Fluorination of 2-substituted benzo[b]furans with Selectfluor

Article abstract of DOI:10.1039/c4ob02691h

An efficient protocol was developed to access 3-fluoro-2-hydroxy-2-substituted benzo[b]furans with Selectfluor as the fluorinating reagent in MeCN and water. By utilizing SOCl₂/Py as the dehydrating agent, the compounds above were readily conve

Full text of DOI:10.1039/c4ob02691h

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Fluorination of 2-substituted benzo[b]furans with
Selectfluor™†
Cite this: DOI: 10.1039/c4ob02691h
Mingliang Wang,a Xixi Liu,a Lu Zhou,b Jidong Zhu*c and Xun Sun*a,d
Received 30th December 2014,
Accepted 28th January 2015
DOI: 10.1039/c4ob02691h
www.rsc.org/obc
An efficient protocol was developed to access 3-fluoro-2-hydroxy-
Initially, various reported methods were screened
2-substituted benzo[b]furans with Selectfluor™ as the fluorinating (Scheme 1): (a) direct difluoro substitution of a ketone using
reagent in MeCN and water. By utilizing SOCl2/Py as the dehydrat- DAST;11 (b) difluoro substitution of a thioketal with Py·HF;12
ing agent, the compounds above were readily converted to (c) trialkylstannyl substitution for electrophilic fluorination;13
3-fluorinated, 2-substituted benzo[b]furans in high yields.
(d) conversion from an alcohol into a F with DAST;14 (e) Br–F
exchange;15 (f) metal-induced introduction of F;16 and (g)
introduction of F by using Selectfluor in MeCN and DMSO.17
Unfortunately, none of these methods gave the fluorinated
product. In 2009, Ritter and co-workers reported an elegant
approach for introducing F onto aromatic rings from boronic
acids18 through AgOTf exchange. Although a benzo[b]furan
ring was not disclosed in the original paper, it is still interest-
ing to explore the chemistry of this new class of substrates.
Benzo[b]furan boronic acid SM-1 was thus prepared according
to the known procedure.19 Surprisingly, instead of the target
compound 2a, a new product, 3-fluoro-2-methoxy-2-(4-methoxy-
phenyl)-2,3-dihydrobenzofuran (3a), was isolated. Treatment of
compound 3a with BBr3, followed by MeI, afforded the desired
product 2a. The structural novelty of intermediate 3a intrigued
us to explore the process with more care. It was later found
that boronic acid SM-1 could be converted to 3a even in the
absence of AgOTf. We hypothesized that the benzo[b]furan
boronic acid, due to its poor stability, could be converted to
compound 1a under the basic conditions, followed by reaction
Heterocyclic structures play a vital role in pharmaceuticals and
bioactive natural products. The benzo[b]furan ring is one of
the most prevalent heterocyclic structural motifs that occur in
a wide variety of isolated natural products1 and is extremely
important in medicinal chemistry.2 2-Arylbenzo[b]furans have
recently attracted considerable attention due to their versatile
pharmaceutical activities, such as inhibition of the cholin-
esterase activity,3 and their antitumour,4 antiviral,5 antiplas-
modial,6 antioxidant7 and anti-HIV properties.8 On the other
hand, fluorinated compounds often exhibit remarkably
different chemical, physical and pharmacological properties
from their fluorine-free analogues,9 which make them widely
applicable in diverse areas ranging from pharmaceuticals to
materials science.10 The C(3)-position in 2-arylbenzo[b]furans
is usually a metabolic soft spot in vivo. Therefore, introduction
of F at this position may block drug metabolism and then
improve pharmacokinetic properties.9e We have recently been
interested in the design of C(3)-F-substituted 2-arylbenzo[b]-
furans for drug discovery and development. Literature mining
revealed very few methods for the synthesis of C(3)-F-substi-
tuted benzo[b]furans. Herein we report an efficient protocol to
generate C(3)-fluorinated benzo[b]furans as important build-
ing blocks for drug discovery.
aDepartment of Natural Products Chemistry, Fudan University, 826 Zhangheng Road,
Shanghai 201203, China. E-mail: sunxunf@shmu.edu.cn; Fax: +8621 51980003
bDepartment of Medicinal Chemistry, Fudan University, 826 Zhangheng Rd.,
Shanghai 201203, China
cInterdisciplinary Research Center on Biology and Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China. E-mail: zhujd@sioc.ac.cn
dShanghai Key Laboratory of Clinical Geriatric Medicine, 221 West Yanan Road,
Shanghai 200040, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob02691h
Scheme 1 Different methods according to the references.
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Table 2 Conditions for dehydration of the tertiary alcohola
By-
Temperature/ Yieldb
productc
(%)
Entry Reagent
Solvent
time
(%)
1
2
3
4
5
6
7
8
9d
BBr3
DCM
DCM
0 °C/30 min
rt/3 h
72
—
71
15
—
21
—
—
—
—
—
<2
Scheme 2 Method explored according to Ritter’s paper.
TsOH·H2O
TsOH·H2O
H2SO4
HCl
MsCl/Et3N
MsCl/Py
Toluene 100 °C/1 h
Dioxane 100 °C/2 h
Dioxane 100 °C/2 h
DCM
DCM
Messy
Messy
Very little
Very little
Very little
85
to 3a. The hypothesis was further proven that 1a could be
directly converted to 3a using Selectfluor (Scheme 2).
rt/18 h
rt/18 h
rt/18 h
rt/18 h
The transformation from benzo[b]furan 1a to 3a was well
(CF3SO2)2O DCM
SOCl2/Py DCM
adapted to
a variety of oxygen nucleophiles, including
a The reactions were run on the 0.3 mmol scale, 3d was about 90%
purity. b Isolated yield. c NMR yield. d This experiment has been carried
out for three trials.
different alcohols and even water (3d), as shown in Table 1.
Interestingly, a spiroacetal structure (3f) was obtained through
intramolecular nucleophilic addition if a tethered oxygen
nucleophile was present. Other nucleophiles, such as
PhCOOH, BnNH2 and CH3NH2, have also been investigated;
however, the desired products were not observed.
SOCl2/Py conditions was very clean with a satisfactory yield of
fluorinated benzo[b]furan 2.
Fluorinations of indoles have been reported in recent
years.20 With Selectfluor, indoles can be either monofluori-
nated21 or difluorinated.22 Unlike the indoles, benzo[b]furans
cannot be difluorinated, even with two or more equivalents of
Selectfluor. In addition, benzofuran cannot be monofluori-
nated in the absence of water or other nucleophiles.
To obtain the desired fluorinated benzo[b]furans, we
further investigated the conditions for dehydration of the ter-
tiary alcohol (Table 2). BBr3 (entry 1) could successfully
perform the dehydration in 72% yield, while other acids, such
as TsOH·H2O, H2SO4, and HCl (entries 2–5), led to various by-
products with the formation of 2 in poor yields. Therefore, we
explored basic conditions to remove the tertiary alcohols, such
as MsCl/Et3N, MsCl/Py, (CF3SO2)2O/Py, and SOCl2/Py. To our
delight, the dehydration of the tertiary alcohol under the
Subsequently, the reaction was further investigated by
screening various parameters (Table 3). The results indicated
that the choice of solvent, the amount of H2O and the tempe-
rature were important for the yield of 2a. The best solvent for
this reaction was MeCN, while other solvents, such as DMF,
acetone, DMSO and DCM, gave unsatisfactory yields. The
optimal ratio of MeCN–H2O is 20 : 1. In our experience, more
water led to poor solubility of 1a, while a lesser amount of
water made the reaction to slow down. To avoid considerable
side reactions, the best temperature for the reaction was 25 °C.
We next examined the reaction scope. As shown in Table 4,
various 2-arylbenzo[b]furans substituted with both electron-
Table 3 Optimization of the reaction of 2-(4-methoxyphenyl)benzo-
furan (1a) with Selectfluora
Table 1 Fluorination of 1a using alcohols and water as nucleophilesa,b
Entry
H2O
Solvent
Temperature/time
Yieldb (%)
1
2
3
4
—
1 equiv.
3 equiv.
5 equiv.
1/20 solvent
1/20 solvent
1/4 solvent
1/20 solvent
1/20 solvent
1/20 solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
25 °C/2 h
25 °C/2 h
25 °C/2 h
25 °C/2 h
0 °C/1 h
25 °C/1 h
25 °C/1 h
25 °C/5 h
25 °C/5 h
25 °C/5 h
<10c
52
62
65
56
87
75
25
42
48
5
6d
7
8
9
10
DMF
Acetone
a Reaction conditions: 1a (0.2 mmol), Selectfluor (1.1 equiv.), solvent
a The reaction was run on the 0.5 mmol scale under air. For details, (2 mL), 3d was about 90% purity. b Isolated yield. c NMR yield. d This
see the ESI. b Isolated yield. c 1.0 eq. NaHCO3 was added.
experiment has been carried out for three trials.
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Table 4 Scope of the 3-fluorination of 2-substituted benzo[b]furansa,b
Table 5 Difluorination of 2a using alcohols as nucleophilesa,b
a Reaction conditions: 2a (0.5 mmol), Selectfluor (0.55 mmol, 1.1 eq.),
MeCN–ROH = (8 mL–0.4 mL), 2 h. b Isolated yields.
Finally, 3,3-difluorobenzofurans were investigated using the
same protocol, and the desired 3,3-difluorobenzo[b]furans
were also produced in satisfactory yields (Table 5).
Conclusions
In summary, we have developed an efficient method for the
synthesis of 3-F-substituted 2-arylbenzo[b]furans. In this
method, the benzo[b]furan ring was fluorinated with high
regioselectivity at the C3 carbon with Selectfluor. In addition,
the mild conditions and practical convenience would make it a
valuable synthetic tool to enrich structural diversity in organic
chemistry. The biological evaluation of these novel compounds
is underway in our laboratory and will be reported in due
course.
a The reaction was run on the 0.5 mmol scale under air. For details,
see the ESI. b Isolated yield. c Scale up reaction was run on the
10 mmol scale.
donating and electron-withdrawing functional groups (e.g.,
ether, halogen, ester, CF3) were applied to the reaction. Most
of the reaction intermediates could not be purified by silica
gel chromatography, most likely due to the instability of the
tertiary alcohol under the acidic silica gel conditions. There-
fore, the tertiary alcohol generated from the first step was
directly removed under the basic conditions to afford the
corresponding 3-fluorinated benzo[b]furans. The total yields
ranged from 43% to 78%, as shown in Table 4.
Based on the results above, the mechanism of this trans-
formation is proposed (Scheme 3). Initially, reaction of 1 with
Selectfluor yields the unstable cation 3-A, which is then
attacked by water to form 3-B. After deprotonation, 3 is sub-
jected to chlorination and elimination to give benzo[b]furan 2.
Acknowledgements
The authors gratefully acknowledge the National Natural
Science Foundation of China (no. 81373276) and the Shanghai
Municipal Committee of Science and Technology
(14XD1400300) for financial support. We also thank Professor
Ran Hong (Shanghai Institute of Organic Chemistry, CAS) for
helpful discussions.
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