Development of Methods for Regioselective Introduction of ... · electrophilic fluorinating agents...
Transcript of Development of Methods for Regioselective Introduction of ... · electrophilic fluorinating agents...
1
Development of Methods for Regioselective Introduction
of Difluoromethylene Unit Using Difluorocarbene
Ryo Takayama
February 2018
2
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
3
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
4
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
5
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
6
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
7
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]
8
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]
9
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,
eq. 12).[15] 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
10
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
11
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)
12
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
13
applied to various alkenes in the presence of a catalytic amount of tetraammonium bromide (TBAB)
(eq. 22).[38] 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.
14
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
15
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.
16
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.
17
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
18
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,
19
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.
20
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
vinyl ketones 34 were obtained in 53–77% yields. Next, when Me3Si B(OTf)4[43] 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
21
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.
Reference
[1] Tsuji, T.;Satoh, H.;Narisada, M.; Hamashima, Y.; Yoshida, T. J. Antibiot. 1985, 38, 466. [2] Messaoudi, S.; Tréguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; De Losada, J. R.; Liu, J.-M.;
Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. J. Med. Chem.
2009, 52, 4538.
[3] Fäh, C.; Hardegger, L. A.; Baitsch, L.; Schweizer, W. B.; Meyer, S.; Bur, D.; Diederich, F. Org.
Biomol. Chem. 2009, 7, 3947.
[4] Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986, 27, 4465.
[5] Banks, R. E.; Lawrence, N. J.; Popplewewel, A. L. J. Chem. Soc. Chem. Commun. 1994, 343.
[6] Differding, E.; Ofner, H. Synlett 1991, 187.
[7] Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A. J. Org. Chem.
1979, 44, 3872.
[8] Liotta, C. L.; Harris, H. P. J. Am. Chem. Soc. 1974, 96, 2250.
[9] Shiuey, S.-J.; Partridge, J. J.; Uskokovic, M. R. J. Org. Chem. 1988, 53, 1040.
[10] Joñczyk, A.; Nawrot, E.; Kisielewski, M. J. Fluorine Chem. 2005, 126, 1587.
[11] Pracash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863.
[12] Stahly, G. P. J. Fluorine Chem. 1989, 43, 53.
[13] Gonzalez, J.; Foti, C. J.; Elsheimer, S. J. Org. Chem. 1991, 56, 4322.
[14] Hallinan, E. A.; Fried, J. Tetrahedron Lett. 1984, 25, 2301.
[15] Ichikawa, J.; Hamada, S; Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1992, 33, 337.
[16] Bégué, J.-P.; Bonnet-Delpon, D.; Rock, M. H. Tetrahedron Lett. 1995, 36, 5003.
[17] Amii, H.; Kobayashi, T.; Terasawa, H.; Uneyama, K. Org. Lett. 2001, 3, 3103.
22
[18] Miller, T. G.; Thanassi, J. W. J. Org. Chem. 1960, 25, 2009.
[19] Dolbier, W. R., Jr.; Wojtowicz, H.; Burkholder, C. R. J. Org. Chem. 1990, 55, 5420.
[20] Seyferth, D.; Hopper, S. P.; Darragh, K. V. J. Am. Chem. Soc. 1969, 91, 6536.
[21] Millauer, H.; Schwertfeger, W.; Siegemund, G. Angew. Chem. Int. Ed. Engl. 1985, 24, 161.
[22] Weaton, G. A.; Burton, D. J. J. Fluorine Chem. 1976, 8, 97.
[23] Chen, Q.; Wu, S. J. Org. Chem. 1989, 54, 3023.
[24] Zhang, W.; Wang, F. Hu, J. Org. Lett. 2009, 11, 2109.
[25] Wang, F.; Huang, W.; Hu, J.; Chin. J. Chem. 2011, 29, 2717.
[26] Fier, P. S.; Hartwig, J. F. Angew. Chem. Int. Ed. 2013, 52, 2092.
[27] Thomoson, C. S.; Dolbier, W. R., Jr. J. Org. Chem. 2013, 78, 8904.
[28] Chen, Q.; Zhu, S. Sci. Sin., Ser. B (Engl. Ed.) 1986, 30, 561.
[29] Zhang, L.; Zheng, J.; Hu, J. J. Org. Chem. 2006, 71, 9845.
[30] Dolbier, W. R., Jr.; Tian, F.; Duan, J. X. J. Fluorine Chem. 2004, 125, 459. See also; Tian, F.;
Kruger, V.; Bautista, O.; Duan, J. X.; Li, A.-R.; Dolbier, W. R., Jr.; Chen, Q. Y. Org. Lett. 2000,
2, 563; Xu, W.; Chen, Q. Y. J. Org. Chem. 2002, 67, 9421; Dolbier, W. R., Jr.; Tian, F.; Duan,
J. X.; Chen, Q. Y. Org. Synth. 2003, 80, 172; Cai, X.; Zhai, Y.; Ghiviriga, I.; Abboud, K. A.;
Dolbier, W. R., Jr. J. Org. Chem. 2004, 69, 4210.
[31] Wang, F.; Zhang, W.; Zhu, J.; Li, H.; Huang, K.-W.; Hu, J. Chem. Commun. 2011, 47, 2411.
[32] Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.; Prakash, G. K.
S.; Olah, G. A. Angew. Chem. Int. Ed. 2011, 50, 7153.
[33] Zafrani, Y.; Sod-Moriah, G.; Segall, Y. Tetrahedron 2009, 65, 5278.
[34] Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel, H.-J. Chem. Commun. 2007,
5149.
[35] Yang, Y.; Lu, X.; Liu, G.; Tokunaga, E.; Shibata, N. ChemistryOpen 2012, 1, 221.
[36] Oshiro, K.; Morimoto, Y.; Amii, H. Synthesis 2010, 2080.
[37] Zheng, J.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Chem. Eur. J. 2013, 19, 15261.
[38] Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem. Int. Ed. 2013, 52, 12390.
23
[39] Cai, X.; Zhai, Y.; Ghiviriga, I.; Abboud, K. A.; Dolbier, W. R., Jr. J. Org. Chem. 2004, 69, 4210.
[40] Fuchibe, K.; Koseki, Y.; Sasagawa, H.; Ichikawa, J. Chem. Lett. 2011, 40, 1189.
[41] Comprehensive Organic Name Reactions and Reagents; Wang, Z., Ed.; Wiley: Hoboken, 1999;
pp 249−253. Original Papers: Barton, D. H. R.; Willis, B. J. J. Chem. Soc. D 1970, 1225; Barton,
D. H. R.; Smith, E. H.; Willis, B. J. J. Chem. Soc. D 1970, 1226; Kellogg, R. M.; Wassenaar, S.
Tetrahedron Lett. 1970, 11, 1987. See also: Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J.
Am. Chem. Soc. 1990, 112, 2003; Honda, T.; Ishige, H.; Araki, J.; Akimoto, S.; Hirayama, K.;
Tsubuki, M. Tetrahedron 1992, 48, 79. [42] Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247; Wong, H. N. C.; Hon, 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.
[43] Davis, A. P.; Jaspars, M. Angew. Chem. Int. Ed. Engl. 1992, 31, 470; Angew. Chem. 1992, 104,
475.
24
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.
25
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
aromatic thiols with difluorocarbene was also achieved by Dolbier (precursor: HCF3),[9] Hu
(PhS(O)(NTs)CF2H),[10] and Segall (PO(OEt)2CF2Br).[11]
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.
26
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]
27
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).
28
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
29
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%
30
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
cm1 (C=N stretching).[15] Thioamide 45 exhibits its 13C NMR signal at 203 ppm (C=S) and an IR
absorption signal at 1247 cm1 (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.
31
Table 4. Selective Synthesis of S-Difluoromethyl Thioimidates.
32
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.
33
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
TFDA in benzene-d6 for 2 h at RT, and then 1H 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.
34
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.
35
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
36
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]
37
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.
38
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.
39
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
40
reactions[28] and (ii) the β-fluorine eliminations from trifluoromethyl compounds[29] as well as (iii)
their SN2′-type[30] and SN1′-type reactions.[31]
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
41
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
42
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).
43
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
44
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.
45
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
46
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.
47
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]
48
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.
49
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
spectrometer in CDCl3 at 500 or 400 MHz (1H NMR), at 126 or 100 MHz (13C NMR), and at 470 or
376 MHz (19F NMR). Chemical shifts were given in ppm relative to internal Me4Si (for 1H NMR: δ
= 0.00), CDCl3 (for 13C NMR: δ = 77.0), and C6F6 (for 19F 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-
50
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).
51
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).
52
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
major isomer: 1H 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,
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; 19F =
NMR (470 MHz, CDCl3): δ = 61.3 (d, J = 56 Hz); IR (neat): ν = 2931, 1628, 1596, 1448, 970 cm–1;
HRMS (EI): m/z calcd. for C14H17F2NS [M]+: 269.1050; found: 269.1050.
Characteristic 1H and 19F NMR signals of the minor isomer: 1H NMR (500 MHz, CDCl3): δ =
6.93 (t, J = 55.2 Hz); 19F 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
major isomer: 1H NMR (500 MHz, CDCl3): δ = 2.06 (s, 3H), 6.76 (d, J = 8.1 Hz, 2H), 7.11 (t, J = 8.1
Hz, 1H), 7.33 (t, J = 8.1 Hz, 2H), 7.68 (t, J = 55.4 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ = 21.7,
119.8, 120.2 (t, J = 270 Hz), 124.2, 129.1, 148.8, 162.1; 19F NMR (470 MHz, CDCl3): δ = 60.9 (d, J
= 55 Hz); IR (neat): ν = 2870, 1645, 1487, 1138, 1068 cm–1; 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).
53
S-Difluoromethyl N-(p-chlorophenyl)ethanethioimidate (26e)
The product 26e was obtained as an inseparable diastereomeric mixture. Spectral data of the
major isomer: 1H NMR (500 MHz, CDCl3): δ = 2.06 (s, 3H), 6.70 (d, J = 8.6 Hz, 2H), 7.29 (d, J =
8.6 Hz, 2H), 7.64 (t, J = 55.4 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ = 21.7, 120.0 (t, J = 270 Hz),
121.2, 129.2, 129.3, 147.2, 163.2; 19F NMR (470 MHz, CDCl3): δ = 60.9 (d, J = 55 Hz); IR (neat): ν
= 2951, 1645, 1161, 1049, 694 cm–1; HRMS (EI): m/z calcd. for C9H8ClF2NOS [M]+: 235.0034;
found: 235.0033.
Characteristic 1H and 19F NMR signals of the minor isomer: 1H NMR (500 MHz, CDCl3): δ =
7.14 (t, J = 55.6 Hz); 19F 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
mixture (50:50): 1H 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,
1049, 762, 690 cm–1; 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.
54
S-Difluoromethyl N-(p-methylphenyl)benzenecarbothioimidate (26g)
The product 26g was obtained as an inseparable diastereomeric mixture. Spectral data of the
mixture (63:37): 1H 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;
19F NMR (470 MHz, CDCl3): δ = 60.5 (d, J = 55 Hz), 69.5 (d, J = 56 Hz); IR (neat): ν = 2924, 1618,
1506, 1072, 769 cm–1; 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
mixture (55:45): 1H 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,
1076, 698 cm–1; 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.
55
S-Difluoromethyl O-methyl N-phenylthioiminocarbonate (26i)
1H 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,
1.0 Hz, 1H), 7.32 (t, J = 7.0 Hz, 2H), 7.37 (t, J = 56.5 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ =
56.9, 119.0 (t, J = 274 Hz), 121.2, 124.6, 129.2, 145.7, 152.6; 19F 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)
1H 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,
CDCl3): δ = 21.6, 55.4, 73.7, 114.4, 119.4 (t, J = 277 Hz), 122.2, 139.2, 151.4, 156.7; 19F NMR (470
MHz, CDCl3): δ = 66.6 (d, J = 57 Hz); IR (neat): ν = 2983, 1639, 1504, 1033, 769 cm–1; 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]
56
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)
1H 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
(d, J = 8.2 Hz, 2H); 13C 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)
1H 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
(d, J = 8.9 Hz, 2H); 13C 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.
57
Phenyl p-chlorobenzenedithiocarboxylate (28e)
1H 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
= 6.7, 2.0 Hz, 2H); 13C 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)
1H NMR (500 MHz, CDCl3): δ = 7.48–7.51 (m, 2H), 7.52–7.54 (m, 3H), 7.68 (d, J = 8.1 Hz,
2H), 8.14 (d, J = 8.1 Hz, 2H); 13C 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,
CDCl3): δ = 99.9 (s); IR (neat): ν = 1406, 1325, 1219, 1115, 1045, 872, 835 cm–1; HRMS (EI): m/z
Calcd. for C14H9F3S2 [M]+: 298.0098; found: 298.0099.
Phenyl o-phenylbenzenedithiocarboxylate (28g)
1H 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
(m, 3H), 7.56 (dd, J = 8.3, 1.3 Hz, 1H); 13C 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,
1431, 1221, 1039, 860, 739, 698 cm–1; HRMS (EI): m/z Calcd. for C19H14S2 [M]+: 306.0537; found:
306.0537.
58
Phenyl o-chlorobenzenedithiocarboxylate (28h)
1H NMR (500 MHz, CDCl3): δ = 7.27–7.32 (m, 2H), 7.38–7.41 (m, 2H), 7.49–7.51 (m, 5H); 13C
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)
1H NMR (500 MHz, CDCl3): δ = 7.36 (t, J = 7.9 Hz, 1H), 7.46–7.48 (m, 2H), 7.51–7.54 (m,
4H), 7.95 (ddd, J = 7.9, 1.9, 1.9 Hz, 1H), 8.06 (t, J = 1.9 Hz, 1H); 13C 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,
1562, 1475, 1412, 1219, 1045, 895 cm–1; HRMS (EI): m/z Calcd. for C13H9ClS2 [M]+: 263.9834;
found: 263.9838.
Phenyl hexanedithioate (28j)
1H 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,
2927, 2858, 1441, 1213, 904, 742, 687 cm–1; HRMS (EI): m/z Calcd. for C12H16S2 [M]+: 224.0693;
found: 224.0690.
59
Methyl p-chlorobenzenedithiocarboxylate (28l)
1H 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,
2.1 Hz, 2H); 13C NMR (126 MHz, CDCl3): δ = 20.7, 128.0, 128.5, 138.7, 143.1, 227.0; IR (neat): ν
= 2912, 1583, 1479, 1398, 1232, 1090, 1047, 823 cm–1; HRMS (EI): m/z Calcd. for C8H7ClS2 [M]+:
201.9678; found: 201.9676.
Benzyl p-chlorobenzenedithiocarboxylate (28n)
1H NMR (500 MHz, CDCl3): δ = 4.58 (s, 2H), 7.20–7.38 (m, 7H), 7.95 (d, J = 8.6 Hz, 2H); 13C
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
(neat): ν = 3028, 1583, 1481, 1227, 1045, 879, 827, 696 cm–1; 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
60
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.
1H NMR (500 MHz, CDCl3): δ = 7.19–7.31 (m); 13C 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,
J = 4 Hz); 19F 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.
61
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)
1H 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,
2H), 7.50 (d, J = 8.0 Hz, 2H); 13C 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,
1236, 1007, 912, 748, 741 cm–1; HRMS (EI): m/z Calcd. for C9H8F2S [M]+: 186.0315; found:
186.0317.
1,1-Difluoro-2-phenylsulfanyl-2-p-tolylethene (30c)
1H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3H), 7.10–7.13 (m, 3H), 7.19 (dd, J = 7.4, 7.4 Hz,
2H), 7.22–7.24 (m, 2H), 7.42 (dd, J = 8.1, 1.5 Hz, 2H); 13C 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,
J = 2, 2 Hz), 137.9, 156.9 (dd, J = 305, 290 Hz); 19F 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.
62
1,1-Difluoro-2-p-methoxyphenyl-2-(phenylsulfanyl)ethene (30d)
1H 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),
7.15–7.24 (m, 4H), 7.46 (d, J = 8.8 Hz, 2H); 13C 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 =
304, 290 Hz), 159.2; 19F 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)
1H 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 =
8.6, 1.3 Hz, 2H); 13C 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,
1682, 1477, 1279, 1009, 933, 737, 688 cm–1; HRMS (EI): m/z Calcd. for C14H9ClF2S [M]+: 282.0082;
found: 282.0087.
63
1,1-Difluoro-2-phenylsulfanyl-2-[p-(trifluoromethyl)phenyl]ethene (30f)
1H NMR (500 MHz, CDCl3): δ = 7.15–7.19 (m, 1H), 7.21–7.25 (m, 4H), 7.56 (d, J = 8.3 Hz,
2H), 7.65 (d, J = 8.3 Hz, 2H); 13C 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),
133.7 (dd, J = 2, 2 Hz), 136.2 (d, J = 5 Hz), 157.5 (dd, J = 307, 292 Hz); 19F 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,
1119, 1068, 1011, 841, 741 cm–1; HRMS (EI): m/z Calcd. for C15H9F5S [M]+: 316.0345; found:
316.0341.
1-(Biphenyl-2-yl)-2,2-difluoro-1-(phenylsulfanyl)ethene (30g)
1H NMR (500 MHz, CDCl3): δ = 7.19–7.26 (m, 9H), 7.29–7.39 (m, 5H); 13C 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,
1277, 1219, 1007, 914, 748 cm–1; HRMS (EI): m/z Calcd. for C20H14F2S [M]+: 324.0784; found:
324.0796.
64
1-o-Chlorophenyl-2,2-difluoro-1-(phenylsulfanyl)ethene (30h)
1H NMR (500 MHz, CDCl3): δ = 7.13–7.25 (m, 6H), 7.33–7.35 (m, 3H); 13C 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),
131.6, 132.9 (dd, J = 2, 2 Hz), 134.2, 156.2 (dd, J = 302, 292 Hz); 19F 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,
688 cm–1; HRMS (EI): m/z Calcd. for C14H9ClF2S [M]+: 282.0082; found: 282.0081.
1-m-Chlorophenyl-2,2-difluoro-1-(phenylsulfanyl)ethene (30i)
1H 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
(m, 1H), 7.53 (s, 1H); 13C 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
= 4 Hz), 134.3, 157.2 (dd, J = 307, 291 Hz); 19F 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.
65
1,1-Difluoro-2-(phenylsulfanyl)hept-1-ene (30j)
1H 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,
129.0, 134.2 (dd, J = 2, 2 Hz), 156.9 (dd, J = 297, 288 Hz); 19F 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,
688 cm–1; HRMS (EI): m/z Calcd. for C13H16F2S [M]+: 242.0941; found: 242.0941.
1,1-Difluoro-2-methylsulfanyl-2-p-tolylethene (30k)
1H 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
= 8.0 Hz, 2H); 13C 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,
1265, 1234, 1011, 931, 816 cm–1; HRMS (EI): m/z Calcd. for C10H10F2S [M]+: 200.0471; found:
200.0480.
66
.1-p-Chlorophenyl-2,2-difluoro-1-(methylsulfanyl)ethene (30l)
1H 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);
13C 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
(dd, J = 4, 2 Hz), 133.9, 154.9 (dd, J = 302, 289 Hz); 19F 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)
1H 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,
1234, 1007, 694 cm–1; HRMS (EI): m/z Calcd. for C15H12F2S [M]+: 262.0628; found: 262.0628.
67
1-Benzylsulfanyl-1-p-chlorophenyl-2,2-difluoroethene (30n)
1H NMR (500 MHz, CDCl3): δ = 3.63 (s, 2H), 7.11–7.13 (m, 2H), 7.21–7.28 (m, 3H), 7.31–
7.36 (m, 4H); 13C 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,
290 Hz); 19F NMR (470 MHz, CDCl3): δ = 84.1 (d, J = 17 Hz, 1F), 86.4 (d, J = 17 Hz, 1F); IR (neat):
ν = 3032, 1685, 1491, 1275, 1090, 1010, 827 cm–1; HRMS (EI): m/z Calcd. for C15H11F2S [M]+:
296.0238; found: 296.0238.
1,1,2,2-Tetrafluoro-3-methylsulfanyl-3-phenylcyclopropane (58b)
1H NMR (500 MHz, CDCl3): δ = 2.08 (s, 3H), 7.29 (d, J = 7.3 Hz, 2H), 7.36–7.44 (m, 3H); 13C
NMR (126 MHz, CDCl3): δ = 13.8, 45.5 (dddd, J = 13, 13, 11, 11 Hz), 106.0 (dddd, J = 313, 313, 12,
12 Hz), 128.7, 129.0, 130.1; 19F 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
68
2-4. References
[1] Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827.
[2] Welch, J. T. Tetrahedron 1987, 43, 3123; Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem.
1993, 58, 2302; Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
[3] Houlton, J. S.; Motherwell, W. B.; Ross, B. C.; Tozer, M. J.; Williams, D. J.; Slawin, A. M. Z.
Tetrahedron 1993, 49, 8087; Lloyd, A. E.; Coe, P. L.; Walker, R. T. J. Fluorine Chem. 1993,
62, 145; Xu, Y.; Qian, L.; Pontsler, A. V.; McIntyre, T. M.; Prestwich, G. D. Tetrahedron 2004,
60, 43; Chowdhury, M. A.; Abdellatif, K. R. A.; Dong, Y.; Das, D.; Suresh, M. R.; Knaus, E. E.
J. Med. Chem. 2009, 52, 1525; Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
[4] Israelachvili, J. N.; Intermolecular and Surface Forces, Academic Press, London, 1985; A.F.M.
Barton, Handbook of Solubility Parameters and Other Cohesion Parameters, CRC Press, FL,
1983.
[5] L.E. Kiss, I. Kövesdi, J. Rábai, J. Fluorine Chem. 2001, 108, 95.
[6] Tsuji, T.; Satoh, H.; Narisada, M.; Hamashima, Y.; Yoshida, T. J. Antibiot. 1985, 38, 466.
[7] Morita, K.; Ide, K.; Hayase, Y.; Takahashi, T.; Hayashi, Y. Agric. Biol. Chem. 1987, 51, 1339.
[8] Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15, 5036.
[9] Thomoson, C. S.; Dolbier, W. R., Jr. J. Org. Chem. 2013, 78, 8904.
[10] Zhang. W.; Wang, F.; Hu, J. Org. Lett. 2009, 11, 2109.
[11] Zafrani, Y.; Sod-Moriah, G.; Segall, Y. J. Fluorine Chem. 2009, 65, 5278.
[12] Fuchibe, K.; Koseki, Y.; Sasagawa, H.; Ichikawa, J. Chem. Lett. 2011, 40, 1189.
[13] Fuchibe, K.; Koseki, Y.; Aono, T.; Sasagawa, H.; Ichikawa, J. J. Fluorine Chem. 2012, 133, 52.
[14] Yde, B.; Yousif, N. M.; Pedersen, U.; Thomsen, I.; Lawesson, S. O. Tetrahedron 1984, 40, 2047.
[15] The Bio-Rad Spectroscopy Database (CAS Registry Number 19255-90-4), from the Bio-Rad
Laboratories, Philadelphia, PA, USA.
[16] The Bio-Rad Spectroscopy Database (CAS Registry Number 200403-56-1), from the Bio-Rad
Laboratories, Philadelphia, PA, USA.
69
[17] Ryabtsova, O. V.; Pozharskii, A. F.; Ozeryanskii, V. A.; Vistorobskii, N. V. Russ. Chem. Bull.,
Int. Ed. 2001, 50, 855
[18] Chambers, R. D.; Korn, S. R.; Sandford, G. J. Fluorine Chem. 1994, 69, 103.
[19] Birchall, J. M.; Cross, G. E.; Haszeldine, R. N. Proc. Chem. Soc., London 1960, 81.
[20] Zhang, L.; Zheng, J.; Hu, J. J. Org. Chem. 2006, 71, 9845.
[21] McDonald, I. A.; Lacoste, J. M.; Bey, P.; Palfreyman, M. G.; Zreika, M. J. Med. Chem. 1985,
28, 186; Bobek, M.; Kavai, I.; De Clercq, E. J. Med. Chem. 1987, 30, 1494; Kumadaki, I.; Ando,
A.; Omote, M. J. Fluorine Chem. 2001, 109, 67; Altenburger, J.-M.; Lassalle, G. Y.; Matrougui,
M.; Galtier, D.; Jetha, J.-C.; Bocskei, Z.; Berry, C. N.; Lunven, C.; Lorrain, J.; Herault, J.-P.;
Schaeffer, P.; O’Connor, S. E.; Herbert, J.-M. Bioorg. Med. Chem. 2004, 12, 1713.
[22] Chelucci, G. Chem. Rev. 2012, 112, 1344; Zhang, X.; Cao, S. Tetrahedron Lett. 2017, 58, 375.
[23] Messaoudi, S.; Tréguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; De Losada, J. R.; Liu, J.-M.;
Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. J. Med. Chem.
2009, 52, 4538.
[24] Bobek, M.; Kavai, I.; De Clercq, E. J. Med. Chem. 1987, 30, 1494.
[25] Fujii, K.; Nakamoto, Y.; Hatano, K.; Kanetsuki, Y. JP 2006016331 A, 2006.
[26] Ichikawa, J.; Wada, Y.; Okauchi, T.; Minami, T. Chem. Commun. 1997. 16. 1537.
[27] Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. Rev. 1996, 96, 1641; Zheng, J.; Cai, J.; Lin, J.-H.;
Guo, Y.; Xiao, J.-C. Chem. Commun. 2013, 49, 7513; Wang, F.; Li, L.; Ni, C.; Hu, J. Beilstein
J. Org. Chem. 2014, 10, 344 and references cited therein. See also: Sabol, J. S.; McCarthy, J. R.
Tetrahedron Lett. 1992, 33, 3101; Prakash, G. K. S.; Wang, Y.; Hu, J.; Olah, G. A. J. Fluorine
Chem. 2005, 126, 1361; Wang, X.-P.; Lin, J.-H.; Xiao, J.-C.; Zheng, X. Eur. J. Org. Chem. 2014,
2014, 928; Krishnamoorthy, S.; Kothandaraman, J.; Saldana, J.; Prakash, G. K. S. Eur. J. Org.
Chem. 2016, 2016, 4965.
[28] Ichikawa, J. J. Fluorine Chem. 2000, 105, 257; Nguyen, B. V.; Burton, D. J. J. Org. Chem. 1997,
62, 7758; Raghavanpillai, A.; Burton, D. J. J. Org. Chem. 2006, 71, 194; Gøgsig, T. M.; Søbjerg,
L. S.; Lindhardt, A. T.; Jensen, K. L.; Skrydstrup, T. J. Org. Chem. 2008, 73, 3404; Fujita, T.;
70
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.;
Bonnet-Delpon, D.; Rock, M. H. ́ J. Chem. Soc., Perkin Trans. 1 1996, 1409; Ichikawa, J.; Fukui,
H.; Ishibashi, Y. J. Org. Chem. 2003, 68, 7800; Hirotaki, K.; Hanamoto, T. Org. Lett. 2013, 15,
1226; Yang, J.; Mao, A.; Yue, Z.; Zhu, W.; Luo, X.; Zhu, C.; Xiao, Y.; Zhang, J. Chem. Commun.
2015, 51, 8326.
[31] Fuchibe, K.; Hatta, H.; Oh, K.; Oki, R.; Ichikawa, J. Angew. Chem., Int. Ed. 2017, 56, 5890.
[32] Choi, J. H.; Jeong, I. H. Tetrahedron Lett. 2008. 49. 952. [33] Jeong, I. H.: Min, Y. K.; Kim, Y. S.; Cho, K. Y. Bull. Korean Chem. Soc. 1991. 12. 355.
[34] Comprehensive Organic Name Reactions and Reagents; Wang, Z., Ed.; Wiley: Hoboken, 1999;
pp 249−253. Original papers: Barton, D. H. R.; Willis, B. J. J. Chem. Soc. D 1970, 1225; Barton,
D. H. R.; Smith, E. H.; Willis, B. J. J. Chem. Soc. D 1970, 1226; Kellogg, R. M.; Wassenaar, S.
Tetrahedron Lett. 1970, 11, 1987. See also: Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J.
Am. Chem. Soc. 1990, 112, 2003; Honda, T.; Ishige, H.; Araki, J.; Akimoto, S.; Hirayama, K.;
Tsubuki, M. Tetrahedron 1992, 48, 79.
[35] Mlostoń, G.; Romański, J.; Heimgartner, H. Heterocycles 1999, 50, 403.
[36] Middleton, W. J.; Howard, E. G.; Sharkey, W. H. J. Org. Chem. 1965, 30, 1375.
[37] Steudel, Y.; Steudel, R.; Wong, M. W. Chem. Eur. J. 2002, 8, 217.
[38] Fuchibe, K.; Morikawa, T.; Ueda, R.; Okauchi, T.; Ichikawa, J. J. Fluorine Chem. 2015, 179,
106.
[39] Dolbier, W. R., Jr.; Tian, F.; Duan, J.-X.; Li, A.-R.; Ait-Mohand, S.; Bautista, O.; Buathong, S.;
71
Baker, J. M.; Crawford, J.; Anselme, P.; Cai, X. H.; Modzelewska, A.; Koroniak, H.; Battiste,
M.A.; Chen, Q.-Y. J. Fluorine Chem. 2004, 125, 459.
[40] Arduengo, A. J.; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.;
Unverzagt, M. Tetrahedron 1999, 55, 14523.
[41] Ranade, S. C.; Kaeothip, S.; Demchenko, A. V. Org. Lett. 2010, 12, 5628.
[42] Lim, Y. W.; Hewitt, R. J.; Burkett, B. A. Eur. J. Org. Chem. 2015, 4840.
[43] Ramesha, A. B.; Sandhya, N. C.; Kumar, C. S. P.; Hiremath, M.; Mantelingu, K.; Rangappa, K.
S. New J. Chem. 2016, 40, 7637.
[44] Olah, G. A.; Bruce, M. R.; Clouet, F. L. J. Org. Chem. 1981, 46, 438.
[45] Li, Q.; Wang, T.; Dai, J.; Ma, C.; Jin, B.; Bai, R. Chem. Commun. 2014, 50, 3331.
72
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.
44),[4] and Mikami using Zn(CF3)2(DMPU)2 (eq. 45).[5] Because of its mild conditions, I supposed
that the difluorocarbene generation from TFDA using organocatalysts would facilitate the
difluorocyclopropanation of enol silyl ethers.
73
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]
74
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]
75
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
76
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.
77
Table 7. Optimization of Catalyst and Reaction Conditions.
78
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.
79
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).
80
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
neurotransmitter GABAB receptor (Figure 9).[12] 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.
81
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
82
(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
83
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,
84
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.
85
Table 11. Metal-Free Synthesis of Cyclic Enol Silyl Ethers 33a–k.
Figure 10. Structure Determination of 33d by NOE.
86
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.
87
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.
88
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]
Prostaglandin J2 shows anticancer activity.[20] 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.
89
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
90
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).
91
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%
92
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)
93
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
94
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
agent Me3Si B(OTf)4[28] 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
95
(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.
96
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.
97
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.
98
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.
99
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.
100
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
spectrometer in CDCl3 at 500 or 400 MHz (1H NMR), at 126 or 100 MHz (13C NMR), and at 470 or
376 MHz (19F NMR). Chemical shifts were given in ppm relative to internal Me4Si (for 1H NMR: δ
= 0.00), CDCl3 (for 13C NMR: δ = 77.0), and C6F6 (for 19F 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.
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-
101
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.
102
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
(neat): ν = 2927, 1624, 1464, 1254, 912, 742 cm–1; HRMS (EI): m/z Calcd. for C18H36OSi [M]+:
296.2535; Found: 296.2532.
103
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%.
104
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):
ν = 2931, 2860, 1491, 1452, 1225, 989, 835 cm–1; 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,
1109, 935, 833, 769 cm–1; HRMS (EI): m/z Calcd. for C20H30F2OSi [M−t-Bu]+: 295.1329; Found:
(1R*,3S*-32d) 295.1327, (1R*,3R*-32d) 295.1326.
105
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
cm–1; 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.
106
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,
1218, 1004, 957, 836 cm–1; HRMS (EI): m/z Calcd. for C13H14BrF2OSi [M−t-Bu]+ : 330.9965; Found:
330.9961.
107
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).
108
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)
1H 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 =
2.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H); 13C 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)
1H 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),
147.6 (dd, J = 23, 23 Hz); 19F 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.
109
3,4-Dibutyl-1-[tert-butyl(dimethyl)silyloxy]-5,5-difluorocyclopent-1-ene (33e)
1H 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
Hz), 147.0 (dd, J = 25, 25 Hz); 19F 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
cm–1. 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)
1H 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
(m, 3H); 13C 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,
4 Hz), 147.2 (dd, J = 7, 4 Hz); 19F 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,
839 cm–1; HRMS (EI): m/z calcd. for C17H23BrF2OSi [M]+: 388.0670; Found: 388.0669.
110
3-[tert-Butyl(dimethyl)silyloxy]-4,4-difluoro-6-methyl-1-phenylhepta-2,5-diene (75d)
1H 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,
1H), 7.19–7.43 (m, 5H); 13C 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),
146.0 (t, J = 30 Hz); 19F 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)
1H 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,
1H); 13C 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.
111
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]
Geometry of the fluoroalkene moiety of 34 was assigned based on their 3JFH values.[35]
(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,
1360, 1070, 940 cm–1; EA: Calcd for C11H9FO: C 74.99%; H 5.15%. Found: C 74.72%; H 5.20%.
112
(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 =
3130, 1660, 1599, 742 cm–1; 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.
113
(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
Hz); IR (neat): ν = 2964, 1646, 1606, 1334, 1205, 763 cm–1; 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,
2861, 1654, 1621, 1303, 983 cm–1; HRMS (EI): m/z Calcd. for C13H21FO [M]+: 212.1576; Found:
212.1563.
114
(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 =
46, 16 Hz); IR (neat): ν = 3055, 1655, 1618, 1178, 1041 cm–1; HRMS (EI): m/z Calcd. for C12H11FO
[M]+: 190.0794; Found: 176.0793.
115
(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%.
116
(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.
117
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.
118
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
(neat): ν = 2929, 1732, 1648, 1340, 1078, 765, 701 cm–1; 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):
ν = 3020, 1730, 1217, 771, 746 cm–1; HRMS (EI): m/z Calcd. for C12H11FO [M]+: 190.0794; Found:
190.0794.
119
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,
781, 762 cm–1; 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 =
2971, 1724, 1658, 1456, 1315, 1070, 701 cm–1; HRMS (EI): m/z Calcd. for C14H15FO [M]+: 218.1107;
Found: 218.1087.
120
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
cm–1; 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.
121
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,
1665, 1360, 1110, 1060, 700 cm–1; EA: Calcd for C13H13FO: C 76.45%; H 6.42%. Found: C 76.22%;
H 6.46%.
122
3-5. Reference
[1] Wu, S.-H.; Yu, Q. Acta. Chim. Sin (Engl. Ed.) 1989, 7, 253. For reviews on difluorocarbene,
see: Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585; Dolbier, W. R., Jr.; Battiste,
M. A. Chem. Rev. 2003, 103, 1071.
[2] Ni, C.; Hu, J. Synthesis 2014, 46, 842.
[3] Oshiro, K.; Morimoto, Y.; Amii, H. Synthesis 2010, 2080.
[4] Kosobokov, M. D.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2015, 17, 760;
Song, X.; Chang, J.; Zhu, D.; Li, J.; Xu, C.; Liu, Q.; Wang, M. Org. Lett. 2015, 17, 1712.
[5] Aikawa, K.; Toya, W.; Nakamura, Y.; Mikami, K. Org. Lett. 2015, 17, 4996.
[6] Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247; Wong, H. N. C.; Hon,
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.
123
[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.
[29] Dolbier, W. R., Jr.; Tian, F.; Duan, J.-X.; Li, A.-R.; Ait-Mohand, S.; Bautista, O.; Buathong, S.;
Baker, J. M.; Crawford, J.; Anselme, P.; Cai, X. H.; Modzelewska, A.; Koroniak, H.; Battiste,
M.A.; Chen, Q.-Y. J. Fluorine Chem. 2004, 125, 459.
[30] Arduengo, A. J.; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.;
Unverzagt, M. Tetrahedron 1999, 55, 14523.
[31] Ishikawa, T.; Okano, M.; Aikawa, T.; Saito, S. J. Org. Chem. 2001, 66, 4635.
[32] Song, J. J.; Tan, Z.; Reeves, J. T.; Fandrick, D. R.; Yee, N. K.; Senanayake, C. H. Org. Lett.
2008, 10, 877.
124
[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.
125
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
126
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.
127
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.
128
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