Expedient chemoselective and catalyst-free synthesis of 3,3-difluorochroman-4-ones from o-hydroxyarylenaminones and Selectfluor

Article abstract of DOI:10.1016/j.cclet.2017.10.027

An expedient and mild strategy for the synthesis of unconventional 2-(dimethylamino)-3,3-difluorochroman-4-one derivatives from o-hydroxyarylenaminones and Selectfluor was developed at room temperature under catalyst-free conditions. This method showed excellent chemoselectivity and great functional groups tolerance.

Full text of DOI:10.1016/j.cclet.2017.10.027

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CCLET 4300 No. of Pages 4
Chinese Chemical Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Expedient chemoselective and catalyst-free synthesis of 3,
3-difluorochroman-4-ones from o-hydroxyarylenaminones and
Selectfluor
1
1
*
Jian Xu , Zhijie Kuang , Qiuling Song
Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, Xiamen 361021, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An expedient and mild strategy for the synthesis of unconventional 2-(dimethylamino)-3,3-
difluorochroman-4-one derivatives from o-hydroxyarylenaminones and Selectfluor was developed at
room temperature under catalyst-free conditions. This method showed excellent chemoselectivity and
great functional groups tolerance.
Received 5 September 2017
Received in revised form 2 October 2017
Accepted 23 October 2017
Available online xxx
© 2017 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Selectfluor
o-Hydroxyarylenaminones
Catalyst-free
Chroman-4-one
Fluorination reaction
Fluorine-contained compound
Molecules with chroman-4-one scaffold are not only ubiquitous
in natural products, but also essential nutrients for the human
body [1]. Moreover, they are also widely applied in pharmaceut-
icals, pigments and dyes [2]. Thus, the studies of these compounds’
syntheses [3] and modifications have attracted more and more
attentions. A variety of bioactive molecules, which are derived
from chroman-4-one, have been well applied in drugs (Fig. 1), such
as the new SIRT2 inhibitor [4], flavonones [5], and GPR119 [6]. It is
worthy to mention that flavonones can effectively prevent cell
degeneration and delay aging process and GPR119 shows agonist
activity.
Moreover, the studies of fluorine-contained compounds’
synthesis have become a field of great interest and great progress
has been made in fluorination reactions [7] among which
Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]
octane bis(tetrafluoroborate)) is the most frequently used fluori-
nation reagents. Reports about electrophilic and free radical
fluorinations, which employed Selectfluor as fluorine sources,
appeared frequently [8]. In 1996, Bolós’s group reported the
synthesis of 3-fluoro-4H-chromen-4-one from 1-fluoro-2,4,6-
trimethylpyridinium triflate (NFTP), which was an expensive
fluorine reagent (Scheme 1a) [9]. And in 2006, Shreeve’s group
obtained 1,1-difluorinated carbonyl compounds from enamines
and Selectfluor (Scheme 1b) [10]. Recently, synthesis of chromone
and its derivatives from o-hydroxyarylenaminones had attracted
considerable attention because of their simple operation and easily
accessible starting materials [11]. During this manuscript prepa-
ration, Yang and coworkers reported a base promoted cyclization
of o-hydroxyarylenaminones with Selectfluor to access 3, 3-
difluorochroman-4-ones [12]. Compared with their work, there are
several advantages of ours: 1) Without the additional of base, 2)
more wider substrate scope including disubstituted o-hydroxyar-
ylenaminone which was not accessed in yang’s report, 3) lower
Selectfluor loading. Therefore, we would like to report our progress
on the synthesis of difluorinated chromanones with Selectfluor as
a fluorine source (Scheme 1c).
Our initial studies were carried out with o-hydroxyarylenami-
none 1a and Selectfluor, and the mixture was stirred in toluene at
room temperature for about 9 h. To our delight, the desired product
2-(dimethylamino)-3,3-difluorochroman-4-one (2a) was obtained
in 73% yield (Table 1, entry 1). The structure of 2a was confirmed by
X-ray analysis (Fig. 2) (see Supporting information for details).
When the reaction time was shortened to 3 h, the yield was almost
kept untouched. To further improve the yield of 2a, various
solvents were tested (Table 1, entries 3–8). It turned out that
solvent affected the reaction greatly, and non-polar solvents
afforded much higher yields than polar ones. Polar solvents such as
DME, CH3CH, DMF could barely afforded any product (Table 1,
entries 4–6), however, non-polar solvents such as petroleum,
* Corresponding author.
E-mail addresses: qsong2002@gmail.com, qsong@hqu.edu.cn (Q. Song).
These two authors contributed equally to this work.
1
https://doi.org/10.1016/j.cclet.2017.10.027
1001-8417/© 2017 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: J. Xu, et al., Expedient chemoselective and catalyst-free synthesis of 3, 3-difluorochroman-4-ones from o-
hydroxyarylenaminones and Selectfluor, Chin. Chem. Lett. (2017), https://doi.org/10.1016/j.cclet.2017.10.027

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Table 1
Optimization of the reaction conditions.a
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Toluene
Toluene
DCM
DME
CH3CN
DMF
Petroleum
n-hexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
9
3
3
3
3
3
3
3
3
2
1
3
73
70
31
trace
trace
trace
75
Fig. 1. Pharmaceuticals derived from chroman-4-ones.
70
9
85(78)c
51
10
11
12d
hexane could gave 2a in acceptable yields (Table 1, entries 7 and 8).
To our delight, when cyclohexane was used as solvent, 2a could be
obtained in 85% yield (Table 1, entry 9). When the reaction time
was further shortened, the yield of 2a decreased significantly
(Table 1, entries 10 and 11). Other fluorine reagent, like NFSI, was
also tested in our reaction systems, unfortunately no desired
product was detected (Table 1, entry 12). By far, the optimal
reaction conditions were obtained as: 1a (1.0 equiv.) and
Selectfluor (2.3 equiv.) were stirred in cyclohexane (3 mL) at room
temperature for 3 h. And, typical experimental procedure was
below: To a 25 mL Schlenk tube, under a nitrogen atmosphere, was
added 0.20 mmol of o-hydroxyarylenaminone (1a) and 0.46 mmol
of Selectfluor (2.3 equiv.), then cyclohexane (3 mL) was added by
syringe. The reaction mixture was stirred violently at room
temperature until yellow emulsion to become clear, even colorless
(3–4 h generally needed). Then, the reaction mixture was filtered
by the sand core funnel. Subsequently, the filtrate was concentrat-
ed to dryness and purified by silica gel chromatography (silica gel,
PE: Et3N = 50:1, v/v) to afford the product 2a (36 mg, 78%) as a
white solid.
41
trace
a
all the reactions were carried out with 1a (1.0 equiv.), Selectfluor (2.3 equiv.) in
solvent (3 mL) under room temperature.
b
Determined by GC.
Isolated yield.
N-Fluorobenzenesulfonimide (2.3 equiv.) was used.
c
d
the ortho one giving the lowest yield, and the steric hindrance
might be the direct cause of the low yield of 2l. Polycyclic
substrates could also go through the cyclization and difluorination
process smoothly rendering 2m in 59% yield, and 2n in 92% yield.
Interestingly, when vinyl and alkynyl groups were placed on the
phenyl rings of the substrates, the desired products were also
successfully obtained (2o–2r). It’s worthy to note that both
terminal and internal unsaturated carbon-carbon bonds were well
compatible. Heterocyclic substituents, such as 3-thienyl, 2-thienyl
and 2-furyl, were also tolerated well under our reaction systems,
and the desired products were obtained in good to excellent yields
(2s–2u). The substituents on the nitrogen atom were also tested
(2v, 2w). When N, N-dimethyl group was replaced with pyrroli-
dinyl, the corresponding product 2v was obtained in 95% yield,
which was much higher than the yield of 2a. However, when
replaced with diisopropyl, the yield of 2w was decreased a little
compared with 2a. At last, when large steric hindered substrate 1x
was applied, the desired product 2x was only afforded in 23% yield.
Large scale experiment was also carried out with 1a (5 mmol)
and Selectfluor (11.5 mmol) under our standard reaction con-
ditions (Scheme 3). The reaction was completed in 6 h with 70% of
2a.
With the optimized conditions in hand, the scope of the
substrate was studied (Scheme 2). Substituents on the phenyl rings
had little effect on the yields of products, either electron-
withdrawing or electron-donating groups could go through the
reactions smoothly, and afforded the desired products in moderate
to high yields (2a–2k). However, the position of some substituents
on the phenyl rings has a great impact on the reaction (2j–2l) with
To gain a better understanding of the reaction process, several
control experiments were conducted (Scheme 4). When the
reaction was carried out in the presence of TMEPO (2.3 equiv.)
under our standard conditions, difluorinated product 2a could still
be isolated in 45% yield (Scheme 4a). Thus, we considered that the
Scheme 1. Reactions of fluorine reagents with arylenaminones.
Fig. 2. The X-ray crystallography of 2a.
Please cite this article in press as: J. Xu, et al., Expedient chemoselective and catalyst-free synthesis of 3, 3-difluorochroman-4-ones from o-
hydroxyarylenaminones and Selectfluor, Chin. Chem. Lett. (2017), https://doi.org/10.1016/j.cclet.2017.10.027

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3
Scheme 2. The scope of the substrates.
Scheme 3. Large scale experiment.
reaction could not proceed via single electron transfer (SET) radical
reaction mechanism. Next, substrates 1y and 1z were investigated
under the standard reaction conditions, and no desired products
were obtained, which illustrated the importance of amino groups
(Scheme 4b and c). So we deem that the reaction might go through
via iminium intermediate (Scheme 5). Meantime, it could also
explain why product 2x was only obtained in 23% yield, since the
presence of methyl group might hinder the formation of iminium
intermediate at a great extent [10]. At last, 3a was synthesized and
exposed to the standard conditions, however, no difluorinated
product was detected (Scheme 4d). The result illustrated that the
difluorination step went before the cyclization process (Scheme 5).
Scheme 5. Plausible mechanism.
Scheme 4. Control experiments.
Please cite this article in press as: J. Xu, et al., Expedient chemoselective and catalyst-free synthesis of 3, 3-difluorochroman-4-ones from o-
hydroxyarylenaminones and Selectfluor, Chin. Chem. Lett. (2017), https://doi.org/10.1016/j.cclet.2017.10.027

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J. Xu et al. / Chinese Chemical Letters xxx (2017) xxx–xxx
A proposed mechanism for the synthesis of 3, 3-difluorochro-
man-4-ones was shown in Scheme 5. It is deemed that species A
might exist in our reaction system, which could swiftly react with
the electrophilic Selectfluor, affording species B. Then, HBF4 is
released and affords intermediate C. Due to the electron
withdrawing character of fluorine, species D is easier to be
generated, which reacted with Selectfluor again and affords
species E. Intramolecular cyclization of E affords product 2a along
with the release of molecular HBF4.
In conclusion, a facile and gentle strategy for the synthesis of 3,
3-difluorochroman-4-ones from o-hydroxyarylenaminones and
Selectfluor was developed in our laboratory. The reaction
processed swiftly in cyclohexane at room temperature under
catalyst-free conditions and completed in 3 h. More importantly,
the products were obtained in moderate to high yields with
excellent chemselectivity. Various kinds of functional groups were
tolerated, especially vinyl and alkynyl groups, which were kept
untouched under standard conditions. The obtained difluorinated
products were useful and their applications were under studies in
our laboratory.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.cclet.2017.10.027.
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Financial support from the Recruitment Program of Global
Experts (1000 Talents Plan), the Natural Science Foundation of
Fujian Province (No. 2016J01064), Fujian Hundred Talents Plan,
Program of Innovative Research Team of Huaqiao University (No.
Z14X0047) and Subsidized Project for Cultivating Postgraduates’
Innovative Ability in Scientific Research of Huaqiao University (for
Z. Kuang) are gratefully acknowledged. We also thank the
Instrumental Analysis Center of Huaqiao University for analysis
support.
Please cite this article in press as: J. Xu, et al., Expedient chemoselective and catalyst-free synthesis of 3, 3-difluorochroman-4-ones from o-
hydroxyarylenaminones and Selectfluor, Chin. Chem. Lett. (2017), https://doi.org/10.1016/j.cclet.2017.10.027