Palladium-Catalyzed C-H Bond Monofluorination of 2-Arylbenzo[ d ]oxazinone Using Nitrate as Crucial Promoter

Article abstract of DOI:10.1055/s-0037-1611700

Monofluorination of 2-arylbenzo[ d ]oxazinones with N -fluorobenzenesulfonimide (NFSI) was achieved by palladium catalysis in moderate to good yields. Promoted by nitrate, the reaction provides an economic and environmentally friendly strategy. The synthesis of monofluorinated 2-arylbenzo[ d ]oxazinones has good compatibility with many common functional groups. The plausible mechanism of this monofluorination is discussed.

Full text of DOI:10.1055/s-0037-1611700

SYNTHESIS
0
0
3
9
-
7
8
8
1
1 4 3 7 - 2 1 0 X
© Georg
Thieme Ver-
lag Stuttgart
· New York
2019, 51, A–G
A
H.-M. Vu et al.
Paper
Synthesis
Palladium-Catalyzed C–H Bond Monofluorination of
2-Arylbenzo[d]oxazinone Using Nitrate as Crucial Promoter
Huu-Manh Vu
Xu-Qin Li*
O
O
PdCl2
nitrate salt
O
O
R1
NFSI
R1
+
Fei-Wu Chen
DCE, 100 °C
under air
N
N
R2
R2
School of Chemical and Biological Engineering,
University of Science and Technology Beijing,
30 Xueyuan Road, Haidian District, Beijing
100083, P.R. of China
H
F
R1 = Me, OMe, F, Cl, Br
R2 = Me, OMe, F, Cl, Br, CF3,
Ph, NO2, CO2Me
22 examples
up to 86% yield
1. Highly site-selective
2. Green: nitrate as promoter
and reaction under air
lixuqin@ustb.edu.cn
Received: 14.10.2018
Accepted after revision: 17.11.2018
Published online: 09.01.2019
2,4,6-trimethylpyridinium triflate as the fluorinating re-
agent, and NMP as the crucial promoter.8 Using two kinds
of directing groups, O-methyloxime and 2-pyridyloxy, Xu et
al. developed a Pd-catalyzed direct C(sp2)–H bond fluorina-
tion.9 The previous C–H bond fluorination studies show
that aryl-N-heterocyclic groups are better directing groups
for this type of transformation. Considerable endeavors
have been made for the selective aromatic C–H bond fluori-
nation by using aryl-N-heterocycle directing groups, in-
cluding quinoxaline, pyrazole, benzo[d]oxazole, and -pyra-
zine,10 benzo[d]thiazole,11 and quinazolinone12 in the past
few years. Meanwhile, many Pd-catalyzed direct C(sp3)−H
fluorination reactions have been reported recently. For ex-
ample, Sanford and coworkers,1b Doyle,13 Yu,14 Shi,15 and
Zhao16 have successfully achieved C(sp3)−H bond fluorina-
tion through palladium catalysis. Moreover, methods for
catalyzing C–H fluorination using other transition metals as
the catalyst have also emerged in the literature.17
2-Arylbenzo[d]oxazinone is a very important nitroge-
nous heterocyclic compound and has a wide range of appli-
cations in pharmaceutical research.18 Particularly, 2-aryl-
benzo[d]oxazinones are common in natural products and
bioactive molecules, and have a variety of biological activi-
ties such as for the treatment of skin diseases, including in-
flammation such as Netherton syndrome,19 antiplatelet
agents, antiproliferative activity against a wide range of hu-
man tumor cell lines,20 use as serine hydrolase inhibitors,21
α-chymotrypsin inhibitor,22 inhibitor of C1r serine prote-
ase,23 and high-density lipoprotein (HDL) elevator.24 A few
representative examples are shown in Figure 1. Conse-
quently, the structures of 2-arylbenzo[d]oxazinone and de-
rivatives have been an intensive research focus in synthetic
chemistry. On the basis of our recent research on 2-aryl-
benzo[d]oxazinone,25 we decided to use benzoxazinone as a
directing group in the work reported here.
DOI: 10.1055/s-0037-1611700; Art ID: ss-2018-h0540-op
Abstract Monofluorination of 2-arylbenzo[d]oxazinones with N-fluo-
robenzenesulfonimide (NFSI) was achieved by palladium catalysis in
moderate to good yields. Promoted by nitrate, the reaction provides an
economic and environmentally friendly strategy. The synthesis of
monofluorinated 2-arylbenzo[d]oxazinones has good compatibility
with many common functional groups. The plausible mechanism of this
monofluorination is discussed.
Key words 2-arylbenzo[d]oxazinones, palladium catalysis, C–H bond
functionalization, fluorination, directing groups
It has become evident that fluorinated compounds are
often valuable in medicinal chemistry, because the substi-
tution of hydrogen with fluorine can have a profound im-
pact on the metabolism, lipophilicity, and biological activi-
ty of organic compounds.1 However, fluorinated organic
molecules are generally challenging to synthesize efficient-
ly because of the highly electronegative nature of fluorine.
Recently, with the rapid development of organometallic
chemistry, Pd-catalyzed C–H bond activation/functional-
ization has emerged as an effective and important approach
to construct C–C bonds,2 C–O bonds,3 C–N bonds,4 and
C–halogen bonds5 in organic synthesis, but the construc-
tion of C–F bonds from C–H bonds is still challenging.
During the last few years, as a result of ligand-directed Pd
catalysis, C–H bond fluorination has begun to make prog-
ress.6 The pioneering work of pyridine-directed Pd-cata-
lyzed C–H bond activation/fluorination with an electrophil-
ic fluorinating reagent was reported by the Sanford group
in 2006.7 In addition, Yu and co-workers studied two types
of triflamide- and N-arylamide-group-directed ortho C–H
bond fluorination using Pd(II) as the catalyst, N-fluoro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

B
H.-M. Vu et al.
Paper
Synthesis
Table 1 Optimization of Reaction Conditionsa
O
N
O
O
N
F
O
Br
O
O
O
N
O
I
[Pd] (10 mol%)
O
additive (x equiv)
O
O
F
NFSI
N
O
+
solvent,
temperature
under air
N
N
F
F
α-chymotrypsin inhibitor
C1r serine protease
inhibitor
HDL-elevator
1a
2a
2aa′
Yieldb (%)
Figure 1 Some bioactive molecules with 2-arylbenzo[d]oxazinone
Entry
Catalyst
Additive (equiv) Solvent
scaffolds
2a
2aa′
1
2
PdCl2
TFA (2.0)
DCE
30
trace
44
68
50
43
42
17
58
trace
37
58
0
0
0
As far as we know, Pd-catalyzed direct C–H bond fluori-
nation using benzo[d]oxazinone as a directing group has
not yet been reported. Herein we report a new protocol for
Pd-catalyzed ortho C–H bond fluorination of 2-arylben-
zo[d]oxazinone employing N-fluorobenzenesulfonimide
(NFSI) as the fluorination reagent, promoted by inexpensive
and non-toxic nitrate.
PdCl2
AcOH (2.0)
NMP (2.0)
DCE
3
PdCl2
DCE
0
4
PdCl2
NaNO3 (0.5)
AgNO3 (0.5)
KNO3 (0.5)
AgNO2 (0.5)
NaNO2 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
–
DCE
trace
25
25
16
0
5
PdCl2
DCE
6
PdCl2
DCE
7
PdCl2
DCE
We started our studies by using 2-phenylbenzo[d]oxazi-
none 1a as the model substrate and electrophilic fluoride
reagent NFSI as the F+ source to optimize the reaction con-
ditions (Table 1). When a mixture of 1a (0.2 mmol) and
NFSI (2 equiv) was treated with PdCl2 (10 mol%) as catalyst
and TFA (2 equiv) as the additive in DCE (3 mL) at 110 °C for
24 hours, the desired ortho-monofluorinated product 2a
was obtained in 30% yield (Table 1, entry 1). An initial
screen of additives showed that when the additive was
switched to AcOH, only a trace of 2a was obtained (entry 2).
The use of NMP instead of TFA gave a slightly higher yield
(entry 3). According to a reported method,9a we used nitrate
or nitrite as the additives (entries 4–8). Interestingly, the
use of NaNO3 showed better selectivity, giving the major
monofluorinated product 2a in 68% yield with only a trace
of the difluorinated product 2aa′ (entry 4). When other ad-
ditives such as AgNO3, KNO3, AgNO2, or NaNO2were used,
the selectivity of the reaction decreased, with a lower yield
of product 2a and formation of product 2aa′ (entries 5–8).
Thus, NaNO3 was selected as the additive. We used a series
of other palladium catalysts such as Pd(OAc)2, Pd(PPh3)4,
and Pd2(dba)3 for screening, but the results were inferior to
those with PdCl2 (entries 9–11). When Pd(NO3)2·2H2O was
used as the catalyst, the desired product 2a was observed in
moderate yield (entry 12). However, no product was detect-
ed in the absence of catalyst (entry 13). Solvent screening
revealed that only the use of DCE as solvent resulted in a
good yield of product 2a (entries 4 and 14–19). The product
yield decreased when Selectfluor was used instead of NFSI
or the reaction temperature was decreased or increased
(entries 20–22). Finally, the optimized reaction conditions
for the selective C–H bond fluorination of 2-phenylben-
zo[d]oxazinone were determined to be the following: PdCl2
as the catalyst, NFSI as the fluorination reagent, a nitrate
salt as the additive, and DCE as the solvent, at 110 °C, under
air, for 24 hours.
8
PdCl2
DCE
9
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
Pd(NO3)2·2H2O
–
DCE
0
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
DCE
0
DCE
0
DCE
0
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
NaNO3 (0.5)
DCE
0
PdCl2
DMF
DMSO
MeNO2
MeCN
toluene
THF
0
0
PdCl2
0
0
PdCl2
25
8
0
PdCl2
0
PdCl2
12
0
0
PdCl2
0
PdCl2
DCE
15
12
56
0
PdCl2
DCE
0
PdCl2
DCE
trace
a Reaction conditions: 1a (0.2 mmol), [Pd] cat. (10 mol%), NFSI (2 equiv),
additive (x equiv), solvent (2 mL), 110 °C, under air, 24 h.
b Isolated yield.
c Selectfluor was used as the F+ source.
d At 80 °C.
e At 130 °C.
With the optimized reaction conditions for C–H bond
fluorination established, the scope and compatibility of 2-
arylbenzo[d]oxazinone substrates were investigated. The
corresponding fluorinated products could be obtained with
either sodium nitrate or silver nitrate as additive. Except for
substrate 1a, the other substrates gave the best yields when
silver nitrate was used as additive. As summarized in
Scheme 1, the reaction has good compatibility with many
common functional groups, and moderate to good yields of
the corresponding products were obtained in most sub-
strates. Substrates with different R1 substituents on the
benzo ring afford fluorinated products 2a–f in moderate
yields under the standard conditions (Scheme 1). Sub-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

C
H.-M. Vu et al.
Paper
Synthesis
sequently, the effects of substituents on the 2-phenyl rings
giving products 2g–p were investigated. Substrates with
substituents Me or F at the ortho position of the 2-phenyl
ring afforded the corresponding products 2g,h in good
yields, while a methyl group at the meta position resulted in
the desired product 2i forming only in a lower yield togeth-
er with a trace amount of another product. In addition, sub-
strates 1j–r bearing electron-donating or electron-with-
drawing groups at the para position of the 2-phenyl ring all
smoothly gave the corresponding fluorinated products 2j–r
in moderate yields under the developed reaction condi-
tions. 2-Naphthyl-substituted substrate 1s was transformed
into the desired product 2s in moderate yield. However, 2-
heteroaryl-substituted benzo[d]oxazinones 1t, u failed to
afford the desired fluorinated products 2t, u.
O
N
O
N
PdCl2 (10 mol%)
NFSI (2.0 equiv)
O
O
AgNO3 (0.5 equiv)
DCE, 110 °C
24 h, under air
F
3v 0%
1v
O
N
O
O
O
PdCl2 (10 mol%)
NFSI (2.0 equiv)
O
O
+
AgNO3 (0.5 equiv)
DCE, 110 °C
24 h, under air
N
F
N
F
3w 0%
2w 55%
1w
Scheme 2 Fluorination of 8-methylbenzo[d]oxazinones
tion pathway (Scheme 3). First, the palladium catalyst re-
acts with the nitrate to generate a highly reactive cationic
[Pd(NO3)]+ species for subsequent C–H activation of two
molecules of 1a , resulting in cyclopalladium(II) intermedi-
ates A and B. Then, Pd(IV) key intermediate C is formed af-
ter oxidative addition of NFSI. Next, intermediate C under-
goes reductive elimination to afford the ortho-fluorinated
product 2a and Pd(II) intermediate D. Finally, intermediate
D reacts with HNO3 to give intermediate A and to continue
the catalytic cycle.
O
O
PdCl2 (10 mol%)
AgNO3 (0.5 equiv)
NFSI (2 equiv)
R1
R1
O
O
N
DCE, 110 °C
under air, 24 h
N
R2
R2
H
F
2
1
O
R1
2a R1 = H, 68%a
2b R1 = Me, 63%
2c R1 = OMe, 41%
2d R1 = F, 59%
2e R1 = Cl, 51%
2f R1 = Br, 57%
O
N
F
–
NO3
2g R2 = 2-Me, 70%
2h R2 = 2-F, 86%
2i R2 = 3-Me, 29%
2j R2 = 4-Me, 49%
2k R2 = 4-OMe, 52%
2l R2 = 4-CF3, 53%
2m R2 = 4-F, 52%
2n R2 = 4-Cl, 63%
2o R2 = 4-Br, 68%
2p R2 = 4-Ph, 53%
2q R2 = 4-NO2, 45%
[PdII(NO3)]+
PdII catalyst
O
N
O
N
1a
O
F
cyclopalladation
2
1
3
O
R2
2r R2 = 4-CO2Me, 55%
O
N
4
O
O
O
O
O
O
N
O
F
(PhSO2)2NH
1a
PdII
S
O
N
N
HNO3
O
NO3
HNO3
F
F
A
2u 0%
2t 0%
O
2s 50%
O
O
Scheme 1 Scope of the fluorination of 2-arylbenzo[d]oxazinones with
NFSI. Reagents and conditions: 1 (0.3 mmol), PdCl2 (0.03 mmol), NFSI
(0.6 mmol), AgNO3 (0.15 mmol), DCE (3 mL), 110 °C, under air, 24 h;
isolated yields. a NaNO3 used as additive.
N
N
PdII
N
PdII
D
N(SO2Ph)2
O
N
To investigate whether C(sp3)–H bond fluorination can
be detected under these reaction conditions, we used 8-
methyl-substituted benzo[d]oxazinones 1v and 1w as sub-
strates for following the progress of the fluorination reac-
tion. As shown in Scheme 2, neither C(sp3)–H fluorination
product 3v nor 3w was observed, and substrate 1w only
provided fluorinated product 2w.
O
O
O
O
N
F
O
B
F
NFSI
PdIV
N(SO2Ph)2
N
2a
O
Based on previous reports,7,9a a possible mechanism for
this reaction is hypothesized, in which oxidation to Pd(IV)
occurs, followed by a C–F bond-forming reductive elimina-
O
C
Scheme 3 Proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

D
H.-M. Vu et al.
Paper
Synthesis
In summary, we have developed a selective Pd-cata-
lyzed ortho C–H bond monofluorination of 2-arylben-
zo[d]oxazinone, by employing NFSI as the fluorination re-
agent and inexpensive and non-toxic nitrate as the promot-
er. This fluorination has the significant advantages of being
economic, highly site-selective, and environmentally
friendly in comparison with the other transition-metal-cat-
alyzed approaches. The reaction has good compatibility
with many common functional groups and smoothly gen-
erates the corresponding valuable monofluorinated prod-
ucts in moderate to good yields. Further studies on other
functionalizations of 2-arylbenzo[d]oxazinones are cur-
rently underway in our laboratory.
HRMS (ESI): m/z [M + H]+ calcd for C15H11FNO2: 256.0768; found:
256.0768.
2-(2-Fluorophenyl)-6-methoxy-4H-benzo[d][1,3]oxazin-4-one
(2c)
Yield: 33 mg (41%); white solid; mp 168–171 °C.
1H NMR (400 MHz, CDCl3): δ = 8.07 (t, J = 7.6 Hz, 1 H), 7.65–7.58 (m, 2
H), 7.50 (dd, J = 13.1, 7.3 Hz, 1 H), 7.38 (d, J = 8.9 Hz, 1 H), 7.26–7.15
(m, 2 H), 3.90 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 162.53, 159.94, 159.58, 152.83,
140.87, 133.75, 130.92, 128.99, 126.35, 124.30, 119.14, 117.81,
117.31, 108.68, 55.97.
19F NMR (471 MHz, CDCl3): δ = –109.55 to –109.67 (m).
HRMS (ESI): m/z [M + H]+ calcd for C15H11FNO3: 272.0717; found:
272.0719.
Chemicals and reagents were purchased from commercial suppliers
6-Fluoro-2-(2-fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2d)
1
and used without special instructions. H and 13C NMR spectra were
Yield: 46 mg (59%); white solid; mp 141–144 °C.
obtained on a Bruker 400 MHz instrument, operating at 400 and 101
MHz, respectively, of samples in CDCl3 and by using TMS as internal
standard. 19F NMR spectra were recorded on a Bruker Avance 500
MHz instrument of samples in CDCl3 at 471 MHz. HRMS was carried
out on an Agilent 6520 LC/MS instrument with an ESI source. Unless
otherwise noted, the purification of products was performed by using
column chromatography on silica gel.
1H NMR (400 MHz, CDCl3): δ = 8.11 (td, J = 7.7, 1.5 Hz, 1 H), 7.90 (dd,
J = 7.7, 2.9 Hz, 1 H), 7.74 (dd, J = 8.9, 4.8 Hz, 1 H), 7.56 (td, J = 8.1, 3.0
Hz, 2 H), 7.29 (t, J = 7.4 Hz, 1 H), 7.23 (dd, J = 10.9, 9.1 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 162.81, 160.26, 158.43, 154.19,
143.29, 134.11, 131.06, 129.78, 124.55, 118.75, 118.35, 117.42,
117.06, 113.93.
19F NMR (471 MHz, CDCl3): δ = –108.98 to –109.09 (m), –109.14 to
–109.18 (m).
HRMS (ESI): m/z [M + H]+ calcd for C14H8F2NO2: 260.0518; found:
260.0521.
2-(2-Fluoroaryl)-4H-benzo[d][1,3]oxazin-4-ones 2; General Proce-
dure
A mixture of 2-arylbenzo[d]oxazinone 1 (0.3 mmol), NFSI (0.6 mmol,
2.0 equiv, 189 mg), PdCl2 (0.03 mmol, 0.1 equiv, 5.3 mg), and MNO3
(M = Na or Ag; 0.15 mmol, 0.5 equiv) in DCE (3 mL) was stirred at 110
°C under air for 24 h, and then the mixture was cooled to r.t. The
crude product was purified by column chromatography (silica gel,
PE/EtOAc) to give the corresponding product 2.
6-Chloro-2-(2-fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2e)
Yield: 42 mg (51%); white solid; mp 146–148 °C.
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 2.3 Hz, 1 H), 8.15–8.09 (m, 1
H), 7.78 (dd, J = 8.6, 2.3 Hz, 1 H), 7.67 (d, J = 8.6 Hz, 1 H), 7.56 (dd, J =
13.3, 7.1 Hz, 1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.26–7.20 (m, 1 H).
2-(2-Fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2a)18b,22a
13C NMR (101 MHz, CDCl3): δ = 162.76, 160.17, 158.10, 155.02,
145.20, 136.94, 134.33, 131.14, 129.01, 127.93, 124.38, 118.68,
118.10, 117.28.
19F NMR (471 MHz, CDCl3): δ = –108.64 to –108.78 (m).
HRMS (ESI): m/z [M + H]+ calcd for C14H8ClFNO2: 276.0222; found:
Yield: 49 mg (68%); white solid; mp 114–116 °C.
1H NMR (400 MHz, CDCl3): δ = 8.26 (d, J = 7.9 Hz, 1 H), 7.89 (d, J = 7.7
Hz, 1 H), 7.84 (t, J = 7.7 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.6
Hz, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1 H), 7.38 (t, J = 7.0
Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 159.25, 156.61, 146.47, 136.66,
133.51, 132.47, 131.47, 131.13, 130.34, 129.00, 128.5, 127.47, 126.89,
117.02.
276.0226.
6-Bromo-2-(2-fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2f)
19F NMR (471 MHz, CDCl3): δ = –109.06 to –109.23 (m).
HRMS (ESI): m/z [M + H]+ calcd for C14H9FNO2: 242.0612; found:
Yield: 55 mg (57%); white solid; mp 169–171 °C.
1H NMR (400 MHz, CDCl3): δ = 8.37 (s, 1 H), 8.12 (t, J = 7.5 Hz, 1 H),
7.93 (dd, J = 8.6, 1.3 Hz, 1 H), 7.64–7.52 (m, 2 H), 7.30 (t, J = 7.6 Hz, 1
H), 7.26–7.18 (m, 1 H).
242.0616.
2-(2-Fluorophenyl)-6-methyl-4H-benzo[d][1,3]oxazin-4-one (2b)
13C NMR (101 MHz, CDCl3): δ = 162.77, 160.17, 157.91, 155.15,
145.56, 139.74, 134.32, 131.05, 129.14, 124.54, 122.06, 118.69,
118.37, 117.51.
19F NMR (471 MHz, CDCl3): δ = –108.60 to –108.73 (m).
HRMS (ESI): m/z [M + H]+ calcd for C14H8BrFNO2: 319.9717; found:
Yield: 48 mg (63%); white solid; mp 147–150 °C.
1H NMR (400 MHz, CDCl3): δ = 8.15–8.08 (m, 1 H), 8.05 (s, 1 H), 7.63
(d, J = 8.3 Hz, 2 H), 7.58–7.48 (m, 1 H), 7.28 (t, J = 6.6 Hz, 1 H), 7.22 (dd,
J = 10.8, 8.7 Hz, 1 H), 2.50 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 162.62, 160.04, 159.39, 154.10,
144.55, 139.28, 137.81, 133.77, 131.04, 128.15, 127.24, 124.81,
119.16, 116.71, 21.30.
319.9719.
2-(2-Fluoro-6-methylphenyl)-4H-benzo[d][1,3]oxazin-4-one (2g)
19F NMR (471 MHz, CDCl3): δ = –109.30 to –109.43 (m).
Yield: 54 mg (70%); white solid; mp 98–101 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

E
H.-M. Vu et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 7.5 Hz, 1 H), 7.84 (t, J = 7.2
Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.37–7.28 (m,
1 H), 7.11–6.96 (m, 2 H), 2.44 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 164.23, 161.52, 159.39, 154.90,
147.06, 136.49, 132.17, 128.49, 128.19, 127.18, 116.81, 111.23,
110.66, 102.75, 55.87.
13C NMR (101 MHz, CDCl3): δ = 162.01, 159.47, 154.87, 146.24,
139.62, 136.66, 131.98, 129.13, 128.64, 127.31, 126.19, 120.34,
117.10, 113.45, 19.73.
19F NMR (471 MHz, CDCl3): δ = –105.44 (dd, J = 13.2, 8.1 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C15H11FNO3: 272.0717; found:
272.0721.
19F NMR (471 MHz, CDCl3): δ = –114.04 (dd, J = 9.5, 5.8 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C15H11FNO2: 256.0768; found:
2-[2-Fluoro-4-(trifluoromethyl)phenyl]-4H-benzo[d][1,3]oxazin-
4-one (2l)
256.0771.
Yield: 49 mg (53%); white solid; mp 88–91 °C.
1H NMR (400 MHz, CDCl3): δ = 8.26 (t, J = 7.0 Hz, 2 H), 7.86 (t, J = 7.7
Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.61–7.46 (m, 3 H).
2-(2,6-Difluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2h)22a
Yield: 68 mg (86%); white solid; mp 115–119 °C.
1H NMR (400 MHz, CDCl3): δ = 8.26 (d, J = 7.8 Hz, 1 H), 7.85 (t, J = 7.1
Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.59 (t, J = 7.3 Hz, 1 H), 7.51–7.43 (m,
1 H), 7.03 (t, J = 8.3 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 162.34, 159.72, 158.67, 153.51,
146.29, 136.82, 132.03, 129.34, 128.76, 127.67, 124.10, 122.43,
121.21, 117.14, 114.88.
13C NMR (101 MHz, CDCl3): δ = 162.12, 159.57, 158.94, 150.84,
146.17, 136.71, 129.42, 128.67, 128.27, 127.49, 117.24, 112.43,
111.39, 110.61.
19F NMR (471 MHz, CDCl3): δ = –63.28 (s), –106.44 (dd, J = 10.3, 7.3
Hz).
HRMS (ESI): m/z [M + H]+ calcd for C15H8F4NO2: 332.0305; found:
332.0310.
19F NMR (471 MHz, CDCl3): δ = –110.43 (t, J = 9.5 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C14H8F2NO2: 260.0518; found:
260.0521.
2-(2,4-Difluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2m)18b
Yield: 40 mg (52%); white solid; mp 154–157 °C.
1H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 7.9 Hz, 1 H), 8.19 (dd, J =
15.1, 8.5 Hz, 1 H), 7.87 (t, J = 7.7 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.57
(t, J = 7.6 Hz, 1 H), 7.11–6.94 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 166.66, 164.11, 160.87, 158.98,
154.05, 146.61, 136.67, 132.73, 128.70, 127.39, 116.94, 115.56,
112.03, 105.63.
2-(2-Fluoro-5-methylphenyl)-4H-benzo[d][1,3]oxazin-4-one (2i)
Yield: 22 mg (29%); white solid; mp 106–108 °C.
1H NMR (400 MHz, CDCl3): δ = 8.26 (dd, J = 7.9, 1.1 Hz, 1 H), 7.92 (dd,
J = 6.9, 1.9 Hz, 1 H), 7.88–7.81 (m, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.56 (t,
J = 7.6 Hz, 1 H), 7.37–7.29 (m, 1 H), 7.11 (dd, J = 10.8, 8.5 Hz, 1 H), 2.41
(s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.93, 159.23, 158.37, 155.04,
146.74, 136.56, 134.57, 133.94, 131.11, 130.88, 128.59, 127.39,
118.43, 116.75, 20.56.
19F NMR (471 MHz, CDCl3): δ = –101.11 to –101.23 (m), –102.28 (dt,
J = 19.3, 7.7 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C14H8F2NO2: 260.0518; found:
19F NMR (471 MHz, CDCl3): δ = –114.37 to –114.52 (m).
260.0520.
HRMS (ESI): m/z [M + H]+ calcd for C15H11FNO2: 256.0768; found:
256.0769.
2-(4-Chloro-2-fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2n)
Yield: 52 mg (63%); white solid; mp 132–134 °C.
1H NMR (400 MHz, CDCl3): δ = 8.25 (dd, J = 8.0, 1.3 Hz, 1 H), 8.15–8.06
(m, 1 H), 7.87–7.82 (m, 1 H), 7.72 (t, J = 4.3 Hz, 1 H), 7.57 (t, J = 7.6 Hz,
1 H), 7.31–7.28 (m, 1 H), 7.10 (d, J = 7.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 162.57, 159.94, 158.88, 154.01,
146.54, 136.67, 131.92, 129.54, 128.92, 128.63, 127.47, 124.94,
118.05, 113.46.
2-(2-Fluoro-4-methylphenyl)-4H-benzo[d][1,3]oxazin-4-one (2j)
Yield: 38 mg (49%); white solid; mp 94–98 °C.
1H NMR (400 MHz, CDCl3): δ = 8.26 (dd, J = 7.9, 1.3 Hz, 1 H), 8.03 (t, J =
7.9 Hz, 1 H), 7.87–7.81 (m, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.58–7.48 (m,
1 H), 7.07 (dd, J = 20.7, 10.1 Hz, 2 H), 2.44 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 162.66, 160.07, 159.29, 155.01,
146.87, 145.60, 136.50, 130.86, 128.50, 127.46, 125.17, 117.70,
116.96, 116.06, 21.50.
19F NMR (471 MHz, CDCl3): δ = –106.19 (dd, J = 11.8, 7.9 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C14H8ClFNO2: 276.0222; found:
19F NMR (471 MHz, CDCl3): δ = –109.78 (dd, J = 11.9, 7.8 Hz).
276.0223.
HRMS (ESI): m/z [M + H]+ calcd for C15H11FNO2: 256.0768; found:
256.0772.
2-(4-Bromo-2-fluorophenyl)-4H-benzo[d][1,3]oxazin-4-one (2o)
Yield: 65 mg (68%); white solid; mp 129–131 °C.
1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 7.9 Hz, 1 H), 8.03 (t, J = 8.2
Hz, 1 H), 7.85 (t, J = 7.7 Hz, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.57 (t, J = 7.6
Hz, 1 H), 7.48–7.40 (m, 2 H).
2-(2-Fluoro-4-methoxyphenyl)-4H-benzo[d][1,3]oxazin-4-one
(2k)
Yield: 42 mg (52%); white solid; mp 139–141 °C.
1H NMR (400 MHz, CDCl3): δ = 8.24 (dd, J = 7.9, 1.3 Hz, 1 H), 8.11 (t, J =
8.7 Hz, 1 H), 7.87–7.78 (m, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.55–7.49 (m,
1 H), 6.82 (dd, J = 8.9, 2.4 Hz, 1 H), 6.74 (dd, J = 12.9, 2.4 Hz, 1 H), 3.90
(s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 162.39, 159.75, 158.90, 154.10,
146.53, 136.74, 132.03, 129.06, 128.61, 127.57, 121.25, 120.99,
118.11, 117.01.
19F NMR (471 MHz, CDCl3): δ = –106.20 (dd, J = 17.9, 7.9 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C14H8BrFNO2: 319.9717; found:
319.9721.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

F
H.-M. Vu et al.
Paper
Synthesis
2-(3-Fluoro-[1,1′-biphenyl]-4-yl)-4H-benzo[d][1,3]oxazin-4-one
(2p)
1H NMR (400 MHz, CDCl3): δ = 8.18 (t, J = 7.6 Hz, 1 H), 8.11 (d, J = 7.9
Hz, 1 H), 7.70 (d, J = 7.4 Hz, 1 H), 7.56 (dd, J = 13.1, 7.3 Hz, 1 H), 7.44 (t,
J = 7.7 Hz, 1 H), 7.32 (d, J = 7.7 Hz, 1 H), 7.27–7.19 (m, 1 H), 2.66 (s, 3
H).
13C NMR (101 MHz, CDCl3): δ = 162.88, 160.24, 159.74, 153.40,
145.06, 137.36, 136.50, 133.77, 131.13, 128.14, 126.10, 124.23,
119.32, 117.17, 16.98.
Yield: 50 mg (53%); white solid; mp 132–134 °C.
1H NMR (400 MHz, CDCl3): δ = 8.27 (dd, J = 7.9, 1.3 Hz, 1 H), 8.21 (t, J =
8.0 Hz, 1 H), 7.89–7.82 (m, 1 H), 7.74 (d, J = 7.9 Hz, 1 H), 7.68–7.63 (m,
2 H), 7.58–7.43 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 163.04, 160.45, 159.22, 158.98,
154.76, 147.33, 146.82, 146.25, 138.52, 136.60, 131.46, 129.30,
128.54, 128.28, 127.38, 127.05, 122.78, 117.39, 117.02, 115.57.
19F NMR (471 MHz, CDCl3): δ = –108.73 to –108.81 (m).
HRMS (ESI): m/z [M + H]+ calcd for C15H11FNO2: 256.0768; found:
19F NMR (471 MHz, CDCl3): δ = –108.49 (dd, J = 12.3, 7.8 Hz).
256.0766.
HRMS (ESI): m/z [M + H]+ calcd for C20H13FNO2: 318.0925; found:
318.0928.
Funding Information
2-(2-Fluoro-4-nitrophenyl)-4H-benzo[d][1,3]oxazin-4-one (2q)
National Standardization Project of Traditional Chinese Medicine (No.
Yield: 39 mg (45%); white solid; mp 184–186 °C.
ZYBZH-Y-JX-27) and China Scholarship Council (No. 201706465059).
NatiSotanadlardTirzaP-tiorofjnect
1H NMR (400 MHz, CDCl3): δ = 8.38 (dd, J = 8.6, 7.2 Hz, 1 H), 8.30 (dd,
J = 7.9, 1.2 Hz, 1 H), 8.18 (dd, J = 8.9, 1.7 Hz, 1 H), 8.12 (dd, J = 10.2, 2.1
Hz, 1 H), 7.95–7.89 (m, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.68–7.62 (m, 1
H).
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Acknowledgment
13C NMR (101 MHz, CDCl3): δ = 162.28, 159.64, 158.33, 152.90,
150.49, 146.09, 136.91, 132.25, 129.50, 128.80, 127.74, 119.11,
117.16, 113.17.
The authors gratefully acknowledge financial support from the Na-
tional Standardization Project of Traditional Chinese Medicine and
the China Scholarship Council.
19F NMR (471 MHz, CDCl3): δ = –103.93 (dd, J = 9.9, 7.3 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C14H8FN2O4: 287.0463; found:
287.0461.
Supporting Information
Supporting information for this article is available online at
Methyl 3-Fluoro-4-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)benzoate
(2r)
https://doi.org/10.1055/s-0037-1611700.
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Yield: 49 mg (55%); white solid; mp 162–164 °C.
References
1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J = 7.9, 1.2 Hz, 1 H), 8.26–8.18
(m, 1 H), 7.96 (dd, J = 8.2, 1.4 Hz, 1 H), 7.92–7.84 (m, 2 H), 7.75 (d, J =
8.1 Hz, 1 H), 7.65–7.56 (m, 1 H), 3.99 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 165.09, 162.35, 159.75, 158.78,
146.41, 136.72, 135.27, 131.42, 129.21, 127.64, 125.11, 122.94,
118.38, 117.11, 52.72.
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2-(2-Fluoronaphthalen-1-yl)-4H-benzo[d][1,3]oxazin-4-one (2s)
Yield: 44 mg (50%); white solid; mp 182–184 °C.
1H NMR (400 MHz, CDCl3): δ = 8.34 (dd, J = 7.9, 1.2 Hz, 1 H), 8.06 (d, J =
8.4 Hz, 1 H), 7.93–7.83 (m, 2 H), 7.76 (d, J = 6.1 Hz, 2 H), 7.62 (dd, J =
15.8, 3.3 Hz, 2 H), 7.52 (td, J = 8.0, 5.1 Hz, 1 H), 7.28–7.22 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 159.73, 157.69, 146.84, 136.60,
134.09, 133.19, 130.79, 130.05, 128.85, 128.60, 128.58, 127.88,
127.43, 127.02, 126.41, 125.81, 124.81, 117.03.
19F NMR (471 MHz, CDCl3): δ = –113.07 to –113.15 (m).
HRMS (ESI): m/z [M + H]+ calcd for C18H11FNO2: 292.0768; found:
292.0773.
2-(2-Fluorophenyl)-8-methyl-4H-benzo[d][1,3]oxazin-4-one
(2w)18c
Yield: 42 mg (55%); white solid; mp 116–118 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

G
H.-M. Vu et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G