A BHT-regulated chemoselective access to monofluorinated chromones

Article abstract of DOI:10.1016/j.tet.2019.130833

A BHT-regulated chemoselective monofluorination of enaminones with Selectfluor under mild reaction conditions was unveiled for the first time. As a result, an array of monofluorinated chromones were efficiently assembled in a simple operational manner. Moreover, the scalability of this protocol and the versatility for the downstream transformations of the obtained fluorinated chromones to installing diverse nitrogen-containing heterocycles greatly broaden the practical applications of this developed protocol.

Full text of DOI:10.1016/j.tet.2019.130833

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A BHT-regulated chemoselective access to monofluorinated chromones
Qing-Lan Zhao, Peng-Jiu Xia, Lan Zheng, Zhen-Zhen Xie, Yuan-Zhuo Hu, Guang-
Jian Chen, Xiao-Qing Chen, Hao-Yue Xiang, Hua Yang
PII:
S0040-4020(19)31241-4
https://doi.org/10.1016/j.tet.2019.130833
TET 130833
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 October 2019
Revised Date: 18 November 2019
Accepted Date: 25 November 2019
Please cite this article as: Zhao Q-L, Xia P-J, Zheng L, Xie Z-Z, Hu Y-Z, Chen G-J, Chen X-Q, Xiang
H-Y, Yang H, A BHT-regulated chemoselective access to monofluorinated chromones, Tetrahedron
(2020), doi: https://doi.org/10.1016/j.tet.2019.130833.
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Qing-Lan Zhaoa , Peng-Jiu Xiaa , Lan Zhenga , Zhen-Zhen Xiea , Yuan-Zhuo Hua , Guang-Jian Chenc , Xiao-Qing
Chenab, Hao-Yue Xiang*a, Hua Yang*ab
a College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
b Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Central South
University, Changsha 410083, P. R. China
c Hunan Center for Drug Evaluation and Research HN-CDER, Changsha 410083, P. R. China

2
Tetrahedron
journal homepage: www.elsevier.com
A BHT-regulated chemoselective access to monofluorinated chromones
Qing-Lan Zhaoa , Peng-Jiu Xiaa , Lan Zhenga , Zhen-Zhen Xiea , Yuan-Zhuo Hua , Guang-Jian Chenc , Xiao-
Qing Chenab, Hao-Yue Xiang*a, Hua Yang*ab
a College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
b Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Central South University, Changsha 410083, P. R. China
c Hunan Center for Drug Evaluation and Research HN-CDER, Changsha 410083, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
A BHT-regulated chemoselective monofluorination of enaminones with Selectfluor under mild
reaction conditions was unveiled for the first time. As a result, an array of monofluorinated
chromones were efficiently assembled in a simple operational manner. Moreover, the scalability
of this protocol and the versatility for the downstream transformations of the obtained
fluorinated chromones to installing diverse nitrogen-containing heterocycles greatly broaden the
practical applications of this developed protocol.
Accepted 28 September 2018
Accepted 06 May 2015
Accepted 15 December 2014
Accepted 20 October 2014
2019 Elsevier Ltd. All rights reserved
.
Keywords:
BHT
selectfluor
monofluorinated
chromone
1. Introduction
enaminone could serve as effective nucleophiles in a wide range
of transformations.6 Not surprisingly, sufficient attention has
been paid to the fluorination of enaminone with N-F based
reagents. Back to 2005, enaminone were firstly employed to react
with Selectfluor by Shreeve and co-workers, giving diverse
Fluorine-containing organic compounds are of significant
interest in the fields of pharmaceuticals, agrochemicals and
materials. It is unquestionable that the incorporation of fluorine
can significantly affect the physical-chemical properties of the
parent molecules, such as hydrophobicity, metabolic stability,
membrane permeability and conformational preference.1 Even
18F-containing compounds have been designed and synthesized
as imaging probes for positron emission tomography (PET), both
in diagnosis and medicinal chemistry.2 As a consequence,
tremendous efforts have been devoted to exploring facile
fluorination methods to address the current issues in the
fluorination including high cost, operational difficulty, high
toxicity, poor selectivity and involvement of transition metals.3
Concurrently, a variety of new fluorinating reagents with N-F
core structure, especially Selectfluor, have emerged as generally
safer and easily manipulated alternative sources of fluorine,
offering a number of synthetic potentials.4 Essentially, these N-F
based reagents are typically regarded as electrophilic fluorinating
agents and thus can react with many kinds of nucleophilic
partners. Following this concept, exploiting the C-F bond
formation by employing these N-F based reagents in newly
designed transformations would enrich the arsenal of fluorination
and extend the boundary of fluorinated scaffolds, which is always
pivotal in the synthetic and medicinal chemistry.
difluorinated
carbonyl
compounds.7
Noticeably,
the
monofluorinated product was only obtained as the minor product
for limited examples while the difluorinated product dominated
(Scheme 1A). Additionally, some limited examples for
monofluorination of enaminones with Selectfluor were also
reported with low to moderate yields.8 However, our group9 and
Song’s group10 independently disclosed that another types of
enamine
derivatives,
o-hydroxyarylenaminones
or
o-
aminoarylenaminones, could react with Selectfluor, but giving
the difluorinated products exclusively. Despite these advances,
we were curious about the possibility of the monofluorination of
the enaminone in this process, which would provide a facile
installation of monofluorinated chromone.11 (Scheme 1B). As
well known, chromones are versatile building blocks for
constructing diversely featured heterocycles with a variety of
physiological and biological activities, such as pyrimidine and
pyridine scaffolds.12 Additionally, the introduction of one fluorine
atom into these nitrogen-containing heterocycles is often adopted
as a strategy to improve their biological and physicochemical
properties (Scheme 1C).1 Given the importance of the fluorinated
heterocycles and our continued research interest,13 we were
attracted by the underdeveloped monofluorination of enamine.
We serendipitously found that the cyclization of o-
hydroxyarylenaminones promoted by Selectfluor could be
manipulated by simply adding radical scavenger – TEMPO or
Enaminone, easily prepared from ketones or aldehydes, have
been long recognized as valuable synthetic intermediates and
synthons.5 Given their structural and electronic features,

3
A. Pr evious wor k: enamine-assisted difluorination
X
Table 1. Optimizations of reaction conditionsa
difluorinated
carbonyl compounds
O
R2
N
R1
R2
F
Cl
N
F
R1
N
2BF4
O
O
X
F
F
3.
F
Entry
1
Solvent
acetone
CH2Cl2
CH3OH
DMSO
toluene
DMF
CH3CN
THF
Base
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
Et3N
Additive
TEMPO
Yield (%)b
58
difluorinated
chromanones
X
R
N
2
TEMPO
51
3
TEMPO
47
B. This wor k: BHT-mediated monofluorination of enamine
4
TEMPO
trace
54
O
5
TEMPO
O
BHT
6
TEMPO
trace
29
F F installed
7
TEMPO
Selectfluor
bis-electrophile
8
TEMPO
70
OH
N
O
9
THF
TEMPO
65
monofluorinated chromone
high chemoselectivity
10
11
12
13
14
15e
16f
17
18
19
20
THF
TEMPO
28
THF
DMAP
TEMPO
50
THF
-
TEMPO
NR
71
C. Examples of monofluorinated pharmaceuticals
THF
NaOAcc
NaOAcd
NaOAcc
NaOAcc
NaOAcc
NaOAcc
NaOAcc
NaOAcc
TEMPO
O
O
THF
TEMPO
68
S
OH
F
THF
TEMPO
15
OH
F
THF
TEMPO
26
O
N
THF
BHT(3 equiv)
BHT (2 equiv.)
BHT (1 equiv.)
BHT (0.2 equiv.)
76
N
N
N
THF
61
H2N
N
O
HN
THF
56
Penetrex
Scheme 1. Synthetic profiles of enamine and selectfluor, and representative
monofluorinated pharmaceuticals
Emtriva
THF
54
aReaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), base (1.0 mmol),
TEMPO (1.5 mmol) in solvent (2 mL), rt, 5 h. Isolated yields. NaOAc (1
equiv.). dNaOAc (3 equiv.). eNSFI was used instead of Selectfluor.
fSelectfluor (2 equiv). NR: no reaction.
.
b
c
BHT,
realizing
the
monofluorination
to
generate
monofluorochromone (Scheme 1B). Furthermore, the resulting
monofluorochromone could serve as a versatile platform to
access diverse fluorinated hetereocycles.
yields. After a series of screening, the optimal conditions were
determined to be Selectfluor (1 equiv.) as the fluorine source,
NaOAc (1 equiv.) as the base, BHT (3 equiv) as the additive, and
THF as the solvent (Table 1, entry 17).
2. Results and Discussion
2.1. Optimization of the reaction conditions
2.2. Scope and limitations of substrates
Our initial investigation started with the addition 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) as the additive to the
reaction of o-hydroxyarylenaminone 1a and Selectfluor (Table 1).
Encouragingly, the desired monofluorinated chromone 3a was
isolated in a moderate yield while only a trace amount of the
corresponding difluorinated product was obtained (Table 1, entry
1). Next, solvent screening demonstrated that THF was the best
choice, while DMSO or DMF was found to be ineffective for this
transformation (Table 1, entries 1-8). Subsequently, several bases
were evaluateded, of which NaOAc provided the highest yield
(Table 1, entries 9-11). Either increasing or reducing the amount
of NaOAc gave a similar chemical yield of 3a, but the reaction
was completely suppressed without base (Table 1, entries 12-14).
N-fluorobenzenesulfonimide (NSFI) was also tested in this
process, but with a relatively lower yield (Table 1, entry 15). The
yield of monofluorinated chromone was obviously reduced with
an increased amount of Selectfluor (Table 1, entry 16).
Finally, instead of TEMPO, butylated hydroxytoluene (BHT)
was employed in this reaction and a slightly improved chemical
yield of 3a was observed. This monofluorinated process can
occur as well in the presence of a reduced, or even catalytic
amount of BHT (Table 1, entries 18-20) albeit with moderate
Having established the optimal conditions, we next explored
the generality and the functional group tolerance of this protocol
(Scheme 2). It was found that the electronic features of
substituents at phenyl moiety slightly affected the efficacy of this
transformation and thus satisfactory yields were thoroughly
secured. Specifically, it was found that the substrate with a
fluorine substituent at the meta-position of phenol moiety gave
lower yield than the analogues substituted at the para-position
(Scheme 2, 3c vs 3e), and the presence of a bromine substituent
undermined the yield in all of the tested cases (Scheme 2, 3d, 3g,
and 3p). Aryl substituents were also suitable substrates,
furnishing the corresponding products with higher yields
(Scheme 2, 3h-3l). Other substrates bearing heteroaromatic rings,
such as thiophene or furan, also produced 3m and 3n in 55% and
74% yield respectively. Moreover, the disubstituted substrates
and naphthalene analogue delivered the corresponding
monofluorinated chromone in modest yields as well (Scheme 2,
3o-3q). Meanwhile, direct C-H monofluorination of the
conventional tertiary enaminones 1r and 1s was verified to
proceed smoothly, further demonstrating the good tolerance of
this synthetic protocol. In contrast to enamine substrate, the
counterpart chalocone was unable to proceed the cyclization

4
Scheme 2. Substrate scope for the synthesis of
Scheme 3. Scale-up, synthetic utility of the protocol and
control experiments
monofluorinated chromonesa,b
aReaction conditions: 3a (0.5 mmol, 1 equiv.), amidines (1 mmol, 2 equiv.),
O
O
A)
Standard
conditions
F
N
O
OH
73 %
1a
3a
0.6280 gram
1 gram
conditionsa
B)
F
F
F
N
N
N
N
N
NH2
N
OH
OH
OH
5a,
5b,
89 %
82 %
5c,
86 %
F
F
N
N
F
COOEt
NH2
N
N
N
OH
5d,
Cl
OH
NH2
OH
5e,
63 %
5f,
73 %
77 %
Synthesis of fluoro carbolineb
F
O
O
F
CN
Zn, AcOH, TEA
+
N
120 oC, 4 h
50%
NO2
HO
N
6
H
7
aReaction conditions: 1 (0.5 mmol, 1 equiv.), 2 (0.5 mmol, 1 equiv.), NaOAc
(0.5 mmol, 1 equiv.), BHT (1.5 mmol, 3 equiv.), in THF (2.0 mL) at room
temperature for 5 h. bIsolated yields.
K2CO3 (1.5 mmol, 3 equiv.), in EtOH (2.0 mL), 80 oC for 3 h; isolated yields.
bReaction conditions: 3a (0.5 mmol), 6 (1 mmol), Zn (4 mmol), TEA (1.5
mmol) in AcOH(15 mmol), heated at 120 oC for 4 h; isolated yield.
under the standard conditions, confirming the key role of the
Scheme 4. Control experiments and possible reaction
mechanism
enamine
in
this
tandem
process.
However,
o-
aminoarylenaminones only gave a fairly complex reaction and
the corresponding monofluorinated quinolone was unobtainable.
Given the mildness of the reaction conditions, the practicality and
scalability of this protocol were subsequently exploited. The
reaction of enaminone 1a was performed on gram scale under the
standard reaction conditions, giving the desired product 3a in
73% yield without any loss of efficiency (Scheme 3A). Giving
the versatile synthetic potentials of chromone, the
monofluorinated chromone 3a was utilized to proceed varied
ring-reorganizations to access other interesting fluorinated
nitrogen-containing heterocycles (Scheme 3B). Initially, various
amidines were employed to react with monofluorinated
chromone 3a, furnishing a range of monofluorinated pyrimidines
in good yields (Scheme 3B, 5a-5e). To our delight, both aliphatic
amidines including guanidine and cyclopropanecarbanidine, and
aromatic amidines with electron-withdrawing or electron-
donating substituents of the benzene ring were all tolerated well.
Notably, cyclopropyl and amino fragment are both versatile
players that frequently appear in drug molecules.14 As expected,
ethyl 2-amidinoacetate hydrochloride with multiple nucleophilic
sites reacted smoothly with monofluorinated chromone 3a,
giving a monofluorinated pyridine 5f.12c Furthermore, fused
tricyclic analogue α-carboline 7 was efficiently assembled by
treating 3a with o-nitrophenylacetonitrile in the presence of zinc
dust, acetic acid and triethylamine.15 Obviously, the diversified
ring-reorganizations of the as-prepared monofluorinated
chromone through simple and straightforward operations would
endow this developed BHT-regulated protocol with greater
impact and significance in drug discovery.
A) control experiments
O
O
O
NaOAc (1 equiv.)
DBU or BHT (3 equiv.)
THF, rt, 5h
O
O
F
H
F
Standard
conditions
F
DBU no reaction
BHT 99%
O
N
8
9
3a
Cl
2BF4
B) plausible mechanism
N
N
Cl
N
2BF4
O
N
O
O
F
H
2
F
F
F
2
R
R
R
OH
N
N
OH
N
OH
O
1
A
B
O
O
O
O
F
F
F
F
F
R
BHT
R
R
OH
C base
N
N
3
D
To further mechanistically probe the reaction, the
corresponding control experiments were carried out (Scheme 4).
When 4H-chromen-4-one 8 was subjected to the standard
conditions, the desired product was not observed. On the contrary,
in the presence of BHT, the preformed difluorinated 2‑ amino-
substituted chromanone 9 could be quantitatively converted to
the corresponding monofluorinated chromone 3a. Additionally, it
was found that the difluorinated 2-amino-substituted chromanone
9
was unable to be converted to the corresponding
monofluorinated chromone 3a in the absence of BHT, even with
a strong base DBU. On the basis of these results, it was found
that BHT played a crucial role in the ultimate formation of the
monofluorinated product. We thus reasoned that a BHT-
2.3. Control experiments and possible reaction mechanism

5
promoted defluorination of difluorinated intermediates was likely
to be involved in this process. Surely, this strategy would provide
a facile pathway to modulate the degree of fluorination.
NMR (400 MHz, Chloroform-d) δ 8.29 (dd, J = 8.0, 1.4 Hz, 1H),
8.18 (d, J = 3.4 Hz, 1H), 7.72 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H),
7.52 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H); 19F NMR (376
MHz, Chloroform-d) δ -165.76; 13C{1H} NMR (100 MHz,
Chloroform-d) δ 170.5 (d, 2JC-F = 15.5 Hz ), 155.8, 149.4 (d, 1JC-F
On the basis of the observed results, a plausible mechanism
involving iminium intermediate was proposed in Scheme 4. It
could be assumed that the first round of fluorination of
enaminone 1 by Selectfluor formed the intermediate iminium ion
A, which facilely tautomerized to form enamine B. Afterthat, the
difluorinated iminium intermediate C could be generated in a
similar manner. The resulting reactive iminium ion would
significantly drive the intramolecular cyclization to accomplish
the difluorinated chromanones D rapidly. The subsequent
defluorination and deamination ultimately delivered the desired
products 3 in the presence of BHT.
2
4
= 249.0 Hz ), 143.0 (d, JC-3F = 40.0 Hz ), 134.1, 126.0 (d, JC-F
=
3.4 Hz ), 125.3, 124.8 (d, JC-F = 7.7 Hz ), 118.4; HRMS (ESI):
m/z [M+H]+ called for C9H6FO2 : 165.0346, found 165.0350.
+
3-Fluorochromone 3b. White solid (57 mg, 59%): m.p. 147-
148 ℃; IR (neat) ν 3094, 1645, 1612, 1440, 1203, 1018, 893, 613
1
cm-1; H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 8.9 Hz,
1H), 8.08 (d, J = 2.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.86 (s,
1H), 3.91 (s, 3H); 19F NMR (376 MHz, Chloroform-d) δ -166.84;
2
13C{1H} NMR (100 MHz, Chloroform-d) δ169.9 (d, JC-F =15.9
1
2
Hz), 164.4, 157.7, 149.4 (d, JC-F = 248.7 Hz), 142.4 (d, JC-F
=
4
3
3. Conclusion
40.5 Hz), 127.2 (d, JC-F = 3.4 Hz), 118.6 (d, JC-F = 7.4 Hz),
115.0, 100.3, 55.9; HRMS (ESI) m/z [M+H]+ calcd for
In conclusion, we successfully developed a facile protocol
accessing a range of monofluorinated chromones under mild
conditions. The key to the monofluorination process is the
addition of BHT or TEMPO. The notable features of this process
include excellent chemoselectivity, mild reaction conditions,
synthetic simplicity, and broad substrate scope. Significantly, the
diversified transformations for the obtained monofluorinated
chromone scaffold will enrich the library of fluorinated
heterocycles and provide more options for drug screening in the
future. Further synthetic applications and studies to unveil the
biological activities of these privileged scaffolds are ongoing in
our laboratory.
+
C10H8FO3 : 195.0452, found 195.0476.
3-Fluorochromone 3c. White solid (47 mg, 52%): m.p. 123-
124 ℃; IR (neat) ν 3086, 2922, 1661, 1617, 1443, 1240, 1201,
1086, 955, 530 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 8.35–
8.28 (m, 1H), 8.16 (s, 1H), 7.19 (t, J = 7.6 Hz, 2H); 19F NMR
(376 MHz, Chloroform-d) δ -101.76, -165.72; 13C{1H} NMR
2
(100 MHz, Chloroform-d) δ 169.7 (d, JC-F = 16.0 Hz), 165.8 (d,
1JC-F = 256.5 Hz), 156.8 (d, 3JC-F = 14 Hz), 149.4 (d, 1JC-F = 250.4
Hz), 143.1 (d, 2JC-F = 40.6 Hz), 128.6 (dd, 3, 4JC-F = 10.8, 3.4 Hz),
121.7 (dd, 3, 4JC-F = 7.8, 1.9 Hz), 114.4 (d, 2JC-F = 23.1 Hz), 105.0
2
(d, JC-F = 25.6 Hz); HRMS (ESI) m/z [M+H]+ calcd for
+
C9H5F2O2 : 183.0252, found 183.0270.
4. Experimental section
3-Fluorochromone 3d. White solid (50 mg, 41%): m.p. 135-
136 ℃; IR (neat) ν 3081, 2363, 1655, 1599, 1430, 1196, 1145,
958, 524 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H),
8.14 (d, J = 4.6 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.56 (dd, J =
8.6, 1.7 Hz, 1H); 19F NMR (376 MHz, Chloroform-d) δ -164.86;
13C{1H} NMR (100 MHz, Chloroform-d) δ 169.8 (d, 2JC-F = 16.0
Hz), 155.7, 149.4 (d, 1JC-F = 250.8 Hz), 143.0 (d, 1JC-F = 40.3 Hz),
Unless otherwise noted, all the reagents were purchased from
commercial suppliers and used without further purification. H
1
NMR spectra were recorded at 400 MHz. The chemical shifts
were recorded in ppm relative to tetramethylsilane and with the
solvent resonance as the internal standard. Data were reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, p = quint, m = multiplet), coupling constants
(Hz), integration. 13C NMR data were collected at 100 MHz with
complete proton decoupling. Chemical shifts were reported in
ppm from the tetramethylsilane with the solvent resonance as
internal standard. 19F NMR data were collected at 376 MHz with
complete proton decoupling. UV–Vis spectra were recorded
using a shimadzu UV-2600. Infrared spectra (IR) were measured
by FT-IR apparatus. High resolution mass spectroscopy (HRMS)
was recorded on TOF MS ES+ mass spectrometer and
acetonitrile was used to dissolve the sample. Column
chromatography was carried out on silica gel (200-300 mesh).
The starting materials enaminones 1 were prepared according to
the previously described method.5
4
3
129.0, 128.6, 127.3 (d, JC-F = 3.5 Hz), 123.7 (d, JC-F = 8.0 Hz),
+
121.5; HRMS (ESI) m/z [M+H]+ calcd for C9H5BrFO2 :
242.9451, found 242.9476.
3-Fluorochromone 3e. White solid (63 mg, 69%): m.p. 270-
271 ℃; IR (neat) ν 3078, 2920, 1645, 1472, 1260, 1176, 885, 563
1
cm-1; H NMR (400 MHz, Chloroform-d) δ 8.18 (d, J = 3.3 Hz,
1H), 7.93 (dd, J = 8.1, 3.3 Hz, 1H), 7.54 (dd, J = 9.2, 4.2 Hz, 1H),
7.45 (ddd, J = 9.3, 7.4, 3.0 Hz, 1H); 19F NMR (376 MHz,
Chloroform-d) δ -114.61, -166.33; 13C{1H} NMR (100 MHz,
Chloroform-d) δ 169.7 (dd, 2 ,4JC-F = 15.9, 2.3 Hz), 159.5 (d, 1JC-F
1, 5
= 248.3 Hz), 152.1, 149.0 (dd,
J
= 249.3, 1.4 Hz), 143.2 (d,
C-F
2
2JC-F = 40.0 Hz), 126.1 (t, JC-F = 8.2 Hz), 122.6 (d, JC-F = 25.7
3
3
2 ,4
Hz), 120.6 (d, JC-F = 8.3 Hz), 110.8 (dd,
J = 24.2, 3.8 Hz);
C-F
+
HRMS (ESI) m/z [M+H]+ calcd for C9H5F2O2 : 183.0252, found
183.0271.
5.1 General procedures for synthesis of 3a-3s.
o-Hydroxyarylenaminone 1 (0.5 mmol, 1 equiv.), Selectfluor
(0.5 mmol, 1.0 equiv), NaOAc (0.5 mmol, 1.0 equiv) and BHT
(1.5 mmol, 3 equiv.) were added to THF (2.0 mL) in a 10 mL
reaction tube equipped with a stirring bar. The reaction mixture
was stirred at room temperature for 5 h. After completion of the
reaction (confirmed by TLC analysis, petroleum ether/ethyl
acetate = 10/1), the solvent was removed in vacuo, and the
resulting residue was purified via silica gel chromatography
(petroleum ether/ethyl acetate = 50/1) to yield the corresponding
monofluorinated chromone 3.
3-Fluorochromone 3f. White solid (63 mg, 63%): m.p. 157-
158 ℃; IR (neat) ν 2923, 1647, 1463, 1373, 1257, 1185, 1117,
893, 633 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J =
2.6 Hz, 1H), 8.18 (d, J = 3.1 Hz, 1H), 7.65 (dd, J = 9.1, 2.6 Hz,
1H), 7.49 (d, J = 9.0 Hz, 1H); 19F NMR (376 MHz, Chloroform-d)
δ -165.23; 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.3 (d,
2JC-F = 16.0 Hz), 154.1, 149.3 (d, 1JC-F = 250.2 Hz), 143.2 (d, 1JC-
F = 40.1 Hz), 134.4, 131.5, 125.8 (d, 3JC-F = 8.2 Hz), 125.2 (d, 4JC-
= 3.6 Hz), 120.2; HRMS (ESI) m/z [M+H]+ calcd for
C9H5ClFO2 : 198.9957, found 199.9971.
F
+
3-Fluorochromone 3a. White solid (62 mg, 76%): m.p. 160-
1
161 ℃; IR (neat) ν 2921, 1640, 1466, 1184, 899, 529 cm-1; H

6
3-Fluorochromone 3g. White solid (64 mg, 53%): m.p. 200-
201 ℃; IR (neat) ν 3745, 2209, 2141, 2026, 1939, 1450, 1268,
648, 574 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J =
2.4 Hz, 1H), 8.18 (d, J = 3.3 Hz, 1H), 7.79 (dd, J = 9.0, 2.4 Hz,
1H), 7.42 (d, J = 9.0 Hz, 1H); 19F NMR (376 MHz, Chloroform-d)
δ -164.93; 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.2 (d,
2JC-F =15.9 Hz), 154.6, 149.3 (d, 1JC-F = 250.5 Hz), 143.2 (d, 2JC-F
137.3, 133.0, 130.3, 129.8, 127.1, 125.1 (d, 3JC-F = 7.9 Hz), 124.2
(d, 4JC-F = 3.4 Hz), 119.2, 52.2; HRMS (ESI) m/z [M+Na]+ calcd
for C17H11FNaO4 : 321.0534, found 321.0565.
+
3-Fluorochromone 3m. White solid (68 mg, 55%): m.p. 143-
144℃; IR (neat) ν 3093, 2921, 1648, 1480, 1269, 1204, 1168,
1
819, 570 cm-1; H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J =
2.4 Hz, 1H), 8.14 (d, J = 3.4 Hz, 1H), 7.91 (dd, J = 8.8, 2.4 Hz,
1H), 7.50 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 3.7 Hz, 1H), 7.34 (d, J
= 5.1 Hz, 1H), 7.10 (t, J = 4.4 Hz, 1H); 19F NMR (376 MHz,
Chloroform-d) δ -165.52; 13C NMR{1H} (100 MHz, Chloroform-
d) δ 170.3 (d, 2JC-F = 15.6 Hz), 154.9, 149.4 (d, 1JC-F = 249.1 Hz),
4
3
= 40.1 Hz), 137.1, 128.5 (d, JC-F = 3.5 Hz), 126.2 (d, JC-F = 8.1
Hz), 120.3, 119.0; HRMS (ESI) m/z [M+H]+ calcd for
+
C9H5BrFO2 : 242.9451, found 242.9474.
3-Fluorochromone 3h. White solid (84 mg, 70%): m.p. 95-96 ℃;
IR (neat) ν 3062, 2920, 1642, 1466, 1260, 1209, 1172, 832, 525
1
143.0 (d, JC-F = 40.1 Hz), 141.8, 132.0, 131.8, 128.4, 126.2,
1
3
4
cm-1; H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 8.15 (d,
125.2 (d, JC-F = 7.9 Hz), 124.5, 121.9 (d, JC-F = 3.6 Hz), 119.1;
HRMS (ESI) m/z [M+Na]+ calcd for C13H7FNaO2S+: 269.0043,
found 269.0067.
J = 3.1 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 7.5 Hz,
2H), 7.56 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.41–7.36
(m, 1H); 19F NMR (376 MHz, Chloroform-d) δ -165.70; 13C{1H}
3-Fluorochromone 3n. White solid (85 mg, 74%): m.p. 150-
151 ℃; IR (neat) ν 3093, 2922, 1462, 1466, 1256, 1175, 985, 823,
2
NMR (100 MHz, Chloroform-d) δ 170.6 (d, JC-F = 15.5 Hz),
155.2, 149.4 (d, 1JC-F = 248.9 Hz), 143.0 (d, 2JC-F = 40 Hz), 138.8,
138.5, 133.1, 129.1, 128.1, 127.2, 125.0 (d, 3JC-F = 7.7 Hz), 123.6
1
594 cm-1; H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H),
8.13 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.50–7.48 (m, 2H), 6.76 (s,
1H), 6.50 (s, 1H); 19F NMR (376 MHz, Chloroform-d) δ -165.73;
13C{1H} NMR (100 MHz, Chloroform-d) δ 170.3 (d, 2JC-F = 15.6
4
(d, JC-F = 3.4 Hz), 118.9; HRMS (ESI) m/z [M+Na]+ calcd for
+
C15H9FNaO2 : 263.0479, found 263.0500.
1
3-Fluorochromone 3i. White solid (71 mg, 56%): m.p. 125-
126 ℃; IR (neat) ν 2925, 1646, 1470, 1263, 1206, 1173, 1110,
Hz), 154.8, 151.8, 149.3 (d, JC-F = 249.0 Hz), 143.0, 142.9 (d,
2JC-F = 40.1 Hz), 129.6, 128.3, 125.0 (d, 3JC-F = 7.8 Hz), 120.0 (d,
4JC-F = 3.6 Hz), 118.9, 112.1, 106.7; HRMS (ESI) m/z [M+Na]+
1
890, 767, 579 cm-1; H NMR (400 MHz, Chloroform-d) δ 8.25 (s,
+
1H), 8.19 (d, J = 3.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.56 (d, J
= 8.7 Hz, 1H), 7.30–7.22 (m, 4H), 2.26 (s, 3H); 19F NMR (376
MHz, Chloroform-d) δ -165.74; 13C{1H} NMR (100 MHz,
calcd for C13H7FNaO3 : 253.0271, found 253.0289.
3-Fluorochromone 3o. White solid (59 mg, 56%): m.p. 172-
173℃; IR (neat) ν 3392, 2918, 1641, 1464, 1186, 895, 753, 683
616 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 8.13
(d, J = 3.4 Hz, 1H), 7.39 (s, 1H), 2.50 (s, 3H); 19F NMR (376
MHz, Chloroform-d) δ -165.72; 13C{1H} NMR (100 MHz,
1
Chloroform-d) δ 170.6 (d, 2JC-F = 15.5 Hz), 154.8, 149.5 (d, JC-F
2
= 249.0 Hz), 143.0 (d, JC-F = 40.0 Hz), 139.6, 139.4, 135.4,
135.3, 130.6, 129.9, 128.1, 126.1, 125.9 (d, 4JC-F = 3.4 Hz), 124.6
(d, 3JC-F = 7.7 Hz), 118.2, 20.5; HRMS (ESI) m/z [M+Na]+ calcd
1
Chloroform-d) δ 169.3 (d, 2JC-F = 16.1 Hz), 154.1, 149.2 (d, JC-F
+
for C16H11FNaO2 : 277.0634, found 277.0659.
2
= 249.6 Hz), 143.6, 142.9 (d, JC-F = 40.2 Hz), 132.3, 125.4 (d,
3
3-Fluorochromone 3j. White solid (100 mg, 74%): m.p. 155-
156 ℃; IR (neat) ν 3091, 1647, 1612, 1472, 1265, 1209, 1181,
1029, 892, 560 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 8.44
(s, 1H), 8.15 (d, J = 3.4 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.54 (d,
J = 8.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H),
7.13 (s, 1H), 6.92 (d, J = 7.4 Hz, 1H), 3.86 (s, 3H); 19F NMR (376
MHz, Chloroform-d) δ -165.72; 13C{1H} NMR (100 MHz,
4JC-F = 3.6 Hz), 123.8 (d, JC-F = 8.0 Hz), 120.1, 20.8; HRMS
(ESI) m/z [M+H]+ calcd for C10H7ClFO2 : 213.0113, found
+
213.0130.
3-Fluorochromone 3p. White solid (61mg, 38%): m.p. 130-
131 ℃; IR (neat) ν 3053, 2921, 1659, 1551, 1443, 1237, 1150,
1
874, 621 cm-1; H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J =
2.1 Hz, 1H), 8.25 (d, J = 2.9 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H);
2
Chloroform-d) δ 170.5 (d, JC-F = 15.6 Hz), 160.1, 155.2, 149.4
19F NMR (376 MHz, Chloroform-d) δ -163.77; 13C{1H} NMR
1
2
(d, JC-F = 248.9 Hz), 143.0 (d, JC-F = 40.1 Hz), 140.2, 138.3,
2
(100 MHz, Chloroform-d) δ 168.5 (d, JC-F = 16.4 Hz), 151.4,
3
4
133.1, 130.1, 124.9 (d, JC-F = 7.7 Hz), 123.6 (d, JC-F = 3.5 Hz),
1
2
149.3 (d, JC-F = 252.5 Hz), 143.4 (d, JC-F = 40.4 Hz), 139.9,
119.6, 118.9, 113.6, 112.8, 55.4; HRMS (ESI) m/z [M+Na]+
4
3
128.0 (d, JC-F = 3.3 Hz), 126.9 (d, JC-F = 8.3 Hz), 118.9, 113.2;
+
calcd for C16H11FNaO3 : 293.0584, found 293.0614.
HRMS (ESI) m/z [M+H]+ calcd for C9H3Br2NaFO2 : 342.8376 ,
+
3-Fluorochromone 3k. White solid (101 mg, 74%): m.p. 149-
150 ℃; IR (neat) ν 2921, 1644, 1467, 1192, 1117, 1086, 575 cm-1;
1H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.17 (d, J =
3.4 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.59–7.56 (m, 3H), 7.44 (d,
J = 8.0 Hz, 2H); 19F NMR (376 MHz, Chloroform-d) δ -165.50;
13C{1H} NMR (100 MHz, Chloroform-d) δ 170.4 (d, 2JC-F = 15.7
Hz), 155.3, 149.5 (d, 1JC-F = 249.7 Hz), 143.0 (d, 2JC-F = 40.1 Hz),
found 342.8392.
Fluorochromone 3q. White solid (65 mg, 61%): m.p. 174-175 ℃;
IR (neat) ν 3391, 2920, 1740, 1642, 1459, 1362, 1196, 1080, 965,
1
766 cm-1; H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 8.0
Hz, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.91
(d, J = 7.6 Hz, 1H), 7.76–7.65 (m, 3H); 19F NMR (376 MHz,
Chloroform-d) δ -164.37; 13C{1H} NMR (100 MHz, Chloroform-
d) δ 170.2 (d, 2JC-F =15.5 Hz), 153.4, 150.6 (d, 1JC-F = 250.6 Hz),
3
137.31, 137.29, 134.4, 132.7, 129.2, 128.5, 125.1 (d, JC-F = 7.9
4
Hz), 123.6 (d, JC-F = 3.6 Hz), 119.1; HRMS (ESI) m/z [M+Na]+
2
142.1 (d, JC-F = 40.2 Hz), 135.8, 129.8, 128.2, 127.6, 125.7,
+
calcd for C15H8ClFNaO2 : 297.0089, found 297.0112.
3
4
123.8, 122.3, 121.4 (d, JC-F = 7.9 Hz), 120.4 (d, JC-F = 3.0 Hz);
+
3-Fluorochromone 3l. White solid (113 mg, 76%): m.p. 202-
203 ℃; IR (neat) ν 3078, 2157, 1712, 1657, 1289, 1178, 1113,
HRMS (ESI) m/z [M+H]+ calcd for C13H8FO2 : 215.0503, found
215.0521.
1
828, 708 cm-1; H NMR (400 MHz, Chloroform-d) δ 8.52 (s, 1H),
Fluoro enaminone 3r. Ilky liquid (47 mg, 49%): IR (neat) ν 2918,
8.19 (s, 1H), 8.13 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 8.6 Hz, 1H),
7.71 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 8.6 Hz, 1H), 3.95 (s, 3H);
19F NMR (376 MHz, Chloroform-d) δ -165.37; 13C{1H} NMR
1656, 1539, 1336, 1116, 946, 847, 699 cm-1; H NMR (400 MHz,
1
Chloroform-d) δ 7.62 (d, J = 7.1 Hz, 2H), 7.45–7.37 (m, 3H),
6.66 (d, J = 27.6 Hz, 1H), 3.08 (s, 6H); 19F NMR (376 MHz,
Chloroform-d) δ -166.45; 13C{1H} NMR (100 MHz, Chloroform-
2
(100 MHz, Chloroform-d) δ 170.3 (d, JC-F = 15.7 Hz), 166.7,
155.6, 149.5 (d, 1JC-F = 250.0 Hz), 143.0 (d, 2JC-F = 40 Hz), 143.1,

7
5
d) δ 185.5 (d, 2JC-F = 19.1 Hz), 140.0 (d, 1JC-F = 228.4 Hz), 138.7,
NMR (100 MHz, Chloroform-d) δ 160.7, 157.7 (d, JC-F = 6.3
3
1
137.4 (br), 130.6, 128.4 (d, JC-F = 3.6 Hz), 128.1, 42.8 (br);
Hz), 153.1 (d, JC-F = 268.8 Hz), 152.1 (d, JC-F = 6.5 Hz), 147.2
HRMS (ESI) m/z [M+H]+ calcd for C11H13FNO+: 194.0976,
found:194.0986.
(d, JC-F = 26.1 Hz), 137.6, 133.9, 130.4 (d, JC-F = 19.5 Hz), 129.2,
119.5 (d, JC-F = 2.2 Hz), 118.7, 114.7 (d, JC-F = 6.1 Hz); HRMS
(ESI) m/z [M+H]+ calcd for C16H11ClFN2O+: 301.0538, found
301.0541.
Fluoro enaminone 3s. Ilky liquid (43 mg, 42%): IR (neat) ν 2920,
1657, 1578, 1433, 1331, 1114, 942, 746 cm-1; 1H NMR (400
MHz, Chloroform-d) δ 7.54 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 7.9
Hz, 2H), 6.68 (d, J = 27.8 Hz, 1H), 3.08 (s, 6H), 2.38 (s, 3H); 19F
NMR (376 MHz, Chloroform-d) δ -166.14; 13C{1H} NMR (100
MHz, Chloroform-d) δ 185.4 (d, 2JC-F = 19.2 Hz), 141.1, 140.2 (d,
Fluoro pyrimidine 5e. White solid (89 mg, 63%): m.p. 227-
228 ℃; IR (neat) ν 3093, 1643, 1500, 1256, 1206, 1175, 986, 823,
732, 593 cm-1; H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H),
1
8.80 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.0 Hz, 1H),
7.40 (t, J = 6.9 Hz, 1H), 7.07–6.92 (m, 2H), 6.67 (d, J = 8.0 Hz,
2H), 5.71 (s, 2H); 19F NMR (376 MHz, Chloroform-d) δ -138.14;
13C{1H} NMR (100 MHz, DMSO-d6) δ 160.2 (d, JC-F = 5.8 Hz),
3
1JC-F = 229.0 Hz), 136.8 (br), 135.8, 128.7, 128.6 (d, JC-F = 4.0
Hz), 42.8 (br), 21.5; HRMS (ESI) m/z [M+H]+ calcd for
C12H15FNO+: 208.1132, found : 208.1137.
1
157.4, 153.4 (d, JC-F = 262.1 Hz), 152.0, 151.96 (d, JC-F = 10.5
5.2 General procedures for synthesis of 5a-5f.
Hz), 146.2 (d, JC-F = 24.3 Hz), 132.6, 131.0 (d, JC-F = 7.0 Hz),
129.6, 123.8, 119.7, 119.6 (d, JC-F = 4.6 Hz), 117.1, 114.0;
HRMS (ESI) m/z [M+H]+ calcd for C16H13FN3O+: 282.1037,
found : 282.1049.
A suspension of 3a (0.5 mmol, 1 equiv.), amidines or
guanidine (1.0 mmol, 2 equiv.), and K2CO3 (1.0 mmol, 2 equiv.)
in EtOH (2.0 mL) was refluxed for 3h. After the solvent was
removed in vacuo, the resulting residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl
acetate = 100/3 to 10/1) to yield fluoro-pyrimidines or fluoro-
pyridine.
Fluoro pyridine 5f. White solid (100 mg, 73%): m.p. 191-192 ℃;
IR (neat) ν 3425, 3291, 2921, 1691, 1575, 1456, 1188, 617 cm-1;
1H NMR (400 MHz, Chloroform-d) δ 13.43 (br s, 1H), 8.08 (d, J
= 8.1 Hz, 1H), 8.02 (d, J = 12.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H),
7.01 (d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.41 (br s, 2H),
4.37 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 19F NMR (376
MHz, Chloroform-d) δ -133.26; 13C{1H} NMR (100 MHz,
Fluoro pyrimidine 5a. White solid (91 mg, 89%): m.p. 212-
213 ℃; IR (neat) ν 3374, 3180, 2920, 1645, 1574, 1453, 1193,
1
753, 542 cm-1; H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H),
1
Chloroform-d) δ 165.5, 159.7, 153.3, 148.9 (d, JC-F = 248.8 Hz),
148.5 (d, JC-F = 9.5 Hz), 132.5 (d, JC-F = 2.1 Hz), 130.0 (d, JC-F
8.43 (d, J = 3.8 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.4
Hz, 1H), 7.04 (s, 2H), 7.00–6.91 (m, 2H); 19F NMR (376 MHz,
DMSO-d6) δ -151.34; 13C{1H} NMR (100 MHz, DMSO-d6) δ
159.3 (d, JC-F = 2.4 Hz), 159.1, 151.4 (d, JC-F = 9.0 Hz), 148.5 (d,
1JC-F = 247.9 Hz), 148.5 (d, JC-F = 26.4 Hz), 132.8, 130.5 (d, JC-F
= 14.5 Hz), 119.3, 118.1, 117.1 (d, JC-F = 5.5 Hz); HRMS (ESI)
m/z [M+H]+ calcd for C10H9FN3O+: 206.0724 , found 206.0720.
=
20.3 Hz), 128.9 (d, JC-F = 24.9 Hz), 119.0 (d, JC-F = 2.3 Hz),
118.3, 116.4 (d, JC-F = 6.7 Hz), 104.8 (d, JC-F = 3.9 Hz), 61.4,
14.3; HRMS (ESI) m/z [M+Na]+ calcd for C14H13FN2NaO3 :
+
299.0802, found 299.0818.
5.3 Synthetic procedure for the preparation of 7.
Fluoro pyrimidine 5b. White solid (94 mg, 82%): m.p. 118-
119 ℃; IR (neat) ν 2691, 1573, 1444, 1302, 1265, 1192, 1060,
923, 540 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 13.45 (s,
1H), 8.47 (d, J = 4.7 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.37 (t, J
= 7.6 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H),
2.26 (p, J = 6.4 Hz, 1H), 1.13 (d, J = 6.5 Hz, 4H); 19F NMR (376
Monofluorinated chromone 3a (0.5 mmol, 1 equiv.), o-
nitrophenylactonitrile (1 mmol, 2 equiv.), Zn dust (4.0 mmol, 8
equiv.), TEA (1.5 mmol, 3 equiv.) and AcOH (15 mmol) were
added to a reaction flask. The reaction mixture was stirred and
heated to reflux for 4 h. After completion of the reaction, the
mixture was diluted with water and extracted by EtOAc. After
drying by anhydrous Na2SO4, EtOAc was removed under
reduced pressure. The residue was purified by was purified by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 20/1) to yield product 7 (70 mg, 50%).
MHz, Chloroform-d) δ −137.14; 13C{1H} NMR (100 MHz,
1
Chloroform-d) δ 165.7 (d, JC-F = 6.0 Hz), 160.8, 152.5 (d, JC-F
=
264.6 Hz), 151.5 (d, JC-F = 6.1 Hz), 146.8 (d, JC-F = 25.8 Hz),
133.5 (d, JC-F = 2.2 Hz), 130.3 (d, JC-F = 19.8 Hz), 119.2 (d, JC-F
=
2.2 Hz), 118.6, 114.7 (d, JC-F = 6.1 Hz), 17.6, 11.0; HRMS (ESI)
m/z [M+H]+ calcd for C13H12FN2O+: 231.0928, found 231.0922.
fluoro carboline 7. White solid, m.p: 240-241 ℃; IR (neat) ν
3275, 2919, 1598, 1492, 1432, 1280, 1165, 825, 744, 629, 593
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.96 (s,
1H), 8.57 (d, J = 11.1 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.63 (d,
J = 7.6 Hz, 1H), 7.55–7.48 (m, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.26
(t, J = 7.3 Hz, 1H), 7.01–6.92 (m, 2H); 19F NMR (376 MHz,
DMSO-d6) δ -131.76; 13C{1H} NMR (100 MHz, DMSO-d6) δ
Fluoro pyrimidine 5c. White solid (114 mg, 86%): m.p. 121-
122 ℃; IR (neat) ν 2919, 1560, 1432, 1280, 1195, 830, 637 cm-1;
1H NMR (400 MHz, Chloroform-d) δ 13.46 (br s, 1H), 8.58 (d, J
= 3.9 Hz, 1H), 8.18–8.09 (m, 2H), 8.01 (d, J = 7.8 Hz, 1H), 7.46–
7.34 (m, 3H), 7.31 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H),
6.84 (t, J = 7.3 Hz, 1H); 19F NMR (376 MHz, Chloroform-d) δ -
134.52; 13C{1H} NMR (100 MHz, Chloroform-d) δ 160.7, 158.7
(d, JC-F = 6.3 Hz), 153.1 (d, 1JC-F = 268.2 Hz), 152.0 (d, JC-F = 6.4
1
156.7, 152.5 (d, JC-F = 244.1 Hz), 147.5, 141.6 (d, JC-F = 17.2
Hz), 140.7, 130.84, 130.78, 127.7, 122.1, 122.0 (d, JC-F = 4.8 Hz),
120.6, 120.1, 119.4, 117.0, 116.99 (d, JC-F = 24.3 Hz), 115.5 (d,
JC-F = 6.8 Hz), 112.0; HRMS (ESI) m/z [M+Na]+ calcd for
C17H11FN2NaO+: 301.0748, found : 301.0768.
Hz), 147.2 (d, JC-F = 26.0 Hz), 135.5, 133.8 (d, JC-F = 2.1 Hz),
2
131.2, 130.4 (d, JC-F = 19.5 Hz), 129.0, 128.0, 119.4 (d, JC-F
=
2.1 Hz), 118.7, 114.9 (d, JC-F = 6.0 Hz); HRMS (ESI) m/z
[M+H]+ calcd for C16H12FN2O+: 267.0928, found 267.0927.
Acknowledgements
Fluoro pyrimidine 5d. White solid (97 mg, 77%): m.p. 157-
158 ℃; IR (neat) ν 2920, 1584, 1429, 1279, 1191, 1084, 800, 569
cm-1; 1H NMR (400 MHz, Chloroform-d) δ 13.32 (br s, 1H), 8.66
(d, J = 4.5 Hz, 1H), 8.15 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.2 Hz,
1H), 7.45–7.39 (m, 3H), 7.05 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.6
Hz, 1H); 19F NMR (376 MHz, Chloroform-d) δ -133.95; 13C{1H}
We gratefully acknowledge the financial support from the
National Natural Science foundation of China (21576296,
21676302, 21776318 & 81703365) and Central South University.
Notes and references

8
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A BHT-regulated chemoselective monofluorination of enaminones with Selectfluor under mild
reaction conditions was unveiled for the first time. As a result, an array of monofluorinated
chromones were efficiently assembled in a simple operational manner. Moreover, the scalability
of this protocol and the versatility for the downstream transformations of the obtained fluorinated
chromones to installing diverse nitrogen-containing heterocycles greatly broaden the practical
applications of this developed protocol.

The authors declared that they have no conflicts of interest to this work.
We declare that we do not have any commercial or associative interest that
represents a conflict of interest in connection with the work submitted.