Fluorination of flavones and chromones using elemental fluorine

Article abstract of DOI:10.1021/jo5009542

Flavonoids are abundant micronutrients in our diet, possessing various biological activities. Fluorine was successfully added across the double bond of various flavones and chromones. The difluoro derivative products were easily dehydrofluorinated to form

Full text of DOI:10.1021/jo5009542

Article
pubs.acs.org/joc
Fluorination of Flavones and Chromones Using Elemental Fluorine
Inna Vints and Shlomo Rozen*
School of Chemistry, Tel-Aviv University, Tel-Aviv 69978, Israel
*
S Supporting Information
ABSTRACT: Flavonoids are abundant micronutrients in our
diet, possessing various biological activities. Fluorine was
successfully added across the double bond of various flavones
and chromones. The difluoro derivative products were easily
dehydrofluorinated to form the corresponding 3-fluoroflavones
and 3-fluorochromones.
INTRODUCTION
employed for activation of “impossible” sites of organic
molecules by the unique electrophilic “front side” substitution
■
Introducing the fluorine atom into organic molecules is
important since quite frequently such compounds possess
unique physical, chemical, and biological properties. They also
play a significant role in drug development because fluorinated
bioactive molecules can have significantly higher chances of
becoming drug candidates and eventually drugs. Many such
compounds made with [18]F are also valuable for positron
emission tomography (PET). No wonder there is an ever-
3
17
of remote tertiary sp CH bonds, by adding it across some
1
8
19
simple olefins and acetylenes, or by using it for creating
20
secondary useful reagents such as acetyl hypofluorite, HOF·
CH CN, MeOF, halogen fluorides, BrF3, and much
21
22
23
24
3
1
,2
more. We present here yet another use of this element for one-
step general and efficient synthesis of fluoroflavones and
fluorochromones from the parent flavonoids.
2
3
increasing demand for new and selective methods for
preparation of organic materials containing one or more
fluorine atoms.
RESULTS AND DISCUSSION
■
Adding chlorine and bromine across various double bonds is a
process almost as old as organic chemistry itself. Adding
fluorine to olefins, however, has almost no precedence. We
concluded from our only work on the reaction of F with some
simple double bonds that there are two main reasons for this
situation. The first reason is the very high enthalpy of any
reaction between a double bond and F . This issue could be
addressed by using quite diluted F2 and conducting the
reactions at low temperatures. The second reason is the low
polarizability and the weak bond between the two fluorine
atoms encouraging non specific radical reactions. In order to
decrease the chances of following such routes, one has to offer a
relatively polar solvent (see details in the Experimental
Section). If, however, the polarity is too high, fluorine seems
to leave the reaction vessel unreacted probably because of its
complete insolubility. We found that a mixture of very nonpolar
Flavones and chromones occur in many different plants and
4
are abundant in our diet, having numerous health effects such
5
as a decreased risk of cardiovascular diseases and are6
2
efficacious in the treatment of chronic inflammatory pain
7
8
and in anticancer activities. They also exhibit antiviral activity,
9
10
serve as antioxidants and anti-HIV agents,
act as
2
1
1
bactericidals, and much more. Studies indicate, however,
that many such compounds can last in the body for only about
0 h before they are metabolized.
Naturally, an efficient synthesis of fluoroflavones and
12
1
chromones is very desirable since there is a good chance they
would outperform the natural starting materials. What’s more,
because numerous fluoro derivatives have proven to be more
stable toward metabolic decomposition, it is reasonable to
assume that this might also be the case here. This led to several
attempts to prepare 3-fluoroflavones and 3-fluorochromones,
but usually the results were obtained by several indirect
methods. Some have used a total synthesis approach requiring
solvents such as CFCl and chloroform gives better results than
3
one of these solvents alone, but what has even a better effect is
the addition of ethanol in various proportions. This solvents’
25
1
3,14
combination increases solubility, and the EtOH serves as a
good acceptor for the negative pole of the F−F molecule.
Generally speaking, addition of too much alcohol prevented the
reaction from taking its desirable course, and most of the
substrate remains unreacted as fluorine escapes the reaction
vessel without doing much. Too little ethanol, however, allows
formation of fluorine radicals that destroy slowly the organic
α-hydroxy acetophenone derivatives
or condensation
between aldehydes and dimethylanilines containing a difluoro-
1
5
chloro moiety. A different approach was taken by Fuchigami,
who electrochemically fluorinated some flavones with Et N·
3
16
3
HF or Et NF·4HF. In most cases, the yields were quite low
4
and the synthetic routes not of general nature. The reasons
these methods were so indirect were in part the unjustified fears
associated with elemental fluorine (even though diluted) and
the readiness to take extra steps to avoid working with it.
We have been using nitrogen-diluted fluorine for many types
of reactions without any problems for years. It was successfully
18
substrate.
Received: May 1, 2014
Published: June 2, 2014
©
2014 American Chemical Society
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The Journal of Organic Chemistry
Article
The addition of fluorine to flavonoids presents yet another
challenge. These compounds possess a unique double bond.
On one hand, it is a conjugated enone, which naturally is less
reactive than an isolated double bond, while on the other hand,
it is an enol derivative making it quite sensitive to ring-opening
forming potentially α-fluorocarbonyl moieties. These two
opposing effects must be balanced, something which could be
achieved mainly through varying the alcohol concentration in
the solvent mixture.
It is of interest to compare this to the addition mechanism. A
well-known fact concerning the reaction of most members of
the halogen family with double bonds is the anti mode addition.
With fluorine, however, the situation is reversed. It is a small
atom which cannot form a bridged fluoronium ion as is the case
with the other halogens. It is bound to create a transition cage
containing a fluoride and the extremely unstable α-fluoro
carbonium ion. The two ions in this cage collapse rapidly
before the fluoride has a chance to move toward the opposite
face of the ring, resulting in the syn addition (Scheme 1). It
should be emphasized that a four center addition of moieties
containing electrophilic fluorine to the π system of the olefin
When diluted fluorine (7−10% F in N ) was bubbled slowly
2
2
through a cold (−78 °C) and well-stirred solution of flavone 1a
in a mixture of CHCl /CFCl /EtOH (usually in 5:4:1 ratio),
3
3
16
28
cis-2,3-difluoro-4-flavanone (2a) was formed in 76% yield
Scheme 1). The cis configuration is revealed by the J
had been discredited in the past.
2
(
The difluorinated product 2a was easily dehydrofluorinated
HF
16
to 3-fluoroflavone (3a) in higher than 90% yield, simply by
adsorbing it on a silica gel column. HF elimination occurred
readily due to the anti configuration of the two atoms.
Dehydrofluorination of 2b on silica-gel similarly led to a
Scheme 1. Fluorination of Flavones
16
formation of 3-fluoro-6-chloroflavone (3b) in 95% yield. The
dehydrofluorination of cis-2,3-difluoro-6-acetoxy-4-flavanone
(
2c), however, could not be conveniently carried on silica
since part of the acetate was simultaneously hydrolyzed.
Nevertheless, dehydrofluorination could be achieved by treating
2
c with BF ·OEt2 for about 3 h to produce 3-fluoro-6-
3
acetoxyflavone (3c) in 85% yield. The difluoro diacetoxy
flavonoid 2d, which as mentioned above was not isolated in
analytical purity, was also treated with BF ·OEt which after
3
2
three hours caused dehydrofluorination, but this time the
acetoxy group at 5 was also hydrolyzed forming 3-fluoro-5-
hydroxy-7-acetoxyflavone (3e) in 49% yield (based on 1d).
When the same crude 2d was slowly passed through a silica
chromatographic column using petroleum ether/EtOAc (as
with 2a and 2b) it formed a complicated mixture. If however,
2d was fast eluted, it did result, as anticipated, in a complete
dehydrofluorination, and without affecting any of the acetate
groups thus obtaining the diacetoxy fluoroflavone 3d in 63%
overall yield based on the starting flavone 1d.
Chromones were treated with fluorine as well. The basic
chromone 4a formed a mixture of difluorinated product 5a and
6a, the latter as a result of partial spontaneous HF elimination.
To complete the elimination, the mixture was absorbed on
29
silica gel leading eventually to 3-fluorochromone (6a) in
overall yield of 75% (Scheme 2).
2
,3-Difluoro-6-bromo-4-chromanone (5b) and 2,3,6-tri-
a
b
fluoro-4-chromanone (5c) were made by adding F to the
corresponding 6-bromo- and 6-fluorochromones 4b and 4c in
Not analytically purified. Yield based on the starting flavone 1d.
2
8
0%, and 82% yield (GC), respectively. They were not isolated
in analytical purity but dehydrofluorinated by flash chromatog-
raphy to provide 3-fluoro-6-bromochromone (6b) and 3,6-
difluorochromone (6c) almost quantitatively. The fluorination
coupling constants of 46 Hz and 3JHF of 28 Hz, in accordance
with the H−C−C−F dihedral angle of about 60°. In addition,
the J coupling constant of 15 Hz is in line with the gauche
with F was also successful when the double bond was
2
FF
conformation. Similar results were obtained when 6-chloro-
trisubstituted as in 3-methylchromone (4d), which formed 2,3-
difluoro-3-methyl-4-chromanone (5d) in 65% yield. When the
fluorination reaction was performed under the standard
conditions described above on derivatives possessing an
electron-withdrawing group attached to the double bond as
in 3-bromochromone (4e), the conversion did not exceed 60%
and the yield of 2,3-difluoro-3-bromo-4-chromanone (5e) was
only 36%. In order to improve the outcome of the reaction, the
amount of the ethanol had to be significantly reduced until a
full conversion and 64% yield of 5e was achieved. In the last
two cases (5d and 5e), neither silica gel nor BF ·OEt could
flavone (1b) was reacted with fluorine, forming cis-2,3-difluoro-
16
6
-chloro-4-flavanone (2b) in 70% yield. Flavones containing
the phenolic moiety did not usually react cleanly with fluorine,
but the situation improved when the hydroxyl groups were
2
6
acetylated. Thus, 6-acetoxyflavone (1c) reacted with
elemental fluorine to form the desired cis-2,3-difluoro-6-
acetoxy-4-flavanone (2c) in 65% yield, and the 5,7-diacetoxy-
2
7
flavone (1d) produced the cis-2,3-difluoro-5,7-diacetoxy-4-
flavanone 2d in about 70% yield, although it was not isolated in
analytical purity and was reacted as is in the planned
consecutive step (see below).
3
2
induce dehydrofluorination since the proton α to etheric
7
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The Journal of Organic Chemistry
Article
derivative was dissolved in benzene and cooled to about 10 °C. Excess
BF ·OEt was added in one portion, and the reaction mixture allowed
Scheme 2. Fluorination of Chromones
3
2
to warm to room temperature and stirred for an additional 3 h. Cold
diluted HCl solution was added, and the organic layer washed with
bicarbonate and worked up as usual. The resulting enones were usually
recrystallized. (B) HF elimination was achieved simply by adsorbing
the crude difluorinated product on a silica gel column (60-H, Merck)
and eluted the organic substances with various proportions of
petroleum ether/EtOAc.
1
6
2
,3-Difluoro-4-flavanone (2a) was prepared from flavone (1a)
(
°
0.76 g, 3.4 mmol) as described above: off-white solid; mp 108−109
1
C (0.68 g, 76% yield); H NMR 7.98 (dd, J = 7.8 Hz, J = 1.3 Hz, 1
1
2
H), 7.73−7.71 (m, 2 H), 7.65 (t, J = 7.7 Hz, 1 H), 7.53−7.52 (m, 3
H), 7.27−7.23 (m, 1 H), 7.16 (d, J = 8.3 Hz, 1 H), 5.45 (dd, J = 28.0
1
13
Hz, J = 45.6 Hz, 1 H); C NMR 185.9 (d, J = 16.4 Hz), 156.3, 137.5,
2
1
1
34.1 (d, J = 25.5 Hz), 130.7, 128.8, 127.2, 126.1 (d, J = 6.7 Hz),
24.1, 119.7, 118.5, 113.9 (dd, J = 22.3 Hz, J = 236.8 Hz), 90.4 (dd,
1
2
19
J = 33.4 Hz, J = 203.0 Hz); F NMR −129.1 (dd, J = 28.1 Hz, J =
1
1
2
1
2
5.3 Hz), −212.8 (dd, J = 45.5 Hz, J = 16.0 Hz).
1
2
16
3
-Fluoroflavone (3a). Compound 2a was flash chromatographed
resulting in a pale yellow solid, mp 85−86 °C (0.57 g, 92% yield).
1
6
2
,3-Difluoro-6-chloro-4-flavanone (2b) was prepared from 6-
chloroflavone (1b) (0.72 g, 2.8 mmol) as described above: white solid;
mp 157−159 °C (0.58 g, 70% yield).
1
6
3
-Fluoro-6-chloroflavone (3b). Compound 2b was flash
chromatographed resulting in a white solid: mp 169−172 °C (0.51
oxygen is not acidic enough, and harsh conditions such as
g, 95% yield).
2
6
30
6
-Acetoxyflavone (1c) was prepared by reacting a solution of 6-
prolonged treatment with NaOH resulted in destruction of
the molecule so at the present we were unable to induce HF
elimination in such cases.
hydroxyflavone (1.30 g, 5.5 mmol) in pyridine with acetic anhydride,
and the mixture was stirred overnight: white solid; mp 157−158 °C
(
1.01 g, 66% yield).
2
7
5
,7-Diacetoxyflavone (1d) was prepared in a similar manner (as
EXPERIMENTAL SECTION
H NMR spectra were recorded using a 400 MHz spectrometer with
■
for 1c) using chrysin (1.27 g, 5.0 mmol) as a starting material: white
solid; mp 203−205 °C (1.5 g, 88% yield).
1
19
CDCl as a solvent and Me Si as an internal standard. The F NMR
3
4
2,3-Difluoro-6-acetoxy-4-flavanone (2c) was prepared from 6-
acetoxyflavone (1c) (0.43 g, 1.5 mmol) as described above: white
spectra were measured at 376.8 MHz with CFCl serving as an internal
3
standard. The proton broadband-decoupled 13C NMR spectra were
1
solid; mp 148−149 °C (0.32 g, 65% yield); H NMR 7.71−7.69 (m, 2
recorded at 100.5 MHz. Here, too, CDCl served as a solvent and
3
H), 7.68 (d, J = 2.8 Hz, 1 H), 7.52−7.53 (m, 3 H), 7.37 (dd, J = 8.9
1
Me Si as an internal standard. IR spectra were recorded with an FTIR
4
Hz, J = 2.8 Hz, 1 H), 7.18 (d, J = 8.9 Hz, 1 H), 5.44 (dd, J = 28.0 Hz,
2
1
ATR spectrometer. MS were measured with a Q-TOF (synapt) mass
analyzer.
13
J2 = 45.5 Hz, 1 H), 2.33 (s, 3 H); C NMR 185.2 (d, J = 16.9 Hz),
69.4, 153.8, 146.7, 133.8 (d, J = 25.2 Hz), 131.0, 130.8, 128.8, 126.1
d, J = 6.6 Hz), 120.2, 119.7, 119.6, 114.0 (dd, J = 21.9 Hz, J = 237.5
1
(
General Fluorination Procedure. Fluorine is a strong oxidant
and corrosive material. In organic chemistry, it is used after dilution
with nitrogen or helium (generally from 1−20% depending on the
reaction type). Such dilution can be achieved by using either an
appropriate copper or monel vacuum line or by purchasing prediluted
fluorine. A detailed description of a simple setup appeared in the
1
2
19
Hz), 90.4 (dd, J = 33.1 Hz, J = 203.1 Hz), 21.1; F NMR −129.1
1
2
(
dd, J = 28.1 Hz, J = 15.2 Hz), −213.2 (dd, J = 45.4 Hz, J = 15.8
1
2
1
2
Hz); HRMS with atmospheric solid analysis probe (ASAP) m/z calcd
+
for C H F O 319.0782 (M + H) , found 319.0779; IR 1759, 1719
1
7
12
2
4
−
1
31
cm . Anal. Calcd for C17
H F O : C, 64.15; H, 3.80; F, 11.94. Found:
12 2 4
previous literature. The reactions themselves are carried out in
C, 63.86; H, 3.49; F, 12.27.
3-Fluoro-6-acetoxyflavone (3c) was formed by treating 2c with
standard glassware. If elementary precautions are taken, work with F
2
32
(which is less toxic than chlorine ) proceeds smoothly, and we have
1
BF ·OEt : white solid; mp 184−185 °C (0.25 g, 85% yield); H NMR
3
2
had no bad experience working with it. Still, the work with this reagent
requires a well-ventilated area and good common sense as thousands
of other reagents in chemistry do.
The reactions were usually carried out on scales of 1−5 mmol
flavone or chromone derivatives, monitored by TLC, GC, or NMR.
The starting flavones and chromones are commercially available, and
we have acetylated the hydroxyl groups where relevant. Fluorine, at
8
.04−8.01 (m, 2 H), 7.99 (d, J = 2.7 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1
H), 7.58−7.56 (m, 3 H), 7.48 (dd, J = 9.1 Hz, J = 2.8 Hz, 1 H), 2.36
1
2
(
2
s, 3 H); 13C NMR 170.4 (d, J = 16.9 Hz), 169.3, 152.8, 151.3 (d, J =
4.2 Hz), 147.7, 146.2 (d, J = 248.8 Hz), 131.8, 129.1, 128.8 (d, J = 4.9
Hz), 128.5, 128.3 (d, J = 7.7 Hz), 125.2 (d, J = 7.5 Hz), 119.7, 118.0
d, J = 3.2 Hz), 21.1; 19F NMR −161.5; HRMS (ASAP) m/z calcd for
(
+
−1
C H FO 299.0720 (M + H) , found 299.0725; IR 1764, 1645 cm .
concentrations of 7−10% in N , was slowly passed through a cold
17 11
4
2
Anal. Calcd for C H FO : F, 6.37. Found: F, 6.07.
(
−78 °C) and vigorously stirred solution of the enone dissolved in 100
17 11
4
3
-Fluoro-5,7-diacetoxyflavone (3d) was prepared from 2,3-
mL of CFCl , 125 mL of CHCl , and 25 mL of EtOH. An efficient
3
3
difluoro-5,7-diacetoxyflavone (2d) whose stability did not permit
analytical purification and therefore was used immediately upon
formation from 1d (0.58 g, 1.7 mmol) as described above. Compound
mixing was achieved by using a vibromixer, which also ensured a fine
dispersion of the gas bubbles. In most cases, the reactions were
completed within 1.5−4 h. They were terminated by pouring into 200
3
d (0.38 g) is a white solid, mp 205−207 °C, 63% yield based on 1d;
mL water, washing the organic layer with NaHCO solution followed
3
1
H NMR 7.98−7.96 (m, 2 H), 7.57−7.55 (m, 3 H), 7.38 (d, J = 2.1
Hz, 1 H), 6.88 (d, J = 1.9 Hz, 1 H), 2.47 (s, 3 H), 2.36 (s, 3 H); C
by water until neutral, drying the organic layer over MgSO , and finally
4
1
3
evaporating the solvent. The crude product was usually purified by
vacuum flash chromatography using silica gel with various proportions
of petroleum ether/EtOAc as eluent or by recrystallization.
Dehydrofluorination Procedures. Two methods were employed
for the described HF elimination. (A) The corresponding fluoro
NMR 169.6, 169.3 (d, J = 18.4 Hz), 168.0, 156.7, 154.4, 150.6 (d, J =
2.7 Hz), 150.3(d, J = 25.0 Hz), 146.3 (d, J = 247.3 Hz), 131.9, 129.1,
128.4 (d, J = 5.5 Hz), 128.1 (d, J = 7.6 Hz), 115.4 (d, J = 6.3 Hz),
113.9, 109.2, 21.3, 21.2; 19F NMR −161.6; HRMS (ESI) m/z calcd for
7
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The Journal of Organic Chemistry
Article
+
1
C H FO 379.0594 (M + Na) , found 379.0596; IR 1768, 1649
64% yield); H NMR 8.01 (dd, J = 7.8 Hz, J = 1.7 Hz, 1 H), 7.69−
1
9
13
6
1
2
−
1
cm .
-Fluoro-5-hydroxy-7-acetoxyflavone (3e) was formed by treating
the crude 2d with BF ·OEt . The determination of which acetate was
hydrolyzed was made by comparing H NMR spectra of 3d and 3e.
Hydrolysis of acetate in position 5 did not affect the aromatic
hydrogen in position 8, and the methyl of the acetate in this position
7.65 (m, 1 H), 7.29−7.25 (m, 1 H), 7.13 (dd, J = 8.4 Hz, J = 0.6 Hz, 1
1
2
3
H), 6.29 (d, J = 53.8 Hz, 1 H); 13C NMR 179.9 (d, J = 20.0 Hz),
154.3, 138.1, 128.3 (d, J = 1.5 Hz), 124.7, 118.6, 117.5, 108.0 (dd, J =
239.6 Hz, J = 28.0 Hz), 91.0 (dd, J = 277.0 Hz, J = 33.2 Hz);
NMR −138.3 (dd, J = 54.0 Hz, J = 17.6 Hz), −147.6 (d, J = 17.6
Hz); HRMS (ASAP) m/z calcd for C H BrF O 262.9519 (M + H) ,
found 262.9524; IR 1718 cm . Anal. Calcd for C H BrF O : C, 41.10;
H, 1.92; F, 14.45. Found: C, 40.86; H, 2.11; F, 14.64.
3
2
1
1
19
F
2
1
2
1
2
+
9
5
2
2
1
−1
disappeared: beige solid; mp 184−186 °C (0.26 g, 49% yield); H
9 5 2 2
NMR 8.00−7.98 (m, 2 H), 7.58−7.56 (m, 3 H), 6.89 (d, J = 2.0 Hz, 1
H), 6.61 (d, J = 2.0 Hz, 1 H), 2.34 (s, 3 H); 13C NMR 174.9 (d, J =
1
7.6 Hz), 168.4, 161.9 (d, J = 3.0 Hz), 156.5, 155.8, 152.2 (d, J = 23.3
ASSOCIATED CONTENT
■
Hz), 144.6 (d, J = 248.9 Hz), 132.2 (d, J = 1.3 Hz), 129.2, 128.3 (d, J =
.8 Hz), 109.5 (d, J = 6.4 Hz), 105.5, 101.4, 21.3; 19F NMR −163.7;
*
S
Supporting Information
7
1
H, C, and 19F NMR spectra and GC data. This material is
13
+
HRMS (ESI) m/z calcd for C H FO 337.0488 (M + Na) , found
1
7
11
5
−
1
337.0486; IR 1767, 1651 cm .
available free of charge via the Internet at http://pubs.acs.org
29
3
-Fluorochromone (6a) was prepared from chromone (4a) (0.69
g, 4.7 mmol) as described above: white solid; mp 138−140 °C (0.58 g,
AUTHOR INFORMATION
Corresponding Author
*Tel: 972-3-6408378. Fax: 972-3-6409293. E-mail: rozens@
post.tau.ac.il.
1
■
7
5% yield); H NMR 8.30 (dd, J = 8.0 Hz, J = 1.3 Hz, 1 H), 8.16 (d,
1 2
J = 3.4 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H),
.44 (t, J = 7.6 Hz, 1 H); 13C NMR 170.7 (d, J = 15.6 Hz), 156.0,
49.5 (d, J = 248.9 Hz), 143.0 (d, J = 39.9 Hz), 134.2, 126.2, 125.4,
7
1
1
25.0 (d, J = 7.6 Hz), 118.5; 19F NMR −166.2; HRMS (ASAP) m/z
Notes
+
calcd for C H FO 165.0352 (M + H) , found 165.0357; IR 1652
9
5
2
The authors declare no competing financial interest.
−1
cm .
,3-Difluoro-6-bromo-4-chromanone (5b) was prepared from 6-
2
ACKNOWLEDGMENTS
bromochromone (4b) (0.81 g, 3.6 mmol) as described above. A crude
oil containing the product in 80% yield (GC, 0.76 g) was immediately
characterized without any purification since it tends to eliminate HF
spontaneously: HRMS (ASAP) m/z calcd for C H BrF O 262.9519
■
This work was supported by the Israel Science Foundation.
9
5
2
2
REFERENCES
+
■
(
M + H) , found 262.9515.
-Fluoro-6-bromochromone (6b) was prepared from 5b (0.81 g,
(
1) (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305−321.
3
(
b) Smart, B. E. J. Fluorine Chem. 2001, 109, 3−11.
3
.6 mmol) as described above: white solid; mp 163 °C dec (0.66 g,
1
(2) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−1886.
̈
95% yield); H NMR 8.43 (d, J = 2.4 Hz, 1 H), 8.16 (d, J = 3.3 Hz, 1
13
(3) See, for example: (a) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A.
H), 7.79 (dd, J = 8.9, J = 2.4 Hz, 1 H), 7.42 (d, J = 8.9 Hz, 1 H);
C
1
2
D. Angew. Chem. 2008, 47, 8998−9033. (b) Tredwell, M.; Gouverneur,
NMR 169.4 (d, J = 14.3 Hz), 154.7, 149.5 (d, J = 250.5 Hz), 143.3 (d,
J = 40.0 Hz),137.3, 128.7 (d, J = 3.2 Hz), 126.3 (d, J = 8.1 Hz), 120.5,
V. Angew. Chem. 2012, 51, 11426−11437.
19.1; 19F NMR −165.3; HRMS (ASAP) m/z calcd for C H BrFO
+ −1
(
́ ́ ́
4) Manach, C.; Scalbert, A.; Morand, C.; Remesy, C.; Jimenez, L.
1
2
9
4
2
Am. J. Clin. Nutr. 2004, 79, 727−747.
5) Testai, L.; Martelli, A.; Cristofaro, M.; Breschi, M. C.; Calderone,
V. J. Pharm. Pharmacol. 2013, 65, 750−756.
6) (a) Bryan, M. C.; Biswas, K.; Peterkin, T. A. N.; Rzasa, R. M.;
42.9457 (M + H) , found 242.9453; IR 1651 cm . Anal. Calcd for
(
C H BrFO : F, 7.82. Found: F, 7.95.
9
4
2
2
,3,6-Trifluoro-4-chromanone (5c) was prepared from 6-fluoro-
(
chromone (4c) (0.75 g, 4.6 mmol) as described above. A crude oil
containing the product in 82% yield (GC, 0.76 g) was immediately
characterized without any purification since it tends to eliminate HF
spontaneously: HRMS (ASAP) m/z calcd for C H F O 203.0320 (M
Arik, L.; Lehto, S. G.; Sun, H.; Hsieh, F. Y.; Xu, C.; Fremeau, R. T.;
Allen, J. R. Bioorg. Med. Chem. Lett. 2012, 22, 619−622. (b) Williams,
D. A.; Zaidi, S. A.; Zhang, Y. Bioorg. Med. Chem. Lett. 2014, 24, 1489−
1492.
9
5
3
2
+
+
H) , found 203.0322.
3
,6-Difluorochromone (6c) was prepared from 5c (0.75 g, 4.6
(7) (a) Kosmider, B.; Osiecka, R. Drug Dev. Res. 2004, 63, 200−211.
(b) Raj, T.; Bhatia, R. K.; Kapur, A.; Sharma, M.; Saxena, A. K.; Ishar,
M. P. Eur. J. Med. Chem. 2010, 45, 790−794.
mmol) as described above: white solid; mp 170−172 °C (0.67 g, 98%
yield); H NMR 8.17 (d, J = 3.3 Hz, 1 H), 7.93 (dd, J = 8.1 Hz, J =
.1 Hz, 1 H), 7.55−7.52 (m, 1H), 7.47−7.42 (m, 1H); C NMR
69.8 (dd, J = 16.0 Hz, J = 2.3 Hz), 159.7 (d, J = 247.9 Hz), 152.2,
49.2 (dd, J = 249.0 Hz, J = 1.6 Hz),143.3 (d, J = 40.0 Hz), 126.3 (t,
J = 8.1 Hz), 122.7 (d, J = 25.7 Hz), 120.7 (d, J = 8.3 Hz), 111.0 (dd, J
1
1
2
13
3
1
1
́ ́
(8) Sanchez, I.; Gomez-Garibay, F.; Taboada, J.; Ruiz, B. H.
Phytother. Res. 2000, 14, 89−92.
(9) Grassmann, J.; Hippeli, S.; Elstner, E. F. Plant Physiol. Biochem.
2002, 40, 471.
1
2
1
2
1
19
=
24.2 Hz, J = 3.8 Hz); F NMR −115.0, −166.6; HRMS (ESI) m/z
(10) (a) Houghton, P. J.; Woldemariam, T. Z.; Khan, A. I.; Burke, A.;
Mahmood, N. Antiviral Res. 1994, 25, 235−44. (b) Wrigley, S. K.;
Latif, M. A.; Gibson, T. M.; Chicarelli, R. M. I.; Williams, D. H. Pure.
Appl. Chem. 1994, 66, 2383−2386. (c) Kaur, R.; Taheam, N.; Sharma,
A. K.; Kharb, R. Res. J. Pharm., Biol. Chem. Sci. 2013, 4, 79−96.
(11) Xu, H. X.; Lee, S. F. Phytother. Res. 2001, 15, 39−43.
(12) Halford, B. Chem. Eng. News 2013, Nov 18, 28.
(13) Bolos, J.; Gubert, S.; Anglada, L.; Planas, J. M.; Burgarolas, C.;
Castello, J. M.; Sacristan, A.; Ortiz, J. A. J. Med. Chem. 1996, 39, 2962−
2970.
2
+
calcd for C H F O 183.0258 (M + H) , found 183.0253; IR 1640
9
4
2
2
−
1
cm . Anal. Calcd for C H F O : C, 59.35; H, 2.21; F, 20.86. Found:
9
4
2
2
C, 58.96; H, 1.90; F, 20.98.
,3-Difluoro-3-methyl-4-chromanone (5d) was prepared from 3-
methylchromone (4d) (0.82 g, 3.6 mmol): white solid; mp 87−90 °C
2
1
(
0.62 g, 65% yield); H NMR 7.82 (d, J = 2.5 Hz, 1 H), 7.68 (d, J = 2.5
Hz, 1 H), 6.07 (dd, J = 52.9 Hz, J = 0.7 Hz, 1 H), 1.70 (dd, J = 21.4
Hz, J = 1.1 Hz, 1 H); C NMR 186.7 (d, J = 18.0 Hz), 149.5, 137.2,
29.9, 125.5 (d, J = 1.7 Hz), 124.8, 121.0 (d, J = 2.2 Hz), 109.2 (dd, J1
1
2
1
13
2
1
=
240.7 Hz, J = 27.9 Hz), 91.0 (dd, J = 198.0 Hz, J = 24.8 Hz), 19.1
(14) Menichincheri, M.; Ballinari, D.; Bargiotti, A.; Bonomini, L.;
Ceccarelli, W.; D’Alessio, R.; Fretta, A.; Moll, J.; Polucci, P.; Soncini,
C.; Tibolla, M.; Trosset, J. Y.; Vanotti, E. J. Med. Chem. 2004, 47,
6466−6475.
2
1
2
19
(
=
dd, J = 24.0 Hz, J = 4.7 Hz),; F NMR −145.2 (dd, J = 52.8 Hz, J
1
2
1
2
2
16.4 Hz), −178.3 (m); HRMS (ASAP) m/z calcd for C H Cl F O
10
6
2 2
+
−
1
2
66.9791 (M + H) , found 266.9787; IR 1720 cm . Anal. Calcd for
C H Cl F O : C, 44.98; H, 2.26; Cl, 26.55. Found: C, 45.04; H, 2.30;
́
(15) Medebielle, M.; Keirouz, R.; Okada, E.; Shibata, D.; Dolbier, W.
10
6
2
2
2
Cl, 26.48.
,3-Difluoro-3-bromo-4-chromanone (5e) was prepared from 3-
bromochromone (4e) (0.64 g, 2.8 mmol): colorless liquid (0.48 g,
R., Jr. Tetrahedron Lett. 2008, 49, 589−593.
(16) Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem. 1999, 64,
3346−3349.
2
7
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(
(
18) Rozen, S.; Brand, M. J. Org. Chem. 1986, 51, 3607−3611.
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(
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(
b) Rozen, S. Acc. Chem. Res. 2005, 38, 803−812.
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25) Fluorine is somewhat soluble in CFCl : Rozen, S.; Lerman, O. J.
3
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(
26) Senboku, H.; Yamauchi, Y.; Kobayashi, N.; Fukui, A.; Hara, S.
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(
(
27) Kumar, P. A. Int. J. Res. Ayurveda Pharm. 2010, 1, 225−233.
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5
(
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0, 4753−4758.
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56.
(
(
(
30) Lerman, O.; Rozen, S. J. Org. Chem. 1980, 45, 4122−4125.
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