Development of Transition Metal-Based Catalytic System for C–F … · 2018-03-26 · oxidative...

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

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

PdF

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

PdF

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


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


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


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



α-FluorineElimination

OxidativeCyclization

Insertion

Amino-metalation


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


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


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


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


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


– BF

– Ni0

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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.

(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. [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,

3537–3545. [Cu] (h) Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.; Hosoya, T. J.

Am. Chem. Soc. 2017, 139, 12855–12862. (i) Zhang, J.; Dai, W.; Liu, Q.; Cao, S. Org. Lett. 2017,

19, 3283–3286. (j) Kojima, R.; Kubota, K.; Ito, H. Chem. Commun. 2017, 53, 10688–10691. (k) Hu,

J.; Han, X.; Yuan, Y.; Shi, Z. Angew. Chem., Int. Ed. 2017, 129, 13527–13531.

18

[19] (a) Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425–4427. (b) Miura, T.; Ito, Y.;

Murakami, M. Chem. Lett. 2008, 37, 1006–1007. (c) Ichitsuka, T.; Fujita, T.; Arita, T.; Ichikawa, J.

Angew. Chem., Int. Ed. 2014, 53, 7564–7568. (d) Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS Catal.

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19460–19463.

[20] Takachi, M.; Kita, Y.; Tobisu, M.; Fukumoto, Y.; Chatani, N. Angew, Chem,, Int. Ed. 2010, 49,

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.


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 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


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,


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


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


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


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)


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))






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)






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


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)


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


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







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)


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


F

Pr

H

Pr

F

Pr

H

Pr

i-Pr

72


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



20 h. Purification by silica gel column chromatography (hexane/ethyl acetate = 20:1) gave 10da (56

mg, 84%) as a colorless oil.



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



20 h. Purification by silica gel column chromatography (hexane/ethyl acetate = 50:1) gave 10ea (60


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



10 h. Purification by silica gel column chromatography (hexane/ethyl acetate = 20:1) gave 10fa (53



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



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.



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


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


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


(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.


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.


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


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


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


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,

107, 3117−3179. (d) Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7, 2835−2840. (e) Murakami,

M.; Matsuda, T. Chem. Commun. 2011, 47, 1100−1105. (f) Ruhland, K. Eur. J. Org. Chem. 2012,

2683−2706. (g) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410−9464. (h) Chen, P.-H.; Billett,

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.

[3] (a) Lu, Z.; Jun, C.-H.; Gala, S. R.; Sigalas, M. P.; Eisenstein, O.; Crabtree, R. H. J. Chem. Soc.,

Chem. Commun. 1993, 1887–1880. (b) Lu, Z.; Hun, C.-H,; Gala, S. R.; Sigalas, M. P.; Eisenstein,

O.; Crabtree, R. H. Organometallics 1995, 14, 1168–1175. (c) Koga, Y.; Kamo, M.; Yamada, Y.;

Matsumoto, T.; Matsubara, K. Eur. J. Inorg. Chem. 2011, 2869–2878. (d) Laviska, D. A.; Guan, C.;

Emge, T. J.; Wilklow-Marnell, M.; Brennessel, W. W.; Jones, W. D.; Krogh-Jespersen, K.; Goldma,

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.;

Edelbach, B. L.; Zubris, D. L.; Jones, W. D. Organometallics 1997, 16, 2016–2023. (d) Wick, D.

90

D.; Jones, W. D. Inorg. Chem. Acta 2009, 362, 4416–4421. (e) Korotvička, A.; Frejka, D.;

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)

Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.; Hosoya, T. J. Am. Chem. Soc. 2017,

139, 12855–12862. (g) Zhang, J.; Dai, W.; Liu, Q.; Cao, S. Org. Lett. 2017, 19, 3283–3286. (h)

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.


General











92




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.


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

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–


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.


General statements








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.


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,


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


N-(2-iodo-4-methoxylphenyl)-4-methylbenzenesulfonamide (403 mg, 1.00 mmol) and CuI (222 mg,


17d (332 mg, 84%) as a white solid.


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


(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.


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


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,


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




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.


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.


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.


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


(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,



(hexane/ethyl acetate = 10:1) gave 18c (71 mg, 98%) as a colorless oil.


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,



(hexane/ethyl acetate = 10:1) gave 18d (40 mg, 53%) as a colorless oil.


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


(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,



(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,



(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,



(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,


NTs

F

Ph

NTs

F

SiMe3

127


(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,



(hexane/ethyl acetate = 10:1) gave 18j (17 mg, 32%) as a colorless oil.


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,



(hexane/ethyl acetate = 10:1) gave 18k (51 mg, 65%) as a colorless oil.


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



(hexane/ethyl acetate = 10:1) gave 17l (73 mg, 98%) as a colorless oil.


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

[1] For selected reviews on Tsuji–Trost reaction, see: (a) Trost, B. M.; Van Vranken, D. L. Chem.

Rev. 1996, 96, 395–422. (b) Trost. B. M.; Crawley. M. L. Chem. Rev. 2003, 103, 2921–2943. (c)

Tamaru, Y. Eur. J. Org. Chem. 2005, 2647–2656. (d) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008,

NiCl2(dppf)(1.0 equiv)

RT, 3 h

Ph

CF3

19a(1.0 equiv)

RT, 4 h

21aa 4%

NH

F

F

Ph

(a)

Lii-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

Ph

(b)


NH

20a

Toluene, RT, 2 h

142

47, 258–297. (e) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427–440. (f) Sundararaju,

B.; Achard, M.; Bruneau, C. Chem. Soc. Rev. 2012, 41, 4467–4483. (g) Zhuo, C.-X.; Zheng, C.;

You, S.-L. Acc. Chem. Res. 2014, 47, 2558–2573. (h) Butt, N. A.; Zhang W. Chem. Soc. Rev. 2015,

44, 7929–7967.

[2] (a) Narumi, T.; Tomita, K.; Inokuchi, E.; Kobayashi, K.; Oishi, S.; Ohno, H.; Fujii, N. Org. Lett.

2007, 9, 3465–3468. (b) Hazari, A.; Gouverneur, V.; Brown, J. M. Angw. Chem., Int. Ed. 2009, 48,

1296–1299. (c) Pigeon, X.; Bergeron, M.; Barabé, F.; Dubé, P.; Frost, H. N.; Paquin, J.-F. Angew.

Chem., Int. Ed. 2010, 49, 1123–1127. (d) Paquin, J.-F. Synlett 2011, 289–293. (e) Benedetto, E.;

Keita, M.; Tredwell, M.; Hollingworth, C.; Brown, J. M.; Gouverneur, V. Organometallics 2012,

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2384.

[3] For selected reviews on C–F bond activation, see: (a) Kiolinger, J. L.; Richmond, T. G.;

Osterberg, C. E. Chem. Rev. 1994, 94, 373–431. (b) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109,

2119–2183. (c) Clot, E.; Eisenstein, O.; Jasim, N.; Macgregor, S. A.; McGrady, J. E.; Perutz, R. N.

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1244. (e) Kuehnel, M. F.; Lentz, D.; Brayn, T. Angew. Chem., Int. Ed. 2013, 52, 3328–3348. (f)

Stahl, T.; Klare, H. F. T.; Oestreich, M. ACS Catal. 2013, 3, 1578–1587. (g) Ahrens, T.; Kohlmann,

J.; Ahrens, M.; Braun, T. Chem. Rev. 2015, 115, 931–972. (h) Unzner, T. A.; Magauer, T.

Tetrahedron Lett. 2015, 56, 877–883. (i) Shen, Q.; Huang, Y.-G.; Liu, C.; Xiao, J.-C.; Chen, Q.-Y.;

Guo, Y. J. Fluorine Chem. 2015, 179, 14–22. (j) Zhang, X.; Cao, S. Tetrahedron Lett. 2017, 58,

375–392.

[4] Recent single C–F bond activation of CF3 group: (a) Kumar, T.; Massicot, F.; Harakat, D.;

Chevreux, S.; Martinez, A.; Bordolinska, K.; Preethalayam, P.; Vasu, R. K.; Behr, J.-B.; Vasse,

J.-L.; Jaroschik, F. Chem.—Eur. J. 2017, 23, 16460–16465. (b) Meißner, G.; Kretschmar, K.; Braun,

143

T.; Kemnitz, E. Angew, Chem., Int. Ed. 2017, 56, 16338–16341. (c) Chen, K.; Berg, N.; Gschwind,

R.; König, B. J. Am. Chem. Soc. 2017, 139, 18444–18447. (d) Mallov, I. Ruddy, A. J.; Zhu, H.;

Grimme, S.; Stephan, D. W. Chem.—Eur. J. 2017, 23, 17692–17696. (e) Wang, H.; Jui, N. T. J. Am.

Chem. Soc. 2018, 140, 163–166. (f) Fuchibe, K.; Hatta, H.; Oh, K.; Oki, R.; Ichikawa, J. Angew.

Chem., Int. Ed. 2017, 56, 5890–5893., and references therein.

[5] (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886. (b) Babudri, F.; Farinola,

G. M.; Naso, F.; Ragni, R. Chem. Commun. 2007, 1003–1022. (c) Purser, S.; Moore, P. R.;

Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330. (d) Hagmann, W. K. J. Med.

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Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496–3508. (g)

Kirsch, P. J. Fluorine Chem. 2015, 177, 29–36. (h) Ni, C.; Hu, J. Chem. Soc. Rev. 2016, 45, 5441–

5454. (i) Usachev, B. I. J. Fluorine. Chem. 2016, 185, 118–167.

[6] Transition metal-catalyzed C–F bond activation of CF3-alkenes via β-fluorine elimination: (a)

Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425–4427. (b) Miura, T.; Ito, Y.;

Murakami, M. Chem. Lett. 2008, 37, 1006–1007. (c) Ichitsuka, T.; Fujita, T.; Arita, T.; Ichikawa, J.

Angew. Chem., Int. Ed. 2014, 53, 7564–7568. (d) Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS Catal.

2015, 5, 5947–5950. (e) Fujita, T.; Arita, T.; Ichitsuka, T.; Ichikawa, J. Dalton Trans. 2015, 44,

19460–19463. (f) Huang, Y.; Hayashi, T. J. Am. Chem. Soc. 2016, 138, 12340–12343. (g) Ahrens,

T.; Teltewskoi, M.; Ahrens, M.; Braun, T.; Laubenstein, R. Dalton, Trans. 2016, 45, 17495–17507.

(h) Liu, Y.; Zhou, Y.; Zhao, Y.; Qu, J. Org. Lett. 2017, 19, 946–949. (i) Sakaguchi, H.; Ohashi, M.;

Ogoshi, S. Angew. Chem., Int. Ed. 2018, 57, 328–332.

[7] Related transition metal-catalyzed C(sp3)–F bond activation reactions: (a) Lin, X.; Zheng, F.;

Qing, F.-L. J. Org. Chem. 2012, 77, 8696–8704. (b) Doi, R.; Ohashi, M.; Ogoshi, S. Angew. Chem.,

Int. Ed. 2016, 55, 341–344. (c) Zell, D.; Dhawa, U.; Müller, V.; Bursch, M.; Grimme, S.;

144

Ackermann, L. ACS Catal. 2017, 7, 4209–4213. (d) Zell, D.; Müller, V.; Dhawa, U.; Bursch, M.;

Presa, R. R.; Grimme, S.; Ackermann, L. Chem.—Eur. J. 2017, 23, 12145–12148. (e) Li, Y.; Xie,

F.; Liu, Y.; Yang, X.; Li, X. Org. Lett. 2018, 20, 437–440.

[8] For selected reviews on functionalization of indoles, see: (a) Bandini, M.; Eichholzer, A. Angew.

Chem., Int. Ed. 2009, 48, 9608–9644. (b) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev.

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Chem.—Eur. J. 2017, 23, 16115–16151.

[9] Recent allylation of indoles: (a) Ma, S.; Yu, S.; Peng, Z.; Guo, H. J. Org. Chem. 2006, 71,

9865–9868. (b) Kagawa, N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381–2384. (c)

Stanley, L. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841–7844. (d) Onitsuka, K.;

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S.-L. Chem. Sci. 2015, 6, 4525–4529. (f) Panda, S.; Ready, J. M. J. Am. Chem. Soc. 2017, 139,

6038–6041.

[10] For selected transition metal-catalyzed 3,3-difluoroallylation reactions, see: (a) Kirihara, M.;

Takuma, T.; Okumura, M.; Wakikawa, T.; Takahata, H.; Momose, T.; Takeuchi, Y.; Nemoto, H.

Chem. Pharm. Bull. 2000, 48, 885–888. (b) Fujita, T.; Sanada, S.; Chiba, Y. Sugiyama, K.;

Ichikawa, J. Org. Lett. 2014, 16, 1398, 1401. (c) Li, C.; Zhang, D.; Zhu, W.; Wan, P.; Liu, H. Org.

Chem. Front. 2016, 3, 1080–1083. (d) Ni, J.; Zhao, H.; Zhang, A. Org. Lett. 2017, 19, 3159–3162.

[11] Ni-catalyzed C–F bond activation: (a) Tobisu, M.; Xu, T.; Shimasaki, T.; Chatani, N. J. Am.

Chem. Soc. 2011, 133, 19505–19511. (b) Sun, A. D.; Leung, K.; Restivo, A. D.; LaBerge, N. A.;

Takasaki, H.; Love, J. A. Chem.—Eur. J. 2014, 20, 3162–3168. (c) Zhu, F.; Wang, Z.-X. J. Org.

Chem. 2014, 79, 4285–4292. (d) Fujita, T.; Watabe, Y.; Ichitsuka, T.; Ichikawa, J. Chem.—Eur. J.

2015, 21, 13225–13228. (e) Liu, X.-W.; Echavarren, J.; Zarate, C.; Martin, R. J. Am. Chem. Soc.

2015, 137, 12470–12473. (f) Niwa, T.; Ochiai, H.; Watanabe, Y.; Hosoya, T. J. Am. Chem. Soc.

145

2015, 137, 14313–14318. (g) Erickson, L. W.; Lucas, E. L.; Tolefson, E. J.; Jarvo, E. R. J. Am.

Chem. Soc. 2016, 138, 14006–14011. (h) Watabe, Y.; Kanazawa, K.; Fujita, T.; Ichikawa, J.

Synthesis 2017, 49, 3569–3575.

[12] Kimura, M.; Mukai, R.; Tanigawa, N.; Tanaka, S.; Tamaru, Y. Tetrahedron 2003, 59, 7767–

7777.

[13] (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592–

4593. (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314–6315. (c) Kiura, M.;

Fukasaka, M.; Tamaru, Y. Synthesis 2006, 3611–3616. (d) Kimura, M.; Tohyama, K.; Yamaguchi,

Y.; Kohno, T. Heterocycles 2010, 80, 787–797.

[14] Guidotti, S.; Camurati, I.; Focante, F.; Angellini, L.; Moscardi, G.; Resconi, L.; Leardini, R.;

Nanni, D.; Mercandelli, P.; Sironi, A.; Beringhelli, T.; Maggioni, D. J. Org. Chem. 2003, 68, 5445–

5465.

[15] (a) Lin, A.; Yang, J.; Hashim, M. Org. Lett. 2013, 15, 1950–1953. (b) Wang, Y.-N.; Li, T.-R.;

Zhang, M.-M.; Cheng, B.-Y.; Lu, L.-Q.; Xiao, W.-J. J. Org. Chem. 2016, 81, 10491–10498. (c)

Zhang. Z.-W.; Xue, H.; Li, H.; Kang, H.; Feng, J.; Lin, A.; Liu, S. Org. Lett. 2016, 18, 3918–3921.

(d) Yi, J.-C.; Liu, C.; Dai, L.-X.; You, S.-L. Chem. Asian J. 2017, 12, 2975–2979.

[16] (a) Brown, H. C.; Srebnik, M.; Cole, T. E. Organometallics 1986, 5, 2300–2303. (b)

Kobayashi, O.; Uraguchi, D.; Yamakawa, T. Org. Lett. 2009, 11, 2679–2682. (c) Peng, D.; Zhang,

M.; Huang, Z. Chem.—Eur. J. 2015, 21, 14737–14741.

[17] Formation of N-borylindole was checked by C3 acylation of N-borylindole with acyl chloride.

For details, see the supporting information. See: Ref. 14c.

[18] Inoue, F.; Saito, T.; Semba, K.; Nakao, Y. Chem. Commun. 2017, 53, 4497–4500.

146

5-5. Experimental section

General














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)


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)


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


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


Toluene, RT, 2 h

Ar

19gAr = p-Ac(C6H4)

Ni

PP CF3

HH

Ar


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


Toluene, RT, 2 h

Ar

19gAr = p-Ac(C6H4)

Ni

PP CF3

HH

Ar


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

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