Synthesis of 2-(2-Hydroxyaryl)-4H-benzo[e][1,3]oxazin-4-ones by Palladium-Catalyzed C(sp2)?H Hydroxylation via Electro-chemical Oxidation

Article abstract of DOI:10.1002/adsc.202000173

An electrochemical direct ortho-hydroxylation of 2-aryl-4H-benzo[e][1,3]oxazin-4-ones was developed with Pd(OAc)₂ as catalyst, oxazine ring as a directing group and Oxone as the hydroxylation reagent. A series of hydroxylation products were obtained under mild conditions, and the yields were from medium to good. This method is characterized by good functional group tolerance and a wide range of substrates. More importantly, use anodic oxidation to avoid the use of potentially toxic and polluting oxidants. A gram-scale direct electrochemical hydroxylation of 2-phenyl-4H-benzo[e][1,3]oxazin-4-one was performed, and the hydroxylation product was applied to synthesize the drug deferasirox. In addition, the single crystal of 2-(2-hydroxyphenyl)-4H-benzo[e][1,3]oxazin-4-one was obtained and determined by X-ray diffraction. Finally, the reaction mechanism was proposed and verified by cyclic voltammetry (CV). This protocol also provides an alternative electrochemical hydroxylation methodology for the functionalization of molecules. (Figure presented.).

Full text of DOI:10.1002/adsc.202000173

Title: Synthesis of 2-(2-Hydroxyaryl)-4H-benzo[e][1,3]oxazin-4-ones by
Palladium-Catalyzed C(sp2)-H Hydroxylation via Electrochemical
Oxidation
Authors: Hongfeng Wu, Qi An, Chaoyin He, Xiaodong Fan, Weihao
Guo, Minghui Zuo, Chunzhao Xu, Rui Guo, wenyi chu, and
zhizhong sun
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000173
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10.1002/adsc.202000173
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202000173
Synthesis of 2-(2-Hydroxyaryl)-4H-benzo[e][1,3]oxazin-4-ones
by Palladium-Catalyzed C(sp2)-H Hydroxylation via Electro-
chemical Oxidation
Hongfeng Wu,a,b Qi An,a,b Chaoyin He,a,b Xiaodong Fan,a,b Weihao Guo,a,b Minghui
Zuo,a,b Chunzhao Xu,a,b Rui Guo,a,b Wenyi Chu,*a,b and Zhizhong Sun*a,b
a
School of Chemistry and Materials Science, Heilongjiang University, Harbin 150080, P. R. China
Corresponding author. Tel.: +86-451-86609135; fax: +86-451-86609135 and E-mail: wenyichu@hlju.edu.cn or
sunzz@hlju.edu.cn
Key Laboratory of Chemical Engineering Process & Technology for High-efficiency Conversion, College of
b
Heilongjiang Province, Harbin 150080, P. R. China
Corresponding author. Tel.: +86-451-86609135; fax: +86-451-86609135 and E-mail: wenyichu@hlju.edu.cn or
sunzz@hlju.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An electrochemical direct ortho-hydroxylation of In addition, the single crystal of 2-(2-hydroxyphenyl)-4H-
2-aryl-4H-benzo[e][1,3]oxazin-4-ones was developed with benzo[e][1,3]oxazin-4-one was obtained and determined by X-
Pd(OAc)2 as catalyst, oxazine ring as a directing group and ray diffraction. Finally, the reaction mechanism was
Oxone as the hydroxylation reagent. A series of hydroxylation proposed and verified by cyclic voltammetry (CV). This
products were obtained under mild conditions, and the yields protocol also provides an alternative electrochemical
were from medium to good. This method is characterized by hydroxylation methodology for the functionalization of molecules.
good functional group tolerance and a wide range of
substrates. More importantly, use anodic oxidation to avoid
the use of potentially toxic and polluting oxidants. A gram-
scale direct electrochemical hydroxylation of 2-phenyl-4H-
benzo[e][1,3]oxazin-4-one was performed, and the hydroxylation
product was applied to synthesize the drug deferasirox.
Keywords: 2-phenyl-4H-benzo[e][1,3]oxazin-4-one; Cyclic
voltammetry; Electrochemical; Hydroxylation; Pd(OAc)2
catalysis
process and the low yield of phenolic compounds.[8]
In order to solve the above problems, we propose to
use C-H hydroxylation reaction to introduce hydroxyl
Introduction
Nitrogen-containing heterocyclic compounds are widely group through nitrogen-containing heterocyclic structure
used, especially in the field of pharmaceuticals.[1] as a directing group, thus avoiding the oxidation of
Benzoxazinone derivatives are important nitrogen- the phenolic hydroxyl group in the synthetic process.
containing heterocyclic compounds with anti-
cardiovascular diseases[2] and anti-cancer[3] activities.
At the same time, as an important functional group,
phenolic hydroxyl group widely exists in natural
products, bioactive molecules and drugs.[4] Most
drugs containing phenolic hydroxyl group have the
characteristics of anti-tumor[5] and anti-cancer[6]
(Figure 1). Therefore, some nitrogen-containing
phenolic hydroxy heterocyclic compounds have been
studied deeply because they can be used as drugs or
important intermediates of drugs. These compounds
can be extracted from natural products, but due to the
existence of phenolic hydroxyl, they are small in
quantity and easy to oxidize.[7] In addition, the
traditional synthesis of these drugs often needs
Figure 1. Representative benzoxazinones and nitrogen-
phenolic hydroxyl protection to prevent oxidation in
containing heterocyclic compounds with phenol hydroxyl.
the synthesis process, resulting in complex reaction
1
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10.1002/adsc.202000173
Advanced Synthesis & Catalysis
In recent years, literature reports the use of transition transition metal-catalyzed C-H functionalization is an
metal-catalyzed C-H bond hydroxylation to prepare attractive approach.[17]
phenolic compounds. In 2015, Sun's research group
Based on the inspiration of electrochemical methods,[18]
reported the palladium-catalyzed ortho-hydroxylation we wondered whether anodic oxidation would be
of 2-arylpyridine (Scheme 1a).[9] Excess TBHP (6 suitable for aromatic C(sp2)-H hydroxylation
equiv.) acted as both oxidant and hydroxylation reactions. Herein, an effective proposal for the ortho-
reagent. The method was applicable to substrates C(sp2)-H hydroxylation of aromatic hydrocarbons by
containing for electron-donating and electron- palladium-catalyzed anodic oxidation was developed
withdrawing, and a series of hydroxylation products by us. We now report that this novel method of
were synthesized efficiently. In 2017, Zhou and co- electrochemical oxidation by using 2-phenyl-4H-
workers used expensive rhodium as a catalyst, benzo[e][1,3]oxazin-4-one derivatives as substrates,
PhI(OAc)2 as an oxidant, and hydrolysis under mild inexpensive and readily available Oxone as the
reaction conditions to obtain hydroxylation products hydroxylation agent and constant current instead of
(Scheme 1b).[10] In 2018, Xu and colleagues reported stoichiometric oxidant to acquire ortho-hydroxylation
the regioselective C-8 hydroxylation of 1,2,3,4- products (Scheme 1d).
tetrahydroquinoline catalyzed by ruthenium. K2S2O8
was used as the oxidant and oxygen source for this
Results and Discussion
Table 1. Optimization of reaction conditionsa)
reaction, and the hydroxylation reaction was smoothly
converted in the presence of the additive HBF4
(Scheme 1c).[11] According to the literature reported
above, transition metal-catalyzed C(sp2)-H hydroxylation
has become a means for constructing C-OH to
synthesize phenolic compounds.[12] However, these
hydroxylation reactions require transformation in the
presence of stoichiometric oxidants. Stoichiometric
oxidants suffer from the disadvantages of being
expensive and potentially toxic, producing by-
products and poor atomic economy.[13] Therefore, the
development of novel oxidation systems has become
an active research area in the field of C-H
activation.[14]
entry
catalyst
electrolyte
current
(mA)
6
6
solvent
temp
(oC)
50
yield
(%)b
66
1
2
Pd(OAc)2
PdCl2
n-Bu4NClO4
n-Bu4NClO4
CH3CN
CH3CN
50
26
3
4
Pd(TFA)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
---
n-Bu4NClO4
n-Bu4NClO4
Et4NClO4
6
6
6
6
6
4
8
6
6
6
6
6
6
6
6
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
50
50
50
50
50
50
50
50
50
50
50
50
40
60
50
50
44
51
55
58
78
68
77
41
21
36
69
62
61
73
0
5
6
Et4NBF4
7
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
---
8
9
10
11
12
13
14
15
16
17
18
Toluene
CH3OH
DMF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
Pd(OAc)2
0
a)
Reaction conditions: 1a (0.3 mmol), catalyst (10 mol%),
Oxone (1.0 equiv.), solvent (3 mL) and electrolyte (1
equiv.) [anode], solvent (3 mL) and electrolyte (1 equiv.)
[cathode] in an H-type divide cell with two platinum
Scheme 1. Different approaches forortho-hydroxylization.
electrodes (each 1.0 × 1.0 cm2) and anion exchange membrane,
the reaction completed (monitored by TLC).
yield by flash column chromatography.
In recent years, electrochemical synthesis technology
has been revived, which represents a promising
alternative to traditional chemical oxidants, because it
avoids the use of potentially toxic and dangerous
reagents.[15] Anodic oxidation provides a convenient
way to convert organometallic intermediates to high-
valent complexes that subsequently undergo reductive
elimination to form product and regenerate the
catalyst.[16] In view of the advantages of this process,
the utilization of the electric current as an oxidant for
b)
Isolated
To verify the feasibility of our previous expectations,
2-phenyl-4H-benzo[e][1,3]oxazin-4-one (1a) was selected
as the model substrate, and the experimental results are
summarized in Table 1. To begin, 1a was chosen as
the model substrate to react with Oxone in the
presence of Pd(OAc)2 as catalyst and n-Bu4NClO4 as
2
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10.1002/adsc.202000173
Advanced Synthesis & Catalysis
electrolyte under constant current electrolysis conditions Cambridge
Crystallographic
Data
Centre
at 6 mA, the reaction monitored by TLC. To our via www.ccdc.cam.ac.uk/data_request/cif.). In view of the
delight, the reaction gave desired product 2a in a 66%
Table 2. Substrates scope of the ortho-C(sp2)-H hydroxylation
yield at 50 oC (Table 1, entry 1). The results show that
the electrochemical oxidative hydroxylation is practical
and that it could be optimized the reaction conditions
by screening catalysts, electrolytes, currents, solvents and
temperatures.
reactiona)
Firstly, the palladium catalyst was identified as the
primary research target. To our disappointment, PdCl2
as catalyst only gave 26% yield (Table 1, entry 2).
The yields of Pd(TFA)2 and Pd(PPh3)4 instead of
Pd(OAc)2 were also relatively low, 44% and 51%,
respectively (Table 1, entries 3-4). Since electrolyte
is one of the important factors affecting
electrochemical reactions, screening for electrolyte is
necessary. Et4NClO4 and Et4NBF4 used as electrolytes
afforded product 2a in 55% and 58% of yields (Table
1, entries 5-6). After several times of screening, n-
Bu4NPF6 was deemed to be the best electrolyte with a
yield of 78% (Table 1, entry 7). Current screening is
also the key to electrochemical oxidation reactions.
When the current reduced to 4 mA, the yield of 2a
dropped to 68% (Table 1, entry 8). Increasing the
current to 8 mA had little effect on the yield of 2a
(Table 1, entry 9). Next the reaction solvents were
investigated. It was found that the use of nonpolar
solvent dichloromethane (DCE) gave a low yield in
41% (Table 1, entry 10). The use of inert solvent
toluene only gave a lower yield of 21% (Table 1,
entry 11). The use of protic solvent methanol (MeOH)
gave also a low yield, in this case 36% (Table 1,
entry 12). Using the polar aprotic solvent N,N-
dimethylformamide (DMF) and dimethyl sulfoxide
(DMSO) was obtained the product 2a in yields of 69% and
62%, respectively (Table 1, entries 13-14). According to
the comparison of different reaction temperatures, it
was found that 50 oC was the best reaction temperature.
o
When the reaction temperature was reduced to 40 C,
the product 2a formed in a 61% yield (Table 1, entry
15). The reaction temperature was increased to 60 oC,
the yield of 2a was also reduced (Table 1, entry 16).
The result of the control experiments showed that the
catalyst and electrolyte were indispensable conditions
for carrying out the reaction (Table 1, entries 17-18).
Based on the above experimental results, the
optimized conditions of the catalytic system were 10
mol% Pd(OAc)2 as the catalyst, 1.0 equiv. of Oxone
as the hydroxylation agent, 1.0 equiv. of n-Bu4NPF6
as electrolyte in CH3CN under constant current
electrolysis conditions at 6 mA at 50 oC.
a)
Reaction conditions: 1a (0.3 mmol), Pd(OAc)2 (10
mol%), Oxone (1.0 equiv.), CH3CN (3 mL) and n-Bu4NPF6
(1 equiv.) [anode], CH3CN (3 mL) and n-Bu4NPF6 (1
equiv.) [cathode] in an H-type divide cell with two
platinum electrodes (each 1.0 × 1.0 cm2) and anion
exchange membrane at 50 oC under 6 mA (janode = 3
mA/cm2), the reaction completed (monitored by TLC).
b)
Isolated yield after purification by column chromatography.
reactivity characteristics of ortho-C(sp2)-H hydroxylation,
we first investigated the expansion of substituent R1
on hydroxylation aryl moiety. The electron-donating
group -CH3 at the para-position brought the desired
product to 81% (2b). The electron-withdrawing
groups -Cl and -Br of the substrate reduced the yield
of the product compared to the electron-donating
groups, with yields of 70% and 68% (2c and 2d).
Reactions using substrates with electron-donating (-
CH3 and -OCH3) and electron-withdrawing groups (-
Cl and -Br) at the meta-position also proceeded
smoothly, affording the corresponding hydroxylation
products in the range of 59-66% (2e-2h). For ortho-
substituents, the yield of hydroxylation product
To study the substrate scope of hydroxylation, the
optimized conditions described above were applied to
a variety of 2-aryl-4H-benzo[e][1,3]oxazin-4-ones. The
results are shown in Table 2. To begin, the 2-phenyl-
4H-benzo[e][1,3]oxazin-4-one (1a) without a substituent
gave the product 2a in a yield of 78%, and the
structure of the compound was determined by X-ray
diffraction
(CCDC-1976750
contains
the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
3
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10.1002/adsc.202000173
Advanced Synthesis & Catalysis
complex reaction.[20] Compared with the previously
reported method, we used the hydroxylation product
2a and 4-hydrazinobenzoic acid as raw materials to
obtain deferasirox in only one step with a yield of 86%
(shown in Scheme 2b). Therefore, this method can be
used to easily and efficiently synthesize deferasirox,
and avoid the side reactions such as phenol hydroxyl
oxidation in the multi-step synthesis process.
containing electron-donating group -CH3 was reduced
to 54% (2i), while the electron-withdrawing group -Br
gave only 46% yield (2j). Furthermore, the substrate
containing naphthalene also obtained the desired
product in 64% of yield (2k). The use of
heteroaromatics as the substrate can also make the
hydroxylation reaction proceed smoothly. Pyridine,
pyrrole, furan and thiophene instead of benzene ring
as the substrate, the target products were obtained in
the range of 49-58% (2l-2o) under this reaction
conditions. According to the above experimental
results, the reaction effect of the electron-donating
groups was superior to the electron-withdrawing
groups. In addition, ortho-substituents can also reduce
the yields of the reaction due to steric hindrance.
Next, we investigated the expansion of substituent
R2 on benzoxazinone phenyl moiety, and the substrate
with both electron-donating and electron-withdrawing
groups gave the expected products in the range of 66-
78% (2p-2v). Compared with substrates containing
electron-donating groups -CH3 (2p) and -OCH3 (2q
and 2t), the electron-withdrawing groups -Cl (2r and
2u) and -Br (2s and 2v) reduced the yield of the
expected product. In order to test the applicability of
the method, the oxygen atom in the heterocyclic ring
of benzoxazinone was replaced by sulfur atom and
nitrogen atom, and the products were received in
Scheme 3. Mechanism research.
To define whether the reaction proceeded via a
radical pathway or not, the control experiment was
carried out to study the hydroxylation reaction (shown
in Scheme 3). When the radical scavenger TEMPO
yields of 71% and 76% (2w and 2x). When was employed in the reaction mixture, the yield of
product 2a was 58%, indicating that the reaction
possibly involved a non-radical pathway (Scheme 3a).
In the standard conditions without current, a trace
amount of the product 2a was detected in the reaction
(Scheme 3b). This illustrated that current was a
critical condition in the reaction. Moreover, in order
to compare the reactivity of the electronically
different substrates, an equimolar amount of 2-phenyl-
4H-benzo[e][1,3]oxazin-4-ones with electron-donating
group (1e) and electron-withdrawing group (1g) was
processed by Oxone under standard conditions
(Scheme 3c). The corresponding hydroxylation
products 2e and 2g were obtained in yields of 52%
and 17%, respectively. Intermolecular competition
experiments showed that the substrate containing the
electron-donating group was more favorable for the
ortho-C(sp2)-H hydroxylation reaction. Because the
electron-withdrawing effect reduces the electron
density of benzene ring, the yield of the
corresponding product decreases, which also indicates
that the reaction is an electrophilic ion type reaction.
To further understand the reaction mechanism of
electrochemical oxidation of ortho-C(sp2)-H hydroxylation,
the C-H conversion during oxidative electrochemical
via palladium catalysis was explored by using cyclic
voltammetry (Figure 2). Firstly, we examined the
voltammetry curve with the acetonitrile solution in
which the electrolyte was dissolved as the background
(curve a), no oxidation peak was observed. When
substrate 1a was added into the background solution,
there was an oxidation peak at 0.75 V versus
Ag/AgCl (curve b). Next, an oxidation peak appeared
at 0.78 V when the hydroxylation reagent Oxone was
benzoxazinone moiety was replaced by benzoxazole,
benzimidazole and pyridine, the hydroxylation
reaction could also be smoothly converted to obtain good
yields in 73%, 74% and 72% (2y, 2z and 2za).
Scheme 2. Application of gram-scale reaction to synthesize the
drug deferasirox.
In order to further demonstrate the practicability of
the electrochemical hydroxylation, a gram-scale
reaction was performed on 1a and the product 2a was
obtained in 65% yield (as shown in Scheme 2a). Then
product 2a was used as raw material to synthesize the
drug deferasirox, which was used in chronic iron
overload therapy for patients with beta-thalassemia as
well as other chronic anemia, and the drug has been
approved by the US FDA.[19] Previous literature
reported that the use of 2-hydroxybenzamidine and 2-
iodophenol as starting materials in the CO atmosphere
resulted in a 41% yield of deferasirox through a
4
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10.1002/adsc.202000173
Advanced Synthesis & Catalysis
added into the background solution containing the of reaction, the pH of the mixture was measured to be
substrate 1a (curve c). Finally, we added Pd(OAc)2 to a 6.99, which proved that the content of the hydroxyl-
background solution containing substrate 1a and the lation product 2a gradually increased. The pH of the
hydroxylation reagent Oxone, and performed a cyclic mixture was measured at the end of the reaction to be
voltammetry test after 4 hours of reaction under 6.91, which indicated that most of the substrate 1a has
standard conditions. We found an obvious oxidation been converted to the hydroxylation product 2a.
peak at 1.09V (curve d), indicating that the anode
On the basis of experimental results and previous
could oxidize the aryl Pd(II) intermediate to a high-
literatures reported,[21,22] a plausible mechanism for
valent Pd(III) or Pd(IV) complex. [21]
the palladium-catalyzed ortho-C(sp2)-H hydroxylation
via electrochemical oxidation is depicted in Scheme 5.
Initially, the N atom of 1a is coordinates with Pd(II)
to form intermediate A, follows by subsequent C−H
activation to generate the intermediate B.
Intermediate B with Oxone form Pd(III) or Pd(IV)
intermediate C under anodic directly oxidation
conditions. Finally, a high-valent palladium intermediate
C undergoes reductive elimination to afford the
hydroxylation product 2a and regenerate the Pd(II)
species.
Figure 2. Mechanism verification by cyclic voltammetry.
Cyclic voltammograms recorded on a platinum electrode
(area 0.03 cm2) at 100 mV•s−1: (a) in CH3CN containing
0.1 M n-Bu4NPF6; (b) in solution (a) after addition of 5
mM 1a; (c) in solution (b) after addition of 5 mM Oxone;
(d) 10 mM Pd(OAc)2 was added to the solution (c) and
reacted for 4 hours.
A kinetic isotope effect (KIE) experiment was
carried out (Scheme 4). The KIE was found to be
kH/kD = 1.26, which indicates that the cleavage of the
Scheme 5. A plausible mechanism.
C–H bond may not be involved in the rate-
determining step of the catalytic cycle. [21]
Conclusion
In conclusion, we developed a method for Pd-
catalyzed electrochemical direct ortho-hydroxylation
of 2-aryl-4H-benzo[e][1,3]oxazin-4-ones by oxazine ring as
directing group under anodic oxidation conditions. A
series of ortho-hydroxylation products were
synthesized with moderate to good yields by using
inexpensive and readily available Oxone as the
hydroxylation agent under mild conditions. This is the
first report on direct electrochemical hydroxylation of
2-phenyl-4H-benzo[e][1,3]oxazin-4-one, the single crystal
of hydroxylation product was obtained and
determined by X-ray diffraction, and hydroxylation
product was applied to synthesize the drug
deferasirox. In addition, the reaction mechanism was
proposed and verified by cyclic voltammetry (CV). C-
H functionalization of other aromatic hydrocarbons
using electrochemical methods is also being
investigated in our laboratory.
Scheme 4. Kinetic isotope effect studies.
To further understand the mechanism of the
hydroxylation reaction, we measured the pH of the
mixture at 0 hour, 2 hours, 4 hours and after the
reaction was completed. Initially, we measured the
pH of the reaction mixture at 7.06. After 2 hours of
reaction, the pH of the mixture was measured to be
7.02, because a small amount of AcOH and the
hydroxylation product 2a were formed. After 4 hours
5
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10.1002/adsc.202000173
Advanced Synthesis & Catalysis
Experimental Section
[5] B. Li, J. Lan, D. Wu, J. You, Angew. Chem., Int. Ed.
2015, 54, 14008-14012.
Preparation of 2-(2-hydroxyaryl)-4H-benzo[e][1,3]oxazin-
4-ones
[6] a) C. A. Gomes, T. Girão da Cruz, J. L. Andrade, N.
Milhazes, F. Borges, M. P. M. Marques, J. Med. Chem.
2003, 46, 5395-5401; b) K. A. Fennell, M. J. Miller,
Org. Lett. 2007, 9, 1683-1685.
Representative
Procedure:
The
electrochemical
hydroxylation was carried out in an H-type divided cell
equipped with two platinum electrodes (1.0 x 1.0 cm2). The
two compartments were separated by an anion-exchange
membrane. 2-aryl-4H-benzo[e][1,3]oxazin-4-ones (0.3
mmol), Oxone (1 equiv.), Pd(OAc)2 (10 mol%) and n-
Bu4NPF6 (1 equiv.) were charged into the anode
compartment and dissolved in CH3CN (3 mL). The
cathodic chamber was charged with n-Bu4NPF6 (1 equiv.)
in CH3CN (3 mL). The mixture in the anode compartment
[7] a) A. Kozubek, J. H. Tyman, Chem. Rev. 1999, 99, 1-26;
b) C. D. Selassie, S. Kapur, R. P. Verma, M. Rosario, J.
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o
was then stirred at 50 C under a constant current of 6 mA.
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After the end of the reaction, the solution in the anode and
cathode compartments were combined and extracted three
times with ethyl acetate. The organic phases were
combined and dried over anhydrous Na2SO4. The Na2SO4
was then filtered off and the solvent was removed under
vacuum, and the crude product was purified by column
chromatography (PE:EA=30:1) to afford the ortho-
hydroxylation products.
[9] J. Dong, P. Liu, P. Sun, J. Org. Chem. 2015, 80, 2925-
2929.
[10] Y. Wu, B. Zhou, Org. Lett. 2017, 19, 3532-3535.
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Acknowledgements
Xi, H. Li, L. Xu, Org. Lett. 2018, 20, 6799-6803.
We are grateful for financial support from the Research Project
of the Natural Science Foundation of Heilongjiang Province of
China (No. B2018012).
[12] a) T. Jintoku, K. Nishimura, K. Takaki, Y. Fujiwara,
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Author contributions
Qi An, Chaoyin He and Xiaodong Fan researched concepts;
Hongfeng Wu, Chunzhao Xu and Rui Guo conducted the
experiments; Weihao Guo and Minghui Zuo collected and
analyzed corresponding data; Hongfeng Wu, Wenyi Chu and
Zhizhong Sun designed the experiments and wrote the paper.
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Conflicts of interest
There are no conflicts to declare.
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7
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Advanced Synthesis & Catalysis
FULL PAPER
Synthesis of 2-(2-Hydroxyaryl)-4H-benzo[e][1,3]-
oxazin-4-ones by Palladium-Catalyzed C(sp2)-H
Hydroxylation via Electrochemical Oxidation
Adv. Synth. Catal. Year, Volume, Page – Page
Hongfeng Wu,a,b Qi An,a,b Chaoyin He,a,b Xiaodong
Fan,a,b Weihao Guo,a,b Minghui Zuo,a,b Chunzhao
Xu,a,b Rui Guo,a,b Wenyi Chu,*a,b and Zhizhong
Sun*a,b
8
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