Facile Synthesis of 2-Fluorobenzofurans: 5-endo-trig Cyclization of β,β-Difluoro-o-hydroxystyrenes

Article abstract of DOI:10.1002/hlca.202000159

Efficient synthetic methods were established for obtaining 2-fluorobenzofurans involving various substituents. Upon being treated with 1,8-diazabicyclo[5.4.0]undec-7-ene under microwave irradiation, the α-unsubstituted β,β-difluoro-o-hydroxystyrenes under

Full text of DOI:10.1002/hlca.202000159

DOI: 10.1002/hlca.202000159
FULL PAPER
Facile Synthesis of 2-Fluorobenzofurans: 5-endo-trig Cyclization of
β,β-Difluoro-o-hydroxystyrenes
Ryutaro Morioka,a Takeshi Fujita,a and Junji Ichikawa*a
a
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571,
Japan, e-mail: junji@chem.tsukuba.ac.jp
Dedicated to Professor Antonio Togni on the occasion of his 65th birthday
Efficient synthetic methods were established for obtaining 2-fluorobenzofurans involving various substituents.
Upon being treated with 1,8-diazabicyclo[5.4.0]undec-7-ene under microwave irradiation, the α-unsubstituted
β,β-difluoro-o-hydroxystyrenes underwent nucleophilic 5-endo-trig cyclization to afford the corresponding 2-
fluorobenzofurans in high yields. Furthermore, 2-fluoro-3-iodobenzofuran was successfully synthesized, and its
transformation to various 3-substituted 2-fluorobenzofurans was demonstrated.
Keywords: Addition-elimination, benzofuran, cyclization, fluorine, styrene.
Previously, we have developed an alternative
approach to obtain ring-fluorinated heterocycles
Introduction
The ring-fluorinated heterocycles have attracted con- through the intramolecular cyclization of fluoroal-
siderable attention as synthetic intermediates, func- kenes, which simultaneously induced the construction
tional materials, and promising candidates for pharma- of heterocycle skeletons and regioselective installation
ceuticals and agrochemicals owing to their unique of the fluorine substituents.[1,15–24] We achieved 5-
characteristics, which are based on the properties of endo-trig cyclization of the β,β-difluorostyrene bearing
the fluorine substituent.[1] Therefore, facile and effi- a hydroxy group at the ortho-position, which leads to
cient methods are required to obtain ring-fluorinated the synthesis of 3-alkylated 2-fluorobenzofuran
heterocycles. To satisfy this requirement, direct fluori- (Scheme 1,a)[20,21]. Although 5-endo-trig cyclization is
nation methods have been developed till date. considered to be difficult according to Baldwin’s
However, there are very few efficient methods to rules[25–35], this type of cyclization is enabled by the
synthesize 2-fluorobenzofuran derivatives.[2–10] The abnormally polarized double bonds in difluoroalkenes.
representative examples include decarboxylative However, the application of this method has limita-
fluorination[4]
using
electrophilic
fluorinating tions. Specifically, moisture-sensitive NaH is required,
agents[11–14] and nucleophilic fluorination using hyper- and the method is observed to be less effective in the
valent iodonium intermediates.[3] Although these fluo- cyclization of substrates without substituents at the α-
rination methods are simple approaches to obtain position such as 1-(2,2-difluorovinyl)-2-hydroxynaph-
heterocyclic ring-fluorinated benzofurans, expensive thalene (Scheme 1,a; 30% yield). Thus, we searched for
reagents for fluorination have to be used at appro- a method that can be applied to various substrates by
priate positions. In addition, the product yields are screening the reaction conditions. Finally, we estab-
generally low during the fluorination processes.
lished a facile method to synthesize 2-fluorobenzofur-
ans without a substituent at the 3-position and 3-
iodinated 2-fluorobenzofuran (Scheme 1,b). In addition,
2-fluoro-3-iodobenzofuran was readily transformed to
2-fluorobenzofurans bearing unsaturated groups at
the 3-position through metal-catalyzed coupling.
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/hlca.202000159
Helv. Chim. Acta 2020, 103, e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
Table 1. Preparation of β,β-difluoro-o-hydroxystyrenes 4.
Entry
1
R1
R2
4
Yield of 4 [%][a]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
Br
4a
4b
4c
4d
4e
4f
89
80
75
32
69
70
77
tBu
MeO
Cl
Br
H
1g
4g
[a]
Yield of isolated product.
Scheme 1. Synthesis of 2-fluorobenzofurans through nucleo-
philic 5-endo-trig cyclization.
tion. Thus, unsubstituted β,β-difluoro-o-hydroxystyr-
ene 4a and ring-substituted and naphthalene-based
difluorostyrenes 4b–4g were readily prepared from
1a–1g. The naphthalene-based difluorostyrene 4h
was obtained from 2h, which was prepared through
Results and Discussion
The commercially available salicylaldehydes 1 were the MOM-protection of 1-naphthol and subsequent
used as the starting materials to prepare the cycliza- formylation (Scheme 3).[37] The aryl substituents of β,β-
tion precursors, that is, β,β-difluoro-o-hydroxystyrenes difluoro-o-hydroxystyrenes 4i–4k were installed
4 (Scheme 2, Table 1). After the protection of the through the Suzuki–Miyaura coupling[38] of the bro-
hydroxy group by the methoxymethyl (MOM) group, mine-bearing MOM-protected salicylaldehyde 2e and
the resulting aldehydes
2
were subjected to difluorostyrenes 3f with arylboronic acids (Scheme 4).
difluoromethylidenation with Ph3P+CF2CO2À (PDFA)[36] In addition, β,β-difluoro-o-hydroxy-α-iodostyrene (4l)
and then deprotected with aqueous hydrochloric acid. was prepared from 1,1,1-trifluoro-2-iodoethane (5,
In this sequence, the intermediary aldehydes 2 and Scheme 5).[39] The Negishi coupling of 1-iodo-2-meth-
difluorostyrenes 3 were used further without purifica- oxybenzene with a 2,2-difluoro-1-iodovinylzinc re-
agent, which was generated by the treatment of 5
with lithium diisopropylamide (LDA) and ZnCl2, gave
β,β-difluoro-α-iodo-o-methoxystyrene (6). The subse-
quent demethylation of 6 with BBr3 afforded 4l.
First, we sought suitable conditions for 5-endo-trig
cyclization of α-unsubstituted β,β-difluoro-o-hydroxy-
styrenes using 4g as a model substrate (Table 2). Upon
the treatment with NaH, which was the best base in
nucleophilic 5-endo-trig cyclization of α-alkylated β,β-
Scheme 2. One-pot procedure for the preparation of β,β-
difluoro-o-hydroxystyrenes 4 from salicylaldehydes 1.
Scheme 3. Preparation of naphthalene-based β,β-difluoro-o-
hydroxystyrene 4h.
www.helv.wiley.com
(2 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
Scheme 4. Preparation of arylated β,β-difluoro-o-hydroxystyrenes 4i–4k.
Scheme 5. Preparation of β,β-difluoro-o-hydroxy-α-iodostyrene (4l).
Table 2. Screening of bases for nucleophilic 5-endo-trig cycliza-
tion of 4g.
promoted the cyclization to improve the yield of 7g
up to 72% (Entry 7).1 Consequently, the use of DBU
under microwave irradiation afforded 7g in 83% yield
(Entry 8).
The optimal conditions for the 5-endo-trig cycliza-
tion obtained above were successfully applied to other
α-unsubstituted
β,β-difluoro-o-hydroxystyrenes
Entry
Base
7g [%][a]
(Scheme 6). Simple β,β-difluoro-o-hydroxystyrene (4a)
underwent cyclization to afford 2-fluorobenzofuran
(7a) in 38% yield. Electron-donating 3-(tert-butyl)- and
3-methoxy-substituted difluorostyrenes 4b and 4c
were applicable in cyclization to afford the corre-
sponding 2-fluorobenzofurans 7b and 7c in 47% and
60% yields, respectively. The cyclization of difluoros-
tyrenes 4d–4f bearing a chlorine or bromine substitu-
1
2
3
4
5
6
NaH
47
9
42
62
NaOEt
K3PO4
KOtBu
iPr2NEt
pyridine
DBU
N.D.[b]
N.D.[b]
72
7
8[c]
DBU
83
[a] Yield was determined by 19F-NMR measurement using PhCF3
as an internal standard. N.D.=Not detected. The reaction
was conducted under microwave irradiation.
[b]
[c]
1
When 4-(2,2-difluorovinyl)-1,1’-biphenyl, a β,β-difluoros-
tyrene bearing no nucleophilic hydroxy group, was
°
treated with DBU in DMF at 100 C for 1 h, the
difluorostyrene was completely consumed. Thus, initial
defluorinative substitution of β,β-difluoro-o-hydroxystyr-
enes with DBU might proceed prior to the cyclization,
which could promote subsequent 5-endo-trig cyclization.
In addition, the possibility that further isomerization into
the iminium intermediate allows 5-exo-trig cyclization
(formal 5-endo-trig cyclization) cannot be ruled out.
difluoro-o-hydroxystyrene, 4g underwent cyclization at
°
100 C to afford fluoronaphthofuran 7g in 47% yield
(Entry 1). When other sodium and potassium salts were
examined (Entries 2–4), KOtBu gave a better yield
(Entry 4). Among organic bases examined (Entries 5–7),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) specifically
www.helv.wiley.com
(3 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
Scheme 7. Synthesis of 5-aryl-2-fluorobenzofurans 7j, 7k, 7m,
7n.
be used as a substitute for the former one (Scheme 6),
which requires pre-arylation of cyclization precursors
4.
To broaden the scope, the 5-endo-trig cyclization of
β,β-difluoro-o-hydroxy-α-iodostyrene (4l) was exam-
ined for the synthesis of 2-fluoro-3-iodobenzofuran
(7l), which would serve as a precursor of 3-substituted
2-fluorobenzofurans (Table 3). While the abovemen-
tioned optimal conditions for the synthesis of 3-
unsubstituted 2-fluorobenzofurans afforded 7l, albeit
in 24% yield (Entry 1), a comparable yield of 7l was
°
observed at 0 C even without microwave irradiation
(Entry 2). Thus, several lithium, sodium, and potassium
Scheme 6. Synthesis of 2-fluorobenzofurans
7 bearing no
°
bases (Entries 3–7) were examined at 0 C without
substituent at the 3-position. Yields are given as yield of
isolated product. MW=under microwave irradiation; t=1 h for
7a, 7c, 7d, 7g, 7h, 7j, and 7k; t=20 min for 7b, 7e, 7f, and 7i.
microwave irradiation. It was determined that
LiOH·H2O was the best base for the cyclization of 4l to
For 7f, nitromethane was used as solvent and MS 3 Å was afford 7l in 63% isolated yield (Entry 5).
added.
Thus, the further transformation of 7l was achieved
through metal-catalyzed coupling. The Suzuki–
ent proceeded without the cleavage of CÀ Cl or CÀ Br
bonds. Naphthalene-based difluorostyrenes 4g and 4h
underwent cyclization to afford fluorinated naphtho-
furans 7g and 7h in 81% and 32% yields, respectively.
7-Phenylated, 5-phenylated, and 5-p-anisylated 2-fluo-
robenzofurans 7i–7k were obtained in 88, 39, and
23% yield from arylated β,β-difluoro-o-hydroxystyr-
enes 4i–4k, respectively.
5-Arylated 2-fluorobenzofurans were also synthe-
sized through the Suzuki–Miyaura coupling of 5-
bromo-2-fluorobenzofuran (7f) with arylboronic acids
(Scheme 7). In the presence of a palladium catalyst, the
treatment of 7f with phenyl- and p-anisylboronic acids
afforded the corresponding 2-fluorobenzofurans 7j
and 7k, respectively. Furthermore, fluorine-, and eth-
oxycarbonyl-bearing benzene rings were successfully
installed, which led to the synthesis of 5-arylated 2-
fluorobenzofurans 7m and 7n. Thus, this protocol can
Table 3. Screening of conditions for nucleophilic 5-endo-trig
cyclization of 4l.
Entry
Base (equiv.)
DBU (1.2)
Conditions
7l [%][a]
°
1
MW, 100 C,
1 h
24
°
2
3
4
5
6
7
DBU (1.2)
NaH (1.2)
KH (1.2)
LiOH·H2O (1.05)
NaOH (1.05)
KOH (1.05)
0 C, 4 h
22
37
°
0 C, 4 h
°
0 C, 4 h
7
67 (63)[b]
°
0 C, 4 h
°
0 C, 4 h
36
34
°
0 C, 4 h
[a] Yield was determined by 19F-NMR measurement using PhCF3
[b]
as an internal standard. Yield of isolated product.
www.helv.wiley.com
(4 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
Miyaura coupling of 7l with arylboronic acids effec- In addition, the obtained ring-halogenated 2-fluoroben-
tively proceeded to afford 3-arylated 2-fluorobenzofur- zofurans were subjected to metal-catalyzed coupling
ans 7o–7q in high yields (Scheme 8). This protocol with organometallic reagents to expand the availability
compensates cyclization of pre-arylated precursors as of substituted 2-fluorobenzofurans.[2–5] The method
a method for the synthesis of 3-aryl-2-fluorobenzofur- shown here allows to systematically synthesize 2-
ans, because cyclization of β,β-difluoro-o-hydroxy-α- fluorobenzofurans with various substituents; these com-
phenylstyrene with NaH, DBU, or LiOH·H2O afforded 2- pounds are expected to be bioactive agents and organic
fluoro-3-phenylbenzofuran 7o only in 33, 15, or 24% semiconductors.[1–10]
yield, respectively. In addition, 7l underwent Sonoga-
shira coupling and Stille coupling with phenylacety-
lene and tributyl(vinyl)stannane, which readily af- Experimental Section
forded the corresponding 3-alkynylated and 3-
alkenylated 2-fluorobenzofurans 7r and 7s in 76% and
General Statement
83% yields, respectively.
1H-NMR, 13C-NMR, and 19F-NMR spectra were recorded
on a Bruker Avance 500 apparatus. 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
Conclusions
In summary, we demonstrated an efficient synthesis of Spectra were recorded on a Horiba FT-300S spectrom-
various 2-fluorinated benzofurans through 5-endo-trig eter by the attenuated total reflectance (ATR) method.
cyclization of β,β-difluoro-o-hydroxystyrenes, which were Mass spectra were measured on a JEOL JMS-T100GCV
readily prepared 1) through difluoromethylidenation of spectrometer. Elemental analyses were carried out at
salicylaldehydes with PDFA or 2) through difluoroiodovi- the Elemental Analysis Laboratory, Division of
nylation of iodoanisoles with 1,1,1-trifluoro-2-iodoethane. Chemistry, Faculty of Pure and Applied Sciences,
University of Tsukuba. Microwave experiments were
conducted in a CEM Discover or a PreeKem APEX.
Column chromatography was conducted on silica
gel (Silica Gel 60 N, Kanto Chemical Co., Inc.). N,N-
Dimethylformamide (DMF), dichloromethane, and tet-
rahydrofuran (THF) was purified by a solvent-purifica-
tion system (GlassContour) equipped with columns of
activated alumina and supported-copper catalyst (Q-5)
before use. 1,4-Dioxane and ethanol were distilled
from sodium and stored over activated molecular
sieves 4 Å or 3 Å. Dimethoxyethane, diglyme, and
triethylamine were distilled from CaH2 and stored over
activated molecular sieves 4 Å. (Triphenylphosphonio)
difluoroacetate (PDFA) was prepared according to the
literature procedure.[36] Methoxymethyl-protected sali-
cylaldehyde 2e[40] and hydroxynaphthaldehyde 2h[41]
and β,β-difluoro-α-iodo-o-methoxystyrenes (6)[42] were
prepared according to the literature procedures.
Unless otherwise noted, materials were obtained from
commercial sources and used directly without further
purifications.
Preparation of β,β-Difluoro-o-Hydroxystyrenes 4
General Procedure 1: Preparation of 2-(2,2-Difluorovin-
yl)phenol (= 2-(2,2-Difluoroethenyl)phenol; 4a). To
a dichloromethane (30 mL) solution of salicylaldehyde
Scheme 8. Synthesis of 3-substituted 2-fluorobenzofurans 7o–
7s.
www.helv.wiley.com
(5 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
(1a, 1.57 mL, 15.0 mmol) and chloromethyl methyl NMR (470 MHz, CDCl3): 79.3 (dd, JFF =27, JFH =26, 1 F);
ether (1.71 mL, 22.5 mmol) was added diisopropyle- 80.5 (d, JFF =27, 1 F). IR (neat): 3554, 2958, 1728, 1435,
thylamine (5.25 mL, 30.1 mmol). After stirring at room 1227, 1167, 964, 744. HR-EI-MS: 212.1009 (C12H14F2O+,
temperature for 12 h, water (30 mL) was added to the M+; calc. 212.1013).
mixture. Organic materials were extracted with di-
chloromethane (20 mL) three times. The combined
extracts were washed with brine and dried over Compound 4c was prepared according to General
Na2SO4. Removal of the solvent under reduced Procedure using salicylaldehyde 1c (457 mg,
pressure gave a crude mixture including 2a. 3.00 mmol), chloromethyl methyl ether (0.340 mL,
4.48 mmol), diisopropylethylamine (1.05 mL,
2-(2,2-Difluoroethenyl)-6-methoxyphenol (4c).
1
To an N-methylpyrrolidone (30 mL) solution of the 6.03 mmol), and PDFA (2.12 g, 5.95 mmol). Purification
obtained crude mixture was added PDFA (10.7 g, of silica gel column chromatography (hexane/diethyl
°
30.0 mmol). After stirring at 80 C for 4 h, water ether 10:1) gave 4c (419 mg, 75%) as a colorless oil.
(150 mL) was added to the mixture. Organic materials 1H-NMR (500 MHz, CDCl3): 3.84 (s, 3 H); 5.65 (dd, JHF
=
were extracted with diethyl ether (20 mL) three times. 26.7, 4.6, 1 H); 5.88 (s, 1 H); 6.72 (dd, J=8.1, 1.2, 1 H);
The combined extracts were washed with brine and 6.81 (dd, J=8.1, 8.1, 1 H); 7.06 (dd, J=8.1, 1.1, 1 H).
dried over Na2SO4. After removal of the solvent under 13C-NMR (126 MHz, CDCl3): 55.9; 75.9 (dd, JCF =32, 14);
reduced pressure, aqueous HCl (6.0 M, 15 mL), 109.1; 116.6 (dd, JCF =6, 6); 119.7; 120.2 (d, JCF =10);
isopropyl alcohol (15 mL), and THF (15 mL) were 142.7 (d, JCF =5); 146.4, 156.3 (dd, JCF =298, 287). 19F-
added to the residue containing 3a. After stirring at NMR (470 MHz, CDCl3): 79.3 (dd, JFF =31, JFH =5, 1 F);
room temperature for 24 h, organic materials were 79.6 (dd, JFF =31, JFH =27, 1 F). IR (neat): 3543, 1728,
extracted with dichloromethane (20 mL) three times. 1473, 1442, 1346, 1070, 966, 725. HR-EI-MS: 186.0497
The combined extracts were washed with brine and (C9H8F2O2+, M+; calc. 186.0492).
dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by silica gel
2-Chloro-6-(2,2-difluoroethenyl)phenol
(4d).
column chromatography (hexane/diethyl ether 10:1) Compound 4d was prepared according to General
1
to give 4a (2.08 g, 89%) as a colorless liquid. H-NMR Procedure
(500 MHz, CDCl3): 4.97 (s, 1 H); 5.54 (dd, JHF =26.4, 4.0, 7.69 mmol), chloromethyl methyl ether (0.870 mL,
1 H); 6.72 (d, J=8.0, 1 H); 6.91 (dd, J=8.0, 7.8, 1 H); 1.15 mmol), diisopropylethylamine (2.69 mL,
1
using salicylaldehyde 1d (1.20 g,
7.09 (ddd, J=7.8, 7.8, 1.5, 1 H); 7.39 (ddd, J=7.8, 1.5, 15.4 mmol), and PDFA (5.45 g, 15.3 mmol). Purification
1.5, 1 H). 13C-NMR (126 MHz, CDCl3): 75.8 (dd, JCF =31, of silica gel column chromatography (hexane/diethyl
14); 115.4; 117.4 (dd, JCF =6, 6); 121.2; 128.3; 128.9 (dd, ether 10:1) gave 4d (475 mg, 32%) as a colorless
1
JCF =2, 2); 152.2 (d, JCF =5); 156.4 (dd, JCF =298, 289). liquid. H-NMR (500 MHz, CDCl3): 5.62 (dd, JHF =24.3,
19F-NMR (470 MHz, CDCl3): 79.6 (dd, JFF =30, JFH =26, 1 6.1, 1 H); 5.69 (s, 1 H); 6.83 (dd, J=8.0, 8.0, 1 H); 7.17
F); 79.8 (dd, JFF =30, JFH =4, 1 F). IR (neat): 3381, 1728, (dd, J=8.0, J=1.5, 1 H); 7.34 (ddd, J=8.0, 1.5, 1.4, 1 H).
1456, 1350, 1167, 939, 750. HR-EI-MS: 156.0387 13C-NMR (126 MHz, CDCl3): 76.0 (dd, JCF =31, 15); 118.7
(C8H6F2O+, M+; calc. 156.0387).
(dd, JCF =5, 5); 120.1; 121.0; 127.1 (dd, JCF =9, 2); 127.3;
148.1 (d, JCF =3); 156.5 (dd, JCF =298, 290). 19F-NMR
2-tert-Butyl-6-(2,2-difluoroethenyl)phenol (4b). (470 MHz, CDCl3): 80.6 (dd, JFF =28, JFH =24, 1 F); 80.7
Compound 4b was prepared according to General (dd, JFF =28, JFH =6, 1 F). IR (neat): 3537, 1730, 1450,
Procedure 1 using salicylaldehyde 1b (0.510 mL, 1248, 1180, 1165, 960, 856, 829, 771, 727, 712, 528. HR-
2.98 mmol), chloromethyl methyl ether (0.340 mL, EI-MS: 189.9990 (C8H5ClF2O+, M+; calc. 189.9997).
4.48 mmol),
6.03 mmol), and PDFA (2.14 g, 6.01 mmol). Purification
of silica gel column chromatography (hexane/diethyl Compound 4e was prepared according to General
ether 10:1) gave 4b (503 mg, 80%) as a colorless oil. Procedure using salicylaldehyde 1e (605 mg,
1H-NMR (500 MHz, CDCl3): 1.40 (s, 9 H); 5.00 (s, 1 H); 3.01 mmol), chloromethyl methyl ether (0.340 mL,
diisopropylethylamine
(1.05 mL,
2-Bromo-6-(2,2-difluoroethenyl)phenol
(4e).
1
5.36 (dd, JHF =25.5, 2.8, 1 H); 6.86 (dd, J=7.9, 7.7, 1 H); 4.48 mmol),
diisopropylethylamine
(1.05 mL,
7.16 (d, J=7.7, 1 H); 7.20 (d, J=7.9, 1 H). 13C-NMR 6.03 mmol), and PDFA (2.14 g, 6.01 mmol). Purification
(126 MHz, CDCl3): 29.7; 34.4; 75.6 (dd, JCF =29, 16); of silica gel column chromatography (hexane/diethyl
117.4 (dd, JCF =5, 4); 120.5; 126.4; 127.3 (dd, JCF =5, 1); ether 10:1) gave 4e (486 mg, 69%) as a colorless
1
136.2; 151.7 (d, JCF =4); 156.7 (dd, JCF =297, 291). 19F- liquid. H-NMR (500 MHz, CDCl3): 5.64 (dd, JHF =25.4,
www.helv.wiley.com
(6 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
4.8, 1 H); 6.79 (dd, J=8.0, 7.9, 1 H); 7.33 (d, J=8.0, 1 H); The combined extracts were washed with brine and
7.39 (d, J=7.9, 1 H). 13C-NMR (126 MHz, CDCl3): 76.3 dried over Na2SO4. After removal of the solvent under
(dd, JCF =31, 14); 110.6; 118.7 (dd, JCF =6, 6); 121.6; reduced pressure, aqueous HCl (6.0 M, 2.0 mL),
127.9 (d, JCF =10); 130.4; 149.0; 156.5 (dd, JCF =298, isopropyl alcohol (2 mL), and THF (2 mL) were added
289). 19F-NMR (470 MHz, CDCl3): 80.6 (dd, JFF =28, JFH
=
to the residue including 3h. After stirring at room
25, 1 F); 80.7 (dd, JFF =28, JFH =5, 1 F). IR (neat): 3508, temperature for 24 h, organic materials were extracted
1723, 1446, 1246, 1180, 1165, 953, 768, 725, 690. HR- with dichloromethane (6 mL) three times. The com-
EI-MS: 233.9493 (C8H579BrF2O+, M+; calc. 233.9492).
bined extracts were washed with brine and dried over
Na2SO4. After removal of the solvent under reduced
4-Bromo-2-(2,2-difluorovinyl)phenol (4f). Com- pressure, the residue was purified by silica gel column
pound 4f was prepared according to General Procedure chromatography (hexane/diethyl ether 10:1) to give
1
1 using salicylaldehyde 1f (4.02 g, 20.0 mmol), 4h (216 mg, 63%) as a pale yellow crystal. H-NMR
chloromethyl methyl ether (3.04 mL, 40.0 mmol), diiso- (500 MHz, CDCl3): 5.30 (s, 1 H); 5.67 (dd, JHF =26.1, 3.6,
propylethylamine (5.27 mL, 30.3 mmol), and PDFA 1 H); 7.45–7.56 (m, 2 H); 7.48–7.53 (m, 2 H); 7.79–7.81
(14.2 g, 40.0 mmol). Purification of silica gel column (m, 1 H); 8.03–8.05 (m, 1 H). 13C-NMR (126 MHz, CDCl3):
chromatography (hexane/diethyl ether 10:1) gave 4f 76.1 (dd, JCF =30, 16); 111.0 (d, JCF =6); 120.6; 121.0;
1
(3.30 g, 70%) as a colorless liquid. H-NMR (500 MHz, 124.2; 125.9; 126.0; 126.4; 128.0; 133.7; 147.9 (dd, JCF =
CDCl3): 4.86 (s, 1 H); 5.51 (dd, JHF =19.8, 10.5, 1 H); 6.64 5, 2); 156.5 (dd, JCF =298, 294). 19F-NMR (470 MHz,
(d, J=8.6, 1 H); 7.20 (dd, J=8.6, J=2.4, 1 H); 7.52 (d, CDCl3): 80.2 (dd, JFF =28, JFH =26, 1 F); 80.4 (dd, JFF =
J=2.4, 1 H). 13C-NMR (126 MHz, CDCl3): 75.3 (dd, JCF = 28, JFH =4, 1 F). IR (neat): 3575, 1728, 1396, 1338, 1271,
26, 20); 113.2; 117.0; 119.6; 131.0; 131.3 (dd, JCF =7, 5); 1215, 1174, 976, 806, 742. HR-EI-MS: 206.0545
151.3 (dd, JCF =3, 3); 156.5 (dd, JCF =296, 293). 19F-NMR (C12H8F2O+, M+; calc. 206.0543).
(470 MHz, CDCl3): 81.2–81.4 (m, 2 F). IR (neat): 3456,
1728, 1491, 1412, 1242, 1178, 1103, 951, 806. HR-EI-
3-(2,2-Difluoroethenyl)[1,1’-biphenyl]-2-ol (4i). A
diglyme (3 mL) and water (1 mL) solution of meth-
oxymethyl-protected salicylaldehyde 2e (246 mg,
MS: 233.9492 (C8H579BrF2O+, M+; calc. 233.9492).
1-(2,2-Difluoroethenyl)naphthalen-2-ol
(4g). 1.00 mmol), phenylboronic acid (194 mg, 1.2 mmol),
Compound 4g was prepared according to General Pd(PPh3)4 (24 mg, 0.021 mmol), and K3PO4 (430 mg,
Procedure 1 using hydroxynaphthaldehyde 1g (1.03 g, 2.03 mmol) was degassed by using the freeze-pump-
°
5.98 mmol), chloromethyl methyl ether (0.680 mL, thaw method three times. After stirring at 100 C for
8.95 mmol),
diisopropylethylamine
(2.10 mL, 16 h, the mixture was filtered through a pad of silica
12.1 mmol), and PDFA (4.28 g, 12.0 mmol). Purification gel (hexane/ethyl acetate 3:1). Removal of the solvent
of silica gel column chromatography (hexane/diethyl under reduced pressure gave a crude mixture includ-
ether 10:1) gave 4g (947 mg, 77%) as a colorless ing
crystal. H-NMR (500 MHz, CDCl3): 5.23 (s, 1 H); 5.46 (d, hyde. To an N-methylpyrrolidone (1 mL) solution of
2-(methoxymethoxy)[1,1’-biphenyl]-3-carbalde-
1
J
HF =26.8, 1 H); 7.15 (d, J=8.9, 1 H); 7.35 (ddd, J=8.0, the obtained crude mixture was added PDFA (712 mg,
°
6.9, 1.1, 1 H); 7.48 (ddd, J=8.3, 6.9, 1.3, 1 H); 7.73–7.77 2.00 mmol). After stirring at 80 C for 4 h, water (5 mL)
(m, 3 H). 13C-NMR (126 MHz, CDCl3): 72.7 (dd, JCF =29, was added to the mixture. Organic materials were
20); 117.4; 123.6 (d, JCF =18); 126.9; 128.3; 128.9; 130.2; extracted with diethyl ether (3 mL) three times. The
132.1; 132.8; 133.7 (d, JCF =20); 151.2; 156.2 (dd, JCF = combined extracts were washed with brine and dried
296, 293). 19F-NMR (470 MHz, CDCl3): 80.6 (d, JFF =24, 1 over Na2SO4. After removal of the solvent under
F); 83.5 (dd, JFH =27, JFF =24, 1 F). IR (neat): 3423, 1738, reduced pressure, aqueous HCl (6.0 M, 1.0 mL),
1593, 1327, 1217, 1184, 1144, 924, 816, 752. HR-EI-MS: isopropyl alcohol (1 mL), and THF (1 mL) were added
206.0541 (C12H8F2O+, M+; calc. 206.0543).
to the residue including 3i. After stirring at room
temperature for 24 h, organic materials were extracted
2-(2,2-Difluoroethenyl)naphthalen-1-ol (4h). To with dichloromethane (6 mL) three times. The com-
an N-methylpyrrolidone (3 mL) solution of meth- bined extracts were washed with brine and dried over
oxymethyl-protected hydroxynaphthaldehyde 2h Na2SO4. After removal of the solvent under reduced
(362 mg, 1.67 mmol) was added PDFA (871 mg, pressure, the residue was purified by silica gel column
°
2.44 mmol). After stirring at 80 C for 4 h, water chromatography (hexane/diethyl ether 10:1) to give 4i
(15 mL) was added to the mixture. Organic materials (188 mg, 81%) as a colorless liquid. H-NMR (500 MHz,
were extracted with diethyl ether (6 mL) three times. CDCl3): 5.38 (s, 1 H); 5.66 (dd, JHF =26.8, 4.1, 1 H); 6.95
1
www.helv.wiley.com
(7 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
(dd, J=7.7, 7.7, 1 H); 7.08 (dd, J=7.6, 1.6, 1 H); 7.37– thane (10 mL) three times. The combined extracts
7.48 (m, 6 H). 13C-NMR (126 MHz, CDCl3): 76.3 (dd, JCF = were washed with brine and dried over Na2SO4. After
31, 13); 117.6 (dd, JCF =6, 6); 120.6; 128.0 (d, JCF =9); removal of the solvent under reduced pressure, the
128.17; 128.22; 128.8; 129.0; 129.5; 136.6; 149.2 (d, residue was purified by silica gel column chromatog-
JCF =5); 156.4 (dd, JCF =298, 288). 19F-NMR (470 MHz, raphy (hexane/diethyl ether 10:1) to give 4j (635 mg,
1
CDCl3): 79.2 (dd, JFF =31, JFH =27, 1 F); 79.7 (d, JFF =31, 91%) as a colorless crystal. H-NMR (500 MHz, CDCl3):
1 F). IR (neat): 3546, 1728, 1454, 1433, 1240, 1161, 951, 4.98 (s, 1 H); 5.58 (dd, JHF =25.8, 4.5, 1 H); 6.79 (d, J=
837, 758, 742, 702. HR-EI-MS: 232.0702 (C14H10F2O+, 8.4, 1 H); 7.28–7.33 (m, 2 H); 7.40 (dd, J=7.8, 7.5, 2 H);
M+; calc. 232.0700).
7.51 (d, J=7.8, 2H) 7.63 (br. s, 1 H). 13C-NMR (126 MHz,
CDCl3): 75.9 (dd, JCF =30, 14); 115.8; 117.6 (dd, JCF =6,
6); 126.8; 126.9; 127.1; 127.6 (dd, JCF =9, 2); 128.7;
4-Bromo-2-(2,2-difluoroethenyl)-1-(meth-
oxymethoxy)benzene (3f). To a dichloromethane 134.4; 140.5; 151.8 (d, JCF =3); 156.4 (dd, JCF =297,
(80 mL) solution of salicylaldehyde 1f (8.04 g, 289). 19F-NMR (470 MHz, CDCl3): 80.1 (dd, JFF =29, JFH
40.0 mmol) and chloromethyl methyl ether (4.56 mL, 26, 1 F); 80.2 (d, JFF =29, 1 F). IR (neat): 3357, 1726,
=
60.0 mmol)
was
added
diisopropylethylamine 1363, 1252, 1207, 953, 889, 760, 692, 573. HR-EI-MS:
(14.1 mL, 80.9 mmol). After stirring at room temper- 232.0703 (C14H10F2O+, M+; calc. 232.0700).
ature for 12 h, water (80 mL) was added to the
mixture. Organic materials were extracted with di-
3-(2,2-Difluoroethenyl)-4’-methoxy[1,1’-biphen-
chloromethane (40 mL) three times. The combined yl]-4-ol (4k). A dimethoxyethane (12 mL) and water
extracts were washed with brine and dried over (3 mL) solution of methoxymethyl-protected difluoros-
Na2SO4. Removal of the solvent under reduced tyrene
3f
(836 mg,
2.99 mmol),
4-meth-
pressure gave a crude mixture including 2f. To an N- oxyphenylboronic acid (592 mg, 3.90 mmol), Pd(PPh3)4
methylpyrrolidone (40 mL) solution of the obtained (70 mg, 0.060 mmol), and K3PO4 (1.27 g, 5.96 mmol)
crude mixture was added PDFA (28.5 g, 80.0 mmol). was degassed by using the freeze-pump-thaw method
°
°
After stirring at 80 C for 4 h, water (200 mL) was three times. After stirring at 80 C for 12 h, aqueous
added to the mixture. Organic materials were ex- HCl (6.0 M, 5.0 mL) was added to the mixture. After
tracted with diethyl ether (40 mL) three times. The stirring at room temperature for 24 h, organic
combined extracts were washed with brine and dried materials were extracted with dichloromethane
over Na2SO4. After removal of the solvent under (10 mL) three times. The combined extracts were
reduced pressure, the residue was purified by silica gel washed with brine and dried over Na2SO4. After
column chromatography (hexane/diethyl ether 40:1) removal of the solvent under reduced pressure, the
1
to give 3f (9.63 g, 86%) as a colorless liquid. H-NMR residue was purified by silica gel column chromatog-
(500 MHz, CDCl3): 3.46 (s, 3 H); 5.16 (s, 2 H); 5.61 (dd, raphy (hexane/diethyl ether 10:1) to give 4k (734 mg,
1
J
HF =22.4, 8.1, 1 H); 6.98 (d, J=8.8, 1 H); 7.27 (d, J=8.8, 94%) as a colorless crystal. H-NMR (500 MHz, CDCl3):
J=2.4, 1 H); 7.57 (d, J=2.4, 1 H). 13C-NMR (126 MHz, 3.83 (s, 3 H); 5.60 (dd, JHF =25.8, 4.6, 1 H); 6.78 (d, J=
CDCl3): 56.1; 75.6 (dd, JCF =29, 16); 94.7; 114.3; 115.9; 8.3, 1 H); 6.95 (d, J=8.8, 2 H); 7.26 (dd, J=8.3, 2.3, 1 H);
122.0; 130.79 (dd, JCF =9, 3); 130.80; 152.9 (d, JCF =2); 7.44 (d, J=8.8, 2 H); 7.58 (br. s, 1 H). 13C-NMR
156.4 (dd, JCF =297, 291). 19F-NMR (470 MHz, CDCl3): (126 MHz, CDCl3): 55.4; 76.0 (dd, JCF =30, 14); 114.2;
80.9–81.0 (m, 2 F). IR (neat): 2956, 2904, 2827, 1724, 115.7; 117.6 (dd, JCF =6, 5); 126.6; 127.1 (dd, JCF =8, 1);
1483, 1221, 1151, 1076, 943, 876, 808. HR-EI-MS: 127.8; 133.3; 133.9; 151.6 (d, JCF =5); 156.4 (dd, JCF =
277.9753 (C10H979BrF2O2+, M+; calc. 277.9754).
297, 289); 158.6. 19F-NMR (470 MHz, CDCl3): 79.8 (dd,
JFF =30, JFH =26, 1 F); 80.0 (d, JFF =30, 1 F). IR (neat):
3-(2,2-Difluoroethenyl)[1,1’-biphenyl]-4-ol (4j). A 3340, 1728, 1608, 1495, 1238, 1176, 951, 808. HR-EI-
dimethoxyethane (12 mL) and water (3 mL) solution of MS: 262.0815 (C15H12F2O2+, M+; calc. 262.0805).
methoxymethyl-protected difluorostyrene 3f (837 mg,
3.00 mmol), phenylboronic acid (475 mg, 3.90 mmol),
2-(2,2-Difluoro-1-iodoethenyl)phenol (4l). To a
Pd(PPh3)4 (69 mg, 0.060 mmol), and K3PO4 (1.28 g, dichloromethane (8 mL) solution of β,β-difluoro-α-
6.01 mmol) was degassed by using the freeze-pump- iodo-o-methoxystyrenes (6, 2.44 g, 8.24 mmol) was
°
°
thaw method three times. After stirring at 80 C for 12 slowly added BBr3 (0.94 mL, 9.9 mmol) at À 20 C. After
h, aqueous HCl (6.0 M, 5.0 mL) was added to the stirring at room temperature for 2 h, the reaction was
mixture. After stirring at room temperature for 24 h, quenched with ice. Organic materials were extracted
organic materials were extracted with dichlorome- with dichloromethane (15 mL) three times. The com-
www.helv.wiley.com
(8 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
bined extracts were washed with brine and dried over 1335, 1161, 985, 795, 742. HR-EI-MS: 192.0955
Na2SO4. After removal of the solvent under reduced (C12H13FO+, M+; calc. 192.0950).
pressure, the residue was purified by silica gel column
chromatography (hexane/diethyl ether 5:1) to give 4l
2-Fluoro-7-methoxy-1-benzofuran (7c). Compound
(1.92 g, 83%) as a pale brown liquid. 1H-NMR 7c was synthesized according to General Procedure 2
(500 MHz, CDCl3): 5.18 (s, 1 H); 6.86 (d, J=8.1, 1 H); using difluorostyrene 4c (373 mg, 2.00 mmol), DBU
6.93 (dd, J=8.1, 7.1, 1 H); 7.20–7.25 (m, 2 H). 13C-NMR (0.360 mL, 2.41 mmol), and DMF (100 mL). Purification
(126 MHz, CDCl3): 39.6 (dd, JCF =32, 32); 116.4; 120.1; of silica gel column chromatography (pentane/diethyl
121.1; 131.2; 131.3; 152.9 (dd, JCF =298, 298); 153.3. ether 10:1) gave 7c (201 mg, 60%) as a colorless
19F-NMR (470 MHz, CDCl3): 89.1 (d, JFF =19, 1 F); 91.3 liquid. H-NMR (500 MHz, CDCl3): 3.97 (s, 3 H); 5.82 (d,
1
(d, JFF =19, 1 F). IR (neat): 3442,1716, 1452, 1257, 978,
JHF =6.7, 1 H); 6.77 (dd, J=8.1, 0.9, 1 H); 7.05 (dd, J=
899, 750, 652. HR-EI-MS: 281.9358 (C8H5F2IO+, M+; 8.0, J=0.9, 1 H); 7.15 (dd, J=8.1, 8.0, 1 H). 13C-NMR
calc. 281.9353).
(126 MHz, CDCl3): 56.0; 78.7 (d, JCF =13); 106.2 (d, JCF =
19); 113.0 (d, JCF =5); 124.2; 129.5 (d, JCF =3); 136.7;
144.8; 160.2 (d, JCF =284). 19F-NMR (470 MHz, CDCl3):
5-endo-trig Cyclization of β,β-Difluoro-o-Hydroxy-
styrenes 4
General Procedure 2: Synthesis of 2-Fluoro-1-benzofur- M+; calc. 166.0430).
an (7a). To a DMF (100 mL) solution of difluorostyrene
50.6 (d, JFH =7). IR (neat): 1637, 1496, 1437, 1294, 1200,
+
1092, 982, 785, 725. HR-EI-MS: 166.0422 (C9H7FO2
,
4a (390 mg, 2.50 mmol) was added DBU (0.450 mL,
7-Chloro-2-fluoro-1-benzofuran (7d). Compound
°
3.02 mmol). After stirring at 100 C for 1 h under 7d was synthesized according to General Procedure 2
microwave irradiation, water (250 mL) was added to using difluorostyrene 4d (420 mg, 2.20 mmol), DBU
the mixture. Organic materials were extracted with (0.390 mL, 2.61 mmol), and DMF (66 mL). Purification
diethyl ether (50 mL) three times. The combined of silica gel column chromatography (hexane) gave 7d
1
extracts were washed with brine and dried over (243 mg, 65%) as a colorless liquid. H-NMR (500 MHz,
Na2SO4. After removal of the solvent under reduced CDCl3): 5.86 (d, JHF =6.6, 1 H); 7.12 (dd, J=8.0, 7.8, 1 H);
pressure, the residue was purified by silica gel column 7.20 (dd, J=8.0, 1.1, 1 H); 7.32 (dd, J=7.8, 1.1, 1 H).
chromatography (pentane/diethyl ether 10:1) to give 13C-NMR (126 MHz, CDCl3): 79.2 (d, JCF =13); 116.3;
7a (129 mg, 38%) as a colorless liquid. 1H-NMR 119.1 (d, JCF =6); 123.7 (d, JCF =4); 124.5; 129.3 (d, JCF =
(500 MHz, CDCl3): 5.80 (d, JHF =6.5, 1 H); 7.18–7.22 (m, 3); 143.6; 160.5 (d, JCF =282). 19F-NMR (470 MHz,
2 H); 7.33–7.35 (m, 1 H); 7.41–7.43 (m, 1 H). 13C-NMR CDCl3): 51.8 (br. s). IR (neat): 1641, 1429, 1327, 1174,
(126 MHz, CDCl3): 78.3 (d, JCF =14); 110.9; 120.6 (d, 951, 787, 729. HR-EI-MS: 169.9927 (C8H4ClFO+, M+;
JCF =6); 123.3 (d, JCF =4); 123.6; 128.0 (d, JCF =3); 147.8; calc. 169.9935).
160.5 (d, JCF =280). 19F-NMR (470 MHz, CDCl3): 50.2 (d,
JFH =6, 1 F). IR (neat): 1631, 1454, 1333, 1180, 980, 771,
7-Bromo-2-fluoro-1-benzofuran (7e). Compound
742, 665. Spectral data for this compound showed 7e was synthesized according to General Procedure 2
good agreement with literature data.[4]
using difluorostyrene 4e (44 mg, 0.19 mmol), DBU (34
μL, 0.23 mmol), and DMF (6 mL) for 20 min. Purifica-
7-tert-Butyl-2-fluoro-1-benzofuran (7b). Com- tion of silica gel column chromatography (hexane)
1
pound 7b was synthesized according to General gave 7e (26 mg, 65%) as a colorless liquid. H-NMR
Procedure
2
using difluorostyrene 4b (43 mg, (500 MHz, CDCl3): 5.94 (d, JHF =6.6, 1 H); 7.10–7.14 (m,
0.20 mmol), DBU (36 μL, 0.24 mmol), and DMF (6 mL) 1 H); 7.39–7.42 (m, 2 H). 13C-NMR (126 MHz, CDCl3):
for 20 min. Purification of silica gel column chromatog- 79.4 (d, JCF =13); 103.5; 119.8 (d, JCF =6); 124.9; 126.6
raphy (hexane/ethyl acetate 10:1) gave 7b (18 mg, (d, JCF =4); 129.1 (d, JCF =3); 145.1; 160.4 (d, JCF =282).
47%) as a colorless liquid. H-NMR (500 MHz, CDCl3): 19F-NMR (470 MHz, CDCl3): 52.3 (d, JFH =7). IR (neat):
1
1.47 (s, 9 H); 5.81 (d, JHF =6.6, 1 H); 7.14–7.18 (m, 2 H); 1641, 1423, 1333, 1173, 976, 924, 785, 729. HR-EI-MS:
7.31 (dd, J=6.5, J=2.4, 1 H). 13C-NMR (126 MHz, 213.9427 (C8H479BrFO+, M+; calc. 213.9430).
CDCl3): 29.8; 34.2; 77.9 (d, JCF =13); 118.6 (d, JCF =5);
120.3 (d, JCF =4); 123.5; 128.5 (d, JCF =3); 134.5; 145.9;
5-Bromo-2-fluoro-1-benzofuran (7f). Compound
159.8 (d, JCF =278). 19F-NMR (470 MHz, CDCl3): 49.7 (d, 7f was synthesized according to General Procedure 2
JFH =7). IR (neat): 2962, 2914, 2873, 1645, 1415, 1342, using difluorostyrene 4f (822 mg, 3.50 mmol), DBU
(0.630 mL, 4.22 mmol), activated molecular sieves 3 Å
www.helv.wiley.com
(9 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
(3.5 g), and nitromethane (105 mL) for 20 min. Purifica- 125.3; 127.9; 128.5; 128.65; 128.72 (d, JCF =3); 135.7;
tion of silica gel column chromatography (hexane/ 144.9; 160.5 (d, JCF =280). 19F-NMR (470 MHz, CDCl3):
ethyl acetate 10:1) gave 7f (200 mg, 27%) as a 50.8 (d, JFH =7, 1 F). IR (neat): 1637, 1479, 1412, 1338,
colorless liquid. 1H-NMR (500 MHz, CDCl3): 5.83 (d, 1284, 1201, 1167, 980, 798, 694. HR-EI-MS: 212.0643
J
HF =6.5, 1 H); 7.25–7.27 (m, 1 H); 7.35 (d, J=8.7, 1 H); (C14H9FO+, M+; calc. 212.0637).
7.60 (s, 1 H). 13C-NMR (126 MHz, CDCl3): 78.3 (d, JCF =
14); 112.5; 116.8; 123.4; 126.4; 129.8; 146.4; 160.8 (d,
2-Fluoro-5-phenyl-1-benzofuran (7j). Compound
JCF =282). 19F-NMR (470 MHz, CDCl3): 53.1 (d, JFH =7). 7j was synthesized according to General Procedure 2
IR (neat): 1633, 1442, 1333, 1267, 1184, 1049, 980, 800, using difluorostyrene 4j (12 mg, 0.050 mmol), DBU (9.0
658. HR-EI-MS: 213.9432 (C8H479BrFO+, M+; calc. μL, 0.060 mmol), and DMF (1.5 mL). Purification of
213.9430).
silica gel column chromatography (hexane) gave 7j
(4.1 mg, 39%) as a colorless liquid. H-NMR (500 MHz,
1
2-Fluoronaphtho[2,1-b]furan (7g). Compound 7g CDCl3): 5.88 (d, JHF =6.5, J=0.5, 1 H); 7.32–7.35 (m, 1
was synthesized according to General Procedure 2 H); 7.41–7.45 (m, 4 H); 7.56–7.58 (m, 2 H); 7.63–7.64
using difluorostyrene 4g (41 mg, 0.20 mmol), DBU (36 (m, 1 H). 13C-NMR (126 MHz, CDCl3): 78.6 (d, JCF =13);
μL, 0.24 mmol), and DMF (6 mL). Purification of silica 111.0; 119.3 (d, JCF =6); 122.9 (d, JCF =4); 127.0; 127.4;
gel column chromatography (hexane) gave 7g (30 mg, 128.4 (d, JCF =3); 128.7; 137.4; 141.4; 147.3; 160.7 (d,
1
81%) as a colorless oil. H-NMR (500 MHz, CDCl3): 6.23 JCF =285). 19F-NMR (470 MHz, CDCl3): 51.7 (d, JFH =7).
(d, JHF =6.6, 1 H); 7.42–7.52 (m, 3 H); 7.61 (d, J=8.9, 1 IR (neat): 1635, 1466, 1331, 1178, 978, 758, 698. HR-EI-
H); 7.90 (d, J=8.2, 1 H); 7.86 (d, J=8.2, 1 H); 7.91 (d, J= MS: 212.0633 (C14H9FO+, M+; calc. 212.0637).
8.2, 1 H). 13C-NMR (126 MHz, CDCl3): 77.9 (d, JCF =13);
111.6; 123.2; 124.0 (d, JCF =4); 124.8; 126.2; 127.3 (d,
2-Fluoro-5-(4-methoxyphenyl)-1-benzofuran
JCF =4); 128.8; 130.5; 144.2; 159.7 (d, JCF =280). 19F- (7k). Compound 7k was synthesized according to
NMR (470 MHz, CDCl3): 50.1 (d, JFH =7). IR (neat): 1637, General Procedure 2 using difluorostyrene 4k (13 mg,
1585, 1387, 1327, 1244, 1215, 989, 802, 766. HR-EI-MS: 0.050 mmol), DBU (9.0 μL, 0.060 mmol), and DMF
186.0485 (C12H7FO+, M+; calc. 186.0481).
(1.5 mL). Purification of silica gel column chromatog-
raphy (hexane) gave 7k (2.8 mg, 23%) as a colorless
1
2-Fluoronaphtho[1,2-b]furan (7h). Compound 7h liquid. H-NMR (500 MHz, CDCl3): 3.82 (s, 3 H); 5.85 (d,
was synthesized according to General Procedure 2
JHF =6.6, 1 H); 6.96 (d, J=8.8, 2 H); 7.38 (s, 2 H); 7.49 (d,
using difluorostyrene 4h (414 mg, 2.01 mmol), DBU J=8.8, 2 H); 7.57 (br. s, 1 H). 13C-NMR (126 MHz,
(0.360 mL, 2.41 mmol), and DMF (60 mL). Purification CDCl3): 55.3; 78.5 (d, JCF =13); 111.0; 114.2; 118.8 (d,
of silica gel column chromatography (hexane) gave 7h JCF =5); 122.6 (d, JCF =4); 127.7; 128.3; 133.9; 137.0;
1
(121 mg, 32%) as a colorless oil. H-NMR (500 MHz, 147.0; 159.0; 160.7 (d, JCF =280). 19F-NMR (470 MHz,
CDCl3): 5.99 (d, JHF =6.8, 1 H); 7.45–7.48 (m, 1 H); 7.55– CDCl3): 51.4 (d, JFH =7). IR (neat): 3136, 2958, 2839,
7.60 (m, 2 H); 7.69 (d, J=8.5, 1 H); 7.91 (d, J=8.3, 1 H); 1639, 1468, 1180, 1038, 976, 800, 739. HR-EI-MS:
8.17 (d, J=8.3, 1 H). 13C-NMR (126 MHz, CDCl3): 79.6 (d, 242.0740 (C15H11FO2+, M+; calc. 242.0743).
JCF =13); 119.1; 119.2 (d, JCF =4); 120.8; 123.6; 124.2;
124.7; 126.7; 128.5; 130.8; 142.2; 159.7 (d, JCF =280).
2-Fluoro-3-iodo-1-benzofuran (7l). To a DMF
19F-NMR (470 MHz, CDCl3): 49.9 (d, JFH =7). IR (neat): (140 mL) solution of difluorostyrene 4l (2.00 g,
1628, 1329, 1259, 1171, 1076, 980, 810, 742, 683. HR- 7.07 mmol) was added LiOH·H2O (312 mg, 7.44 mmol).
EI-MS: 186.0483 (C12H7FO+, M+; calc. 186.0481).
After stirring at 0 C for 4 h, the reaction was quenched
with phosphate buffer (pH 7, 10 mL), and water
°
2-Fluoro-7-phenyl-1-benzofuran (7i). Compound (300 mL) was then added to the mixture. Organic
7i was synthesized according to General Procedure 2 materials were extracted with diethyl ether (75 mL)
using difluorostyrene 4i (53 mg, 0.23 mmol), DBU (41 three times. The combined extracts were washed with
μL, 0.27 mmol), and DMF (7 mL) for 20 min. Purifica- brine and dried over Na2SO4. After removal of the
tion of silica gel column chromatography (hexane) solvent under reduced pressure, the residue was
1
gave 7i (43 mg, 88%) as a colorless liquid. H-NMR purified by silica gel column chromatography (hexane/
(500 MHz, CDCl3): 5.90 (d, JHF =6.6, 1 H); 7.31 (dd, J= ethyl acetate 10:1) to give 7l (1.16 g, 63%) as a
7.7, 7.7, 1 H); 7.38–7.44 (m, 3 H); 7.47–7.50 (m, 2 H); colorless oil. 1H-NMR (500 MHz, CDCl3): 7.30–7.33 (m, 3
7.77–7.79 (m, 2 H). 13C-NMR (126 MHz, CDCl3): 78.5 (d, H); 7.36–7.38 (m, 1 H). 13C-NMR (126 MHz, CDCl3): 33.8
JCF =13); 119.7 (d, JCF =6); 123.2 (d, JCF =4); 124.2; (d, JCF =19); 111.2; 120.9 (d, JCF =5); 124.3 (d, JCF =4);
www.helv.wiley.com
(10 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
129.9; 147.7; 160.0 (d, JCF =277). 19F-NMR (470 MHz, 1228, 1184, 980, 834, 806. HR-EI-MS: 230.0533
CDCl3): 52.1 (s). IR (neat): 2924, 1641, 1448, 1327, 1178, (C14H8F2O+, M+; calc. 230.0543).
1041, 741. HR-EI-MS: 261.9289 (C8H4FIO+, M+; calc.
261.9291).
Ethyl
4-(2-Fluoro-1-benzofuran-5-yl)benzoate
(7n). Compound 7n was synthesized according to
General Procedure 3 using 5-bromo-2-fluoro-1-benzo-
furan (7f, 108 mg, 0.50 mmol), [4-(ethoxycarbonyl)
phenyl]boronic acid (146 mg, 0.75 mmol), PdCl2
Chemical
1-Benzofuran (7f)
Transformation
of
5-Bromo-2-Fluoro-
General Procedure 3: Synthesis of 2-Fluoro-5-phenyl-1- (0.4 mg, 2 μmol), K2CO3 (140 mg, 1.0 mmol), ethanol
benzofuran (7j). To an ethanol (0.4 mL) and water (2 mL), and water (2 mL). Purification of silica gel
(0.4 mL) solution of 5-bromo-2-fluoro-1-benzofuran column chromatography (hexane/ethyl acetate 10:1)
1
(7f, 21 mg, 0.10 mmol), phenylboronic acid (19 mg, gave 7n (141 mg, 99%) as a colorless crystal. H-NMR
0.15 mmol), and K2CO3 (28.0 mg, 0.20 mmol) was (500 MHz, CDCl3): 1.42 (t, J=7.1, 3 H); 4.40 (q, J=7.1, 2
added PdCl2 (0.1 mg, 0.5 μmol). After stirring at room H); 5.92 (d, JHF =6.6, 1 H); 7.45–7.50 (m, 2 H); 7.65 (d,
temperature for 36 h, organic materials were extracted J=8.2, 2 H); 7.70 (d, J=1.8, 1 H); 8.11 (d, J=8.2, 2 H).
with dichloromethane (1 mL) three times. The com- 13C-NMR (126 MHz, CDCl3): 14.3; 60.9; 78.6 (d, JCF =14);
bined extracts were washed with brine and dried over 111.2; 119.4 (d, JCF =6); 122.9 (d, JCF =4); 127.2; 128.5
Na2SO4. After removal of the solvent under reduced (d, JCF =3); 129.0; 130.0; 136.2; 145.6; 147.7; 160.8 (d,
pressure, the residue was purified by silica gel column JCF =281); 166.4. 19F-NMR (470 MHz, CDCl3): 52.0 (d,
chromatography (hexane) to give 7j (15 mg, 73%) as a
JFH =7). IR (neat): 3140, 2982, 1712, 1637, 1468, 972,
+
colorless oil. Spectral data for this compound showed 768. HR-EI-MS: 284.0857 (C17H13FO3
good agreement with 7j synthesized according to 284.0849).
General Procedure 2 (vide supra).
,
M+; calc.
Chemical Transformation of 2-Fluoro-3-iodo-1-benzo-
furan (7l)
2-Fluoro-5-(4-methoxyphenyl)-1-benzofuran
(7k). Compound 7k was synthesized according to
General Procedure 3 using 5-bromo-2-fluoro-1-benzo- General Procedure 4: Synthesis of 2-Fluoro-3-phenyl-1-
furan (7f, 107 mg, 0.50 mmol), (4-methoxyphenyl)bor- benzofuran (7o). A 1,4-dioxane (2.0 mL) and water
onic acid (117 mg, 0.77 mmol), PdCl2 (0.4 mg, 2 μmol), (0.2 mL) solution of 2-fluoro-3-iodo-1-benzofuran (7l,
K2CO3 (141 mg, 1.0 mmol), ethanol (2 mL), and water 262 mg, 1.00 mmol), phenylboronic acid (145 mg,
(2 mL). Purification of silica gel column chromatogra- 1.2 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol), and K2CO3
phy (hexane) gave 7k (63 mg, 52%) as a colorless oil. (417 mg, 3.01 mmol) was degassed by using the
Spectral data for this compound showed good agree- freeze-pump-thaw method three times. After stirring
°
ment with 7k synthesized according to General at 100 C for 36 h, water (5 mL) was added to the
Procedure 2 (vide supra).
mixture. Organic materials were extracted with di-
chloromethane (5 mL) three times. The combined
2-Fluoro-5-(4-fluorophenyl)-1-benzofuran (7m). extracts were washed with brine and dried over
Compound 7m was synthesized according to General Na2SO4. After removal of the solvent under reduced
Procedure 3 using 5-bromo-2-fluoro-1-benzofuran (7f, pressure, the residue was purified by silica gel column
107 mg, 0.50 mmol), (4-fluorophenyl)boronic acid chromatography (hexane) to give 7o (178 mg, 84%) as
1
(105 mg, 0.75 mmol), PdCl2 (0.4 mg, 2 μmol), K2CO3 a colorless liquid. H-NMR (500 MHz, CDCl3): 7.26–7.31
(140 mg, 1.0 mmol), ethanol (2 mL), and water (2 mL). (m, 2 H); 7.32–7.35 (m, 1 H); 7.40–7.43 (m, 1 H); 7.46
Purification of silica gel column chromatography (dd, J=8.0, 7.7, 2 H); 7.64 (d, J=8.0, 2 H); 7.72–7.75 (m,
1
(hexane) gave 7m (90 mg, 79%) as a colorless oil. H- 1 H). 13C-NMR (126 MHz, CDCl3): 93.2 (d, JCF =8); 111.1;
NMR (500 MHz, CDCl3): 5.90 (d, JHF =6.6, 1 H); 7.11– 120.0 (d, JCF =6); 123.8 (d, JCF =4); 123.9; 127.2; 127.7
7.16 (m, 2 H); 7.39–7.44 (m, 2 H); 7.52–7.56 (m, 2 H); (d, JCF =3); 128.7; 128.9; 129.5 (d, JCF =5); 147.1; 156.5
7.60 (d, J=1.8, 1 H). 13C-NMR (126 MHz, CDCl3): 78.6 (d, (d, JCF =283). 19F-NMR (470 MHz, CDCl3): 47.3 (s). IR
JCF =13); 111.1; 115.6 (d, JCF =21); 119.2 (d, JCF =6); (neat): 1653, 1452, 1385, 1296, 1211, 1003, 766, 741,
122.8 (d, JCF =4); 128.5 (d, JCF =8); 128.9 (d, JCF =8); 694. HR-EI-MS: 212.0635 (C14H9FO+, M+; calc.
136.5; 137.5 (d, JCF =3); 147.3; 160.8 (d, JCF =281); 212.0637).
162.3 (d, JCF =247). 19F-NMR (470 MHz, CDCl3): 46.8 (1
F); 52.0 (d, JFH =7, 1 F). IR (neat): 1637, 1466, 1335,
www.helv.wiley.com
(11 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
2-Fluoro-3-(4-methoxyphenyl)-1-benzofuran
column chromatography (hexane) to give 7r (179 mg,
1
(7p). Compound 7p was synthesized according to 76%) as a colorless liquid. H-NMR (500 MHz, CDCl3):
General Procedure 4 using 2-fluoro-3-iodo-1-benzofur- 7.29–7.41 (m, 6 H); 7.56–7.58 (m, 2 H); 7.62–7.64 (m, 1
an (7l, 209 mg, 0.796 mmol), (4-methoxyphenyl)bor- H). 13C-NMR (126 MHz, CDCl3): 75.6 (d, JCF =2); 78.2 (d,
onic acid (158 mg, 1.0 mmol), Pd(PPh3)4 (28 mg, JCF =11); 94.4; 111.1; 120.2 (d, JCF =5); 122.8; 124.3;
0.024 mmol), K2CO3 (332 mg, 2.40 mmol), 1,4-dioxane 124.5 (d, JCF =4); 127.9; 128.4; 128.5; 131.6; 146.7; 160.6
(2.0 mL), and water (0.2 mL) at 100 C for 12 h. (d, JCF =289). 19F-NMR (470 MHz, CDCl3): 57.1 (s). IR
°
Purification of silica gel column chromatography (neat): 1655, 1454, 1396, 1304, 1120, 957, 742, 688. HR-
(hexane) gave 7p (151 mg, 78%) as a colorless liquid. EI-MS: 236.0642 (C16H9FO+, M+; calc. 236.0637).
1H-NMR (500 MHz, CDCl3): 3.83 (s, 3 H); 7.00 (d, J=8.9,
2 H); 7.26–7.28 (m, 2 H); 7.40–7.42 (m, 1 H); 7.56 (d, J=
3-Ethenyl-2-fluoro-1-benzofuran (7s). A DMF
8.9, 2 H); 7.68–7.70 (m, 1 H). 13C-NMR (126 MHz, (2 mL) solution of 2-fluoro-3-iodo-1-benzofuran (7l,
CDCl3): 55.3, 92.8 (d, JCF =9); 111.1; 114.4; 119.9 (d, 135 mg, 0.51 mmol), tributyl(vinyl)stannane (145 mg,
JCF =6); 121.8 (d, JCF =5); 123.66 (d, JCF =4); 123.74; 0.50 mmol), and Pd(PPh3)4 (24 mg, 0.021 mmol) was
127.6; 128.9 (d, JCF =3); 147.0; 156.2 (d, JCF =282); degassed by using the freeze-pump-thaw method
158.7. 19F-NMR (470 MHz, CDCl3): 45.9 (s, 1 F). IR (neat): three times. After stirring at 60 C for 16 h, water
°
2837, 1658, 1610, 1514, 11452, 1211, 1176, 1020, 995, (10 mL) was added to the mixture. Organic materials
827, 741. HR-EI-MS: 242.0751 (C15H11FO2+, M+; calc. were extracted with diethyl ether (5 mL) three times.
242.0743).
The combined extracts were washed with brine and
dried over Na2SO4. After removal of the solvent under
2-Fluoro-3-(4-fluorophenyl)-1-benzofuran (7q). reduced pressure, the residue was purified by silica gel
Compound 7q was synthesized according to General column chromatography (hexane) to give 7s (67 mg,
1
Procedure 4 using 2-fluoro-3-iodo-1-benzofuran (7l, 83%) as a colorless liquid. H-NMR (500 MHz, CDCl3):
209 mg, 0.799 mmol), (4-fluorophenyl)boronic acid 5.35 (d, J=11.5, 1 H); 5.73 (dd, J=17.9, 1.0, 1 H); 6.62
(146 mg, 1.0 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol), (dd, J=17.9, 11.5, 1 H); 7.23–7.29 (m, 2 H); 7.35–7.37
K2CO3 (331 mg, 2.40 mmol), 1,4-dioxane (2.0 mL), and (m, 1 H); 7.66–7.68 (m, 1 H). 13C-NMR (126 MHz, CDCl3):
°
water (0.2 mL) at 100 C for 12 h. Purification of silica 91.7 (d, JCF =9); 111.1; 114.9 (d, JCF =4); 120.3 (d, JCF =
gel column chromatography (hexane) gave 7q 5); 123.2 (d, JCF =4); 123.8 (d, JCF =4); 123.9; 126.7;
1
(179 mg, 97%) as a colorless liquid. H-NMR (500 MHz, 147.2; 157.5 (d, JCF =286). 19F-NMR (470 MHz, CDCl3):
CDCl3): 7.15 (dd, JHF =8.7, J=8.7, 2 H); 7.27–7.32 (m, 2 49.6 (s). IR (neat): 1662, 1456, 1381, 1196, 742. HR-EI-
H); 7.40–7.44 (m, 1 H); 7.57–7.60 (m, 2 H); 7.65–7.69 MS: 162.0485 (C10H7FO+, M+; calc. 162.0481).
(m, 1 H). 13C-NMR (126 MHz, CDCl3): 92.4 (d, JCF =9);
111.2; 115.9 (d, JCF =22); 119.7 (d, JCF =6); 123.92;
123.95; 129.3 (d, JCF =3); 129.4 (d, JCF =3); 133.7 (d,
JCF =19); 147.1; 156.4 (d, JCF =283); 161.9 (d, JCF =248).
Acknowledgements
19F-NMR (470 MHz, CDCl3): 46.7 (s, 1 F); 48.50–48.54 This work was financially supported by JSPS KAKENHI
(m, 1 F). IR (neat): 1655, 1512, 1454, 1213, 999, 833, Grant Number JP19H02707 (J. I.) in Grant-in-Aid for
742. HR-EI-MS: 230.0552 (C14H8F2O+, M+; calc. Scientific Research (B), JSPS KAKENHI Grant Number
230.0543).
JP18H04234 (J. I.) in Precisely Designed Catalysts with
Customized Scaffolding, JSPS KAKENHI Grant Number
2-Fluoro-3-(phenylethynyl)-1-benzofuran (7r). A JP20 K21186 (J. I.) in Grant-in-Aid for Challenging
triethylamine (5 mL) solution of 2-fluoro-3-iodo-1- Research (Exploratory), and JSPS KAKENHI Grant
benzofuran (7l, 261 mg, 0.994 mmol), ethynylbenzene Number JP18 K05116 (T. F.) in Grant-in-Aid for Scien-
(0.12 mL, 1.1 mmol), PdCl2(PPh3)2 (21 mg, 0.030 mmol), tific Research (C). We acknowledge TOSOH FINECHEM
and CuI (5.7 mg, 0.030 mmol) was degassed by using CORPORATION for a generous gift of 1,1,1-trifluoro-2-
the freeze-pump-thaw method three times. After iodoethane.
stirring at room temperature for 12 h, water (10 mL)
was added to the mixture. Organic materials were
extracted with dichloromethane (5 mL) three times.
The combined extracts were washed with brine and
Author Contribution Statement
dried over Na2SO4. After removal of the solvent under J. I. directed the project. J. I. and T. F. conceived and
reduced pressure, the residue was purified by silica gel designed the project. R. M. conducted the experi-
www.helv.wiley.com
(12 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
kenes: Ring-Fluorinated Hetero- and Carbocycle Synthesis
and Remarkable Effect of the Vinylic Fluorines on the
Disfavored Process’, Synthesis 2002, 1917–1936.
ments. R. M. and T. F. wrote the manuscript with the
assistance of J. I. All authors participated in data
analyses and discussions.
[17] J. Ichikawa, ‘Construction of Fluorinated Heterocycles:
Intramolecular Substitution and Addition of Fluoro Al-
kenes’, Chim. Oggi 2007, 25(4), 54–57.
[18] J. Ichikawa, ‘Synthetic Methods for Heterocycles and
Carbocycles Bearing Fluorinated One-Carbon Units (=CF2,
CHF2, or CF3): Intramolecular Reaction of 2-Trifluoromethyl-
1-alkenes’, J. Synth. Org. Chem. Jpn. 2010, 68, 1175–1184.
[19] T. Fujita, J. Ichikawa, ‘Synthetic Methods for Ring-Fluori-
nated Pyrrole Derivatives’, Heterocycles 2017, 95, 694–714.
[20] J. Ichikawa, Y. Wada, T. Okauchi, T. Minami, ‘5-endo-
Trigonal cyclization of o-substituted gem-difluorostyrenes:
syntheses of 2-fluorinated indoles, benzo[b]furans and
benzo[b]thiophenes’, Chem. Commun. 1997, 1537–1538.
[21] J. Ichikawa, M. Fujiwara, Y. Wada, T. Okauchi, T. Minami,
‘The nucleophilic 5-endo-trig cyclization of gem-difluoroo-
lefins with homoallylic functional groups: syntheses of
ring-fluorinated dihydroheteroaromatics’, Chem. Commun.
2000, 1887–1888.
References
[1] V. Nenajdenko, ‘Fluorine in Heterocyclic Chemistry Vol. 1
and Vol. 2’, Springer, Heidelberg, 2014.
[2] S. A. Nash, R. B. Gammill, ‘The synthesis of 2- and 3-
fluorokhellin’, Tetrahedron Lett. 1987, 28, 4003–4006.
[3] S. Martín-Santamaría, M. A. Carroll, C. M. Carroll, C. D.
Carter, V. W. Pike, H. S. Rzepa, D. A. Widdowson, ‘Fluorida-
tion of heteroaromatic iodonium salts – experimental
evidence supporting theoretical prediction of selectivity of
the process’, Chem. Commun. 2000, 649–650.
[4] X. Yuan, J.-F. Yao, Z.-Y. Tang, ‘Decarboxylative Fluorination
of Electron-Rich Heteroaromatic Carboxylic Acids with
Selectfluor’, Org. Lett. 2017, 19, 1410–1413.
[5] B. Lu, X. Shen, L. Zhang, D. Liu, C. Zhang, J. Cao, R. Shen, J.
Zhang, D. Wang, H. Wan, Z. Xu, M.-H. Ho, M. Zhang, L.
Zhang, F. He, W. Tao, ‘Discovery of EBI-2511: A Highly
Potent and Orally Active EZH2 Inhibitor for the Treatment
of Non-Hodgkin’s Lymphoma’, ACS Med. Chem. Lett. 2018,
9, 98–102.
[6] D. H. R. Barton, R. H. Hesse, G. P. Jackman, M. M. Pechet,
‘Fluorination of benzofuran and of N-acylindoles with
trifluorofluorooxymethane’, J. Chem. Soc. Perkin Trans. 1
1977, 2604–2608.
[7] M. Wang, X. Liu, L. Zhou, J. Zhu, X. Sun, ‘Fluorination of 2-
substituted benzo[b]furans with SelectfluorTM’, Org. Biomol.
Chem. 2015, 13, 3190–3193.
[8] P. J. Milner, Y. Yang, S. L. Buchwald, ‘In–Depth Assessment
of the Palladium-Catalyzed Fluorination of Five-Membered
Heteroaryl Bromides’, Organometallics 2015, 34, 4775–
4780.
[9] L. Hariss, K. H. Bouhadir, T. Roisnel, R. Grée, A. Hachem,
‘Synthesis of Novel Fluorinated Benzofurans and Dihydro-
benzofurans’, Synlett 2017, 28, 195–200.
[10] M. K. Narayanam, G. Ma, P. A. Champagne, K. N. Houk, J. M.
Murphy, ‘Nucleophilic 18F-Fluorination of Anilines via N-
Arylsydnone Intermediates’, Synlett 2018, 29, 1131–1135.
[11] S. D. Taylor, C. C. Kotoris, G. Hum, ‘Recent advances in
electrophilic fluorination’, Tetrahedron 1999, 55, 12431–
12477.
[22] T. Fujita, R. Morioka, T. Arita, J. Ichikawa, ‘sp3 carbon–
fluorine bond activation in 2,2-difluorohomoallylic alcohols
via nucleophilic 5-endo-trig cyclisation: synthesis of 3-
fluorinated furan derivatives’, Chem. Commun. 2018, 54,
12938–12941.
[23] T. Fujita, M. Hattori, M. Matsuda, R. Morioka, T. C. Jankins,
M. Ikeda, J. Ichikawa, ‘Nucleophilic 5-endo-trig cyclization
of 2-(trifluoromethyl)allylic metal enolates and enamides:
Synthesis of tetrahydrofurans and pyrrolidines bearing exo-
difluoromethylene units’, Tetrahedron 2019, 75, 36–46.
[24] K. Fuchibe, K. Fushihara, J. Ichikawa, ‘Synthesis of Ring-
Fluorinated Thiophene Derivatives Based on Single CÀ F
Bond Activation of CF3-Cyclopropanes: Sulfanylation and
5-endo-trig Cyclization’, Org. Lett. 2020, 22, 2201–2205.
[25] J. E. Baldwin, ‘Rules for ring closure’, J. Chem. Soc. Chem.
Commun. 1976, 734–736.
[26] J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman,
R. C. Thomas, ‘5-Endo-trigonal reactions: a disfavoured ring
closure’, J. Chem. Soc. Chem. Commun. 1976, 736–738.
[27] C. P. Johnston, A. Kothari, T. Sergeieva, S. I. Okovytyy, K. E.
Jackson, R. S. Paton, M. D. Smith, ‘Catalytic enantioselective
synthesis of indanes by a cation-directed 5-endo-trig
cyclization’, Nat. Chem. 2015, 7, 171–177.
[28] R. Kapoorr, S. N. Singh, S. Tripathi, L. D. S. Yadav, ‘Photo-
catalytic Oxidative Heterocyclization of Semicarbazones:
An Efficient Approach for the Synthesis of 1,3,4-Oxadia-
zoles’, Synlett 2015, 26, 1201–1206.
[29] K. Sharma, J. R. Wolstenhulme, P. P. Painter, D. Yeo, F.
Grande-Carmona, C. P. Johnston, D. J. Tantillo, M. D. Smith,
‘Cation-Controlled Enantioselective and Diastereoselective
Synthesis of Indolines: An Autoinductive Phase-Transfer
Initiated 5-endo-trig Process’, J. Am. Chem. Soc. 2015, 137,
13414–13424.
[12] R. P. Singh, J. M. Shreeve, ‘Recent Highlights in Electrophilic
Fluorination with 1-Chloromethyl-4-fluoro-1,4-diazoniabi-
cyclo[2.2.2]octane Bis(tetrafluoroborate)’, Acc. Chem. Res.
2004, 37, 31–44.
[13] P. T. Nyffeler, S. G. Durón, M. D. Burkart, S. P. Vincent, C.-H.
Wong, ‘Selectfluor: Mechanistic Insight and Applications’,
Angew. Chem. Int. Ed. 2005, 44, 192–212; Angew. Chem.
2005, 117, 196–217.
[14] A. S. Kiselyov, ‘Chemistry of N-fluoropyridinium salts’,
Chem. Soc. Rev. 2005, 34, 1031–1037.
[15] J. Ichikawa, ‘Ring constructions by the use of fluorine
substituent as activator and controller’, Pure Appl. Chem.
2000, 72, 1685–1689.
[30] B. M. Williams, D. Trauner, ‘Expedient Synthesis of (+)-Lyco-
palhine A’, Angew. Chem. Int. Ed. 2016, 55, 2191–2194;
Angew. Chem. 2016, 128, 2231–2234.
[31] A. W. Markwell-Heys, J. H. George, ‘Some chemical spec-
ulation on the biosynthesis of corallidictyals A–D’, Org.
Biomol. Chem. 2016, 14, 5546–5549.
[16] J. Ichikawa, Y. Wada, M. Fujiwara, K. Sakoda, ‘The
Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-al-
www.helv.wiley.com
(13 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Helv. Chim. Acta 2020, 103, e2000159
[32] T. Xiao, L. Li, L. Zhou, ‘Synthesis of Functionalized gem-
mers’, Angew. Chem. Int. Ed. 2013, 52, 12536–12540;
Angew. Chem. 2013, 125, 12768–12772.
[39] R. Anilkumar, D. J. Burton, ‘The first preparation of the α-
Difluoroalkenes via a Photocatalytic Decarboxylative/De-
fluorinative Reaction’, J. Org. Chem. 2016, 81, 7908–7916.
[33] B. Zhang, X. Zhang, J. Hao, C. Yang, ‘Direct Approach to N-
Substituted-2-Fluoroindoles by Sequential Construction of
CÀ N Bonds from gem-Difluorostyrenes’, Org. Lett. 2017, 19,
1780–1783.
[34] J. Hao, T. Milcent, P. Retailleau, V. A. Soloshonok, S. Ongeri,
B. Crousse, ‘Asymmetric Synthesis of Cyclic Fluorinated
Amino Acids’, Eur. J. Org. Chem. 2018, 3688–3692.
[35] X. Zhang, J. He, S. Cao, ‘Facile Synthesis of Unsymmetrical
2,5-Disubstituted 1,3,4-Oxadiazoles by Cyclization of gem-
Difluoroalkenes with Acyl Hydrazides’, Asian J. Org. Chem.
2019, 8, 279–282.
[36] J. Zheng, J. Cai, J.-H. Lin, Y. Guo, J.-C. Xiao, ‘Synthesis and
decarboxylative Wittig reaction of difluoromethylene phos-
phobetaine’, Chem. Commun. 2013, 49, 7513–7515.
[37] Z.-Q. Guo, W.-Q. Chen, X.-M. Duan, ‘Highly Selective Visual
Detection of Cu(II) Utilizing Intramolecular Hydrogen
Bond-Stabilized Merocyanine in Aqueous Buffer Solution’,
Org. Lett. 2010, 12, 2202–2205.
iodo-β,β-difluorovinylzinc reagent (CF2=CIZnCl) and
a
high-yield one-pot synthesis of α-iodo-β,β-difluorostyr-
enes’, J. Fluorine Chem. 2005, 126, 455–461.
[40] H. R. M. Aitken, D. P. Furkert, J. G. Hubert, J. M. Wood, M. A.
Brimble, ‘Enantioselective access to benzannulated spiro-
ketals using a chiral sulfoxide auxiliary’, Org. Biomol. Chem.
2013, 11, 5147–5155.
[41] R. G. Harvey, C. Cortez, T. P. Ananthanarayan, S. Schmolka,
‘A new coumarin synthesis and its utilization for the
synthesis of polycyclic coumarin compounds with anti-
carcinogenic properties’, J. Org. Chem. 1988, 53, 3936–
3943.
[42] G. Landelle, M.-O. Turcotte-Savard, J. Marterer, P. A.
Champagne, J.-F. Paquin, ‘Stereocontrolled Access to
Unsymmetrical 1,1-Diaryl-2-fluoroethenes’, Org. Lett. 2009,
11, 5406–5409.
[38] D. Takeuchi, Y. Chiba, S. Takano, K. Osakada, ‘Double-
Decker-Type Dinuclear Nickel Catalyst for Olefin Polymer-
ization: Efficient Incorporation of Functional Co-mono-
Received August 19, 2020
Accepted September 25, 2020
www.helv.wiley.com
(14 of 14) e2000159
© 2020 Wiley-VHCA AG, Zurich, Switzerland