Intramolecular functionalization of C(sp3)–H bonds adjacent to an amide nitrogen atom: Metal-free synthesis of 2-hydroxy-benzoxazinone derivatives

Article abstract of DOI:10.1016/j.tet.2017.09.001

An intramolecular C(sp³)–H bond functionalization adjacent to an amide nitrogen atom was successfully developed for synthesis of 2-hydroxybenzoxazinone derivatives under environment-friendly conditions. The method featured no metal catalyst, broad substrate scopes and high yields. Besides, a radical mechanism was proposed in the reaction process. Additionally, most of target compounds exhibited potent anti-proliferative activities against MCF-7 and Hela cells.

Full text of DOI:10.1016/j.tet.2017.09.001

Accepted Manuscript
3
Intramolecular functionalization of C(sp )-H bonds adjacent to an amide nitrogen
atom: Metal-free synthesis of 2-hydroxy-benzoxazinone derivatives
Biao Gao, Kaili Chen, Xiaoling Bi, Jinxin Wang
PII:
S0040-4020(17)30914-6
10.1016/j.tet.2017.09.001
TET 28952
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 June 2017
Revised Date: 26 August 2017
Accepted Date: 4 September 2017
3
Please cite this article as: Gao B, Chen K, Bi X, Wang J, Intramolecular functionalization of C(sp )-
H bonds adjacent to an amide nitrogen atom: Metal-free synthesis of 2-hydroxy-benzoxazinone
derivatives, Tetrahedron (2017), doi: 10.1016/j.tet.2017.09.001.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
3
Intramolecular Functionalization of C(sp )-H Bonds Adjacent to An Amide Nitrogen Atom:
Metal-free Synthesis of 2-Hydroxy-benzoxazinone Derivatives
Biao Gao, Kaili Chen, Xiaoling Bi* and Jinxin Wang*
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 24
Nanjing 210009, China.
，Tongjiaxiang Road,
ARTICLE INFO
ABSTRACT
3
Article history:
Received
Received in revised form
Accepted
An intramolecular C(sp )-H bond functionalization adjacent to an amide nitrogen atom was
successfully developed for synthesis of 2-hydroxybenzoxazinone derivatives under
environment-friendly conditions. The method featured no metal catalyst, broad substrate scopes
and high yields. Besides, a radical mechanism was proposed in the reaction process.
Additionally, most of target compounds exhibited potent anti-proliferative activities against
MCF-7 and Hela cells.
Available online
Keywords:
Synthetic methods
C–H activation
2
017 Elsevier Ltd. All rights reserved.
Intramolecular cyclization
Metal-free catalysis
2
-Hydroxy-benzoxazinone
1
. Introduction
the efficient installation of a malonate or a phenylethynyl group
10
in an oxidative C-H/C-H coupling process (Scheme 1, path b).
Amide moiety represents a privileged structural motif in a
Recently, You et al. developed a coordinating activation strategy
variety of natural products, pharmaceuticals and bioactive
compounds. In recent years, the demand for the amide-based
structures is increasing rapidly in drug discovery. Various
approaches were explored for efficient construction of this
significant skeleton. However, the limitation of substrates, harsh
reaction conditions and other shortcomings severely restrict the
diversity of amide synthesis. Thus, a simple and efficient
method of synthesizing diverse structurally novel amides is
highly desirable.
to furnish α-quaternary α-amino acids through the iron(III)-
1
3
catalyzed oxidative functionalization of α-C(sp )-H bonds of α-
2
11
tertiary α-amino acid esters (Scheme 1, path c). Although the
aforementioned methods have made great contributions, most of
these reactions are transition metal catalyst-dependent, which
3
12
lead to heavy metal impurities in the final products. Therefore,
4
we developed a method for direct functionalization of C-H bonds
adjacent to a nitrogen atom under mild and transition metal-free
conditions.
The direct functionalizations of C-H bond adjacent to a
nitrogen atom of an amide take advantage of existing structures
5
and provide rapid access to various amides . In addition, these
reactions do not require prefunctionalization of substrates.
Therefore, this strategy has been recognized as one of the most
efficient, atom-economical, and environment-friendly ways for
6
the formation of various amides. Most of these reactions are
reported to proceed with the in situ generated iminium ion or
imine as the intermediate, which is subsequently attacked by a
7
nucleophile to synthesize complex compounds. This strategy has
attracted extensive attention and achieved noticeable progress in
8
recent years. For example, Mao et al. reported that a series of N-
(
3-oxoalkyl) amides could be directly assembled via the copper-
3
catalyzed oxidative coupling of α-C(sp )-H centers of amides
with vinylarenes (Scheme 1, path a). In 2008, Li et al.
performed the direct reaction at α-peptido C(sp )-H bonds
9
3
employing Cu(OAc) as a stoichiometric oxidant, which realized
2
∗
Corresponding author
E-mail: jinxinwang@cpu.edu.cn.
3
Scheme 1 The direct functionalization of C(sp )-H adjacent to an
amide nitrogen atom.

2
Tetrahedron
Benzoxazinones are widely found in ph
A
arm
C
a
C
ce
E
uti
P
ca
T
l
E
ar
D
ea MApe
NU
ro
xid
S
e
CR(D
I
TBP), and K S O failed to facilitate the
2 2 8
P
T
which are endowed with a wide range of pharmacological and
biological activities. For example (Figure 1), CX-614 is
dehydrogenative coupling reaction, dicumyl peroxide (DCP) and
13
H O2 provided 2a in 87 % and 10 % yields, respectively.
2
developed by Cortex Pharmaceuticals and has great potential in
Screening of solvents revealed that MeCN was the best solvent
(Table 1, entries 12−17). After investigating various reaction
parameters including bases, oxidants, and solvents, the optimized
reaction conditions were eventually identified as 1a (0.2 mmol),
5.0 equiv of aq TBHP, and 2 equiv of Cs CO in 2 mL of MeCN
14
the treatment of Parkinson’s and Alzheimer’s diseases. DRF-
519 exhibited potent inhibition activity on dual PPAR-α and -
2
15
γ. However, their applications are limited by substitution
16
diversity or harsh reaction conditions. We developed a metal-
free method for the synthesis of benzoxazinones by the activation
of C-H bonds adjacent to a nitrogen atom of an amide. Herein,
we for the first time realized the synthesis of a series of 2-
hydroxy-benzoxazinone derivatives by employing different
2
3
at 80 °C for 5 h (Table 1, entry 3).
O
O
aq TBHP (5.0 eq)
Cs CO (2.0 eq)
2
3
NH
N
R2
R1
R1
H
OH
substituted salicylamides as substrates under the TBHP/Cs CO3
2
CH3CN, 80 o
C
O
OH
R2
condition (Scheme 1, path d). The underlying mechanism was
also explored. Furthermore, the antineoplastic effects of these
compounds were examined. And some of them showed potent
inhibition effect on the proliferation of human breast carcinoma
MCF-7 cells and cervical carcinoma HeLa cells.
1
2
O
O
O
O
O
NH
NH
NH
OH
OH
OH
O
O
O
2
a, 95%
2b, 93%
2c, 95%
O
O
O
Br
F
Cl
NH
NH
NH
OH
OH
OH
O
O
O
2d, 98%
2e, 93%
2
f, 92%
Figure 1. Bioactive benzoxazinone derivates
O
O
H
O
O
N
2
. Results and Discussion
As shown in Table 1, we used N-benzylsalicylamide 1a as
2
O N
S
NH
NH
O
NH
O
OH
OH
OH
17
O
O
the model substrate to optimize the reaction conditions, including
base, oxidant, and solvent. When 1a was treated with aq TBHP
NO2
2
i, 83%
2g, 90%
2h, 92%
O
O
and CH COOK in MeCN at 80 °C for 5 h, the desired product 2-
O
3
O2N
hydroxy-benzoxazinone (2a) was isolated in only 15 % yield
NH
O
NH
NH
OH
OH
OH
(Table 1, entry 1). Subsequent screening of different bases with
O
O
S
MeCN as a solvent at 80 °C under an air atmosphere was carried
out (Table 1, entries 1−6). The highest yield was achieved in the
presence of Cs CO . No product was formed with Et N (Table 1,
O
O
2j, trace
2k, 87%
2l, 84%
2
3
3
Scheme 2 Substrate scope of differently substituted salicylic acid.
entry 2). Next, various oxidants were screened (Table 1, entries
7
−11). Although tert-butylperbenzoate (TBPB), di-tertbu-tyl
a
With the optimized reaction conditions in hand, we examined
a variety of differently substituted salicylic acid rings of N-
benzylsalicylamides (Scheme 2). The reactions proceeded
smoothly to give the corresponding products in excellent isolated
yields (83-98 %, 2a−2i) regardless of electron-donating or -
withdrawing groups on salicylic acid rings. No significant steric
hindrance effect was observed as the reaction could tolerate
substitutes at different position on the salicylic acid ring (2b, 2c,
Table 1. Screening of reaction conditions
c
b
Entry
Oxidant
aq TBHP
aq TBHP
aq TBHP
aq TBHP
aq TBHP
aq TBHP
TBPB
Base
CH COOK
Et
Cs
PO
CO
NaOH
Solvent
CH
CH
Yield(%)
15
Trace
95
53
62
85
Trace
87
10
Trace
Trace
Trace
Trace
62
80
Trace
Trace
2
g, 2h). Regarding the substrates bearing either F, Cl, or Br on
1
2
3
4
5
6
7
8
9
3
3
CN
CN
the salicylic acid ring, the desired products were also successfully
achieved in good yields (Scheme 2, 2d−2f), which provided the
3
N
3
2
CO
3
CH
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
K
K
3
4
CH
CH
CH
CH
CH
CH
CH
CH
3
possibility
for
further
functionalization.
N-
2
3
3
3
3
3
3
3
3
benzylthiosalicylamide was also tested under the optimized
reaction conditions, but no desired product was found (Scheme
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
2
, 2j). Interestingly, when the substituent was a sulfonamide, the
DCP
3
3
3
3
3
3
3
3
3
3
C-H bonds adjacent to an amide nitrogen atom was selectively
oxidized in the reaction to give the desired product in 83 % yield
(Scheme 2, 2i).
H
2
O
2
1
0
DTBP
K S O
2 2 8
1
1
1
1
1
1
1
1
a
2
3
4
5
6
7
aq TBHP
aq TBHP
aq TBHP
aq TBHP
aq TBHP
aq TBHP
MeOH
H
2
O
Next, we further investigated the scope of various substituted
N-arylamine of N-benzylsalicylamides (Scheme 3). The
corresponding 2-hydroxy-benzoxazinone derivatives were
obtained in good yields regardless of the electron-donating or -
withdrawing groups on the N-arylamine (Scheme 3, 2m-2v). The
position of methoxy group on the N-benzyl group of N-
benzylsalicylamides has an obvious influence on this reaction.
DMSO
DMF
THF
Toluene
Reaction conditions: A solution of 1a (0.2 mmol), base (0.4 mmol) and
oxidant (1.0 mmol) in the indicated solvent (2.0 mL) at 80 °C for 5 h.
b
c
Isolated yield. 70 % aqueous TBHP solution.

The substrate with the methoxy group on the para-position
ACCEPTED MANUSCRIPT
afforded
Scheme 4 Control experiments.
was isolated as the main product in 36 % yield.
To gain deeper insights into the mechanism of this
transformation, some control experiments were carried out
(
Scheme 4). A negative influence on the yield was observed
when 5.0 equiv of TEMPO was added to the reaction system
Scheme 4, a), which suggested that the reaction probably
Scheme 3 Substrate scope of differently substituted N-arylamine.
(
18
proceeded via a free radical process. The compound 3a was
detected and identified during the reaction process. Subsequently,
we found that 3a was directly converted to 2-hydroxy-
benzoxazinone 2a under alkaline conditions, indicating that 3a
might be the key intermediate in the process (Scheme 4, b).
Moreover, the reaction of 1a under the optimized conditions in
the absence of Cs CO could not afford the desired product,
the desired product in 94 % yield (Scheme 3, 2m), while the
methoxy group in the ortho-position yielded the product in 79 %
(Scheme 3, 2o). In contrast, no significant steric hindrance effect
was observed in substrates with halogen substituted on the N-
benzyl group of N-benzylsalicylamides, and the corresponding
products were obtained in good yields (Scheme 3, 2q-2s). The
heterocyclic substrate N-(furan-2-ylmethyl)-2-hydroxybenzamide
also gave a good yield (Scheme 3, 2w). Interestingly, when the
aliphatic substrate 2-hydroxy-N-isobutylbenzamide was used, 2x
2
3
which suggested that Cs CO3 not only enhanced the
2
nucleophilicity of phenol hydroxyl, but also promoted TBHP to
generate free radicals (Scheme 4, c). In order to further prove the
mechanism, compound 3b was used, but no products were
19
detected (Scheme 4, d). Thus, it was reasonably assumed that
C-H bond adjacent to nitrogen atom of amide 3b could not be
carbonylated due to the presence of methyl.
On the basis of the above experiments and previous
20
literatures, a plausible reaction mechanism was proposed as
shown in Scheme 5. Firstly, the tert-butoxyl and hydroxide
radicals were generated from the TBHP/Cs CO system.
2
3
Subsequently, the H atom adjacent to the nitrogen atom of the
amide 1a was abstracted by the tert-butoxyl radical to form
radical A. Coupling of the kinetically stable radical A and
hydroxide radical generated intermediate B. Next, the oxidative
dehydrogenation of B formed intermediate imide 3a, which
subsequently underwent intramolecular cyclization to give the
desired product 2a.

4
Tetrahedron
ACCEPTED MAN
U
U
nle
S
s
C
s o
R
th
I
e
P
rwise indicated, all reagents were obtained from
T
commercial suppliers used without further purification. All
reactions were carried out in air with undistilled solvents and
without any precautions to exclude moisture. Melting points
HeLa
Inhibition ratio
%）
MCF-7
Inhibition ratio
Compound
Compound
（
（%）
81.78
42.37
74.03
72.83
85.09
62.16
88.12
74.31
(m.p.) were taken on an XT-4 micro melting point apparatus and
2
2
2
b
g
i
39.81
36.48
35.11
32.19
27.64
22.43
65.70
67.28
2b
2g
2i
2m
2p
2r
1 13
uncorrected. H NMR and C NMR spectra were recorded on
Bruker-300 spectrometers, and were referenced to the residual
peaks of CDCl at 7.26 ppm or DMSO-d at 2.50 ppm ( H NMR)
1
2
m
3
6
1
3
2
2
2
p
r
u
and CDCl at 77.0 ppm or DMSO-d at 39.5 ppm ( C NMR).
3
6
Data are reported as follows: chemical shift in ppm (δ),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, brs =
broad singlet, m = multiplet), coupling constant (Hz), and
integration. High Resolution Mass measurement was performed
on Agilent QTOF 6520 mass spectrometer with electron spray
ionization (ESI) as the ion source. Flash column chromatography
was carried out using commercially available 200-300 mesh
under pressure.
2u
2w
2w
4
.2. General Procedure for the Preparation of 2-hydroxy-
benzoxazinones 2a–2x
A 10 mL Schlenk tube equipped with a stirrer bar was charged
with 2-hydroxy aryl amide 1 (0.2 mmol), Cs CO (0.4 mmol) and
2
3
aq TBHP (1.0 mmol) in CH CN (2 mL). Then, the reaction
3
mixture was stirred at 80 °C for 5 h. Upon cooling to room
temperature, the solvents were removed under reduced pressure
and the crude reaction mixture was purified by flash
chromatography (petroleum ether: ethyl acetate, 1:1 v/v) to
obtain the desired product 2.
4
4
.2.1 2-hydroxy-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-
-one (2a)
Yellow solid (45.8 mg, 95 %); m.p. 178-179 °C; IR (KBr):
433, 3179, 1719, 1605, 1481, 1400, 1275, 1131, 1087, 754, 702
cm ; H NMR (300 MHz, DMSO) δ 11.78 (brs, 2H), 7.94-7.91
3
-
1
1
Scheme 5 Proposed reaction mechanism
(
7
m, 2H), 7.88 (dd, J = 6.1, 1.7 Hz, 1H), 7.71-7.65 (m, 1H), 7.60-
.55 (m, 2H), 7.49-7.43 (m, 1H), 7.04-6.97 (m, 2H); C NMR
1
3
(
1
100 MHz, DMSO) δ 167.0, 166.9, 163.2, 134.8, 134.0, 132.5,
To further explore the biological activities of these
derivatives, we also tested their potential antineoplastic effect
against human breast carcinoma MCF-7 cell lines and human
cervical carcinoma HeLa cell lines. The results showed that 2-
hydroxy-benzoxazinone derivatives had antiproliferative activity
against both cell lines at 10 ꢀM (Table 2). Among them,
compound 2u showed the most potent activity against MCF-7
and HeLa cells (65.70 % and 88.12 %, respectively). These
findings indicated that 2-hydroxy-benzoxazinone derivatives may
be of great value for cancer treatment.
30.5, 128.7, 127.8, 118.7, 118.94, 116.5; HRMS (ESI)
+
+
calculated for C H NO [M + H] 242.0812, found 242.0818.
14 12
3
4
[
.2.2 2-hydroxy-6-methoxy-2-phenyl-2,3-dihydro-4H-benzo[e]-
1,3]-oxazin-4-one (2b)
Yellow solid (50.4 mg, 93 %); m.p. 202-203 °C; IR (KBr):
3
6
8
7
1
1
451, 3216, 1719, 1655, 1607, 1478, 1401, 1267, 1099, 748, 727,
-1 1
19 cm ; H NMR (300 MHz, DMSO) δ 11.95 (brs, 2H), 8.13-
.02 (m, 4H), 7.85 (d, J = 6.6, Hz, 1H), 7.46 (t, J = 6.9 Hz, 1H),
13
.03-6.95 (m, 2H), 3.90 (s, 3 H); C NMR (75 MHz, DMSO) δ
65.5, 164.7, 156.9, 137.9, 134.3, 133.0, 131.0, 129.6, 128.2,
19.7, 119.0, 117.2, 52.6; HRMS (ESI) calculated for
Table 2. Antiproliferative activity of target compounds.
+
+
C H NO [M+H] 272.0917, found 272.0918.
15
14
4
3
. Conclusions
4
.2.3 2-hydroxy-7-methoxy-2-phenyl-2,3-dihydro-4H-benzo[e]-
[
1,3]-oxazin-4-one (2c)
Yellow solid (51.5 mg, 95 %); m.p. 176-177 °C；IR (KBr):
In summary, we developed an efficient method for synthesis
of 2-hydroxy-benzoxazinone derivatives under metal-free
conditions. The reaction showed good tolerance towards various
substrates under a radical pathway. In addition, most of the target
compounds exhibited potent growth inhibitory activity in MCF-7
and HeLa cells. Further explorations of new organic
transformations and the application of this methodology in the
synthesis of biologically relevant molecules are under
investigation in our laboratory.
3
9
2
476, 3139, 1719, 1649, 1529, 1481, 1434, 1401, 1230, 1098,
-1 1
66, 842, 707 cm ; H NMR (300 MHz, DMSO) δ 12.36 (brs,
H), 7.93 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.65 (t, J
=
7.2 Hz, 1H), 7.54 (t, J = 7.2 Hz, 2H), 6.54-6.49 (m, 2H), 3.75
13
(s, 3H); C NMR (75 MHz, DMSO) δ 165.1, 164.2, 160.5,
1
34.2, 132.7, 128.8, 127.6, 111.3, 106.3, 101.6, 55.3; HRMS
+
+
(ESI) calculated for C H NO [M+H] 272.0917, found
15 14 4
2
72.0924.
4
. Experimental section
4
.2.4
6-fluoro-2-hydroxy-2-phenyl-2,3-dihydro-4H-benzo[e]-
[
1,3]oxazin-4-one (2d)
Yellow solid (50.8 mg, 98 %); m.p. 197-198 C; IR (KBr):
434, 3163, 1707, 1612, 1473, 1400, 1210, 1095, 706 cm ; H
4
.1. General Information
o
-
1
1
3

NMR (300 MHz, DMSO) δ 15.81 (brs, 2H), 8.04 (s, 2H), 7.79 (s,
129.3, 114.0, 113.7, 113.4, 111.4, 104.6, 102.0, 55.5, 55.0;
+ +
ACCEPTED MANUSCRIPT
13
1
H), 7.61-7.54 (m, 3H), 6.30 (s, 2H); C NMR (75 MHz,
DMSO) δ 170.0, 168.0, 166.0, 164.7, 134.5, 132.6, 132.4, 128.8,
27.9, 115.1, 105.4, 105.2, 101.6; HRMS (ESI) calculated for
HRMS (ESI) calculated for C H NO [M+H] 302.1023, found
16 16 5
302.1019.
1
+
+
4
.2.11 2-hydroxy-2-(4-methoxyphenyl)-6-nitro-2,3-dihydro-4H-
C H FNO [M+H] 260.0717, found 260.0714.
14
11
3
benzo[e]-[1,3]oxazin-4-one (2l)
4
.2.5
6-chloro-2-hydroxy-2-phenyl-2,3-dihydro-4H-benzo[e]-
Red solid (53.1 mg, 84 %); m.p. 180-182 °C; IR (KBr): 3433,
1676, 1603, 1508, 1400, 1331, 1273, 1180, 1098, 1013, 583 cm ;
H NMR (300 MHz, DMSO) δ 15.71 (brs, 2H), 8.71 (d, J = 3.0
-
1
[
1,3]oxazin -4-one (2e)
1
Yellow solid (51.3 mg, 93 %); m.p. 204-205 °C; IR (KBr):
458, 3137, 1724, 1605, 1551, 1480, 1400, 1281, 1092, 700 cm ;
-
1
3
Hz, 1H), 8.03 (d, J = 9.0 Hz, 2H), 8.93-7.89 (m, 1H), 7.10 (d, J =
1
13
H NMR (300 MHz, DMSO) δ 13.79 (brs, 2H), 7.98 (d, J = 6.9
Hz, 2H), 7.73 (d, J = 2.1 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.54
8.7 Hz, 2H), 7.45 (d, J = 9.6 Hz, 1H), 3.84 (s, 3H); C NMR (75
MHz, DMSO) δ 178.7, 163.2, 131.8, 130.3, 129.3, 128.7, 123.6,
117.1, 114.6,+ 114.2, + 56.0; HRMS (ESI) calculated for
C H N O Na [M+Na] 339.0588, found 339.0585.
(
t, J = 7.5 Hz, 2H), 7.33-7.31 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H);
1
3
C NMR (75 MHz, DMSO) δ 165.3, 163.8, 158.1, 133.8, 133.6,
1
5
12
2
6
1
32.9, 139.7, 128.8, 127.7, 122.0, 120.3, 119.9; HRMS (ESI)
+ +
4
.2.12
2-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-4H-benzo-
calculated for C H ClNO [M+H] 276.0422, found 276.0422.
14
11
3
[
e][1,3]-oxazin-4-one (2m)
4
[
.2.6
1,3]oxaz-in-4-one (2f)
Yellow solid (58.9 mg, 92 %); m.p. 209-210 C; IR (KBr):
6-bromo-2-hydroxy-2-phenyl-2,3-dihydro-4H-benzo[e]-
Yellow solid (50.9 mg, 94 %); m.p. 167-168 °C; IR (KBr):
-
1
1
3449, 3217, 1655, 1400, 1254, 1097, 848, 594 cm ; H NMR
(300 MHz, DMSO) δ 12.30 (brs, 2H), 7.92 (d, J = 8.7 Hz, 2H),
7.86 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 6.9 Hz, 1H), 7.08 (d, J = 8.4
o
-
1
1
3
456, 2979, 1723, 1593, 1476, 1405, 1066, 695 cm ; H NMR
13
(300 MHz, DMSO) δ 14.23 (brs, 2H), 7.99 (d, J = 7.2 Hz, 2H),
Hz, 2H), 7.00-6.89 (m, 2H), 3.85 (s, 3H); C NMR (75 MHz,
DMSO) δ 164.6, 162.9, 158.1, 134.2, 133.4, 131.0, 129.9, 129.4,
126.0, 1119.0, 117.6, 114.2, 55.6; HRMS (ESI) calculated for
7
7
.82 (m, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H),
13
.38-7.35 (m, 1H), 6.72 (d, J = 6.0 Hz, 1H); C NMR (75 MHz,
+
+
DMSO) δ 171.5, 160.1, 159.5, 136.4, 132.9, 132.5, 128.9, 127.8,
20.8, 120.5, 119.8, 108.7; HRMS (ESI) calculated for
C H NO [M+H] 272.0917, found 272.0917.
1
5
14
4
1
+
+
4
[
.2.13
2-hydroxy-2-(3-methoxyphenyl)-2,3-dihydro-4H-benzo-
C H BrNO [M+H] 319.9917, found 319.9911.
14
11
3
e][1,3] oxazin-4-one (2n)
4
.2.7 2-hydroxy-6-nitro-2-phenyl-2,3-dihydro-4H-benzo[e][1,3-
Yellow solid (48.8 mg, 90 %); m.p. 157-158 °C; IR (KBr):
-
1 1
]
-oxaz-in-4-one (2g)
3449, 2988, 2361, 1720, 1638, 1483, 1400, 1075 cm ; H NMR
(300 MHz, DMSO) δ 14.02 (brs, 2H), 7.87-7.85 (m, 1H), 7.58-
7.45 (m, 4H), 7.37-7.33 (m, 1H), 7.19 (d, J = 7.8, 1H), 6.86 (d, J
Red solid (51.5 mg, 90 %); m.p. 218-219 °C; IR (KBr): 3458,
-
1 1
2
360, 1649, 1509, 1400, 1316, 1092 cm ; H NMR (300 MHz,
13
DMSO) δ 15.62 (brs, 2H), 8.71 (s, 1H), 8.07-7.95 (m, 3H), 7.61
= 8.1, 1H), 3.82 (s, 3H); C NMR (75 MHz, DMSO) δ 166.4,
159.4, 134.1, 132.1, 130.5, 130.4, 129.9, 120.0, 118.6, 118.4,
117.3, 115.9, 113.9, 112.9, 55.2; HRMS (ESI) calculated for
13
(s, 3H), 6.49 (d, J = 5.4 Hz, 1H); C NMR (75 MHz, DMSO) δ
1
1
77.5, 165.1, 165.0, 134.0, 132.7, 129.0, 128.8, 128.4, 127.8,
+
+
+
22.9, 118.6, 116.9; HRMS (ESI) calculated for C H N O
C H NO [M+H] 272.0917, found 272.0920.
14
11
2
5
15 14
4
+
[
M+H] 287.0662, found 287.0665.
4
.2.14
2-hydroxy-2-(2-methoxyphenyl)-2,3-dihydro-4H-benzo-
4
.2.8 2-hydroxy-8-nitro-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]-
[e][1,3]oxazin-4-one (2o)
oxazin-4-one (2h)
Yellow solid (42.8 mg, 79 %); m.p. 183-184 °C; IR (KBr):
3434, 3246, 1702, 1655, 1601, 1468, 1401, 1284, 1124, 1096,
Red solid (52.6 mg, 92 %); m.p. 234-235 °C; IR (KBr): 3449,
-
1
1
-1
1
2
991, 1638, 1401, 1255, 1077 cm ; H NMR (300 MHz, DMSO)
754, 608 cm ; H NMR (300 MHz, DMSO) δ 11.95 (brs, 1H),
11.40 (brs, 1H), 7.89 (dd, J = 7.8, 1.8, 1H), 7.83 (dd, J = 7.8, 1.8,
1H), 7.61-7.56 (m, 1H), 7.48-7.43 (m, 1H), 7.22 (d, J = 8.4, 1H),
7.11 (t, J = 7.5, 1H), 7.04 (d, J = 7.8, 1H), 6.98 (t, J = 7.5, 1H),
δ 16.20 (brs, 2H), 8.05 (d, J = 7.2 Hz, 2H), 8.01-7.98 (m, 1H),
7
.78-7.75 (m, 1H), 7.66-7.57 (m, 3H), 6.24 (t, J = 7.8 Hz, 1H);
C NMR (75 MHz, DMSO) δ 166.1, 165.3, 141.8, 135.8, 134.2,
32.5, 130.2, 128.8, 127.7, 122.4, 107.6; HRMS (ESI) calculated
13
13
1
3.94 (s, 3H); C NMR (75 MHz, DMSO) δ 164.3, 157.5, 157.1,
+
+
for C H N O [M+H] 287.0662, found 287.0664.
134.8, 134.3, 131.7, 122.8, 121.4, 120.2, 119.2, 117.5, 112.7,
14
11
2
5
+
+
5
6.5; HRMS (ESI) calculated for C H NO [M+H] 272.0917,
15 14 4
4
.2.9 N-benzyl-2-hydroxy-4-oxo-2-phenyl-3,4-dihydro-2H-benz-
found 272.0922.
o[e][1,3]-oxazine-6-sulfonamide (2i)
Yellow solid (68.1 mg, 83 %); m.p. 169-172 °C; IR (KBr):
398, 3189, 1649, 1400, 1082, 557 cm ; H NMR (300 MHz,
4.2.15 2-(benzo[d][1,3]dioxol-5-yl)-2-hydroxy-2,3-dihydro-4H-
benzo[e] [1,3]oxazin-4-one (2p)
-
1
1
3
DMSO) δ 14.52 (brs, 2H), 8.22 (s, 1H), 8.01 (d, J = 7.2 Hz, 2H),
Yellow solid (51.9 mg, 91 %); m.p. 213-215 °C; IR (KBr):
3448, 2988, 1686, 1606, 1473, 1400, 1302, 1252, 1039, 752 cm ;
H NMR (300 MHz, DMSO) δ 14.00 (brs, 2H), 7.87-7.84 (m,
-
1
7
8
.81-7.79 (m, 1H), 6.64-7.53 (m, 4H), 7.25 (brs, 5H), 6.78 (d, J =
.7 Hz, 1H), 3.90 (d, J = 5.7 Hz, 2H); C NMR (75 MHz,
13
1
DMSO) δ 168.8, 165.6, 138.4, 134.5, 133.1, 131.9, 131.0, 129.7,
1H), 7.62-7.60 (m, 1H), 7.46 (brs, 1H), 7.35-7.30 (m, 1H), 7.07-
7.04 (m, 1H), 6.88-6.84 (m, 1H), 6.78-6.74 (m, 1H), 6.14 (s, 2H);
C NMR (75 MHz, DMSO) δ 166.3, 151.0, 147.8, 134.0, 132.2,
1
4
4
29.3, 129.0, 128.6, 128.3, 128.0, 127.5, 125.6, 121.0, 118.6,
+ +
13
6.6; HRMS (ESI) calculated for C H N O S [M+H]
21
19
2
5
11.1009, found 411.1013.
130.5, 123.3, 118.6, 118.1, 117.3, 116.8, 115.9, 108.2, 107.6,
+
+
1
2
02.0; HRMS (ESI) calculated for C H NO
86.0710, found 286.0710.
[M+H]
15
12
5
4
4
.2.10 2-hydroxy-7-methoxy-2-(4-methoxyphenyl)-2,3-dihyd-ro-
H-benzo[e]-[1,3]oxazin-4-one (2k)
Yellow solid (52.4 mg, 87 %); m.p. 174-175 °C; IR (KBr):
433, 3151, 1686, 1604, 1451, 1401, 1218, 1170, 1104, 1016,
4.2.16 2-(4-chlorophenyl)-2-hydroxy-2,3-dihydro-4H-benzo[e]-
[1,3]oxazin -4-one (2q)
3
8
7
-
1
1
48, 771 cm ; H NMR (300 MHz, DMSO) δ 14.76 (brs, 2H),
.99 (d, J = 8.7 Hz, 2H), 7.82 (d, J = 9.9 Hz, 1H), 7.03 (d, J = 8.1
Yellow solid (51.3 mg, 93 %); m.p. 201-203 °C; IR (KBr):
3481, 3137, 1719, 1664, 1607, 1473, 1458, 1400, 1268, 1131,
13
-1 1
Hz, 2H), 6.33 (d, J =9.0 Hz, 2H), 3.82 (s, 3H), 3.69 (s, 3H); C
NMR (75 MHz, DMSO) δ 164.3, 162.7, 131.9, 131.3, 130.0,
1092, 848, 754 cm ; H NMR (300 MHz, DMSO) δ 13.00 (brs,
2H), 7.95 (d, J = 7.8, 2H), 7.83 (d, J = 7.8, 1H), 7.62 (d, J = 8.1,

6
Tetrahedron
.8, MA
2
H), 7.37 (t, J = 6.0, 1H), 6.92(d, J = 7.8, 1H
A
), 6
C
.8
C
6
E
(d
P
, J
T
=
E
7
D
N
N
MRUS(7
C
5
R
M
I
H
P
z,
T
DMSO) δ 151.5, 148.3, 134.5, 130.9, 124.0,
13
1
1
H); C NMR (75 MHz, DMSO) δ 166.0, 165.3, 159.7, 138.0,
34.6, 131.6, 131.2, 130.2, 129.4, 119.3, 118.8, 118.2; HRMS
119.1, 118.6, 117.8, 116.5, 108.6, 108.2, 102.5; HRMS (ESI)
+
+
calculated for C H NO Na [M+Na] 254.0424, found 254.0426.
12 9 4
+
+
(ESI) calculated for C H ClNO [M+H] 276.0422, found
14 11 3
4
(
.2.23
2x)
White solid (13.7 mg, 36 %); m.p. 97-98 °C; IR (KBr): 3449,
2-isopropyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one
2
76.0427.
.2.17 2-(2-chlorophenyl)-2-hydroxy-2,3-dihydro-4H-benzo[e]-
4
-
1
1
[
1,3]oxazin-4-one (2r)
2971, 2901, 1685, 1612, 1470, 1395, 1232, 1075, 759 cm ; H
NMR (300 MHz, CDCl3) δ 7.94 (dd, J = 6.3, 1.5 Hz, 1H), 7.48-
7.43 (m, 1H), 7.12-7.06 (m, 1H), 6.98 (dd, J = 7.8, 0.6 Hz, 1H),
6.75 (s, 1H), 5.08 (dd, J = 3.3, 1.5 Hz, 1H), 2.17-2.10 (m, 1H),
Yellow solid (50.2 mg, 91 %); m.p. 137-138 °C; IR (KBr):
3
1
1
7
435, 3232, 2366, 1736, 1676, 1609, 1475, 1458, 1400, 1257,
207, 1075, 1036, 746, 609 cm ; H NMR (300 MHz, DMSO) δ
1.99 (brs, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.50-7.42 (m, 3H),
-1 1
13
1.12 (d, J = 6.9 Hz, 6H); C NMR (75 MHz, CDCl3) δ 164.4,
134.5, 128.1, 122.2, 116.6, 88.0, 31.6, 16.8, 16.3; HRMS (ESI)
calculated for C H NO [M+H] 192.1019, found 192.1020.
13
.38-7.30 (m, 2H), 6.86-6.77 (m, 2H); C NMR (75 MHz,
+
+
DMSO) δ 167.2, 165.4, 159.5, 136.8, 135.1, 133.8, 131.1, 130.1,
29.0, 127.8, 119.1, 118.1, 116.6; HRMS (ESI) calculated for
11 14 2
1
+
+
4
.2.24 N-benzoyl-2-hydroxybenzamide(3a)
C H ClNO [M+H] 276.0422, found 276.0419.
14
11
3
White solid; m.p. 82-83 °C; IR (KBr): 3443, 3217, 2989,
-
1
1
4
.2.18 2-(4-bromophenyl)-2-hydroxy-2,3-dihydro-4H-benzo[e]-
1638, 1401, 1081, 745 cm ; H NMR (300 MHz, DMSO) δ
12.20 (s, 1H), 9.62 (d, J = 8.7 Hz, 1H), 8.09 (dd, J = 7.8, 1.2 Hz,
1H), 7.23 (d, J = 6.9 Hz, 2H), 7.47-7.39 (m, 3H), 6.98-6.91 (m,
[
1,3]oxaz-in-4-one (2s)
Yellow solid (60.8 mg, 95 %); m.p. 207-208 °C; IR (KBr):
-
1
13
3
433, 3152, 1719, 1605, 1476, 1400, 1260, 1075, 749, 618 cm ;
2H), 6.83 (d, J = 8.7 Hz, 1H); C NMR (75 MHz, CDCl3) δ
1
H NMR (300 MHz, DMSO) δ 12.16 (brs, 2H),7.89-7.86 (m,
H), 7.76 (d, J = 8.4 Hz, 2H),, 7.41 (t, J = 8.1 Hz, 1H), 6.97 (d, J
169.9, 161.8, 136.2, 134.7, 129.2, 128.8, 126.5, 125.9, 118.9,
118.7, 113.9; HRMS (ESI) calculated for C H NO Na [M+H]
+
+
3
14 11 3
13
=
8.1 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H); C NMR (75 MHz,
264.0631, found 264.0632.
DMSO) δ 165.7, 168.9, 134.6, 132.3, 131.2, 130.3, 127.0, 119.3,
+
+
Acknowledgments
1
3
18.0; HRMS (ESI) calculated for C H BrNO [M+H]
14 11 3
19.9917, found 319.9923.
This work was supported financially by the key research &
development program of Jiangsu Province (NO. BE2015683), the
introduction program of leading scientific and technological
entrepreneurship in Nanjing (NO. 2013B14007), and the
Innovation project of Jiangsu Province (No. KYLX16_1170).
4
.2.19 2-hydroxy-2-(p-tolyl)-2,3-dihydro-4H-benzo[e][1,3]-
oxazin-4-one (2t)
Yellow solid (50.0 mg, 96 %); m.p. 189-190 °C; IR (KBr):
-
1
1
3
481, 3221, 1719, 1607, 1484, 1273, 1204, 848, 749 cm ; H
NMR (300 MHz, DMSO) δ 11.77 (brs, 2H), 7.88 (d, J = 8.5 Hz,
References and notes
1
=
H), 7.83 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 6.9 Hz, 1H), 7.38 (d, J
13
7.2 Hz, 2H), 7.02 (t, J = 7.8 Hz, 2H), 2.41 (s, 3H); C NMR
1
.
(
a) Prudhomme, M. Eur. J. Med. Chem. 2003, 38, 123; (b) Luesch, H.;
Yoshida, W. Y.; Moore, R. E.; Paul, V. J. Tetrahedron 2002, 58, 7959;
c) Zhang, C. W.; Ondeyka, J.; Zink, D. L.; Burgess, B.; Wang, J.;
(75 MHz, DMSO) δ 164.6, 164.1, 156.5, 143.3, 134.3, 131.1,
1
29.5, 127.7, 119.9, 119.0, 117.1, 21.1; HRMS (ESI) calculated
(
+
for C H NO + [M+H] 256.0968, found 256.0970.
15
14
3
Singh, S. B. Chem. Commun. 2008, 40, 5034.
2
.
(a) Gerspacher, M.; Lewis, C.; Ball, H. A.; Howes, C.; Subramanian,
N.; Ryffel, K.; Fozard, J. R J. Med. Chem. 2003, 46, 3508; (b) Pillai, O.;
Panchagnula, R. Drug Discovery Today 2001, 6, 1056.
4
.2.20
Methyl-4-(2-hydroxy-4-oxo-3,4-dihydro-2H-benzo[e]-
[
1,3]oxaz-in-2-yl)benzoate (2u)
Yellow solid (58.6 mg, 98 %); m.p. 189-191 °C; IR (KBr):
434, 3213, 1719, 1648, 1400, 1272, 1107 cm ; H NMR (300
MHz, DMSO) δ 12.60 (brs, 2H), 7.90 (d, J = 6.1 Hz, 2H), 7.83
3. (a) Hong, G.; Wu, S. Y.; Zhu, X. Y.; Mao, D.; Wang, L. M.
Tetrahedron 2016, 72, 436; (b) Bantreil, X.; Kanfar, N.; Gehin, N.;
Golliard, E.; Ohlmann, P.; Martinez, J.; Lamaty, F. Tetrahedron 2014,
-
1
1
3
7
2
0, 5093; (c) Liu, Z. H.; Ma, Q. Q.; Liu, Y. X.; Wang, Q. M. Org. Lett.
014, 16, 236; (d) Li, X. H.; Fang, Y. Y.; Deng, P. C.; Hu, J. C.; T. Li,
(
2
(
1
d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 8.7 Hz,
13
H), 6.92 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H); C NMR
Feng, W. Yuan, L. H. Org. Lett. 2011, 13, 4628; (e) Bantreil, X.;
Kanfar, N.; Gehin, N.; Golliard, E.; Ohlmann, P.; Martinez, J.; Lamaty,
F. Tetrahedron 2014, 70, 5093.
75 MHz, DMSO) δ 168.1, 165.2, 165.0, 163.3, 134.6, 131.3,
30.3, 119.4, 119.2, 118.1, 114.6, 114.2, 56.0; HRMS (ESI)
+
+
4
5
.
.
(a) Wang, P.; Xia, J.; Gu, Y. Tetrahedron Lett. 2015, 56, 7120; (b) Mai,
W. P.; Song, G.; Yuan, J. W.; Yang, L.R.; Sun, G. C.; Xiao, Y. M.;
Mao, P.; Qu, L. B. RSC Adv. 2013, 3, 3869; (c) Bhakuni, B. S.; Yadav,
A.; Kumar, S.; Patel, S.; Sharma, S.; Kumar, S. J. Org. Chem. 2014, 79,
calculated for C H NO [M+H] 300.0866, found 300.0866.
16
14
5
4
2
.2.21 4-(2-hydroxy-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-
-yl)be-nzonitrile (2v)
2
944.
White solid (47.3 mg, 89 %); m.p. 190-191 °C; IR (KBr):
(a) Eiji, S.; Nanase, U.; Tamio, H. J. Org. Chem. 2011, 76, 25; (b) Dai,
C. H.; Francesco, M.; Jagan, M. N.; Corey, R. S.; J. Org. Chem. 2012,
77, 4425; (c) Yu, H.; Xu, Y. L.; Dong, R.; Fang, Y.; Adv. Synth. Catal.
-
1
1
3
434, 3201, 2360, 1655, 1400, 1078, 669 cm ; H NMR (300
MHz, DMSO) δ 13.32 (brs, 2H), 8.14-8.07 (m, 4H), 8.02 (d, J =
.8 Hz, 1H), 7.43-7.42 (m, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.87 (t,
2
017, 359, 39.
6. (a) Priyadarshini, S.; Joseph, P.J. A.; Kantam, M. L. Tetrahedron 2014,
0, 6068; (b) Scheuermann, C. J. Chem. Asian. J. 2010, 5, 436; (c) Dai,
7
13
J = 7.5 Hz, 1H); C NMR (75 MHz, DMSO) δ 167.3, 137.2,
34.8, 133.2, 132.8, 130.3, 129.1, 119.1, 118.6, 118.4, 115.1;
7
1
C.; Meschini, F.; Narayanam, J. M. R.; Stephenson, C. R. J. J. Org.
Chem. 2012, 77, 4425; (d) Zhang, N. N.; Cheng, R.; Negrerie, D. Z.;
Du, Y. F.; Zhao, K. J. Org. Chem. 2014, 79, 10581; (e) Velingkar, V.
S.; Dandekar, V. D. Chin. J. Chem. 2011, 29, 5040; (f) Song, Z. Q.;
Antonchick, A. P. Tetrahedron 2016, 72, 7715.
+
+
HRMS (ESI) calculated for C H N O Na [M+Na] 289.0584,
15
10
2
3
found 289.0580.
4
.2.22 2-(furan-2-yl)-2-hydroxy-2,3-dihydro-4H-benzo[e][1,3]-
oxazin-4-one (2w)
7
.
(a) Yu, H.; Xu, Y. l.; Dong,R.; Fang, Y. Adv. Synth. Catal. 2017, 359,
3
9; (b) Shono, T. Tetrahedron 1984, 40, 811; (c) Yu H.; Shen, J. Org.
Yellow solid (38.3 mg, 83 %); m.p. 202-203 °C; IR (KBr):
Lett. 2014, 16, 3204; (d) Modak, A.; Dutta, U.; Kancherla, R.; Maity,
S.; Bhadra, M.; Mobin, S. M.; Maiti, D. Org. Lett. 2014, 16, 2602.
-
1
3
464, 3192, 1649, 1638, 1400, 1257, 1080, 883, 839, 750 cm ;
1
H NMR (300 MHz, DMSO) δ 14.00 (brs, 2H), 7.87-7.85 (m,
H), 7.61 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.35-7.30 (m, 1H),
8. (a) Huo, C.; Wang, C.; Wu, M.; Jia, X.; Xie, H.; Yuan, Y. Adv. Synth.
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Chem. Soc. 2004, 126, 6556; (c) Tsuchikama, K.; Kasagawa, M.; Endo,
1
7
13
.05-7.03 (m, 1H), 6.87-6.84 (m, 1H), 6.77-6.75 (m, 1H);
C

K.; Shibata, T. Org. Lett. 2009, 11, 1821; (d) Xu, W.; Nachtsheim, B. J.
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ACCEPTED MANUSCRIPT
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Intramolecular functionalization of C-H bond adjacent to an amide nitrogen atom was developed.
This method constructs a benzoxazinone skeleton through C-H bond activation/C-O bond formation.
This method was proceeded under mild and transition metal-free conditions.
2-hydroxy-benzoxazinone derivatives were afforded with this method for the first time.
2-hydroxy-benzoxazinone derivatives were obtained in good to excellent yields.