Acid-mediated intermolecular C-F/C-H cross-coupling of 2-fluorobenzofurans with arenes: Synthesis of 2-arylbenzofurans

Article abstract of DOI:10.1039/d1cc03453g

Transition-metal-free acid-promoted biaryl construction was achieved via intermolecular C-F/C-H cross-coupling. By treating 2-fluorobenzofurans with arenes in the presence of AlCl3, 2-arylbenzofurans were obtained. This protocol was successfully applied to the short-step orthogonal synthesis of a bioactive 2-arylbenzofuran natural product, which allows independent transformations of C-F and C-Br bonds. Mechanistic studies indicated that α-fluorine-stabilized carbocations, generated via the protonation of 2-fluorobenzofurans, served as key intermediates. The Friedel-Crafts-type C-C bond formation between the α-fluorocarbocations and arenes, followed by hydrogen fluoride elimination, afforded 2-arylbenzofurans. This journal is

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Acid-mediated intermolecular C–F/C–H
cross-coupling of 2-fluorobenzofurans with
arenes: synthesis of 2-arylbenzofurans†
Cite this: Chem. Commun., 2021,
57, 8500
Received 28th June 2021,
Accepted 27th July 2021
Takeshi Fujita, * Ryutaro Morioka, Takuya Fukuda, Naoto Suzuki
Junji Ichikawa
and
*
DOI: 10.1039/d1cc03453g
rsc.li/chemcomm
Transition-metal-free acid-promoted biaryl construction was achieved Ar2H. Although this approach is an improved alternative to the
via intermolecular C–F/C–H cross-coupling. By treating 2-fluoroben- aforementioned methods for intermolecular cross-coupling, the
zofurans with arenes in the presence of AlCl3, 2-arylbenzofurans were aryl (pseudo)halide substrates have been limited to aryl iodides,
obtained. This protocol was successfully applied to the short-step bromides, chlorides, or sulfonates. Aryl fluorides have never been
orthogonal synthesis of a bioactive 2-arylbenzofuran natural product, applicable to this type of reaction, presumably because aryl radical
which allows independent transformations of C–F and C–Br bonds. species are difficult to generate via the homolytic cleavage of C–F
Mechanistic studies indicated that a-fluorine-stabilized carbocations, bonds, which exhibit higher dissociation energy.
generated via the protonation of 2-fluorobenzofurans, served as key
In contrast, we have already developed a strategy for acid-
intermediates. The Friedel–Crafts-type C–C bond formation between mediated intramolecular cross-coupling via aromatic C–F bond
the a-fluorocarbocations and arenes, followed by hydrogen fluoride activation involving C(sp2)–C(sp2) bond formation (Scheme 1b).4
elimination, afforded 2-arylbenzofurans.
In our strategy, the initial protonation of Ar1F generated intermedi-
ary arenium ions, which were stabilized by the fluorine
For a long time, biaryl construction through intermolecular substituent.5 The arenium ions reacted with nucleophilic Ar2H
cross-coupling via C(sp2)–C(sp2) bond formation has been one units via the intramolecular Friedel–Crafts-type C–C bond for-
of the most important studies in synthetic organic chemistry. mation. Subsequent hydrogen fluoride elimination afforded a
For the past half-century, a wide variety of transition-metal- benzene-fused aromatic system. As the next challenge of our formal
catalyzed cross-coupling reactions typically between aryl cross-coupling reactions, we explored acid-mediated C–F/C–H cou-
halides (Ar1X) and arylmetal species (Ar2M0) have been develo- pling of aryl fluorides with arenes in an intermolecular fashion,
ped to provide tremendous support for pharmaceutical and which is considered more difficult entropically. In this study, we
material sciences (Scheme 1a, top).1 Among the transition- chose 2-fluorobenzofurans 16 as substrates because intermediary
metal-catalyzed cross-coupling reactions, the intermolecular arenium ions would be readily generated through double stabili-
direct arylation of aryl halides (Ar1X) with arenes (Ar2H) via zation by the fluorine and oxygen substituents. We discovered that
C–H bond cleavage has been exponentially studied (Scheme 1a, AlCl3 was effective in promoting the intermolecular coupling of 1
middle).2 This protocol allows an improved atom-economical with Ar2H 2, resulting in the synthesis of 2-arylbenzofurans 3
alternative for biaryl construction because Ar2H instead of (Scheme 1c). Although defluorinative C(sp2)–C(sp2) coupling by
8
Ar2M0 can be used. More recently, the transition-metal-free silylium ions7 or g-Al2O3 have recently been reported, these are
cross-coupling of Ar1X with Ar2H in an intermolecular fashion limited to intramolecular reactions or require silyl groups on the
has also been reported (Scheme 1a, bottom).3 In these reac- fluorine-containing substrates because they proceed via extremely
tions, nitrogen-containing substrates or additives were often unstable aryl cation(-like) species.
combined with metal tert-butoxide to generate aryl radical
First, we investigated this intermolecular C–F/C–H coupling
species from Ar1X, which undergo C–C bond formation with reaction using 2-fluorobenzofuran (1a) and 5 equiv. of p-xylene
(2a) as model compounds (Table 1). Although no coupling product
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba,
Tsukuba, Ibaraki 305-8571, Japan. E-mail: fujita@chem.tsukuba.ac.jp,
junji@chem.tsukuba.ac.jp
was obtained in the presence of acetic acid or p-toluenesulfonic
acid (Table 1, entries 1 and 2), the use of trifluoromethanesulfonic
acid in CH2Cl2 at ꢀ20 1C afforded the expected defluorinated
coupling product, 2-xylylbenzofuran (3aa), in an 8% yield (Table 1,
entry 3). Among the Lewis acids screened (Table 1, entries 4–6),
AlCl3 was found to be the best, affording 3aa in a 63% isolated
† Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data of new compounds. CCDC 2075144. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1cc03453g
8500 | Chem. Commun., 2021, 57, 8500–8503
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Table 1 Screening of the conditions for C–F/C–H cross-coupling of 1a
with 2a
Entry
Acid
Solvent
3aaa (%)
1
2
3
4
AcOH
TsOH
TfOH
FeCl3
BF3ꢁOEt2
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
N.D.b
N.D.b
8
N.D.b
N.D.b
68 (63)c
34
5
6
7d
8
N.D.b
N.D.b
N.D.b
Trace
96 (91)c
9
MeCN
10
11e
12f
MeNO2
(CF3)2CHOH
None
a
Yield was determined by 1H NMR spectroscopy using CH2Br2 as an
b
c
d
internal standard. N.D. = not detected. Isolated yield. Molecular
sieves 4 A (250 wt%) was added. 0 1C. Reaction was conducted at
room temperature using 2a (20 equiv.).
e
f
Method B, the yields of 2-arylated 5-phenylbenzofurans 3ea and 3eb
were drastically improved up to 96% and 99% yields, respectively.
The coupling of 2-fluorobenzofurans 1i–1k bearing a methoxy group
at the 5-, 6-, or 7-position proceeded regardless of the position of the
substituent. Not only 2-fluorobenzofurans but also 2-fluoronaphtho-
[2,1-b]furan (1l) and 2-fluorobenzothiophene (1m) participated in
the reaction to afford the corresponding 2-arylated naphthofuran 3la
in a 43% yield (Method B) and benzothiophene 3mb in a 33%
Scheme 1 Cross-coupling via C(sp2)–C(sp2) bond formation.
yield (Table 1, entry 6). The cross-coupling was sluggish in the yield (Method A), respectively. The one-step synthesis of 2-(2,4-
presence of molecular sieves, to afford 3aa in a 34% yield (Table 1, dihydroxyphenyl)benzofuran (3ag, DHBF),12 which possesses a bac-
entry 7).9 To improve the yield of 3aa, we screened the solvents. Out terial biofilm formation inhibitory activity, was achieved through the
of the several solvents that were examined (Table 1, entries 6 and AlCl3-mediated coupling of 1a with resorcinol (2g) in a CH2Cl2–
8–11), CH2Cl2 was found to be an exceptionally effective solvent. (CF3)2CHOH (10/1) mixed solvent system at room temperature. In
Oxygen- or nitrogen-containing solvents probably coordinate to addition, the coupling of 7-chloro-2-fluorobenzofuran (1n) with 2d
AlCl3 to retard the reaction. When the reaction was conducted with proceeded at room temperature to afford the corresponding benzo-
20 equiv. of 2a without any solvent, 3aa was obtained in a 91% furan 3nd in a 54% yield, which served as a cholinesterase inhibitor
isolated yield (Table 1, entry 12). Based on these results, we (ChEI).13 It is noteworthy that bromine- and chlorine-bearing fluor-
concluded that two types of conditions are suitable: one can obenzofurans 1h and 1n exclusively underwent defluorinative cou-
suppress the amount of Ar2H used (Table 1, entry 6; Method A) pling without C–Br and C–Cl bond cleavage (3ha–3hc and 3nd).
and the other does not use any solvent (Table 1, entry 12; Furthermore, even electron-withdrawing groups (CO2Et 3ga, Br, and
Method B).
Cl) on 2-fluorobenzofurans are not only tolerated in the reaction but
The coupling reactions of a variety of substituted 1 with several also do not reduce the efficiency.
arenes 2 were investigated using Method A and/or Method B
This protocol was successfully applied to the short-step
mentioned above (Table 2).10,11 Relatively electron-rich Ar2H, such synthesis of bioactive eupomatenoid 6 (4), which is a member
as 2a, m-xylene (2b), thiophene (2c), phenol (2d), 1,3-dimetho- of a family of naturally occurring 2-aryl-3-methyl-5-[(E)-prop-1-
xybenzene (2e), and 1,4-dimethoxybenzene (2f), were successfully en-1-yl]benzofurans with antifungal, insecticidal, and antioxi-
coupled with unsubstituted and substituted 1. Notably, C–C bond dant properties.14 The strategy is based on the orthogonal
formation, rather than C–O bond formation, occurred exclusively in coupling reaction using fluorine and bromine substituents on
the case of the reaction with 2d to produce 3ad, despite substantial the benzofuran nucleus. In the presence of AlCl3, the treatment
nucleophilicity of the hydroxyl group. To afford 3ba–3bc, 3bf, 3ca, of readily available 5-bromo-2-fluoro-3-methylbenzofuran (1o)
and 3da, 2-fluorobenzofurans 1b–1d bearing an alkyl or an aryl with 2d in 1,2-dichloroethane (DCE) at 80 1C afforded the
group at the 3-position underwent defluorinative coupling. Using corresponding coupling product 3od in a 71% yield via the
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Table 2 Synthesis of 2-arylbenzofurans 3a
a
i
b
c
d
e
f
g
h
Isolated yield. Room temperature. 40 1C, 24 h. 3 h. 2 h. 2f (2.0 equiv.). AlCl3 (2.0 equiv.), 2a (26 equiv.). 2a (23 equiv.).
CH2Cl2–(CF3)2CHOH (10/1).
exclusive C–F bond cleavage and C–C bond formation
(Scheme 2). Subsequent Suzuki–Miyaura coupling of 3od with
potassium (E)-(prop-1-en-1-yl)trifluoroborate afforded 4 quanti-
tatively. The unambiguous structural determination of 4 was
achieved by X-ray crystallographic analysis (Scheme 2).
To gain mechanistic insight, we conducted control experi-
ments using a deuterated substrate. In the presence of AlCl3,
the treatment of 1a with fully deuterated 2a (2a-d10) afforded
benzofuran ring-deuterated 3aa (3aa-d), which exhibited sig-
nificant deuterium incorporation at the 3-position (56% D) and
a low level of deuterium incorporation at the 4- and 6-positions
(Scheme 3a). The source of the deuterium incorporated on the
benzofuran ring should be the deuteron (D+) generated not only
via the elimination of the deuteron during the C–C bond
Scheme 2 Orthogonal synthesis of eupomatenoid 6 (4).
formation but also via the H–D exchange of 2a-d10 by residual presence of AlCl3 (Table 3). Compared to the fluorine substituent
protons. Thus, when nondeuterated product 3aa was subjected (1a: X = F, Table 3, entry 1), chlorine (1a-Cl), bromine (1a-Br), and
to the same conditions, only a relatively small amount of iodine (1a-I) substituents hardly promoted the reaction (Table 3,
deuterium incorporation was observed at the 3-position (25% entries 2–4). These results, along with those of the aforemen-
D, Scheme 3b). The results of these experiments strongly tioned control experiments (Scheme 3), clearly indicate that the
suggest that substrates 1 are susceptible to protonation at the fluorine substituent plays a crucial role in the stabilization of
3-position, which results in the generation of fluorine- the intermediary carbocations,4,5 resulting in an acceleration of
stabilized carbocation intermediates4,5 during the coupling the cation generation, that is, the rate-determining step in the
process (Scheme 1c).
Friedel–Crafts-type coupling reaction (Scheme 1c).
Furthermore, the effect of halogens on the 2-positions in
In summary, we developed an intermolecular cross-coupling
benzofurans was investigated by reacting 2-halogenated benzo- reaction of 2-fluorobenzofurans with arenes via acid-mediated
furans (1a-Cl: X = Cl; 1a-Br: X = Br; 1a-I: X = I) with 2a in the C–F bond activation. In this reaction, a-fluorocarbocations,
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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Scheme 3 Control experiments using deuterated 2a.
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Table 3 Effect of halogens on the 2-positions in benzofurans
6 2-Fluorobenzofurans are now more readily available than other
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Entry
1a
X
3aaa (%)
1
2
3
4
1a
F
68
10
1a-Cl
1a-Br
1a-I
Cl
Br
I
3
N.D.b
a
Yield was determined by 1H NMR spectroscopy using CH2Br2 as an
b
internal standard. N.D. = not detected.
9 The protons might be initially present in the reaction system as the
superacid [HAlCl4ꢀn(OH)n] formed from AlCl3 and a tiny amount of
contaminating water. This is supported by the decrease in the
reaction rate by the addition of molecular sieves. The full mecha-
nism is shown in Fig. S2 of ESI†.
10 Even when the yields of 3 were low, 2-fluorobenzofurans 1 were
completely consumed, and the dimers and/or trimers of 1 were
obtained by their self-coupling.
which are generated from the treatment of 2-fluorobenzofurans
with an acid, served as key intermediates. This renders our
method significantly different from other methods for C–F
bond arylation using transition metals.15 This protocol allows
coupling under mild conditions and enables the direct and
efficient synthesis of 2-arylbenzofurans, which includes bioac-
tive agents and a natural product. Furthermore, because of the
difficulty in the cleavage (stability) of the C–F bonds, we expect
this method to be useful for the orthogonal synthesis of
complex molecules via late-stage C–F bond activation.
This work was financially supported by JSPS KAKENHI Grant
Number JP19H02707 in Grant-in-Aid for Scientific Research (B)
(J. I.), JSPS KAKENHI Grant Number JP18H04234 in Precisely
Designed Catalysts with Customized Scaffolding (J. I.), JSPS
KAKENHI Grant Number JP20K21186 in Grant-in-Aid for Chal-
lenging Research (Exploratory) (J. I.), JSPS KAKENHI Grant
Number JP21K05066 in Grant-in-Aid for Scientific Research
(C) (T. Fujita), and the Environment Research and Technology
Development Fund (JPMEERF20192R01) of the Environmental
Restoration and Conservation Agency of Japan (T. Fujita).
We acknowledge TOSOH FINECHEM CORPORATION for a
generous gift of 1,1,1-trifluoro-2-iodoethane used in the pre-
paration of 3-arylated 2-fluorobenzofurans.
11 When the reactions were initiated at room temperature in Method A
with smaller amounts of arenes 2, the formation of the dimers and/
or trimers of 2-fluorobenzofurans 1 increased. Thus, Method A was
applied mainly at ꢀ20 1C.
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