Development of Transition Metal-Based Catalytic System
for C–F Bond Activation via Fluorine Elimination
Watabe Yota
February 2018
Development of Transition Metal-Based Catalytic System
for C–F Bond Activation via Fluorine Elimination
Watabe Yota
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
TABLE OF CONTENTS
CHAPTER 1
General Introduction ............................................................................................... 1 1-1. C–F Bond Activation ........................................................................................ 1
1-2. Transition Metal-Catalyzed C–F Bond Activation of Fluoroalkenes ............... 3
1-3. Survey of This Thesis ..................................................................................... 10
1-4. References ....................................................................................................... 15
CHAPTER 2
Nickel-Catalyzed Defluorinative Couplings of 1,1-Difluoro-1-alkenes with
Alkynes ..................................................................................................................... 19
2-1. Introduction ..................................................................................................... 20 2-2. [2+2+2] Cyclization of 1,1-Difluoroethylene
with Alkynes via α-Fluorine Elimination ....................................................... 22
2-3. Hydroalkenylation of Alkynes
with β,β-Difluorostyrenes via β-Fluorine Elimination ................................... 30
2-4. References ....................................................................................................... 40
2-5. Experimental Section ...................................................................................... 44
CHAPTER 3
Rhodium-Catalyzed [4+2] Cyclization of 1,1-Difluoro-1-alkenes with
Biphenylenes ............................................................................................................ 82
3-1. Introduction ..................................................................................................... 83
3-2. Synthesis of 9-Fluorophenanthrenes via β-Fluorine Elimination ................... 84
3-3. References ....................................................................................................... 89
3-4. Experimental Section ...................................................................................... 91
4
CHAPTER 4
Silver-Catalyzed Intramolecular Defluoroamination of
β ,β-Difluoro-o-sulfonamidostyrenes .................................................................. 97
4-1. Introduction ..................................................................................................... 98
4-2. Synthesis of 2-Fluoroindoles via β-Fluorine Elimination ............................... 99
4-3. Mechanistic Studies on Generation from Metal Fluoride Species ................ 103
4-4. References ..................................................................................................... 106
4-5. Experimental Section .................................................................................... 109
CHAPTER 5
Nickel-Catalyzed Site-Selective Difluoroallylation of Indoles with
2-Trifluoromethyl-1-alkenes .............................................................................. 132
5-1. Introduction ................................................................................................... 133 5-2. Synthesis of 3-(3,3-Difluoroallyl)indoles via β-Fluorine Elimination .......... 134
5-3. Mechanistic Studies on Selective 3,3-Difluoroallylation of Indoles ............ 138
5-5. References ..................................................................................................... 141
4-6. Experimental Section .................................................................................... 146
CHAPTER 6
Conclusions ................................................................................................... 156
LIST OF PUBLICATIONS .......................................................................... 158
ACKNOWLEDGEMENT ............................................................................ 159
5
1
CHAPTER 1
General Introduction
1-1. C–F Bond Activation of Fluoroalkenes
The activation of the carbon–fluorine (C–F) bond has been regarded as a challenging task
because of unique characteristics of a fluorine substituent such as (i) a high bond dissociation
energy among carbon-containing σ bonds, (ii) a short bond length, and (iii) a low-lying σ*C–F
antibonding orbital (Table 1-1).[1,2] Furthermore, the fluorine atom has (iv) a weak Lewis basicity
and (v) a weak leaving group ability, which also makes it difficult to activate C–F bonds.
Thus, developing the C–F bond activation reaction is not only solving difficult problems but also
providing important methodologies for the synthesis of useful fluorinated pharmaceuticals,
agrochemicals, and materials starting from inexpensive multi-fluorinated compounds.[3,4] For
example, levofloxacin, a synthetic antibacterial drug, was synthesized from a trifluoroarene through
C–F bond activation, that is , two nucleophilic aromatic substitutions (SNAr, Scheme 1-1).[5]
Table 1-1. Properties of atoms (X) and their single bonds with carbon (C–X) [1,2]
HCNOFClBrI
2.12.53.03.54.03.02.82.5
Atom (X) Electronegativity
a a
1.201.701.551.521.471.741.851.98
van der Waalsradii (Bondi)/ Å
a
1.091.541.471.431.351.771.932.13
Average C–Xbond lengths/ Å
98.883.169.784.0105.4
78.565.957.4
Bond dissociationenergy (C–X)/ kcal mol–1
2
Scheme 1-1. Utility of C–F bond activation for pharmaceutical synthesis
Classically, transformations of the C–F bonds of multi-fluorinated alkenes have been achieved by
nucleophilic substitution using organometallic species via addition–elimination processes (Scheme
1-2).[2] In case of 1,1-difluoro-1-alkenes, since they have polarized alkene moieties, nucleophilic
addition occurs at the carbon atoms α to the fluorine substituents. Subsequent β-fluorine elimination
affords the corresponding monofluorinated alkene products. For example, the substitution reactions
of 1,1-difluoro-1-alkenes with lithium enolates (eq 1-1),[6] Grignard reagents (eq 1-2),[7] aluminum
hydrides (eq 1-3),[8] and intramolecular heteroatom nucleophiles (eq 1-4)[9] have been reported.
However, these reactions require stoichiometric alkali or alkali earth metal species (strong
nucleophiles).
Scheme 1-2. Nucleophilic substitution of 1,1-difluoro-1-alkenes
FF
F
NO2
NO
F
NN
OCO2H
MeMeLevofloxacin
FOH
F
NO2
KOH, H2O
FO
F
N
OCO2H
Me
DMSO, RT
DMSO, 100–140 °C
NHNMe
Nu
F
FNu
FF
F Nu
F
–R
RR
3
Compared to abovementioned nucleophilic reactions, reactions of transition metal species are
much more attractive for C–F bond activation, because transition metal species provide a wide
variety of elementary processes by varying their valencies. Furthermore, rational design of reactions
enables catalytic processes. In the next section, efficient C–F bond activation reactions promoted by
transition metal catalysts are described.
1-2. Transition Metal-Catalyzed C–F Bond Activation of Fluoroalkenes
1-2-1. C–F Bond Activation via Oxidative Addition
F THF–HMPA, – 60 °C58%
(1-1)F
OEt
O
OEt
OFLi
Cl F PhEt2O, reflux
64%
(1-2)
F
Cl
PhMgBrF
Cl
Cl
Benzene, reflux(1-3)
n-Hex F H
F NaAlH2(OC2H4OCH3)2
n-HexF
78%
F
DMF, 60–80 °C
X = O 80% = NTs 73–84%
(1-4)F
n-BuNaH
XH X
n-Bu
F
4
To date, transition metal-catalyzed reactions for C–F bond activation of multi-fluorinated alkenes
have been achieved mostly by oxidative addition of C–F bonds. [2] These reactions proceed via (i)
oxidative addition of C–F bonds to low-valent transition metal complexes, (ii) ligand exchange with
organometallic species, and (iii) reductive elimination (Scheme 1-3). In such reactions is required
smooth ligand exchange on the metals with the inert metal–fluorine bonds that are generated via the
oxidative addition.
Scheme 1-3. C–F bond transformation of 1,1-difluoro-1-alkenes via oxidative addition
As a pioneering work on C–F bond activation by transition metal catalysts, the nickel-catalyzed
coupling reaction of fluoroarenes with Grignard reagents was reported by Kumada and Tamao in
1973.[10] Since three decades later, C–F bond activation for C–C bond formation has been actively
studied and various reactions via oxidative addition have been reported.[2] Negishi coupling (eq.
1-5),[11] Suzuki–Miyaura coupling (eq. 1-6),[12] and Hiyama coupling (eq. 1-7)[13] have been applied
to vinylic C–F bond activation of fluoroalkenes. In contrast, allylic C–F bond activation has been
achieved in fluoroalkenes such as difluoroallylic compounds through Tsuji–Trost-type reactions
with hydrosilanes (eq. 1-8)[14] and amines (eq. 1-9).[15,16] These reactions mentioned above required
heating to achieve C–F bond activation.
cat. M
F
F
M
Fm
R’
F
F
R’
M
F
R’m F–Oxidative
Addition
RR R
R
5
F
F
F
Pd
cat. PdCl2dppp
THF, reflux, 48 h
FArZnCl
F
– FZn(1-5)
F
F
Pd
cat. Pd(dba)2, Pi-Pr3ArBnep
Ar
47–86%
– FBTHF, 100–105 °Cautocrave
(1-6)F
F
F
(excess: 3.5 atm)
F
FF
F
F
F
F
cat. Pd(dba)3(C6H6)cat. PCyp3, FSi(OEt)3
ArSi(OMe)3
Ar– FSiTHF, 100 °Cautocrave
(1.7)F
F
F
(excess: 3.5 atm)
F
F
FF
F
F
(1-8)
cat. [Pd(η3-C3H5)Cl]2, dppe
NEt3EtOH, 50 °C
NHBocCO2Et
F F
CO2Et
F PdF
CO2Et
F H
– FSi
PhSiH3
cat. [Pd(dppf)Cl2]•CH2Cl2
CH3CN, 70 °C, 22 h
OHNFF F
F
NO
–FH(1-9)
6
1-2-2. C–F Bond Activation via Fluorine Elimination
In contrast to oxidative addition, transition metal-catalyzed fluorine elimination is an
undeveloped process but has a significant potential for C–F bond activation.[2] Fluorine elimination
is mainly divided into (i) α-fluorine elimination[17] and (ii) β-fluorine elimination[18] according to the
positional relationship between metal centers and C–F bonds (Figure 1-1).
Figure 1-1. Fluorine elimination by transition metal complexes
α-Fluorine elimination has been applied to stoichiometric reactions for the generation of
difluorocarbene complexes from trifluoromethylmetal complexes, such as trifluoromethyl
molybdenum,[17a] ruthenium,[17b] rhodium,[17c] osmium,[17d], iridium,[17e] and gold complexes.[17f]
Difluorocarbene complexes, for example, were prepared via α-fluorine elimination from
trifluoromethyl ruthenium complexes, and underwent hydrolysis to afford the corresponding
carbonyl complexes (eq. 1-10).[17b]
M F M
β
F
(ii) β-Fluorine elimination(i) α-Fluorine elimination
MF
M
α
RF
R
MR
α
F
L
Ru
LCF3
MeCN
OC
Cl HCl
– HF
L
Ru
LCF2
Cl
OC
Cl H2O
– HF
L
Ru
LC
Cl
OC
Cl OH
F
H2O
– HF
L
Ru
LCO
Cl
OC
Cl (1-10)
7
On the other hand, β-fluorine elimination has been also known to proceed from fluoroalkyl metal
complexes such as a zirconacyclopropane.[18a] On treatment with zirconocene, a
1,1-difluoro-1-alkene was converted to the zirconacyclopropane, which inturn underwent β-fluorine
elimination at –78 °C. This process was further applied to the palladium-catalyzed coupling
reaction with aryl iodides (eq. 1-11). As seen in this reaction, fluorine elimination is an elementary
process that can readily cleave C–F bonds even under mild conditions (at extremely low
temperatures).
1-2-3. Catalytic C–F Bond Activation via Fluorine Elimination
Previously, a couple of catalytic C–F bond activation reactions via fluorine elimination have been
reported. For example, in 1991 Heitz developed the Pd-catalyzed coupling of 1,1-difluoroethylene
and aryl halides via β-fluorine elimination, which led to the synthesis of α-fluorostyrenes (eq.
1-12).[18b] In 2005, Ichikawa reported intramolecular cyclization of oximes bearing a
1,1-difluoro-1-alkene moiety via β-fluorine elimination (eq. 1-13).[18c] Quite recently, the devised
generation of organometallics (Ar–M) has allowed C–F bond activation of 1,1-difluoro-1-alkenes
via β-fluorine elimination. Thus, Pd-catalyzed defluoroarylation with aryl boronic acids (eq.
1-14),[18d] Rh-catalyzed defluoroarylation of indole derivertives via C–H bond activation (eq.
1-15),[18f] and Cu-catalyzed defluoroborylation with diborones has been achieved (eq. 1-16).[18i]
CF2X
HCp2Zr
(2.0 equiv)
THF– 78°C
XZrCp2
FF
H
X
HZrCp2Y
F
Y = F, ClX = 4-Me2NC6H4O
X
HAr
F
cat. PdArI, ZnI2
THFreflux
(1-11)
8
+Ph X
cat. Pd(OAc)2NEt3
(X = Br or I)
DMF, 115 °C β-FluorineElimination
F
F XPd F
FPh
Ph
FPhXPd
F
F
FXPdPd0Ph X NEt3
– F–, X–
(1-12)
(1-13)CF2
Ph
NXcat. Pd(PPh3)4
PPh3
DMA, 110 °C
NPd
FF
Ph
NPh
F
β-FluorineElimination
CF2
Ph
N
X = OCOC6F5
PdX
X
FXPdPd0RN X PPh3
– F–, X–
(1-14)Ar
+Ph(HO)2B
cat. Pd(OCOCF3)2cat. dtbbpy
DMF, 115 °C β-FluorineElimination
F
F XPd F
FPhAr Ar
Ph
FPhXPd
Ar
F
F
FXPdPh B(OH)2
– FB(OH)2
dtbbpyN N
t-Bu t-Bu
(1-15)
N
NN
β-FluorineElimination
cat. Rh
MeOH, 80 °C+ Ar
R
F F
Rh
RF
F
H
ArF
R
Ar H
Rh = [Cp*Rh(MeCN)3](SbF6)2
Ar RhR
FF
FRhAr H
– FH
9
2-(Trifluoeomethyl)-1-alkenes have been used as substrates in the reactions via β-fluorine
elimination. Ichikawa reported Pd-catalyzed intramolecular cyclization of oximes bearing a
trifluoromethylalkene moiety via β-fluorine elimination (eq. 1-17).[19a] Then, Murakami used a
Rh-catalyst to conduct defluoroarylation of trifluoromethylalkenes with aryl boronic esters via
C(sp3)–F bond activation by β-fluorine elimination (eq. 1-18).[19b] Furthermore, Ichikawa again
reported three-component coupling of 2-trifluoromethyl-1-alkenes, alkynes, and hydrosilanes via
β-fluorine elimination (Scheme 1-4).[19d] In this reaction, the intermediary nickel fluorides
generated via β-fluorine elimination were transformed by hydrosilanes.
(1-16)+
B(OR)2
cat. (Cy3P)2CuClKOAc
THF, 40 °C β-FluorineElimination
R
F
F F
R B(OR)2F
Cu
R
B(OR)2
F
Ar
F
F
FCu(RO)B B(OR)2
– FB(OR)2
Cu B(OR)2
B(OR)2
(1-17)Ph
NXcat. Pd(PPh3)4
PPh3
DMA, 110 °C
NPh
NPh
β-FluorineElimination
Ph
N
X = OCOC6F5
PdX
FXPdPd0RN X PPh3
– F–, X–
F3C F3C F3CPdX
F2C
10
Scheme 1-4. Ni-catalyzed hydroallylation of alkynes via β-fluorine elimination
For the catalytic C–F bond activation via α-fluorine elimination, Chatani reported Ni-catalyzed
cyclization of 1,1-difluoro-1,6-eneynes with organozinc reagents (Scheme 1-5).[20] In this reaction,
α-fluorine elimination proceeded from difluoronikelacyclopentene intermediates and the resulting
metal–fluorine bonds were transformed by zinc reagents.
Scheme 1-5. Ni-catalyzed cyclization of 1,1-difluoro-1,6-eneynes via α-fluorine elimination
1-3. Survey of This Thesis
As mentioned above, synthetic reactions using catalytic C–F bond activation via fluorine
elimination have been increasingly reported in these five years. However, they have been
+
Bnep
cat. [RhCl(cod)]2MeMgBr
1,4-Dioxane, 100 °C β-FluorineElimination
Ar1
Ar2
F3C
Ar2 Ar1
Ar2
FRhAr2 Bnep
– FBnep
Rh Ar
F3C
Ar2
2
F3C
Rh
Ar1
F2C(1-18)
R
CF3
R'
R'
NiF2CR
R'
R'β-FluorineElimination R
F2CNiF
R'
R'
F
cat. Ni(cod)2cat. PCy3
HSiEt3+
R
F2CH
R'
R'HSi
– FSiToluene50 °C 65–99%
α
R
CF2
Dioxane, 50 °C
Ar = p-OMe(C6H4)
EE
NiEE
F F
R
EE
R'
F
Rα-FluorineElimination
cat. Ni(cod)2 / PAr3R’2Zn E
ER
FNi
FR'2Zn
– FZnX
E = CO2Et
11
sporadically reported without systematic investigation. Thus, in this study I tried to expand the
versatility of catalytic C–F bond activation via fluorine elimination (i) by adopting a wide variety of
elementary reactions to fluoroalkenes, such as 1,1-difluoro-1-alkenes and
2-trifluoromethyl-1-alkenes, to construct fluorine-containing transition metal intermediates suitable
for the fluorine elimination (Figure 1-2) and (ii) by choosing appropriate fluorine captors, such as
organic boron, lithium, and silicon reagents, to regenerate catalytically active species from inert
transition metal fluorides generated by fluorine elimination (Figure 1-3).
Figure 1-2. Catalytic C–F bond activation of fluoroalkenes via fluorine elimination
β-FluorineElimination
Ni
R
R’
F F
β
α Ni
FF
R
R’R’
R
RhFF
X
N
FF
AgR
Ts
β
HH
β
Ar
R
R
R’ R’
R
HH
FNiIIF
FAr
R
Ni
R’
F
R
Rh FF
X
NF
R
Ts
F
F
β-FluorineElimination
β-FluorineElimination
α-FluorineElimination
OxidativeCyclization
Insertion
Amino-metalation
OxidativeCyclization
R’
R
R’
R
12
Figure 1-3. Regeneration of catalytic species
Chapter 2 describes the Ni-catalyzed defluorinative couplings of 1,1-difluoro-1-alkenes with
alkynes via oxidative cyclization and fluorine elimination (Scheme 1-6). I developed two catalytic
reactions: (i) [2+2+2] cyclization of 1,1-difluoroethylene with alkynes via α-fluorine elimination
and (ii) hydroalkenylation of alkynes with β,β-difluorostyrenes via β-fluorine elimination. The
catalytic system for both (i) and (ii) was established by addition of a borate generated from Et3B
and i-PrOLi as a fluoride scavenger. I conducted mechanistic studies on each reaction to furnish the
evidence for fluorine elimination.
Scheme 1-6. Ni-catalyzed defluorinative couplings of 1,1-difluoro-1-alkenes with alkynes
In Chapter 3, I developed a method for the synthesis of fluorophenanthrenes via Rh-catalyzed
M Fm R
M Rm F–
inertspecies
activespeciesm = B, Li, Si
Fluoride captor
β-FluorineElimination
R'
R'
F
F
Ni
R'
R'
R
F FAr Ar
F
R'R'β
H
Ni
R'
R'
αFFR = H
R = Ar
R'
R'
H–
F
R’R’
R’ R’
Hcat. Ni
cat. Ni
α-FluorineElimination
13
coupling of 1,1-difluoro-1-alkenes and biphenylenes (Scheme 1-7). In this reaction,
fluorine-containing seven-membered rhodacycles were prepared via insertion of
1,1-difluoro-1-alkenes into five-membered rhodacycles generated through C–C bond cleavage of
biphenylenes by a rhodium catalyst. Addition of a copper co-catalyst and a stoichiometric amount
of lithium salt extremely improved the catalytic cycle to raise the yield of fluorophenanthrene
products.
Scheme 1.7. Rh-catalyzed [4+2] cyclization of 1,1-difluoro-1-alkenes with biphenylenes
Chapter 4 demonstrates the intramolecular amino-metalation of
β,β-difluoro-o-sulfonamidostyrenes via electrophilic activation of the fluoroalkene moieties by
coordination to a cationic metal complex. In the presence of a silver(I) complex,
β,β-difluoro-o-sulfonamidostyrenes underwent cyclization in 1,1,1,3,3,3-hexafluoropropan-2-ol
(HFIP) to afford 2-fluoroindoles. Although the reaction did not proceed catalytically without any
[RhCl(cod)]2 (5 mol%)Cu(OTf)2 (5 mol%)LiOTf (1.0 equiv)F
F Toluene, reflux, 4 h
R = p-Ph(C6H4)
+
R FR
81%
Rh
R FF
R
Rh FF RhH FR
F
β-FluorineElimination
X
X
X
H
RhIIIH FCu/Li R’
– Cu/LiF– HR’ XRhIIIH R’X
RhI
X
14
additives, because of concomitant formation of inert silver fluoride by β-fluorine elimination,
addition of N,O-bis(trimethylsilyl)acetamide (BSA) as a fluoride captor realized the catalytic cycle
(Scheme 1-8).
Scheme 1-8. Ag-catalyzed intramolecular cyclization of β,β-difluoro-o-sulfonamidostyrenes
In Chapter 5, I succeeded in site-selective difluoroallylation of indoles through allylic C(sp3)–F
bond activation of 2-trifluoromethyl-1-alkenes via fluorine elimination (Scheme 1-9). Treatment of
2-trifluoromethyl-1-alkenes with indoles in the presence of a nickel catalyst and a borate afforded
3-(difluoroallyl)indoles. In this reaction, both β-fluorine elimination from fluorine-containing
nickelacyclopropanes and introduction of indolyl functions onto the nickel atom proceeded
simultaneously by the aid of N-indolylbotrates generated from indoles and a borate.
R1
N
FF
AgIR2
NHR3
CF2
R2 AgSbF6 (10 mol%)BSA (1.0 equiv)*
N
CF2
R2 AgIR
R1
HR3
NF
R2
R1
R3
β-FluorineElimination
Amino-metalation
32–99%
R3
R1
(CF3)2CHOH, reflux4–6 h
β
* slow addition over 1 h
AgIFSi R
– SiF
– HR
NSiMe3
OSiMe3BSA
15
Scheme 1-9. Difluoroallylation of indoles with 2-trifluoromethyl-1-alkenes
1-4. References
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CPME, RT, 12 hNH N
H
CF2
R2R2
R1
R1
36–96%
NiII FB
R
NiIIFF
B R
β-FluorineElimination
– BF
– Ni0
NiIIR
F
FR1F
FF
N
B
Ni0
B R =
16
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[11] Saeki, T.; Takashima, Y.; Tamao, K. Synlett. 2005, 1771–1774.
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[13] Saijo, H.; Sakaguchi, H.; Ohashi, M.; Ogoshi, S. Organometallics 2014, 33, 3669–3672.
[14] Narumi, T.; Tomita, K.; Inokuchi, E.; Kobayashi, K.; Oishi, S.; Ohno, H.; Fujii, N. Org. Lett.
2007, 9, 3465–3468.
17
[15] Pigeon, X.; Bergeron, M.; Barabé, F.; Dubé, P.; Frost, H. B.; Paquin, J.-F. Angew. Chem., Int.
Ed. 2010, 49, 1123–1127.
[16] (a) Hazari, A.; Gouverneur, V.; Brown, J. M. Angew. Chem., Int. Ed. 2009, 48, 1296–1299. (b)
Paquin, J.-F. Synlett 2011, 289–293.
[17] (a) Reger, D. L.; Dukes,, M.D. J. Organomet. Chem. 1978, 153, 67–72. (b) Clark, G. R.;
Hoskins, S. V.; Roper, W. R. J. Organomet. Chem. 1982, 234, C9–C12. (c) Burrell, A. K.; Clark, G.
R.; Jeffrey, J. G.; Rickard, C. E. F.; Roper, W. R. J. Organomet. Chem. 1990, 388, 391–408. (d)
Huang, D.; Koren, P. R.; Folting, K.; Davidson, E. R.; Caulton, K. G. J. Am. Chem. Soc. 2000, 122,
8916–8931. (e) Choi, J.; Wang, D. Y.; Kundu, S.; Choliy, Y.; Emge, T. J.; Krogh-Jespersen, K.;
Goldman, A. S. Science 2011, 332, 1545–1548. (f) Levin, M. D.; Chen, T. Q.; Neubig, M. E.; Hong,
C. M.; Theulier, C. A.; Kobylianskii, I. J.; Janabi, M.; O’Neil, J. P.; Toste, F. D. Science 2017, 356,
1272–1276. (g) Hughes, R. P. Eur. J. Inorg. Chem. 2009, 4591–4606.
[18] [Pd] (a) Fujiwara, M.; Ichikawa, J.; Okauchi, T.; Minami, T. Tetrahedron Lett. 1999, 40,
7261–7265. (b) Heitz, W.; Knebelkamp, A. Makromol. Chem., Rapid Commun. 1991, 12, 69–75.
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8235. (e) Thornbury, R. T.; Toste, F. D. Angew. Chem., Int. Ed. 2016, 55, 11629–11632. [Rh] (f)
Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472. (g) Wu, J.-Q; Zhang, S.-S.; Gao, H.; Qi,
Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.; Chn, Y.; Li, Q.; Li, X.; Wang, H. J. Am. Chem. Soc. 2017, 139,
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18
[19] (a) Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425–4427. (b) Miura, T.; Ito, Y.;
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8717–8720.
19
CHAPTER 2
Nickel-Catalyzed Defluorinative Couplings of 1,1-Difluoro-1-alkenes
with Alkynes
Abstract
Nickel-catalyzed defluorinative coupling reactions of 1,1-difluoro-1-alkenes with alkynes were
accomplished. 1,1-Difluoroethene or β,β-difluorostyrenes underwent single C–F bond activation via
α- or β-fluorine elimination from the intermediary nickelacycles, generated via oxidative cyclization
of difluoroalkenes and alkynes, to afford tetrasubstituted fluoroarenes or 2-fluoro-1,3-dienes,
respectively. The catalytic cycles were established by addition of a borate generated from Et3B and
i-PrOLi, which promoted regeneration of active nickel catalysts from nickel(II) fluoride species.
β-FluorineElimination
R'
R'
F
F
NiIIR'
R'
R
FF Ar
ArF
R'R'
H
NiIIR'
R'
FF
R = H
R = Ar
F
R’R’
R’ R’
cat. Ni
cat. Ni
α-FluorineElimination
α NiIIF
F
R’
R’R’
R’
R'
R'
ArF
R'R'
NiIIF
B R’’
– BF
20
2-1. Introduction
Fluorinated compounds involving C(sp2)–F bonds such as fluoroarenes and fluoroalkenes
constitute an important class of organic compounds and are used as pharmaceuticals, agrochemicals
and materials.[1] Fluoroarenes have been traditionally synthesized by thermolysis of arene
diazonium tetrafluoroborates (Balz–Shiemann reaction)[2] or nucleophilic substitution of
electron-deficient aryl halides with fluoride salts (Halex reaction).[3] In contrast, general methods
for the synthesis of monofluoroalkenes have not been well established. Recent developments in
fluorinating reagents have given rise to alternative methods for the synthesis of fluoroarenes and
fluoroalkenes, including (i) reactions of carbon nucleophiles (e.g. arenes[4] or alkenes[5] bearing a
C–B or C–Sn bond) with electrophilic fluorine sources and (ii) reactions of carbon electrophiles (e.g.
haloarenes[6] or alkynes[7]) with nucleophilic fluorine sources. Furthermore, the use of transition
metal catalysts has enabled (a) directing group-assisted aromatic or vinylic C–H bond
fluorination,[8] (b) fluorination of arylmetal reagents,[9] (c) intramolecular cyclization of alkynes
with fluorination (Scheme 2-1),[7c, 10] (d) fluorination of nonactivated aryl halides,[11] and (e)
fluorohydrogenation of alkynes (Scheme 2-2).[12] Thus, to date, most of transition metal catalyzed
methods for synthesizing fluorinated arenes or alkenes required regioselective by prefunctionalized
substrates to conduct or assist fluorination.
21
Scheme 2-1. Transition metal-catalyzed fluoroarene or -alkene synthesis
via electrophilic fluorination (DG: directing group)
Scheme 2-2. Transition metal-catalyzed fluoroarene or -alkene synthesis
via nucleophilic fluorination
Herein, I demonstrate the synthesis of fluoroarenes and fluoroalkenes via C–F bond activation of
1,1-difluoro-1-alkenes. The synthesis of fluoroarenes was established via nickel-catalyzed [2+2+2]
cyclization involving one molecule of 1,1-difluoroethylene and two molecules of alkyne (Scheme
2-3a). Furthermore, the nickel-catalyzed defluorinative coupling of β,β-difluorostyrenes with
alkynes and a hydride source afforded fluoroalkenes, 2-fluoro1,3-dienes (Scheme 2-3b). The details
of the abovementioned two types of reactions are described in the following sections.
cat. Pd, Cu or Ag
R
M
R
F
R
H
R
FDG DG
M = B, Sn
Nu
R
Nu = O, N
DG
R
H
cat. Pd or Ag
or or
sourceof “ F+ ”
DG
R
F
R
Nu
F
oror
(a),(b)
(a),(c)
cat. Pd or Cu
R
X
R
F
X = I, Br, Cl, OTf
Rcat. Au
sourceof “ F– ”
FR’
H
R R’
(d)
(e)
22
Scheme 2-3. Ni-catalyzed fluoroarene or -alkene synthesis via defluorinative couplings of
1,1-difluoro-1-alkenes and alkynes
2-2. [2+2+2] Cyclization of 1,1-Difluoroethylene with Alkynes via α-Fluorine
Elimination
2-2-1. [2+2+2] Cyclization by catalytic C–F bond activation
To synthesize fluoroarenes 3, I sought suitable conditions for the [2+2+2] cyclization of
1,1-difluoroethylene (1, 2.3 mmol) and diphenylacetylene (2a, 0.50 mmol) in the presence of a
catalytic amount of a Ni(0) complex (Table 2-1). The choice of ligands used with [Ni(cod)2] (5
mol % based on the amount of 2a; cod = 1,5-cyclooctadiene) was critical for the efficiency of the
reaction. Use of IMes·HCl with KH (5 mol% each) or P(t-Bu)3 (10 mol%) afforded
1-fluoro-2,3,4,5-tetraphenylbenzene (3a), albeit in low yields (Table 2-1, entries 2 and 4). Among
the ligands examined, PCy3 (5 mol%) was found to be the best (Table 2-1, entry 6). No
improvement in reaction yields was observed on addition of bases, such as Hünig’s base and DBU,
which suggested that fluoroarene 3a might be formed directly and not through HF elimination after
the formation of 4a (Table 2-1, entries 9 and 10). Addition of Et3SiH, i-PrOLi, or i-PrOBpin (Table
2-1, entries 11–13) was only marginally effective in increasing the yield of 3a. However, Et3B
R'
R'F
FF
R'R'
H
(R = H)
(R = Ar)
F
R’R’
R’ R’
cat. Ni
cat. NiH– source
(a) Fluoroarene Synthesis: [2+2+2] Cyclization
(b) Fluorodiene Synthesis: Hydroalkenylation
R
Ar
23
indicated potential for regeneration of the nickel catalyst (Table 2-1, entry 14). To activate
Et3B, i-PrOLi was added, which improved the turnover number of the Ni(0) complex significantly
(Table 2-1, entry 15). Finally, the use of equimolar quantities of 1 and 2a afforded 3a in 82% yield
(isolated product; Table 2-1, entry 16).
Table 2-1. Optimization of reaction conditions for the Ni-catalyzed [2+2+2] cyclization[a]
Ni(cod)2 (5 mol%)Ligand
Additiv (1.0 equiv)
Toluene, 40 °C
1
12345678910111213141516[e]
–IMes·HCl (5)[d]
dppp (5)P(t-Bu)3 (10)PCy3 (10)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)PCy3 (5)
––––––LiOAcEt3Ni-Pr2NEtDBUEt3SiHi-PrOLii-PrOBpinEt3BEt3B + i-PrOLiEt3B + i-PrOLi
14142214222222227791531221212
N.D.[b]
N.D.[b]
[a] Molar percentages of Ni(cod)2, ligands, and additives are based on the amount of 2a. Reaction conditions, unless otherwise stated: Ni(cod)2 (0.025 mmol), 1 (2.3 mmol), 2a (0.50 mmol), and toluene (2.0 mL). [b] N.D. = Not detected. [c] Yield was determined by 19F NMR spectroscopy with PhCF3 as an internal standard.Yield of isolated product is given in parentheses [d] KH (5 mol%) was added. [e] 2a (2.3 mmol)
Ph
Ph
F
F F
PhPh
Ph Ph2a
PhPh
Ph Ph3a 4a N.D.[b]
4
39897
109
2037264483 84
(80) (82)
3a / %[c]Time / hAdditiveLigand (mol%)Entry
F F
24
2-2-2. Substrate scope
With the optimal conditions in hand, the scope of the reaction was investigated by using various
alkynes (Table 2-2). Diarylacetylenes 2b–e, bearing electron-donating groups (m-Me, p-Me, p-Bu,
and p-OMe), underwent cyclization effectively to afford the corresponding tetraarylated
fluorobenzenes 3b–e in 72%, 81%, 79%, and 80% yields (Table 2-2, entries 2–5), respectively. The
reaction of diarylacetylene 2f, bearing electron-withdrawing CF3 groups, also proceeded to give 3f
in 76% yield (Table 2-2, entry 6). Chlorine-substituted diarylacetylene 2g underwent catalytic
cyclization without loss of Cl groups (Table 2-2, entry 7). Aliphatic alkyne 2h participated in the
reaction to provide tetraalkylated fluorobenzene 3h in 79% yield (Table 2-2, entry 8). Ester, benzyl
ether, acetal, and silyl ether moieties on dialkylacetylenes 2i–l were also tolerated in this reaction,
which effectively afforded the corresponding fluoroarenes 3i–l (Table 2-2, entries 9–12). The
cyclization of unsymmetrical alkynes 2m and 2n proceeded with substantial regioselectivities
(84:16 and 85:15) to afford o-terphenyl derivatives 3m and 3n, respectively, as major products
(Table 2-2, entries 13 and 14). [13,14]
25
Table 2-2. Ni-catalyzed synthesis of fluoroarenes 3 from 1,1-difluoroehtylene (1) and alkynes 2
2-2-3. Mechanistic studies on Ni-catalyzed [2+2+2] cyclization
To gain some insights into the reaction mechanism, the initial rate of the formation of product 3a
[(Δ[3a]/Δt)t=0] was measured. I first monitored the dependency of (Δ[3a]/Δt)t=0 by changing the
partial pressure of 1 (p(1); 0.3–1.0 atm). A linear correlation between p(1) and (Δ[3a]/Δt)t=0 was
Ni(cod)2 (5 mol%)PCy3 (5 mol%)
Et3B (1.0 equiv)i-PrOLi (1.0 equiv)
Toluene, 40 °C1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Ph, Ph
C6H4(m-Me), C6H4(m-Me)
C6H4(p-Me), C6H4(p-Me)
12
16
12
12
12
15
12
15
16
14
14
14
18
14
[a] Molar percentages of Ni(cod)2, PCy3, Et3B and i-PrOLi are based on the amount of 2. Reaction conditions: Ni(cod)2 (0.12 mmol), PCy3(0.12 mmol), 1 (2.3 mmol), 2a (2.3mmol), Et3B (2.3 mmol)and toluene (2.0 mL). [b]
R1
R2
F
F
F
R1R1
R2 R2
2 3
82
72
81
79
80
76
45
79
39
58
67
62
59
60
Yield / %[b]Time / hR1, R22Entry
C6H4(p-Bu), C6H4(p-Bu)
C6H4(p-OMe), C6H4(p-OMe)
C6H4(p-CF3), C6H4(p-CF3)
C6H4(m-Cl), C6H4(m-Cl)
Pr, Pr
(CH2)2CO2t-Bu, (CH2)2CO2t-Bu
(CH2)3OCH2Ph, (CH2)3OCH2Ph
(CH2)3OTHP, (CH2)3OTHP
(CH2)3OSiMe3, (CH2)3OSiMe3
Me, Ph
Pr, C6H4(p-OMe)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3
[c]
[d]
Et3B (2.3 mmol), i-PrOLi (2.3 mmol) and toluene (4.7 mL). [b] Yield of isolated product. [c] TheThe regioisomer ratio (84:16) was determined by 19F NMR spectroscopy. [d] The regioisomer ratioregioisomer ratio (85:15) was determined by 19F NMR spectroscopy.
26
observed (Figure 2-1a). Furthermore, a straight line (slope = 1.12) provided a good fit for the log–
log plot of (Δ[3a]/Δt)t=0 against p(1), indicating that the reaction had a nearly first-order dependence
on the concentration of 1 in the solution (Figure 2-1b). Next, the dependency of the initial rate
[(Δ[3a]/Δt)t=0] on the initial concentration of alkyne 2a ([2a]0; 0.2–0.9 M) under a constant pressure
(1.0 atm) of 1 was examined. A linear correlation between the two was observed (Figure 2-1c). The
linear fitting of the log–log plot with a slope of 1.02 shows a first-order dependence of the reaction
rate on [2a]0 (Figure 2-1d). Furthermore, the dependency of (Δ[3a]/Δt)t=0 on the initial
concentration of the Ni(0) complex ([Ni]0; 0.013–0.11 M) was estimated by the reactions with a
constant concentration (0.25 M) of 2a under a constant pressure (1.0 atm) of 1 in the absence of
Et3B and i-PrOLi. Not only a linear correlation between [Ni]0 and (Δ[3a]/Δt)t=0 (Figure 1e) but also
the linear fitting of the log–log plot (slope=1.09) clearly exhibits a first-order dependence of the
reaction rate on [Ni]0 (Figure 1f). These results suggest that the initial rate-limiting oxidative
cyclization proceeds with the involvement of one component each of 1, 2a, and Ni0.[15]
27
Figure 2-1. (a) Initial reaction rate versus p(1) and (b) the corresponding log-log plot. (c) Initial
reaction rate versus [2a]0 and (d) the corresponding log-log plot. (e) Initial reaction rate versus [Ni]0
and (f) the corresponding log-log plot.
Reaction conditions (a,b): Ni(cod)2 (0.025 mmol), PCy3 (0.025 mmol), 1 (partial pressure: 0.30–1.0 atm), 2a (0.50 mmol), Et3B (0.50 mmol), i-PrOLi (0.50 mmol), and toluene (1.0 mL) at 40 °C for 15 min. (c,d): Ni(cod)2 (0.025 mmol), PCy3 (0.025 mmol), 1 (excess in balloon, 1 atm), 2a (0.20–0.90 mmol), Et3B (0.50 mmol), i-PrOLi (0.50 mmol), and toluene (1.0 mL) at 40 °C for 15 min. (e,f): Ni(cod)2 (0.013–0.11 mmol), PCy3 (0.013–0.11 mmol), 1 (excess in balloon, 1 atm), 2a (0.25 mmol), and toluene (1.0 mL) at 40 °C for 5 min.
28
To elucidate the mechanism further, the stoichiometric reaction of 1,1-difluoro-1,6-enyne 5 and
alkyne 2a with Ni0 was performed. Treatment of equimolar amounts of enyne 5 and alkyne 2a with
stoichiometric amounts of [Ni(cod)2] and PCy3 afforded the ring-monofluorinated indane 6 in 60 %
yield (eq. 2-1). Since one difluoroalkene moiety and two alkyne components were involved in the
formation of 6, this reaction was presumed to proceed through a cycloaddition process similar to
that in the case of the reaction involving 1 and 2. The formation of 6 is likely to involve the initial
intramolecular oxidative cyclization of difluoroalkene and alkyne moieties in 5 with
Ni(0).[16,17] This cyclization mode would be consistent with the aforementioned result of the
reaction between 1 and 2a. Correspondingly, the oxidative cyclization of 1, 2, and Ni(0) probably
afforded the intermediary nickelacyclopentenes, wherein the difluoromethylene moiety
regioselectively occupied the position α to the nickel atom.
Taking these observations together, I propose a mechanism for the Ni(0)-catalyzed cycloaddition
(Scheme 2). This reaction starts with oxidative cyclization, rate-limiting chemo- and regioselective
formation of nickelacyclopentenes A, resulting from the combination of one molecule each of 1 and
2. The nickelacyclopentenes A thus formed facilitate the insertion of another molecule of 2 to
generate nickelaheptadienes B. Subsequent α-fluorine elimination from B gives
Ph
EtO2C
F
F
2a (1.0 equiv)Ni(cod)2 (1.0 equiv)
PCy3 (1.0 equiv)
5
F
Ph
PhPh
EtO2CEtO2CEtO2C
6 60%
Toluene, 60 °C, 6 h(2-1)
29
cyclohexadienylnickel(II) fluorides C.[18,19] Finally, β-hydrogen elimination affords fluoroarenes 3
and nickel(II) hydrofluoride D, which can then be reduced to the Ni(0) complex through
transmetalation with the borate derived from Et3B and i-PrOLi.[20]
Scheme 2--4. Plausible reaction mechanism
2-2-4. Transformation of tetraarylfluoroarenes for construction of planer π-systems
The obtained tetraarylated fluoroarene products can serve as building blocks in further
transformations. For example, treatment of fluoroarene 3d with excess FeCl3 led to ring fusions via
three oxidative C–H/C–H couplings[21] to afford tribenzoperylene 7 with a fluorine substituent in
74% yield (eq. 2-2).[22] The resulting pinpoint-fluorinated planar π-conjugated system can be a
Ni0
NiII
FF
RR
NiII
F FR
RR
RR
R
R
RNiII
F
R
R
R
R
F
H NiII F
H NiII Et
F
F
R
R1 2
+
R
R2
α-FluorineElimination
i-PrO BEt3
i-PrO BEt2F
H Et
3
A
BC
D
Li
Li
F
CH2=CH2 + H2
(and )
30
promising candidate as organic electronic materials.[23]
2-2-5. Conclusion
In summary, I have developed a nickel-catalyzed method for direct synthesis of fluoroarenes via
α-fluorine elimination. This method for fluoroarene synthesis complements conventional methods,
which install fluorine on preformed benzene rings. With proper choice of alkyne substrates, our
method enables modular synthesis of diversely substituted fluoroarenes[24] from
1,1-difluoroethylene, a raw material.
2-3. Hydroalkenylation of Alkynes with β,β-Difluorostyrenes via β-Fluorine
Elimination
2-3-1. Hydroalkenylation of alkynes by catalytic C–F bond activation
In contrast to fluoroarene synthesis by Ni-catalyzed [2+2+2] cyclization (Chapter 2-2: Scheme
2-5), the regioselectivity in the reaction of β,β-difluorostyrenes 8 seemed to be controlled by
coordination of the arene moiety to the nickel center. That is, β,β-difluorinated
nickelacyclopentenes E might be generated through oxidative cyclization of one molecule each of 8
and alkyne 9 with Ni(0) (Scheme 2-6). Subsequent endocyclic β-fluorine elimination from E would
F
Bu
Bu Bu
Bu
F
Bu
Bu Bu
BuFeCl3
(30 equiv)
DCM–MeNO2(5:1)
0 °C, 1 h
7 74%
(2-2)
3d
31
produce 2-fluoro-1,3-dienes 10.
Scheme 2-6. Nickel-catalyzed [2+2+2] cyclization of 1,1-difluoroethylene with alkynes
Scheme 2-7. Nickel-catalyzed hydroalkenylation of alkynes with β,β-difluorostyrenes
2-3-2 Ni-catalyzed synthesis of 2-fluoro-1,3-dienes
To synthesize 2-fluoro-1,3-dienes 10, I sought suitable conditions for the synthesis of
2-fluorohepta-1,3-diene 10aa by using β,β-difluorostyrenes 8a and 4-octyne (9a) as model
substrates (Table 2-3). Initially, we adopted the Ni(cod)2/PCy3 catalyst system, which was effective
in defluorinative coupling between difluoroethylene and alkynes.[25] No product was obtained
R
R+
cat. Ni0
α−Fluorine elimination
F
F
NiII
R
R
RF
H
R
R
R
R
FF
R
R
R
NiIIFHH
RR
F
NiII
F FR3
R2
Ar FAr
R3
NiII
R2
F
FAr
R3
H
R2R2
R3+
E
cat. Ni0
H– source
β−Fluorine elimination
F
FAr
8 9 10
32
without a hydride source (Table 2-3, entry 1). Whereas ZnEt2, Et3SiH, and Et3B were not effective
hydride sources (Table 2-3, entries 2-4), the combination of Et3B and i-PrOLi afforded 10aa in 46%
yield as the sole product, without formation of fluoroarenes (Table 2-3, entry 5). As the result of
screening extra additives, a catalytic mount of ZrF4[26] was found to improve the yield to 59%
(Table 2-3, entry 6). Additionally, the yield of 10aa was drastically increased to 89% by lowering
the reaction temperature to room temperature (Table 2-3, entry 7).
Table 2-3. Optimization of reaction conditions for Ni-catalyzed hydroalkenylation[a]
FAr
Pr
H
Pr
Ni(cod)2 (10 mol%)PCy3 (10 mol%)Hydride source
Toluene, Conditions
8aAr = C6H4(p-Ph)
1
2
3
4
5
6
7
–
Et2Zn (1.0)
Et3SiH (1.0)
Et3B (1.5)
Et3B (1.0) + i-PrOLi[d] (1.5)
Et3B (1.0) + i-PrOLi[d] (1.5) + ZrF4 (0.1)
Et3B (1.0) + i-PrOLi[d] (1.5) + ZrF4 (0.1)
40 °C, 12 h
40 °C, 12 h
40 °C, 16 h
40 °C, 10 h
40 °C, 12 h
40 °C, 3.5 h
RT, 24 h
[a] Reaction conditions: Ni(cod)2 (0.025 mmol), PCy3 (0.025 mmol), 8a (0.25 mmol), 9a (0.50mmol), , and toluene (2.0 mL). [b] Yield was determided by 19F NMR spectroscopy using PhCF3 as an internal standard. Yield of isolated product is given in parentheses. [c] N.D. = Not detected. [d] i-PrOLi was generated in situ from i-PrOH and n-BuLi.
Pr
Pr
F
F
9a(2.0 equiv)
10aa
N.D.[c]
N.D.[c]
N.D.[c]
N.D.[c]
Yield / %[b]ConditionsHydride source (equiv)Entry
Ar
46
59
89 (89)
33
2-3-3. Substrate scope
With the optimal conditions established, the scope of the reaction with respect to
β,β-difluorostyrenes 8 and alkynes 9 was investigated (Table 2-4). When simple β,β-difluorostyrene
(8b) was employed, the corresponding 2-fluoro-1,3-diene 10ba was obtained in 77% yield.
β,β-Difluorostyrene 8c, bearing an electron-donating substituent (i-Pr), successfully underwent
hydroalkenylation to afford the corresponding 2-fluoro-1,3-diene 10ca in 62% yield. The reaction
of chlorine-bearing β,β-difluorostyrene 8d also provided 10da in 84% yield without C–Cl bond
cleavage. The hydroalkenylation of 9a with 1-(2,2-difluoroethenyl)naphthalene (1e) proceeded
smoothly to afford 3ea in 86% yield. Heterocycle-containing 1,3-dienes 10fa and 10ga were
obtained by the reaction with 2-(2,2-difluoroethenyl)benzofuran (8f) and -benzothiophene (8g),
respectively. In addition to symmetrical alkynes such as 9a and 9b, unsymmetrical alkynes 9c and
9d participated in the hydroalkenylation to afford the corresponding 2-fluoro-1,3-dienes 10ac and
10ad with strict regioselectivities.[27] Furthermore, hydrodienylation of 9a with
1,1-difluorobuta-1,3-diene 8h also proceeded to give 3-fluorinated 1,3,5-triene 10ha in 62% yield
(eq. 2-3).
34
Table 2-4. Ni-catalyzed synthesis of 2-fluoro-1,3-dienes 10[a]
[a] Reaction conditions: Ni(cod)2 (0.025 mmol), PCy3 (0.025 mmol), 8 (0.25 mmol), 9 (0.50mmol), Et3B (0.38 mmol), i-PrOLi (0.38 mmol) and toluene (2.0 mL). [b] Single regioisomer
F
FR1
8
+R3
R2
9(2.0 equiv)
Ni(cod)2 (10 mol%)PCy3 (10 mol%)ZrF4 (10 mol%) F
R1
10R2
H
R3Et3B (1.5 equiv)i-PrOLi (1.5 equiv)
Toluene, RT
F
Pr
H
Pr
R F
Pr
H
Pr
F
Pr
H
PrS
F
Me
H
i-Pr
Ph
F
Pr
H
PrO
F
Et
H
Et
Ph
F
Me
H
Ph
Ph
10aa (R = Ph), 89% (24 h)10ba (R = H), 77% (11 h)10ca (R = i-Pr), 62% (18 h)10da (R = Cl), 84% (20 h)
10ea 86% (20 h)
10ab 80% (17 h)10ga 85% (12 h)10fa 77% (10 h)
10ac 33%[b] (15 h)10ac 64%[b] (12 h)
F
F
8h
+Pr
Pr
9a(2.0 equiv)
Ni(cod)2 (10 mol%)PCy3 (10 mol%)ZrF4 (10 mol%)
10ha 62%
Et3B (1.5 equiv)i-PrOLi (1.5 equiv)
Toluene, 40 °C, 12 h
F
Pr
H
Pr
Ph Ph
(2-3)
35
2-3-5. Mechanistic study on Ni-catalyzed hydroalkenylation of alkynes
For hydroalkenylation of alkynes 9 with difluorostyrenes 8, there are two possible reaction
pathways initiated by different elementary steps that involve 8 (Scheme 2-7). Path (I) starts with
oxidative cyclization of 8 and 9 with the Ni catalyst, inducing regioselective formation of
β,β-difluorinated nickelacyclopentenes E with the help of coordination of the aryl group to the Ni
center (Scheme 2-8). Subsequent β-fluorine elimination from E generates vinylnickels F. Thus,
2-fluoro-1,3-dienes 10 are obtained through transmetalation of F with the borate generated from
Et3B and i-PrOLi. In path (II), vinylnickel intermediates E’ are initially formed by oxidative
addition of a vinylic C–F bond of 8 to Ni0 (Scheme 2-8). Subsequent insertion of 9 to E’ affords the
common intermediates F.
36
Scheme 2-7. Possible reaction pathways (I) and (II).
To determine the initial steps of the reaction pathway, we examined the dependency in the initial
formation rate of 2-fluoro-1,3-diene 10ea [(Δ[10ea]/Δt) t=0] based on changing the initial
concentrations of difluorostyrene 8e([8e]0), alkyne 9a ([9a]0), and Ni catalyst ([Ni]0) (Figure 2-2).
On the basis of these experiments, linear correlations of (Δ[10ea]/Δt) t=0 with [8e]0 and [9a]0 were
obtained (Figure 2-2a and 2-2c). In addition, linear fitting of the corresponding log–log plots with
slopes of 1.01 and 1.08 exhibited first-order dependence of (Δ[10ea]/Δt) t=0 on [8e]0 and [9a]0,
respectively (Figure 2-2b and 2-2d). Thus, both 8e and 9a were shown to be involved in the
rate-limiting initial step. Furthermore, when a similar analysis was performed on the dependency of
F
FAr
8
FAr
10R
H
R
E
Ni
ArF F
R
R
FAr
R
NiII
R
F
F
F
NiIIAr
H–
F
path (I) path (II)
Oxidativecyclization
OxidativeadditionNi0
9
Ni0
E’
β-Fluorineelimination
Alkyneinsertion
R
R
9
R
R
II
37
(Δ[10ea]/Δt) t=0 on [Ni]0, first-order dependence (slope of 0.910) was confirmed (Figure 2-2e and
2-2f). These results indicate that oxidative cyclization of 8e and 9a with Ni0 is involved in the
rate-limiting initial step as path (I).
38
Figure 2-2. (a) Initial reaction rate versus [8e] and (b) the corresponding log-log plot. (c) Initial
reaction rate versus [9a]0 and (d) the corresponding log-log plot. (e) Initial reaction rate versus [Ni]0
and (f) the corresponding log-log plot.
Reaction conditions (a,b): Ni(cod)2 (0.025 mmol), PCy3 (0.025 mmol), ZrF4 (0.025 mmol), 8e (0.25–0.60 mmol), 9a (0.50 mmol), Et3B (0.38 mmol), i-PrOLi (0.38 mmol), and toluene (2.0 mL) at room temperature for 10 min. (c,d): Ni(cod)2 (0.025 mmol), PCy3 (0.025 mmol), ZrF4 (0.025 mmol), 8e (0.25 mmol), 9a (0.12–0.50 mmol), Et3B (0.38 mmol), i-PrOLi (0.38 mmol), and toluene (2.0 mL) at room temperature for 10 min. (e,f): Ni(cod)2 (0.0050–0.05 mmol), PCy3 (0.0050–0.05 mmol), 8e (0.50 mmol), 9a (1.0 mmol), Et3B (0.75 mmol), i-PrOLi (0.75 mmol), and toluene (2.0 mL) at room temperature for 10 min.
(e)
(b)
(d)
(f)
(c)
(a)
39
To clarify which hydrogen of the borate formed from triethylborane and lithium isopropoxide
was installed as a hydride source in the 2-fluoro-1,3-dienes 10, a deuterium-labeling experiment
was conducted using i-PrOLi-d7 (eq. 2-4). Nickel-catalyzed hydroalkenylation of 9a with 8a in the
presence of the borate generated from Et3B and i-PrOLi-d7 gave a 64:36 mixture of deuterated
2-fluoro-1,3-diene 10aa-d and non-deuterated diene 10aa. In addition, the formation of ethylene
was confirmed by a gas detector. These results indicate that both an ethyl group on boron and an
isopropoxy group serve as the hydride source.
On the basis of the aforementioned experiments, we propose the following reaction mechanism
(Scheme 2-8). This reaction is initiated by regioselective oxidative cyclization of difluoroalkene 8
and alkyne 9 with Ni0 to generate the intermediary β,β-difluorinated nickelacyclopentenes E.
β-Fluorine elimination proceeds from E to generate vinylnickel fluorides F. Replacement of the
fluorine on the nickel in F with an isopropoxy group or an ethyl group is accomplished through
transmetalation with the borate, derived from Et3B and i-PrOLi. Subsequent β-hydrogen elimination
induces the formation of vinylnickel hydrides G along with acetone or ethylene. Finally, reductive
elimination from G affords 1,3-dienes 10 to regenerate nickel(0).
F
FAr
8a
+Pr
Pr
9a(2.0 equiv)
Ni(cod)2 (10 mol%)PCy3 (10 mol%)ZrF4 (10 mol%)
10aa-d 93%(D/H = 64/36)
Et3B (1.5 equiv)(CD3)2CDOLi (1.5 equiv)
Toluene, RT, 12 h
F
Pr
D (H)
PrAr (2-4)
40
Scheme 2-8. Proposed catalytic cycle
2-3-6. Conclusion
In summary, we have developed a method for the synthesis of 2-fluoro-1,3-dienes through
nickel-catalyzed hydroalkenylation of alkynes 9 with β,β-difluorostyrenes 8 and a borate. The
vinylic C–F bonds of 8 are readily cleaved through β-fluorine elimination under mild conditions.
The monofluorinated 1,3-dienes[28] obtained above are expected to serve as components of bioactive
compounds in pharmaceuticals and monomers for functional polymers.
2-4. References
[1] (a) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160–171. (b) Furuya, T.; Klein J. E. M. N.; Ritter,
β-FluorineElimination
FAr
R
NiII
R
H
G
i-PrO BEt3i-PrO BEt2FLi Li
+
FAr
10 R
H
R
BFEt3Li
O+ or
Ni0
E
NiIIAr
F FR
R
FAr
R
NiII
R
F
F
R
R
F
FAr +8 9
LigandExchange
OxidativeCyclization
ReductiveElimination
41
T. Synthesis 2010, 1804–1821. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470–477.
(d) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929–2942. (e) Li, Y.; Qu, Y.; Li,
G.-S.; Wang, X.-S. Adv. Synth. Catal. 2014, 356, 1412–1418. (f) Brooks, A. F.; Topczewski, J. J.;
Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. Chem. Sci. 2014, 5, 4545–4553. (g) Campbell, M. G.;
Ritter, T. Chem. Rev. 2015, 115, 612–633. (h) Champagne, P. A.; Desroches, J.; Hamel, J.-D.;
Vandamme, M.; Paquin, J.-F. Chem. Rev. 2015, 115, 9073–9174. (i) Liu, Q.; Ni, C.; Hu, J. Nat. Sci.
Rev. 2017, 4, 303–325.
[2] (a) Roe, A. Org. React. 1949, 5, 193–228. (b) Laali, K. K.; Gettwert, V. J. J. Fluorine Chem.
2001, 107, 31–34., and references therein
[3] (a) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225–231. (b) Lacour, M.-A.; Zablocka,
M.; Duhayon, C.; Majoral, J.-P.; Taillefer, M. Adv. Synth. Catal. 2008, 350, 2677–2682., and
references therein
[4] (a) Cazorla, C; Métay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50, 3936–3938.
(b) Yamada, S.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 2215–2218. (c)
Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 2265–2268.
[5] (a) Tius, M. A.; Kawakami, J. K. Synth. Commun. 1992, 22, 1461–1471. (b) Tius, M. A.;
Kannangara, G. S. K.; Kerr, M. A.; Grace, K. J. S. Tetrahedron, 1993, 49, 3291–3304. (c) Furuya,
T.; Ritter, T. Org. Lett. 2009, 11, 2860–2863. (d) Ranjbar-Karimi, R. Ultrason. Sonochem. 2010, 17,
768–769.
[6] (a) Grushin, V. V.; Marshall, W. J. Organometallics 2008, 27, 4825–4828. (b) Wang, B.; Qin,
L.; Neumann, K. D.; Uppaluri, S.; Cerny, R. L.; DiMango, S. G. Org. Lett. 2010, 12, 3352–3355.
(c) Saito, M.; Miyamoto, K.; Ichiai, M. Chem. Commun. 2011, 47, 3410–3412. (d) Tang, P.; Wang,
W.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482–11484. (e) Yoshida, H.; Yoshida, R,; Takai, K.
Angew. Chem., Int. Ed. 2013, 52, 8629–8632.
42
[7] (a) Ochiai, M.; Nichi, Y.; Mori, T.; Tada, N.; Suefuji, T.; Frohn, H. J. J. Am. Chem. Soc. 2005,
127, 10460–10461. (b) Li, Y.; Liu, X.; Ma, D.; Liu, B.; Jiang, H. Adv. Synth. Catal. 2012, 354,
2683–2688. (c) Liu, Q.; Wu, Y.; Chen, P.; Liu, G. Org. Lett. 2013, 15, 6210–6213. (d) Yoshida, M.;
Komata, A.; Hara, S. Tetrahedron 2006, 62, 8636–8645. (e) Nguyen, T.-H; Abarbri, M.; Guilloteau,
D.; Mavel, S.; Emond, P. Tetrahedron 2011, 67, 3434–3439. (f) Yoshida, M.; Osafune, K.; Hara, S.
Synthesis 2007, 1542–1546. (g) Compain, G.; Jouvin, K.; Martin-Mingot, A.; Evano, G.; Marrot, J.;
Thibeaudeau, S. Chem. Commun. 2012, 48, 5196–5198.
[8] (a) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134–7135. (b)
Truong, T.; Kimovica, K.; Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342–9345.
[9] Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132, 12150–12154.
[10] Schuler, M.; Silva, F.; Babbio, C.; Tessier, A.; Gouverneur, V. Angew. Chem., Int. Ed. 2008,
47, 7927–7930.
[11] Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y. Garaía-Fortanet, J.; Kinzel, T.; Buchwald,
S. L. Science 2009, 325, 1661–1664.
[12] (a) Akana, J. A.; Bhattacharyya, K. X.; Müller, P.; Sadghi, J. P. J. Am. Chem. Soc. 2007, 129,
7736–7737. (b) Gorske, B. C.; Mbofana, C. T.; Miller, S. J. Org. Lett. 2009, 11, 4318–4321. (c)
Okoromoba, O. E.; Han, J.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2014, 136, 14381–14384.
(d) Nahra, F.; Patrick, S. R.; Bello, D.; Brill, M.; Obled, A.; Cordes, D. B.; Slawin, A. M. Z.;
O’Hagan, D.; Nolan, S. P. ChemCatChem 2015, 7, 240–244.
[13] Structures of major and minor regioisomers were characterized by 2D NMR measurements.
Minor products were thus found to be m-terphenyl derivatives. For regioselectivity on
nickel-catalyzed coupling reactions of alkynes via oxidative cyclization, see: Liu, P.; McCarren, P.;
Cheong, P. H. -Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050–2057.
[14] Reactions with terminal alkynes such as 1-hexyne, phenylacetylene, and
43
trimethylsilylacetylene afforded the corresponding fluoroarenes, albeit in 5%, 3%, and 5% yields
(determined by 19F NMR spectroscopy with PhCF3 as an internal standard), respectively.
[15] A stepwise oxidative cyclization model satisfactorily illustrates the experimental results. This
stepwise model consists of (i) rapid pre-equilibrium between the reactants (Ni0 and 1) and
intermediary nickelacyclropropane and (ii) subsequent slow insertion of 2 into the
nickelacyclopropanes.
[16] The proposed oxidative cyclization is supported by Hoberg’s and Chatani’s reports. See: (a)
Hoberg, H.; Guhl, D. J. Organomet. Chem. 1989, 378, 279–292. (b) Takauchi, M.; Chatani, N. Org.
Lett. 2010, 12, 5132–5134.
[17] In the case of the reaction of 1,1-difluoro-1,6-enyne 5 with diphenylacetylene (2a), β-hydrogen
elimination yielding the corresponding fluoroarene 6 was sluggish, probably due to the rigid
bicyclic system of the intermediate. Thus, in the presence of the reductant, Et3B–i-PrOLi,
transmetalation from the intermediary cyclohexadienylnickel(II) fluoride corresponding to C in
Scheme 2-5 preferably occurred rather than β-hydrogen elimination, leading to the cyclohexadiene.
To avoid confusion, we herein demonstrate that the stoichiometric reaction, conducted in the
absence of the reductant, selectively afforded the corresponding fluoroarene 6 (Eq. 2-1).
[18] Hughes, R. P. Eur. J. Inorg. Chem. 2009, 4591–4606.
[19] Takauchi, M.; Kita, Y.; Tobisu, M.; Fukumoto, Y.; Chatani, N. Angew. Chem., Int. Ed. 2010,
122, 8899–8902.
[20] Since generation of ethylene and dihydrogen during the reaction was confirmed by each gas
detector, a β-hydrogen elimination-reductive elimination sequence definitely occurred as a route
from NiII to Ni0.
[21] (a) Sarhan, A. A. O.; Bolm, C. Chem Soc. Rev. 2009, 38, 2730–2744. (b) Grzybowski, M.;
Skonieczny, K.; Butenschön, H.; Gryko, D. T. Angew. Chem., Int. Ed. 2013, 52, 9900–9930.
44
[22] Danz, M.; Tonner, R.; Hilt, G. Chem. Commun. 2012, 48, 377–379.
[23] Fuchibe, K.; Morikawa, T.; Shigeno, K.; Fujita, T.; Ichikawa, J. Org. Lett. 2015, 17, 1126–
1129.
[24] Wang, Y.; Burton, D. J. Tetrahedron Lett. 2006, 47, 9279–9281.
[25] (a) Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS Catal. 2015, 5, 5947–5950. (b) Fujita, T.; Watabe,
Y.; Ichitsuka, T.; Ichikawa, J. Chem.—Eur. J. 2015, 21, 13225–13228. (c) Ichitsuka, T.; Fujita, T;
Arita, T.; Ichikawa, J. Angew. Chem., Int. Ed. 2014, 53, 7564–7568. (d) Fujita, T.; Arita, T.;
Ichitsuka, T.; Ichikawa, J. Dalton Trans. 2015, 19460–19463.
[26] Tobisu, M.; Xu, T.; Shimasaki, T.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 19505–19511.
[27] (a) Liu, P.; McCarren, P.; Cheong, P. H.-Y.; Jamison, T. F. Houk, K. N. J. Am. Chem. Soc.
2010, 132, 2050–2057. (b) Liu, P.; Montgomery, J.; Houk, K. N. J. Am. Chem. Soc. 2011, 133,
6956–6959.
[28] (a) Konev, A. S.; Khlebnikov, A. F. Collect. Czech. Chem. Commun. 2008, 73, 1553–1834. (b)
Hayashi, T.; Usuki, Y.; Wakamatsu, Y.; Iio, H. Synlett 2010, 2843–2846.
2-5. Experimental Section
General
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a Bruker Avance 500 or a JEOL
ECS-400 spectrometer. Chemical shift values are given in ppm relative to internal Me4Si (for 1H
NMR: δ = 0.00 ppm), CDCl3 (for 13C NMR: δ = 77.0 ppm), and C6F6 (for 19F NMR: δ = 0.00 ppm).
IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance
(ATR) method. Mass spectra were measured on a JEOL JMS-T100GCV or a JMS-T100CS
spectrometer. Elemental analyses were carried out at the Elemental Analysis Laboratory, Division
45
of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba. All reactions were
carried out under argon. Reactions using 1,1-difluoroethylene were carried out on an EYELA
Personal Organic Synthesizer Zodiac CCX-11A apparatus. Column chromatography was performed
on silica gel (Kanto Chemical Co. Inc., Silica Gel 60). Medium pressure liquid chromatography
(MPLC) was performed on a Yamazen YFLC-AI-580 apparatus equipped with tandemly-arrayed
two silica gel columns (Universal Column f30 x 165 mm). Gel permeation chromatography (GPC)
was performed on a JAI LC-908 apparatus equipped with a JAIGEL-1H and -2H assembly. Toluene
and dichloromethane (DCM) were purified by a solvent-purification system (Glass Contour)
equipped with columns of activated alumina and supported-copper catalyst (Q-5) before use.
i-PrOH and MeNO2 were distilled from CaH2 prior to use. Diarylacetylenes 2b–2g,[1,2] di-tert-butyl
oct-4-ynedioate (2i),[3] 1,8-bis(benzyloxy)oct-4-yne (2j),[4] 1-phenylprop-1-yne (2m),[5] and
1-(4-methoxyphenyl)prop-1-yne (2n)[6] were prepared according to the literature procedures. Unless
otherwise noted, reagents were purchased from commercial suppliers, and were used as received.
46
Synthesis of Alkynes
1,8-Bis(tetrahydro-2H-pyran-2-yloxy)oct-4-yne (2k)[7]
In a 30-mL two-necked flask were placed 4-octyn-1,8-diol (569 mg 4.00 mmol) and
dichloromethane (3.0 mL). To the mixture were added 3,4-dihydro-2H-pyran (1.02 mL, 11.2 mmol)
and Al(OTf)3 (19 mg, 0.040 mmol). After stirring for 4 h at room temperature, aqueous sodium
bicarbonate was added to the reaction mixture. Organic materials were extracted three times with
dichloromethane. The combined extracts were washed with brine and dried over anhydrous Na2SO4.
After removal of the solvent under reduced pressure, the residue was purified by silica gel column
chromatography (hexane/EtOAc = 10:1) to give alkyne 2k as a colorless oil (1.18 g, 95%).
1H NMR (500 MHz, CDCl3): δ 1.48–1.62 (m, 8H), 1.68–1.87 (m, 8H), 2.26 (t, J = 6.5 Hz, 4H),
3.44–3.54 (m, 4H), 3.78–3.92 (m, 4H), 4.60 (t, J = 3.5 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ
15.7, 19.5, 25.5, 29.3, 30.7, 62.1, 66.1, 79.8, 98.8. IR (neat): ν~ 2939, 2870, 1441, 1354, 1230, 1136,
1119, 1061, 1032, 1018, 987, 868, 793, 752 cm–1. HRMS (EI+): m/z Calcd. for C18H30O4 [M]+:
310.2144. Found: 310.2132.
2,2,13,13-Tetramethyl-3,12-dioxa-2,13-disilatetradec-7-yne (2l)[8]
In a 200-mL two-necked flask were placed imidazole (762 mg, 11.2 mmol), dichloromethane (20
Al(OTf)3 (1 mol %)
DCM, RT, 4 h
Ref. 7OHHO O
(2.8 eq)
+OO
O O
2k
Imidazole (2.8 equiv)
DCM, 0 °C, 2 h
Ref. 8OHHO
(3.6 eq)
+OOSi Si
Cl Si
2l
47
mL), and 4-octyn-1,8-diol (568 mg, 3.99 mmol). To the mixture was slowly added a trimethylsilyl
chloride (1.83 mL, 14.4 mmol) at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was
filtered through a pad of silica gel (EtOAc). After the filtrate was concentrated under reduced
pressure, the residue was purified by silica gel column chromatography (hexane/EtOAc =1:1) to
give alkyne 2l as a colorless oil (1.05 g, 92%).
1H NMR (500 MHz, CDCl3): δ 0.12 (s, 18H), 1.69 (tt, J = 6.7, 6.7 Hz, 4H), 2.22 (t, J = 6.7 Hz, 4H),
3.66 (t, J = 6.7 Hz, 4H). 13C NMR (126 MHz, CDCl3): δ –0.5, 15.2, 32.0, 61.2, 79.8. IR (neat): ν~
2952, 2866, 1437, 1387, 1250, 1097, 960, 847, 752, 692 cm–1. HRMS (EI+): m/z Calcd. for
C14H30O2Si2 [M]+: 286.1784. Found: 286.1789.
Synthesis of Fluoroarenes via Nickel-Catalyzed [2+2+2] Cycloaddition
Typical procedure for synthesis of fluoroarenes 3
1-Fluoro-2,3,4,5-tetraphenylbenzene (3a)
In an argon-purged 50-mL test tube equipped with a PTFE cap (EYELA, PPS25-TC) were placed
i-PrOH (179 µL, 2.3 mmol) and toluene (2.4 mL). To the mixture was slowly added n-BuLi (1.58
M in hexane, 1.47 mL, 2.32 mmol) at 0 °C. After stirring for 10 min at 0 °C, BEt3 (1.0 M in hexane,
2.32 mL, 2.3 mmol) was added to the reaction mixture at the same temperature. The reaction
mixture was warmed to room temperature, and was stirred for another 30 min. To the reaction
mixture were added diphenylacetylene (2a, 414 mg, 2.32 mmol), Ni(cod)2 (32 mg, 0.12 mmol),
PCy3 (33 mg, 0.12 mmol), and toluene (2.3 mL). The reaction vessel was evacuated, filled with
F
48
1,1-difluoroethylene (1, 1.0 atm, 56 mL, 2.3 mmol) through a balloon, and then sealed by closing
the stopcock of the PTFE cap. After stirring for 12 h at 40 °C, the reaction mixture was filtered
through a pad of silica gel (EtOAc). The filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane/EtOAc = 20:1) to give
fluoroarene 3a as a white solid (380 mg, 82%).
1H NMR (500 MHz, CDCl3): δ 6.75–6.80 (m, 4H), 6.88–6.92 (m, 6H), 7.10–7.20 (m, 10H), 7.28 (d,
JHF = 10.1 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 116.2 (d, JCF = 24 Hz), 125.7, 125.8, 126.6,
126.8, 126.9, 127.0, 127.5, 127.7, 128.2 (d, JCF = 15 Hz), 129.7, 130.8, 131.2, 131.7, 134.6, 136.3
(d, JCF = 4 Hz), 139.0 (d, JCF = 3 Hz), 139.3, 140.9, 142.5 (d, JCF = 8 Hz), 143.2 (d, JCF = 3 Hz),
158.8 (d, JCF = 246 Hz). 19F NMR (471 MHz, CDCl3): δ 47.0 (d, JFH = 10 Hz). IR (neat): ν~ 3059,
3026, 1601, 1556, 1442, 1394, 1336, 1142, 908, 762, 737, 698, 577 cm–1. Elemental analysis: Calcd.
for C30H21F: C, 89.97; H, 5.29. Found: C, 89.85; H, 5.50.
1-Fluoro-2,3,4,5-tetrakis(3-methylphenyl)benzene (3b)
Fluoroarene 3b was synthesized by the method described for 3a using
bis(3-methylphenyl)acetylene (2b, 478 mg, 2.32 mmol). Purification by silica gel column
chromatography (hexane/EtOAc = 40:1) gave fluoroarene 3b as a white solid (380 mg, 72%).
1H NMR (500 MHz, CDCl3): δ 2.01 (s, 6H), 2.22 (s, 6H), 6.51–6.65 (m, 4H), 6.67–6.72 (m, 2H),
6.74–6.82 (m, 2H), 6.85–6.90 (m, 2H), 6.94–6.98 (m, 4H), 7.00–7.08 (m, 2H), 7.24 (d, JHF = 10.7
Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 21.0, 21.1, 21.28, 21.30, 115.9 (d, JCF = 24 Hz), 126.2,
F
49
126.3, 126.5, 126.6, 126.8, 127.18, 127.25, 127.4, 127.5, 127.8, 128.1 (d, JCF = 15 Hz), 128.3,
128.6, 130.5, 131.5, 132.1, 132.5, 134.6, 135.9 (d, JCF = 2 Hz), 136.1 (d, JCF = 3 Hz), 136.4 (d, JCF
= 3 Hz), 136.8, 137.1, 138.9 (d, JCF = 1 Hz), 139.2, 140.9, 142.3 (d, JCF = 9 Hz), 143.3 (d, JCF = 2
Hz), 158.7 (d, JCF = 246 Hz). 19F NMR (471 MHz, CDCl3): δ 45.3 (d, JFH = 11 Hz). IR (neat): ν~
3033, 2920, 2862, 1604, 1448, 870, 783, 756, 731, 702 cm–1. HRMS (EI+): m/z Calcd. for C34H29F
[M]+: 456.2253. Found: 456.2247.
1-Fluoro-2,3,4,5-tetrakis(4-methylphenyl)benzene (3c)
Fluoroarene 3c was synthesized by the method described for 3a using
bis(4-methylphenyl)acetylene (2c, 478 mg, 2.32 mmol). Purification by silica gel column
chromatography (hexane/EtOAc = 30:1) gave fluoroarene 3c as a white solid (435 mg, 81%).
1H NMR (500 MHz, CDCl3): δ 2.13 (s, 3H), 2.15 (s, 3H), 2.27 (s, 3H), 2.27 (s, 3H), 6.62–6.65 (m,
4H), 6.69–6.73 (m, 4H), 6.97–6.98 (m, 8H), 7.21 (d, JHF = 10.3 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ 21.11, 21.11, 21.11, 21.2, 116.1 (d, JCF = 24 Hz), 127.6, 127.7, 128.0 (d, JCF = 15 Hz),
128.3, 128.4, 129.6, 130.6, 131.1, 131.5, 131.8, 134.9, 135.0, 136.0, 136.2, 136.2, 136.3 (d, JCF = 3
Hz), 136.5, 138.3 (d, JCF = 2 Hz), 142.3 (d, JCF = 8 Hz), 143.2 (d, JCF = 3 Hz), 158.8 (d, JCF = 245
Hz). 19F NMR (471 MHz, CDCl3): δ 46.4 (d, JFH = 10 Hz). IR (neat): ν~ 3055, 3024, 1520, 1446,
814, 742 cm–1. HRMS (EI+): m/z Calcd. for C34H29F [M]+: 456.2248. Found: 456.2254.
1,2,3,4-Tetrakis(4-butylphenyl)-5-fluorobenzene (3d)
F
50
Fluoroarene 3d was synthesized by the method described for 3a using
bis(4-butylphenyl)acetylene (2d, 670 mg, 2.31 mmol). Purification by silica gel column
chromatography (hexane/EtOAc = 40:1) gave fluoroarene 3d as a pale yellow solid (572 mg, 79%).
1H NMR (500 MHz, CDCl3): δ 0.84 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 7.3 Hz,
3H), 0.90 (t, J = 7.3 Hz, 3H), 1.11–1.20 (m, 4H), 1.25–1.34 (m, 4H), 1.37–1.45 (m, 4H), 1.50–1.57
(m, 4H), 2.33–2.42 (m, 4H), 2.51–2.54 (m, 4H), 6.60–6.70 (m, 8H), 6.94–7.00 (m, 8H), 7.24 (d, JHF
= 10.3 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 13.92, 13.92, 13.93, 13.93, 21.77, 21.78, 22.2, 22.3,
33.34, 33.34, 33.36, 33.40, 35.02, 35.02, 35.2, 35.3, 115.9 (d, JCF = 24 Hz), 126.5, 126.8, 127.0,
237.4, 127.6, 129.6, 130.6, 131.1, 131.4, 131.5, 132.0, 136.4 (d, JCF = 3 Hz), 136.5 (d, JCF = 3 Hz),
136.8, 139.8, 139.9, 141.0, 141.1, 142.2 (d, JCF = 9 Hz), 143.4 (d, JCF = 3 Hz), 158.8 (d, JCF = 245
Hz). 19F NMR (471 MHz, CDCl3): δ 45.7 (d, JFH = 10 Hz). IR (neat): ν~ 2956, 2927, 2858, 1518,
1458, 1095, 1020, 800, 733, 542 cm–1. HRMS (EI+): m/z Calcd. for C46H53F [M]+: 624.4126.
Found: 624.4142.
1-Fluoro-2,3,4,5-tetrakis(4-methoxyphenyl)benzene (3e)
Fluoroarene 3e was synthesized by the method described for 3a using
F
Bu
Bu Bu
Bu
F
MeO
MeO OMe
OMe
51
bis(4-methoxyphenyl)acetylene (2e, 551 mg, 2.31 mmol). Purification by silica gel column
chromatography (hexane/EtOAc = 10:1) gave fluoroarene 3e as a white solid (480 mg, 80%).
1H NMR (500 MHz, CDCl3): δ 3.65 (s, 3H), 3.67 (s, 3H), 3.76 (s, 3H), 3.76 (s, 3H), 6.45–6.50 (m,
4H), 6.63–6.67 (m, 4H), 6.70–6.75 (m, 4H), 6.99–7.02 (m, 4H), 7.20 (d, JHF = 10.3 Hz, 1H). 13C
NMR (126 MHz, CDCl3): δ 54.96, 54.98, 55.1, 55.2, 112.5, 112.6, 113.1, 113.2, 116.0 (d, JCF = 23
Hz), 127.1, 127.7 (d, JCF = 15 Hz), 130.8, 131.8, 131.9, 132.0, 132.3, 132.7, 133.7, 136.1 (d, JCF = 3
Hz), 142.0 (d, JCF = 9 Hz), 143.1 (d, JCF = 4 Hz), 157.3, 157.3, 158.2, 158.2, 158.9 (d, JCF = 245
Hz). 19F NMR (471 MHz, CDCl3): δ 46.6 (d, JFH = 10 Hz). IR (neat): ν~ 2962, 2935, 2837, 1608,
1516, 1450, 1286, 1242, 1176, 1032, 906, 831, 731 cm–1. HRMS (EI+): m/z Calcd. for C34H29FO4
[M]+: 520.2044. Found: 520.2068.
1-Fluoro-2,3,4,5-tetrakis[4-(trifluoromethyl)phenyl]benzene (3f)
Fluoroarene 3f was synthesized by the method described for 3a using
bis[4-(trifluoromethyl)phenyl]acetylene (2f, 728 mg, 2.32 mmol). Purification by silica gel column
chromatography (hexane/CHCl3 = 8:1) gave fluoroarene 3f as a white solid (589 mg, 76%).
1H NMR (500 MHz, CDCl3): δ 6.87–6.92 (m, 4H), 7.19–7.25 (m, 8H), 7.35 (d, JHF = 9.7 Hz, 1H),
7.45–7.50 (m, 4H). 13C NMR (126 MHz, CDCl3): δ 117.3 (d, JCF = 24 Hz), 121.1–126.6 (4C),
124.5 (q, JCF = 4 Hz), 124.6 (q, JCF = 4 Hz), 124.9 (q, JCF = 4 Hz), 125.1 (q, JCF = 4 Hz), 127.8–
130.2 (4C), 129.9, 130.9, 131.2, 131.5, 131.6, 135.1 (d, JCF = 4 Hz), 137.3, 141.5, 141.79, 141.82,
F
F3C
F3C CF3
CF3
52
142.0 (d, JCF = 9 Hz), 143.4, 159.0 (d, JCF = 250 Hz). 19F NMR (471 MHz, CDCl3): δ 49.4 (d, JFH =
10 Hz, 1F), 100.3 (s, 3F), 100.37 (s, 3F), 100.38 (s, 3F), 100.5 (s, 3F). IR (neat): ν~ 2931, 1618,
1325, 1167, 1124, 1066, 1018 cm–1. HRMS (EI+): m/z Calcd. for C34H17F13 [M]+: 672.1117. Found:
672.1096.
1,2,3,4-Tetrakis(3-chlorophenyl)-5-fluorobenzene (3g)
Fluoroarene 3g was synthesized by the method described for 3a using
bis(3-chlorophenyl)acetylene (2g, 581 mg, 2.35 mmol). Purification by silica gel column
chromatography (hexane/EtOAc = 20:1) gave fluoroarene 3g as a white solid (285 mg, 45%).
1H NMR (500 MHz, CDCl3): δ 6.64 (dd, J = 7.4, 7.4 Hz, 1H), 6.69 (dd, J = 7.4, 7.4 Hz, 1H), 6.76
(d, J = 6.5 Hz, 1H), 6.80–6.83 (m, 1H), 6.87–7.00 (m, 6H), 7.11 (dd, J = 8.0, 8.0 Hz, 1H), 7.14–
7.16 (m, 3H), 7.17–7.20 (m, 2H), 7.28 (d, JHF = 9.8 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 116.7
(d, JCF = 23 Hz), 126.7, 126.8, 127.3, 127.5 (d, JCF = 18 Hz), 127.6, 127.8, 128.6 (d, JCF = 13 Hz),
128.65 (d, JCF = 12 Hz), 128.75, 129.0, 129.06 (d, JCF = 17 Hz), 129.13, 129.5 (d, JCF = 14 Hz),
129.6, 130.6, 130.8, 131.2, 133.2 (d, JCF = 8 Hz), 133.4 (d, JCF = 7 Hz), 133.7, 133.9, 135.0 (d, JCF
= 3 Hz), 135.5, 139.7 (d, JCF = 2 Hz), 140.0, 141.65 (d, JCF = 8 Hz), 141.68, 141.75 (d, JCF = 3 Hz),
158.8 (d, JCF = 251 Hz). 19F NMR (471 MHz, CDCl3): δ 47.6 (d, JFH = 10 Hz). IR (neat): ν~ 2362,
1595, 1564, 1441, 1412, 1138, 1080, 1036, 906, 887, 835, 783, 719, 698 cm–1. HRMS (EI+): m/z
Calcd. for C30H17Cl4F [M]+: 536.0068. Found: 536.0091.
FCl Cl
ClCl
53
1-Fluoro-2,3,4,5-tetra(propyl)benzene (3h)
Fluoroarene 3h was synthesized by the method described for 3a using 4-octyne (3h, 258 mg,
2.34 mmol). Purification by silica gel column chromatography (hexane/CHCl3 = 8:1) gave
fluoroarene 3h as a colorless oil (244 mg, 79%).
1H NMR (500 MHz, CDCl3): δ 0.98–1.05 (m, 12H), 1.43–1.63 (m, 8H), 2.49–2.57 (m, 8H), 6.68 (d,
JHF = 11.2 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 14.3, 14.5, 14.86, 14.88, 24.0, 24.3, 24.8, 24.9,
28.0 (d, JCF = 4 Hz), 31.2, 31.7 (d, JCF = 2 Hz), 35.0, 113.0 (d, JCF = 23 Hz), 125.2 (d, JCF = 15 Hz),
134.2 (d, JCF = 3 Hz), 139.8 (d, JCF = 6 Hz), 140.9 (d, JCF = 4 Hz), 159.7 (d, JCF = 241 Hz). 19F
NMR (471 MHz, CDCl3): δ 41.8 (d, JFH = 11 Hz). IR (neat): ν~ 2956, 2929, 2870, 1577, 1464, 1377,
1092, 856, 742 cm–1. Elemental analysis: Calcd. for C18H24F: C, 81.76; H, 11.05. Found: C, 81.90;
H, 11.19. HRMS (EI+): m/z Calcd. for C18H29F [M]+: 264.2248. Found: 264.2259.
tert-Butyl 3,3',3'',3'''-(5-fluorobenzene-1,2,3,4-tetrayl)tetrapropanoate (3i)
Fluoroarene 3i was synthesized by the method described for 3a using
1,8-bis(tetrahydro-2H-pyran-2-yloxy)oct-4-yne (2i, 670 mg, 2.37 mmol). Purification by silica gel
column chromatography (hexane/EtOAc = 10:1) gave fluoroarene 3i as a colorless oil (281 mg,
39%).
F
F
CO2t-Bu
CO2t-Bu
t-BuO2C
t-BuO2C
54
1H NMR (500 MHz, CDCl3): δ 1.43 (s, 18H), 1.44 (s, 18H), 2.40–2.48 (m, 8H), 2.84–2.90 (m, 8H),
6.75 (brs, 1H). 13C NMR (126 MHz, CDCl3): δ 20.99, 21.03, 27.46, 27.48, 28.08, 28.08, 28.08,
28.08, 35.55, 35.55, 36.59, 36.59, 80.36, 80.36, 80.49, 80.49, 123.8 (d, JCF = 17 Hz), 124.8 (d, JCF =
2 Hz), 129.5, 136.6, 138.4 (d, JCF = 5 Hz), 160.1 (d, JCF = 244 Hz), 171.93, 171.93, 172.08, 172.08.
19F NMR (471 MHz, CDCl3): δ 41.2 (brs). IR (neat): ν~ 2978, 2360, 1730, 1367, 1151, 771 cm–1.
HRMS (EI+): m/z Calcd. for C34H53FO8 [M]+: 608.3726. Found: 608.3717.
1,2,3,4-Tetrakis(3-benzyloxyprop-1-yl)-5-fluorobenzene (3j)
Fluoroarene 3j was synthesized by the method described for 3a using
1,8-bis(benzyloxy)oct-4-yne (2j, 745 mg, 2.31 mmol). Purification by silica gel column
chromatography (hexane/EtOAc = 10:1) gave fluoroarene 3j as a colorless oil (460 mg, 58%).
1H NMR (500 MHz, CDCl3): δ 1.75–1.79 (m, 4H), 1.81–1.91 (m, 4H), 2.66–2.75 (m, 8H), 3.47–
3.52 (m, 8H), 4.46 (s, 2H), 4.47 (s, 2H), 4.49 (s, 4H), 6.71 (d, JHF = 11.1 Hz, 1H), 7.25–7.29 (m,
2H), 7.31–7.34 (m, 18H). 13C NMR (126 MHz, CDCl3): δ 22.3 (d, JCF = 3 Hz), 25.2, 25.7, 29.2,
30.5, 31.0, 31.4, 31.5, 69.6, 69.9, 70.05, 70.12, 72.7, 72.79, 72.79, 72.79, 113.3 (d, JCF = 22 Hz),
125.0 (d, JCF = 14 Hz), 127.36, 127.39, 127.39, 127.39, 127.44, 127.44, 127.52, 127.55, 128.25,
128.25, 128.25, 128.3, 133.9 (d, JCF = 3 Hz), 138.5, 138.60, 138.60, 138.60, 139.5 (d, JCF = 8 Hz),
140.6 (d, JCF = 4 Hz), 159.8 (d, JCF = 241 Hz). 19F NMR (471 MHz, CDCl3): δ 42.3 (d, JFH = 11
Hz). IR (neat): ν~ 2935, 2862, 1454, 1363, 1099, 1074, 1028, 735, 696 cm–1. HRMS (EI+): m/z
Calcd. for C46H53FO4 [M]+: 688.3928. Found: 688.3931.
F
OBnBnO
OBnBnO
55
2,2',2'',2'''-[3,3',3'',3'''-(5-Fluorobenzene-1,2,3,4-tetrayl)tetrakis(propane-3,1-diyl)]tetrakis(ox
y)tetrakis(tetrahydro-2H-pyran) (3k)
Fluoroarene 3k was synthesized by the method described for 3a using
1,8-bis(tetrahydro-2H-pyran-2-yloxy)oct-4-yne (2k, 712 mg, 2.29 mmol). Purification by silica gel
column chromatography (hexane/EtOAc = 5:1) gave fluoroarene 3k as a pale yellow oil (511 mg,
67%).
1H NMR (500 MHz, CDCl3): δ 1.50–1.64 (m, 16H), 1.69–1.79 (m, 8H), 1.79–1.91 (m, 8H), 2.62–
2.79 (m, 8H), 3.40–3.48 (m, 4H), 3.48–3.55 (m, 4H), 3.77–3.93 (m, 8H), 4.58–4.64 (m, 4H), 6.73
(d, JHF = 11.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 19.64, 19.64, 19.64, 19.64, 22.5 (d, JCF = 3
Hz), 25.4, 25.52, 25.52, 25.52, 25.52, 26.0, 29.3, 30.6, 30.79, 30.79, 30.79, 30.79, 31.1, 31.57,
31.64, 62.25, 62.25, 62.25, 62.30, 66.9, 67.18, 67.24, 67.3, 98.8, 98.85, 98.85, 98.85, 113.3 (d, JCF
= 23 Hz), 125.1 (d, JCF = 14 Hz), 133.9, 139.6 (d, JCF = 8 Hz), 140.6, 159.8 (d, JCF = 242 Hz). 19F
NMR (471 MHz, CDCl3): δ 42.2 (d, JFH = 11 Hz). IR (neat): ν~ 2939, 2868, 1452, 1352, 1200, 1119,
1074, 1032, 1020, 989, 904, 868, 814 cm–1. HRMS (EI+): m/z Calcd. for C38H61FO8 [M]+: 664.4351.
Found: 664.4361.
1-Fluoro-2,3,4,5-Tetrakis(3-trimethylsiloxyprop-1-yl)benzene (3l)
F
OTHPTHPO
OTHPTHPO
F
OSiMe3Me3SiO
OSiMe3Me3SiO
56
Fluoroarene 3l was synthesized by the method described for 3a using
2,2,13,13-tetramethyl-3,12-dioxa-2,13-disilatetradec-7-yne (2l, 675 mg, 2.36 mmol). Purification
by silica gel column chromatography (hexane/EtOAc = 1:1) gave fluoroarene 3l as a pale yellow oil
(451 mg, 62%).
1H NMR (500 MHz, CDCl3): δ 0.71 (s, 9H), 0.12 (s, 9H), 0.13 (s, 18H), 1.65–1.83 (m, 8H), 2.58–
2.70 (m, 8H), 3.61–3.69 (m, 8H), 6.71 (d, JHF = 11.1 Hz). 13C NMR (126 MHz, CDCl3): δ –0.5, –
0.44, –0.44, 1.0, 22.1 (d, JCF = 3 Hz), 25.5 (d, JCF = 3 Hz), 28.9, 29.7, 33.5, 33.9, 34.4, 34.5, 62.1,
62.39, 62.41, 62.5, 113.2 (d, JCF = 22 Hz), 125.0 (d, JCF = 14 Hz), 133.9 (d, JCF = 3 Hz), 139.5 (d,
JCF = 8 Hz), 140.6 (d, JCF = 4 Hz), 159.8 (d, JCF = 241 Hz). 19F NMR (471 MHz, CDCl3): δ 41.0 (d,
JFH = 11 Hz). IR (neat): ν~ 2956, 1250, 1097, 866, 839, 746 cm–1. HRMS (EI+): m/z Calcd. for
C30H61FO4Si4 [M]+: 616.3631. Found: 616.3610.
1-Fluoro-2,5-dimethyl-3,4-diphenylbenzene (3m)
Fluoroarene 3m was synthesized by the method described for 3a using 1-phenylprop-1-yne (2m,
270 mg, 2.32 mmol). The crude product was purified by silica gel chromatography (hexane) and
further preparative thin-layer chromatography to gave a mixture of fluoroarene 3m and another
minor isomer 3m' as a pale yellow oil (189 mg, 59% with a 84:16 regioisomer ratio). The structural
characterization of 3m and 3m' was performed by 1H–13C heteronuclear multiple-bond correlation
(HMBC) measurement (See pages S41 and S43) as well as 1D NMR measurements (1H, 13C, and
F
+
F
3m(major)
3m'(minor)
57
19F). Compounds 3m and 3m' were isolated by iterated silica gel column chromatography (hexane).
3m: 1H NMR (500 MHz, CDCl3): δ 1.80 (s, 3H), 2.04 (s, 3H), 6.92 (d, JHF = 10.0 Hz, 1H), 7.15–
7.17 (m, 2H), 7.29–7.31 (m, 2H), 7.33–7.38 (m, 2H), 7.42–7.45 (m, 4H). 13C NMR (126 MHz,
CDCl3): δ 18.7 (d, JCF = 3 Hz), 21.0, 113.8 (d, JCF = 23 Hz), 126.8, 127.0, 127.5, 128.2, 128.6,
129.3, 130.1, 135.4, 135.6, 137.1 (d, JCF = 8 Hz), 138.1, 140.9, 158.7 (d, JCF = 236 Hz). 19F NMR
(471 MHz, CDCl3): δ 46.1 (d, JFH = 10 Hz). IR (neat): ν~ 3057, 3024, 2924, 1466, 1442, 1032, 766,
561 cm–1. HRMS (EI+): m/z Calcd. for C20H17F [M]+: 276.1309. Found: 276.1314.
3m': 1H NMR (500 MHz, CDCl3): δ 1.98 (d, JHF = 2.2 Hz, 3H), 2.07 (s, 3H), 6.90–6.93 (m, 4H),
6.97 (d, JHF = 10.4 Hz, 1H) 7.06–7.14 (m, 6H). 13C NMR (126 MHz, CDCl3): δ 12.4 (d, JCF = 4 Hz),
20.8, 115.0 (d, JCF = 23 Hz), 120.5 (d, JCF = 16 Hz), 126.1, 126.2, 127.46, 127.46, 130.0, 130.3,
135.1 (d, JCF = 9 Hz), 137.3 (d, JCF = 4 Hz), 139.8 (d, JCF = 2 Hz), 140.2, 143.5 (d, JCF = 4 Hz),
160.2 (d, JCF = 244 Hz). 19F NMR (471 MHz, CDCl3): δ 43.5 (dq, JFH = 10, 2 Hz). IR (neat): ν~
2960, 2924, 1462, 1439, 1317, 1111, 750, 700 cm–1. HRMS (EI+): m/z Calcd. for C20H17F [M]+:
276.1314. Found: 276.1315.
1-Fluoro-3,4-bis(4-methoxyphenyl)-2,5-propylbenzene (3n)
Fluoroarene 3n was synthesized by the method described for 3a using 1-(4-methoxyphenyl)
pent-1-yne (2n, 404 mg, 2.32 mmol). The crude product was purified by silica gel chromatography
(hexane/EtOAc = 20:1) to gave a mixture of fluoroarene 3n and another minor isomer 3n' as a
F
+
F
3n(major)
3n'(minor)
OMeMeO OMe
MeO
58
white solid (274 mg, 60% with a 85:15 regioisomer ratio). Compounds 3n and 3n’ were isolated by
iterated preparative thin-layer chromatography (hexane/EtOAc = 10:1).
3n: 1H NMR (500 MHz, CDCl3): δ 0.42 (t, J = 7.7 Hz, 3H), 0.80 (t, J = 7.7 Hz, 3H), 1.08 (qt, J =
7.7, 7.7 Hz, 2H), 1.46 (qt, J = 7.7, 7.7 Hz, 2H), 2.16 (t, J = 7.7 Hz, 2H), 2.26 (t, J = 7.7 Hz, 2H),
3.85 (s, 3H), 3.87 (s, 3H), 6.88 (d, JHF = 10.3 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz,
2H), 7.08 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 14.1, 14.3,
23.97, 23.99, 33.1 (d, JCF = 3 Hz), 35.8, 55.20, 55.20, 112.5 (d, JCF = 23 Hz), 113.3, 113.5, 126.3 (d,
JCF = 16 Hz), 127.5, 131.0, 131.2, 132.4, 137.0 (d, JCF = 3 Hz), 142.39 (d, JCF = 2 Hz), 142.43 (d,
JCF = 3 Hz), 158.3, 158.7, 159.3 (d, JCF = 242 Hz). 19F NMR (471 MHz, CDCl3): δ 45.8 (d, JFH = 10
Hz). IR (neat): ν~ 2958, 2870, 1608, 1514, 1458, 1284, 1242, 1174, 1036, 831, 557 cm–1. HRMS
(EI+): m/z Calcd. for C26H29FO2 [M]+: 392.2152. Found: 392.2153.
3n': 1H NMR (500 MHz, CDCl3): δ 0.77 (t, J = 7.4 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H), 1.36–1.48 (m,
4H), 2.28–2.37 (m, 4H), 3.73 (s, 3H), 3.74 (s, 3H), 6.65 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz,
2H), 6.80 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.94 (d, JHF = 11.1 Hz, 1H). 13C NMR (126
MHz, CDCl3): δ 14.0, 14.2, 23.6, 24.0, 28.9 (d, JCF = 2 Hz), 35.6, 54.99, 54.99, 112.6, 112.7, 113.9
(d, JCF = 23 Hz), 125.7 (d, JCF = 16 Hz), 129.0, 131.0, 131.4, 132.2 (d, JCF = 3 Hz), 137.2 (d, JCF = 3
Hz), 140.3 (d, JCF = 8 Hz), 143.3 (d, JCF = 5 Hz), 157.5, 157.6, 160.4 (d, JCF = 244 Hz). 19F NMR
(471 MHz, CDCl3): δ 42.3 (d, JFH = 11 Hz). IR (neat): ν~ 2958, 2929, 1610, 1516, 1456, 1286, 1244,
1176, 1036, 835, 795, 775 cm–1. HRMS (EI+): m/z Calcd. for C26H29FO2 [M]+: 392.2152. Found:
392.2148.
Preparation and Reaction of Difluoroenyne
Preparation of 1,1-difluoro-1,6-enyne 5
1,1-Difluoro-1,6-enyne 5 was prepared according to the literature procedures.[9–11] Spectral data
59
for compound 5 showed good agreement with the literature data.[11]
Synthesis of Fluoroindane
Diethyl 4-fluoro-5,6,7-triphenyl-1H-indene-2,2(3H)-dicarboxylate (6)
In an argon-purged 50-mL test tube equipped with a PTFE cap (EYELA, PPS25-TC) were placed
Ni(cod)2 (69 mg, 0.25 mmol) and PCy3 (70 mg, 0.25 mmol). To the reaction mixture were added
toluene (5 mL), enyne 5 (88 mg, 0.25 mmol), and diphenylacetylene (2a, 45 mg, 0.25 mmol). After
stirring for 6 h at 60 °C, the reaction mixture was filtered through a pad of silica gel (EtOAc). The
filtrate was concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 20:1) gave fluoroindane 6 as a white solid (77 mg, 60%).
1H NMR (500 MHz, CDCl3): δ 1.20–1.29 (m, 6H), 3.45 (s, 2H), 3.75 (s, 2H), 4.16–4.25 (m, 4H),
6.71–6.77 (m, 2H), 6.87–6.92 (m, 3H), 6.99–7.06 (m, 3H), 7.08–7.18 (m, 5H) 7.25–7.28 (m, 2H).
13C NMR (126 MHz, CDCl3): δ 13.9, 14.0, 37.1 (d, JCF = 2 Hz), 37.3, 41.2 (d, JCF = 26 Hz), 55.0,
58.0, 61.7, 61.9, 116.9 (d, JCF = 8 Hz), 126.5, 127.1 (d, JCF = 1 Hz), 127.9, 128.0, 128.1, 128.2,
128.67, 128.70, 128.72, 133.5 (d, JCF = 7 Hz), 134.2 (d, JCF = 2 Hz), 135.1, 139.2, 141.6 (d, JCF = 2
Hz), 155.3 (d, JCF = 261 Hz), 171.3, 172.1. 19F NMR (471 MHz, CDCl3): δ 42.5 (s, 1F). IR (neat):
ν~ = 2981, 2359, 1730, 1444, 1431, 1255, 1234, 1188, 1157, 1070, 764, 700, 513 cm–1. HRMS
NaCH(CO2Et)2 (2.0 equiv)Pd(OAc)2 (4 mol %)
PPh3 (14 mol %)
THF, 40 °C, 2 hCBrF2
NaH (1.2 equiv)
THF, RT, 10 h
PhBr
(1.2 equiv)
EtO2CEtO2C
F
F
Ph
F
F
5
EtO2C
EtO2CRef. 9 Ref. 10
F
Ph
EtO2CEtO2C
Ph Ph
60
(EI+): m/z Calcd. For C33H29FO4 [M]+: 508.2050. Found: 508.2056.
Synthesis of Tribenzoperylene
2,3,12,13-Tetrabutyl-15-fluorotribenzo[b,n,pqr]perylene (7):
In a 200-mL two-necked flask were placed fluoroarene 3c (46 mg, 0.074 mmol) and
dichloromethane (74 mL). To the mixture was slowly added a CH3NO2 solution (15 mL) of FeCl3
(362 mg, 2.23 mmol) at 0 °C. After stirring for 1 h at 0 °C, the reaction was quenched with
methanol at 0 °C. The reaction mixture was filtered through a pad of silica gel (EtOAc), and the
filtrate was concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane) to give tribenzoperylene 7 as a pale yellow solid (34 mg, 74%).
1H NMR (500 MHz, CDCl3): δ 1.05 (t, J = 7.4 Hz, 3H), 1.05 (t, J = 7.4 Hz, 3H), 1.07 (t, J = 7.4 Hz,
3H), 1.08 (t, J = 7.4 Hz, 3H), 1.50–1.62 (m, 8H), 1.81–1.88 (m, 4H), 1.88–1.96 (m, 4H), 2.92 (t, J =
9.1 Hz, 2H), 2.94 (t, J = 8.1 Hz, 2H), 3.07 (t, J = 8.2 Hz, 2H), 3.09 (t, J = 8.1 Hz, 2H), 7.50 (d, J =
7.7 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 8.45 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.49 (d, JHF = 15.5 Hz,
1H), 8.52 (s, 1H), 8.53 (s, 1H), 8.57 (s, 1H), 8.60 (s, 1H), 8.62 (s, 1H), 9.10 (dd, J = 8.5 Hz, JHF =
3.8 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 14.10, 14.10, 14.14, 14.14, 22.65, 22.65, 22.79, 22.79,
33.88, 33.91, 34.4, 34.5, 36.1, 36.2, 36.8, 36.9, 107.5 (d, JCF = 28 Hz), 115.8 (d, JCF = 7 Hz), 119.4,
121.3, 121.5, 121.7, 121.8, 122.4, 122.57, 122.61 (d, JCF = 4 Hz), 122.8, 123.7, 125.7 (d, JCF = 5
Hz), 126.1 (d, JCF = 5 Hz), 127.2 (d, JCF = 3 Hz), 127.8 (d, JCF = 10 Hz), 128.0, 128.2 (d, JCF = 2
Hz), 128.3, 128.5, 129.0, 129.2, 130.1 (d, JCF = 5 Hz), 130.2, 130.3, 140.3, 141.1, 141.8, 142.3,
n-Bu
F
n-Bun-Bu
n-Bu
61
159.3 (d, JCF = 247 Hz). 19F NMR (471 MHz, CDCl3): δ 53.6–53.7 (m). IR (neat): ν~ 2952, 2925,
2854, 2359, 1614, 1456, 1390, 773 cm–1. HRMS (APCI+): m/z Calcd. for C46H48F [M+H]+:
619.3735. Found: 619.3717.
Mechanistic Studies
Kinetics
Dependency of the initial rate ((Δ[3a]/Δt)t=0) on the partial pressure of 1 (p(1))
In an argon-purged 50-mL test tube equipped with a PTFE cap (EYELA, PPS25-TC) were placed
i-PrOH (39 µL, 0.50 mmol) and toluene (1.0 mL). To the mixture was slowly added n-BuLi (1.58
M in hexane, 0.32 mL, 0.50 mmol) at 0 °C. After stirring for 10 min at 0 °C, BEt3 (1.0 M in hexane,
0.50 mL, 0.50 mmol) was added to the reaction mixture at the same temperature. The reaction
mixture was warmed to room temperature, and was stirred for another 30 min. To the reaction
mixture were added diphenylacetylene (2a, 89 mg, 0.50 mmol) and PCy3 (7.0 mg, 0.025 mmol).
The reaction vessel was evacuated and filled with 1,1-difluoroethylene (1, 1.0 atm, 56 mL, 2.3
mmol) through a balloon. After closing the stopcock of the PTFE cap, the balloon was replaced
with a pre-evacuated balloon. After opening the stopcock, Ar and 1 (e.g. 48 mL and 56 mL,
respectively, for p(1) = 0.7 atm) was added to the reaction vessel via a syringe. To the reaction
mixture was then added Ni(cod)2 (6.9 mg, 0.025 mmol). After stirring for 15 min at 40 °C, the
reaction mixture was quenched with phosphate buffer (pH 7). The yield of 3a was determined by
19F NMR using PhCF3 as an internal standard (Table S1).
In this experiment, the concentration of 1 in solution would be proportional to p(1) in the reaction
vessel on the basis of the assumption that the solubility of 1 in toluene follows Henry’s law. The
total pressure of a 1/Ar mixed gas in the reaction vessel was maintained at 1.0 atm by using a
balloon.
62
Table S1. Dependency of (Δ[3a]/Δt)t=0 on p(1) (See Figure 1a,b)
p(1) (atm) (Δ[3a]/Δt)t=0 x 104 (Ms–1) Standard error
Run 1 Run 2 Run 3 Average
0.3 0.232 0.170 0.140 0.181 0.027
0.5 0.338 0.244 0.383 0.322 0.041
0.7 0.481 0.458 0.529 0.486 0.018
1.0 0.559 0.706 0.809 0.691 0.073
Dependency of the initial rate ((Δ[3a]/Δt)t=0) on the initial concentration of 2a ([2a]0)
In an argon-purged 50-mL test tube equipped with a PTFE cap (EYELA, PPS25-TC) were placed
i-PrOH (39 µL, 0.50 mmol) and toluene (1.0 mL). To the mixture was slowly added n-BuLi (1.58
M in hexane, 0.32 mL, 0.50 mmol) at 0 °C. After stirring for 10 min at 0 °C, BEt3 (1.0 M in hexane,
0.50 mL, 0.50 mmol) was added to the reaction mixture at the same temperature. The reaction
mixture was warmed to room temperature, and was stirred for another 30 min. To the reaction
mixture were added diphenylacetylene (2a, e.g. 36 mg, 0.20 mmol: [2a]0 = 0.20 M) and PCy3 (7.0
mg, 0.025 mmol). The reaction vessel was evacuated (10 mm Hg, 3 s) and filled with
1,1-difluoroethylene (1) through a balloon (1.0 atm, ca. 2.5 L, ca. 0.10 mol). To the reaction
mixture was then added Ni(cod)2 (6.9 mg, 0.025 mmol). After stirring for 15 min at 40 °C, the
reaction mixture was quenched by phosphate buffer (pH 7). The yield of 3a was determined by 19F
NMR using PhCF3 as an internal standard (Table S2).
In this experiment, the concentration of 1 in solution was assumed to be constant because p(1) in
the reaction vessel was maintained at 1.0 atm by using a balloon.
63
Table S2. Dependency of (Δ[3a]/Δt)t=0 on [2a]0 (See Figure 1c,d)
[2a]0 (M) (Δ[3a]/Δt)t=0 x 104 (Ms–1) Standard error
Run 1 Run 2 Run 3 Average
0.2 0.0236 0.268 0.329 0.277 0.027
0.3 0.433 0.391 0.479 0.434 0.025
0.5 0.806 0.559 0.706 0.690 0.072
0.7 1.04 0.752 0.980 0.923 0.087
0.9 1.40 1.36 1.39 1.38 0.01
Dependency of the initial rate ((Δ[3a]/Δt)t=0) on the initial concentration of Ni(cod)2 and PCy3
([Ni]0)
In an argon-purged 50-mL test tube equipped with a PTFE cap (EYELA, PPS25-TC) were placed
diphenylacetylene (2a, 45 mg, 0.25 mmol), Ni(cod)2 (e.g. 3.5 mg, 0.013 mmol: [Ni]0 = 0.20 M) and
PCy3 (e.g. 3.6 mg, 0.013 mmol: [Ni]0 = 0.20 M). The reaction vessel was evacuated (10 mm Hg, 10
s) and filled with 1,1-difluoroethylene (1) through a balloon (1.0 atm, ca. 2.5 L, ca. 0.10 mol). To
the mixture was added toluene (1.0 mL). After stirring for 5 min at 40 °C, the reaction mixture was
quenched by phosphate buffer (pH 7). The yield of 3a was determined by 19F NMR using PhCF3 as
an internal standard (Table S3).
In this experiment, the concentration of 1 in solution was assumed to be constant because p(1) in
the reaction vessel was maintained at 1.0 atm by using a balloon.
Table S3. Dependency of (Δ[3a]/Δt)t=0 on [Ni]0 (See Figure 1e,f)
[Ni]0 (M) (Δ[3a]/Δt)t=0 x 104 (Ms–1) Standard error
64
Run 1 Run 2 Run 3 Average
0.013 0.140 0.168 0.170 0.159 0.01
0.038 0.340 0.546 0.611 0.499 0.082
0.063 0.963 0.888 1.21 1.02 0.097
0.088 1.39 1.44 1.24 1.36 0.060
0.11 1.68 1.56 1.61 1.62 0.035
Rate Equation
A stepwise oxidative cyclization model satisfactorily illustrates the experimental results (Scheme
S1). This stepwise model consists of (i) rapid pre-equilibrium between the reactants (Ni(0) and 1)
and the intermediary nickelacyclopropane E and (ii) subsequent slow insertion of 2 into E.
Scheme S1. Rate Equation of Nickel-Catalyzed [2+2+2] Cycloaddition of 1 and 2a
The steady state approximation is applied to [E].
![𝐄]!"
= 𝑘! 𝟏 𝐍𝐢 – 𝑘–![𝐄]– 𝑘![𝐄][𝟐𝐚] = 0 (1)
[𝐄] = !![𝟏][𝐍𝐢]!–!!!![𝟐𝐚]
(2)
Similarly, the steady state approximation is also applied to [A].
Ni
Ph
Ph
FF
II
A
k1
k–1 k2
Ph
Ph2aF
F
1
Ni
L
L L
L
0
Ni
NiL L
L
E
FF
Ph
F
Ph
Ph Ph
3a
k3
II2a
L = Ligand
65
![𝐀]!"
= 𝑘![𝐄][𝟐𝐚]– 𝑘![𝐀][𝟐𝐚] = 0 (3)
[𝐀] = !![𝐄]!! (4)
By combining eqs 2 and 4, we obtain
[𝐀] = !!!![𝟏][𝐍𝐢]!!(!–!!!![𝟐𝐚])
(5)
The rate equation for [3a] is written as follows
![𝟑𝐚]!"
= 𝑘![𝐀][𝟐𝐚] (6)
By combining eqs 5 and 6, we obtain
![𝟑𝐚]!"
= !!!![𝟏][𝟐𝐚][𝐍𝐢]!–!!!![𝟐𝐚]
= !!!![𝟏][𝟐𝐚][𝐍𝐢]
!–! !!!![𝟐𝐚] !–! (7)
Since k–1 >> k2[2a], we obtain
![𝟑𝐚]!"
= !!!!!–!
[𝟏][𝟐𝐚][𝐍𝐢] (8)
In the case of t = 0, we obtain [1] = [1]0, [2a] = [2a]0, and [Ni] = [Ni]0. Thus, the initial rate is
written as follows
![𝟑𝐚]!" !!!
= !!!!!–!
[𝟏]![𝟐𝐚]![𝐍𝐢]! (9)
Therefore, the first-order dependency of the initial rate on the initial concentration of each
component ([1]0, [2a]0, and [Ni]0) is theoretically derived.
Confirmation of Gas Generation
Generation of ethylene (Figure S1) and dihydrogen (Figure S2) was confirmed by each gas
detector after the reaction of 1,1-difluoroethylene (1) and diphenylacetylene (2a).
66
Figure S1. Change of the gas detector of ethylene (left: unused, right: after use)
Figure S2. Change of the gas detector of dihydrogen (left: unused, right: after use)
References
[1] M. J. Mio, L. C. Kopel, J. B. Braun, T. L. Gadzikwa, K. L. Hull. R. G. Brisbois, C. J.
Markworth, P. A. Grieco, Org. Lett. 2002, 4, 3199–3202.
[2] A.-F. Tran-Van, E. Huxol, J. M. Basler, M. Neuburger, J.-J. Adjizian, C. P. Ewels, H. A.
Wegner, Org. Lett. 2014, 16, 1594–1597.
[3] T. Hirschheydt, V. Wolfart, R. Glriter, H. Irngartinger, T. Oeser, F. Rominger, F. Eisenträger, J.
Chem. Soc., Perkin Trans. 2 2000, 175–183.
[4] K. Gao, P.-S. Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc. 2010, 132, 12249–12251.
67
[5] D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou, J. Am. Chem. Soc. 2008, 130,
16474–16475.
[6] S. R. Chidipudi, I. Khan, H. W. Lam, Angew. Chem. 2012, 124, 12281–12285; Angew. Chem.
Int. Ed. 2012, 51, 12115–12119.
[7] D. B. G. Williams, S. B. Simelane, M. Lawton, H. H. Kinfe, Tetrahedron 2010, 66, 4573–4576.
[8] B. Gold, P. Batsomboon, G. B. Dudley, I. V. Alabugin, J. Org. Chem. 2014, 79, 6221–6232.
[9] M. Kirihara, T. Takuwa, M. Okumura, T. Wakikawa, H. Takahata, T. Momose, Y. Takeuchi, H.
Nemoto, Chem. Pharm. Bull. 2000, 48, 885–888.
[10] T. Morimoto, K. Fuji, K. Tsutsumi, K. Kakiuchi, J. Am. Chem. Soc. 2002, 124, 3806–3807.
[11] M. Takachi, Y. Kita, M. Tobisu, Y. Fukumoto, N. Chatani, Angew. Chem. 2010, 122, 8899–
8902; Angew. Chem. Int. Ed. 2010, 49, 8717–8720.
Experimental section 2
General statements
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a Bruker Avance 500 or a JEOL
ECS-400 spectrometer. Chemical shift values are given in ppm relative to internal Me4Si (for 1H
NMR: δ = 0.00 ppm), CDCl3 (for 13C NMR: δ = 77.0 ppm), and C6F6 (for 19F NMR: δ = 0.00 ppm).
IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance
(ATR) method. Mass spectra were measured on a JEOL JMS-T100GCV or a JMS-T100CS
spectrometer. Elemental analyses were carried out at the Elemental Analysis Laboratory, Division
of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba. Melting points were
measured on a Yanaco micro melting point apparatus, and were uncorrected. Column
68
chromatography was performed on silica gel (Silica Gel 60N, Kanto Chemical Co., Inc., 63–210
mm). All the reactions were conducted under argon or nitrogen. Diethyl ether (Et2O),
tetrahydrofuran (THF), and toluene were purified by a solvent-purification system (Glass Contour)
equipped with columns of activated alumina and supported-copper catalyst (Q-5) before use.
Benzene was dried over CaCl2 for 1 d, then distilled from CaCl2, and stored over activated
molecular sieves 4A. i-PrOH was distilled from CaH2 prior to use. β,β-Difluorostyrenes[1] 8a,8b
and 8d–8h and 1-phenyl-2-propyne[2] (9d) were prepared according to the literature procedures.
Unless otherwise noted, materials were obtained from commercial sources and used directly
without further purifications.
69
Synthesis of β ,β-Difluorostyrene 8c
1-(2,2-Difluoroethenyl)-4-isopropylbenzene (8c)
To an N-methylpyrrolidone (20 mL) solution of (triphenylphosphonio)difluoroacetate (7.06 g,
19.8 mmol) was added 4-isopropylbenzaldehyde (1.48 g, 10.0 mmol). After stirring at 80 °C for 11
h, the reaction was quenched with brine. Organic materials were extracted with ether three times.
The combined extracts were washed with brine and dried over anhydrous Na2SO4. After the solvent
was removed under reduced pressure, the residue was purified by silica gel column chromatography
(hexane) to give difluorostyrene 8d as a colorless oil; yield 1.29 g (71%).
1H NMR (CDCl3, 500 MHz): δ = 1.24 (d, J = 6.9 Hz, 6H), 2.88 (septet, J = 6.9 Hz, 1H), 5.22 (dd,
JHF = 26.5, 3.8 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 126
MHz): δ = 23.9, 33.8, 81.9 (dd, JCF = 29, 14 Hz), 126.7, 127.6 (dd, JCF = 6, 4 Hz), 127.8 (dd, JCF =
6, 6 Hz), 147.8, 156.2 (dd, JCF = 298, 288 Hz). 19F NMR (CDCl3, 471 MHz): δ = 77.6 (dd, JFF = 34
Hz, JFH = 4 Hz, 1F), 79.7 (dd, JFF = 34 Hz, JFH = 26 Hz 1F). IR (neat): 2962, 1730, 1516, 1466,
1421, 1348, 1248, 1165, 1055, 937, 841, 544 cm–1. HRMS (EI+): m/z [M]+ calcd for C11H12F2:
182.0907; found: 182.0904. Anal. Calcd for C11H12F2: C, 72.51; H, 6.64. Found: C, 72.37; H, 6.88.
Synthesis of Fluoro-1,3-dienes via Hydroalkenylation of Alkynes
Typical procedure for synthesis of fluoroarenes 10
4-[(1Z,3E)-2-Fluoro-3-propylhepta-1,3-dien-1-yl]-1,1´-biphenyl (10aa); Typical Procedure
CF2
F
Pr
H
Pr
Ph
70
Typical procedure for the synthesis of fluoro-1,3-dienes 10 via nickel-catalyzed reaction: In an
argon-purged 50 mL test tube equipped with a PTFE cap (EYELA, PPS25-TC) were placed i-PrOH
(29 mL, 0.38 mmol) and toluene (1.0 mL). To the mixture was slowly added n-BuLi (1.57 M in
hexane, 0.24 mL, 0.38 mmol) at 0 °C. After stirring at 0 °C for 10 min, Et3B (1.0 M in hexane, 0.38
mL, 0.38 mmol) was added to the reaction mixture at the same temperature. The reaction mixture
was warmed to room temperature, and was stirred for another 30 min. To the reaction mixture were
added β,β-difluorostyrene (8a, 54 mg, 0.25 mmol), 4-octyne (9a, 55 mg, 0.50 mmol), Ni(cod)2 (6.9
mg, 0.025 mmol), PCy3 (7.0 mg, 0.025 mmol), ZrF4 (4.1 mg, 0.025 mmol), and toluene (1.0 mL).
After stirring at room temperature for 24 h, the reaction mixture was filtered through a pad of silica
gel (EtOAc). The filtrate was concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/EtOAc = 20:1) to give 2-fluoro-1,3-diene 10aa as a
white solid; yield 69 mg (89%); mp 90.6–92.2 °C.
1H NMR (CDCl3, 500 MHz): δ = 0.97 (t, J = 7.4 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H), 1.45–1.57 (m,
4H), 2.18 (td, J = 7.4, 7.4 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H), 5.78 (d, JHF = 40.4 Hz, 1H), 6.09 (t, J =
7.4 Hz, 1H), 7.33 (tt, J = 7.4, 1.4 Hz, 1H), 7.43 (dd, J = 7.4, 7.4 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H),
7.60–7.63 (m, 4H). 13C NMR (CDCl3, 126 MHz): δ = 14.0, 14.2, 22.4, 22.7, 29.0 (d, JCF = 3 Hz),
30.3, 104.4 (d, JCF = 11 Hz), 126.9, 127.1, 127.2, 128.8, 129.2 (d, JCF = 8 Hz), 130.2 (d, JCF = 9 Hz),
131.8 (d, JCF = 19 Hz), 133.5 (d, JCF = 2 Hz), 139.3 (d, JCF = 2 Hz), 140.7, 158.8 (d, JCF = 260 Hz).
19F NMR (CDCl3, 471 MHz): δ = 48.6 (d, JFH = 40 Hz). IR (neat): 2958, 2929, 2871, 1639, 1487,
856, 839, 760, 723, 694 cm–1. HRMS (EI+): m/z [M]+ calcd for C22H25F: 308.1940; found:
308.1943.
[(1Z,3E)-2-Fluoro-3-propylhepta-1,3-dien-1-yl]benzene (10ba)
71
Compound 10ba was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8b (35 mg, 0.25
mmol), 9a (56 mg, 0.51 mmol), Ni(cod)2 (7.0 mg, 0.025 mmol), PCy3 (7.0 mg, 0.025 mmol), ZrF4
(4.1 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at room temperature for
11 h. Purification by silica gel column chromatography (hexane) gave 10ba (45 mg, 77%) as a
colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 0.94 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 1.46 (qt, J = 7.4,
7.4 Hz, 2H), 1.51 (qt, J = 7.4, 7.4 Hz, 2H), 2.15 (td, J = 7.4, 7.4 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H),
5.73 (d, JHF = 40.4 Hz, 1H), 6.07 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.30 (dd, J = 7.5, 7.5
Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H). 13C NMR (CDCl3, 126 MHz): δ = 13.9, 14.1, 22.4, 22.7, 29.0 (d,
JCF = 3 Hz), 30.3, 104.8 (d, JCF = 12 Hz), 126.7 (d, JCF = 2 Hz), 128.4, 128.8 (d, JCF = 8 Hz), 130.0
(d, JCF = 9 Hz), 131.7 (d, JCF = 19 Hz), 134.3 (d, JCF = 2 Hz), 158.5 (d, JCF = 260 Hz). 19F NMR
(CDCl3, 471 MHz): δ = 48.3 (d, JFH = 40 Hz). IR (neat): 2958, 2871, 1639, 1456, 1377, 831, 748,
690 cm–1. HRMS (EI+): m/z [M]+ calcd for C16H21F: 232.1627; found: 232.1628. Anal. Calcd for
C16H21F: C, 82.71; H, 9.11. Found: C, 82.33; H, 9.14.
1-[(1Z,3E)-2-Fluoro-3-propylhepta-1,3-dien-1-yl]-4-isopropylbenzene (10ca)
Compound 10ca was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8c (46 mg, 0.25
mmol), 9a (55 mg, 0.50 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol), PCy3 (7.0 mg, 0.025 mmol), ZrF4
F
Pr
H
Pr
F
Pr
H
Pr
i-Pr
72
(4.2 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at room temperature for
18 h. Purification by silica gel column chromatography (hexane) gave 10ca (42 mg, 62%) as a
colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 0.95 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 1.24 (d, J = 6.9
Hz, 6H), 1.43–1.55 (m, 4H), 2.16 (td, J = 7.4, 7.4 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H), 2.88 (septet, J =
6.9 Hz, 1H), 5.71 (d, JHF = 40.7 Hz, 1H), 6.04 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.47 (d,
J = 8.2 Hz, 2H). 13C NMR (CDCl3, 126 MHz): δ = 14.0, 14.1, 22.4, 22.8, 23.9, 29.0 (d, JCF = 3 Hz),
30.3, 33.9, 104.7 (d, JCF = 12 Hz), 126.5, 128.8 (d, JCF = 8 Hz), 129.5 (d, JCF = 9 Hz), 131.8 (d, JCF
= 19 Hz), 131.9, 147.5 (d, JCF = 2 Hz), 158.1 (d, JCF = 259 Hz). 19F NMR (CDCl3, 471 MHz): δ =
47.1 (d, JFH = 41 Hz). IR (neat): 2958, 2871, 1643, 1510, 1458, 1419, 1379, 1055, 1018, 964, 895,
854, 561 cm–1. HRMS (EI+): m/z [M]+ calcd for C19H27F: 274.2097; found: 274.2096.
1-Chloro-4-[(1Z,3E)-2-fluoro-3-propylhepta-1,3-dien-1-yl]-4-benzene (10da)
Compound 3da was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8d (44 mg, 0.25
mmol), 9a (55 mg, 0.50 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol), PCy3 (7.0 mg, 0.025 mmol), ZrF4
(4.1 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at room temperature for
20 h. Purification by silica gel column chromatography (hexane/ethyl acetate = 20:1) gave 10da (56
mg, 84%) as a colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 0.96 (t, J = 7.5 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H), 1.43–1.54 (m,
4H), 2.17 (td, J = 7.5, 7.5 Hz, 2H), 2.25 (t, J = 7.5 Hz, 2H), 5.69 (d, JHF = 39.9 Hz, 1H), 6.08 (t, J =
7.5 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3, 126 MHz): δ =
F
Pr
H
Pr
Cl
73
13.9, 14.1, 22.4, 22.7, 28.9 (d, JCF = 3 Hz), 30.3, 103.7 (d, JCF = 12 Hz), 128.6, 130.0 (d, JCF = 8
Hz), 130.7 (d, JCF = 9 Hz), 131.6 (d, JCF = 18 Hz), 132.2 (d, JCF = 3 Hz), 132.9 (d, JCF = 2 Hz),
158.9 (d, JCF = 261 Hz). 19F NMR (CDCl3, 471 MHz): δ = 48.7 (d, JFH = 40 Hz). IR (neat): 2958,
2871, 1641, 1491, 1456, 1092, 1012, 849, 748, 548, 511 cm–1. HRMS (EI+): m/z [M]+ calcd for
C16H20ClF: 266.1238; found: 266.1238.
1-[(1Z,3E)-2-Fluoro-3-propylhepta-1,3-dien-1-yl]naphthalene (10ea)
Compound 10ea was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8e (47 mg, 0.25
mmol), 9a (55 mg, 0.50 mmol), Ni(cod)2 (6.8 mg, 0.025 mmol), PCy3 (6.9 mg, 0.025 mmol), ZrF4
(4.1 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at room temperature for
20 h. Purification by silica gel column chromatography (hexane/ethyl acetate = 50:1) gave 10ea (60
mg, 86%) as a colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 0.98 (t, J = 7.4 Hz, 3H), 1.04 (t, J = 7.4 Hz, 3H), 1.49 (qt, J = 7.4,
7.4 Hz, 2H), 1.64 (qt, J = 7.4, 7.4 Hz, 2H), 2.20 (td, J = 7.4, 7.4 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H),
6.13 (t, J = 7.4 Hz, 1H), 6.40 (d, JHF = 37.8 Hz, 1H), 7.45–7.52 (m, 3H), 7.74 (d, J = 7.9 Hz, 1H),
7.81 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H). 13C NMR (CDCl3, 126
MHz): δ = 14.0, 14.2, 22.6, 22.7, 29.2 (d, JCF = 3 Hz), 30.3, 101.3 (d, JCF = 14 Hz), 124.0, 125.52,
125.53, 125.9, 127.31 (d, JCF = 6 Hz), 127.34, 128.6, 130.3 (d, JCF = 6 Hz), 130.4 (d, JCF = 9 Hz),
131.5, 131.7 (d, JCF = 19 Hz), 133.7, 158.9 (d, JCF = 259 Hz). 19F NMR (CDCl3, 471 MHz): δ =
46.7 (d, JFH = 38 Hz). IR (neat): 2958, 2871, 1637, 1508, 1458, 1394, 1381, 1103, 899, 795, 773,
731 cm–1. HRMS (EI+): m/z [M]+ calcd for C20H23F: 282.1784; found: 282.1784.
F
Pr
H
Pr
74
2-[(1Z,3E)-2-Fluoro-3-propylhepta-1,3-dien-1-yl]benzofuran (10fa)
Compound 10fa was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8f (45 mg, 0.25
mmol), 9a (54 mg, 0.49 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol), PCy3 (6.9 mg, 0.025 mmol), ZrF4
(4.1 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at room temperature for
10 h. Purification by silica gel column chromatography (hexane/ethyl acetate = 20:1) gave 10fa (53
mg, 77%) as a colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 0.93 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H), 1.42–1.53 (m,
4H), 2.16 (td, J = 7.5, 7.5 Hz, 2H), 2.23 (t, J = 7.5 Hz, 2H), 5.91 (d, JHF = 38.7 Hz, 1H), 6.13 (t, J
= 7.5 Hz, 1H), 6.91 (s, 1H), 7.15–7.22 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H).
13C NMR (CDCl3, 126 MHz): δ = 13.9, 14.1, 22.4, 22.6, 28.8 (d, JCF = 4 Hz), 30.4, 95.4 (d, JCF =
14 Hz), 105.7 (d, JCF = 13 Hz), 110.7, 120.7, 122.8, 124.0, 129.4, 130.9 (d, JCF = 17 Hz), 131.8 (d,
JCF = 8 Hz), 151.6, 153.9, 159.8 (d, JCF = 263 Hz). 19F NMR (CDCl3, 471 MHz): δ = 55.4 (d, JFH =
39 Hz). IR (neat): 2960, 2931, 2873, 1641, 1558, 1450, 1259, 1169, 1099, 1011, 978, 812, 739 cm–1.
HRMS (EI+): m/z [M]+ calcd for C18H21FO: 272.1576; found: 272.1576.
2-[(1Z,3E)-2-Fluoro-3-propylhepta-1,3-dien-1-yl]benzo[b]thiophene (10ga)
Compound 10ga was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8g (48 mg, 0.25
F
Pr
H
PrO
F
Pr
H
PrS
75
mmol), 9a (55 mg, 0.50 mmol), Ni(cod)2 (7.0 mg, 0.025 mmol), PCy3 (7.0 mg, 0.025 mmol), ZrF4
(4.1 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at room temperature for
12 h. Purification by silica gel column chromatography (hexane/ethyl acetate = 20:1) gave 10ga (60
mg, 85%) as a colorless solid; mp 50.6–51.2 °C.
1H NMR (CDCl3, 500 MHz): δ = 0.96 (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H), 1.44–1.56 (m,
4H), 2.18 (td, J = 7.5, 7.5 Hz, 2H), 2.26 (t, J = 7.5 Hz, 2H), 6.12 (d, JHF = 38.9 Hz, 1H), 6.14 (t, J =
7.5 Hz, 1H), 7.23–7.32 (m, 3H), 7.69 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H). 13C NMR
(CDCl3, 126 MHz): δ = 13.9, 14.1, 22.4, 22.7, 28.8 (d, JCF = 3 Hz), 30.4, 99.9 (d, JCF = 15 Hz),
121.9, 122.9 (d, JCF = 4 Hz), 123.0 (d, JCF = 1 Hz), 124.1, 124.2, 130.8 (d, JCF = 17 Hz), 131.3 (d,
JCF = 8 Hz), 137.2 (d, JCF = 4 Hz), 139.4, 140.3 (d, JCF = 9 Hz), 158.6 (d, JCF = 261 Hz). 19F NMR
(CDCl3, 471 MHz): δ = 51.3 (d, JFH = 39 Hz). IR (neat): 3049, 2956, 2870, 1633, 1456, 1311, 1230,
845, 742, 577 cm–1. Anal. Calcd for C18H21FS: C, 74.96; H, 7.34. Found: C, 74.64; H, 7.25.
4-[(1Z,3E)-2-Fluoro-3-propylhexa-1,3-dien-1-yl]-1,1´-biphenyl (10ab)
Compound 10ab was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8a (54 mg, 0.25
mmol), 3-hexyne (9b, 41 mg, 0.50 mmol), Ni(cod)2 (7.0 mg, 0.025 mmol), PCy3 (6.9 mg, 0.025
mmol), ZrF4 (4.1 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at room
temperature for 17 h. Purification by silica gel column chromatography (hexane/ethyl acetate =
20:1) gave 10ab (56 mg, 80%) as a colorless solid; mp 64.3–65.9 °C.
1H NMR (CDCl3, 500 MHz): δ = 1.07 (t, J = 7.5 Hz, 3H), 1.11 (t, J = 7.5 Hz, 3H), 2.21 (qd, J = 7.5,
7.5 Hz, 2H), 2.31 (q, J = 7.5 Hz, 2H), 5.79 (d, JHF = 40.4 Hz, 1H), 6.04 (t, J = 7.5 Hz, 1H), 7.33 (t, J
F
Et
H
Et
Ph
76
= 7.6 Hz, 1H), 7.43 (dd, J = 7.6, 7.6 Hz, 2H), 7.54–7.63 (m, 6H). 13C NMR (CDCl3, 126 MHz): δ =
13.9, 14.1, 20.1 (d, JCF = 4 Hz), 21.3, 104.4 (d, JCF = 12 Hz), 126.9, 127.1, 127.2, 128.8, 129.2 (d,
JCF = 8 Hz), 131.1 (d, JCF = 9 Hz), 132.9 (d, JCF = 19 Hz), 133.5 (d, JCF = 2 Hz), 139.3 (d, JCF = 2
Hz), 140.7, 158.4 (d, JCF = 260 Hz). 19F NMR (CDCl3, 471 MHz): δ = 48.0 (d, JFH = 40 Hz).
HRMS (EI+): m/z [M]+ calcd for C20H21F: 280.1627; found: 280.1628.
4-[(1Z,3E)-2-Fluoro-3,5-dimethylhexa-1,3-dien-1-yl]-1,1´-biphenyl (10ac)
Compound 10ac was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8a (55 mg, 0.25
mmol), 4-methyl-2-pentyne (9c, 41 mg, 0.50 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol), PCy3 (6.9 mg,
0.025 mmol), ZrF4 (4.1 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at
room temperature for 12 h. Purification by silica gel column chromatography (hexane/ethyl acetate
= 20:1) gave 10ac (45 mg, 64%) as a colorless solid; mp 112.9–114.3 °C.
1H NMR (CDCl3, 500 MHz): δ = 1.04 (d, J = 6.6 Hz, 6H), 1.88 (s, 3H), 2.69 (dseptet, J = 9.5, 6.6
Hz, 1H), 5.75 (d, JHF = 40.1 Hz, 1H), 5.94 (d, J = 9.5 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.43 (dd, J =
7.8, 7.8 Hz, 2H), 7.56–7.58 (m, 2H), 7.60–7.62 (m, 4H). 13C NMR (CDCl3, 126 MHz): δ = 12.6 (d,
JCF = 4 Hz), 22.8, 27.6, 104.7 (d, JCF = 11 Hz), 124.7 (d, JCF = 20 Hz), 126.9, 127.1, 127.2, 128.8,
129.2 (d, JCF = 8 Hz), 133.4 (d, JCF = 2 Hz), 136.9 (d, JCF = 8 Hz), 139.3 (d, JCF = 2 Hz), 140.7,
159.2 (d, JCF = 260 Hz). 19F NMR (CDCl3, 471 MHz): δ = 47.1 (d, JFH = 40 Hz). IR (neat): 2960,
2866, 1641, 1489, 1410, 1362, 1323, 1138, 1059, 995, 860, 760, 719, 688 cm–1. HRMS (EI+): m/z
[M]+ calcd for C20H21F: 280.1627; found: 280.1628.
F
Me
H
i-Pr
Ph
77
4-[(1Z,3E)-2-Fluoro-3-methyl-4-phenylbuta-1,3-dien-1-yl]-1,1´-biphenyl (10ad)
Compound 10ad was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8a (55 mg, 0.25
mmol), 1-phenyl-1-propyne (9d, 58 mg, 0.50 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol), PCy3 (6.9 mg,
0.025 mmol), ZrF4 (4.2 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at
room temperature for 15 h. Purification by silica gel column chromatography (hexane/ethyl acetate
= 20:1) gave 10ad (26 mg, 33%) as a colorless solid; mp 149.9–150.2 °C.
1H NMR (CDCl3, 500 MHz): δ = 2.12 (s, 3H), 5.98 (d, JHF = 39.8 Hz, 1H), 7.13 (s, 1H), 7.25–7.29
(m, 1H), 7.36–7.39 (m, 5H), 7.45 (dd, J = 7.4, 7.4 Hz, 2H), 7.62 (dd, J = 9.4, 9.4 Hz, 4H), 7.68 (d, J
= 8.0 Hz, 2H). 13C NMR (CDCl3, 126 MHz): δ = 14.1 (d, JCF = 3 Hz), 106.8 (d, JCF = 11 Hz), 126.9,
127.1, 127.2, 127.3, 127.7 (d, JCF = 10 Hz), 128.2, 128.4 (d, JCF = 19 Hz), 128.8, 129.44 (d, JCF = 8
Hz), 129.45, 133.1, 137.1, 139.8, 140.6, 159.2 (d, JCF = 260 Hz). 19F NMR (CDCl3, 471 MHz): δ =
48.1 (d, JFH = 40 Hz). IR (neat): 3028, 2970, 1489, 1441, 1219, 1068, 856, 771, 698 cm–1. HRMS
(EI+): m/z [M]+ calcd for C23H19F: 314.1471; found: 314.1474.
[(1E,3Z,5E)-4-Fluoro-5-propylnona-1,3,5-trien-1-yl]benzene (10ha)
Compound 10ha was synthesized according to the procedure described for 10aa using i-PrOH (29
mL, 0.38 mmol), n-BuLi (0.24 mL, 0.38 mmol), Et3B (0.38 mL, 0.38 mmol), 8h (42 mg, 0.25
mmol), 9a (55 mg, 0.50 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol), PCy3 (7.0 mg, 0.025 mmol), ZrF4
(4.2 mg, 0.025 mmol), and toluene (2.0 mL). The reaction was conducted at 40 °C for 12 h.
F
Me
H
Ph
Ph
F
Pr
H
Pr
Ph
78
Purification by silica gel column chromatography (hexane/ethyl acetate = 50:1) gave 10ha (40 mg,
62%) as a colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 0.95 (t, J = 7.8 Hz, 3H), 0.96 (t, J = 7.8 Hz, 3H), 1.42–1.52 (m,
4H), 2.15 (td, J = 7.6, 7.6 Hz, 2H), 2.20 (t, J = 7.9 Hz, 2H), 5.71 (dd, JHF = 35.3 Hz, J = 10.9 Hz,
1H), 6.02 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 15.8 Hz, 1H), 7.15 (dd, J = 15.8, 10.9 Hz, 1H), 7.21 (t, J
= 7.5 Hz, 1H), 7.31 (dd, J = 7.5, 7.5 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H). 13C NMR (CDCl3, 126
MHz): δ = 14.0, 14.2, 22.5, 22.7, 28.8 (d, JCF = 4 Hz), 30.3, 106.1 (d, JCF = 15 Hz), 121.7 (d, JCF =
7 Hz), 126.3, 127.3, 128.6, 130.1 (d, JCF = 8 Hz), 130.9 (d, JCF = 3 Hz), 131.1, 137.6, 158.5 (d, JCF
= 258 Hz). 19F NMR (CDCl3, 471 MHz): δ = 45.1 (d, JFH = 35 Hz). IR (neat): 2958, 2871, 1624,
1595, 1495, 1454, 1377, 1309, 1113, 1072, 964, 860, 746, 690 cm–1. HRMS (EI+): m/z [M]+ calcd
for C18H23F: 258.1784; found: 258.1784.
Mechanistic Experiments
A 50 mL test tube with a teflon cap (EYELA, PPS25-TC) was charged with i-PrOH (29 mL, 0.38
mmol) and toluene (2.0 mL). To the mixture was slowly added n-BuLi (1.58 M in hexane, 0.24 mL,
0.38 mmol) at 0 °C. The mixture was stirred at the same temperature for 10 min. To the reaction
mixture was added Et3B (1.0 M in hexane, 0.38 mL, 0.38 mmol) at 0 °C. The reaction temperature
was elevated to room temperature, and the reaction mixture was stirred for further 30 min. To the
reaction mixture were added 8e (58 mg, 0.30 mmol), 4-octyne (9a: 55 mg, 0.50 mmol), PCy3 (7.0
mg, 0.25 mmol), and ZrF4 (4.2 mg, 0.25 mmol). To the reaction mixture were added Ni(cod)2 (6.9
mg, 0.25 mmol). After stirring for 10 min at room temperature, the reaction mixture was quenched
by phosphate buffer solution. A toluene solution of 10ea was obtained (0.032 mmol; The yield was
determined by 19F NMR using PhCF3 as an internal standard).
79
Other kinetic experiments to study the rate dependence on the substrate were performed by
similar procedure. The initial rate date obtained to construct the plots in Figure S1, S2 are tabulated
below.
Table S1. Initial Rate Data Obtained by Varying 8e Concentration (for Figure 2-2a, b)
[8e]0 (M) Initial Δ[10ea]/Δt x 104 (Ms–1) Std. dev.
Run 1 Run 2 Run 3 Run 4 Average
0.12 0.266 0.337 0.289 0.297 0.297 0.020
0.15 0.277 0.403 0.285 0.359 0.331 0.030
0.19 0.400 0.495 0.368 0.371 0.408 0.030
0.25 0.475 0.621 0.518 0.602 0.554 0.031
0.30 0.727 0.708 0.757 0.674 0.716 0.024
Table S2. Initial Rate Data Obtained by Varying 9a Concentration (for Figure 2-2c, d)
[9a]0 (M) Initial Δ[10ea]/Δt x 104 (Ms–1) Std. dev.
Run 1 Run 2 Run 3 Average
0.062 0.172 0.158 0.138 0156 0.010
0.10 0.253 0.209 0.269 0.244 0.018
0.12 0.266 0.337 0.289 0.297 0.021
0.19 0.548 0.501 0.539 0.529 0.014
0.25 0.688 0.623 0.667 0.659 0.019
80
Table S3. Dependency of (Δ[10a]/Δt)t=0 on [Ni]0 (See Figure 2-2e,f)
[Ni]0 (M) (Δ[10ea]/Δt)t=0 x 104 (Ms–1) Standard error
Run 1 Run 2 Run 3 Average
0.0025 0.033 0.036 0.040 0.036 0.002
0.0050 0.054 0.081 0.057 0.064 0.008
0.012 0.164 0.139 0.135 0.146 0.009
0.025 0.266 0.337 0.289 0.297 0.020
Deuterium-labeling Experiment
A 50 mL test tube with a teflon cap (EYELA, PPS25-TC) was charged with i-PrOH-d8 (102 mg,
1.5 mmol) and toluene (5.0 mL). To the mixture was slowly added n-BuLi (1.58 M in hexane, 0.96
mL, 1.5 mmol) at 0 °C. The mixture was stirred at the same temperature for 10 min. To the reaction
mixture was added Et3B (1.0 M in hexane, 1.5 mL, 1.5 mmol) at 0 °C. The reaction temperature
was elevated to room temperature, and the reaction mixture was stirred for further 30 min. To the
reaction mixture were added 8a (216 mg, 1.0 mmol), 4-octyne (9a: 220 mg, 2.0 mmol), PCy3 (28.0
mg, 0.10 mmol), ZrF4 (16.7 mg, 0.10 mmol), and Ni(cod)2 (27.5 mg, 0.10 mmol). After stirring at
room temperature for 12 h, the reaction mixture was filtered through a pad of silica gel (EtOAc).
The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 20:1) to give 2-fluoro-1,3-diene 10aa and 10aa-d (36:64) as a
white solid; yield 287 mg (93%)
Confirmation of Gas Generation
81
Generation of ethylene was confirmed by gas detector after the reaction of β,β-difluorostyrene 8a
and 4-octyne (9a) (Figure S1).
Figure S1. Color change of an ethylene detector (left: unused, right: after use)
References
[1] Zheng, J.; Cai, J.; Lin, J.-H,; Guo, Y.; Xiao, J.-C. Chem. Commun. 2013, 7513.
[2] Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
16474.
82
CHAPTER 3
Rhodium-Catalyzed [4 + 2] Cyclization of 1,1-Difluoro-1-alkenes with
Biphenylenes
Abstract
The synthesis of fluorophenanthrenes was accomplished via Rh-catalyzed [4+2] cyclization of
1,1-difluoro-1-alkenes with biphenylenes. This reaction proceeds with cleavage of a C–C bond in
biphenylenes and C–F and C–H bonds in 1,1-difluoro-1-alkenes. The catalytic cycle was
established by addition of a catalytic amount of Cu(OTf)2 and an equimolar amount of LiOTf as a
fluorine captor.
cat. Rh/CuLiOTf
F
F+
R F
R
Rh
R FF
β-FluorineElimination
H
83
3-1. Introduction
In recent years, transformations of smaller carbocyclic compounds such as cyclopropanes and
cyclobutanes have been achieved via transition metal-catalyzed carbon–carbon (C–C) bond
cleavage.[1] Especially, biphenylene, which contains a strained cyclobutene ring, readily undergoes
C–C bond cleavage via oxidative addition to transition metal complexes, including nickel,[2]
iridium,[3] rhodium,[3d,4] cobalt,[4b,5] platinum,[6] iron,[7] and palladium complexes.[6c,8] The
dibenzometalacyclopentadienes thus formed act as versatile intermediates via oxidative addition
(Scheme 3-1). For example, transition metal-catalyzed [4+2] cyclization of biphenylene with
unsaturated compounds such as alkynes and nitriles proceeded via dibenzometalacyclopentadienes
proceeded to afford fused aromatic compounds through formation of two C–C bonds (Scheme 3-1a).
[9] In contrast, when alkenes are used as unsaturated compounds, styrene or fluorene derivatives
have been selectively obtained through formation of one or two C–C bonds, respectively (Scheme
3-1b,c).[8,10] Herein, I demonstrate the Rh-catalyzed synthesis of selectively fluorinated
phenanthrenes via [4+2] cyclization of biphenylene with 1,1-difluoro-1-alkenes (Scheme 3-1d).
Triple σ-bond activation was involved in the reaction, where vinylic C–F and C–H bonds of
1,1-difluoro-1-alkenes[11] and a C–C bond of biphenylene were cleaved and two C–C bonds were
newly formed.
84
Scheme 3-1. Transition metal catalyzed C–C bond transformations of biphenylene
3-2. Synthesis of 9-Fluorophenanthrenes via β-Fluorine Elimination
I sought suitable conditions for the [4+2] cyclization of biphenylene with
4-(2,2-difluoroethenyl)-1,1’-biphenyl (11a) as a model substrate (Table 3-1), using a series of
transition metal complexes. First, the reactions of 11a and biphenylene in the presence of transition
metal complexs such as Rh, Ir, Ni, Pd, and Pt complexes were performed (Table 3-1. entries 1–5).
Only when Rh complexes were employed, fluorinated phenanthrene 13a was obtained (Table 3-1,
entry 1). However, when using a catalytic amount of [RhCl(cod)]2, the yield of 13a decreased to
10% (Table 3-1, entry 6). Screening of additives, such as AgOTf, CuOTf·C6H6, Cu(OTf)2, and
Me3SiOTf, revealed that the yield of 13a was dramatically improved which CuOTf·C6H6 or
Cu(OTf)2 up to 53% or 50%, respectively (Table 3-1, entries 7–10). Furthermore, when an
equimolar amount of LiOTf was added with a catalytic amount of Cu(OTf)2, 13a was obtained in
M
MXR
XR
M = Ni, Ir, Rh
M = Rh
F
FH
R
FR
R
(X = CR, or N)
R R
M = Pd, Rh M = Ir
(b) arylation of alkenes
(a) [4+2] cyclization (d) This work: [4+2] cyclization
(c) [4+1] cyclization
85
80% isolated yield, although LiOTf or Cu(OTf)2 separately afforded 13a only in 20% and 12%
yield (Table 3-1, entries 11–13).
Table 3-1. Optimization of [4+2] cyclization of biphenylene with 1,1-difluoro-1-alkene 11a[a]
With the optimal conditions in hand, I examined the scope this reaction with respect to various
1,1-difluoro-1-alkenes 11 (Table 3-2). When β,β-difluorostyrenes 11b and 11c were employed, the
1
2
3
4
5
6
7
8
9
10
11
12
13
[RhCl(cod)]2 (50)
[IrCl(cod)]2 (50)
Ni(cod)2 (100)
Pd(PPh3)4 (100)
Pt(PPh3)4 (100)
[RhCl(cod)]2 (5)
[RhCl(cod)]2 (5)
[RhCl(cod)]2 (5)
[RhCl(cod)]2 (5)
[RhCl(cod)]2 (5)
[RhCl(cod)]2 (5)
[RhCl(cod)]2 (5)
[RhCl(cod)]2 (5)
–
–
–
–
–
–
AgOTf (1.0)
CuOTf•C6H6 (1.0)
Cu(OTf)2 (1.0)
Me3SiOTf (1.0)
Cu(OTf)2 (0.05) + LiOTf (1.0)
Cu(OTf)2 (0.05)
LiOTf (1.0)
12
12
12
12
12
4
12
12
12
12
4
4
12
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
[a] Molar percentages of Metal and additives are based on the amount of 11a. Reaction conditions: 11a (0.2 mmol), 12 (0.22 mmol), and toluene (2.0 mL). [b] N.D. = Not detected. [c] Yield was determined by 19F NMR spectroscopy with PhCF3 as an internal standard.Yield of isolated product is given in parentheses.
60
10
12
53
50
35
80
20
10
(58)
(80)
13a / %[c]Time / hAdditive (equiv)Metal (mol%)Entry
Metal (x mol%)Additive (y equiv)F
R FR
H F+
11aR = C6H4(p-Ph)
Toluene, reflux
12(1.1 equiv)
13a
86
corresponding fluorophenanthrenes 13b and 13c were obtained in 57% and 54% yield, respectively.
The reaction of 1,1-difluoro-1-alkene bearing aliphatic substrate 11d also provided 13d in 58%
yield. In addition, the most simple difluoroalkene, 1,1-difluoroethylene (11e) participated in the
[4+2] cyclization to afford the desired 9-fluorophenanthlene (13e).
Table 3-1. Substrate scope for 11[a]
To gain insights into the reaction mechanism several experiments were investigated. On
treatment of 11a with stoichiometric amount of the rhodium complex, no reaction occurred (eq.
[RhCl(cod)]2 (5 mol%)Cu(OTf)2 (5 mol%)
LiOTf (1.0 eq)
Toluene, Reflux, 4 h
F
13a 80%
Ph
F
13b 57%[b]
H F
13e 75%[d]
F
13d 58%[c]
Ph
[a] Reaction conditions: 11 (0.20 mmol), 12 (0.22 mmol), [RhCl(cod)]2 (0.010 mmol), Cu(OTf)2 (0.010 mmol), LiOTf (0.20 mmol), and toluene (2.0 mL). [b] PhB(nep) (10 mol%) was added. [c] [RhCl(cod)]2 (50 mol%) was used without Cu(OTf)2 and LiOTf. [d] Excess amount of 11e (1.0 atm) was used.
FR F
R
H F+
11 12(1.1 equiv)
13
F
(13c 54%[b])
87
3-1), which indicates that the [4+2] cyclization did not involve the oxidative addition of C–F bond.
Furthermore, when 2,2-difluorovinyl tosylate 14 was subjected to the Rh-catalyzed [4+2]
cyclization, 9-fluorophenanthrene (13e) was obtained without formation of
difluorodibenzocyclohexadiene 15 and fluorophenanthrene 16 bearing a tosyloxy group. This result
suggests that fluorophenanthrenes 13 would be formed directly and not through HF elimination
from difluorodibenzocyclohexadienes 15 (Scheme 3-2).
Scheme 3-2. Stoichiometric reaction of 2,2-difluorovinyl tosylate 14 with biphenylene 12
On the basis of these results, I outlined one possible reaction pathway (Scheme 3-3). First,
dibenzorhodacyclopentadiene A was generated via oxidative addition of biphenylene to Rh(I)
complex. Subsequent regioselective insertion of 11[12] to A afforded β,β-difluoroalkylrhodium
complex B, which underwent β-fluorine elimination[13] to give the intermediary arylrhodium C.
[RhCl(cod)]2 (50 mol%)F
F Toluene, reflux, 12 h
R
11aR = p-Ph(C6H4)
(3-1)F
F
R
Recovery 11a94%
[RhCl(cod)]2 (50 mol%)
Toluene, reflux, 12 h
F
+
12 (1.5 eq)
H F
TsO14 13e 96%
F
TsO F
16 N.D.
H
15 N.D.
H FFTsO
– HF
88
Intermolecular insertion of the alkene moiety into the C–Rh bond led to formation of
cyclohexadienylrhodium D, followed by β-hydrogen elimination, which gave the product 13 and a
Rh(III) fluoride. The Rh(III) complex was reduced to the Rh(I) complex through transmetalation
with the Cu cocatalyst and LiOTf and reductive elimination.
Scheme 3-3. Possible reaction mechanism
In summary, I have developed the Rh-catalyzed [4+2] cyclization for the synthesis of
fluorophenanthrenes via C–F and C–H bond activation of 1,1-difluoro-1-alkenes and C–C bond
activation of biphenylene. The reaction is proposed to proceed through β-fluorine elimination from
the intermediary Rh(III) complex under catalysis. The catalytically active Rh(I) complex in
probably regenerated from the formed Rh(III) hydrofluoride complex with Cu cocatalyst and
LiOTf.
Rh
R FF
R
Rh FF
X
X
III
IIIF
RhR H
F
X
RF
III
BD
C
β-FluorineElimination
RhIX
RhX
III
RhIIIX
Insertion
Insertion
F
H FR
H F1113
Cu/LiOTf
Cu/LiF+HOTf 12
β-HydrogenElimination
A
OxidativeAddition
δ+δ–
89
3-3. References
[1] (a) Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870−883. (b) Jun, C.-H.
Chem. Soc. Rev. 2004, 33, 610−618. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007,
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M.; Matsuda, T. Chem. Commun. 2011, 47, 1100−1105. (f) Ruhland, K. Eur. J. Org. Chem. 2012,
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B. A.; Tsukamoto, T.; Dong, G. ACS Catal. 2017, 7, 1340–1360. (i) Fumagalli, G.; Stanton, S.;
Bower, J. F. Chem. Rev. 2017, 117, 9404–9432.
[2] (a) Eisch, J. J.; Piotrowski, A. M.; Han, K. I.; Krüger, C.; Tsay, Y. H. Organometallics 1985, 4,
224–231. (b) Becker, S.; Vanderesse, Y. F. R.; Caubére, P. J. Org. Chem. 1989, 54, 4848–4853. (c)
Schwager, H.; Spyroudis, S.; Vollhardt, K. P. C. J. Organomet. Chem. 1990, 382, 191–200. (d)
Edelbach, B. L.; Lachicotte, R. J.; Jones, W. D. Organometallics 1999, 18, 4660–4668. (e) Schaub,
T.; Radius, U. Chem.—Eur. J. 2005, 11, 5024–5030. (f) Schaub, T.; Backes, M.; Radius, U.
Organometallics 2006, 25, 4196–4206. (g) Beck, R.; Johnson, S. A. Chem. Commun. 2011, 47,
9233–9235.
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O.; Crabtree, R. H. Organometallics 1995, 14, 1168–1175. (c) Koga, Y.; Kamo, M.; Yamada, Y.;
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A. S. Dalton Trans. 2014, 43, 16354–16365.
[4] (a) Perthuisot, C.; Jones, W. D. J. Am. Chem. Soc. 1994, 116, 3647–3648. (b) Perthuisot, C.;
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Hampejsová, Z.; Císařová, I.; Kotora, M. Synthesis 2016, 48, 987–996.
[5] Kumaraswamy, S.; Jalisatgi, S. S.; Matzger, A. J.; Miljanić, O. Š.; Vollhardt, K. P. C. Angew.
Chem., Int. Ed. 2004, 43, 3711–3715.
[6] (a) Edelbach, B. L.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem. Soc. 1998, 120, 2843–2853.
(b) Ximhai, N.; Iverson, C. N.; Edelbach, B. L.; Jones, W. D. Organometalics 2001, 20, 2759–2766.
(c) Yu, K.; Li, H.; Watson, E. J.; Virkaitis, K. L.; Carpernter, G. B.; Sweigart, D. A.
Organometallics 2001, 20, 3550–3559.
[7] (a) Yeh, W.-Y.; Hsu, S. C. N. Organometallics 1998, 17, 2477–2483. (b) Darmon, J. M.; Stieber,
S. C. E.; Sylvester, K. T.; Fernández, I.; Lobkovsky, E.; Semproni, S. P.; Bill, E.; Wieghardt, K.;
DeBeer, S.; Chirik, P. J. J. Am. Chem. Soc. 2012, 134, 17125–17137.
[8] Satoh, T.; Jones, W. D. Organometallics 2001, 20, 2916–2919.
[9] (a) Müller, C.; Lachicotte, R. J.; Jones, E. D. Organometallics 2002, 21, 1975–1981. (b) Shibata,
T.; Nishizawa, G.; Endo, K. Synlett 2008, 765–768. (c) Gu, Z.; Boursalian, G. B.; Gandon, V.;
Padilla, R.; Shen, H.; Timofeeva, T. V.; Tongwa, P.; Vollhardt, P. C.; Yakovenko, A. A. Angew.
Chem., Int. Ed. 2011, 50, 9413–9417. (d) Korotvička, A.; Císařová, I.; Roithová, J.; Kotora, M.
Chem.—Eur. J. 2012, 18, 4200–4207.
[10] (a) Takano, H.; Kanyiva, K. S.; Shibata, T. Org. Lett. 2016, 18, 1860–1863. (b) Takano, H.;
Sugimura, N.; Kanyiva, K. S.; Shibata, T. ACS Omega 2017, 2, 5228–5234.
[11] Fujita, T.; Watabe, Y.; Ichitsuka, T.; Ichikawa, J. Chem.—Eur. J. 2015, 21, 13225–13228.
[12] (a) Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472. Nat. Commun. 2015, 6, 7472.
(b) Wu, J.-Q; Zhang, S.-S.; Gao, H.; Qi, Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.; Chn, Y.; Li, Q.; Li, X.;
Wang, H. J. Am. Chem. Soc. 2017, 139, 3537–3545. (c) Kong, L.; Liu, B.; Zhou, X.; Wang, F.; Li,
X. Chem. Commun. 2017, 53, 10326–10329. (d) Liu, H.; Song, S.; Wang, C.-Q.; Feng, C.; Loh,
91
T.-P. ChemSusChem 2017, 10, 58–61
[13] [Pd] (a) Fujiwara, M.; Ichikawa, J.; Okauchi, T.; Minami, T. Tetrahedron Lett. 1999, 40,
7261–7265. (b) Heitz, W.; Knebelkamp, A. Makromol. Chem., Rapid Commun. 1991, 12, 69–75.
(c) Sakoda, K.; Mihara, J.; Ichikawa, J. Chem. Commun. 2005, 4684–4686. (d) Xu, J.; Ahmed,
E.-A.; Xiao, B.; Lu, Q.-Q.; Wang, Y.-L.; Yu, C.-G.; Fu, Y. Angew. Chem. Int. Ed. 2015, 54, 8231–
8235. (e) Thornbury, R. T.; Toste, F. D. Angew. Chem. Int. Ed. 2016, 55, 11629–11632. [Cu] (f)
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Kojima, R.; Kubota, K.; Ito, H. Chem. Commun. 2017, 53, 10688–10691. (i) Hu, J.; Han, X.; Yuan,
Y.; Shi, Z. Angew. Chem., Int. Ed. 2017, 129, 13527–13531.
3-4. Experimental Section
General
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a Bruker Avance 500 or a JEOL
ECS-400 spectrometer. Chemical shift values are given in ppm relative to internal Me4Si (for 1H
NMR: δ = 0.00 ppm), CDCl3 (for 13C NMR: δ = 77.0 ppm), and C6F6 (for 19F NMR: δ = 0.00 ppm).
IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance
(ATR) method. Mass spectra were measured on a JEOL JMS-T100GCV or a JMS-T100CS
spectrometer. Elemental analyses were carried out at the Elemental Analysis Laboratory, Division
of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba. Melting points were
measured on a Yanaco micro melting point apparatus, and were uncorrected. Column
chromatography was performed on silica gel (Silica Gel 60N, Kanto Chemical Co., Inc., 63–210
mm). All the reactions were conducted under argon or nitrogen. Diethyl ether (Et2O),
92
tetrahydrofuran (THF), and toluene were purified by a solvent-purification system (Glass Contour)
equipped with columns of activated alumina and supported-copper catalyst (Q-5) before use.
Benzene was dried over CaCl2 for 1 d, then distilled from CaCl2, and stored over activated
molecular sieves 4A. i-PrOH was distilled from CaH2 prior to use. β,β-Difluorostyrenes 11a,[1]
11b,[1] 11c,[2] 11d,[1] and 14[3] and biphenylene[4] (12) were prepared according to the literature
procedures. Unless otherwise noted, materials were obtained from commercial sources and used
directly without further purifications.
93
Synthesis of 9-Fluorophenanthrene via Rh-catalyzed [4+2] Cyclization
Typical procedure for synthesis of fluorophenanthrenes
9-[1,1’-Biphenyl]-4-yl-10-fluorophenanthrene (13a); Typical Procedure
β,β-difluorostyrene 11a (43.2 mg, 0.20 mmol), biphenylene 12a (33.5 mg, 0.22 mmol),
[RhCl(cod)]2 (4.9 mg, 0.0099 mmol), Cu(OTf)2 (3.6 mg, 0.010 mmol), and LiOTf (31.2 mg, 0.20
mmol) were placed in a test tube under nitrogen atmosphere, and toluene (2.0 mL) was added. After
being refluxed for 4 h, the reaction mixture was filtered through a pad of silica gel (ethyl acetate).
The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel
column chromatography (hexane/ethyl acetate = 20:1) to give 13a (55.7 mg, 80%) as a colorless
solid.
1H NMR (CDCl3, 500 MHz): δ = 7.38–7.41 (m, 1H), 7.48–7.57 (m, 5H), 7.61–7.64 (m, 1H), 7.68–
7.79 (m, 7H), 8.24 (d, J = 7.8 Hz, 1H), 8.73 (t, J = 6.9 Hz, 2H). 13C NMR (CDCl3, 126 MHz): δ =
14.0, 14.2, 22.4, 22.7, 29.0 (d, JCF = 3 Hz), 30.3, 104.4 (d, JCF = 11 Hz), 126.9, 127.1, 127.2, 128.8,
129.2 (d, JCF = 8 Hz), 130.2 (d, JCF = 9 Hz), 131.8 (d, JCF = 19 Hz), 133.5 (d, JCF = 2 Hz), 139.3 (d,
JCF = 2 Hz), 140.7, 158.8 (d, JCF = 260 Hz). 19F NMR (CDCl3, 471 MHz): δ = 37,5 (s, 1F). HRMS
(EI+): m/z [M]+ calcd for C26H17F: 348.1314; found: 348.1314.
9-Fluoro-10-phenylphenanthrene (13b)
F
Ph
94
Compound 13b was synthesized according to the procedure described for 13a using 11b (28.0
mg, 0.20 mmol), 12a (33.5 mg, 0.20 mmol), [RhCl(cod)]2 (5.0 mg, 0.010 mmol), Cu(OTf)2 (3.6 mg,
0.010 mmol), LiOTf (31.2 mg, 0.20 mmol), PhBnep (3.8 mg, 0.020 mg) and toluene (2.0 mL). The
reaction was conducted at reflux for 4 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 20:1) gave 13b (31.0 mg, 57%) as a colorless solid.
Spectral data for this compound showed good agreement with the literature data.[3]
9-Fluorophenanthrene (13e)
Compound 13e was synthesized according to the procedure described for 13a using 11e (1.0 atm,
excess), 12a (33.5 mg, 0.20 mmol), [RhCl(cod)]2 (5.0 mg, 0.010 mmol), Cu(OTf)2 (3.6 mg, 0.010
mmol), LiOTf (31.2 mg, 0.20 mmol), and toluene (2.0 mL). The reaction was conducted at reflux
for 4 h. Purification by silica gel column chromatography (hexane) gave 13e (29.4 mg, 75%) as a
colorless solid.
Spectral data for this compound showed good agreement with the literature data.[3]
F
F
95
Mechanistic Study
To a mixture of 14 (47 mg, 0.20 mmol), biphenylene 12 (46 mg, 0.30 mmol), and [RhCl(cod)]2
(49 mg, 0.10 mmol) was added toluene (2.0 mL). After being refluxed for 12 h, the reaction mixture
was filtered through a pad of silica gel (ethyl acetate). The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column chromatography (hexane) to give 13e
(38 mg, 96%) as a colorless solid.
References
[1] Zheng, J.; Cai, J.; Lin, J.-H,; Guo, Y.; Xiao, J.-C. Chem. Commun. 2013, 7513.
[2] Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
16474.
[3] Fuchibe, K.; Mayumi, Y.; Zhao, N.; Watanabe, S.; Yokota, M. Ichikawa, J. Angew. Chem., Int.
Ed. 2013, 52, 7825–7828.
[4] Schaub, T.; Radius, U. Tetrahedron Lett. 2005, 46, 8195–8197.
[RhCl(cod)]2 (50 mol%)
Toluene, reflux, 12 h
F
+
12 (1.5 eq)
H F
TsO14 13e 96%
F
TsO F
16 N.D.
H
15 N.D.
H FFTsO
– HF
96
97
CHAPTER 4
Silver-Catalyzed Intramolecular Defluoroamination of
β,β-Difluoro-o-sulfonamidostyrenes
Abstract
An electrophilic 5-endo-trig cyclization of β,β-difluoro-o-sulfonamidostyrenes was performed in
1,1,1,3,3,3-hexafluoropropan-2-ol using a Ag(I) catalyst and N,O-bis(trimethylsilyl)acetamide. In
this process, vinylic C–F bond activation was achieved via silver-catalyzed β-fluorine elimination,
accompanied by C–N bond formation, which led to the synthesis of 2-fluoroindoles.
R1
NHR3
CF2
R2cat. AgI
N
CF2
R2 AgI
R1
HR3
NF
R2
R1
R3Si X β-FluorineElimination
5-endo-trigAddition
98
4-1. Introduction
Because 1,1-difluoro-1-alkenes are electron-deficient substances, they readily react with strong
nucleophiles at the carbon α to the fluorine substituents. The nucleophilic addition, followed by
β-fluorine elimination, affords monofluoroalkenes.[1] By conducting this addition–elimination
process in an intramolecular fashion, Ichikawa previously synthesized ring-fluorinated hetero- and
carbocyclic compounds.[2] Particularly, 5-endo-trig cyclization, which is disfavored in Baldwin’s
rules,[3] was achieved by using β,β-difluoro-o-sulfonamidostyrenes 17 as substrates, leading to
fluoroindole synthesis (Scheme 4-1a).
Addition–elimination reactions of 1,1-difluoro-1-alkenes with weak nucleophiles require
electrophilic activation of the alkene moiety,[4] which was recently achieved by acids[5] or
transition-metal complexes.[6] This type of addition–elimination to 1,1-difluoro-1-alkenes
potentially exhibits a wider substrate scope by excluding strong basic conditions. In some cases,
however, monofluoroalkene products are susceptible to hydrolysis under such acidic conditions and
converted to carbonyl compounds.[5c,5g,6a,6b] Thus, I have developed a transition-metal catalysis
providing 2-fluoroindoles 18 via an electrophilic 5-endo-trig cyclization[7] of
difluorosulfonamidostyrenes 17 without hydrolysis (Scheme 4-1b). The use of a Ag(I) catalyst
and N,O-bis(trimethylsilyl)acetamide (BSA) as a fluoride captor is highly effective for vinylic C–F
bond transformation[8] via β-elimination of AgF, which is an unprecedented process for C–F bond
activation.[9]
99
Scheme 4-1. Synthesis of 2-fluoroindoles via 5-endo-trig cyclization of
β,β-difluoro-o-sulfonamidostyrenes
4-2. Synthesis of 2-Fluoroindoles via β-Fluorine Elimination
First, I sought suitable conditions for fluoroindole synthesis using β,β-difluorostyrene 17a
bearing a tosylamide group as a model substrate (Table 4-1). Heating 17a in
1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP)[10,11] in the presence of a catalytic amount of palladium
complexes yielded no cyclized product (Table 4-1, entries 2–4), although cationic Pd(II) complexes
in HFIP were effective for carbocycle construction from β,β-difluorostyrene derivatives (Table 4-1,
entries 3 and 4).[6b,6c,6d] While PtCl2 was ineffective (Table 4-1, entry 5), the use of 10 mol% of
Cu(OTf)2 or AuCl afforded 2-fluoroindole 18a, albeit in extremely low yields (Table 4-1, entries 6
and 7). As a result of screening several Ag(I) complexes (Table 4-1, entries 8–12), AgSbF6 was
found to be prospective because the quantitative formation of 18a was observed on the basis of the
amount of AgSbF6 (10 mol%) used (Table 4-1, entry 12).[12] Thus, with the aim of regenerating an
cat. Ag(I)
NHR’’
CF2
R’ Na
NaH
BSA
R17
NR’’
CF2
R’
R
NHR’’
CF2
R’
R
Ag(I)R
18
N
R’
F
R’’
NSiMe3
OSiMe3BSA
(a) Previous Work
(b) This Work
100
active Ag species, silylating agents were examined as fluoride captors with 10 mol% of
AgSbF6 (Table 4-1, entries 13–15). Among them, 1.0 equiv of BSA[13] drastically promoted
defluorinative 5-endo-trig cyclization to afford 18a in 52% yield (Table 4-1, entry 15). This
reaction definitively proceeded with a metal catalyst in HFIP because the formation of 18a was not
observed in the absence of the catalyst (Table 4-1, entry 1) or in other solvents (Table 4-1, entries
16–18). Eventually, the slow addition of BSA over 2 h was found to be a significant operation,
which led to an almost quantitative formation of 18a (Table 4-1, entry 19). Notably, the
combination of 10 mol% of AgF and 1.0 equiv of BSA also successfully afforded 18a in 82%
isolated yield (Table 4-1, entry 20), although AgF caused no cyclization without BSA (Table 4-1,
entry 8).
101
Table 4-1. Screening of conditions for electrophilic 5-endo-trig cyclization of β,β-difluorostyrene
Using the above-mentioned optimal conditions, the scope of the cyclization of
difluoroamidostyrenes 17 was then investigated (Table 4-2). β,β-Difluorostyrenes 17b and 17c
bearing a methyl group successfully underwent cyclization, leading to an almost quantitative
NHTs
CF2
Bu Catalyst (10 mol%)Additive (1.0 equiv)
NF
Bu
TsSolvent, reflux, 5 h
12345678910111213141516171819[f]
20[h]
–Pd(OAc)2
[Pd(MeCN)4](BF4)2
PdCl2, AgOTf (1:2)PtCl2Cu(OTf)2
AuClAgFAgOTfAgNTf2AgBF4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgF
––BF3•OEtBF3•OEt––––––––TMSImd[c]
HMDSO[d]
BSA[e]
BSA[e]
BSA[e]
BSA[e]
BSA[e]
BSA[e]
HFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPHFIPTolueneCH2Cl2DMFHFIPHFIP
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
N.D.[b]
quant.
[a] Yield was determined by 19F NMR spectroscopy with PhCF3 as an internal standard. [b] N.D.: not detected. [c] TMSImd: N-trimethylsilylimidazole. [d] HMDSO: hexamethyldisiloxane. [e] BSA: N,O-bis(trimethylsilyl)acetamide. [f] After a dropwise addition of BSA to the refluxed solution over 2 h, the mixture was stirred for another 1 h. [g] Isolated yield. [h] After a dropwis addition of BSA to the refluxed solution over 2 h, the mixture was stirred for another 3 h.
17a
< 11
6< 1
710
3152
82(99)[g]
(82)[g]
18a / %[a]SolventAdditiveCatalystEntry
18a
102
formation of the corresponding 2-fluoroindoles 18b and 18c, respectively. Ether (MeO), ester
(EtO2C), and halogen (Cl) substituents in difluorostyrenes 17d–17f were tolerated in this reaction,
which afforded the corresponding fluoroindoles 18d–18f. AgF was more effective than AgSbF6 for
the cyclization of 17e and 17f. Secondary alkyl (sec-Bu), benzyl, and silyl (Me3Si) groups were
installed instead of a primary alkyl group at the 3-position of the pyrrole rings of fluoroindoles 18g–
18i. The substitution of mesyl, nosyl, and mesitylenesulfonyl groups on the nitrogen atom was
achieved to afford diversely sulfonylated 2-fluoroindoles 18j–18l.
Table 4-2. Ag(I)-catalyzed synthesis of 2-fluoroindoles[a]
NTs
F
Bu
18a 99% (3 h)
NTs
F
Bu
18b 99% (4 h)
NTs
F
Bu
18c 98% (6 h)
NTs
F
Bu
18d 52% (6 h)
Me
Me
EtO2C
NTs
F
s-Bu
18g 88% (3 h)
NTs
F
SiMe3
18i 82% (5 h)
NTs
F
Bn
18h 52% (5 h)[c]
NMs
F
Bu
18j 32% (6 h)
NTs
F
Bu
18f 79% (4 h)[c]
NTs
F
Bu
18e 87% (3 h)[c]
Cl
MeO
NNs
F
Bu
NS
F
Bu
18k 66% (6 h) 18l 98% (3 h)
[a] Isolated yield. [b] BSA was slowly added over 2 h. [c] AgF (20 mol%) was used instead of AgSbF6
O2Mes
NHR’’
CF2
R’ AgSbF6 (10 mol%)BSA (1.0 equiv)[b]
NF
R’
R’’18
HFIP, refluxR R
17
103
4-3. Mechanistic Studies on Generation from Metal Fluoride Species
To gain information on the role of BSA, I performed experiments shown in Scheme 4-2. In the
presence of 10 mol% of AgF, an HFIP solution of β,β-difluorostyrene 17a was refluxed, and no
reaction was observed (Scheme 4-2a; see also Table 4-1, entry 8); however, further addition of a
stoichiometric amount of BSA promoted 5-endo-trig cyclization to afford 2-fluoroindole 18a in
81% yield. Conversely, BSA alone did not cause cyclization (Scheme 4-2a). When AgF was treated
with BSA, trimethylsilyl fluoride was obtained in 92% yield, indicating the formation of a Ag(I)
amidate complex (Scheme 4-2b). The addition of 17a to the reaction mixture afforded 18a in 80%
yield (Scheme 4-2b). Furthermore, on treatment with a stoichiometric amount of AgSbF6 in the
absence of BSA, 17a gave 18a in only 25% yield (Scheme 4-2c). These results suggest that the
active species is Ag(I) amidate and not AgSbF6.
104
Scheme 4-2. Mechanistic studies on Ag(I)-catalyzed cyclization of β,β-difluorostyrene
Based on all these observations, I propose a mechanism for the Ag(I)-catalyzed
5-endo-trig cyclization of β,β-difluorostyrenes 17 (Scheme 4-3). The reaction starts with the
generation of the Ag(I) amidate complex from AgSbF6 and BSA. The coordination of 17 to the
Ag(I) amidate complex induces 5-endo-trig addition of the sulfonamido group. Unprecedented
β-elimination of AgF causes C–F bond cleavage to afford 2-fluoroindoles 18. The reaction of AgF
with BSA then regenerates Ag(I) amidate to complete the catalytic cycle.
NoReaction
NHTs
Bu
AgF(1.0 equiv)
HFIPreflux, 1 h
NoReaction
BSA(1.0 equiv)
HFIPreflux, 5 h
CF2
NTs
F
BuBSA*(1.0 equiv)
reflux, 5 h
18a 81%
17a
* slow additionover 2 h
(a)
NTs
Bu
F
17a(1.0 equiv)
AgF
BSA(1.0 equiv)
HFIPreflux, 20 min
reflux, 30 minO
NSiMe3Ag+
+Me3SiF 92%
18a 80%
(19F NMR yield)
–
(b)
NHTs
CF2
Bu AgSbF6 (1.0 equiv)
NF
Bu
Ts
18a 25%(19F NMR yield)
HFIP, reflux, 5 h
(c)
17a
105
Scheme 4-3. Proposed mechanism for Ag(I)-catalyzed 5-endo-trig cyclization
of β,β-difluorostyrene via C–F bond activation.
In summary, I developed a synthetic method for the formation of 2-fluoroindoles via
Ag-catalyzed vinylic C–F bond activation achieved by a 5-endo-trig addition/β-fluorine elimination
sequence. The current method enables the simultaneous construction of an indole framework and
the installation of a fluorine substituent at the 2-position. The obtained fluoroindoles are expected to
constitute a new class of bioactive compounds because the indole ring and fluorine substituent are
common components in pharmaceuticals.[14]
O
NSiMe3Ag+–
5-endo-trigAddition
NR
AgF
NR
F
R’
FF
AgR’
OSiMe3
NSiMe3
O
NHSiMe3
FSiMe3NHR’’
R’
O
NSiMe3–
β-FluorineElimination
CF2
NR
CF2
R’ Ag+
H
AgSbF6
OSiMe3
NSiMe3
’’’’
’’
R
R
R
R
106
4-4. References
[1] For reviews, see: (a) Uneyama, K. Organofluorine Chemistry, Blackwell, 2006, pp. 112–
121. (b) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119–2183.
[2] (a) Ichikawa, J; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 1917–1936, and references
cited therein. (b) Ichikawa, J. Chim. Oggi 2007, 25, 54–57, and references cited therein. (c) Fujita,
T.; Sakoda, K.; Ikeda, M.; Hattori, M.; Ichikawa, J. Synlett 2013, 24, 57–60. (d) Fujita, T.; Ikeda,
M.; Hattori, M.; Sakoda, K.; Ichikawa, J. Synthesis 2014, 46, 1493–1505.
[3] (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736. (b) Baldwin, J. E.; Cutting, J.;
Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 736–
738.
[4] For electrophilic activation of 1,1-difluoro-1-alkenes, see: (a) Suda, M. Tetrahedron Lett. 1980,
21, 2555–2556. (b) Morikawa, T.; Kumadaki, I.; Shiro, M. Chem. Pharm. Bull. 1985, 33, 5144–
5146. (c) Kendrick, D. A.; Kolb, M. J. Fluorine Chem. 1989, 45, 273–276. (d) Saito, A.; Okada,
M.; Nakamura, Y.; Kitagawa, O.; Horikawa, H.; Taguchi, T. J. Fluorine Chem. 2003, 123, 75–80.
[5] (a) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T. J. Org. Chem. 1995, 60, 2320–2321.
(b) Ichikawa, J. Pure Appl. Chem. 2000, 72, 1685–1689. (c) Ichikawa, J.; Jyono, H.; Kudo, T.;
Fujiwara, M.; Yokota, M. Synthesis 2005, 39–46. (d) Ichikawa, J.; Kaneko, M.; Yokota, M.;
Itonaga, M.; Yokoyama, T. Org. Lett. 2006, 8, 3167–3170. (e) Ichikawa, J.; Yokota, M.; Kudo, T.;
Umezaki, S. Angew. Chem., Int. Ed. 2008, 47, 4870–4873. (f) Isobe, H.; Hitosugi, S.; Matsuno, T.;
Iwamoto, T.; Ichikawa, J. Org. Lett. 2009, 11, 4026–4028. (g) Fuchibe, K.; Jyono, H.; Fujiwara,
M.; Kudo, T.; Yokota, M.; Ichikawa, J. Chem.—Eur. J. 2011, 17, 12175–12185. (h) Suzuki, N.;
Fujita, T.; Ichikawa, J. Org. Lett. 2015, 17, 4984–4987.
107
[6] (a) Yokota, M.; Fujita, D.; Ichikawa, J. Org. Lett. 2007, 9, 4639–4642. (b) Tanabe, H.; Ichikawa,
J. Chem. Lett. 2010, 39, 248–249. (c) Fuchibe, K.; Morikawa, T.; Shigeno, K.; Fujita, T.; Ichikawa,
J. Org. Lett. 2015, 17, 1126–1129. (d) Fuchibe, K.; Morikawa, T.; Ueda, R.; Okauchi, T.; Ichikawa,
J. J. Fluorine Chem. 2015, 179, 106–115.
[7] For recent reports on electrophile-driven 5-endo-trig cyclization, see: (a) Kalamkar, N. B.;
Kasture, V. M.; Dhavale, D. D. Tetrahedron Lett. 2010, 51, 6745–6747. (b) Bajracharya, G. B.;
Koranne, P. S.; Nadaf, R. N.; Gabr, R. K. M.; Takenaka, K.; Takizawa, S.; Sasai, H. Chem.
Commun. 2010, 46, 9064–9066. (c) Karjalainen, O. K.; Nieger, M.; Koskinen, A. M. P. Angew.
Chem., Int. Ed. 2013, 52, 2551–2254. (d) Singh, P.; Panda, G. RSC Adv. 2014, 4, 2161–2166. (e)
Tata, R. R.; Harmata, M. J. Org. Chem. 2015, 80, 6839–6842.
[8] For transition-metal-catalyzed vinylic C–F bond activation of fluoroalkenes, see: (a) Dai, W.;
Xiao, J.; Jin, G.; Wu, J.; Cao, S. J. Org. Chem. 2014, 79, 10537–10546. (b) Ohashi, M.; Ogoshi, S.
in Topics in Organometallic Chemistry, ed. by Braun, T; Hughes, R. P. Springer, 2014, Vol. 52, pp.
197–215, and references cited therein. doi:10.1007/3418_2014_89. (c) Ahrens, T.; Kohlmann, J.;
Ahrens, M.; Braun, T. Chem. Rev. 2015, 115, 931–972., and references cited therein. (d) Dai, W.;
Zhang, X.; Zhang, J.; Lin, Y.; Cao, S. Adv. Synth. Catal. 2016, 358, 183–187.
[9] For reports on bond formation (C–C and C–N) via transition-metal-mediated β-fluorine
elimination, see: [Zr]: (a) Fujiwara, M.; Ichikawa, J.; Okauchi, T.; Minami, T. Tetrahedron Lett.
1999, 40, 7261–7265. [Rh]: (b) Miura, T.; Ito, Y.; Murakami, M. Chem. Lett. 2008, 37, 1006–1007.
(c) Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472. [Ni]: (d) Ichitsuka, T.; Fujita, T.;
Arita, T.; Ichikawa, J. Angew. Chem., Int. Ed. 2014, 53, 7564–7568. (e) Ichitsuka, T.; Fujita, T.;
Ichikawa, J. ACS Catal. 2015, 5, 5947–5950. (f) Fujita, T.; Arita, T.; Ichitsuka, T.; Ichikawa, J.
Dalton Trans. 2015, 44, 19460–19463. [Pd]: (g) Heitz, W.; Knebelkamp, A. Makromol. Chem.,
Rapid. Commun. 1991, 12, 69. (h) Sakoda, K.; Mihara, J.; Ichikawa, J. Chem. Commun. 2005,
108
4684–4686. (i) Ichikawa, J.; Sakoda, K.; Mihara, J.; Ito, N. J. Fluorine Chem. 2006, 127, 489. (j)
Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425–4427. (k) Xu, J.; Ahmed, E.-A.; Xiao,
B.; Lu, Q.-Q.; Wang, Y.-L. Yu, C.-G. Fu, Y. Angew. Chem., Int. Ed. 2015, 54, 8231–8235, and see
also ref 6. [Cu]: (l) Hu, M.; He, Z.; Gao, B.; Li, L. Ni, C.; Hu, J. J. Am. Chem. Soc. 2013, 135,
17302–17305. (m) Kikushima, K.; Sakaguchi, H.; Saijo, H.; Ohashi, M.; Ogoshi, S. Chem. Lett.
2015, 44, 1019–1021. (n) Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang, J. Org.
Lett. 2015, 17, 2474–2477.
[10] For selected papers on carbocationic processes in HFIP, see:(a) Nishiwaki, N.; Kamimura, R.;
Shono, K.; Kawakami, T.; Nakayama, K.; Nishino, K.; Nakayama, T.; Takahashi, K.; Nakamura,
A.; Hosokawa, T. Tetrahedron Lett. 2010, 51, 3590. (b) Champagne, P. A.; Benhassine, Y.;
Desroches, J.; Paquin, J.-F. Angew. Chem., Int. Ed. 2014, 53, 13835–13839. (c) Gaster, E.; Vainer,
Y.; Regev, A.; Narute, S.; Sudheendran, K.; Werbeloff, A.; Shalit, H.; Pappo, D. Angew. Chem., Int.
Ed. 2015, 54, 4198–4202. (d) Ricardo, C. L.; Mo, X.; McCubbin, J. A.; Hall, D. G. Chem.—Eur. J.
2015, 21, 4218–4223. (e) Motiwala, H. F.; Vekariya, R. H.; Aubé, J. Org. Lett. 2015, 17, 5484–
5487, and see also refs 5 and 6.
[11] For reviews on fluorinated alcohols, see: (a) Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B.
Synlett 2004, 18–29. (b) Shuklov, I. A.; Dubrovina, N. V.; Börner, A. Synthesis 2007, 2925–2943.
(c) Dohi, T.; Yamaoka, N.; Kita, Y. Tetrahedron 2010, 66, 5775–5785. (d) Khaksar, S. J. Fluorine
Chem. 2015, 172, 51–61.
[12] For selected papers on silver-catalyzed indole synthesis via 5-endo-dig cyclization of
arylacetylenes, see: (a) McNulty, J.; Keskar, K. Eur. J. Org. Chem. 2014, 1622–1629, and
references cited therein. (b) Otani, T.; Jiang, X.; Cho, K.; Araki, R.; Kutsumura, N.; Saito, T. Adv.
Synth. Catal. 2015, 57, 1483–1536, and references cited therein.
109
[13] For use of BSA as a fluoride captor, see: Haufe, G.; Suzuki, S.; Yasui, H.; Terada, C.;
Kitayama, T.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2012, 51, 12275–12279.
[14] For patents on bioactive 2-fluoroindoles, see: a) Bjeldanes, L.; Le, H.; Firestone, G. U.S. Pat.
US 2005/0058600 A1, 2005. (b) Guzzo, P. R.; Henderson, A. J.; Nacro, K.; Isherwood, M. L.;
Ghosh, L.; Xiang, K Pat. Appl. WO 2011/044134 A1, 2011.
4-5. Experimental Section
General statements
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a Bruker Avance 500 or a JEOL
ECS-400 spectrometer. Chemical shift values are given in ppm relative to internal Me4Si (for 1H
NMR: δ = 0.00 ppm), CDCl3 (for 13C NMR: δ = 77.0 ppm), and C6F6 (for 19F NMR: δ = 0.00 ppm).
IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance
(ATR) method. Mass spectra were measured on a JEOL JMS-T100GCV or a JMS-T100CS
spectrometer. Elemental analyses were carried out at the Elemental Analysis Laboratory, Division
of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba. Melting points were
measured on a Yanaco micro melting point apparatus, and were uncorrected.
Column chromatography was performed on silica gel (Kanto Chemical Co. Inc., Silica Gel 60).
Medium pressure liquid chromatography (MPLC) was performed on a Yamazen YFLC-AI-580
apparatus equipped with tandemly-arrayed two silica gel columns (Universal Column f30 x 165
mm). Gel permeation chromatography (GPC) was performed on a JAI LC-908 apparatus equipped
with a JAIGEL-1H and -2H assembly. All the reactions were conducted under argon or nitrogen.
110
Diethyl ether (Et2O), tetrahydrofuran (THF) and toluene were purified by a solvent-purification
system (Glass Contour) equipped with columns of activated alumina and supported-copper catalyst
(Q-5) before use. Benzene was dried over CaCl2 for 1 d, then distilled from CaCl2, and stored over
activated molecular sieves 4A. 1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) and
Hexamethylphosphoric triamide (HMPA) were distilled from CaH2, and stored over activated
molecular sieves 4A. Pyridine was dried over KOH for 1 d, then distilled from KOH, and stored
over activated molecular sieves 4A. Bis(trimethylsilyl)acetamide (BSA) was purified by fractional
distillation. 2-[1-(Difluoromethylene)pentyl]-benzenamine,[1] N-(2-iodoaryl)benzenesulfonamides,
[2] 2-aminophenylboronic acid,[3] (2,2-difluoro-1-iodovinyl)trimethylsilane,[4] and 4-methyl-N-[2-
[1-(trifluoromethyl)ethenyl]phenyl][5] were prepared according to the literature procedures. Unless
otherwise noted, materials were obtained from commercial sources and used directly without
further purifications.
Preparation of o-Sulfonamido-β,β-difluorostyrenes 17
[General Procedure A][1]
To a pyridine solution (0.4 M) of o-amino-β,β-difluorostyrenes (1.0 equiv) was added sulfonyl
chloride (1.1 equiv) at room temperature. After stirring at room temperature for the specified length
of time, the reaction was quenched with saturated aqueous NaHCO3. The organic materials were
extracted with ethyl acetate three times, and the combined extracts were dried over Na2SO4. After
removal of the solvent under reduced pressure, the residue was purified by silica gel column
chromatography to give the corresponding o-sulfonamido-β,β-difluorostyrenes 17.
NH2
CF2
BuRCl (1.1 equiv)
Pyridine, RTNHR
CF2
Bu
111
[General Procedure B][1]
To a THF solution (0.13 M) of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.1 equiv) was
added butyllithium (1.60 M in hexane, 2.3 equiv) at –78 ºC over 10 min. After stirring at the same
temperature for 20 min, trialkylborane (1.00 M in THF, 1.2 equiv) was added at –78 ºC. After
stirring at –78 ºC for 1 h, the reaction mixture was warmed to room temperature and stirred for
another 3 h. To the reaction mixture were added PPh3 (10 mol%), Pd2(dba)3·CHCl3 (2.5 mol%), and
HMPA. After stirring for 20 min, N-(2-iodoaryl)-4-methylbenzenesulfonamides (1.0 equiv)2 and
CuI (1.2 equiv) were added. After stirring at room temperature for another 1 h, the reaction was
quenched with phosphate buffer (pH 7). The mixture was filtered through a pad of Celite (diethyl
ether), and organic materials were extracted with diethyl ether three times. The combined extracts
were washed with brine and dried over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by silica gel column chromatography to give the corresponding
o-sulfonamido-β,β-difluorostyrenes 17.
N-(2-(1,1-Difluorohex-1-en-2-yl)phenyl)-4-methylbenzenesulfonamide (17a)
CF3CH2OTs
1. n-BuLi (2.3 equiv) THF, –78 °C, 20 min
(1.1 eq)
2. BR3 (1.2 equiv) –78 °C, 1 h then RT, 3 h
F2CR
BR2
Pd2(dba)3 (2.5 mol%)PPh3 (10 mol%)CuI (1.2 equiv)
THF–HMPA (4:1), RT
I
NHTs(1.0 equiv)
NHTs
CF2
Bu
R
R
112
Compound 17a was prepared according to General Procedure A using
2-(1,1-difluorohex-1-en-2-yl)aniline (1.06 g, 5.00 mmol),1 4-methylbenzenesulfonyl chloride (1.07
g, 5.61 mmol), and pyridine (12 mL). The reaction was conducted for 8 h. Purification by silica gel
column chromatography (hexane/ethyl acetate = 10:1) gave 17a (1.68 g, 92%) as a white solid.
Spectral data for this compound showed good agreement with the literature data.[1]
N-(2-(1,1-Difluorohex-1-en-2-yl)-5-methylphenyl)-4-methylbenzenesulfonamide (17b)
Compound 17b was prepared according to General Procedure B using 2,2,2-trifluoroethyl
4-methylbenzenesulfonate (847 mg, 3.33 mmol), butyllithium (1.60 M in hexane, 4.40 mL, 7.04
mmol), tributylborane (1.00 M in THF, 3.70 mL, 3.70 mmol), and THF (20 mL). The subsequent
coupling reaction was conducted at room temperature for 12 h using Pd2(dba)3·CHCl3 (86 mg,
0.083 mmol), PPh3 (87 mg, 0.33 mmol), HMPA (6.0 mL),
N-(2-iodo-5-methylphenyl)-4-methylbenzenesulfonamide (1.16 g, 3.00 mmol), and CuI (760 mg,
3.99 mmol). Purification by silica gel column chromatography (hexane/ethyl acetate = 10:1) gave
17b (785 mg, 69%) as a white solid.
mp 103.1–104.0 °C. 1H NMR (500 MHz, CDCl3): δ 0.81 (t, J = 7.6 Hz, 3H), 1.09 (qt, J = 7.6, 7.6
Hz, 2H), 1.17 (tt, J = 7.6, 7.6 Hz, 2H), 1.90–2.03 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 6.45 (br s, 1H),
6.88 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.45 (s, 1H), 7.70 (d, J =
8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 13.6, 21.4, 21.5, 22.2, 28.1, 29.4 (dd, JCF = 3, 3 Hz),
87.8 (dd, JCF = 23, 16 Hz), 120.3, 121.1 (d, JCF = 4 Hz), 125.2, 127.2, 129.6, 130.3, 134.7 (d, JCF =
CF2
Bu
NHTs
CF2
Bu
NHTs
113
2 Hz), 136.4, 139.3, 144.0, 153.0 (dd, JCF = 292, 289 Hz). 19F NMR (471 MHz, CDCl3): δ 72.7 (d,
JFF = 39 Hz, 1F), 75.9 (d, JFF = 39 Hz, 1F). IR (neat): ν~ 3273, 2956, 2927, 1739, 1508, 1394, 1336,
1248, 1092, 1157, 814, 667, 571 cm-1. HRMS (ESI+): m/z Calcd for C20H23F2NNaO2S [M+Na]+
402.1315; Found: 402.1297.
N-(2-(1,1-Difluorohex-1-en-2-yl)-4-methylphenyl)-4-methylbenzenesulfonamide (17c)
Compound 17c was prepared according to General Procedure B using
2,2,2-trifluoroethyl4-methylbenzenesulfonate (286 mg, 1.13 mmol), butyllithium (1.60 M in hexane,
1.50 mL, 2.40 mmol), tributylborane (1.00 M in THF, 1.20 mL, 1.20 mmol), and THF (10 mL). The
subsequent coupling reaction was conducted at room temperature for 12 h using Pd2(dba)3·CHCl3
(24 mg, 0.023 mmol), PPh3 (24 mg, 0.092 mmol), HMPA (1.0 mL),
N-(2-iodo-4-methylphenyl)-4-methylbenzenesulfonamide (387 mg, 1.00 mmol), and CuI (222 mg,
1.16 mmol). Purification by silica gel column chromatography (hexane/ethyl acetate = 10:1) gave
17c (304 mg, 80%) as a white solid.
mp 78.8–80.2 °C. 1H NMR (500 MHz, CDCl3): δ 0.81 (t, J = 7.4 Hz, 3H), 1.10 (qt, J = 7.4, 7.4 Hz,
2H), 1.17 (tt, J = 7.4, 7.4 Hz, 2H), 1.90–2.00 (m, 2H), 2.26 (s, 3H), 2.37 (s, 3H), 6.44 (br s, 1H),
6.82 (s, 1H), 7.07 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 7.9 Hz, 1H), 7.68 (d, J =
8.2 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 13.6, 20.7, 21.5, 22.2, 28.1, 29.5 (dd, JCF = 2, 2 Hz),
88.1 (dd, JCF = 23, 16 Hz), 120.3, 124.5 (d, JCF = 6 Hz), 127.2, 129.6, 129.8, 131.0, 132.3, 134.3,
136.5, 143.9, 152.9 (dd, JCF = 292, 288 Hz). 19F NMR (471 MHz, CDCl3): δ 72.5 (d, JFF = 39 Hz,
1F), 75.9 (d, JFF = 39 Hz, 1F). IR (neat): ν~ 3271, 2927, 2860, 1739, 1498, 1396, 1336, 1252,
1163, 1092, 908, 814, 665, 550 cm-1. Elem. Anal. Calcd for C20H23F2NO2S: C, 63.30; H, 6.11; N,
CF2
Bu
NHTs
114
3.69. Found: C, 63.36; H, 6.24; N, 3.55.
N-(2-(1,1-Difluorohex-1-en-2-yl)-4-methoxyphenyl)-4-methylbenzenesulfonamide (17d)
Compound 17d was prepared according to General Procedure B using
2,2,2-trifluoroethyl-p-toluenesulfonate (276 mg, 1.09 mmol), n-butyllithium (1.50 mL, 1.60 M in
hexane, 2.4 mmol), tributylborane (1.20 mL, 1.00 M in THF, 1.2 mmol) and THF (5.0 mL). The
subsequent coupling reaction was conducted at room temperature for 12 h using Pd2(dba)3•CHCl3
(29 mg, 0.028 mmol), PPh3 (30 mg, 0.11 mmol), HMPA (1.0 mL),
N-(2-iodo-4-methoxylphenyl)-4-methylbenzenesulfonamide (403 mg, 1.00 mmol) and CuI (222 mg,
1.16 mmol). Purification by silica gel column chromatography (hexane/ethyl acetate = 10:1) gave
17d (332 mg, 84%) as a white solid.
mp 63.4–65.0 °C. 1H NMR (500 MHz, CDCl3): δ 0.81 (t, J = 7.3 Hz, 3H), 1.10 (qt, J = 7.3, 7.3 Hz,
2H), 1.16 (tt, J = 7.3, 7.3 Hz, 2H), 1.86–1.95 (m, 2H), 2.37 (s, 3H), 3.76 (s, 3H), 6.31 (br s, 1H),
6.56 (d, J = 3.0 Hz, 1H), 6.82 (dd, J = 9.0, 3.0 Hz, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 9.0 Hz,
1H), 7.64 (d, J = 8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 13.6, 21.5, 22.2, 27.9, 29.5, 55.4,
88.4 (dd, JCF = 23, 15 Hz), 114.0, 116.2, 123.7, 127.2, 127.58, 127.61, 129.6, 136.5, 143.9, 152.9
(dd, JCF = 290, 290 Hz), 156.8. 19F NMR (471 MHz, CDCl3): δ 72.2 (d, JFF = 39 Hz, 1F), 75.9 (d,
JFF = 39 Hz, 1F). IR (neat): n~ 3269, 2958, 1739, 1496, 1334, 1396, 1254, 1209, 1163, 1092, 1039,
771, 663, 550 cm-1. Elem. Anal. Calcd for C20H23F2NO3S: C, 60.74; H, 5.86; N, 3.54. Found: C,
60.54; H, 5.86; N, 3.37.
N-(4-Chloro-2-(1,1-difluorohex-1-en-2-yl)phenyl)-4-methylbenzenesulfonamide (17e)
CF2
Bu
NHTs
MeO
115
Compound 17e was prepared according to General Procedure B using
2,2,2-trifluoroethyl-p-toluenesulfonate (2.80 g, 11.0 mmol), n-butyllithium (14.6 mL, 1.60 M in
hexane, 23.4 mmol), tributylborane (12.0 mL, 1.00 M in THF, 12.0 mmol) and THF (40 mL). The
subsequent coupling reaction was conducted at room temperature for 12 h using Pd2(dba)3•CHCl3
(536 mg, 0.519 mmol), PPh3 (544 mg, 2.08 mmol), HMPA (7.0 mL), ethyl
3-iodo-4-[(4-methylphenyl)sulfonamido]benzene (4.16 g, 10.2 mmol) and CuI (2.10 g, 11.0 mmol).
Purification by silica gel column chromatography (hexane/ethyl acetate = 10:1) gave 17e (2.81 g,
69%) as a white solid.
mp 58.5–60.0 °C. 1H NMR (500 MHz, CDCl3): δ 0.81 (t, J = 7.7 Hz, 3H), 1.10 (qt, J = 7.7, 7.7 Hz,
2H), 1.17 (tt, J = 7.7, 7.7 Hz, 2H), 1.92–2.00 (m, 2H), 2.38 (s, 3H), 6.63 (br s, 1H), 7.01 (d, J = 2.5
Hz, 1H), 7.24 (dd, J = 8.8, 2.5 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.69 (d, J
= 8.2 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 13.6, 21.5, 22.2, 27.9, 29.4, 87.3 (dd, JCF = 24, 16
Hz), 121.1, 125.9 (d, JCF = 5 Hz), 127.2, 129.2, 129.6, 129.8, 130.4, 133.7, 136.0, 144.4, 153.0 (dd,
JCF = 293, 290 Hz). 19F NMR (471 MHz, CDCl3): δ 73.9 (d, JFF = 36 Hz, 1F), 77.3 (d, JFF = 36 Hz,
1F). IR (neat): ν~ 3271, 2958, 2929, 1741, 1489, 1392, 1338, 1165, 771 cm-1. Elem. Anal. Calcd
for C19H20ClF2NO2S: C, 57.07; H, 5.04; N, 3.50. Found: C, 56.87; H, 5.06; N, 3.43.
Ethyl 3-(1,1-difluorohex-1-en-2-yl)-4-(4-methylphenylsulfonamido)benzoate (17f)
Compound 17f was prepared according to General Procedure B using
2,2,2-trifluoroethyl-p-toluenesulfonate (504 mg, 1.98 mmol), n-butyllithium (2.72 mL, 1.60 M in
CF2
Bu
NHTs
Cl
CF2
Bu
NHTs
EtO2C
116
hexane, 23.4 mmol), tributylborane (2.20 mL, 1.00 M in THF, 2.2 mmol) and THF (20 mL). The
subsequent coupling reaction was conducted at 40 °C for 5 h using Pd2(dba)3•CHCl3 (52.0 mg,
0.050 mmol), PPh3 (52.0 mg, 0.20 mmol), HMPA (5.0 mL),
N-(4-chloro-2-iodophenyl)-4-methylbenzenesulfonamide (748 mg, 1.68 mmol) and CuI (448 mg,
2.35 mmol). Purification by silica gel column chromatography (hexane/ethyl acetate = 10:1) gave
17f (218 mg, 30%) as a white solid.
mp 125.1–126.9 °C. 1H NMR (500 MHz, CDCl3): δ 0.82 (t, J = 7.2 Hz, 3 H), 1.13 (qt, J = 7.4, 7.4
Hz, 2H), 1.21 (tt, J = 7.4, 7.4 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H), 2.04–2.13 (m, 2H), 2.38 (s, 3H),
4.33 (q, J = 7.2 Hz, 2H), 6.88 (brs, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.71 (d, J
= 2.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.93 (dd, J = 8.7, 2.0 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ = 13.6, 14.3, 21.5, 22.3, 28.1, 29.4, 61.1, 87.2 (dd, JCF = 23, 16 Hz), 117.5, 122.9, 125.9,
127.3, 129.8, 130.6, 132.1, 135.8, 139.1, 144.6, 153.0 (dd, JCF = 292, 292 Hz), 165.6. 19F NMR
(471 MHz, CDCl3): δ 74.2 (d, JFF = 36 Hz, 1F), 77.3 (d, JFF = 36 Hz, 1F). IR (neat): ν~ 3298, 2962,
1743, 1716, 1263, 1238, 1169, 1092 cm-1. HRMS (ESI+): m/z Calcd for C22H25F2NNaO4S
[M+Na]+ 460.1370; Found: 460.1348.
N-(2-(1-cyclohexyl-2,2-difluorovinyl)phenyl)-4-methylbenzenesulfonamide (17g)
Compound 17g was prepared according to General Procedure B using
2,2,2-trifluoroethyl-p-toluenesulfonate (1.41 g, 5.55 mmol), n-butyllithium (7.40 mL, 1.60 M in
hexane, 11.8 mmol), tributylborane (6.10 mL, 1.00 M in THF, 6.10 mmol) and THF (20 mL). The
subsequent coupling reaction was conducted at room temperature for 12 h using Pd2(dba)3•CHCl3
(145 mg, 0.14 mmol), PPh3 (145 mg, 0.55 mmol), HMPA (2.6 mL),
CF2
s-Bu
NHTs
117
N-(2-iodophenyl)-4-methylbenzenesulfonamide (1.86 g, 5.00 mmol) and CuI (1.26 g, 6.62 mmol).
Purification by silica gel column chromatography (hexane/ethyl acetate = 20:1) gave 17g (931 mg,
51%) as a white solid.
Spectral date for this compound showed good agreement with the literature date.[1]
N-(2-(1,1-difluoro-3-phenylprop-1-en-2-yl)phenyl)-4-methylbenzenesulfonamide (17i)
To a THF (12 mL) solution of 4-methyl-N-[2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl]
benzenesulfonamide (1.23 g, 5.00 mmol) was added phenyl lithium (1.59 mL, 1.60 M in butyl ether,
2.54 mmol) at –90 ºC over 10 min under argon. The mixture was then warmed to room temperature
over 1 h. After stirring at the same temperature for 4 h, the reaction was quenched with saturated
aqueous NH4Cl. The organic materials were extracted with dichloromethane three times, and the
combined extracts were dried over Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10:1) to give
17i (427 mg, 88%) as a colorless solid.
mp = 105.6–107.0 °C. 1H NMR (500 MHz, CDCl3): δ 2.37 (s, 3H), 3.30 (s, 2H), 6.29 (br s, 1H),
6.71 (dd, J = 7.8 Hz, 1H), 6.84–6.93 (m, 2H), 6.94 (dd, J = 7.8, 7.8 Hz, 1H), 7.18–7.27 (m, 6H),
7.47 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3): d 21.5, 35.0, 88.2
(dd, JCF = 22, 17 Hz), 120.1, 124.0 (d, JCF = 5 Hz), 124.4, 127.0, 127.2, 128.6, 128.8, 129.3, 129.7,
130.9 (d, JCF = 3 Hz), 134.9, 136.5, 137.3 (dd, JCF = 2, 2 Hz), 144.0, 153.3 (dd, JCF = 292, 290 Hz).
19F NMR (471 MHz, CDCl3): δ 73.0 (d, JFF = 36 Hz, 1F), 76.0 (d, JFF = 36 Hz, 1F). IR (neat): ν~
3267, 1741, 1495, 1400, 1338, 1252, 1163, 1093, 920, 567 cm-1. HRMS (EI+) m/z Calcd for
NHTs
CF2
Ph
NHTs
CF3PhLi (2.1 equiv)
THF, –90 °C, 1 hthen RT, 4 h
118
C22H19F2NO2S [M]+: 399.1105; Found: 399.1106.
2-[2,2-Difluoro-1-(trimethylsilyl)vinyl]aniline
To a degassed benzene–EtOH–H2O mixed solvent (3:1:1) solution (15.0 mL) of
2-aminophenylboronic acid (205 mg, 1.50 mmol) and (2,2-difluoro-1-iodovinyl)trimethylsilane
(520 mg, 1.98 mmol) were added Pd2(dba)3•CHCl3 (38 mg, 0.036 mmol),
2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos; 31 mg, 0.075 mmol), and potassium
carbonate (621 mg, 4.49 mmol) at room temperature. After the mixture was refluxed for 18 h, the
solution was diluted with ethyl acetate. The organic layer was washed twice with water and dried
over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by
silica gel column chromatography (hexane/ethyl acetate = 20:1) give
2-[2,2-difluoro-1-(trimethylsilyl)vinyl]aniline (282 mg, 83%) as a pale yellow oil.
1H NMR (500 MHz, CDCl3): δ 0.21 (d, J = 0.8 Hz, 9H), 3.63 (br s, 2H), 6.73 (dd, J = 7.6 Hz, JHF =
0.4 Hz, 1H), 6.77 (ddd, J = 7.6, 7.6 Hz, JHF = 1.2 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 7.11 (ddd, J =
7.6, 7.6 Hz, JHF = 1.6 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ –1.2, 83.6 (dd, JCF = 34, 4 Hz),
115.1, 118.3, 119.4 (dd, JCF = 9, 2 Hz), 127.9, 129.8, 143.8, 154.8 (dd, JCF = 309, 288 Hz). 19F
NMR (471 MHz, CDCl3): δ 87.2 (d, JFF = 24 Hz, 1F), 95.1 (d, JFF = 24 Hz, 1F). IR (neat): ν~ 3481,
3384, 2958, 1684, 1614, 1495, 1236, 1211, 841, 748 cm-1. HRMS (ESI+): m/z Calcd for
C11155F2NNaSi [M+Na]+ 250.0840; Found: 250.0846.
NH2
CF2
SiMe3
Pd2(dba)3•CHCl3 (2.5 mol%)SPhos (5.0 mol%)K2CO3 (5.0 equiv)
Benzene–EtOH–H2O (3:1:1)reflux, 18 h
B(OH)2
NH2CF2I
SiMe3+
(1.3 eq)
119
N-(2-(2,2-difluoro-1-(trimethylsilyl)vinyl)phenyl)-4-methylbenzenesulfonamide (17h)
Compound 17h was prepared according to General Procedure A using
2-[2,2-difluoro-1-(trimethylsilyl)vinyl]aniline (227 mg, 1.00 mmol), 4-methylbenzenesulfonyl
chloride (279 mg, 1.47 mmol) and pyridine (2.5 mL) at room temp for 24 h. Purification by silica
gel column chromatography (hexane/ethyl acetate = 10:1) gave 17h (1.68 g, 92%) as a white solid.
mp = 150.1–152.9 °C. 1H NMR (500 MHz, CDCl3): δ 0.09 (s, 9H), 2.37 (s, 3H), 6.58 (br s, 1H),
6.88 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.4, 7.4 Hz, 1H), 7.17 (dd, J = 7.4, 7.4 Hz, 1H), 7.24 (d, J =
8.3 Hz, 2H), 7.49 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ –1.3,
21.5, 82.9 (dd, JCF = 35, 5 Hz), 118.4, 123.95, 124.04 (d, JCF = 11 Hz), 127.3, 128.0, 129.7, 130.0,
134.5, 136.5, 144.0, 154.9 (dd, JCF = 311, 290 Hz). 19F NMR (471 MHz, CDCl3): δ 89.8 (d, JFF =
18 Hz, 1F), 98.5 (d, JFF = 18 Hz, 1F). IR (neat): n~ 3278, 2958, 1689, 1493, 1338, 1234, 1161, 843
cm-1. Elem. Anal. Calcd for C18H21F2NO2SSi: C, 56.67; H, 5.55; N, 3.67. Found: C, 56.39; H,
5.57; N, 3.66.
N-[2-(1,1-Difluorohex-1-en-2-yl)phenyl]methanesulfonamide (17j)
Compound 17j was prepared according to General Procedure A using
2-(1,1-difluorohex-1-en-2-yl)aniline (211 mg, 1.00 mmol), methanesulfonyl chloride (126 mg, 1.1
mmol) and pyridine (3.0 mL) at room temp for 17 h. Purification by silica gel column
chromatography (hexane/ethyl acetate = 10:1) gave 17j (264 mg, 91%) as a white solid.
NHTs
CF2
SiMe3
CF2
Bu
NHMs
120
mp 91.2–91.9 °C. 1H NMR (500 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.29–1.35 (m, 4H), 2.25–
2.32 (m, 2H), 3.04 (s, 3H), 6.40 (br s, 1H), 7.13–7.19 (m, 2H), 7.33–7.38 (m, 1H), 7.65 (d, J = 8.2
Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 13.7, 22.3, 28.4, 29.6 (dd, JCF = 2, 2 Hz), 39.7, 88.0 (dd,
JCF = 23, 16 Hz), 118.6, 123.7, 124.5, 129.5, 130.8 (d, JCF = 2 Hz), 135.2, 152.9 (dd, JCF = 293, 288
Hz). 19F NMR (471 MHz, CDCl3): δ 73.1 (d, JFF = 39 Hz, 1F), 76.4 (d, JFF = 39 Hz, 1F). IR (neat):
ν~ 3280, 2958, 2862, 1741, 1495, 1398, 1336, 1246, 1159, 970, 762 cm-1. HRMS (ESI+): m/z
Calcd for C13H17F2NNaO2S [M+Na]+ 312.0846; Found: 312.0846. Elem. Anal. Calcd for
C18H21F2NO2SSi: C, 53.97; H, 5.92; N, 4.84. Found: C, 53.63; H, 5.77; N, 4.88.
N-[2-(1,1-Difluorohex-1-en-2-yl)phenyl]-2-nitrobenzenesulfonamide (17k)
Compound 17k was prepared according to General Procedure A using
2-(1,1-difluorohex-1-en-2-yl)aniline (211 mg, 1.00 mmol), 2-nitrobenzenesulfonyl chloride (247
mg, 1.11 mmol) and pyridine (3.0 mL) at room temp for 17 h. Purification by silica gel column
chromatography (hexane/ethyl acetate = 10:1) gave 17k (363 mg, 88%) as a pale brown solid.
mp 71.8–73.9 °C. 1H NMR (500 MHz, CDCl3): δ 0.83 (t, J = 7.0 Hz, 3H), 1.16–1.29 (m, 4H), 2.09–
2.15 (m, 2H), 7.07 (dd, J = 7.6, 1.3 Hz, 1H), 7.18 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H), 7.35 (ddd, J = 8.0,
8.0, 1.3 Hz, 1H), 7.37 (br s, 1H), 7.62 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H), 7.69–7.73 (m, 2H), 7.87 (dd, J
= 8.0, 1.3 Hz, 1H), 7.91 (dd, J = 8.0, 1.3 Hz 1H). 13C NMR (126 MHz, CDCl3): δ 13.6, 22.2, 28.4,
29.4, 88.2 (dd, JCF = 23, 16 Hz), 123.3, 125.3, 125.9, 126.8 (d, JCF = 5 Hz), 129.2, 130.8, 131.0,
132.8, 133.3, 133.9, 134.3, 147.9, 153.0 (dd, JCF = 292, 287 Hz). 19F NMR (471 MHz, CDCl3): δ
71.9 (d, JFF = 39 Hz, 1F), 75.8 (d, JFF = 39 Hz, 1F). IR (neat): ν~ 3332, 2958, 1739, 1541, 1408,
CF2
Bu
NHNs
121
1354, 1174 cm-1. HRMS (ESI+): m/z Calcd for C18H18F2N2NaO4S [M+Na]+ 419.0872; Found:
419.0853.
N-[2-(1,1-Difluorohex-1-en-2-yl)phenyl]-2,4,6-trimethylbenzenesulfonamide (17l)
Compound 17l was prepared according to General Procedure A using
2-(1,1-difluorohex-1-en-2-yl)aniline (211 mg, 1.00 mmol), 2,4,6-trimethylbenzenesulfonyl chloride
(241 mg, 1.10 mmol) and pyridine (3.0 mL) at room temp for 17 h. Purification by silica gel
column chromatography (hexane/ethyl acetate = 10:1) gave 17l (374 mg, 95%) as a white solid.
mp 89.5–90.3 °C. 1H NMR (500 MHz, CDCl3): δ 0.86 (t, J = 6.8 Hz, 3H), 1.25–1.33 (m, 4H), 2.15–
2.23 (m, 2H), 2.29 (s, 3H), 2.61 (s, 6H), 6.52 (br s, 1H), 6.95 (br s, 2H), 7.04–7.11 (m, 3H), 7.17–
7.21 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 13.6, 20.9, 22.2, 22.9, 28.1, 29.6 (dd, JCF = 2, 2 Hz),
88.5 (dd, JCF = 23, 16 Hz), 120.3, 124.4, 125.0 (d, JCF = 4 Hz), 129.0, 130.7, 132.2, 134.3, 135.1,
139.1, 142.8, 153.1 (dd, JCF = 292, 288 Hz). 19F NMR (471 MHz, CDCl3): δ 72.3 (d, JFF = 40 Hz,
1F), 76.0 (d, JFF = 40 Hz, 1F). IR (neat): ν~ 3280, 2958, 2933, 1739, 1335, 1155 cm-1. HRMS
(ESI+): m/z Calcd for C21H25F2NNaO2S [M+Na]+ 416.1472; Found: 416.1484.
3. Synthesis of 2-Fluoroindoles
3-Butyl-2-fluoro-1-tosyl-1H-indole (18a)
To a refluxed HFIP (2.0 mL) solution of o-sulfonamido-β,β-difluorostyrene 17a (73 mg, 0.20
CF2
Bu
NHSO2Mes
NTs
F
Bu
122
mmol) and silver(I) hexafluoroantimonate (6.9 mg, 0.020 mmol) was added BSA (49 µL, 0.20
mmol) dropwise via a syringe over 2 h. After being refluxed for another 1 h, the reaction mixture
was filtered through a pad of silica gel (ethyl acetate). The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate =
10:1) to give 18a (68 mg, 99%) as a colorless oil.
Spectral data for this compound showed good agreement with the literature data.[1]
3-Butyl-2-fluoro-6-methyl-1-(4-methylbenzenesulfonyl)-1H-indole (18b)
Compound 18b was synthesized according to the procedure described for 18a using 17b (76 mg,
0.20 mmol), AgSbF6 (6.7 mg, 0.019 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 4 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18b (71 mg, 99%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.84 (t, J = 7.4 Hz, 3H), 1.19 (qt, J = 7.4, 7.4 Hz, 2H), 1.51 (tt, J =
7.4, 7.4 Hz, 2H), 2.35 (s, 3H), 2.47 (s, 3H), 2.50 (t, J = 7.4 Hz, 2H), 7.06 (d, J = 7.9 Hz, 1H), 7.21
(d, J = 8.5 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.90 (s, 1H). 13C NMR (126
MHz, CDCl3): δ 13.7, 21.3 (d, JCF = 2 Hz), 21.6, 22.0, 22.1, 30.5 (d, JCF = 2 Hz), 99.5 (d, JCF = 11
Hz), 114.6, 118.6 (d, JCF = 7 Hz), 125.2, 125.6 (d, JCF = 5 Hz), 126.8, 129.8, 130.9, 134.0 (d, JCF =
4 Hz), 134.8, 145.1, 147.0 (d, JCF = 277 Hz). 19F NMR (471 MHz, CDCl3): δ 29.4 (s, 1F). IR (neat):
ν~ 2956, 2929, 1660, 1427, 1390, 1267, 1178, 1092, 667, 582, 544 cm-1. HRMS (ESI+): m/z Calcd
for C20H22FNNaO2S [M+Na]+ 382.1253; Found: 382.1259.
3-Butyl-2-fluoro-5-methyl-1-(4-methylbenzenesulfonyl)-1H-indole (18c)
NTs
Bu
F
123
Compound 18c was synthesized according to the procedure described for 18a using 17c (76 mg,
0.20 mmol), AgSbF6 (6.9 mg, 0.020 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 6 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18c (71 mg, 98%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.86 (t, J = 7.4 Hz, 3H), 1.20 (qt, J = 7.4, 7.4 Hz, 2H), 1.52 (tt, J =
7.4, 7.4 Hz, 2H), 2.34 (s, 3H), 2.39 (s, 3H), 2.49 (td, J = 7.4 Hz, JHF = 0.9 Hz, 2H), 7.09 (dd, J = 8.4,
1.0 Hz, 1H), 7.11 (d, J = 1.0 Hz, 1H), 7.19 (dd, J = 8.4 Hz, JHF = 1.0 Hz, 2H), 7.71 (d, J = 8.4 Hz,
2H), 7.94 (d, J = 8.4 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 13.7, 21.3 (d, JCF = 2 Hz), 21.4, 21.6,
22.1, 30.5, 99.7 (d, JCF = 11 Hz), 114.3, 119.0 (d, JCF = 7 Hz), 125.2 (d, JCF = 4 Hz), 126.8, 128.3 (d,
JCF = 5 Hz), 128.7, 129.8, 133.7, 134.6, 145.1, 147.5 (d, JCF = 277 Hz). 19F NMR (471 MHz,
CDCl3): δ 30.4 (s, 1F). IR (neat): ν~ 2956, 2929, 1657, 1466, 1392, 1176, 810, 665, 542 cm-1.
HRMS (ESI+): m/z Calcd for C20H22FNNaO2S [M+Na]+ 382.1253; Found: 382.1265.
3-Butyl-2-fluoro-5-methoxy-1-(4-methylbenzenesulfonyl)-1H-indole (18d)
Compound 18d was synthesized according to the procedure described for 18a using 17d (82 mg,
0.20 mmol), AgSbF6 (6.9 mg, 0.020 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 6 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18d (40 mg, 53%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.85 (t, J = 7.4 Hz, 3H), 1.18 (qt, J = 7.4, 7.4 Hz, 2H), 1.51 (tt, J =
7.4, 7.4 Hz, 2H), 2.35 (s, 3H), 2.47 (t, J = 7.4 Hz, 2H), 3.82 (s, 3H), 6.79 (d, J = 2.6 Hz, 1H), 6.87
NTs
Bu
F
NTs
Bu
FMeO
124
(dd, J = 9.0, 2.6 Hz, 1H), 7.20 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 9.0 Hz, 1H).
13C NMR (126 MHz, CDCl3): δ 13.7, 21.3 (d, JCF = 2 Hz), 21.6, 22.0, 30.3 (d, JCF = 2 Hz), 55.6,
100.2 (d, JCF = 12 Hz), 102.8 (d, JCF = 6 Hz), 111.5 (d, JCF = 4 Hz), 115.7, 124.9, 126.8, 129.4 (d,
JCF = 5 Hz), 129.7, 134.4, 145.1, 148.1 (d, JCF = 277 Hz), 156.9. 19F NMR (471 MHz, CDCl3): δ
31.1 (s, 1F). IR (neat): ν~ 2958, 1477, 1392, 1217, 1176, 771, 667 cm-1. HRMS (ESI+): m/z Calcd
for C20H22FNNaO3S [M+Na]+ 398.1202; Found: 398.1220. Elem. Anal. Calcd for C20H22FNNaO3S:
C, 63.98; H, 5.41; N, 3.73. Found: C, 64.36; H, 5.76; N, 3.92.
Ethyl 3-butyl-2-fluoro-1-(4-methylbenzenesulfonyl)-1H-indole-5-carboxylate (18e)
Compound 18f was synthesized according to the procedure described for 18a using 17f (85 mg,
0.19 mmol), AgF (5.0 mg, 0.039 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 3 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18f (71 mg, 85%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 7.4 Hz, 3H), 1.19–1.31 (m, 2H), 1.41 (t, J = 7.1 Hz,
3H), 1.52–1.63 (m, 2H), 2.37 (s, 3H), 2.57 (t, J = 7.4 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 7.24 (d, J =
8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.99 (dd, J = 8.8, 1.7 Hz, 1H), 8.07 (d, J = 1.7 Hz, 1H), 8.13
(d, J = 8.8 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ = 13.7, 14.4, 21.3 (d, JCF = 3Hz), 21.6, 22.1,
30.6 (d, JCF = 2 Hz), 61.0, 99.9 (d, JCF = 11 Hz), 113.9, 120.9 (d, JCF = 7 Hz), 125.3, 126.3, 126.9,
127.8 (d, JCF = 5 Hz), 130.0, 133.2, 134.6, 145.7, 147.8 (d, JCF = 279 Hz), 166.6. 19F NMR (471
MHz, CDCl3): δ 32.2 (s, 1F). IR (neat): ν~ 2956, 2933, 1716,1396, 1255, 1178, 580 cm-1. HRMS
(ESI+): m/z Calcd for C22H24FNNaO4S [M+Na]+ 440.1308; Found: 440.1303.
NTs
F
BuEtO2C
125
3-Butyl-5-chloro-2-fluoro-1-(4-methylbenzenesulfonyl)-1H-indole (18f)
Compound 18e was synthesized according to the procedure described for 18a using 17e (83 mg,
0.20 mmol), AgF (5.1 mg, 0.040 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 4 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18e (62 mg, 81%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.86 (t, J = 7.3Hz, 3H), 1.20 (qt, J = 7.3, 7.3 Hz, 2H), 1.51 (tt, J =
7.3, 7.3 Hz, 2H), 2.37 (s, 3H), 2.49 (t, J = 7.3 Hz, 2H), 7.21–7.28 (m, 3H), 7.31 (s, 1H), 7.72 (d, J =
7.9 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 13.7, 21.2 (d, JCF = 2 Hz),
21.6, 22.1, 30.4, 99.5 (d, JCF = 12 Hz), 115.6, 118.8 (d, JCF = 7 Hz), 124.2 (d, JCF = 4 Hz), 126.8,
128.7, 129.4 (d, JCF = 5 Hz), 129.8, 129.9, 134.4, 145.6, 148.0 (d, JCF = 279 Hz). 19F NMR (471
MHz, CDCl3): δ 32.2 (s, 1F). IR (neat): ν~ 2958, 2929, 1655, 1599, 1444, 1394, 1259, 1180, 810,
663, 582, 544 cm-1. HRMS (ESI+): m/z Calcd for C19H19ClFNNaO2S [M+Na]+ 402.0707; Found:
402.0691.
3-(sec-Butyl)-2-fluoro-1-(4-methylbenzenesulfonyl)-1H-indole (18g)
Compound 18g was synthesized according to the procedure described for 18a using 17g (73 mg,
0.20 mmol), AgSbF6 (7.0 mg, 0.020 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 3 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18g (61 mg, 88%) as a colorless oil.
NTs
F
BuCl
NTs
F
s-Bu
126
Spectral date for this compound showed good agreement with the literature date.5
3-Benzyl-2-fluoro-1-(4-methylbenzenesulfonyl)-1H-indole (18h)
Compound 18i was synthesized according to the procedure described for 18a using 17i (80 mg,
0.20 mmol), AgF (5.1 mg, 0.040 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 5 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18f (39 mg, 52%) as a white solid.
mp = 139.8–140.1 °C. 1H NMR (500 MHz, CDCl3): δ 2.38 (s, 3H), 3.89 (s, 2H), 7.05 (d, J = 6.8 Hz,
2H), 7.14–7.29 (m, 8H), 7.75 (d, J = 8.3 Hz, 2H), 8.08 (d, J = 8.3 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ 21.6, 27.7 (d, JCF = 2 Hz), 98.5 (d, JCF = 10 Hz), 114.5, 119.3 (d, JCF = 7 Hz), 124.16,
124.25 (d, JCF = 4 Hz), 126.4, 126.9, 127.7 (d, JCF = 5 Hz), 128.1, 128.4, 129.9, 130.7, 134.7, 138.3,
145.4, 148.0 (d, JCF = 278 Hz). 19F NMR (471 MHz, CDCl3): δ 30.9 (s, 1F). IR (neat): ν~ 1666,
1454, 1390, 1176, 758, 579 cm-1. HRMS (EI+) m/z Calcd for C22H18FNO2S [M]+: 379.1042.
Found: 379.1042.
2-Fluoro-1-(4-methylbenzenesulfonyl)-3-(trimethylsilyl)-1H-indole (18i)
Compound 18h was synthesized according to the procedure described for 18a using 17h (76 mg,
0.20 mmol), AgSbF6 (7.0 mg, 0.020 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
NTs
F
Ph
NTs
F
SiMe3
127
reaction was conducted at reflux for 5 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18h (59 mg, 82%) as a white solid.
mp = 121.8–122.6 °C. 1H NMR (500 MHz, CDCl3): δ 0.32 (s, 9H), 2.38 (s, 3H), 7.22 (dd, J = 7.7,
7.7 Hz, 1H), 7.26–7.31 (m, 3 H), 7.45 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 8.08 (d, J = 7.7
Hz, 1H). 13C NMR (126 MHz, CDCl3): δ –0.6, 21.6, 93.0 (d, JCF = 19 Hz), 113.9, 121.6 (d, JCF = 7
Hz), 123.69 (d, JCF = 5 Hz), 123.71, 127.0, 130.0, 130.4 (d, JCF = 10 Hz), 132.1 (d, JCF = 3 Hz),
135.3, 145.4, 154.0 (d, JCF = 277 Hz). 19F NMR (471 MHz, CDCl3): δ 44.7 (s, 1F). IR (neat); n~ =
2954, 1608, 1579, 1450, 1377, 1327, 1250, 1174, 841, 660, 573 cm–1. HRMS (ESI+): m/z Calcd for
C18H20FNNaO2SSi [M+Na]+ 384.0866; Found: 384.0873.
3-Butyl-2-fluoro-1-(methanesulfonyl)-1H-indole (18j)
Compound 18j was synthesized according to the procedure described for 18a using 17j (58 mg,
0.20 mmol), AgSbF6 (7.0 mg, 0.020 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 6 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18j (17 mg, 32%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.95 (t, J = 7.4 Hz, 3H), 1.39 (qt, J = 7.4, 7.4 Hz, 2H), 1.66 (tt, J =
7.4, 7.4 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 3.15 (s, 3H), 7.28–7.33 (m, 2H), 7.48 (dd, J = 5.8, 3.1 Hz,
1H), 7.91 (dd, J = 5.8, 3.1 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 13.8, 21.4 (d, JCF = 2 Hz), 22.4,
30.7, 41.0, 99.3 (d, JCF = 11 Hz), 113.8, 119.2 (d, JCF = 7 Hz), 124.1, 124.2 (d, JCF = 4 Hz ), 127.8
(d, JCF = 5 Hz), 130.4, 147.1 (d, JCF = 278 Hz). 19F NMR (471 MHz, CDCl3): δ 29.2 (s, 1F). IR
NMs
F
Bu
128
(neat): ν~ 2933, 2862, 1660, 1454, 1388, 1174, 962, 744, 540 cm-1. HRMS (ESI+): m/z Calcd for
C13H16FNNaO2S [M+Na]+ 292.0774; Found: 292.0784.
3-Butyl-2-fluoro-1-(2,4,6-trimethylbenzenesulfonyl)-1H-indole (18l)
Compound 18k was synthesized according to the procedure described for 18a using 17k (82 mg,
0.20 mmol), AgSbF6 (7.1 mg, 0.021 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 6 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 18k (51 mg, 65%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.91 (t, J = 7.5 Hz, 3H), 1.35 (qt, J = 7.5, 7.5 Hz, 2H), 1.63 (tt, J =
7.5, 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 7.28–7.34 (m, 2H), 7.45 (dd, J = 7.4, 2.0 Hz, 1 H),
7.69-7.50 (m, 1H), 7.76-7.79 (m, 2H), 7.90 (dd, J = 7.4, 1.4 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H). 13C
NMR (126 MHz, CDCl3): d 13.7, 21.4 (d, JCF = 2 Hz), 22.4, 30.6 (d, JCF = 2 Hz), 99.3 (d, JCF = 10
Hz), 114.4, 119.2 (d, JCF = 7 Hz), 124.2, 124.4 (d, JCF = 4 Hz), 125.0 (d, JCF = 5 Hz), 130.7, 130.8
(d, JCF = 2 Hz),132.1, 132.3, 135.1, 146.9 (d, JCF = 278 Hz), 147.9. 19F NMR (471 MHz, CDCl3): d
30.3 (s, 1F). IR (neat): n~ 2958, 2933, 2860, 1664, 1545, 1454, 1398, 1255, 1286, 742, 592 cm-1.
HRMS (ESI+): m/z Calcd for C18H17FN2NaO5S [M+Na]+ 415.0740; Found: 415.0419.
3-Butyl-2-fluoro-1-(mesitylsulfonyl)l-1H-indole (18l)
Compound 18l was synthesized according to the procedure described for 18a using 17l (79 mg,
NNs
F
Bu
NSO2Mes
F
Bu
129
0.20 mmol), AgSbF6 (7.1 mg, 0.021 mmol), BSA (49 µL, 0.020 mmol), and HFIP (2.0 mL). The
reaction was conducted at reflux for 3 h. Purification by silica gel column chromatography
(hexane/ethyl acetate = 10:1) gave 17l (73 mg, 98%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.89 (t, J = 7.5 Hz, 3H), 1.31 (qt, J = 7.5, 7.5 Hz, 2H), 1.58 (tt, J =
7.5, 7.5 Hz, 2H), 2.31 (s, 3H), 2.55 (s, 6H), 6.97 (s, 2H), 7.22–7.30 (m, 2H), 7.44 (dd, J = 8.1, 1.1
Hz, 1H), 7.99 (dd, J = 8.1, 1.1 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 13.7, 21.1, 21.3 (d, JCF = 2
Hz), 22.4, 30.8 (d, JCF = 1 Hz), 97.4 (d, JCF = 10 Hz), 114.1, 119.0 (d, JCF = 7 Hz), 123.0, 123.6 (d,
JCF = 4 Hz), 126.8, (d, JCF = 6 Hz), 131.1, 132.1, 133.7, 140.5, 144.1, 147.4 (d, JCF = 274 Hz). 19F
NMR (471 MHz, CDCl3): δ 28.3 (s, 1F). IR (neat): ν~ 2931, 1658, 1450, 1362, 1257, 1169, 741,
654, 588, 525 cm-1. HRMS (ESI+): m/z Calcd for C21H24FNNaO5S [M+Na]+ 396.1410; Found:
396.1428.
Mechanistic Studies
Addition of BSA after Reaction of 17a with a Catalytic Amount of AgF
To a mixture of 17a (182 mg, 0.50 mmol) and AgF (63 mg, 0.50 mmol) was added HFIP (2.0
mL). After refluxing for 1 h, no cyclized product was observed by thin-layer chromatography on
silica gel. To the mixture was then added BSA (123 µL, 0.50 mmol) dropwise via a syringe over 2 h.
After being refluxed for another 3 h, the reaction mixture was filtered through a pad of silica gel
(ethyl acetate). The filtrate was concentrated under reduced pressure, and the residue was purified
NHTs
CF2
n-Bu AgF (10 mol%)
NF
n-Bu
Ts81%
HFIP, reflux1 h
BSA*(1.0 equiv)
reflux, 5 hNo Reaction
* Slow addition over 2 h
130
by silica gel column chromatography (hexane/ethyl acetate = 10:1) to give 18a (140 mg, 81%) as a
colorless oil.
Reaction of 17a with Stoichiometric Silver(I) Amidate Generated from AgF and BSA
To a HFIP (2.0 mL) solution of AgF was added BSA (123 µL, 0.50 mmol). After refluxing for 1 h,
fluorotrimethylsilane was obtained in 92% yield (The yield was determined by 19F NMR using
PhCF3 as an internal standard). To the mixture was then added 17a (182 mg, 0.50 mmol). After
being refluxed for another 30 min, the reaction mixture was filtered through a pad of silica gel
(ethyl acetate). The filtrate was concentrated under reduced pressure, and the residue was purified
by silica gel column chromatography (hexane/ethyl acetate = 10:1) to give 18a (138 mg, 80%) as a
colorless oil.
Reaction of 1a with Stoichiometric AgSbF6
To a mixture of 17a (37 mg, 0.10 mmol) and AgSbF6 (34 mg, 0.10 mmol) was added HFIP (1.0
mL). After refluxing for 5 h, 18a was obtained in 25% yield (The yield was determined by 19F
NMR using PhCF3 as an internal standard).
NTs
Bu
F
9a(1.0 equiv)
AgF
BSA(1.0 equiv)
HFIPreflux, 20 min
reflux, 30 minO
NSiMe3Ag+
+ Me3SiF 92%80%
Detected by 19F NMR
–
NHTs
CF2
n-Bu AgSbF6 (1.0equiv)
NF
n-Bu
Ts25%
19F NMR yield
HFIP, reflux, 5 h
131
References
[1] Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis, 2002, 1917–1936.
[2] Huang, A.; Chem, Y.; Zhou, Y.; Guo, W.; Wu, X.; Ma, C. Org. Lett. 2013, 15, 5480–5483.
[3] Groziak, M. P.; Ganguly, A. D.; Robinson, Paul. D. J. Am. Chem. Soc. 1994, 116, 7597–7605.
[4] Turcotte-Savard. M.-O.; Paquin, J.-F. Org. Biomol. Chem. 2013, 11, 1367–1375.
[5] Ichikawa, J.; Iwai, Y.; Nadano, R.; Mori, T.; Ikeda, M. Chem. Asian J. 2008, 3, 393–406.
132
CHAPTER 5
Nickel-Catalyzed Site-Selective Difluoroallylation of Indoles with
2-Trifluoromethyl-1-alkenes
Abstract
On treatment with Lii-PrOBEt3 generated from i-PrOLi and BEt3, the nickel-catalyzed
defluorinative coupling of indoles with 3,3,3-trifluoro-1-propenes was achieved to afford
difluoroallylindoles. In this reaction, single allylic C(sp3)–F bond activation of the trifluoromethyl
group was accomplished via β-fluorine elimination under mild conditions. Unlike typical
cross-coupling reactions via oxidative addition, mechanistic study revealed that cleavage of C–F
bond was promoted by the cooperative effect of nickelacyclopropanes and indolylborates in this
reaction. This results suggest the strategy for functionalization of a single C–F bond of
trifluoromethyl group, which enabled us to synthesize and the synthesis of various
fluorine-containing organic compounds.
CF2cat. Ni
NH
CF2+NH
R1
R2R2
R1
F
H
Lii-PrOBEt3
133
5-1. Introduction
The transition metal-catalyzed cross-coupling reaction between allylic halides with weak
nucleophiles is well known as the Tsuji–Trost reaction, which has been widely used as a significant
and powerful tool for allylation via carbon–carbon (C–C) bond formation.[1] Typical Tsuji–Trost
reactions proceed via oxidative addition of allylic electrophiles to metal catalysts, followed by the
reaction of the resulting π-allyl metal intermediates with nucleophiles (Scheme 5-1a). Not only
allylic halides (X = I, Br, Cl) but also other allylic electrophiles such as allylic alcohol derivatives
(X = OAc, OCO2R, etc.) are widely applied to the Tsuji–Trost reaction. However, only a few
examples using allylic fluorides have been reported presumably due to high bond energy of the
carbon–fluorine (C–F) bond.[2] Although Fujii, Gouveneur, and Paquin independently reported the
defluorinative Tsuji–Trost reactions using hydrosilanes, malonates, and amines as nucleophiles,
respectively, the substrates were limited to mono- and difluoroallylic compounds. In contrast, single
C–F bond activation of trifluoromethyl (CF3) compounds, which are commonly found and rather
easy to prepare by using CF3 sources, has been a particularly difficult task. It is due to the shielding
effect of the lone-pair electrons of three fluorine atoms, which renders the first C–F bond of the
CF3 group the hardest to cleave.[3,4] Thus, there have been no reports dealing with the Tsuji–Trost
reaction of CF3-alkenes via oxidative addition of allylic C–F bonds, whereas this type of reaction
possesses high potential for the synthesis of fluorine-containing compounds.[5]
In this context, I conceived an alternative idea for defluorinative difluoroallylation of weak
nucleophiles using CF3-alkenes via metal-mediated fluorine elimination, which typically proceeds
under milder conditions than oxidative addition.[6,7] I assumed that the formal Tsuji–Trost reaction
might proceed through metalacyclopropanes bearing a CF3 group. Strongly electrophilic
CF3-alkenes and electron-rich low-valent metals would generate the metalacyclopropanes, which
might react with nucleophiles via fluorine elimination and C–C bond formation. Herein, I
134
demonstrate the nickel-catalyzed defluorinative coupling of 2-trifluoromethyl-1-alkenes with
indoles as nucleophiles in the presence of a borate (Scheme 5-1b). In this reaction, the selective C–
C bond formation between the C-3 carbon in indoles[8,9] and the carbon γ to fluorine substituents in
CF3-alkenes was accomplished to afford a variety of 3-(3,3-difluoroallyl)indoles (Scheme
5-1c).[3,4,6,10]
Scheme 5-1. (a) Metal-catalyzed allylation, (b) defluorinative coupling of CF3-alkenes via fluorine
elimination and (c) defluorinative coupling of CF3-alkenes with indoles.
5-2. Synthesis of 3-(3,3-Difluoroallyl)indoles via β-Fluorine Elimination
BondFormation
OxidativeAddition
– X
MX
Nu
M
F F FNu
F F
(a) Metal-catalyzed allylation (Tsuji–Trost reaction)
(b) Concept (Formal Tsuji–Trost reaction)
X
OxidativeAddition
MM
F
F
F
M FM’
Nu
MFF
F
FF
M
NuM’
FluorineElimination
– M’F
– M BondFormation
X = I, Br, OAc, etc.
Nu ,
MNu
F
F
F F
F
(c) This work
cat. Ni
NH
F
F+ NB
R1
R2
R2
R1
135
I adopted the Ni catalyst, which was effective for C–F bond activation of fluoroalkenes.[6c–6e,11]
for the defluorinative coupling reaction of indolyl metals with 2-trifluoromethyl-1-alkene 19a. To
optimize reaction conditions, I screened additives for generation of indolyl metals (Table 5-1).
Although triethylborane-promoted coupling of allylic alcohols with indole derivatives was reported,
where triethylborane effectively activated indoles,[1c,12,13] the desired product was not obtained in
the reaction with triethylborane (Table 5-1, entry 2). Then, when combinations of triethylborane
with bases were investigated.[11d,11h,14,15,16] By use of t-BuOK difluoroallylindole 21aa was obtained
in 16% yield (Table 5-1, entry 3). Especially, use of LiOi-Pr along with triethylborane afforded
21aa in an almost quantitative yield (Table 5-1, entry 4).[17]
Table 5-1. Defluorinative coupling reactions of 2-trifluoromethyl-1-alkenes 19a with indoles.[a]
CF3
19a(1.0 equiv)
+
20a(1.0 equiv)
NiCl2(dppf) (10 mol%)Additive (x equiv)
21aa
CPME[b], Conditions
Ph
NH N
H
CF2
Ph
1
2
3
4
5
–
BEt3 (1.5)
BEt3 + KOt-Bu (2.0)
BEt3 + LiOi-Pr[d] (2.0)
B(Oi-Pr)3 + LiOi-Pr[d] (2.0)
60 °C, 6 h
60 °C, 6 h
RT, 10 h
RT, 12 h
RT, 10 h
[a] Reaction conditions: NiCl2(dppf) (0.01 mmol), 19a (0.10 mmol), 20a (0.10mmol), and CPME (1.0 mL). [b] CPME = cyclopentyl methyl ether. [c] Yield was determided by 19F NMR spectroscopy using PhCF3 as an internal standard. Yield of isolated product is given in parentheses. [d] i-PrOLi was generated in situ from i-PrOH and n-BuLi.
0
0
16
97
0
Yield / %[c]ConditionsAdditive (equiv)Entry
(96)
136
Under optimized conditions obtained above several 2-trifluoromethyl-1-alkenes and indoles were
investigated for 3,3-difluoroallylation of indoles (Table 5-2). When α-trifluoromethylstyrene 19b
bearing an electron-donating methyl groups was used, the corresponding 3-(3,3-difluoroallyl)indole
21ba was obtained in 86% yield. α-Trifluoromethylstyrenes bearing electron-withdrawing cyano
(19c), trifluoromethyl (19d), phenyl (19e), and chlorine (19f) groups successfully underwent
defluoroarylation to afford the corresponding 3-(3,3-difluoroallyl)indoles 21ca–21fa. In the case of
the substrate 19g bearing acyl group, reduction of the acyl moiety was suppressed at 0 °C, and the
desired product 19ga was obtained in 57% yield. ortho-Substituted α-trifluoromethylstyrene 19h
also gave the difluoroallylated indole 21ha in 69% yield. Difluoroallylation of 20a with
1-[1-(trifluoromethyl)ethenyl]naphthalene (19i) proceeded to afford 21ia in 63% yield. In addition,
CF3-alkenes 19j,19k bearing alkyl groups and gaseous 3,3,3-trifluoroprop-1-en 19l afforded the
corresponding 3-(3,3-difluoroallyl)indoles 21ja–21la. Methoxyindoles 20b–20e participated in the
difluoroallylation, regardless of the positions of the methoxy group. Furthermore, difluoroallylation
of 1H-indole-3-ethanol (20f) and tryptamine (20g) with 19a occurred with accompanying
intramolecular (hemi)aminal formation, providing furoindoline 21af and pyrroloindoline 21ag,
respectively (eq. 5-1).[15a,15d]
137
Table 5-2. Substrate scope[a]
NH
CF2
NH
CF2
21ja 96%
SiMe3
NH
CF2
21ha (69%)
NH
CF2
21ia (63%)
NH
CF2
21ka (53%)
Ph
NH
CF2
21la (39%)[c]
R R = HMeCNCF3
PhClAc
21aa21ba21ca21da21ea21fa21ga
96%86%(98%)(89%)(45%)(33%)(57%)[b]
NC
NH
CF2
Ph
NH
CF2
Ph
MeO
21ac (38%)
NH
CF2
Ph
NH
CF2
Ph
21ad (80%)
OMe
MeOOMe
21ae (53%)
[a] Reaction conditions: NiCl2(dppf) (0.020 mmol), 19 (0.22 mmol), 20 (0.20 mmol), Lii-PrOBEt3 (0.40 mmol; 0.25 M in CPME) and CPME (2.0 mL). [b] Reaction was conducted at 0 °C. [c] Excess amount of 19i (1.0 atm) was used.
CF3+
NiCl2(dppf) (10 mol%)Lii-PrOBEt3 (2.0 equiv)
CPME, RT, 12 hNH
NH
CF2
R2R2
R1R1
19(1.1 equiv)
20(1.0 equiv)
21
21ab 42%
138
5-3. Mechanistic Studies on Selective 3,3-Difluoroallylation of Indoles
For difluoroallylation of indoles 20 with 2-trifluoromethylalkenes 19, there are three plausible
reaction pathways initiated by different initial steps. Path (a) starts with formation of
nickelacyclopropanes A from 2-trifluoromethyl-1-alkenes 19 with Ni(0) complex (Scheme 5-2, path
a).[6c–6e] Thereafter, β-fluorine elimination is promoted by N-borylindoles B, generated from
Lii-PrOBEt3 and indoles 20, to give allylnickel intermediates C. Thus, difluoroallylindoles 21 are
obtained through reductive elimination from C. In path (b), the reaction starts with oxidative
addition of a C–F bond of 19 to Ni(0) (Scheme 5-2, path b).[2] The formed difluoroallylnikels D are
attacked by nucleophilic N-borylindoles B to afford difluoroallylindoles 21. In path (c) first
N-borylindoles B react with Ni(II) to produce indolylnickels E (Scheme 5-2, path c).[8,18] Insertion
of 2-trifluoromethyl-1-alkenes 19 into the C–Ni bond of E leads to alkylnickel intermediates F,
followed by β-fluorine elimiantion to give the same product 21.
21af: X = O (43%)21ag: X = NH (43%)
NH
NH
20f: XH = OH20g: XH = NH2
XH
X
CF2Ph
CF3+
NiCl2(dppf) (10 mol%)Lii-PrOBEt3 (2.0 equiv)
CPME, RT, 12 h
Ph
19a(1.1 equiv)
(5-1)
139
Scheme 5-2. Plausible reaction mechanisms
To gain insights into the reaction mechanism, the stoichiometric reaction of
2-trifluoromethyl-1-alkene 19g with Ni(cod)2 and 1,1’-bis(diphenylphosphino)ferocene were
conducted in toluene at room temperature (Scheme 5-3).[6c,6d] As a result, nickelacyclopropane 22
was observed in 98% yield, which was confirmed by 19F and 31P NMR spectroscopy. Addition of an
N-borylindole, generated from a Lii-PrOBEt3 and indole, to the solution of 22 afforded the
corresponding difluoroallylindole 21ga in 73% yield. These results indicate that difluoroallylindoles
21 was formed through path (a).
N
NiIIX
E
R1
CF319
A
path (a) path (b)
Metala-cyclopropanation
OxidativeadditionNi0 Ni0
D
β-Fluorineelimination Nucleophilic
addition
NiIIF
FF
FM’
Nu
NiIIFF
NiIINu
FF
NH
F
F
NB
R2
R2
R1
Nu M’
– Ni0
– M’F
R1
R1
R1
Nu M’– M’F
Reductiveelimination
21C
NB
R2
Trans-mettalation
NiIIX2– B X
R2
InsertionR1
CF319
F
β-Fluorineelimination
path (c)
– Ni0 – FNiIIX
NH
F
R2
NiIIXR1
F F
B
B
140
Scheme 5-3. Reaction of nickelacyclopropane with N-borylindole.
Furthermore, on treatment with a stoichiometric amount of NiCl2(dppf) and then
2-trifluoromethyl-1-alkene 19a in this order, the in situ generated N-borylindoles afforded 21aa in
only 4% yield (Scheme 5-4a). This result excluded the possibility of path (c). Conversely, changing
the addition order of the nickel complex and 19a gave 21aa in 90% yield (Scheme 5-4b). These
results rule out path (c) and further support path (a).
CF3
Ni(cod)2 (1.0 equiv)dppf (1.0 equiv)
Toluene, RT, 2 h
Ar
19gAr = p-Ac(C6H4)
Ni
PP CF3
Ar
22 98%(not isolated)
N
BX3LiB
X = Et or Oi-Pr
Lii-PrOBEt3 (1.1 equiv)
Toluene, RT, 30 minNH
20a(1.2 eq)
RT, 16 h NH
F
F
Ar
21ga 73%
19F NMR (470 MHz, C6D6): δ 108.2 (d, JFP = 10 Hz, 3F).31P NMR (202 Hz, C6D6): δ 23.4 (d, JPP =19 Hz, 1P), 34.2 (dq, JPP = 19 Hz, JPF = 10 Hz, 1P)
22:
141
Scheme 5-4. Mechanistic studies on difluoroallylation of indoles by stoichiometric amount of
nickel complex
In summary, I developed a new method for the synthesis of 3-(3,3-difluoroallyl)indoles via
Ni-catalyzed allylic C–F bond activation of 2-trifluoromethyl-1-alkenes. In this reaction, exclusive
single C–F bond activation of the trifluoromethyl group was successfully accomplished via
β-fluorine elimination under mild conditions. Mechanistic studies revealed that cleavage of the
remarkably strong C–F bond in the CF3 group proceeded due to the cooperative effect of
nickelacyclopropanes and N-borylindoles generated in situ.
5-4. References
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Ph
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NH
F
F
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NH
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dppf(1.0 equiv)
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F
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(b)
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20a
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142
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[17] Formation of N-borylindole was checked by C3 acylation of N-borylindole with acyl chloride.
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146
5-5. Experimental section
General
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a Bruker Avance 500 or a JEOL
ECS-400 spectrometer. Chemical shift values are given in ppm relative to internal Me4Si (for 1H
NMR: δ = 0.00 ppm), CDCl3 (for 13C NMR: δ = 77.0 ppm), and C6F6 (for 19F NMR: δ = 0.00 ppm).
IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance
(ATR) method. Mass spectra were measured on a JEOL JMS-T100GCV or a JMS-T100CS
spectrometer. Elemental analyses were carried out at the Elemental Analysis Laboratory, Division
of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba. Melting points were
measured on a Yanaco micro melting point apparatus, and were uncorrected. Column
chromatography was performed on silica gel (Silica Gel 60N, Kanto Chemical Co., Inc., 63–210
mm). All the reactions were conducted under argon or nitrogen. Diethyl ether (Et2O),
tetrahydrofuran (THF), and toluene were purified by a solvent-purification system (Glass Contour)
equipped with columns of activated alumina and supported-copper catalyst (Q-5) before use.
Benzene was dried over CaCl2 for 1 d, then distilled from CaCl2, and stored over activated
molecular sieves 4A. i-PrOH was distilled from CaH2 prior to use. CPME was distilled from
benzophenone and Na. 2-Trifluoromethyl-1-alkenes 19a–19i,[1], 19j,[2] and 19k[1] were prepared
according to the literature procedures. CPME or Toluene solution of Lii-PrOBEt3 was prepared
from n-BuLi, i-PrOH, and BEt3. Unless otherwise noted, materials were obtained from commercial
sources and used directly without further purifications.
147
Synthesis of 3-(3,3-Difluoroallyl)indole via Ni-Catalyzed 3,3-Difluoroallylation of Indole
Typical procedure for synthesis of 3-(3,3-Difluoroallyl)indoles
3-(1,1-Difluoro-2-phenyl-1-propen-1-yl)-1H-indole (21aa); Typical Procedure
Typical procedure for the synthesis of 3-(3,3-difluoroallyl)indole 21 via nickel-catalyzed
reaction: To a CPME (2.0 mL) solution of 2-trifluoromethyl-1-alkene 19a (38 mg, 0.22 mmol),
indole 20a (23 mg, 0.20 mmol), and NiCl2(dppf) (14 mg, 0.020 mmol) was added Lii-PrOBEt3 (1.6
mL, 0.40 mmol; 0.25 M in CPME). After 12 h, the reaction mixture was filtered through a pad of
silica gel (ethyl acetate). The filtrate was concentrated under reduced pressure, and the residue was
purified by silica gel column chromatography to give 3-(3,3-difluoroallyl)indole 21aa (52 mg,
96%) as a colorless solid.
1H NMR (CDCl3, 500 MHz): δ = 3.86 (s, 2H), 6,83 (s, 1H), 7.12–7.34 (m, 8H), 7.58 (d, J = 7.8 Hz,
1H), 7.87, (brs, 1H). 13C NMR (CDCl3, 126 MHz): δ = 24.1, 91.6 (dd, JCF = 21, 13 Hz), 111.1,
113.1 (dd, JCF = 3, 3 Hz), 118.7, 119.4, 122.1, 122.2, 127.1, 127.2, 128.25 (d, JCF = 4 Hz), 128.28
(d, JCF = 3 Hz), 133.9 (dd, JCF = 4, 4 Hz), 136.3, 154.0 (dd, JCF = 292, 288 Hz). 19F NMR (CDCl3,
471 MHz): δ = 71.8 (d, JFF = 42 Hz), 72.7 (d, JFF = 42 Hz). IR (neat): 3396, 1728, 1446, 1244, 1230,
1120, 1003, 750, 723, 696 cm–1. Elem. Anal. Calcd for C17H13F2N: C, 75.8; H, 4.87; N, 5.20.
Found: C, 76.2; H, 5.07; N, 5.23.
3-[1,1-Difluoro-2-(4-acetylphenyl)-1-propen-1-yl]-1H-indole (21ga)
NH
CF2
Ph
148
Compound 21ga was synthesized according to the procedure described for 21aa using 19g (47
mg, 0.22 mmol), 20a (23 mg, 0.20 mmol), NiCl2(dppf) (14 mg, 0.020 mmol), and Lii-PrOBEt3 (1.6
mL, 0.40 mmol; 0.25 M in CPME). The reaction was conducted at room temperature for 12 h.
Purification by silica gel column chromatography (hexane/ethyl acetate = 5:1) gave 21ga (35 mg,
57%) as a colorless oil.
1H NMR (CDCl3, 500 MHz): δ = 2.54 (s, 3H), 3.89 (brs, 2H), 6. (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.5
Hz, 3H), 1.42–1.53 (m, 4H), 2.16 (td, J = 7.5, 7.5 Hz, 2H), 2.23 (t, J = 7.5 Hz, 2H), 5.91 (d, JHF =
38.7 Hz, 1H), 6.13 (t, J = 7.5 Hz, 1H), 6.91 (s, 1H), 7.15–7.22 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H),
7.51 (d, J = 7.6 Hz, 1H). 13C NMR (CDCl3, 126 MHz): δ = 23.7, 26.5, 91.4 (dd, JCF = 22, 12 Hz),
111.2, 112.5, 118.6, 119.5, 122.17, 122.22 126.9, 128.3, 128.3 (d, JCF = 3 Hz), 135.7, 136.3, 138.8
(d, JCF = 5 Hz), 154.2 (dd, JCF = 294, 290 Hz). 19F NMR (CDCl3, 471 MHz): δ = 74.2 (d, JFF = 36
Hz), 75.1 (d, JFF = 36 Hz).IR (neat): 3411, 1718, 1674, 1604, 1456,1406, 1358, 1238, 101, 989, 958,
841 cm–1.
3-[1,1-Difluoro-2-[(trimethylsilyl)methyl]-2-propen-1-yl]-1H-indole (21ja)
NH
CF2
O
NH
CF2
SiMe3
149
Compound 21ja was synthesized according to the procedure described for 21aa using 19j (40 mg,
0.22 mmol), 20a (23 mg, 0.20 mmol), NiCl2(dppf) (14 mg, 0.020 mmol), and Lii-PrOBEt3 (1.6 mL,
0.40 mmol; 0.25 M in CPME). The reaction was conducted at room temperature for 12 h.
Purification by silica gel column chromatography (hexane/ethyl acetate = 20:1 to 10:1) gave 21ja
(54 mg, 96%) as pale yellow oil.
1H NMR (CDCl3, 500 MHz): δ = 0.12 (s, 9H), 1.33 (dd, J = 2.4, 2.4 Hz, 2H), 3.49 (d, J = 0.9 Hz,
2H), 7.05 (s, 1H), 7.21 (ddd, J = 7.8, 7.8, 0.9 Hz, 1H), 7.28 (ddd, J = 7.8, 7.8, 0.9 Hz, 1H), 7.43 (dd,
J = 7.8, 0.9 Hz, 1H), 7.68 (d, J = 7.9, 1H), 8.00 (brs, 1H). 13C NMR (CDCl3, 126 MHz): δ = –1.14,
14.9, 24.3, 86.8 (dd, JCF = 18, 18 Hz), 111.1, 113.0, 118.9, 119.5, 122.1, 122.2, 127.4, 136.4, 152.5
(dd, JCF = 282, 282 Hz). 19F NMR (CDCl3, 471 MHz): δ = 64.4 (d, JFF = 62 Hz), 66.3 (d, JFF = 62
Hz). IR (neat): 3419, 2954, 1743, 1456, 1417, 1354, 1250, 1205, 1092, 1026, 837 cm–1. Elem. Anal.
Calcd for C15H19F2NSi: C, 64.48; H, 6.85; N, 5.01. Found: C, 64.38; H, 6.83; N, 5.14.
150
Screening of ligands (Table S1)
CF3
Ph+
NH
Ni(cod)2 (1.0 equiv)Ligand (x equiv)
Lii-PrOBEt3 (1.5 equiv)
Toluene, RT, 5 hNH
CF2
Ph
20a (1.0 equiv)19a 21aa
Table S1.
Entry Ligand (eq) Yield /%a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
trace
51
50 (44)
26
18
73 (69)
36
45
34
39
14
30
36
N.D.
N.D.
a: 19F NMR yield. Isolated yield in parentheses.
–
PCy3 (4)
PCy3 (2)
PCy3 (1)
PCy3 (0.5)
Pt-Bu3 (2)
Pt-Bu3 (1)
PPh3 (2)
PPh3 (1)
IPr (1)
SIPr (1)
IMes (1)
SIMes (1)
phen (1)
bpy (1)
Entry Ligand (eq) Yield /%a
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
N.D.
65
71
46
trace
N.D.
N.D.
N.D.
13
6
trace
22
N.D.
23
27
P[o-Me(C6H4)]3 (2)
P[m-Me(C6H4)]3 (2)
P[p-Me(C6H4)]3 (2)
P[3,5-Me2(C6H3)]3 (2)
P[p-OMe(C6H4)]3 (2)
P[p-Cl(C6H4)]3 (2)
P[p-CF3(C6H4)]3 (2)
P[3,5-(CF3)2(C6H3)]3 (2)
P(C6F5)3 (2)
P(2-furyl)3 (2)
JohnPhos (2)
Cy-JohnPhos (2)
XPhos (2)
Cy-XPhos (2)
DavePhos (2)
Entry Ligand (eq) Yield /%a
31
32
33
34
35
36
37
38
39
40
41
32
71
86 (82)
41
45
trace
23
trace
23
N.D.
23
XantPhos (1)
DPEPhos (1)
dppf (1)
dppb (1)
(S)-BINAP (1)
dppp (1)
dppe (1)
dcype (1)
dppbz (1)
dppm (1)
P(OEt)3 (2)
N NR RR = 2,6-(i-Pr)2C6H3 IPr or SIPrR = 2,4,5-(Me)3C6H2 IMes or SIMes N N N N
phen bpy
PO
3
P(2-furyl)
PR2R = t-Bu JohnPhosR = Cy Cy-JohnPhos
PR2R = t-Bu XPhosR = Cy Cy-XPhos
i-Pr
i-Pri-Pr
PCy2
NMe2
DavePhos
OPPh2 PPh2
XantPhos
OPPh2 PPh2
DPEPhos
Fe
PPh2
PPh2 PPh2PPh2
dppf (S)-BINAP
PPh2
PPh2
dppbz
PCy2Cy2P
dcype
151
To a toluene solution of 19a (17 mg, 0.10 mmol), 20a (12 mg, 0.10 mmol), Ni(cod)2 (28 mg,
0.10 mmol), and ligand was added Lii-PrOBEt3 (0.6 mL, 0.15 mmol; 0.25 M in CPME). After 5 h,
21aa was observed (The yield was determined by 19F NMR using PhCF3 as an internal standard).
Confirmation of N-borylindole formation
To a CPME (2.0 mL) solution of indole (23 mg, 0.20 mmol), pivaloyl chloride (49 mg, 0.41
mmol) was added Lii-PrOBEt3 (1.0 mL, 0.25 mmol; 0.25 M in CPME). After12 h, the reaction
mixture was filtered through a pad of silica gel (ethyl acetate). The filtrate was concentrated under
reduced pressure, and the residue was purified by silica gel column chromatography to give
1-(1H-indol-3-yl)-2,2-dimethyl-1-propanone (21 mg, 51%) as a colorless solid. On the other hand,
1-(1H-indol-3-yl)-2,2-dimethyl-1-propanone was not obtained without Lii-PrOBEt3.
Spectral date for 1-(1H-indol-3-yl)-2,2-dimethyl-1-propanone showed good agreement with the
literature date.[3]
NH
Lii-PrOBEt3(1.25 equiv)
CPMERT, 12 h
NBX3Li
+Cl
O
t-Bu
(2.0 eq)
NH
t-BuO
51%
CPMERT, 12 h
NH
t-BuO
N.D.
Without borate
X = Et or Oi-Pr
152
Mechanistic Studies
Stoichiometric Reaction of 2-Trifluoromethyl-1-alkene with Ni(0) Complex[1]
To a toluene solution (0.55 mL) of Ni(cod)2 (14 mg, 0.050 mmol) and dppf (28 mg, 0.051 mmol)
was added 2-trifluoromethyl-1-alkene 19g (11 mg, 0.050 mmol) at room temperature. After stirring
for 2 h at room temperature, a toluene solution of 22 was obtained as a dark red solution. The
formation of complex 22 was confirmed by 19F and 31P NMR.
22: 19F NMR (470 MHz, C6D6): δ 108.2 (d, JFP = 10.4 Hz, 3F). 31P NMR (202 Hz, C6D6): δ 23.4 (d,
JPP =19 Hz,1P), 34.2 (dq, JPP = 19 Hz, JPF = 10 Hz,1P).
Coupling of Nickelacyclopropane Complex 22 with N-Borylindole B
CF3
Ni(cod)2 (1.0 equiv)dppf (1.0 equiv)
Toluene, RT, 2 h
Ar
19gAr = p-Ac(C6H4)
Ni
PP CF3
HH
Ar
22 98%(not isolated)
153
To a toluene (0.5 mL) solution of Ni(cod)2 (14 mg, 0.050 mmol) and dppf (28 mg, 0.051 mmol)
was added 2-trifluoromethyl-1-alkene 19g (11 mg, 0.050 mmol) at room temperature. After 2 h, 22
was obtained in 98% yield (The yield was determined by 19F NMR using PhCF3 as an internal
standard). To the mixture was then added a toluene solution of B (0.72mL, ca. 0.055 mmol)
generated from 20a (14 mg, 0.12 mmol), Lii-PrOBEt3 (0.44 mL, 0.11 mmol; 0.25 M in toluene),
and toluene (1.0 mL). After another 16 h, the reaction mixture was filtered through a pad of silica
gel (ethyl acetate). The filtrate was concentrated under reduced pressure, and the residue was
purified by silica gel column chromatography (hexane/ethyl acetate = 5:1 to 2:1) to give 21ga (11.2
mg, 73%) as a colorless solid.
Stoichiometric Reaction of Difluoroallylation of indole 20a with NiCl2(dppf)
CF3
Ni(cod)2 (1.0 equiv)dppf (1.0 equiv)
Toluene, RT, 2 h
Ar
19gAr = p-Ac(C6H4)
Ni
PP CF3
HH
Ar
22 98%(not isolated)
N
BX3LiB
X = Et or Oi-Pr
Lii-PrOBEt3 (1.1 eq)
Toluene, RT, 30 minNH
20a(1.2 eq)
RT, 16 hNH
F
F
Ar
21ga 73%
154
To a toluene (1.0 mL) solution of 20a was added Lii-PrOBEt3 (0.40 mL, 0.10 mmol; 0.25 M in
toluene). After 2 h, to the mixture was then added NiCl2(dppf) (68 mg, 0.10 mmol). After another 3
h, to the mixture was then added 19a (17 mg, 0.10 mmol). After another 4 h, 21aa was observed in
4% yield (The yield was determined by 19F NMR using PhCF3 as an internal standard).
Stoichiometric Reaction of Difluoroallylation of indole 20a with Ni(0) Complex
To a toluene (1.0 mL) solution of 20a was added Lii-PrOBEt3 (4.0 mL, 0.10 mmol; 0.25 M in
toluene). After 2 h, to the mixture was then added 19a (17 mg, 0.10 mmol). After another 3 h, to the
mixture was then added Ni(cod)2 (28 mg, 0.10 mmol) and dppf (55 mg, 0.10 mmol). After another
4 h, the reaction mixture was filtered through a pad of silica gel (ethyl acetate). The filtrate was
concentrated under reduced pressure, and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 10:1 to 5:1) to give 21aa (24.2 mg, 90%) as a colorless
solid.
NiCl2(dppf)(1.0 equiv)
RT, 3 h
Ph
CF3
19a(1.0 equiv)
RT, 4 h
21aa 4%
NH
F
F
PhLii-PrOBEt3(1.0 equiv)
NH
20a
Toluene, RT, 2 h
Ni(cod)2(1.0 equiv)
dppf(1.0 equiv)
RT, 3 h
Ph
CF3
19a(1.0 equiv)
RT, 4 h
21aa 90%
NH
F
F
PhLii-PrOBEt3(1.0 equiv)
NH
20a
Toluene, RT, 2 h
155
References
[1] Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS Catal. 2015, 5, 5947–5950.
[2] Yamazaki, T.; Ishikawa, N. Chem. Lett. 1984, 13, 521–524.
[3] Zhang. Z.-W.; Xue, H.; Li, H.; Kang, H.; Feng, J.; Lin, A.; Liu, S. Org. Lett. 2016, 18, 3918–
3921.
156
CHAPTER 6 Conclusions I developed new and facile methodologies for single C–F bond activation of fluoroalkenes via
transition metal-catalyzed fluorine elimination directed toward fluorinated arene and alkene
syntheses. Fluorine-containing arenes and alkenes thus obtained are expected to serve as advanced
materials, pharmaceuticals, and agrochemicals. The key to success in establishing catalytic systems
was (i) effective C–C bond formation via oxidative cyclization, insertion, and aminometalation and
(ii) transformation of inert metal fluorides into active species by a borate generated from i-PrOLi
and BEt3.
In Chapter 2, two types of nickel-catalyzed defluorinative coupling reactions of
1,1-difluoro-1-alkenes with alkynes were developed. First, the fluoroarene synthesis was achieved
via [2+2+2] cyclization of 1,1-difluoroethylene with alkynes involving α-fluorine elimination.
Furthermore, I succeeded in the 2-fluoro-1,3-diene synthesis via hydroalkenylation of alkynes with
β,β-difluorostyrenes involving β-fluorine elimination.
In Chapter 3, the synthesis of fluorophenanthrenes via rhodium-catalyzed [4+2] cyclization of
1,1-difluoro-1-alkenes with biphenylenes was demonstrated. The catalytic activation of both C–F
bond of 1,1-difluoro-1-alkenes and C–C bond of biphenylenes was effected to form two C–C bonds
by using a Rh catalyst along with a Cu cocatalyst and LiOTf.
In Chapter 4, the 2-fluoroindole synthesis from β,β-difluoro-o-sulfonamidostyrenes was achieved
via intramolecular defluoroamination. On treatment with silver(I) catalyst and
N,O-bis(trimethylsilyl)acetamide (BSA), β,β-difluoro-o-sulfonamidostyrenes underwent
5-endo-trig cyclization involving C–N bond formation via aminometalation and C–F bond cleavage
via β-fluorine elimination. In this reaction, mechanistic studies revealed that the active catalyst is a
157
silver amidate complex generated from a silver(I) complex and BSA.
In Chapter 5, the synthesis of 3-(3,3-difluoroallyl)indoles was established via nickel-catalyzed
site-selective difluoroallylation of indoles with 2-trifluoromethyl-1-alkenes. In this reaction, single
allylic C–F bond activation of 2-trifluoromethyl-1-alkenes was accomplished via β-fluorine
elimination under mild conditions. Mechanistic studies revealed that cleavage of the C–F bond
proceeded due to the cooperative effect of nickelacyclopropanes and indolylborates generated in
situ.
Throughout these studies, I developed methods for transition metal-catalyzed vinylic and allylic
C–F bond activation of fluoroalkenes. These protocols consisted of (i) efficient C–C or C–N bond
formation for constructing fluorine-containing organometallic intermediates by transition metal
catalysts and (ii) C–F bond cleavage by α- or β-fluorine elimination. The addition of fluorine
captors, having a high affinity to fluorine such as organoboranes, organosilanes, and lithium salts,
effectively transformed transition metal fluorides generated in fluorine elimination step to
regenerate catalytically active species.
158
LIST OF PUBLICATIONS
(1) Takeshi Fujita, Yota Watabe, Tomohiro Ichitsuka, Junji Ichikawa
Ni-Catalyzed Synthesis of Fluoroarenes via [2+2+2] Cycloaddition Involving α-Fluorine
Elimination
Chem.—Eur. J. 2015, 21, 13225–13228.
(2) Takeshi Fujita, Yota Watabe, Shigeyuki Yamashita, Hiroyuki Tanabe, Tomoya Nojima, Junji
Ichikawa
Silver-Catalyzed Vinylic C–F Bond Activation: Synthesis of 2-Fluoroindoles from
o-Sulfonamido-β,β-difluorostyrenes
Chem. Lett. 2016, 45, 964–966.
(3) Yota Watabe, Kohei Kanazawa, Takeshi Fujita, Junji Ichikawa
Nickel-Catalyzed Hydroalkenylation of Alkynes via C–F Bond Activation: Synthesis of
2-Fluoro-1,3-dienes
Synthesis 2017, 49, 3569–3575.
SUPPLEMENTARY PUBLICATIONS
(1) Takeshi Fujita, Naruki Konno, Yota Watabe, Tomohiro Ichitsuka, Aiichiro Nagaki, Jun-ichi
Yoshida, Junji Ichikawa
Flash generation and borylation of 1-(trifluoromethyl)vinyllithium toward synthesis of
α-(trifluoromethyl)styrenes
J. Fluor. Chem. doi: 10.1016/j.jfluchem.2018.01.004
159
ACKNOWLEDGEMENT
The studies described in this thesis have been carried out under the direction of Professor Junji
Ichikawa at the Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, from April 2012 to March 2018.
I would like to express my deepest appreciation to Professor Junji Ichikawa for great support,
valuable suggestions and hearty encouragement throughout this work. His advice on research
attitude as well as research content have been invaluable. Research Associate Takeshi Fujita.
always encouraged and advised me with a warm and generous heart. I was helped by Associate
Professor Kohei Fuchibe’s valuable suggestions and interesting ideas many times.
I also wish to express his appreciation to Professor Tatsuya Nabeshima, Professor Li-Biao Han
and Professor Masahiko Yamaguchi for their nice guidance and helpful discussions during the
course of study.
I must make special mention of Dr. Tomohiro Ichitsuka for his helpful guidance and supports. I
owe much inspiration to him. It was really my pleasure to be a comrade of Mr. Naruki Konno, Mr.
Kohei Kanazawa, Ms. Yuki Inarimori, and Mr. Masahumi Takeishi during master and bachelor
thesis studies. I am deeply indebted to my senior alumni of Ichikawa group, Dr. Naoto Suzuki, Dr.
Ikko Takahashi, Dr. Tatsuya Aono, Mr. Tsuyoshi Takanohashi, Mr. Ryu Ueda, Mr. Hiroto Matsuno,
Mr. Keisuke Miura, Mr. Shingo Komatsuzaki, Mr. Nojima Tomoya, Mr. Kazuki Sugiyama, Mr.
Masaki Bando, Mr. Hiromichi Aihara, Mr. Tsubasa Kitagawa, and Mr. Shun-ichiro Nakamura, for
their kind advices. I would like to express my thanks to the other colleagues in Ichikawa group, Mr.
Ryo Takayama, Mr. Kento Shigeno, Mr. Hibiki Hatta, Mr. Shumpei Watanabe, Mr. Ryo Kinoshita,
Mr. Ji Hu, Mr. Jingchen Wang, Mr. Tomohiro Arita, Ms. Marina Takazawa, Mr. Masashi Abe, Mr.
Tomohiro Hakozaki, Ms. Shiori Ijima, Mr. Ryota Shimizu, Mr. Yutaro Kobayashi, Mr. Fumiya
Tomura, Mr. Hisanori Imaoka, Ms. Rie Oki, Mr. Keisuke Watanabe, Mr. Masaki Hayashi, Mr.
160
Takuya Fukuda, Mr. Rikuo Akisaka, Mr. Kyosuke Suto, Mr. Tomohiro Hidano, Mr. Atsushi
Yamada, Mr. Ryutaro Morioka, Mr. Nobushige Tsuda, Mr. Hiroto Watanabe, Ms. Kyoko
Kanematsu, Mr. Keisuke Ide, Mr. Kazuki Sakon, Mr. Noriaki Shoji, Mr. Kosei Hachinohe and Mr.
Tatsuki Hushihara for their helpful assistance and dedication.
I am grateful to the Japan Society for the Promotion of Science (JSPS) for the research
fellowship for young scientists (DC2).
Finally, I wish to express my deepest gratitude to my parent and my brother, Mayumi Watabe
and Kohei Watabe for their kindly continuous encouragement and for providing a very comfortable
environment, which allows me to concentrate on research.
February 2018
Yota Watabe