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
Introducing the fluorine atom into organic molecules is
employed for activation of “impossible” sites of organic
molecules by the unique electrophilic “front side” substitution
important since quite frequently such compounds possess of remote tertiary sp3 CH bonds,17 by adding it across some
simple olefins18 and acetylenes,19 or by using it for creating
unique physical, chemical, and biological properties. They also
secondary useful reagents such as acetyl hypofluorite,20 HOF·
play a significant role in drug development because fluorinated
CH3CN,21 MeOF,22 halogen fluorides,23 BrF3,24 and much
bioactive molecules can have significantly higher chances of
more. We present here yet another use of this element for one-
becoming drug candidates and eventually drugs.1,2 Many such
step general and efficient synthesis of fluoroflavones and
compounds made with [18]F2 are also valuable for positron
fluorochromones from the parent flavonoids.

■
emission tomography (PET).3 No wonder there is an ever-
increasing demand for new and selective methods for
RESULTS AND DISCUSSION
preparation of organic materials containing one or more
fluorine atoms. Adding chlorine and bromine across various double bonds is a
Flavones and chromones occur in many different plants and process almost as old as organic chemistry itself. Adding
are abundant in our diet,4 having numerous health effects such fluorine to olefins, however, has almost no precedence. We
as a decreased risk of cardiovascular diseases5 and are concluded from our only work on the reaction of F2 with some
efficacious in the treatment of chronic inflammatory pain6 simple double bonds that there are two main reasons for this
and in anticancer activities.7 They also exhibit antiviral activity,8 situation. The first reason is the very high enthalpy of any
serve as antioxidants 9 and anti-HIV agents, 10 act as reaction between a double bond and F2. This issue could be
bactericidals,11 and much more. Studies indicate, however, addressed by using quite diluted F2 and conducting the
that many such compounds can last in the body for only about reactions at low temperatures. The second reason is the low
10 h before they are metabolized.12 polarizability and the weak bond between the two fluorine
Naturally, an efficient synthesis of fluoroflavones and atoms encouraging non specific radical reactions. In order to
chromones is very desirable since there is a good chance they decrease the chances of following such routes, one has to offer a
would outperform the natural starting materials. What’s more, relatively polar solvent (see details in the Experimental
because numerous fluoro derivatives have proven to be more Section). If, however, the polarity is too high, fluorine seems
stable toward metabolic decomposition, it is reasonable to to leave the reaction vessel unreacted probably because of its
assume that this might also be the case here. This led to several complete insolubility. We found that a mixture of very nonpolar
attempts to prepare 3-fluoroflavones and 3-fluorochromones, solvents such as CFCl3 and chloroform gives better results than
but usually the results were obtained by several indirect one of these solvents alone, but what has even a better effect is
methods. Some have used a total synthesis approach requiring the addition of ethanol in various proportions. This solvents’
α-hydroxy acetophenone derivatives13,14 or condensation combination increases solubility,25 and the EtOH serves as a
between aldehydes and dimethylanilines containing a difluoro- good acceptor for the negative pole of the F−F molecule.
chloro moiety.15 A different approach was taken by Fuchigami, Generally speaking, addition of too much alcohol prevented the
who electrochemically fluorinated some flavones with Et3N· reaction from taking its desirable course, and most of the
3HF or Et4NF·4HF.16 In most cases, the yields were quite low substrate remains unreacted as fluorine escapes the reaction
and the synthetic routes not of general nature. The reasons vessel without doing much. Too little ethanol, however, allows
these methods were so indirect were in part the unjustified fears formation of fluorine radicals that destroy slowly the organic
associated with elemental fluorine (even though diluted) and substrate.18
the readiness to take extra steps to avoid working with it.
We have been using nitrogen-diluted fluorine for many types Received: May 1, 2014
of reactions without any problems for years. It was successfully Published: June 2, 2014

© 2014 American Chemical Society 7261 dx.doi.org/10.1021/jo5009542 | J. Org. Chem. 2014, 79, 7261−7265
The Journal of Organic Chemistry Article

The addition of fluorine to flavonoids presents yet another It is of interest to compare this to the addition mechanism. A
challenge. These compounds possess a unique double bond. well-known fact concerning the reaction of most members of
On one hand, it is a conjugated enone, which naturally is less the halogen family with double bonds is the anti mode addition.
reactive than an isolated double bond, while on the other hand, With fluorine, however, the situation is reversed. It is a small
it is an enol derivative making it quite sensitive to ring-opening atom which cannot form a bridged fluoronium ion as is the case
forming potentially α-fluorocarbonyl moieties. These two with the other halogens. It is bound to create a transition cage
opposing effects must be balanced, something which could be containing a fluoride and the extremely unstable α-fluoro
achieved mainly through varying the alcohol concentration in carbonium ion. The two ions in this cage collapse rapidly
the solvent mixture. before the fluoride has a chance to move toward the opposite
When diluted fluorine (7−10% F2 in N2) was bubbled slowly face of the ring, resulting in the syn addition (Scheme 1). It
through a cold (−78 °C) and well-stirred solution of flavone 1a should be emphasized that a four center addition of moieties
in a mixture of CHCl3/CFCl3/EtOH (usually in 5:4:1 ratio), containing electrophilic fluorine to the π system of the olefin
cis-2,3-difluoro-4-flavanone (2a)16 was formed in 76% yield had been discredited in the past.28
(Scheme 1). The cis configuration is revealed by the 2JHF The difluorinated product 2a was easily dehydrofluorinated
to 3-fluoroflavone (3a)16 in higher than 90% yield, simply by
Scheme 1. Fluorination of Flavones 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
formation of 3-fluoro-6-chloroflavone (3b)16 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
2c with BF3·OEt2 for about 3 h to produce 3-fluoro-6-
acetoxyflavone (3c) in 85% yield. The difluoro diacetoxy
flavonoid 2d, which as mentioned above was not isolated in
analytical purity, was also treated with BF3·OEt2 which after
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
silica gel leading eventually to 3-fluorochromone (6a)29 in
overall yield of 75% (Scheme 2).
2,3-Difluoro-6-bromo-4-chromanone (5b) and 2,3,6-tri-
a
Not analytically purified. bYield based on the starting flavone 1d. fluoro-4-chromanone (5c) were made by adding F2 to the
corresponding 6-bromo- and 6-fluorochromones 4b and 4c in
80%, and 82% yield (GC), respectively. They were not isolated
in analytical purity but dehydrofluorinated by flash chromatog-
coupling constants of 46 Hz and 3JHF of 28 Hz, in accordance raphy to provide 3-fluoro-6-bromochromone (6b) and 3,6-
with the H−C−C−F dihedral angle of about 60°. In addition, difluorochromone (6c) almost quantitatively. The fluorination
the JFF coupling constant of 15 Hz is in line with the gauche with F2 was also successful when the double bond was
conformation. Similar results were obtained when 6-chloro- trisubstituted as in 3-methylchromone (4d), which formed 2,3-
flavone (1b) was reacted with fluorine, forming cis-2,3-difluoro- difluoro-3-methyl-4-chromanone (5d) in 65% yield. When the
6-chloro-4-flavanone (2b)16 in 70% yield. Flavones containing fluorination reaction was performed under the standard
the phenolic moiety did not usually react cleanly with fluorine, conditions described above on derivatives possessing an
but the situation improved when the hydroxyl groups were electron-withdrawing group attached to the double bond as
acetylated. Thus, 6-acetoxyflavone (1c) 26 reacted with in 3-bromochromone (4e), the conversion did not exceed 60%
elemental fluorine to form the desired cis-2,3-difluoro-6- and the yield of 2,3-difluoro-3-bromo-4-chromanone (5e) was
acetoxy-4-flavanone (2c) in 65% yield, and the 5,7-diacetoxy- only 36%. In order to improve the outcome of the reaction, the
flavone (1d)27 produced the cis-2,3-difluoro-5,7-diacetoxy-4- amount of the ethanol had to be significantly reduced until a
flavanone 2d in about 70% yield, although it was not isolated in full conversion and 64% yield of 5e was achieved. In the last
analytical purity and was reacted as is in the planned two cases (5d and 5e), neither silica gel nor BF3·OEt2 could
consecutive step (see below). induce dehydrofluorination since the proton α to etheric
7262 dx.doi.org/10.1021/jo5009542 | J. Org. Chem. 2014, 79, 7261−7265
The Journal of Organic Chemistry Article

Scheme 2. Fluorination of Chromones derivative was dissolved in benzene and cooled to about 10 °C. Excess
BF3·OEt2 was added in one portion, and the reaction mixture allowed
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.
2,3-Difluoro-4-flavanone (2a)16 was prepared from flavone (1a)
(0.76 g, 3.4 mmol) as described above: off-white solid; mp 108−109
°C (0.68 g, 76% yield); 1H NMR 7.98 (dd, J1 = 7.8 Hz, J2 = 1.3 Hz, 1
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, J1 = 28.0
Hz, J2 = 45.6 Hz, 1 H); 13C NMR 185.9 (d, J = 16.4 Hz), 156.3, 137.5,
134.1 (d, J = 25.5 Hz), 130.7, 128.8, 127.2, 126.1 (d, J = 6.7 Hz),
124.1, 119.7, 118.5, 113.9 (dd, J1 = 22.3 Hz, J2 = 236.8 Hz), 90.4 (dd,
J1 = 33.4 Hz, J2 = 203.0 Hz); 19F NMR −129.1 (dd, J1 = 28.1 Hz, J2 =
15.3 Hz), −212.8 (dd, J1 = 45.5 Hz, J2 = 16.0 Hz).
3-Fluoroflavone (3a).16 Compound 2a was flash chromatographed
resulting in a pale yellow solid, mp 85−86 °C (0.57 g, 92% yield).
2,3-Difluoro-6-chloro-4-flavanone (2b)16 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).
3-Fluoro-6-chloroflavone (3b).16 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).
prolonged treatment with NaOH30 resulted in destruction of 6-Acetoxyflavone (1c)26 was prepared by reacting a solution of 6-
the molecule so at the present we were unable to induce HF hydroxyflavone (1.30 g, 5.5 mmol) in pyridine with acetic anhydride,
elimination in such cases. and the mixture was stirred overnight: white solid; mp 157−158 °C

■
(1.01 g, 66% yield).
5,7-Diacetoxyflavone (1d)27 was prepared in a similar manner (as
EXPERIMENTAL SECTION
1
for 1c) using chrysin (1.27 g, 5.0 mmol) as a starting material: white
H NMR spectra were recorded using a 400 MHz spectrometer with solid; mp 203−205 °C (1.5 g, 88% yield).
CDCl3 as a solvent and Me4Si as an internal standard. The 19F NMR 2,3-Difluoro-6-acetoxy-4-flavanone (2c) was prepared from 6-
spectra were measured at 376.8 MHz with CFCl3 serving as an internal acetoxyflavone (1c) (0.43 g, 1.5 mmol) as described above: white
standard. The proton broadband-decoupled 13C NMR spectra were solid; mp 148−149 °C (0.32 g, 65% yield); 1H NMR 7.71−7.69 (m, 2
recorded at 100.5 MHz. Here, too, CDCl3 served as a solvent and H), 7.68 (d, J = 2.8 Hz, 1 H), 7.52−7.53 (m, 3 H), 7.37 (dd, J1 = 8.9
Me4Si as an internal standard. IR spectra were recorded with an FTIR Hz, J2 = 2.8 Hz, 1 H), 7.18 (d, J = 8.9 Hz, 1 H), 5.44 (dd, J1 = 28.0 Hz,
ATR spectrometer. MS were measured with a Q-TOF (synapt) mass J2 = 45.5 Hz, 1 H), 2.33 (s, 3 H); 13C NMR 185.2 (d, J = 16.9 Hz),
analyzer. 169.4, 153.8, 146.7, 133.8 (d, J = 25.2 Hz), 131.0, 130.8, 128.8, 126.1
General Fluorination Procedure. Fluorine is a strong oxidant (d, J = 6.6 Hz), 120.2, 119.7, 119.6, 114.0 (dd, J1 = 21.9 Hz, J2 = 237.5
and corrosive material. In organic chemistry, it is used after dilution Hz), 90.4 (dd, J1 = 33.1 Hz, J2 = 203.1 Hz), 21.1; 19F NMR −129.1
with nitrogen or helium (generally from 1−20% depending on the
(dd, J1 = 28.1 Hz, J2 = 15.2 Hz), −213.2 (dd, J1 = 45.4 Hz, J2 = 15.8
reaction type). Such dilution can be achieved by using either an
Hz); HRMS with atmospheric solid analysis probe (ASAP) m/z calcd
appropriate copper or monel vacuum line or by purchasing prediluted
for C17H12F2O4 319.0782 (M + H)+, found 319.0779; IR 1759, 1719
fluorine. A detailed description of a simple setup appeared in the
cm−1. Anal. Calcd for C17H12F2O4: C, 64.15; H, 3.80; F, 11.94. Found:
previous literature.31 The reactions themselves are carried out in
C, 63.86; H, 3.49; F, 12.27.
standard glassware. If elementary precautions are taken, work with F2
3-Fluoro-6-acetoxyflavone (3c) was formed by treating 2c with
(which is less toxic than chlorine32) proceeds smoothly, and we have
had no bad experience working with it. Still, the work with this reagent BF3·OEt2: white solid; mp 184−185 °C (0.25 g, 85% yield); 1H NMR
requires a well-ventilated area and good common sense as thousands 8.04−8.01 (m, 2 H), 7.99 (d, J = 2.7 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1
of other reagents in chemistry do. H), 7.58−7.56 (m, 3 H), 7.48 (dd, J1 = 9.1 Hz, J2 = 2.8 Hz, 1 H), 2.36
The reactions were usually carried out on scales of 1−5 mmol (s, 3 H); 13C NMR 170.4 (d, J = 16.9 Hz), 169.3, 152.8, 151.3 (d, J =
flavone or chromone derivatives, monitored by TLC, GC, or NMR. 24.2 Hz), 147.7, 146.2 (d, J = 248.8 Hz), 131.8, 129.1, 128.8 (d, J = 4.9
The starting flavones and chromones are commercially available, and Hz), 128.5, 128.3 (d, J = 7.7 Hz), 125.2 (d, J = 7.5 Hz), 119.7, 118.0
we have acetylated the hydroxyl groups where relevant. Fluorine, at (d, J = 3.2 Hz), 21.1; 19F NMR −161.5; HRMS (ASAP) m/z calcd for
concentrations of 7−10% in N2, was slowly passed through a cold C17H11FO4 299.0720 (M + H)+, found 299.0725; IR 1764, 1645 cm−1.
(−78 °C) and vigorously stirred solution of the enone dissolved in 100 Anal. Calcd for C17H11FO4: F, 6.37. Found: F, 6.07.
mL of CFCl3, 125 mL of CHCl3, and 25 mL of EtOH. An efficient 3-Fluoro-5,7-diacetoxyflavone (3d) was prepared from 2,3-
mixing was achieved by using a vibromixer, which also ensured a fine difluoro-5,7-diacetoxyflavone (2d) whose stability did not permit
dispersion of the gas bubbles. In most cases, the reactions were analytical purification and therefore was used immediately upon
completed within 1.5−4 h. They were terminated by pouring into 200 formation from 1d (0.58 g, 1.7 mmol) as described above. Compound
mL water, washing the organic layer with NaHCO3 solution followed 3d (0.38 g) is a white solid, mp 205−207 °C, 63% yield based on 1d;
1
by water until neutral, drying the organic layer over MgSO4, and finally H NMR 7.98−7.96 (m, 2 H), 7.57−7.55 (m, 3 H), 7.38 (d, J = 2.1
evaporating the solvent. The crude product was usually purified by Hz, 1 H), 6.88 (d, J = 1.9 Hz, 1 H), 2.47 (s, 3 H), 2.36 (s, 3 H); 13C
vacuum flash chromatography using silica gel with various proportions NMR 169.6, 169.3 (d, J = 18.4 Hz), 168.0, 156.7, 154.4, 150.6 (d, J =
of petroleum ether/EtOAc as eluent or by recrystallization. 2.7 Hz), 150.3(d, J = 25.0 Hz), 146.3 (d, J = 247.3 Hz), 131.9, 129.1,
Dehydrofluorination Procedures. Two methods were employed 128.4 (d, J = 5.5 Hz), 128.1 (d, J = 7.6 Hz), 115.4 (d, J = 6.3 Hz),
for the described HF elimination. (A) The corresponding fluoro 113.9, 109.2, 21.3, 21.2; 19F NMR −161.6; HRMS (ESI) m/z calcd for

7263 dx.doi.org/10.1021/jo5009542 | J. Org. Chem. 2014, 79, 7261−7265

The Journal of Organic Chemistry Article

C19H13FO6 379.0594 (M + Na)+, found 379.0596; IR 1768, 1649 64% yield); 1H NMR 8.01 (dd, J1 = 7.8 Hz, J2 = 1.7 Hz, 1 H), 7.69−
cm−1. 7.65 (m, 1 H), 7.29−7.25 (m, 1 H), 7.13 (dd, J1= 8.4 Hz, J2 = 0.6 Hz, 1
3-Fluoro-5-hydroxy-7-acetoxyflavone (3e) was formed by treating H), 6.29 (d, J = 53.8 Hz, 1 H); 13C NMR 179.9 (d, J = 20.0 Hz),
the crude 2d with BF3·OEt2. The determination of which acetate was 154.3, 138.1, 128.3 (d, J = 1.5 Hz), 124.7, 118.6, 117.5, 108.0 (dd, J1 =
hydrolyzed was made by comparing 1H NMR spectra of 3d and 3e. 239.6 Hz, J2 = 28.0 Hz), 91.0 (dd, J1 = 277.0 Hz, J2 = 33.2 Hz); 19F
Hydrolysis of acetate in position 5 did not affect the aromatic NMR −138.3 (dd, J1 = 54.0 Hz, J2 = 17.6 Hz), −147.6 (d, J = 17.6
hydrogen in position 8, and the methyl of the acetate in this position Hz); HRMS (ASAP) m/z calcd for C9H5BrF2O2 262.9519 (M + H)+,
disappeared: beige solid; mp 184−186 °C (0.26 g, 49% yield); 1H found 262.9524; IR 1718 cm−1. Anal. Calcd for C9H5BrF2O2: C, 41.10;
NMR 8.00−7.98 (m, 2 H), 7.58−7.56 (m, 3 H), 6.89 (d, J = 2.0 Hz, 1 H, 1.92; F, 14.45. Found: C, 40.86; H, 2.11; F, 14.64.
H), 6.61 (d, J = 2.0 Hz, 1 H), 2.34 (s, 3 H); 13C NMR 174.9 (d, J =
17.6 Hz), 168.4, 161.9 (d, J = 3.0 Hz), 156.5, 155.8, 152.2 (d, J = 23.3
Hz), 144.6 (d, J = 248.9 Hz), 132.2 (d, J = 1.3 Hz), 129.2, 128.3 (d, J =
7.8 Hz), 109.5 (d, J = 6.4 Hz), 105.5, 101.4, 21.3; 19F NMR −163.7;
■
*
ASSOCIATED CONTENT
S Supporting Information
1
HRMS (ESI) m/z calcd for C17H11FO5 337.0488 (M + Na)+, found H, 13C, and 19F NMR spectra and GC data. This material is
337.0486; IR 1767, 1651 cm−1. available free of charge via the Internet at http://pubs.acs.org
3-Fluorochromone (6a)29 was prepared from chromone (4a) (0.69
g, 4.7 mmol) as described above: white solid; mp 138−140 °C (0.58 g,
75% yield); 1H NMR 8.30 (dd, J1 = 8.0 Hz, J2 = 1.3 Hz, 1 H), 8.16 (d,
J = 3.4 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H),
■ AUTHOR INFORMATION
Corresponding Author
7.44 (t, J = 7.6 Hz, 1 H); 13C NMR 170.7 (d, J = 15.6 Hz), 156.0, *Tel: 972-3-6408378. Fax: 972-3-6409293. E-mail: rozens@
149.5 (d, J = 248.9 Hz), 143.0 (d, J = 39.9 Hz), 134.2, 126.2, 125.4, post.tau.ac.il.
125.0 (d, J = 7.6 Hz), 118.5; 19F NMR −166.2; HRMS (ASAP) m/z Notes
calcd for C9H5FO2 165.0352 (M + H)+, found 165.0357; IR 1652 The authors declare no competing financial interest.

■
cm−1.
2,3-Difluoro-6-bromo-4-chromanone (5b) was prepared from 6-
bromochromone (4b) (0.81 g, 3.6 mmol) as described above. A crude ACKNOWLEDGMENTS
oil containing the product in 80% yield (GC, 0.76 g) was immediately This work was supported by the Israel Science Foundation.

■
characterized without any purification since it tends to eliminate HF
spontaneously: HRMS (ASAP) m/z calcd for C9H5BrF2O2 262.9519 REFERENCES
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149.2 (dd, J1 = 249.0 Hz, J2 = 1.6 Hz),143.3 (d, J = 40.0 Hz), 126.3 (t, (9) Grassmann, J.; Hippeli, S.; Elstner, E. F. Plant Physiol. Biochem.
J = 8.1 Hz), 122.7 (d, J = 25.7 Hz), 120.7 (d, J = 8.3 Hz), 111.0 (dd, J1 2002, 40, 471.
= 24.2 Hz, J2 = 3.8 Hz); 19F NMR −115.0, −166.6; HRMS (ESI) m/z (10) (a) Houghton, P. J.; Woldemariam, T. Z.; Khan, A. I.; Burke, A.;
calcd for C9H4F2O2 183.0258 (M + H)+, found 183.0253; IR 1640 Mahmood, N. Antiviral Res. 1994, 25, 235−44. (b) Wrigley, S. K.;
cm−1. Anal. Calcd for C9H4F2O2: C, 59.35; H, 2.21; F, 20.86. Found: Latif, M. A.; Gibson, T. M.; Chicarelli, R. M. I.; Williams, D. H. Pure.
C, 58.96; H, 1.90; F, 20.98. Appl. Chem. 1994, 66, 2383−2386. (c) Kaur, R.; Taheam, N.; Sharma,
2,3-Difluoro-3-methyl-4-chromanone (5d) was prepared from 3- A. K.; Kharb, R. Res. J. Pharm., Biol. Chem. Sci. 2013, 4, 79−96.
methylchromone (4d) (0.82 g, 3.6 mmol): white solid; mp 87−90 °C (11) Xu, H. X.; Lee, S. F. Phytother. Res. 2001, 15, 39−43.
(0.62 g, 65% yield); 1H NMR 7.82 (d, J = 2.5 Hz, 1 H), 7.68 (d, J = 2.5 (12) Halford, B. Chem. Eng. News 2013, Nov 18, 28.
Hz, 1 H), 6.07 (dd, J1 = 52.9 Hz, J2 = 0.7 Hz, 1 H), 1.70 (dd, J1 = 21.4 (13) Bolos, J.; Gubert, S.; Anglada, L.; Planas, J. M.; Burgarolas, C.;
Hz, J2 = 1.1 Hz, 1 H); 13C NMR 186.7 (d, J = 18.0 Hz), 149.5, 137.2, Castello, J. M.; Sacristan, A.; Ortiz, J. A. J. Med. Chem. 1996, 39, 2962−
129.9, 125.5 (d, J = 1.7 Hz), 124.8, 121.0 (d, J = 2.2 Hz), 109.2 (dd, J1 2970.
= 240.7 Hz, J2 = 27.9 Hz), 91.0 (dd, J1 = 198.0 Hz, J2 = 24.8 Hz), 19.1 (14) Menichincheri, M.; Ballinari, D.; Bargiotti, A.; Bonomini, L.;
(dd, J1 = 24.0 Hz, J2 = 4.7 Hz),; 19F NMR −145.2 (dd, J1 = 52.8 Hz, J2 Ceccarelli, W.; D’Alessio, R.; Fretta, A.; Moll, J.; Polucci, P.; Soncini,
= 16.4 Hz), −178.3 (m); HRMS (ASAP) m/z calcd for C10H6Cl2F2O2 C.; Tibolla, M.; Trosset, J. Y.; Vanotti, E. J. Med. Chem. 2004, 47,
266.9791 (M + H)+, found 266.9787; IR 1720 cm−1. Anal. Calcd for 6466−6475.
C10H6Cl2F2O2: C, 44.98; H, 2.26; Cl, 26.55. Found: C, 45.04; H, 2.30; (15) Médebielle, M.; Keirouz, R.; Okada, E.; Shibata, D.; Dolbier, W.
Cl, 26.48. R., Jr. Tetrahedron Lett. 2008, 49, 589−593.
2,3-Difluoro-3-bromo-4-chromanone (5e) was prepared from 3- (16) Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem. 1999, 64,
bromochromone (4e) (0.64 g, 2.8 mmol): colorless liquid (0.48 g, 3346−3349.

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