Indium-Catalyzed C?F Bond Transformation through Oxymetalation/β-Fluorine Elimination to Access Fluorinated Isocoumarins

Article abstract of DOI:10.1002/chem.202100672

Fluorinated heterocycles have attracted much attention in the pharmaceutical and agrochemical industries. Many strategies have already been developed to achieve the synthesis of fluorinated heterocycles. Formidable challenges remain, however, in the synthesis of fluorinated isocoumarin derivatives that are among the most alluring structural motifs. Herein, the indium-catalyzed C?F bond transformation of 2-(2,2-difluorovinyl) benzoates is reported, which are readily accessible compounds, to give a diverse array of fluorinated isocoumarins. The present reaction proceeds smoothly using inexpensive reagents: a catalytic amount of indium salt in the presence of zinc salt. A theoretical calculation of potential energy profiles showed that the reaction consists of oxymetalation with the elimination of alkyl halide and the β-fluorine elimination.

Full text of DOI:10.1002/chem.202100672

Accepted Article
Accepted Article
Title: Indium-catalyzed C–F Bond Transformation through
Oxymetalation/β-fluorine Elimination to Access Fluorinated
Isocoumarins
Authors: Tetsuji Yata, Yoshihiro Nishimoto, Kouji Chiba, and Makoto
Yasuda
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202100672
Link to VoR: https://doi.org/10.1002/chem.202100672
01/2020

10.1002/chem.202100672
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Indium-catalyzed C–F Bond Transformation through
Oxymetalation/β-fluorine Elimination to Access Fluorinated
Isocoumarins
Tetsuji Yata[a], Yoshihiro Nishimoto*[a][b], Kouji Chiba[c], and Makoto Yasuda*[a][b]
[a]
[b]
[c]
T. Yata, Dr. Y. Nishimoto*, Prof. Dr. M. Yasuda
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
E-mail: nishimoto@chem.eng.osaka-u.ac.jp, yasuda@chem.eng.osaka-u.ac.jp
Dr. Y. Nishimoto*, Prof. Dr. M. Yasuda*
Innovative Catalysis Science Division, Institute for Open and Transdisciplinary Research Initiatives (ICS-OTRI), Osaka University, Suita, Osaka 565-0871,
Japan
Dr. K. Chiba
Material Science Division, MOLSIS Inc., 1-28-38 Shinkawa, Chuo-ku, Tokyo 104-0033, Japan
Supporting information for this article is given via a link at the end of the document.
Abstract: Fluorinated heterocycles have attracted much attention in
the pharmaceutical and agrochemical industries. Many strategies
have already been developed to achieve the synthesis of fluorinated
heterocycles. Formidable challenges remain, however, in the
synthesis of fluorinated isocoumarin derivatives that are among the
most alluring structural motifs. Herein, we report the indium-
treatment of the fluorine source (Scheme 1C, right). Using this
method, a wide variety of fluorinated heterocycles has been
synthesized: thiophenes,[6] pyrroles,[6b] furans,[6b, 7] and so forth.[8]
The second method involves direct fluorination using
electrophilic fluorinating reagents (Scheme 1C, left). Badland et
al. reported this strategy for the fluorination of thiophene to
catalyzed C–F bond transformation of 2-(2,2-difluorovinyl) benzoates, synthesize additional matrix metalloproteinase 12 inhibitors.[9a]
which are readily accessible compounds, to give a diverse array of
fluorinated isocoumarins. The present reaction proceeds smoothly
using inexpensive reagents: catalytic amount of indium salt in the
presence of zinc salt. A theoretical calculation of potential energy
profiles showed that the reaction consists of oxymetalation with the
elimination of alkyl halide and the β-fluorine elimination.
Sandford et al. has achieved the synthesis of fluorinated pyrrole
derivatives using SelectfluorTM [9b]
Zhu and Sun et al. have
.
developed an efficient one-pot method for the synthesis of
fluorinated benzofuran with high regioselectivity using
SelectfluorTM [9c]
.
However, these methodologies are not
applicable to the fluorination of isocoumarin. In the case of the
lithiation method, a ring-opening reaction would proceed instead
of lithiation because of the presence of carbonyl group (Scheme
1D, right). In addition, a direct fluorination of isocoumarins has
never been reported due to the lack of their reactivity to common
fluorination reagents. In fact, we investigated the electrophilic
fluorination of isocoumarin with a SelectfluorTM reagent,[10] but no
fluorinated products were obtained (Scheme 1D, left, See
Introduction
Fluorine has played an important role in many fields of science
due to inherent properties such as
a small size and
electronegativity that surpasses that of other halogens.[1] The
introduction of fluorine or fluorine-containing structural motifs
into organic molecules often brings about desirable bioactivity
and provides unique chemical and physical properties. Such
attributes have resulted in widespread strategic incorporation of
fluorine in the field of medicinal chemistry (Scheme 1A).[2]
Although the assembly of fluorinated heterocycles has been an
ongoing topic of interest,[3] formidable challenges remain for the
synthesis of fluorinated isocoumarin derivatives, yet they
possess one of the most alluring structural motifs.[4] Several
methods for fluorinated isocoumarins have been reported.
Zonov et al. have developed the synthesis of fluorinated
isocoumarins using superacids from highly electron-deficient
compounds. Xu, Zhou, and Yi et al. have achieved the synthesis
of difluorinated isocoumarins using iridium catalyst. However,
these reported methods are limited to the synthesis of
perfluorinated isocoumarin or difluorinated isocoumarin so the
selective introduction of only one fluorine atom to the
heterocyclic moiety has never been accomplished (Scheme
1B).[5] Many groups have developed methodologies for the direct
incorporation of fluorine into heterocycles. Two approaches are
the most reliable (Scheme 1C). The first approach involves a
regiospecific lithiation of the starting heterocycle followed by
Supporting Information). Therefore,
efficient strategy for the synthesis of fluorinated isocoumarin
remains in great demand.
a comprehensive and
1
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16]
main-group metal catalysis has remained a challenge.[15,
A) Representative bioactive compounds containing fluorinated heterocycles
F
F
O
Herein, we present a C–F bond transformation strategy for the
synthesis of fluorinated isocoumarin using an indium catalyst
(Scheme 2C).
H
O
MeO
MeO
O
N
O
Et
N
N
O
N
O
F
O
F
OEt
Et
NOS inhibitor
Tegafur
Tumor necrosis factor
B) Synthesis of fluorinated isocoumarin
O
F
O
O
O
F
O
O
F
F
F
F
F
simply fluorinated
isocoumarin
R1
R2
F
R
perfluorinated
isocoumarin
(Zonov group)
difluorinated
isocoumarin
No reports
(Xu, Zhou and Yi group)
C) Fluorination of heterocycles
Lithiation & Fluorination
Direct Fluorination
X
1) Lithium reagent
2) F+ source
X
X
F+ source
F
F
(X = S, O, N)
Electron-rich
(ref. 6-8)
(ref. 9)
D) Fluorination of isocoumarin
reactive site
O
O
R
O
O
F+ source
O
R-Li
O
F
0%
Electron-poor
ring-opening
No reaction
Scheme 1. Bioactive compounds containing fluorinated heterocycles and
synthesis of fluorinated heterocycles.
Scheme 2. Related work and This work.
The gem-difluoroalkenes have gained much attention as
versatile fluorinated building blocks for the synthesis of
pharmaceuticals, agrochemicals, and functional materials.[11] In
recent years, significant progress has been made in the
development of useful reactions involving cleavage of the C–F
bonds in gem-difluoroalkenes.[12] We envisioned the introduction
of gem-difluoroalkene as starting materials for the synthesis of
fluorinated isocoumarin to overcome the difficulties in the
fluorination of isocoumarin (Scheme 2A). In the case of direct
fluorination, an oxidation state of the carbon atoms at the 3-
position of isocoumarin changes from 0 to +2. We thought the
Results and Discussion
Reaction optimization for the synthesis of
fluorinated isocoumarin
For optimization of the reaction conditions, 2-(2,2-
difluoroethenyl)benzoate 1a was selected as
a standard
substrate (Table 1). Heating a mixture of 1a and 0.5 equivalent
of InI3 in toluene at 80 °C for 24 h afforded annulated product 2a
bearing a fluorine at the C-3 position in an excellent yield (Table
1, entry 1). The structure of 2a was confirmed by NMR
spectroscopy and X-ray crystallography (CCDC 2051246
contains the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum
installation of
oxidation state of the corresponding carbon atom from 0 to +2 to
facilitate the synthesis of fluorinated isocoumarin via
a gem-difluoroalkene moiety increases the
a
cyclization reaction. Moreover, the gem-difluoroalkenes are
easily accessible from readily available bromobenzoates via
formylation and Wittig difluoroolefination. Thus, the introduction
of a difluoro moiety in advance can overcome the difficulties
associated with direct electrophilic fluorination. Recently, we
developed a process for the oxymetalation of 2-alkynylbenzoic
esters using stoichiometric amounts of indium salts without
activation of the nucleophilic ester moiety to access metalated
isocumarins (Scheme 2B).[13] Also, our group has been
developing the carboindation of alkenes using indium salts and
organosilicon nucleophiles via the activation of alkene moiety by
indium salts.[14] Thus, we suspected that the oxyindation of a
gem-difluoroalkene unit in benzoic esters 1 followed by β-
fluorine elimination would achieve the synthesis of fluorinated
isocumarins. Moreover, though C–F bond transformation is well
known for transition metals, the application of this synthesis to
Karlsruhe
Access
Structures
service
www.ccdc.cam.ac.uk/structures). Employment of other transition
metals was less efficient (Table 1, entries 2-6). The use of other
main group metal salts was inefficient (Table 1, entries 7-11).
Reducing the amount of the loading catalyst resulted in a low
yield of 2a (Table 1, entries 12 and 13), which revealed that InI3
is a fluoride anion acceptor that changes into InFxI3-x to weaken
the catalytic activity. The use of InF3 was less efficient due to the
lack of solubility to solvent (Table 1, entry 14)[17]. In the cases of
using catalytic amount of InI3 (Table 1, entries 12 and 13), the
turnover number is about 2.5, which means that InI3 and InI2F
2
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work well as a catalyst, but InIF2 is a moderate active catalyst
and InF3 does not work as shown in entry 14.
Scope of the gem-difluoroalkenes
We envisioned that the addition of a scavenger for fluoride
anions could regenerate InI3 as a catalyst. The use of ZnI2 as an
additive promoted the expected catalytic reaction in the
presence of a catalytic amount of InI3 to give 2a in a good yield
(Table 1, entry 18), whereas the use of other fluorine-trapping
reagents was ineffective (Table 1, entries 15-17). Finally, the
use of InCl3 instead of InI3 in the catalytic system provided 2a
quantitatively (Table 1, entry 19) (See Supporting Information in
detail). The loading of InCl3 was successfully lowered to 1 mol%
and returned a good yield of 2a (Table 1, entries 19-21).
The substrate generality of the present synthetic method was
investigated via the use of a wide variety of substituted gem-
difluoroalkenes (Table 2). Fluorinated isocoumarin 2a was
isolated in 97% yield. Substrates with methyl groups at different
positions in the benzene ring were also applicable to afford the
desired products 2b-2e in high yields. Commonly encountered
functional groups such as fluoro (2f–2g), chloro (2i and 2j),
bromo (2k), cyano (2l), methoxy (2m), phenoxy (2o), and phenyl
(2p) were well tolerated, giving the corresponding products in
55–86% yields regardless of their electronic properties.
Gratifyingly, the substrate bearing a Bpin (pinacolatoboronyl)
group furnished the desired product 2q in 74% yield. Notably,
vinyl (2r) and acetyl (2s) groups, which could poison InCl3 and
ZnI2 also survived. Heterocyclic groups were amenable to this
reaction process and afforded the corresponding products in
good yields (2t and 2u). Furthermore, a substrate with a n-butyl
substituted difluoroalkene moiety, which should retard the
reaction based on steric reasoning, also proceeded to afford the
desired product (2v). Next, the scope of ester moieties was
evaluated. A substoichiometric amount of InI3 in the reaction of
substrates bearing a bulky ester moiety (1ab, 1ad, and 1ae) was
required to achieve reasonable yields. In particular, the
annulation of 1ac gave diminished yields, presumably due to the
competitive substrate decomposition via 1,5-migration.[18]
Table 1. Reaction optimization of the synthesis of fluorinated isocoumarin.
Entry
1
Catalyst (x mol%)
InI3 (50)
Additive
Yield %[a]
-
>97
0
2
PdCl2 (50)
CuBr2 (50)
FeBr3 (50)
AgOTf (50)
AgSbF6 (50)
ClBcat (50)
AlI3 (50)
-
3
-
0
4
-
0
5
-
0
6
-
29
0
7
-
8
-
0
9
GaI3 (50)
ZnI2 (50)
BiBr3 (50)
InI3 (10)
-
33
6
10
11
12
13
14
15
16
17
18
19
20
21
-
-
-
33
23
48
0
InI3 (20)
-
InF3 (20)
InI3 (20)
-
Me3SiI
BF3･OEt2
Bu4NI
ZnI2
ZnI2
ZnI2
ZnI2
40
58
0
InI3 (20)
InI3 (20)
InI3 (10)
72
>97
95
75[b]
InCl3 (10)
InCl3 (5)
InCl3 (1)
[a] Reaction conditions: x mol% catalyst, 1 equiv additives, 1a (0.3 mmol, 1
equiv) in 0.6 mL of toluene at 80 °C for 24 h under nitrogen. Yields were
determined by 1H NMR. [b] 3 days
3
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Table 2. Substrate scope of 2-(2,2-difluorovinyl)benzoates for the synthesis of fluorinated isocoumarins
[a] Reaction conditions: 1 (0.2 mmol, 1 equiv), InCl3 (0.02 mmol, 10 mol%), ZnI2 (0.2 mmol, 1 equiv), in toluene (0.5 M, 0.4 mL), 80 °C, 24 h. Isolated yields are
shown. [b] 2 mmol scale. [c] 20 mol% InCl3 was used. [d] 1 (0.2 mmol, 1 equiv), InI3 (0.1 mmol, 50 mol%), in toluene (0.5 M, 0.4 mL), 80 °C, 1 h
Experimental and DFT investigation of the reaction
mechanism
Based on our developed oxyindation[13a] and other groups’
proposed mechanisms,[19] we propose two plausible reaction
mechanisms, as outlined in Figure 1. In catalytic cycle B,
intermediate
II
is
generated
from
the
2-(2,2-
difluoroethenyl)benzoate 1a with InX3 (I) via oxyindation.[20] The
elimination of an alkyl halide (R–X) from II leads to organoindium
species III,[21] which then undergoes β-fluorine elimination to give
product 2a and InX2F (IV). Lastly, a halide exchange between
InX2F and ZnI2 occurs to give catalytically active InX3 (I) and zinc
fluoride salt. In catalytic cycle A, a nucleophilic addition of the
ester moiety to the gem-difluoroalkene moiety proceeds to form
zwitterionic species V, and subsequently the abstraction of a
fluoride anion by InX3 produces product 2a.
At first, the reaction mixture was monitored by 1H NMR
spectroscopy to investigate the reaction mechanism (Scheme 3).
When starting material 1a was reacted with InI3 (1 equiv) in
CDCl3 at 80 °C for 30min in sealed tube, MeI (12%) was
observed at 2.18 ppm with the same amount of fluorinated
isocoumarin 2a (13%). However, no intermediates were
observed except for the starting material 1a and MeI and the
final product 2a.
Figure 1. Proposed catalytic cycle: (A) nucleophilic addition-elimination
pathway (B) The pathway via an oxymetalation step.
4
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Scheme 3. Monitoring of the reaction of gem-difluoroalkene 1a with InI3 in
CDCl3 by 1H NMR spectroscopic analysis. Dibromomethane was used as an
internal standard (IS). Reagents and conditions: 1a (0.2 mmol), InI3 (1 equiv),
CDCl3 (0.4 mL), 80 °C, 30min.
Figure 2. A comparison of plausible mechanisms: (A) nucleophilic addition-
elimination pathway and (B) oxymetalation pathway; Free energies (ΔG, 300 K,
in kcal mol-1) of intermediates and transition states are given
5
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(A) Calculated reaction energy profile
Me
I
I
I
G (300K, toluene)
I
O
I
In
InI
In
2 H
O
(kcal/mol)
F
O
O
H
H
O
F
F
F
F
F
O
F
O
O
I
F
H
O
O
I2In
F
Me
I
I
F
O
F
H
I
F
O
I2In
Me
H
TS2
22.0
In
In
O
H
I
H
I
I
Me
O
F
F
In
O
TS3
16.5
H
O
F
F
O
I
TS4
12.3
F
F
O
O
I
2
I
O
O
F
F
F
In
IN5
O
F
MeI
I
H
InI3
6.3
Me
In
I
IN3
0.0
TS5
0.6
IN4
I
O
IN7
InI
IN8
2 H
-1.0
I
IN6
F
Me
O
O
F
-3.6
I
-4.9
-5.5
InI
2 H
MeI
H
O
F
F
IN9
I
I
O
F
F
In
H
I
O
-12.5
I2In
Me
In
O
O
F
IN10
I
I
I
O
F
H
F
F
H
O
In
O
F
F
I2In
Me
-18.8
I
O
O
H
O
I
I
O
F
F
O
F
IN11
F
F
H
O
O
I
In
F
H
I2In
Me
O
H
-28.4
O
Me
I2In
F
I
F
I
I
I
F
F
F
O
H
O
I
F
In
H
O
I
O
F
I
In
I
F
F
O
O
O
In
H
In
O
F
I
H
intermolecular
stabilization
conformation
change
1st -fluorine elimination
2nd -fluorine elimination
2nd elimination of methyl iodide
1st elimination of methyl iodide
(B) 1st -fluorine elimination intermediates and transition state
(C) Second-order perturbation analysis
In2
In2
F
2.43
F
1.34
1.82
O
C1
1.41
C2
C1
1.50
C2
F
F
2.05
2.13
3.27
2.55
In1
C1
In1
2.23
In
In
1.34
C2
IN10
C1: 1.102 F: -0.364
C2: -0.807 In: 1.258
IN9
C1: 1.013
F: -0.615
C2: -0.664 In: 1.338
LP F
10.84 kcal/mol
LV In2
IN10
TS4
Figure 3. (A) Computed mechanism for the elimination of alkyl halide and the β-fluorine elimination. DFT calculation was performed at ωB97XD/Def2SVPD. The
solvation effect was introduced using the IEFPCM model, and toluene was used as a solvent. (B) Optimized structures of the 1st β-fluorine elimination step. The
values denoted in the structures are the bond lengths in Å. Values underlined are the relevant natural charges for the selected atoms. (C) Second-order
perturbation theory analysis of IN10.
We performed density functional theory (DFT) calculations to
investigate the possibilities of the two proposed paths. Figure 2
shows the computational results for cyclization steps via
nucleophilic addition-elimination (Figure 2, A) and via
oxymetalation (Figure 2, B) (See the supporting information for
computational details). Indium complex IN1 is initially formed by
the coordination of a carbonyl moiety of 1a. In the addition-
elimination mechanism, the coordination of the fluorine group to
InI3 activates the fluoroalkene moiety. The resulting species
(IN2’) undergo cyclization via TS1’ (26.7 kcal/mol) to form
intermediate IN3’. In the oxymetalation path, InI3 acts as a π-
electrophilic Lewis acid to activate the gem-difluoroalkene (IN2),
thereby facilitating intramolecular cyclization to give zwitterionic
intermediate IN3 via TS1 with free energy of only 8.8
kcal/mol.[13a] Cyclization via nucleophilic addition-elimination is
accompanied by an activation energy of 39.4 kcal/mol, which is
much higher than that in the oxymetalation path (21.5 kcal/mol).
Therefore, the oxymetalation mechanism is an operative
reaction path (See Supporting Information in detail).
The computed mechanism for the generation of IN3 by
oxyindation is shown in Figure 3. The intramolecular elimination
of MeI in a single molecule does not proceed (See Supporting
Information). Initially, the association between two IN3s leads to
complex IN4 with slight stabilization. Subsequently, abstraction
6
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of the Me group by the iodine atom of the anionic indium moiety
occurs via the transition state TS2 with an activation energy of
24.0 kcal/mol and yields intermediate IN5. The dissociation of
MeI from IN5 then gives intermediate IN6. The second
elimination of MeI occurs through a mechanism similar to the
first elimination to give symmetric indium complex IN9 via
metastable intermediates IN7 and IN8. The β-fluorine
elimination from IN9 occurs via transition state TS4 (ΔG‡ = 24.8
kcal/mol) to give IN10. In transition state TS4, the cleavage of
C1–F and C2–In and the bonding of In–F occur synchronously
at distances of 1.82 and 2.55 and 2.13 Å, respectively (Figure 3,
B). The In–F bond is significantly shortened from 3.27 Å to 2.13
Å, and the C1–F bond is moderately extended from 1.34 Å to
1.82 Å while the C1–C2 and C2–In bonds are changed less
compared with the In–F and C1–F bonds. NBO analysis of TS4
and In9 indicates an apparent increased negative charge on
the fluorine atom. Therefore, abstraction of the fluoride anion
with assistance of the indium center as a Lewis acid proceeds
preferentially in the β-fluorine elimination step. The second-
order-perturbation theory analysis for the interaction between
the indium and fluorine atoms in IN10 is depicted in Figure 3C.
There is a meaningful interaction between the lone pair on the
F atom and the vacant orbital on the In2 atom (10.84 kcal/mol),
which indicates that the fluorine atom is stabilized by the two
indium atoms in IN10. Finally, the second β-fluorine elimination
process proceeds via TS5 (ΔG‡ = 19.4 kcal/mol) to produce
final product 2a (IN11).
Figure 4. Further investigations: (A) Friedel-Crafts-type alkenylation (B)
Domino reaction of cyclization via oxymetalation and Friedel-Crafts-type
alkenylation; Isolated yield.
Further transformation
Conclusions
Further transformation of the C–F bonds in fluorinated
isocoumarins was successful, as shown in Figure 4.
In summary, we have developed an indium-catalyzed system
that transforms the C–F bond of 2-(2,2-difluoroethennyl)
benzoate derivatives via an oxymetalation process using an
indium catalyst to produce various fluorinated isocoumarins.
The reactions proceeded under mild conditions without
transition metals. The obtained fluorinated compound was
transformed via Friedel-Crafts-type alkenylation. Mechanistic
studies using a computational approach were conducted to
interpret the reaction mechanism. Given the importance of
fluorinated heterocyclic compounds in functional molecules, our
method may find significant applications.
Fluoroalkenes
readily
underwent
Friedel-Crafts-type
intramolecular cyclization mediated by Brønsted or Lewis
acids.[22] In contrast, there have been few reports of
intermolecular types of reactions, and those that have been
reported require electron-rich arenes.[22a] Gratifyingly, we
discovered the C–F bond of 2a was transformed with
alkylbenzenes such as toluene and xylenes in the presence of
an indium catalyst and Me3SiOTf. Finally, the double C–F bond
domino transformation from compound 1a was examined.
When 1a was exposed to an indium catalyst and Me3SiOTf in
toluene, the cyclization via oxymetalation and the Friedel-crafts
type alkenylation proceeded sequentially through fluorinated
isocoumarin 2a (Figure 4, B).
Acknowledgements
This work was supported by JST CREST Grant Number
JPMJCR20R3, Japan. It was also supported by JSPS
KAKENHI grant numbers JP18K19079, JP18H01977, and
JP19K05455.
Keywords: C-F bond transformation • catalysis • gem-
difluoroalkene • fluorinated heterocycles • Indium
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Applications, Wiley-VCH, Weinheim, 2004.
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2008, 51, 4359-4369; c) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330; d) K. Müller, C.
7
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Thus, we conclude that InF3 does not have a π-Lewis acidity enough
8
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10.1002/chem.202100672
Chemistry - A European Journal
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We have developed an indium-catalyzed system that transforms the C–F bond of 2-(2,2-difluoroethenyl)benzoate derivatives via an
oxymetalation process using an indium catalyst to produce various fluorinated isocoumarins. The reactions proceeded under mild
conditions without transition metals.
9
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