactions were facilitated.

In chapter 2, the sulfur-selective difluoromethylation of thioamides was achieved. When thioamides were treated with TFDA in the presence of a proton sponge catalyst, difluoromethylation proceeded selectively on the sulfur atoms to afford S-difluoromethyl thioimidates in good yields.

Isomerization from S-difluoromethylated products to N-difluoromethylated products, which were observed under the conventional, thermal generation of difluorocarbene, was completely suppressed.

Furthermore, in chapter 2, the efficient synthesis of sulfanylated 1,1-difluoroalkenes was achieved. Treatment of dithioesters with TFDA in the presence of a proton sponge catalyst afforded

2-sulfanyl-1,1-difluoro-1-alkenes in good yields. The reaction of dithioesters with difluorocarbene forms difluorinated thiirane intermediates, which in turn undergo desulfurization to afford the sulfanylated difluoroalkenes.

In chapter 3, the regioselective reactions on carbon atoms were developed. Most importantly, dienol silyl ethers underwent the regioselective difluorocyclopropanation at the electron-rich alkene moiety at lower temperatures to allow the preparation of thermally less stable 1,1-difluoro-2-siloxy-

2-vinylcyclopropanes.

Using the vinylated difluorocyclopropanes, the metal-free synthesis of 5,5-difluorocyclopent-1- en-1-yl silyl ethers via regioselective ring-expansion was developed. When the obtained vinylated difluorocyclopropanes were heated to 140 °C, [3 + 2] type thermal ring-expansion (VCP rearrangement) proceeded regioselectively to afford 5,5-difluorocyclopent-1-en-1-yl silyl ethers. The key to achieve the regioselective ring-expansion of the vinylated difluorocyclopropanes is the C–C bond elongation at the position distal to the CF2 moiety, which is caused by the electron-withdrawing effect of fluorine substituents. 5,5-Difluorocyclopent-1-en-1-yl silyl ethers are promising synthetic

125 intermediates for fluorine-containing cyclopentanone derivatives

Using the vinylated difluorocyclopropanes, in addition, the regioselective Nazarov cyclization utilizing the α-cation stabilizing effect of fluorine was achieved. When the above-obtained vinylated difluorocyclopropanes were treated with a catalytic amount of fluoride ion, ring opening proceeded to give 1-fluorovinyl vinyl ketones. Treatment of the 1-fluorovinyl vinyl ketones with Me3Si B(OTf)4 promoted the regioselective Nazarov cyclization to give 2-fluorocyclopent-2-en-1-ones in good yields. The theoretical calculations suggested that the position of the formed double bond was controlled by the +R effect of fluorine (fluorine-directed Nazarov cyclization). In addition, the reaction was also accelerated by the +R effect of fluorine (fluorine-activated Nazarov cyclization).

In this doctoral thesis, I achieved the regioselective reactions (regioselective difluoromethylation of thioamides and regioselective difluorocyclopropanation of dienol silyl ethers) using proton sponge as an effective organocatalyst for difluorocarbene generation. Regio- and stereoselective synthesis of difluorinated cyclopentenyl silyl ethers and regioselective synthesis of fluorinated cyclopentenones were also developed utilizing the obtained vinylated difluorocyclopropanes. These results contribute to the efficient synthesis of difluoromethylene and difluoromethylidene which are important in the fields of pharmaceuticals and agrochemicals.

126

Publication Lists

1. Fuchibe, K.; Bando, M.; Takayama, R.; Ichikawa, J. “Organocatalytic, Difluorocarbene-

Based S-Difluoromethylation of Thiocarbonyl Compounds” J. Fluorine Chem. 2015, 171, 133–

138.

2. Takayama, R.; Yamada, A.; Fuchibe, K.; Ichikawa, J. “Synthesis of Sulfanylated

Difluoroalkenes: Electrophilic Difluoromethylidenation of Dithioesters with

Difluorocarbene” Org. Lett. 2017, 19, 5050–5053.

3. Takayama, R.; Fuchibe, K.; Ichikawa, J. “Metal-Free Synthesis of α,α-Difluorocyclopentanone

Derivatives via Regioselective Difluorocyclopropanation/VCP Rearrangement of Silyl Dienol

Ethers” ARKIVOC. 2018, ii, 72–80.

4. Fuchibe, K.; Takayama, R.; Yokoyama, T.; Ichikawa, J. “Regioselective Synthesis of α-

Fluorinated Cyclopentenones via Organocatalytic Difluorocyclopropanation and Fluorine-

Directed and -Activated Nazarov Cyclization” Chem. Eur. J. 2017, 23, 2831–2838.

5. Fuchibe, K.; Takayama, R.; Aono, T.; Hu, J.; Hidano, T.; Sasagawa, H.; Fujiwara, M.; Miyazaki,

S.; Nadano, R.; Ichikawa, J. “Regioselective Syntheses of Fluorinated Cyclopentanone

Derivatives: Ring Construction Strategy Using Transition Metal and Free

Difluorocarbene” Synthesis 2018, 50, 514.

127

Acknowledgements

The studies described in this thesis have been performed under the direction of Professor Junji

Ichikawa at the Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, from April 2012 to March 2018.

The author is deeply grateful to Professor Junji Ichikawa for his helpful discussions, experimental guidance, hearty advice, contribution to revising the author’s manuscripts, and encouragement throughout the course of the studies. He would like to express his deep gratitude to

Associate Professor Kohei Fuchibe for the helpful discussion, experimental guidance, and contribution to revising the author’s manuscript. He is deeply grateful to Dr. Takeshi Fujita for his practical guidance, helpful discussions, and considerate suggestions.

The author wishes to thank the member of Ichikawa laboratory. Dr. Tatsuya Aono, Dr. Tomohiro

Ichitsuka, Dr. Ikko Takahashi, Dr. Naoto Suzuki, and Mr. Masaki Bando are appreciated for their technical advices and helpful suggestions. Mr. Keisuke Watanabe, Mr. Atsushi Yamada, and Mr.

Kosei Hachinohe are acknowledged for helpful suggestions and kind assistance. Mr. Ryo Kinoshita,

Mr. Kento Shigeno, Mr. Hibiki Hatta, Mr. Ji Hu, Mr. Yota Watabe, Mr. Shunpei Watanabe, Jingchen

Wang, and Tomohiro Hidano are acknowledged for their continuous encouragement and kind assistance.

Finally, the author wishes to express his deep gratitude to his parents and brother, Mr. Hisakiyo

Takayama, Ms. Masami Takayama, and Mr. Kazuaki Takayama for their financial support or continuous and heart-worming encouragement through the research.

Ryo Takayama

128